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Non-melanoma
Skin Cancer of the
Head and Neck
Faruque Ri at
Carsten E. Palme
Michael Veness Editors
Head and Neck Cancer Clinics
Series Editors: Rehan Kazi · Raghav C. Dwivedi
Head and Neck Cancer Clinics
malcolm_buchanan123@hotmail.com
Series editors
Rehan Kazi
Head and Neck Cancer
Manipal University
Manipal, Karnataka , India
Raghav C. Dwivedi
Head and Neck Cancer
Royal Marsden Hospital
London , United Kingdom
Other titles in the series
Clinical Approach to Well-Differentiated Thyroid Cancers
Frederick L. Greene and Andrzej L. Komorowski
Tumours of the Skull Base and Paranasal Sinuses
Ziv Gil and Dan M. Fliss
Controversies in Oral Cancer
K.A. Pathak and Richard W. Nason
Management of Thyroid Cancer: Special Considerations
K.A. Pathak, Richard W. Nason and Janice L. Pasieka
HPV and Head and Neck Cancers
Carole Fakhry and Gypsyamber D’Souza
malcolm_buchanan123@hotmail.com
Faruque Riffat • Carsten E. Palme
Michael Veness
Editors
Non-melanoma
Skin Cancer of the
Head and Neck
malcolm_buchanan123@hotmail.com
Editors
Faruque Riffat
Westmead Hospital
University of Sydney
Sydney
Australia
Carsten E. Palme
Westmead Hospital
University of Sydney
Sydney
Australia
Michael Veness
Westmead Hospital
University of Sydney
Sydney
Australia
ISSN 2364-4060 ISSN 2364-4079 (electronic)
Head and Neck Cancer Clinics
ISBN 978-81-322-2496-9 ISBN 978-81-322-2497-6 (eBook)
DOI 10.1007/978-81-322-2497-6
Library of Congress Control Number: 2015949116
Springer New Delhi Heidelberg New York Dordrecht London
© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made.
Cover illustration by Dan Gibbons DCR(R), PgCert(CT)
Printed on acid-free paper
Springer India Ltd. is part of Springer Science+Business Media (www.springer.com)
Byword Books Private Limited, New Delhi, India (www.bywordbooks.in)
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This series is dedicated to the research and charity
efforts of Cancer Aid and Research Foundation (CARF),
Mumbai, India (www.cancerarfoundation.org).
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vii
A Note on the Series
Head and neck cancer (HNC) is a major public health challenge. Its management
involves a multidisciplinary team approach, which varies depending upon the subtle
differences in the location of the tumor, stage and biology of disease, and availabil-
ity of resources. In the wake of rapidly evolving diagnostic technologies and man-
agement techniques, and advances in the basic sciences related to HNC, it is
important for both clinicians and basic scientists to be up to date in their knowledge
of new diagnostic and management protocols.
This series aims to cover the entire range of HNC-related issues through inde-
pendent volumes on specifi c topics. Each volume focuses on a single topic relevant
to the current practice of HNC and contains comprehensive chapters written by
experts in the fi eld. The reviews in each volume provide vast information on key
clinical advances and novel approaches to enable a better understanding of relevant
aspects in HNC.
Individual volumes present different perspectives and have the potential to serve
as stand-alone reference guides. We believe these volumes will prove useful for the
practice of head and neck surgery and oncology. Medical students, residents, clini-
cians, and general practitioners seeking to develop their knowledge of HNC will
benefi t from them.
Rehan Kazi
Raghav C. Dwivedi
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ix
Foreword
Randal S. Weber
Non-melanoma skin cancer is a signifi cant public health problem for the popula-
tions of North America, Australia, and parts of Europe. The disease is rising in
incidence and has a signifi cant economic impact on healthcare expenditures in these
regions. Noneconomic cost is signifi cant and includes disturbance of body image,
function, and quality of life.
Non-melanoma Skin Cancer of the Head and Neck edited by Riffat, Palme, and
Veness is a concise volume devoted to the biology, pathology, and clinical charac-
teristics of non-melanoma skin cancer. Current and future therapeutic modalities are
addressed in the setting of multidisciplinary care. The editors are recognized clini-
cal experts in the fi eld of cutaneous malignancy management and bring their knowl-
edge and practical experience to bear in the creation of this text. Their focus on both
cutaneous and adnexal cancers of the skin is useful and will serve as a ready resource
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x
for both these common and uncommon malignancies. The theme of the text on
multidisciplinary intervention and care for the patient is both current and timely.
The authors are to be commended for providing a succinct source of current knowl-
edge that will inform evidence-based decisions in the management of patients with
cutaneous malignancies of the head and neck.
Randal S. Weber, MD
Professor and Chairman
Department of Head and Neck Surgery, Unit 1445
University of Texas MD Anderson Cancer Center
Houston, Texas, USA
Foreword
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xi
Pref ace
Non-melanoma skin cancer is a global public health issue. With an ever-increasing,
and aging, world population coupled with the increasing number of immunosup-
pressed individuals, the number of patients continues to rise. The head and neck is
overwhelmingly the most frequent location for the development of a non-melanoma
skin cancer and as such challenges the clinician with its complex anatomy. The impor-
tance of maintaining the aesthetics of the face and the function of the anatomy cannot
be overstated, yet ultimately it is always the aim of curing a patient with the minimum
of morbidity that clinicians strive for. However, the spectrum of presentations and
subsequent management varies widely, ranging from patients with the ubiquitous low-
risk midface basal cell carcinoma to those diagnosed with relatively uncommon but
potentially life-threatening high-risk squamous cell carcinomas (e.g., involving meta-
static lymph nodes or with perineural invasion present) and Merkel cell carcinomas.
The concept of a multidisciplinary team approach is now the gold standard para-
digm for most patients diagnosed with cancer, and this applies no less to patients
diagnosed with non-melanoma skin cancer. While many patients with superfi cial
and small lesions are cured by relatively simple often non-morbid treatment, others
with more advanced cancers require a multidisciplinary team approach and often
the institution of morbid treatment.
Australians experience the highest incidence of skin cancer in the world, and Australian
clinicians are highly experienced in the management of these patients. It is the drawing
from this local experience that is the impetus behind the writing of this book. As only one
example, the requirement for extensive surgery often involving complex reconstruction
and the important role of radiotherapy are expanded on in relevant chapters by authors
widely published in their respective specialties. Many of the contributors are internation-
ally recognized experts in their particular fi eld at the cutting edge of clinical research and
in treating patients—it is this knowledge and skill base that forms the basis of this book.
The aim of writing this book is to provide busy clinicians with easily readable informa-
tion and in most cases practical advice on managing patients with non-melanoma skin
cancer. More comprehensive textbooks are available but few offer the concise, informa-
tive, and up-to-date approach that we hope this book provides to the reader.
Faruque Riffat
Carsten Palme
Michael Veness
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xiii
Contents
1 Epidemiology and Aetiology of Non- melanoma Skin Cancer. . . . . . . . . 1
Zubair Hasan and Faruque Riffat
2 Pathology Reporting of Non-melanoma Skin Cancer
at the ICPMR, Westmead Hospital . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Hedley Coleman and Jeanne Tomlinson
3 Evaluation, Staging and Prognostication . . . . . . . . . . . . . . . . . . . . . . . . 25
Zubair Hasan , Carsten Palme , and Faruque Riffat
4 Non-melanoma Skin Cancer: Primary Non-surgical
Therapies and Prevention Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Malcolm A. Buchanan , Brett Levin , and Michael Veness
5 Mohs Surgery and Facial Flaps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Dan Robinson and Jason Roth
6 Merkel Cell Carcinoma, Adnexal Carcinoma
and Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Michael Veness and Julie Howle
7 The Role of Sentinel Lymph Node Biopsy
in Non-melanoma Skin Cancer of the Head and Neck . . . . . . . . . . . . . 83
James Wykes , Jonathan Clark , and Navin Niles
8 Metastatic Cutaneous Squamous Cell Carcinoma
of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Carolyn Jameson , Gary Morgan , Carsten E. Palme ,
and Michael Veness
9 Managing Perineural and Skull Base Involvement . . . . . . . . . . . . . . . 117
Timothy A. Warren and Benedict Panizza
10 Squamous Cell Carcinoma Extending to the Temporal Bone . . . . . . 131
Shane Anderson , Parag Patel , and Benedict Panizza
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xiv
11 Reconstructive Options for the Face . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Ashlin J. Alexander , Sinclair M. Gore , and Jonathan Clark
12 Management of Critically Ill Head and Neck Surgical Patients . . . . . 171
Vineet Nayyar
13 Future Directions in the Management
of Non-melanoma Skin Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Gerard Adams and Sandro V. Porceddu
Contents
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xv
Contributors
Gerard Adams , BSc, MB ChB, MRCP, FRCR, FRANZCR Radiation
Oncology, Oceania Oncology Bundaberg , Bundaberg , QLD , Australia
School of Medicine, University of Queensland , St Lucia , QLD , Australia
Ashlin J. Alexander , MD, FRCSC Division of Facial Plastic
and Reconstructive Surgery, Department of Otolaryngology-Head
and Neck Surgery , University of Toronto, Mount Sinai Hospital
and Rouge Valley Hospital , Toronto , ON , Canada
Shane Anderson , B Biomed Sc, MBBS, FRACS, MPhil Otolaryngology-Head
and Neck Surgery, The Townsville Hospital , Townsville , QLD , Australia
Malcolm A. Buchanan , BSc, MBChB, PhD, FRCS Otolaryngology-Head and
Neck Surgery, Glasgow Royal Infi rmary , Glasgow , UK
Jonathan Clark , MBBS, BSc, MBiostat, FRACS Head and Neck Surgery,
Sydney Head and Neck Cancer Institute, Royal Prince Alfred Hospital , Sydney ,
NSW , Australia
Hedley Coleman , BDS, BChD, MDent, FCPath, FFOP Department
of Tissue Pathology and Diagnostic Oncology , Institute for Clinical
Pathology and Medical Research, Pathology West, New South
Wales Health Pathology , Sydney , NSW , Australia
Sinclair M. Gore , MD, FRCS (Plast) Plastic and Reconstructive Surgery,
Oxford University Hospitals , Oxford , UK
Zubair Hasan , MBBS, MIPH, MS Otolaryngology-Head and Neck Surgery,
Westmead Hospital, University of New South Wales , Sydney , NSW , Australia
Julie Howle , MBBS, MSurg, FRACS Department of Surgical Oncology ,
Westmead Cancer Care Centre, Westmead Hospital, Westmead,
University of Sydney , Sydney , NSW , Australia
Carolyn Jameson , FRACS, PhD Head and Neck Surgery, Royal Prince Alfred
Hospital and Westmead Hospital , Sydney , NSW , Australia
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xvi
Brett Levin , BMedSci, MBBS, MMedSci, FRACS Otolaryngology-Head and
Neck Surgery, Westmead Hospital , Sydney , NSW , Australia
Gary Morgan Head and Neck Surgery, Westmead Hospital, University of
Sydney , Sydney , NSW , Australia
Vineet Nayyar , MBBS, MD, MPH, FRACP, FCICM Department
Intensive Care Unit , Westmead Hospital , Sydney , NSW , Australia
Navin Niles , BSc (Med), MBBS, FRACS Head and Neck Surgery, University of
New South Wales , Sydney , NSW , Australia
Carsten Palme , MBBS, FRACS Otolaryngology Head and Neck Surgery ,
Royal Prince Alfred Hospital and Westmead Hospital , Sydney , NSW , Australia
Benedict Panizza , MBBS, MBA, FRACS Department of Otolaryngology − Head
and Neck Surgery , School of Medicine, University of Queensland,
Queensland Head and Neck Cancer Centre, Queensland Skull Base Unit,
Princess Alexandra Hospital , Brisbane , QLD , Australia
Parag Patel , MSc, MBBS, BSc, DO-HNS FRCS Otolaryngology-Head and
Neck Surgery, St Georges Hospitals NHS Trust , London , UK
Sandro V. Porceddu Radiation Oncology, University of Queensland , St Lucia ,
QLD , Australia
Princess Alexandra Hospital , Brisbane , QLD , Australia
Faruque Riffat , BSc, MBBS, FRACS Otolaryngology-Head and Neck Surgery
Westmead Hospital, University of Sydney , Sydney , NSW , Australia
Dan Robinson , BIT, BCom, MBBS (Hons), FRACS Otolaryngology-Head and
Neck Surgery, Gold Coast University Hospital , South Port , QLD , Australia
Jason Roth , BSc, MBBS, AMusA, FRACS Otolaryngology-Head and Neck
Surgery, Private Practice , Sydney , Australia
Jeanne Tomlinson , MBBS, MBA, FRCPA FIAC Department of Tissue
Pathology and Diagnostic Oncology , Westmead Hospital , Sydney ,
NSW , Australia
Michael Veness , MBBS, MMed, MD, MD, FRANZCR Radiation Oncology,
Westmead Hospital, University of Sydney , Sydney , NSW , Australia
Timothy A. Warren , BSc (Hons), MBBS Department of Otolaryngology − Head
and Neck Surgery , School of Medicine, University of Queensland,
Princess Alexandra Hospital, QIMR Berghofer Institute of Medical
Research , Brisbane , QLD , Australia
James Wykes , BSci (Med), MBBS, FRACS Head and Neck Surgery, Liverpool
Hospital , Sydney , NSW , Australia
Contributors
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xvii
Abbreviations
AACR Australian Association of Cancer Registries
ACE Adult comorbidity evaluation
AEC Airway exchange catheter
AIHW Australian Institute of Health and Welfare
AJCC American Joint Committee on Cancer
AK Actinic keratosis
ASA American Society of Anesthesiologists
BCC Basal cell carcinoma
CAM-ICU Confusion assessment method for ICU
CI Charlson index
CIRS Cumulative illness rating scale
CK Cytokeratin
CLL Chronic lymphocytic leukemia
CNI Calcineurin inhibitor
CNS Central nervous system
COPD Chronic obstructive pulmonary disease
COSA Clinical Oncological Society of Australia
cSCC Cutaneous squamous cell carcinoma
CT Computed tomography
DAS Diffi cult Airway Society
DFS Disease-free survival
DFSP Dermatofi brosarcoma protuberans
DSS Disease-specifi c survival
DVT Deep vein thrombosis
EAC External auditory canal
EAM External auditory meatus
EBV Epstein−Barr virus
ECS Extracapsular spread
EGFR Epidermal growth factor receptor
ENS Extranodal spread
ENT-HNS Otorhinolaryngology and head and neck surgeon
ETT Endotracheal tube
FAMM Facial artery musculomucosal
FDG-PET [18F] Fluorodeoxyglucose positron emission tomography
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xviii
HIV Human immunodefi ciency virus
HN Head and neck
HNC Head and neck cancer
HNcSCC Head and neck cutaneous squamous cell carcinoma
HNMDT Head and neck multidisciplinary team
HPV Human papillomavirus
HR Hazard ratio
ICU Intensive care unit
IMRT Intensity-modulated radiation therapy
ITEM score Immunosuppression, treatment, extranodal spread, and margin sta-
tus score
LMWH Low molecular weight heparin
LOS Length of stay
LTBR Lateral temporal bone resection
LVI Lymphovascular invasion
MAC Microcystic adnexal carcinoma
MCC Merkel cell carcinoma
MCT Medial canthal tendon
MCV Merkel cell polyomavirus
MMS Mohs micrographic surgery
MRI Magnetic resonance imaging
mSCC Mucosal squamous cell carcinoma
mTOR Mammalian target of rapamycin
NCCN National Comprehensive Cancer Network
NICE National Institute for Health and Clinical Excellence
NMSC Non-melanoma skin cancer
OMF Oral and maxillofacial surgeon
OS Overall survival
OSA Obstructive sleep apnea
PCA Patient-controlled analgesia
PDGFB Platelet-derived growth factor band
PDT Photodynamic therapy
PE Pulmonary embolism
PET Positron emission tomography
PN Parenteral nutrition
PNI Perineural invasion
PNS Perineural spread
PRS Plastic and reconstructive surgeon
PUVA Psoralen and ultraviolet A
RASS Richmond agitation–sedation scale
RCRI Revised cardiac risk index
RCT Randomized controlled trial
RSTL Relaxed skin tension line
RT Radiotherapy
SCC Squamous cell carcinoma
Abbreviations
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xix
SHNCI Sydney Head and Neck Cancer Institute
SLN Sentinel lymph node
SMAS Superfi cial musculoaponeurotic system
SNB Sentinel node biopsy
SNLB Sentinel lymph node biopsy
SSI Surgical site infection
STBR Subtotal temporal bone resection
STM Soft tissue metastases
STSG Split-thickness skin graft
TKI Tyrosine kinase inhibitor
TLR7 Toll-like receptor 7
TMJ Temporomandibular joint
TROG Trans-Tasman Radiation Oncology Group
TTBR Total temporal bone resection
UFH Unfractionated heparin
US Ultrasound
UVA Ultraviolet A
VAP Ventilator-associated pneumonia
VTE Venous thromboembolism
XP Xeroderma pigmentosum
Abbreviations
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1
© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_1
Z. Hasan , MBBS, MIPH, MS
Otolaryngology-Head and Neck Surgery, Westmead Hospital, University of New South
Wales , Sydney , NSW , Australia
e-mail: zubairhasan_112@hotmail.com
F. Riffat , BSc, MBBS, FRACS (*)
Otolaryngology-Head and Neck Surgery, Westmead Hospital, University of Sydney ,
Sydney , NSW , Australia
e-mail: faruque.riffat@health.nsw.gov.au
1
Epidemiology and Aetiology
of Non- melanoma Skin Cancer
Zubair Hasan and Faruque Riffat
Introduction
Skin cancer can be categorized broadly into cutaneous melanoma and nonmela-
noma skin cancer (NMSC). Squamous cell carcinoma (SCC) and basal cell carci-
noma (BCC) are the most common types of NMSC. Apart from these, rarer
cutaneous malignancies, such as Merkel cell carcinoma (MCC) and malignancies of
the adnexal structures, also occur. NMSC is by far the most common malignancy
encountered in the human body, and is found frequently in primary care settings,
which makes it an important public health consideration. It is managed by a variety
of medical practitioners, being of multidisciplinary interest to otolaryngologists,
head and neck surgeons, plastic surgeons, dermatologists, radiation oncologists, and
primary care physicians.
When detected early, NMSC usually is easily amenable to treatment in low-risk
outpatient settings; it is associated with low mortality. As such, most cancer regis-
tries the world over do not collect information pertaining to NMSC routinely, and
therefore, precise epidemiological data are diffi cult to ascertain. Nonetheless,
because of its overall high incidence, NMSC is associated with signifi cant burden of
disease and economic cost, particularly in the setting of advanced disease.
Accordingly, the epidemiology of NMSC is important to defi ne, as it establishes the
magnitude of the problem and can dictate future planning and research priorities.
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2
The head and neck is the region most frequently affected by NMSC. This is not
surprising, given that this is an area of maximal sun exposure, and UV radiation has
long been known to be the most important aetiological factor in the pathogenesis of
NMSC. However, a myriad of other genetic and environmental factors also contrib-
ute to the development of NMSC.
Epidemiology
Although a common disease, in particular in fair-skinned populations across Europe,
North America and Australia, the epidemiology of NMSC shows marked geograph-
ical variations [ 1 ]. NMSC is more common than any other malignancy and BCC is
more than two times as common as SCC [ 2 ]. In Australia, a country with the highest
worldwide incidence, the prevalence of both SCC and BCC is on the rise [ 2 – 4 ]. This
trend has occurred despite signifi cant public health campaigns in recent decades,
such as ‘SunSmart’, which advocates protective clothing, SPF 30+ sunscreen and
avoidance of excessive sunlight, in particular during peak sunlight hours [ 5 ].
Generally considered to be easily amenable to treatment, NMSC nevertheless incurs
a signifi cant burden upon individuals and the healthcare system on account of its
high incidence. With the average age of the Australian population increasing, it is
anticipated that this burden will rise in coming years [ 4 ].
While cancer registries usually do not record epidemiological data, a series of
cross-sectional studies in 1985, 1990, 1995 and, most recently, in 2002 has provided
periodic estimates of the incidence of NMSC in Australia [ 2 ]. In the most recent
survey from 2002, the age-standardized incidence of NMSC was estimated to be
1170 per 100,000 [ 2 ]. By comparison, the estimated incidence of cutaneous mela-
noma in 2012 was 62.7 in males and 39.9 in females per 100,000, respectively [ 6 ].
NMSC affects all age groups, although it is uncommon in individuals <40 years of
age who otherwise have no other risk factors. Incidence rises markedly with age,
with a signifi cant increase in risk in those over the age of 70 years [
2 ].
The 2002 survey also indicated roughly 1.8 % of the population were treated for
NMSC in the preceding year, and confi rmed rates of both BCC and SCC were
higher in the northern latitudes of Australia, which are areas of greater sunlight
exposure, in Australia-born residents and in poor skin tanners [ 2 ]. The median age
in Denmark was found recently to be 68 years for BCC and 78 years for SCC [ 7 ].
Males are typically affected more commonly than females, especially in older age
groups. Multiple tumours are common, and occur in ~25 % of patients with both
BCC and SCC.
In contrast, NMSC is a rare disease in darker skinned populations. In India, for
example, the estimated incidence is between 0.5 and 2 per 100,000 [ 8 ]. In Asian and
black races, SCC occurs more frequently than BCC, is a more aggressive disease,
occurring preferentially in sun-protected rather than sun-exposed areas and in areas
of chronic scarring and ulceration [ 8 – 11 ].
Mortality associated with NMSC is relatively low compared with other cancers.
Between 1998 and 2005 there was an average of 382 deaths per year in Australia,
i.e. approximately 1–3 per 100,000, a fi gure representing <1 % of total cancer
Z. Hasan and F. Riffat
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3
deaths in this period [ 3 ]. This is not to say that NMSC does not contribute to signifi -
cant morbidity and mortality. The overall high incidence of disease translates into
signifi cant healthcare costs [ 12 ]. Morbidity related to NMSC is in terms of lost
productivity and perceived loss of quality of life. As an aesthetically important
region of the body, surgery involving the head and neck may impact negatively upon
patients’ quality of life because of cosmetic disfi gurement [ 13 ]. Furthermore, a
recent systematic review of the literature examining the morbidity and mortality
costs of NMSC found substantial costs arose because of premature death and lost
productivity, which could have been averted with early detection and preventive
strategies [
14 ].
Increasing Incidence
Notwithstanding that NMSC is already the most common cancer in fair-skinned
populations globally, data accumulated over the past two to three decades indicate
that the incidence of NMSC is further on the rise. In Australia, between the 1985
and 2002 surveys, a statistically signifi cant (p < 0.0005) rise in the age-standardized
incidence was observed in both SCC and BCC—2.1 and 1.3 times the 1985 rates,
respectively [ 2 ]. Furthermore, data obtained from Medicare Australia for items
billed for treatment of NMSC by excision, curettage, laser, or cyrotherapy also indi-
cate a steady annual rise in the number of NMSC cases treated by these methods
between 1997 and 2010, with a more signifi cant rise in the older age groups
(>55 years of age) [ 4 ]. Suggested explanations for this phenomenon include (1) an
ageing population, (2) increased detection, (3) changes in recreational outdoor
activities, (4) clothing style, and (5) ozone depletion [ 12 , 15 ].
Similar trends have been observed in Europe and North America, with a sug-
gested ‘epidemic’ of NMSC. Nevertheless, the magnitude of NMSC in these conti-
nents pales in comparison to the absolute fi gures in Australia [ 15 ]. Exact fi gures are
diffi cult to ascertain because of similar challenges in obtaining epidemiological data.
In the USA, data collected between 1994 and 2006 on the basis of Medicare claims
show an almost doubling of the incidence of NMSC [
16 ]. In Northern Ireland, the
incidence of SCC and BCC was 23–46 per 100,000 and 72–94 per 100,000 between
1993 and 2004, with a rise of 62 % in the number of skin cancer specimens handled
by pathology laboratories during this period [ 17 ]. Examination of data in a number
of other European nations has also shown increased incidence [ 12 ].
The implications of the increase in NMSC incidence will be felt over the coming
decades and policy-makers will have to respond to the changing needs in treating a
cancer that already incurs signifi cant economic burden upon healthcare systems
globally. The expense associated with treating individual NMSC cases is not sub-
stantial; Medicare data from the USA indicate that the cost of treating NMSC per
case is 5–10 % of the cost for other cancers, but overall, it is the fi fth most expensive
cancer to treat [ 18 ]. In Australia it has been estimated that the costs are ~$700 per
case. Given the high incidence of NMSC in Australia, it is not surprising that it is
the most expensive cancer to treat overall, costing the healthcare system $264 mil-
lion, or 9 % of total cancer expenditure [
19 ]. Whereas the bulk of NMSC is treated
1 Epidemiology and Aetiology of Non-melanoma Skin Cancer
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4
in outpatient settings, it is important to note that this cancer also incurs signifi cant
inpatient costs, with approximately 95,000 hospital admissions in Australia in
2010–11, a fi gure that is greater than that for any other type of cancer [ 6 ].
Aetiology
Risk Factors
The single most important aetiological factor in the pathogenesis of NMSC is
UV-induced DNA damage [ 1 ]. NMSC is rare in dark-skinned races because of the
protective role of melanin in UV-induced damage of skin cells [ 20 ]. The pathogen-
esis of SCC strongly correlates with cumulative exposure of UV radiation, in par-
ticular, UV-B (290–320 nm). In contrast, intermittent exposure is more signifi cant
in the development of BCC. Consequently, the distribution of NMSC is predomi-
nantly in the head and neck and in other areas of maximal sun exposure, such as the
arms and back [ 21 ]. In Australia, factors shown consistently to be associated with
an increased risk of NMSC are: (1) living in northern latitudes where exposure to
the sun is maximal, (2) being fair-skinned with poor skin-tanning, and (3) high
cumulative sun exposure. In addition, the male gender is affected more commonly
than the female gender, as are fair-skinned races over Blacks or Asians. The risk of
developing NMSC increases markedly with age [ 2 ].
Other risk factors include infection with human papillomavirus (HPV), chemical
carcinogens, as well as acquired or inherited immunosuppression [ 22 ]. Tobacco
smoking is an established risk factor for SCC but not for BCC [ 23 ]. Arsenic is a
chemical carcinogen, which with chronic exposure is associated strongly with the
development of a variety of dermatological manifestations and malignancies,
including SCC and BCC [ 24 ]. Areas of chronic irritation and scarring also predis-
pose to SCC, which is known to arise in the setting of chronic ‘Marjolin’ ulcers,
sinus tracts and scars [
25 ].
Immunosuppression and NMSC
NMSC is associated with signifi cant morbidity in post-transplantation patients and in
patients with autoimmune disorders who are on immunosuppressive agents, with
increasing risk associated with an increasing duration of immunosuppression [ 26 ,
27 ]. The risk of cutaneous as well as systemic cancers is increased in this group of
patients. The risk of developing SCC is particularly high in this group of patients.
Recipients of solid organ transplants have an approximate 100-fold increase in the
risk of developing SCC compared with a 10–16-fold increase in risk of developing
BCC [ 28 ]. In a series of Australian heart transplant recipients, the cumulative inci-
dence of NMSC was 43 % over 10 years [ 29 ], while in a series of Italian heart trans-
plant recipients the corresponding fi gure was 35 % [
30 ]. NMSC in this cohort of
patients may be particularly aggressive, manifest as recurrent, multifocal, or
Z. Hasan and F. Riffat
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5
metastatic disease, and is therefore far more diffi cult to manage when compared to
the non-immunosuppressed patient [ 31 ]. Risk of mortality is approximately 5 % in
patients who develop SCC after a renal transplant [ 32 ]. With increasing numbers of
transplant recipients and longer survival times of such patients, the burden of disease
represented by this cohort of patients is likely to increase over the coming years.
Gene Mutations
As with all malignancies, acquired and inherited mutations in genetic code play a
role in the pathogenesis of NMSC. The p53 gene is a tumour-suppressor gene
located on chromosome 17, mutations of which strongly correlate with an array of
cancers, including SCC and BCC. The p53 gene plays an important regulatory role
in the cell cycle, in DNA repair, and in apoptosis [ 21 ]. Alterations in pyrimidine
dimers, induced by UV radiation, may inactivate the gene, subsequently causing
dysregulation of the cell cycle, failure of apoptosis and tumour formation [ 33 ].
Another relevant gene in the pathogenesis of BCC is patched ( PTCH1 ). The
PTCH1 gene located on chromosome 9 is involved in the sonic hedgehog signal-
ling cascade. Its involvement in disease was fi rst identifi ed in individuals with the
nevoid BCC syndrome, an autosomal-dominant syndrome [ 25 ]. Patients with this
syndrome have associated defects in the sonic hedgehog pathway and present with
multiple BCCs, odontogenic cysts, skeletal defects, palmar and plantar pits, and
calcifi cation of the falx cerebri [ 25 ]. Mutations, however, also occur in sporadic
cases of BCC. PTCH1 is a tumour suppressor gene that binds to and inhibits
smoothened (SMOH), a transmembrane protein that promotes cellular growth.
Mutations in the PTCH1 gene leads to failure of this inhibition and aberrant cel-
lular growth [ 34 ].
Other inherited conditions, such as xerodermapigmentosum, also predispose
individuals to NMSC. Xerodermapigmentosum is an autosomal-recessive condition
wherein cells have a reduced capacity to repair UV-induced damage, leading to
multiple SCC and other skin cancers. The mutation involved in xerodermapigmen-
tosum disrupts the nucleotide excision repair, which enzymatically repairs
UV-induced DNA damage [
21 ]. Epidermodysplasiaverruciformis is another
autosomal- recessive condition, wherein increased susceptibility to viral oncogene-
sis secondary to HPV leads to widespread wart formation followed by the emer-
gence of cutaneous SCC [ 35 ].
Other Cutaneous Malignancies of the Head and Neck
Merkel Cell Carcinoma
MCC is a rare but highly malignant neuroendocrine tumour. Aetiology is also
thought to be sunlight-related, although recently additional links have been made
with polyomavirus and immunosuppression [
36 ]. As with other types of NMSC,
1 Epidemiology and Aetiology of Non-melanoma Skin Cancer
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6
the head and neck is the most commonly affected region of the body [ 37 ]. Data
pertaining to the epidemiology of MCC have not been studied extensively.
However, a cancer registry from Western Australia between 1993 and 2007 indi-
cated that this region had the highest reported incidence of MCC in the world
[ 38 ]. Males were found to be affected more commonly than females—1 per
100,000 in males compared to 0.63 per 100,000 in females, with the median age
being 77 years [ 38 ]. MCC can also often occur in patients with pre-existing SCC
or BCC. Prognosis is generally poor, particularly in metastatic disease, with a
5-year survival of 75 %, 59 %, and 25 % for local, regional, and distant disease,
respectively [
37 ].
Appendigeal Malignancies
Malignancies arising from the adnexal structures of the skin with apocrine, eccrine,
follicular, or sebaceous differentiation are rare, representing <1 % of cutaneous
head and neck malignancies [ 25 , 39 ]. Although sebaceous carcinoma is rare, it is a
highly malignant appendigeal neoplasm, with an incidence of ~1 case per million
of the population [ 40 ]. Although it may occur outside the eyelid, an ocular distribu-
tion is more likely usually from a meibomian gland or from the glands of Zeis. The
tumour most commonly occurs in patients aged 60–80 years, and affects Asian
people more than other races [ 41 ]. Women are generally reported to have a higher
incidence than men. However, this distribution is questionable, as in a series of
1349 patients, 54 % were men [ 42 ]. The presence of other aetiological factors is
unclear, although Muir–Torre syndrome, an autosomal-dominant inherited condi-
tion, is characterized by sebaceous tumours and visceral neoplasms, and previous
irradiation [ 41 , 42 ].
Dermatofi brosarcoma protuberans: Dermatofi brosarcoma protuberans
(DFSP) is a mesenchymal neoplasm of intermediate malignant potential.
Although a rare skin tumour overall, it is the most common cutaneous sarcoma.
The tumour demonstrates aggressive local growth with a high propensity for
recurrence, despite surgical excision [
43 ]. On the basis of population-based
cancer registry data, the incidence of DFSP in the USA was found to be ~4 per
million, with a small but statistically signifi cant higher incidence in women than
in men (4.4 vs. 4.2) [ 44 ].
DFSP occurs most commonly on the trunk. However, 10–15 % of cases occur in
the head and neck, where it commonly affects the scalp and supraclavicular fossa
[ 43 , 44 ]. Aetiological factors are unclear, although recent advances in the molecular
pathogenesis of DFSP have indicated that >90 % of cases are caused by reciprocal
translocations between chromosomes 17 and 22. The resultant gene is a fusion
between platelet-derived growth factor band (PDGFB) collagen 1A1, which leads
to upregulation of the PDGFB protein. This is thought to underlie the pathogenesis
of DFSP [ 45 , 46 ]. Imatinib, an inhibitor of PDGFB, has recently been used to show
demonstrable effi cacy against DFSP [
47 , 48 ]. An association with antecedent
trauma to the affected area has also been reported [ 43 ].
Z. Hasan and F. Riffat
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7
Angiosarcoma
Angiosarcoma of the head and neck is an exceedingly rare yet extremely aggres-
sive malignancy of vascular origin. Data relating to head and neck angiosarcoma
are sparse. Approximately half of all angiosarcomas occur in the head and neck
and the scalp has been found to be affected more commonly than any other part of
the body [ 49 ]. The male gender is affected more than two times than the female
gender [ 50 , 51 ]. One of the largest series of patients with head and neck angiosar-
coma reported in the literature is from the Connecticut Tumour Registry between
1980 and 2001 [ 52 ]. Of 54 patients studied over a 21-year period, 29 patients had
angiosarcoma of the head and neck, with a mean age at diagnosis of 71 years. The
authors found a 1-year mortality of 48 % and a 5-year mortality of 28 %. This
series also contained one instance of familial angiosarcoma of the head and neck.
Documented risk factors include chemical exposure (vinyl chloride, thorium, arse-
nic) and radiation [ 53 – 55 ].
Summary
Precise epidemiological data pertaining to NMSC of the head and neck are unavail-
able. Nevertheless, it is clear that the burden of NMSC is increasing globally and
that this burden can be signifi cant in terms of personal and societal costs. While a
variety of aetiological factors have been associated with NMSC, UV exposure
remains the single most important factor for the development of NMSC, particu-
larly in males of fair skin who live in equatorial longitudes.
References
1. Kricker A, Armstrong BK, English DR. Sun exposure and non-melanocytic skin cancer.
Cancer Causes Control. 1994;5:367–92.
2. Staples MP, Elwood M, Burton RC, et al. Non-melanoma skin cancer in Australia: the 2002
national survey and trends since 1985. Med J Aust. 2006;184:6–10.
3. Melissa Goodwin, Australian Institute of Health and Welfare, Cancer Australia. Non-
melanoma skin cancer: general practice consultations, hospitalisation and mortality. Canberra:
Australian Institute of Health and Welfare; 2008.
4. Fransen M, Karahalios A, Sharma N, et al. Non-melanoma skin cancer in Australia. Med
J Aust. 2012;197:565–8.
5. Montague M, Borland R, Sinclair C. Slip! Slop! Slap! and SunSmart, 1980–2000: skin cancer
control and 20 years of population-based campaigning. Health Educ Behav. 2001;28:
290–305.
6. Australian Institute of Health and Welfare, Australasian Association of Cancer Registries.
Cancer in Australia: an overview 2012. Canberra: Australian Institute of Health and Welfare
and Australasian Association of Cancer Registries; 2012.
7. Jensen AØ, Lamberg AL, Jacobsen JB, et al. Non-melanoma skin cancer and ten-year all-
cause mortality: a population-based cohort study. Acta Derm Venereol. 2010;90:362–7.
8. Laishram RS, Banerjee A, Punyabati P, et al. Pattern of skin malignancies in Manipur, India:
a 5-year histopathological review. J Pak Assoc Dermatol. 2012;20:4.
1 Epidemiology and Aetiology of Non-melanoma Skin Cancer
malcolm_buchanan123@hotmail.com
8
9. Deo SV, Hazarika S, Shukla NK, et al. Surgical management of skin cancers: experience from
a regional cancer centre in North India. Indian J Cancer. 2005;42:145–50.
10. Panda S. Non-melanoma skin cancer in India: current scenario. Indian J Dermatol. 2010;
55:373–8.
11. Mora RG, Perniciaro C. Cancer of the skin in blacks. I. A review of 163 black patients with
cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1981;5:535–43.
12. Trakatelli M, Ulrich C, del Marmol V, et al. Epidemiology of nonmelanoma skin cancer
(NMSC) in Europe: accurate and comparable data are needed for effective public health moni-
toring and interventions. Br J Dermatol. 2007;156 Suppl 3:1–7.
13. Rhee JS, Matthews BA, Neuburg M, et al. Creation of a quality of life instrument for non-
melanoma skin cancer patients. Laryngoscope. 2005;115:1178–85.
14. Guy GP, Ekwueme DU. Years of potential life lost and indirect costs of melanoma and non- melanoma
skin cancer: a systematic review of the literature. Pharmacoeconomics. 2011;29:863–74.
15. Donaldson MR, Coldiron BM. No end in sight: the skin cancer epidemic continues. Semin
Cutan Med Surg. 2011;30:3–5.
16. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer
in the United States, 2006. Arch Dermatol. 2010;146:283–7.
17. Hoey SE, Devereux CE, Murray L, et al. Skin cancer trends in Northern Ireland and conse-
quences for provision of dermatology services. Br J Dermatol. 2007;156:1301–7.
18. Housman TS, Feldman SR, Williford PM, et al. Skin cancer is among the most costly of all
cancers to treat for the Medicare population. J Am Acad Dermatol. 2003;48:425–9.
19. Australian Institute of Health and Welfare (AIHW). Health system expenditures on cancer and
other neoplasms in Australia 2000–01. Canberra: AIHW; 2005.
20. Yamaguchi Y, Beer JZ, Hearing VJ. Melanin mediated apoptosis of epidermal cells damaged
by ultraviolet radiation: factors infl uencing the incidence of skin cancer. Arch Dermatol Res.
2008;300 Suppl 1:S43–50.
21. de Gruijl FR, van Kranen HJ, Mullenders LH. UV-induced DNA damage, repair, mutations
and oncogenic pathways in skin cancer. J Photochem Photobiol B. 2001;63:19–27.
22. Glover MT, Deeks JJ, Raftery MJ, et al. Immunosuppression and risk of non-melanoma skin
cancer in renal transplant recipients. Lancet. 1997;349:398.
23. Rollison DE, Iannacone MR, Messina JL, et al. Case–control study of smoking and non-
melanoma skin cancer. Cancer Causes Control. 2012;23:245–54.
24. Yu HS, Liao WT, Chai CY. Arsenic carcinogenesis in the skin. J Biomed Sci. 2006;13:657–66.
25. Ouyang YH. Skin cancer of the head and neck. Semin Plast Surg. 2010;24:117–26.
26. Ramsay HM, Reece SM, Fryer AA, et al. Seven-year prospective study of nonmelanoma skin
cancer incidence in UK renal transplant recipients. Transplantation. 2007;84:437–9.
27. Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for non-melanoma skin cancer in
patients with infl ammatory bowel disease. Clin Gastroenterol Hepatol. 2010;8:268–74.
28. Stoff B, Salisbury C, Parker D, et al. Dermatopathology of skin cancer in solid organ transplant
recipients. Transplant Rev (Orlando). 2010;24:172–89.
29. Ong CS, Keogh AM, Kossard S, et al. Skin cancer in Australian heart transplant recipients.
J Am Acad Dermatol. 1999;40:27–34.
30. Caforio AL, Fortina AB, Piaserico S, et al. Skin cancer in heart transplant recipients: risk fac-
tor analysis and relevance of immunosuppressive therapy. Circulation. 2000;102(19 Suppl 3):
III222–7.
31. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and
management. J Am Acad Dermatol. 2002;47:1–17; quiz 18–20.
32. Sheil AG, Disney AP, Mathew TH, et al. De novo malignancy emerges as a major cause of
morbidity and late failure in renal transplantation. Transplant Proc. 1993;25:1383–4.
33. Kanjilal S, Strom SS, Clayman GL, et al. p53 mutations in nonmelanoma skin cancer of the
head and neck: molecular evidence for fi eld cancerization. Cancer Res. 1995;55:3604–9.
34. Iwasaki JK, Srivastava D, Moy RL, et al. The molecular genetics underlying basal cell carci-
noma pathogenesis and links to targeted therapeutics. J Am Acad Dermatol. 2012;66:
e167–78.
Z. Hasan and F. Riffat
malcolm_buchanan123@hotmail.com
9
35. Molho-Pessach V, Lotem M. Viral carcinogenesis in skin cancer. Curr Probl Dermatol.
2007;35:39–51.
36. Kaae J, Hansen AV, Biggar RJ, et al. Merkel cell carcinoma: incidence, mortality, and risk of
other cancers. J Natl Cancer Inst. 2010;102:793–801.
37. Agelli M, Clegg LX. Epidemiology of primary merkel cell carcinoma in the United States.
J Am Acad Dermatol. 2003;49:832–41.
38. Girschik J, Thorn K, Beer TW, et al. Merkel cell carcinoma in Western Australia: a population-
based study of incidence and survival. Br J Dermatol. 2011;165:1051–7.
39. Güerrissi JO, Quiroga JP. Adnexal carcinomas of the head and neck. Indian J Plast Surg.
2008;41:229–34.
40. Dores GM, Curtis RE, Toro JR, et al. Incidence of cutaneous sebaceous carcinoma and risk of
associated neoplasms. Cancer. 2008;113:3372–81.
41. Nelson BR, Hamlet KR, Gillard M, et al. Sebaceous carcinoma. J Am Acad Dermatol.
1995;33:1–15; quiz 16–8.
42. Dasgupta T, Wilson LD, Yu JB. A retrospective review of 1349 cases of sebaceous carcinoma.
Cancer. 2009;115:158–65.
43. Gloster Jr HM. Dermatofi brosarcoma protuberans. J Am Acad Dermatol. 1996;35:355–74;
quiz 375–6.
44. Criscione VD, Weinstock MA. Descriptive epidemiology of dermatofi brosarcoma protuberans
in the United States, 1973 to 2002. J Am Acad Dermatol. 2007;56:968–73.
45. McArthur G. Dermatofi brosarcoma protuberans: recent clinical progress. Ann Surg Oncol.
2007;14:2876–86.
46. Dimitropoulos VA. Dermatofi brosarcoma protuberans. Dermatol Ther. 2008;21:428–32.
47. Stacchiotti S, Pedeutour F, Negri T, et al. Dermatofi brosarcoma protuberans-derived fi brosar-
coma: clinical history, biological profi le and sensitivity to imatinib. Int J Cancer. 2011;129:
1761–72.
48. McArthur GA, Demetri GD, van Oosterom A, et al. Molecular and clinical analysis of locally
advanced dermatofi brosarcoma protuberans treated with imatinib: imatinib target exploration
consortium study B2225. J Clin Oncol. 2005;23:866–73.
49. Mark RJ, Tran LM, Sercarz J, et al. Angiosarcoma of the head and neck. The UCLA experi-
ence 1955 through 1990. Arch Otolaryngol Head Neck Surg. 1993;119:973–8.
50. Aust MR, Olsen KD, Lewis JE, et al. Angiosarcomas of the head and neck: clinical and patho-
logic characteristics. Ann Otol Rhinol Laryngol. 1997;106:943–51.
51. Lydiatt WM, Shaha AR, Shah JP. Angiosarcoma of the head and neck. Am J Surg.
1994;168:451–4.
52. McIntosh BC, Narayan D. Head and neck angiosarcomas. J Craniofac Surg. 2005;16:
699–703.
53. Williamson IG, Ramsden RT. Angiosarcoma of maxillary antrum—association with vinyl
chloride exposure. J Laryngol Otol. 1988;102:464–7.
54. Chen KT, Hoffman KD, Hendricks EJ. Angiosarcoma following therapeutic irradiation.
Cancer. 1979;44:2044–8.
55. Narula AA, Vallis MP, el-Silimy OE, et al. Radiation induced angiosarcomas of the nasophar-
ynx. Eur J Surg Oncol. 1986;12:147–52.
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© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_2
H. Coleman , BDS, BChD, MDent, FCPath, FFOP (*)
Department of Tissue Pathology and Diagnostic Oncology , Institute for Clinical Pathology
and Medical Research, Pathology West, New South Wales Health Pathology ,
Sydney , NSW , Australia
e-mail: hedley.coleman@health.nsw.gov.au
J. Tomlinson , MBBS, MBA, FRCPA, FIAC
Department of Tissue Pathology and Diagnostic Oncology , Westmead Hospital ,
Sydney , NSW , Australia
e-mail: tomlinson@austpath.com.au
2
Pathology Reporting of Non-melanoma
Skin Cancer at the ICPMR, Westmead
Hospital
Hedley Coleman and Jeanne Tomlinson
Introduction
It is well known that Australia has the highest skin cancer incidence in the world [ 1 ]
and approximately two-thirds of Australians will be diagnosed with skin cancer
before the age of 70 years [ 2 ]. Non-melanoma skin cancers (NMSC) are the most
commonly diagnosed form of cancer in Australia, with approximately 430,000 new
cases estimated to have been diagnosed in 2008 [ 3 ].
It is vital that our head and neck pathology reports contain all of the relevant
information in the form of minimum datasets. Information obtained from these
pathology reports has a key role in the rational planning of patient management,
which is then used to guide clinical decisions [ 4 , 5 ]. Structured reporting of cancer,
including NMSC, by pathologists aims to improve the standardization, complete-
ness and usability of pathology reports for clinicians, and thereby improves decision
support for cancer treatment [ 6 – 8 ]. The reporting of the grade, pathological stage,
as well as other relevant information should provide the clinicians in the multidisci-
plinary setting with accurate staging and prognostic information in a consistent
manner, thereby resulting in a high standard of care and appropriate management
[ 4 , 5 ]. Clinicians will thus be able to make suitable adjuvant therapy recommenda-
tions and provide accurate information on prognosis [ 5 ].
malcolm_buchanan123@hotmail.com
12
Laboratory Considerations for the Skin Resection Specimen
The preparation in the laboratory of all skin specimens that are suspected of being
malignant neoplasms should be standardized for the required consistency in report-
ing. The cut-up protocol that is followed in the Department of Tissue Pathology and
Diagnostic Oncology at the Institute for Clinical Pathology and Medical Research
(ICPMR), Westmead Hospital (the department), is based upon the standards and
datasets for reporting of cancers of the Royal College of Pathologists, and is out-
lined below [ 6 – 8 ].
When preparing skin specimens in the laboratory, the overall size of the speci-
men should be measured and, particularly with excision specimens, this should
incorporate three dimensions. The presence of the surface lesion or abnormality
must be recorded and measurements should include the maximum diameter and
elevation, if possible [ 6 – 8 ].
It is desirable and useful for multidisciplinary meetings that complex gross speci-
mens suspected of harbouring a malignant lesion be photographed before dissection.
The overall conformation of the tumour, its relation to the resection margins and how
the tumour and margins have been sampled can be presented and assessed [ 5 ].
The surgical margin must be inked. Inking of the excised skin specimen assists in
obtaining an accurate assessment of the surgical margins and thereby allows the determi-
nation of the adequacy of tumour excision and clearance from the margins (Fig. 2.1 ). The
potential for dye to track and spread, which gives rise to false margins, should always be
taken into account in the fi nal histopathological assessment of the specimen [ 6 – 8 ].
When the lesion is clearly identifi ed on the skin surface, sampling the polar mar-
gins of the skin ellipse should be discretionary and based predominantly on whether
the lesion is close to the margin (<1–2 mm) or is less than that in the short/trans-
verse axes [ 6 – 8 ].
When the lesion cannot be identifi ed, or if there is uncertainty, the whole of the
specimen should be sampled. In this situation, the polar ends from the long axis of
a skin ellipse should also be examined. In certain very large specimens, in addition
to sampling the lesion, the cruciate margins at 3, 6, 9 and 12 o’clock can be sam-
pled, although the limitation in assessing margin clearance in these situations should
be appreciated by the treating clinicians [
6 – 8 ].
It is not possible usually to ink small and fragmented curetted or shave speci-
mens. For these small specimens it is recommended that at least three levels be
examined to reduce the possibility of sampling error [ 6 – 8 ].
Histopathology Reporting Protocol
The AJCC 7th edition divides NMSC into the following two separate chapters, each
of which has a different staging system: [ 9 ]
• Cutaneous squamous cell carcinoma (SCC) and other cutaneous carcinomas
(including basal cell carcinoma)
• Merkel cell carcinoma (MCC)
H. Coleman and J. Tomlinson
malcolm_buchanan123@hotmail.com
13
This review of the pathological reporting of NMSC as practised within the
department will, therefore, briefl y address NMSC under these two broad headings.
In addition, the standardized protocol for neck dissections for cases of head and
neck NMSC is discussed briefl y, as these tumours may present with regional lymph
node metastases.
The minimum datasets produced as a result are based upon the Royal College of
Pathologists [ 6 – 8 , 10 ] and the Royal College of Pathologists of Australasia stan-
dards, as well as datasets for reporting cancers [ 5 ].
Cutaneous SCC and Other Cutaneous Carcinomas
Of the 430,000 newly diagnosed cases in Australia, basal cell carcinoma (BCC)
accounts for at least two-thirds of NMSC, with most other NMSC being SCC [ 11 ].
In 2010, there were 445 reported deaths resulting from NMSC [ 12 ]. BCC rarely
metastasizes to other organs, but it may be highly invasive and cause signifi cant
destruction of local tissues. SCC is also invasive but has a greater potential than
BCC to metastasize. The true incidence of BCC and SCC is, however, not known in
Australia as NMSCs are not reportable by law to the relevant state and national
Fig. 2.1 Skin resection
specimen that has been inked
with attached sutures which
allow for correct orientation
and assessment of the
surgical margin
2 Pathology Reporting of Non-melanoma Skin Cancer at the ICPMR
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14
cancer registries [ 11 ]. The total numbers of cases of BCC and SCC that involve the
skin of the scalp, face and neck is therefore unknown; however, it is believed that
they would be fewer in number than the total number of estimated cases.
Cutaneous SCC
Most cutaneous SCCs arise in the skin of the sun-damaged head and neck and fre-
quently involve the lower lip [ 13 , 14 ]. Patients with rare genetically inherited disor-
ders, such as albinism and xeroderma pigmentosum, as well as patients with
systemic immunosuppression also have a high incidence of SCC [ 14 ]. Pathologists
should separate neoplasms of the hair-bearing lip from those involving the vermil-
ion zone, as these are staged according to the Head and Neck TNM staging system
for the lip and oral cavity [ 9 ]. The AJCC 7th edition also excludes the eyelid from
cutaneous SCC staging [ 9 ]. In the department, 80 cases of primary SCC of the skin
of the face and neck, excluding the scalp and metastatic tumours to the parotid
gland, were reported between 2007 and 2009 (unpublished data).
Histologically, SCC is composed of islands of squamous epithelial cells that
arise from the epidermis in sun-damaged skin or within a pre-existing solar kerato-
sis, and invade into the underlying dermis. The individual tumour cells have eosino-
philic cytoplasm with large pleomorphic vesicular nuclei that exhibit mitotic fi gures.
Individual cell keratinization and keratin pearls may be observed (Fig. 2.2 ). The
degree of pleomorphism and deviation from normal squamous epithelium have
Fig. 2.2 Moderately differentiated squamous cell carcinoma showing vesicular nuclei and keratin
eddies (H&E)
H. Coleman and J. Tomlinson
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15
been used historically to subjectively grade SCC into well, moderately and poorly
differentiated categories [ 13 , 14 ]. The tumour islands and strands may be sur-
rounded by a desmoplastic stromal reaction with a variable infl ammatory response
that may include eosinophils. The tumour cells may also infi ltrate along nerves and
invade lymphovascular channels [ 13 , 14 ].
Immunohistochemical stains are of limited practical importance except in the
spindle cell variant of SCC in which a broad-spectrum cytokeratin cocktail, such as
MNF116, may be requested to confi rm carcinoma; p63 may also be useful [ 15 ]. In
addition, staining for Ber-EP4 is uniformly negative, which allows distinction from
keratotic BCC, as BCC demonstrates diffuse positive staining [
15 ].
The World Health Organization’s Pathology and Genetics of Skin Tumours
(2006) outlines several histological variants of SCC [ 13 ].
• Acantholytic SCC . This variant is found often involving the head and neck. The
islands of tumour cells demonstrate central acantholysis resulting in a pattern
that appears gland-like [ 13 , 15 ].
• Spindle cell SCC is rare and usually arises in sun-damaged or previously irradi-
ated skin. These spindle-shaped tumour cells have large vesicular nuclei with
numerous mitoses and minimal eosinophilc cytoplasm [ 13 , 15 ].
Immunohistochemical stains are usually employed to exclude other spindle cell
malignancies such as spindle cell melanoma and atypical fi broxanthoma.
• Verrucous carcinoma is a distinctive and well-differentiated variant of SCC that
may occur on the skin of the head and neck but more commonly involves the oral
cavity [ 13 , 15 ].
• Pseudovascular SCC is an aggressive variant with prominent acantholysis [ 13 , 15 ].
• Adenosquamous carcinoma is a rare variant that is characterized by the forma-
tion of mucin-secreting glands [ 13 , 15 ].
• Other variants: Clear cell, signet-ring, infi ltrating and rhabdoid (Table 2.1 ) [ 13 , 15 ].
Basal Cell Carcinoma (BCC)
BCC is the most common variety of NMSC that usually arises in sun-damaged skin
[ 13 ]. The tumour rarely occurs in black and oriental people [ 14 ]. Additionally, BCC
that is indistinguishable from acquired types may be associated with the Gorlin
Goltz syndrome (naevoid BCC syndrome) in younger patients [ 13 ]. In the head and
neck region, BCCs are usually located in the central mid-face region; however, they
may also rarely involve the external auditory canal. In our department, 246 cases of
BCC of the skin of the face and neck, excluding the scalp, were reported between
2007 and 2009 (unpublished data).
Histologically, the tumours are composed of islands and nests of basaloid cells that
exhibit palisading of cells at the periphery. The overlying epidermis may also show
features of a solar keratosis. The cells have hyperchromatic nuclei with scanty, pale
cytoplasm. Intercellular bridges are not observed. Numerous mitotic fi gures are seen
with prominent numbers of apoptotic tumour cells (Fig.
2.3a ) [ 13 – 15 ]. Surface
2 Pathology Reporting of Non-melanoma Skin Cancer at the ICPMR
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16
ulceration may be observed in larger lesions [ 15 ]. More aggressive tumours usually
extend into the subcutis, with involvement of underlying cartilage in the nose and ears
being relatively uncommon [ 15 ]. Perineural invasion might be observed; however, it
is also relatively uncommon and is described more frequently in the infi ltrating, mor-
phoeic and basosquamous subtypes [ 15 ]. The tumour islands are surrounded by newly
formed stroma, with retraction artefact or clefting at the tumourstromal interface
being observed (Fig. 2.3b ) [ 13 – 15 ]. The surrounding stroma may also show loss of
appendages, amyloid deposition and contain a variable chronic infl ammatory cell
infi ltrate. Calcifi cation may also be observed within the centre of keratin eddies [ 15 ].
Immunohistochemical stains are of limited practical importance; however, dif-
fuse positive staining for Ber-EP4 may be useful in separating BCC from SCC, as
outlined previously [ 15 ].
The World Health Organization’s Pathology and Genetics of Skin Tumours
(2006) outlines several histological variants of BCC and any single lesion may dem-
onstrate the features of more than one of these subtypes [ 13 ].
Table 2.1 Diagnostic summary: squamous cell carcinoma (SCC)
Macroscopy
Site, type and size of specimen Exclude vermilion of the lip and eyelid
Maximum diameter of lesion
Microscopy
Histological subtype High-risk variants – invasive SCC associated with
in situ SCC (Bowen disease), acantholytic,
desmoplastic and spindle cell variants
Grade (according to most poorly
differentiated area)
Well; moderately; poorly
Poorly differentiated contributes to upstaging
from pT1 to pT2
Tumour thickness (measured from the
granular cell layer)
<2 mm; 2–4 mm; >4 mm
<2 mm low risk for metastasis
>10 mm high risk for metastasis
Level of invasion Invasion of fat, facial/cranial bones and
muscle – pT3 Invasion of skull base – pT4
Perineural invasion Into skull base – pT4
High risk of local recurrence and mortality
Lymphovascular invasion Document presence
Margins 0 mm – involved; <1 mm – close; >1 mm – clear
Immunohistochemistry Cytokeratin, such as MNF116, positive in spindle
cell variant
Ber-EP4 negative
Lymph nodes
Level and number of nodes involved Primary pN staging determinant
Maximum size of metastatic deposit pN staging determinant
Tumour deposits >30 and >60 mm
Extracapsular extension Widely regarded as a manifestation of potential
biological aggression, considered to be associated
with a worse prognosis
Adapted from RCP dataset for histopathology reporting of primary cutaneous squamous cell
carcinoma, 2012 [
6 ]
H. Coleman and J. Tomlinson
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17
• The superfi cial ( multifocal ) variant usually presents clinically as an erythema-
tous, scaly plaque and histologically is composed of multiple foci of budding
basaloid cells arising from multiple points along the under-surface of the epider-
mis. This pattern accounts for 10–15 % of all lesions [ 13 , 15 ].
• Solid or nodular: The clinical noduloulcerative lesion or rodent ulcer translates
to a solid or nodular histological subtype. This accounts for almost 70 % of BCC
a
b
Fig. 2.3 ( a ) Nodular basal cell carcinoma with central necrosis and peripherally palisaded basa-
loid cells. ( b ) Micronodular basal cell carcinoma showing ‘retraction artefact’ around the tumour
islands (H&E)
2 Pathology Reporting of Non-melanoma Skin Cancer at the ICPMR
malcolm_buchanan123@hotmail.com
18
and is composed of islands of basaloid cells that exhibit apoptosis, focal necrosis
and increased numbers of mitoses. Peripherally palisaded cells are present with
retraction of the surrounding stroma being observed (Fig. 2.3a ) [ 13 , 15 ].
• The micronodular subtype resembles the solid type. However, the tumour islands
are smaller with less pronounced peripheral palisading. The tumour also has a
higher propensity for recurrence (Fig.
2.3b ) [ 13 , 15 ].
• The infi ltrating type has an infi ltrative pattern of growth without associated stro-
mal fi brosis. This subtype accounts for about 5 % of cases and the tumour is
composed of elongated strands of tumour cells that infi ltrate between the colla-
gen fi bres (Fig.
2.4 ) [ 15 ].
• The fi broepithelial type is characterized by a unique clinicopathological presen-
tation and an indolent behaviour [ 13 ].
• BCC with adnexal differentiation [ 13 ].
• The metatypical or basosquamous types are rare variants that are composed of
islands of basaloid cells which mature into larger and paler cells [ 13 , 15 ].
• Keratotic BCC is similar to the solid type. The centre of the tumour islands, how-
ever, demonstrates squamous differentiation and keratinization [ 13 , 15 ].
• Other variants account for less than 10 % of all BCCs [ 13 ].
– Cystic subtype is found most commonly on the face as a small well circum-
scribed tumour with little stroma and interspersed small cystlike structures
containing keratinous debris and melanin pigment.
– Adenoid BCC consists of thin strands of basaloid cells arranged in a reticular
pattern. These may occur in association with the solid type.
Fig. 2.4 Infi ltrative basal cell carcinoma with irregular strands of basaloid cells surrounded by
hyalinized collagen (H&E)
H. Coleman and J. Tomlinson
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19
– Morphoeic or sclerosing BCC is composed of thin, elongated strands of
tumour cells within a surrounding dense, fi brous stroma.
– Pigmented BCC shows melanin pigment being formed within tumour cells. It
is seen in several BCC variants, and can be clinically mistaken for melanoma
(Table 2.2 ).
Merkel Cell Carcinoma (MCC)
MCC is a rare and aggressive cutaneous tumour with a high mortality rate that tends
to occur in sun-exposed skin of elderly people, particularly on the head and neck. It
occurs rarely in children. MCC exhibits both epithelial and neuroendocrine differen-
tiation [ 13 , 14 , 16 ]. Only four cases involving the skin of the face and neck, excluding
the scalp, were reported in the department between 2007 and 2009 (unpublished data).
MCC is presumed to be derived from Merkel cells that are located within the
basal cell layer of the epidermis where they are concentrated in the touch-sensitive
areas [ 13 , 14 , 16 ]. MCC produces ectopic peptides; however, the levels appear to be
insuffi cient to result in a paraneoplastic syndrome, which is rare [ 16 ]. Merkel cell
polyomavirus (MCV) is the fi rst polyomavirus directly linked to human cancer [ 17 ].
MCV is clonally integrated into MCC tumour cells, which then require continued
MCV oncoprotein expression to survive. Identifi cation of this tumour virus has led
to possible new opportunities for early diagnosis and targeted treatment of MCC.
It has been suggested that there may, therefore, be two independent pathways for the
development of MCC—one driven by UV irradiation and the other by the presence
of MCV [ 17 ].
