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Chapter
CURRENT TRENDS AND MANAGEMENT IN HEAD
AND NECK CANCERS
Arutha Kulasinghe1, Yenkai Lim1, Chris F. L Perry2,3
and Chamindie Punyadeera1*
1 Queensland University of Technology, Institute of Health and Biomedical Innovations,
60 Musk Avenue, Kelvin Grove, Australia.
Queensland University of Technology, Australia
2 Department of Otolaryngology, Princess Alexandra Hospital, Woolloongabba, Australia
and the University of Queensland, the School of Medicine,
University of Queensland, Herston, Australia.
ABSTRACT
There is a general lack of public awareness on the daunting statistics of head and
neck squamous cell carcinoma (HNSCC) when compared with other mainstay cancers
such as breast and prostate cancers. HNSCC includes malignancies in five major
anatomical sites, namely, oral cavity, oropharynx, nasopharynx, hypopharynx and larynx.
HNSCC is diverse in nature both biologically and clinically. HNSCC is the 6 th most
common cancer globally with less than 50% survival beyond 5 years resulting in over
900 000 deaths annually. Risk factors include smoking and alcohol consumption, betel
nut chewing, wearing dentures, trauma to the gums and oral cavity and as well as
exposure to the human papillomavirus (HPV). HNSCC is more prevalent in men,
however, the prevalence in women has been increasing due to changes in lifestyle over
the last few decades. Whilst, smoking associated HNSCC is in on the decline, HPV
associated HNSCC is on the riseincreasing. The therapy of choice for newly diagnosed
patients consists of combined modality treatment of surgery, chemotherapy and
radiotherapy. Despite this aggressive first line treatment, over 30% of HNSCC patients
develop locoregional and distant metastasis and succumb to the disease. Early diagnostics
are the key to early interventions at the disease stage which can improve patient
outcomes. This chapter aims to outline HNSCC trends and statistics, research based
prognostic and diagnostic tools, treatments and patient management.
* Correspondence: Associate Professor Chamindie Punyadeera; Institute of Health and Biomedical Innovations,
Queensland University of Technology; 60 Musk Avenue, GPO Box 2434; Brisbane QLD 4001; Australia.
Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
1. HEAD AND NECK SQUAMOUS CELL CARCINOMA
Head and neck squamous cell carcinoma (HNSCC) refers to cancer around the upper
aerodigestive regions [1]. These regions include the oral cavity, nasal cavity, paranasal
sinuses, pharynx and larynx [1, 2] (see Fig 1.). HNSCC originates from the mucosal lining in
the head and neck region with squamous cell carcinoma as the most common histological
variant, comprising 90% of all cases cancer types [3-5]. As the sixth most common cancer
worldwide, HNSCC is responsible for 900,000 new cases and 300,000 deaths annually [1].
With poor prognosis, HNSCC patients have a five-year mortality rate of 40 to 50% [5-7].
Despite improvements in the locoregional control and reduced treatment-related morbidities,
the five-year survival rates in HNSCC have not improved [8]. The lower 5-year survival rate
is due to the late diagnosis of HNSCC (i.e. at stage II) and often associated with cervical
lympnode metastasis [9]. In addition, it has been also been reported that only 30% of HNSCC
cases in the USA are diagnosed at an early clinical stage and two-thirds of patients present
with advanced stage III or IV tumours [10]. The lack of early diagnostic tools methods are
responsible for poor five-year survival rate [11].
Figure 1. Anatomical sites where head and neck cancers arise.
Successful treatments of in HSNCC patients depend rely on early detection and targeted
therapy for each cancer phasesubtype. However, currently most cases of HNSCC are detected
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Current Trends and Management in Head and Neck Cancers
when the patient has become symptomatic from the effects of the primary disease or when
lymphatic metastases are palpable. Despite the obvious advantages of earlier diagnosis of
HNSCC, no strategy is currently being implemented to effectively treat HNSCC patients at an
earlier stage when the tumour burden is minimal (i.e. during neoplasia).
Over the past five years, high incidence of HNSCC was reported in Southeast Asia,
Central and Southeast Europe [1]. Increasing trends of HNSCC was also observed in Central,
and Eastern Europe, Scandinavia, Canada, Japan and Australia [1]. In contrast, an overall
decreasing trend was noted in India, Hong Kong, Brazil, Unite States USA and West Africa
[1]. Majority The majority of the people who develop HNSCC is are in their sixth and
seventh years deacdes (93.3%) [12]. Men are at a 2-fold higher risk of developing HNSCC
than women [13]. Tobacco & alcohol consumptions and Human papilloma virus (HPV)
(others include poor diet, betel nut chewing and mouth wash use) as well as genetic
susceptibility (others include poor diet, betel nut chewing and mouth wash use) are major risk
factors for developing HNSCC [1, 2, 14, 15]. Tobacco use has decreased over the past decade
in high-income and upper middle-income countries due to the successful tobacco awareness
campaigns [1]. However, there is an increasing trend of tobacco use in many developing
countries, contributing to the increase prevalence of HNSCC [1]. As an example, oral cancers
are higher in the Asian sub-continent [1]. In contrast, alcohol consumption is more popular in
developed countries due to the expensive price-tag [1]. Overall, in the past five years, there
has been no significant change in the rate of alcohol consumption worldwide [1]. Genetic
predisposition also plays a major role in HNSCC development [1]. Patients suffering from
Fanconi anemia, FAMMM, Bloom’s syndrome, Xeroderma pigmentosum, Ataxia
telangiectasia and Li-Fraumeni have 700 to 1000 fold risk in of developing HNSCC
compared to normal individuals [1]. These patients usually develop HNSCC at a younger age
[1].
Currently, a slight decrease in the incidence of smoking associated HNSCC is
documented [16]. Excessive tobacco and alcohol consumption remain important risk factors
of HNSCC, however the global incidence of human papillomavirus (HPV)- positive HNSCC
(oropharngeal squamous cell carcinoma, OPSCC) is on the rise. Over the past decade, there
has been a rise of over 70% prevalence of HPV related oropharyngeal SCCs with the
prevalence in Europe increasing at a faster rate than North America. As opposed toIn contrast
to HPV-negative HNSCC, HPV-positive HNSCC targets young patients within the third and
fourth decade due to high oral sex activities. As such, 89% of HPV-associated HNSCC are
based within the oral cavity and oropharyngeal anatomical sites. There is limited data for the
developing regions. Approximately 90% of HPV-related oropharyngeal cancers are due to
HPV-16 subtype infections and most often found in the tonsils and base of tongue. It is
estimated that tumours in the oropharynx are five times more likely to be HPV positive than
those in the oral cavity, larynx or hypopharynx [17]. Loco-regional control is also
significantly better in HPV-positive OPSCC but the rate of distant metastasis increases after 2
years unlike in patients with HPV-negative tumours [18]. Furthermore, metastases are more
likely to occur significantly later in HPV-positive OPSCC compared to HPV-negative
tumours, involving multiple organs, such as the skin, intra-abdominal lymph nodes and brain
[19]. However, the implication of HPV status on non-oropharyngeal sites on prognosis and
distant metastasis remains unclear. HPV positive oropharyngeal SCCs tend to be poorly
differentiated and presents clinically with a lower tumour stage and higher nodal spread.
What is of interest is that, patients present with a more favourable prognosis. Patients tend to
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Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
respond with better outcomes to combined modality chemoradiotherapy as well as stand-
alone surgery. HPV status has been clinically relevant and played an important role in the
treatment regimens of patients.
HPV-positive HNSCCs have genetic alterations that are direct result of HPV
oncoproteins, E6 and E7, which inactivate the tumour suppressor gene products, p53 and Rb
respectively. In HPV, the functional inactivation of p53 and pRB results in over expression of
p16INK4A (p16); the inhibitor of cyclin-dependent kindases (CDK) in a negative feedback
loop. Therefore p16 expression by immunohistochemistry (IHC) and/or in situ hybridization
(ISH) for high risk HPV DNA has provided a routine clinical assay for rapid HPV detection
screens in patients. p16 overexpression by IHC has become the surrogate screening marker
for HPV positive HNSCC.
However, loco-regional control is also significantly better in HPV-positive OPSCC but
the rate of distant metastasis increases after 2 years unlike in patients with HPV-negative
tumours [18]. Furthermore, metastases are more likely to occur significantly later in HPV-
positive OPSCC compared to HPV-negative tumours, involving multiple organs, such as the
skin, intra-abdominal lymph nodes and brain [19]. However, the implication of HPV status in
non-oropharyngeal sites on prognosis and distant metastasis remains unclear. In HPV, the
functional inactivation of p53 and pRB results in over expression of p16INK4A (p16); the
inhibitor of cyclin-dependent kindases (CDK) in a negative feedback loop. Therefore p16
expression by immunohistochemistry (IHC) and/or in situ hybridization (ISH) for high risk
HPV DNA has provided a routine clinical assay for rapid HPV detection screens in patients.
p16 overexpression by IHC has become the surrogate screening marker for HPV positive
HNSCC.
