REVIEWS

Primary mucosal melanoma

Ronald J. Patrick, MD, Neil A. Fenske, MD, and Jane L. Messina, MD
Tampa, Florida
Primary mucosal melanomas are rare, biologically aggressive neoplasms. The distribution of head and
neck, female genital tract, anal/rectal, and urinary tract sites is 55.4%, 18.0%, 23.8%, and 2.8%, respectively.
The median age at presentation is the seventh decade, and women are given the diagnosis more frequently
than men. Unfortunately, most afflicted individuals harbor micrometastatic disease and experience a course
characterized by multiple local recurrences before the clinical development of distant disease. Approximately a third of patients have nodal involvement at presentation, and the overall 5-year survival is only
25%. Despite aggressive surgical resection and a multitude of adjuvant treatments, the prognosis remains
grave. Early detection, which is difficult because of the occult anatomic locations in which these tumors
occur, allows the best hope for cure. ( J Am Acad Dermatol 2007;56:828-34.)

rimary mucosal melanoma is an exceedingly

rare neoplasm. As a result, there is a paucity of
data elucidating its etiopathogenesis and predictive factors. Overall, primary mucosal melanomas
behave more aggressively and have a poorer prognosis than their cutaneous counterparts. Because of
the unusual anatomic locations in which they occur
and the lack of early presenting signs and symptoms,
mucosal melanomas are virtually always diagnosed
at advanced stages.
This article will detail the key pathogenic and
diagnostic features of this vexing disease. Special
emphasis will be placed on the presentation, diagnosis, and treatment of tumors from the head and
neck, female genital tract, and anorectum.

EPIDEMIOLOGY
Mucosal melanoma remains a rare disease, accounting for 0.03% of all new cancer diagnoses.
According to the National Cancer Data Base Report
on Cutaneous and Noncutaneous Melanoma, cutaneous melanoma comprises 91.2% of all melanoma,
whereas ocular, mucosal, and unknown primaries
account for 5.2%, 1.3%, and 2.2% of cases, respectively. Mucosal melanoma is most common in the

From the Department of Dermatology, University of South Florida

College of Medicine.
Funding sources: None.
Conflicts of interest: None declared.
Reprint requests: Jane L. Messina, MD, University of South Florida
College of Medicine, 12901 Bruce B. Downs Blvd, MDC 79,
Tampa, FL 33612. E-mail: jmessina@hsc.usf.edu.
Published online March 15, 2007.
0190-9622/$32.00
2007 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2006.06.017

828

head and neck (55.4% of cases), with female genital

tract, anal/rectal, and urinary tract sites responsible
for 18.0%, 23.8%, and 2.8% of cases, respectively.1
Unlike the dramatically increasing incidence of
cutaneous melanoma, the incidence of mucosal
melanoma has remained relatively stable.2 Because
of lesions arising in the female genital tract, it is
found more frequently in women (65%). However, a
slight male predominance exists among oral cavity
and sinonasal lesions. The peak age for diagnosis of
mucosal melanoma is between 70 and 79 years, on
average one to two decades later than cutaneous
melanoma. Overall, the incidence of mucosal melanoma is similar among African Americans, Asians,
and Caucasians.1 Reports of skewing toward African
Americans and Asians are most likely secondary to
the markedly lower incidence of cutaneous melanoma in these racial groups.

PATHOGENESIS
The etiopathogenesis of mucosal melanomas is
not yet fully elucidated. As neuroectodermal derivatives, melanocytes are known to migrate to the skin,
retina, uveal tract, and other ectodermally derived
mucosa. Melanocytes migrate much less frequently
to endodermally derived mucosa, such as the
nasopharynx, larynx, tracheobronchial tree, and
esophagus.3 This explains the lower frequency
of melanoma in these locations.
Although their function is not fully understood,
the presence of melanocytes in the mucous membranes is well established. Several investigators have
quantified the density of melanocytes specific to
certain mucosal epithelia. For example, the density
of melanocytes in the nasal and oral mucosa is
1500/mm2 (compared with 800/mm2 on the abdomen and 2380/mm2 on the skin of the penis).4,5

