Malignant Melanoma Guidelines

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 asymptomatic general adult populations.[1] However, these recommendations are currently in the process of being updated. While the USPSTF has not provided formal guidance on whether high-risk adult populations should be screened, the Australian Cancer Network and the Canadian Cancer Society both suggest screening in high-risk populations.[2, 3] See "Follow-up for Melanoma Cancer Survivors”, below, for skin surveillance guidelines of melanoma cancer survivors. 

The USPSTF provided the following clinical considerations[1] :

• 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 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, and evolution over time (ABCDE criteria).

Websites such as the American Academy of Dermatology (AAD) and The Skin Cancer Foundation provide education on self-examination.[4, 5] The AAD also 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.

There are three main methods to help clinically identify a melanoma[6] :

1. The “ugly duckling” sign (ie, a nevus that is obviously different from the others in a given individual) ^{[7, 8]}
2. The ABCDE rule of melanoma
3. The Glasgow revised seven-point checklist ^[9]

To improve early recognition of melanoma, National Comprehensive Cancer Network (NCCN) guidelines suggest using imaging technologies such as dermoscopy, sequential digital dermoscopy imaging, and total body photography.[10] With training, dermoscopy can be used to increase the sensitivity and specificity of a clinical diagnosis of melanoma, reducing the number of unnecessary biopsies.[11, 12] Dermatoscopic features of melanoma include the following:

• An atypical pigment network
• Irregular brown-black dots or globules
• Streaks
• Multiple and asymmetrically distributed colors
• A blue-white veil
• A polymorphic, vascular pattern

Sequential digital dermoscopy documentation can also be used for short- and long-term follow-up of patients with multiple atypical nevi for the detection of melanoma and to reduce the number of unnecessary excisions.[13] Total body photography, using comparison with baseline photographs at each follow-up examination, can also help with the clinical surveillance of new or changed lesions, especially in patients with numerous nevi.[14, 15]

A diagnosis of melanoma is histopathologic and therefore a biopsy is required. Most guidelines recommend a full-thickness biopsy for suspicious lesions. In the United States, both the AAD and the NCCN suggest that a superficial shave biopsy can be used for lesions of low suspicion for melanoma.[10, 16] However, the NCCN states that a broad shave biopsy may be optimal for histological assessment of melanoma in situ (MIS) or lentigo maligna (LM). This is in contrast to the revised United Kingdom guidelines, which suggest that shave biopsies should be avoided in all cases due to the risk of incorrect diagnosis.[17]

American Academy of Dermatology

Guidelines from the AAD, established in 2011 and updated in 2019, are as follows[16, 18] :

• 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. ^[19]
• 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.
• 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 the 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. ^{[20, 21, 22, 23, 10]}
• 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 thickest, most clinically and/or dermoscopically atypical portion(s) of the lesion. ^[24]
• 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. ^[25]
• A pathologist trained in evaluation of pigmented lesions ^[26] should be provided the following clinical information: age, gender, and anatomic location (including laterality). ^[27] Additional information that is strongly recommended includes: biopsy intent (excisional/complete vs partial/incomplete) and technique (elliptical, punch shave/saucerization); size of the lesion; clinical impression/differential diagnosis; macroscopic satellites; and a clinical photograph. 
• Based on their prognostic value, the pathology report should include the following histologic features as recommended by organizations including the American Joint Committee on Cancer (AJCC) and the College of American Pathologists ^{[28, 29, 30]} : tumor thickness (Breslow) to the nearest 0.1 mm, ulceration, size of specimen, peripheral and deep margin status (negative/positive [broad vs focal transection at deep margin]), and microsatellitosis. The College of American Pathologists 2020 protocol also noted that lymphovascular invasion, neurotropism, and regression are histopathologic elements required for wide excision specimens. Dermal mitotic rate (“hotspot” method; number of mitoses/mm ²) was included in the seventh edition of the AJCC staging system, but removed from the eighth edition. It is still recommended for synoptic summaries.
• Baseline radiologic imaging and laboratory studies are not recommended for asymptomatic patients with newly diagnosed stage 0-II primary cutaneous melanoma.
• Regular clinical follow-up is recommended. Findings from history and physical examination should direct need for further studies to detect local, regional, and distant metastasis. ^{[10, 18]}
• Surveillance imaging varies according to the risk of disease recurrence (as determined by stage of disease and other factors) and risk of new primary cutaneous melanoma (determined by mole pattern, presence of atypical nevi, and family history). Laboratory study surveillance of asymptomatic patients is not recommended.
• Patient education on self-examination of the skin and lymph nodes for detection of primary or recurrent disease is recommended.
• 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. ^{[31, 32, 33, 34]}
• Testing of a primary cutaneous melanoma for oncogenic mutations (eg, BRAF, NRAS, KIT) is not recommended in the absence of metastatic disease. ^[10]