2. EPIDEMIOLOGY OF HEAD AND NECK CANCERS
The rate of incidence of HNSCC is significantly higher in Southeast Asia and Eastern
Europe compared to other regions due to geographic differences in ethnicity, culture and
socioeconomics [20]. Table 1 summaries the global epidemiology of HNSCC per anatomical
site.
Table 1. The summary of head and neck squamous cell carcinoma epidemiology
worldwide based on the anatomical site of tumour origin [20]
Cancer location Incidence (2010) Mortality (2010)
Male Female Male Female
Oral cavity and lip 170496 92524 83109 44545
Nasopharynx 57852 26589 35984 15609
Other pharynx 108588 28034 76458 19092
Larynx 129651 21026 70336 11556
The incidence of HNSCC in Australia rose from 2475 in 1982 to 3896 in 2009 (22%
increase) [21]. However, the incidence rate has fallen from 19.3 per 100000 persons in 1982
to 16.8 per 100000 persons in 2009 due to an increase in life expectancy [21]. As of 2009,
incidence of HNSCC in males were 73.8% while incidence of HNSCC in females were was
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Current Trends and Management in Head and Neck Cancers
26.2% [21]. In terms of mortality, the number of HNSCC deaths increased from 752 in 1998
to 944 in 2011 (11% increase) [21]. HNSCC survival rate improved via 6.4% across the 20th
and 21st century [21]. Table 1.1 summaries the epidemiology of HNSCC in Australia per for
each anatomical site.
In the United Kingdom (UK), HNSCC accounts for less than 5% of all cancers [22].
There are more than 150 new HNSCC cases each year [22]. The HNSCC incidence rate in
Thames and Oxford regions are roughly around 8 per 100000 persons while whilst in the
Wales and North-western regions have a higher incidence rate of 13 to 15 per 100000 persons
[22]. The most common HNSCC in the UK are oral cavity and pharynx, in which the
incidence rate of both cancer types have increased by 20% over the last three decades [22]
(Table 1.2).
Table 1.1. The summary of head and neck squamous cell carcinoma epidemiology in
Australia based on anatomical sites [21]
Cancer location Incidence
(2009)
Incidence rate
(2009)
Mortality rates
(1982-2011)
Survival rate
(2006-2010)
Oral cavity 2037 8.8/100000
persons
1.5 deaths/100000
persons 75%
Pharynx 739 3.2/100000
persons
1.2 deaths/100000
persons 55.50%
Larynx 606 2.6/100000
persons
1.2 deaths/100000
persons 64.80%
Salivary glands 265 1.2/100000
persons
0.3 deaths/100000
persons 70.40%
Nasal cavity and
paranasal sinus 166 0.8/100000
persons
0.2 deaths/100000
persons 60.30%
Table 1.2. The summary of head and neck squamous cell carcinoma epidemiology in
United Kingdom based on anatomical sites [22]
Cancer location Incidence (2010)
Cases Male Female
Oral cavity 4329 62% 38%
Oropharynx 1456 73% 27%
Other 754 74% 26%
HNSCC is the 8th most common cancer in the United States [23]. Similar to the United
Kingdom, HNSCC accounts for 3 to 5% of all cancers in the United States [24]. In 2014, it is
estimated that there will be 55070 new HNSCC cases with 12000 deaths [24]. As cCompared
to with the estimated figure of 47500 HNSCC cases in 2008, the incidence rate decreased due
to increased population and life expectancy [24] (see Table 1.3).
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Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
Table 1.3. The summary of head and neck squamous cell carcinoma epidemiology in
United States based on anatomical sites [24]
Cancer location Incidence (1973-2006) Survival rate (2002-2006)
Oral cavity 19221 62.9%
Nasopharynx 4745 62.3%
Oropharynx 2014 42.2%
Larynx 28348 66.8%
HNSCC is a major problem in India, it accounts for 30 to 40% of all cancer s [25][26].
There are over 200000 new cases of HNSCC in India each year [25-26]. It is the sixth most
common cause of death in males and seventh in females [25-26]. On a global scale, India
contributes 31% to pharyngeal cancers and 18% to laryngeal cancers every year [25-26].
Bhopal alone, has the world’s highest rate of HNSCC incidence in the oral cavity in males
[25-26]. However, a slow decreasing trend in incidence can be observed in all anatomical
sites in general except for the oral cavity [25-26]. This is due to the etiological factor of betel
quid abuse [25-26]. In India, HNSCC has a clear predilection towards males at 79% of the
total HNSCC cases [25-26] (see Figure 2). Unfortunately, no statistical data was is available
from India (Figure 2).
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Current Trends and Management in Head and Neck Cancers
Figure 2. The summary of head and neck squamous cell carcinoma epidemiology on in males in India
(2004-2006) based on anatomical sites [25].
3. PATHOGENESIS OF HEAD AND NECK CANCERS
The pathogeniesis of HNSCC are is considered as a multistep process which begins with
the accumulation of genetic alterations leading to aberrant protein expression facilitating
tumour growth and progression. HNSCC arises due to a series of molecular alterations giving
rise to from dysplasia to carcinoma in situ, and finally invasive carcinoma. There are genetic
and epigenetic alterations in pre-cancerous cells that contribute to transformation of these
cells into malignant forms. The factors that govern the transformation of pre-cancer cells into
malignant transformations include accumulation of genetic alterations as well as tumour
microenvironment which enables tumour progression. Genetic and epigenetic changes (DNA
methylation and miRNA over or under expression as well as aberent histone modifications)
lead to protein changes affecting tumour initiation and progression.
Epigenetic and genetic alterations changes differ between HPV-positive and HPV-
negative HNSCCs. Examples of altered pathways in HNSCC include p53, epidermal growth
factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3) and
vascular endothelial growth factor receptor (VEGFR).
(i) p53 Pathway
TP53 is a well-known frequently mutated HNSCC gene. It is a tumour suppressor gene
that is a transcription factor and regulates many downstream gene targets in response to
cellular stress. In HNSCC, it has been estimated that between 46-73% of cases have this p53
mutation [27-29]. As an example, in HPV-negative tumours, the p53 gene is one of the most
commonly mutated genes with mutations detected in over 50% of HNSCC malignancies. In
contrast, p53 is wild-type in HPV-positive HNSCC tumours. TP53 is made up of 393 amino
acids and 4 domains including a highly conserved region which play important roles in
cellular mechanisms including responses to DNA damage and oncogenic stressors [29].
In normal cells, p53 is activated via stress signals such as DNA-double strand break or
aberrant growth signals and activates the transcription of genes necessary for apoptosis and
the inhibition of cell cycle progression. When DNA damage and/or a multitude of stress
signals, p53 can induce expression of Bax leading to apoptosis. Due to either double stranded
DNA breaks or aberrant growth signal activation, p53 increases the expression of p21 and
p21 inhibits cyclin-dependent kinases (CDKs) leading to the inhibition of cell cycle
progression from the G1 phase to the S phase [30]. Inactivation of the tumour suppressor p53
on chromosome 17q13 leads to a lack of aberent cell growth control and renders cells unable
to respond to stress or DNA damage. AlsoMore over, other genes in the p53 pathway are
often mutated or dysregulated causing dysfunction of the p53 pathway. As an example,
silencing of Ataxia telangiectasia mutated (ATM, is a kinase) is a mechanism of loss-of-
function of p53 [31]. p14arf lies upstream of p53 and binds the p53 inhibitor HDM2 in order
to activate p53. Mutations in ARF locus expression is a common molecular event in the
pathogenesis of HNSCC.
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Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
(ii) Epidermal Growth Factor Receptor Pathway
Epidermal growth factor receptor (EGFR), is a member of the HER/erb B family of
tyrosine kinase receptors that is highly expressed in epithelial cells. EGFR mediates multiple
signalling pathways that control, proliferation, invasion, migration, survival and angiogenesis.
EGFR pathway is upstream of phosphoinositol-3-kinase (PI3K), Akt as well as the mitogen
activated protein kinase pathways (MAPK, stimulated through the Ras/Raf pathway). EGFR
(ErbB-1 or HER1) is a tyrosine kinase receptor that is highly expressed in epithelial cells.