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Furthermore, there is a marked variation in the

numbers of dopa-positive melanocytes on the gingival epithelia in adults.6 Melanocytes have also been
documented in the deep stroma of the nasal cavity
(including the nasal septum and middle and lower
turbinates), respiratory mucosa, mucous glands,
esophagus, small bowel, and urogenital tract.7
Because mucosal melanomas are frequently
found at mucocutaneous junctions, they were once
believed to arise only as extensions of melanocytic
hyperplasia from adjacent skin. Indeed, some mucosal melanomas do evolve in this manner. However,
there are now several cases describing primary melanocytic junctional activity solely within the mucosal
epithelium.8

DIAGNOSIS
Differentiating a primary mucosal melanoma from
a metastasis of an unknown or regressed cutaneous
tumor can be diagnostically challenging. Reliable
clinical findings include the presence of a precursor
lesion such as melanoma in situ in the mucosa.8
Unfortunately, these features are typically absent,
given the delayed diagnosis and presence of secondary changes such as ulceration. When biopsying
these lesions for pathologic diagnosis, it is imperative to include a rim of normal-appearing tissue,
which may harbor the precursor lesion. Contributing
to the diagnostic dilemma is the frequent lack of
melanin pigmentation in these tumors (amelanotic
melanoma), which clinically may resemble lymphoma or angiosarcoma.
Histologically, primary lesions are characterized
by nested and single growth of atypical melanocytes in the surrounding mucosa. Similar to the
methods used for cutaneous melanoma, immunohistochemical stains, such as S-100, HMB-45, MelanA, and Mart-1, can aid in the diagnosis of these
tumors. Other histopathologic features of mucosal
melanomas include frequent angioinvasion and
multicentricity.9,10 These findings are important
factors in the aggressive behavior, early metastatic
spread, and local control failure characteristic of
mucosal melanoma.11
In a recent study by Curtin et al12 using DNA for
comparative genomic hybridization, distinct sets
of genetic alterations were identified in different
subtypes of melanoma. Whereas melanomas arising
on skin without chronic sun damage had frequent
mutations in BRAF, those mutations were much less
common in melanomas occurring on acral skin,
mucosal surfaces, and chronically sun-damaged
skin. These findings suggest differing routes by
which these tumors develop, which may ultimately
impact response to treatment.

STAGING
In general, the growth of mucosal melanoma
closely resembles the nodular pattern of its cutaneous counterpart. This characteristic, in part, explains
the poor prognosis of these lesions, and several
studies have corroborating data that link survival
most closely with tumor thickness. Patients with
lesions less than 2-mm thick have a significant
survival advantage over those with lesions greater
that 2 mm.13 Because of the typical delay in diagnosis, the vast majority of mucosal melanomas
present to clinicians as large, polypoid tumors
with nodal involvement. Because of this advanced
presentation, Breslow depth alone is of little use in
the staging of the majority of primary mucosal
melanomas. With this in mind, most authors advocate continued use of the clinical staging system
developed for cutaneous melanoma, where stage I
is clinically localized disease, stage II is regional
lymph node disease, and stage III is disseminated
disease.
Most patients with mucosal melanomas present
with clinically localized disease.1,8,9,11,14,15 However,
despite garnering local control surgically, 5-year
survivors are rare. The rich vascular and lymphatic
submucosal network contributes greatly to the early
development of metastases in mucosal melanomas.
As such, local recurrence usually does not occur in
isolation, but rather represents a marker for distant
disease.8,15-17 A more thorough understanding of
the prognostic factors involved is needed so that
a comprehensive, uniform staging system can be
developed.

