Malignant Melanoma Guidelines

Updated: Sep 01, 2020
  • Author: Winston W Tan, MD, FACP; Chief Editor: Dirk M Elston, MD  more...
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Guidelines

Guidelines Summary

Guidelines contributors:  Wesley Wu, MD,  Resident Physician, Department of Dermatology, Baylor College of Medicine; Mohsin R Mir, MD, Director, High Risk Skin Cancer Clinic, Assistant Professor, Mohs Surgery, Laser and Cosmetic Surgery, Department of Dermatology, Baylor College of Medicine

Screening

In 2016, the U.S. Preventive Services Task Force (USPSTF) concluded there is not enough evidence to recommend for or against routine screening (total body examination by a primary care physician or patient self-examination) for early detection of skin cancers in the adult general population. [87]  

The USPSTF did note the following clinical considerations:

  • Skin cancer of any type occurs more commonly in men than in women and among persons with a fair complexion, persons who use indoor tanning beds, and persons with a history of sunburns or previous skin cancer. 
  • Specific risk factors for melanoma include having an atypical mole, multiple (ie, ≥100) moles, and having a family history of melanoma.
  • The risk of melanoma increases with age; the median age at diagnosis is 63 years, and the median age at death is 69 years.
  • Clinical visual skin examination should assess skin lesions for asymmetry, border irregularity, color variability, diameter greater than 6 mm or evolution over time (ABCDE criteria)

The American Academy of Dermatology (AAD) promotes free skin examinations by volunteer dermatologists for the general population through the Academy's SPOTme™ Screening Program. The program also provides education about the importance of sun protection and early cancer detection. [88]

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Clinical Presentation and Workup

Guidelines from the American Academy of Dermatology (AAD), established in 2011 and updated in 2019, are as follows [89, 90] :

  • Skin biopsy remains the first step to establish a definitive diagnosis of cutaneous melanoma.

  • Preferred biopsy technique is a narrow excisional/complete biopsy with 1- to 3-mm margins that encompass the entire breadth of lesion and is of sufficient depth to prevent transection at the base. Diagnostic excisional biopsy can be accomplished by (1) elliptical (fusiform) excision, (2) punch excision around the clinical lesion, or (3) deep shave/saucerization to a depth below the anticipated plane of the lesion, usually extending to the deep reticular dermis.

  • Partial/incomplete sampling (incisional biopsy) is acceptable for lesions whose large size or location in a challenging anatomic site (eg, facial, acral) precludes excisional biopsy, and for lesions with low clinical suspicion or uncertainty of diagnosis. Such biopsies should include the most clinically and/or dermoscopically atypical portion(s) of the lesion

  • Narrow-margin excisional biopsy may be performed if an initial partial biopsy is inadequate for diagnosis or microstaging, but it should not generally be performed if the initial specimen meets the criteria for consideration of sentinel lymph node biopsy.

  • Dermoscopy can improve diagnostic accuracy in lesions of clinical concern; it may help direct optimal and adequate tissue sampling of very large lesions or those in cosmetically or functionally sensitive areas.

  • Prebiopsy photographs are an important aid to clinical/pathologic correlation and help to prevent wrong-site surgery if further treatment is required. Photographs may be taken by the patient and/or health care provider and should include a regional photograph that encompasses anatomic landmarks.

  • Findings from history and physical examination should direct need for further studies to detect local, regional, and distant metastasis

  • Ancillary diagnostic molecular techniques (eg, comparative genomic hybridization; fluorescence in situ hybridization, gene expression profiling [GEP]) may be used for equivocal melanocytic neoplasms, but routine molecular testing, including GEP, for prognostication is discouraged until better use criteria are defined. Testing of the primary cutaneous melanoma for oncogenic mutations (eg, BRAF, NRAS) is not recommended in the absence of metastatic disease.

