Oral Melanoma - StatPearls - NCBI Bookshelf 04/06/23 20:17

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

Oral Melanoma
Patrick M. Zito; Melina Brizuela; Thomas Mazzoni.
Author Information and Affiliations
Last Update: April 10, 2023.

Continuing Education Activity

Oral melanoma is a very rare malignancy that progresses rapidly and proves to be particularly
aggressive. The clinical aspect of oral melanoma is varied. Still, it usually presents as a black-
brown patch, macule, or nodular lesion with different shades of grey, red, purple, or areas of
depigmentation. This activity reviews the etiology, pathophysiology, epidemiology, history and
physical evaluation, and diagnosis of oral melanoma, with its differential diagnosis and
highlights the role of the interprofessional team in its management.

Objectives:

Review the current knowledge regarding the etiology and pathophysiology of oral
melanoma.

Describe the history and physical evaluation, and histopathology of oral melanoma.

Outline the differential diagnosis of oral melanoma.

Summarize the management options for oral melanoma.

Access free multiple choice questions on this topic.

Introduction
Oral melanoma is a very rare malignancy that progresses rapidly and proves to be particularly
aggressive. This lesion accounts for 0.2% to 8% of all melanomas[1] and 1% to 2% of all oral
malignancies.[2] Compared with other melanomas, mucosal melanomas have the lowest
percentage of 5-year survival rate, likely due to delayed detection.[3][4][5][6] The clinical aspect
of oral melanoma is varied. Still, it usually presents as a black-brown patch, macule, or nodular
lesion with different shades of grey, red, purple, or areas of depigmentation.[7] Amelanotic
lesions have also been reported.[2] The etiology, risk factors, and pathophysiology are
still poorly understood. Biopsy remains the gold standard for diagnosing oral melanomas,[2] and
radical surgical excision is the treatment of choice. Additional treatment modalities include
radiotherapy, chemotherapy, and immunotherapy.

Etiology
The etiology, risk factors, and pathogenesis of oral melanoma remain poorly understood.

https://www.ncbi.nlm.nih.gov/books/NBK513276/ Página 1 de 8
Oral Melanoma - StatPearls - NCBI Bookshelf 04/06/23 20:17

Unlike its skin counterpart, it is not related to sun exposure as the oral mucosa is protected from
ultraviolet light.[8] Primary oral mucosa melanomas mainly originate de novo, but up to 37% are
preceded by pigmented lesions, lasting for months to years.[7] Denture irritation, infection, and
tobacco smoking have been listed as possible risk factors, but a direct relationship is not
substantiated.[2]

Epidemiology
Oral melanoma is a very rare and aggressive carcinoma that accounts for 0.2% to 8% of all
melanomas [1] and 1% to 2% of all oral malignancies.[2] Interestingly, unlike its skin
counterpart, its incidence remained steady over the last years.[7]

Oral melanoma prevalence increases with age.[2] It develops between the 4th and 7th decade of
life, [1] with an average age of 60.[7] The gender difference is not significant; some studies
report female predominance, others male prevalence, or do not report any discrepancy.
[2] Regarding ethnicity, oral melanoma is uncommon in white individuals [7] and more frequent
in Japanese,[2] black, and Indian populations.[2]

Pathophysiology
Melanoma develops from a malignant transformation of melanocytes. Even though the exact
pathophysiology of mucosal melanomas is yet to be determined, some pathways have been
identified.

Mutations in c-KIT

Recent data indicates that c-KIT (CD117) is overexpressed in many mucosal melanoma cases.
This pathway is important and common in acral and mucosal melanoma, melanomas unrelated to
sun exposure.[9] KIT is a transmembrane tyrosine kinase receptor expressed on hematopoietic
progenitor cells, melanocytes, mast cells, primordial germ cells, and interstitial cells of
Cajal. Activating mutations and amplifications cause activation of growth and proliferation
pathways. Drugs that work on the tyrosine kinase activities, such as imatinib, show some
promise in treating mucosal melanomas expressing the c-kit protein, but treatment failure has
also been reported.[9]