Table 2.2 Diagnostic summary: basal cell carcinoma
Macroscopy
Site, type and size of specimen Exclude vermilion of the lip and eyelid
Microscopy
Histological subtype Infi ltrating, morphoeic, micronodular and
basosquamous are clinical high-risk variants
Level of invasion Invasion of fat, facial/cranial bones and muscle – pT3
Invasion of skull base – pT4
Perineural invasion Below the dermis, within tumour or advancing front
Perineural invasion of skull base – pT4
Lymphovascular invasion Particularly basosquamous
Margins 0 mm – involved; <1 mm – close; >1 mm – clear
Maximum diameter of lesion T1 < 20 mm; T2 > 20 mm squamous cell carcinoma
Immunohistochemistry Ber-EP4 positive – to differentiate from squamous cell
carcinoma
Lymph nodes Rare (if present follow cutaneous SCC nodal reporting
proforma)
Adapted from RCP dataset for histopathology reporting of primary cutaneous basal cell
carcinoma, 2012 [
7 ]
2 Pathology Reporting of Non-melanoma Skin Cancer at the ICPMR
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Histologically, MCC is composed of ‘small round-to-oval blue cells’ which have
hyperchromatic nuclei and scant cytoplasm, located within the dermis and subcuta-
neous fat [ 13 , 14 , 16 ]. The epidermis generally is not involved and it is separated
from the tumour by a ‘grenz zone’ of normal papillary dermis. Rarely, tumour cells
might invade the epidermis. The tumour cell nuclei typically have an evenly dis-
persed ‘salt-and-pepper’ type of chromatin pattern with two or three inconspicuous
nucleoli and numerous mitotic fi gures (Fig. 2.5 ) [ 13 , 14 , 16 ]. The scanty cytoplasm
is amphophilic and the cell borders are ill-defi ned. The tumour cells are arranged in
densely packed sheets, cords and small nests. Extensive apoptosis and focal areas of
necrosis are observed frequently within the tumour. Adverse histopathological fea-
tures include small cell size, lymphovascular invasion and more than ten mitoses per
high-power fi eld [
13 ].
Intermediate, small cell, trabecular and combined subtypes have been
described [ 16 ]. The histological growth pattern of the intermediate variant is
composed of a diffuse, sheet-like growth with relatively large cells. The small
cell variant has small, round and dyscohesive groups of cells, whereas the tra-
becular variant has columns of tumour cells. The prognostic signifi cance of the
subtypes is not certain at this time. However, the small cell type may have some
survival advantage. The surrounding stroma contains a variable infl ammatory
cell infi ltrate. Occasionally, extensive infi ltration into underlying muscle and
lymphovascular spaces is identifi ed. The differential diagnosis includes BCC,
melanoma, lymphoma and metastatic neuroendocrine carcinomas, particularly
small cell lung carcinoma (Table 2.3 ) [ 13 ].
Fig. 2.5 Merkel cell carcinoma comprising nests of pleomorphic ‘small blue cells’ with hyper-
chromatic nuclei, small nucleoli and numerous mitoses (H&E)
H. Coleman and J. Tomlinson
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21
MCC expresses both epithelial and neuroendocrine features. The immunohisto-
chemical profi le of the tumours include positive ‘paranuclear dot’ staining with
cytokeratin, such as AE1/AE3 or Cam 5.2 (Fig. 2.6 ). Neuron-specifi c enolase, syn-
aptophysin, chromogranin A, neurofi lament protein and CD117 are also positive
[ 13 , 16 ]. Cytokeratin 20 (CK-20), a stain for low molecular weight keratin fi la-
ments, is a highly sensitive marker for MCC. The tumour is negative for cytokeratin
7 (CK-7) and thyroid transcription factor-1 (TTF-1), both of which usually are posi-
tive in small cell carcinoma of the lung [ 13 , 16 ]. MCC is also negative for S-100,
melan-A, leucocyte common antigen and desmin; excluding melanoma, lymphoma
and rhabdomyosarcoma, respectively.
The tumour exhibits frequent locoregional recurrence and distant metastases.
Lymph Node Dissection of the Head and Neck
for Metastatic NMSC
Seven major anatomical levels or groups of lymph nodes are described in the drain-
age of the head and neck. Neck dissection specimens should either be orientated by
the surgeon and pinned or sutured to a cork/polystyrene board, or separated into the
various nodal groups by marking the superior margin of each group with a suture,
or by placing each group in a separately labelled container [ 5 , 10 ].
These nodal levels should be designated as follows: Level I—nodes of the sub-
mandibular (IB) and submental (IA) triangles; Levels II, III and IV—nodes of the
upper, middle and lower deep cervical chain; Level V—nodes of the posterior tri-
angle; Level VI—nodes of the anterior compartment, around the midline structures
Table 2.3 Diagnostic summary: merkel cell carcinoma
Macroscopy
Site, type and size of specimen
Maximum diameter of lesion T1, T2, T3
Microscopy
Level of invasion Invasion of fat, bone, fascia cartilage and
muscle – pT4
Lymphovascular invasion
Margins Involved – <1 mm, 1–5 mm, >5 mm
Maximum diameter of lesion pT1 < 20 mm; pT2 20–50 mm; pT3 > 50 mm
Immunohistochemistry CK-20, AE1/AE3, TTF-1, S-100, melan-A, desmin,
leucocyte common antigen
Lymph nodes
Level and number of nodes involved pN0, pN1, pN2
Extracapsular extension and margin
Adapted from RCP dataset for histopathology reporting of primary cutaneous Merkel cell
carcinoma, 2012 [
8 ]
CK cytokeratin, TTF-1 thyroid transcription factor-1
2 Pathology Reporting of Non-melanoma Skin Cancer at the ICPMR
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22
of the neck from the hyoid bone to the suprasternal notch; and Level VII—nodes
that are located in the superior mediastinum [ 5 , 10 ].
At present, the AJCC does not contain any specific advice on sentinel
lymph node protocol for cutaneous SCC [ 6 , 9 ]. Sentinel lymph node proto-
cols, as performed for breast cancer, may however be undertaken for MCC,
as requested [ 8 ].
Laboratory Considerations for Neck Dissection
For each anatomical level, when dissecting the specimen, the total number of
nodes identifi ed and number of nodes involved by carcinoma must be docu-
mented (Table 2.4 ). Record the size of the largest metastatic deposit in mm,
which is a determinant in the TNM staging [ 5 , 10 ]. The presence or absence of
extracapsular spread (ECS) should also be documented as this is a manifestation
of the biological aggression of the carcinoma and is associated with a poorer
prognosis [
10 ]. If ECS is present, the nodal levels showing this feature should
be documented [ 5 , 10 ]. The extent of ECS may be recorded by direct measure-
ment (in mm) from the edge of the residual node when present, or as ‘extensive’
if residual node is not identifi ed. If histological evidence of ECS is equivocal, it
should rather be documented as being ‘present’ and this should prompt the use
of adjuvant radiotherapy [ 10 ].
Fig. 2.6 Merkel cells exhibiting ‘paranuclear dot’ positive staining for keratin (AE1/AE3)
H. Coleman and J. Tomlinson
malcolm_buchanan123@hotmail.com
23
References
1. Australian Institute of Health and Welfare (AIHW), Australian Association of Cancer
Registries (AACR). Cancer in Australia 2001. Canberra: AIHW; 2004. Cat. no. CAN 23.
2. Staples MP, Elwood M, Burton RC, et al. Non-melanoma skin cancer in Australia: the 2002
national survey and trends since 1985. Med J Aust. 2006;184:6–10.
3. Australian Institute of Health and Welfare (AIHW), Cancer Australia. Nonmelanoma skin
cancer. General practice consultations, hospitalisation and mortality. Canberra: AIHW; 2008.
Cat. no. CAN 39.
4. King B, Corry J. Pathology reporting in head and neck cancer—snapshot of current status.
Head Neck. 2009;31:227–31; discussion 232–3.
5. Oral cancer structured reporting protocol. 1st ed, 2011. Available from: rcpa. http://edu.au//
static/File/Asset%20library/public%20documents/Publications/StructuredReporting/
V1.1%20Oral%20Cancer%20Protocol.pdf .
6. RCP (Royal College of Pathologists). Datasets and tissue pathways. Dataset for histopathol-
ogy reporting of primary cutaneous squamous cell carcinoma. 2nd ed. 2012. Available from:
http://www.rcpath.org/index.asp?PageID=254 .
7. RCP (Royal College of Pathologists). Datasets and tissue pathways. Dataset for histopathol-
ogy reporting of primary cutaneous basal cell carcinoma, 2nd ed. 2012. Available from:
http://
www.rcpath.org/index.asp?PageID=254 .
8. RCP (Royal College of Pathologists). Datasets and tissue pathways. Dataset for histopathol-
ogy reporting of primary Merkel cell carcinoma. 2nd ed. 2012. Available from:
http://www.
rcpath.org/index.asp?PageID=254 .
9. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging man-
ual. 7th ed. New York: Springer; 2010. p. 299–344.
10. RCP (Royal College of Pathologists). Datasets and tissue pathways. Dataset for histopathol-
ogy reporting of nodal excisions and neck dissection specimens associated with head and neck.
2013. Available from:
http://www.rcpath.org/index.asp?PageID=254 .
Table 2.4 Diagnostic summary: neck dissection
Neck dissection: left/right
Levels submitted I □ IIA □ IIB □ III □ IV □ V □ VI □ Other □
Nodal level No. nodes present No. positive nodes Extracapsular spread present
IA Yes □ No □
IB Yes □ No □
IIA Yes □ No □
IIB Yes □ No □
III Yes □ No □
IV Yes □ No □
V Yes □ No □
VI Yes □ No □
Other Yes □ No □
Size of deposit(s) ……mm, level □
Margins clear Yes □ No □
Adapted from RCP dataset for histopathology reporting of nodal excisions and neck dissection
specimens associated with head and neck carcinomas, 2013 [
10 ]
2 Pathology Reporting of Non-melanoma Skin Cancer at the ICPMR
malcolm_buchanan123@hotmail.com
24
11. Australian Institute of Health and Welfare, Australasian Association of Cancer Registries.
Cancer in Australia: an overview 2008. Canberra: AIHW; 2008. Cat. no. CAN 42.
12. Australian Institute of Health and Welfare AIHW, Australasian Association of Cancer
Registries (AACR). Cancer in Australia: an overview 2012. Canberra: AIHW; 2012. Cat. no.
CAN 70.
13. Weedon D, Morgan MB, Gross C, Nagore E, Yu LL. World Health Organization Classifi cation
of tumours. In: LeBoit PE, Burg G, Weedon D, Sarasain A, editors. Pathology and genetics of
skin tumours. Lyon: IARC Press; 2006.
14. Hiatt KM, Pashaei S, Smoller BR. Pathology of selected skin lesions of the head and neck. In:
Barnes L, editor. Surgical pathology of the head and neck. 3rd ed. New York: Informa
Healthcare Inc; 2009. p. 1475–550.
15. Weedon D. Tumours of the epidermis. In: Weedon’s skin pathology. Chapter 31. Edinburgh:
Churchill Livingstone/Elsevier; 2010. p. 667–708.
16. Weedon D. Neural and neuroendocrine tumours. In: Weedon’s skin pathology, chapter 37.
Edinburgh: Churchill Livingstone/Elsevier; 2010. p. 867–86.
17. Chang Y, Moore PS. Merkel cell carcinoma: a virus-induced human cancer. Annu Rev Pathol.
2012;7:123–44.
H. Coleman and J. Tomlinson
malcolm_buchanan123@hotmail.com
25
© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_3
Z. Hasan , MBBS, MIPH, MS
Otolaryngology-Head and Neck Surgery, Westmead Hospital, University of New South
Wales , Sydney , NSW , Australia
e-mail: zubairhasan_112@hotmail.com
C. Palme , MBBS, FRACS
Otolaryngology Head and Neck Surgery , Royal Prince Alfred Hospital
and Westmead Hospital , Sydney , NSW , Australia
e-mail: carsten.palme@specialistservices.com.au
F. Riffat , BSc, MBBS, FRACS (*)
Otolaryngology-Head and Neck Surgery, University of Sydney, Westmead Hospital ,
Sydney , NSW , Australia
e-mail: faruque.riffat@health.nsw.gov.au
3
Evaluation, Staging and Prognostication
Zubair Hasan , Carsten Palme , and Faruque Riffat
Initial Evaluation
The majority of non-melanoma skin cancers (NMSCs), particularly those encoun-
tered in primary care settings, will be identifi ed and are easily amenable to local
therapy. The most common types of NMSC are basal cell carcinoma (BCC), squa-
mous cell carcinoma (SCC) and rarer tumours, including Merkel cell cancer (MCC)
and sarcoma. Metastatic SCC is a rare entity (<5 % of cases); metastatic BCC even
more so [ 1 ]. However, it is important to identify high-risk patients because of the
signifi cant morbidity and mortality experienced by this subgroup of patients.
Optimal management of these patients requires multidisciplinary input. Considerable
research has been conducted into early identifi cation of such high-risk patients. The
initial approach involves a thorough clinical assessment, including detailed history
and evaluation of any relevant systemic disease, risk factors and comorbidities, fol-
lowed by histological analysis. Advanced lesions will require more detailed investi-
gations, including cross-sectional imaging in the form of computed tomography
(CT) and or magnetic resonance imaging (MRI). The investigation should not only
malcolm_buchanan123@hotmail.com
26
focus on the primary lesion but also on any potential regional and distant metastatic
disease. One approach to the initial assessment of NMSC is shown in Fig. 3.1 .
Basal Cell Carcinoma (BCC)
In contrast to SCC, there are no known precursor lesions for BCC. The classic pre-
sentation described for nodular BCC is a ‘pearly’ telangiectatic nodule with rolled
borders. Central ulceration or crusting may occur. The nodular subtype accounts for
approximately 60 % of BCC, but it can also be superfi cial or morpheaform.
Superfi cial BCC may be a plaque or a papule and is pink/red in colour. Morpheaform
lesions are smooth, fl esh-coloured plaques or papules resembling scars with ill-
defi ned borders [
2 ].
In the head and neck, the nose is most commonly affected, followed by other
sun-exposed areas, such as the scalp and ear [ 3 , 4 ]. Prospectively acquired data in
an Australian setting examining site-specifi c distribution of BCC has shown that
57 % (379 out of 663) of BCCs were in the head and neck, with the nose, cheek,
forehead and ears most commonly affected (Table 3.1 ) [ 5 ].
Growth of BCC is slow and usually occurs over a number of years. BCC typi-
cally remains a local disease. Metastatic spread is extremely rare and usually occurs
via the draining lymphatics. Recurrence is associated with anatomical location, with
midfacial BCC associated with the highest recurrence rate. Local invasion may
occur, with growth into the adjacent and underlying structures, leading to the
description of the ‘rodent ulcer’.
History +
examination
Biopsy
No palpable nodes;
absence of high-risk
features
Further radiological
investigation ±
SNLB
Palpable nodes
FNA biopsy ±
Further radiological
investigation
Evidence of regional
metastases
CT/PET/PET-CT
No palpable nodes;
absence of high-risk
features
Excision
Fig. 3.1 Algorithm for initial evaluation of a patient with suspected NMSC. CT computed tomog-
raphy, PET positron emission tomography, SNLB sentinel lymph node biopsy, FNA fi ne-needle
aspiration
Z. Hasan et al.
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27
Squamous Cell Carcinoma (SCC)
Actinic keratosis is the most common precursor lesion leading to SCC. Sometimes
multiple, these lesions typically are rough, scaly and macular. Few actinic keratoses
eventually will develop into SCC and the majority of these lesions will rescind, in
particular in the event of withdrawal of sunlight exposure [ 6 ]. Bowen disease, or
intraepithelial SCC, presents as well demarcated, erythematous scaly keratotic pap-
ules and plaques. The natural history of Bowen disease is not entirely clear, and it is
thought the lesion may persist for years before invasion [ 7 ]. Verrucous carcinoma is
a subtype of SCC, which in the head and neck most commonly affects the face and
oral cavity. It presents as fl orid exophytic lesions. These lesions rarely metastasize;
however, they may be locally invasive [ 8 ].
Morphologically, the appearance of SCC exhibits a range of phenotypic vari-
ability. Similar to BCC, sun-exposed areas of the head and neck are most com-
monly affected, with involvement of the lip or ear associated with poorer prognosis
and increased metastatic potential. Patients with SCC may have a history of
numerous premalignant lesions, which may be visible on examination or have
been self- reported. Invasive SCC may also occur in the absence of a history of
premalignant lesions. In such patients, SCC presents as a fi rm, hyperkeratotic
lesion, although larger tumours may be associated with induration, ulceration,
haemorrhage and necrotic areas. Local symptoms and signs—numbness, pain,
trismus, immobility, paraesthesia, dysaesthesia, cranial nerve palsy—may indi-
cate deep tissue invasion and/or underlying perineural spread, which is a poor
prognostic factor [ 9 ].
SCC may metastasize to regional lymph nodes found within the parotid gland
and lateral deep cervical chain. The presence of such metastases has a signifi cant
potential adverse impact on prognosis in terms of morbidity, mortality and quality
of life [ 10 ].
Distant spread is rare but may occur in more advanced and/or recurrent disease
and involve the lung, liver, brain and bone [ 9 ]. Dermal metastases are rare and may
occur in the immunocompromised patient, often in the terminal phase of their ill-
ness, and are similar in appearance to primary SCC.
Table 3.1 Distribution of
basal cell carcinoma in the
head and neck in Queensland,
Australia, 1997–2006 [
5 ]
Anatomical site No. of tumours
Nose 110
Cheek/perioral 64
Forehead/temple 61
Neck 47
Ears 38
Eyes 31
Chin/jaw 14
Scalp 5
3 Evaluation, Staging and Prognostication
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28
Histopathological Evaluation
Histopathological investigation must be carried out for any lesion suspected to be an
NMSC; it is important for defi nitive diagnosis, treatment selection and prognostica-
tion. Tissue sampling may be carried out as excision or punch biopsies. Care should
be taken in cosmetically sensitive areas of the face where punch biopsy may be
preferred. Whereas punch biopsy is often carried out, a proportion of cases will be
missed using this modality. In one study punch biopsy was successful in diagnosing
BCC in 81 % of cases [ 11 ].
Histologically, BCC is characterized by collections of cells resembling the basal
layer of the epithelium. Retraction between the stroma and tumour may be present
as an artefact and helps to differentiate BCC from appendageal tumours of similar
appearance [ 12 ].
SCC and its precursor lesions—actinic keratosis and Bowen disease— are char-
acterized by sheets and ridges of squamous cells. Actinic keratosis involves only
part of the epidermis, Bowen disease involves the full thickness of the epidermis,
and invasive SCC invades past the basement membrane. The degree of differentia-
tion can be categorized as mild, moderate or severe and is related to prognosis. The
degree of differentiation correlates with the extent of keratinization, nuclear hyper-
chromasia and increased mitotic activity [ 12 ].
Histological subtype is not the only means of fi rmly establishing a diagnosis, but
it further permits identifi cation of high-risk features, such as perineural invasion,
degree of tumour differentiation and tumour depth. Histological subtype may also
predict disease behaviour. Poor tumour differentiation, increasing tumour depth
(Clark stage ≥ IV) and perineural spread collectively predict a poor prognosis
(Table 3.2 ) [ 13 ].
Clinical or Histological Features Predictive of Advanced
Disease
In addition to the features listed by the American Joint Committee on Cancer
(AJCC), risk of advanced disease in SCC has been associated with a variety of clini-
cal and histological patient and tumour factors, summarized in Table 3.3 .
Table 3.2 High-risk
features of non-melanoma
skin cancer according to the
American Joint Committee
on Cancer Staging Manual ,
7th Edition [ 13 ]
Depth
>2 mm thickness
Clark level >IV
Perineural invasion
Location
Primary site ear
Primary site non-glabrous lip
Differentiation
Poorly differentiated
Undifferentiated
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29
Previous editions of the AJCC staging manual have emphasized that horizontal
tumour depth is an important prognostic factor. In reality, it is likely to be associated
weakly with disease prognosis and risk of metastatic disease. In a series of 266
patients with nodal metastatic disease reported by Veness et al., 70 % of lesions
were <2 cm in size [ 14 ]. In these patients who had primary T1 lesions (<2 cm),
tumour thickness was found to be >4 mm in 60 % of them. The authors found a
signifi cant correlation in these patients between increasing tumour thickness and
lesion size and nodal metastasis, suggesting that these tumours had a propensity for
both vertical and horizontal growth. However, not all large SCCs were found to
metastasize, suggesting that horizontally large tumours (2–3 cm) with minimal
thickness (2–3 mm) may lack the propensity to metastasize.
Kraus et al. also showed that both tumour thickness and diameter are important
for predicting metastatic disease. In their cohort of 45 patients with metastatic cuta-
neous SCC, 81 % had tumours of >2 cm in diameter, while 83 % had tumours with
a depth of invasion of >3 mm [ 15 ]. Poorly differentiated SCC is more likely to be
associated with the development of regional metastases. Breuninger and colleagues
reported a signifi cant difference in the rate of nodal metastasis between high-and
low-grade SCC (17 % vs. 4 %) [ 16 ].
Perineural invasion is a relatively uncommon yet important fi nding on histologi-
cal evaluation and is associated with larger primary tumours, a higher risk of local
recurrence, and metastatic disease. Geist et al. report a 2.5–14 % incidence of peri-
neural invasion in SCC and 3 % in BCC [ 17 ]. In a large series of patients with 967
cutaneous SCCs, Goepfert et al. found a 14 % prevalence of perineural invasion and
a 47 % local recurrence rate, and a metastatic rate of 34.8 % in patients with peri-
neural invasion treated surgically [ 18 ]. Lymphovascular invasion, at least in one
study, has also been reported to increase the risk of developing nodal metastatic
disease. In this study, Moore and colleagues documented 40 % of patients with
nodal metastasis having lymphovascular invasion compared with only 8 % of node-
negative subjects [ 19 ].
Table 3.3 Patient and tumour risk factors for metastatic squamous cell carcinoma
Patient Tumour
Male gender Size
Diameter >2 cm
Immunosuppression
Organ transplantation
Haematological cancers
AIDS
Depth
Depth >4 mm
Clark level >IV
Late presentation Anatomical location
Ear
Non-hair bearing lip
Cheek
Perineural or lymphovascular invasion
Grade
Poor differentiation
Undifferentiated
Recurrent or poorly excised tumour
3 Evaluation, Staging and Prognostication
malcolm_buchanan123@hotmail.com
30
Anatomically, high-risk lesions include those draining to the parotid basin—lateral scalp,
temple, forehead, ear or cheek. A study of 295 patients who underwent neck dissection
for metastatic disease in the setting of primary cutaneous SCC revealed that 38 % of
lesions originated in the anterior face, 15.2 % were from the external ear, and 22.4 %
were from the posterior head; the primary site was not identifi able in 25 % of cases [ 20 ].
Incomplete resection margins and failure to consider re-excision or adjuvant
external beam radiotherapy with subsequent persistent disease or the development
of local recurrence are important treatment factors to bear in mind. Patients devel-
oping local recurrence are at a much higher risk of nodal metastases [
14 , 21 , 22 ].
Further Evaluation in Advanced NMSC
Regional or distant metastases occur in a small, but prognostically signifi cant, num-
ber of NMSCs. While SCC and BCC of the head and neck region are often consid-
ered to be associated with relatively good prognosis, the group that develop regional
disease are at an increased risk of morbidity and mortality. These patients require
expert assessment and evaluation within a multidisciplinary setting [ 23 ].
Clinical examination should be performed in all patients with suspicious skin
lesions to assess for palpable lymph nodes (Fig. 3.2 ). A complete skin examination
should also be performed to assess for other skin lesions, in particular for ‘in-transit’
metastases in close proximity to the primary lesion [ 2 ]. Palpation, however, is not
an entirely accurate method for diagnosis of neck disease. Haberal et al. conducted
a prospective study of 48 patients with head and neck cancer undergoing neck dis-
section, and compared the modalities of palpation, ultrasound and CT fi ndings to
the gold standard of histopathology of lymph nodes [ 25 ]. They found palpation had
a positive predictive value and negative predictive value of 78 % and 74 %,
respectively.
In comparison, the corresponding values for ultrasound were 94 and 80 %, and
for CT 90 and 85 %. Similar data specifi c to cutaneous NMSC are lacking.
In patients with palpable lymph nodes, radiological evaluation is required to
ascertain further locoregional and distal metastasis [
26 ]. The most superior imaging
modality of radiological investigation has yet to be identifi ed in the context of
NMSC; modalities available include ultrasonography, CT, MRI and positron emis-
sion tomography (PET) scanning [ 27 ]. If clinical or radiological suspicion of meta-
static disease is raised, further assessment and cytological confi rmation via
fi ne-needle aspiration biopsy should be performed. If this subsequent analysis is
positive for metastatic disease, the patient then undergoes therapeutic neck lymph
node dissection to remove metastatic disease. The addition of adjuvant external
beam radiotherapy increases the 5-year disease-specifi c survival (DSS) rate from
54 % for those patients treated with surgery alone, to 73 % in patients treated with
a dual modality. The disease-free interval is also improved [ 28 ].
Low-risk patients with no palpable lymph nodes typically do not require further
evaluation. The presence of high-risk clinical or histological features—large or
neglected tumours, recurrent disease, suspected or documented cranial nerve
involvement, including the facial and/or trigeminal nerves, the immunocompro-
mized host, or extracutaneous involvement—may indicate a need for further
Z. Hasan et al.
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31
radiological evaluation [ 24 ]. The value of sentinel lymph node biopsy is currently
uncertain, although it has been advocated by some authors [ 29 , 30 ].
Metastatic BCC represents a rare entity, and is reported to occur in as little as
0.0028–0.55 % of cases [ 1 ]. BCC is more likely to cause deep local invasion rather
than metastatic spread. As such, reliable data are lacking on further evaluation and
management of patients with metastatic disease. Locoregional lymph nodes, lung,
bone and liver are most commonly affected. Metastases are more likely to occur
with large, deeply invasive tumours and in tumours with perineural involvement.
Data are limited regarding how best to evaluate such patients, but indicate the poten-
tial need for early aggressive treatment in selected patients [ 31 ].
Staging
The AJCC TNM (T, tumour; N, node; M, distant metastasis) system is used for stag-
ing of NMSC. Previous editions of the TNM staging, importantly, failed to separate
NMSC accurately on the basis of histology and disease extent. This had a signifi cant
adverse impact on treatment allocation and prognostication. In 2002, O’Brien et al.
proposed an alternative staging system (i.e. PN staging system), which sought to
Pre-
auricular
Malar node
Parotid
Post-
auricular
Occipital
Submental
Sub-
mandibular
Superficial
cervical
node
Internal
jugular
chain
Spinal
accessory
chain
Transverse cervical
chain
Facial
Intraorbital node
Buccinator
nodes
Mandibular
node
Fig. 3.2 Lymph node drainage of the head and neck [ 24 ]
3 Evaluation, Staging and Prognostication
malcolm_buchanan123@hotmail.com
32
separate patients into prognostic groups on the basis of disease extent and involve-
ment of parotid and/or cervical nodal regions (Table 3.4 ) [ 32 ]. Some of the sug-
gested changes have been adopted into the current edition of the AJCC staging
manual, as well as omission of MCC from staging of NMSC, in favour of its own
unique staging system. The P classifi cation, although subsequently shown to be a
signifi cant prognostic factor in patients with cutaneous SCC of the head and neck
[ 33 ], has been omitted from the current TNM staging system, which has been
devised for NMSC of the entire body.
The current T system classifies patients on the basis of size of primary
tumour, as well as presence or absence of high-risk features, and invasion into
underlying structures. The N classification examines size and number of lymph
node metastases in the ipsilateral and contralateral sides to the site of primary
disease. The M classification indicates the presence or absence of distant meta-
static disease.
Table 3.4 TNM staging for cutaneous squamous cell carcinoma and other cutaneous carcinomas
a
based on the American Joint Committee on Cancer Staging Manual , 7th edition [ 13 ]
Tumour (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour ≤2 cm in greatest dimension with fewer than two high-risk features
b
T2 Tumour >2 cm in greatest dimension or tumour any size with two or more high-risk
features
T3 Tumour with invasion of maxilla, mandible, orbit or temporal bone
T4 Tumour with invasion of skeleton (axial or appendicular) or perineural invasion of skull
base
Node (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension
N2 Metastasis in a single ipsilateral lymph node, >3 cm but not >6 cm in greatest
dimension; or in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension; or
in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N2a Metastasis in a single ipsilateral lymph node, >3 cm but not >6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N3 Metastasis in a lymph node, >6 cm in greatest dimension
Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
a Excludes cutaneous squamous cell carcinoma of the eyelid
b High-risk features for the primary tumour (T) staging: (1) Depth/invasion: >2 mm thickness,
Clark level >IV, or perineural invasion; (2) anatomical location: primary site ear, or primary site
non-hair bearing lip; (3) differentiation: poorly differentiated or undifferentiated
Z. Hasan et al.
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33
Prognostication
The O’Brien et al. [ 32 ] classifi cation (Table 3.5 ) has been tested by Palme et al . [ 33 ]
on a cohort of 126 patients with cutaneous SCC with parotid or neck disease.
Patients were retrospectively re-stratifi ed into groups on the basis of the O’Brien
classifi cation system. The results of multivariate analysis showed a statistically sig-
nifi cant decrease in 5-year DSS, which ranged from 66 % for P0 to 33 % in patients
with P3 disease. They did not, however, fi nd that the status of neck disease signifi -
cantly altered survival. Subsequent multicentre analysis involving 322 patients from
3 Australian and 3 North American centres showed statistically signifi cant (p = 0.027)
differences in survival between patients with pathological N-positive and P-positive
disease when compared with N0 and P0 patients, without showing the value of sub-
groupings within the N and P stages [ 34 ].
The Immunosuppression, Treatment, Extranodal spread and Margin status
(ITEM) score is a useful tool in prognostication of patients with metastatic cuta-
neous SCC. A study conducted by the Westmead Hospital Group (Sydney,
Australia) involved a cohort of 250 patients to identify prognostic markers in
patients with metastatic cutaneous SCC [ 35 ]. Multivariate analysis showed the
following four important factors of strong prognostic signifi cance: (1) immuno-
suppression, which was associated with negative outcome (HR 0.32, 95 % CI
0.16–0.66), (2) absence of extranodal spread (HR 9.92, 95 % CI 1.28–77.09), (3)
surgery and radiotherapy over surgery only (HR 0.32, 95 % CI 0.16–0.66) and (4)
clear resection margins (HR 1.85, 95 % CI 1.85–3.37). Presence of extranodal
spread, therefore, is the strongest predictor of poor prognosis. Other factors stud-
ied, which apparently were not prognostic of statistical signifi cance, included (1)
presence of parotid disease, (2) lymph node size and number and, importantly, (3)
the P or N stage of the O’Brien staging system [
32 ], which was found not to pro-
vide a signifi cant difference in outcome.
Ch’ng et al . have also found recently that epidermal growth factor receptor
(EGFR) expression in cutaneous SCC is associated with poorer prognosis [ 36 ].
They discovered that EGFR was expressed in 79 % of lesions that originate as
primary lesions and subsequently metastasize, although only 43 % of tumours that
had metastasized expressed EGFR [ 36 ]. However, further research is warranted to
more accurately defi ne the impact of EGFR expression upon prognosis in patients
with NMSC.
Table 3.5 The O’Brien et al. system for clinical staging of metastatic cutaneous SCC involving
the parotid gland and neck [
32 ]
Parotid Neck
P1 – Metastatic node ≤3 cm N0 – No clinical neck disease
P2 – Metastatic node >3 cm but ≤6 cm OR
Multiple parotid nodes
N1 – single ipsilateral neck node ≤3 cm
P3 – Metastatic node >6 cm OR disease
involving facial nerve or skull base
N2 – Single node >3 cm OR Multiple nodes or
contralateral neck nodes
3 Evaluation, Staging and Prognostication
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34
Prognostic factors in NMSC can thus be summarized on the basis of the follow-
ing patient, tumour and treatment factors:
• Patient factors
– Immunosuppression (in particular in the context of solid organ transplantation)
– Recurrent NMSC
• Tumour factors
– Tumour size
– Tumour location
– Metastasis
• Treatment factors
– Degree of completion of resection
– Use of radiotherapy
Summary
Evaluation of NMSC includes an accurate and systematic history and examination.
Assessment must include the primary skin lesion as well as draining lymph nodes.
Tissue sampling is crucial for histological evaluation and to assess the presence of
high-risk features of NMSC. A number of imaging modalities are available; how-
ever, the optimal modality is yet to be clarifi ed. Patients with complex or metastatic
disease or those with high-risk features, in particular, will require further imaging.
Such patients should be managed in a multidisciplinary setting with input from a
variety of clinicians. A number of strong prognostic factors have been identifi ed for
predicting outcome in patients with NMSC; nevertheless, further research is essen-
tial to develop a precise prognostic model.
References
1. Snow SN, Mohs FE. Metastatic basal cell carcinoma. In: Roenigk RK, Roenigk Jr HH, editors.
Surgical dermatology: advances in current practice. London: Martin Dunitz; 1993. p. 109–23.
2. Tufaro AP, Prasad NB, Fischer AC et al. The clinicopathologic and molecular aspects of
non- melanoma skin cancer. In: Khopkar U, editor. Skin biopsy: perspectives. InTech; 2011.
pp. 197–208. Available at:
http://www.intechopen.com/books/skin-biopsy-perspectives/
the-clinicopathologic-and-molecular-aspects-of-non-melanoma-skin-cancer .
3. Abbas OL, Borman H. Basal cell carcinoma: a single-center experience. ISRN Dermatol.
2012;2012:246542.
4. Raasch BA, Buettner PG, Garbe C. Basal cell carcinoma: histological classifi cation and body-
site distribution. Br J Dermatol. 2006;155:401–7.
5. Richmond-Sinclair NM, Pandeya N, Ware RS, et al. Incidence of basal cell carcinoma multi-
plicity and detailed anatomic distribution: longitudinal study of an Australian population.
J Invest Dermatol. 2009;129:323–8.
6. Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol. 1997;36:650–3.
7. Kao GF. Carcinoma arising in Bowen’s disease. Arch Dermatol. 1986;122:1124–6.
Z. Hasan et al.
malcolm_buchanan123@hotmail.com
35
8. LeBoit PE, Burg G, Weedon D, Sarasain A (eds.). World Health Organization Classifi cation of
Tumours. Pathology and Genetics of Skin Tumours. Lyon: IARC Press; 2006.
9. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med. 2001;344:975–83.
10. Goh RY, Bova R, Fogarty GB. Cutaneous squamous cell carcinoma metastatic to parotid –
analysis of prognostic factors and treatment outcome. World J Surg Oncol. 2012;10:117.
11. Russell EB, Carrington PR, Smoller BR. Basal cell carcinoma: a comparison of shave biopsy
versus punch biopsy techniques in subtype diagnosis. J Am Acad Dermatol. 1999;41:69–71.
12. McGuire JF, Ge NN, Dyson S. Nonmelanoma skin cancer of the head and neck I: histopathol-
ogy and clinical behavior. Am J Otolaryngol. 2009;30:121–33.
13. Edge S, Byrd DR, Compton CC, et al. AJCC cancer staging manual. 7th ed. New York:
Springer; 2010.
14. Veness MJ, Palme CE, Morgan GJ. High-risk cutaneous squamous cell carcinoma of the head
and neck: results from 266 treated patients with metastatic lymph node disease. Cancer.
2006;106:2389–96.
15. Kraus DH, Carew JF, Harrison LB. Regional lymph node metastasis from cutaneous squamous
cell carcinoma. Arch Otolaryngol Head Neck Surg. 1998;124:582–7.
16. Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin
Pathol. 1990;94:624–7.
17. Geist DE, Garcia-Moliner M, Fitzek MM, et al. Perineural invasion of cutaneous squamous
cell carcinoma and basal cell carcinoma: raising awareness and optimizing management.
Dermatol Surg. 2008;34:1642–51.
18. Goepfert H, Dichtel WJ, Medina JE, et al. Perineural invasion in squamous cell skin carcinoma
of the head and neck. Am J Surg. 1984;148:542–7.
19. Moore BA, Weber RS, Prieto V, et al. Lymph node metastases from cutaneous squamous cell
carcinoma of the head and neck. Laryngoscope. 2005;115:1561–7.
20. Ebrahimi A, Moncrieff MD, Clark JR, et al. Predicting the pattern of regional metastases from
cutaneous squamous cell carcinoma of the head and neck based on location of the primary.
Head Neck. 2010;32:1288–94.
21. Rowe DE, Carroll RJ, Day Jr CL. Prognostic factors for local recurrence, metastasis, and sur-
vival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment
modality selection. J Am Acad Dermatol. 1992;26:976–90.
22. Brantsch KD, Meisner C, Schönfi sch B, et al. Analysis of risk factors determining prognosis
of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008;9:713–20.
23. Motley R, Kersey P, Lawrence C, British Association of Dermatologists, British Association
of Plastic Surgeons, Royal College of Radiologists, Faculty of Clinical Oncology.
Multiprofessional guidelines for the management of the patient with primary cutaneous squa-
mous cell carcinoma. Br J Dermatol. 2002;146:18–25.
24. Martinez JC, Cook JL. High-risk cutaneous squamous cell carcinoma without palpable lymphade-
nopathy: is there a therapeutic role for elective neck dissection? Dermatol Surg. 2007;33:410–20.
25. Haberal I, Celik H, Göçmen H, et al. Which is important in the evaluation of metastatic lymph
nodes in head and neck cancer: palpation, ultrasonography, or computed tomography?
Otolaryngol Head Neck Surg. 2004;130:197–201.
26. Farasat S, Yu SS, Neel VA, et al. A new American Joint Committee on Cancer staging system
for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) char-
acteristics. J Am Acad Dermatol. 2011;64:1051–9.
27. Jennings L, Schmults CD. Management of high-risk cutaneous squamous cell carcinoma.
J Clin Aesthet Dermatol. 2010;3:39–48.
28. Veness MJ, Morgan GJ, Palme CE, et al. Surgery and adjuvant radiotherapy in patients with
cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treat-
ment should be considered best practice. Laryngoscope. 2005;115:870–5.
29. Matthey-Giè ML, Boubaker A, Letovanec I, et al. Sentinel lymph node biopsy in nonmela-
noma skin cancer patients. J Skin Cancer. 2013;2013:267474.
30. Wagner JD, Evdokimow DZ, Weisberger E, et al. Sentinel node biopsy for high-risk nonmela-
noma cutaneous malignancy. Arch Dermatol. 2004;140:75–9.
3 Evaluation, Staging and Prognostication
malcolm_buchanan123@hotmail.com
36
31. Ting PT, Kasper R, Arlette JP. Metastatic basal cell carcinoma: report of two cases and litera-
ture review. J Cutan Med Surg. 2005;9:10–5.
32. O’Brien CJ, McNeil EB, McMahon JD, et al. Signifi cance of clinical stage, extent of surgery,
and pathologic fi ndings in metastatic cutaneous squamous carcinoma of the parotid gland.
Head Neck. 2002;24:417–22.
33. Palme CE, O’Brien CJ, Veness MJ, et al. Extent of parotid disease infl uences outcome in
patients with metastatic cutaneous squamous cell carcinoma. Arch Otolaryngol Head Neck
Surg. 2003;129:750–3.
34. Andruchow JL, Veness MJ, Morgan GJ, et al. Implications for clinical staging of metastatic
cutaneous squamous carcinoma of the head and neck based on a multicenter study of treatment
outcomes. Cancer. 2006;106:1078–83.
35. Oddone N, Morgan GJ, Palme CE, et al. Metastatic cutaneous squamous cell carcinoma of the
head and neck. Cancer. 2009;115:1883–91.
36. Ch’ng S, Low I, Ng D, et al. Epidermal growth factor receptor: a novel biomarker for aggres-
sive head and neck cutaneous squamous cell carcinoma. Hum Pathol. 2008;39:344–9.
Z. Hasan et al.
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37
© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_4
M. A. Buchanan , BSc, MBChB, PhD, FRCS (*)
Otolaryngology-Head and Neck Surgery, Glasgow Royal Infi rmary , Glasgow , UK
e-mail: malcolm_buchanan123@hotmail.com
B. Levin , BMedSci, MBBS, MMedSci, FRACS
Otolaryngology-Head and Neck Surgery, Westmead Hospital , Sydney , NSW , Australia
e-mail: brett.levin@health.nsw.gov.au
M. Veness , MBBS, MMed, MD, MD, FRANZCR
Radiation Oncology, Westmead Hospital, University of Sydney , Sydney , NSW , Australia
e-mail: Michael.Veness@health.nsw.gov.au
4
Non-melanoma Skin Cancer:
Primary Non-surgical Therapies
and Prevention Strategies
Malcolm A. Buchanan , Brett Levin , and Michael Veness
Introduction
Patients with non-melanoma skin cancer (NMSC) may be managed non-surgically on
the basis of relevant tumour and patient factors. This chapter presents non- surgical
treatment options for the two most common NMSCs—basal cell carcinoma (BCC) and
squamous cell carcinoma (SCC). The management of Merkel cell carcinoma (often
non-surgically) is discussed in Chap. 6 . Excision, although considered the gold stan-
dard, is not always possible or considered the best option (Box 4.1 ). Numerous topical
(e.g. 5-fl uorouracil [5-FU], imiquimod) and intralesional (e.g. methotrexate, inter-
feron) [ 1 ] options, as well as other modalities are widely available, often with ill-
defi ned criteria for using them. Additionally, because the evidence to support these
treatments is predominantly low-level with long-term follow-up (≤5 years) lacking,
clinicians need to consider various issues before using any recommendation.
An effi cacious non-surgical modality for invasive NMSC available to the clini-
cian is radiotherapy (RT), which has a well-established and documented role in the
defi nitive treatment of NMSC [ 2 ]. The outcome, with regard to cure for small
(<2 cm) NMSCs treated with RT, is similar to surgery and provides the clinician
with an alternative option in appropriate circumstances [ 3 ]. The role of adjuvant
malcolm_buchanan123@hotmail.com
38
RT in treating microscopic cancer following excision is not as well documented
but recommended in circumstances in which the risk of recurrence is present
(close/positive margins) and re-excision is not possible [ 4 ].
Radiotherapy
RT (or external beam RT) may be recommended as defi nitive treatment when sur-
gery is not optimal or possible, and also in the adjuvant setting, to reduce the risk of
recurrence (Box 4.2 ). A recommendation of defi nitive RT may be determined by the
site or size of a tumour and when the functional and/or cosmetic outcome may be
better achieved non-surgically by RT. Adjuvant RT aims to reduce the risk of locore-
gional recurrence, usually when close or positive excision margins are present.
Palliative RT is useful in symptom control in patients with advanced disease, typi-
cally in the presence of advanced ulcerative lesions in patients with poor perfor-
mance status who are often well palliated with 1–5 fractions of RT.
Advantages of RT
RT avoids the need for an operation and the associated surgical morbidity, scarring
and the requirement for reconstruction. It has the benefi t of being able to treat tissue
extensively and deeply (5–30+ mm margins) that may otherwise require excision
Box 4.1 Non-surgical Options
• Excision remains the treatment of choice in select patients.
• Patient and tumour factors may better suit a non-surgical approach.
• Clinicians have numerous topical, intralesional and destructive options
available.
• Superfi cial lesions can often be treated non-surgically.
• Radiotherapy plays a greater role in invasive NMSC.
• The supportive evidence for most options is often low level.
Box 4.2 Role of Radiotherapy
• Radiotherapy is an effi cacious non-surgical treatment option for select
patients with NMSC.
• The cosmetic outcome of radiotherapy compares favourably with surgery,
especially if surgical defects require graft or fl ap reconstruction.
• Adjuvant radiotherapy decreases the risk of local recurrence where surgical
margins are inadequate and re-excision may compromise form or function.
• Patients with NMSC located on the mid-face may particularly benefi t from
an opinion on the role of radiotherapy, in appropriate circumstances.
M.A. Buchanan et al.
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39
(+/− reconstruction) (Fig. 4.1 ). An obvious benefi t is improved cosmesis, especially
in situations in which a fl ap or graft is required (Fig. 4.2 ) [ 5 ]. RT is particularly
benefi cial in areas of the mid-face where excision and reconstruction could have a
greater impact on form and function (e.g. the periorbital region—especially the
medial canthus—lower eyelid, nose [in particular the ala and tip], nasolabial fold,
and lip and chin) (Fig. 4.3a, b ) [ 6 ]. Elderly patients with co-morbid conditions are
also often better approached with RT.
Fig. 4.1 Elderly man with a
large area of in situ SCC
(Bowen disease) treated with
widefi eld local radiotherapy,
as opposed to wide excision
and graft reconstruction. Note
the marks delineating the
planned radiotherapy fi eld
Fig. 4.2 Woman having
previously undergone wide
excision of a mid-nasal BCC
and repair with a skin graft.
The difference in skin colour
and elasticity from the donor
site compared with the nose
is obvious. The patient may
have been better treated, or at
least offered the option,
non-surgically, with
radiotherapy with the
likelihood of achieving a
better cosmetic result
4 Non-melanoma Skin Cancer: Primary Non-surgical Therapies
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40
Disadvantages of RT
The time required to undergo a course of RT is a disadvantage compared with day-
case surgery. A typical course of fractionated RT ranges from 10 to 25 once a day
(minus weekends) with 10-min outpatient treatments (or fractions). However, in
older, sicker patients fewer (3–5) fractions can be used. On account of the risk of
potential late complications, such as soft tissue/cartilage necrosis, RT cannot be
delivered a second time to the same site. Younger patients (<50 years) can still
receive RT, but the late (>5 years) in-fi eld cosmetic outcome (i.e. hypopigmenta-
tion, telangiectasia, epidermal atrophy), especially with continued unprotected sun
exposure, may not be ideal (Fig.
4.4 ). The risk of an in-fi eld radiation-induced
malignancy many years after small-fi eld cutaneous RT is theoretically possible, but
rare, and should not be a reason to avoid RT in younger patients.
Patients with xerodermapigmentosum (XP) should not undergo RT because of
the risk of inducing skin cancers, especially at a younger age. Similarly, lower limb
lesions, especially in older patients suffering from diabetes and peripheral vascular
disease, should not be irradiated if possible, because of the risk of delayed wound
healing [ 7 ].
Basal Cell Carcinoma (BCC)
BCCs are the most common NMSC diagnosed, with the majority located on the
head and neck. They are often excised (with margin assessment); typically with a
margin of 3–5 mm. Surgery can also be performed under real-time margin control
ab
Fig. 4.3 ( a , b ) Patient with a moderately large nodular BCC located on the medial canthus.
Excision with appropriate margins and reconstruction may result in suboptimal cosmesis. The
patient proceeded to defi nitive radiotherapy (55 Gy in 25 daily fractions). The patient had an inter-
nal eye shield inserted to protect the orbital contents. She had an excellent response to radiotherapy
and at 4 weeks post-completion had complete regression of her BCC and a resolving radiotherapy
reaction
M.A. Buchanan et al.
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41
with frozen sections to determine the extent of clearance (Mohs micrographic sur-
gery). However, a variety of non-surgical options are available to the clinician,
including RT, cryosurgery, photodynamic therapy (PDT), curettage and cautery,
topical treatment, and intralesional injection.
Radiotherapy (RT)
Only a few randomized controlled trials have reported on the outcome of RT on
patients with BCC. A Cochrane review of seven treatment modalities suggested that
either RT or surgery results in the lowest recurrence rates [ 8 ].
A trial of 347 patients examining RT versus excision of facial BCCs of <40 mm
in diameter showed fewer recurrences in the surgical cohort at 4 years (RR 0.09),
and that cosmetic outcome was enhanced post-surgery (87 % rated as ‘good’) at 4
years compared with RT (69 %) [ 9 ]. Conversely, in a separate trial of 374 patients,
no signifi cant difference was seen in recurrence rate between patients receiving RT
or Mohs surgery, and overall cosmetic outcome did not differ between treatment
groups [ 10 ]. Of note, primary tumours with aggressive histology were likely to be
excised more incompletely than non-aggressive ones. The evidence suggests that
RT offers patients an effective option if surgery is declined or the outcome (form
and/or function) is likely to be better non-surgically (Fig. 4.5a, b ).
Fig. 4.4 Elderly man 5 years
after receiving adjuvant
radiotherapy to his left
temple. Note the well
delineated in-fi eld
hypopigmentation, scattered
telangiectasia and epidermal
atrophy (or smoothness). Late
cosmetic changes in older
patients, even midface, are
usually of little concern to the
patient. Women will often
apply foundation makeup
with good effect
4 Non-melanoma Skin Cancer: Primary Non-surgical Therapies
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42
Adjuvant RT is an option in the setting of close/positive excision margins, espe-
cially if a fl ap has been used for reconstruction, as detecting deep recurrence, especially
in the mid-face, can be diffi cult. Up to 30 % of incompletely excised BCCs will recur
locally [ 11 ], making RT a useful modality, especially if re-excision is not considered.
In a trial of adjuvant RT versus surgery alone, RT improved the 5-year local control rate
from 61 to 91 % [ 12 ]. Ten-year local control rates were similar between the two groups
(92 % vs. 90 %), indicating that most local recurrences can be salvaged surgically,
although some patients require reconstruction after wide local excision.
Cryotherapy
Cryotherapy (aka cryosurgery) is selective freezing of tissue (using liquid nitrogen
at −50–60 °C). It results in local necrosis and is utilized in a broad spectrum of
benign, pre-malignant (actinic keratosis [AK]) and malignant conditions (including
NMSC). Studies consistently report cure rates of >95 % with excellent cosmesis
[
13 ]. A study of 96 patients with BCCs of <2 cm in diameter in the head and neck
compared cryosurgery administered with a cone spray technique and double freeze/
thaw cycle, with excision, and reported no signifi cant difference in the rate of recur-
rence at 1 year and a slightly improved cosmetic outcome with surgery [ 14 ].
Cryotherapy is a relatively cheap, versatile and convenient (rooms-based) modality
but does require appropriate selection and application to be effective. Relative con-
traindications to its application include recurrent NMSC, lesions that are deeply
invasive, and those with indistinct borders.
ab
Fig. 4.5 ( a , b ) A 62-year-old man with a moderately advanced left side lower lip SCC. Although
technically operable, the patient elected to proceed with defi nitive radiotherapy, thereby avoiding
the potential risk of microstomia, as he would have required wedge excision. The patient received
55 Gy in 25 daily fractions using orthovoltage energy photons and following insertion of an oral
cavity lead shield. At 3 months post-treatment he has experienced complete clinical regression of
his cancer with no impact on function
M.A. Buchanan et al.
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43
Photodynamic Therapy (PDT)
PDT uses topically applied non-toxic photosensitive compounds, such as
5- aminolevulinic acid and methyl aminolevulinate, which are exposed selectively to
light and which activate these photosensitizers that localize in malignant cutaneous
lesions. In one study of 103 patients, PDT was compared to surgery for facial BCCs
[ 15 ]. Despite more recurrences in the PDT group at 12 months (RR 4.42), the cos-
metic outcome was signifi cantly better (p < 0.001). Local adverse effects of PDT
were found to include burning sensation, pain and erythema in 52 % of PDT patients
compared with 29 % in the surgical group (p = 0.03) [ 15 ].
PDT is an option with an excellent cosmetic outcome that can be repeated on
multiple occasions. Unlike cryotherapy it is less likely to complicate the need for
future surgery in a treated area secondary to scarring. It is highly effective in treat-
ing in situ SCC and AK, as well as superfi cial BCC, especially when extensive
lesions are present. Nodular BCC of <2 mm in depth is also treatable. Currently, its
use is not recommended for invasive SCC and alternative modalities should be con-
sidered for these patients (e.g. RT) [ 16 ]. Unlike many other treatments, PDT requires
treatment within a hospital setting.
Intralesional Interferon
Interferon, an immunomodulator, activates cells of the immune system and increases
recognition of tumour cells by upregulating antigen presentation to T-lymphocytes.
Trials of interferon-β versus placebo have shown a reduction in recurrence of BCCs
in the interferon group [ 17 ]. The combination of interferon-α-2a and 2b does not
seem to improve effi cacy. Pain at the injection site and ‘fl u-like’ symptoms are typi-
cal side-effects of interferon treatment.
Curettage and Cautery (or Electrodissection)
Curettage and cautery, similar to cryotherapy, is a destructive modality best utilized
in selected, non-recurrent low-risk lesions, such as well-defi ned superfi cial and
nodular BCC. The practical application of this technique varies, but when used by
experienced clinicians, it achieves cure rates of >95 % [ 18 ].
Fluorouracil
5-FU is a pyrimidine analogue, which is transformed inside cancer cells into cytotoxic
metabolites resulting in apoptosis by inhibition of thymidylate synthase and the cell’s
ability to synthesize DNA. It is applied topically (twice daily for ≥3–6 weeks), and a
vehicle, such as phosphatidyl choline, can be used to enable penetration of 5-FU into
lesions. It is often applied widely to the face and scalp, but because patients can experi-
ence symptomatic erythema/desquamation, they may modify or even discontinue
4 Non-melanoma Skin Cancer: Primary Non-surgical Therapies
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44
treatment. The evidence for its application in nodular/invasive BCC or invasive SCC is
lacking and, therefore, its use is recommended predominantly for relatively small, super-
fi cial BCC, especially if other better established modalities are not considered options.
Clearance rates of >90 % have been documented when applied appropriately [ 19 ].
Imiquimod
Imiquimod is a topical immunomodulator that activates immune cells through the toll-
like receptor 7 (TLR7). Natural killer cells, macrophages and B-lymphocytes are acti-
vated by imiquimod via TLR7, with resultant production of cytokines, including
interferon-α, interleukin-6 and tumour necrosis factor-α. It is applied once or twice per
weekday for 6–12 weeks, and as with 5-FU, results in an intense local cutaneous reac-
tion. Cost can also be an issue relative to most other treatment options. Although used
in many settings, including nodular BCC, its application is best limited to superfi cial
BCC where clearance rates of >80 % have been documented consistently [ 20 ].
Hedgehog-Pathway Inhibitors
A recent fi nding in patients with BCC has been genetic alterations resulting in upreg-
ulation in the hedgehog signalling pathway. A new oral drug, vismodegib, inhibits
this pathway and may offer a potentially new treatment for patients with advanced
(inoperable and/or previously treated) and metastatic BCC, and for those with Gorlin
syndrome (basal cell nevus syndrome). A recent study reported a complete response
of 21 % in eligible patients, although the median duration of response was short
(7.6 months) and serious adverse effects and even death were reported [ 21 ]. With
further research it is likely that the outcome for these patients will improve with
molecular inhibition of the hedgehog signalling and other pathways.
Conclusion
Many studies (often small) document the treatment of patients with low-risk BCC
(superfi cial, nodular), and it is therefore diffi cult to extrapolate these results to more
aggressive (high-risk) subtypes, such as infi ltrative/sclerosing BCC and recurrent
lesions. Not all trials have adequate follow up. Also, variations in the size, location
and histological subtypes of BCC limit any valid comparisons between treatments.
However, numerous non-surgical options remain, which, in appropriate circum-
stances, offer an effi cacious non-surgical option for the patient diagnosed with a BCC.
Squamous Cell Carcinoma (SCC)
SCCs are the second commonest NMSC and, in contrast to BCC, have a greater
potential to recur and to metastasize to regional lymph nodes, especially in the
recurrent setting [ 22 ]. Most SCCs are considered low-risk for recurrence and
M.A. Buchanan et al.
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45
developing metastases. However, a subset are referred to as high-risk SCCs on the
basis of the following patient and tumour factors: (1) tumour of >4–5 mm thickness
and >2 cm in diameter, (2) recurrent, high-grade histologically, (3) occurrence of
perineural invasion, (4) location near the parotid gland, and (5) immunosuppressed
patients [ 23 ]. The optimal approach to a high-risk patient is surgery, preferably
Mohs micrographic surgery; [ 24 ] however, this option is not always available and
alternatives include wide excision +/− adjuvant RT, or defi nitive RT.
The aim of surgery for a patient with SCC (low- or high-risk) is to obtain nega-
tive excision margins, which typically range from 3 to 10 mm, depending on the
patient and tumour variables. It is unacceptable to observe patients with inade-
quately excised SCC because of the risk associated with recurrence. Re-excision or
adjuvant RT should be offered.
Defi nitive RT is an effi cacious option for both low- and high-risk SCCs [
25 ] and,
as with BCC, needs to be given to the cosmetic and functional outcomes of surgery
versus RT. One benefi t of RT is the ability to treat widely (and deeply) to encompass
microscopic subclinical spread that, if surgically approached, would leave a large
defect necessitating reconstruction.
Lip SCC
The sun-exposed lower lip is a site ideally suited to treatment with defi nitive RT
where extensive surgery could result in signifi cant morbidity from microstomia
(reduction in oral cavity opening). RT can achieve excellent preservation of oral
function and achieve a comparable outcome to surgery [ 26 ]. This is particularly use-
ful for lesions involving 30–50 % of the lower lip where surgery with wide onco-
logical margins (>5 mm) could impair oral function. Adjuvant local RT has a role in
the treatment of an inadequately excised lower lip SCC. In an Australian study,
patients with close (<2 mm) or positive margins after surgery, experienced a 37 %
recurrence rate compared with 6 % of those receiving adjuvant RT [
27 ]. While
wedge resection and primary closure for an early lower lip SCC is usually uncom-
plicated and recommended in patients with larger lesions and those who may not be
surgical candidates should be considered for defi nitive RT (50–55 Gy in 20–25
daily fractions using orthovoltage photons and a 3 mm oral cavity lead shield).
Evidence
High-level evidence assessing the effi cacy of different interventions for primary
cutaneous SCCs is scanty. A Cochrane review on interventions for primary non-
metastatic SCC identifi ed only one small RCT and concluded the need for future,
well-designed studies [ 28 ]. However, similar to BCC, non-surgical options for
superfi cial SCC include a variety of approaches [ 29 ]. Invasive low-risk SCCs can be
treated by similar modalities, provided that the tumour is limited to the papillary
dermis, is not recurrent, and does not have high-risk features.
The only published study assessing RCT treatment in SCC is of 66 patients with
high-risk SCC undergoing excision with or without RT [
30 ]. The treatment arm
4 Non-melanoma Skin Cancer: Primary Non-surgical Therapies
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46
received a chemotherapeutic regimen of 13-cis-retinoic acid plus interferon-a over a
consecutive 6-month period [ 30 ]. No signifi cant difference in time to recurrence was
noted at 21.5 months median follow-up. In addition, the treatment did not prevent sec-
ondary SCCs from occurring. Therefore, the results did not support the role of 13-cis-
retinoic acid plus interferon-a as adjuvant therapy for aggressive cutaneous SCC.
Metastatic Nodal SCC
A minority (<5 %) of patients with head and neck SCCs develop metastatic nodal
SCC to the parotid gland nodes including or excluding cervical nodes. Metastatic
SCC to cervical nodes, without parotid involvement, is also well documented.
Patients invariably have a past history of treated NMSC of the head and neck and
most will have an identifi able index lesion from which the metastatic SCC has
arisen. However, in 25–30 % of cases an index lesion is not present. Many patients
will have been treated for a recurrent primary SCC, emphasizing the importance of
effective initial treatment. Best practice for patients with metastatic cutaneous nodal
SCC is appropriate surgery and adjuvant RT [ 31 ]. Very few patients will not benefi t
from combined treatment, excluding perhaps those with a single involved node and
no extracapsular spread [ 32 ]. The addition of adjuvant RT is well documented to
improve locoregional control and survival.
Prevention of NMSC
Introduction
Up to 40–50 % of patients with a NMSC will develop another skin cancer within 5
years of treatment [ 33 ]. Important risk factors for developing further NMSC are
exposure to sunlight (ultraviolet [UV] radiation), age and skin type. Less common
risk factors include immunosuppression, history of previous skin cancers, inherited
genetic skin disorders (e.g. XP), skin trauma, arsenic exposure, albinism, and previ-
ous treatment with psoralen and UVA (PUVA). Human papillomavirus is also pos-
tulated to be a risk factor [
34 ]. Limited evidence exists to assess interventions to
prevent the ongoing development of NMSC in these high-risk groups as evidenced
by a Cochrane review [ 35 ].
Precursor Lesions
Patients with a precursor lesion are at risk of developing NMSC. Bowen disease ( in
situ SCC) transforms to an invasive SCC in 4–6 % of patients, while 0.025–20 % of
AK can progress to SCC [ 36 ]. Numerous therapies have been used to treat precursor
lesions, with a Cochrane review indicating PDT as an effi cacious approach, among
many, in the setting of AK [
37 ]. A recent topical fi eld treatment for AK (ingenol
M.A. Buchanan et al.
malcolm_buchanan123@hotmail.com
47
mebutate) was tested in a randomized controlled trial and was shown to be highly
effective in obtaining complete clearance when compared to a placebo (34.1 % vs.
4.7 %, p < 0.001) [ 38 ].
Reduced Immunity
Organ transplant recipients are 3–4 times more likely to develop cancer compared
to the immunocompetent population and are at an even greater risk of developing
skin cancer [
39 ]. Patients immunosuppressed secondary to haematological malig-
nancy or HIV infection are similarly at increased risk of developing skin cancers.
All patients ideally should have a regular dermatological review and treatment as
indicated. In select circumstances transplant recipients may be candidates for a
reduction in their level of immunosuppression.