The 2015 guidelines from the European Society for Medical Oncology (ESMO) require diagnosis based on a full-thickness excisional biopsy with a minimal side margin that has been processed by an experienced pathology institute. Histology reports should include the following [91] :

  • Information on the type of melanoma
  • Actinic damage
  • Maximum vertical thickness in millimetres
  • Information on mitotic rate in case of pT1
  • Presence of ulceration
  • Presence and extent of regression
  • Clearance of the surgical margins

Physical examination with special attention to other suspicious pigmented lesions, tumour satellites, in-transit metastases, regional LN and distant metastases is requried. Imaging is not needed for low-risk melanomas but is required in higher tumor stages for accurate staging. [91]

The National Comprehensive Cancer Network (NCCN) supports the concept that most melanoma recurrences are diagnosed clinically. Current NCCN guidelines state that no further workup (ie, baseline laboratory tests and imaging studies) is required in stage 0 (melanoma in situ) and for asymptomatic patients with stage IA, IB, or IIA melanoma. (Physician Quality Reporting System [PQRS] measure #224 concerns overutilization of imaging studies in melanoma.)

Current NCCN guidelines do not recommend surveillance (follow-up) laboratory or imaging studies for asymptomatic patients with stage IA, IB, and IIA melanoma (ie, tumors ≤4 mm depth). Imaging studies (chest radiograph, CT and/or PET-CT) should be obtained as clinically indicated for confirmation of suspected metastasis or to delineate the extent of disease. [21]

The NCCN advises that imaging studies may be considered to screen for recurrent/metastatic disease in patients with stage IIB-IV disease, although this recommendation remains controversial. Routine laboratory or radiologic imaging in asymptomatic melanoma patients of any stage is not recommended after 5 years of follow-up. [21]

While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum lactate dehydrogenase (LDH) levels are incorporated into the American Joint Committee on Cancer (AJCC) melanoma staging guidelines for the classification of stage IV (distant) disease. Elevated LDH levels are associated with worse survival in this subgroup. [25]

Joint guidelines from the European Dermatology Forum, the European Association of Dermato-Oncology, and the European Organization for Research and Treatment of Cancer include the following recommendations on diagnosis of melanoma [92] :

  • The 8 th edition of the AJCC staging manual should be used for classification into prognostic stages.
  • When melanoma is suspected based on clinical findings, it should be confirmed using histopathology studies.
  • Dermatoscopy should be used for assessing all nonpigmented and pigmented skin lesions. Training in dermatoscopy is considered mandatory.
  • Use whole-body photography with sequential examinations when assessing high-risk patients for early melanoma detection.
  • Use sequential digital dermatoscopy to help improve early melanoma detection; this technique should be used in high-risk patients in whom the total nevus count is high.
  • The use of confocal laser microscopy can be considered for the further evaluation of clinically or dermatoscopically equivocal skin lesions.
  • Ultrasonography on locoregional lymph nodes should be performed  as part of the initial workup for all primary melanomas staged pT1b or higher.
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Surgical Management

American Academy of Dermatology

American Academy of Dermatology (AAD) recommendations for surgical management of primary cutaneous melanoma are as follows [90] :

  • Surgical excision with histologically negative margins is the recommended and first-line treatment for primary cutaneous melanoma of any thickness, as well as for melanoma in situ.
  • Surgical margins should be based on tumor thickness. 
  • Depth of excision is recommended to (but not including) the fascia.
  • Sentinel lymph node biopsy, when indicated, should be performed before wide excision of the primary tumor, and in the same operative setting, whenever possible.
  • Mohs micrographic surgery or staged excision with paraffin-embedded permanent sections may be utilized for melanoma in situ, lentigo maligna type, on the face, ears, or scalp for tissue-sparing excision and exhaustive histologic assessment of peripheral margins.

European Society for Medical Oncology

The European Society for Medical Oncology (ESMO) updated its guidelines on the management of locoregional melanoma in 2020.

Wide local excision:

  • In the context of resectable clinical stage III disease, primary melanomas should be removed with clear margins to ensure local control. Wide local excision (WLE), ideally with a clinical 1 cm margin, is advised, with primary closure to avoid reconstruction whenever possible.
  • In the context of clinical stage IV disease, in the absence of symptoms or need for diagnostic tissue, there is no need to resect the primary tumor. If there is an indication to resect the primary lesion, resection should be with clear margins, but without additional safety margins.

Radical lymph node dissection:

  • Radical lymph node dissection is recommended for cases of clinically detected lymph node metastases in resectable stage III disease after pathological assessment (cytology or histology of lesion preoperatively) and adequate staging.
  • When lymph node surgery is indicated, radical node dissection is recommended over “node picking” (ie, removal of only lymph nodes with clinically apparent disease).
  • Groin: If imaging does not show any iliac involvement, an inguinal dissection is sufficient. If iliac disease is also present, a combined ilio-inguinal dissection should be performed.
  • Axilla: Complete clearance of the axilla, including level I–III, should be performed.
  • Neck: Modified radical neck dissection is recommended. Parotidectomy should be performed only if there is evidence of involvement of the parotid.