Mutations in BRAF

Bioinformatics Resources and Applications Facility (BRAF) protein mutations are uncommon in
mucosal melanoma and found in less than 10% of cases. However, in cutaneous melanoma,
BRAF mutations are found in up to 80% of cases. Dabrafenib and vemurafenib are used for
patients exhibiting BRAF mutation-positive melanoma.[2]

Histopathology
The anatomy of the mouth differs from the skin. Due to the lack of histological landmarks
analogous to the papillary, reticular dermis, and muscle bundles, a pathological leveling system,
and description cannot be appropriately applied for mucosal melanomas. Therefore, Clark’s

https://www.ncbi.nlm.nih.gov/books/NBK513276/ Página 2 de 8
Oral Melanoma - StatPearls - NCBI Bookshelf 04/06/23 20:17

levels, commonly used in cutaneous melanoma, cannot be implemented. Many melanomas in the
mouth have a histologic similarity with lentigo maligna melanoma in a radial growth phase.

Mucosal melanomas can show three principal patterns. An in situ melanoma is in the epithelium
and does not cross the epithelial-connective tissue interface.[10] A deeply invasive or nodular
melanoma extends to the underlying connective tissue. A combined pattern is characterized by an
in situ or radially growing pattern combined with a nodular component.[10]

The characteristic histopathological features of mucosal melanomas include atypical melanocytes

(hyperchromatism and nuclear pleomorphism) in the epithelium and connective tissue junction.
This, combined with positive S-100 and HMB-45 markers, is confirmatory of mucosal
melanoma.[11]

Approximately 15% of cases of oral melanoma are in situ mucosal lesions, 30% of cases are
invasive lesions, and 55% of cases have a combined pattern of invasive with in situ components.
Most advanced lesions have a combination pattern of invasive melanoma with an in situ
component.

Immunohistochemistry

Although not specific, S-100 and HMB-45 are helpful markers that are positive in almost all oral
melanomas (94%).[2] Fatty acid synthase (FASN) can help to differentiate oral melanomas from
oral melanocytic nevi since this marker is strongly expressed in melanomas of the mucosal
surfaces.[2]

History and Physical

Oral melanomas show an aggressive nature and worse prognosis than cutaneous melanoma.
Almost a third of patients already have signs of lymph node metastasis at the moment of
diagnosis,[7] probably because this malignancy goes unnoticed due to a lack of symptoms in the
early stages.[12] Pain, bleeding, and ulceration are uncommon until late in the disease.

Primary oral melanomas have a strong preference for the maxilla, mainly developing in the hard
palate, gingiva, or alveolar ridge.[7][1] Secondary oral melanomas (even rarer than primary
tumors) commonly occur in the tongue.[1] Most oral melanomas arise de novo in an apparently
normal oral mucosa, but up to a third are preceded by melanosis.[2] This pigmented area
is believed to represent the radial expansion phase before the deep invasion of the underlying
tissue.[2]

The clinical aspect of oral melanomas is indeed diverse. They can present as macules, patches, or
nodules, showing various colors: brown, black, grey, red, or purple shades and even
depigmentation.[7] The lesions are asymmetric, with an irregular outline, and can be sometimes
multiple.[2] Satellite foci surrounding the tumor have been reported.[2][7] Up to a third of oral
melanomas are ulcerated.[7]

The most typical presentation comprises three particular features: a) a brown-black pigmented
plaque that is flat or slightly raised, b) a light brown macular feature, and c) a central area of

https://www.ncbi.nlm.nih.gov/books/NBK513276/ Página 3 de 8
Oral Melanoma - StatPearls - NCBI Bookshelf 04/06/23 20:17

nodular aspect.[2][13]

Amelanotic melanomas are not uncommon, accounting for around a third of oral melanomas.
[2] These lesions pose a diagnostic challenge since they may be misdiagnosed as benign tumors,
like epulis, or as squamous cell carcinoma.[2]

