Mucosal Melanoma

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Chapters

Epidemiology and Risk Factors
of Mucosal Melanoma

Genetic Drivers of
Mucosal Melanoma

Presentation and Outcomes
of Mucosal Melanoma

Management of
Mucosal Melanoma

REFERENCES

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Epidemiology and Risk Factors
of Mucosal Melanoma

Mucosal melanoma is a rare and aggressive disease that is distinct from the more common cutaneous melanoma. Key differences include:

Epidemiology

Genetic drivers

Presentation/anatomical patterns

Lerner et al, 2017
Shoushtari et al, 2017
Wang et al, 2014

Mucosal melanoma represents approximately 1.3% of melanomas
in the United States with an estimated 600 new diagnoses annually.

Chang et al, 1998
McLaughlin et al, 2005

Onset of mucosal melanoma tends
to develop later in life compared
with cutaneous melanoma.

Chang et al, 1998
McLaughlin et al, 2005

There are significant racial and ethnic disparities in incidence rates.
Mucosal melanoma makes up a large proportion of melanoma cases in
Asian and Black populations compared to White populations.

Chi et al, 2011
Fujisawa et al, 2019
Jang et al, 2014
Lerner et al, 2017

In contrast to cutaneous melanoma, where sun damage and
exposure to environmental risk factors such as radiation, solvents,
vinyl chloride, and polychlorinated biphenyls (PCBs) have been
linked to increased risk of disease, no clear environmental risk
factors have been identified for mucosal melanoma.

Lerner et al, 2017
PDQ, 2021

What percentage of all melanoma cases in the United States are represented by mucosal melanoma?

Mucosal melanoma represents approximately 1.3% of melanomas
in the United States with an estimated 600 new diagnoses annually

QUIZ QUESTION 1

What environmental risk factors have been identified
as increasing risk for mucosal melanoma?

In contrast to cutaneous melanoma, where sun damage and exposure
to a variety of environmental risk factors have been linked to increased
risk of disease, no clear environmental risk factors have been identified
for mucosal melanoma.

QUIZ QUESTION 2

Among White, Black, and Chinese populations, what
is the incidence of mucosal melanoma as a proportion
of all melanoma cases?

White patients

1-2%

Black patients

5-13%

Chinese patients

23%

In fact, the absolute incidence rate of mucosal melanoma is twice
as high in White compared with Black individuals.

QUIZ QUESTION 3

Genetic Drivers of Mucosal Melanoma

A distinct pattern of genetic drivers, epidemiology, and clinical features underpin mucosal melanoma.

Compared with cutaneous disease,
the mutational burden for mucosal
melanoma is much lower, averaging
10-fold fewer single-nucleotide variants per tumor.

Most mutations observed
with cutaneous melanoma are
associated with chronic exposure
to UV radiation, which is known
to damage DNA.

Alexandrov et al, 2013
Lerner et al, 2017

Mucosal melanoma is characterized by a high rate of structural variants and gene amplifications which are rare in its cutaneous counterpart.

Lerner et al, 2017

BRAF mutations are rare with only
an estimated 3% to 11% of mucosal
melanomas showing this mutation
vs approximately 50% in cutaneous
melanoma.

The same is true for NRAS
(5-14% vs 10-20%).

Conversely, amplifications and activating
mutations of KIT, SCFR, c-KIT are
somewhat common in mucosal
melanoma (14% to 39%) but are rarely
seen in cutaneous melanoma.

Lerner et al, 2017

BRAF, v-Raf murine sarcoma viral oncogene homolog B; c-KIT, CD117; NRAS, neuroblastoma RAS viral (v-ras) oncogene
homolog; SCFR, stem cell growth factor receptor.

How does the mutational burden of mucosal melanoma
compare with that of cutaneous melanoma?

10x Lower

-10

-5

QUIZ QUESTION 1

What are more common driver mutations in mucosal melanoma?
[choose all that apply]

KIT

c-KIT

SCFR

BRAF

BRCA

HER

QUIZ QUESTION 2

Presentation and Outcomes
of Mucosal Melanoma

Management of Mucosal Melanoma

In earlier stage disease,
surgery is the primary
therapy and the only
treatment that offers the
potential for long-term
disease-free survival.

However, even
with complete
surgical resection,
most patients will
experience recurrence.

Carvajal et al, 2011

Despite evidence that targeted
therapy, chemotherapy, and
immunotherapy approaches
are less effective at treating
mucosal melanoma, treatment
of metastatic disease for
mucosal melanoma generally
relies upon the same therapies
approved for cutaneous
melanoma.

The FDA has granted
orphan drug designation
to therapies intended to
treat mucosal melanoma.

Alkermes plc, 2021
Tyrrell et al, 2018
US FDA, 2021

Immunotherapies include mono or
combination therapy of anti-PD-1
therapy +/- anti-CTLA-4 therapy,
with the combination being
generally more effective than
either agent alone.