Treatment of satellite or in-transit metastases:

  • For resectable in-transit metastases that can comprise few, small, and non–rapidly-recurrent lesions, resection with clear margins—but without additional safety margins—is recommended. Extensive and multiple repeated resections and reconstructions should be avoided.
  • Unresectable satellite/in-transit metastases, or inoperable primary tumors of the limbs without additional metastases, may be treated with locoregional treatments (eg, isolated limb perfusion or infusion, talimogene laherparepvec [T-VEC], electrochemotherapy, 10% rose Bengal solution [PV-10]).

Adjuvant radiotherapy after node dissection:

  • For patients with advanced stage III disease that has been treated with lymphadenectomy, the primary recommendation is adjuvant systemic therapy and observation, reserving additional surgery and radiotherapy (RT) for any recurrent disease. However, adjuvant RT could be useful for high-risk patients where regional control is a major issue and/or where systemic therapy is not possible.

Neoadjuvant therapy:

  • For easily resectable stage III disease with acceptable surgical morbidity, neoadjuvant strategies should be considered only in the context of a clinical trial. Outside of a clinical trial, neoadjuvant strategies should be considered for technically resectable but bulky nodal and/or in-transit disease when surgery will be associated with significant morbidity, likely to result in positive resection margin status, or necessitate postoperative RT.
  • Continuing treatment after surgery should be considered based on the pathological response evaluation of the surgical specimen.
  • In principle, the standard surgical approach should be used after neoadjuvant therapy until studies show that it is safe to omit or modify surgery. Tailoring of the extent of surgery can be considered if there is a major radiological or pathological response for disease that extends outside of the nodal basin.

BRAF-mutated melanomas:

  • Current evidence suggests that patients with BRAF-mutated melanoma can derive a recurrence-free survival benefit from either adjuvant BRAF/MEK inhibition or adjuvant PD-1 blockade. In the absence of a direct efficacy comparison, individual treatment decisions should be made with the patient, factoring in the toxicity profiles for the different adjuvant treatment approaches.

Adjuvant therapy in stage IIIA melanoma:

  • An absolute survival benefit of 5% at 5 years would be considered strong evidence to recommend adjuvant therapy in stage III melanoma. However, surrogate markers of overall survival benefit are currently acceptable.
  • There is currently insufficient evidence to support the routine use of adjuvant therapy in stage IIIA melanoma.
  • There may be some subsets of stage IIIA patients with a higher risk of relapse (eg, tumor burden in sentinel node >1 mm). In these patients, a balanced discussion of risk reduction and long-term side effects of adjuvant therapy can be considered.

Management of toxicity in the adjuvant setting:

  • The management of toxicity from adjuvant therapy should be done according to the established management algorithms for metastatic disease.
  • When adjuvant immunotherapy is withheld because of severe toxicity, the recommendation is neither to restart treatment nor to start an alternative adjuvant therapy.

Adjuvant therapy for in-transit metastases and resected stage IV disease:

  • Adjuvant dabrafenib plus trametinib can be considered in patients with completely resected BRAF V600–mutated stage IV melanoma if there is a contraindication to immunotherapy.
  • Adjuvant therapy may be considered for patients with completely resected in-transit melanoma or microsatellites, including patients without evidence of nodal metastasis.
  • In cases of resectable locoregional relapse in patients receiving adjuvant therapy, whether to resume adjuvant therapy after complete resection remains controversial in the absence of prospective clinical data.
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Sentinel Lymph Node Dissection

The melanoma guidelines from the National Comprehensive Cancer Network (NCCN) do not recommend sentinel lymph node biopsy for patients with in situ melanoma (stage 0). [21]

Evidence supporting routine sentinel lymph node biopsy for patients with thin melanomas (T1; Breslow thickness < 1 mm) is lacking and recommendations remain controversial. The NCCN does not recommend sentinel lymph node biopsy for patients with lesions 0.75 mm or thinner. [2]

The 2020 update of the European Society for Medical Oncology melanoma guidelines includes the following recommendations on sentinel lymph node biopsy [93] :

  • Sentinel lymph node biopsy is recommended for staging in melanomas of stage pT2a or higher (> 1.0 mm Breslow thickness).
  • Sentinel lymph node biopsy should be discussed with patients with a melanoma of stage pT1b (ie, with tumor thickness > 0.8–1.0 mm, or <  0.8 mm with ulceration).
  • Sentinel lymph node biopsy is not routinely recommended for patients with a melanoma of stage pT1a (eg, with tumor thickness <  0.8 mm and no ulceration).
  • Sentinel lymph node biopsy can be discussed in pT1a for special cases (eg, ≥3 mitoses/mm 2, positive deep margin, or when Breslow thickness cannot be reliably determined [pTx]).