Due to EGFR gene amplifications and transcriptional activations in HNSCC, EGFR is
ubiquitously expressed in HNSCC [32, 33]. EGFR pathway is activated by autocrine growth
factors such as TGFalpha, amphiregulin as well as EGF. When EGF binds to EGFR, EGFR
dimerizes, autophosphorylation occurs and downstream signalling is activated. Besides the
over expression of EGFR, a mutant form of EGFR known as EGFRvIII, which is
characterized by a deletion mutation in exons 2–7 giving give rise to a truncated ligand
binding domain, rendering it constitutively active [34]. In a clinical setting, therapeutics
targeting of EGFR have been used for HNSCC. Cetuximab, which is a chimeric
murine/human monocolonal antibody which is used against EGFR has been used in locally
advanced stage and metastatic patients with improved survival in these patients over standard
therapies [29].
(iii) Signal Transducers and Activators of Transcription (STAT3) Pathway
STAT-3 is a transcriptional factor downstream of EGFR pathway and facilitates in
tumourigenesis.
Activation of STAT-3 besides EGFR pathway includes the activation of src kinases as
well as the interleukin-6 (IL-6)/gp130 receptor pathway through janus kinase (JAK) mediated
phosphorylation [16]. STAT3 activation leads to transcriptional activation of genes that
control cell cycle progression, apoptosis and angiogenesis including Cyclin D1, Bcl-XL and
VEGF.
(iv) Vascular Endothelial Growth Factor and Receptor Pathway
In numerous tumour types including HNSCC, STAT3 induces the expression of VEGF.
VEGF binds to VEGFR which are found on endothelial cells which that leads to the initiation
of angiogenesis. The binding of VEGF to its receptor on endothelial cells results in
endothelial proliferation, migration and an increase in the permeability of the vasculature.
Lymphatic endothelial cells also show an increase in the expression of endothelial specific
adhesion molecule (esam1), VEGFR-3, transforming growth factors beta 2 (TGF β2) and
platelet derived growth factor beta (PDGF-β2) [35]. In HNSCC patients expressing high
levels of VEGF and VEGF receptor, it has been shown to correlate to poor patient outcomes
and worse survival as a result of higher tumour proliferative rates [36].
(v) Transforming Growth Factor-β (TGF-β) / Ras Pathway
TGF-β plays an important role in cell differentiation, regeneration and regulatory
functions of the immune system. TGF-β receptors are from the family of serine/threonine
kinase receptors.
The pathways that Ras signal transduction regulate include proliferation, migration,
differentiation, cell adhesion, apoptosis as well as the regulation of cytoskeletal composition
[36]. Dysregulation of Ras activation has been associated with malignancy. Ras
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Current Trends and Management in Head and Neck Cancers
overexpression is common in HNSCC whereas Ras mutations are rare [37]. Studies suggest
that Ras may play a role in tumour initiation whereas TGF-β appears to present with tumour
progression effects at a later stage.
4. CURRENT DIAGNOSTIC STRATEGIES FOR HEAD AND NECK
CANCERS
Despite the rapid advancements in cancer diagnostics over the past four decades, there
has been marginal improvements in the survival of HNSCC patients [38]. This is further
compounded complicated by the heterogeneity of HNSCC and variations in tissues of origin.
These can range from mucosal epithelia in the oral cavity, pharynx and larynx. Therefore,
HNCs are considered to be a heterogeneous disease representing a plethora of histology and
differentiation patterns [39].
For the last forty to fifty years the evolution of HNC treatments has been based on
outcome measures for the differing treatment options available. Tumours are first pigeon-
holed into different categories containing similar tumours using the Tumour, Nodal and
distant Metastatic (TNM) classifications of size on presentation as an indicator of
aggressiveness and how advanced and overwhelming a cancer has become. The size and
extent of a tumour on presentation is assessed clinically and radiologically using the TNM
staging system. Historically two systems were in use – the UICC 1 (Union for International
Cancer Control) and the AJCC 2 (American Joint Committee on Cancer). These
classifications have evolved over time to more accurately reflect prognosis, and are now
similar/interchangeable. The T classification goes from levels one to four with increasing size
indicated by an increased T number. T1 is a small tumour. Currently a T4a tumour is very
large but possibly still curable, while a T4b lesion is generally so advanced and destructive
locally that the chance of cure is quite small. Similarly an N1 is small – a single node less
than 3cm in size, whereas an N3 is large (> 6 cm), and often fixed by invading surrounding
structures with consequent decreased survival. The N2 nodal metastases take into account
bigger nodes (3-6 cm), more than one node and bilaterality of nodes which all indicate
worsening prognosis by adding ‘a’, ‘b’ and ‘c’ subsets (N2a, N2b, N2c). By looking at the
survivals by T stage of various treatment modalities, real advances have finally been made
over the last twenty five years, bearing in mind that radiotherapy has been available for only
about one hundred years and only very small cancers were are curable surgically before the
last fifty years or so. Good reconstructive flaps have been available for about thirty to forty
years and now microvascular free flaps are almost the norm in reconstruction.
It has been standard of care for some time now that the large centres have
multidisciplinary clinics and teams (MDT) to assess a patients’ TNM stage and then suggest
the ideal modality of therapy, bearing in mind all the factors involved in actually determining
what is the best treatment for that individual patient is. The patients’ age, immune-
competence, their general health and their wishes all play a part in determining their best
treatment option. Tumour factors include the TNM staging, the differentiation, and the
presence of viral markers. Local expertise factors come in to play, as well as the availability
of drugs and treatment, including expertise of the surgeon and radiation oncologist. What
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Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
radiotherapy machines are available and whether there is local expertise in the more
technically challenging Intensity Modulated Radiotherapy (IMRT) also plays a part.
Generally in OECD countries funding should be adequate, but there is a misdistribution of
health funding across many OECD countries [40]. The treatment options for most patients in
developing countries are limited and this effects survival chances for the patient [41].
Upon presentation to the clinic, patients will be physically and visually be examined by
the clinicians. These inspections can be carried out by the use of a spatula and as such they
are able to reach areas that are hidden within the head and neck regions, palpitation of lymph
nodes around the neck area. For other areas of the head and neck which are difficult to see,
clinicians may use various equipments. These include nasoendoscopy, laryngoscopy and
tissue biopsy (sampling). Nasendoscopy is an examination of the nose or throat using a
flexible fibre optic cable which has a light and camera attached to one end. It is a form of an
endoscope. A numbing agent or local anaesthetic is sprayed within the area to numb and as
such there is minimal pain to the patients when the nasoendoscope is passed through. The
nasendoscopy allows the clinician to look into the patients nasal cavity, nasopharynx,
oropharynx and larynx easily and can be viewed in real-time. The examination is termed by
various names depending on the area of examination, for example, if the larynx is viewed;
laryngoscopy, pharynx; pharyngoscopy. When these areas are combined during a clinical
examination, it is referred to as a panendoscopy (http://www.cancer.net/cancer-types/head-
and-neck-cancer/diagnosis).
Medical imaging is another means of diagnosing HNSCC and includes techniques such
as ultrasound, x-rays, computed tomography (CT/CAT) scan, Magnetic resonance imaging
(MRI) or Positron emission tomography (PET) scan. Ultrasound scans use sound waves to
create an image of the internal organs. X-rays of the head and neck regions are quick and
painless. Chest x-rays may be done for patients with mouth or pharyngeal cancers to assess
whether the cancer have spread to the lungs. X rays of facial bones may also be done for signs
of spreading of the cancer. CT scans are able to create three-dimensional images of the body
with an x-ray machine. This allows for cross sectional views showing abnormalities in the
body and possible tumours. The dimensions of the tumours may be measured using a CT
scan. This allows the radiologist to stage the patient according to tumour size, nodal spread
and metastasis, commonly called TNM. A MRI scan uses magnets and magnetic fields to
produce detailed images of the body, notably soft tissue in the head and neck region such as
the tongue and tonsils. A contrast dye may be given to the patient prior to the scan to produce
better imaging. PET scans use a small amount of radioactive dye, which is taken up by cells
with the highest metabolic turn around, in particularly, tumour cells. Due to the biology of
cancer cells and their tendency to use energy actively, it absorbs more of the radioactive dye
and this shows up on imaging.
