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Benign and malignant cutaneous nasal lesions

Wiley
Eye & ENT Research
Authors:

Abstract and Figures

The nose is a structure of both cosmetic and functional importance. Cutaneous lesions of the nose occasionally represent a diagnostic challenge and involve the expertise of several specialties from dermatology, otolaryngology—head and neck surgery, infectious disease, and pathology, among others. We present a review of salient features of malignant and benign cutaneous nasal lesions which are of importance to physicians treating these complicated pathologies.
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Received: 27 January 2024
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Accepted: 3 June 2024
DOI: 10.1002/eer3.16
REVIEW ARTICLE
Benign and malignant cutaneous nasal lesions
Hamed Sarikhani
1
|Karena Zhao
2
|Marc A. Polacco
3
|Charles Gropper
4
|
Samuel N. Helman
5
1
Department of Internal Medicine, St. Barnabas Hospital, City University of New York, New York, New York, USA
2
Department of OtolaryngologyHead and Neck Surgery, Weill Cornell Medicine, New York, New York, USA
3
Department of OtolaryngologyHead and Neck Surgery, University of Iowa, Iowa City, Iowa, USA
4
Department of Dermatology, Icahn School of Medicine, Mount Sinai, New York, New York, USA
5
Department of OtolaryngologyHead and Neck Surgery, White Plains Hospital, White Plains, New York, USA
Correspondence
Samuel N. Helman, Department of
OtolaryngologyHead and Neck Surgery,
White Plains Hospital, 160 N. Midland Ave,
Nyack, White Plains, NY 10960, USA.
Email: sahelman@wphospital.org
Abstract
The nose is a structure of both cosmetic and functional importance. Cutaneous le-
sions of the nose occasionally represent a diagnostic challenge and involve the
expertise of several specialties from dermatology, otolaryngology—head and neck
surgery, infectious disease, and pathology, among others. We present a review of
salient features of malignant and benign cutaneous nasal lesions which are of
importance to physicians treating these complicated pathologies.
KEYWORDS
basal cell carcinoma, cutaneous lymphoma, cutaneous nasal lesion, histiocytosis, melanoma,
squamous cell carcinoma
INTRODUCTION
The nose can be afflicted by a host of benign and malignant lesions
and is one of the most common locations for skin cancer. The nose's
prominent location and critical esthetic features are of particular
importance when planning to treat cutaneous lesions. The nose has
welldefined anatomic subsites, and important physiologic functions,
including heating and humidifying air and serving as an immunologic
gateway by sampling inhaled particles such as viruses and aero-
allergens. In this article, we identify common and rare nasal pathol-
ogies alike and collate the lesions into four diagnostic categories:
(1) neoplastic and neoplastic look alike lesions, (2) cutaneous
lymphomas, (3) infectious disease with cutaneous involvement, and
(4) inflammatory lesions. (Graph 1).
METHOD
A comprehensive literature search was performed using PubMed
database with key words “cutaneous nasal lesion,” “cutaneous lym-
phoma,” “facial cutaneous malignancies,” “the latest treatment of
melanoma,” “nasal lesion and infectious disease,” “facial cutaneous
lesion in adults,” “pathology of nasal lesions,” and “cutaneous malig-
nancies” for all papers published between January 2000 and May
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro-
vided the original work is properly cited.
© 2024 The Author(s). Eye & ENT Research published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.
Eye & ENT Res. 2024;1:6591. wileyonlinelibrary.com/journal/eer3
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GRAPH 1 Cutaneous nasal lesions are divided into four categories: (1) neoplastic and neoplastic look alike lesions, (2) cutaneous
lymphomas, (3) infectious disease with cutaneous involvement, and (4) inflammatory lesions.
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2022. The relevant articles were reviewed and the key findings were
extracted.
NEOPLASTIC AND NEOPLASTIC LOOK ALIKE
LESIONS
Malignant melanoma
Malignant melanoma (MM) is an aggressive and often insidious
cutaneous cancer and has the highest rate of metastasis among all
skin cancers [1]. According to the American Cancer Society, more
than 8000 patients will die due to MM in 2024, and nearly 100,000
new cases will be diagnosed in the USA [2]. The rate of MM (Figure 1)
is 20 times higher in Caucasians. Several studies have reported a
higher rate of cutaneous MM on the left side of the body with no
satisfactory explanation even in countries with rightsided cars [3].
MM has a dual etiologic pathway: 70% of MM tumors occur de novo,
and 30% originate from preexisting common nevi [3–5].
The main risk factor for skin MM is UV light exposure, especially
from the sun and tanning beds [5–8]. Other risk factors include a
history of sunburn, atypical nevi, a weakened immune system,
repeated Xray exposure, and xeroderma pigmentosum [1]. Ten
percent of patients with MM have a positive family history.
Kosec et al. reported that out of 159 head and neck cutaneous
MM, 36% were nodular, 31% were lentigo maligna, 30% were su-
perficial spreading, and 2.5% were desmoplastic melanoma. Sentinel
lymph node biopsy (SLNB) was performed in 39% of cases and nearly
1 out of 4 showed metastatic disease. 45 out of 159 patients had
regional metastasis, and 31 patients underwent superficial or total
parotidectomy [3].
Approximately 5% of head and neck MMs are from nasal origin
[9]. In a study by Wee et al. on 5141 patients investigating the
melanoma anatomical distribution per unit area, the female nose and
cheek and the male ear had the highest incidence [10]. In this study,
67 (2.7%) out of 2481 females with melanoma had cutaneous nasal
melanoma, and 58 (2.18%) out of 2660 men had cutaneous nasal
melanoma. More than 62% of nasal melanomas are diagnosed in
patients over 60 years of age [10]. Lesions of the nose had the
highest rate of in situ disease among all parts of the body, perhaps
due to its visibility leading to early diagnosis [10]. The role of SLNB
and its value as a prognostic factor in nasal cutaneous melanoma is
still unclear. Overall 5year survival is reported to be 96% [9, 11].
The TNM staging system for melanoma is the same as previous
guidelines [12]. However, the sentinel lymph node status improves
prognostic information. Site, depth, mitotic rate (MR), and melanoma
extension are significant factors determining the risk of metastasis
[13]. A combination of highfrequency ultrasound and dermatoscopy
has been shown as an acceptable methodology for the classification
and diagnosis of melanomas [14].
Geneexpression profiling has shown promising results in esti-
mating the probability of finding a positive sentinel lymph node
and the need for further adjuvant systemic therapy. Although this
profiling is common in the management of melanoma, it is not included
in the AJCC melanoma staging system [15]. The National Compre-
hensive Cancer Network (NCCN) recommends genetic testing for
cyclindependent kinase inhibitor 2A (CDKN2A) and P16 gene muta-
tion in patients with a family history of invasive melanoma [1].
As per the NCCN, the main factors that should be considered in
biopsy results are (1) Breslow thickness; (2) dermal MR, which shows
the number of cancer cells dividing in the dermis; (3) margin status;
(4) microsatellites, which refers to tiny nests of melanotic lesions that
is present within 2 cm of the primary tumor; and (5) lymphovascular
invasion of MM [1].
Treatment: Historically, melanoma was treated with the excision of
a 5cm free margin and prophylactic removal of lymph nodes [16].
However, guidelines from the American Cancer Society now recom-
mend a 1cm free margin for tumors with a depth of <2 mm and a 2cm
free margin for melanomas with a depth of >2 mm. Micrographic
controlled surgery is recommended for melanomas on the face [13, 15].
Previously patients with metastatic MM to a sentinelnode underwent
complete lymph node dissection; however, due to the safety of nodal
observation, current standard practice prefers nodal observation with
ultrasonography rather than complete nodal dissection [15, 17]
(A) Mohs surgery:
After Frederic Mohs introduced the Mohs procedure in 1930, it
became the treatment of choice for many cutaneous neoplasms.
The goal of the procedure is to leave as much unaffected skin
behind as possible by examining tissue for remaining pathology
using small incremental excisions [18]. Recent studies show
Mohs surgery has a lower recurrence rate than wide local
excision and staged excision in managing early stage head and
neck cutaneous melanoma [19].
(B) Checkpoint immunotherapy:
The cytotoxic Tlymphocyteassociated antigen 4 (CTLA4) and
programmed death 1 (PD1) are two immune checkpoints that
FIGURE 1 A 60yearold man with melanoma in situ excised by
dermatologist. The patient declined paramedian forehead flap and
thus the lesion was repaired using a full thickness skin graft which
was harvested from the left supraclavicular region and bolstered in
place.
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downregulate Tcell immune function. Inhibition of these two
immune checkpoints increases the immune system's activation
and eventually helps fight the tumor cells [20]. Blockage of
CTLA4 with antagonistic antibodies will improve Tcell function
and lead to eventual tumor cell eradication [21].
Examples of these antibodies include ipilimumab (a CTLA4
antagonist), pembrolizumab, and nivolumab (PD1 antagonists).
