Cutaneous Melanoma Guidelines

Updated: Mar 22, 2022
  • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
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Clinical Practice Guidelines

American Academy of Dermatology clinical practice guidelines

Guidelines have been published by the American Academy of Dermatology (last in 2019) regarding biopsy, pathology reporting, and management of primary cutaneous melanoma. [66]

Evidence strongly indicates that Breslow thickness, ulceration, and dermal mitotic rate are important predictors of patient outcome in primary cutaneous melanoma.

The recommended first-line treatment for any-thickness primary cutaneous melanoma, as well as for melanoma in situ, is surgical excision with histologically negative margins; tumor thickness should dictate the margins.

Surgical margins for invasive cutaneous melanoma, as measured clinically around the primary tumor, should be a minimum of 1 cm and a maximum of 2 cm, although narrower margins can be used to accommodate function and/or anatomic location. It is recommended that the excision be as deep as, but not inclusive of, the fascia.

It is not recommended that asymptomatic patients with newly diagnosed stage 0-II primary cutaneous melanoma undergo baseline radiologic imaging and laboratory studies. Routine testing of the primary tumor with available gene expression profiling tests is not recommended.

For cutaneous melanoma at baseline, radiologic imaging and laboratory studies should be conducted only to assess the specific signs or symptoms of synchronous metastasis (regional nodal or distant).

At baseline or when physical examination of lymph nodes is equivocal and requires surveillance, the use of lymph node ultrasonography is encouraged. Surveillance with such imaging is also encouraged in the following patients:

  • Those who meet criteria for sentinel lymph node biopsy (SLNB) but do not undergo the procedure
  • Patients in whom SLNB is not possible or is technically unsuccessful (eg, when lymphoscintigraphic dye migration has failed and a draining sentinel lymph node cannot be identified)
  • Those with a positive SLNB who do not undergo complete lymph node dissection

Regular clinical follow-up represents the most important strategy for detecting cutaneous melanoma recurrence. The need for further radiologic or laboratory studies to detect local, regional, or distant metastatic disease should be determined via history (review of systems) and physical examination findings.

Patients should be taught self-examination of the skin and lymph nodes in order to detect recurrent disease or new primary cutaneous melanoma.

For the first 3 months of BRAF inhibitor monotherapy, patients with numerous squamoproliferative neoplasms should undergo dermatologic evaluation every 2-4 weeks, although less skin toxicity is associated with the standard treatment, combination BRAF/MEK inhibition.

Patients being treated with immune checkpoint inhibitors should undergo dermatologic evaluation within the first month of therapy, with such assessment being continued as needed to manage dermatologic adverse effects, which can have delayed onset and develop or persist off therapy.

National Comprehensive Cancer Network clinical practice guidelines

Guidelines on cutaneous melanoma management and systemic therapy for metastatic or unresectable cutaneous melanoma and recommendations for adjuvant systemic therapies were revised in December 2021 (v1.2022) by the National Comprehensive Cancer Network (NCCN). The NCCN clinical practice guidelines are continually updated based on new evidence and FDA approval for therapeutics. [38]

Systemic therapy for metastatic or unresectable disease

Recommended first-line therapy (metastatic or unresectable disease):

  • Anti–programmed cell death protein 1 (PD1) monotherapy: pembrolizumab, nivolumab
  • Combination nivolumab/ipilimumab
  • Combination targeted therapy for BRAF V600–activating mutation: dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib
  • Other recommended regimens: pembrolizumab/low-dose ipilimumab
  • Combination targeted therapy and immunotherapy if BRAF V600-activiting mutation present: vemurafenib/cobimetinib + atezolizumab

Recommended second-line or subsequent therapy

  • Preferred regimens: Anti-PD1 monotherapy (pembrolizumab, nivolumab); nivolumab/ipilimumab; pembrolizumab/low-dose ipiliumab for tumors that progressed following prior anti-PD1 therapy); combination targeted therapy for BRAF V600–activating mutation (dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib)
  • Other regimens: ipilimumab; high-dose interleukin 2 (IL-2)
  • Useful in certain circumstances: imatinib for tumors with KIT-activating mutations; larotrectinib or entrectinib for NTRK gene fusion-positive tumors; binimetinib for NRAS-mutated tumors that progressed following prior immune checkpoint inhibitor therapy; cytotoxic agents (mainly for palliative therapy); ipilimumab/intralesional talimogene laherparepvec (T-VEC); pembrolizumab/levatinib

Recommended adjuvant systemic therapies

For stage III (sentinel lymph node positive) disease:

  • Primary treatment: Wide local excision of primary lesion with positive sentinel lymph node biopsy, followed by nodal basin ultrasound (generally preferred) or complete lymph node dissection
  • Recommended adjuvant options: systemic therapy based on risk of recurrence: nivolumab, pembrolizumab, dabrafenib/trametinib for BRAF-activating mutation, or observation

For stage III (clinically positive nodes [no in-transit or satellite metastases]) disease, including recurrence:

  • Primary treatment: Wide local excision of primary lesion and therapeutic lymph node dissection or consideration of neoadjuvant therapy, preferably in the context of a clinical trial
  • Recommended adjuvant options: Preferred: nivolumab, pembrolizumab, dabrafenib/trametinib for BRAF-activating mutation and/or locoregional therapy with radiation therapy to the nodal basin in selected high risk patients, or observation

For stage III (clinical or microscopic satellite/in-transit) disease, including recurrence:

  • Primary treatment for limited resectable disease: complete surgical excision to clear margins, talimogene laherparepvec (T-VEC)/intralesional therapy, or systemic therapy
  • Recommended adjuvant options: nivolumab, pembrolizumab, dabrafenib/trametinib BRAF-activating mutation, observation
  • Primary treatment of unresectable disease: Preferred: systemic therapy with above agents
  • Local therapy options: intralesional injection (T-VEC, IL-2), topical imiquimod for superficial dermal lesions, radiation therapy, palliation of symptomatic disease (limited excision, ablation), regional therapy with isolated limb infusion/perfusion with melphalan

For stage IV oligometastatic disease:

  • Primary treatment: metastasis-directed therapy with resection or stereotactic ablative therapy or systemic therapy
  • Recommended options: Preferred: nivolumab, pembrolizumab; Other recommended regimens: nivolumab/ipilimumab, combination BRAF/MEK inhibitors for BRAF-activating mutation; Useful in certain circumstances: ipilimumab if prior exposure to anti-PD1 agents

For stage IV widely disseminated disease:

  • Without brain metastasis: Preferred: systemic therapy; For extracranial lesions: intralesional T-VEC, consider palliative resection and/or radiation therapy for symptomatic extracranial disease, best supportive care; multidisciplinary consultation for brain metastasis, with above options