When the tumours are visible, then a biopsy is taken from the suspicious anatomical site
for routine histopathological examinations by a pathologist. The biopsy is the ‘gold standard’
for a definitive diagnosis. The pathologist is specialized in the analysis and interpretation of
cells, tissues and organs to diagnose disease. A common type of biopsy in head and neck
cancer is a fine needle aspiration (FNA). During a FNA, cells are taken up from a tissue by a
thin needle inserted directly into the tumour or lymph node. The cells are then examined
under a microscope to determine whether there are abnormal/ cancer cells, termed a cytologic
examination. Further molecular testing on a tumour sample may be recommended by a
consulting doctor for identification of genes and proteins. These results would allow the
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Current Trends and Management in Head and Neck Cancers
doctor to treat a patient based on the clinical confirmatory diagnosis. Currently, there is no
consensus on the optimal way to identify HPV-positive HNSCC. The different methods
include the detection of p16 protein expression using immunohistochemistry (IHC) as well as
HPV-related genetic material using polymerase chain reaction (PCR) and in situ hybridization
(ISH) in tumour biopsy samples. In addition, the presence of HPV-specific antibodies in
serum has also been associated with increased risk of developing OPSCC [42].
p16 Immunohistochemistry
During immortalisation of host cells, the E7 protein of High risk (HR(-HPV-16 binds to
Rb, resulting in the compensatory over-expression of the tumour suppressor gene p16 in
HPV-infected tumour cells [43]. The IHC analysis of p16INK4A in HNSCC tumour biopsies
has been shown to serve as a surrogate marker to identify HPV infection in histologic
preparations from HNSCCs [44]. However, in a pooled analysis of 496 patients with OPSCC
from different studies utilizing DNA-based HPV testing, 5% of cases were p16INK4A
positive/HPV negative and 8% were p16INK4A negative/HPV positive [45]. Another study
has shown that p16INK4A is also over-expressed in a subset of HNSCC lacking HPV DNA,
with is close to 14% of tumours that were p16 positive were negative by HPV-specific ISH
and PCR [46]. Strikingly, Hoffmann et al. reported that no over-expression of p16INK4A
was observed in 3/14 (21.4%) patients who were positive for HPV DNA and mRNA [47].
Furthermore, Harris et al. demonstrated an over-expression of p16 in young patients with oral
tongue SCC without evidence of HPV infections [48-50]. Liang et al., also showed that
OPSCC patients who were p16 positive and seronegative for HPV antibodies had
significantly increased hazard of all causes of death [49]. These data support the notion that
p16 over expression alone is not sufficient to accurately identify HPV infection in HNSCC.
However, p16 IHC has been shown to be a suitable test for risk stratifying patients with
OPSCC as p16 positivity in tumour correlates with better survival [50]. p16 IHC has been
adopted as the single test of choice for many medical practitioners due to the fact that it has
been extensively studied, cost effective with clear staining interpretation guidelines [50].
Direct identification of HPV using DNA and RNA-based methods will still be required for
clinically relevant infection and may replace p16 IHC or used in conjunction with it [50].
Premalignant lesions/precancerous lesions demonstrate histological changes consistent
with an increased risk of progression to squamous cell carcinoma. The changes may include
hyperplasia and dysplasia. Leukoplakia is a term used to describe a white patch or plaque
which cannot be rubbed off. The prevalence in the US is almost 3%, most commonly found in
patients ranging aged from 50-70 years. Tobacco use is consistently found in this patient
population. Other reasons which may lead to white patches include dental trauma and chronic
irritation of the area [36]. Erythroplakia is characteristically red and presents with a velvet-
like presentation and clear borders. This is the most common presentation of early HNSCC
with approximately half of erythroplakic lesions possibly harbouring invasive HNSCC. These
lesions do not subside.
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Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
Figure 3. The development of head and neck cancers from premalignant lesions.
12
Current Trends and Management in Head and Neck Cancers
(i) Squamous Dysplasia
Squamous dysplasia occurs when certain architectural features appear such as ‘drop-
shaped’ rete ridges, keratin pearly, irregularities in the epithelial stratification, abnormal
superficial mitosis and loss of cellular polarity. There are certain criteria involved in the
grading of dysplasia such as variations in the nucleus size, the cellular morphology, shape,
nuclear to cytoplasmic ratios, atypical mitotic figures as well as dyskeratosis [36].
(ii) Carcinoma in-Situ
Carcinoma in-situ (CIS) presents a malignant transformation process, however invasion
has not taken place. The characteristic trait of malignancy is that of invasion which is easily
determined by cytologically abnormal squamous cells showing perineural or vascular
infiltration. The presentation of an invasive HNSCC include atypical squamous cells with
atypical nuclei, increased nucleus to cytoplasmic ration, atypical mitotic figures, basement
membrane invasion and an inflammatory response [36]. Moreover, the invasive cells tend to
become more mesenchymal-like reflecting their aggressive nature [38].
5. MOLECULAR TECHNIQUES TO DETERMINE DISTANT
METASTASIS IN HEAD AND NECK CANCERS
The presence of metastatic disease in the cervical lymph nodes of HNC patients
significantly affects the resulting therapy and prognosis for the patients. Accurate staging of
the locoregional metastasis is important [51]. However, current clinically available diagnostic
tools (CT scans, MRI and PET scans) do not allow for the detection of micrometastasis.
Micrometastatic deposits (smaller than 5mm) cannot be detected with the current imaging
techniques[52]. An invasive approach would be an ultrasound guided fine-needle aspiration.
Cytology, however thisas a tool also has limitations in its sensitivity. These limitations in
staging have resulted in elective treatment of the neck, generally by neck dissection in
surgically treated patients. Whilst this is effective, it does come with morbidity risks [53].
Molecular tests could allow for better diagnostics by the detection of micrometastasis and the
identification of mutations in the circulating cancer cells which has led to their entry into the
lymphovasculature [38, 54].
5.1. The Detection of Micrometastasis
A strategy that has been employed for the detection of micrometastasis is that of
circulating tumour cells (CTCs) in the peripheral blood of HNC patients by the expression of
epithelial cancer specific markers [55]. Currently, there are multiple approaches to isolate and
characterize these cells, however, only one U.S. Food and Drug Administration (FDA)
approved technology. This technology is based on positive immunomagnetic enrichment of
cells using expression of the epithelial cell adhesion molecule (EpCAM). In metastatic
prostate, breast and colon cancer, the enumeration of CTCs has been correlated to survival
13
Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
and disease outcomes [55]. However, larger studies are required for in HNCs to evaluate the
clinic utlity of CTC in patient managementto warrant the clinical utility of CTCs in patients.
A clinical trial has begun in France at the University Hospital Montpellier where they aim to
utilize the CellSearch®, EPISPOT and flow cytometer to detect and characterize viable CTCs
in HNSCC patients [56]. More importantly, as a result of a large scaled pooled analysis in
breast cancer, distant metastases have been included in the cancer staging. cM0(i+) indicating
that no clinical or radiographic evidence of distant metastases, but “deposits of molecularly or
microscopically detected tumour cells in circulating bloods, bone marrow or other non-
regional nodal tissue [57].
Numerous isolation devices are currently under review; incorporating positive/negative
selection techniques, size based isolation, microfluidic approaches to capture the largest
possible population of circulating tumour cellsCTCs in a background of normal blood cells.
Other avenues that researchers are looking into implement are circulating tumour DNA
(ctDNA) which research groups have been able to detect in early and late stages of
malignancies, however the use of ctDNA over CTCs is currently under vigorous debate [58].
In a recent study by Bettegowda et al., 2014, demonstrated that cdDNA ctDNA was
detectable in the absence of CTCs suggesting that ctDNA and CTCs were separate entities
and that ctDNA was is a sensitive and specific biomarker across numerous types of cancer
typess including pancreatic, ovarian, bladder, breast and head and neckHNCs [59].
Epithelial-mesenchymal transition (EMT) is a complex process which leads to increase
motility and cell dedifferentiation and is thought to be one of the key transitions that cells
undergo in order to intravasate into the vasculature. CTCs are thought to arise from these
epithelial cells in the primary tissue which lose their epithelial antigens, gain migratory and
invasive capabilities causing disruptions to the basements and extracellular matrix, expressing
markers of the EMT transition and presenting with a mesenchymal phenotype [38]. In
HNSCC cells, it has been shown that EGFR, neurothropin receptor B (TrkB) and
inflammatory cytokines (interleukin-1β) are involved in EMT [60]. The reverse process of
mesenchymal-epithelial transition (MET), where mesenchymal cells re-gain their epithelial
phenotype is thought to allow CTCs to seed at distant sites such as the lungs, liver and bone
for HNSCC. It has been suggested that CTCs presenting with high EMT/MET plasticity tend
to be the most aggressive [61].
