How should acral melanoma be diagnosed, staged, and treated, including biopsy, surgical margins, sentinel lymph‑node biopsy, adjuvant pembrolizumab, and systemic therapy options?

Acral Melanoma: Diagnosis, Staging, and Treatment

Diagnosis and Biopsy Technique

Acral melanoma should be diagnosed with a full-thickness excisional biopsy including a 2-5 mm margin of normal skin laterally and a cuff of subdermal fat. 1

• Shave and punch biopsies are contraindicated as they make pathological staging impossible and cannot accurately assess Breslow thickness 1
• For subungual melanomas specifically, the nail must be removed and the nail matrix adequately sampled by surgeons experienced in these procedures 1
• Incisional biopsy is occasionally acceptable for acral sites when full excision would compromise function, though this should be performed by specialists, not in primary care 1

Clinical Recognition

• Use the ABCDE rule: Asymmetry, Border irregularities, Color heterogeneity, Diameter >6 mm (though many are now <5 mm), and Dynamics/Evolution 1
• Apply the "ugly duckling" concept: acral melanomas often appear different from the patient's other pigmented lesions 1
• Dermoscopy by an experienced physician significantly enhances diagnostic accuracy 1

Pathology Reporting Requirements

The histopathology report must include 1:

• Breslow thickness measured to the nearest 0.1 mm from the granular layer (or ulcer base if ulcerated) to the tumor base
• Mitotic rate (particularly critical for tumors <1 mm)
• Presence of ulceration
• Surgical margin clearance status
• Melanoma subtype (acral lentiginous melanoma specifically)
• Anatomical site and degree of sun damage
• Presence and extent of regression
• Clark level (optional, as Breslow thickness is more prognostically reliable)

Staging Workup

Physical Examination

• Mandatory examination for tumor satellites, in-transit metastases, regional lymph nodes, and hepatomegaly 1

Imaging Based on Tumor Stage

For pT1a (low-risk) melanomas: No additional imaging is necessary 1

For pT1b-pT3a: Ultrasound of regional lymph nodes is recommended 1

For pT stages >pT3a: CT or PET scans are recommended before surgical treatment and sentinel node biopsy 1

For advanced disease planning: Mandatory CT chest/abdomen/pelvis and/or PET scan to exclude distant metastases before aggressive local treatments 2

Brain MRI: Essential given melanoma's propensity for CNS metastases, particularly when planning systemic therapy 2

Molecular Testing

Mutation testing is mandatory in patients with advanced disease (unresectable stage III or stage IV) and highly recommended in high-risk resected disease (stage IIc, IIIb-IIIc). 1

• Test for BRAF mutations first 1
• If BRAF wild-type, test for NRAS and c-KIT mutations as acral lentiginous melanomas have a higher probability of c-KIT mutations compared to other melanoma subtypes 1
• Mutation analysis must be performed in accredited/certified institutes with quality controls 1
• Do not perform mutational testing on primary tumors without metastases 1

Surgical Treatment of Primary Tumor

Surgical Margins

Wide excision with histologically negative margins is the primary treatment, with margins determined by Breslow thickness: 2

• In situ melanoma: 0.5-1.0 cm margins 1, 2
• Invasive melanoma ≤2 mm thickness: 1 cm margins 1, 2
• Invasive melanoma >2 mm thickness: 2 cm margins 1, 2

Special Considerations for Acral Sites

• Acral sites 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, 2
• Modifications with reduced safety margins are acceptable for preservation of function in acral melanomas and should be performed with micrographic surgery 1
• Depth of excision should extend to (but not including) the fascia 2

Staged Excision and Mohs Surgery

• For lentigo maligna type melanoma in situ on cosmetically sensitive areas, Mohs micrographic surgery or staged excision with permanent sections may be utilized for tissue-sparing excision 1, 3
• Permanent section analysis of the central debulking specimen is mandatory to identify potential invasive melanoma, as sampling error can miss microinvasion 3

Sentinel Lymph Node Biopsy (SLNB)

SLNB is recommended for melanomas with Breslow thickness >1 mm and for tumors >0.75 mm with additional risk factors such as ulceration or elevated mitotic rate (pT1b). 1

• SLNB should be performed before wide excision if the tumor is found to be invasive 3
• SLNB should only be performed in experienced centers by skilled teams 1
• Complete lymphadenectomy of regional lymph nodes should be discussed with the patient if the sentinel node is positive, though this offers only relapse-free survival benefit without proven overall survival benefit 1
• Routine elective lymphadenectomy or radiation to regional lymph nodes is not recommended 1

Adjuvant Therapy for Stage III Disease (After Complete Resection)

Anti-PD-1 monotherapy (pembrolizumab or nivolumab) is the preferred first-line adjuvant option after complete surgical resection of stage III disease. 2

• Combination ipilimumab plus nivolumab is considered for high-risk features, though it carries significantly higher toxicity including severe colitis and endocrinopathies 2
• BRAF/MEK inhibitor combination is reserved for BRAF-mutated disease requiring rapid disease control 2
• Historical note: High-dose interferon-α showed only disease-free survival benefit without overall survival benefit and must be balanced against significant toxicity 1

Treatment of Locoregional Metastatic Disease

Resectable In-Transit Metastases

• Resectable in-transit metastases should be surgically removed including the surrounding lymph node region 2
• Complete resection of positive regional lymph nodes must be performed for all patients tolerating surgery 1, 2

Unresectable In-Transit Metastases

• Unresectable in-transit metastases of the limbs without distant metastases can be treated with isolated limb perfusion using melphalan and/or tumor necrosis factor-α 1, 2
• This treatment requires major surgery and should be restricted to experienced centers 1
• Radiation therapy may be used as an alternative 1

Systemic Therapy for Stage IV Disease

BRAF Wild-Type Disease

First-line treatment is anti-PD-1 monotherapy (pembrolizumab or nivolumab) 2

BRAF-Mutated Disease

First-line treatment is BRAF/MEK inhibitor combination therapy 2

General Considerations

• Patients should preferentially be treated within clinical trials when available 1
• For palliative chemotherapy in patients with preserved performance status, single agents (dacarbazine, vindesine, temozolomide, taxanes, fotemustina) may be considered 1

Surveillance and Follow-Up

Imaging Schedule

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

Patient Education

• Patients must receive instructions on avoiding sunburns and prolonged unprotected UV exposure (though acral melanoma is not UV-related, patients remain at risk for other melanomas) 1
• Lifelong regular self-examination of skin and peripheral lymph nodes 1
• Patients with prior melanoma or atypical mole syndrome should be taught melanoma recognition and perform monthly self-examination 1

Critical Pitfalls to Avoid

• Never perform shave or punch biopsies on suspected acral melanomas—this compromises staging 1
• Do not delay referral: All patients with lesions removed by general practitioners subsequently reported as melanoma should be referred immediately to specialists 1
• Avoid inadequate initial biopsy: If clinical evaluation suggests the initial biopsy was inadequate for microstaging, perform a narrow-margin excision to obtain deeper tissue before proceeding to wide excision 3
• Do not skip molecular testing in advanced disease—c-KIT mutations are more common in acral melanomas and may guide targeted therapy 1
• Recognize delayed diagnosis risk: Acral melanomas are more likely to be diagnosed at later stages with worse prognosis, particularly in non-Caucasian populations where this is the most common melanoma subtype 4, 5, 6