Xeroderma Pigmentosum (XP)
Patients with this autosomal recessive disorder have an inability to repair UV skin dam-
age. Skin cancers can develop from the age of 2 years, with a median age of developing
NMSC of 8 years compared with 60 years in the general population. Such patients have
a 100-fold increase in the incidence of SCC or BCC [ 40 ]. RT should not be given to
these patients as it can predispose to further cutaneous malignancies.
Albinism
Patients with this condition lack skin pigment and the ability to tan, and are thus
predisposed to developing skin cancers, particularly SCCs. A study of 164 albinos
in Tanzania reported that 91 % of those in their 20s had AC, rising to 100 % in
Albinos over 30 years of age [
41 ].
Basal Cell Nevus Syndrome
This autosomal dominant condition, also known as Gorlin syndrome, is typifi ed by
skin and skeletal abnormalities, with an increased incidence of two or more BCCs
by the age of 30 years [ 42 ]. These patients should be reviewed regularly.
Previous Psoralen and Ultraviolet A (PUVA) Treatment
PUVA is often used to treat psoriasis and other chronic skin conditions. Exposure to
PUVA increases the risk of developing SCCs in a dose-dependent manner; this is not
so for BCC. PUVA has an immunosuppressive effect on the skin, in addition to being
4 Non-melanoma Skin Cancer: Primary Non-surgical Therapies
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48
mutagenic and carcinogenic, and has been shown to result in a >100-fold increase in
the risk of developing SCC within 10 years of completing treatment [ 43 ].
Prevention
Primary prevention of NMSCs involves decreasing excessive unprotected UV expo-
sure. Educating people about the dangers of UV exposure is important [ 44 ].
Secondary prevention educates people about the signs of skin damage so that they
can seek earlier diagnosis and treatment. Tertiary prevention entails interventions
after treatment to reduce the risk of further NMSC, but supportive evidence for this
is minimal.
Sunscreens and Sun Avoidance
Sunscreens contain titanium dioxide or zinc oxide, which scatter or absorb UV radia-
tion. Damage by UV exposure is irreversible, but further damage can be avoided by
use of sunscreens and, ideally, minimizing outdoor summer sunlight exposure from
10 am to 3 pm, and wearing hats and protective clothing [ 45 ]. Periodic cutaneous
screening is particularly important for high-risk patients, viz. those with a family his-
tory of skin cancer, fair skin type, multiple naevi, or a past history of skin cancers.
Retinoids
Retinoids are vitamin A derivatives which control growth, differentiation and death
of cells, and inhibit growth and induce normal differentiation in experimental malig-
nant cell lines. Retinoids have the potential to prevent NMSC in high-risk patients.
A number of studies have compared vitamin A compounds with a placebo. One
study compared 30 mg/day of oral acitretin with placebo in 115 renal transplant
patients over a 6-month period [
46 ]. No signifi cant differences were evident in the
time to developing a new NMSC between groups during this period (HR 0.51);
however, a 78 % reduction occurred in the risk of NMSC in the acitretin groups
compared to placebo (RR 0.22) [ 46 ].
Evidence on the role of acitretin in high-risk NMSC is currently limited and
confl icting, although renal transplant recipients may benefi t. Despite this, toxicity is
not inconsequential and needs to be considered.
Antioxidants
Selenium is an essential trace element found in fi sh and garlic, and is required for
the detoxifying enzyme glutathione peroxidase to function. This enzyme reduces
free radicals, which are known to be mutagenic. Murine studies have suggested that
M.A. Buchanan et al.
malcolm_buchanan123@hotmail.com
49
increased dietary selenium may offer protection against UV-induced skin cancers.
Comparison of oral administration of 200 μg/day of selenium with placebo given to
1312 patients for 4.5 years showed that patients in the selenium group were 17 %
signifi cantly more likely to develop NMSC (typically SCC) (HR 1.25) [ 47 ]. There
was no signifi cant difference between numbers of patients with a developing new
SCC or BCC between the two groups (RR 1.09). Not surprisingly, a Cochrane
review on the available evidence concluded that there was no convincing evidence
that selenium prevented the development of cancer—NMSC or otherwise [ 48 ] .
References
1. Chitwood K, Etzkorn J, Cohen G. Topical and intralesional treatment of nonmelanoma skin
cancer: effi cacy and cost comparisons. Dermatol Surg. 2013;39:1306–16.
2. Veness MJ. The important role of radiotherapy in patients with non-melanoma skin cancer and
other cutaneous entities. J Med Imaging Radiat Oncol. 2008;52:278–86.
3. National Comprehensive Cancer Network (NCCN). Practice guidelines in oncology: basal cell
and squamous cell skin cancers. Version 2.2013. Accessed at
www.nccn.org/professionals/
physician_gls/PDF/nmsc.pdf on 24 Sept 2013.
4. Najim M, Cross S, Gebski V, et al. Early-stage squamous cell carcinoma of the lip: the
Australian experience and the benefi ts of radiotherapy in improving outcome in high-risk
patients after resection. Head Neck. 2013;35:142630.
5. Poulsen M, Burmeister B, Kennedy D. Preservation of form and function in the management
of head and neck skin cancer. World J Surg. 2003;27:868–74.
6. Veness M, Richards S. Role of modern radiotherapy in treating skin cancer. Australas
J Dermatol. 2003;44:159–66; quiz 167–8.
7. Dupree MT, Kiteley RA, Weismantle K, et al. Radiation therapy for Bowen’s disease: lessons
for lesions of the lower extremity. J Am Acad Dermatol. 2001;45:401–4.
8. Beth-Hextall FJ, Perkins W, Bong J et al. Interventions for basal cell carcinoma of the skin.
Cochrane Database Syst Rev. 2007;(1):CD003412.
9. Petit JY, Avril MF, Margulis A, et al. Evaluation of cosmetic results of a randomized trial
comparing surgery and radiotherapy in the treatment of basal cell carcinoma of the face. Plast
Reconstr Surg. 2000;105:2544–51.
10. Smeets NWJ, Krekels GAM, Ostertag JU, et al. Surgical excision vs Mohs’ micrographic
surgery for basal-cell carcinoma of the face: randomised controlled trial. Lancet. 2004;364:
1766–72.
11. Wilson AW, Howsam G, Santhanam V, et al. Surgical management of incompletely excised
basal cell carcinomas of the head and neck. Br J Oral Maxillofac Surg. 2004;42:311–4.
12. Liu FF, Maki E, Warde P, et al. A management approach to incompletely excised basal cell
carcinomas of the skin. Int J Radiat Oncol Biol Phys. 1991;20:423–8.
13. Kufl ik G. Cryosurgery for skin cancer: 30-year experience and cure rates. Dermatol Surg.
2004;30:297–300.
14. Thissen MR, Nieman FH, Ideler AH, et al. Cosmetic results of cryosurgery versus surgical
excision for primary uncomplicated basal cell carcinoma of the head and neck. Dermatol Surg.
2000;26:759–64.
15. Rhodes LE, de Rie M, Enström Y, et al. Photodynamic therapy using topical methyl ami-
nolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized
prospective trial. Arch Dermatol. 2004;140:17–23.
16. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic
therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol.
2007;56:125–43.
4 Non-melanoma Skin Cancer: Primary Non-surgical Therapies
malcolm_buchanan123@hotmail.com
50
17. Cornell RC, Greenway HT, Tucker SB, et al. Intralesional interferon therapy for basal cell
carcinoma. J Am Acad Dermatol. 1990;23:694–700.
18. Sterry W, European Dermatology Forum Guideline Committee. Guidelines: the management
of basal cell carcinoma. Eur J Dermatol. 2006;16:467–75.
19. Gross K, Kircik L, Kricorian G. 5% 5-fl uorouacil cream for the treatment of small superfi cial
basal cell carcinoma: effi cacy, tolerability, cosmetic outcome and patient satisfaction. Dermatol
Surg. 2007;33:433–9; discussion 440.
20. Geisse JK, Rich P, Pandya A, et al. Imiquimod 5% cream for the treatment of superfi cial basal
cell carcinoma: a double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol.
2002;47:390–8.
21. Sekulic A, Migden MR, Oro AE, et al. Effi cacy and safety of vismodegib in advanced basal-
cell carcinoma. N Engl J Med. 2012;366:2171–9.
22. Rowe DE, Carroll RJ, Day Jr CL. Prognostic factors for local recurrence, metastasis, and sur-
vival rates in squamous cell carcinoma of the skin, ear and lip. Implications for treatment
modality selection. J Am Acad Dermatol. 1992;26:976–90.
23. Veness MJ. Defi ning patients with high-risk cutaneous squamous cell carcinoma. Australas
J Dermatol. 2006;47:28–33.
24. Pugliano-Mauro M, Goldman G. Mohs surgery is effective for high-risk cutaneous squamous
cell carcinoma. Dermatol Surg. 2010;36:1544–53.
25. Mendenhall WM, Amdur RJ, Hinerman RW, et al. Radiotherapy for cutaneous squamous and
basal cell carcinomas of the head and neck. Laryngoscope. 2009;119:1994–9.
26. Veness MJ, Ong C, Cakir B, et al. Squamous cell carcinoma of the lip. Patterns of relapse and out-
come: reporting the Westmead Hospital experience, 1980–1997. Australas Radiol. 2001;45:195–9.
27. Babington S, Veness MJ, Cakir B, et al. Squamous cell carcinoma of the lip: is there a role for
adjuvant radiotherapy in improving local control following incomplete or inadequate excision?
ANZ J Surg. 2003;73:621–5.
28. Lansbury L, Leonardi-Bee J, Perkins W et al. Interventions for non-metastatic squamous cell
carcinoma of the skin. Cochrane Database Syst Rev. 2010;(4):CD007869.
29. Nguyen TH, Ho DQ. Nonmelanoma skin cancer. Curr Treat Options Oncol. 2002;3:193–203.
30. Brewster AM, Lee JJ, Clayman GL, et al. Randomized trial of adjuvant 13-cis-retinoic acid
and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol.
2007;25:1974–8.
31. Wang JT, Palme CE, Morgan GJ, et al. Predictors of outcome in patients with metastatic cuta-
neous head and neck cutaneous squamous cell carcinoma involving cervical lymph nodes:
improved survival with the addition of adjuvant radiotherapy. Head Neck. 2012;34:1524–8.
32. Ebrahimi A, Clark JR, Lorincz BB, et al. Metastatic head and neck cutaneous squamous cell
carcinoma: defi ning a low risk patient. Head Neck. 2012;34:365–70.
33. Marcil I, Stern RS. Risk of developing a subsequent non-melanoma skin cancer in patients
with a history of non-melanoma skin cancer: a critical review of the literature and meta-
analysis. Arch Dermatol. 2000;136:1524–30.
34. Karagas MR, Nelson HH, Sehr P, et al. Human papillomavirus infection and incidence of
squamous cell and basal cell carcinomas of the skin. J Natl Cancer Inst. 2006;98:389–95.
35. Bath-Hextall FJ, Leonardi-Bee J, Somchand N et al. Interventions for preventing non-
melanoma skin cancers in high-risk groups. Cochrane Database Syst Rev. 2007;(4):CD005414.
36. Cox NH, Eedy DJ, Morton CA, Therapy Guidelines and Audit Subcommittee, British
Association of Dermatologists. Guidelines for management of Bowen’s disease: 2006 update.
Br J Dermatol. 2006;156:11–21.
37. Gupta AK, Paquet M, Villanueva E, Brintnell W. Interventions for actinic keratosis. Cochrane
Database Syst Rev. 2012;12:CD004415.
38. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis.
N Engl J Med. 2012;366:1010–9.
39. Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and
management: part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am
Acad Dermatol. 2011;65:253–61; quiz 262.
M.A. Buchanan et al.
malcolm_buchanan123@hotmail.com
51
40. Kraemer KH, Lee MM, Andrews AD, et al. The role of sunlight and DNA repair in melanoma
and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol.
1994;130:1018–21.
41. Lookingbill DP, Lookingbill GL, Leppard B. Actinic damage and skin cancer in albinos in
northern Tanzania: fi ndings in 164 patients enrolled in an outreach skin care program. J Am
Acad Dermatol. 1995;32:653–8.
42. Goldberg LH, Firoz BF, Weiss GJ, et al. Basal cell nevus syndrome. Arch Dermatol.
2010;146:17–9.
43. Stern RS, Liebman EJ, Väkevä L. Oral psoralen and ultraviolet-A Light (PUVA) treatment of
psoriasis and persistent risk of nonmelanoma skin cancer. J Natl Cancer Inst. 1998;90:
1278–84.
44. Naldi L, Buzzetti R, Cecchi C et al. Educational programmes for the skin cancer prevention
(protocol for a cochrane review). Cochrane Database Syst Rev. 2004;(2).
45. Hill L, Ferrini RL. Skin cancer prevention and screening: summary of the American College
of Preventive Medicine’s practice policy statements. CA Cancer J Clin. 1998;48:232–5.
46. Bavnick JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer and reduction of
keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind,
placebo-controlled study. J Clin Oncol. 1995;13:1933–8.
47. Clark LC, Combs Jr GF, Turnbull BW, et al. Effects of selenium supplementation for cancer
prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional
Prevention of Cancer Study Group. JAMA. 1996;276:1957–63.
48. Dennert G, Zwahlen M, Brinkman M et al. Selenium for preventing cancer. Cochrane Database
Syst Rev. 2011;(5):CD005195.
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53
© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_5
D. Robinson , BIT, BCom, MBBS (Hons), FRACS (*)
Otolaryngology-Head and Neck Surgery, Gold Coast University Hospital ,
South Port , QLD , Australia
e-mail: danrobinson@ausdoctors.net
J. Roth , BSc, MBBS, AMusA, FRACS
Otolaryngology-Head and Neck Surgery, Private Practice , Sydney , NSW , Australia
e-mail: jason@drjasonroth.com.au
5
Mohs Surgery and Facial Flaps
Dan Robinson and Jason Roth
From the early 1930s, Frederic E. Mohs developed the idea of cancer excision
with microscopic assistance, a concept which has become known as Mohs
micrographic surgery [ 1 ]. Initially, a fi xed tissue technique was employed using
zinc chloride solution; however, today most practitioners employ a fresh-tissue
approach [ 2 ]. Mohs surgery is a microscopically controlled procedure that
allows maximal excision of involved tumour in cutaneous neoplasms while min-
imizing the excision of uninvolved tissue. It achieves this through mapping the
surgical site and successive resection of tumour and subsequent histological
analysis of resected borders until clear margins are achieved [ 3 ]. Mohs surgery
is suited to cutaneous neoplasms in areas with high risk of local recurrence or
where for functional or cosmetic reasons tissue is required to be preserved, or in
recurrent neoplasms, in particular, large and aggressive tumours with irregular
or incomplete resection borders [ 1 ].
Reconstruction of defects after Mohs excision requires assessment of the size
of the subunits that are involved, with the goal of surgery being to maintain
function and appropriate cosmesis. Each area of the face has its unique recon-
structive technique aimed to achieve optimal results. This chapter covers only
some of the more common defects; for others the reader is referred to specialist
textbooks.
malcolm_buchanan123@hotmail.com
54
Nose Reconstruction
Modern techniques in nasal reconstruction emphasize replacing surgically removed
tissue with like tissue. The nose consists of three layers—mucosa, a structural sup-
port layer, and skin. Removal of any of these layers ideally should be replaced with
similar tissue.
Incisions for local fl aps on the nose are best placed along the borders of aesthetic
units and, wherever possible, local fl aps are designed so that they do not cross the
borders of these aesthetic units [ 4 , 5 ]. The nose is reconstructed separately from any
extension of a lesion onto the cheek or lip, which in turn is repaired by tissue with
the respective aesthetic region [ 6 ]. Ensuring that this principle is adhered to facili-
tates preservation of the alar-facial sulcus, which in turn results in better overall
cosmetic results [ 7 ].
The nose has nine aesthetic subunits [ 8 ]. These are the lobule, dorsum, two side-
walls, two alae, two soft tissue facets, and the columella. Reconstructive nasal sur-
gery should focus on reconstructing entire subunits. If the majority of a subunit is
lost, replacing the entire subunit gives optimal results. This may require discarding
normal skin to optimize scar placement along the junction of the subunits.
Covering fl aps should be designed using a template based on the contralateral
normal unit, if possible. It is important to reconstruct skeletal elements by attaching
them to the remaining stable structures, such as nasal cartilage of the maxillary
bone. These skeletal elements should span the entire defect.
Not all defects require reconstruction. Small defects in concave locations on the
nose may be best left to heal by secondary intention [ 9 ]. The most favourable areas
for secondary intention healing are the medial canthus and alar crease. The least
favourable areas are the convex sites of the nasal dorsum and tip which tend to fl at-
ten when healing. Alar and columellar margins tend to retract during healing.
Lining Flaps
Full thickness defects of the nose may require replacement of the internal nasal lin-
ing. Options include skin grafts, folding the distal aspect of the cutaneous fl ap on
itself, or septal mucosal fl aps. Techniques that create an inevitable septal perforation
may cause signifi cant secondary donor site morbidity.
Skin grafts can be used to replace small areas of nasal lining but they do tend to
contract and do not survive well when placed directly on cartilage. A composite
auricular cartilage-skin graft can be used for reconstruction of both the internal lin-
ing and the cartilage.
Mucosal fl aps based on the septal branch of the superior labial artery can be
mobilized either unilaterally or bilaterally with excellent survival [ 4 ]. Flaps can be
used both ipsilaterally or contralaterally [ 10 ]. Anteriorly based inferior turbinate-
based fl aps are also possible [ 11 ]. The donor sites are left to heal by secondary
intention.
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Bipedicled bucket-handle fl aps are useful to create lining for through-and-
through defects of the alar rim of <1 cm in vertical dimension [ 12 ].
Epithelial turn-in fl aps are also useful. Here external tissue is folded in to provide
a lining and hinged along aesthetic nasal units. Folding the distal end of a forehead
fl ap around the alar rim is the commonest application of this technique.
Local Flaps: Bilobe Flaps
The nasal dorsum and lateral nasal wall represent a relative tissue reservoir that can
be used for transposition fl aps. These are useful for defects of ≤2 cm. Options
include the 30° transposition fl ap [ 13 ], note fl aps [ 14 ], rhomboid fl aps [ 15 ] and
bilobe fl aps [ 16 – 18 ] Bilobe fl aps are the most notable and utilize two adjacent fl aps
of skin in series that are transposed over intervening skin. The fl aps have a com-
mon base and each fl ap is slightly smaller than the defect it fi lls. Each fl ap should
rotate no more than 45° to reduce the amount of redundant tissue and excess ten-
sion along the fl ap margins [
19 ]. Disadvantages of the bilobe fl ap are how the inci-
sions often do not fall in subunit junctions and the ‘pin cushioning’ can occur at
incision edges [ 20 ]. The bilobe fl ap is best used to repair skin defects in the lower-
third of the nose (Fig. 5.1 ).
Melolabial Interpolated Flap
The melolabial fl ap recruits tissue lateral to the melolabial fold and transfers them
via interpolation so as not to violate the aesthetic boundaries between the nose and
other regions of the face. It is based on random terminal branches of the facial
artery. Cheek advancement is used to hide the scar in the lip − cheek junction [ 21 ].
Fig. 5.1 Bilobed fl ap on
the nose
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56
It is most useful for defects of <2.5 cm of the ala, lateral side wall, tip and columel-
lar [ 22 ]. Melolabial fl aps tend to contract as they heal and become more rounded.
This resembles the normal contour of the ala.
The fl ap is designed by taking a template of the contralateral ala, if possible.
The fl ap is based superiorly and generally contains skin and fat. The centre of the
template is used to position the fl ap on a horizontal plane in line with the lateral
commissure of the lip, with the medial border in the melolabial sulcus. The fl ap is
designed as an island fl ap on a subcutaneous pedicle with the base tapered supe-
riorly to facilitate transposition and reduce skin loss from the upper part of the
melolabial fold [
10 ].
The interpolated fl ap is revised at 3 weeks. It can be designed as a non-
interpolated rotation fl ap and performed as a single-stage procedure. However, this
tends to cause blunting of the alar-facial sulcus and supra-alar concavity [ 7 ]. At
revision, it is defatted aggressively, sculpted, and the skin is inset into the cuff of
preserved alar skin.
Paramedian Interpolated Forehead Flap
Defects of the nose that are larger than 2.5 cm in horizontal length and those not
amenable to the previous reconstructive methods are usually best closed with a
paramedian forehead fl ap [ 5 , 23 , 24 ]. This fl ap is also useful when periosteum or
perichondrium is missing or where tissue has been irradiated. The paramedian
forehead fl ap is an axial interpolated fl ap and has an excellent blood supply. It is
based on the supratrochlear artery but has many collateral vessels in the medial
canthal area, including the angular artery and supraorbital arteries [ 11 ]. The
supratrochlear artery crosses the superior orbital rim 1.7 − 2.2 cm lateral to the
midline. After perforating the orbital septum, followed by the orbicularis and
frontalis muscles, it then travels vertically 2 cm lateral to the midline in a subcu-
taneous plane [
23 ].
The fl ap can be designed on either the same side or the contralateral side of the
nasal defect and is raised in a supraperiosteal plane. An advantage of using the fl ap
from the contralateral side is that the pedicle of the fl ap does not obstruct the
patient’s vision. A template is made of the defect to be closed and this is marked on
the forehead skin. It is important to measure the length of the fl ap. Sometimes it is
necessary to curve the fl ap obliquely along the non-hair-bearing skin to obtain addi-
tional length [ 6 ]. The pedicle can be narrowed to as much as 1.2 cm [ 25 ]. The tissue
between the brow and hairline can be thinned aggressively of frontalis muscle and
fat in order to match the much thinner nasal skin at the point of inset. The excellent
blood supply allows positioning over cartilage grafts and permits the skin to be
thinned to all but 1 mm of fat beneath the dermis.
Donor-site closure is achieved through extensive soft tissue undermining with
possible vertical fasciotomies through the galea aponeurosis to facilitate skin mobil-
zation. Any donor site defect that cannot be closed can either be left to heal by
secondary intention or can be covered with a split skin graft.
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The pedicle is detached at 3 weeks. The fl ap may need to be further thinned to
match the thinner skin of the middle-third of the nose [ 4 ]. The base of the pedicle is
rotated back into the donor site, but never higher than the eyebrows. An attempt is
made to return symmetry to the eyebrows and glabella region.
Lip Reconstruction
The anatomical subunits of the lip are lateral and central upper lip subunits and a
single lower lip subunit. The upper lip is bounded by the melolabial creases and
base of the nose. The lower lip is bounded inferiorly by the mental crease. The phil-
tral columns divide the central from the lateral upper lip unit. Other important land-
marks are the white roll and vermilion border. The boundaries of the aesthetic units
afford an excellent location to hide incisions. When a large portion of a subunit has
been excised, aesthetic results are often better if the entire subunit is removed before
reconstruction.
Lateral Upper Lip
Small defects can often be removed with simple advancement and primary closure.
Medium-sized defects can be closed with local rotation, advancement and island
fl aps. As a general rule, if the defect is greater than one-third of the lip length then
it should be reconstructed with a fl ap and not closed primarily.
The melolabial advancement fl ap recruits cheek skin and subcutaneous tissue
and advances it medially. The main disadvantage of this fl ap is obliteration of the
mesolabial fold; however, this can be corrected secondarily by placing an incision
to simulate where the fold would normally lie [ 26 ].
Vermilionectomy
Diffuse involvement of the lip mucosa may require extensive removal of the vermil-
ion. Vermilion can be removed to the level of orbicular oris, and the mucosa
advanced from the buccal surface to close the defect. Intraoral releasing or a V-to-Y
advancement fl ap of lip mucosa can help to relieve closure tension.
Full Thickness Upper Lip
Full thickness upper lip defects that are less than one-third the size of the lip can
usually be closed with a wedge excision or W-plasty. Lesions up to two-thirds the
lip size are best closed with an abbe cross-lip fl ap or, if more laterally located, a
melolabial advancement fl ap. Lesions of more than two-thirds the lip size can be
addressed with bilateral advancement fl aps with or without an additional abbe fl ap.
5 Mohs Surgery and Facial Flaps
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Abbe Flap
The abbe fl ap [ 27 ] is a cross-lip fl ap from the central lower lip. When used to
reconstruct lower lip defects the abbe fl ap is designed to be one-half the width
of the defect, thereby both lips end up shortened by equal amounts. However,
better aesthetic results are obtained in the upper lip if the flap is designed
using a foil template from the contralateral normal lip and a size-matched fl ap
is created.
Estlander Flap
The estlander fl ap [ 28 ] is a cross-lip fl ap used for lesions that involve the
commissure.
Lateral Advancement Flaps
Lateral advancement fl aps from the medial cheek can be used to repair more lateral
defects or used in patients without a prominent philtrum. Incisions are made imme-
diately below the nose and immediately above the vermilion. Excision of perialar
crescents [ 29 ] can facilitate fl ap advancement and reduce closure tension.
Lower Lip
Lesions of up to one-third the size of the lip are best closed with a wedge excision
or W-plasty (Fig. 5.2 ). Lesions that are one-third to two-thirds the lip size are best
closed with cross-lip fl aps or a Karapandzic fl ap. Lesions larger than two-thirds the
lip size can be addressed with a free fl ap or bilateral abbe, bilateral Karapandzic or
a Bernard-Burrow-Webster fl ap.
Fig. 5.2 Primary excision of
the lower lip with W-plasty
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Karapandzic Flap
The Karapandzic fl ap [ 30 ] is a musculocutaneous fl ap and is a modifi cation of the
Gilles fan fl ap that preserves the neurovascular pedicle to the lip [ 31 ]. A unilateral
or bilateral circumoral advancement-rotation fl ap is created with releasing incisions
placed around the periphery of the lip subunits. Neurovascular structures are identi-
fi ed and preserved in order to maintain oral competence and sensation. Microstomia
may occur; however, the ability of the mouth to widen increases with time.
Bernard-Burrow-Webster Flap
This fl ap is useful for reconstructing defects that are more than two-thirds the size
of the lower lip using tissue recruited from the cheeks. Over the years it has been
modifi ed by several workers to reach its modern form. [ 32 , 33 ] A full thickness inci-
sion is extended laterally from each commissure, a triangular standing cutaneous
deformity along the melolabial fold is excised and the fl aps are advanced medially.
Vermilion is created with a buccal mucosal fl ap or a tongue fl ap.
Forehead Reconstruction
Mohs defects of the forehead are approached with a similar algorithm for cutane-
ous reconstruction elsewhere on the head and neck. Options for closure include
primary closure, secondary intention healing, skin grafts, local fl aps and, rarely,
distant fl aps.
Healing of the forehead via secondary intention does not achieve excellent
results, aside from the areas of the lateral forehead and temple. As a general rule,
healing by secondary intention should be reserved for lesions that cannot be closed
via other means [
34 ].
Skin grafts for reconstruction of the forehead are an option but should be consid-
ered only when local fl ap or primary closure options are not available, as they do not
provide good colour matching with the rest of the forehead [ 34 ].
Primary closure of forehead defects can allow for closure of defects and hiding
the scar within an existing forehead furrow. Axially orientated closure, especially in
males, can facilitate closure of small defects with the resultant scar hidden in a skin
crease, provided the closure will not raise the eyebrows adversely.
Advancement fl aps provide excellent options for closure of defects on the fore-
head, allowing for adequate skin coverage, and can be incorporated into bilateral
advancement fl aps to achieve greater fl ap surface area. Rotation fl aps can be used on
the forehead; however, given the curving incision of a rotation fl ap it is diffi cult to
camoufl age the incision adequately within the natural crease of the forehead.
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H-plasty Advancement Flap
An H-plasty advancement with axially orientated skin incisions shows excellent
healing in most cases and allows for the resultant scar to be hidden in the skin creases
(Fig. 5.3 ). In order to hide the scar properly, it might be appropriate to make the fl ap
wider than would be planned normally. The advancement fl ap is designed with a
length-to-width ratio of ≤4:1 so that the blood supply is not compromised [ 34 ]. The
dissection of the fl ap should be in the subcutaneous plane. The fl ap can then be
repeated on the contralateral side to close the defect. Standing cutaneous deformities
at the lateral aspect of the incision might need to be excised after advancing the fl aps.
A-T or O-T Flap
An A-T fl ap or O-T fl ap (Fig. 5.4 ) is useful when closing defects at the lateral aspect
of the forehead or along the tricheon where a wedge excision is not appropriate. The
incision of the base of the fl ap should be hidden, where practical, in the hairline.
Cheek Reconstruction
Defects of the cheek need to be assessed on the basis of the size of the defect and
the adjacent structures that the defect might affect. Structures that are relevant in
cheek reconstruction are the nose, lip and orbit, which may be distorted with exces-
sive tension or scar contracture. Consequently, each reconstruction option must be
evaluated to achieve the best cosmetic outcome by recruiting tissue from an area of
appropriate laxity that can be borrowed. Scars on the cheek can be disfi guring and
it is important that these scars are hidden within the relaxed skin tension lines of the
face to ensure they do not become overly disfi guring (Fig. 5.5 ).
While there are many options for closure of cheek defects, this section will focus
on some of the more commonly used methods of closure. For more in-depth techni-
cal descriptions refer to specialist textbooks.
Fig. 5.3 H-plasty with
advancement fl aps hidden in
the existing furrows
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61
Primary Closure
Primary closure in patients with signifi cant skin laxity allows for excellent aesthetic
outcomes. As a general rule, skin should be recruited medially to allow for adequate
closure. The planned incision line should aim to rest in the relaxed skin tension lines
Fig. 5.4 An A-T fl ap on the
lateral aspect of the forehead
with the advancement
incisions hidden in the
hairline
Fig. 5.5 Wedge planned for
the right cheek with scar
hidden in relaxed skin tension
lines
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62
[ 35 ]. When performing primary closure it is essential that the wound be closed with
a deep layer of suturing to ensure that the skin closure is completely tension-free.
Failure to do this may result in an unsightly scar.
V-Y
A V-Y island pedicle advancement fl ap is appropriate for use in the medial cheek region
(Fig. 5.6 ). This fl ap is moved into the defect it is designed to fi ll with tension- free clo-
sure, achieved with appropriate deep-layered sutures [ 36 ]. The integrity of the fl ap is
dependent on the preservation of the subcutaneous tissue beneath the advancing fl ap,
which carries the perforating vessels supplying the overlying skin [ 35 ].
Fig. 5.6 V-Y fl ap planned
for the medial cheek
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63
Rhomboid
Rhomboid fl aps on the cheek usually are reserved for the lateral and inferior aspects
of the cheek (Fig. 5.7 ). Regardless of their design, one of the closure lines will be
perpendicular to the relaxed skin tension lines, making them slightly more visible
than other closure options. The skin that is borrowed for a rhomboid closure should
have appropriate laxity.
Planning for a rhomboid fl ap involves creating a rhomboid around the defect
with two angles of 120°, that are opposite each other and two angles of 60° [ 36 ].
The defect is excised and the fi rst limb of the fl ap is taken perpendicular to the
120° angle of the defect with the second limb for the fl ap parallel to one of the
adjacent defects. This tissue is then transposed into the defect. Modifi cations of
this fl ap include the Dufourmental fl ap and Webster fl ap, which do not rely on a
rhomboid- shaped excision [
37 ].
Rotation Flap
Large cheek defects of >4 cm can be repaired with good cosmetic results with a
rotation fl ap. The upper cervical skin usually provides enough laxity to close signifi -
cant cheek defects (Fig. 5.8 ) [ 36 ]. Excision of the lesion and rotation of the fl ap
often requires excision of a standing cutaneous deformity adjacent the lesion to
provide adequate rotation. The incision for the fl ap can either extend upwards pos-
terior to the ear or alternatively along a skin crease in the neck [ 35 ].
Fig. 5.7 Rhomboid fl ap
planned for the cheek
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64
References
1. Shriner DL, McCoy DK, Goldberg DJ, et al. Mohs micrographic surgery. J Am Acad Dermatol.
1998;39:79–97.
2. Brodland DG, Amonette R, Hanke CW, et al. The history and evolution of Mohs micrographic
surgery. Dermatol Surg. 2000;26:303–8.
3. Rosai J. Mohs micrographic surgery: a pathologist’s view. Arch Dermatol. 1999;135:1171–3.
4. Burget GC, Menick FJ. Nasal support and lining: the marriage of beauty and blood supply.
Plast Reconstr Surg. 1989;84:189–202.
Fig. 5.8 Cervicofacial
rotation fl ap planned for a
lesion inferior to the left eye
D. Robinson and J. Roth
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65
5. Burget GC, Menick FJ. Aesthetic reconstruction of the nose. St. Louis: Mosby; 1993.
6. Baker SR. Major nasal reconstruction. In: Facial plastic and reconstructive surgery. New York:
Thieme Medical; 2008. p. 807–20.
7. Baker SR, Johnson TM, Nelson BR, et al. The importance of maintaining the alar-facial sulcus
in nasal reconstruction. Arch Otolaryngol Head Neck Surg. 1995;121:617–22.
8. Baker SR. Contemporary aspects of nasal reconstruction. In: Myers EN, Bluestone CD,
Brackmann DE, Kranse CJ, editors. Advances in otolaryngology: head and neck surgery. St.
Louis: Mosby; 1998. p. 235–61.
9. Zitelli JA. Secondary intention healing: an alternative to surgical repair. Clin Dermatol.
1984;2:92–106.
10. Baker SR. Principles of nasal reconstruction. St. Louis: Mosby; 2002.
11. Park SS. Reconstruction of nasal defects larger than 1.5 centimeters in diameter. Laryngoscope.
2000;110:1241–50.
12. Vuyk HD. Facial plastic and reconstructive surgery. Boca Raton, Florida: CRC Press; 2006.
13. Webster RC, Davidson TM, Smith RC. The thirty degree transposition fl ap. Laryngoscope.
1978;88:85–94.
14. Walike JW, Larrabee Jr WF. The ‘note fl ap’. Arch Otolaryngol. 1985;111:430–3.
15. Larrabee Jr WF, Trachy R, Sutton D, et al. Rhomboid fl ap dynamics. Arch Otolaryngol.
1981;107:755–7.
16. Tardy Jr ME, Tenta LT, Azem K. The bilobed fl ap in nasal repair. Arch Otolaryngol.
1972;95:1–5.
17. Zitelli JA. The bilobed fl ap for nasal reconstruction. Arch Dermatol. 1989;125:957–9.
18. Flint ID, Siegle RJ. The bipedicle fl ap revisited. J Dermatol Surg Oncol. 1994;20:394–400.
19. McGregor JC, Soutar DS. A critical assessment of the bilobed fl ap. Br J Plast Surg.
1981;34:197–205.
20. Menick FJ. Facial reconstruction with local and distant tissue: the interface of aesthetic and
reconstructive surgery. Plast Reconstr Surg. 1998;102:1424–33.
21. Becker F. Facial reconstruction with local and regional fl aps. New York: Thieme Medical;
1985.
22. Zitelli JA. The nasolabial fl ap as a single-stage procedure. Arch Dermatol. 1990;126:1445–8.
23. Shumrick KA, Smith TL. The anatomic basis for the design of forehead fl aps in nasal recon-
struction. Arch Otolaryngol Head Neck Surg. 1992;118:373–9.
24. El A. Midforehead fl aps. In: Baker S, editor. Local fl aps in facial reconstruction. Philadelphia:
Mosby; 1995. p. 197–223.
25. Menick FJ. Aesthetic refi nements in use of forehead for nasal reconstruction: the paramedian
forehead fl ap. Clin Plast Surg. 1990;17:607–22.
26. Renner G. Reconstruction of the lip. In: Baker SR, Swanson NA, editors. Local fl aps in facial
reconstruction. St. Louis: Mosby; 1995. p. 345–89.
27. Abbe R. A new plastic operation for the relief of deformity due to double harelip. Plast
Reconstr Surg. 1968;42:481–3.
28. Estlander JA. A method of reconstructing loss of substance in one lip from the other lip. Plast
Reconstr Surg. 1968;42:360–4.
29. Webster JP. Crescentic peri-alar cheek excision for upper lip fl ap advancement with a short
history of upper lip repair. Plast Reconstr Surg. 1955;16:434–64.
30. Karapandzic M. Reconstruction of lip defects by local arterial fl aps. Br J Plast Surg.
1974;27:93–7.
31. Gillies H, Millard Jr DR. The principles and art of plastic surgery. London: Butterworth;
1957.
32. Freeman BS. Myoplastic modifi cation of the Bernard cheiloplasty. Plast Reconstr Surg
Transplant Bull. 1958;21:453–60.
33. Webster RC, Coffey RJ, Kelleher RE, et al. Total and partial reconstruction of the lower
lip with innervated musclebearing fl aps. Plast Reconstr Surg Transplant Bull. 1960;25:
360–71.
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66
34. Siegle RJ. Reconstruction of the forehead. In: Baker SR, editor. Local fl aps in facial recon-
struction. 2nd ed. Philadelphia: Mosby; 2007. p. 557–79.
35. Bradley DT. Reconstruction of the cheek. In: Baker SR, editor. Local fl aps in facial reconstruc-
tion. 2nd ed. Philadelphia: Mosby; 2007. p. 525–56.
36. Baker SR. Advancement fl aps. In: Baker SR, editor. Local fl aps in facial reconstruction.
2nd ed. Philadelphia: Mosby; 2007. p. 157–87.
37. Park SS, Little S. Rhombic fl aps. In: Baker SR, editor. Local fl aps in facial reconstruction.
2nd ed. Philadelphia: Mosby; 2007. p. 213–30.
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67
© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_6
M. Veness , MBBS, MMed, MD, MD, FRANZCR (*)
Radiation Oncology, Westmead Hospital, Westmead University of Sydney ,
Sydney , NSW , Australia
e-mail: Michael.Veness@health.nsw.gov.au
J. Howle , MBBS, MSurg, FRACS
Department of Surgical Oncology , Westmead Cancer Care Centre, Westmead Hospital,
Westmead, University of Sydney , Sydney , NSW , Australia
e-mail: julie.howle@health.nsw.gov.au
6
Merkel Cell Carcinoma, Adnexal
Carcinoma and Basal Cell Carcinoma
Michael Veness and Julie Howle
Merkel Cell Carcinoma
Background
Merkel cell carcinomas (MCCs) are derived from the mechanoreceptor cells located
in the basal layer of the epidermis and are considered a primary cutaneous neuroen-
docrine malignancy with characteristically small, round blue cells seen on micros-
copy [ 1 ]. MCC is uncommon, but the incidence is rising and markedly increased in
immunosuppressed patients. Chronic sun exposure is presumed to be the chief aeti-
ological factor but, more recently, emerging evidence suggests that merkel cell
polyomavirus may also contribute to its development [ 2 ]. MCC is considered an
aggressive skin malignancy in most patients, with a propensity to locoregional and
distant relapse.
Patients are usually caucasian, >65 years old; men slightly outnumber women. It
is rarely diagnosed clinically and requires biopsy confi rmation. Lesions may appear
as a purplish nodule and grow rapidly, with 50 % arising in the head and neck. Most
patients will require investigations to exclude regional and distant metastases, usu-
ally via computed tomography (CT) and/or positron emission tomography (PET).
malcolm_buchanan123@hotmail.com
68
Patients with a primary lesion, but without clinically present nodes, should in most
cases have draining lymph nodes either electively treated or pathologically investi-
gated with sentinel lymph node biopsies (SLNB) [ 3 ].
MCC is diffi cult to diagnose clinically and often mistaken for BCC or amela-
notic melanoma. Growth is often rapid and lesions are usually <2 cm at diagnosis.
Lesions can be painless, asymptomatic and appear blue or violaceous in colour
(Fig. 6.1 ). Clinically, the epidermis is usually intact and lesions rarely arise in non-
sun exposed skin, e.g. mucosal surface.
At presentation, 50−60 % of patients have primary disease, with only a
minority of these already harbouring microscopic (occult) nodal metastases in
draining nodes. Approximately l5−20 % of MCCs arise in lymph nodes without
an obvious index lesion present. In these cases the aetiology is unclear but pre-
sumed regression of the primary lesion, although a nodal origin, has also been
postulated. Groin nodes are the most frequent site for an unknown primary to
metastasize to nodes [
4 ].
Only 5 % of patients actually present with distant metastases (e.g. to liver, lung,
etc.); however, 30−40 % of patients will subsequently develop distant relapse
despite treatment and become incurable. Effective systemic adjuvant treatment is
currently lacking.
Similar to other non-cutaneous small cell malignancies, MCC is highly respon-
sive to moderate doses (50−55 Gy in 2 Gy fractions) of radiotherapy (RT). Presently,
routine chemotherapy has no defi ned role in the curative setting, although suitable
patients may be enrolled into clinical trials (Box 6.1 ). Similar to other small cell
malignancies, the combination of carboplatinum and etoposide are used most often.
Management of patients should ideally be undertaken by a multidisciplinary team
with experience in treating patients with MCC.
Fig. 6.1 A 65-year-old
woman with a rapidly
growing non-ulcerative
epidermal-based lesion
located on her left forearm.
Biopsy confi rmed this as a
CK 20-positive small cell
malignancy consistent with
a diagnosis of Merkel cell
carcinoma
M. Veness and J. Howle
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69
Investigations
A biopsy is essential to confi rm a diagnosis. It is important to document a history of
immunosuppression. Most patients (60−80 %) present with a primary lesion and
20−30 % will have clinical lymph nodes. Distant metastases are uncommon (5 %)
at presentation. Investigations using CT scans of the draining nodal basin might
improve detection of small nodes otherwise undetected clinically. SLNB should be
utilized in select patients; it is especially useful in midline and extremity lesions.
FDG CT/PET may also detect sites of subclinical metastases; it is considered the
investigation of choice if available, although equivocal sites of uptake may require
biopsy confi rmation [ 5 ]. Various studies suggest that the management of many
patients is altered as patients are upstaged after fi nding undetected sites of disease.
An Australian study (TROG 09.03 MP3 study) currently is under way with a sec-
ondary aim to investigate the role of FDG CT/PET scans by obtaining pathological
confi rmation of sites of uptake, thereby establishing the sensitivity and specifi city of
this modality.
Pathology
The histological features are those of a small blue cell with hyperchromatic nuclei,
abundant mitoses and minimal cytoplasm. Three separate cellular patterns are
reported—intermediate, small cell and trabecular. The intermediate cell variant is
most common although histological variants are not prognostic. MCCs are positive
for pancytokeratins and cytokeratin 20 (CK20) stains are positive in the majority,
with a perinuclear dot-like staining. The presence (or absence) of lymphovascular
invasion (LVI) is important to document as it is prognostic for metastases [ 6 ]. Of
note, thyroid transcription factor 1 is positive in small cell lung cancer, but rarely in
MCC, and occasionally small cell cutaneous lesions thought to be MCC are actually
metastases in smokers.
Box 6.1 Key Aspects of Merkel Cell Carcinoma (MCC)
• MCC has a high propensity initially to spread to regional lymph nodes.
• The risk of occult nodal metastases is 30−50 %. All patients should have
draining nodes either investigated or electively treated.
• MCC is a highly radioresponsive malignancy; hence radiotherapy has an
important role in reducing the risk of locoregional recurrence.
• Any surgery need only be limited to achieving a negative microscopic
excision margin prior to adjuvant RT.
• The routine addition of adjuvant chemotherapy has no current role.
6 Merkel Cell Carcinoma, Adnexal Carcinoma and Basal Cell Carcinoma
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70
Prognostic Factors
The presence of macroscopic lymph node metastases is the most important
prognostic factor. Patients identifi ed as having pathologically proven occult (or
microscopic) metastases also have a worse prognosis compared with patients hav-
ing MCC confi ned only to the primary site. Increasing size of the primary lesion is
moderately predictive of outcome, although other tumour variables, such as
thickness and Clark level are probably less helpful. Recently, the identifi cation of
LVI has been reported as predictive for the development of metastases.
Immunosuppression secondary to organ transplantation, haematological malig-
nancy (e.g. non-Hodgkin lymphoma, chronic lymphocytic leukaemia) or AIDS/
HIV patients is predictive of a poor outcome.
The addition of RT is associated with improved locoregional control and sur-
vival, compared to patients undergoing surgery alone [ 7 ]. Patients with nodal metas-
tases and without a primary (index) lesion have a better prognosis compared to
patients presenting with a concomitant primary and nodal metastases. The reason
for this more favourable outcome is unclear.
Staging System
Multiple staging systems have been used over the years; however, the updated AJCC
7th edition TNM stages used data from >5000 patients to establish a new prognostic
staging system and reaffi rming stage at diagnosis as prognostic [ 8 ]. Patients with
stages I and II MCC (node-negative patients) with pathologically evaluated negative
lymph nodes have the best survival, compared with those determined to be clini-
cally node-negative. Of the stages documenting non-distant spread, stages I and II
are classifi ed by tumour size of >2 cm, and within each stage further categorized
(A, B), depending on whether draining nodes have been evaluated pathologically or
clinically. Because of the high false-negative rate (30−40 %) for clinically detecting
occult metastatic nodal metastases, patients within the same stage but with clini-
cally staged nodes, have a documented worse prognosis compared with patients that
undergo pathological staging of nodes (e.g. SLNB). Patients with stage III disease
have pathologically confi rmed nodal metastases and are further divided into those
with micrometastases (i.e. occult) or macrometastases (clinically detectable).
Treatment
It is debatable whether all patients should be recommended RT. Patients presenting
with local disease should undergo excision to achieve, at least, negative excision
margins (if possible) followed, in many cases, by adjuvant RT. Wider (5−10 mm)
margins are desirable but only within constraints of the location, which can be dif-
fi cult to achieve in the head and neck. Any delay in re-excision surgery should be
avoided with consideration of patients proceeding directly to RT.
M. Veness and J. Howle
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71
Regional lymph nodes must be investigated or treated and a SLNB should be
considered, if the expertise is available. The fi nding of positive SLNs dictates treat-
ment to the nodal region, whereas a negative SLNB means nodal regions can be
observed closely. With reports of false-negative SLNBs and subsequent regional
relapse it remains important to monitor the patient closely (every 6−8 weeks). An
alternative to SLNB is elective nodal treatment (RT or surgery), although this will
needlessly treat some patients without nodal metastases. Patients presenting with
clinical nodal metastases, if operable, should proceed to nodal surgery, with most
patients also undergoing locoregional adjuvant RT. An option is to consider nodal
RT alone if only low volume nodal metastases (single node <3 cm) are present.
Adjuvant RT should be recommended if margins are positive or close (<10 mm)
and RT fi elds of 3−4 cm (respecting organs at risk, e.g. eye) are recommended so as
to encompass in-transit lymphatics (Fig.
6.2 ). If the draining nodal region is also to
be irradiated this should be performed en bloc with the primary site and in-transit
tissue. However, in patients with extremity lesions this may not be possible and
separate fi elds will be required. Doses of 50−55 Gy in 20−25 fractions are recom-
mended, often using ipsilateral moderate energy electron fi elds or simple two-fi eld
megavoltage photon beams. The toxicity from this limited volume RT is usually
acceptable even in this older population group.
Patients should be considered for defi nitive RT alone in inoperable cases and
similar doses to the adjuvant setting are recommended. Studies have reported excel-
lent (75−80 %) in-fi eld control in inoperable patients [ 9 ].
Surgery alone may be acceptable in select patients with small lesions (<10 mm)
with adequate excision margins achieved (5−10 mm) that are SLNB-negative (or
negative node dissection). These patients should not be immunosuppressed and
must be able to return for regular review over a 5-year period.
Fig. 6.2 A 70-year-old man
undergoing right face and
neck wide-fi eld adjuvant RT
(55 Gy in 25 fractions) using
moderate energy electrons.
Note the dark lines
delineating the RT fi eld and
the central marked scar
delineating the excision site.
Superiorly the orbit and eye
limit the RT fi eld while the
other fi eld margins are
generous (>3–4 cm) to
adequately treat subclinical
and in-transit metastases
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72
The role of routine chemotherapy is unclear and the toxicity, although generally
tolerable, is not inconsequential in this mainly elderly population [ 10 ]. Despite this
a previous single-arm study from the Trans Tasman Radiation Oncology Group
(TROG 96:07) reported an excellent outcome in high-risk MCC patients receiving
RT and synchronous carboplatinum/etoposide [ 11 ]. However, the addition of che-
motherapy should still be considered only within the context of a clinical trial.
Recurrence
In the setting of recurrence, prognosis is poor and patients should be restaged to
exclude distant recurrence. It is important to assess patient fi tness for re-treatment
in the elderly population. The majority of recurrences arise in the fi rst 12 months
post-treatment, and in the case of locoregional recurrence may be suitable for sal-
vage surgery if operable. Patients should have adjuvant (postoperative) RT if out-
side of a previous RT fi eld. If inoperable, low-dose re-irradiation can be undertaken
if symptomatic, or a higher dose RT used if previously unirradiated. In the setting of
distant metastatic recurrence, isolated symptomatic sites might benefi t from pallia-
tive RT and a single fraction (6−8 Gy) is often effective. Suitable patients may be
considered for palliative CT, although toxicity, especially haematological, is an
issue.
Follow-up
The role of post-treatment CT/PET or CT scans is unclear. It is unlikely that surveil-
lance investigations in an asymptomatic patient are helpful. Our group recommends
close clinical examination and investigations, as warranted—with 2−3 monthly
reviews for the fi rst 12 months, 3−4 monthly reviews for the second 12-months, and
6-monthly reviews for next 3−4 years.
Malignant Skin Adnexal Tumours
Malignant skin adnexal tumours are a rare group of tumours that can be classifi ed
broadly into tumours arising from the pilo-sebaceous unit, eccrine and apocrine
glands and mixed tumours (Table 6.1 ) [ 12 , 13 ]. The site of malignant skin adnexal
tumours refl ects the distribution of the different types of sweat glands in the skin,
with eccrine sweat glands being distributed widely throughout the skin, and apo-
crine sweat glands more commonly found in the skin of the axilla, groin, umbilicus,
eyelid and external auditory meatus.
The head and neck region is the commonest site for microcystic adnexal carci-
noma (MAC), malignant cylindroma, sebaceous carcinoma, primary cutaneous
mucinous carcinoma, pilomatrix carcinoma, and adenoid cystic carcinoma [
13 ].
Eccrine porocarcinoma is commonest on the distal extremities, but can also occur in
M. Veness and J. Howle
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73
the head and neck [ 14 ]. In general, most malignant skin adnexal tumours are slow-
growing tumours with a low rate of metastasis.
Microcystic Adnexal Carcinoma (MAC)
MAC is a rare tumour that is derived from sweat ducts and hair follicle cells.
Previous irradiation and immunosuppression are risk factors for developing MAC
[ 15 ]. MAC presents as a slow-growing, solitary, fl esh-coloured nodule or plaque
and is an infi ltrative tumour with a high rate of perineural invasion [ 16 ]. It can be
locally aggressive with involvement of underlying soft tissue and bone. Lymph
node metastases are rare and survival rates are excellent (10-year survival 97 %).
Sebaceous Carcinoma
Sebaceous carcinomas often arise from orbital sebaceous glands with 25 % arising
from extraorbital sites. Over 70 % occur in the head and neck region, with the eyelid
(meibomian glands of the tarsal plate) being the commonest site [ 17 ]. Aetiological
risk factors for sebaceous carcinoma include increasing age, previous radiation
exposure and Muir Torre syndrome, an autosomal dominant syndrome character-
ized by visceral malignancies (colorectal, upper gastrointestinal, endometrial and
urological malignant neoplasms), tumours of the sebaceous glands, or keratoacan-
thomas. Clinically, lesions present as slowly enlarging fi rm nodules. At least one
Table 6.1 A classifi cation of malignant skin adnexal tumours
Skin adnexal structure Malignant tumour
Eccrine sweat gland Porocarcinoma
Malignant cylindroma
Adenoid cystic carcinoma
Primary cutaneous mucinous carcinoma
Syringoid carcinoma
Malignant chondroidsyringoma
Hidradenocarcinoma
Spiradenocarcinoma
Aggressive digital papillary adenocarcinoma
Apocrine sweat gland Apocrine carcinoma
Extramammary Paget disease
Pilosebaceous unit
Hair and hair follicle Trichilemmal carcinoma
Trichoblastic carcinoma
Malignant proliferating trichilemmal cyst
Pilomatrix carcinoma
Sebaceous gland Sebaceous carcinoma
Basal cell carcinoma with sebaceous differentiation
Mixed Microcystic adnexal carcinoma
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74
study has documented a 60 % incidence of occult nodal metastases, and patients
with lower eyelid lesions as having the worst prognosis [ 18 ].
Apocrine Carcinoma
Apocrine carcinomas occur predominantly in middle-aged women. Given its
low incidence, information is scant on its clinical or pathological characteris-
tics. It most commonly occurs in the axilla, but it can also arise on the eyelid,
ear and scalp. Histologically, lesions may resemble metastatic adenocarcinoma
of the breast and, therefore, it is important to exclude this diagnosis with rele-
vant investigations. Apocrine carcinoma generally presents as a solitary slow-
growing cutaneous nodule. The development of metastatic disease has been
recorded in one small series [
19 ]. In a series of 24 patients, only one developed
nodal metastases [ 20 ].
Primary Cutaneous Mucinous Carcinoma
Primary cutaneous mucinous carcinoma is a low-grade tumour that occurs most
commonly in the elderly. It is most frequently found on the eyelid, cheek and scalp,
and generally presents as a slow-growing asymptomatic nodule. Histologically, it
often resembles a metastatic deposit of mucinous carcinoma. Thus, it is impor-
tant to exclude primary mucinous carcinomas arising in sites, such as the breast,
gastrointestinal tract and lung, with appropriate investigations. Primary cutane-
ous mucinous carcinomas have a propensity for local recurrence, but metastases
are rare [ 21 ].
Adenoid Cystic Carcinoma
Primary cutaneous adenoid cystic carcinoma occurs most frequently in the scalp,
and is more common in the elderly [ 22 , 23 ]. Adenoid cystic carcinoma may also
occur as a primary tumour of other sites, such as the salivary glands and lung. Thus,
appropriate clinical examination and imaging must be performed to exclude a pri-
mary tumour in these sites. Metastases are infrequent and the 5-year survival rate is
excellent.
Eccrine Porocarcinoma
Eccrine porocarcinomas develop de novo or within a pre-existing eccrineporoma
and commonly occur on the lower limb, but may occur in the head and neck region.
Lesions develop as red or purple cutaneous nodules or plaques. Nodal metastasis
occurs in ~20 % and distant metastases in ~10 % of patients [
24 ].
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75
Investigations
Before starting defi nitive treatment, we recommend that a biopsy be performed to
establish a tissue diagnosis. Patients with lymphadenopathy should undergo a fi ne-
needle aspiration biopsy to assess for metastatic disease. If nodal metastases are pres-
ent, CT scans of the chest, abdomen and pelvis, or a PET/CT should be done. In patients
with mucinous carcinoma, apocrine carcinoma and adenoid cystic carcinoma, investi-
gations should be done to exclude a primary tumour arising from another organ.
Management
Achieving local control is the greatest challenge facing clinicians in the treatment of
malignant skin adnexal tumours, most of which have signifi cant rates of local
recurrence.
Surgery
Wide local excision is the mainstay of treatment for malignant adnexal skin tumours.
Evidence is lacking on the optimal margin of excision. However, our group recom-
mends a margin of at least 1 cm, where possible, respecting form and function in
order to minimize the risk of local recurrence.
If expertise is available, and in select patients, Mohs micrographic surgery might
be benefi cial in reducing the rate of local recurrence and has been shown to be an
effective treatment for MAC; it is associated with a lower rate of recurrence than a
simple wide excision [ 25 ].
Sentinel Lymph Node Biopsy
Most malignant skin adnexal neoplasms have a low rate of nodal metastasis, and
there is little evidence in the literature regarding the use of SLNB. However, in
select patients with high-risk eccrine porocarcinoma (tumour thickness >7 mm, LVI
present), sentinel node biopsy might be benefi cial.
Radiotherapy
Limited evidence exists for using RT, in either the defi nitive or adjuvant setting, for
the treatment of malignant adnexal skin tumours. An Australian study on the use of
adjuvant RT for MAC, however, did report an excellent local control rate with the
addition of RT. [ 16 ] RT should be considered in patients in whom surgery is contra-
indicated, or in the adjuvant setting where there are positive margins, or if perineu-
ral invasion is present.
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76
Basal Cell Carcinoma
Introduction
BCC is the commonest malignancy worldwide and in many countries, such as
Australia, is a major public health issue. Most occur on sun-exposed regions of
the body, with the head and neck being the commonest sites. BCCs arise from
basal keratinocytes, and unlike most other malignancies of the skin, rarely
metastasize.
Apart from sun exposure, which is the main risk factor for the development of
BCCs, others include arsenic exposure, immunosuppression, exposure to ionizing
radiation, and scars. Gorlin syndrome is an autosomal dominant condition caused
by a mutation in the PTCH1 gene. It is characterized by the following features:
multiple BCCs, odontogenic cysts of the mandible, palmar or plantar pits, skeletal
abnormalities, and medulloblastoma. BCCs are also more common in patients with
xeroderma pigmentosa, a rare, autosomal recessive condition in which UV-induced
DNA repair is defi cient.
Types of BCC
BCC consists broadly of three main types: nodular, morphoeic and superfi cial.
Nodular and morphoeic are the most common subtypes in the head and neck region;
superfi cial BCCs commonly occur on the trunk [ 25 ].
Nodular BCC is the commonest subtype of BCC and presents as a pearly nodule
with telangiectasia, and often ulcerates and bleeds. Morphoeic BCC appears as an
ill-defi ned indurated macule, often resembling a scar. It is often a long-standing
asymptomatic lesion and may be deeply invasive by the time of diagnosis. Perineural
invasion is frequently present. Superfi cial BCC generally develops as an erythema-
tous scaly macule. Most are asymptomatic, with ulceration, itching and bleeding
being uncommon.
Investigations
It is usual to biopsy lesions of the head and neck region before recommending
defi nitive treatment. In general, a punch or incisional biopsy of the lesion is ade-
quate. CT scans of the head and/or neck are performed for patients with locally
advanced disease in order to assess the depth of invasion. As BCCs rarely metasta-
size, staging investigations are unnecessary.
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77
Treatment
Treatment choice is dictated by a number of factors, including tumour size and site,
patient age and co-morbidities, cosmesis and function.
Surgery
Where possible, surgical excision is the preferred treatment approach, aiming for a
3−4 mm clinical margin. A positive margin(s) has been reported to be associated with
a 30–40 % local recurrence rate [ 26 ], and in many cases patients should be considered
for further surgery or adjuvant RT. Positive margins underlying local fl aps should
rarely be left untreated because of the risk of undetected deep recurrence.
The majority of lesions can be excised and closed primarily. In patients in whom
primary closure is not feasible, local fl aps and skin grafts are used. Patients with
lesions requiring complex local fl aps should be referred to a plastic surgeon.
Selected patients, such as those with morphoeic or recurrent BCC, can be referred
for Mohs micrographic surgery, a technique in which serial sections of skin are
excised and the peripheral and deep margins are examined, so that 100 % of the
surgical margins are evaluated. A randomized controlled trial comparing surgical
excision with Mohs surgery for the treatment of BCC of the face found no signifi -
cant difference in recurrence rate for primary BCCs, but in the treatment of recur-
rent BCC, the use of Mohs surgery resulted in a signifi cantly lower recurrence rate
[ 27 ]. The higher cost and relative inaccessibility of Mohs surgery has limited its
widespread application in many countries.
Radiotherapy
Definitive Setting
Randomized data comparing different modalities is scarce, with a Cochrane review
[ 28 ] reporting surgery or RT as the most effi cacious treatment with surgery proba-
bly showing the lowest recurrence rates (Box 6.2 ). However, local control rates
(90–95 %) and cosmesis (>90 % rated as excellent or good) after RT are excellent
and management decisions are often based on multiple factors.
RT remains an option when tumour and patient factors favour this modality; typi-
cally patients are older, with a mid-face or nasal (alanasi or nasal tip) BCC for which
small skin grafts or fl aps may be required (Fig. 6.3 ) [ 29 ]. Locations, such as the inner
canthus or lower eyelid, may also be better approached with RT. Larger lesions can still
be treated with defi nitive RT, although with increasing size and deeper invasion local
control decreases and excision (+/− adjuvant RT) may result in better local control.
6 Merkel Cell Carcinoma, Adnexal Carcinoma and Basal Cell Carcinoma
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78
Box 6.2 Radiotherapy and Basal Cell Carcinoma (BCC)
• BCC can be treated adequately with either surgery or RT.
• Patients with non-mid-face operable lesions that can be closed primarily
should undergo surgery, unless contraindicated.
• Lesions located on the mid-face, especially in older patients, may benefi t
from defi nitive RT, especially if graft or fl ap reconstruction is required.
• Patients with inadequately excised BCC with positive margins are at risk
of developing local recurrence and should be considered for re-excision or
adjuvant local RT.
