Mucosal Melanoma: Symptoms, Types, Causes and Treatment

Mucosal melanoma is a rare, aggressive form of melanoma that develops in the mucous membranes lining various internal surfaces of the body. While cutaneous (skin) melanomas are more commonly discussed, mucosal melanomas are often diagnosed at a later stage due to their hidden locations and nonspecific symptoms. Despite advances in melanoma care, mucosal melanomas present unique challenges in terms of detection, understanding their causes, and treatment. This article explores the symptoms, types, causes, and treatment options for mucosal melanoma, providing a comprehensive overview for patients, caregivers, and clinicians.

Symptoms of Mucosal Melanoma

Mucosal melanoma can be difficult to detect early because it arises in areas not easily visible, and its symptoms often mimic those of more common, benign conditions. Awareness of the possible signs is critical for earlier detection and improved outcomes.

Symptom	Description	Common Sites	Source(s)
Bleeding	Unexplained bleeding from mucosa	Nose, mouth, rectum, vagina	1 2 6 11
Mass/Lesion	Noticeable lump or growth	Oral cavity, anorectal, vulva	1 2 6 8 11
Pain	Localized discomfort or pain	Head/neck, anorectal, genital	1 2 6
Obstruction	Difficulty breathing, eating, defecating	Nasal, oral, anorectal	2 6 8

Table 1: Key Symptoms

Common Presenting Symptoms

Mucosal melanomas frequently present with nonspecific symptoms related to the affected site. For example, bleeding is common—such as nosebleeds, oral bleeding, rectal bleeding (hematochezia), or abnormal vaginal bleeding—often mistaken for other, less serious conditions. Similarly, patients may notice a mass or lump in the mouth, vagina, or rectum, which may or may not be pigmented 1 2 6 11.

Site-Specific Manifestations

• Head and Neck: Symptoms include nosebleeds, nasal obstruction, difficulty swallowing, or an oral mass. These tumors often go unnoticed until they cause significant issues 1 6 8.
• Anorectal Region: Patients may report rectal bleeding, pain, constipation, a feeling of incomplete evacuation (tenesmus), or a palpable mass 2 11.
• Female Genital Tract: Unusual bleeding, discharge, or a mass in the vulva or vagina are common initial signs 1 11.

Why Symptoms Are Often Overlooked

Symptoms of mucosal melanoma are generally not specific to melanoma and can be confused with benign or more common conditions, such as hemorrhoids, sinusitis, or gynecological infections. This often leads to delays in diagnosis until the disease is at an advanced stage 1 2 6 11.

Types of Mucosal Melanoma

Mucosal melanomas can occur in various anatomical locations, each with its own clinical and biological features. Understanding the different types is important for diagnosis and management.

Type/Location	Prevalence	Typical Age Group	Source(s)
Head & Neck	~50% of cases	60+ years	1 6 8 11 14
Female Genital Tract	2nd most frequent	6th-7th decade	1 11
Anorectal	3rd most frequent	Elderly	2 11
Conjunctival	Less common	Older adults	11
Oral Cavity	Rare	Middle-aged men	1 6 11

Table 2: Major Types of Mucosal Melanoma

Head and Neck Mucosal Melanoma

This is the most common site for mucosal melanoma, accounting for approximately half of all cases. These tumors typically arise in the nasal cavity, paranasal sinuses, and oral cavity. They tend to present in older adults and show a slight male predominance in some sites 1 6 8 11 14.

Anorectal Mucosal Melanoma

Anorectal melanoma is rare and extremely aggressive, representing about 0.4 cases per million per year. It is more frequently diagnosed in women and commonly presents with rectal bleeding, pain, and changes in bowel habits 2 11.

Female Genital Tract Melanoma

These occur most often in the vulva, with the vagina and cervix being less common sites. Female genital tract melanomas are notable for their slightly higher incidence in women, attributed to vulvar involvement 1 11.

Other Sites

• Conjunctival: A rare form affecting the eye’s mucous membrane 11.
• Oral Cavity: Uncommon but particularly aggressive, more frequent in men 1 6 11.

Site-Specific Clinical Features

Each site may have unique clinical and pathological characteristics, influencing both prognosis and treatment approach. For example, conjunctival melanomas have a better prognosis compared to gastric or anorectal mucosal melanomas 11.

Causes of Mucosal Melanoma

Unlike cutaneous melanoma, which is strongly linked to sun exposure, the causes of mucosal melanoma are less well understood. However, research highlights key genetic, environmental, and demographic factors.

Cause/Factor	Description/Notes	Associated Sites	Source(s)
Genetic Mutations	KIT, SF3B1, TERT, TP53, NRAS, BRAF	All mucosal sites	3 4 9 10 13
Structural Variants	High frequency of gene rearrangements	All	3 4 10 13
Demographics	More common in elderly, slight female bias	Vulva, anorectal	1 2 11
Unknown Factors	No clear environmental cause identified	All	5 15 16

Table 3: Major Causes and Risk Factors

Genetic Drivers

Mucosal melanomas are characterized by unique genetic alterations. Unlike skin melanoma, which often harbors BRAF or NRAS mutations linked to UV exposure, mucosal melanomas more frequently show mutations in the KIT gene, SF3B1, TERT promoter, and display a higher rate of complex structural changes 3 4 9 10 13. Notably, SF3B1 mutations are particularly common in anorectal and female genital tract melanomas 9 13.