DIAGNOSTIC WORKUP
When a mucosal melanoma is diagnosed,
there is frequently debate among clinicians concerning the extent of workup necessary to exclude
metastatic melanoma, either as the source of the
mucosal lesion or from the mucosal primary itself.
Certainly, when a mucosal melanoma is detected,
a total body skin examination is paramount to
rule out a primary cutaneous melanoma that has
metastasized. To evaluate the primary site, a computed axial tomography scan or magnetic resonance image may help determine the extent of
involvement around various anatomic structures.
Given the propensity for mucosal melanoma to disseminate and to exclude metastatic melanoma from
a cutaneous primary, a basic metastatic workup
should be considered. This workup includes serum
lactate dehydrogenase, chest radiograph, and combined positron emission tomography/computed
tomography scanning of the chest, abdomen, and
pelvis.

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SUBTYPES OF MUCOSAL MELANOMA

Head and neck
Primary mucosal melanomas of the head and
neck comprise 55% of all mucosal melanomas.1
These tumors arise most frequently in the nasal
cavity (55% of reported cases), followed by the oral
cavity (40%).9,15 As with most mucosal melanomas,
those in the sinonasal region typically affect the
elderly, with a mean age of onset of 70 years. Oral
melanomas, on the other hand, tend to occur at a
younger age than their sinonasal counterparts, with
most afflicted individuals younger than 40 years.18
The youngest case reported to date involved an
8-month-old African American girl with sinonasal
melanoma.19 A slight male preponderance exists in
both oral cavity and sinonasal mucosal melanomas.9,15
In the oral cavity, the hard palate and maxillary
alveolus are the predominant sites of involvement.9,15 Patients may have a friable pigmented
lesion, ill-fitting dentures, ulceration, or bleeding.
In addition, many of these lesions are incidentally
discovered during routine oral or dental examinations. Unfortunately, the vast majority of patients lack
early symptoms, and the average time from the
appearance of symptoms to evaluation by a health
care professional is 9 months. Contributing to this
delay in diagnosis, approximately a third of oral
melanomas are amelanotic.20 As a direct result of
these obstacles, most mucosal melanomas of the
oral cavity are diagnosed at an advanced stage,
with a Breslow depth greater than 4 mm on
presentation.15,21,22
There appears to be a racial discrepancy in the
incidence of oral melanomas. Among the Japanese,
oral mucosal melanoma accounts for 7.5% of all
melanomas, versus less than 1% for Caucasians.18,23
This difference has led many investigators to speculate the role of hereditary or environmental influences. Given the disproportionately low incidence
of cutaneous melanomas among African Americans
and Asians, the data pertaining to the incidence of
oral melanomas in these groups are difficult to
interpret. A study involving Ugandan Africans revealed a disproportionately high incidence of oral
mucosal melanomas,24 whereas similar reports of
African Americans and Asians showed an incidence
comparable with that of Caucasians.1,3
Several case series have demonstrated that up to a
third of oral melanomas are preceded by melanosis, which is postulated to represent the radial
growth phase occurring before the development
of vertical growth.18,25,26 Whether a survival advantage exists in cases with preceding melanosis is
debatable, and numerous studies have had conflicting outcomes.

The exact origin of sinonasal melanomas is

often difficult to determine because of anatomic
limitations and locally advanced presenting stage.
Approximately 80% of cases occur in the nasal cavity
and 20% in the sinuses. Within the nasal cavity, the
lateral wall and turbinates are most frequently involved. Among the paranasal sinuses, the maxillary
sinus is the most common site, followed by the
ethmoid, frontal, and sphenoid sinuses.9,16 Most
patients present with epistaxis or unilateral obstruction. More advanced presentations may include pain
and facial distortion. Unlike oral lesions, sinonasal
melanomas are only rarely diagnosed incidentally
during routine examinations, such as flexible endoscopy. Because the role of melanocytes in the
sinonasal region is thought to be detoxification by
metabolizing polycyclic aromatic hydrocarbons,
some investigators have speculated a possible link
between environmental and immune factors and the
pathogenesis of these melanomas.20,27
Sinonasal mucosal melanomas have a slightly
better prognosis than those in the oral cavity.10,11,15,26 Nonetheless, the mean 5-year survival
for head and neck lesions is only 10% to 25%
(reported range: 0%-48%), regardless of the primary
site.9-11,15,17,25,26 As with all mucosal melanomas, the
most frequent scenario is local recurrence followed
by metastatic disease. Reinforcing the observation
that local recurrence is rarely an isolated phenomenon, a study conducted at M.D. Anderson Cancer
Center (Houston, Tex) revealed that 90% of metastatic disease was associated with local recurrence.17
Once a lesion recurs, metastases are usually discovered within 3 months. The development of nodal
disease appears to have a direct negative effect on
prognosis.1 Because of the virtually universal advanced stage at presentation, the significance of
Breslow depth is undetermined.
Treatment modalities for head and neck mucosal
melanomas have yielded disappointing results. The
general consensus is to attempt complete surgical
excision of the primary site, followed by postoperative radiation therapy for microscopic or macroscopic residual disease or nodal involvement.
Unfortunately, complete resection is frequently compromised by critical anatomic structures. Further,
because melanoma has a high capacity for sublethal
damage repair, these tumors are unresponsive to
conventional radiation therapy.28 Newer methods,
such as hypofractionation and neutron beam therapy, may play an adjunctive role in the future.
Adjunctive chemotherapy using dacarbazine alone
or in combination with other agents has not affected
survival outcome.15 Prophylactic lymph node dissection also does not impact the outcome and is