Fig. 6.3 An elderly man
with a large nodular BCC
occupying his mid dorsum
nose. The patient was
recommended wide-fi eld
defi nitive RT to the clinical
basal cell carcinoma with
10 mm fi eld margins to a
dose of 45 Gy in 15 daily
fractions
Adjuvant (postoperative) Setting
At least 30 % of incompletely excised BCCs recur and further treatment is often
recommended rather than observation and expectant treatment [ 30 ]. A positive deep
margin resulting in deep recurrence, particularly deep to a local fl ap, can be diffi cult
to detect. When located around the mid-face and periorbit, undetected deep recur-
rence of can result in signifi cant local morbidity. Re-excision is often an option
although in certain circumstances the involved margin precludes simple re-excision
and, therefore, adjuvant RT is also an option. Although recurrences are rarely
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79
associated with serious consequences, extensive salvage surgery might be required.
Patients with the more aggressive subtype of sclerosing (morpheaform) BCC are at
a higher risk of local recurrence and are best not left untreated in the setting of an
inadequate excision (Fig.
6.4 ).
Dose Fractionation Schedules
An appropriate schedule, in the absence of a defi ned optimal dose fractionation
schedule, encompasses both patient and tumour factors. Smaller lesions (20−30 mm)
in older patients (>70 years) are treated adequately using 40−45 Gy in 10−15 daily
fractions with acceptable local control and cosmesis. The data suggest that the dose-
response is not marked, and local control is similar—whether 40 Gy in 10 fractions
or 50 Gy in 20 fractions is prescribed.
Elderly or infi rm patients can be prescribed single large fractions (10−20 Gy) or
even 3−5 fractions of 6−7 Gy. Larger invasive lesions (>3–4 cm) and/or younger
patients should be approached using a lower fraction size (2−2.5 Gy) and a ‘hotter’
total dose of 50−60 Gy to achieve the best chance of durable local control and
acceptable late effects.
Data from a large centre in the United Kingdom suggest that small BCC/SCC
of the head and neck, encompassed in a RT fi eld size of <3 cm, can be treated
with a single fraction of 20 Gy [
31 ]. Although the authors documented a low
recurrence rate (<5 %) and acceptable necrosis rate (6 %), late cosmetic out-
come was not reported. In general, single large fractions should not be recom-
mended although it may be an option in select older patients who decline
fractionated treatment.
A fi eld margin of 5−10 mm beyond macroscopic disease, or surgical site, is usu-
ally adequate for a well-defi ned nodular BCC, but for an infi ltrative BCC a wider
margin of 10−15 mm is required to encompass surrounding subclinical spread.
a b
Fig. 6.4 ( a , b ) A 73-year-old man with wide local recurrence of a previously excised right fore-
head morphoeic BCC with positive margins and no further treatment. Note the multiple punch
biopsy sites are all positive for recurrence. The patient underwent wide-fi eld defi nitive RT (50 Gy
in 20 fractions) to his right hemi-forehead with excellent results
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80
Other Treatment Modalities
Whereas surgery is the mainstay of treatment for BCC, a variety of topical treat-
ments is available that may be suitable for patients with small and superfi cial
tumours, who are not able to undergo surgery.
Imiquimod
Imiquimod is a topical immunomodulator that is approved in some countries for
treatment of superfi cial BCCs; its clearance rates are reported as ~80 % [ 32 ].
Photodynamic Therapy
Photodynamic therapy involves the application of a photosensitizing agent to the
tumour and a 5 mm margin of surrounding skin, followed by irradiation by a light
source; it is generally used to treat superfi cial or thin nodular BCC with an expected
good cosmetic outcome.
Cryotherapy
Cryotherapy involves the application of a cryogenic agent (most commonly liquid
nitrogen) to the tumour leading to destruction of tissue. BCCs can be treated with
cryotherapy, but is generally not used for BCCs of the head and neck because of
higher recurrence rates.
Curettage and Diathermy
Curettage and diathermy can be used to treat non-morphoeic BCCs successfully in
most areas of the body. However, this method is generally not used for BCCs of the
head (in particular areas such as the nose, lips, eyelids, ears) on account of unpre-
dictable cosmetic outcome and the risk of recurrence.
Hedgehog Pathway Inhibitors
Most BCCs arise because of upregulation of the hedgehog signalling pathway,
which is caused by mutations of the patched homologue 1 (PTCH1), which results
in a lack of inhibition of the smoothened homologue. Vismodegib, an inhibitor of
smoothened, has been studied recently in clinical trials. A phase II study in which
patients with metastatic or locally advanced BCC were treated with vismodegib
reported response rates of ≤43 % [ 26 ]. At this stage, vismodegib and other hedge-
hog pathway inhibitors are accessible to patients only in the setting of a clinical
trial. However, they represent a promising treatment modality for those with locally
advanced or metastatic disease and potentially those with Gorlin syndrome.
References
1. Mendenhall WM, Kirwan JM, Morris CG, et al. Cutaneous Merkel cell carcinoma. Am J
Otololaryngol Head Neck Med Surg. 2012;33:88–92.
2. Amber K, McLeod MP, Nouri K. The Merkel cell polyomavirus and its involvement in Merkel
cell carcinoma. Dermatol Surg. 2013;39:232–8.
M. Veness and J. Howle
malcolm_buchanan123@hotmail.com
81
3. Howle J, Veness M. Sentinel lymph node biopsy in patients with Merkel cell carcinoma: an
emerging role and the Westmead hospital experience. Australas J Dermatol. 2012;53:26–31.
4. Foote M, Veness M, Zarate D, et al. Merkel cell carcinoma: the prognostic implications of an
occult primary in stage 3B (nodal) disease. J Am Acad Dermatol. 2012;67:395–9.
5. Concannon R, Larcos GS, Veness M. The impact of 18FDG PET/CT scanning for staging and
management of Merkel cell carcinoma: results from Westmead hospital, Sydney, Australia. J
Am Acad Dermatol. 2010;62:76–84.
6. Fields RC, Busan KJ, Chou JF, et al. Five hundred patients with Merkel cell carcinoma evalu-
ated at a single institution. Ann Surg. 2011;254:465–75.
7. Howle J, Hughes M, Gebski V, et al. Merkel cell carcinoma: an Australian perspective and the
importance of addressing the regional lymph nodes in clinically node negative patients. J Am
Acad Dermatol. 2012;67:33–40.
8. Lemos BD, Storer BE, Iyer JG, et al. Pathological nodal evaluation improves prognostic accu-
racy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the fi rst consensus staging
system. J Am Acad Dermatol. 2010;63:751–61.
9. Veness M, Foote M, Gebski V, et al. The role of radiotherapy alone in patients with Merkel cell
carcinoma: reporting the australian experience of 43 patients. Int J Radiat Oncol Biol Phys.
2010;78:703–9.
10. Poulsen M, Rischin D, Porter I, et al. Does chemotherapy improve survival in high-risk stage
1 and 2 Merkel cell carcinoma of the skin? Int J Radiat Oncol Biol Phys. 2006;64:114–9.
11. Poulsen M, Rischin D, Walpole E, et al. High-risk Merkel cell carcinoma of the skin treated
with synchronous carboplatinum/etoposide and radiation: a Trans Tasman Radiation Oncology
Group Study-TROG 96:07. J Clin Oncol. 2003;21:4371–6.
12. Alsaad K, Obaidat N, Ghazarian D. Skin adnexal neoplasms-part 1: an approach to tumours of
the pilosebaceous unit. J Clin Pathol. 2007;60:129–44.
13. Obaidat N, Alsaad K, Ghazarain D. Skin adnexal neoplasms-part 2: an approach to tumours of
cutaneous sweat glands. J Clin Pathol. 2007;60:145–59.
14. Brown C, Dy L. Eccrine porocarcinoma. Dermatol Ther. 2008;21:433–8.
15. Yu J, Patel S, Decker R, Wilson L. Surveillance, Epidemiology and End Results (SEER) data-
base analysis of microcystic adnexal carcinoma (sclerosing sweat duct carcinoma) of the skin.
Am J Clin Oncol. 2010;33:125–7.
16. Baxi S, Deb S, Weedon D, et al. Microcystic adnexal carcinoma of the skin: the role of adju-
vant radiotherapy. J Med Imaging Radiat Oncol. 2010;54:477–82.
17. Dasgupta T, Wilson L, Yu J. A retrospective review of 134 cases of sebaceous carcinoma.
Cancer. 2009;115:158–65.
18. Erovic BM, Goldstein DP, Kim D, et al. Sebaceous gland carcinoma of the head and neck: the
Princess Margaret Hospital experience. Head Neck. 2013;35:316–20.
19. Miyamoto T, Haggari Y, Inoue S, et al. Axillary apocrine carcinoma with benign apocrine
tumours: a case report involving a pathological and immunohistochemical study and review of
the literature. J Clin Pathol. 2005;58:757–61.
20. Robson A, Lazar A, Nagi B, et al. Primary cutaneous apocrine carcinoma: a clinico-pathologic
analysis of 24 cases. Am J Surg Pathol. 2008;32:682–90.
21. Ming H, Jih M, Friedman P, et al. A rare case of fatal primary cutaneous mucinous carcinoma of
the scalp with multiple in-transit and pulmonary metastases. J Am Acad Dermatol.
2005;52:S76–80.
22. Naylor E, Sarkar P, Perlis C, et al. Primary cutaneous adenoid cystic carcinoma. J Am Acad
Dermatol. 2008;58:636–41.
23. Dores G, Huycke M, Devesa S, et al. Primary cutaneous adenoid cystic carcinoma in the
United States: incidence, survival, and associated cancers 1976 to 2005. J Am Acad Dermatol.
2010;63:71–8.
24. Robson A, Greene J, Ansari N, et al. Eccrine porocarcinoma (malignant eccrine poroma): a
clinic-pathologic study of 69 cases. Am J Surg Pathol. 2001;25:710–20.
25. Clinical Practice Guide: Basal cell carcinoma, squamous cell carcinoma (and related lesions)–a
guide to clinical management in Australia. Sydney: Cancer Council Australia and Australian
6 Merkel Cell Carcinoma, Adnexal Carcinoma and Basal Cell Carcinoma
malcolm_buchanan123@hotmail.com
82
Cancer Network; 2008. Available at:
http://www.cancer.org.au/content/pdf/HealthProfessionals/
ClinicalGuidelines/Basal_cell_carcinoma_Squamous_cell_carcinoma_Guide_Nov_2008-
Final_with_Corrigendums.pdf
26. Gulleth Y, Goldberg N, Silverman RP, et al. What is the best surgical margin for a basal cell
carcinoma: a meta-analysis of the literature. Plast Reconstr Surg. 2010;126:1222–31.
27. Mosterd K, Krekels G, Nieman F, et al. Surgical excision versus Mohs’ micrographic surgery
for primary and recurrent basal cell carcinoma of the face: a prospective randomised- controlled
trial with 5-years follow-up. Lancet Oncol. 2008;9:1149–56.
28. Beth-Hextall FJ, Perkins W, Bong J, et al. Interventions for basal cell carcinoma of the skin.
Cochrane Database Syst Rev. 2007;(1):CD003412.
29. Veness MJ. The important role of radiotherapy in patients with non-melanoma skin cancer and
other cutaneous entities. J Med Imaging Radiat Oncol. 2008;52:278–86.
30. Palmer VM, Wilson PR. Incompletely excised basal cell carcinoma: residual rates at Moh’s
surgery. Dermatol Surg. 2013;39:706–18.
31. Chan S, Dhadda AS, Swindell R. Single fraction radiotherapy for small superfi cial carcinoma
of the skin. Clin Oncol. 2007;19:256–9.
32. Geisse J, Caro I, Lindholm J, et al. Imiquimod 5 % cream for the treatment of superfi cial basal
cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad
Dermatol. 2004;50:722–33.
M. Veness and J. Howle
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© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_7
J. Wykes , BSci (Med), MBBS, FRACS (*) • N. Niles , BSc (Med), MBBS, FRACS
Head and Neck Surgery, Liverpool Hospital , Sydney , NSW , Australia
e-mail: wykesy@gmail.com; navinniles@me.com
J. Clark , MBBS, BSc, MBiostat, FRACS
Head and Neck Surgery, Sydney Head and Neck Cancer Institute, Royal Prince Alfred
Hospital , Sydney , NSW , Australia
e-mail: jcjc@tpg.com.au
7
The Role of Sentinel Lymph Node Biopsy
in Non-melanoma Skin Cancer
of the Head and Neck
James Wykes , Jonathan Clark , and Navin Niles
Non-melanoma skin cancer (NMSC) is the most common form of skin cancer and
often affects the frequently sun-exposed areas of the head and neck. In 2008, an
estimated 430,000 new cases were diagnosed in Australia [ 1 ]. Two-thirds of
Australians over the age of 70 years will develop a NMSC, most of which are basal
cell carcinomas (BCCs) that rarely metastasize to lymph nodes. The occurrence of
squamous cell carcinomas (SCCs) is approximately half that of BCCs but their
capacity for lymph node metastases is much greater [ 2 ]. Merkel cell carcinoma
(MCC) is a rare but aggressive cutaneous neuroendocrine tumour that has a high
propensity for regional and distant spread.
Cutaneous Squamous Cell Carcinoma
While the majority of cutaneous SCC (cSCC) of the head and neck can be con-
trolled with local ablation, <5 % of tumours will metastasize [ 3 ]. Metastatic cSCC
of the head and neck is potentially curable with more extensive surgery and postop-
erative radiotherapy; however, as many as 30 % of patients will die of their disease
[ 3 ]. Morbidity associated with these treatments is also signifi cant [ 4 ].
malcolm_buchanan123@hotmail.com
84
Several tumour and patient factors render a subset of patients at increased risk of
nodal metastases. These higher-risk patients who are node-negative have no consen-
sus therapeutic option other than observation. As in melanoma skin cancer [ 5 , 6 ]
and breast cancer [ 7 ], sentinel node biopsy (SNB) offers potential to identify occult
metastases, alter staging and management, and infl uence local control and overall
survival. In contrast to melanoma of the head and neck and mucosal SCC, the iden-
tifi cation of patients at risk of metastatic disease is more challenging, due to the
lower propensity of cSCC to metastasize [ 8 , 9 ] and the lack of a single risk factor
that stratifi es risk, such as Breslow thickness in melanoma [
5 ].
Much work has been done to identify those head and neck cSCC patients who
are at higher risk of nodal metastasis [ 4 , 10 ]. A number of risk factors associated
with a higher risk have been identifi ed: (i) macroscopic tumour features: e.g.
diameter of >2 cm, depth of >5 mm and location, particularly around the ear, lips
and nose; (ii) histopathological features: e.g. lymphovascular invasion, perineural
invasion and poorly differentiated tumours; and (iii) patient factors: e.g. immuno-
suppression and recurrence. Quantifying risk factors is diffi cult. While individual
studies show high metastastic risk rates for given risk factors (Table 7.1 ), prospec-
tive studies often fail to show a metastatic rate much greater than 10 % for patients
deemed to be high-risk [ 11 ].
Oddone et al. developed an ITEM score comprising Immunosuppression,
Treatment, Extranodal spread and Margin status [ 10 ]. This was shown to be a good
predictor of 5-year mortality. Patients were stratifi ed into high-risk (>3.0), moderate
risk (>2.6–3.0), and low-risk (<2.6) groups correlating with 5-year mortality of
56 %, 24 % and 6 %, respectively. Within the high-risk group the rate of lymph node
metastases approached 20 % [ 10 ]. However, this study looked at patients who had
established nodal metastases following treatment, and so cannot be employed in a
prospective way to calculate the risk of lymph node metastases.
In contrast to other body sites, lymphatic drainage of cSCC of the head and neck
is relatively unpredictable, due to multiple overlapping lymph node basins. One
constant fi nding is that intraparotid lymph nodes are a frequently involved site of
Table 7.1 Risk factors
associated with the
development of lymph node
metastasis in cSCC [
11 ]
Risk factor Metastatic rate
Size >2 cm 20–30 %
Invasion into subcutaneous fat (depth
≥5 mm)
16–45 %
Poorly differentiated/metatypical phenotype 12–32 %
Desmoplasia 12 %
Perineural invasion 40–47 %
Lymphovascular invasion 40 %
Site: ear or lip 10–30 %
Local recurrence 25–62 %
Squamous cell carcinoma in pre- existing
scar
38 %
Immunosuppression 13–20 %
J. Wykes et al.
malcolm_buchanan123@hotmail.com
85
metastasis. A review of 43 patients with metastatic NMSC of the head and neck
found the parotid gland was affected in 56 %, neck level II in 39 % and level V in
22 % [ 9 ]. The PN clinical staging system developed by O’Brien et al. [ 12 ] separated
and graded parotid and cervical metastases [ 11 ]. Application of this system suggests
that cervical disease confers a worse prognosis than parotid disease alone. In one
study a majority (67 %) had parotid disease alone, with the bulk of these patients
having early-stage disease (P1) [ 12 ]. Neck disease alone was found in 19 % patients,
with more than half of them having advanced metastatic disease. A total of 13 % had
clinical disease in both the parotid gland and the neck [
13 ]. Also, survival was sig-
nifi cantly worse for patients with advanced P stage—69 % 5-year survival com-
pared with 82 % for those with early P stage [ 13 ].
In contrast to SNB in melanoma of the head and neck [ 14 ] and to a lesser degree
SNB in oral cavity SCC [ 15 ], data on the accuracy of SNB and its impact on treat-
ment, local recurrence and survival are restricted to small series with a limited num-
ber of patients and a short follow-up. Several studies using SNB in cSCC of the
head and neck have been designed as feasibility studies. The results from most
studies are limiting, as they are based on small patient numbers and are heteroge-
neous in terms of pathology—i.e. by combining SCCs with Merkel cell tumours
and melanoma, and also site, with lesions on extremities often included. Because of
a lack of fi xed criteria to assess high-risk SCC, the tumour characteristics vary from
study to study. However, most authors cite a lesion size of >2 cm, depth and site as
important prognostic factors.
Existing Literature
In 2002, Altinyollar et al. published a series of 20 patients with SCC of the lower lip
who underwent SNB [ 16 ]. His group identifi ed a sentinel node in 18 patients (90 %),
3 of which were positive (16.6 %). Of these positive patients, two had no further
positive disease at neck dissection and the third patient had an additional 3 positive
nodes. Bilateral supraomohyoid neck dissections were performed for the remaining
patients with no positive nodes in a total of 440 nodes. No recurrence or survival
data were published [
16 ].
In 2003, Reschly et al. published a series of 9 patients with high-risk cSCC who
underwent SNB, of which 4 patients had primary lesions of the head and neck.
Sentinel nodes were isolated in all 4 patients, all of which were negative. The
patients remained disease-free at median follow-up of 13 months [ 17 ].
In 2003, Michl et al. sought to evaluate the feasibility of SNB in 37 patients with
NMSC, of which 13 patients had primary lesions of the head and neck. Two of these
patients had positive sentinel nodes, although their primary pathologies were lym-
phoma and MCC [ 18 ].
In 2004, Nouri et al. reported a series of 8 patients with cSCC of the head and
neck who underwent a SNB with one positive result. That patient went on to have
an ipsilateral neck dissection and adjuvant radiotherapy and was disease-free at 18
months [
19 ].
7 The Role of Sentinel Lymph Node Biopsy in Non-melanoma Skin Cancer
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86
In 2004, Wagner et al. published a series of 24 patients who underwent SNB for high-
risk NMSC across multiple body sites and involving merkel cell, squamous cell and
adenocarcinoma. Five patients had cSCC of the head and neck, with consistent drainage
to the parotid basin, of which 2 patients had positive sentinel nodes. These patients went
on to receive radiotherapy and were followed up for 7 and 44 months [ 20 ].
In 2008, Civantos et al. identifi ed 1 micro metastasis in 10 patients with high-risk
cSCC who underwent SNB as part of a larger review of 106 patients with cutaneous
and mucosal malignancy of the head and neck [ 20 ]. This paper also highlighted
some of the technical challenges of re-operating on a previously biopsied fi eld in the
setting of a positive SNB, as well as the challenge of removing multiple ‘hot’ senti-
nel nodes from different drainage basins [
15 , 21 ].
In 2007, Renzi et al. reported a case series of 22 patients who underwent SNB for
high-risk SCC, of which 15 lesions were on the face, none of which were positive.
The median follow-up for SNB-negative patients was 17 months, with one nodal
recurrence [ 22 ].
In 2010, Rastrelli et al. published a retrospective review of 20 patients with
high- risk non-anogenital SCC who underwent SNB, of which 11 patients had pri-
mary lesions of the head and neck. One patient had a positive SNB and went on to
receive a parotidectomy and ipsilateral neck dissection; however, only 10 nodes
were removed. This patient had regional disease at follow-up. Two of the 10
patients with negative SNB developed regional nodal recurrence and underwent
neck dissection. One died of disease after 17 months and the other was disease-free
at 30 months [ 23 ].
Pooled data across these studies reveal 73 patients with high-risk cSCC of the
head and neck who underwent SNB. One or more sentinel nodes were identifi ed in
71 patients (97 %). Seven patients (10 %) had positive sentinel nodes and their thera-
peutic management involved neck dissection, parotidectomy or radiotherapy. Three
Box 7.1 Cutaneous Squamous Cell Carcinoma (cSCC)
• cSCC of the head and neck spreads regionally in a small but signifi cant
percentage of patients. Regional spread is associated with a substantially
increased risk of morbidity and mortality.
• A combination of the following factors increases the risk of nodal metasta-
ses: Primary tumours >2 cm in diameter and/or >5 mm in thickness, recur-
rent tumours, tumours around the ears, lips and nose, and immunosuppressed
patients. Microscopic features that increase risk include lymphovascular
invasion, perineural invasion, and poorly differentiated tumours.
• Identifying occult nodal disease in these patients is challenging. SNB is a
well-tolerated procedure that can identify a draining lymph node consis-
tently; however, the rate of sentinel node positivity is low and it is not pos-
sible to make decisions regarding prognosis and treatment on the basis of
the current literature.
J. Wykes et al.
malcolm_buchanan123@hotmail.com
87
patients (4 %) had regional nodal recurrence after negative SNB, of which one died
of disease. Follow up of patients ranged from 7 to 24 months.
These pooled data are heterogeneous and, therefore, must be interpreted with cau-
tion (Box
7.1 ). Compared with melanoma or oral SCC, the rate of sentinel node posi-
tivity is low (10 % vs. 20 %) [
14 ]. Most series consistently were able to identify
sentinel nodes with minimal morbidity associated with their excision. Lymphatic
mapping appears to be predictable, with the parotid basin an important reservoir, as
is the case in melanoma [
24 ]. Management of positive and negative sentinel nodes
varied between trials from observation to irradiation of the nodal basin to lymphad-
enectomy, and the range for follow-up was wide.
As such, data are insuffi cient to clarify the staging or prognostic implications of
SNB in cSCC. However, the accuracy of sentinel node mapping and low morbidity
associated with the procedure provide hope that SNB may prove an important tool in
the management of patients with high-risk cSCC of the head and neck who are at
increased risk of metastatic disease.
Interim data from the SNIC trial, a prospective study aimed at determining the
rate of subclinical metastases from cSCC of the head and neck, are available which
helps to better identify which patients with cSCC are most at risk of lymph node
metastases [
24 ]. This showed a lymph node metastasis rate of 14 % in 57 high-risk
patients, and multivariate analysis revealed that the presence of multiple risk factors,
perineural invasion and lymphovascular invasion were signifi cant predictors of met-
astatic disease [
11 ].
Technique
The technique employed at our institution is similar to that of sentinel node biopsy
in melanoma. Sentinel node biopsy is typically performed concurrently with primary
tumour excision in patients identifi ed to have high-risk disease based on risk factors
enumerated earlier; however, a number of patients are either referred with a high-risk
tumour that has undergone excision already or are thought to be at increased risk
based on pathological fi ndings and thus have a delayed sentinel node biopsy
procedure.
Radiolabelled sulphur colloid dye is injected peri-tumourally as per local nuclear
medicine protocols. Intraoperatively, patent blue dye in injected intradermally at
four points around the edge of the scar or tumour.
Sentinel node incisions are planned based on sentinel node location and potential
further lymph node dissection and sentinel nodes are identifi ed via a combination of
visually identifi ed blue nodes and hand-held gamma probe fi ndings.
Sentinel nodes are examined using standard haematoxylin and eosin protocols
and cytokeratins for immunohistochemistry. Patients with positive sentinel nodes
are offered completion lymph node dissection.
The experience at our local institution is corroborated by the literature. SNB can
regularly identify a sentinel node; however, the overall rate of sentinel node
7 The Role of Sentinel Lymph Node Biopsy in Non-melanoma Skin Cancer
malcolm_buchanan123@hotmail.com
88
positivity is low. Two frequently encountered technical issues relating to SNB are
multiple sentinel node drainage sites (Fig. 7.1 ) and the operative approach to the
sentinel node region. Our group often elects to regionally clear the area of sentinel
node drainage to prevent potentially having to re-operate on a previously operated
fi eld (e.g. a selective level II neck dissection for a sentinel node localizing to level II
on imaging and gamma probe). This approach is an attempt to balance the risk of
over- treating against the increased risk of morbidity and diffi culty of re-operating
on a previously operated fi eld.
Basal Cell Carcinoma (BCC)
BCC has an extremely low metastatic potential, with one widely quoted study indi-
cating a metastatic risk of 0.03 % [ 25 ]. Patients with metastatic disease usually have
a poor prognosis [ 26 ]. Risk factors for metastatic BCC include large-diameter
Fig. 7.1 A right cervical cutaneous SCC showing lymphatic drainage to right level II and left level
IV sentinel nodes (Image provided by Professor Roger Uren, Alfred Nuclear Medicine and
Ultrasound, Sydney, NSW, Australia)
J. Wykes et al.
malcolm_buchanan123@hotmail.com
89
lesions of >3 cm, perineural or lymphovascular invasion, and invasion into deeper
structures [ 27 ]. Aggressive surgical therapy appears to offer the best chance of cure
for these patients. On account of the exceedingly low metastatic rate of BCC, the
utility of SNB is minimal (Box 7.2 ), and only a couple of case reports on SNB for
metastatic BCC are available [ 27 ], and none for BCC of the head and neck.
Furthermore, BCC metastasizes through haematogenous and lymphatic routes in
approximately equal proportions [ 28 ].
Therefore, the extremely low yield would suggest that SNB is an ineffi cient way
to assess for metastatic BCC, even in high-risk disease.
Merkel Cell Carcinoma (MCC)
MCC is a rare and aggressive neuroendocrine malignancy of the skin. Similar to
other cutaneous malignancies, it is frequently seen in sun-exposed areas and thus
has a propensity to affect the head and neck.
The hallmark of the disease is frequent metastases to draining lymph nodes,
which occur in 15–66 % of patients [ 29 ]. Most patients will develop regional or
distant metastatic disease over time [ 29 ], which makes SNB an ideal method for
assessing a clinically negative nodal basin for a given primary tumour.
SNB consistently detects occult metastatic disease in MCC, which occurs in
approximately 30 % of patients with MCC [ 29 , 30 ]. Lymphatic drainage patterns
are similar to those of other cutaneous malignancies, with parotid and cervical
lymph nodes frequently involved in cases of head and neck MCC. Positive SNB
upstages disease and leads to adjuvant treatment [
31 ]. However, a negative sentinel
node does not predict regional disease control consistently, with a number of studies
showing that a signifi cant percentage of patients with a negative sentinel node
develop regional disease (Box 7.3 ) [ 30 , 32 ].
While SNB assists in more accurate staging, it does not appear to confer a sur-
vival advantage [ 32 – 34 ]. One study suggested that the addition of adjuvant nodal
therapy after the discovery of a positive sentinel node provided a survival advan-
tage; however, a negative sentinel node result was not superior to observation of
nodal basins [ 30 ]. The discordance between the positive predictive nature of SNB in
MCC and its impact on survival is possibly explained by the overall aggressive
regional and distant spread patterns of the disease.
MCC has a high rate of local and distant spread, and SNB has a role in accurately
staging draining nodal basins; however, a negative SNB does not predict regional
control accurately, and offers no overall survival advantage.
Box 7.2 Basal Cell Carcinoma (BCC)
• BCC of the head and neck rarely metastasizes and SNB is of little use in
assessing the nodal basin.
7 The Role of Sentinel Lymph Node Biopsy in Non-melanoma Skin Cancer
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90
References
1. Cancer Australia and AIHW. Non-melanoma skin cancer: general practice consultations, hos-
pitalisation and mortality. Cat. no. CAN 39. Canberra: AIHW; 2008.
2. Buettner P, Raasch B. Incidence rates of skin cancer in townsville, Australia. Int J Cancer.
1998;78:587–93.
3. Joseph MG, Zulueta WP, Kennedy PJ. Squamous cell carcinoma of the skin of the trunk and
limbs: the incidence of metastases and their outcome. Aust N Z J Surg. 1992;62:697–701.
4. Veness MJ, Palme CE, Morgan GJ. High-risk cutaneous squamous cell carcinoma of the head
and neck: results from 266 treated patients with metastatic lymph node disease. Cancer.
2006;106:2389–96.
5. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in
melanoma. N Engl J Med. 2006;355:1307–17.
6. Valsecchi ME, Silbermins D, de Rosa N, et al. Lymphatic mapping and sentinel lymph node
biopsy in patients with melanoma: a meta-analysis. J Clin Oncol. 2011;29:1479–87.
7. Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with con-
ventional axillary-lymph-node dissection in clinically node-negative patients with breast can-
cer: overall survival fi ndings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol.
2010;11:927–33.
8. Kowalski LP, Sanabria A. Elective neck dissection in oral carcinoma: a critical review of the
evidence. Acta Otorhinolaryngol Ital. 2007;27:113–7.
9. Jol AD, van Velthuysen ML, Hilgers FJ, et al. Treatment results of regional metastasis from
cutaneous head and neck squamous cell carcinoma. Eur J Surg Oncol. 2003;29:81–6.
10. Oddone N, Morgan GJ, Palme CE, et al. Metastatic cutaneous squamous cell carcinoma of the
head and neck: the immunosuppression, treatment, extranodal spread, and margin status
(ITEM) prognostic score to predict outcome and the need to improve survival. Cancer.
2009;115:1883–91.
11. Gore SM, Shaw D, Martin RCW, et al. Prospective study of sentinel node biopsy for high risk
cutaneous squamous cell carcinoma of the head and neck. Head and Neck. 2015 [ahead of
print] doi:
10.1002/hed.24120
12. O’Brien CJ, McNeil EB, McMahon JD, et al. Signifi cance of clinical stage, extent of surgery,
and pathologic fi ndings in metastatic cutaneous squamous carcinoma of the parotid gland.
Head Neck. 2002;24:417–22.
13. Andruchow JL, Veness MJ, Morgan GJ, et al. Implications for clinical staging of metastatic
cutaneous squamous carcinoma of the head and neck based on a multicenter study of treatment
outcomes. Cancer. 2006;106:1078–83.
14. Erman AB, Collar RM, Griffi th KA, et al. Sentinel lymph node biopsy is accurate and prog-
nostic in head and neck melanoma. Cancer. 2012;118:1040–7.
15. Civantos FJ, Moffat FL, Goodwin WJ. Lymphatic mapping and sentinel lymphadenectomy for
106 head and neck lesions: contrasts between oral cavity and cutaneous malignancy.
Laryngoscope. 2006;112 Suppl 109:1–15.
Box 7.3 Merkel Cell Carcinoma (MCC)
• MCC has a high rate of local and distant spread, and SNB has a role in
accurately staging draining nodal basins; however, a negative SNB does
not predict regional control accurately, and offers no overall survival
advantage.
J. Wykes et al.
malcolm_buchanan123@hotmail.com
91
16. Altinyollar H, Berberoglu U, Celen O. Lymphatic mapping and sentinel lymph node biopsy in
squamous cell carcinoma of the lower lip. Eur J Surg Oncol. 2002;28:72–4.
17. Reschly MJ, Messina JL, Zaulyanov LL, et al. Utility of sentinel lymphadenectomy in the
management of patients with high-risk cutaneous squamous cell carcinoma. Dermatol Surg.
2003;29:135–40.
18. Michl C, Starz H, Bachter D. Sentinel lymphonodectomy in nonmelanoma skin malignancies.
Br J Dermatol. 2003;149:763–9.
19. Nouri KR, Pedroso F, Bhatia R, et al. Sentinel lymph node biopsy for high-risk cutaneous
squamous cell carcinoma of the head and neck. Arch Dermatol. 2004;140:1284.
20. Wagner JD, Evdokimow DZ, Weisberger E, et al. Sentinel node biopsy for high-risk nonmela-
noma cutaneous malignancy. Arch Dermatol. 2004;140:75–9.
21. Civantos Jr F, Zitsch R, Bared A, et al. Sentinel node biopsy for squamous cell carcinoma of
the head and neck. J Surg Oncol. 2008;97:683–90.
22. Renzi C, Caggiati A, Mannooranparampil TJ, et al. Sentinel lymph node biopsy for high risk
cutaneous squamous cell carcinoma: case series and review of the literature. Eur J Surg Oncol.
2007;33:364–9.
23. Rastrelli M, Soteldo J, Zonta M, et al. Sentinel node biopsy for high-risk cutaneous non-
anogenital squamous cell carcinoma: a preliminary result. Eur Surg Res. 2010;44:
204–8.
24. D’Souza J, Clark J. Management of the neck in metastatic cutaneous squamous cell carcinoma
of the head and neck. Curr Opin Otolaryngol Head Neck Surg. 2011;19:99–105.
25. Lo JS, Snow SN, Reizner GT, et al. Metastatic basal cell carcinoma: report of twelve cases
with a review of the literature. J Am Acad Dermatol. 1991;24:715–9.
26. Cracchiolo JR, Liu JC. Lymphadenectomy for anterior cutaneous malignancies of the head and
neck. Oper Tech Otolaryngol Head Neck Surg. 2013;24:19–23.
27. Harwood M, Wu H, Tanabe K, et al. Metastatic basal cell carcinoma diagnosed by sentinel
lymph node biopsy. J Am Acad Dermatol. 2005;53:475–8.
28. Ducic Y, Marra DE. Metastatic basal cell carcinoma. Am J Otolaryngol. 2011;32:455–8.
29. Eng TY, Boersma MG, Fuller CD, et al. A comprehensive review of the treatment of Merkel
cell carcinoma. Am J Clin Oncol. 2007;30:624–36.
30. Gupta SG, Wang LC, Peñas PF, et al. Sentinel lymph node biopsy for evaluation and treatment
of patients with Merkel cell carcinoma: the dana-farber experience and meta-analysis of the
literature. Arch Dermatol. 2006;142:685–90.
31. Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accu-
racy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the fi rst consensus staging
system. J Am Acad Dermatol. 2010;63:751–61.
32. Fields RC, Busam KJ, Chou JF, et al. Recurrence and survival in patients undergoing sentinel
lymph node biopsy for Merkel cell carcinoma: analysis of 153 patients from a single institu-
tion. Ann Surg Oncol. 2011;18:2529–37.
33. Maza S, Trefzer U, Hofmann M, et al. Impact of sentinel lymph node biopsy in patients with
Merkel cell carcinoma: results of a prospective study and review of the literature. Eur J Nucl
Med Mol Imaging. 2006;33:433–40.
34. Kouzmina M, Leikola J, Böhling T, et al. Positive sentinel lymph node biopsy predicts local
metastases during the course of disease in Merkel cell carcinoma. J Plast Surg Hand Surg.
2013;47:139–43.
7 The Role of Sentinel Lymph Node Biopsy in Non-melanoma Skin Cancer
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93
© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_8
C. Jameson , FRACS, PhD (*)
Head and Neck Surgery, Royal Prince Alfred Hospital and Westmead Hospital ,
Sydney , NSW , Australia
e-mail: cajameson@gmail.com
G. Morgan • M. Veness , MBBS, MMed, MD, MD, FRANZCR
Head and Neck Surgery, Westmead Hospital, University of Sydney , Sydney , NSW , Australia
e-mail: gary.morgan@health.nsw.gov.au
C. E. Palme , MBBS, FRACS
Otolaryngology Head and Neck Surgery , Royal Prince Alfred Hospital and Westmead
Hospital , Sydney , NSW , Australia
e-mail: carsten.palme@specialistservices.com.au
M. Veness , MBBS, MMed, MD, MD, FRANZCR
Radiation Oncology, Westmead Hospital, University of Sydney , Sydney , NSW , Australia
e-mail: Michael.Veness@health.nsw.gov.au
8
Metastatic Cutaneous Squamous Cell
Carcinoma of the Head and Neck
Carolyn Jameson , Gary Morgan , Carsten E. Palme ,
and Michael Veness
Epidemiology
Non-melanoma skin cancer (NMSC), comprising basal cell carcinoma (BCC) and
cutaneous squamous cell carcinoma (cSCC), is the most common malignancy world-
wide. The incidence of NMSC is increasing with 2–3 million new diagnoses per year
globally. Australia, with chronic high ultraviolet (UV) exposure, has the highest inci-
dence of NMSC in the world, with the majority of cSCCs (70–90 %) arising on the
sun-exposed skin of the head and neck (HN) in older Caucasian males [ 1 – 4 ].
Epidemiology of Primary and Metastatic Head and Neck
Cutaneous Squamous Cell Carcinoma (HNcSCC)
The second most common skin cancer worldwide, representing 25 % of all
NMSCs, is cSCC [ 5 ]. The annual incidence of cSCC is related directly to
malcolm_buchanan123@hotmail.com
94
equatorial proximity, and ranges from 16 cases per 100,000 people in central
Europe to 300 cases per 100,000 people in Australia. In northern Australia, the
annual incidence is an alarming 1300 cases per 100,000 males [ 6 , 7 ]. The inci-
dence of cSCC is increasing with increased sun exposure over decades through
atmospheric ozone depletion, changes in style of clothing and increased lifespan.
In addition, there is an increasingly larger cohort of patients who are immunosup-
pressed through solid-organ transplant schemes.
In a German study of 615 patients with primary HNcSCC, 63 % of patients were
male with a median age 73 years [ 8 ]. In an Australian study of 282 patients with
metastatic cSCC, treated by the Sydney Head and Neck Cancer Institute (SHNCI),
87 % were male with a median age 72 years (range 37–98 years) [ 4 ].
Currently, the majority of primary cSCC is treated by primary healthcare profes-
sionals and dermatologists. Despite the excellent prognosis with local treatment and
cure rates exceeding 95 %, the median delay in diagnosis is reported to be 3 years,
leading to a number of patients presenting with locally advanced disease and not
infrequently, with regional metastases (Fig.
8.1 ) [ 9 ]. Patients who have been diag-
nosed with cSCC have an 18 % increased risk of developing a subsequent cSCC
compared with the general population [ 10 ].
Theoretically, all patients with primary HNcSCC are at risk of developing metas-
tases and patients with regional metastases are at the highest risk of poor outcome.
Nodal metastases occur in 2–5 % of patients [ 8 , 11 ]. However, patients with high-
risk cSCC have a >20 % risk of developing metastatic disease [ 12 , 13 ]. Most present
with chronically sun-damaged skin and invariably have had numerous cSCC
Fig. 8.1 An Australian man with a very late presentation of facial cSCC. This patient presented
via emergency with a large bleeding, necrotic mass, lethargy, shortness of breath and haemoglobin
of 54 g/L. He required immediate blood transfusion and the mass was amputated at its base under
general anaesthesia. Histopathology revealed a moderately differentiated cSCC without perineural
invasion. Depth of dermal invasion was 19 mm. One month later, wide excision with a 1 cm clini-
cal margin was performed with primary closure of the defect
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previously excised from the HN region. In almost one quarter of patients the site of
the primary index lesion is unidentifi able [ 4 , 14 ].
It is important to be aware of the potential for development of metastatic nodal
cSCC. The median time from excision of a primary HNcSCC to presentation of
metastatic disease is approximately 12 months (range 8.5–13 months) [ 4 , 8 , 14 – 16 ].
Fifty to sixty percent of patients who present with nodal metastases do so after treat-
ment of primary HNcSCC [ 16 , 17 ]. Failure to detect and adequately treat both pri-
mary and regional disease is associated with a signifi cant risk of death.
Quality of Life
Primary and metastatic cSCC can have a substantial impact on quality of life,
through multimodality treatment. Morbidity associated with metastatic cSCC is
considerable, with most lesions requiring major surgery and adjuvant radiotherapy.
Despite appropriate treatment, a small number of patients will die as a consequence
of metastatic disease to regional lymph nodes [ 18 , 19 ].
Few patients develop distant metastatic disease. Lung and bone are reported to
be the most common sites of distant disease [ 14 , 19 ]. In a study of 122 patients
treated for metastatic cSCC, 7 % developed distant metastatic disease, with lung the
most common site [ 14 ].
Risk Factors
There are a number of factors which, in combination, increase the risk of developing
metastases. Newer staging systems consider clinicopathological risk factors,
described in the National Comprehensive Cancer Network (NCCN) guidelines and
Multi-Professional Guidelines for the British Association of Dermatologists [ 12 ,
20 , 21 ]. These newer staging systems allow better prognostication and include (1)
location of the primary tumour, (2) diameter ≥2 cm, (3) thickness ≥2 mm/Clark
level IV or V, (4) penetration into the subcutaneous tissue, (5) moderate or poor dif-
ferentiation, (6) desmoplastic, adenoid and adenosquamous subtypes, (7) perineural
invasion (PNI), (8) lymphovascular invasion (LVI), and (9) tumour recurrence.
Patient factors include immunosuppression and older age.
Using the following histopathological risk factors—poor histological differentiation,
PNI, LVI, diameter ≥20 mm and tumour thickness >4 mm, or Clark level V with pene-
tration into the subcutaneous tissue—Peat et al. reported signifi cant differences in the
metastatic potential of primary cSCC [ 15 ]. High-risk cSCC had a predicted incidence of
37 % for developing nodal metastases compared with 0.3 % in low-risk cSCC [ 15 ].
Tumour Location
Generally, cSCC located on thin skin with a rich vasculature or lymphatic network,
or in close proximity to the parotid, have a higher metastatic potential. The most
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common primary tumour sites leading to parotid and/ or neck metastases, in
descending order of frequency, are unknown primary, lip, cheek, ear, temple, fore-
head, scalp and nose [ 14 , 22 , 23 ]. The most common primary sites leading to parotid
metastases are pre-auricular and cheek.
Tumour Size
Evidence shows cSCC >20 mm has a greater propensity to metastasize than a
smaller lesion. In a New Zealand study of 170 patients, 46 % of patients developed
metastatic cSCC. In that study, a hazard ratio (HR) of 3.10 was reported for devel-
oping metastatic disease when tumour diameter was ≥20 mm [ 15 ]. In a large review
of skin and lip SCC, the rate of metastatic disease in lesions <20 mm was 9 % com-
pared with 30 % in lesions >20 mm [ 24 ]. Interestingly, in a prospective cohort study
of 612 patients, no metastatic disease was reported in cSCC <10 mm [ 8 ].
Although increasing tumour size contributes to metastatic potential, it does not
explain the full extent of risk, and other factors need to be considered.
Tumour Thickness and Depth of Invasion
Tumour thickness and depth of invasion are important predictors of metastatic
potential. It is well documented that tumours >4 mm have an increased risk of
metastasis [ 25 – 28 ]. An early report by Breuninger et al. identifi ed no metastases
from lesions <2 mm thick and stated that when depth of invasion did not extend
beyond the subcutis, a cSCC could be classifi ed as low-risk [ 29 ].
In a recent study of 615 patients, who were reviewed at least once after treatment
for primary cSCC and contacted by mail for up to 10 years, no patient developed
metastatic disease when the primary cSCC was <2 mm thick [ 8 ]. In contrast, 4 % of
patients with tumour thickness 2.1–6.0 mm and 16 % of patients with tumour thick-
ness >6.0 mm developed metastatic disease [
8 ].
A recent study compared 78 patients with metastatic cSCC with 92 patients who
had no metastatic disease within 5 years of primary cSCC treatment [ 15 ]. A HR of
2.33 was reported for developing metastases when primary cSCC was present in
subcutaneous tissue (Clark level V) [ 15 ].
Tumour Grade
Poorly differentiated cSCC is associated with a higher rate of regional metastases. Risk
of metastatic disease was reported as 17 % in high-grade tumours compared with 5 %
for other grades (p < 0.01) [ 29 ]. A HR of 5.63 for poorly differentiated cSCC was
reported in a study of 170 patients, which compared patients with metastatic cSCC
with those who did not develop metastatic disease [
15 ]. In a review of primary cSCC,
63 % of 95 patients with metastatic cSCC were assigned a moderate or poorly differ-
entiated tumour grade, with tumour grade unreported in 14 % of 122 patients [ 14 ].
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Desmoplasia
Desmoplastic cSCC is an aggressive variant, most frequently found on the ears,
nose and forehead. It is characterized by the presence of PNI, an invasive clinical
course and poor prognosis [ 30 ]. Patients with desmoplastic cSCC have 10 times the
risk of local recurrence and six times the risk of metastasis compared with other
cSCC subtypes [ 31 ].
Brantsch et al. reported desmoplasia to be the most important histological feature
for local recurrence, with 24 % of 51 patients with desmoplasia versus 1 % of 564
patients without desmoplasia developing local recurrence [ 8 ].
Perineural Invasion (PNI)
When tumour cells gain access to the perineural space they have the potential to spread
both antegrade and retrograde along the nerve. The most common nerves associated
with PNI in the HN region are the facial (CN VII) and trigeminal (CN V) nerves. PNI
can be diagnosed clinically, radiologically or pathologically. It is a risk factor for later
metastatic disease and overall poor survival, associated with retrograde spread to the
brainstem. The rate of PNI in cSCC ranges between 2.5 and 14 % [ 32 , 33 ].
A New Zealand publication examined PNI in primary cSCC and identifi ed 32 %
of primary cSCC with PNI in patients who later developed metastatic disease, com-
pared with PNI in <1 % who did not develop metastatic disease [ 15 ].
Tumour involvement of large calibre nerves appears to be a worse prognostic
factor than involvement of small calibre nerves. In a study of 48 patients, tumour
involvement of nerves with a diameter ≥0.1 mm was associated with signifi cantly
worse outcomes with respect to nodal metastases, distant metastases and disease-
specifi c death. In contrast, patients with PNI associated with nerves <0.1 mm diam-
eter had a disease-specifi c death of 0 % [ 34 ].
The Queensland Perineural Invasion Group at the Dermatology Research Centre,
University of Queensland, Australia, has established a PNI data registry to prospec-
tively study the association between patient outcome and PNI [
35 ]. Factors include
(1) degree of nerve involvement within the tumour, (2) number of nerves involved,
(3) nerve involvement with respect to surgical and tumour margins, (4) nerve size
and type, and (5) tumour size. The group aims to identify and defi ne best practice in
managing PNI and to elucidate underlying causes and mechanisms [ 35 ].
Lymphovascular Invasion (LVI)
LVI is a risk factor for metastatic disease. It denotes invasion of tumour cells into
the microvasculature of the dermis and lodgement within a vessel lumen. A New
Zealand study reported an HR of 4.53 for metastatic disease in the presence of
LVI. Ten of 78 patients with metastatic disease had LVI identifi ed in the primary
lesion. Interestingly, no LVI was identifi ed in any primary lesion in 92 patients
without metastatic disease [ 15 ].
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In a large study of 6164 patients treated for cSCC, a subset of 4740 patients was
treated for HNcSCC. Multivariate analysis of this subset group identifi ed LVI as a signifi -
cant risk factor for metastatic disease in patients with a lesion in the cheek or peri- auricular
region (HR 3.18 and HR 3.31, respectively), but not at other sites of the HN [ 36 ].
Recurrent cSCC
Recurrent cSCC is associated with increasing primary tumour size and invasion and
a signifi cantly higher incidence of nodal metastases compared with a non-recurrent
cSCC. Patients with inadequately excised lesions are at risk of both recurrence and
subsequent nodal metastases [ 37 ]. A literature review reported nodal disease in
32 % and 45 % of recurrent lip SCC and ear cSCC, respectively [ 24 ].
In one study, 18 % of 78 patients had metastatic disease following tumour recur-
rence [ 15 ]. In a review of 122 patients with metastatic cSCC, 11 % of patients had
lesions that were recurrent [ 14 ].
Excision Margins
Excision margins that are positive with tumour are associated with recurrent cSCC
in up to 50 % of patients [ 37 ]. An excision margin of 6 mm in patients with high-risk
cSCC is recommended. In two studies, an excision margin of 4–5 mm for low-risk
cSCC resulted in tumour clearance in 95–97 % of cases compared with 78 % clear-
ance when a 2 mm excision margin was applied [ 38 , 39 ].
The long-term prognostic benefi t of negative margins is highlighted by the results
of Mohs micrographic surgery. Mohs surgery involves tumour excision, horizontal
sectioning and examination of the entire margin intraoperatively. Rowe et al.
reported 5-year disease-free survival (DFS) for lip and ear primary cSCC treated
with Mohs surgery as 97.7 % and 94.7 %, respectively [
24 ]. In a multicentre
Australian study with 1263 patients, 5-year DFS was reported as 97.4 % with >95 %
of lesions located on the HN [ 40 ].
The practice of observation and expectant treatment in inadequately excised
HNcSCC should be discouraged with current knowledge of the increased risk of
metastases in the setting of recurrent cSCC. Re-excision or adjuvant local radio-
therapy should be considered in select patients; for example, to achieve optimal
excision margins, superfi cial parotidectomy should be considered in treatment of
deeply invasive cSCC (Fig. 8.2 ).
Assessment of Lymph Nodes
In contrast to the improved DFS after nodal assessment and treatment of mucosal
squamous cell carcinoma (mSCC) of the oral cavity and oropharynx, opinion is
divided on elective nodal assessment of HNcSCC [
41 ].
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Elective nodal treatment is not undertaken routinely, as compelling evidence of
benefi t is lacking.
Sentinel lymph nodes (SLNs) are the fi rst echelon nodes to receive lymphatic
fl uid from a site of primary malignancy. Sentinel lymph node biopsy (SLNB) was
fi rst developed in the late 1970s and has been used successfully as an accurate and
reproducible technique in detecting early metastatic disease in cutaneous malignan-
cies, including melanoma and Merkel cell carcinoma [
42 – 44 ]. Subsequent early
intervention in melanoma in the presence of a positive SLN improves patient out-
come and has cost–benefi t advantages in terms of earlier detection and treatment of
clinically negative but pathologically positive regional lymph nodes [ 45 ]. SLNB
involves preoperative lymphoscintigraphy with a radioisotope tracer plus intraop-
erative peritumoural dermal infi ltration with Patent Blue V dye. A SLN is identifi ed
intraoperatively with a hand-held gamma probe and the presence of blue dye stain-
ing (Fig. 8.3a, b ). The recent addition of preoperative hybrid imaging with single-
photon emission computed tomography with CT (SPECT/CT) provides enhanced
resolution of areas of increased radiotracer activity that correspond to the
SLN. SPECT/CT has provided signifi cant improvement in the anatomical localiza-
tion of SLN, particularly in the HN region [
46 ].
Data on SLNB for HNcSCC are sparse. Most studies are limited by having a
small number of patients and varying defi nitions for a high-risk lesion. The NCCN
guidelines recommend consideration of SLNB in high-risk lesions, but acknowl-
edge that the benefi t in cSCC remains to be proven [ 21 ].
Fig. 8.2 Deeply invasive
2 cm primary cSCC overlying
the left parotid. There was
no clinical or radiological
evidence of CN VII
involvement. Surgical
management involved
excision with a 1 cm margin
plus superfi cial
parotidectomy with
preservation of CN
VII. Selective neck dissection
of levels II and III lymph
nodes was performed for
pathological staging
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Civantos et al. reported the results of SLNB in 60 patients with HN cutane-
ous cancer, which included 15 patients with HNcSCC that met at least two
high-risk features [ 47 ]. One patient with HNcSCC had a positive SLN and was
treated with completion nodal dissection of the neck. These data, however, are
confounded by 12.7 % of patients with pathologically negative SLNs having a
completion neck dissection on the basis of intraoperative suspicion of metasta-
ses. Interestingly, no patient had metastases on histological examination and
none of the 15 patients had recurrent disease within the median follow-up
period of 21 months [
47 ].
In a study of 20 patients with lower lip SCCs >2 cm in size, 90 % of SLNs were
identifi ed. Metastases were found in 16.6 % with no false-positive results [ 48 ]. A
literature review of high-risk cSCC involving all skin sites reported 130 patients
with SLNB from 11 case series and 4 case reports [ 49 ]. A SLN was identifi ed in
98.5 % of cases. The positivity rate ranged between 10 and 18 %. In 51 patients with
HNcSCC with a negative SLN, none developed regional recurrent nodal disease
[ 49 ]. These data suggest that SLNB may play a future role in a high-risk subset of
HNcSCC.
Currently, a 30-patient, non-randomized, 5-year follow-up study is under
way at SHNCI [ 50 ]. This pilot study will assess the feasibility of SLNB for
patients with high-risk clinicopathological features of cSCC. The aim of the
study is to compare survival in patients who undergo SLNB followed by com-
pletion lymph node dissection when SLNB is positive for metastatic cSCC,
with patients who have ultrasound (US) observation of the regional lymphatic
basin without SLNB [ 50 ].
ab
Fig. 8.3 ( a , b ) Technique for SLNB of cSCC of the scalp. Lymphoscintigraphy was performed:
( a ) 2 cm surgical margin marked and Patent Blue V injected intradermally for SLN identifi cation
and harvest; ( b ) post-auricular SLN. Blue dye staining is visible on the SLN. The SLN was
removed for histopathological assessment
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Immunosuppression
Solid-organ transplant recipients and other immunosuppressed patients tend to develop
aggressive malignancies at a younger age and with poorer prognosis than their immu-
nocompetent counterparts. The incidence of cancer is increasing in the transplant recip-
ient population, with skin cancer the most prevalent malignancy in renal transplant
recipients. With recent advances in transplant surgery and medicine, cancer has now
become a leading cause of late mortality in renal transplant patients [ 51 ].
Immunosuppressed patients have 18–250 times higher risk of developing skin
cancer than age-matched controls [ 52 – 54 ]. They are more likely to develop recur-
rent lesions and metastatic disease can occur with smaller, thinner primary lesions
[ 55 , 56 ]. The cumulative incidence of developing skin cancers increases from 7 %
after the fi rst year of immunosuppressive therapy to 70 % after 20 years [ 57 ].
Furthermore, in contrast to immunocompetent patients, in whom BCCs are four
times more common than cSCC, this trend is reversed in immunocompromised
patients, with cSCC fi ve times more prevalent than BCC [ 58 ].
Solid-organ transplant recipients constitute the majority of immuno-suppressed
patients with metastatic HNcSCC. However, patients with leukaemia, lymphoma or
human immunodefi ency virus are also at increased risk. In a review of 122 patients,
7 % of patients with metastatic HNcSCC were immunosuppressed as a consequence
of transplantation or haematological disease [ 14 ]. In another study, 22 % of 51
patients with metastatic HNcSCC were immunosuppressed; 5 patients with a solid-
organ transplant and 6 patients with leukaemia or lymphoma [ 17 ].
Adjuvant Radiotherapy for Primary cSCC
Adjuvant radiotherapy reduces the risk of local and regional recurrence and may be
considered in high-risk patients treated for primary cSCC with close or positive
surgical excision margins (Box
8.1 ) [ 59 ]. A lack of high quality prospective data
has led to varied approaches by clinicians in utilizing adjuvant radiotherapy. The
majority of outcome data are based on retrospective institutional case series or
systematic reviews, which include BCC with PNI and cSCC, and are subject to
treatment bias [ 60 , 61 ].
Extensive PNI of multiple small nerves is an indication in the NCCN guidelines
for recommending adjuvant radiotherapy, particularly if the primary is recurrent,
has a mid-face location, or is in proximity to CN V or CN VII [ 21 , 62 ]. Interestingly,
despite guidelines, variability exists in use of adjuvant radiotherapy in the presence
of PNI. A lack of consensus was identifi ed in scenarios when an unnamed nerve was
involved with tumour, with Mohs surgeons less likely to refer for consideration of
adjuvant radiotherapy [ 63 ].
In an Australian study, in which 21 patients with clinical PNI were treated surgi-
cally, all but one patient received adjuvant radiotherapy either as a component of
prior treatment and/or as part of defi nitive treatment. Five-year disease-specifi c sur-
vival (DSS) in that study was 64 % [ 64 ].
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Follow-Up of Primary cSCC with High-Risk Features
As nodal metastasis is the most important prognosticator in HN cancer, accurate
staging and surveillance is important. High-risk patients should be reviewed every
3–4 months for 4–5 years following treatment, particularly patients who are immu-
nosuppressed and those with features of high-risk tumours. In the absence of clini-
cally metastatic disease, imaging is not warranted as a routine investigation. In
contrast, patients with clinically evident metastatic cSCC should undergo relevant
imaging, the choice of which is dependent on clinician preference, availability of
imaging modality, and patient-specifi c factors. Imaging options include US, CT,
MRI and PET/CT.
The highly sensitive and specifi c nature of US, combined with low cost, low
morbidity, availability and ability to guide biopsies, warrants considering its routine
use in screening for regional nodal metastases in HNcSCC during follow-up. In a
study of 42 patients, sensitivity and specifi city of US in predicting malignancy in
the HN region was 96.8 % and 93.3 %, respectively [ 65 ]. The low incidence and
incurable nature of distant disease does not justify screening asymptomatic patients
for distant metastases.
Lymph Node Site
Regional nodes can be separated broadly into two groups, viz. parotid (pre-auricular
and parotid tail) and cervical nodes (levels I–V). The location of a primary index
cSCC is an important determinant of the site of nodal metastasis. The most frequent
location for an index lesion is the lateral aspect of the head and metastatic disease is
most commonly identifi ed in parotid, level II cervical and external jugular nodes.
Parotid nodes represent the fi rst echelon of lymphatic drainage from the face, fore-
head, anterior scalp, temple and ear, and in Australia and New Zealand, metastatic
Box 8.1 Risk Factors for Developing Metastatic Nodal cSCC
• Location of primary tumour
• Tumour diameter ≥2 cm
• Tumour thickness ≥6 mm or penetration into subcutaneous tissue
• Moderate or poor tumour differentiation
• Desmoplastic, adenoid and adenosquamous tumour subtype
• Perineural invasion
• Lymphovascular invasion
• Tumour recurrence
• Positive/close excision margin
• Immunosuppression
• Older age
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cSCC is the most common malignant neoplasm of the parotid (Fig. 8.4 ) [ 66 ]. Facial
lesions tend to metastasize to level I and II cervical nodes, whereas anterior lesions of
the scalp, ear, temple and forehead usually metastasize to parotid ± level II cervical
lymph nodes [ 4 ]. Drainage to multiple SLNs is common. Drainage to contralateral
nodes occurs in 10 % of patients, predominantly in those with midline lesions [ 67 ].
Lymph Node Size and Number
The size and number of metastatic lymph nodes in HNcSCC varies considerably. In
a study of 603 patients in Sydney, the median size of the largest metastatic node was
25 mm (range 3–100 mm) [ 68 ]. In the same study, the median number of metastatic
nodes was 1 (range 1–67 nodes) [ 68 ].
Fig. 8.4 An elderly man with
metastatic cSCC to the
parotid. Treatment included
wide excision, parotidectomy,
free-fl ap reconstruction and
adjuvant radiotherapy
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Extranodal Spread and Soft Tissue Metastases
High rates of extranodal spread (ENS) and soft tissue metastases (STM) are features
of metastatic cSCC. The presence of ENS and STM have a negative impact on prog-
nosis because of their association with regional failure and distant metastases.
ENS predicts a poor outcome [ 19 , 68 ]. Oddone et al. documented that ENS is
associated with reduced overall survival (OS) with an HR 9.92 [ 16 ]. A review of
clinicopathological data from SHNCI and Westmead Hospital patients with
HNcSCC lymph node metastases revealed that 58 % of 215 patients and 82 % of
250 patients, respectively, had ENS [ 69 ].
STMs are defi ned as free soft tissue tumour deposits lacking continuity with the
primary tumour and without discernible lymph node tissue [ 69 ]. STMs possibly
represent nodes that are completely replaced by tumour, with no remaining evi-
dence of the pre-existing node. On reviewing pathology slides of 164 patients,
44.5 % were shown to have STMs, accounting for worse DFS and OS (HR 2.35 and
2.91, respectively) [ 69 ]. Since the adverse effect on survival from STM is compa-
rable to that of multiple nodal metastases, adjuvant radiotherapy should be consid-
ered for all patients, even when only a single, small STM deposit is identifi ed.
Staging Systems
In 2002, a revised clinical staging system was proposed to defi ne the extent of meta-
static HNcSCC to the parotid and/or neck [ 70 ]. At the time, the prognostic capacity
of the TNM classifi cation was limited in that it described only N0 and N1 to identify
the absence or presence of neck disease, respectively. Involvement of parotid gland
lymph nodes and CN VII with metastatic tumour was excluded. The proposed
O’Brien staging system stratifi ed size and number of involved lymph nodes within
the parotid and neck, and incorporated metastatic cSCC of the parotid, facial nerve,
skull base and contralateral neck [
70 ].
A retrospective, multicentre trial of the new staging system reviewed data
from 322 patients with metastatic HNcSCC across six centres in Australia and
the USA [ 71 ]. Overall, DSS was 74 %. Patients with metastatic cSCC in both the
parotid and neck had a signifi cantly worse DSS of 61 % compared with 79 % for
patients with only parotid metastases (p = 0.027). In addition, patients with
advanced parotid disease had a DSS of 69 % compared with 82 % for patients
with P1 disease (p = 0.02) [ 71 ]. The O’Brien staging system proved to be a supe-
rior staging system in terms of stratifi cation and prognostication of patients with
metastatic HNcSCC.