Combination therapy with ipilimumab and nivolumab is now
standard care for patients with advanced melanoma, with a 53%
response rate, even with brain metastasis. Ten percent of pa-
tients do not require any further therapy. However, prolonged
exposure to anti–PD1 antibodies can cause tumormediated
resistance mutation. For example, Janus kinase (JAK1/2) muta-
tions decrease PDL1 expression, which in turn downregulates
the immune system [22].
(C) Therapy targeting BRAF and MEK:
BRAF mutations are found in 50%–70% of skin melanomas [1].
Vemurafenib was the first FDAapproved BRAFtargeted
therapy developed in 2012 with a 48% response rate. How-
ever, due to rapid resistance through MAP kinase activation,
combination therapy with BRAF inhibitors and MEK inhibitors
quickly became the standard of care in the treatment of pa-
tients with high tumor burden with a response rate of over
60% [23].
(D) Other targeted therapies:
KIT mutations, which encode protooncogene receptor tyrosine
kinase, are found in 36% of acral melanomas. It is responsible for
the activation of two major intracellular pathways, PI3K and
MAP kinase. KIT inhibitors such as imatinib have a 53% response
rate [24, 25].
(E) Adjuvant and neoadjuvant therapy:
Today, a combination of ipilimumab and MEK inhibitors is a
standard adjuvant therapy in stage III BRAF mutated melanomas
with a 52% recurrencefree survival over 5 years [26].
(F) Oncolytic virus therapy:
In 2015, the FDA approved talimogene laherparepvec (TVEC), a
modified oncolytic herpes virus. This intratumoral injection agent
is approved for patients with inoperable metastatic melanoma. T
VEC preferentially infects melanoma cells and leads to tumor cell
lysis and enhancement of antitumor immune response. The TVEC
and PD1 combination therapy is currently under evaluation [27].
(G) Radiotherapy (RT):
Although surgery remains the preferred choice for definitive
treatment for MM, RT can be used in Lentigo maligna, melanoma
in situ, and desmoplastic melanoma lesions located in the head
and neck [28]. Conventional and hypofractionated RT as part of
adjuvant RT are effective, especially for desmoplastic melanoma
[1, 28].
RT can also be used in locally recurred melanoma, extensive
neurotropism, and where the surgeon cannot resect greater
margins due to cosmesis or technical issues. Hypofractionated
RT has a higher risk of longterm side effects such as cuta-
neous fibrosis and lymphedema compared to surgical resec-
tion [28].
Squamous cell carcinoma
Cutaneous Squamous Cell Carcinoma (CSCC) accounts for 10% of all
cutaneous nasal malignancies [29]. CSCC causes nearly 3000 to 8000
deaths each year in the United States, the most common cause of
death among nonmelanoma skin cancers [30]. There is an expected
increase in the rate of nonmelanoma skin cancer, which may double
by 2030 [24–27]. SCC incidence has a maletofemale ratio of 3:1
[30], and incidence increases with age [31–33].
Significant risk factors for SCC include UVA and sun exposure,
actinic keratosis, chemicals such as arsenic and pesticides, and
immunosuppression [30, 31, 34, 35]. Although SCC is more common
in people with fair skin, it has a higher mortality rate in the Black
population (18%) due to delayed diagnosis [30].
CSSC commonly presents as a crusting erythematous ulcer with
a red granular base and a tendency to bleed with minor trauma
(Figure 2). Chronic ulcers found on top of scar tissue that do not heal
should raise concern for CSCC [4]. Only 5.2% of facial CSSC is found
on the nose, with the majority of facial CSSC (39.5%) on the buccal or
parotidmasseteric units [36]. The 5year recurrence rate of nasal
CSCC is reported to be between 8% and 16%, depending on tumor
size and other risk factors [11].
The mutational burden in CSCC, in comparison with other solid
tumors, is much greater. P53 is the most mutated gene, found in 47%
of head and neck cutaneous squamous cell carcinomas (HNCSCC).
This mutation occurs early in the development of CSCC and is most
likely due to exposure to carcinogens such as cigarette smoke, and is
heavily correlated with CSCC development [6, 34, 37]. Clinically, p53
mutations directly relate to an increase in local recurrence rate,
decreased response to chemoradiotherapy, and decreased 5year
overall survival [6, 34, 37].
NOTCH1–2 gene, which determines cell fate [6], and CDKN2A,
which encodes several tumor suppressor proteins, play a role in the
development of CSCC. NOTCH1 and NOTCH2 mutations have been
reported in more than 75% of CSCC [38]. Clinically, HNSCC with
NOTCH1 mutations have greater extra nodal spread and poorly
FIGURE 2 A 65year old man with exophytic left malar SCC.
Wide local excision performed involved lower eyelid. Cervicofacial
advancement flap and tarsal strip procedure performed with
excellent cosmesis.
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differentiated pathology [6, 34, 39]. EGFR overexpression in CSCC
has a significant correlation with lower overall survival [40].
Treatment: Mohs micrographic surgery is the preferred modality
of choice in treating HNCSCC [41]. Although a margin of 4 mm for
lesions smaller than 2 cm and a margin of 6 mm for lesions greater
than 2 cm has been suggested, no large studies have been conducted
to confirm these values [4, 42]. CSCC is highly sensitive to RT;
however, risk of bone necrosis, cataracts, and uncertain cosmetic
outcomes limit it as an adjuvant therapy for the face [43, 44]. The
FDA approved pembrolizumab and cemiplimab, PD1 receptor
monoclonal antibodies, for use as firstline treatment of metastatic or
locally advanced CSCC [45]. Another class of immunotherapies is
EGFR inhibitors such as cetuximab. Cetuximab was approved for
advanced HNSCC and is the most efficacious antiEGFR antibody for
CSCC. A combination of cetuximab with RT for unresectable CSCC
was promising. There are ongoing clinical trials on the combination of
cetuximab and PD1 inhibitors.
As per NCCN stratification, any CSCC on the face, regardless of
the size, is considered a highrisk CSCC [46]. Other criteria for high
risk CSCC are shown below (Table 1).
3%–5% of all CSCCs become metastatic within 2–3 years of
diagnosis. The risk of metastasis increases 12 times if the depth of
the lesion is >2 mm, perineural invasion is present, or the lesion
arises from a scar. Metastatic CSCC involves regional head and neck
lymph nodes or parotid glands [31, 49]. In cases with high suspicion of
nodal involvement, dissection of head and neck lymph nodes should
be considered. If metastasis involves the parotid gland, parotidec-
tomy is usually suggested; however, the role of SLNB in increasing
the survival rate of patients with CSCC is not clear [50–52].
Merkel cell carcinoma
Merkel cell carcinoma (MCC) is a rare skin tumor that occurs more
often in elderly Caucasian men at a mean age of 75. It presents as a
rapidly growing, purple spherical tumor with a shiny surface, often
developing within a few weeks (Figure 3). The head and neck region is
the most commonly affected area (50%) [53, 54]. The incidence of
MCC in the United States is about 0.66/100,000 [55]. Major RF is UV
light, and most patients have a history of other UVassociated skin
tumors [56].
MCC is a neuroendocrine malignancy of the skin. Although
MCC's pathogenesis is unclear, Merkel cell polyomavirus (MCPyV) is
a possible culprit. In a study, MCPyV was found in half of the patients
[56]. Histopathologically, MCC has a high nucleocytoplasmic ratio
with small chromatin bubbles that mimic salt and pepper patterns
(small blue round cell tumor) [57, 58].
The diagnosis of MCC can be confirmed with cytokeratin 20 (CK
20). Other neuroendocrine markers, such as chromogranin A and
synaptophysin, also can be positive (Figure 4) [57, 58]. The presence
of CD8þT lymphocytes is associated with a better outcome [59].
After a diagnosis of MCC, lymphogenic metastasis should be
ruled out. Due to the propensity to metastasize to regional lymph
nodes and a high number of occult lymph node metastasis, sentinel
node biopsy should be done [60, 61]. Lymphatic metastasis, even
after a negative sentinel node, is up to 17% [61, 62]. Most cases of
recurrence occur in the first 2 years [63]. Fiveyear survival for MCC
depends on the tumor size and varies between 35% and 75% [64].
Treatment: Complete excision of the primary tumor is preferable
to biopsy if MCC is clinically suspected. Wound closure under tension
or free grafts should be avoided [63, 65]. Due to occult satellite
metastasis, MCC should be excised with a margin 1–2 cm, depending
on the stage. For the same reason, the use of Mohs surgery is
controversial [65, 66]. Adjuvant RT is recommended irrespective of
the surgical margin used [67, 68].
Radiotherapy is a definitive modality in patients with inoperable
primary tumors [69]. Studies show that even a dose of 8 Gy can
achieve high response rates (45% complete remission in large tu-
mors) [70].
Systemic therapy: Immune checkpoint inhibitors (ICI) are the first
line treatment in inoperable advanced MMC. Pembrolizumab and
nivolumab are FDA approved for metastatic MCC. Talimogene
laherparepvec (TVEC), either as monotherapy or combined with ICI,
has been used in multiple case reports [71].