6. BIOMARKERS FOR HEAD AND NECK CANCERS
The definition of a biomarker varies and currently there is no one definition that
encompasses all aspects of biomarker applications. A biomarker, or biological marker as
termed by the World Health Organisation (WHO) is defined as “any substance, structure, or
process that can be measured in the body or its products and influence or predict the incidence
of outcome or disease [62].”, and aAccording to the National Cancer Institute’s (NCI) Early
Detection Research Network (EDRN) define biomarkers as cellular, biochemical, molecular,
or genetic alterations by which a normal, abnormal, or simply biologic process can be
recognized or monitored [63].
A broader definition includes the effects of treatment, interventions and the influences of
environmental exposure. This definition describes the usefulness of biomarkers for diagnostic
14
Current Trends and Management in Head and Neck Cancers
purposes by detecting the presence of pathogenic processes or the absence of normal
biological processes in disease. A biomarker may be a molecule that is secreted during
malignancy itself, or it can be a specific response of the body to the presence of cancer [64].
15
Figure 4. A subpopulation of the primary tumour that undergoes EMT and acquires invasive properties leading to intravasation into circulation. CTCs
may be guided to apoptosis, some may survive and either circulate as singlet/doublets or clusters of cells. CTCs undergoing MET can lead to
proliferation, angiogenesis and metastases (locoregional and/or distant). CTC: Circulating tumour cell; CK: Cytokeratin; CD44: Cell surface
glycoprotein; EpCAM: Epithelial cell adhesion molecule; EGFR: Epidermal growth factor receptor; EMT: Epithelial-mesenchymal transition; MET:
Mesenchymal-epithelial transition; ECM: Extra cellular matrix.
Current Trends and Management in Head and Neck Cancers
The biomarkers can be for (a) diagnostic (commonly used in people with signs and
symptoms to aid in assessing whether they have a condition); (b) screening (used in
asymptomatic people to detect a disease or condition at an early stage) and (c) prognostic
(used in subjects diagnosed with a condition to predict subsequent outcomes). The potential
for earlier diagnosis compared to current methodology is what makes biomarkers a promising
research avenue. The clinical benefits of early diagnostics are great and more importantly
presymptomatic screening becomes vital due to an aging and a growing world population.
The ability for the early detection of disease in is in its infancy, provides clinicians with more
treatment options as well as additional time to make more informed decisions and ultimately
better patient outcomes and stratifications. The most relevant biological alterations in head
and neck cancerHNCs by frequency are FGFR3 (19%).
6.1. Biomarker Development
It is important to question as to why a large number of biomarker discoveries have not
made it into the clinic. There are a large number of biomarker studies undertaken in the field
of HNC investigating various body fluids as well as biomolecules ranging from proteins and
their modifications, RNA, miRNA and, DNA methylation [65]. One way to address this issue
is to look into the requirements for biomarker development paying more attention to the study
design. It is highly unlikely that a single marker would be a biomolecule that can differentiate
between healthy and HNC patients due to disease heterogeneity. As an example, consider a
biomarker with high sensitivity and low specificity. In this case this biomarker will identify
people with the disease but fails to identify people who do not have the disease. This would
mean that there is unnecessary healthcare costs are added to the healthcare system and people
who are free of disease may be targeted for treatments. Clearly, a biomarker should present
good specificity and sensitivity.
The key aspects of the clinical study design for each of the phases have been extensively
discussed [66], which has generated ideas and many interesting thoughts on the clinical
relevance and clinical translational of biomarkers. Pepe and colleagues proposed a
prospective-specimen collection, retrospective-blinded-evaluation (PRoBE) design in which
biologic specimens are collected prospectively from a cohort that represents the target
population of interest for clinical application of the biomarker. Further, NCI’s Early Detection
Research Network (EDRN) has developed and implemented systematic, comprehensive
guidelines to develop, evaluate, and validate biomarkers. This five-phase approach clearly
defines the steps that should be adhered priort to the transition of biomarker(s) can make into
a clinical setting. Phase 1 is called the validation phase and includes a feasibility study to
identify potentially candidate biomarkers. In Phase 2, the strategy would be to develop
biomarkers that could have higher differentiated capacity for to distinguishing between cases
with HNSCC and controls without the disease. Phase 3 is designed to determine the capacity
of biomarker(s) or panels to detect pre-clinical disease. Repositories of longitudinally
collected clinical specimens from research cohorts are used. Phase 4 is designed as
prospective screening study. Phase 5 is a phase large-scale population based studies study that
evaluate the role of the biomarker(s) or panels for detection of HNSCC as well as the overall
impact of screening the general population. Future biomarker development studies should
follow this basic be based on these 5 steps pathway to suceed.
17
Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
Figure 5. Variouauos phases of Biomarker biomarker development and relevant phases adopted from
Pepe et al 2008 [66].
6.2. Biomarker Analysis in Body Fluids
Depending on the location of the tumour, one may not be able to access and swab the
tumour bed. As an example, if the tumour is in the vocal cord area, it is difficult to take a
biopsy without damaging the vocal cords. In such a setting, the use of human saliva may
show unique advantages over the use of exfoliated cells. We and others have shown that one
is able to detect early tumour activities in body fluids that drain from the organ that is affected
by the tumour. As an example, the use of saliva to detect oral and oropharynx cancers is
possible because the cancer-specific biomolecules are secreted in to saliva and by collecting
and analysing the saliva, one is able to detect tumour activities [67-73]. We have shown in a
recent publication that we could analyse HNSCC-specific miRNAs in saliva collected from
18
Current Trends and Management in Head and Neck Cancers
HNSCC patients and we were also able to validate these findings also using the publically
available data interrogating from the The Cancer Genome Analysis data base [71].
Human saliva has come to the fore front recently as an alternative diagnostic medium for
detecting oral and systemic diseases. Saliva is a multi-constituent oral bio-fluid which has the
potential for use in the surveillance of general health and disease states. The National Cancer
Institute in the USA has identified saliva as an important cancer biomarker fluid. Saliva can
be used as a biological fluid as it has proteins, nucleic acids, electrolytes and hormones
originating from a number of local and systemic sources. Moreover, it has been shown that
saliva contains 30% of biomolecules found in blood. Listed below are some of the biomarkers
found in body fluids.
(i) Microsatellite Instability
Microsatellite regions are genomic 1–5 bp tandem repeats, normally noncoding, and the
CA 2 bp repeat is the most common form [74]. These regions may cause instability due to
replication errors caused by DNA polymerase and is referred to as microsatellite instability
(MSI). Instability frequency is related to the repeat unit length and overall size of the short
tandem repeat (STR), affecting the probability of error during DNA replication [75]. These
replication errors can lead to tumourigenesis by activating oncogenes and silencing tumour
suppressor genes. Two studies shave identified MSI of D3S1611 in HNSCC markers with
13.5% and 40% [76, 77]. In contrast, a lack of MSI in HNSCC was reported by other studies
[77, 78]. MSI studies showed lack of uniformity of the study methods, choice and number of
markers. To date, no standard approach for the study of MSI has been developed for the early
detection of HNSCC.
(ii) DNA Methylation
DNA methylation is an earlier tumorigenicity event in eukaryotes [79]. This process
involves the attachment of a methyl group to the fifth carbon around the cytosine ring [80].
This formation creates an extension on the overall DNA alpha-helical structure [81]. Such
extension hinders the binding of the transcription factor during DNA replication process,
resulting suppressed expression of the involved genes [81]. In addition, transcription
repressors have a predilection toward methylated promoters, this process further instigate the
inactivation of the genes [81]. In a case where the involved genes function as tumour
suppressor, it encourages the formation of neoplasm as the cells loss lose the ability to control
cell-growth [4, 80, 81]. As such, DNA methylation of tumour suppressor genes are excellent
biomarker(s) for the early detection of cancer [79]. Furthermore, researches have showed
shown that alcohol and tobacco consumption have a strong correlation with the methylation
level of tumour suppressor genes, indicating the use of these genes in large population based
screening studies in to potential for high-risk screening individuals [79]. Numerous HNSCC
biomarkers have been detected from the cancer secretome in saliva over the past decade [82-
86]. These biomarkers show promising results when screening for HNSCC. In addition,
certain biomarkers are able to determine the severity of the disease [5]. Some of the more
popular HNSCC biomarkers in the field include Ras Association Domain Family 1 Isoform A
(RASSF1a), Cyclin-dependent Kinase Inhibitor 2A (p16INK4a), Death-associated Protein
Kinase 1 (DAPK1) and Methylguanine-DNA Methyltransferase (MGMT) [82-84, 86].
