What is melanoma and how is it treated?

Melanoma: Diagnosis and Treatment

Melanoma is a malignant skin cancer arising from melanocytes that requires prompt surgical treatment for the best outcomes in terms of morbidity and mortality. 1

What is Melanoma?

• Melanoma is the fifth most common cancer in the US, with incidence increasing from 8.8 per 100,000 in 1975 to 28.42 per 100,000 in 2022 1
• Cutaneous melanoma comprises 94% of cases, with over 100,000 US cases projected for 2025 1
• Melanoma typically presents as a new, changing, or irregularly pigmented skin lesion 1
• Common subtypes include superficial spreading (≈70%), lentigo maligna (≈15%), nodular (≈5%), desmoplastic (≈4%), amelanotic (2%-8%), and acral (≈1%) 1

Risk Factors

• UV radiation exposure from sunlight and indoor tanning is the major environmental risk factor 2
• Fair skin that burns easily and never tans 1
• Presence of increased numbers of benign and atypical nevi (moles) 1, 3
• Personal or family history of melanoma 1
• Older age and male sex are associated with increased risk 2

Diagnosis

• Diagnosis is based on clinical assessment of pigmented lesions using the "ABCDE" rule (Asymmetry, Border irregularity, Color variation, Diameter >6mm, Evolution over time) 2
• The "ugly duckling" sign identifies pigmented lesions that look different from other moles on the patient 2
• Biopsy of a suspicious lesion is needed for definitive diagnosis 2
• Architectural features of malignant melanoma include asymmetry, confluence of growth, marked cellularity, and poor circumscription 4
• Cytological features include irregular and thick nuclear membrane and prominent nucleoli 4

Staging

• Melanoma staging ranges from stage 0 (melanoma in situ) to stage IV (distant metastasis) 1
• Staging includes assessment of tumor thickness, ulceration, and presence of lymph node or distant metastasis 1
• Based on US Cancer Statistics data (1999-2021), 77% of patients have localized disease, 9.5% have regional disease, 4.7% have distant metastasis, and 8.8% are unstaged 1

Treatment

Primary Melanoma

• Surgery is the only curative treatment for melanoma 4
• Wide excision with margins determined by Breslow thickness is the standard approach 1, 2:
  • In situ melanoma: 0.5 cm margin 2
  • Tumors 1-2 mm thick: 1 cm margin 2
  • Tumors >2 mm thick: 2-3 cm margin 2
• Sentinel lymph node biopsy is recommended for melanomas that are ulcerated or ≥0.8 mm thick 1

Regional Disease

• Complete surgical removal of positive regional lymph nodes is indicated for patients with isolated locoregional lymph node metastases 2
• Removal of the tumor-bearing lymph node alone is insufficient; the surrounding lymph node region should also be removed 2
• Non-resectable in-transit metastases may be treated with isolated limb perfusion using melphalan and tumor necrosis factor, but this should be restricted to experienced centers 2

Advanced Disease (Stage III-IV)

• For stage IIB-C melanoma, adjuvant anti-PD-1 immunotherapy (pembrolizumab or nivolumab) after surgery improves recurrence-free survival 1
• For stage III disease, options include 1:
  • Anti-PD-1 immunotherapy (nivolumab or pembrolizumab)
  • BRAF + MEK inhibitor therapy (dabrafenib + trametinib) for patients with BRAF mutations
• First-line treatment for metastatic or unresectable melanoma is dual checkpoint blockade with ipilimumab (anti-CTLA-4) and nivolumab 1
• Surgery of visceral metastases may be appropriate for selected cases with good performance status and isolated tumor manifestations 2
• Palliative radiotherapy should be considered for symptomatic brain or localized bone metastases 2

Prevention and Follow-up

• Primary prevention consists of avoiding direct sunlight and indoor tanning, and using photoprotection (sunscreen and sun-protective clothing) 1, 4
• Patients should be instructed to avoid sunburns and extended unprotected UV exposure 2
• Lifelong regular self-examination of the skin and peripheral lymph nodes is recommended 2
• Follow-up recommendations typically include 2:
  • Clinical examinations every 3 months during the first 3 years
  • Every 6-12 months thereafter
• Patients with thin primary melanomas have a small risk of relapse and do not require routine imaging 2
• For high-risk patients (thick primary tumors or following treatment of metastases), ultrasound of lymph nodes, CT, or PET/CT scans may be considered 2

Prognosis

• 10-year melanoma-specific survival rates (as of 2017) 1:
  • Stage IA-B: 98-94%
  • Stage IIA-C: 88-75%
  • Stage IIIA: 88%
  • Stage IIIB-C: 77-60%
  • Stage IIID: 24%
• Patients with metastatic or unresectable melanoma treated with ipilimumab and nivolumab had a 10-year overall survival rate of 43% (as of 2024) 1

Important Considerations

• 8% of melanoma patients develop a secondary melanoma within 2 years of initial diagnosis 2
• Family members of melanoma patients have an increased risk of developing melanoma 2
• Multidisciplinary care is essential, particularly for advanced disease 5