Chemotherapy with anthracyclines, cyclophosphamide, etc., can
be considered a second line of treatment [72]. The use of peptide
receptor radioligand therapy based on somatostatin has been
mentioned in some case reports [73].
TABLE 1Risk factors for metastasis of invasive cutaneous
squamous cell carcinoma.
Tumor thickness: >2 mm (high risk: tumor thickness >6 mm)
Diameter: >2 cm
Arising within a scar (e.g., burn, radiation)
Location: ear, lips, mucosa including the tongue
Immunosuppression [47]
Histopathological features: Poorly differentiated or undifferentiated,
developing within Bowen disease [47], recurrent type, rapidly growing,
presence of neurological symptoms [30], any vascular involvement [48]
Clark level of IV, V [48]
FIGURE 3 Merkel cell carcinoma of the tip of the nose. Source:
Wollina U, Langer D, Tchernev G. MushroomLike Skin Tumors:
Report of Three Cases, Open Access Maced J Med Sci. 2017 Jul 21;
5(4):515–517. Reprinted with permission under CCBYNC
license 4.0.
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FIGURE 4 Shave biopsy of skin displaying a Merkel cell carcinoma with pure neuroendocrine morphology at scanning, (a) and high,
(b) magnification. The neoplastic small blue round cells exhibit spotty nuclear positivity for Merkel cell polyomavirus, (c) and cytoplasmic
positivity for CK20 (paranuclear dot and circumferential patterns), (d) synaptophysin (diffuse cytoplasmic pattern), (e) and neurofilament
(scant dotlike pattern), (f). Source: Walsh NM, Cerroni L. Merkel cell carcinoma: A review. J Cutan Pathol. 2021, Mar; 48(3):411–421.
Reprinted with permission under license number 5601670806482.
Basal cell carcinoma
Basal cell carcinoma (BCC) is the most common cutaneous cancer and
accounts for 75% of nonmelanotic skin cancers and 90% of malig-
nant cutaneous head and neck cancers [74]. Two million Americans
each year develop BCC with a maletofemale ratio of 2:1; however,
other studies report nasal BCC incidence in females as almost 1.6
times higher than in males [75, 76]. Nearly 70% of all BCCs occur on
the head and neck, and the nose is the most commonly affected
subunit [76]. UVA and UVB exposure are significant risk factors, and
people who live in countries near the equator have a higher risk for
BCC [47]. Other risk factors include prior RT, albinism, xeroderma
pigmentosum, fair skin, and immunosuppression [77, 78]. Notably, the
incidence of BCC among patients with organ transplants is 5–10
times higher than the general population [79] (Figure 5).
Although metastatic BCC is rare (0.1%), lesions greater than
6 mm in the H zone (mask area Figure 6) or greater than 10 mm in
other face areas have a higher chance of recurrence. There are more
than 26 subtypes of BCC but with no universally accepted classifi-
cation. In general, the four main subtypes of BCC are nodular, su-
perficial, morphea form, and fibroepithelial [80].
The nodular subtype is the most common type of BCC and in-
cludes 50% of all BCC. It presents as a pearly nodule or papule with
arborizing telangiectasias and a smooth surface. As tumor growth can
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be ulcerated (Rodent ulcer), a rolled border usually remains. Nodular
BCC involves the nose, cheeks, and nasolabial folds; it is rarely seen
in nonhairbearing sites.
The superficial subtype is the most common BCC in younger
patients, with a mean diagnosis at age 57. It presents as a well
circumscribed erythematous patch or macule. Focal scale or crust,
atrophy, and hypopigmentation can be observed as tumors grow
[81, 82].
Morphea form (desmoplastic) BCC is the most insidious and a
less common subtype. It presents as a light pink or white plaque with
illdefined borders and a typically smooth surface that can range
from slightly elevated to depressed. Usually, a degree of infiltration
exceeds what is clinically visible. The fibroepithelial subtype is a rare
variant and tends to be found on the lower back and trunk [47, 78].
PTCH1 (patched 1) gene mutation on chromosome 9q has a
pivotal role in BCC formation. This mutation is present in 30%–90%
of sporadic BCC [83].
Treatment: As per NCCN guidelines, treatment of BCCs depends
on determining highrisk or lowrisk lesions. The primary treatments
for lowrisk BCC are (1) curettage and electrodesiccation (C&E) in
areas without hair growth, (2) standard excision with 4mm clinical
margins if possible, and (3) radiotherapy (RT) for nonsurgical candi-
dates. Recommended options for treatment of highrisk BCC are (1)
standard excision with wider margins, (2) Mohs surgery or complete
circumferential peripheral and deep margin assessment, and (3) RT if
surgery is not feasible.
Standard excision with a margin of 4mm has been suggested for
wellcircumscribed lowrisk BCC which is <2 cm in diameter. This
yields complete removal in more than 95% of cases [84, 85]. How-
ever, recent studies show that an excision margin of 2–3 mm is safe
for most head and neck BCC regardless of size and histopathology.
The rate of recurrence was comparable with wide excision [86].
Curettage and electrodesiccation is a fast and costeffective
procedure for superficial lesions, with a cure rate of more than
97% [87]. However, assessment of histological margin is not possible;
in some studies, the chance of recurrence was 7%–20%, possibly
related to operator performance [88–90].
Mohs micrograph surgery is the method of choice and mainstay
for highrisk BCC (Table 2). In a metaanalysis of studies from 1947
to 1989, there was a 1% chance for 5year recurrence in primary
BCC after Mohs surgery, lower than all other modalities [88, 90, 91].
RT can be used as adjuvant therapy, especially in a highrisk pa-
tient with substantial perineural involvement [92]. However, a ran-
domized study that compared excisional treatment and RT showed
the rate of recurrence and cosmetic results were meaningfully worse
in the RT group [93]. Although there is no exact age limit, it is best to
avoid RT in patients under age 50 with uncomplicated skin tumors as
scars from RT tend to get worse following treatment [94].
Topical treatments (5fluorouracil (5FU) and imiquimod) and
superficial treatments (photodynamic therapy (PDT) and cryo-
therapy) should be considered when radiotherapy or surgery is
impractical or contraindicated [95]. 85% of superficial BCC treated
FIGURE 5 A 51year old man with right nasal side wall basal
cell carcinoma 1.2 cm in size. Under went excision and
reconstruction using a right melolabial flap. The flap was divided
3 weeks after inset and debulked with favorable cosmetic
outcomes.
FIGURE 6 H zone.
TABLE 2Risk factors for recurrence of facial Bacall cell
carcinoma [47].
Size >6 mm
Poorly defined borders
Recurrent BCC
Tumor at the site of prior radiation therapy
Pathologic risk factors: Perineural involvement, micronodular,
infiltrating, and sclerosing type
Immunosuppressed patient
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with imiquimod were diseasefree after 5 years [96]. There was no
significant difference between 5FU and imiquimod regarding
cosmetic or efficacy results [36, 97].
In PDT, a topical photosensitizing agent (5aminolaevulinic acid
(ALA) or methyl aminolaevulinate (MAL) is applied on the lesion.
Introduction of a light source after 4–6 h activates the agent in
malignant cells due to their selective agent uptake [98]. Compared to
surgery, PDT offers a better cosmetic result, especially in the su-
perficial subtype with a diameter of 8–20 mm. However, PDT has a
higher rate of 5year recurrence (22%) [99, 100].
Cryosurgery eliminates tumor cells through freezethaw cycles.
The recurrence rate for this method varied from zero to nearly 40%,
which is most likely related to differences in technique, operator
performance, and followup durations. Cryosurgery is also limited by
cosmetic outcomes, ranking last in comparison to other methods [99,
101, 102].
FDA recently approved systemic therapy with hedgehog
pathway inhibitors (HHI) such as vismodegib and sonidegib. HHI can
be used in locally advanced BCC, Metastatic BCC (Just Vismodegib)
that has recurred following surgery, patients not candidates for
surgery or RT [103]. Cemiplimabrwlc, a PDL1 inhibitor, can be used
for patients for whom HHI is not appropriate [103].
Histiocytosis
Histiocytosis is a rare and clinically heterogeneous group of pathol-
ogies seen in patients of all ages. In 2016, the society of histiocytosis
endorsed a new classification for histiocytosis with five main groups:
(1) Langerhansrelated (L), (2) cutaneous and mucocutaneous (C), (3)
malignant histiocytosis (M), (4) Rosai–Dorfman disease (R), and (5)
hemophagocytic lymphohistiocytosis and macrophage activation
syndrome (H). Previously, detection of phenotypic markers specifying
Langerhans cells, such as CD207, CD1a, and birbeck granules was
defined as the difference between Langerhans cell histiocytosis (LCH)
and nonLCH [104]. Most lesions that occur in histiocytosis harbor
common mutations in RET, NTRK, RAS, RAF, MAP2K, etc. Different
types of histiocytosis can also share radiological or clinical features
[79, 105]. Here, we will focus on the LCH and cutaneous/mucocu-
taneous subtypes as they have more tendency to head and neck.