In 2010, Forest et al. proposed a relatively simple staging system entitled N1S3
[ 68 ]. N1S3 stratifi ed patients into three stages according to the number and size of
involved nodes and incorporated parotid nodes as one of the regional nodal levels.
The N1S3 staging system is as follows: stage I represents a single lymph node
<3 cm; stage II represents a single lymph node >3 cm or multiple nodes <3 cm; and
stage III represents multiple nodes >3 cm. Patients with ENS are excluded. In a
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105
review of 215 patients, the N1S3 staging system was predictive of locoregional
control (p < 0.001), DSS (p < 0.0001) and OS (p < 0.0001) [ 68 ].
The 7th edition of the American Joint Commission of Cancer ( AJCC ) Staging
Manual incorporates results from previous publications and has introduced further
changes to the staging of HNcSCC [ 72 ]. To improve patient stratifi cation, classifi ca-
tion of lymph node metastases was adjusted from the two-tiered N0/N1 system in
the 6th edition to the well established N0, N1, N2, N3 system that is used for muco-
sal HN cancer. In the current edition, N1 represents a single involved lymph node
≤3 cm; N2 represents ≥1 involved lymph node 3–6 cm; N3 represents ≥1 involved
lymph node ≥6 cm [
72 ].
The 7th AJCC staging system has not yet been evaluated extensively. In 2012,
Brunner et al. published a retrospective multicentre analysis of 603 patients with
metastatic HNcSCC that compared survival data for AJCC stage IV disease—
regional N2 or N3 disease versus distant metastases [ 73 ]. Survival was signifi cantly
better in N2 and N3 disease, with 5-year survival 75 % (312 patients) and 65 % (37
patients) respectively, compared with 11 % (35 patients) of patients with distant
metastatic disease. Brunner concluded that stage IV disease, based on the 7th edi-
tion of the AJCC TNM staging system, was heterogeneous, with signifi cant varia-
tion in DSS and OS and would hence benefi t from further revision [ 73 ].
Treatment
To improve locoregional control and OS, optimal treatment for metastatic HNcSCC
involves a multimodality approach with surgery followed by adjuvant radiotherapy
[ 4 , 74 ]. As patients are often older and treatment for metastatic cSCC is associated
with morbidity, opinions vary regarding the extent of each treatment modality. The
most common concerns of patients after treatment for metastatic HNcSCC include
the following: alteration to physical appearance, xerostomia, and change in voice
quality and strength [
14 ]. In addition, a subset of patients have co-morbidities,
which may limit optimal treatment.
Surgery
For patients with metastatic cSCC to cervical lymph nodes, surgery has traditionally
involved a modifi ed radical neck dissection. A trend has been initiated towards
selective neck dissection in patients with a low burden of metastatic disease (N1 and
N2) with HNmSCC, with the aim of reducing surgical morbidity [ 75 – 79 ]. A recent
Australian study of patients with HNcSCC reported no statistically signifi cant dif-
ference in 5-year OS (61 % vs. 57 %) or 5-year DFS (74 % vs. 60 %) for selective
neck dissection or radical neck dissection, respectively [ 80 ].
Recent data have simplifi ed the relationship between the site of the primary
cSCC and nodal disease, allowing more selective treatment of the neck, both surgi-
cally and with adjuvant radiotherapy [
4 ]. However, almost one quarter of patients
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106
have metastatic HNcSCC with an unknown site of the primary index lesion (Fig. 8.5 )
[ 4 , 14 ]. One study of patients with an anterior facial cSCC, identifi ed metastases to
level I nodes in 17.9 %, whereas only 5.4 % of patients were identifi ed with meta-
static cSCC in level V lymph nodes [ 4 ]. When no metastases were identifi ed in level
II lymph nodes, only 6 % of patients with an anterior facial primary cSCC had meta-
static cSCC in level I [ 4 ]. Involvement of level II lymph nodes is, therefore, a pre-
dictor of metastatic disease in level I cervical nodes.
Furthermore, patients with metastases in levels II/III were signifi cantly more
likely to have metastatic disease in levels IV/V than patients without levels II/III
lymph node involvement (33.3 % vs. 6.7 %, respectively; p < 0.001) [
4 ]. Examination
of primary site subgroups of patients reported 15.8 % of posterior facial primary,
2.7 % of anterior facial and 0 % of external ear cSCC, without level II/III metastases
had levels IV/V lymph node involvement [ 4 ].
Parotid Metastases
Parotid nodes are the most frequent site for metastatic disease from a primary
HNcSCC. Metastases travel via a rich lymphatic network from the primary site to
15–20 superfi cial periparotid lymph nodes and 4–5 lymph nodes within the deep
parotid lobe. Involvement of parotid lymph nodes has implications with respect to
prognosis and management. All patients with metastatic cSCC to the parotid region
and a clinically node-negative neck should undergo parotidectomy and ipsilateral
selective neck dissection [ 3 , 4 , 81 ].
Fig. 8.5 A typical elderly
Australian man with
chronically sun-damaged skin
who presented with left level
II cervical lymphadenopathy.
He had previously received
treatment for multiple
HNcSCC. This case
highlights the diffi culty in
identifying the primary lesion
responsible for metastatic
nodal cSCC
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Parotidectomy usually involves superfi cial lobectomy with preservation of CN
VII. Less commonly, an extended parotidectomy is required, with sacrifi ce of either
the main trunk or at least one of the main branches of CN VII. If CN VII is sacrifi ced,
facial reanimation is recommended either immediately or as a delayed procedure. As
resection rarely achieves margins >5 mm, CN VII should be sacrifi ced only in the
presence of preoperative facial nerve palsy. Consideration should be given preopera-
tively to both the extent of resection of involved skin overlying the parotid and recon-
structive options, including local and free-fl ap reconstruction. Adjuvant radiotherapy
should be recommended routinely to treat residual microscopic disease.
Iyer et al. examined outcomes for patients with involved margins, in whom meta-
static tumour had been dissected from CN VII [
82 ]. Data for 15 patients treated with
nerve-sparing surgery plus adjuvant radiotherapy from a database of 176 patients
were analysed. Two patients had residual CN VII palsy despite nerve-sparing sur-
gery. Three patients developed recurrent disease in the parotid bed, which was sal-
vaged successfully with radical surgery and nerve sacrifi ce [ 82 ]. Iyer concluded that
10 of 15 patients had normal CN VII function post-treatment with no difference in
DSS when compared with patients who had clear or close margins [ 82 ]. Therefore,
patients without macroscopic involvement of CN VII, but with close margins, can
still undergo nerve-sparing surgery provided adjuvant radiotherapy is delivered.
Ebrahimi et al. reported 21 % of patients who underwent parotidectomy and
elective neck dissection for a clinically N0 neck had pathologically proven meta-
static disease in cervical lymph nodes [ 4 ]. Importantly, in the same study, patients
with metastatic cSCC to the parotid region and a clinically N0 neck, had no metas-
tases in levels IV/V in the absence of pathological metastatic disease in levels II/
III. Therefore, selective neck dissection of cervical lymph node levels II and III is
recommended for patients undergoing parotidectomy for metastatic cSCC.
Complications of Surgery
Complications of surgery include permanent nerve injury, most commonly caused
by intentional nerve sacrifi ce as a consequence of proximity of a nerve to tumour,
temporary neuropraxia, wound infection, haematoma, chyle leak, pneumonia and
myocardial infarction.
Clinical signs and symptoms of accessory nerve dysfunction are subtle and gen-
erally missed in the immediate postoperative period, and are thus underreported.
Previous studies describe shoulder dysfunction in 30 % of patients treated with level
V lymph node dissection with consequent deleterious effects on activities of daily
living and quality of life [ 83 , 84 ].
Adjuvant Radiotherapy
Current best practice for most patients with operable metastatic nodal cSCC is surgery
plus adjuvant radiotherapy. In a study of 74 Australian patients with metastatic cSCC
8 Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck
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108
to cervical nodes, those treated with surgery and adjuvant radiotherapy had a lower
recurrence rate (15 % vs. 77 %) and better 3-year DFS (70 % vs. 45 %) compared with
patients treated with surgery alone [ 85 ]. More recently, a review of 122 Australian
patients reported a 5-year OS 66 % with adjuvant radiotherapy compared with 27 %
with surgery alone [ 14 ]. Patients should receive 60 Gy in 2 Gy fractions to an operative
bed and 50 Gy in 2 Gy fractions to undissected regions including the lower neck.
Extent of Radiotherapy
Patients with metastatic cSCC to the parotid region, with a clinically N0 neck, who
undergo parotidectomy and selective neck dissection, who are found to have patho-
logically evident disease in the neck, require adjuvant radiotherapy to both the
parotid bed and ipsilateral neck. Selective radiotherapy only to the parotid bed may
be considered in patients with a pathological N0 neck [ 4 , 86 ]. Furthermore, it may
be reasonable to manage with surgery, as a single treatment modality, a small group
of select patients with low-risk disease, those who are immunocompetent with a
single, small, low-grade metastatic node with no ECS or STM, and no PNI or LVI
who have clear surgical margins [ 87 ].
Complications of Radiotherapy
Most patients do not require hospitalization or treatment interruption. Potential ben-
efi ts of treatment should be considered against side-effects. Acute toxicity is most
commonly cutaneous: dermatitis, skin erythema and ulceration, which may require
dressings or treatment interruption. Early radiotherapy toxicity includes mucositis,
xerostomia, lethargy, anorexia and taste alteration.
Late effects of concern, although relatively uncommon, affect the central ner-
vous system and include hearing loss, retinopathy and blindness. Other late effects
include xerostomia, dental caries, neck fi brosis, hypothyroidism, accelerated ath-
erosclerosis and osteoradionecrosis.
Adjuvant Chemotherapy
Addition of concurrent platinum-based chemotherapy as a radiosensitizer is well doc-
umented in HNmSCC. Analogous data are limited in metastatic cSCC. The Trans-
Tasman Radiation Oncology Group Trial (Post Operative Skin Trial 05.01) is
investigating postoperative concurrent chemoradiotherapy versus postoperative radio-
therapy alone for high-risk HNcSCC, and is under way at multicentre sites in Australia
and New Zealand. The primary objective of the trial is to determine whether there is a
difference in time to locoregional relapse between patients treated with adjuvant con-
current chemoradiotherapy with carboplatin or adjuvant radiotherapy alone.
Modification of Immunosuppression
In renal transplant recipients, it may be possible to reduce immunosuppressive
medication. Unfortunately, worsening renal function with requirement for renal
dialysis may complicate reduction in immunotherapy. The option of reducing
C. Jameson et al.
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109
immunotherapy for heart, lung and liver transplant patients also has the potentially
deleterious consequence of graft loss.
Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) with
antineoplastic properties. It might reduce the rate of cSCC in renal transplant recipi-
ents. In a large cohort study (TUMORAPA) of 110 renal transplant patients who
were receiving calcineurin inhibitors (CNI) and who had had at least one cSCC, 64
patients were randomized to switch from CNI to sirolimus, and 56 patients were
randomized to continue with CNI [ 88 ]. Patients who switched to sirolimus experi-
enced signifi cantly longer cSCC-free survival. A new cSCC occurred in 22 % of
patients in the sirolimus group and in 39 % of patients in the CNI group, within a
median time of 15 months versus 7 months (RR 0.56; 95 % CI 0.32–0.98). Serious
adverse events were more common in the sirolimus group, with 60 events versus 14
events in the CNI group. Graft function remained stable in the two study groups
[
88 ]. This study shows early evidence that rates of cSCC can be reduced with modi-
fi cation of immunosuppressive medication. Further studies are warranted to mini-
mize associated side-effects of treatment.
Outcome and Survival
Clinical stage is the most important prognostic factor and is assigned through delin-
eation of the extent of disease, specifi cally, tumour (T) and regional nodes (N).
Distant disease (M) is rare in HNcSCC and is investigated in cases of high
suspicion.
With respect to survival, published studies are based primarily on retrospective
patient selection and heterogeneous groups of patients with inherent uncontrolled
patient, tumour and treatment factors. Consequently, prognostic factors and patient
outcome vary signifi cantly among studies reported in the literature. High-risk fea-
tures are summarized in Box 8.2 . In general, patients with metastatic HNcSCC have
an OS of 30–75 % at 5 years, with markedly improved survival seen in patients
treated with multimodality therapy.
Survival
Regional recurrent cSCC occurs both as dermal metastases (Fig. 8.6 ) and isolated
nodal disease, and may occur in the contralateral neck [ 89 ]. Five-year DFS rates
vary between studies and are dependent on a variety of factors, including treatment
modality (surgery only versus surgery plus adjuvant radiotherapy), patient
Box 8.2 Poor Prognostic Factors of Metatstatic Nodal cSCC
• Immunosuppression
• Size of involved lymph node >3 cm
• Involvement of multiple lymph nodes
• Involvement of multiple lymph node levels
• Extranodal spread Soft tissue metastases
8 Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck
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immunosuppression, ENS and STM, and number and size of involved lymph nodes
[ 14 , 23 , 69 ].
In a study of 75 patients treated with multimodality therapy for metastatic cSCC
to parotid lymph nodes, the median time to regional recurrence was 9.7 months
(range 2–80 months) [ 89 ]. Select patients with regional recurrent metastatic
HNcSCC are treated with salvage surgery, radiotherapy, chemotherapy or a combi-
nation of these modalities. However, 60–70 % of patients, who have been treated
previously with surgery plus adjuvant radiotherapy, are not amenable to further
treatment and are deemed incurable (Fig.
8.7a, b ).
Fig. 8.6 A man with regional
metastatic dermal deposits of
cSCC. Dermal metastatic
cSCC is not amenable to
surgical management. This
patient was treated with
radiotherapy
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When patients are stratifi ed according to the N1S3 staging system, improved
rates of survival in early-stage disease are highlighted. In a cohort of 168 stage I
patients, DSS was 92 % at 5 years [
81 ]. A small subset of 33 of those patients with
low-risk nodal disease, who were treated with unimodality surgical resection only,
had a 5-year survival of 97 %. In contrast N1S3 stage III patients had a 42 % DSS
at 5 years [ 81 ]. In a larger review of 603 patients with metastatic HNcSCC treated
at two large cancer centres in Sydney, 5-year DSS was reported as follows for N1S3
staging; stage I 83 % (95 % CI 75.1–88), stage II 78 % (95 % CI 70.7–83.5), and
stage III 63 % (95 % CI 48.6–74.3) [ 68 ].
Conclusion
Our understanding of the pathological behaviour of HNcSCC has improved sig-
nifi cantly. Adequate staging requires meticulous surgical technique and detailed
synoptic, pathological evaluation. Strict adherence to accurate pathological
reporting guidelines is imperative with respect to implications for future deci-
sion-making, patient prognosis and treatment pathways. Examination of all
tumour deposits and lymph nodes should be undertaken, along with documenta-
tion of all aspects of the primary tumour, site, size, depth, PNI, LVI, number, size
and location of involved lymph nodes, and description of every metastatic
deposit, including ENS and STM.
ab
Fig. 8.7 ( a , b ) A 76-year-old man previously treated with surgery for a primary cSCC and with
multimodality therapy for metastatic nodal cSCC to the parotid region; ( a ) incurable recurrent
metastatic cSCC to the parotid; ( b ) progression of incurable metastatic cSCC 3 months later
8 Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck
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112
Multimodality treatment is now accepted as standard of care for metastatic
HNcSCC. Surgery and radiotherapy techniques are being refi ned, with subse-
quent improvements in patient care and outcome. Treatment modalities will con-
tinue to improve and become more tumour- and patient-specifi c as we gain a
better understanding of the molecular and genetic features of this disease.
References
1. de Vries E, van de Poll-Franse LV, Louwman WJ, et al. Predictions of skin cancer incidence in
the Netherlands up to 2015. Br J Dermatol. 2005;152:481–8.
2. Locke J, Karimpour S, Young G, et al. Radiotherapy for epithelial skin cancers. Int J Radiat
Oncol Biol Phys. 2001;51:748–55.
3. Veness MJ, Porceddu S, Palme CE, et al. Cutaneous head and neck squamous cell carcinoma
metastatic to parotid and cervical lymph nodes. Head Neck. 2007;29:621–31.
4. Ebrahimi A, Moncrieff MD, Clark JR, et al. Predicting the pattern of regional metastases from
cutaneous squamous cell carcinoma of the head and neck based on location of the primary.
Head Neck. 2010;32:1288–94.
5. Rodgers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin can-
cer in the United States, 2006. Arch Dermatol. 2010;146:283–7.
6. Buettner PG, Raasch BA. Incidence rates of skin cancer in Townsville, Australia. Int J Cancer.
1998;78:587–93.
7. Staples M, Marks R, Giles G. Trends in the incidence of non-melanocytic skin cancer (NMSC)
treated in Australia 1985–1995: are primary prevention programs starting to have an effect? Int
J Cancer. 1998;78:144–8.
8. Brantsch KD, Meisner C, Schönfi sch B, et al. Analysis of risk factors determining prognosis
of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008;9:713–20.
9. Katz MH. Nonmelanoma skin cancer. Md Med J. 1997;46:239–42.
10. Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with
a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis.
Arch Dermatol. 2000;136:1524–30.
11. Schmults CD, Karia PS, Carter JB, et al. Factors predictive of recurrence and death from cuta-
neous squamous cell carcinoma: a 10-year, single-institution cohort study. JAMA Dermatol.
2013;149:541–7.
12. Motley RJ, Kersey P, Lawrence CM. Multi-professional guidelines for the management of the
patient with primary cutaneous squamous cell carcinoma. Br J Dermatol. 2003;56:85–91.
13. Czarnecki D, Staples M, Mar A, et al. Metastases from squamous cell carcinoma of the skin in
southern Australia. Dermatology. 1994;189:52–4.
14. Wang JT, Palme CE, Morgan GJ, et al. Predictors of outcome in patients with metastatic cuta-
neous head and neck squamous cell carcinoma involving cervical lymph nodes: improved
survival with the addition of adjuvant radiotherapy. Head Neck. 2011;34:1524–8.
15. Peat B, Insull P, Ayers R. Risk stratifi cation for metastasis from cutaneous squamous cell car-
cinoma of the head and neck. ANZ J Surg. 2012;82:230–3.
16. Oddone N, Morgan GJ, Palme CE, et al. Metastatic cutaneous squamous cell carcinoma of the
head and neck: the Immunosuppression, Treatment, Extranodal spread and Margin status
(ITEM) prognostic score to predict outcome and the need to improve survival. Cancer.
2009;115:1883–91.
17. Givi B, Andersen PE, Diggs BS, et al. Outcome of patients treated surgically for lymph node
metastases from cutaneous squamous cell carcinoma of the head and neck. Head Neck.
2011;33:999–1004.
18. Nolan RC, Chan MT, Heenan PJ. A clinicopathologic review of lethal nonmelanoma skin
cancers in Western Australia. J Am Acad Dermatol. 2005;52:101–8.
C. Jameson et al.
malcolm_buchanan123@hotmail.com
113
19. Veness MJ, Morgan GJ, Palme CE, et al. Surgery and adjuvant radiotherapy in patients with
cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treat-
ment should be considered best practice. Laryngoscope. 2005;115:870–5.
20. Motley RJ, Preston PW, Lawrence CM. Multi-professional guidelines for the management of
the patient with primary cutaneous squamous cell carcinoma. London: British Association of
Dermatology (BAD); 2009. p. 34.
http://www.guideline.gov/content.aspx?id=15882 .
21. National Comprehensive Cancer Network (NCCN). Practice guidelines in oncology: basal cell
and squamous cell skin cancers. Available at
www.nccn.org/professionals/5hysician_gls/PDF/
nmsc.pdf . Accessed on 24 Sept 2013.
22. Vauterin TJ, Veness MJ, Morgan GJ, et al. Patterns of lymph node spread of cutaneous squa-
mous cell carcinoma of the head and neck. Head Neck. 2006;28:785–91.
23. Hinerman RW, Indelicato DJ, Amdur RJ, et al. Cutaneous squamous cell carcinoma metastatic
to parotid-area lymph nodes. Laryngoscope. 2008;118:1989–96.
24. Rowe DE, Carroll RJ, Day Jr CL. Prognostic factors for local recurrence, metastasis, and survival
rates in squamous cell carcinoma of the skin, ear and lip. J Am Acad Dermatol. 1992;26:976–90.
25. Dinehart SM, Pollack SV. Metastases from squamous cell carcinoma of the skin and lip. J Am
Acad Dermatol. 1989;21:241–8.
26. Stein AL, Tahan SR. Histologic correlates of metastasis in primary invasive squamous cell
carcinoma of the lip. J Cutan Pathol. 1994;21:16–21.
27. Kraus DH, Carew JF, Harrison LB. Regional lymph node metastasis from cutaneous squamous
cell carcinoma. Arch Otolaryngol Head Neck Surg. 1998;124:582–7.
28. Rodolico V, Barresi E, Di Lorenzo R, et al. Lymph node metastasis in lower lip squamous cell
carcinoma in relation to tumour size, histologic variables and p27kip1 protein expression. Oral
Oncol. 2004;40:92–8.
29. Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin
Pathol. 1990;94:624–7.
30. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive
clinicopathologic classifi cation—part two. J Cutan Pathol. 2006;33:261–79.
31. Breuninger H, Schaumburg-Lever G, Holzschuh J, et al. Desmoplastic squamous cell carci-
noma of the skin and vermilion surface: a highly malignant subtype of skin cancer. Cancer.
1997;79:915–9.
32. Ballantyne AJ. Perineural invasion by squamous cell carcinoma. J Dermatol Surg Oncol.
1984;10:502–4.
33. Leibovitch I, Huilgol SC, Selva D, et al. Cutaneous squamous cell carcinoma treated with
Moh’s micrographic surgery in Australia II. Perineural invasion. J Am Acad Dermatol.
2005;53:261–6.
34. Ross AS, Whalen FM, Elenitsas R, et al. Diameter of involved nerves predicts outcome in
cutaneous squamous cell carcinoma with perineural invasion: an investigator blinded retro-
spective cohort study. Dermatol Surg. 2009;35:1859–66.
35. https://intranet.som.uq.edu.au/PNIRegistry .
36. Brougham ND, Dennett ER, Cameron R, et al. The incidence of metastasis from cutaneous
squamous cell carcinoma and the impact of its risk factors. J Surg Oncol. 2012;106:811–5.
37. Huang CC, Boyce SM. Surgical margins of excision for basal cell carcinoma and squamous
cell carcinoma. Semin Cutan Med Surg. 2004;23:163–73.
38. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell
carcinoma. J Am Acad Dermatol. 1992;27:241–8.
39. Thomas DJ, King AR, Peat BG. Excision margins for nonmelanotic skin cancer. Plast Reconstr
Surg. 2003;112:57–63.
40. Leibovitch I, Huilgol SC, Selva D, et al. Cutaneous squamous cell carcinoma treated with
Moh’s micrographic surgery in Australia I. Experience over 10 years. J Am Acad Dermatol.
2005;53:253–60.
41. Duvvuri U, Simental Jr AA, D’Angelo G, et al. Elective neck dissection and survival in
patients with squamous cell carcinoma of the oral cavity and oropharynx. Laryngoscope.
2004;114:2228–34.
8 Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck
malcolm_buchanan123@hotmail.com
114
42. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma:
accuracy and morbidity in MSLT-1, an international multicenter trial. Ann Surg. 2005;242:302–
11; discussion 311–13.
43. Fields RC, Busam KJ, Chou JF, et al. Recurrence and survival in patients undergoing sentinel
lymph node biopsy for merkel cell carcinoma: analysis of 153 patients from a single institu-
tion. Ann Surg Oncol. 2011;18:2529–37.
44. Howle J, Veness M. Sentinel lymph node biopsy in patients with Merkel cell carcinoma: an
emerging role and the Westmead Hospital experience. Australas J Dermatol. 2012;53:26–31.
45. Morton DL. Overview and update of the phase III MSLT-I and MSLT-II in melanoma. Clin
Exp Metastasis. 2012;29:699–706.
46. Vermeeren L, Valdés Olmos RA, Klop WM, et al. SPECT/CT for sentinel lymph node map-
ping in head and neck melanoma. Head Neck. 2011;33:1–6.
47. Civantos FJ, Moffat FL, Goodwin WJ. Lymphatic mapping and sentinel lymphadenectomy for
106 head and neck lesions: contrasts between oral cavity and cutaneous malignancy.
Laryngoscope. 2006;112 Suppl 109:1–15.
48. Altinyollar H, Berberoglu U, Çelen O, et al. Lymphatic mapping and sentinel lymph node
biopsy in squamous cell carcinoma of the lower lip. Eur J Surg Oncol. 2002;28:72–4.
49. Kwon S, Dong ZM, Wu PC. Sentinel lymph node biopsy for high-risk cutaneous squamous
cell carcinoma: clinical experience and review of literature. World J Surg Oncol. 2011;9:80.
50. http://www.shnci.org/snic-trial.html .
51. Wong G, Chapman JR. Cancers after renal transplantation. Transplant Rev. 2008;22:141–9.
52. Hartevelt MM, Bavinck JN, Kootte AM, et al. Incidence of skin cancer after renal transplanta-
tion in The Netherlands. Transplantation. 1990;49:506–9.
53. Jensen P, Hansen S, Møller B, et al. Skin cancer in kidney and heart transplant recipients and differ-
ent long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40:177–86.
54. Lindelöf B, Sigurgeirsson B, Gäbel H, et al. Incidence of skin cancer in 5356 patients follow-
ing organ transplantation. Br J Dermatol. 2000;143:513–9.
55. Cooper JZ, Brown MD. Special concern about squamous cell carcinoma of the scalp in organ
transplant recipients. Arch Dermatol. 2006;142:755–8.
56. Deeb R, Sharma S, Mahan M, et al. Head and neck cancer in transplant recipients.
Laryngoscope. 2012;122:1566–9.
57. Bouwes Bavinck JN, Hardie DR, Green A, et al. The risk of skin cancer in renal transplant
recipients in Queensland, Australia. A follow-up study. Transplantation. 1996;61:715–21.
58. Webb MC, Compton F, Andrews PA, et al. Skin tumours post-transplantation: a retrospective
analysis of 28 years’ experience at a single centre. Transplant Proc. 1997;29:828–30.
59. Veness MJ. The important role of radiotherapy in patients with NMSC and other cutaneous
entities. J Med Imaging Radiat Oncol. 2008;52:278–86.
60. Jambusaria-Pahlajani A, Miller CJ, Quon H, et al. Surgical monotherapy versus surgery plus
adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: a systematic review of
outcomes. Dermatol Surg. 2009;35:574–85.
61. Han A, Ratner D. What is the role of adjuvant radiotherapy in the treatment of cutaneous squa-
mous cell carcinoma with perineural invasion? Cancer. 2007;109:1053–9.
62. Mendenhall WM, Ferlito A, Takes RP, et al. Cutaneous head and neck basal and squamous cell
carcinomas with perineural invasion. Oral Oncol. 2012;48:918–22.
63. Jambusaria-Pahlajani A, Hess SD, Katz KA, et al. Uncertainty in the perioperative manage-
ment of high-risk cutaneous squamous cell carcinoma among Mohs surgeons. Arch Dermatol.
2010;146:1225–31.
64. Panizza B, Solares CA, Redmond M, et al. Surgical resection for clinical perineural invasion
from cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2012;34:1622–7.
65. Hwang H, Perez D, Orloff L. Comparison of positron emission tomography/computed tomog-
raphy imaging and ultrasound in staging and surveillance of head and neck and thyroid cancer.
Laryngoscope. 2009;119:1958–65.
66. Bron LP, Traynor SJ, McNeil EB, et al. Primary and metastatic cancer of the parotid: compari-
son of clinical behavior in 232 cases. Laryngoscope. 2003;113:1070–5.
67. Uren RF. Lymphatic drainage of skin. Ann Surg Oncol. 2004;11(3 Suppl):179S–85.
C. Jameson et al.
malcolm_buchanan123@hotmail.com
115
68. Forest VI, Clark JJ, Veness MJ, et al. N1S3: a revised staging system for head and neck cutane-
ous squamous cell carcinoma with lymph node metastases: results of 2 Australian Cancer
Centers. Cancer. 2010;116:1298–304.
69. Kelder W, Ebrahimi A, Forest V, et al. Cutaneous head and neck squamous cell carcinoma with
regional metastases: the prognostic importance of soft tissue metastases and extranodal spread.
Ann Surg Oncol. 2012;19:274–9.
70. O’Brien CJ, McNeil EB, McMahon JD, et al. Signifi cance of clinical stages, extent of surgery
and pathologic fi ndings in metastatic cutaneous squamous cell carcinoma of the parotid gland.
Head Neck. 2002;24:417–22.
71. Andruchow JL, Veness MJ, Morgan GJ, et al. Implications for clinical staging of metastatic
cutaneous squamous carcinoma of the head and neck based on a mulitcenter study of treatment
outcomes. Cancer. 2006;106:1078–83.
72. American Joint Committee on Cancer. AJCC cancer staging handbook. Cutaneous squamous
cell carcinoma and other cutaneous carcinomas. In: Edge SB, Byrd DR, Compton CC, et al.,
editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. p. 301–14.
73. Brunner M, Veness MJ, Ch’ng S, et al. Distant metastases from cutaneous squamous cell car-
cinoma—analysis of AJCC stage IV. Head Neck. 2013;35:72–5.
74. O’Hara J, Ferlito A, Takes RP, et al. Cutaneous squamous cell carcinoma of the head and neck
metastasizing to the parotid gland—a review of current recommendations. Head Neck.
2011;33:1789–95.
75. Ambrosch P, Kron M, Pradier O, et al. Effi cacy of selective neck dissection: a review of 503
cases of elective and therapeutic treatment of the neck in squamous cell carcinoma of the upper
aerodigestive tract. Otolaryngol Head Neck Surg. 2001;124:180–7.
76. Chepeha DB, Hoff PT, Taylor RJ, et al. Selective neck dissection for the treatment of neck metas-
tasis from squamous cell carcinoma of the head and neck. Laryngoscope. 2002;112:434–8.
77. Patel RS, Clark JR, Gao K, et al. Effectiveness of selective neck dissection in the treatment of
the clinically positive neck. Head Neck. 2008;30:1231–6.
78. Shepard PM, Olsen J, Harari PM, et al. Therapeutic selective neck dissection outcomes.
Otolaryngol Head Neck Surg. 2010;142:741–6.
79. Robbins KT, Ferlito A, Shah JP, et al. The evolving role of selective neck dissection for head
and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2013;270:1195–202.
80. Wang JT, Palme CE, Wang AY, et al. In patients with metastatic cutaneous head and neck
squamous cell carcinoma to cervical lymph nodes, the extent of neck dissection does not infl u-
ence outcome. J Laryngol Otol. 2013;127 Suppl 1:S2–7.
81. D’Souza J, Clark J. Management of the neck in metastatic cutaneous squamous cell carcinoma
of the head and neck. Curr Opin Otolaryngol Head Neck. 2011;19:99–105.
82. Iyer NG, Clark JR, Murali R, et al. Outcomes following parotidectomy for metastatic squa-
mous cell carcinoma with microscopic residual disease: implications for facial nerve preserva-
tion. Head Neck. 2009;31:21–7.
83. Cappiello J, Piazza C, Giudice M, et al. Shoulder disability after different selective neck dissec-
tions (levels II–IV versus levels II–V): a comparative study. Laryngoscope. 2005;115:259–63.
84. Stuiver MM, van Wilgen CP, de Boer EM, et al. Impact of shoulder complaints after neck dissec-
tion on shoulder disability and quality of life. Otolaryngol Head Neck Surg. 2008;139:32–9.
85. Veness MJ, Palme CE, Smith M, et al. Cutaneous head and neck squamous cell carcioma meta-
static to cervical lymph nodes (non-parotid): a better outcome with surgery and adjuvant radio-
therapy. Laryngoscope. 2003;113:1827–33.
86. Mendenhall WM, Amdur RJ, Hinerman RW, et al. Radiotherapy for cutaneous squamous and
basal cell carcinomas of the head and neck. Laryngoscope. 2009;119:1994–9.
87. Ebrahimi A, Clark J, Lorincz BB, et al. Metastatic head and neck cutaneous squamous cell
carcinoma: defi ning a low-risk patient. Head Neck. 2012;34:365–70.
88. Euvrard S, Morelon E, Rostaing L, TUMORAPA Study Group, et al. Sirolimus and secondary
skin-cancer prevention in kidney transplantation. N Engl J Med. 2012;367:329–39.
89. Pramana A, Browne L, Graham PH. Metastatic cutaneous squamous cell carcinoma to parotid
nodes: the role of bolus with adjuvant radiotherapy. J Med Imaging Radiat Oncol. 2012;
56:100–8.
8 Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck
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© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_9
T. A. Warren , BSc (Hons), MBBS (*)
Department of Otolaryngology-Head and Neck Surgery , School of Medicine, University
of Queensland, Princess Alexandra Hospital, QIMR Berghofer Institute of Medical Research ,
Brisbane , QLD , Australia
e-mail: tawarren1@me.com
B. Panizza , MBBS, MBA, FRACS
Department of Otolaryngology-Head and Neck Surgery , School of Medicine, University
of Queensland, Queensland Head and Neck Cancer Centre, Queensland Skull Base Unit,
Princess Alexandra Hospital , Brisbane , QLD , Australia
e-mail: ben@panizza.com.au
9
Managing Perineural and Skull Base
Involvement
Timothy A. Warren and Benedict Panizza
Introduction
Australia is recognized as the non-melanoma skin cancer (NMSC) capital of the
world with approximately 300,000 cases diagnosed annually [ 1 ]. NMSC with peri-
neural invasion (PNI) is an aggressive feature, which carries a worse prognosis
through higher rates of locoregional recurrence and reduced survival [ 2 – 5 ]. NMSC
with PNI has been shown to be associated with a disease-specifi c survival at 3 years
of 64 %, compared to NMSC without PNI of 91 % [ 6 ].
PNI is the presence of tumour cells in the perineural space of a peripheral nerve.
Despite being fi rst described almost 180 years ago with several subsequent attempts at
clarifi cation, there remains no consensus on the defi nition [ 7 , 8 ]. In 1835, Cruveilhier
used the term ‘neurotropism’ to describe a tumour’s propensity to invade neural tissue
[ 7 ]. This histopathological feature, now known as perineural invasion, is a poor prog-
nostic indicator in several malignancies, including those of the prostate [ 9 ], pancreas
[ 10 ], cervix [ 11 ], stomach [ 12 ], colorectum [ 13 ], and head and neck mucosa [ 14 ].
PNI is estimated to occur in less than 5 % of NMSCs and is more common in
squamous cell carcinoma (SCC) than in basal cell carcinoma (BCC) [ 15 – 17 ].
Perineural spread (PNS) represents extension of a tumour along the perineural
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space, and this occurs over a variable timeframe (months to years) [ 18 ]. The major-
ity of cases involve small-calibre peritumoural cutaneous nerves, which are diag-
nosed only after biopsy or excision with careful histological sectioning and
microscopy. This subtype is known as ‘incidental PNI’ and is asymptomatic in the
patient. Typically, it is managed with defi nitive surgical excision, yet postoperative
radiotherapy should be considered, particularly when other high-risk features of the
patient and/ or primary tumour are present (Table 9.1 ) [ 3 , 5 , 19 – 21 ].
The aggressive reputation of PNI stems from the ability of tumour cells to invade
the perineural space and spread continuously via this conduit to the central nervous
system (CNS). A form of tumour metastasis, PNS is otherwise known as ‘clinical
PNI’, a term that refl ects clinically evident defi cits in the distribution of the involved
nerve at presentation. Clinical PNI has a well-recognized, worse prognosis than
incidental PNI [ 4 , 5 , 19 , 22 ]. Patients present with progressive symptoms and/or
signs of nerve dysfunction. Depending on the nerve and branch involved, these can
include facial paralysis and/or sensory nerve dysfunction. The trigeminal (V) and
facial (VII) cranial nerves are the most common nerves involved. PNS is detected
on magnetic resonance (MR) imaging in the majority of cases using a targeted neu-
rography study [ 23 ]. Imaging-defi ned disease extent guides treatment, which is
typically a combination of surgery and postoperative radiotherapy.
This disease is often under-recognized clinically and pathologically, leading to
critical delays in diagnosis [
18 , 24 ]. The terminology utilized varies throughout the
literature, limiting efforts to produce clinical practice guidelines [ 7 , 8 ]. This chapter
reviews the natural history of NMSC with PNI and outlines the approach to diagno-
sis and treatment, with particular focus on the surgical management of skull base
disease. The limitations within the current staging system for perineural disease are
also discussed.
Natural History
The perineural space is a potential space between or beneath the layers of the peri-
neurium, the middle-layer of the peripheral nerve sheath. The perineurium is formed
from tightly packed perineural cells arranged as a tubular structure that protects
nerve fascicles from the surrounding environment as part of the blood–nerve barrier
Table 9.1 Features
of high-risk cutaneous
squamous cell
carcinoma [
21 ]
Large size >2 cm
Deeply invasive >4 mm
Incomplete excision
Recurrent disease
Poorly differentiated
Perineural invasion
Location on or around ear or lower lip
Immunosuppressed
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119
[ 25 ]. It also appears to provide an anatomical barrier to tumour spread, especially in
the proximal aspect of cranial nerves at the skull base where it is multilayered.
Animal models have shown anatomical continuity of the perineural space proxi-
mally with the subarachnoid space and distally with the dermis, thus providing a
conduit for disease in the periphery to spread into the CNS [ 26 , 27 ].
The ability of tumour cells to invade the perineural space and then spread con-
tiguously into the CNS has long been understood [ 28 , 29 ]. The tumour likely invades
the perineurium at the periphery where it is thin and unilayered, and then spreads
axially along the perineural space with relatively low resistance [
30 ]. However, the
precise mechanism remains unclear. Nerves are maintained and stimulated to pro-
liferate by neurotrophins, growth factors and axon-guidance molecules [ 31 , 32 ].
The potential importance of these factors in PNI was shown in an in vitro model of
PNI using prostate cancer cells cultured alongside mouse dorsal root ganglia tissue
[ 33 ]. This process demonstrated reciprocal signalling within the tumour microenvi-
ronment, consistently resulting in simultaneous tumour growth and neurite axono-
genesis to culminate in nerve invasion [ 33 – 36 ]. This seemingly symbiotic process
may result from the presence of tumour cells within an especially favourable envi-
ronment for growth and proliferation, and probably involves complex tumour, nerve
and stromal signalling [ 37 ].
PNI appears to occur in regions with a high incidence of cutaneous malignancies
[ 4 , 38 , 39 ]. Middle-aged men are the most commonly affected; however, patients
with clinical PNI aged 34–91 years have required treatment at our institution. The
typical patient is a middle-aged man, and the intrinsic primary tumour factors that
are associated with PNI include large size (>2 cm diameter), location on the mid-
face or cheek, recurrent disease and poor differentiation [ 40 ]. The head and neck is
the most frequent site of disease for NMSC. That this region is richly innervated by
the trigeminal and facial cranial nerves is consistent with the fact that these nerves
are the most frequently affected by PNS [ 41 ].
PNS occurs over a variable timeframe, from months to years [ 18 ]. Without timely
treatment, the natural history of NMSC with PNS is a slow central spread of disease
to the brainstem, with poor prognosis (i.e. ‘central failure’) [
42 – 44 ]. PNS is con-
tiguous along the nerve and occurs in the absence of ‘skip lesions’. Skip lesions
describe non-contiguous spread, akin to embolic spread, and have been reported in
the literature without clear histological evidence [ 2 ]. However, this phenomena is
probably the product of technical processing artifact [ 45 ]. Our group has recently
assessed 50 cranial nerve specimens affected by PNS and found no evidence of a
skip in tumour growth [ 46 ].
The direction of PNS is either centripetal (toward the brainstem) or centrifugal
(toward the skin). Centripetal spread is the more common pattern, and it occurs after
PNI in the periphery with subsequent primary PNS along a cranial nerve. Centrifugal
spread is seen less frequently and typically represents secondary PNS that com-
mences at nerve branching points or after ganglion invasion [ 39 ]. These features of
tumour spread are unique to PNS in the head and neck.
Most central failure is by direct spread into the brainstem; however, leptomenin-
geal carcinomatosis (also known as drop metastases), a form of central failure, can
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120
occur less commonly as advanced end-stage disease [ 44 ]. It refers to the spread of
perineural disease into the subarachnoid space and extensive disease dissemination
throughout the meninges via the cerebrospinal fl uid. This refl ects the anatomical
continuity of the perineural space with the subarachnoid space. Palliative radio-
therapy for symptom control might be required.
PNI has been shown to portend a higher risk of nodal metastasis in patients with
cutaneous SCC (cSCC) and PNI [ 47 ]. One study in patients with cSCC showed that
those with incidental PNI in the primary had a rate of nodal metastasis of 40 %
compared to those with no PNI in the primary who had a rate of nodal metastasis of
18.2 %, and this was independent of tumour size (p = 005; OR 2.0) [
47 ]. Yet interest-
ingly, several recent, focused studies have shown that regional nodal disease at pre-
sentation in clinical PNI patients is uncommon, with recorded rates of between 0
and 16 % [ 38 , 39 , 48 , 49 ]. This suggests that PNS is a form of tumour spread that is
often distinct from metastasis via a lymphatic or haematogenous route, and can
often exist independent of nodal or distant disease [ 40 , 50 ]. Primary tumour biology
is clearly a signifi cant factor, and is presently little understood.
Diagnosis
Clinicopathological Features
The diagnosis of PNI requires a high index of suspicion by the treating surgeon,
radiologist and histopathologist. Incidental PNI can be diagnosed only on histol-
ogy with careful sectioning and staining. Common stains include haemotoxylin
and eosin, broad-spectrum keratin (AE1/AE3), cytokeratin (MNF116) and S100
(Fig. 9.1 ). The microscopic detection of PNI and clarifi cation of margin status
can be challenging on account of the inherent ramifi cation pattern of small nerves
throughout the dermis and soft tissues. This is particularly relevant in Mohs
micrographic surgery (MMS) because of the use of horizontal sectioning, which
can generate artifact and the false impression of margin clearance, or even a
‘skip’ in tumour growth [
24 , 45 ]. The use of longitudinal and/or perpendicular
sectioning can improve accuracy [ 24 , 45 ]. Currently, standardized histopatho-
logical reporting schemes for PNI are unavailable. The assessment of incidental
PNI typically includes the maximum nerve diameter involved. A diameter
>0.1 mm is an aggressive feature and this has been shown recently to be associ-
ated with worse outcomes [ 51 , 52 ].
In a recent series of 50 patients with clinical PNI from cSCC treated with surgery
and postoperative radiotherapy, approximately one-third of patients had either unas-
sessable or unknown primary tumours (i.e. TX or T0) [ 49 ]. Also, over a third of
patients with a known primary tumour did not have PNI reported. This could refl ect
either of the following facts: (i) PNI did not exist in the primary; (ii) PNI did exist
in the primary but remained undetected; or (iii) another NMSC may be the ‘culprit’
primary, as many of these patients have had chronic sun exposure and multiple
NMSCs.
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Symptoms and signs are likely to be the result of gradual nerve fascicle invasion
and/or compression by the tumour. It is not uncommon for a patient’s symptoms/
signs to be present for several years and the diagnostic clues misinterpreted as
benign conditions, such as Bell’s palsy or trigeminal neuralgia. The typical patient
with trigeminal nerve disease presents with a slowly progressive dysaesthesia in the
distribution of one of the three main branches (V1, V2 or V3). Symptoms can
include any combination of numbness, paraesthesia, burning, neuropathic pain or
formication (i.e. crawling of ants), which progressively spread over time into the
dermal distribution of other V nerve branches, refl ecting retrograde invasion into the
gasserian ganglion. Direct questioning of the patient for these symptoms is often
required. Also, a local subcutaneous mass or nodule might be present concurrently,
and can be useful to facilitate initial tissue diagnosis.
While facial nerve involvement is generally a more obvious presentation, it is
often misinterpreted as Bell’s palsy. The typical patient presents with a partial yet
progressive facial paralysis in the distribution of one of the major facial nerve
branches. As disease slowly spreads antegrade to the stylomastoid foramen, unilat-
eral complete facial paralysis develops. Bell’s palsy can be distinguished by its ten-
dency to manifest as a sudden partial or complete facial nerve palsy that affects all
the branches and which shows at least some recovery over a period of weeks.
Fig. 9.1 Histopathological section showing perineural spread along the perineural space of cranial
nerve ( arrows ) with areas of intraneural invasion ( arrowheads : H&E staining; magnifi cation 100×)
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The trigeminal and facial nerves can be involved simultaneously in a patient,
probably resulting from the known extensive communicating branches between
these nerves [ 53 , 54 ]. These communications can be between the temporal branch
of the facial nerve and the zygomaticotemporal nerve, the facial nerve and the buc-
cal nerve, and the facial nerve and the infraorbital nerve [ 55 , 56 ]. Involvement of the
great auricular nerve with PNI is rare, yet can spread via the cervical spinal nerve
root to the CNS [ 57 , 58 ].
Imaging Features
Targeted MR neurography reviewed by a skull base radiologist is the gold standard
for imaging assessment of PNS, and is vital for diagnosis, treatment planning and
surveillance [ 23 ]. MR neurography utilizes a targeted high resolution matrix, small
fi eld of view, thin slices and gadolinium enhancement to improve spatial resolution
and diagnostic ability, preferably with a 3.0-T platform [ 23 ]. MR neurography can
detect and assess the extent of PNS accurately in the majority of cases. Gandhi et al.
detected PNS in 100 % of nerves (30/30), and correctly identifi ed the extent of PNS
in 83.3 % (25/30) using targeted 1.5 T MR neurography when matched to patho-
logical specimens [
23 ].
PNS is typically shown by the presence of thickening and enhancement of involved
nerve(s) (Fig. 9.2 ), with obliteration of the fat planes that surround skull base foram-
ina [ 59 ]. Denervation from motor nerve involvement (V3, VII) can also produce T2
hyperintensity and abnormal gadolinium enhancement of the innervated muscle,
which should not be misinterpreted as primary pathology within the muscle.
The imaging zonal system described by Williams et al . is useful for grading the
extent of disease spread (Table 9.2 ) [ 60 ]. The zonal extent infl uences clinical
ab
Fig. 9.2 ( a ) Coronal, ( b ) sagittal: magnetic resonance neurography showing perineural spread
from cutaneous squamous cell carcinoma of the head and neck. Zone 1 disease is present in the
right infraorbital nerve ( arrow )
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123
decision- making and has been shown to be a predictor of overall survival at 5 years:
(i) zone 1—71.4 %; (ii) zone 2—66.7 %, and (iii) zone 3—18.2 % (p = 0.025) [ 61 ].
Computed tomography (CT) is useful to stage regional lymph nodes and assess
bone involvement. It can detect only advanced perineural disease evidenced by
bulky advanced disease or skull base foraminal erosion/expansion by the tumour
[ 50 , 59 , 62 ]. In cases in which the diagnosis of PNS is uncertain after adequate
imaging, a nerve biopsy should be considered. A segment of nerve of ≤2 cm in
length should be resected, preferably under frozen-section control.
Imaging is generally not necessary for patients with incidental PNI. However,
if postoperative symptoms or signs (i.e. those present immediately after sur-
gery) progressively worsen during follow-up, imaging with MR neurogram is
required. In the experience of our team, detecting PNS on imaging in the absence
of symptoms is rare.
The use of standard, unfocused MR imaging or CT of the brain will not appreci-
ate perineural disease as effectively as tailored protocols, such as MR neurography
[ 23 ]. Some centres report imaging-negative PNS at rates of 22–52 %, yet the imag-
ing modality and protocol used are not always defi ned [
3 , 4 ]. At our institution, all
clinical PNI patients with trigeminal nerve symptoms had positive preoperative MR
neurography, and this probably refl ects both improved technology and targeted
imaging [ 23 ]. Small-calibre, low-volume peripheral nerve involvement cannot
always be detected. Detecting distal VII nerve branches with early PNS (i.e. those
presenting with partial facial palsy) remains a challenge with current MR technol-
ogy. This problem may also be compounded by an irradiated or postoperative
parotid bed.
Staging
Acknowledging its aggressive nature, the American Joint Committee on Cancer
(AJCC) recognize the presence of PNI for staging cutaneous malignancies. Evidence
of PNI in the primary tumour (T) is regarded as T1 or T2, depending on the co-
presence of other high-risk features, such as size and depth of invasion. PNS to the
Table 9.2 Classifi cation of imaging-defi ned extent of perineural spread of cutaneous malignancy
in the head and neck
Zone Imaging-defi ned extent
1 V1 (ophthalmic nerve) to the superior orbital fi ssure; V2 (infraorbital nerve) to the
external aperture of the foramen rotundum; V3 (mandibular nerve) to the external
aperture of the foramen ovale; VII (facial nerve) to the external aperture of the
stylomastoid foramen
2 V1, V2, V3: From Zone 1 to the gasserian ganglion cistern; VII: From Zone 1 up to the
lateral end of the internal auditory canal, including the geniculate ganglion and the
labyrinthine segment
3 All nerves: proximal to the ganglion, into the cisterns, or into the brainstem
Adapted from Williams et al. [
60 ]
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skull base is classifi ed as T4 [ 63 ]. At present, this system does not refl ect clinical
practice and has limited applicability for PNI patients. It classifi es PNS as a feature
of the primary tumour, despite being a distinct form of tumour spread. In addition,
it would be useful to include the zonal system, as this has been shown to correlate
with prognosis [ 61 ]. Under the current system, zone 1 PNS that does not reach the
skull base can be classifi ed as T1 or T2, despite clearly worse outcomes when com-
pared with a NMSC without PNI [ 6 , 61 ].
In addition, the involved nerve diameter for incidental PNI has been shown to
correlate with prognosis [
51 ]. Ross et al. recorded the maximal diameter of involved
nerves in 48 patients with incidental PNI of cSCC, and found that a nerve diameter
of >0.1 mm was associated with signifi cantly worse outcomes (local recurrence,
disease-specifi c death, metastasis and overall survival; p < 0.05) [ 51 ]. Similarly,
Carter et al. showed a higher risk of death from disease and nodal metastasis in
patients with nerve diameter of >0.1 mm [ 52 ]. Currently, it is unclear whether a
greater nerve diameter is associated with higher risk of PNS.
At our institution, patients with NMSC and PNS are staged using the primary
tumour characteristics (to predict regional nodal risk) and the zonal extent of PNS
on imaging (Table 9.2 ). It is important to note that many patients present with PNS
as recurrence, and this, therefore, requires appropriate notation (i.e. ‘rTNM’ stage).
Management
Incidental PNI
Incidental PNI is most often diagnosed at treatment after surgical excision of a
NMSC. This may be via routine wide-local excision or MMS. The aim should
always be to obtain a clear margin, if possible. Consideration should be given to
postoperative radiotherapy, particularly in cases with a positive margin, large nerve
diameter (>0.1 mm), or the co-presence of features associated with increased
aggressiveness (Table
9.1 ) [ 2 , 52 ]. Radiotherapy should encompass the primary
tumour with a surrounding margin for PNI [ 2 ]. The decision to offer postoperative
radiotherapy is often the most challenging aspect in management, with ‘under-
treatment’ being a common feature in many patients seen later with recurrent dis-
ease and PNS. However, clear treatment guidelines remain unavailable.
Clinical PNI
The more aggressive nature of clinical PNI ultimately necessitates more complex
multidisciplinary management involving surgical resection and/or radiotherapy
(defi nitive or postoperative). Surgical resection is a signifi cant undertaking, typi-
cally requiring input from many teams, including an otolaryngologist/head and
neck surgeon, neurosurgeon and plastic/reconstructive surgeon.
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Effective management requires an understanding of the natural history of the
disease. Each operation is designed to resect the involved nerve en-bloc , with the
extent of surgery determined by the zonal extent on MR neurography (Figs. 9.2 and
9.3 ). The aim of surgery is to prevent the central progression of disease (with a clear
margin if safe and technically feasible), while maintaining form and function [ 38 ].
Patients need to be aware of the sometimes disfi guring nature of surgery, and the
need for reconstruction. The surgical approach of our group, based on nerve and
zonal extent, is detailed in Table 9.3 [ 64 ].
Surgery does not play a role in removing the entire peripheral spread of the disease,
from which skin involvement can be diffuse. As nerves travel proximally toward the
brainstem, branches should be assessed for involvement with biopsy and frozen sec-
tion or removed en-bloc . One must be cognizant of not disturbing anatomical barriers
that can result in iatrogenic tumour spread and decreased survival, such as subarach-
noid or dural tears, which can lead to cerebrospinal fl uid dissemination. Therefore,
bulky disease into zone 3 is generally managed with defi nitive radiotherapy, yet sub-
total resection may be offered on a case-by-case basis, being mindful of precise imag-
ing extent and patient factors (age, general health and patient wishes).
Trigeminal nerve disease into zone 2 typically requires a craniotomy for disease
clearance. Tumour invading the supraorbital nerve extending approximately 1 cm
beyond the supraorbital notch usually warrants orbital exenteration, and this can
provide access to the ganglion via a transorbital approach for zone 2 disease.
Alternatively, a pterional craniotomy can be used to access the ganglion. A func-
tioning orbit is diffi cult to preserve after postoperative radiotherapy and associated
morbidity. A neck dissection is undertaken only for the following reasons: (i) if
AJCC ≥ N1 nodal disease is present on imaging/clinical assessment; or (ii) if access
to the neck vessels is required to enable reconstruction.
Radiotherapy plays a key role in the management of PNS; yet there are no stan-
dardized treatment recommendations and the approach is largely case-dependent.
Using intensity-modulated radiation therapy (IMRT) to minimize morbidity, radia-
tion fi elds generally cover the following: (i) primary tumour (if present) and the
Fig. 9.3 Surgical specimen
from en-bloc resection of
infraorbital nerve
( arrowhead ) with
subcutaneous soft tissues
( arrow ), along with
ptyergopalatine fossa
contents and initial part of
V2 ( broken arrow ) via a
trans-facial approach
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peripheral branches of the involved nerve(s); and (ii) the proximal course of the
involved nerve(s) back to the ganglion for zone 1, to the prepontine aspect of the
nerve for zone 2, and up to the brainstem for zone 3. Delayed contralateral spread
of perineural disease has been reported ( n = 6), and consideration should be given to
limited fi eld coverage across the facial midline to the contralateral mid-face, par-
ticularly given the relative safety profi le of IMRT [ 65 , 66 ]. A standardized approach
to the radiotherapy management of the regional lymph nodes in PNI patients is lack-
ing, yet many centres still advocate elective nodal irradiation because of the risk of
subclinical nodal disease with PNI and documented regional failure rates of 6–11 %
[ 3 , 4 , 39 ]. However, quality controlled trials are lacking.
Treatment outcome data should be interpreted with caution because of inherent
limitations in earlier studies, which include the following: (i) varying defi nitions as
to what constitutes PNI; [ 7 , 8 , 67 ] (ii) varying defi nitions of clinical and incidental
PNI, and therefore potential pooling of subgroups; [ 3 , 50 ] (iii) pooling of BCC and
SCC patients; [ 19 , 57 , 60 ] and (iv) varying treatment approaches. Large-scale con-
trolled trials that assess clearly defi ned patient subgroups are inherently lacking.
However, studies in patients treated with surgery and/or radiotherapy consistently
show worse 5-year local control rates for clinical PNI (25–48 %) compared to
Table 9.3 Surgical approach based on the nerve involved and zonal extent of PNS on imaging [ 63 ]
Nerve
involved Zone 1 Zone 2 Zone 3
V1 To supraorbital ridge: resect
nerve
Approximately 1 cm beyond
ridge: orbital exenteration ±
superior orbital fi ssure
Include gasserian
ganglion via a lateral
craniotomy or
transorbital approach
XRT alone
Consider subtotal
resection
V2 Infraorbital nerve resection +
PPF contents + maxillary
division via trans-facial
(endoscopic or sublabial)
Include gasserian
ganglion via trans-facial
or lateral craniotomy
approach
XRT alone
Consider subtotal
resection
V3 Ascending mandibulectomy +
ITF contents preserving
parotid, VII and masseter
muscle
Include gasserian
ganglion via a lateral
craniotomy
XRT alone
Consider subtotal
resection
VII Radical parotidectomy +
mastoid segment of VII
Include geniculate
ganglion via lateral
temporal bone resection
XRT alone
Consider surgery:
geniculate ganglion +
surrounding dura +
contents of IAM
VII + V3 Radical parotidectomy +
ascending mandibulectomy +
ITF contents
Include gasserian and
geniculate ganglia via
lateral craniotomy and
lateral temporal bone
resection
XRT alone
Consider subtotal
resection
PPF pterygopalatine fossa, XRT defi nitive radiotherapy, ITF infratemporal fossa, IAM internal
auditory meatus
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incidental PNI (78–92 %) [ 3 , 4 , 19 , 22 , 39 ]. Local control is a signifi cant issue, and
the common mode of recurrence [ 5 , 39 , 48 ]. In addition, 5-year disease-specifi c
survival (DSS) is reduced in clinical PNI (54–61 %), compared to incidental PNI
(73–90 %) [ 3 , 22 , 39 ].
Our institution reported on the outcomes of 21 consecutive patients with clinical
PNI from cSCC after treatment with surgery and postoperative radiotherapy, and
showed a 5-year DSS rate of 64.3 % and local control rate of 64 % [ 38 ]. An updated
series of 50 consecutive patients shows an improved DSS rate of 74 % at 5 years [ 49 ].
Follow-Up
It is recommended that patients be closely monitored for 2 years, reducing visits in
frequency until 5 years post-treatment. This is based on the observation that the
majority of recurrences occur within the fi rst 2 years post-treatment [ 3 , 4 , 38 , 49 ].
At our institution, patients also undergo MR neurography at regular intervals for
surveillance of early recurrence.
Summary
NMSC with PNI is an aggressive disease that signifi cantly reduces patient out-
comes, particularly once disease has spread along cranial nerves and elicited clini-
cal features. The disease is frequently misinterpreted, with signifi cant delays in
potentially curable patients. Diagnosis is aided by MR neurography, and the zonal
extent guides surgical resection and planning for radiotherapy. Universally accepted
management guidelines for NMSC with PNI or PNS are lacking. Surgical resection
requires a clear understanding of the natural history of the disease. With increased
awareness and management within specialized centres, patient outcomes can be
improved signifi cantly.
Key Points
• Perineural invasion and perineural spread should be recognized as distinct
prognostic features of a disease process.
• Perineural spread is often misdiagnosed and treatment delays can have
poor consequences for patient outcomes.
• Patients with perineural spread may present without an obvious primary cuta-
neous lesion, or with no evidence of perineural invasion in the primary itself.
• In patients with perineural spread, the rate of nodal metastasis at presenta-
tion is low (~10 %).
• 3-T magnetic resonance (MR) neurography is the gold standard for the
imaging assessment of perineural spread, and the zonal extent of disease is
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128
Acknowledgement The authors wish to thank Dr Mitesh Gandhi for his input regarding radio-
logical assessment and diagnosis.
References
1. Fransen M, Karahalios A, Sharma N, et al. Non-melanoma skin cancer in Australia. Med J
Aust. 2012;197:565–8.
2. Mendenhall WM, Ferlito A, Takes RP, et al. Cutaneous head and neck basal and squamous cell
carcinomas with perineural invasion. Oral Oncol. 2012;48:918–22.
3. Jackson JE, Dickie GJ, Wiltshire KL, et al. Radiotherapy for perineural invasion in cutaneous
head and neck carcinomas: toward a risk-adapted treatment approach. Head Neck.
2009;31:604–10.
4. Lin C, Tripcony L, Keller J, et al. Cutaneous carcinoma of the head and neck with clinical
features of perineural infi ltration treated with radiotherapy. Clin Oncol (R Coll Radiol).
2013;25:362–7.
5. Lin C, Tripcony L, Keller J, et al. Perineural infi ltration of cutaneous squamous cell carcinoma and
basal cell carcinoma without clinical features. Int J Radiat Oncol Biol Phys. 2012;82:334–40.
6. Clayman GL. Mortality risk from squamous cell skin cancer. J Clin Oncol. 2005;23:759–65.
7. Liebig C, Ayala G, Wilks JA, et al. Perineural invasion in cancer. Cancer. 2009;115:3379–91.
8. Dunn M, Morgan MB, Beer TW. Perineural invasion: identifi cation, signifi cance, and a stan-
dardized defi nition. Dermatol Surg. 2009;35:214–21.
9. Maru N, Ohori M, Kattan MW, et al. Prognostic signifi cance of the diameter of perineural
invasion in radical prostatectomy specimens. Hum Pathol. 2001;32:828–33.
10. Bapat AA, Hostetter G, Von Hoff DD, et al. Perineural invasion and associated pain in pancre-
atic cancer. Nat Rev Cancer. 2011;11:695–707.
11. Horn LC, Meinel A, Fischer U, et al. Perineural invasion in carcinoma of the cervix uteri:
prognostic impact. J Cancer Res Clin Oncol. 2010;136:1557–62.
