What are the treatment options for a patient diagnosed with mucosa melanoma?

Treatment of Mucosal Melanoma

Surgery with or without adjuvant radiation therapy is the primary treatment for localized mucosal melanoma (stage III), while stage IV disease requires surgery followed by radiation therapy or systemic therapy depending on the extent of systemic involvement. 1

Initial Evaluation and Workup

Before initiating any treatment, all patients must be evaluated by a multidisciplinary team including a head and neck surgical oncologist. 1, 2 The diagnostic workup should include:

• Complete head and neck examination with mirror and fiberoptic examination for head/neck sites 1
• Pathologic confirmation using immunohistochemical staining (HMB-45, S-100, Melan-A) 1
• CT and/or MRI to determine anatomic extent, particularly for sinus disease 1
• Chest imaging to assess for metastatic disease 1
• PET-CT scan should be considered to rule out distant metastases 1
• Molecular testing for BRAF, c-KIT, and NRAS mutations to guide systemic therapy selection 1, 2, 3

This last point is critical: do not assume all mucosal melanomas are BRAF wild-type—mucosal melanomas have only 3% BRAF mutations but 39% c-KIT aberrations, making molecular profiling essential. 1, 2, 3

Primary Treatment by Stage

Stage III Disease (Localized)

Surgical resection is the cornerstone of treatment, with the goal of leaving no gross residual disease. 1, 2 The surgical approach should include:

• Wide local excision with adequate tumor-free surgical margins 1, 2
• Elective neck dissection is generally not performed for mucosal melanoma except for oral cavity sites 1
• For oral cavity tumors approaching or crossing the midline, contralateral submandibular dissection should be performed 1

Adjuvant postoperative radiation therapy (60-66 Gy conventional fractionation) is strongly recommended for high-risk features including satellitosis, positive nodes, or extracapsular spread. 1, 2 Intensity-modulated radiation therapy (IMRT) is particularly useful for paranasal sinus sites to achieve homogenous dose distributions while sparing critical organs. 1, 2

Stage IV Disease (Metastatic or Unresectable)

For unresectable locally advanced disease, radiation therapy to 66-74 Gy is recommended. 1, 2 However, systemic therapy becomes the primary treatment modality for metastatic disease.

Systemic Therapy Selection

The choice of systemic therapy should be guided by molecular testing results:

For Patients Without Actionable Mutations

Ipilimumab-nivolumab combination is the preferred first-line treatment, achieving response rates of approximately 50% with durable responses. 2, 3 This combination demonstrates superior efficacy compared to single-agent therapy in mucosal melanoma. 4, 5

While the ASCO guideline acknowledges that evidence-based cutaneous melanoma therapies can be recommended for mucosal melanoma patients, it notes that overall responses to immunotherapy in mucosal melanoma are often lower and less robust compared to cutaneous melanoma. 1, 5

For c-KIT Mutated Disease

Imatinib is reasonable to use for c-KIT mutated mucosal melanoma. 2 The ASCO guideline panel recognizes that while evidence for KIT inhibitors in mucosal melanoma is limited, KIT-positive mucosal melanoma may be responsive to imatinib based on small phase II studies. 1

For BRAF-Mutated Disease

For the rare BRAF-mutated mucosal melanoma (only 3% of cases), combined BRAF/MEK inhibition achieves response rates up to 60%. 2, 3

Critical Management Pitfalls

Several important caveats must be considered:

• Never delay surgical intervention in patients with symptomatic tumoral bleeding to pursue systemic therapy first—hemorrhage control takes absolute priority 2, 3
• Do not use hypofractionated radiation in mucosal melanoma due to proximity of neural structures and risk of late effects, despite its convenience in cutaneous melanoma 2, 3
• Do not withhold immunotherapy indefinitely due to prior bleeding; surgery followed by immunotherapy offers the best long-term outcomes 2, 3
• Avoid aggressive surgical interventions with significant morbidity without considering the common presence of multifocal disease and high rate of distant recurrence 6

Radiation Therapy Considerations

Conventional fractionation is strongly preferred over hypofractionation for mucosal melanoma. 2, 3 While adjuvant radiotherapy using 30 Gy in 5 fractions over 2.5 weeks (6.0 Gy per fraction) has been described for cutaneous melanoma, this hypofractionated approach should be avoided in mucosal melanoma. 1, 2

For postoperative radiation:

• Paranasal sites: RT to primary site plus 2-3 cm margins or to anatomic compartment 1
• Oral cavity, oropharynx, hypopharynx sites: RT to primary site (plus 2-3 cm margins or anatomic zone) and elective treatment to neck unless negative pathology findings from neck dissection 1

Surveillance After Treatment

Intensive follow-up is essential given the high recurrence rate:

• Year 1: Every 1-3 months 1, 2
• Year 2: Every 2-6 months 1, 2
• Years 3-5: Every 4-8 months 1, 2
• Beyond 5 years: Every 12 months 1, 2

Each visit should include physical examination with endoscopic inspection for paranasal sinus disease. 1, 2 Post-treatment baseline imaging of the primary site (and neck if treated) is recommended within 6 months of treatment completion (category 2B). 1, 2

Additional surveillance should include:

• TSH monitoring every 6-12 months if neck was irradiated 1
• Speech/hearing and swallowing evaluation as clinically indicated 1
• Dental evaluation as appropriate for the site treated 1

Role of Clinical Trials

Given the rarity of mucosal melanoma and limited high-quality randomized data, patients should be offered or referred for enrollment in clinical trials where possible. 1 Novel approaches including adoptive TIL therapy have shown promise and represent important areas of ongoing investigation. 5