Evaluation
Early diagnosis is essential since oral melanomas show a very aggressive evolution with a poor
prognosis. However, there are still no criteria to aid the diagnosis in the oral cavity. Clinical
examination can be supported by dermoscopy, but the complex oral mucosa anatomy and
irregular surface represent a technical limitation.[7] Biopsy remains the gold standard to
diagnose oral melanomas. Incisional biopsy from the thickest part of a large lesion and excisional
biopsy of small lesions are indicated.[2] Ultrasound or CT scan of the head and neck and
thoracoabdominal regions is required to stage the tumor correctly.[7]

Dermoscopy

The most common dermoscopic features include diffuse and irregular pigmentation with pseudo-
network, regression structures, and a blue-white veil.[2] Other characteristics are asymmetrical
structures, irregular margins, and the abrupt interruption of the reticular pattern.[7] Atypical
vessels, dots, and globules can also be seen.[7]

Treatment / Management
Surgery is the mainstay of treatment in oral malignant melanoma.[11] Radical excision with
disease-free margins is the first goal in surgical management. Adjuvant therapy includes
radiation, chemotherapy, and immunotherapy.[2]

Even though melanoma is classically non-radiosensitive,[2] some authors have seen

improvement after radiotherapy, especially better local control and survival.[11]

Chemotherapy with platinum analog, nitrosoureas, dacarbazine, and immunotherapy with IL-2
have shown low response.[2] Metastatic melanomas with a c-kit mutation have benefited from
imatinib therapy.[9] Dabrafenib and vemurafenib are used for patients exhibiting a positive
BRAF mutation melanoma.[2]

Differential Diagnosis
The differential diagnosis of oral melanoma is extensive; it needs to be differentiated from focal
and diffuse oral pigmentations. Amalgam tattoos most commonly mimic oral melanomas, and
dermoscopy may aid in differentiating them.[2]

The following are included in the differential diagnosis of an oral melanoma:[7]

Focal Oral Pigmentations

Amalgam tattoo (exogenous pigment)

https://www.ncbi.nlm.nih.gov/books/NBK513276/ Página 4 de 8
Oral Melanoma - StatPearls - NCBI Bookshelf 04/06/23 20:17

Melanoacanthoma

Melanotic macules

Melanocytic nevi

Diffuse Oral Pigmentations

Physiological/racial pigmentations

Smoker’s melanosis

Drug-induced hyperpigmentation

Postinflammatory hyperpigmentation

Systemic Diseases

Peutz–Jeghers syndrome

Laugier–Hunzikerdisease

Leopard syndrome

Carney complex syndrome

McCune-Albright syndrome

Adrenal gland diseases

Staging
Tumor, T [14]

There is no T1 or T2 in mucosal melanoma.

T3: Tumors limited to the mucosa and immediately underlying soft tissue, regardless of
thickness or greatest dimension; for example, polypoid nasal disease, pigmented or non-
pigmented lesions of the oral cavity, pharynx, or larynx

T4: Moderately advanced or very advanced

T4a: Moderately advanced disease. Tumor involving deep soft tissue, cartilage, bone, or
overlying skin

T4b: Very advanced disease. Tumor involving the brain, dura, skull base, lower cranial
nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, or mediastinal
structures

Lymph Nodes, N

NX: Regional lymph nodes cannot be assessed

https://www.ncbi.nlm.nih.gov/books/NBK513276/ Página 5 de 8
Oral Melanoma - StatPearls - NCBI Bookshelf 04/06/23 20:17

N0: No regional lymph node metastases

N1: Regional lymph node metastases present

Distant Metastases, M

M0: No distance metastasis

M1: Distant metastasis

Prognosis
Patients with oral melanomas are often diagnosed at an advanced stage of the disease and have a
very poor prognosis.[15] The five-year survival rate is 25,5% for mucosal melanomas in the head
and neck.[2] Around a third of patients present lymph node metastasis at the moment of
diagnosis.[7] This is believed to be partly because the region is highly vascularized and also due
to its lymphatic drainage anatomy.[7] The expression of bcl-2 is linked to a better prognosis of
mucosal melanomas.[16] Aberrant expression of p53 protein and loss of expression of p16
protein are associated with a poor prognosis.[16]

After complete surgical excision, relapse rates have been reported to be about 20%.[11]
Recurrence has been noted even up to 11 years following surgery. Metastases in the lymph nodes
of the neck, lungs, liver, and brain can be seen.