The method of choice toTo interrogate the investigate the methylation status of a gene,
onen e of the first steps isn to convert gDNA into is though DNA bisulfite conversion,
19
Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
introduced by Formmer et al. in 1992 [80]. This method utilises sodium bisulfite (NaHSO3) to
actively induce oxidative deamination under the right conditions [80]. The reaction converts
cytosine to uracil via replacing the amine group on the forth carbon with an oxide [80].
However, a methylated cytosine is significantly less susceptible to the reaction, holding the
reaction backward by two orders of magnitude [87]. With two different primer sets
(methylated-specific and unmethylated-specific) running in the same set of PCR condition
(methylation-specific PCR), the methylation status of a gene can be determine via quantifying
the band intensity of an electrophoresis gel [88]. Other advanced DNA methylation analysis
assays include mass spectrometry, multiplex-PCR and pyrosequencing [89].
Table 2. The prominent DNA methylation biomarkers in saliva that have been
associated with the development of head and neck cancers over the past five-years
Gene Function Reference
CCNA1 Cell cycle regulator [5]
DAPK1 Programmed cell death [5]
DCC Receptor for nectrin required for axon guidance [5]
EDNRB G protein-coupled receptor [5]
ERCC1 Nuclear hormone receptor [5]
HOXA9 Promotes mammary epithelial cell growth and survival [86]
KIF1A
Protein kinase involved in apoptosis and DNA damage
response [5]
MED-15 RNA polymerase II regulator [90]
MGMT DNA mismatch repair system [5]
MINT-31 Calcium channel regulator [5]
NID2 Cell adhesion [86]
p16INK2a Receptor of sonic hedgehog [5]
RASSF1a
Induce growth inhibition along the RAS-activated signalling
pathway [91]
TIMP3 T-cell antigen receptor, recognition of foreign antigens [5]
PAX1 Transcription factor for chordate development [92]
TCF21 Inhibitor of the matrix metalloproteinase [7]
While DNA methylation status controls the expression level of a gene, miRNAs play an
important role in post-transcriptional regulation [71]. miRNAs are small non-coding RNAs
(approximately 22 nucleotides long) that function by targeting specific mRNA moieties for
translational repression or degradation thereby regulation regulating several biological
process including cell proliferation, migration, invasion, survival and metastasis [71]. It is
known that miRNAs are responsible for 67% of the gene expression in mammalian cells [71].
Currently, there are 1872 successfully identified human miRNA precursors, contributing to
2578 mature miRNAs [71]. miRNAs can be found within the intergenic, intronic or exonic
regions in both protein-coding or non-protein-coding genes, together they constitute 3-5% of
predicted genes in the human genome [71]. Many miRNAs have been identified in regions
that are related to cancer causation [71]. These regions are usually responsible in cell
proliferation, differentiation, apoptosis and cell cycle regulation [71]. As a result, many
researchers believe that miRNAs may play a significant role in cancer outset, development
and/or metastasis [71].
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Current Trends and Management in Head and Neck Cancers
miRNAs in HNSCC have been extensively studied over the years, multiple miRNAs
dysregulation were found in HNSCC cell lines that are specific to various anatomical sites,
indicating the potential clinical utility as early diagnostic biomarkers [71]. Most HNSCC
miRNA biomarker studies are carried out via miRNA PCR array assays to determine the the
miRNA expression levels in HNSCC tumour cells compared to adjacent healthy cells [71].
According to literature, commonly up-regulated miRNA in HNSCC tumours include miR-
363, miR-497, miR-33, miR-21, miR-31, miR-195star, miR-150, miR-146b-5p, miR-15a,
miR-20b and miR-146a while commonly down-regulated miRNAs in HNSCC include miR-
155, miR-181a, miR-181b, miR-29a, miR-218, miR-222, miR-221, miR-143-5p, miR-375
and miR-133a [71]. In recent publications, miR-9, miR-134 and miR-191 were found to be
dysregulated in HNSCC patient saliva compared to healthy controls; serving as a potential
novel biomarker panel to detect HNSCC in a non-invasive manner [71].
In HPV-related HNSCC specifically, miR-34a is significantly down-regulated as the
viral-protein E6 destabilizes p53 [71]. It was revealed later that the cross-talk between miR-
34a and p53 plays a major role as tumour suppressor [71]. As transcriptional target of p53,
miR-34a induces cell cycle arrest and apoptosis [71]. miR-34a therefore, could be
incorporated into potential miRNA HNSCC biomarker panel to determine the HPV status of
of a person [71]. Other lesser known dysregulated miRNA in HPV-related HNSCC include
miR-125a, miR-126, miR-127-3p, miR142-5p, miR-145, miR-155, miR-181a, miR-181a,
miR-181b, miR-20b, miR-218, miR-221, miR-222, miR-24a, miR-29a, miR-33, miR-363,
miR-379, miR-497, miR-15a, miR-145, miR-20b, miR-21, miR-127-3p and miR-224 [71].
7. CURRENT AND FUTURE TRENDS IN THE TREATMENT OF HEAD
AND NECK CANCERS
Open surgery remains as the first-line of treatment for HNSCC patients followed by
chemotherapy and radiation [93]. It is the primary treatment for HNSCC in the oral cavity and
salivary glands [93]. Open surgery is a popular choice for HNSCC patients living in
developing countries because of the poor socioeconomic status and cannot effort afford
advanced treatments [93]. There are two types of open surgeries currently in clinical practice
depending on the severity of the tumour [94]. Tumours with tumour circumference smaller
than 2cm would usually receive a negative surgical margin (complete removal of the cancer
cells) while tumour with circumference larger than 2cm would usually receive a positive
surgical margin (fragmentary removal of the cancer cells) to prevent the impairment of vital
functions such as speech, chewing and ingesting [94]. The risk of open surgery has decreased
significantly for the past decade as technology progress [93]. Inventions such as image-
guided surgery and robotics increase the accuracy and precision of the operation, minimizing
deformity to allow a better quality of life [93].
(i) Oral Cavity
Generally the treatment for oral cavity cancer is surgery to the primary lesion and to the
necks. High dose radiotherapy to the mouth is regarded as very morbid with significant
21
Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
complications of a dry mouth and dental sepsis which can lead on to osteoradionecrosis [95].
Transoral resections, the splitting of the lip for access, or dropping the tongue into the neck
are ways of accessing mouth cancers. Frequently, part of the jaw needs to be removed. In
general, radiotherapy is given post-operatively if a tongue primary has more than 7-10 mm
depth invasion. Generally for head and neck cancers, treatment of the seemingly uninvolved
neck is indicated if the depth of invasion of the primary on histological sectioning is more
than 4-5 mm. This is because aA 5 mm cancer depth generally indicates a 15% chance of
microscopic nodal disease, while a 10 mm depth or worse higher indicates a 30% chance of
subclinical nodal disease [96]. Generally, the nodes are best treated if there is a 15% or more
chance of later neck disease, bearing in mind the complications of such treatment are not
insignificant. Chemotherapy is added to radiotherapy if the primary has positive margins on
surgical excision, or the lymph nodes show histological evidence of extracapsular spread.
There is emerging evidence that chronic irritation is a causative factor in oral cavity
cancer. It seems to be especially important in young women [97]. Twenty percent of mouth
cancers occur in lifelong non-smokers, generally in areas of chronic dental trauma [98]. Flap
reconstruction has improved with the buccinator flap being used for small lateral defects.
Radial forearm and anterior thigh flaps are used for bigger reconstructions. The fibula and hip
bone are used for large reconstructions of the jaw and when there may be a role for later
dental implants, especially if the reconstructed bone hasn’t needed radiotherapy [99].
(ii) Oropharynx
Oropharyngeal cancers have seen the most changes in the last twenty years. There is an
emerging trend in OECD developing countries for the HPV to be involved in the
carcinogenesis of oropharyngeal SCC, especially in smokers and ex-smokers. At our clinic in
the last ten years nearly four hundred people have presented with oral cavity cancer and four
hundred with oropharyngeal cancer. Lifelong non-smokers comprised 22% of the oral cavity
group and 14% of the oropharyngeal group [98]. Of these, very few non-smoking women had
oropharyngeal tumours, but women made up the majority of the oral cancer non-smokers.
The incidence of HPV associated cancers is rising and in lifelong non-smokers HPV
associated oropharyngeal cancer may well overtake oral cavity cancer. Around 80-90% of
oropharyngeal malignancies now have HPV as a factor in their carcinogenesis and in their
treatment paradigm. It is hoped that the Gardasil vaccine when given to boys will stop this
emerging cancer in decades to come. At present, however, the incidence of HPV
oropharyngeal cancer is now rising at about 2% per year [100].