Copy Number Variations and Rearrangements

Higher frequency of gene amplifications, deletions, and structural rearrangements (e.g., involving TERT, CDK4, MDM2) are observed in mucosal melanomas, underscoring their genetic complexity 3 4 10 13.

Demographic and Environmental Factors

• Most cases occur in older adults, typically in the sixth or seventh decade of life 1 11.
• There is a slightly higher incidence in women, especially due to vulvar involvement 1 2 11.
• Unlike skin melanoma, there is no strong association with ethnicity, except for some site-related variations (e.g., sinonasal melanomas are rare in Black populations) 11.
• Environmental or lifestyle risk factors, such as cigarette smoking, have been proposed but lack strong evidence 6 15 16.

Etiology Remains Unclear

Despite advances in genomics, the exact cause of mucosal melanoma remains elusive. There is no established link with UV exposure or other clear environmental triggers. The rarity and heterogeneity of the disease make epidemiological studies challenging 5 15 16.

Treatment of Mucosal Melanoma

Managing mucosal melanoma is particularly challenging due to its late presentation, aggressive behavior, and limited evidence base for therapy. Recent years, however, have seen significant advances in treatment options.

Treatment	Description/Role	Key Considerations	Source(s)
Surgery	Mainstay; aim for complete excision	Clear margins essential	2 6 8 11 14 15
Radiotherapy	Adjuvant for local control	Improves local, not survival	6 8 14 15
Immunotherapy	Anti-PD-1, Anti-CTLA-4 agents	Lower efficacy than in skin	6 12 15 16
Targeted Therapy	c-KIT, MEK, CDK4/6 inhibitors	For selected mutations	6 8 9 13

Table 4: Main Treatments for Mucosal Melanoma

Surgery

Surgical excision with free margins is the cornerstone of treatment for localized mucosal melanoma. Because these tumors are often diagnosed late, achieving clear margins can be difficult, and surgery may not always be feasible 2 6 8 11 14 15. For example, in the anorectal region, wide local excision is preferred when possible 2.

Radiotherapy

Radiotherapy is commonly used as an adjuvant to surgery to improve local disease control. However, studies show it does not significantly improve overall survival. It is especially valuable in cases where complete surgical resection is not possible 6 8 14 15.

Immunotherapy

Checkpoint inhibitors such as anti-PD-1 (nivolumab) alone or combined with anti-CTLA-4 (ipilimumab) are now standard for advanced cutaneous melanoma and are increasingly being used for mucosal melanoma. However, response rates are generally lower in mucosal melanoma compared to cutaneous cases 12 15 16:

• Nivolumab monotherapy: ~23% response rate in mucosal melanoma versus ~41% in cutaneous 12.
• Combination therapy (nivolumab + ipilimumab): ~37% response rate in mucosal melanoma 12.

Despite these lower rates, immunotherapy remains a promising option, with ongoing research aiming to improve outcomes.

Targeted Therapy

For patients with specific genetic mutations (e.g., KIT, SF3B1), targeted therapies such as tyrosine kinase inhibitors (e.g., imatinib for KIT mutations), MEK inhibitors, or CDK4/6 inhibitors are being explored. These are especially relevant given the distinct genetic landscape of mucosal melanoma 6 8 9 13.

Challenges and Future Directions

• The rarity of mucosal melanoma means that most treatment recommendations are based on small studies or extrapolated from cutaneous melanoma data.
• Multimodality therapy is not standardized, and optimal combinations of surgery, radiotherapy, and systemic therapy are still being investigated 6 8 14 15 16.
• Precision medicine approaches, including routine genetic testing for actionable mutations, are increasingly recommended to guide targeted therapy 9 13.

Conclusion

Mucosal melanoma is a rare and aggressive cancer that presents unique challenges in detection, understanding, and treatment. While recent advances in genetics and immunotherapy are offering new hope, further research and clinical trials are needed to improve outcomes for patients with this difficult disease.

Key Points:

• Mucosal melanoma symptoms are often nonspecific and related to the tumor’s location, leading to late diagnosis.
• The main types are head and neck, anorectal, and female genital tract melanomas, each with distinct features.
• The causes are largely unknown, but unique genetic mutations and structural variants are key contributors.
• Treatment relies on surgery when possible, with adjuvant radiotherapy, immunotherapy, and targeted therapies as important adjuncts.
• Outcomes remain poorer than for cutaneous melanoma, but advances in precision medicine and immunotherapy are promising for the future.

By increasing awareness, encouraging early diagnosis, and supporting further research, there is hope for better prognosis and management of mucosal melanoma in the years to come.