Langerhans histiocytosis
LCH, also known as histiocytosis X or eosinophilic granuloma, is a
rare disease characterized by a clonal proliferation of Langerhans
cells (white blood cells with a large cell nuclei that may contain
cytoplasmic histiocytosis X bodies) within a heterogeneous lesion
[106, 107]. LCH can arise in almost any tissue with an unpredictable
course [108]. Although some prevailing models suggest that LCH
arises from malignant transformation and metastasis of epidermal
Langerhans cells (55%–60% of LCH specimens were positive for
BRAF V600 E mutation), the etiology of LCH remains speculative [76,
78–80]. LCH has an annual incidence of about 3–5 cases per million
in children aged 0–15 years [109, 110], and at least 0.07 per million in
patients older than 18 years [111, 112]. In children, the maleto
female ratio is nearly 2:1. However, in adults, there is a slight fe-
male predominance [47].
In a study by Howarth et al. on 314 cases of LCH ranging from
patients aged 2 months to 83 years of age, 36.3% of cases were
osseous, 30.5% were multisystemic, and 33.12% were singlesystem
nonosseous in origin. Only 14 cases (4.4%) had isolated skin LCH
lesions. Six cases of isolated cutaneous LCH were treated with
excisional surgery without recurrence, and two cases had sponta-
neous remission. Other cases received various types of treatment,
such as RT, chemotherapy or both [113]. In a recent study by AiTram
N Bui et al. on 31 adult patients ranging from 24 to 84 years old with
cutaneous LCH, facial involvement was mentioned in only three
cases, which was in addition to the involvement of other anatomical
locations [114]. Therefore, solitary adult lesions of LCH are very rare,
but involvement as a part of multisystemic or disseminated cuta-
neous LCH has been reported (Figure 7) [115].
The key factor in the management of LCH is determining if the
disease is skinlimited or multisystemic. The most common manifes-
tation of systemic LCH is bone lesions. Treatment with topical
corticosteroids or watchful waiting in skinlimited lesions is
FIGURE 7 (a, b) A 27yearold male with refractory disseminated cutaneous Langerhans cell histiocytosis on face, nasal ala, trunk, axillae,
and nails. (c) After treatment with etoposide and systemic steroid. Source: An unusual case of adult disseminated cutaneous Langerhans cell
histiocytosis, 2006, Moravvej, Hamideh, et al. l, Dermatology Online Journal Volume 12, Issue 6. Reprinted with permission under CCBY
license.
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recommended as spontaneous regression is possible (Figure 8) [113].
Guidelines recommend following patients with skinlimited LCH
every 2–4 weeks in active lesions and every 6 months for 5 years
after regression of the skin lesions [116–118].
Cutaneous and mucosal histiocytosis (type C)
The most common type of cutaneous mucosal histiocytosis is juvenile
xanthogranuloma (JXG), which is a common nonLCH CD1 negative
lesion with a predilection to the head and neck. Cutaneous lesions
usually appear as a few small redyellowish to brownish benign
papules or nodules on the head and neck in the first year of life with
spontaneous resolution (Figure 9). There are a few case reports of
adult nasal (JXG) on the nose [119–121]. In a study on the distri-
bution of solitary cutaneous JXG, 13% of lesions were located on the
face and 17% on the scalp. Neck and eyelids distribution rates were
6% each [122]. Due to the selflimiting nature of the JXG, treatment
is not required.
Kaposi sarcoma
Kaposi sarcoma (KS) is a multifocal angioproliferative disease
involving vascular endothelium that can involve the gastrointestinal
system and lungs. KS is extremely rare, with a rate of six person in
one million and a 5year mean survival of 74% [123]. HHV8, which
can be transmitted with saliva, is found in all KS types [124, 125].
Seroprevalence of HHV8 in North America is <5%; however, HHV8
antibodies are present in 80%–95% of HIV seropositive patient with
KS [126].
There are four types of KS: (1) classic form, which is seen in older
patients of Mediterranean or Ashkenazi Jewish descent [127], (2)
African endemic form, which occurs mostly in young men and chil-
dren, (3) Iatrogenic immunosuppressionassociated form, which af-
fects solid organ transplant recipients with an aggressive course, and
(4) AIDSrelated epidemic forms [128]. AIDSassociated KS is the
most common subtype with protean clinical manifestations [128].
AIDSassociated KS is an aggressive vascular tumor with a red
purplish dark violet patch, plaques or papules, and nodules with a
predilection for the face, nose, and upper body (Figure 10). The
respiratory and gastrointestinal tracts are usually affected in this
subtype.
The number of studies on nasal KS is trending down due to a
significant decrease in the rate of KS (nearly eight times less since
1990). In a study in 1996, more than 68% of cases with pulmonary KS
had tipofthenose KS lesions, and the author suggested considering
the lesion as a sentinel sign for pulmonary KS. However, the popu-
lation of the study was only 19 cases, and there are no more studies
on this subject.
A skin biopsy confirms a KS diagnosis. The histologic features of
KS do not vary significantly between subtypes but do vary with the
FIGURE 8 (a–c) A 15yearold male presented to a dermatology clinic initially for acne. Biopsy demonstrated Langerhans cell histiocytosis.
(a) Papule on the left nasal ala at initial dermatologic consultation. (b) Regrowth of the papule after biopsy. (c) Complete resolution of the left
nasal alar papule with clobetasol therapy as observed at the 3month followup visit. Source: Skinlimited langerhans cell histiocytosis
presenting as crusted papules in an acneiform distribution in an adolescent man, Rachek Choi, JAAD Case Rep. 2022 Feb; 20: 37–39.
Reprinted with permission under CCBYND license.
FIGURE 9 (a) A 5yearold girl with a 4mm, firm, domeshaped, papule with overlying telangiectasias below the nasal columella.
(b) Dermoscopy view of the lesion with a Pinkred rim “settingsun” pattern. (c) Shave biopsy with dense infiltrate and multiple giant cells
abundance of lipidized histiocytes. HematoxylinEosin 40.Source: Elsevier publication, A Persiste “Pimple” in a 5YearOld Girl, Katheryn A
Bell, Journal of Pediatric 2020 Sep; 224:172–173. Reprinted with permission under license number 5390590469033.
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lesion stage. The endothelial nature of KS has been well established,
but controversy regarding whether this endothelial phenotype is
lymphatic, vascular, or both remains. Spindled cells with markers of
endothelial cells (like CD31), blood vascular differentiation marker
(CD34), and lymphatic differentiation (VEGFR3) form most KS le-
sions [129, 130]. The spindle cells form intersecting fascicles and are
separated by characteristic slitlike spaces containing erythrocytes
(Figure 11). This sievelike pattern of vascular spaces is highly
characteristic of KS [131]. Interestingly, HHV8 can infect both
vascular and lymphatic endothelial cells [131]. Staining for latency
associated nuclear antigen (LANA1) can detect HHV8 with high
sensitivity and specificity.
Different treatment modalities including topical alitretinoin,
topical imiquimod, PDT, liposomal anthracyclines, paclitaxel, intrale-
sional vinblastine or vincristine, cryotherapy, and laser surgery, have
been used for superficial patches [132–134]. RT on AIDSrelated KS
was less effective than on the classic type. 5yearsurvival among
patients on HAART was significantly higher in AIDSrelated KS
compared to the nonHAART group [134–137].
LYMPHOMA
Primary cutaneous lymphomas (PCL) are nonHodgkin lymphomas
that involve cutaneous tissues at the time of diagnosis. PCL are
classified as cutaneous Tcell lymphoma (CTCL) or cutaneous Bcell
lymphoma (CBCL). CTCLs make up 75%–80% of cutaneous lym-
phomas; CBCLs make up 20%–25% of cases [138].
Cutaneous T cell lymphoma
CTCL describes a group of Tcell neoplasms, each varying in pre-
sentation, histologically and immunologically. For years, it was
thought that mycosis fungoides (MF) and sezary syndrome (SS) were
the only subtypes of CTCL; however, in 2018, the classification of T
cell lymphomas was modified to include three subtypes. The first is
the classical group which includes MF, the variants of MF, and SS. The
FIGURE 10 Kaposi sarcoma in a patient with acquired
immunodeficiency syndrome. Erythematousviolaceous plaques on
the tip of the nose, corner of the mouth, and left cheek. Source:
Kaposi Sarcoma and Cutaneous Angiosarcoma: Guidelines for
Diagnosis and Treatment, C.serraGuillen et al, Actas Dermo
Sifiliográficas (English Edition) Volume 109, Issue 10, December
2018, Pages 878–887. Reprinted with permission under CC license
BYNCND.
FIGURE 11 Histology of Kaposi sarcoma. (a) Lowmagnification view of Kaposi sarcoma in nodular phase. Welldefined dermal nodule.
(b) Highly cellular lesion with some gaps in the form of cracks. (c) Detail of spindle cells and red blood cells within the small vessels.
(d) Immunohistochemical nuclear positivity for HHV8 specific to Kaposi sarcoma. Source: Kaposi Sarcoma and Cutaneous Angiosarcoma:
Guidelines for Diagnosis and Treatment, C.serraGuillen et al, Actas DermoSifiliográficas (English Edition) Volume 109, Issue 10, December
2018, Pages 878–887. Reprinted with permission under CC license BYNCND.