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reserved for patients with clinically evident nodal

involvement. There are no case series reporting the
use of a polyvalent melanoma vaccine in patients
with mucosal melanomas.

DIFFERENTIAL DIAGNOSIS OF
PIGMENTED ORAL LESIONS
Mucosal melanomas in the oral cavity can be
confused with several benign lesions. Melanosis is
an extremely common benign pigmentation of the
attached gingiva, especially among African Americans.
Based on its location, bilaterality, and symmetry,
melanosis may be differentiated clinically from malignancy. Oral nevi are only present in 0.1% of the
general population. Intramucosal nevi account for
55%, blue nevi for 36%, and junctional nevi for 3%.
Because some investigators have suggested that
repeated mechanical trauma may lead to malignant
transformation, prophylactic excision is recommended.14,18,23 Patients with Peutz-Jeghers syndrome
have pigmented lesions of the oral mucosa with
intestinal polyposis, and a family history can typically be elucidated. Mucosal lentigines may also be
found in patients with LAMB syndrome or LEOPARD
syndrome. The characteristic systemic features of
these syndromes allows for a clinical diagnosis. The
clinical spectrum of Addisons disease typically includes diffuse pigmentation of mucosal surfaces, in
particular the buccal mucosa, gingiva, and tongue.
Dental amalgam, a mercury-containing alloy for
dental fillings, represents the most common source
for oral pigmentation. Obtaining a dental history may
aid the diagnosis. Melanotic macules are common
benign pigmented lesions most commonly found on
the vermilion border of the lip and gingival and
buccal mucosa. Characterized histologically by a
normal number of basal melanocytes with increased
basal melanin deposition, these macules have no
malignant potential. Macular pigmentation of
Laugier and Hunziker is an uncommon disorder
that may present with pigmented macules on the
lips, oral cavity, fingernails, and toenails.29 Melanoacanthoma is a benign, rapidly growing lesion on
the buccal mucosa of black women in the third
and fourth decades. Finally, several medications are
associated with oral pigmentation, including minocycline,30 estrogen, cyclophosphamide, ketoconazole, clofazimine, doxorubicin, 5-fluorouracil,
azathioprine, and antimalarials.
Angiomata and other vascular lesions may resemble amelanotic mucosal melanomas. Erythroplakia
and oral squamous cell carcinoma most commonly
occur on the lateral and ventral surfaces of the
tongue and the floor of the mouth. Granular cell
tumors occur more commonly in women and darkly

pigmented races and have a predilection for the

tongue.
In general, one should have a low threshold for
performing a biopsy of a suggestive oral lesion. Any
change in color or texture of the oral mucosa,
especially fixed, solitary lesions, must be definitively
explained. Though mucosal melanomas are rare,
their overall poor prognosis warrants prudent investigation in the hope of an earlier diagnosis.