National Comprehensive Cancer Network

NCCN guidelines support the concept that most melanoma recurrences are diagnosed clinically. Current NCCN guidelines recommend the following for biopsy of a suspicious pigmented lesion[10] :

• Excisional/complete biopsy (elliptical, punch, or saucerization/deep shave) with 1- to 3-mm margins is preferred. Avoid wider margins to permit accurate subsequent lymphatic mapping.
• The orientation of an elliptical/fusiform excisional biopsy should be planned with definitive wide local excision in mind (e.g., longitudinally [axially] and parallel to the underlying lymphatics on the extremities). 
• Full-thickness incisional or punch biopsy of clinically thickest or most atypical portion of lesion is acceptable in certain anatomic areas (e.g., palm/sole, digit, face, ear) or for very large lesions. Multiple "scouting" biopsies may help guide management for very large lesions.
• Superficial shave biopsy may compromise pathologic diagnosis and complete assessment of Breslow thickness, but is acceptable when the index of suspicion is low. However, a broad shave biopsy may be optimal for histologic assessment for melanoma in situ (MIS), lentigo maligna (LM) type (ie, melanoma on skin with high cumulative sun damage).
• Repeat narrow-margin excisional biopsy is recommended if an initial partial biopsy is inadequate for diagnosis or microstaging but should not be performed if the initial specimen meets criteria for sentinel lymph node biopsy (SLNB).

The biopsy should be reported by a pathologist experienced in melanocytic neoplasms. The following should be included in the pathology report: 

• Breslow thickness (reported to the nearest 0.1 mm)
• Ulceration
• Microsatellites
• Margin status

The following is encouraged to be included in the pathology report: 

• Macroscopic satellite lesions in the gross tumor specimen
• Dermal mitotic rate per mm2
• Lymphovascular/angiolymphatic invasion
• Histologic subtype (if desmoplastic, specify pure or mixed)
• Regression (if extensive [> 75%] or extending beneath measured Breslow thickness)
• Neurotropism/perineural invasion

Molecular testing should be considered for histologically equivocal lesions. The NCCN also noted that the utility of prognostic GEP testing remains unclear as an independent predictor of worse outcome, and was not superior to Breslow thickness or sentinel lymph node status, and should not replace pathological staging procedures. GEP testing has yet to receive approval from the US Food and Drug Administration (FDA), and further large prospective investigation and validity studies are required. 

Regarding genomic testing, the NCCN stated:

• For resected stage I–II cutaneous melanoma,  BRAF or next-generation sequencing (NGS) testing is not recommended unless it will inform clinical trial participation.
• For stage III cutaneous melanoma that are at high risk for recurrence and for whom future  BRAF-directed therapy may be an option,  BRAF mutation testing is recommended.
• For initial presentation with stage IV disease or clinical recurrence, obtaining tissue is recommended to determine alterations in  BRAF, and in the appropriate clinical setting,  KIT from either biopsy of the metastasis (preferred) or archival material if the patient is being considered for targeted therapy. Broader genomic profiling (eg, larger NGS panels,  BRAF non-V600 mutations) is recommended, especially if the test results might guide future treatment decisions or eligibility for participation in a clinical trial.
• If  BRAF single-gene testing was the initial test performed, and is negative, clinicians should strongly consider larger NGS panels to identify other potential genetic targets (eg, KIT,  BRAF non-V600).

NCCN recommendations for baseline imaging vary as follows[10]

• Asymptomatic patients with stage 0 (melanoma in situ), IA, IB, or II - Cross-sectional imaging is not recommended.
• Patients with stage IIIA (sentinel node positive) melanoma - Cross-sectional imaging may be considered.
• Patients with stage IIIB/C/D melanoma, and those with local satellite/in-transit recurrence or nodal recurrence - Cross-sectional imaging is recommended, with or without brain imaging.
• Patients with stage IV melanoma or recurrence with distant metastatic disease - Cross-sectional imaging with brain imaging is recommended.