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second group is the CD30þlymphoproliferative disorders which
include cutaneous anaplastic large cell lymphoma. The last group
includes rare entities such as extranodular natural killer (NK)/Tcell
lymphoma and primary cutaneous acral CD8þT cell lymphoma, along
with other neoplasms [139–141]. Here, we will discuss several of
these neoplasms under the CTCL group.
Mycosis fungoides
MF is the most common CTCL, comprising up to 50% of cases. It is
typically seen in males aged 60–70 years. The causes of MF are
unknown, and no consistent genetic pattern has been identified.
Persistent antigen stimulation may play a role; however, the source
of antigens is unknown [140, 141]. The continuous stimulation of T
cells may result in inflammationmediated mutations of Tcells.
HTLV1 induction has also been discussed; however, there have been
no clinical associations found [142]. Several other viruses such as
cytomegalovirus, human papilloma virus, and Epstein–Barr virus
(EBV), have been seen in MF patients [143–145], although no causal
relationship has been established. MF is clinically categorized into
patches, plaques, or tumors. Diagnosis is made by histology, and
staging is based on TNMB (tumor, node, visceral, blood) classifica-
tion [145].
Follicular mycosis fungoides
There are variants of MF which have different clinical presentations,
such as follicular MF (FMF). FMF accounts for 10% of MF cases. It is
associated with alopecia which can present as nonscarring eyebrow
hair loss. The patient may present with grouped follicular papules,
acneiform rash, or indurated plaques [146]. In some instances, nasal
involvement occurs as part of leonine face manifestation of FMF;
local cutaneous nasal involvement has not been reported as of our
literature review (Figure 12) [147]. Histologically, follicular MF is
similar to standard MF. However, follicular FMF shows atypical
lymphocytic infiltrate and mucin (follicular mucinosis). The atypical
lymphocytes can be CD30þ. The deeper the infiltration, the poorer
the prognosis (Figure 13) [141].
Given the perifollicular involvement, treatment is less amenable
to typical MF treatment such as psoralen ultraviolet light A (PUVA)
or topicals. Instead, radiotherapy and total skin electron beam (TSEB)
therapy may be used. TSEB is a form of radiation utilizing electrons
which is directed to the entire skin [141].
Cutaneous anaplastic large cell lymphoma
Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a
CD30þlymphoproliferative disorder (LPD) with a fairly good prog-
nosis. PCALCL accounts for about 12% of CTCLs and about 25%–
30% of CD30þLPDs. Typically, these lesions are found in adults
(aged 50–70 on average) and have a male dominance (M:F ratio is
2:1) [141, 148]. Tumors are red to violaceous firm ulcerations and can
grow within a matter of weeks. These typically solitary lesions are
predominantly found in the upper part of the body. Lesions often
regress spontaneously with a favorable prognosis, especially in pa-
tients under the age of 60 (Figure 14). Lesions may appear extrac-
utaneously, which is reported to have a poor prognosis. There are
reports of involvement of the head or neck conferring a poor prog-
nosis, but no consistent literature is noted [141, 148–150]. PCALCL
is commonly mistaken for lymphomatoid papulosis (LYP). These le-
sions can be differentiated by size: PCALCL tend to be larger (up to
10 cm), while LYP is smaller and do not fluctuate in size. A biopsy aids
in diagnosis [141].
Histologically, PCALCL reveals anaplastic cells with varied
nuclei (round to oval to irregularly shape) and CD30þcells. Eosin-
ophils and pleomorphic Reed–Sternberglike cells are uncommon.
CD4þcells have also been reported, and PCALTL may be CD2,
CD5, or CD3 negative. There are reports of positive anaplastic
lymphoma kinase on immunohistochemistry in systemic disease, but
negative in PCALCL. Although not seen in all cases of PCALCL,
there is an increased chance of progression to systemic disease
[141, 148, 151].
Depending on the tumor burden, there are several treatment
options. Excision of PCALCL or chemotherapy drugs such as imi-
quimod and lowdose methotrexate may be considered. Local
radiotherapy has been used on larger tumors. Recent studies have
also examined monoclonal CD30 antibodies such as brentuximab
FIGURE 12 A case of folliculotropic mycosis fungoides with
with predominant infiltrating plaques, leonine facies, and alopecia
of the eyebrows. Source: Mantaka, P., et al., Clinical and
histopathological features of folliculotropic mycosis fungoides: a
Norwegian patient series. Acta Derm Venereol, 2013. 93(3):
p.325–9. Reprinted with permission under CC license CCBYNC.
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vedotin, which showed to be efficacious in PCALTL; however, pe-
ripheral neuropathy was seen in 65% of patients [152–156].
Primary cutaneous CD4þsmall/medium Tcell
lymphoproliferative disorder (PCSMLPD)
PCSMLPD was recently added to the WHO classification (the pre-
vious name was PCSM lymphoma). It generally presents as a single
cutaneous nodule, plaque, or tumor on the face, neck, or upper trunk.
The mean age of diagnosis is 59 years. Nearly one third of the cases
regress spontaneously. Two histopathological subtypes have been
reported. A nodular or diffuse lymphoproliferating subtype in the
entire dermis typically presents as a nodule or tumor on the face
(Figure 15) and is commonly misdiagnosed as BCC (Figure 16). The
second subtype presents as a subepidermal bandlike infiltrate with a
plaque or papule on the trunk [157]. Staging is typically not required.
Intralesional steroids, surgical excision, and rarely RT is suggested for
lesions without spontaneous regression [138].
Extranodal NKT lymphoma, nasal type
Extranodal NK Tcell lymphoma (ENKTL) (Figure 17) is a rare
aggressive entity of CTCL that is mostly seen in Asian, Central
American, and South American populations. ENKT is commonly
diagnosed at 50–60 years of age and shows a 2:1 male predominance
[141]. Around 80% of ENKTL presents in the upper aerodigestive
system or nasal tissue. In other cases (20%–30%), neoplasms pre-
sented in other areas of the gastrointestinal tract, testis, lungs, and
skin [158–160]. Patients will present with an abrupt onset of ulcer-
ated tumors. The tumors can necrotize and migrate, resulting in fis-
tula formation and, ultimately death [158, 161, 162]. Although the
pathogenesis is unknown, some studies discuss latent EBV infection
as a possible cause. On histology, Tcell and NK markers (CD2 and
CD56, respectively), are positive (Figure 18). Cytoplasmic CD3
markers are also positive. There are rare cases highlighting CD56
negative markers in the setting of EBV. Nonspecific superficial or
deep lymphocytic infiltrates with angiodestruction are seen [141,
158]. Chemotherapy, radiotherapy, or a combination of both have
FIGURE 13 Varied histological features of folliculotropic mycosis fungoides (FMF). (a, b) Massive infiltration of atypical T cells around a
hair follicle. Source: Mantaka, P., et al., Clinical and histopathological features of folliculotropic mycosis fungoides: a Norwegian patient series.
Acta Derm Venereol, 2013. 93(3): p. 325–9. Reprinted with permission under CC license CCBYNC.
FIGURE 14 A 4year old boy with primary cutaneous anaplastic large cell lymphoma on the nasal tip. (a) Lesion located on the nasal tip
with necrotic tissue and erythematous borders (b) spontaneous resolution after 4 months. Source: SantiagoetSánchezMateos, D., et al.,
Primary cutaneous anaplastic large cell lymphoma of the nasal tip in a child. Pediatr Dermatol, 2011.28 (5): p.570–5. Reprinted with
permission under CC license CCBY.
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been reported; however, there are no guidelines given the rarity of
the disease. Radiotherapy is the firstline treatment; however, mon-
otherapy has been noted to result in relapse [164].
Primary cutaneous acral CD8þT cell lymphoma
Primary cutaneous acral CD8 positive Tcell lymphoma is a rare
entity of Tcell lymphoma seen in adults over 50 years of age. Most
commonly, it presents as a growing solitary nodule. However, it can
also present as multiple papules or nodules (Figure 19) [165, 166].
Histologically, diffuse dermal and subcuticular infiltration of medium
CD8þT cells with blastlike nuclei, are noted. There is a grenz zone
with no epidermotropism; irregular neoplastic cells; and CD3, CD8,
and Tcell intracytoplasmic antigen1 positive lymphoid cells. Wob-
ster et al. noted dotlike features surrounding the nucleus in five cases
and concluded that CD68 markers may help distinguish between T
cell lymphomas [165, 166]. Topical steroids have successfully
treated primary cutaneous acral CD8þTcell lymphoma with some
cases of relapse. Surgical excision and radiotherapy have also been
successful (Figure 20) [165].