12. Bilici A, Seker M, Ustaalioglu BBO, et al. Prognostic signifi cance of perineural invasion in
patients with gastric cancer who underwent curative resection. Ann Surg Oncol. 2010;17:
2037–44.
13. Liebig C, Ayala G, Wilks J, et al. Perineural invasion is an independent predictor of outcome
in colorectal cancer. J Clin Oncol. 2009;27:5131–7.
14. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med.
2008;359:1143–54.
15. Leibovitch I, Huilgol SC, Selva D, et al. Basal cell carcinoma treated with Mohs surgery in
Australia I. Experience over 10 years. J Am Acad Dermatol. 2005;53:445–51.
16. Leibovitch I, Huilgol SC, Selva D, et al. Basal cell carcinoma treated with Mohs surgery in
Australia III. Perineural invasion. J Am Acad Dermatol. 2005;53:458–63.
17. Hassanein AM, Proper SA, Depcik-Smith ND, et al. Peritumoral fi brosis in basal cell and
squamous cell carcinoma mimicking perineural invasion: potential pitfall in Mohs micro-
graphic surgery. Dermatol Surg. 2005;31:1101–6.
useful for staging and treatment planning. MR neurography-negative peri-
neural spread is rare.
• Skip lesions almost certainly do not exist and are the result of technical
processing artifact.
• En-bloc surgical resection of disease with a clear margin and postoperative
radiotherapy offers improved survival outcomes.
T.A. Warren and B. Panizza
malcolm_buchanan123@hotmail.com
129
18. Warner GC, Gandhi M, Panizza B. Slowly progressive cranial nerve palsies. Med J Aust.
2006;184:641–3.
19. McCord MW, Mendenhall WM, Parsons JT, et al. Skin cancer of the head and neck with inci-
dental microscopic perineural invasion. Int J Radiat Oncol Biol Phys. 1999;43:591–5.
20. Ampil FL, Hardin JC, Peskind SP, et al. Perineural invasion in skin cancer of the head and
neck. J Oral Maxillofac Surg. 1995;53:34–8.
21. Veness MJ. Defi ning patients with high-risk cutaneous squamous cell carcinoma. Australas
J Dermatol. 2006;47:28–33.
22. McCord MW, Mendenhall WM, Parsons JT, et al. Skin cancer of the head and neck with clini-
cal perineural invasion. Int J Radiat Oncol Biol Phys. 2000;47:89–93.
23. Gandhi MR, Panizza B, Kennedy D. Detecting and defi ning the anatomic extent of large nerve
perineural spread of malignancy: comparing ‘targeted’ MRI with the histologic fi ndings fol-
lowing surgery. Head Neck. 2011;33:469–75.
24. Cernea CR, Ferraz AR, de Castro IESV, et al. Perineural invasion in aggressive skin carcinomas
of the head and neck: potentially dangerous but frequently overlooked. ORL J Otorhinolaryngol
Relat Spec. 2009;71:21–6.
25. Pina-Oviedo S, Ortiz-Hidalgo C. The normal and neoplastic perineurium: a review. Adv Anat
Pathol. 2008;15:147–64.
26. Shanthaveerappa T, Bourne GH. Perineural epithelium: a new concept of its role in the integ-
rity of the peripheral nervous system. Science. 1966;154:1464–7.
27. Selander D, Sjostrand J. Longitudinal spread of intraneurally injected local anaesthetics. Acta
Anaeth Scand. 1978;22:622–34.
28. Ballantyne A, McCarten AB, Ibanez ML. The extension of cancer of the head and neck
through peripheral nerves. Am J Surg. 1963;106:651–67.
29. Warren S, Harris PN, Graves RC. Osseous metastasis of carcinoma of the prostate, with special
reference to the perineural lymphatics. Arch Pathol. 1936;22:139–60.
30. Shattock S. Invasion of the nerves in carcinoma of the sublingual salivary gland, associated
with carcinoma of the tongue. Proc R Soc Med. 1922;15:13–6.
31. Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic
value. Nat Rev Neurosci. 2002;3:383–94.
32. Chilton JK. Molecular mechanisms of axon guidance. Dev Biol. 2006;292:13–24.
33. Ayala GE, Wheeler TM, Shine HD, et al. In vitro dorsal root ganglia and human prostate cell
line interaction: redefi ning perineural invasion in prostate cancer. Prostate. 2001;49:
213–23.
34. Ayala GE, Dai H, Ittman M, et al. Growth and survival mechanisms associated with perineural
invasion in prostate cancer. Cancer Res. 2004;64:6082–90.
35. Ayala GE, Dai H, Powell M, et al. Cancer-related axonogenesis and neurogenesis in prostate
cancer. Clin Cancer Res. 2008;14:7593–603.
36. Dai H, Li R, Wheeler T, et al. Enhanced survival in perineural invasion of pancreatic cancer:
an in vitro approach. Hum Pathol. 2007;38:299–307.
37. Chédotal A, Kerjan G, Moreau-Fauvarque C. The brain within the tumor: new roles for axon
guidance molecules in cancers. Cell Death Differ. 2005;12:1044–56.
38. Panizza B, Solares CA, Redmond M, et al. Surgical resection for clinical perineural invasion
from cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2011;34:1622–7.
39. Balamucki CJ, Mancuso AA, Amdur RJ, et al. Skin carcinoma of the head and neck with
perineural invasion. Am J Otolaryngol. 2011;33:447–54.
40. Mendenhall WM, Amdur RJ, Hinerman RW, et al. Skin cancer of the head and neck with
perineural invasion. Am J Clin Oncol. 2007;30:93–6.
41. Staples MP, Elwood M, Burton RC, et al. Non-melanoma skin cancer in Australia: the 2002
national survey and trends since 1985. Med J Aust. 2006;184:6–10.
42. Fowler BZ, Crocker IR, Johnstone PAS. Perineural spread of cutaneous malignancy to the
brain. Cancer. 2005;103:2143–53.
43. Clouston PD, Sharpe DM, Corbett AJ, et al. Perineural spread of cutaneous head and neck
cancer. Arch Neurol. 1990;47:73–7.
9 Managing Perineural and Skull Base Involvement
malcolm_buchanan123@hotmail.com
130
44. Dunn M, Morgan MB. Perineural invasion progressing to leptomeningeal carcinomatosis: is
the absence of peripheral nerves an important sign? J Am Acad Dermatol. 2010;62:270–6.
45. Matorin PA, Wagner Jr RF. Mohs micrographic surgery: technical diffi culties posed by peri-
neural invasion. Int J Dermatol. 1992;31:83–6.
46. Panizza B, Warren TA, Solares CA, et al. Histopathological features of clinical perineural inva-
sion of cutaneous squamous cell carcinoma of the head and neck and the potential implications
for treatment. Head Neck. 2014;36:1611–8.
47. Moore BA, Weber RS, Prieto V, et al. Lymph node metastases from cutaneous squamous cell
carcinoma of the head and neck. Laryngoscope. 2005;115:1561–7.
48. Garcia-Serra A, Hinerman RW, Mendenhall WM, et al. Carcinoma of the skin with perineural
invasion. Head Neck. 2003;25:1027–33.
49. Warren TA, Panizza B, Porceddu SV, et al. Outcomes following surgery and postoperative
radiotherapy for perineural spread of head and neck cutaneous squamous cell carcinoma. Head
Neck. 2014. doi:
10.1002/hed.23982 . [Epub ahead of print].
50. Galloway TJ, Morris CG, Mancuso AA, et al. Impact of radiographic fi ndings on prognosis for
skin carcinoma with clinical perineural invasion. Cancer. 2005;103:1254–7.
51. Ross AS, Miller Whalen F, Elenitsas R, et al. Diameter of involved nerves predicts outcomes
in cutaneous squamous cell carcinoma with perineural invasion: an investigator-blinded retro-
spective cohort study. Dermatol Surg. 2009;35:1859–66.
52. Carter JB, Johnson MM, Chua TL, et al. Outcomes of primary cutaneous squamous cell carci-
noma with perineural invasion. JAMA Dermatol. 2013;149:35–42.
53. Odobescu A, Williams HB, Gilardino MS. Description of a communication between the facial
and zygomaticotemporal nerves. Br J Plast Surg. 2012;65:1188–92.
54. Baumel JJ. Trigeminal-facial nerve communications. Arch Otolarnygol. 1974;99:34–44.
55. Hwang K, Han JY, Battuvshin D, et al. Communication of infraorbital nerve and facial nerve:
anatomic and histologic study. J Craniofac Surg. 2004;15:88–91.
56. Tohma A, Mine K, Tamatsu Y, et al. Communication between the buccal nerve (V) and facial
nerve (VII) in the human face. Ann Anat. 2004;186:173–8.
57. Goepfert H, Dichtel W, Medina J, et al. Perineural invasion in squamous cell carcinoma of the
head and neck. Am J Surg. 1984;148:542–7.
58. Repanos C, Mitchell D, Gandhi M, et al. Great auricular nerve perineural spread of squamous
cell carcinoma. ANZ J Surg. 2012;82:179–80.
59. Moonis G, Cunnane MB, Emerick K, et al. Patterns of perineural tumor spread in head and
neck cancer. Magn Reson Imaging Clin N Am. 2012;20:435–46.
60. Williams LS, Mancuso AA, Mendenhall WM. Perineural spread of cutaneous squamous and
basal cell carcinoma: CT and MR detection and its impact on patient management and prog-
nosis. Int J Radiat Oncol Biol Phys. 2001;49:1061–9.
61. Solares CA, Lee K, Parmar P, et al. Epidemiology of clinical perineural invasion in cutaneous squa-
mous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg. 2012;146:746–51.
62. Nemzek WR, Hecht S, Gandour-Edwards R, et al. Perineural spread of head and neck tumors:
how accurate is MR imaging? AJNR Am J Neuroradiol. 1998;19:701–6.
63. American Joint Committee on Cancer. In: Edge SB, Byrd DR, Compton CC, et al., editors.
AJCC staging manual. 7th ed. New York: Springer; 2010. p. 301–14.
64. Panizza B, Warren T. Perineural invasion of head and neck skin cancer: diagnostic and thera-
peutic implications. Curr Oncol Rep. 2012;15:128–33.
65. Barnett CM, Foote MC, Panizza B. Cutaneous head and neck malignancies with perineural
spread to contralateral cranial nerves: an argument for extending postoperative radiotherapy
volume. J Clin Oncol. 2012;31:e291–3.
66. Mendenhall WM. Intensity-modulated radiotherapy in the standard management of head and
neck cancer: promises and pitfalls. J Clin Oncol. 2006;24:2618–23.
67. Batsakis JG. Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol. 1985;94:426–7.
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© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_10
S. Anderson , Biomed Sc, MBBS, FRACS, MPhil (*)
Otolaryngology-Head and Neck Surgery, The Townsville Hospital , Townsville ,
QLD , Australia
e-mail: andotown@me.com
P. Patel , MSc, MBBS, BSc, DO-HNS, FRCS
Otolaryngology-Head and Neck Surgery, St Georges Hospitals NHS Trust ,
Blackshaw Road , London , UK
e-mail: paraguk@gmail.com
B. Panizza , MBBS, MBA, FRACS
Department of Otolaryngology-Head and Neck Surgery , School of Medicine, University
of Queensland, Queensland Head and Neck Cancer Centre, Queensland Skull Base Unit,
Princess Alexandra Hospital , Brisbane , QLD , Australia
e-mail: ben@panizza.com.au
1 0
Squamous Cell Carcinoma Extending
to the Temporal Bone
Shane Anderson , Parag Patel , and Benedict Panizza
Introduction
Squamous cell carcinoma (SCC) of the temporal bone is an aggressive malignancy.
It presents as a primary tumour of the temporal bone arising in the middle ear or
external auditory canal (EAC). Secondary invasion of the temporal bone occurs
because of direct spread from a primary lesion of the pinna and its surrounds, or
from cutaneous SCC (cSCC) metastasis to the fi rst echelon lymph node bed. In
Australia, SCC of the temporal bone typically presents from direct invasion from a
cutaneous primary, or from metastatic spread from a cutaneous primary to the
parotid lymph nodes abutting the temporal bone [ 1 ].
The rarity of disease, variety of histological subtypes, location of the primary,
lack of a universally accepted staging, and surgical nomenclature make evidence-
based management problematic. Most reports include primary and secondary inva-
sive malignancy in the same cohort [ 1 ]. Hence, treatment is driven by consensus and
observational studies.
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132
The aggressive nature of this disease mandates aggressive surgery with a focus
on achieving clear margins. Management requires a motivated patient who accepts
the signifi cant morbidity associated with achieving this result.
This chapter discusses the pathology and epidemiology of temporal bone
SCC. An overview is given of the special circumstances and controversies in stag-
ing; and strategies to achieve clear surgical margins are also outlined.
Pathology and Epidemiology
Primary SCC of the temporal bone is rare (6:1,000,000) [ 2 ]. Most primary tumours
occur in the EAC with only 5 % occurring in the middle ear [ 3 ]. The majority of
SCCs involving the temporal bone is secondary, with direct invasion from primary
lesions of adjacent structures (Fig. 10.1 ) or invasion from cutaneous metastatic
deposits of the parotid or occipital lymph node beds. In our institution, 90 % of
lateral temporal bone resections (LTBR) performed are for the treatment of meta-
static cutaneous malignancy [ 1 ].
Whereas the risk factors for primary skin cancers are well documented, meta-
static spread is relatively uncommon and occurs more frequently in the immuno-
compromised patient [ 4 ]. Primary carcinoma of the temporal bone arises in the
setting of chronic infl ammation [ 5 ]. Histologically, the majority of neoplasms
encountered on the pinna are basal cell carcinomas (BCCs). SCC, on the other hand,
is found chiefl y in the EAC and middle ear. Carcinoma in the middle ear can also
have an origin in the salivary gland, but this is rare [ 6 ].
Most cSCCs do not metastasize. Therefore, when they do spread to the adja-
cent lymph node beds of the temporal bone and become invasive, they are an
aggressive phenotype [ 4 ]. SCC involving the temporal bone spreads rapidly, as
the embryological fusion planes that form the temporal bone facilitate spread by
the path of least resistance. Primary cutaneous malignancy of the pinna has easy
access to the EAC by direct invasion. Typically, metastatic cutaneous carcinoma
to the fi rst echelon lymph nodes of the parotid bed will grow and abut the
Fig. 10.1 Cutaneous SCC
invading the parotid and
anterior temporal bone
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EAC. From here tumour can spread into the ear canal by the fi ssure of santorini in
the tragal cartilage. This same pathway allows anterior spread of primary EAC
malignancy to the fi rst echelon lymph node bed in the parotid gland. Within the
cartilaginous EAC a tumour can spread posteriorly through the conchae into the
post-auricular sulcus. Once the bony EAC is involved, the tumour spreads rapidly
under the thin skin of the EAC medially through to the tympanic membrane before
entering the middle ear [ 7 ]. The skin within the EAC is thin and its proximity to
underlying cartilage and bone make complete excision challenging [ 8 ]. Regardless
of the origin of temporal bone malignancy, once the EAC is involved, the tumours
tend to spread in a similar fashion [ 9 ].
Within the middle ear, the tumour can spread in multiple directions, depending
on aeration of the middle ear and path of least resistance. Anteriorly, the tumour
spreads through the mesotympanum into the carotid canal and eustachian tube.
Once the carotid canal is involved, spread can proceed superiorly into Meckel’s
cave and the cavernous sinus. Medially, weak points in the otic capsule at the
round and oval windows allow spread into the vestibule, cochlea, internal acoustic
meatus and posterior cranial fossa. Inferior spread allows invasion to the jugular
foramen and lower cranial nerves. Superior spread can cause tegmen erosion and
dural/ temporal lobe involvement (Figs. 10.2 and 10.3 ).
Fig. 10.2 Coronal view of the temporal bone showing tumour spread from ( a ) the cartilaginous
EAC to the annulus. Once the annulus is breached, tumour in the middle ear can spread by the path
of least resistance, ( b ) superiorly to the tegmen, ( c ) medially through the otic capsule, and ( d )
inferiorly into the hypotympanum
10 Squamous Cell Carcinoma Extending to the Temporal Bone
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The facial nerve can be involved by several mechanisms. Direct invasion in the
mesotympanic portion of the facial nerve or, in advanced disease, direct invasion of
the mastoid segment can occur. More commonly, the facial nerve is involved by
metastatic deposits in the extra-tympanic portion of the facial nerve. This occurs
because of large nerve perineural spread or direct invasion at the stylomastoid fora-
men [ 7 ].
Clinical Presentation
Primary pinna lesions often present after attempts at local excision result in a posi-
tive margin. Typically, in this scenario the degree of spread is underestimated and
extends medially along tissue planes underneath the approximated skin. Metastatic
cSCC spread to the temporal bone is usually obvious, with a history of progressive
swelling in the adjacent lymph node beds prior to otological symptoms. The rarity
of primary temporal bone carcinoma results in complacency; in the early stages it
Fig. 10.3 Axial view of the temporal bone showing tumour spread ( a ) directly from the parotid
bed into the temporo-mandibular joint, ( b ) from the parotid bed through the fi ssure of santorini into
the external auditory canal (EAC), ( c ) the cartilaginous EAC to the annulus. Once the annulus is
breached, tumour in the middle ear can spread by the path of least resistance, ( d ) anteriorly to the
eustachian tube and internal carotid artery, ( e ) medially through the otic capsule and facial nerve,
and ( f ) posteriorly to the mastoid cavity
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135
tends to be misdiagnosed as symptoms of otalgia and otorrhoea are non-specifi c [ 2 ].
Deep unrelenting pain that does not improve rapidly with standard treatment should
prompt a biopsy [ 7 ]. As the tumour advances, the presentation becomes more obvi-
ous, with a facial nerve palsy or noticeable tumour extension.
A thorough clinical examination is paramount, and includes skin survey, cranial
nerve examination and comprehensive head and neck examination of the nodal
basins. Often, signs and symptoms can predict the path of invasion (Table 10.1 ).
Facial nerve palsy indicates advanced disease. It is important to differentiate facial
nerve weakness as a consequence of previous surgical excisions and progressive
weakness indicative of perineural invasion. Often the medial EAC and tympanic
membrane are not accessible because of the tumour or pain—hence imaging is vital.
Imaging
Arriaga et al . studied the correlation between computed tomography (CT) and surgical
fi ndings and concluded that CT helps to defi ne the pathological extent of tumour and
bone erosion but is limited in that mucosal infl ammation cannot be distinguished from
tumour without bone erosion [ 10 ]. MRI (magnetic resonance imaging) can be useful to
evaluate soft tissue extension and to differentiate the contents of the middle ear [ 11 ].
The 3-Tesla (3 T) platform improves resolution and signal to noise ratio when defi ning
cranial nerves and the skull base [ 12 ]. In our institution, we routinely perform a high-
resolution CT with contrast using both bone and soft tissue windows in conjunction
with a 3 T MRI neurogram. This differentiates pathological soft tissue growth from
retained mucosal secretions, temporomandibular joint (TMJ) capsule invasion, and
perineural spread (PNS) within the facial nerve and auriculotemporal nerve.
Staging
The complexity of anatomical relations within the temporal bone mandates accurate
preoperative staging [ 13 ]. This imaging is essential for prognostication and staging
when developing a surgical plan with other specialties, such as neurosurgery.
Table 10.1 Signs and symptoms that often predict the path of invasion in temporal bone
malignancy
Path of invasion Signs and symptoms
Middle ear and eustachian tube Conductive hearing loss, otalgia, taste disturbance
Otic capsule Sensorineural hearing loss, facial nerve palsy, vertigo
Carotid canal Horner syndrome, syncopal episodes
Temporomandibular joint Trismus, malocclusion
Jugular foramen Lower cranial nerve palsies
Intracranial Seizure, cognitive defi cits, meningitis/encephalitis
Infratemporal fossa Mandibular nerve (V3) paresis
10 Squamous Cell Carcinoma Extending to the Temporal Bone
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Staging of invasive cSCC of the temporal bone with the American Joint Committee
on Cancer (AJCC) guideline for cutaneous malignancy is problematic, as even early
SCC of the EAC which has easy access to bone, is given a T4 status [ 8 ]. These
tumours are allocated the same status as deep parotid tumours with facial nerve
palsy that is clearly not representative of the extent of tumour spread.
Arriaga et al . developed a comprehensive system to stage tumours of the EAC on
the basis of CT and pathological fi ndings [ 13 ]. Moody et al. argue that by defi nition,
facial nerve paralysis, when the middle ear is involved, refl ects extension through
the annulus and into bone of the medial wall of the middle ear [
11 ]. If paralysis
occurs on account of extra-temporal invasion, >5 mm of soft tissue is likely to be
involved; thus they recommended upstaging facial paralysis to T4 (Table 10.2 ) [ 11 ].
The Pittsburgh tumour staging system for EAC SCC is gaining support in the litera-
ture and has been validated by other studies [ 8 ].
The N and M status of the Pittsburgh staging system is based on the original AJCC
classifi cation [ 14 ]. The staging system places considerable importance on metastasis as
a T2 lesion, with any cervical metastasis considered to be stage IV disease.
Prognosis
Poor prognostic indicators are debated in the literature and refl ect the variability in
presentations and management. Although still debated, the following features are sug-
gestive of a poor outcome: (i) bone invasion [ 15 , 16 ], (ii) extension to middle ear [ 15 , 17 ],
Table 10.2 Comparison of the evolution of staging of external auditory canal (EAC) squamous
cell carcinoma from the standard American Joint Committee on Cancer (AJCC) cutaneous malig-
nancy staging system with the Pittsburgh staging system
AJCC Arriaga et al. [ 13 ] Moody et al. [
11 ]
T1 Tumour <2 cm
with <2 high-risk
features
Tumour limited to the EAM
without bony erosion or
evidence of soft-tissue
extension
Tumour limited to the EAM
without bony erosion or evidence
of soft-tissue involvement
T2 Tumour >2 cm in
greatest dimension
or tumour of any
size, with ≥2
high-risk features
Limited EAM bone erosion
(not full thickness) or
radiographic fi nding consistent
with limited (<5 mm)
soft-tissue involvement
Tumour limited to the EAC with
bone erosion (not full thickness)
or limited soft-tissue
involvement (<5 mm)
T3 Tumour with
invasion of
maxilla, orbit or
temporal bone
Full thickness erosion of the
EAM bone, tumour involving
the middle ear or mastoid—
facial nerve palsy
Tumour eroding the osseous
EAC with limited soft-tissue
involvement (<5 mm) or tumour
in the middle ear or mastoid
T4 Tumour invasion
of skeleton or
perineural invasion
of the skull base
Tumour eroding cochlea,
petrous apex, medial wall of
middle ear, carotid canal,
jugular foramen or dura, with
5 mm soft-tissue involvement
Tumour eroding cochlea, petrous
apex, medial wall of middle ear,
carotid canal, jugular foramen,
dura, with >5 mm soft-tissue
involvement, or evidence of
facial paresis
EAM external auditory meatus, EAC external auditory canal
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137
(iii) facial paralysis [ 9 ], (iv) dural involvement [ 5 ], (v) PNS [ 8 ], (vi) early (T1−T2)
versus late (T3−T4) presentation [ 1 ], and (vii) regional lymphadenopathy [ 18 ].
Whereas these features might be debatable, the fact that recurrence after initial
management offers a dismal outcome is undisputed [ 18 ], as is the fact that achieving
clear margins signifi cantly improves survival [ 1 , 10 , 19 ]. Often, recurrence occurs
quickly and aggressively, prompting many investigators to believe that a disease-
free survival of 2 years can be considered a cure [ 18 ]. Arriaga et al. quote a 75 %
disease-specifi c survival (DSS) in patients with negative margins compared with a
25 % DSS in patients with positive margins [
13 ]. This is corroborated by Prasad and
Janecka who report that in locations where clear margins cannot be achieved, such
as the petrous apex, ICA, dura and brain, survival is poor [ 5 ]. In the senior author’s
experience (BP), DSS was 79 % and 62 % for 2 and 5 years, respectively, with T1−2
tumours having a 100 % 5-year survival [ 1 ].
Management (History and Surgical Rationale)
Management requires close collaboration in the setting of a head and neck multidis-
ciplinary team (HNMDT) meeting. Importantly, the meeting must have a skill mix
that allows for accurate radiological staging so that an appropriate surgical plan can
be established. Resection should aim to achieve clear margins, if possible. The abla-
tive surgeon should plan to achieve this either with primary surgery to the temporal
bone or in association with ancillary manoeuvres, such as parotidectomy, TMJ
resection, infratemporal fossa resection, access to the middle cranial fossa, and neck
dissection to gain clearance. Like others in the fi eld, our team considers involve-
ment of the internal carotid artery, cavernous sinus and jugular bulb incurable, and
hence would offer debulking surgery or palliative radiotherapy [ 19 ]. Reconstruction
is required after ablation. In our institution, this is usually achieved with a vascular-
ized free fl ap. Finally, detailed specimen labelling and description is required so that
a specialized head and neck pathologist can give an accurate report of the relevant
margins and be aware of the air–tumour interface in the mastoid cavity for postop-
erative treatment by radiation and medical oncologists.
Oncologically sound surgery mandates resection with clear surgical margins
[
20 ]. Incomplete excision, in an effort to preserve cosmesis and function, places the
patient at risk of local recurrence, metastasis [ 21 ], and a poor prognosis [ 18 , 22 ].
The aggressive nature of this disease mandates a surgical plan that can result in
morbidity. Before undertaking surgery, patient comorbidities must be taken into
account by the HNMDT, who should make a decision with a motivated patient only
after a frank discussion on the risks and benefi ts of surgery. Surgical management to
address the temporal bone component of disease does not vary for primary or sec-
ondary disease [ 9 ]. Our group does not advocate the use of sleeve resection in SCC
of the EAC. Less aggressive procedures, such as local canal resection, make clear
margins diffi cult to achieve, with 54 % of tumours treated this way showing positive
margins in one cohort [
23 ] In this study, recurrence rates of 46 % for T1 and T2
tumours were reported [ 23 ].
10 Squamous Cell Carcinoma Extending to the Temporal Bone
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Confusion has occurred because descriptions for temporal bone resection vary
[ 11 ]. Traditionally, these malignancies were addressed with a radical mastoidec-
tomy and ablation of the EAC. Parsons and Lewis proposed an en-bloc subtotal
temporal bone resection (STBR) as an alternative to a radical mastoidectomy, with
resection of the medial surface of the mesotympanum, leaving only the air cells of
the petrous apex and internal carotid artery [ 24 ]. The total temporal bone resection
(TTBR) is an extension of this with incorporation of the petrous apex and sacrifi ce
of the internal carotid artery. To preserve facial nerve function, Conley and Novack
described the lateral temporal bone resection (LTBR) [
25 ]. In 1997, Hirsch and
Chang rationalized the nomenclature for temporal bone resection with LTBR,
STBR, TTBR [ 7 ].
Surgical Philosophy
To achieve a reasonable outcome, the intent of surgery must be to resect with clear
margins. The temporal bone resection allows for clear medial margins in the prop-
erly selected patient. To achieve a clear peripheral margin requires the use of ancil-
lary manoeuvres. At a minimum, Leong et al . advocate a superfi cial parotidectomy
in conjunction with a LTBR to ensure resection of SCCs that involve the EAC [ 22 ].
The rationale for this is that often invasion through the fi ssure of santorini is not
detected on radiology. The operation is extended to a radical parotidectomy if evi-
dence exists of facial nerve involvement, or if there is obvious tumour medial to the
facial nerve, as in this scenario facial nerve involvement is inevitable. Our group
does not advocate a prophylactic comprehensive neck dissection, as only 7.5–15 %
of patients will have occult cervical lymphadenopathy at the time of presentation [ 6 ,
26 , 27 ]. Often, a limited level 1B-III neck dissection is performed to facilitate vas-
cular access for free-fl ap reconstruction. Further spread medially is often limited by
the tough capsule of the TMJ. This can be resected as a medial margin with a paroti-
dectomy. If involvement of the TMJ or mandible is evident on preoperative staging,
then this is sacrifi ced to gain clear margins (Figs.
10.4 and 10.5 ). In the experience
of the senior author, the incorporation of the TMJ or mandible en bloc with the
temporal bone resection was required in 30 % of the advanced cases seen in our
institution [ 1 ].
A signifi cant factor in the evolution of skull base surgery has been the use of
radiology to improve surgical planning. Specifi cally, in lateral skull base surgery a
3 T MRI neurogram allows for proper surgical planning to address PNS and soft-
tissue extension. In obvious facial nerve PNS to the stylomastoid foramen, the facial
nerve is sacrifi ced to the second genu and frozen section assessment is carried out
to determine clearance. If PNS exists, then further resection with a STBR is required
and more frozen sections are taken to achieve at least a 5 mm clearance margin.
Surgery for perineural spread beyond the geniculate ganglion is controversial.
However, as the tumour is often confi ned within the perineurium [
28 ] and the nerve
is surrounded by the cerebrospinal fl uid, the senior author will resect the facial
nerve back to the brainstem to achieve a clear margin. Perineural spread along the
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auriculotemporal branch of the mandibular nerve requires clearance of the infratem-
poral fossa. This is achieved by resecting the TMJ, ascending mandible and ptery-
goid muscles. Again, frozen section control of the mandibular nerve at the foramen
ovale is performed. The philosophy of preserving the facial nerve, if it is fully func-
tioning, is well documented in parotid malignancy [ 29 ]. Whereas every effort is
made to preserve the facial nerve if it is functioning, this is not done at the expense
of involved margins, in temporal bone resection.
Using this philosophy, the senior author has achieved a 2-year overall survival
rate of 79 % for all stages of disease. This compares favourably to other cohorts in
which large tumours of the parotid (>6 cm or involving skull base) treated with a
radical parotidectomy have achieved survival rates for 2 years of only 37 % [ 30 ].
Although these cohorts are small it shows the importance of aggressive surgery for
this disease.
Fig. 10.4 Clinical photo
after lateral temporal bone
resection with extended
resection to include the
temporo-mandibular joint
demonstrating ( a ) intact
facial nerve from second
genu to periphery, ( b )
sino-dural angle, ( c ) glenoid
fossa, ( d ) cut end of the
neck of mandible, ( e )
posterior belly of digastric
with removal of mastoid tip,
and ( f ) remaining deep lobe
of parotid
Fig. 10.5 Clinical photo of
en-bloc specimen
demonstrating ( a ) lateral
temporal bone, ( b )
conservative parotid, ( c ) head
of malleus, and ( d ) neck of
mandible
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Lateral Temporal Bone Resection (LTBR)
The surgical goal of a LTBR is to completely excise the EAC with its bony margins.
The medial boundary of resection is the tympanic membrane which is excised with
the specimen, leaving the intact facial nerve.
Soft-tissue incisions are dictated by the location of the primary lesion but require
enough exposure to identify the sigmoid sinus posteriorly and the tegmen superi-
orly. Once this is achieved a standard mastoidectomy is performed to expose the
bony plate over the sigmoid sinus and the middle cranial fossa dura. A posterior
tympanotomy is formed and the incudostapedial joint is disarticulated. The poste-
rior tympanotomy is extended inferiorly into the hypotympanum, sacrifi cing the
chorda tympani with sharp dissection; this is extended into the hypotympanum and
extended anteriorly into the TMJ. The mastoidectomy is extended into the epitym-
panum to the root of the zygoma to reach the superior TMJ. The specimen can be
rolled forward with digital pressure on the remaining EAC bone. Sometimes an
osteotome passed though the posterior tympanotomy is required to liberate the tym-
panic plate [ 26 ]. This manoeuvre can also be used to gain access if the posterior
tympanotomy is narrow (for a detailed description of this procedure, see Ref. [ 26 ]).
Subtotal Temporal Bone Resection (STBR) and Total
Temporal Bone Resection (TTBR)
The STBR describes resection of the medial surface of the mesotympanum, leaving
only the air cells of the petrous apex and internal carotid artery. Before proceeding,
it is important to inspect both the middle and posterior cranial fossa dura for inva-
sion before committing to a large resection. Invasion through the dura results in
meningeal carcinomatosis and is irresectable.
Again, soft-tissue exposure is dictated by the location of the primary lesion but
needs to be suffi cient for access to the middle and posterior cranial fossa. A middle
and posterior temporal craniotomy is performed, extending to the root of the
zygoma. The middle cranial fossa is dissected from the petrous bone to ensure that
the dura is not involved. Posteriorly the dissection is extended to identify the sig-
moid sinus and jugular bulb before exposing the pre- and post-sigmoid dura. It is at
this point a decision is made to proceed, if the dura is not breached. Once this deci-
sion is made, venous control is gained by incising the sigmoid sinus with packing
proximally and opening the jugular bulb and packing the inferior petrosal sinus to
gain infl ow control. A preoperative MRI venogram is performed to assess the tor-
cula for patency. If the contralateral fl ow is inadequate, sacrifi cing the jugular bulb
may lead to venous infarction. To free the temporal bone, a diamond drill is used to
make a cut along the superomedial aspect of the jugular bulb into the hypotympa-
num and up to the posterior wall of the carotid canal. Next, the middle cranial fossa
is dissected free to the foramen ovale. The middle meningeal artery is coagulated at
the foramen spinosum and the dissection is continued to the connective tissue of the
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posterolateral margin of the foramen lacerum. The roof and lateral wall of the inter-
nal carotid canal are removed using a diamond drill all the way to the cochlea. A
diamond drill is then used to create an osteotomy via the middle cranial fossa from
the petrous bone just lateral to the porus acousticus anteriorly to the carotid canal
and inferiorly to the jugular foramen. Finally, a cut is made from the root of the
zygoma, across the fl oor of the middle cranial fossa immediately behind the fora-
men ovale to the carotid canal. The specimen is then freed by pushing anteroinferi-
orly and using sharp dissection to free any soft-tissue attachments, including the
nerves of the internal acoustic meatus. Haemostasis is achieved and the dural defect
is repaired. This can be completed with primary closure or the use of a fascial graft,
such as tensor fascia lata followed by free-fl ap reconstruction (for a detailed descrip-
tion, see Ref. [
26 ]).
The morbidity of a STBR is limited to facial nerve palsy, loss of hearing and bal-
ance, which most patients can compensate. However, a TTBR involves extending
the dissection to include the petrous apex with resection of the internal carotid
artery. The potential damage to the cavernous sinus, internal carotid artery and post-
operative cranial nerve 3–6 palsy makes this procedure extremely morbid. The con-
sensus is that TTBR is unjustifi ed because of the increased morbidity with no proven
survival benefi t [ 20 ].
Postoperative Radiotherapy
In the experience of our group and that of others, the greatest chance of survival
occurs with clear margins and postoperative radiotherapy [ 1 , 8 , 20 , 29 ]. In the set-
ting of positive margins, postoperative radiotherapy improves survival [ 20 ]. Several
groups advocate surgery alone for limited T1 surgical disease [ 2 , 20 ] and radiation
in the event of adverse histological markers only [ 22 ].
We advocate adjuvant radiation for stage T2 − 3 cancers. In the setting of T4
temporal bone cancer, the outcomes are dismal, with 5-year DSS varying between
10 and 50 % [
11 , 20 ]. In the setting of T4 disease, our group advocates surgery with
radiotherapy only if clear margins can be achieved or if debulking will aid in pallia-
tion. If clear margins cannot be achieved, several workers advocate radiotherapy
alone, giving comparable results to palliative surgery [ 20 , 31 ].
Conclusion
Typically in Australia, temporal bone carcinoma occurs in the setting of meta-
static cSCC to the parotid bed with tumour abutting the EAC. In order to achieve
satisfactory cure rates this requires an aggressive surgical resection with a focus
on clear margins. The temporal bone resection allows for posterior and medial
clearance of the temporal bone. In association with ancillary manoeuvres, such
as parotidectomy, TMJ resection, infratemporal fossa resection and neck dissec-
tion, temporal bone resection also allows for anterior and inferior control. Our
group advocates the use of postoperative radiotherapy to improve survival.
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References
1. Essig G, Kitipornchai L, Adams F, et al. Lateral temporal bone resection in advanced cutane-
ous squamous cell carcinoma: report of 35 patients. J Neurol Surg B Skull Base.
2013;74:54–9.
2. Chi FL, Gu FM, Dai CF, et al. Survival outcomes in surgical treatment of 72 cases of SCC of
the temporal bone. Otol Neurotol. 2011;32:665–9.
3. Conley JJ, Novack AJ. Surgical treatment of cancer of the ear and temporal bone. Trans Am
Acad Ophthalmol Otolaryngol. 1960;64:83–92.
4. Chu A, Osguthorpe JD. Nonmealanoma cutaneous malignancy with regional metastasis.
Otolaryngol Head Neck Surg. 2003;128:663–73.
5. Prasad S, Janecka IP. Effi cacy of surgical treatments for SCC of the temporal bone: a literature
review. Otolaryngol Head Neck Surg. 1994;110:210–80.
6. Goodwin W, Jesse R. Malignant neoplasms of the EAC and temporal bone. Arch Otolaryngol.
1980;106:675–9.
7. Hirsch BE, Chang CYJ. Carcinoma of the temporal bone. In: Myers EN, editor. Operative
otolaryngology head and neck surgery. Philadelphia: WB Saunders; 1997. p. 1434–58.
8. Gaudet JE, Walvekar RR, Arriaga MA, et al. Applicability of the Pittsburgh Staging System
for advanced cutaneous malignancy of the temporal bone. Skull Base. 2010;20:409–14.
9. Lassig AA, Spector ME, Soliman S, et al. Squamous cell carcinoma involving the temporal
bone: lateral temporal bone resection as primary intervention. Otol Neurotol. 2013;34:141–50.
10. Arriaga M, Curtin HD, Takahashi H, et al. The role of preoperative CT scans in staging exter-
nal auditory meatus carcinoma: radiologic-pathologic correlation study. Otolaryngol Head
Neck Surg. 1991;105:6–11.
11. Moody SA, Hirsch BE, Myers EN. Squamous cell carcinoma of the external auditory canal: an
evaluation of a staging system. Am J Otol. 2000;21:582–8.
12. Gandhi MR, Panizza B, Kennedy D. Detecting and defi ning the anatomical extent of large
nerve perineural spread of malignancy: comparing ‘targeted’ MRI with the histologic fi ndings
following surgery. Head Neck. 2011;33:469–75.
13. Arriaga M, Curtin H, Takahashi H, et al. Staging proposal for EAC carcinoma based on preop-
erative clinical examination and CT fi ndings. Ann Otol Rhinol Laryngol. 1990;99:714–21.
14. Edge SB, Byrd DR, Compton CC, et al. Cutaneous squamous cell carcinoma and other cutane-
ous carcinomas. AJCC cancer staging manual. 7th ed. New York: Springer; 2010, p. 301–14.
15. Kinney S, Wood B. Malignancies of the external ear canal and temporal bone: surgical tech-
niques and results. Laryngoscope. 1987;97:158–64.
16. Spector JG. Management of temporal bone carcinomas: a therapeutic analysis of two groups
of patients and long term follow-up. Otolaryngol Head Neck Surg. 1991;104:58–66.
17. Morris LG, Mehra S, Shah JP, et al. Predictors of survival and recurrence after temporal bone
resection for cancer. Head Neck. 2012;34:1231–9.
18. Mantravadi AV, Marzo SJ, Leonetti JP, et al. Lateral temporal bone and parotid malignancy
with facial nerve involvement. Otolaryngol Head Neck Surg. 2011;144:395–401.
19. Pensak ML, Gleich LL, Gluckman JL, et al. Temporal bone carcinoma: contemporary perspec-
tives in the skull base era. Laryngoscope. 1996;106:1234–7.
20. Bacciu A, Clemente IA, Piccirillo E, et al. Guidelines for treating temporal bone carcinoma
based on long term outcomes. Otol Neurotol. 2013;34:898–907.
21. Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous cell skin cancer. J Clin
Oncol. 2005;23:759–65.
22. Leong SC, Youssef A, Lesser TH. Squamous cell carcinoma of the temporal bone: outcomes
of radical surgery and postoperative radiotherapy. Laryngoscope. 2013;123:2442–8.
23. Zhang T, Li W, Dai C, et al. Evidence-based surgical management of T1 or T2 temporal bone
malignancies. Laryngoscope. 2013;123:244–8.
24. Parsons H, Lewis JS. Subtotal resection of the temporal bone for cancer of the ear. Cancer.
1954;7:995–1001.
S. Anderson et al.
malcolm_buchanan123@hotmail.com
143
25. Conley JJ, Novack AJ. The surgical treatment of malignant tumours of the ear and temporal
bone. Part I. AMA Arch Otolaryngol. 1960;71:635–52.
26. Panizza B, Solares CA, Gleeson M. Lateral skull base surgery (Chapter 40). In: Watkinson JC,
Gilbert RW, editors. Stell and Maran’s textbook of head and neck surgery. London: Hodder
Arnold; 2012. p. 779–90.
27. Zanoletti E, Danesi G. The problem of nodal disease in squamous cell carcinoma of the tem-
poral bone. Acta Otolaryngol. 2010;130:913–6.
28. Panizza B, Warren TA, Solares CA, et al. Histopathological features of clinical perineural inva-
sion of cutaneous squamous cell carcinoma of the head and neck and the potential implications
for treatment. Head Neck. 2014;36:1611–8.
29. O’Brien C, Adams JR. Surgical management of the facial nerve in the presence of malignancy
about the face. Curr Opin Otolaryngol Head Neck Surg. 2001;9:90–4.
30. O’Brien CJ, McNeil EB, McMahon JD, et al. Signifi cance of clinical stage, extent of surgery,
and pathological fi ndings in metastatic cutaneous squamous carcinoma of the parotid gland.
Head Neck. 2002;24:417–22.
31. Pemberton LS, Swindell R, Sykes AJ. Primary radical radiotherapy for squamous cell carci-
noma of the middle ear and external auditory canal: an historical series. Clin Oncol.
2006;18:390–4.
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© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_11
145
A. J. Alexander , MD, FRCSC (*)
Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head
and Neck Surgery , University of Toronto, Mount Sinai Hospital and Rouge Valley Hospital ,
Toronto , ON , Canada
e-mail: ashlin.alexander@gmail.com
S. M. Gore , MD, FRCS (Plast)
Plastic and Reconstructive Surgery, Oxford University Hospitals , Oxford , UK
J. Clark , MBBS, BSc, MBiostat, FRACS
Head and Neck Surgery, Sydney Head and Neck Cancer Institute, Royal Prince Alfred
Hospital , Sydney , NSW , Australia
e-mail: jcjc@tpg.com.au
1 1
Reconstructive Options for the Face
Ashlin J. Alexander , Sinclair M. Gore , and Jonathan Clark
Introduction
Non-melanoma skin cancer (NMSC) is the most common form of cancer world-
wide. In 2008, approximately 430,000 cases of NMSC were diagnosed in Australia;
of these, 296,000 were basal cell carcinoma (BCC) and 138,000 were squamous cell
carcinoma (SCC) [ 1 , 2 ]. Whereas many treatment options exist, the mainstay of
management is surgical excision with adequate margins, followed by reconstruc-
tion. The functional and aesthetic consequences of surgery of the face, more than
that of any other part of the body, can be dramatic. Therefore, the reconstructive
surgeon must apply a thorough and thoughtful approach to the repair of facial
defects. While a full analysis of the topic is outside the scope of this chapter, an
overview of the general concepts and techniques used to address the various sub-
units of the face are discussed.
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Principles of Reconstruction
Since the time of Sushruta in 1500 bc , facial reconstruction techniques have
advanced considerably. Yet, the overriding goals have remained the same, i.e. to
restore form and function. As one climbs the reconstructive ladder, the choice of
reconstructive options is wide. Healing by secondary intention can provide a per-
fectly satisfactory result for certain concave areas, such as the conchal bowl, and
perialar and medial canthal regions. Primary closure, with the incision oriented
along a relaxed skin tension line, is especially feasible in elderly patients with skin
and soft tissue laxity. Full-thickness skin grafting can provide an aesthetically satis-
factory result for superfi cial defects of the nasal dorsum, or as a temporizing mea-
sure while awaiting fi nal pathological assessment of resection margins. Although
regional and distant (free fl ap) options can be considered for larger and more com-
plex defects, local fl ap reconstruction is the workhorse technique for facial defect
repair. Local fl aps offer the ability to replace ‘like with like’ tissue, while maintain-
ing minimal donor site morbidity and ease of harvest. Local fl aps are defi ned as
tissue adjacent to the wound, which resurface the wound by means of advancement,
rotation or transposition. Numerous composite terms and eponymous fl aps have
been described, but these three methods of tissue movement are constant.
Preoperative Assessment
Surgical planning begins with a thorough history and physical examination. A prior
history of poor wound healing or keloid formation should be elicited, and any old
scars should be examined. Co-morbid conditions should be considered that could
affect healing, such as diabetes, immunosuppressive medications, or previous radio-
therapy to the region. Radiological investigations should be employed, when war-
ranted, to assess local extent of disease and to rule out regional or distant metastases.
Finally, the patient’s own goals should be reviewed, and expectations should be
appropriately managed.
Intraoperative Assessment
The primary factors for consideration in facial reconstruction involve an under-
standing of facial subunits, and orientation of relaxed skin tension lines (RSTLs). In
general, subunits should be reconstructed separately so that the junctions between
the different facial subunits are not effaced. For optimal scar camoufl age, incision
lines ought to be placed within or parallel to RSTLs, and/or within the boundaries
between subunits. For defects in the vicinity of the lower eyelid, careful consider-
ation must be given to the risk of postoperative lower lid malposition and ectropion;
local fl aps should be anchored to the periosteum where feasible, and a Frost stitch
or temporary lateral tarsorrhaphy may be employed to resist downward pull on the
lower eyelid during the healing period. With a Frost stitch, a 5–0 nylon suture is
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147
passed into and out of the grey line of the lower eyelid to engage the tarsal plate, at
the lateral limbus; the needle is then removed and the two loose ends are fi xated to
the forehead with steristrips such that the eyelids are in apposition. If lower eyelid
laxity is already present, additional support could be provided using a canthopexy
or lateral tarsal strip technique.
Postoperative Considerations
Wound closure is accomplished in at least two layers, with interrupted deep absorb-
able sutures, and a non-absorbable cutaneous suture. Timing of cutaneous suture
removal is dependent on the tissue characteristics of the wound (patient age, dimin-
ished wound healing capacity, tension, previous radiotherapy). In general, skin
sutures would be removed 5–7 days postoperatively in non-irradiated patients, and
at 10–14 days in irradiated tissue beds. Steristrips may be applied at the time of
surgery to further reduce wound tension, and the liberal use of ointment applied to
the incision line is recommended for the week following suture removal. Patients
are advised to avoid sun exposure for 6–9 months post-surgery to prevent scar
hyperpigmentation. In the appropriate patient, dermabrasion or laser resurfacing
can be considered to optimize scar camoufl age by smoothing and blending wound
edges with surrounding skin. Finally, consultation with an experienced aesthetician
can help patients apply cosmetic products to further camoufl age scars, as needed.
Reconstruction by Subunit
Scalp
Scalp tissue is relatively immobile, limited by the galea aponeurotica, which makes
the repair of even small scalp defects challenging. Defects <3 cm can be closed
primarily, with the aid of various manoeuvres. These include wide subgaleal under-
mining, intraoperative tissue stretching, and performing galeotomies. Raposio et al.
showed that three full-thickness galeotomies parallel to a sagittal scalp incision pro-
duced a 40 % reduction in scalp closing tension and 1.7 mm gain of tissue length,
per galeotomy [
3 ].
Intermediate-sized defects are best reconstructed using two or more rotation
fl aps. Rotation fl aps have a curvilinear confi guration, which suits the spherical
shape of the scalp, and they do not rely on tissue advancement, which is diffi cult to
achieve on account of the scalp’s inherent inelasticity. If using a single rotation fl ap,
the arc of the fl ap should be at least four times the diameter of the defect, and back
cuts at the base of the fl ap may be required [ 4 , 5 ]. Commonly, the secondary defect
might necessitate skin grafting. Standing cutaneous deformities should not be
resected at this time to maintain as much fl ap width as possible. If the deformity has
not fl attened at 6 weeks, it can be resected in a delayed fashion, as recipient site
vascularity will be suffi cient to maintain fl ap viability. Where possible, multiple
11 Reconstructive Options for the Face
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148
rotation fl aps are preferred because this recruits tissue from different locations on
the scalp, and also shares the burden of secondary defect closure between the fl aps.
Ideally, two or three rotation fl aps are used, thereby producing an O-Z or pinwheel
confi guration, respectively (Fig. 11.1a–d ).
Large (≥6 cm) partial thickness defects can be repaired with a fullthickness
skin graft if a vascularized wound base is preserved (pericranium or muscle). The
disadvantage of skin grafting is that a contour discrepancy will occur between
the native tissue and the grafted region. To overcome this, provided that the
patient does not need radiotherapy soon after extirpation, the wound can be left
to granulate; the area can then be skin grafted secondarily in order to reduce the
contour irregularity. Large fullthickness defects or near-total scalp defects are
suited to resurfacing with free tissue transfer. Particularly in the setting of a pre-
viously irradiated scalp, these large scalp defects are best reconstructed with a
latissimus dorsi muscle-only free fl ap combined with split-thickness skin graft
(STSG) [
6 ]. In this case, the fl ap is designed to be excessively bulky in the fi rst
instance, with the understanding that muscle atrophy will eventually lead to an
ideal contour (Figs. 11.1e–h ). If the scalp defect includes the full thickness of the
cranium, a chimeric free fl ap, including latissimus dorsi and the bony scapular
tip, can be employed [ 7 ].
Forehead
The forehead is that region of the face which is bounded superiorly by the frontal
hairline, inferiorly by the supraorbital ridge and laterally by the temporal regions.
The area can be divided into three zones: midline, paramedian and lateral. The mid-
pupillary line separates the latter two regions. Aesthetically, rhytides are oriented
horizontally, except in the glabellar region where they are vertical.
Defects of the central one-third, if closed with a vertically oriented scar (which
is perpendicular to the RSTLs), may still produce a cosmetically pleasing result;
this is because of the natural attenuation or dehiscence of the frontalis muscle in the
midline. Tissue should be elevated in a subgaleal plane and closed primarily, leaving
any areas that cannot be closed directly to heal by secondary intention.
In the paramedian and lateral regions, one or more advancement fl aps provide
the best aesthetic result because the incisions can be placed in a horizontal orienta-
tion, parallel to the hairline, eyebrows and forehead creases.
Because forehead tissue is relatively inelastic, bilateral advancement fl aps are
preferred in order to reduce wound closure tension. These fl aps should be elevated
in the subcutaneous plane to avoid damage to the supraorbital and supratrochlear
nerves. Defects of the upper central forehead can be approached using a large
scalp rotation fl ap, with the incision camoufl aged within the frontal hairline
(Fig. 11.1i–k ). Laterally, care should be taken not to damage the frontal branch of
the facial nerve, which lies within the temporoparietal fascia along a line from a
point 5 mm below the tragus to a point 15 mm lateral to the lateral eyebrow (the
so-called Pitanguy line).
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Fig. 11.1 ( a ) Scalp vertex squamous cell carcinoma. Black arrows indicate which markings were
incised. ( b ) Full-thickness vertex scalp defect involving the outer table of calvarium. Flaps ele-
vated in a subgaleal plane. ( c ) Large O-to-Z fl ap with clockwise rotation of the individual fl aps into
the defect. ( d ) Donor site resultant defects covered with split-thickness skin grafts. ( e ) Scalp squa-
mous cell carcinoma involving calvarium, requiring full-thickness soft tissue and bone resection.
( f ) Sagittal computer tomography scan showing calvarial inner table involvement. ( g )
Reconstruction with latissimus dorsi and scapular tip chimeric free fl ap, splitthickness skin graft
on muscle. ( h ) A different patient with a larger scalp defect also reconstructed with latissimus dorsi
free fl ap; approximately 4 months postoperatively. Notice atrophy of the latissimus dorsi muscle to
provide excellent scalp contour. ( i ) Upper central forehead basal cell carcinoma. Large scalp rota-
tion fl ap designed, with resultant standing cutaneous deformity to be excised marked out. ( j ) Note
primary limb of fl ap design is camoufl aged in frontal hairline. ( k ) Six months postoperative result
a
c
e
b
d
f
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Defects involving 25–30 % of the forehead region may be treated using a multi-
stage approach involving initial stabilization of the wound with a skin graft, fol-
lowed by serial tissue expansion [ 8 , 9 ]. Alternatively, secondary intention can
provide a highly satisfactory result in this setting. Defects >50 % of the forehead
surface area may be reconstructed with free tissue transfer. Although adequate con-
tour is feasible, colour match is commonly a problem. Gilbert and colleagues rec-
ommend a scapular free fl ap, or latissimus dorsi free fl ap with STSG for this defect
[
6 ]. The best split skin graft colour match for the face comes from the scalp. Shaving
the hair, tumescently infi ltrating the scalp with >1000 mm of saline, and harvesting
the graft with a dermatome aid this process. Subsequent hair re-growth leaves a
non-visible donor site and the risk of alopecia is low.
g
i
k
j
h
Fig. 11.1 (continued)
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Cheek
The cheek covers a large area of the face, and is a common site for cutaneous malig-
nancy. The parotid gland overlies the masseter muscle, and the facial nerve ema-
nates from the parotid gland into the cheek, deep to the superfi cial musculoaponeurotic
system.
The medial cheek region typically has an abundance of redundant skin and sub-
cutaneous tissue, which greatly aids in the reconstruction of medial cheek defects.
Transposition or advancement fl aps provide the best options. Transposition fl aps are
designed to recruit the redundancy of the jowl region, which can often allow pri-
mary closure of the donor site; fl aps are usually superiorly based, and incisions are
designed such that their closure will lie in the melolabial and labial mandibular
creases. A V-Y subcutaneous tissue pedicle island advancement fl ap provides a
good option for defects situated at or below the level of the nasal alae. A triangle-
shaped fl ap is designed to move along an axis parallel to the melolabial crease, with
the width equal to that of the defect, and the length equal to twice the height of the
defect. A subcutaneous pedicle is dissected to allow fl ap mobility, and the fl ap is
advanced into the defect in a V-Y fashion.
Lateral cheek tissue adheres more to the underlying fascia, and lacks the elasticity
of the medial cheek. Therefore, smaller defects in this region rely on transposition
fl aps, typically recruited from the skin immediately above the angle of the mandible;
this tissue has increased mobility compared to the skin near the temple. Larger
defects (>3–4 cm) are better suited to reconstruction using rotation- advancement
fl aps recruiting cervical skin. These fl aps are based medially and inferiorly, and can
transfer large amounts of skin from the remaining cheek and upper neck tissue. These
cervicofacial rotation fl aps can be used to cover defects as large as 10 cm [ 10 ].
Defects >10 cm, and full-thickness defects of the cheek, can be reconstructed
using free tissue transfer. Many options are available, and the type of tissue needed,
colour match and donor site morbidity must be factored into the decision. Through-
and- through full-thickness cheek defects require either two skin paddles or a single
folded paddle with a central de-epithelialized section. Options with inherent fl exi-
bility include the anterolateral thigh, scapular/parascapular or radial forearm free
fl aps. Cheek contour is critical to the aesthetics of the region; to that end, free tissue
transfer can also be employed solely for the purpose of providing volume, followed
by coverage with a skin graft or local fl ap. Free fl ap options with relatively low
donor site morbidity include the groin fl ap or the anterolateral thigh fl ap.
For cheek reconstruction, the surgeon must remain mindful of the surrounding
important structures. Gravity-induced ectropion can be prevented by suspending
fl aps to the periosteum with permanent sutures. If the facial nerve is involved with
the tumour and requires resection, interposition nerve grafts and/or static sling pro-
cedures can be incorporated. Parotid duct resection requires management via liga-
tion or duct repositioning.
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Radical Parotidectomy Defect Reconstruction
Australia has among the world’s highest rates of parotidectomy for malignancy,
secondary to the prevalence of cutaneous SCC with metastatic spread to the parotid.
The need for radical parotidectomy, however, remains relatively infrequent. When
radical extirpation is required, the resultant defect poses signifi cant morbidity for
patients. Reconstruction of the radical parotidectomy defect should aim to achieve
complete rehabilitation, i.e. full eye closure, facial symmetry, oral competence,
nasal valve support, normal facial contour, appropriate skin colour match, and even-
tual facial muscle tone. The Sydney Head and Neck Cancer Institute paradigm has
been to utilize the anterolateral thigh free fl ap to achieve many of these goals
(Fig. 11.2a–h ); a fasciocutaneous fl ap provides bulk to restore cheek contour and
replace skin defects that cannot be otherwise repaired with a cervicofacial rotation
fl ap. Fascia lata is harvested in three strips in order to suspend the oral commissure
and nasal ala, and nasolabial crease. The temporalis tendon is released from the
Fig. 11.2 ( a ) Radical parotidectomy defect. ( b ) Strip of fascia lata and motor nerve to vastuslate-
ralis which has been split to provide multiple branches for anastomosis. ( c ) Individual fascia lata
strips applied at 3 points of fi xation along melolabial fold. Proximal ends of fascia lata strips will
be attached to the detached temporalis tendon. ( d ) Immediately postoperatively, exaggeration of
the smile is intentionally performed to account for eventual relaxation of the suspension. ( e )
Insertion of upper lid platinum chain. ( f ) Lateral tarsal strip (different patient). ( g ) Re-suspension
of the lateral tarsal plate to provide close apposition of the lower lid to globe with minimal laxity.
( h ) Two years postoperatively. Full eye closure, and good facial symmetry at rest. Melolabial fold
elevation has relaxed partially, but the patient remains mildly overcorrected
d
ab
c
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coronoid process and is fi xated to the fascia lata slings. This provides an element of
dynamic reanimation. Alternatively, standard fascia lata static slings can be sus-
pended to the deep temporal fascia. The motor nerve to the vastus lateralis muscle
is harvested and used for interposition grafting where appropriate. An anterior belly
of digastric muscle transposition allows for lower lip eversion. A gold weight is
fi xed to the tarsal plate of the upper lid, and the lower lid is stabilized with a lateral
tarsal strip technique [ 11 ].
Lip
The lips play an important role in speech, deglutition and cosmesis. Structurally,
they are composed of the skin of the lip externally, the dry and wet vermilion, the
intraoral mucosa internally and the lip musculature between these layers. Key aes-
thetic landmarks include the vermilion border, the upper lip Cupid bow and phil-
trum. Several muscles coordinate to produce the complex movements of the lips. As
such, reconstruction can be challenging.
e
g
f
h
Fig. 11.2 (continued)
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Vermilion-only defects can be repaired with a labial mucosal advancement proce-
dure or by using a facial artery musculomucosal fl ap [ 12 ]. Defects up to one-third the
length of the lower lip typically can be closed primarily as a V-shaped wedge resection.
Primary closure requires closing mucosa, muscle and skin as three separate layers, with
precise realignment of the vermilion border. Cutaneous defects of this size can be con-
verted to full-thickness defects to facilitate primary closure. If the wedge resection
transgresses the mental crease, a W-plasty modifi cation can be employed. Lower lip
defects that are one-third to two-thirds the length of the lip are best managed using
either transoral cross-lip fl aps (Abbe [
13 ], Estlander) or circumoral advancement-
rotation fl aps (Karapandzic) (Fig. 11.3a–d ). Advantages of the Karapandzic fl ap
include a single-stage procedure, incisions placed in melolabial and mentolabial
creases, and preservation of the neurovascular bundles within the mobilized tissue. The
main disadvantage is microstomia. Another option for full- thickness lower lip defects
greater than one-half the lip length is the Webster modifi cation of the Bernard–Burow
cheiloplasty (bilateral cheek advancement fl ap) [ 14 ]. Webster et al.’s modifi cations
placed the Burow’s triangles in more aesthetic locations while at the same time pre-
serving more chin tissue. Their design also minimized the tendency for vertical defi -
ciency at the midline of the reconstructed lip (Fig. 11.3e–h ) [ 14 ].
Total lower lip reconstruction can be achieved with a radial forearm free fl ap
incorporating the palmaris longus tendon to provide a sling from which to suspend
the reconstructed lower lip from each modiolus (Fig. 11.3i–n ) [ 15 ].
Upper lip reconstruction is challenging because of its relatively less elasticity com-
pared with the lower lip, and because of the presence of a number of important aesthetic
features. Central upper lip defects can be repaired with an Abbe fl ap from the midline
lower lip [ 13 ], which can replicate the philtrum; to that end, Abbe fl aps are harvested
more commonly from the lower lip than from the upper lip. The fl ap remains pedicled
on the contralateral labial artery; in a second stage a few weeks later, the pedicle is
divided and inset is completed. Alternatively, bilateral advancement fl aps with perialar-
crescentric resections can be utilized. Total upper lip defects can be repaired using bilat-
eral island nasolabial fold fl aps [
16 ] (so-called Fujimori gate fl aps), or a pedicled or free
temporal scalp fl ap, which is hair-bearing and suitable for men [ 17 ].
The Estlander fl ap is the classic reconstruction for oral commissure defects. Again,
this is a lip switch technique involving the rotation of full-thickness lower lip tissue, ped-
icled on the labial artery, into the commissure/upper lip defect. The main disadvantage is
rounding of the commissure, which might necessitate a subsequent commissuroplasty.