In patients with true scar recurrence, imaging workup should be appropriate to the primary tumor characteristics and melanoma stage.

For surveillance (follow-up), the NCCN guidelines advise 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.[10] In patients with an equivocal lymph node exam, additional imaging can be considered with short-term follow-up. Additionally, for patients with a positive SLNB who did not have a complete lymph node dissection (CLND), regional lymph node ultrasonography (US) is preferred at a frequency consistent with the MSLT-II and DeCOG trials: every 4 months during the first 2 years, then every 6 months during years 3 through 5.[10]

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.[35]

European Society for Medical Oncology (ESMO)

The 2019 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 follow the eighth edition of the AJCC tumor, node, metastasis (TNM) classification and include the following[28, 36] :

• Maximum thickness in millimeters (Breslow) to the nearest 0.1mm
• Presence of ulceration
• Clearance of the surgical margins
• Mitotic rate and regression assessment 
• Anatomical site 
• Type of melanoma
• Actinic damage of the surrounding skin

ESMO guidelines consider mutation testing for actionable mutations mandatory in patients with resectable or unresectable stage III or stage IV melanoma, and highly recommended in high-risk resected disease stage IIC, but not for stage I or stage IIA–IIB. BRAF testing is mandatory. Physical examination with special attention to other suspicious pigmented lesions, tumor satellites, in-transit metastases, regional lymph nodes, and distant metastases is required. Imaging is not needed for low-risk melanomas (pT1a) but in higher-stage tumors (pT1b-pT4b), US, computed tomography (CT), brain magnetic resonance imaging (MRI), and positron emission tomography (PET) scans can be considered to allow proper tumor assessment for accurate staging.[36]

European Consensus-based Interdisciplinary Guidelines

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 and follow-up of melanoma[13] :

• 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.
• Dermoscopy should be used for assessing all nonpigmented and pigmented skin lesions. Training in dermoscopy is considered mandatory.
• Use whole-body photography with sequential examinations when assessing high-risk patients for early melanoma detection.
• Use sequential digital dermoscopy 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 dermoscopically 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.
• Stage-specific follow-up for detection of recurrence should be performed for at least 5 years.
• Follow-up for the detection of new primaries and other skin cancers should be performed for at least 10 years.

Surgical management is important for the diagnosis, staging, and optimal treatment of primary cutaneous melanoma. The recommendations for surgical management in melanoma are outlined below. 

American Academy of Dermatology

The AAD recommendations for surgical management of primary cutaneous melanoma are as follows[16] :

• 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

ESMO updated its guidelines on the surgical management of locoregional melanoma in 2020.[37]

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, 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.

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.

Wide local excision margins

For wide excision of primary melanoma, the AAD, NCCN, and ESMO practice guidelines agree on the following surgical margin recommendations for primary melanoma[10, 16, 36] : 

• 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.[16]

Mohs micrographic surgery

Mohs micrographic surgery (MMS) is a specialized surgical technique that can be used to treat recurrent and primary melanomas at specific anatomical sites.[38, 39, 40, 41] The NCCN states that the gold standard for histologic assessment of a melanoma excision is through the use of permanent sections.

MMS is supported by the AAD and American College of Mohs Surgery (ACMS) for use on melanoma in situ (MIS) and lentigo maligna (LM), and may be considered selectively in medium and high risk areas for minimally invasive (T1a) melanomas in anatomically constrained areas (ie, face, ears, acral sites), along with other surgical methods that provide comprehensive histologic assessment, such as staged excision with permanent sections for dermatopathology review.[42]  Although no prospective disease-specific outcome studies of MMS versus staged excision versus wide local excision have been reported, it is recommended that regardless of the resection method, permanent section analysis of at least the central debulking be available for dermatopathologic review. These recommendations are evidence level 2A.[42]

The NCCN also cites a study of Mohs micrographic surgery (MMS) that employed MMS enhanced by immunohistochemical staining as the primary treatment modality for MIS, which resulted in 99% removal of  when a total surgical margin of 9 mm was used, versus an 86% rate of removal with 6-mm margins.[10, 43] The stain is composed of antibodies to a melanoma antigen recognized by T-cells (MART-1).[10, 43] The NCCN also supports the use of MMS or staged excision (slow MMS) as a treatment option for LM. When performed with or without immunohistochemical staining, high local control rates and low recurrence rates have been seen. Specifically, for LM excised by MMS, there was a recurrence rate of 0-2% after follow-up of up to 44 months and for LM excised by staged excision, there was a recurrence rate of 0-6% after a follow-up time of up to 138 months.[44]