Chemoradiotherapy has seen cure rates of above 90% for HPV associated oropharyngeal
cancers in the lifelong non-smokers, even for the larger tumours [101].The cure rate for the
HPV negative tumours – nearly always in smokers – is still quite low, possibly even as low as
half those cure rate figures [102]. The cure rate of HPV associated oropharyngeal tumours is
so high that there is a move to de-escalate therapy. Tonsil cancers when small and lateralised
can often be dealt with by simply treating the lymph nodes on the ipsilateral side. Some
centres are also doing this for small, well-lateralised base of tongue tumours [103]. When the
nodes are bigger than 4cm, there is a tendency to treat lymph nodes in both sides of the neck.
An emerging trend is to use the PET CT scan as an indicator of successful therapy and the
PET CT is done four months after treatment is finished [104]. If there is a significant
22
Current Trends and Management in Head and Neck Cancers
improvement in the amount of PET avidity in the primary site and neck nodes, that PET CT is
repeated four to six weeks later. If there’s minimal activity there is ongoing observation of the
neck nodes with CT scans, but if there is residual activity a salvage neck dissection is
performed often with the need for a pectoralis major flap or similar flap to reinforce the skin
after the neck dissection to stop wound breakdown, exposure of the carotid artery and carotid
artery blowout. When patients don’t survive this cancer it’s either due to distant metastatic
spread to the liver, lungs and sometimes bones, or uncontrollable neck node disease after
chemoradiotherapy. Normally the primary tumour is readily controlled with
chemoradiotherapy, but nodes and metastases are harder to cure.
There’s an emerging role for transoral resection of the small oropharyngeal tumours
using either laser or robotic surgical techniques [105-107]. If clear margins can be obtained
and the neck node burden is light, the patients may simply be treated with single modality
surgical treatment. There’s an emerging trend for the bigger primaries and bigger nodal
burdens to have de-escalated therapy, having 50 - 55 Gray of radiotherapy rather than 65 - 72
Gray in the unoperated neck. However this de-escalation of therapy is very controversial and
needs to be done in a controlled way. Overshooting de-escalation will decrease survival.
(iii) Nasopharynx
Nasopharyngeal carcinoma is very common in East Asian people and is associated with
the Epstein Barr virus. The mainstay of treatment is chemoradiotherapy. For very large
tumours induction chemotherapy is sometimes given. There is a limited role for surgery for
small nasopharyngeal tumours that may recur [108, 109]. It’s unusual for it to be used as the
primary treatment modality. Some nasal and nasopharyngeal tumours are associated with
HPV and would expect to do reasonably well with radiotherapy, but the Ebstein Barr virus
tumours seem to respond quite well considering they often present with penetration of skull
base and lymph node involvement at multiple levels. There are vaccine trials and novel drugs
being trialled in various centres [110].
(iv) Larynx
Laryngeal treatment is very much associated with the organ-sparing techniques of
radiotherapy or chemoradiotherapy. The initial VA study showed very high cure rates with
high dose chemoradiotherapy over previous treatment protocols using the lower doses and
that has resulted in many fewer laryngectomies and partial laryngectomies [111, 112].
However it has been shown that laryngeal cancer cure rates have, if anything, fallen over time
[113].
The original VA study showed high incidence of trachesotomies and percutaneous
gastrostomy feeding tubes being required post this non-surgical treatment and this has led to
some controversy as to when this treatment should be given. There is a move for lasers to be
used on small glottic cancers to avoid radiotherapy. Chemoradiotherapy is the standard
treatment for intermediate size tumours, but there are transoral resection modalities using
laser or robotic machines for the smaller and moderate sized supraglottic tumours.
23
Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
Laryngectomy is still used for the large tumours where there is an incompetent larynx or wide
laryngeal cartilage involvement.
(v) Hypopharynx
Hypopharynx is regarded as generally as a surgical disease although there have been
good results with chemoradiotherapy from Toronto. Our own clinic uses
pharyngolaryngectomy with jejunal replacement as the standard therapy, and compares other
treatments to that. For smaller tumours or at patient request chemoradiotherapy is given and
we are yet to see what those figures are like. With surgery in our hands five year survival rate
is in the order of 65% [114]. Other departments use tube skin flaps or stomach pull-ups.
Hypopharynx is regarded as an aggressive cancer and not particularly radiosensitive
[115].The transoral robotic surgery may well find a place here for the very small tumours.
(vi) Neck Disease
The selective and highly selective neck dissections are getting to be more the norm.
Instead of the full radical neck dissection taking the sternomastoid muscle, internal jugular
vein and accessory nerve, the standard operation for most head and neck cancer procedures is
a ll-lV neck dissection, sometimes taking level l for something anterior in the upper airway
and level V possibly for something more posterior. If there’s a midline primary tumour both
necks need to be addressed. Generally we look at treatment to the other side of the neck if a
node is bigger than 4cm suggesting there could be retrograde spread, or there’s been previous
radiotherapy or surgery to the neck. There is an emerging trend to take the lingual tonsils off
the base of tongue, sometimes called a tongue base mucosectomy, to identify primary tumour
site of origin when traditional tonsillectomy and panendoscopy with biopsy have been
unsuccessful. This is especially so when the nodal disease is p16 positive [116-118].
(vii) Excision Repair Cross-Complementation Group 1
Excision Repair Cross-Complementation Group 1, ERCC1 protein plays a significant
role in the repair of DNA damage caused by platinum agents and is useful in identifying
patients which who will benefit from platinum based therapy. The mode of action of platinum
based therapies is by creating DNA adducts which inhibit DNA replication and transcription
in cancer cells. Preliminary data does show demonstrates that ERCC1 has a role in predicting
patient responders to cisplatin based therapy in HNSCC. In a study by Handra-Luca et al,
where ERCC1 was measured by IHC in 96 pre-treatment tissue samples 71% had high
ERCC1 expression. The study found that pre-treatment ERCC1 expression levels inversely
correlated with response and survival following cisplating based therapy. In further studies,
24
Current Trends and Management in Head and Neck Cancers
low ERCC1 patients were found to have longer 3 year progression free survival (PFS) than
those with high expression of ERCC1 (83.3% vs 49.4%). The 3 year overall survival (OS)
was also found to be significantly higher in patients with low ERCC1 expression (91.7% vs
45.5%). The clinical relevance of ERCC1 is yet to be validated, however it shows significant
progress. High ERCC1 expression in HNSCC tumours can suggest poor platinum-based
therapy responses and a probably switch to non-platinum based therapies.
(viii) Ribonucleotide Reductase M1
The Ribonucleotide Reductase M1 (RRM1) gene codes for a regulatory subunit of the
enzyme ribonucleotide reductase which is a molecular target of a nucleoside analogue used
for chemotherapy, Gemcitabine. Pre-clinical studies have demonstrated that elevated levels or
mutations in RRM1 have been attributed to gemcitabine resistance. Further studies are
warranted to determine the role of RRM1 in determining the chemosensitivity in HNSCC.
(ix) β-Tubulin
In HNSCC, docetaxel in combination with cisplatin and 5-fluorouracil (5-FU) has
become part of the standard induction regimen. Taxanes mode of action in anticancer activity
works by binding to β-tubulin polymers and inhibiting microtubule depolymerisation as well
as mitotic progression. In a phase 3 trial comparing induction with 5-FU to induction with
cisplatin and 5-FU showed that β-tubulin II as measured by IHC is associated with clinical
outcomes. In 265 patients out of 501, patients with low β-tubulin II expression had better PFS
and OS. In this subset of the patient cohort, there was greater benefit from the addition of
docetaxel to the induction therapy. In the high β-tubulin II expression groups, there were
negligible differences as per the 2 induction regimens. The use of taxanes in HNSCC is
increasing and therefore, the clinical utility of β-tubulin isoforms may play an important role
for therapeutic purposes.
(x) Palliation
Palliation is an important part of HNC treatment. Hypofractionated regimens of four, six
or twenty treatments over four weeks are sometimes used in patients to just get local control
for a year or two with minimal side effects from that radiotherapy while the disease takes its
course; either in the head and neck cancer disease with metastasis or the patient being very
elderly or infirm from other conditions. Palliative chemotherapy may have a part to play and
Gemcitabine, Cisplatinum and Taxol medications seem to have a role in this.
8. COMPANIES THOSE THAT ARE ACTIVE IN SALIVARY
DIAGNOSTICS AND HEAD AND NECK CANCERS
25
Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
I. Oasis Diagnostics ® Corporation
Oasis Diagnostics ® Corporation is a company founded in 2002 which has pioneered
saliva based technologies for rapid screening, sample collection and molecular diagnostics.