The American Academy of Dermatology (AAD) recommends consideration of sentinel lymph node biopsy in patients with lesions, including those less than 0.76 mm, with any of the following high-risk features [89, 90] :

  • Ulceration
  • Mitosis
  • Angiolymphatic invasion
  • Positive deep margin
  • Young patient age

However, data suggest that the presence of a single mitotic figure may not correlate well with sentinel node status in thin lesions. [94]  In addition, the presence of regression in thin lesions is associated with a lower risk of nodal metastasis. [95]

The 2018 update of joint guidelines from the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) includes the following recommendations [27] :

  • Routine sentinel lymph node biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions < 0.8 mm in Breslow thickness).
  • Sentinel lymph node biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure.
  • Sentinel lymph node biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of >1.0 to 4.0 mm).
  • Sentinel lymph node biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm.

In the case of a positive sentinel lymph node biopsy, completion lymph node dissection (CLND) or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathologic factors. For higher-risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. [27]

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Mohs Surgery

The NCCN cites a study of Mohs micrographic surgery (MMS) that employed MMS enhanced by immunohistochemical staining as the primary treatment modality for melanoma in situ, which resulted in 99% removal of melanoma in situ when a total surgical margin of 9 mm was used, versus an 86% rate of removal with 6-mm margins. The stain comprised antibodies to a melanoma antigen recognized by T cells (MART-1). [21, 96]

The appropriate-use criteria for MMS from the AAD, American College of Mohs Surgery (ACMS), American Society for Dermatologic Surgery Association (ASDSA), and the American Society for Mohs Surgery (ASMS) further state that MMS is appropriate for all recurrent melanoma in situ and lentigo maligna, as well as primary lesions at the following sites [97] :

  • Head
  • Neck
  • Hands
  • Feet
  • Pretibial surface
  • Nails
  • Ankles

For melanoma in situ, lentigo maligna type type, the AAD recommends permanent section analysis of the central MMS debulking specimen to identify and appropriately stage potential invasive cutaneous melanoma. If invasive cutaneous melanoma is identified on an MMS section intraoperatively, the tissue should be submitted for formal pathology review. [90]

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Wide Excision Surgical Margins

For wide excision of primary melanoma, the NCCN, AAD, and ESMO practice guidelines agree on the following surgical margin recommendations for primary melanoma [21, 90, 91]

  • Tumor in situ – Margin size 0.5-1.0 cm
  • Tumor ≤ 1 mm – Margin size 1 cm
  • Tumor > 1 to 2 mm – Margin size 1-2 cm
  • Tumor > 2 mm – Margin size 2 cm

The AAD guidelines note that margins may be narrower to accommodate function and/or anatomic location.However, for primary invasive melanomas at anatomically constrained sites (eg, head and neck, acral), margins of < 1 cm (by either wide excision or Mohs micrographic surgery) are generally not recommended until further studies are available. [90]

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Radiation Therapy

NCCN guidelines recommend consideration of radiation therapy in the following situations [21] :

  • Primary disease: As adjuvant treatment in selected patients with factors that include deep desmoplastic melanoma with narrow margins, extensive neurotropism, or locally recurrent disease

  • Regional disease: As adjuvant treatment following resection of category 2B nodes and LDH < 1.5 times the upper limit of normal, and extranodal tumor extension; as palliative treatment for unresectable disease

  • Metastatic disease: As either adjuvant or primary treatment for brain metastases

ESMO recommends considering stereotactic radiation of regional or single distant metastatic disease. [91]

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Treatment for Advanced Melanoma

NCCN recommendations for treatment of melanoma stage IV disease with distant metastasis include the following [21] :