Complications
The complications are related to the surgical excision of the melanoma, including loss of tissue,
prolonged healing, grafting, and prothesis need. Also, xerostomia, candidiasis, and hypernasal
speech are side effects of the surgery.

Consultations
Depending on complications and distant metastases, consultations with otolaryngology (head and
neck surgery), surgical oncology, oral and maxillofacial surgery, oral pathology, speech therapy,
and other specialties are warranted.

Deterrence and Patient Education

Early recognition and treatment of oral mucosal melanomas significantly improve the prognosis.
Preventive strategies are unknown, but some experts suggest educating patients on regular oral
self-examination to help identify early suspicious pigmented or non-pigmented lesions.

An appropriate self-examination requires a mouth mirror, standard mirror, and good

lightning. Patients should also be instructed to grab their tongue with the help of gauze for a
better view of the oral tissues.

Due to the high risk of recurrence, patients with a history of oral melanoma require lifelong
follow-up.

https://www.ncbi.nlm.nih.gov/books/NBK513276/ Página 6 de 8
Oral Melanoma - StatPearls - NCBI Bookshelf 04/06/23 20:17

Enhancing Healthcare Team Outcomes

Primary mucosal melanomas are aggressive tumors that are exceedingly rare but rapidly
lethal. This disease is particularly hard to treat because it is usually discovered at an advanced
stage. Dentists have a unique opportunity to diagnose this lesion promptly and improve the
patient’s prognosis. Other healthcare professionals, including dermatologists and general
practitioners, should add an oral examination to their regular appointments and be familiar with
the aspect of this carcinoma. Asymptomatic irregular melanotic lesions should raise concern and
be further investigated,[11] especially those in sites most common to oral melanoma.

Patients need should be instructed to implement self-examinations for early detection. Trained
primary care nurses can educate the patient in this regard. They also need to inform the patient
on what constitutes a high-risk lesion and communicate these findings to the clinician as soon as
they arise. Despite the low incidence of oral melanoma, a collaborative interprofessional team
can help reduce morbidity and mortality associated with it. [Level 5]

Review Questions

Access free multiple choice questions on this topic.

Comment on this article.

References
1. Aguas SC, Quarracino MC, Lence AN, Lanfranchi-Tizeira HE. Primary melanoma of the
oral cavity: ten cases and review of 177 cases from literature. Med Oral Patol Oral Cir Bucal.
2009 Jun 01;14(6):E265-71. [PubMed: 19300378]
2. Warszawik-Hendzel O, Słowińska M, Olszewska M, Rudnicka L. Melanoma of the oral
cavity: pathogenesis, dermoscopy, clinical features, staging and management. J Dermatol
Case Rep. 2014 Sep 30;8(3):60-6. [PMC free article: PMC4195501] [PubMed: 25324906]
3. PDQ Pediatric Treatment Editorial Board. PDQ Cancer Information Summaries [Internet].
National Cancer Institute (US); Bethesda (MD): Mar 30, 2023. Rare Cancers of Childhood
Treatment (PDQ®): Health Professional Version. [PubMed: 26389315]
4. Panda S, Dash S, Besra K, Samantaray S, Pathy PC, Rout N. Clinicopathological study of
malignant melanoma in a regional cancer center. Indian J Cancer. 2018 Jul-Sep;55(3):292-
296. [PubMed: 30693897]
5. Natarajan E. Black and Brown Oro-facial Mucocutaneous Neoplasms. Head Neck Pathol.
2019 Mar;13(1):56-70. [PMC free article: PMC6406009] [PubMed: 30693458]
6. Lee JS, Lee H, Lee S, Kang JH, Lee SH, Kim SG, Cho ES, Kim NH, Yook JI, Kim SY. Loss
of SLC25A11 causes suppression of NSCLC and melanoma tumor formation.
EBioMedicine. 2019 Feb;40:184-197. [PMC free article: PMC6413681] [PubMed:
30686754]
7. Lambertini M, Patrizi A, Fanti PA, Melotti B, Caliceti U, Magnoni C, Misciali C, Baraldi C,
Ravaioli GM, Dika E. Oral melanoma and other pigmentations: when to biopsy? J Eur Acad
Dermatol Venereol. 2018 Feb;32(2):209-214. [PubMed: 28862771]