B cell lymphoma
CBCL can be primary or secondary to extracutaneous Bcell lym-
phoma. Primary cutaneous Bcell lymphoma accounts for up to 25%
of cutaneous lymphomas. Nasal involvement has been documented in
several types of cutaneous Bcell lymphomas. Lowgrade lymphoma
patients are closely monitored every 6 months for lesion growth or
new developments. Antibiotics have also been used, especially in
Primary cutaneous marginal zone Bcell lymphoma (PCMZBCL), as it
has been linked to Borrelia. Solitary lesions can be surgically excised,
and local radiotherapy is an effective treatment for solitary or mul-
tiple lesions, with a low recurrence rate. Intralesional interferon
alpha2a has a 50% complete response rate. Rituximab, an anti
CD20 monoclonal antibody, has helped with tumor reduction, and
there has been success with the combination of chemotherapy for
highgrade lymphomas [167].
Primary cutaneous follicle center lymphoma
Primary cutaneous follicle center lymphoma (PCFCL) is the most
common type of CBCL, representing about 55% of all cutaneous B
cell lymphomas [168]. Typically, patients present with localized
papules, plaques, or nodules, which can increase in size and number
(Figure 21). These rarely become extracutaneous. Lymph node or
internal organ involvement is seen in only 5% of cases and generally
FIGURE 15 (a, b) A 36 yearold female with a firm shiny 1.5 cm nodule on the left nasal ala which had grown progressively for 1.5 months.
Immunohistochemistry panel and histopathological examination demonstrated primary cutaneous CD4þsmall/medium Tcell
lymphoproliferative disorder. Source: Valentim, F.O., C.C. Oliveira, and H.A. Miot, Case for diagnosis. Primary cutaneous CD4+small/medium
Tcell lymphoproliferative disorder. An Bras Dermatol, 2019. 94(1): p.99–101. Reprinted with permission under CC license CCBY.
FIGURE 16 Histology of the lesion. (a) Dense lymphocytic
infiltrate of the dermis (Hematoxylin & eosin, x50). (b) The nuclear
pattern of the lymphocytes: small to mediumsized nuclei with
predominantly regular karyotheca, hyperchromasia and
perivascular and periadnexal arrangement (Hematoxylin & eosin,
x400). Source: Valentim, F.O., C.C. Oliveira, and H.A. Miot, Case for
diagnosis. Primary cutaneous CD4+small/medium Tcell
lymphoproliferative disorder. An Bras Dermatol, 2019. 94(1):
p.99–101. Reprinted with permission under CC license CCBY.
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indicates a worse prognosis. Cutaneouslimited PCFCL has a 95%–
100% 5year survival rate [167, 168]. PCFCL is commonly seen on
the scalp and forehead, although Wanczinsnki et al. reported a case
on the nose [168]. Diagnosis, as in all lymphoma cases, is made via
biopsy. Histologically, there is nonspecific infiltrates throughout the
dermis with very few cases revealing germinal center structures. B
cell markers CD20 and CD79a, monotypic immunoglobins (kappa
or lambda), and Bcl16 are generally positive while Bcl2 is generally
negative (Figure 22) [168].
Primary cutaneous marginal zone Bcell lymphoma
PCMZBCL is the second most common BCL and can present as a
solitary, red, violaceous plaque or multiple subcutaneous nodules. It
demonstrates a female predominance (Figures 23, 24). PCMZBCL
typically has an indolent course with local recurrence, but rare cases
FIGURE 17 (a) Welldefined, infiltrated reddish plaques
affecting the right cheek and lower eyelid of the right eye, causing
partial occlusion of the eye. (b) Infiltrated erythematous plaques on
the tip of the nose and border of the right nares (arrows). Source:
SánchezRomero, C., et al., Extranodal NK/T cell lymphoma, nasal
type: An updated overview. Crit Rev Oncol Hematol, 2021.159:
p. 103237. Reprinted with permission under CC license CCBY
NCND.
FIGURE 18 (a) Dense lymphocytic infiltrate with a perivascular distribution in the mid and deep dermis, extending partially toward the
epidermis and hair follicles. Edematous superficial dermis. Hyperplastic epidermis with preserved architecture and maturation. Hematoxylin
and eosin, original magnification 100. (b) Population of lymphocytes with scant, pale eosinophilic cytoplasm and atypical nuclei with
clumped chromatin and irregular borders. Hematoxylin and eosin, original magnification 400). Source: SánchezRomero, C., et al., Extranodal
NK/T cell lymphoma, nasal type: An updated overview. Crit Rev Oncol Hematol, 2021.159: p. 103237. Reprinted with permission under CC
license CCBYNCND [163].
FIGURE 19 A 69yearold man with a history of relapsing
nodules on ears, thighs, buttocks, feet, and nasal lesion with
involvement of bony nasal septum. Histopathology studies showed
“primary cutaneous acral CD8 positive Tcell lymphoma at the
dorsum of the nose”. Source: AlbertiVioletti, S., et al., Primary
cutaneous acral CD8 positive Tcell lymphoma with extra
cutaneous involvement: A longstanding case with an unexpected
progression. J Cutan Pathol, 2017. 44(11): p. 964–968. Reprinted
with permission under CC-BY license.
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of systemic spreading have been reported [169, 170]. PCMZBCL may
be correlated with Borrelia infection [167]. Although typically seen on
the upper trunk and extremities, nasal skin and mucosal involvement
have been documented [171]. Regression in localized PCMSBCL can
be achieved by antibiotic therapy, although surgical excision and local
radiotherapy is the mainstay of treatment in solitary localized lesions.
Recurrent lesions can be treated with rituximab, interferon, chemo-
therapy, and corticosteroids [172].
Primary cutaneous diffuse large Bcell lymphomaleg
type
PCDLBCLLT is a rare form of CBCL (Figure 25) with a poor prog-
nosis and typically presents with lower extremity violaceous plaques
and nodules in the elderly. However, 2.5%–8.6% of cases involve the
head and neck. The periorbital region is the most common facial area
where PCDLBCLLT is found [173, 174]. However, Bostan and col-
leagues reported a rare case where a patient had secondary nasal
involvement [173]. The 5year survival rate is approximately 50%. A
combination of rituximab and polychemotherapy has been reported
to improve the survival rate. Radiotherapy for localized lesions has
also been used [174].
INFECTIOUS DISORDERS
Blastomycosis
Blastomycosis is a systemic granulomatous disease endemic to North
American regions close to the Mississippi and Ohio River basins,
Great Lakes, and St. Lawrence River (Figure 26). It is caused by
blastomyces dermatitidis and blastomyces gilchristii [175, 176].
In North America, the annual incidence of blastomycosis ranges
from 0.2 to 1.94 cases per 100,000 people [177]. Cutaneous blas-
tomycosis manifestations are common, representing 40%–80% of
the cases [175]. Although primary nasal cutaneous blastomycosis is
rare, Aleksandra, et al. described this presentation in an immuno-
competent patient from a nonendemic area [178]. Clinically, blasto-
mycosis is heterogeneous and can be classified as pulmonary
blastomycosis or extrapulmonary/disseminated blastomycosis.
Extrapulmonary blastomycosis is characterized by cutaneous mani-
festations that begin as papulopustular lesions that progress to
ulcerative, verrucous, or crusted lesions. This can lead to disfigure-
ment, necrosis, and permanent scarring. These lesions can occur
anywhere in the body, predominantly in sunexposed areas [177].
Histopathological examination shows pseudoepitheliomatous hy-
perplasia with neutrophilic abscesses. Organisms are found within
histiocytes or abscesses in the dermis (Figure 26b). Blastomyces is not
well visualized with Gram or hematoxylin and eosin stains; however,
sputum or tissue samples stained with other preparations such as 10%
potassium hydroxide, Gomori methenamine silver, or periodic acid–
Schiff can facilitate visualization of the characteristic yeast forms (8–
20 mm). Blastomyces show broadbased budding and a doubly
refractile cell wall. Definitive diagnosis is made by cultures [177, 179].
Antifungal treatment is recommended for all patients diagnosed
with blastomycosis and is based on the site infection, severity, host
FIGURE 20 (a, b) Histological features of ear nodule: (a) lymphoid infiltrate in the subcutis and dermis with a Grenz zone. [Hematoxylin
and eosin (H&E), 4X] (b) infiltration of large lymphocytes with a blastlike appearance, hyperchromatic nuclei, and abundant clear cytoplasm.
(H&E, 20X). Source: AlbertiVioletti, S., et al., Primary cutaneous acral CD8 positive Tcell lymphoma with extracutaneous involvement: A long
standing case with an unexpected progression. J Cutan Pathol, 2017. 44(11): p. 964–968. Reprinted with permission under CC-BY license.
FIGURE 21 A case of 65yearold man with an asymptomatic,
1.2 cm, erythematous nodular lesion on the left nasal ala for eight
months that was simulating basal cell carcinoma, diagnosed with
primary cutaneous follicle center lymphoma. Source: Wanczinsnki,
M.I., et al., Primary cutaneous follicle center lymphoma simulating
basalcell carcinoma on the nasal ala. An Bras Dermatol, 2015. 90(3
Suppl 1): p. 111–4. Reprinted with permission under CC-BY license.