Alternatively, Robotti and colleagues [ 18 ] describe using the elastic fl ap, fi rst described
by Goldstein [ 19 ], to reconstruct the commissure by taking advantage of the inherent
elasticity of the vermilion and orbicular oris muscle. This is a single-stage reconstruction
of the orbicularis ring that keeps scars within the vermilion and oral mucosa.
Eyelids
The eyelids are complex trilaminar structures whose principal function is to protect
the cornea. To conceptualize the reconstructive approach, the eyelid can be divided
into an anterior lamella (skin, orbicularis oculi muscle) and posterior lamella
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(conjunctiva, tarsus, eyelid retractors); the orbital septum can be considered as a
middle lamella. The tarsal plates are anchored posteriorly and superolaterally by the
lateral canthal tendon, which attaches to Whitnall’s tubercle inside the lateral orbital
rim. The medial canthal tendon (MCT) supports the medial canthus by enveloping
the lacrimal sac and inserting into the maxilla and posterior lacrimal crest. Tears
Fig. 11.3 ( a ) Subtotal lower lip defect with incisions for Karapandzic fl ap. ( b ) Bilateral fl aps
rotated and sutured into position. ( c ) Six months postoperatively, with good oral competence with
whistling. ( d ) Six months postoperatively, smiling view. ( e ) Greater than 50 % lower lip defect
with planned incisions for Bernard-Webster fl ap reconstruction. ( f ) Incisions for Bernard-Webster
fl ap. ( g ) Flap inset. Left neck incision secondary to sentinel node biopsy as part of a clinical trial.
( h ) Six month postoperative result at rest. ( i ) Lower lip squamous cell carcinoma. ( j ) Position of
radial forearm free fl ap with palmaris longus tendon after total lower lip resection. ( k ) Each end of
the palmaris longus tendon is anchored to the modiolus using permanent suture to provide a ten-
sioned suspension of the neo-lip. ( l ) Two-year postoperative view at rest. ( m ) Two-year postopera-
tive view on smiling. ( n ) Two-year postoperative view with mouth opening
abc
def
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drain from the superolateral lacrimal gland to the medially placed puncta of the
lacrimaldrainage system. Awareness of the lacrimal drainage system is important
for functionally successful medial eyelid reconstruction. The anatomy of the perior-
bital region is complex and is reviewed comprehensively elsewhere [ 20 ].
Eyelid defects should be considered by location, size, orientation and lamellar
involvement. For full-thickness defects, both lamellae must be reconstructed.
Tables 11.1 and 11.2 provide an algorithm for reconstruction [ 21 ]. If direct closure
can be achieved, this will usually give the best functional and aesthetic results in a
single stage. Wherever possible, vertical closure tension should be converted to hori-
zontally directed tension to avoid cicatricial ectropion. Primary closure is typically
best suited for defects of ≥25 % of eyelid length, although it can be applied to ≤50 %
defects if suffi cient eyelid laxity is present. Conversion to a pentagonal defect, with
clean tarsal edges, which are perpendicular to the lid margin, can aid in primary clo-
sure. Meticulous closure of each layer is critical, and begins with reapproximation of
the tarsal edges to achieve perfect vertical alignment of the eyelid margin, followed
by closure of the posterior lamella, and then vertical mattress sutures in the grey line.
jk
lmn
Fig. 11.3 (continued)
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Subsequently, the orbicularis layer and skin are closed, with careful attention to
suture placement in order to avoid irritation of the cornea from the stitches. If wound
closure tension is excessive at the start, a lateral cantholysis can be performed.
Anterior lamella-only defects are reconstructed more favourably with local fl aps
than skin grafts on account of the advantages of better colour match, less contrac-
tion with healing, and an improved vascular supply that can support free grafts for
posterior lamella reconstruction (in the absence of prior surgeries or irradiation).
Rhombic fl aps are best suited to periocular cutaneous defects, with the caveat that
the vector of maximal tension should be oriented parallel to the lid margin. Another
option is the uni- or bi-pedicled transposition fl ap from the upper eyelid used to
reconstitute defects of the lower lid anterior lamella (Tripier fl ap). Secondary inten-
tion healing is suitable for defects of the medial canthus <1 cm in diameter and
centred about the MCT; otherwise it should be avoided.
Larger full-thickness defects (approximately one-third to two-thirds) of the cen-
tral or lateral eyelid can be repaired using the Tenzel semicircular advancement fl ap
[ 22 ]. This technique is conceptually similar to a Mustarde fl ap, but has the added
advantage of better dynamic reconstruction. When no lateral tarsus is present, recon-
struction is aided with the use of a periosteal fl ap, or auricular cartilage, hard palate
mucosa or nasal septalchondromucosal graft for posterior lamella reconstitution.
Larger full-thickness defects (greater than two-thirds) of the lower eyelid can be
repaired with a Hughes tarsoconjunctival fl ap [ 23 ]. This two-stage procedure bor-
rows tissue from the upper eyelid, and provides vascularized autogenous tarsus
lined with conjunctiva; the anterior lamella is repaired with a skin graft or local fl ap.
Alternatively, a single-stage operation using a composite nasal septalchondromuco-
sal graft fi xated in position, and overlayed with a temporal forehead cutaneous fl ap
pedicled on the superfi cial temporal artery, can be performed [ 24 ].
Full-thickness total upper eyelid reconstruction is best achieved using a Cutler–
Beard lid-sharing fl ap [ 25 ]. This skin-muscle-conjunctiva fl ap is harvested from the
lower lid, and subsequently divided 4–6 weeks postoperatively.
Table 11.2 Full-thickness upper eyelid reconstruction [ 21 ]
Size of eyelid margin defect (% of eyelid width) Reconstruction
<25 % Direct closure
25–50 % Direct closure with lateral cantholysis
33–66 % Semicircular fl ap with periosteal fl ap
50–100 % Cutler–Beard fl ap
Table 11.1 Full-thickness lower eyelid reconstruction [
21 ]
Size of eyelid margin defect (% of eyelid width) Reconstruction
<25 % Direct closure
25–50 % Direct closure with lateral cantholysis
33–66 % Semicircular fl ap
50–75 % Semicircular fl ap with periosteal fl ap
50–100 % Transconjunctival fl ap
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In general, potential complications of eyelid reconstruction include infection,
fl ap dehiscence, entropion, ectropion, lagophthalmos, upper eyelid ptosis, and lid
margin notching.
Postoperatively it can be expected that signifi cant swelling might be present for
some weeks, but a well designed thin, bilaminar, mobile eyelid reconstruction
should provide robust corneal protection and good cosmesis in the long term.
Nose
The nose is of central importance in the mid-face and nasal defects have particular
impact on facial form and function. Nasal reconstruction is one of the oldest forms
of plastic surgery, having been described in the Edwin Smith Papyrus, dating from
approximately 3000 bc . As in the eyelid, the nose should be reconstructed by paying
attention to individual layers—lining, structure, and cover. Without adequate provi-
sion for lining and support, wound contraction and structural collapse will mar the
fi nal contour needed for a good functional and aesthetic outcome.
Topographically, the nose is composed of subunits, both convex (tip, columella,
alae nasi and dorsum) and concave (sidewalls, soft triangles). Burget and Menick
elegantly described the reconstruction of the nose according to subunits, emphasiz-
ing the need to use fl aps for convexities, place scars between subunits and consider
sacrifi ce of normal tissue to achieve total subunit reconstruction [ 26 ].
Nasal lining can be replaced in a number of ways, including intranasal mucosal
fl aps (local bipedicled fl aps, pedicled transposition fl aps), skin grafts (including as
part of composite grafts from the ear) and skin fl aps (local hinge fl aps, turnover naso-
labial fl aps, folded forehead fl aps and free fl aps) [ 27 ]. All these options, however,
need to be thin to maintain an adequate nasal airway and, as such, their transfer may
need to be refi ned over a number of surgical stages. Skeletal support may need to be
provided; autologous options include the use of conchal ear cartilage (for support of
convex alar subunits), nasal septal cartilage, rib cartilage and cranial bone graft. Skin
replacement should be the fi nal stage of any such reconstruction—without an ade-
quate foundation the outer layer cannot correct underlying contour problems.
The ideal source of skin for nasal reconstruction comes from the forehead. The
paramedian forehead fl ap based on the supratrochlear vessels is the workhorse in
this setting. It may be transferred as a pedicled fl ap based at the medial brow; the
pedicle can be divided some weeks later when the transferred tissue has gained
vascularity from the recipient site. Inclusion of frontalis muscle will enhance vascu-
larity of the fl ap tip; additional stages are usually required to thin the fl ap adequately,
but this extra effort will bring rewards in terms of fi nal contour and healing.
Advantages of the forehead donor site include excellent colour match, suitable tis-
sue thickness, reliable blood supply and, if carefully managed, an acceptable donor
site scar (Fig. 11.4a–b ). Alternative options for nasal skin replacement include
interpolated cheek fl aps, transposition fl aps of nasolabial skin or nasal skin
(Fig.
11.4c–e ), advancement of cheek or nasal skin [ 28 , 29 ] (Fig. 11.4f–i ), regional
fl aps from postauricular skin [ 30 ], or free fl aps from the ear [ 31 ]. Many of these
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Fig. 11.4 ( a ) Full-thickness defect of lower third of the nose, with planned incisions for parame-
dian forehead fl ap. ( b ) Three months following initial reconstruction, following fl ap pedicle divi-
sion and two separate contouring procedures. ( c ) Nasal tip defect with planned incisions for bilobe
fl ap reconstruction. ( d ) Flap elevation with wide undermining in the sub-nasal SMAS plane. ( e )
Flap inset and closure. ( f ) Nasal dorsum defect following basal cell carcinoma resection, with
planned incisions for nasal dorsum advancement fl ap (Rieger fl ap). ( g ) Flap elevation in the sub-
nasal SMAS plane. ( h ) Flap inset. ( i ) Six weeks postoperative result
ab
c
d
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ef
g
h
i
Fig. 11.4 (continued)
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options are suitable for small skin defects but none have the inherent versatility of
the paramedian forehead fl ap for larger defects.
As with many reconstructive endeavours, adequate results can be obtained with
fewer steps; however, extra stages for fl ap thinning, contour refi nement and scar
revision invariably result in better aesthetic outcomes. It is useful when planning
such treatment to tailor the refi nement to the expectations of the patient and suit-
ability for multiple operations. In some advanced cases, rhinectomy defects may be
more appropriately managed with a nasal prosthesis, both from a cosmetic stand-
point, and for minimizing the number of trips to the operating theatre.
Ear
Post-resection reconstruction of the pinna has both functional (wearing of specta-
cles) and aesthetic consequences. Particular zones of the pinna may be reconstructed
in different ways using local skin fl aps; total and subtotal defects, however, should
be reconstructed either by means of prostheses (which may be anchored to osseoin-
tegrated implants) or autologous constructs using combinations of rib cartilage,
temporoparietal fascia fl aps, expanded local mastoid skin, and skin grafts.
Defects of the conchal bowl and helical root have a number of reconstructive
options. Wounds in this area left to heal by secondary intention typically produce
excellent cosmetic results. Subtotal conchal bowl defects can be repaired with a
full-thickness skin graft, which is harvested from the post-auricular region or supra-
clavicular neck skin. If exposed cartilage is devoid of perichondrium, the cartilage
can be resected and the skin graft applied to the medial auricular skin. Large defects
involving lateral conchal bowl skin and cartilage can be repaired using a post-
auricular subcutaneous tissue pedicle island advancement fl ap. The main advantage
is the avoidance of a skin graft and bolster. The fl ap is transferred through a slit in
the medial auricular skin into the defect, and the post-auricular donor site is closed
primarily (Fig.
11.5a–g ). If the medial skin of the pinna is also absent, this fl ap can
be bi-valved, or simply skin grafted on its medial surface.
The superior one-third of the auricle can be closed primarily, in the form of a
wedge or stellate closure, when the defect is <1.5 cm in width. Cupping of the ear
should be avoided with primary closure. If the defect is limited to the helix and
measures 1.5–2.5 cm in length, bilateral helical chondrocutaneous advancement
fl aps (Antia–Buch) can be performed. This technique often requires reduction of
the outer margin of the conchal bowl to decrease the circumference required for
the advancement fl aps to traverse. Defects of >2.5 cm confi ned to the helical rim
should be considered for a pre-auricular or post-auricular interpolated tubed fl ap.
The fl ap is initially tubed with maintenance of intact superior and inferior attach-
ments, then two subsequent stages to allow inset of the tubed fl ap into the helical
defect.
Large defects of the superior third, involving helix, scapha and triangular fossa,
require incorporation of a rigid framework using rib, which is covered by a tempo-
roparietal fascia fl ap and STSG.
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Defects of the middle third of the auricle can again be closed primarily as a wedge
excision if <1.5 cm in width. Full-thickness helical defects that are <2.5 cm can be
addressed with superior and inferior chondrocutaneous helical advancement fl aps.
Larger helical defects are again repaired with a tubed skin and subcutaneous tissue
fl ap. Large defects of the helix and antihelix require a multi-staged procedure involv-
ing a posteriorly based scalp advancement fl ap sutured to the lateral edge of the
auricular defect, with a piece of septal or conchal cartilage sutured to the defect
edges and buried under the fl ap to provide structural support. Three weeks later, the
second stage involves division of the scalp fl ap and folding of this tissue around the
cartilage graft; the skin fl ap is then sutured to the medial edge of the auricular defect.
If the scalp donor site cannot be closed primarily, a full-thickness skin graft is applied.
The inferior third of the auricle is relatively easier to reconstruct, owing to the laxity of
skin in the region. Up to 50 % of the lobule can be resected as a wedge and closed primar-
ily with minimal effect on cosmesis. Total earlobe reconstruction requires two stages. In
the fi rst, a piece of cartilage shaped like an earlobe is embedded in a subcutaneous pocket
created in approximately the position where the new earlobe will be; the leading edge of
the pocket is sutured up to the lateral edge of the lobule defect. Six weeks later, the skin
and cartilage are elevated as a composite fl ap based superiorly off the auricle, and the
back of this composite fl ap is skin grafted. The donor site is closed primarily.
ab c
def
g
Fig. 11.5 ( a ) Subtotal conchal bowl defect involving cartilage and lateral skin (medial auricular
skin preserved). ( b ) Post-auricular pedicled fl ap incised. ( c ) Through-and-through tunnel. ( d ) Post-
auricular fl ap elevated just above the mastoid periosteal layer and maintained on a subcutaneous
deep soft tissue pedicle. ( e ) Inset of fl ap into conchal bowl defect, primary closure of post-auricular
donor site. ( f ) Four weeks postoperative result conchal bowl. ( g ) Post-auricular region
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Conclusion
Facial reconstruction presents a unique subset of functional and aesthetic chal-
lenges. However, with a stepwise analytical approach, careful planning and precise
execution, form and function can be restored satisfactorily.
Step-by-Step Approach to Selected Local Flaps
Scalp Rotation Flaps: O-to-Z or Pinwheel Flap
A single rotation scalp fl ap is designed 4–6 times as long as the width of the defect.
Multiple rotation fl aps offer the advantage of distributing wound closure tension
over a larger area, and recruiting tissue from multiple areas of the scalp where more
laxity may be present (occiput, or overlying the temporalis muscle). Centrally
located scalp defects can be repaired with two rotation fl aps, whereas three rotation
fl aps can be used to repair central scalp defects situated anteriorly or posteriorly. In
this case, all three fl aps are designed to rotate in the same direction, as in a pin-
wheel. Each rotation fl aps should be designed symmetrically to its counterpart(s),
and should curve to meet the defect border at a 90° angle. Incisions should always
parallel hair follicle direction, and cautery should be used judiciously to avoid alo-
pecia. Wide undermining in the subgaleal plane, from ear to ear and from forehead
to occiput, typically is required (Fig. 11.1a–d ).
Scalp Rotation Flap for Upper Forehead Defects
Forehead defects are often challenging to close primarily because of limited tissue elas-
ticity. Direct closure by advancing tissue in a vertical direction might alter the position
of the brows, especially in lower and lateral defects. Direct closure by advancing tissue
in a horizontal plane will result in a vertical scar that could be aesthetically unpleasing.
This technique recruits tissue from the upper forehead and temple bay by designing a
large forehead and scalp rotation fl ap to enable advancement of tissue vertically down-
wards into the defect with minimal distortion of the lower forehead and brow.
Steps (Fig. 11.1i–k )
A large rotation fl ap is designed with the lower aspect of the semicircular fl ap run-
ning vertically upwards from the medial edge of the tissue defect.
This fl ap incision should run into the interface between the anterior central hair-
line and the temple bay. The fl ap margin continues into the scalp curving down
behind the ear.
The rotation fl ap is then raised in a subgaleal plane and horizontal galeotomies in
the inferior fl ap may help advance the upper forehead tissue into the defect. Excess
tissue lateral to the defect (a ‘dog-ear’) can be excised at this point. This will elon-
gate the horizontal scar but will produce a better contour.
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Closure of the forehead should be achieved in layers with particular attention
paid to accurate apposition of forehead layers. Thus, a fi ne vertical scar can be
achieved that can fade well over time.
Using this method some hair-bearing scalp is advanced forward but in a manner
that has minimal aesthetic impact on the forehead. The orientation of the anterior
hairline is variable and some patients are more suitable for this technique than
others.
Karapandzic Flap
The Karapandzic fl ap is best suited to full-thickness defects involving one-third to
two-thirds of the central lower lip; a modifi ed approach can be used for the upper
lip. Essentially, it is a circumoral composite rotation advancement lip fl ap with pres-
ervation of the neurovascular supply, which allows maximum functionality to the
reconstructed lip.
Steps (Fig. 11.3a–d )
Incision lines are marked parallel to the free margin of the lip, thereby maintaining
uniform width. The incision is made along the mental crease and then carried around
the oral commissure and into the melolabial crease, typically up to the level of the
nasal alae. In order to ensure equal fl ap width, take the incision lateral to the melo-
labial fold at the level of the oral commissure. The width of the fl ap must be at least
equal to the height of the defect. For lateral defects, the fl aps will be designed to be
of unequal lengths.
Incisions are made through skin and subcutaneous tissue, but not through mus-
cle. Separate incisions are made through the intraoral mucosa, but typically do not
need to be as long. Scissors are used to gently spread through the muscular layer in
a radial direction, thereby allowing the identifi cation and preservation of vessels and
nerves. Suffi cient dissection is performed to allow the neurovascular bundles to
stretch with fl ap mobilization.
After fl ap dissection, the two fl ap edges are fi rst secured together, and the remain-
ing wound closure is then adjusted accordingly. The wound is closed in layers, care-
fully re-approximating muscles in the correct anatomical orientation.
Bernard–Webster Cheiloplasty
The Webster cheiloplasty is a modifi cation of the Bernard–Burow fl ap for lower lip
reconstruction.
Steps (Fig. 11.3e–h )
Incisions are placed along the junctions of aesthetic subunits; triangles of skin and
subcutaneous tissue are resected from the bilateral melolabial folds and the mento-
labial folds to allow linear horizontal advancement of cheek skin into the lower lip
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defect, as required. Transverse incisions are then made from the base of the melola-
bial fold Burow’s triangle to the oral commissure and along the mental crease. It is
preferred to take the fl ap incisions through skin and subcutaneous tissue only, and
make separate oral mucosal incisions; the intraoral incisions can be offset superiorly
from the skin incisions to provide extra mucosa for vermilion reconstruction. Blunt
spreading through the orbicularis muscle to permit suffi cient mobilization is
performed.
The advancing edges of the bilateral fl aps are re-approximated in layers, fol-
lowed by the remainder of the incisions. The offset mucosal incisions allow for
advancement of this mucosa to create a neo-vermilion. Whereas excessive wound
tension is undesirable, a slightly tight fl ap helps to counterbalance the essentially
dynamic nature of the reconstruction.
Abbe Flap from Lower Lip to Upper Lip Defects
This fl ap comprises a section of full-thickness lower lip that is transposed up into an
upper lip defect. Because of relative lower lip laxity and upper lip aesthetics, it is a
more common procedure than transferring upper lip to lower lip. As a lip sharing
technique, it is performed in a minimum of two stages.
Steps
The fl ap is outlined with upper incisions perpendicular to the lip margin. The lip is
incised through skin, fat, muscle and mucosa except for where the pedicle is pre-
served. This area includes the vermilion, lower lip mucosa and labial vessels deep
to the orbicularis muscle layer.
The fl ap is hinged at this point and is transferred up into the upper lip. The sec-
ondary defect in the lower lip is closed directly, ensuring accurate muscle and skin
layer apposition. The uppermost section is not closed at this stage because of the
fl ap remaining attached.
At least 2 weeks later the fl ap pedicle is divided and inset is completed of both
the fl ap into the upper lip and the lower lip donor site. Nutrition during this interven-
ing period can be achieved by eating soft or pureed foods.
Tenzel Semicircular Flap
The Tenzel fl ap is well suited for reconstruction of full-thickness defects involv-
ing 33–75 % of the horizontal length of the upper eyelid, and 30–66 % of the
lower eyelid. The fl ap is conceptually similar to a Mustarde cheek rotation fl ap,
but offers better dynamic reconstruction with less tissue manipulation. It is best
applied in the setting of adequate lateral canthal skin laxity and availability of a
small segment of full-thickness eyelid on either side of the defect. If the lateral
tarsal plate is absent, a periosteal fl ap or auricular cartilage graft can be
utilized.
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Steps
First, the actual defect size is estimated by pulling the edges of the defect together
using fi ne-toothed forceps. If the edges are within 1–2 mm, primary closure with a
lateral cantholysis might be adequate.
Starting at the lateral canthus, a semicircular line is drawn arching superiorly
with a diameter of ~20 mm, extending to the lateral eyebrow. The mirror image is
used for upper eyelid reconstruction.
Next, the defect margins are revised so that they are perpendicular to the lid mar-
gin. This is followed by undermining a musculocutaneous fl ap widely ~10 mm
below the orbital rim. Lateral canthotomy and inferior cantholysis is performed
subsequently to allow complete mobilization of the lateral lower eyelid soft tissue
toward the medial defect margin.
The most critical step of the reconstruction is the re-approximation of the tarsal
edges using interrupted absorbable sutures, followed by simple or vertical mattress
silk sutures through the grey line to align the wound edges perfectly.
In order to provide adequate lateral eyelid support, lateral canthal fi xation can be
performed by suturing the deep tissue up onto the lateral orbital rim periosteum.
Alternatively, a strip of periosteum, pedicled on the arcus marginalis, hinged high at
least at the level of the pupil and angled at 45°, can be fl ipped down and attached to
the deep lateral fl ap tissue for improved contour and support.
For large defects or those lacking tarsus at the lateral edge, posterior lamella
reconstruction can be accomplished using a nasal septal chondromucosal graft, or a
tarsoconjunctival fl ap from the upper lid. If a mucosal graft or periosteal fl ap is not
used laterally, then the musculocutaneous fl ap should be lined internally with con-
junctiva by advancing it from the inferolateral fornix.
Finally, skin incisions are closed in layers. The standing cutaneous deformity,
which may develop at the inferior margin of the defect, is now resected. Ointment
is applied to the incision lines.
Tripier Flap
Defi ciencies of the anterior lamella of the lower eyelid, because of oncological
resection, trauma or leading to ectropion, can be repaired with a uni- or bi-pedicle
musculocutaneous fl ap from the upper eyelid. For fullthickness defects, the poste-
rior lamella can be reconstituted with a septal condromucosal graft, with a Tripier
fl ap placed on top. The bi-pedicled fl ap has a more robust blood supply, but is not
well suited to extreme medial or lateral defects, and requires a second stage.
Bi-pedicled fl aps are typically used for defects greater than two-thirds of the lower
lid, whereas medial or lateral defects are addressed with a uni-pedicle fl ap.
Steps
In the case of generalized cicatricial ectropion, a releasing subciliary incision (2 mm
below the lid margin) is made along the length of the lower lid. The skin is then
undermined down into the cheek to release any scar band tethering. The lower lid is
A.J. Alexander et al.
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167
pushed up slightly and the vertical height of the anterior lamella defect is measured;
this will ensure that the defect will be slightly smaller than the fl ap height.
The supratarsal crease is marked along the upper eyelid. With the eyelids gently
closed, the maximum amount of skin that can be pinched with forceps before elevating
the upper eyelid lashes is determined, and this point is marked along the upper lid,
parallel to the supratarsal crease, to defi ne the fl ap’s upper incision. The vertical height
of this fl ap will be the limiting factor in determining how large a defect can be repaired
with this technique. In adults, the vertical height of this fl ap will typically be 10–15 mm.
For a bi-pedicled fl ap, the superior and inferior upper lid incisions are made
through skin and orbicularis oculi, and the fl ap is undermined in a sub-orbicularis
plane, while maintaining the pedicle on either end. The fl ap can then be transposed
down to the lower lid defect.
Prior to fl ap inset, medial and lateral canthal support can be achieved by suturing
each edge of the lower tarsal plate to the corresponding orbital rim periosteum with
a 5–0 clear permanent suture. The fl ap is then inset with a 6–0 absorbable suture,
and the upper lid defect is closed primarily with the same stitch. The pedicles can be
divided 2 weeks postoperatively.
Paramedian Forehead Flap for Large Nasal Defects
Forehead tissue undoubtedly supplies the best tissue for reconstructing the skin of the
nose for moderate to large defects. This is an axial fl ap based on the supratrochlear
vessels that pass superiorly within the forehead. Details of raising this fl ap are
described eloquently elsewhere [ 32 ]. Several methods have been employed and are
valid; this description of a full-thickness three-stage approach permits accurate sculpt-
ing of the reconstructed nose compared to two-stage alternatives. The inclusion of
frontalis along its whole length increases vascularity of the fl ap tip and thereby reduces
delayed healing and adverse scarring at its inset. Additionally, the process of raising it
from the nose and thinning it as an intermediate step both enables accurate contour
creation and enhances blood supply by the lengthened period of surgical delay.
Steps (Fig. 11.4a–b )
Under general anaesthesia a template is used to measure the nasal defect. This tem-
plate is transferred to the forehead, allowing for a pivot point of the fl ap at the
medial brow. For a lower nasal defect (tip/alar subunit) the fl ap island will be high
on the forehead or temple bay.
The fl ap is raised by incising the lateral, superior and medial borders, continuing
vertically down to the brow. A fl ap pedicle skin width of 1.5 cm is adequate in most
cases, and is based on the medial aspect of the brow.
The fl ap is raised, including frontalis, along its whole length. Subperiosteal dis-
section lower in the forehead is not required, as the supratrochlear vessels are supra-
periosteal in location deep to the brow.
Following haemostasis the raised fl ap is transposed into the nasal defect and
sutured. The deep aspect of the pedicle may be dressed or resurfaced using a small
11 Reconstructive Options for the Face
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168
skin graft to reduce dressing requirements. The forehead wound should be closed in
layers. The upper forehead defect will usually not be closed completely—secondary
intention healing will give a superior long-term result compared to skin grafting.
After approximately 4 weeks, the fl ap may be raised with 2–3 mm of subcutane-
ous fat. The underlying tissue can be sculpted to an appropriate contour. Cartilage
grafts can be placed at this stage if required. The thinned fl ap is then re-sutured. The
pedicle is not adjusted at this stage.
After a further 4 weeks, the pedicle of the fl ap is divided and a small inverted ‘V’
is replaced into the forehead and medial brow. The upper part of the nasal fl ap is
refi ned and sutured into the remaining nasal defect. It can be expected that after
some weeks the fi nal contour will be seen.
At each of these additional procedures the forehead scar can be revised, progres-
sively recruiting tissue from the lateral forehead, as stress relaxation permits.
Excellent outcomes of vertical forehead scars can be achieved with good technique,
multiple stages, and quality wound care.
Bilobed Flap for Small Nasal Defects
This random-pattern local skin fl ap is a transposition fl ap that aims to redistribute
tissue from adjacent to the circular primary defect while closing the secondary
defect with an additional transposition fl ap.
Steps (Fig. 11.4c–e )
Templates of many designs have been described. A reliable method is described by
Zitelli [ 33 ]. The fl ap is designed to include a primary ‘lobe’ adjacent to the defect
with a semicircular margin; the axis of this lobe is at 45° to a line drawn from the
centre of the defect to the pivot point lateral to the primary defect. The triangular
secondary fl ap runs at 45° to the primary fl ap and is longer than the primary fl ap. By
raising this oddly-shaped fl ap in a plane above the nasal skeleton, the primary fl ap
can be transposed into the primary defect, while the secondary fl ap moves in to
resurface the secondary defect. The triangular tertiary defect (under what was the
secondary fl ap) is closed primarily, ensuring no tension is transmitted to the eyelids
to cause ectropion.
All wound margins are sutured. Longer-term problems with this fl ap include ‘pin-
cushioning’ of the convex fl ap because of persistent oedema and peri- and sub- fl ap
wound contraction. This may detract from the longer-term contour appearance.
References
1. Australian Institute of Health and Welfare and Australasian Association of Cancer Registries.
Cancer in Australia: an overview, 2008. Cat. no. CAN 32. Canberra: AIHW; 2008.
2. Australian Institute of Health and Welfare and Cancer Australia. Non-melanoma skin cancer:
General practice consultations, hospitalization and mortality. Cancer series no. 43. Cat. no. 39.
Canberra: AIHW; 2008.
A.J. Alexander et al.
malcolm_buchanan123@hotmail.com
169
3. Raposio E, Santi P, Nordstrom RE. Effects of galeotomies on scalp fl aps. Ann Plast Surg.
1998;41:17–21.
4. Ahuja RB. Geometric consideration in the design of rotational fl aps in the scalp and forehead
region. Plast Reconstr Surg. 1988;81:900–6.
5. Terkonda RP, Sykes JM. Concepts in scalp and forehead reconstruction. Otolaryngol Clin N
Am. 1997;30:519–39.
6. Beasley NJ, Gilbert RW, Gullane PJ, et al. Scalp and forehead reconstruction using free revas-
cularized tissue transfer. Arch Facial Plast Surg. 2004;6:16–20.
7. Ch’ng S, Clark JR. The scapular angle adds versatility to the latissimus dorsi free fl ap in com-
plicated scalp reconstruction. J Plast Reconstr Aesthet Surg. 2011;64:e248–9.
8. Konior RJ, Kridel RWH. Tissue expansion in scalp surgery. Fac Plast Surg Clin N Am.
1994;2:203.
9. Baker SR, Swanson NA. Clinical applications of tissue expansion in head and neck surgery.
Laryngoscope. 1990;10:313–9.
10. Cook TA, Israel JM, Wang TD, et al. Cervical rotation fl aps for midface resurfacing. Arch
Otolaryngol Head Neck Surg. 1991;117:77–82.
11. Ch’ng S, Ashford BG, Gao K, et al. Reconstruction of post-radical parotidectomy defects.
Plast Reconstr Surg. 2012;129:275e–87e.
12. Pribaz JJ, Meara JG, Wright S, et al. Lip and vermilion reconstruction with the facial artery
musculomucosal fl ap. Plast Reconstr Surg. 2000;105:864–72.
13. Burget GC, Menick FJ. Aesthetic restoration of one-half the upper lip. Plast Reconstr Surg.
1986;78:583–93.
14. Webster RC, Coffey RJ, Kelleher RE. Total and partial reconstruction of the lower lip with
innervated muscle-bearing fl aps. Plast Reconstr Surg. 1960;25:360–71.
15. Carroll CM, Pathak I, Irish J, et al. Reconstruction of total lower lip and chin defects using the
composite radial forearm-palmaris longus tendon free fl ap. Arch Facial Plast Surg. 2000;2:53–6.
16. Fujimori R. ‘Gate fl ap’ for the total reconstruction of the lower lip. Br J Plast Surg. 1980;33:340–5.
17. Chang KP, Lai CS, Tsai CC, et al. Total upper lip reconstruction with a free temporal scalp
fl ap: long term follow up. Head Neck. 2003;25:602–5.
18. Robotti E, Righi B, Carminati M, et al. Oral commissure reconstruction with orbicularis oris
elastic musculomucosal fl aps. J Plast Reconstr Aesthet Surg. 2010;63:431–9.
19. Goldstein MH. The elastic fl ap for lip repair. Plast Reconstr Surg. 1990;85:446–52.
20. Zide BM. Anatomy of the eyelids. Clin Plast Surg. 1981;8:623–34.
21. Baker S. Local fl aps in facial reconstruction. 2nd ed. Philadelphia: Elsevier Inc; 2007.
22. Tenzel RR, Stewart WB. Eyelid reconstruction by the semicircular fl ap technique.
Ophthalmology. 1978;85:1164–9.
23. Hughes WL. A new method for rebuilding a lower lid. Arch Ophthalmol. 1937;17:1008.
24. Uchinuma E, Sakurai H, Shioya N. Anterofrontal superfi cial temporal artery island fl ap for
full-thickness eyelid reconstruction. Ann Plast Surg. 1989;23:433–6.
25. Cutler NL, Beard C. A method for partial and total upper lid reconstruction. Am J Ophthalmol.
1955;39:1–7.
26. Burget GC, Menick FJ. The subunit principle for nasal reconstruction. Plast Reconstr Surg.
1985;76:239–47.
27. Burget GC, Menick FJ. Nasal support and lining: the marriage of beauty and blood supply.
Plast Reconstr Surg. 1989;84:189–202.
28. Fliss DM, Freeman JL. The nasal glabellar fl ap. J Otolaryngol. 1994;23:6–7.
29. Ebrahimi A, Nejadsarvari N, Koushki ES. Application of modifi ed rintalafl ap in nasal tip
reconstruction. Am J Otolaryngol. 2012;33:685–8.
30. Washio H. Retroauricular-temporal fl ap. Plast Reconstr Surg. 1969;43:162–6.
31. Parkhouse N, Evans D. Reconstruction of the ala of the nose using a composite free fl ap from
the pinna. Br J Plast Surg. 1985;38:306–13.
32. Menick FJ. A 10-year experience in nasal reconstruction with the three-stage forehead fl ap.
Plast Reconstr Surg. 2002;109:1839–55.
33. Zitelli JA. The bilobed fl ap for nasal reconstruction. Arch Dermatol. 1989;125:957–9.
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© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_12
V. Nayyar , MBBS, MD, MPH, FRACP, FCICM
Department Intensive Care Unit , Westmead Hospital , Sydney , NSW , Australia
e-mail: Vineet.Nayyar@health.nsw.gov.au
1 2
Management of Critically Ill Head
and Neck Surgical Patients
Vineet Nayyar
Introduction
Head and neck surgery has made tremendous advances during the past 50 years.
These advances have led to increasing specialization and offering of complex surgi-
cal therapy to high-risk individuals, such that many head and neck patients now
require critical care inputs as a key component of their care. The complex anatomy,
rich vasculature and proximity to structures within a narrow space predispose
patients to serious complications from infectious and non-infectious processes in
the perioperative period. Yet, in spite of its importance, critical care literature on the
topic has remained agonizingly sparse. The last substantial review was undertaken
in 2003 [ 1 ].
Issues of clinical importance identifi ed in the 2003 review form the backbone of
this chapter. Only two prototype disease processes (cancer and infection) have been
highlighted in this chapter, as much of the published literature centres around these
two themes. In a signifi cant departure from the norm, this chapter avoids too narrow
a focus on individual disease entities, but summarizes information relevant to the
critically ill adult; it is, therefore, written from the perspective of an intensivist, and
although comprehensive, it is not exhaustive. For an overview of the impact of
comorbid conditions and disease entities, the reader is referred to two good reviews
on the topic [ 1 , 2 ].
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172
Head and Neck Surgery: Overview
In different parts of the world, many surgical specialists undertake surgery of the
head and neck region either alone or as part of a multidisciplinary team [ 3 ]. The
latter includes general surgeons, oral and maxillofacial surgeons, plastic and recon-
structive surgeons, and otorhinolaryngology and head and neck surgeons, each
bringing their own perspective to the patient’s care and management.
Irrespective of the surgical specialty involved, patients with a head and neck
problem usually undergo an extensive and often prolonged surgery that involves
large fl uid shifts, blood loss, and results in signifi cant postoperative pain and infl am-
mation. All these factors are considered important contributors to postoperative
morbidity. These, coupled with pre-existing co-morbid medical conditions, such as
advanced age and lifestyle choices, make postoperative complications not only
more likely, but also considerably more serious.
Need for Intensive Care
Options for postoperative management depend on the country of practice, available
healthcare resources, volume of cases, and expertise of nursing and medical staff
[ 3 ]. The three main categories of head and neck patients that require admission to
an intensive care unit (ICU) are; (i) the head and neck cancer (HNC) patient; (ii) the
head and neck trauma patient; and (iii) the head and neck patient with medical com-
plications [ 1 ].
HNC patients require intensive care for the following reasons:
• Routine close observation and nursing care postoperatively
• Treatment of complications after surgery, such as wound dehiscence, fl ap necro-
sis, airway compromise, bleeding or infection
• Management of underlying medical conditions, such as chronic obstructive air-
ways disease, ischaemic heart disease, renal failure or uncontrolled diabetes
• Management of new medical conditions, e.g. myocardial infarction (MI), pulmo-
nary embolism, respiratory failure, persistent hypotension, delirium or sepsis
• Complications related to progression of disease, including airway obstruction,
aspiration, respiratory distress caused by pleural effusions, or malnutrition
• Complications related to chemotherapy or radiotherapy, such as mucositis, neu-
tropenic sepsis, immune-compromised status or metabolic.
The risk of developing complications in HNC patients does not necessarily
equate with the need for a critical-care bed. Not surprisingly, reports from Hong
Kong [
4 ], UK [ 5 ] and USA [ 6 ] have questioned the rationale for routinely admitting
postoperative major HNC patients to the ICU, citing no advantage of this approach
compared to postoperative observation in a specialist ward. While it is hard to
ignore the evidence that the rate of complications remains unaffected, whether or
not patients are admitted electively to the ICU, it is also diffi cult to extrapolate the
V. Nayyar
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173
fi ndings of singlecentre studies [ 2 ]. Morton recommended caution, believing that
decision making about postoperative care may not be as simple as an argument over
observed complication rates reported from highly specialized centres [ 7 ]. It is con-
ceivable that prompt recognition of adverse events in an ICU environment may
guide proactive interventions early and might improve survival. Clearly, each
healthcare facility must be able to establish whether such benefi ts outweigh the
costs of a day’s observation in the ICU. To ensure that these benefi ts accrue to
patients, favourable policies related to staffi ng and skill-mix in the ICU are essen-
tial, as they are important determinants of outcome among patients undergoing free
fl ap reconstruction [
9 ].
A stratifi cation of postoperative cases on the basis of pre-existing conditions, the
nature and extent of surgical procedures, and intraoperative complications has been
proposed [ 8 ] but has not been adopted widely. Clearly, the type and site of surgery
and duration of anaesthesia are some of the important determinants of the need for
a critical-care bed. Although traditionally not thought to be risk factor, duration of
time under anaesthesia appears to be predictive of postoperative surgical complica-
tions and length of hospital stay. In a retrospective study of 157 patients by Boruk
et al., 10 patients were found to develop major complications in the postoperative
period [ 10 ]. In this study, they estimated the odds of having a complication (major
or minor) increased by 0.6 % with every minute of anaesthesia [ 10 ].
In view of the available evidence, it is reasonable to conclude that all patients with
major head and neck problems do not require routine postoperative admission to the
ICU. However, those who do, require a level of care consistent with the extensive
nature of surgery, and co-morbid conditions that often accompany diseases of the
head and neck. A decision to admit to the ICU requires close cooperation and active
communication between the surgical team, the anaesthetist and the intensivist.
Co-morbid Conditions
The literature is expanding on factors associated with increased risk of mortality
and postoperative complications [ 11 – 13 ]. Many of these factors can be identifi ed
before surgery, making them particularly important targets for preventative mea-
sures. With improved safety of operative techniques, the relative risk of complica-
tions associated with the surgery is substantially less compared to risk associated
with pre-morbid conditions. Multiple studies have established the importance of
frequently encountered patient factors [ 13 , 14 ]. These include age, American
Society of Anesthesiologist (ASA) physical status, and albumin. The odds of 30-day
mortality double for every decade after 70 years of age; an increment in the ASA
status roughly doubles postoperative death rate, and a drop in preoperative albumin
level to <30 g/L is associated with an OR of 2.5 for 30-day mortality [ 13 , 14 ].
Major co-morbidities identifi ed in head and neck patients include hypertension,
diabetes mellitus, cardiac disease, excessive alcohol intake, and a history of pro-
tracted and heavy smoking. These co-morbid conditions are believed to be a better
predictor of patient outcome than staging of cancer [
15 ]. Age is an important issue
12 Management of Critically Ill Head and Neck Surgical Patients
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174
in head and neck surgery [ 1 ]. As expected, medical morbidity and mortality is
increased in the elderly, but this is more so as a result of concurrent illness in patients
rather than age alone. The impact of co-morbidity is greater in older than in younger
patients, although it affects both. When complications occur, they are more severe
in older patients and are associated with a higher mortality and costs [ 1 ].
Several instruments are available to quantify co-morbidity in patients planned for
head and neck surgery. These include the adult co-morbidity evaluation 27 (ACE-
27), Charlson index (CI) and cumulative illness rating scale. ACE-27 has been vali-
dated extensively in HNC for the purpose of predicting survival [
16 ], complications
[ 17 ], functional outcome [ 18 ], and quality of life [ 19 ]. CI too has been evaluated by
several authors and has been found to be a signifi cant predictor of postoperative
complications among head and neck patients [ 20 , 21 ]. In addition, ICU scoring sys-
tems (e.g. APACHE II) [ 22 ] have been used to predict immediate surgical complica-
tions, but have not been adopted widely. The Revised Cardiac Risk Index (RCRI),
derived from using rigorous statistical methodology, is another useful measure that is
robust, but guidelines on the action to undertake once the risk estimates are obtained
are lacking [ 23 ]. Some head-to-head comparison [ 24 ] of disease-specifi c and general
indices suggest that all these instruments have similar prognostic ability, whereas
others have shown ACE-27 to be most successful in stratifying HNC patients with
prognostic ability comparable to that of nodal staging [ 25 ].
Patients with HNC have a risk profi le not dissimilar to those with vascular dis-
ease, which predisposes them to atherosclerotic disease and its complications. Some
patients with pre-existing coronary artery disease and stents in situ need to discon-
tinue antiplatelet therapy, exposing them to substantial risk of stent closure in the
postoperative period. Although interest in and hope for revascularization was high
5 years ago, the weight of evidence subsequently has suggested no benefi t of pro-
phylactic revascularization in patients before major surgery [ 26 ].
The presence of chronic obstructive pulmonary disease (COPD) is associated with
an increased risk of pneumonia and respiratory failure in the postoperative period
[
26 ]. The severity of the underlying lung disease and the magnitude of risk is roughly
correlated. As many as 75–80 % of patients undergoing surgery for HNC have a his-
tory of smoking and a signifi cant proportion have COPD [ 2 ]. Among these, 10 % have
severe disease. Patients with undiagnosed obstructive sleep apnoea (OSA) are also
likely to develop postoperative complications if the condition is not recognized and
managed appropriately. Patients at risk can be identifi ed preoperatively by the STOP-
BANG questionnaire, which has been validated for use in head and neck patients [ 27 ].
Evidence is mounting to suggest a link between HNC treated with either primary
surgical resection [ 28 ] or radiation therapy [ 29 ] and the development of OSA.
Postoperative Complications
The most dreaded complication after head and neck surgery is airway compromise
and bleeding (or haematoma formation). However, the commonest complications
post-surgery are either respiratory or cardiovascular.
V. Nayyar
malcolm_buchanan123@hotmail.com
175
Bhattacharya and Fried’s seminal work published in 2001 remains widely quoted
even though nearly half of all patients included in their case series were postopera-
tive after a thyroid or parathyroid operation [ 30 ]. Among 3309 patients undergoing
a primary head and neck procedure, the authors reported an overall mortality of only
3.55 %. Death occurred in 12.6 % of those who experienced a complication com-
pared with 1.71 % mortality in patients without a complication. Postoperative pneu-
monia was common, occurring in 3.26 % of patients and was associated with a
mortality of 10.94 %. The majority of deaths occurred during the fi rst 3 days after
surgery, and among these, more patients died from medical rather than surgical
complications. These data were similar to the fi ndings reported earlier by Downey
et al. [
6 ], who retrospectively evaluated the need for an ICU after HNC surgery at a
single, large, specialized cancer centre. Only 1.5 % of patients in this case series
required ICU admission. Approximately two-thirds (29/43) of patients developed
respiratory or cardiovascular complications; of these about 25 % died [ 6 ].
A recent analysis of patients admitted postoperatively to an ICU in the Netherlands
has added to the knowledge base in this area [ 31 ]. In this large dataset of >28,000
patients admitted to the ICU postoperative after elective cancer surgery, 3.1 % (888
patients) were admitted after a major head and neck procedure. In this group, the
commonest co-morbidity was COPD (~12 %) followed by diabetes mellitus (~9 %).
The incidence of postoperative pneumonia was ~1 % and the rate of cardiac dys-
rhythmias was 1.5 %. Overall, the hospital mortality in this case series was 3.3 %,
exceeded only by patients with colorectal malignancy, oesophageal surgery, and
pancreatic (and/or biliary) surgery [ 31 ]. Postoperative pulmonary complications
were the focus of a recent retrospective study of patients undergoing major head and
neck surgery at a tertiary care centre in Canada [ 32 ]. In this case series, ~45 %
developed one or more complications; the most common was postoperative respira-
tory failure. Development of pulmonary complication was associated with higher
mortality (12.7 % vs. 1.7 %), and longer ICU and hospital length of stay (LOS).
The aforementioned studies have shaped our current understanding of the post-
operative course of patients after head and neck surgery. Without doubt, patients
who suffer medical complications do badly, but to identify them preoperatively
remains a major challenge. The primary means of assessing risk is through history
and a clinical examination. Needless to say, history must be elicited carefully.
Head and Neck Malignancy
HNC, or cancer of the upper aerodigetive tract, is an uncommon malignancy compris-
ing only 3 % of all malignancies in the USA [ 33 ]. In many parts of the world, particu-
larly France and India, HNC is a major cause of death. The most common pathology is
that of a squamous cell carcinoma (SCC), comprising >90 % of all malignancies of the
upper aerodigestive tract. Treatment includes radiotherapy and chemotherapy but sur-
gery has been the mainstay of management for >30 years. Surgery as defi nitive treat-
ment is preferred for oral cavity lesions whereas radiotherapy and/or chemotherapy are
favoured for oropharyngeal or laryngeal disease, unless local spread is extensive.
12 Management of Critically Ill Head and Neck Surgical Patients
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176
Risk factors most commonly associated with HNC include smoking, alcohol
consumption, human papillomavirus (HPV) infection and Epstein–Barr virus infec-
tion [ 34 ]. Among these, smoking and alcohol consumption are important in terms
of additive risk for oral and oropharyngeal cancer.
Severe Soft Tissue Infections of Head and Neck
Infections of potential spaces of the head and neck may be associated with airway
compromise, jugular septic thrombophlebitis, aspiration pneumonitis, lung abscess,
mediastinitis or, in the worst case scenario, septic shock with multi-organ failure. An
understanding of the anatomical boundaries, interconnections, clinical manifestation
and microbiology are crucial to the management of these serious infections [ 35 ].
Submandibular Space Infections
In submandibular, lateral pharyngeal and retropharyngeal space infections, the por-
tal of infection is the oral cavity and thus antibiotic therapy invariably is directed
towards organisms commonly found in the mouth. Although severe infection in any
deep spaces of the head and neck can affect airway patency, submandibular space
infection is more commonly associated with a compromise of the airway. As a
result, such patients require early airway involvement of the critical-care team and
placement of a defi nitive airway. Not all patients require intubation, but if an initial
course of close observation is pursued, it should be carried out in an environment in
which frequent monitoring and airway intervention is possible [ 36 ].
Infections in the submandibular space are typically odontogenic in nature and arise
from the spread of periapical abscesses of the mandibular molars, most typically the
second or third molars where bone is the thinnest [ 35 ]. Other pathological processes
that involve the submandibular space include sialadenitis, mandibular or lingual malig-
nancy, laceration of mouth fl oor, lymphadenitis, and foreign bodies. The distinguishing
feature of submandibular space infection is a rapidly spreading woody infl ammation
with or without overlying cellulitis. A striking aspect of the physical examination is the
protruding tongue, which is forced outwards due to internal pressure and limitation
imposed by fi bres of the deep cervical fascia. At times, the whole fl oor of the orophar-
ynx is elevated and tender to touch. Multivariate analysis has identifi ed some indepen-
dent risk factors associated with severe complications after submandibular space
infections [
37 , 38 ]. These include anterior visceral space involvement, bilateral neck
swelling, presence of diabetes mellitus, and other co-morbidities.
Over the past decade or so, the proportion of deep space infections arising from
an odotogenic source has increased relative to other types of infections [ 39 ].
Odontogenic infections are associated with poor dental hygiene and low socioeco-
nomic status. In a single-centre observational study, 144 patients with an odonto-
genic infection treated in a tertiary care ICU had indicies of socioeconomic
disadvantage that were signifi cantly worse than the rest of the ICU patients [
40 ].
V. Nayyar
malcolm_buchanan123@hotmail.com
177
Lateral Pharyngeal Space Infections
Infections involving the lateral pharyngeal space can develop from a variety of
sources but most commonly follow a pharyngitis or tonsillitis. Often, the infection
yielding a portal of entry into the lateral pharyngeal space is minor or may even
have resolved by the time symptoms of the deep space infection appear. The classi-
cal clinical signs are dysphagia, trismus and ipsilateral pain extending up to the jaw
or pain referred to the ear. Complications of lateral pharyngeal space infection
include laryngeal oedema, sudden death, carotid artery involvement or suppurative
jugular vein thrombophlebitis (Lemierre syndrome) [ 41 ].
Retropharyngeal Space Infections
The retropharyngeal, danger and prevertebral spaces are a common pathway for
extension of head and neck infections into the thorax. Although separated by fascial
planes, these spaces are considered as a unit because of their anatomical proximity
and their propensity for spread beyond the head and neck. Suppurative adenitis of
deep cervical lymph nodes in children, trauma from oesophageal instrumentation,
and foreign bodies are causes of retropharyngeal abscesses.
The most lethal complication of retropharyngeal and danger space infection is
descending necrotizing mediastinitis. Infections, if untreated, can spread into the
pleural, pericardial and the retroperitoneal space. Debridement and appropriate
antibiotics are the foundations of treatment for mediastinitis, which even if treated
effectively can be associated with a high mortality [ 41 ].
Infections of the prevertebral space are primarily haematogenous in nature and
their microbiology is markedly different to other infections of the head and neck
discussed so far. Complications arise from spread to the epidural space with cord
compression, spread to the vertebrae or disc with mechanical instability of the spine,
loculation of pus at distant sites, and ongoing bacteraemia. Initial coverage for
Gram-positive organisms, including methicillin-resistant Staphylococcus aureus is
recommended.
ICU Management: General
Anticipating, recognizing and treating complications is integral to operative suc-
cess. Optimal management requires ongoing close cooperation between the surgical
team and the critical-care team.
Patient Position
Nosocomial pneumonia is the most frequent problem in the postoperative period of
patients undergoing a major head and neck procedure [ 30 ]. The recognized
12 Management of Critically Ill Head and Neck Surgical Patients
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pathogenetic sequence is abnormal oropharyngeal colonization and subsequent
aspiration. Bacterial colonization of the stomach and gastric refl ux might also play
a part in the pathogenesis of lung infection. Approximately 20 years ago, studies
using radio-labelled gastric contents showed that refl ux could be reduced and aspi-
ration could be avoided by positioning patients in a semi-recumbent position [ 42 ,
43 ]. A subsequent clinical study indicated the risk of nosocomial pneumonia to be
the highest among ventilated patients receiving enteral feeds in the supine position
[ 44 ]. A recent meta-analysis of three randomized trials (337 patients) confi rmed that
the odds of developing clinically proven pneumonia were signifi cantly lower among
ventilated patients in the semi-recumbent 45° position compared to the supine posi-
tion (OR 0.47; 95 % CI 0.27–0.82) [
45 ].
Not surprisingly, an elevated head position (angle >30°) has become a standard
of care for all mechanically ventilated patients in the ICU [ 46 ]. It stands to reason
that the same concept can be extrapolated to prevent pneumonia in postoperative
head and neck patients, although these patients have additional factors that contrib-
ute to nosocomial infections. The semi-recumbent position is one of the simplest
and most cost-effective preventative measures in healthcare.
Analgesia and Sedation
Patient comfort and safety are two important priorities of analgesia and sedation in
critically ill patients [ 47 ]. Analgesia and sedation are provided in the postoperative
period by means of a pharmacological agent. Opioids are time-honoured, valuable
and powerful analgesics for the management of moderate-to-severe postoperative
pain. The effi cacy of different opioids is similar as far as clinically relevant out-
comes are concerned. However, evidence suggests that more sophisticated methods
of administration, such as patient-controlled analgesia (PCA) may improve pulmo-
nary outcome. The most commonly used opioids for intravenous (i.v.) PCA are
morphine, fentanyl or hydromorphone. The common setting for administration of
these drugs is summarized in Table
12.1 . In general, the depth of analgesia should
be adapted to the needs of individual patients. Management of patients is best
guided by simple clinical scales [ 48 , 49 ], although there is no consensus on how
frequently pain and sedation scores should be evaluated. Whereas there is some
agreement on what constitutes an acceptable level of pain relief, the same is not true
of sedation. Recent data from clinical trials have shown that sedation of ICU patients
with benzodiazepines might contribute to confusion or overt delirium [ 50 , 51 ].
Table 12.1 Commonly used opioids in intravenous patient-controlled analgesia (PCA)
Drug Demand dose Lockout interval Basal infusion rate
a
Morphine 1–2 mg 5–10 min <0.5 mg/h
Hydromorphone 0.25–0.5 mg 5–10 min <0.4 mg/h
Fentanyl 10–50 mcg 5–10 min <50 mcg/h
a Basal infusions are recommended only in opioid-tolerant patients
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Patients receiving sedatives and opioids are also at risk of excessive sedation,
respiratory depression, nausea and vomiting. These side-effects are likely to be
most evident in elderly patients or those with renal or hepatic dysfunction, although
large individual variations are known to occur. Opioids suppress hypoglossal activ-
ity, thereby diminishing the activity of genioglossus muscle during inspiration,
while concomitantly decreasing the responsiveness of upper airway muscles to
hypercapnia. Consequently, patients with known OSA have a higher frequency of
apnoeic episodes postoperatively [ 52 ]. Patients with nasal obstruction, tonsillar or
adenoidal hypertrophy, or those with upper airway surgery appear to have an
increased risk of complications in the immediate perioperative period.
Postoperative delirium is a common complication of head and neck surgery
because of the high prevalence of certain risk factors (e.g. age, cognitive decline,
alcohol use). Patients who become agitated are at increased risk of self-harm
[
53 , 54 ], increased length of ICU and hospital stay, increased costs, and a higher
all- cause mortality. The relationship between delirium and increased mortality
is independent of age, illness severity, and whether or not these patients receive
mechanical ventilation in the ICU. The confusion assessment method for ICU
(CAM-ICU) [ 55 ] is an objective scoring system for delirium, which comple-
ments the Richmond agitation–sedation scale [ 56 ] for use in ICU patients. A
scoring system to identify patients at-risk of postoperative delirium is probably
more useful but it has not been validated in head and neck surgery patients [ 57 ].
Given the high prevalence of alcohol consumption, it is prudent to screen all
patients preoperatively for current alcohol intake using the standard CAGE ques-
tionnaire. In general, the severity of withdrawal symptoms is proportional to the
duration and amount of alcohol intake, with patients who have experienced delirium
tremens or seizures being at the highest risk. Symptom-triggered approach with
early introduction of benzodiazepines is preferable at the onset of withdrawal symp-
toms. The α-2 agonists, clonidine and dexmetetomidine, have been used for alcohol
withdrawal in the ICU. These agents have little effect on respiratory function but
have several useful cardiovascular effects, including blunting of the tachycardic and
hypertensive response of patients emerging from effects of prolonged alcohol
intake. α-2 agonists have also been shown to reduce behavioural and autonomic
responses after termination of conventional sedation and facilitate extubation [
58 ].
In a separate study by Reade et al. [ 59 ] dexmetetomidine was compared with halo-
peridol for treating patients deemed otherwise ready, but were not extubated because
of agitated delirium. Patients receiving dexmetetomidine went onto extubation ear-
lier compared with those receiving haloperidol [ 59 ].
Venous Thromboembolism Prophylaxis
Deep vein thrombosis (DVT) and pulmonary embolism (PE) are important causes
of morbidity and mortality among surgical patients. Guidelines for thrombo-
prophylaxis are well established and based on the results of several randomized
trials [
60 ]. In contradistinction to these guidelines, chemoprophylaxis is not
12 Management of Critically Ill Head and Neck Surgical Patients
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recommended routinely for patients undergoing head and neck surgery, including
HNC surgery [ 61 ]. The generally low incidence of perioperative DVT or PE (0.1–
2.5 %) in head and neck surgery patients [ 62 – 65 ] and the risk of bleeding or related
complications means that chemoprophylaxis targeted to a high-risk group is a better
strategy. Chemoprophylaxis for low-risk, ambulatory (or day care) patients is not
justifi ed and currently is not recommended.
Several patient-specifi c risk factors for venous thromboembolism (VTE) have
been identifi ed in surgical patients [ 26 ]. These can either be elicited from history or
more formally in the form of a risk stratifi cation scale [
66 ]. Among patients with
multiple risk factors who are undergoing a major procedure that is likely to result in
prolonged immobilization, VTE prophylaxis is considered reasonable. A dispropor-
tionately high number of VTE events have been recorded among patients undergo-
ing microvascular fl aps, implying that this group of patients should also be managed
as a high-risk group. The American College of Chest Physicians guidelines recom-
mend the use of pneumatic compression devices, unfractionated heparin (UFH) or
low-molecular weight heparin (LMWH) for prophylaxis [ 67 ]. If prophylaxis is
used, it should commence within 2 h of completion of surgery to be effective [ 67 ].
For pneumatic compression to be effective, the compression device must be worn
for at least 90 % of the duration of immobility [ 68 ].
A recent meta-analysis of clinical trials on ICU patients has confi rmed a benefi -
cial effect of chemoprophylaxis with UFH compared with placebo in reducing the
risk of DVT, but more importantly, the statistical analysis showed a decreased risk
of PE with the use of LMWH compared with UFH (RR 0.62; 95 % CI 0.39–1.00;
p = 0.05) [ 69 ]. Although rates of major bleeding were not signifi cantly different, it
is worth noting that the effects of UFH can be easily quantifi ed and reversed, if
needed.
Nutrition
Nutrition has long been recognized as the second most important factor in predict-
ing long-term prognosis in HNC. Whereas the National Institute for Health and
Clinical Excellence (NICE) guidelines provide the best framework for a multidisci-
plinary approach to nutritional management of patients, the most comprehensive
guidelines have been issued recently by the Clinical Oncological Society of
Australia (COSA) [ 70 ]. COSA guidelines have provided a grade A recommenda-
tion for inclusion of a dietitian in the multidisciplinary team looking after HNC
patients, and for dietary intervention during treatment to maintain or improve nutri-
tional status. The European Society of Parenteral and Enteral Nutrition (ESPEN)
guidelines on enteral nutrition (EN) recommend preoperative nutritional supple-
mentation for 10–14 days prior to surgery in patients with BMI of <18.5 kg/m
2 , or
those with weight loss of >10–15 % in past 6 months [ 71 ]. This is applicable to
preoperative head and neck patients as well.
Standard polymeric fi bre feeds are recommended for use postoperatively with an
aim to deliver ≥30 kcal/kg/day. Postoperative tube feeds should commence within
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24 h with consideration given to individual patients, depending on the extent of the
surgical procedure performed and other priorities identifi ed by the multidisciplinary
team. This recommendation is supported by a recent meta-analysis, which showed
that early EN (within 24 h) compared to standard care was associated with a signifi -
cant reduction in mortality and rate of pneumonia among adult ICU patients [ 72 ].
The optimal method of tube feeding remains unclear. Evidence does not favour
post-pyloric feeds over the standard nasogastric feeds [ 73 ].
The role of parenteral nutrition (PN) in critically ill adults has been clarifi ed
recently by two large multi-centre trials [
74 , 75 ]. Published in 2011, the EPaNIC trial
did not fi nd any benefi t with the addition of PN to deliver calories up to a desired goal
in patients who were already receiving some EN [ 74 ]. Therefore, sick ICU patients
who tolerate some enteral feeds in the fi rst 24–48 h may not derive any additional
benefi t from rapidly reaching a pre-specifi ed but empirical nutritional target. A sec-
ond trial (Early Parenteral Nutrition trial) was designed to study a small subset of
ICU patients with relative contraindications for early EN (within 24 h of ICU admis-
sion) [ 75 ]. In this trial, early PN commenced on day 1 of ICU was compared with
standard care; no difference was observed in 60-day mortality between the early PN
group and standard care group in which nutritional therapy was started on day 3.
Early PN resulted in signifi cantly fewer days of invasive ventilation but no change in
the ICU or LOS. In other words, starting PN within 24 h of admission in ICU patients
who are not ready to be fed enterally is not associated with improvement in mortality.
One salient fi nding of the early PN study was that the rate of central line infection in
patients receiving PN was comparable to that in the EN arm of the study [ 74 ].