https://www.ncbi.nlm.nih.gov/books/NBK513276/ Página 7 de 8
Oral Melanoma - StatPearls - NCBI Bookshelf 04/06/23 20:17

8. Prasad ML, Jungbluth AA, Patel SG, Iversen K, Hoshaw-Woodard S, Busam KJ. Expression and
significance of cancer testis antigens in primary mucosal melanoma of the head and neck. Head
Neck. 2004 Dec;26(12):1053-7. [PubMed: 15515159]
9. Rivera RS, Nagatsuka H, Gunduz M, Cengiz B, Gunduz E, Siar CH, Tsujigiwa H, Tamamura
R, Han KN, Nagai N. C-kit protein expression correlated with activating mutations in KIT
gene in oral mucosal melanoma. Virchows Arch. 2008 Jan;452(1):27-32. [PubMed:
18066592]
10. Barker BF, Carpenter WM, Daniels TE, Kahn MA, Leider AS, Lozada-Nur F, Lynch DP,
Melrose R, Merrell P, Morton T, Peters E, Regezi JA, Richards SD, Rick GM, Rohrer MD,
Slater L, Stewart JC, Tomich CE, Vickers RA, Wood NK, Young SK. Oral mucosal
melanomas: the WESTOP Banff workshop proceedings. Western Society of Teachers of
Oral Pathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Jun;83(6):672-9.
[PubMed: 9195622]
11. Misra SR, Tripathy UR, Das R, Mohanty N. Oral malignant melanoma: a rarity! BMJ Case
Rep. 2021 Nov 11;14(11) [PMC free article: PMC8587506] [PubMed: 34764097]
12. Sen S, Sen S, Kumari MG, Khan S, Singh S. Oral Malignant Melanoma: A Case Report.
Prague Med Rep. 2021;122(3):222-227. [PubMed: 34606435]
13. Umeda M, Komatsubara H, Shigeta T, Ojima Y, Minamikawa T, Shibuya Y, Yokoo S,
Komori T. Treatment and prognosis of malignant melanoma of the oral cavity: preoperative
surgical procedure increases risk of distant metastasis. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod. 2008 Jul;106(1):51-7. [PubMed: 18504155]
14. Aloua R, Kaouani A, Kerdoud O, Salissou I, Slimani F. Melanoma of the oral cavity: A
silent killer. Ann Med Surg (Lond). 2021 Feb;62:182-185. [PMC free article:
PMC7829076] [PubMed: 33532067]
15. Hicks MJ, Flaitz CM. Oral mucosal melanoma: epidemiology and pathobiology. Oral
Oncol. 2000 Mar;36(2):152-69. [PubMed: 10745167]
16. Prasad ML, Patel SG, Shah JP, Hoshaw-Woodard S, Busam KJ. Prognostic significance of
regulators of cell cycle and apoptosis, p16(INK4a), p53, and bcl-2 in primary mucosal
melanomas of the head and neck. Head Neck Pathol. 2012 Jun;6(2):184-90. [PMC free
article: PMC3370030] [PubMed: 22160615]
Disclosure: Patrick Zito declares no relevant financial relationships with ineligible companies.

Disclosure: Melina Brizuela declares no relevant financial relationships with ineligible companies.

Disclosure: Thomas Mazzoni declares no relevant financial relationships with ineligible companies.

Copyright © 2023, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
(CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work,
provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article,
provided that you credit the author and journal.

Bookshelf ID: NBK513276 PMID: 30020648

https://www.ncbi.nlm.nih.gov/books/NBK513276/ Página 8 de 8