  • Treatment depends on whether melanoma is limited (resectable) or disseminated (unresectable)
  • In limited disease, resection is recommended; alternatively, observation or systemic therapy may be chosen
  • Treatment for limited disease includes clinical trial enrollment or systemic therapy 
  • For patients with unresectable disease without brain metastases, treatment includes systemic therapy; patients with brain metastases require treatment of the central nervous disease

First-line immunotherapy regimens for systemic therapy (category 1), according to the NCCN guidelines, are as follows [21] :

  • Anti–programmed cell death protein 1 (PD-1) monotherapy: Pembrolizumab or nivolumab 
  • Nivolumab/ipilimumab 

If the tumor contains a BRAF V600 activating mutation, category 1 recommendations for first-line therapy are as follows [21] :

  • Dabrafenib plus trametinib
  • Vemurafenib plus cobimetinib
  • Encorafenib plus binimetinib 

Second-line or subsequent therapy recommendations are as follows [21] :

  • Anti PD-1 monotherapy: Pembrolizumab or nivolumab
  • Nivolumab/ipilimumab
  • Targeted therapy if a BRAF V600 activating mutation is present: Dabrafenib/trametinib or vemurafenib/cobimetinib
  • Ipilimumab
  • High-dose interleukin-2 (IL-2)
  • Cytotoxic agents
  • Imatinib for tumors with activating mutations of KIT 

Joint guidelines from the European Dermatology Forum, the European Association of Dermato-Oncology, and the European Organization for Research and Treatment of Cancer include the following recommendations on adjuvant therapy in stage III disease [98] :

  • Stage IIIA-IIID and fully resected stage IV: Adjuvant therapy should be offered, with anti–PD-1 therapy or targeted therapy.
  • Stage IIIA-IIID and fully resected stage IV, regardless of mutational status: Adjuvant therapy can be offered, with anti–PD-1 therapy or targeted therapy.
  • Stage IIIA-IIID with BRAF-V600 E/K mutation: Adjuvant therapy can be offered, with BRAF/MEK inhibitor therapy.
  • Stage IIIA with nodal metastasis of < 1 mm in diameter: Risk-to-benefit ratio should be carefully discussed with the patient.

The joint European guidelines include the following recommendations for stage IV melanoma [98] :

  • First-line therapy in patients with stage IV disease is immunotherapy with checkpoint inhibitors; options include anti–PD-1 monotherapy and combination anti–PD-1 plus anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy.
  • In certain situations, such as in patients with stage IV melanoma and BRAF-V600 E/K mutation, an alternative to immunotherapy is first-line therapy with BRAF/MEK inhibitors.
  • Chemotherapy should only be considered if resistance to immunotherapy and targeted therapies is present.

The joint European guidelines include the following recommendations for brain metastases [98] :

  • Treat brain metastases with stereotactic radiotherapy.
  • Surgery is an option if stereotactic radiotherapy is not possible.
  • Do not use whole-brain radiotherapy for melanoma brain metastases.
  • Regarding systemic therapy for brain metastases, preferred therapy is combined immunotherapy. An alternative in patients with BRAF-V600 E/K mutations is targeted therapy.
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Follow-up for Melanoma Cancer Survivors

Follow-up guidelines from the National Comprehensive Cancer Network are listed below. [21]

Follow-up for stage 0 in situ is as follows:

  • At least annual skin examination for life
  • Educate patient in monthly self-examination of skin
  • Routine blood tests are not recommended
  • Routine imaging to screen for asymptomatic recurrence or metastatic disease is not recommended

Follow-up for stage IA-IIA is as follows:

  • History and physical examination (H&P), with emphasis on lymph nodes and skin, every 6-12 mo for 5 y, then annually as clinically indicated
  • At least annual skin examination for life
  • Educate patient in monthly self-examination of skin and lymph nodes
  • Routine blood tests are not recommended
  • Routine imaging to screen for asymptomatic recurrence or metastatic disease is not recommended
  • Imaging as indicated to investigate specific signs or symptoms

Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:

  • H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2 y, then annually as clinically indicated
  • Routine blood tests are not recommended
  • Imaging as indicated to investigate specific signs or symptoms
  • Consider imaging every 3–12 mo for 2 y, then every 6–12 mo for another 3 y (unless otherwise mandated by clinical trial participation) to screen for recurrence or metastatic disease
  • Routine imaging to screen for asymptomatic recurrence or metastatic disease is not recommended after 5 y
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