What is the treatment for acral lentiginous melanoma?

Treatment of Acral Lentiginous Melanoma

Surgical excision with histologically negative margins is the primary and first-line treatment for acral lentiginous melanoma, with margins of 0.5 cm for in situ disease, 1 cm for tumors ≤2 mm Breslow thickness, and 2 cm for thicker tumors, though functional preservation at acral sites often necessitates narrower margins. 1, 2

Surgical Management of Primary Disease

Excision Margins

• For melanoma in situ: Wide excision with 0.5-1.0 cm margins is recommended 1, 2
• For invasive melanoma ≤2 mm thickness: 1 cm margins 1, 2
• For invasive melanoma >2 mm thickness: 2 cm margins 1, 2
• Critical caveat: Acral sites (palms, soles, subungual areas) frequently require narrower margins to preserve function, though sub-1 cm margins for invasive melanomas at anatomically constrained acral sites are generally not recommended until further studies are available 1
• Depth of excision should extend to (but not including) the fascia 1

Sentinel Lymph Node Biopsy

• Indicated for: Melanomas with Breslow thickness >1 mm, or >0.75 mm with high-risk features (ulceration, elevated mitotic rate) 1, 2
• Should be performed before wide excision, ideally in the same operative setting 1
• Important consideration: ALM is more likely to present with thicker tumors, ulceration, and lymph node positivity compared to non-acral melanomas, making SLNB particularly relevant 3

Complete Lymph Node Dissection

• Therapeutic lymph node dissection of the entire regional basin is required when sentinel nodes are positive or when there are clinically evident regional metastases 4, 2
• The goal is R0 resection; incomplete resection negates survival benefit 4

Adjuvant Therapy After Complete Resection (Stage III)

First-Line Adjuvant Options

• Anti-PD-1 monotherapy (pembrolizumab or nivolumab) is the preferred first-line adjuvant option after complete surgical resection of stage III disease 4
• Combination ipilimumab plus nivolumab is considered for high-risk features, though it carries significantly higher toxicity including severe colitis and endocrinopathies 1, 4
• BRAF/MEK inhibitor combination is reserved for BRAF-mutated disease requiring rapid disease control 4

Molecular Testing Requirements

• Mandatory: BRAF mutation testing in all patients with stage III/IV disease 4
• If BRAF-negative, test for NRAS and c-KIT mutations, as ALM has a distinct molecular profile with higher frequency of KIT mutations compared to non-acral melanomas 2

Adjuvant Radiation Therapy

• Consider adjuvant radiation after resection of bulky disease, when R1 resection cannot be re-excised, or after lymph node dissection in high-risk situations (multiple bulky lymph node metastases) 1, 4
• Postoperative irradiation reduces locoregional relapse risk by approximately 50% but does not impact overall survival 1

Treatment of Locoregional Disease

In-Transit Metastases

• Resectable disease: Surgical removal including the surrounding lymph node region 1
• Unresectable in-transit metastases of the limbs without distant metastases: Isolated limb perfusion using melphalan and/or tumor necrosis factor-α 1, 2
• Alternative approaches: Electrochemotherapy or intralesional therapy with T-Vec (talimogene laherparepvec) 1

Treatment of Metastatic Disease (Stage IV)

Systemic Therapy Selection

For BRAF Wild-Type Disease:

• First-line: Anti-PD-1 monotherapy (pembrolizumab or nivolumab) 4
• For symptomatic, bulky, or rapidly progressive disease: Combination ipilimumab/nivolumab 4
• Important caveat: ALM has a suppressed immune environment and lower tumor mutational burden compared to non-acral melanomas, which may limit response to immunotherapy 5, 6

For BRAF-Mutated Disease:

• First-line: BRAF/MEK inhibitor combination therapy 4
• Alternative: Combination ipilimumab/nivolumab has shown particular benefit for BRAF-mutant acral melanoma 5

Novel Therapies

• Adoptive cell transfer of tumor-infiltrating lymphocytes (ACT-TIL) has demonstrated a 43% objective response rate in metastatic acral melanoma, comparable to non-acral melanoma despite lower tumor mutational burden 6
• Enrollment in clinical trials is strongly encouraged given the rarity and unique biology of ALM 1, 2

Palliative Chemotherapy

• For advanced disease with multiple metastases, well-tolerated cytostatics such as dacarbazine, taxanes, or fotemustine may be used 2
• Palliative radiation achieves 49-77% overall response rates for symptomatic metastases 4

Surveillance and Monitoring

Staging Workup Before Aggressive Treatment

• Mandatory imaging: CT chest/abdomen/pelvis and/or PET scan to exclude distant metastases before undertaking aggressive local surgical treatments 1, 4
• Brain MRI: Essential given melanoma's propensity for CNS metastases 4

Follow-Up During Treatment

• CT chest/abdomen/pelvis every 2-3 months initially to assess response 4
• Brain MRI at baseline and during follow-up 4
• Close monitoring for immune-related adverse events with immunotherapy 4

Critical Prognostic Considerations

• Stage-specific survival: ALM has worse survival compared to non-ALM melanomas when stratified by stage, most notably in stage III patients (5-year survival 47.5% vs 56.7%) 3
• Adverse prognostic factors: Older age, male sex, higher comorbidity burden, increased tumor thickness, ulceration, positive lymph nodes, and positive margins independently predict lower survival 3
• Multimodality therapy (surgery plus systemic therapy and/or radiation) is associated with higher survival in stage III patients 3
• Diagnostic delay: ALM frequently presents at more advanced stages due to diagnostic difficulty and delays, contributing to worse outcomes 3, 7, 8