What is the recommended molecular test and treatment approach for a patient with suspected conjunctival melanoma, fair skin, and a history of sun exposure?

Molecular Testing for Conjunctival Melanoma

Recommended Molecular Testing

For suspected conjunctival melanoma, perform full-thickness excisional biopsy with minimal side margins (2mm) for histopathologic diagnosis, followed by molecular testing for BRAF, NRAS, and NF1 mutations if metastatic disease is present or suspected. 1, 2

Initial Diagnostic Approach

• Obtain full-thickness excisional biopsy using scalpel (not shave, laser, or electrocautery) with 2mm margins for any suspicious conjunctival lesion, particularly in fair-skinned patients with chronic sun exposure history 3, 4

• The histopathology report must include: Breslow thickness, presence of ulceration, mitotic rate, clearance of surgical margins, and melanocytic confirmation via immunohistochemistry (S100, Sox10, Melan-A/MART1, HMB45) 1

Molecular Testing Strategy

Testing for oncogenic driver mutations is NOT recommended in primary conjunctival melanoma without metastatic disease 1

However, when metastatic or unresectable disease is present:

• BRAF mutation testing is mandatory - present in approximately 47% of conjunctival melanomas 2, 5
• NRAS mutation testing should follow if BRAF-wild type - present in approximately 27% of cases 2, 5
• NF1 mutation testing should be considered - present in approximately 20% of cases 2, 5
• TERT promoter mutations are frequently present (47%) and associated with poor prognosis 2, 5

Key Molecular Characteristics

Conjunctival melanoma exhibits distinct genetic features:

• UV signature mutations (C>T and CC>TT transitions) are common, reflecting sun exposure etiology 2, 5
• High tumor mutational burden compared to uveal melanoma 2, 5
• MAPK and PI3K/AKT/mTOR pathway dysregulation predominates 2, 6
• Uveal melanoma-related mutations (GNAQ/11, BAP1, SF3B1) are rare in conjunctival melanoma 2, 7

Treatment Approach Based on Molecular Profile

For Localized Disease (Early-Stage)

Wide local excision with "no touch" technique, followed by cryotherapy to surgical margins and adjuvant topical therapy 6, 8

• Surgical margins: 3-5mm clinically measured from lesion edge 8
• Cryotherapy: Double freeze-thaw cycles to margins 6, 8
• Adjuvant options: Topical mitomycin C or interferon alfa-2b 6, 8

For Advanced/Metastatic Disease

Treatment selection depends on molecular profile:

BRAF-Mutant Disease

• BRAF inhibitors ± MEK inhibitors (dabrafenib/trametinib or vemurafenib/cobimetinib) 6, 5
• Median PFS: 12.6 months with first-line targeted therapy 5
• One-year PFS rate: 54.7% 5

BRAF-Wild Type Disease

• Immune checkpoint inhibitors (anti-PD-1 ± anti-CTLA-4) as first-line therapy 6, 5
• Median PFS: 6.2 months with first-line immunotherapy 5
• One-year PFS rate: 42.0% 5

Critical Pitfalls to Avoid

• Do not perform shave or partial biopsies - these compromise histologic assessment and may lead to misdiagnosis 4
• Do not order molecular testing on primary tumors without metastatic disease - this is not recommended and does not alter management 1
• Do not use frozen sections - they compromise diagnostic accuracy 4
• Avoid tumor manipulation during excision - use "no touch" technique to minimize seeding risk 8
• Do not rely solely on immunohistochemistry for malignancy diagnosis - comprehensive histopathologic assessment is required 4

Surveillance Considerations

For patients with conjunctival melanoma:

• Metastatic risk approaches 30% depending on AJCC stage, tumor origin, and management technique 8
• Poor prognosis markers include: NRAS mutations, TERT promoter mutations, and chromosome 10q deletions 2
• Regular surveillance with physical examination and imaging (based on stage) is essential for early metastasis detection 8