The company understands that early detection and non-invasive diagnostics are key for
disease prevention globally and aims to push the boundaries to improve the quality of
healthcare [119] (http://4saliva.com/about). The company has a specialized proprietary range
of products ranging from oral fluid rapid test platforms, oral fluid collection devices, salivary
DNA collection devices, universal saliva collection devices as well as novel products for
RNA/protein collection for genomic/proteomic studies [120].
II. Forsyth
Forsyth is an institute founded quite recently in 2013, which has attracted over 4 million
dollars in funding for salivary diagnostics. The broade scope of this institute with the goal of
Forsyth’s Center for Salivary Diagnostics to revolutionize the medical diagnostics world byis
to providing provide a simple, non-invasive test which could one day replace blood based
technologiesmethods. The company institute envisages a medical diagnostics world where
salivary tests could provide valuable information pertaining to systemic diseasesan all-
encompassing biological fluid which could provide as much if not more information than
blood in a non-invasive manner. The companyThe institute has currently four keen areas of
that involved salivary diagnostic projects.applications and include Firstly salivary biomarkers
that can predict pre-diabetes/metabolic syndrome which delves into salivary biomarkers in
8400 children which can be used to predict disease. An active tuberculosis (TB) project which
aims to distinguish active TB from the latent or inactive state and is supported by the Bill &
Melinda Gates Foundation. Progressive periodontitis project which aims to identify
individuals who have progressive disease allowing clinicians to better treat the patients and
finally, the Inflammatory profile project which aims to identify salivary biomarkers that can
identify individuals at a higher risk of heart disease, stroke, Type 2 diabetes and Alzheimer’s
disease to name a few [121].
III. ViennaLab Diagnostics
ViennaLab Diagnostics is a company frombased in Austria that and produces simple in
vitro diagnostic kits for the detection of genetic mutations, methylation status and genetic
predispositions. Amongst their products are genetic tests which can identify oncogene
mutations which can inform the best approach for treatment, such as somatic mutations in the
epidermal growth factor receptor tyrosine kinase (EGFR-TK) which can influence the
treatment by EGFR-TK inhibitors. The assays identify the most prevalent mutations relevant
for anti EGFR-TK therapy. Other oncology assays that the company focus are mutations
assays for KRAS & NRAS, PGC-5FU, PGXX-TMPT, BRAF and FCGR [122].
26
Current Trends and Management in Head and Neck Cancers
IV. Proteocyte Diagnostics
Proteocycte Diagnostics Inc is a company from Canada which develops novel diagnostic
technologies for management of HNCs. Their products include Straticyte™ assay to
determine the risk of oral premalignant lesions transforming into cancers. This company
identified proteins by comparing HNCs tumour tissue to with normal tissue. The Straticyte™
test uses antibodies to determine and quantity cancer biomarkers and also by referencing to
databases allows it them to score the progression risk of a lesion. This technology took over
10 years of research, has over 7 peer reviewed publications and is protected by 5 patent
applications [123].
V. Navidea Biopharmaceuticals
Navida Biopharmaceuticals is a leading diagnostics company which that aims to pinpoint
molecular sites and pathways to identify disease states. A recent product by the company,
Lymphoseek® (technetium Tc 99m tilmanocept) is the first and only FDA approved sentinel
lymph node biopsy agent for use in HNC patients and oral cavity carcinoma. Conventional
standard care for HNC patients include the removal of multiple lymph nodes during a surgical
procedure. Whereas, sentinel lymph node mapping could provide an effective alternative to
elective neck dissection. As a result of this, Lymphoseek® has the potential to more easily
stage cancers and direct surgical treatment and thereby improve improving patient survival
[124].
VI. Zenalux Biomedical
Zenalux Biomedical, a leader in biophotonic diagnostics has in collaborations with
Roswell Park Cancer Institute (RPCI) developed the Zenascope PC1 system which allows
basic quantitative spectroscopy, pressure sensing, imaging and illumination. With their
collaborative efforts, the company aims to design a system able to detect oral cancers at an
early stage. The new preclinical, Zenascope IM1 system aims to compliment imaging with
spectrographic data as well as provide better visualization of cellular changes and tumour
margins. The instrument works by shining a white light onto opaque target media and
measure and analyses the reflected signals. The system is able to provide targeted endpoints
to haemoglobin concentration, saturation and scattering as a measure of cell density and
necrosis to name a few. Other areas of interest where the device is currently being used is in
accelerated feedback in drug discovery, response to therapy, breast tumour margin
assessment, breast biopsy and cervical cancer detection [125].
9. THE FUTURE PERSPECTIVES
Whilst HNSCC stands as the six most common cancer worldwide, the incidence rate is
on the decline in the western world [126]. Since majority of the big pharma companies are
27
Arutha Kulasinghe, Yen kai Lim, Chris F. L Perry et al.
situated in the western world, they are less interested in developing new drugs for HNSCC
[126]. As a result, there is no new therapy in the pipeline; causing HNSCC to fall into the
category of ‘neglected disease’ [126]. In addition, the development of the new targeted
therapies for HNSCC requires larger investments and is also time consuming, an effective
way to solve this unmet clinical need is to merge existing HNSCC disease causing targets
with existing drugs [126]. This strategy bypasses the discovery and validation phase that are
required by pharma companies when introducing new drug targets into clinical trials to
discern to efficacy and safety [126]. As 50% of all new drugs fail under the safety aspect, said
method not only decreases the expenses and development time but also the risk of getting
rejected due to safety issues [126].
Early diagnosis and good prognosis decreases the mortality rate due to HNSCC [91, 127,
128]. As such, biomarkers with the power to diagnose and prognosis the disease are
invaluable. Many HNSCC biomarkers have been discovered, however, these data need to be
integrated into patient care for these to be valuable [129]. Conversely, the focus should not
fall solely on diagnostic and prognostic biomarkers; predictive biomarkers are just as
important to determine the ideal treatment response in HNSCC patients [129]. For example in
HPV-unrelated negative HNSCC patients, the focus revolved around the improvement of
patient survival [129]. With regards to this subject matter, the presence of predictive
biomarkers would be beneficial in patient selection for precise therapeutic treatment; assisting
in better therapeutic window estimation [129].
The future for molecular screening requires a close collaboration between imaging and
biomarker-based investigations. While biomarkers will have the ability to provide
quantifiable characteristics, imaging will provide temporal and special features of the disease
space and amplify biomarker visualization in real time. Smart reagents and probes are needed
to exploit the power of imaging, and biomarkers could provide some needed probes. A
comprehensive database of biomarkers needs to be developed, integrating genomics,
proteomics, metabolomics, glycomics, and imaging features of a broad spectrum of disease
states. As technologies continue to mature, reference reagents and samples must be made
available to investigators to provide standards for their exploratory studies and allow for
consistencies in cross-validation among studies. However, standards should not be imposed in
the initial discovery processes phase that could impede innovations. The future could well be
involved with small molecules, circulating tumour cells and novel markers suggesting
different treatments are required [38, 130]. Tropical plant agents and Taxols come into play.
Intensity Modulated Radiotherapy and Proton Therapy are emerging. The free availability of
reconstruction options in our department has led on to a pectoralis major flap frequently being
used to reinforce suture lines in necks which have been irradiated. Free flap reconstructions
are the standard, although sometimes we get away with a buccinator flap or local flap. Earlier
diagnosis would be ideal as smaller tumours have a better prognosis. Blood and saliva tests
for markers of respiratory and Head and Neck cancersHNCs may emerge [71].
In order to move forward the fields of early diagnosis, prognosis and risk stratification in
HNSCC patients, communications and integration between basic researchers and clinicians is
highly warranted [129]. Both professions need to work closely together to better interpret the
laboratory data and translate them into useful clinical information [129]. Therefore, is itit is
highly recommended that clinicians should educate themselves to understand the basic
principle of the technology used in the laboratory and their respective limitations [129]. We
forecast that in the next few years, there will be early diagnostic strategies in place for
28
Current Trends and Management in Head and Neck Cancers
HNSCC whereby improving patient care and management and whereby significantly
reducing the mortalities and morbidities associated with this devastating disease.
ACKNOWLEDGMENTS
This work is supported by the Garnett Passe & Rodney Williams Memorial Foundation,
QUT start-up grant and the Queensland Centre for Head and Neck Cancer funded by Atlantic
Philanthropies, the Queensland Government and the Princess Alexandra Hospital. We also
thank Mr Roberto Chata for helping us with figure illustrations.
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