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immune status, and pregnancy status. Itraconazole is the firstline
agent for primary cutaneous blastomycosis [178]. Polyene ampho-
tericin B (AmB) formulations are recommended for the treatment of
patients with severe pulmonary infection, disseminated disease, and
central nervous system involvement [177].
Primary nasal tuberculosis
Nasal tuberculosis (TB) is a rare disease with fewer than 100 cases
reported, mainly in women between 20 and 84 years of age [180].
Tuberculous involvement of the nose, nasopharynx, and paranasal
sinus is extremely rare, even in countries with a high incidence of
pulmonary TB. Nasal and sinus tuberculosis remains asymptomatic
until an advanced stage [181].
The initial symptoms of nasal tuberculosis include nasal
obstruction associated with mucoid or mucopurulent rhinorrhea and
postnasal drip [182]. Epistaxis, nasal discharge, incrustation, recur-
rent nasal polyps, and ulcers have also been described. The lesions
can be ulcerative, infiltrative, or proliferative and, in most cases, are
unilateral. Nodules on anatrophicor cicatriceformed lesions are
characteristic of nasal tuberculosis [181].
FIGURE 22 Immunohistochemistry of the lesion 40X: (a) Bcells with strongly positive immunohistochemical staining for CD20 in
cytoplasm. Respectively germinal center cells with positive CD 10 (b), Bcl6 (c), and negative Bcl2 (d). Source: Wanczinsnki, M.I., et al., Primary
cutaneous follicle center lymphoma simulating basalcell carcinoma on the nasal ala. An Bras Dermatol, 2015. 90(3 Suppl 1): p. 111–4.
Reprinted with permission under CC license CCBY license.
FIGURE 23 (a) A case of 80yearold women with a painless, 2 cm plaque on the tip or the nose since 7 months ago diagnosed with
Primary Cutaneous Marginal Zone Bcell Lymphoma. Figure 20. (b) Same patient after treatment with interferon2a for 3 months. Source:
Rosmaninho, A., et al., Red nose: primary cutaneous marginal zone Bcell lymphoma. Leuk Res, 2010. 34(5): p. 682–4. Reprinted with
permission under license number 5407980993487.
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FIGURE 24 Immunohistochemical staining of the lesion was remarkable for lymphocytic infiltrates with CD20þ, Bcl2þ, CD3, CD10,
and CD5.Source: Rosmaninho, A., et al., Red nose: primary cutaneous marginal zone Bcell lymphoma. Leuk Res, 2010. 34(5): p. 682–4.
Reprinted with permission under license number 5407980993487.
A definitive diagnosis can be made by biopsy (the sample should
be sent in formalin 10%) and isolation of the tubercle bacillus from
surgically excised tissue. Microscopy shows ulceration of the mucosa,
with multiple coalescing granulomas of epithelioid cells with Lan-
ghans giant cells [181].
Nasal tuberculosis is known to respond well to the classic
treatment for tuberculosis: a 6–9 months antibiotic regimen
FIGURE 25 A 65yearold woman with an erythematous rash
on the left nasolabial fold, nose and left cheek since 4 moths ago first
was misdiagnosed with erysipelas. The rash eventually disseminated
on the trunk, and lower extremity. Source: TeresiakMikołajczak, E.,
M. Szymańska, and M. CzarneckaOperacz, A case of diffuse large B
cell lymphoma misdiagnosed as an erysipelas of the face. Postepy
Dermatol Alergol, 2013. 30(4): p. 268–70). Reprinted with
permission under creative common license CCBYNCSA.
FIGURE 26 (a) Blastomycosis presented as a nodule, measuring
1.5 cm in diameter, involving multiple nasal subsites including right
nasal ala and soft tissue triangle. (b): A periodic acidSchiffstained
specimen from the nasal biopsy showed a (b) dermatitidis yeast cell
(arrow). Source: Abdalla, M., et al., clinical problemsolving. On the
Nose. N Engl J Med, 2015. 373(10): p. 955–61. Reprinted with
permission under license number5376080099549.
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(2 months INH, RIF, PZA, and EMB followed by 4–7 months of INH
and RIF). This regimen is effective except in regions where multidrug
resistant tuberculosis is prevalent [183].
Herpes vegetans
Herpes vegetans (HV) is an atypical and rare cutaneous herpes simplex
virus infection that can be caused by HSV1 and HSV2 (Figure 27a).
HV is commonly described in patients with acquired immune deficiency
syndrome, common variable immunodeficiency, leukemia, or other
immunodeficiency syndromes [184]. The majority of lesions develop on
the face, genitals, and occasionally leukemiaaffected skin [185, 186].
HV can present clinically as a rapidly growing cutaneous, verrucous,
ulcerative, exudative mass. Diagnosis relies upon tissue biopsy and
direct immunofluorescence [187]. Firstline treatments include
acyclovir or valacyclovir; however, resistance to acyclovir is common
[188, 189]. In these cases, alternative antivirals, including foscarnet,
intralesional cidofovir, and topical imiquimod can be used (Figure 27b)
[190]. Recurrence of HV is common in patients with HIV [191].
Rhinoscleroma
Rhinoescleroma (RS) is a rare, chronic granulomatous infectious
disease caused by Klebsiella rhinoscleromatis (KR), a subspecies of
Klebsiella pneumoniae. KR is an immotile Gramnegative coccoba-
cillus that is spread by contaminated droplets. RS involves the upper
respiratory tract and almost always the nose [47]. RS usually presents
in the second and third decades of life, with a female predominance
[192]. RS is an endemic disease in Egypt and sporadically in Central
America, Chile, Central Africa, India, and Indonesia. Poor hygiene and
nutritional deficiencies can promote RS infection. Cases in the USA
are usually reported among immigrants [193]. It has three clinically
overlapping stages: (1) an atrophic stage with atrophy of nasal mu-
cosa and mucopurulent nasal discharge, (2) a granulomatous stage
with an indurated granulomatous mass, and (3) a fibrotic stage with
nasal deformity and stenosis (Figure 28) [193].
Histologic changes are only seen in the granulomatous stage,
which reveals dense infiltration by lymphocytes, plasma cells, Russell
bodies (dilated endoplasmic reticulum cisternae within plasma cells),
and pathognomonic Mikulicz cells (large histiocyte containing
FIGURE 27 (a) A case of 18yearold female with common variable immune deficiency presents due to a monthlong history of yellow
brown progressive, painful, vegetative plaques and facial lesions involving bilateral nares, cheek, and right oral commissure diagnosed with
herpes vegetans (b) the Same patient after 10day treatment with foscarnet. Source: Parsons, K., et al., Severe Facial Herpes Vegetans and
Viremia in NFKB2Deficient Common Variable Immunodeficiency. Front Pediatr, 2019. 7: p. 61. Reprinted with permission under CCBY
license.
FIGURE 28 (a–c): A 63yearold man with bilateral nostril obliteration, palate infiltration, and loss of upper teeth (Panel a).
Histopathological examination revealed foamy macrophages (Mikulicz's cells; Panel b, yellow arrow; hematoxylin and eosin) with
intracytoplasmic bacilli plasma cells with Russell bodies (green arrow). Culture of tissue fragments showed the presence of klebsiella. Panel c
shows intracellular Klebsiella rhinoscleromatis (black arrow; Warthin–Starry stain), but no cellular forms are clearly shown; the inset shows
the area of interest on a larger scale [194]. Source: Castanedo Cázares, J.P. and K.I. Martinez Rosales, Rhinoscleroma. 2015. 372(25): p. e33).
Reprinted with permission under license 5375970512718.
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EYE & ENT RESEARCH
organisms) (Figure 26b) [192]. Giemsa stains are also sent for iden-
tification of KR [195]. There is no consensus on the treatment of RS
[196]. Some reports suggest tetracycline with surgical correction of
obstructed airways as firstline therapy [47]. However, recent studies
showed that ciprofloxacin ointment for 12–24 weeks on lesions
limited to the nasal cavity demonstrated a 100% clinical and bacte-
riological cure rate [192, 197].
Leishmaniasis
Leishmaniasis is a parasitic infection caused by intracellular pro-
tozoans of the Leishmania genus. [198] Leishmaniasis can be trans-
mitted by sandfly bites or contaminated needles. As per WHO
classification, there are three forms of leishmaniasis: cutaneous,
mucocutaneous, and visceral [199]. Cutaneous leishmaniasis (CL) is
the most common form.
Globally, there are 700,000–1.2 million new CL cases per year
[200]. Although CL is found in more than 90 countries, more than 90%
of cases occur in the Middle East and South America [201]. CL is
characterized by two geographical subsets. The first subset is old
world CL, usually observed in the Middle East with infection by L.ma-
jor or L.tropica. The second subset is newworld CL, generally found in
Brazil, Peru, and Bolivia with infection by L.Braziliensis or Mexicana
[198]. Almost all CL cases in the USA were acquired from travelers to
countries such as Costa Rica or military personnel returning from Iraq
or Afghanistan [200]. Other cases in the USA are found in endemic
areas such as southcentral Texas and perhaps Oklahoma [198].