LARYNX/PHARYNX
Primary mucosal melanoma of the larynx and
pharynx is exceedingly rare. Only 10 cases of laryngeal melanomas have been reported. Most laryngeal
melanomas occur in the supraglottic region.18 The
5-year survival for patients with pharyngeal melanoma is only 13%.10,11,26

ESOPHAGUS
Approximately 200 cases of esophageal mucosal
melanoma have been described. Dysphagia, weight
loss, and hematemesis are common presenting symptoms. The origin of these tumors is thought to be related to the embryologic migration of melanocytes
down the upper two thirds of the esophagus.31 As
the majority of patients present with disseminated
disease, radical resections with nodal dissections
have not improved the average survival time of 7.5
months.16,20

FEMALE GENITAL TRACT

Primary mucosal melanomas of the female genital
tract account for 18% of all mucosal melanomas and
3% of melanomas diagnosed in women.1 Usually
affecting postmenopausal women between 60 and
70 years of age, approximately 500 cases have been
reported to date. Vulvar melanomas, which are the
second most common vulvar malignancy, greatly
outnumber vaginal melanomas. Primary cervical and
uterine melanomas are much more rare, with only 15
case reports in the literature. Presenting symptoms
are similar to other tumors and include abnormal
discharge, bleeding, pruritus, and the presence of a
polypoid mass. Most of these lesions are black or
gray-black in color, whereas only 6% are amelanotic.32 In an excellent review by Wechter et al,33
15% of patients with vulvar melanoma reported a
family history of cutaneous melanoma, and one
patient was found to have a germline mutation in
the melanocortin type I receptor.
Although case series have reported conflicting
frequencies regarding exact anatomic sites, most
vulvar melanomas appear to be located on the
mucosa of the labia minora, followed by the labia
majora and clitoris. Obscuring this distribution is the

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ANAL/RECTAL

Fig 1. Vulvar melanoma demonstrating melanoma in situ

within squamous mucosa, beneath which are sheets of
invasive tumor cells. (Hematoxylin-eosin stain; original
magnification: 3200.)

observation that many of these lesions extend to the

mucocutaneous border of the vagina, where melanocytes are most concentrated.16 Most vaginal melanomas arise in the lower vagina. Postulated to represent
precursor cells, melanoblasts within the vaginal epithelium are present in approximately 3% of women.34
Although 70% of patients present with clinically
localized disease, the overall prognosis is dismal.34,35
For vulvar melanomas, which had a mean Breslow
depth of 2.8 mm in one series33 (Fig 1), the 5-year
survival is 15% (with nodal metastases) to 54%
(without nodal metastases).1,34-36 Even more grim,
the 5-year survival for vaginal melanomas is less than
10%.37,38 Unfortunately, any surgical approach has
been disappointing, and there appears to be no
difference in the survival of radical versus local
resections.32,36,39 Because these melanomas are
typically surrounded by large areas of atypical melanocytic hyperplasia or melanoma in situ, most
conservative approaches end up resembling modified radical operations.
As lymph node status appears to be the most
powerful prognostic factor, a highly advocated approach is the use of intraoperative lymphatic mapping to identify nodal disease earlier.32,33,40 Given
the extremely poor prognosis associated with nodal
disease and the unresponsiveness to adjuvant chemotherapy, the survival benefits of this technique are
uncertain. The use of radiation therapy is currently
reserved for palliative purposes to control extensive
local disease.
Exemplifying the aggressiveness of mucosal melanomas of the female genital tract, a recent case
report in this journal described a pregnant woman
with metastatic vulvar melanoma who presented
with diffuse cutaneous melanosis. The authors of
this report stressed the importance of including the
genitalia in routine total body skin examinations.41