Diabetes is a common co-morbid condition among head and neck patients and is
considered a risk factor for several postoperative complications, such as infections,
cardiac and metabolic problems, and delirium. Although a review has focused on
the postoperative care of the diabetic patient, it has not addressed the issue of dia-
betic patients undergoing head and neck surgery [ 76 ]. In general, targets for glycae-
mic control among the critically ill have been clarifi ed recently by a large
multi-centre, randomized trial NICE-SUGAR [
77 ]. Contrary to the prevailing view
at that time, the study showed an increased risk of mortality and adverse effects
(hypoglycaemia) among patients randomized to the strict glycaemic control arm
(4.5–6.0 mmol/L) [ 77 ]. Consequently, the currently recommended insulin therapy
is targeted to achieve blood glucose levels of 6.0–10.0 mmol/L.
Antibiotic Prophylaxis
The effi cacy of antibiotic prophylaxis for reducing surgical site infection (SSI) has
been clearly established. Patients who receive prophylaxis within 1 h or 2 h before
the surgical incision have lower rates of SSI compared with those who receive anti-
biotics sooner or later than this window [ 78 , 79 ]. In general, antimicrobial selection
for SSI prophylaxis is based on type of surgery, safety, bactericidal activity and cost.
Elective procedures of the head and neck are predominantly clean or clean-
contaminated. Clean procedures include thyroidectomy and lymph node dissections.
12 Management of Critically Ill Head and Neck Surgical Patients
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Clean-contaminated procedures include all surgeries involving an incision through
the oral or pharyngeal mucosa. These range from parotidectomy, submandibular
gland excision, tonsillectomy, adenoidectomy and rhinoplasty, to complex proce-
dures, such as tumour debulking and mandibular fracture repair. The infection rate
among patients undergoing complex head and neck procedures in the absence of
antimicrobial prophylaxis is high (24–78 %); infection rates are markedly lower with
prophylaxis (5–38 %) [
80 ].
Most infections arising after clean-contaminated head and neck procedures are
caused by microorganisms residing in the oral cavity. These include anaerobic bac-
teria, and therefore postoperative SSI are polymicrobial [ 81 , 82 ]. The predominant
oropharyngeal organisms include various streptococci (aerobic and anerobic), other
anaerobes, including Bacteroides species (but not B. fragilis ), Peptostreptococcus
species, Fusobacterium species, Veillonella species and, rarely, Enterobacteriaceae,
and Staphylococcus species.
Antimicrobial prophylaxis is not warranted for patients undergoing clean proce-
dures of the head and neck [
83 , 84 ]. A single preoperative dose of cefazolin (or
clindamycin in the setting of β-lactam allergy) is reasonable in the setting of pros-
thetic material placement, although data on the effi cacy of this practice have not
been clarifi ed. Prophylaxis with antibiotics is recommended routinely for most
other head and neck procedures [ 80 ], although randomized trials have not shown
any benefi t in the setting of adenoidectomy, tonsillectomy or septoplasty [ 85 , 86 ]. A
reasonable regimen for patients undergoing surgery includes a cephalosporin
(cefazolin or cefuroxime) plus metronidazole or ampilcillin-sulbactam. Clindamycin
is an alternative for patients with β-lactam allergy (Table 12.2 ).
In general, repeat antibiotic dosing after wound closure is not necessary. In a
systematic review of controlled trials, no difference was seen in the rate of SSI with
a single dose compared with multiple dose regimens given for less than or more
than 24 h [ 87 ]. For cases in which perioperative antibiotic coverage is required
beyond the period of surgery, the duration should be <24 h.
Table 12.2 Antimicrobial prophylaxis for head and neck surgery patients
Type of surgery Pathogens
Antimicrobial
prophylaxis Usual adult dose
Clean None
Clean with
placement of
prosthesis
S. aureus, S. epidermidis,
Strep. species
Cefazolin <120 kg: 2 g i.v.
>120 kg: 3 g i.v.
OR cefuroxime 1.5 g i.v.
OR clindamycin 600–900 mg i.v.
Clean –
contaminated
Anaerobes, enteric
Gram-negative bacteria,
S. aureus
Cefazolin
PLUS metronidazole 500 mg i.v.
OR cefuroxime 1.5 g i.v.
OR ampicillin- sulbactam 3 g i.v.
OR clindamycin 900 mg i.v.
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Errors in the selection and timing of prophylactic antibiotics remain a major con-
cern. Among 34,133 patients undergoing major surgery in the USA, an antimicrobial
was administered within 1 h before incision to only 56 % of patients, and antimicro-
bials were discontinued within 24 h of surgery in only 41 % of patients [ 88 ].
ICU Management: Specific
Patients with active head and neck pathology or those who have undergone surgical
or radiation treatment for HNC are at increased risk of adverse airway events. These
need to be recognized and managed appropriately.
Airway
A number of head and neck procedures involve the upper airway. When airway com-
promise is not an issue, most procedures are routine and largely uneventful [ 89 ]. All
patients with airway compromise should be considered as having a potential diffi cult
airway for which well-established guidelines now exist [ 90 ]. Unfortunately, there is
no universal recipe for the management of the airway for head and neck procedures.
Each procedure requires an appraisal of the urgency of the procedure, size and site of
lesion, level of obstruction, and degree of airway compromise [ 89 ].
The recently published report of the Fourth National Audit Project of the Royal
College of Anaesthetists and Diffi cult Airway Society (DAS) identifi ed serious air-
way complications occurring during anaesthesia in the ICU and in the emergency
department [ 91 ]. In the presence of head and neck pathology and after maxillofacial
or major neck surgery, a number of airway-related complications were encountered.
Approximately 70 % were associated with obstructive lesions within the airway [ 91 ].
Early fi bre-optic intubation by an experienced anaesthetist or tracheostomy by
an experienced surgeon is a reasonable consideration in patients with a threatened
airway. Patients with airway compromise are easily identifi ed in the presence of
tachypnoea and stridor, but should be recognized even in the presence of subtle
signs, such as an inability to lie down fl at in bed or silent breathing with adoption of
the sniffi ng position while sitting upright. Routine endotracheal intubation in these
patients is complicated by trismus, distorted anatomy, immobility of soft tissue
structures, friability and bleeding, or in the worst case scenario, complete obstruc-
tion of the airway after anaesthetic induction. Awake fi bre-optic techniques are suit-
able for oral cavity, oropharyngeal and tongue base lesions, but might be unsuitable
for lesions in the larynx in which the fi brescope has to pass through the mass.
Inhaled induction techniques in which spontaneous ventilation is maintained
have been used for potentially diffi cult airways. However, such an approach is not
without its problems. A reduction in airfl ow, increased collapsibility of airway,
increased work of breathing, and reduction in functional residual capacity can
impair the onset and depth of anaesthesia and preclude placement of an endotra-
cheal or nasotracheal tube, as required.
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Following major head and neck surgery, the risk of upper airway obstruction
remains high and the optimal postoperative airway management remains controver-
sial. Bilateral neck dissections, use of bulky reconstruction fl aps, resection of man-
dible, tongue or fl oor of mouth carry the greatest risk. It is uncertain if the risks of
tracheostomy outweigh anticipated airway problems in the postoperative period.
Cameron and colleagues used an old dataset to derive a clinical score to guide clini-
cal decision-making that reliably identifi ed the need for elective tracheostomy at the
time of the initial procedure [ 92 ]. The score was validated in their sample of 148
major head and neck procedures and indicated a variable positive and negative pre-
dictive value, depending on the cut-off threshold used. The scoring system has since
neither been refi ned nor applied widely, but remains a useful adjunct to clinical
judgement.
Airway Devices
Humidity is important throughout the postoperative period to prevent drying of
secretions and blockage of the airway, particularly in patients with a fresh trache-
ostomy or tracheostoma. Tracheostomy reduces the risk of glottic damage com-
pared with long-term use of a tracheal tube, and is particularly important if slow
resolution of oedema or infl ammation is anticipated. Elective tracheostomy should
be considered in patients with HNC in whom either the location or the extent of
cancer precludes translaryngeal tube placement. Wherever possible, a tracheos-
tomy tube with suction above the cuff should be considered. Two randomized trials
[ 93 , 94 ] and a meta-analysis [ 95 ] have shown that endotracheal tubes (ETT)
equipped with subglottic suction signifi cantly reduced the incidence of ventilator-
associated pneumonia (VAP) in patients ventilated for ≤3 days without a corre-
sponding increase in adverse events. A recently published randomized trial has
extended these observations to a group of mechanically ventilated patients who
required a tracheostomy in the ICU [
96 ]. In this study involving only 18 patients,
the researchers were able to show a signifi cant reduction in the incidence of VAP
(56 % vs. 11 %; p = 0.02) with the use of tracheostomy tubes with a suction port
above the cuff [ 96 ].
Tracheostomy care has traditionally been provided by surgical teams that
performed the procedure, but this has changed with the introduction of newer
techniques [ 97 ] and with the growing recognition of the complex needs of tra-
cheosomy patients. Tracheostomy insertion has implications for communica-
tion, swallowing, airway management and overall nursing care, thereby
justifying the need for involvement of a multidisciplinary team. In 2009,
Garrubba et al., conducted a systematic review of multidisciplinary care for
ward-based tracheostomy patients [ 98 ]. They identifi ed three studies and con-
cluded that time to decannulation, LOS and adverse events were better with a
tracheostomy team compared with the standard approach. A more recent, sec-
ond systematic review also confi rmed a reduction in total tracheostomy time
after the introduction of tracheostomy teams [
99 ].
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Postoperative Care
Scheduled administration of steroids is a common practice. Steroids reduce infl am-
matory oedema but have no direct effect on oedema arising from mechanical trauma
or venous obstruction. The evidence suggests that all steroids are equally effi ca-
cious, provided they are given in equivalent doses. When considered for use, ste-
roids should be continued for ≥12 h [ 100 ]. Single-dose steroids given immediately
before extubation are ineffective.
The perioperative use of β-blockers in naïve patients undergoing non-cardiac
surgery is controversial since the publication of the POISE study [ 101 ]. In this large
multicentre trial, patients >45 years of age randomized to receive metoprolol peri-
operatively had fewer MIs (4.2 % vs. 5.7 %; p = 0.05; NNT 67) but an increased rate
of stroke and overall mortality. A metaanalysis of clinical trials on the same topic
published within a month of the POISE study showed a reduction in the risk of non-
fatal MIs in the postoperative period [ 102 ]. In fact, trials showing a benefi cial effect
of intervention were the ones that studied β-blockers in high-risk patients. Other
studies showing benefi t without any adverse events were ones that used a lower dose
of β-blockers compared with the POISE study. These controversies notwithstand-
ing, patients with an indication for β-blockers or those already on the drug derive a
benefi t, if they are continued on the drug throughout the surgical period [ 103 ].
Extubation in ICU
Many patients are transported to the ICU intubated and are extubated after what is
deemed as a suitable period of observation. In 2012, the DAS—acknowledging the
lack of large randomized trials of extubation practices—released a set of guidelines
for the management of tracheal extubation on the basis of expert opinion [ 104 ].
Extubation in the ICU is an elective process even if intubation of the trachea was
undertaken during an emergency. Planning for tracheal extubation is a critical com-
ponent of a successful airway management strategy, particularly when dealing with
patients with a diffi cult airway. This involves assessment of the airway and general
risk factors. Extubation is considered ‘low risk’ if the airway anatomy was normal at
induction and remained so until the end of surgery with no complications superven-
ing. ‘At-risk’ extubation, on the other hand, is one in which an airway or a general
risk factor has been identifi ed. However, evaluating these risks in a patient whose
airway is still protected is a more subtle task. While reliable anatomical predictors of
inability to perform effective mask ventilation and intubation have been identifi ed,
the same is not true for answering the question, ‘Is it safe to remove the tube?’
Whereas oedema of the tongue and pharyngeal structures is easily visualized,
laryngeal oedema is more diffi cult to assess and quantify, especially in the presence
of an ETT. If the tube is small compared with the size of the airway, as is frequently
the case with upper airway pathology, direct laryngoscopy to visualize the degree
and anatomical distribution of oedema is helpful. However, the degree of inter-
observer agreement is only modest [
105 ]. A quantitative cuff leak test can be used
12 Management of Critically Ill Head and Neck Surgical Patients
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186
along with laryngoscopy (direct or video-assisted) to increase the predictive value
of assessment [ 106 ]. The discriminatory power of this test depends on the method
and cut-off values chosen. Choice of a higher cut-off value minimizes the risk of
false-negatives (presence of leak = negative test) may be valuable in patients in
whom diffi cult tracheal intubation is expected. In a systematic review and a meta-
analysis, Ochoa et al . [ 107 ] concluded that whereas a negative test is not necessarily
reassuring, a positive cuff-leak test should alert the clinician about the risk of upper
airway obstruction. This test has been validated only in patients who have received
mechanical ventilation for 48 h rather than those ventilated overnight. The test itself
requires measurement of expired tidal volumes after six complete respiratory cycles
while on an assist-control mode or control mode of ventilation with the ETT cuff
defl ated. A leak volume of 10–25 % (~100–130 ml in a 70 kg adult) of the expired
tidal volume before cuff defl ation is considered safe for extubation.
With the exception of tube exchangers to guide and expedite reintubation, no
other specifi c tool or procedure to increase safety at extubation has gained wide-
spread acceptance or has been adopted in clinical algorithms [
108 ]. Airway exchange
catheters (AEC) are long, thin, hollow tubes made of semi-rigid polyurethane and are
supplied with 15 mm connectors compatible with anaesthetic circuits and Luer lock
connectors for use with jet ventilation. They can be inserted through the tracheal tube
before extubation because they can be used as a guide over which a tracheal tube can
be passed, should reintubation become necessary [ 109 ]. They can also be used to
oxygenate patients’ lungs. In a recent review, Duggan et al. reported that oxygen
insuffl ation might be associated with a signifi cant risk of barotrauma [ 110 ]. The
authors therefore concluded that priority be given to reintubation over attempting
oxygenation and ventilation through the lumen of the catheter. To enhance safety, the
recently published DAS guidelines suggest that an AEC should not be inserted
beyond 25 cm, but this only applies to orally intubated, adult patients [ 104 ].
Extubation failure after a well-planned extubation is uncommon, but it is rela-
tively more common in critically ill patients. In the presence of head and neck
pathology and after maxillofacial or major neck surgery, the rate of tracheal reintu-
bation has been reported to vary between 0.7 and 11 %. Conditions, such as obesity,
OSA, rheumatoid arthritis and other cervical spine pathologies also carry a signifi -
cant risk of extubation failure. This usually follows loss of upper airway patency
because of oedema, soft tissue collapse, laryngospasm, bleeding, secretions, or col-
lapse of upper airway structures. A few investigators have reported that ICU patients
requiring reintubation for respiratory failure have a higher mortality (30–53 %) than
patients reintubated because of airway obstruction (7–17 %), suggesting that wean-
ing failure may carry a higher mortality compared with extubation failure [
111 ].
One explanation to account for this difference is that patients who fail extubation
because of airway obstruction are reintubated earlier than those who fail because of
respiratory complications [ 108 ], and time to reintubation is a well known indepen-
dent risk factor for mortality in this group [ 111 ].
In this context, it is reasonable to consider extubation in the operating theatre to
ensure availability of equipment and, most importantly, availability of the surgical
team, in case a surgical airway is required.
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Conclusion
Care of the critically ill head and neck patient poses many challenges many of
which arise as a result of the primary disorder, but increasingly because of asso-
ciated co- morbidities and complications of treatment. Some, more often than
not, complicate airway management, and pose a signifi cant threat to life. These
need to be recognized by the primary surgical team and the anaesthetist in a
timely manner, and treated appropriately. A multidisciplinary approach is essen-
tial to achieve high quality care.
References
1. Garantziotis S, Kyrmizakis DE, Liolios AD. Critical care of the head and neck patient. Crit
Care Clin. 2003;19:73–90.
2. Bansal A, Miskoff J, Lis RJ. Otolaryngologic critical care. Crit Care Clin. 2003;19:55–72.
3. Bradley PJ. Should all head and neck cancer patients be nursed in intensive therapy units fol-
lowing major surgery? Curr Opin Otolarygol Head Neck Surg. 2007;15:63–7.
4. To EW, Tsang WM, Lai EC, et al. Retrospective study on the need of intensive care unit
admission after major head and neck surgery. ANZ J Surg. 2002;72:11–4.
5. Godden DR, Patel M, Baldwin A, et al. Need for intensive care after operations for head and
neck cancer surgery. Br J Oral Maxillofac Surg. 1999;37:502–5.
6. Downey RJ, Friedlander P, Groeger J, et al. Critical care for severely ill head and neck patient.
Crit Care Med. 1999;27:95–7.
7. Morton RP. The need for ITU admission after major head and neck surgery [Editorial]. ANZ
J Surg. 2002;72:3–4.
8. Sivagnanam T, Langton SG. Need for intensive care after operations for head and neck cancer
surgery. Br J Oral Maxillofac Surg. 2001;39:77.
9. Bhama PK, Davis GE, Bhrany AD, et al. The effects of intensive care unit staffi ng on patient
outcomes following microvascular free fl ap reconstruction of the head and neck: a pilot study.
JAMA Otolaryngol Head Neck Surg. 2013;139:37–42.
10. Boruk M, Chernobilsky B, Rosenfeld R, et al. Age as a prognostic factor for complications
of major head and neck surgery. Arch Otolaryngol Head Neck Surg. 2005;131:605–9.
11. Pearse RM, Moreno RP, Bauer P, et al. Mortality after surgery in Europe: a 7-day cohort
study. Lancet. 2012;380:1059–65.
12. Ghaferi AA, Birkmeyer JD, Dimick JB. Variation in hospital mortality associated with inpa-
tient surgery. N Engl J Med. 2009;361:1368–75.
13. Story DA, Leslie K, Myles PS, et al. Complications and mortality in older surgical patients in
Australia and New Zealand (the REASON Study): a multi-centre, prospective, observational
study. Anaesthesia. 2010;65:1022–30.
14. Khuri SF, Hendersen WG, DePalma RG, et al. Determinants of long term survival after major
surgery and the adverse effect of postoperative complications. Ann Surg. 2005;242:326–41.
15. Piccrillo JF. Importance of co-morbidity in head and neck cancer. Laryngoscope. 2000;110:
593–602.
16. Sabin SL, Rosenfeld RM, Sundaram K, et al. The impact of co-morbidity and age on survival
with laryngeal cancer. Ear Nose Throat J. 1999;78:581–4.
17. Sanabria A, Carvalho AL, Melo RL, et al. Predictive factors for complications in elderly
patients who underwent head and neck oncological surgery. Head Neck. 2008;30:170–7.
18. Borggreven PA, Verdonck-de Leeuw I, Rinkel RN, et al. Swallowing after major surgery of
the oral cavity or oropharynx: a prospective and longitudinal assessment of patients treated
by microvascular soft tissue reconstruction. Head Neck. 2007;29:638–47.
12 Management of Critically Ill Head and Neck Surgical Patients
malcolm_buchanan123@hotmail.com
188
19. Le-Diery MW, Futran ND, McDowell JA, et al. Infl uences and predictors of long-term qual-
ity of life in head and neck cancer survivors. Arch Otolaryngol Head Neck Surg.
2009;135:380–4.
20. Charlson ME, Pompei P, Alex KL, et al. A new method of classifying prognostic co- morbidity
in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83.
21. Singh B, Bhaya M, Stern J, et al. Validation of Charlson co-morbidity index in patients with
head and neck cancer: a multi-institutional study. Laryngoscope. 1997;107:1469–75.
22. Grant CA, Dempsey GA, Lowe D, et al. APACHE II scoring for the prediction of immediate
surgical complications in head and neck cancer patients. Plast Reconstr Surg.
2007;119:1751–8.
23. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a
simple index for prediction of cardiac risk of major non-cardiac surgery. Circulation.
1999;100:1043–9.
24. Piccirillo JF, Spitznagel Jr EL, Vermani N, et al. Comparison of co-morbidity indicies for
patients with head and neck cancer. Med Care. 2004;42:482–6.
25. Paleri V, Wight RG, Silver CE, et al. Co-morbidity in head and neck cancer: a critical
appraisal and recommendations for practice. Oral Oncol. 2010;46:712–9.
26. Adler JS, Auerbach AD. Medical complications of head and neck surgery. In: Eisele DW,
Smith RV, editors. Complications in head and neck surgery. 2nd ed. Philadelphia: Mosby
Elsevier; 2009. p. 55–66.
27. Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool to screen patients for
obstructive sleep apnea. Anaesthesiology. 2008;108:812–21.
28. Payne RJ, Hier MP, Kost KM, et al. High prevalence of obstructive sleep apnea among
patients with head and neck cancer. J Otolaryngol. 2005;34:304–11.
29. Stern TP, Auckley D. Obstructive sleep apnea following treatment of head and neck cancer.
Ear Nose Throat J. 2007;86:101–3.
30. Bhattacharya N, Fried MP. Benchmarks for mortality, morbidity and length of stay for head
and neck surgery procedures. Arch Otolarygngol Head Neck Surg. 2001;127:127–32.
31. Bos MM, Bakshi-Raiez F, Dekker JW, et al. Outcomes of intensive care unit admissions after
elective cancer surgery. Eur J Surg Oncol. 2013;39:584–92.
32. Petrar S, Bartlett C, Hart RD, et al. Pulmonary complications after major head and neck sur-
gery: a retrospective cohort study. Laryngoscope. 2012;122:1057–61.
33. Chen AY. Medical management of head and neck patients. In: Lubin MF, Smith III RB,
Dodson TF, Spell NO, Walker HK, editors. Medical management of the surgical patient. 4th
ed. Cambridge: Cambridge University Press; 2006. p. 767.
34. Stenson KM, Brockstein BE, Ross ME. Epidemiology and risk factors for head and neck
cancer.
www.uptodate.com . Accessed 27 July 2013.
35. Reynolds SC, Chow AW. Severe soft tissue infections of the head and neck: a primer for criti-
cal care physicians. Lung. 2009;187:271–9.
36. Ramadan HH, El-Soh AA. An update on otolaryngology in critical care. Am J Respir Crit
Care Med. 2004;169:1273–7.
37. Chen MK, Wen YS, Chang CC, et al. Predisposing factors of life threatening deep neck infec-
tions: logistic regressions analysis of 214 cases. J Otolaryngol. 1998;27:141–4.
38. Boscolo-Rizzo P, Da Mosto MC. Submandibular space infection: a potentially lethal infec-
tion. Int J Infect Dis. 2009;13:322–33.
39. Vieira F, Allen SM, Stocks RM, et al. Deep neck infections. Otolarygngol Clin North Am.
2008;41:459–83.
40. Salvi M, Gallagher JE, Nayyar V, et al. Intensive care admissions for odontogenic infec-
tions – a clinical and socio-economic marker of the need for dental care. Abstract, ANZICS
ASM meeting, Adelaide; Oct 2012.
41. Reynolds SC, Chow AW. Life-threatening infections of the periphayngeal and deep fascial
spaces of the head and neck. Infect Dis Clin North Am. 2007;21:557–76.
42. Torres A, Serra-Battles J, Ros E, et al. Pulmonary aspiration of gastric contents in patients receiv-
ing mechanical ventilation: the effect of body position. Ann Intern Med. 1992;116:540–3.
V. Nayyar
malcolm_buchanan123@hotmail.com
189
43. Centers for Disease Control and Prevention. Guidelines for prevention of nosocomial pneu-
monia. MMWR Morb Mortal Wkly Rep. 1997;46:1–79.
44. Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial
pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999;354:1851–4.
45. Alexiou VG, Ierodiakonou V, Dimopoulos G, et al. Impact of patient position on the inci-
dence of ventilator associated pneumonia: a meta-analysis of randomised trials. J Crit Care.
2009;24:515–22.
46. The American Thoracic Society and the Infectious Diseases Society of America Guidelines
Committee. Guidelines for the management of adults with hospital-acquired, ventilator- acquired
and healthcare-acquired pneumonia. Am J Respir Crit Care Med. 2005;171:388–416.
47. Jacobi J, Fraser GL, Coursin DB, et al. Task force of the American College of Critical Care
Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of
Health-Systems Pharmacists (ASPH), American College of Chest Physicians: clinical prac-
tice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit
Care Med. 2002;30:119–41.
48. Kremer F, Atkinson JH, Ignelzi RJ. Measurement of pain: patient preference does not con-
found pain measurement. Pain. 1981;10:241–8.
49. Palmer PP, Miller RD. Current and developing methods of patient controlled analgesia.
Anesthesiol Clin. 2010;28:587–99.
50. Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for
transitioning to delirium in intensive care units patients. Anesthesiology. 2006;104:21–6.
51. Saito M, Terao Y, Fukusaki M, et al. Sequential use of midazolam and propofol for long-term
sedation in postoperative mechanically ventilated patients. Anesth Analg. 2003;96:834–8.
52. Memtsoudis SG, Besculides MC, Mazumdar M. A rude awakening – the perioperative sleep
apnea epidemic. N Engl J Med. 2013;368:2352–3.
53. Woods JC, Mion LC, Connor JT, et al. Severe agitation among ventilated medical intensive
care unit patients: frequency, characteristics and outcomes. Intensive Care Med. 2004;20:
1066–72.
54. Thomason JW, Shintani A, Petersen JF, et al. Intensive care unit delirium is an independent
predictor of longer hospital stay: a prospective analysis of 261 nonventilated patients. Crit
Care. 2005;9:R375–81.
55. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: valida-
tion of the Confusion Assessment Method for the Intensive care Unit (CAM-ICU). Crit Care
Med. 2001;29:1370–9.
56. Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients:
reliability and validity of the Richmond Agitation–Sedation Scale (RASS). JAMA.
2003;289:2983–91.
57. Marcantonio ER, Goldman L, Magnione CM, et al. A clinical prediction rule for delirium
after elective non-cardiac surgery. JAMA. 1994;271:134–9.
58. Liatsi D, Tsapas B, Pampori S, et al. Respiratory, metabolic, and hemodynamic effects of
clonidine in ventilated patients presenting with withdrawal syndrome. Intensive Care Med.
2009;35:275–81.
59. Reade MC, O’Sullivan K, Bates S, et al. Dexmetetomidine vs haloperidol in delirious, agi-
tated, intubated patients: a randomised open-label trial. Crit Care. 2009;13:R75.
60. McLeod AG, Geerts W. Venous thromboembolism prophylaxis in critically ill patients. Crit
Care Clin. 2011;27:765–80.
61. Prevention of venous thromboembolism (VTE) in patients admitted to Australian hospitals:
Guideline summary.
www.nhmrc.gov.au . Accessed 14 Aug 2013.
62. Jaggi R, Taylor SM, Trites J, et al. Review of thromboprophylaxis in otolarygngology head
and neck surgery. J Otolaryngol Head Neck Surg. 2011;40:261–5.
63. Hennessey P, Semenov YR, Gourin CG. The effect of deep venous thrombosis on short-term out-
comes and cost of care after head and neck cancer surgery. Laryngoscope. 2012;122:2199–204.
64. Gavriel H, Thompson E, Kleid S, et al. Safety of thromboprophylaxis after oncologic head
and neck surgery. Study of 1018 patients. Head Neck. 2013;35:1410–4.
12 Management of Critically Ill Head and Neck Surgical Patients
malcolm_buchanan123@hotmail.com
190
65. Garritano FG, Lehman EB, Andrews GA. Incidence of venous thromboembolism in otolar-
yngology head and neck surgery. JAMA Otolaryngol Head Neck Surg. 2012;139:21–7.
66. Shuman AG, Hsou MH, Pannucci CJ, et al. Stratifying risk of venous thromboembolism in
otolaryngology. Otolaryngol Head Neck Surg. 2011;146:719–24.
67. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the seventh
ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126 Suppl
3:338S–400.
68. Samamma CM, Albaladejo P, Benhamou D. Venous thromboembolism prevention in surgery
and obstetrics: clinical practice guideline. Eur J Anaesthesiol. 2006;23:95–116.
69. Alhazzani W, Lim W, Jaeschke RZ, et al. Heparin prophylaxis in medical-surgical critically
ill patients: a systematic review and meta-analysis of randomised trials. Crit Care Med.
2013;41:2088–98.
70. Evidence based practice guidelines for the nutritional management of adult patients with
head and neck cancer.
www.cosa.org.au . Accessed 17 Aug 2013.
71. Weimann A, Braga M, Harsanyi L, et al. ESPEN guidelines on enteral nutrition: surgery
including organ transplantation. Clin Nutr. 2006;25:224–44.
72. Doig GS, Heighes PT, Simpson F, et al. Early enteral nutrition, provided within 24 hours
of injury or intensive care admission, signifi cantly reduces mortality in critically ill
patients: a meta-analysis of randomised controlled trials. Intensive Care Med.
2009;35:2018–27.
73. Davies AR, Morrison SS, Bailey MJ, et al. A multi-centre, randomised trial comparing
early nasojejunal with nasogastric nutrition in critical illness. Crit Care Med.
2012;40:2342–8.
74. Casear MP, Mesotten D, Hermans G, et al. Early vs. late parenteral nutrition in critically ill
adults. N Engl J Med. 2011;365:506–17.
75. Doig DS, Simpson F, Sweetman EA, et al. Early parenteral nutrition in critically ill patients
with short term relative contraindications to early enteral nutrition: a randomized, controlled
trial. JAMA. 2013;309:2130–8.
76. Hoogwerf BJ. Perioperative management of diabetes mellitus: how should we act on the
limited evidence? Cleve Clin J Med. 2006;73 Suppl 1:S95–9.
77. NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in criti-
cally ill patients. N Engl J Med. 2009;360:1283–97.
78. Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of
antibiotics and the risk of surgical wound infection. N Engl J Med. 1992;326:281–6.
79. Van Kasteren ME, Mannien J, Ott A, et al. Antibiotic prophylaxis and the risk of surgical site
infections following total hip arthroplasty: timely administration is the most important factor.
Clin Infect Dis. 2007;44:921–7.
80. Simo R, French G. The use of prophylactic antibiotics in head and neck oncological surgery.
Curr Opin Otolaryngol Head Neck Surg. 2006;14:55–61.
81. Skitarelic N, Morovic M, Manestar D. Antibiotic prophylaxis in clean-contaminated head
and neck oncological surgery. J Craniomaxillofac Surg. 2007;35:15–20.
82. Brook I. Microbiology and principles of antimicrobial therapy for head and neck infections.
Infect Dis Clin North Am. 2007;21:355–91.
83. Anderson DJ, Sexton DJ. Antimicrobial prophylaxis for prevention of surgical site infection
in adults.
www.uptodate.com . Accessed 14 Aug 2013.
84. Avenia N, Sanguinetti A, Cirocchi R, et al. Antibiotic prophylaxis in thyroid surgery: a pre-
liminary multi-centre Italian experience. Ann Surg Innov Res. 2009;3:10.
85. O’Reilly BJ, Black S, Fernandes J, et al. Is the routine use of antibiotics justifi ed in adult
tonsillectomy? J Larnygol Otol. 2003;117:382–5.
86. Caniello M, Passerotti GH, Goto EY, et al. Antibiotics in septoplasty: is it necessary? Braz J
Otorhinolaryngol. 2005;71:734–8.
87. McDonald M, Grabsch E, Marshall C, et al. Single versus multiple dose antimicrobial pro-
phylaxis for major surgery: a systematic review. Aust NZ J Surg. 1998;68:388–96.
88. Bratzler DW, Houck PM, Richards C, et al. Use of antimicrobial prophylaxis for major sur-
gery: baseline results from the national surgical infection prevention project. Arch Surg.
2005;140:174–82.
V. Nayyar
malcolm_buchanan123@hotmail.com
191
89. Feldman MA, Patel A. Anesthesia for eye, ear, nose and throat surgery. In: Miller RD,
Eriksson LI, Fleisher LA, Weiner-Kronish JA, Young WL, editors. Miller’s anesthesia. 7th ed.
Philadelphia: Churchill Livingstone; 2009. p. 2357–88.
90. American Society of Anesthesiologist Task Force on Management of the Diffi cult Airway.
Practice guidelines for management of the diffi cult airway: an updated report. Anesthesiology.
2003;98:1269–77.
91. Cook TM, Woodall N, Frerk C. on behalf of the fourth national audit project. Major compli-
cations of airway management in the UK: results of the fourth national audit project of the
Royal College of Anaesthetists and the Diffi cult Airway Society. Part I: Anaesthesia. Br J
Anaesth. 2011;106:617–31.
92. Cameron M, Corner A, Diba A, et al. Development of a tracheostomy scoring system to guide
airway management after major head and neck surgery. Int J Oral Maxillofac Surg.
2009;38:846–9.
93. Kollef MH, Skubas NJ, Sundt TM. A randomised clinical trial of continuous aspiration of
subglottic secretions in cardiac surgery patients. Chest. 1999;116:1339–46.
94. Shorr AF, O’Malley PG. Continuous subglottic suctioning for the prevention of ventilator
associated pneumonia: potential economic implications. Chest. 2001;119:228–35.
95. Muscedere J, Rewa O, McKechnie K, et al. Subglottic secretion drainage for the prevention
of ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care Med.
2011;39:1985–91.
96. Ledgerwood LG, Salgado MD, Black H, et al. Tracheostomy tubes with suction above the
cuff reduce the rate of ventilator-associated pneumonia in intensive care unit patients. Ann
Otol Rhinol Laryngol. 2013;122:3–8.
97. Kornblith LZ, Burlew CC, Moore EE, et al. One thousand bedside percutaneous tracheosto-
mies in the surgical intensive care unit: time to change the gold standard. J Am Coll Surg.
2011;212:163–70.
98. Garrubba M, Turner T, Grieveson C. Multi-disciplinary care for tracheostomy patients:
a systematic review. Crit Care. 2009;13:R177.
99. Speed L, Harding KE. Tracheostomy teams reduce total tracheostomy time and increase
speaking valve use: a systematic review and meta-analysis. J Crit Care. 2013;28:216.e1–10.
100. Francois B, Bellissant E, Gissot V, et al. 12-h pretreatment with methylprednisolone versus
placebo for prevention of post-extubation laryngeal oedema: a randomised double blind trial.
Lancet. 2007;369:1083–9.
101. POISE Study Group. Effects of extended release metoprolol succinate in patients undergoing
non-cardiac surgery (POISE trial): a randomised trial. Lancet. 2008;371:1839–47.
102. Bangalore S, Wetterslev J, Pranesh S, et al. Perioperative beta blockers in patients having
non-cardiac surgery: a meta-analysis. Lancet. 2008;372:964–9.
103. Graber MA, Dachs R, Darby-Stewart A. Beta blockers and non-cardiac surgery: why POISE
study alone should not change your practice. Am Fam Physician. 2010;81:717–9.
104. Popat M, Mitchell V, Dravid R, et al. Diffi cult Airway Society guidelines for the management
of tracheal extubation. Anaesthesia. 2012;67:318–40.
105. Pattersen JM, Hildreth A, Wilson JA. Measuring edema in irradiated head and neck cancer
patients. Ann Otol Rhinol Laryngol. 2007;116:559–64.
106. De Backker D. The cuff leak test: what are we measuring? Crit Care. 2005;9:31–3.
107. Ochoa ME, Marin Mdel C, Frutos-Vivar F, et al. Cuff-leak test for the diagnosis of upper
airway obstruction in adults: a systematic review and meta-analysis. Intensive Care Med.
2009;35:1171–9.
108. Cavallone LF, Vannucci A. Extubation of the diffi cult airway and extubation failure. Anesth
Analg. 2013;116:368–83.
109. Mort TC. Continuous airway access for the diffi cult extubation: the effi cacy of the airway
exchange catheter. Anesth Analg. 2007;105:1357–62.
110. Duggan LV, Law JA, Murphy MF. Brief review: supplementing oxygen through an airway
exchange catheter – effi cacy, complications and recommendations. Can J Anaesth. 2011;58:
560–8.
111. Epstein SK, Ciubotaru RL. Independent effects of etiology of failure and time to reintubation
on outcome for patients failing extubation. Am J Respir Crit Care Med. 1998;158:489–933.
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© Faruque Riffat, Carsten E. Palme, Michael Veness, Rehan Kazi, Raghav C. Dwivedi 2015
Springer India/Byword Books
F. Riffat et al. (eds.), Non-melanoma Skin Cancer of the Head and Neck,
Head and Neck Cancer Clinics, DOI 10.1007/978-81-322-2497-6_13
G. Adams , BSc, MB ChB, MRCP, FRCR, FRANZCR (*)
Radiation Oncology, Oceania Oncology Bundaberg , Bundaberg , QLD , Australia
School of Medicine, University of Queensland , St Lucia , QLD , Australia
e-mail: adams_gerard@hotmail.com
S. V. Porceddu
Radiation Oncology, University of Queensland , St Lucia , QLD , Australia
Princess Alexandra Hospital , Brisbane , QLD , Australia
e-mail: sandro_porceddu@health.qld.gov.au
1 3
Future Directions in the Management
of Non-melanoma Skin Cancer
Gerard Adams and Sandro V. Porceddu
Introduction
The current and future management of non-melanoma skin cancer (NMSC)—predom-
inantly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)—represents
a signifi cant public health problem worldwide. Australia has one of the highest rates of
skin cancer in the world, with data showing that NMSC is fi ve times more common
than all other cancers combined [ 1 ]. The sun-exposed head and neck (HN) is the most
common location, with incidence rates continuing to rise 3–10 % per year. Although
BCC is more common, the vast majority of NMSCs are localized and easily treated
with simple excision. However, 5 % are considered high-risk (nearly always SCC) and
metastasize to regional lymph nodes with the potential for distant spread [ 2 ].
Campaigns to reduce sun exposure may mitigate this rising incidence in the
future. However, the risk of NMSC (mainly SCC) has been shown to be raised sig-
nifi cantly in conditions in which immunity is suppressed, either naturally (e.g.
chronic lymphocytic leukaemia (CLL) [ 3 ], infection with human immunodefi ciency
virus (HIV) [ 4 ] or iatrogenically (e.g. organ transplant recipients [ 5 ], treatment for
rheumatoid arthritis [ 6 ]). With more people with these conditions surviving, as well
as an ageing global population, the rates of NMSC are likely to remain high, with,
perhaps, even an increasing rate of high-risk disease.
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194
NMSC already represents the most expensive cancer burden on the Australian
Health system [ 7 ]. The predominant treatment is surgery, as it is generally curative
and provides histopathological information. Modalities, such as radiotherapy, topi-
cal treatments and photodynamic therapy, are used when surgery is not the preferred
option [ 8 ]. Issues surrounding current management are dealt with elsewhere in this
book. This chapter examines how management of NMSC might alter in the future,
with an emphasis on high-risk SCC of the HN.
Operable Disease
Adjuvant Chemotherapy in High-Risk Disease?
As with other cancers, modern management aims to stratify patients into high- and
low-risk groups. Research is aimed towards intensifying treatment in the higher-risk
group in the hope of improving control or de-escalating treatment in the lower-risk
groups with the aim to maintain high control rates, yet minimize toxicity and
improve quality of life for survivors.
The current focus of treatment intensifi cation in high-risk groups with cutaneous
HNSCC (cHNSCC) is centred on the addition of chemotherapy. High-risk features
include size (>2 cm), deep invasion (4–6 mm), incomplete excision, presence of
perineural invasion (PNI) and/or lymphovascular invasion, recurrent disease, poor
differentiation, location (ear or lips), and immunosupression [ 9 ]. Currently consen-
sus is lacking on what role, if any, the addition of adjuvant chemotherapy plays in
management. Advocates for adding chemotherapy point to the improved survival
when adjuvant high-dose cisplatin-based chemoradiotherapy is used, compared
with to radiotherapy alone in the postoperative management of mucosal HNSCC
(mHNSCC) [ 10 , 11 ]. However, those cautious about chemotherapy point to the pau-
city of data on its use for cHNSCC [ 12 , 13 ], as well as the fact that many patients
with this disease are elderly, have signifi cant co-morbidities or hearing impairment,
which would preclude the use of these chemotherapy regimens, especially without
clear evidence of benefi t.
In order to investigate the role of adding chemotherapy, the Trans-Tasman
Radiation Oncology Group (TROG) is currently accruing to a multicentre, random-
ized phase III trial in which patients in the investigational arm receive chemother-
apy with weekly carboplatin (area under the curve [AUC] 2), in addition to the
standard postoperative radiotherapy. This trial, viz. TROG 05.01 Post-Operative
Skin Trial (POST) NCT00193895, is outlined in Fig.
13.1 . The use of weekly car-
boplatin (AUC 2) is a pragmatic choice, as this regimen is better tolerated than the
high-dose cisplatin regimens used for mHNSCC, and hence more appropriate for
this population. Also, the investigators have evidence of similar results using this
regimen and weekly low-dose cisplatin—a regimen used for those unable to tolerate
high-dose cisplatin—in postoperative mHNSCC [ 14 ]. As of March 2013, a total of
307 of the required 350 patients had been accrued. When the results of this trial are
available, clinicians may have a better idea about the role of chemotherapy in
G. Adams and S.V. Porceddu
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195
addition to radiotherapy in the management of high-risk cHNSCC, although further
studies may be required to optimize the chemotherapy regimen or better character-
ize the high-risk factors.
De-intensification—Reducing Extent of Surgery
(or Radiotherapy) in Lower-Risk Disease?
Apart from treatment escalation in high-risk groups, efforts are under way to de-
intensify treatment in lower-risk groups. Metastatic involvement of the parotid
gland lymph nodes from cHNSCC is in itself considered to be a high-risk feature
and would fulfi l the requirements of entry into the POST study (Fig. 13.1 ).
Current best practice includes parotidectomy (with attempt to preserve facial nerve
function, if appropriate), a neck dissection (with levels according to possible primary
ELIGIBLE PATIENTS
Cutaneous squamous cell carcinoma of the head and neck
(above clavicles)
Definitive surgery with removal of all macroscopic disease
ADVANCED PRIMARY DISEASE
T3/T4 in transit disease
HIGH-RISK NODAL DISEASE
• Any parotid
• Cervical - 2 nodes, or any
node >3 cm, or any node with
extracapsular extension
HIGH-RISK FEATURES
RANDOMIZATION
RADIOTHERAPY ALONE (60–66 Gy) RADIOTHERAPY and CHEMOTHERAPY
(Carboplatin)
Fig. 13.1 Schema for Trans-Tasman Radiation Oncology Group phase III randomized controlled
trial of postoperative concurrent chemoradiotherapy versus postoperative radiotherapy in high-risk
cutaneous squamous cell carcinoma of the head and neck. TROG 05.01 Post-Operative Skin Trial
13 Future Directions in the Management of Non-melanoma Skin Cancer
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196
sites) followed by adjuvant radiotherapy [ 15 ]. Adjuvant radiotherapy to the parotid
bed is almost always required because of the inevitable close margins, especially if the
facial nerve is preserved. The rationale for elective neck treatment has arisen from
multiple studies showing a signifi cant rate of occult disease in the cervical nodes in
patients undergoing neck dissection for cHNSCC that has metastasized to the parotid
[ 16 – 20 ]. These studies were carried out in both Australia and North America and are
summarized in Table 13.1 . The rate of occult neck disease ranged from 15 to 44 %.
This wide range may refl ect the small sample size of each retrospective, single-insti-
tution study, or alternatively, it may refl ect differences in case selection, utility of
staging investigations or treatment philosophy between centres. Nevertheless, all
these factors point to the need for some form of elective node treatment. However,
only one study, by Kirke and colleagues from Brisbane, specifi cally addresses the rate
of occult nodes in a group with ‘clinically and radiologically’ negative necks [ 16 ].
None of the other studies mention the use of imaging to assess the neck. Indeed the
starting point of most studies pre-dates the routine use of modern imaging techniques,
the use of which will inevitably reduce the rate of occult disease.
Routine preoperative imaging with computed tomography (CT) scans is now
commonplace, and so the incidence of occult neck disease may not be as high as
some of the earlier reports suggest.
If postoperative radiotherapy is required for the parotid bed, many radiation
oncologists will also treat the surgical bed, albeit to a lower dose. However, if the
rate of occult neck disease is closer to 15 % then the routine use of neck dissection
and adjuvant radiotherapy is likely to represent overtreatment for the majority, espe-
cially given the known detrimental effects on long-term quality of life when radio-
therapy and neck dissection are combined in patients with mHNSCC [
21 , 22 ]. This
forms the rationale for the current DROPNECK study under way in Brisbane, which
attempts carefully to select a group of patients with clinically and radiologically
negative necks in whom neck dissection can be eliminated safely and the elective
neck treatment delivered in conjunction with the adjuvant radiotherapy to the
parotid bed. This low-risk group is limited to those with nodes of <6 cm, no dermal
infi ltration, immunocompetent patients, and patients not requiring vascular fl ap
reconstruction. This is a single-arm safety study with the primary end-point being
the rate of neck node failure as the site of fi rst relapse. The policy will be deemed
Table 13.1 Summary of published series showing the rates of clinically occult neck lymph nodes
in patients undergoing neck dissection for cutaneous squamous cell carcinoma metastasizing to the
parotid gland
Study Study period Total cN+ cN0 ND in cN0 pN+ after ND
Kirke et al. [
16 ] 1999–2008 81 30 51 a 34 5/34 (15 %)
Audet et al. [
17 ] 1970–2001 56 6 50 24 4/24 (17 %)
Dona et al. [
18 ] 1983–2000 74 9 65 43 7/43 (16 %)
Ying et al . [ 19 ] 1982–2003 41 6 35 27 12/27 (44 %)
O’Brien et al. [
20 ] 1987–1999 73 19 54 37 13/37 (35 %)
cN+ clinically node positive, cN0 clinically node negative, ND neck dissection, pN+ pathologi-
cally node positive
a clinically and radiologically negative
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197
safe if this rate is found to be ≤7 % at 2 years. A careful follow-up schedule has been
established and early stopping rules are in place to terminate the study if it becomes
apparent that this primary end-point is unlikely to be met.
Studies such as this can help identify a cohort of patients with lower risk in
whom treatment can be de-intensifi ed. Indeed, there may be a cohort who may be
best managed with surgery and limited neck dissection without the need for radio-
therapy. If such studies take place it is important that outcome measures include
quality of life and cost-effectiveness, as well as standard clinical measures.
Extending the Radiotherapy Fields with High-Risk
Perineural Invasion?
PNI in cHNSCC is a marker for poor outcome even with aggressive surgical and
radiotherapy approaches [ 23 ]. The trigeminal (V) and facial (VII) are the most
likely to be involved. In addition to the characteristic signs and symptoms, magnetic
resonance imaging (MRI) can help defi ne the extent of involvement and help plan
surgery [ 24 ].
Radiotherapy is indicated after resection, usually targeting the involved primary
site with a generous margin as well as ‘chasing’ the involved nerve. Crossover of
disease from one nerve to another can occur, and this might even involve switch
inside (e.g. left to right) for disease close to the midline [ 25 ].
There are also interconnections between named nerves (subdivisions of V and/or
VII) on the same side that might help facilitate spread [ 26 ].
Adjuvant radiotherapy requires knowledge of the course of the relevant cranial
nerves. Whereas their courses are well known [ 27 ], precise knowledge of boundar-
ies between subdivisions and/or degree of overlap at the level of the skin is unknown.
Variation exists between oncologists as to the boundaries used to demarcate fi elds.
The choice of boundaries, such as midline [ 28 ], may be pragmatic because of limit-
ing toxicity rather than potential routes of spread.
Fortunately, modern radiotherapy can be delivered more conformally to the
shape of the target volume using intensity-modulated radiotherapy (IMRT). This
will allow extension of the treatment fi elds to target the areas at risk while sparing
low-risk tissue, thus minimizing toxicity.
However, much is still unknown about the precise pathways of spread as well as
the individual variation in anatomy. Although further research is required, work is
ongoing to establish consensus guidelines along similar lines to those already in
common use for nodal HN volumes [
29 ]—in order to allow a more standardized
approach to radiotherapy for this uncommon clinical scenario.
Improvements in Staging
As already discussed, staging of cHNSCC involves a CT scan and an MRI scan if
there is a suggestion of PNI. Whereas functional imaging, typically with [18 F] fl uo-
rodeoxyglucose positron emission tomography (FDG-PET) has an established role
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198
and changes management in both mHNSCC [ 30 ] and advanced melanoma [ 31 ], the
role of functional imaging with NMSC is less well established. Routine use of
FDG-PET is not recommended with BCC because of its low risk of distant spread.
However, there have been reports of metastatic BCC identifi ed by FDG-PET [ 32 ].
Similarly, there have been reports of FDG-PET being used in the staging of cHN-
SCC; [ 33 ] however, high-quality evidence about its role in cSCC is lacking. This
probably refl ects the tendency to perform lymph node dissection followed by radio-
therapy in all high-risk tumours, especially in cases of cHNSCC.
However, as focus shifts towards identifying subgroups with lower risk that may
benefi t from less aggressive locoregional treatment, it is likely that FDG-PET will be
used more. Yet, it is important that well-designed studies are developed to try to evalu-
ate its utility in this setting rather than simply assuming that the benefi ts in mHNSCC
and melanoma are automatically transferred. There is a danger that routine use of
FDG-PET may result in over-treatment of some patients, especially if the DROPNECK
study outlined above identifi es a group in which clinical assessment and CT are able
to identify a group that might be safely spared routine neck dissection.
Efforts are under way in Brisbane to establish a study in which patients not eligible
for DROPNECK, and thus who are planned for parotidectomy and neck dissection,
undergo a FDG-PET as well as diagnostic CT before surgery. Given the consistent
management approach, this study will be able to provide information on the sensitiv-
ity, specifi city and clinical usefulness of FDG-PET in the management of this group
of patients. This is a similar approach currently being used in the Merkel PET Phase
II ‘MP3’ study discussed in an earlier chapter on Merkel cell carcinoma [
34 ].
It is hoped that results of this FDG-PET cHNSCC study and the DROPNECK
study will drive further research that will ultimately result in improvements in man-
aging patients with operable cHNSCC.
Inoperable or Metastatic Disease
Chemoradiotherapy
Whereas most patients with locally advanced tumours are able to undergo curative
intent surgery, a small proportion present with inoperable disease. Results with
radiotherapy alone have been disappointing in this group. However, evidence has
emerged showing favourable results in a small cohort of inoperable patients treated
with primary chemoradiotherapy [ 35 ]. In this prospective single-centre phase II
trial, 14 patients were treated with cisplatin 40 mg/m
2 or carboplatin (AUC2) con-
currently with radiotherapy to a total dose of 70 Gy in 35 fractions. Encouragingly,
all but one patient was able to complete radiotherapy with 42 % also receiving the
planned chemotherapy. Toxicity was acceptable and the complete response rate was
57 % (8/14) with a further 2 (14 %) achieving a complete response after surgical
salvage. The 3-year overall survival rate was 54 % [ 35 ].
Given the previous poor outcomes in this group, this study should form the basis of
further research in order to further defi ne the role of chemoradiation as the initial
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199
management in cHNSCC. Similar to mHNSCC, over time there may be an increasing
use of this modality to downstage tumours that are operable at presentation but where
the long-term functional or cosmetic outcomes are improved by initial chemoradiation.
Targeted Therapies
As stated earlier, there is no evidence for the use of conventional cytotoxic chemo-
therapy as a sole agent with cHNSCC [
12 , 13 ] Therefore, current research continues
to focus on the role of targeted therapies in advanced disease.
Targeting the epithelial growth factor receptor (EGFR) has recently shown some
success. Both large molecule antibodies (cetuximab) [ 36 ] and small molecule tyro-
sine kinase inhibitors (TKIs), such as gefi tinib [ 37 ], have had moderate success in
treating locally advanced or metastatic SCC. Targeting the EGFR in both these
phase II studies of patients with either locally advanced or metastatic cSCC showed
response rates of ~70 %. While encouraging for further research, it is not yet clear
how durable the response is and whether response is related to levels of receptor
expression or mutations in downstream proteins.
A different pathway has been identifi ed in advanced BCC. In 2009, a phase I
study by Von Hoff and colleagues showed that an oral inhibitor of the hedgehog
pathway had anti-tumour effect in metastatic BCC [ 38 ]. Further studies have shown
objective response rates of 30–40 % when this drug (vismodegib) is used in inoper-
able or metastatic BCC [ 39 ].
Also, in a randomized phase III trial of vismodegib versus placebo, established
BCCs were more likely to regress and new BCCs were less likely to occur in patients
with the basal cell nevus syndrome who were on active treatment. However, 54 %
of patients discontinued the drug due to toxicity (mainly loss of taste, hair and
weight, and muscle cramps) [ 40 ].
The clinical role of vismodegib, although clearly an active drug, needs to be bet-
ter defi ned, given its toxicity. An active research programme is under way targeting
the hedgehog pathway with the hope that other drugs might be identifi ed that may
be clinically useful for the rare phenomenon of advanced or metastatic BCC [
41 ].
Key Points
• NMSC will remain an important health issue in the future.
• Current research is aimed at methods of escalating treatment in high-risk
disease (chemoradiation) or de-intensifying treatment in lower-risk
patients (reducing the extent of surgery and/or radiotherapy fi elds).
• Concurrent defi nitive chemoradiation is likely to become the treatment of
choice in suitable patients with inoperable disease.
• Functional imaging with PET scanning may become useful in tailoring
treatment to individual patients.
• Targeted drugs will have an increasing role in the management of advanced
SCC and BCC.
13 Future Directions in the Management of Non-melanoma Skin Cancer
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200
References
1. Staples MP, Elwood E, Burton RC, et al. Non-melanoma skin cancer in Australia: the 2002
national survey and trends since 1985. Med J Aust. 2006;184:6–10.
2. Alam M, Ratner D. Cutaneous squamous cell carcinoma. N Engl J Med. 2001;344:975–83.
3. Schollkopf C, Rosendahl D, Rostgaard K, et al. Risk of second cancer after chronic lympho-
cytic leukemia. Int J Cancer. 2007;121:151–6.
4. Cooksley CD, Hwang LY, Waller DK, et al. HIV-related malignancies: community-based study
using linkage of cancer registry and HIV registry data. Int J STD AIDS. 1999;10:795–802.
5. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and
different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40:
177–86.
6. Askling J, Fored CM, Brandt L, et al. Risks of solid cancers in patients with rheumatoid arthritis
and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis. 2005;64:1421–6.
7. Australian Institute of Health and Welfare (AIHW). Health system expenditures on cancer and
other neoplasms in Australia 2000–2001. AIHW cat. no. HWE 29. Health and Welfare
Expenditure Series No. 22. Canberra: Australian Institute of Health and Welfare; 2005.
8. Oddone N, Gary J, Morgan GJ, et al. Metastatic cutaneous squamous cell carcinoma of the
head and neck. The Immunosuppression, Treatment, Extranodal Spread, and Margin Status
(ITEM) Prognostic Score to Predict Outcome and the Need to Improve Survival. Cancer.
2009;115:1883–91.
9. Veness MJ, Porceddu S, Palme CE, et al. Cutaneous head and neck squamous cell carcinoma
metastatic to parotid and cervical lymph nodes. Head Neck. 2007;29:621–31.
10. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemo-
therapy for high-risk squamous cell carcinoma of the head and neck. N Engl J Med.
2004;350:1937–44.
11. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant
chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945–52.
12. Denic S. Preoperative treatment of advanced skin carcinoma with cisplatin and bleomycin. Am
J Clin Oncol. 1999;22:32–4.
13. Sadek H, Azli N, Wendling JL, et al. Treatment of advanced squamous cell carcinoma of the
skin with cisplatin, 5-fl uorouracil and bleomycin. Cancer. 1990;66:1692–6.
14. Porceddu SV, Campbell B, Rischin D, et al. Postoperative chemo-radiotherapy for high-risk
head and neck squamous cell carcinoma (HNSCC). Int J Radiat Oncol Biol Phys.
2004;60:365–73.
15. O’Hara J, Ferlito A, Takes RP, Rinaldo A, et al. Cutaneous squamous cell carcinoma of the
head and neck metastasizing to the parotid gland – a review of current recommendations. Head
Neck. 2011;33:1789–95.
16. Kirke DN, Porceddu S, Wallwork BD, et al. Pathologic occult neck disease in patients with
metastatic cutaneous squamous cell carcinoma to the parotid. Otolaryngol Head Neck Surg.
2011;144:549–51.
17. Audet N, Palme CE, Gullane PJ, et al. Cutaneous metastatic squamous cell carcinoma to the
parotid gland: analysis and outcome. Head Neck. 2004;26:727–32.
18. Dona E, Veness MJ, Cakir B, et al. Metastatic cutaneous squamous cell carcinoma to the
parotid: the role of surgery and adjuvant radiotherapy to achieve best outcome. ANZ J Surg.
2003;73:692–6.
19. Ying YM, Johnson JT, Myers EN. Squamous cell carcinoma of the parotid gland. Head Neck.
2006;28:626–32.
20. O’Brien CJ, McNeil EB, McMahon JD, et al. Incidence of cervical node involvement in meta-
static cutaneous malignancy involving the parotid gland. Head Neck. 2001;23:744–8.
21. Machtay M, Moughan M, Trotti T, et al. Factors associated with severe late toxicity after con-
current chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin
Oncol. 2008;26:3582–9.
G. Adams and S.V. Porceddu
malcolm_buchanan123@hotmail.com
201
22. Donatelli-Lassig AA, Duffy SA, Fowler KE, et al. The effect of neck dissection on quality of
life after chemoradiation. Otolaryngol Head Neck Surg. 2008;139:511–8.
23. Panizza B, Solares CA, Redmond M, et al. Surgical resection for clinical perineural invasion
from cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2012;34:1622–7.
24. Gandhi MR, Panizza B, Kennedy D. Detecting and defi ning the anatomic extent of large nerve
perinerual spread of malignancy: comparing ‘targeted MRI’ with the historic fi ndings follow-
ing surgery. Head Neck. 2011;33:469–75.
25. Barnett CM, Foote MC, Panizza B. Cutaneous head and neck malignancies with perineural
spread to contralateral cranial nerves: an argument for extending postoperative radiotherapy
volume. J Clin Oncol. 2013;31:2291–3.
26. Bischoff EPE. Microscopic analysis of the anastamosis between the cranial nerves. Hanover:
University Press of New England; 1997. p. 1–138.
27. Myckatyn TM, Mackinnon SE. A review of facial nerve anatomy. Semin Plast Surg.
2004;18:5–12.
28. Ballantyne AJ, McCarten AB, Ibanez ML. The extension of cancer of the head and neck
through peripheral nerves. Am J Surg. 1963;106:651–7.
29. Grégoire V, Levendag P. CT-based delineation of lymph node levels in the N0 neck:
DAHANCA, EORTC, GORTEC, RTOG consensus guidelines.
http://www.rtog.org/LinkClick.
aspx?fi leticket=TjrmNiHXly8%3d&tabid=229 . Accessed 16 June 2013.
30. Scott AM, Gunawardana DH, Bartholomeusz D, et al. PET changes management and improves
prognostic stratifi cation in patients with head and neck cancer: results of a multicenter pro-
spective study. J Nucl Med. 2008;49:1593–600.
31. Wagner JD, Schauwecker DS, Davidson D, et al. FDG-PET sensitivity for melanoma lymph
node metastases is dependent on tumor volume. J Surg Oncol. 2001;77:237–42.
32. Boswell JS, Flam MS, Tashjian DN, et al. Basal cell carcinoma metastatic to cervical lymph
nodes and lungs. Dermatol Online J. 2006;12:9.
33. Cho SB, Chung WG, Yun M, et al. Fluorodeoxyglucose positron emission tomography in
cutaneous squamous cell carcinoma: retrospective analysis of 12 patients. Dermatol Surg.
2005;31:442–6.
34. Merkel PET Phase II ‘MP3’ Study (NCT01013779).
http://www.trog.com.au/Portals/0/
Open%20Trials/TROG%2009%2003_Amend%202%2010%20March%202011_Clean.pdf .
Accessed 16 June 2013.
35. Nottage M, Francesconi A, Houston K, et al. A prospective study investigating the impact of
defi nitive chemoradiation in locoregionally advanced squamous cell carcinoma of the skin.
J Clin Oncol. 2012;30(suppl; abstr 8538).
36. Maubec E, Petrow P, Duvillard P, et al. Cetuximab as fi rst-line monotherapy in patients with
skin unresectable squamous cell carcinoma: fi nal results of a phase II multicenter study. J Clin
Oncol. 2010;28(suppl; abstr 8510).
37. Weber RS, Lustig RA, El-Naggar AK, et al. Gefi tinib for advanced cutaneous squamous cell
carcinoma of head and neck: phase II trial. J Clin Oncol. 2009;27(suppl; abstr 6054).
38. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced
basal cell carcinoma. N Engl J Med. 2009;361:1164–72.
39. Cirrone F, Harris CS. Vismodegib and the hedgehog pathway: a new treatment for basal cell
carcinoma. Clin Ther. 2012;34:2039–50.
40. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in
patients with the basal cell nevus syndrome. N Engl J Med. 2012;366:2180–8.
41. Atwood SX, Mischa L, Lee A, et al. GLI activation by atypical protein kinase Cι/λ regulates
the growth of basal cell carcinomas. Nature. 2013;494:484–90.
13 Future Directions in the Management of Non-melanoma Skin Cancer
malcolm_buchanan123@hotmail.com