Data on effective treatments in
the post-checkpoint setting is
sparse, further highlighting the
need for new therapies.

D’Angelo et al, 2017

What is standard-of-care for early-stage mucosal melanoma?

Surgery is the primary therapy for early-stage disease and the only
treatment that offers the potential for long-term disease-free survival.

QUIZ QUESTION 1

What are the recommended treatments for advanced mucosal melanoma?

Treatment of metastatic disease for mucosal melanoma generally relies
upon the same therapies approved for cutaneous melanoma despite
evidence that targeted therapy, chemotherapy, and immunotherapy
approaches are less effective at treating mucosal melanoma.

QUIZ QUESTION 2

References

Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-21

Al-Haseni A, Vrable A, Qureshi MM, et al. Survival outcomes of mucosal melanoma in the USA. Future oncology. 2019;15(34):3977-3986.

Alkermes, plc. Alkermes announces FDA orphan drug designation for Nemvaleukin Alfa for treatment of mucosal melanoma [Press release]. 2021. Available at: https://investor.alkermes.com/news-releases/news-release-details/alkermes-announces-fda-orphan-drug-designation-nemvaleukin-alfa. [Accessed March 11, 2021]

Bishop KD, Olszewski AJ. Epidemiology and survival outcomes of ocular and mucosal melanomas: A population-based analysis. Int J Cancer. 2014;134:2961-2971.

Carvajal RD, Spencer SA, Lydiatt W. Mucosal Melanoma: A Clinically and Biologically Unique Disease Entity. J Natl Compr Canc Netw. 2011;10(3):345-356.

Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83:1664-78

Chi Z, Li S, Sheng X, et al. Clinical presentation, histology,and prognoses of malignant melanoma in ethnic Chinese. BMC Cancer. 2011;11:85.

D'Angelo SP, Larkin J, Sosman JA, et al. Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis. J Clin Oncol. 2017;35(2):226-235.

Fujisawa Y, Yoshikawa S, Minagawa A, et al. Clinical and histopathological characteristics and survival analysis of 4594 Japanese patients with melanoma. Cancer medicine. 2019;8(5):2146-2156.

Jang HS, Kim JH, Park KH, et al. Comparison of Melanoma Subtypes among Korean Patients by Morphologic Features and Ultraviolet Exposure. Annals of Dermatology. 2014;26(4):485-490. doi: 10.5021/ad.2014.26.4.485.

Kuk D, Shoushtari AN, Barker CA, et al. Prognosis of mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma from the time of first metastasis. Oncologist. 2016;21(7):848-854.

Lerner BA, Stewart LA, Horowitz DP, Carvajal RD. Mucosal Melanoma: New Insights and Therapeutic Options for a Unique and Aggressive Disease. Oncology. 2017;31:e23.

Lian B, Cui CL, Zhhou L, et al. The natural history and patternsof metastases from mucosal melanoma: an analysis of 706 prospectively-followed patients. Ann Oncol. 2017;28:868-873. doi: 10.1093/annonc/mdw694.

McLaughlin CC, Wu XC, Jemal A, Martin HJ, Roche LM, Chen VW. Incidence of noncutaneous melanomas in the US. Cancer. 2005;103(5):1000-1007. doi: 10.1002/cncr.20866.

National Cancer Institute. SEER Cancer Stat Facts:Melanoma of the Skin. Bethesda, MD2021.

PDQ® Adult Treatment Editorial Board. PDQ Melanoma Treatment. Bethesda, MD: National Cancer Institute. Updated 9/3/2021. Available at: https://www.cancer.gov/types/skin/patient/melanoma-treatment-pdq. Accessed 9/9/2021.

Shoushtari AN, Bluth MJ, Goldman DA, et al. Clinical features and response to systemic therapy in a historical cohort of advanced or unresectable mucosal melanoma. Melanoma Res. 2017;27(1):57-64.

Tyrrell H, Payne M. Combatting mucosal melanoma: recent advances and future perspectives. Melanoma Manag. 2018;5(3):MMT11.

U.S. Food & Drug Administration. Toripalimab in combination with axitinib orphan drug designation. Accessed August 24, 2021. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=730120.

Wang X, Si L, Guo J. Treatment algorithm of metastatic mucosal melanoma. Linchuang Zhongliuxue Zazhi 2014;3(38):1-9.

Mucosal Melanoma

Epidemiology and Risk Factorsof Mucosal Melanoma

Genetic Drivers of Mucosal Melanoma

Presentation and Outcomes of Mucosal Melanoma

Management of Mucosal Melanoma

References

Epidemiology and Risk Factors
of Mucosal Melanoma

Presentation and Outcomes
of Mucosal Melanoma