Primary mucosal melanomas of the anorectum

account for 24% of all mucosal melanomas and less
than 1% of malignant tumors of this site.1 Presenting
symptoms include pain, rectal bleeding, and the
presence of a large ulcerated, polypoid mass. Up to
30% of lesions may be amelanotic and, thus, unrecognized until an advanced mass develops.20 Most
anorectal mucosal melanomas are believed to arise
from the transitional zone of the anal canal, where
melanocytes are present in the highest numbers.20
Approximately 80% of patients present with stage I
disease (local disease), 10% with stage II (palpable
nodes), and 10% with stage III (distant metastases).42
Unfortunately, most series have shown that only a
small minority of these melanomas have a tumor
thickness less than 2 mm.13 The overall 5-year survival
is only 6%, and the mean survival time is 25 months.43
Treatment strategies have yielded conflicting
results. In a series presented by Memorial Sloan
Kettering (New York, NY), the only patient to survive
5 years underwent radical abdominoperitoneal resection.42 However, other studies have yielded contradictory data, reporting favorable survival outcome
from local excision alone.13 Before definitive conclusions can be made, large matched groups of
patients comparing these modalities is needed. The
role for adjuvant chemotherapy and radiotherapy
is still debatable, but experience with cisplatin and
interferon has not been promising.19 The benefit of
lymphadenectomy is unknown, and prophylactic
dissection has not increased survival.

URINARY TRACT
Accounting for only 3% of all mucosal melanomas, melanomas of the urethral mucosa are an
extremely rare entity. To date, 25 cases in male
patients and 40 cases in female patients have been
reported.44 Of all genitourinary sites, the penis is
most commonly affected, but the vast majority of
these cases are cutaneous.
Among male patients, the most common presenting symptoms include hematuria, dysuria, and
the presence of a black lesion. The distal urethra is the
most frequent site, followed by the meatus. However,
melanomas involving more proximal locations along
the urethra have been reported.16 For the more
common distal lesions, treatment options include
partial penectomy or urethrectomy with or without
inguinal node dissection. Radical cystoprostourethrectomy with pelvic node dissection is advocated for
proximal lesions. Unfortunately, no survival benefit
has been obtained with either approach.16,20
Most female patients with primary urethral mucosal melanoma present with similar symptoms of

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VOLUME 56, NUMBER 5

urinary frequency, dysuria, hematuria, and hesitancy.

A black necrotic mass is frequently evident, which
may resemble a urethral polyp, prolapse, or carbuncle.16 Various treatment strategies, including local
excision, radiotherapy, cryosurgery, and anterior
exenteration, have been disappointing. Of the 40
reported cases, only two survived for 5 years.44
Only 3 cases of primary mucosal melanoma of the
urinary bladder have been reported. The 3 patients
presented with clinically localized disease but died
of distant metastases less than 3 years after radical
operation.44

CONCLUSION
Primary mucosal melanomas are exceedingly
rare and biologically aggressive malignancies. Unlike
cutaneous melanomas, the occult locations in which
mucosal melanomas occur preclude sun exposure as
a predisposing risk factor. The relatively inaccessible
and various locations in which these tumors arise
also make consistent early screening difficult.
Although the majority of patients present with clinically localized disease, the thickness and growth
pattern of the primary tumors at diagnosis causes
them to behave in a manner similar to thick, ulcerated nodular cutaneous melanomas. As such, most
patients harbor micrometastatic disease at presentation and experience a course characterized by
multiple local recurrences before the clinical development of distant disease and eventual death.
A multitude of adjuvant treatments, including
various chemotherapy regimens and radiotherapy,
have been unsuccessful in improving the dismal
prognosis, and aggressive surgical resection remains the primary modality of choice. Regardless
of the therapy used, the prognosis is grave.
Approximately a third of patients have nodal involvement at presentation, and the overall 5-year
survival is only 25%. Because of the rarity of this
disease, there are no randomized clinical trials
comparing the efficacy of various treatment modalities, which, in turn, hinders significant therapeutic
advancements. As experience with the polyvalent
melanoma vaccine continues to grow, perhaps it
will prove beneficial in the treatment of this ominous disease.
As with all melanomas, early detection allows
the best hope for cure. Therefore, we believe that
educating our primary care, gynecology, otolaryngology, and dental colleagues concerning the presenting characteristics of this disease is of paramount
importance. Practitioners in these fields must maintain a low threshold for performing biopsies of suggestive lesions in these occult anatomic locations.

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