CL clinical manifestations and prognosis depends on the patient's
immune status and Leishmania species [198]. The lesion generally
presents as a solitary ulcer on exposed areas, such as the head, neck,
and extremities (Figure 29a) [198]. Usually, the inoculation site
changes to a small, wellcircumscribed papule. Within weeks, it turns
into a plaque or nodule. However, a sand fly bite may go unnoticed,
and CL may develop months after the bite. Some forms may not be
noticed for years; others, such as verrucous ulcerated lesions, may be
mistaken for BCC [198].
The face is the most common site of involvement in CL (39% of
lesions) [203]. The most common diagnostic study of CL is micro-
scopic examination [204]. In half of the skin biopsies from the edge of
new ulcers, amastigotes have been observed, especially inside mac-
rophages in the papillary dermis [198]. Immunostaining with CD1a is
also helpful in detecting amastigotes. Intradermal injection of leish-
manial antigen (Montenegro skin test) can induce cellmediated
response and has high sensitivity and specificity. However, it
cannot distinguish between previous or new infections [204]. The
PCRbased method has the highest specificity and sensitivity [198].
At least three samples from the active border of the lesion
should be sent: one sterile sample for culture and PCR (buffered
medium, for example, buffered saline, RPMI, Eagle's growth,
Schneider's, or Tobie's), one for impressions smear within CDC
guidelines, and one for the histologic exam (fixed in 10% formalin,
embedded in paraffin). It is preferable to use 70% alcohol because
iodine could inhibit parasite growth in culture [200].
Treatment of cutaneous leishmaniosis depends on species,
geographical region, and severity. The WHO recommends pentava-
lent antimonial drugs such as sodium stibogluconate or meglumine
antimonate for 3–4 weeks [204]. Other options such as miltefosine,
AmB, allopurinol, cryotherapy, and heat therapy are also
mentioned [201].
INFLAMMATORY DISORDERS
Granuloma faciale
Wigley first described “Eosinophilic granuloma” in 1945, now known
as Granuloma faciale (GF). [205]. GF is part of the eosinophil
associated dermatoses, a wide range of diseases characterized by
eosinophil granules in the skin or mucosa. GF is a rare and benign
skin condition without a wellunderstood etiology. It typically pre-
sents as a welldemarcated, solitary, asymptomatic, redbrown
DERMAL plaque on the face, forehead, or preauricular area
(Figure 30). However, nearly 33% of cases may present with multiple
FIGURE 29 (a, b) A 25yearold man presented to our clinic with a 1year history of skin lesions on his nose and arm. Physical
examination was notable for painless erythematous papules and nodules with overlying scale and crust, some of which had central ulceration
[202]. Source: Malekpour, M. and M. Esfandbod, Cutaneous Leishmaniasis. 2010. 362(6): p. e15. Reprinted with permission under license
number 5376071492536.
EYE & ENT RESEARCH
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83
lesions [206]. GF is not associated with underlying systemic diseases
[207–210], and is most common in Caucasian men between the
second and seventh decades of life [2, 3].
Biopsy and histopathology studies diagnose GF (Figure 31) [211].
GF's precise pathogenesis is not well understood; however, granular
deposition of IgG, IgM, and IgA in direct immunofluorescence mi-
croscopy of blood vessel walls suggests that immune complexes play
a role [211]. Focal vasculitis with dense dermal infiltrates of inflam-
matory cells and eosinophils that spare the papillary dermis (Grenz
zone) has been reported. Local increases in IL5 and IgG4positive
plasma cells have led some authors to consider GF an IgG4related
disorder [212].
Firstline treatment includes intralesional triamcinolone sus-
pension injection and pulsed dye laser [206, 211]. However, GF
frequently is unresponsive to therapy. Other treatments, such as oral
or topical dapsone, oral clofazimine, psoralen plus ultraviolet A
(PUVA), calcineurin inhibitors (tacrolimus), and prednisone have been
mentioned [206, 211]. Some suggest excision of the lesion with
surgery or cryosurgery; however, this yields poor cosmetic results
and an increased recurrence [213].
Jessner lymphatic infiltration
Jessner lymphatic infiltration (JLI), or benign chronic Tcell infiltrative
disease, is a rare cutaneous skin condition affecting sunexposed areas
such as the face and neck of an individual, between 30 and 50 years of
age [214, 215]. Although the etiology is unknown, JLI could be an early
manifestation of cutaneous systemic lupus erythematosus.
It is characterized by an asymptomatic single or multiple well
demarcated erythematous plaques with resolve spontaneously after
a few months. Lesions are photosensitive and have similarities with
cutaneous lupus erythematosus [214, 216]. Histopathology is
remarkable for a dense perivascular CD8þT cell lymphocytic infil-
trate and clusters of plasmacytoid dendritic cells with no epidermal
changes (Figure 32) [217]. Firstline therapy is steroids (topical or
intralesional). Tacrolimus, thalidomide, and methotrexate have been
used in some case reports [215].
Lupus pernio
Lupus pernio (LP) is a rare cutaneous manifestation of sarcoidosis,
starting insidiously with a shiny nodule, violaceous lesion, or
erythematous plaque on the central face, usually involving the nose
FIGURE 30 Granuloma faciale: (a) sharply bordered (3 2.5 cm), erythemolivid plaque over the back and the tip of the nose; (b) orange
peel surface markings and prominent telangiectasia; (c) in the center of the lesion there is an atrophic cicatrix on the site of the biopsy. Source:
Damevska, K., Granuloma Faciale A Difficult Diagnosis? A Case Report Nikolovska, Suzana/Gocev, Đorđi/Damevska, Katerina. 2013. Reprinted
with permission under CC license CC BYNCND.
FIGURE 31 Histopathological presentation of granuloma
faciale: dense, mixed inflammatory infiltrate composed of numerous
eosinophils, neutrophils, lymphocytes, hystiocites, and plasma cells.
(H&E, x100). Source: Damevska, K., Granuloma Faciale A Difficult
Diagnosis? A Case Report Nikolovska, Suzana/Gocev, Đorđi/
Damevska, Katerina. 2013. Reprinted with permission under CC
license of CCBYNCND.
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(Figure 33). LP is more common in AfricanAmerican females aged
25–40 [218, 219].
LP can be an early manifestation of sarcoidosis and correlated with
a higher chance of pulmonary involvement [220]. Although the etiol-
ogy of LP is unclear, environmental exposures and some microorgan-
isms such as mycobacteria have been mentioned [219].
The histopathologic hallmark of LP is the presence of non
caseating epithelioid cells and granulomas with various Langerhans
giant cells [221].
The lesion is hard to treat and surgical excision is not recom-
mended [222]. Topical or intralesional corticosteroids (triamcinolone)
is the first line of treatment. Hydroxychloroquine, methotrexate, and
thalidomide have been used also. Infliximab has a better effect than
systemic steroids for resistant lesions [223].
CONCLUSION
Treatment of cutaneous lesions starts with an accurate diagnosis;
however, using an outline as described can help physicians generate a
clear differential.
AUTHOR CONTRIBUTIONS
Hamed Sarikhani: Conceptualization (equal); data curation (equal);
formal analysis (equal); funding acquisition (equal); investigation
(equal); methodology (equal); project administration (equal); re-
sources (equal); software (equal); supervision (equal); validation
(equal); visualization (equal); writing original draft (equal); writing
review & editing (equal). Karena Zhao: Conceptualization (equal);
data curation (equal); formal analysis (equal); funding acquisition
(equal); investigation (equal); methodology (equal); project adminis-
tration (equal); resources (equal); software (equal); supervision
(equal); validation (equal); visualization (equal); writing original
draft (equal); writing review & editing (equal). Marc Polacco:
Conceptualization (equal); data curation (equal); formal analysis
(equal); funding acquisition (equal); investigation (equal); methodol-
ogy (equal); project administration (equal); resources (equal); soft-
ware (equal); supervision (equal); validation (equal); visualization
(equal); writing original draft (equal); writing review & editing
(equal). Charles Gropper: Conceptualization (equal); data curation
(equal); formal analysis (equal); funding acquisition (equal); investi-
gation (equal); methodology (equal); project administration (equal);
resources (equal); software (equal); supervision (equal); validation
(equal); visualization (equal); writing original draft (equal); writing
review & editing (equal). Samuel N. Helman: Conceptualization
(equal); data curation (equal); formal analysis (equal); funding acqui-
sition (equal); investigation (equal); methodology (equal); project
administration (equal); resources (equal); software (equal); supervi-
sion (equal); validation (equal); visualization (equal); writing original
draft (equal); writing review & editing (equal).
ACKNOWLEDGMENTS
Authors wish to thank various people for their contributions to re-
view this article; Dr. Marjorie Mailing Flores Chang and Dr.Katerina
Warda to help in reviewing the article, and Dr. Ashley Keyes for
providing select clinical pictures. The authors received no financial
support for the research, authorship, or publication of this article.
This research did not receive any specific grant from funding agencies
in the public, commercial, or notforprofit sectors.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
CONSENT
All the figures used in this review article are permitted under creative
common license or documented permission from the publisher.
Informed consent was obtained from other patients.
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