The appropriate-use criteria for MMS from the AAD, 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[38] :

• Head
• Neck
• Hands
• Feet
• Pretibial surface
• Nails
• Ankles
• Nipples/areola
• Genitalia (including perineal and perianal)

However, the use of MMS for primary MIS and LM is uncertain for low-risk sites such as the trunk and extremities excluding pretibial surfaces, hands, feed, nail units, and ankles. For MIS, LM type, the AAD also 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.[16]

Sentinel lymph node dissection

Regional lymph node status remains a valuable tool to determine prognosis and to select patients for adjuvant therapy or clinical trials, although alternatives such as gene profiling are evolving. For example, in patients with clinical stage I/II melanoma, sentinel lymph node status is the strongest predictor of survival. The Multicenter Selective Lymphadenectomy Trial (MSLT-1) confirmed the role of lymphatic mapping with sentinel lymph node biopsy (SNLB) as a prognostic tool.[45] While post-hoc analysis in this trial found a survival advantage for patients with intermediate-thickness melanoma and microscopic lymph node involvement who underwent SLNB and subsequently early regional lymphadenectomy, post-hoc analysis is subject to error and prospective data are needed. These findings were supported by the retrospective series of 5840 patients in the Melanoma Institute Australia database from 1992-2008.[45]

American Academy of Dermatology

The AAD recommends consideration of SLNB in patients with stage T1b or in T1a with any of the following high-risk features[16] :

• High mitotic rate
• Angiolymphatic invasio
• Positive deep margin (if close to 0.8 mm)
• 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.[46] In addition, the presence of regression in thin lesions is associated with a lower risk of nodal metastasis.[47]

Following a positive SLNB, the decision to proceed with lymph node dissection versus regional nodal ultrasound surveillance, the AAD recommends interdisciplinary collaboration between surgical and medical oncologists.

National Comprehensive Cancer Network

The NCCN guidelines do not recommend SLNB for patients with MIS (stage 0).[10] Evidence supporting routine SLNB for patients with very thin stage IA or IB lesions remains controversial. SLNB is not recommended in such cases unless there are high-risk features such as ulceration, high mitotic rate, and lymphovascular invasion; in these cases, the patient and provider should decide whether to proceed. However, the NCCN recommends considering SLNB for patients with higher-risk stage IB (> 1 mm thick or 0.8–1.0 mm thick with ulceration or mitotic rate ≥1 per mm2) or stage II melanoma. Patients with positive SLNB findings may be a candidate for completion lymph node dissection (CLND).[10]

American Society of Clinical Oncology and Society of Surgical Oncology

The 2018 update of joint guidelines from the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) includes the following recommendations[48] :

• Routine SLNB is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions < 0.8 mm in Breslow thickness).
• SLNB 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.
• SLNB is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of > 1.0 to 4.0 mm).
• SLNB 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 SLNB, 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.[48]

European Society for Medical Oncology

The ESMO consensus conference in 2020 recommended the following updates regarding SLNB and lymph node dissection[37] :

• SLNB is recommended for staging in melanomas of stage pT2a or higher (> 1.0 mm Breslow thickness).
• SLNB 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).
• SLNB is not routinely recommended for patients with a melanoma of stage pT1a (eg, with tumor thickness <  0.8 mm and no ulceration).
• SLNB 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]).
• 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.

European Consensus-based Interdisciplinary Guidelines

The 2022 update of the European Consensus-based interdisciplinary guideline for melanoma includes the following recommendations for SLNB[49] :

• SLNB should be offered to patients with tumor thickness at least 1 mm or at least 0.8 mm with additional histological risk factors
• In patients with sentinel lymph node micrometastasis, CLND should not be performed. Adjuvant systemic therapy is indicated.
• If regional lymph node macrometastases are detected clinically or with imaging without in-transit and distant metastasis, CLND should be offered.  

Non-surgical management of melanoma can be used in cases of advanced melanoma, in the presence of specific oncogenic mutations, and for palliation. The recommendations for non-surgical management in melanoma are outlined below. 

Radiation therapy

NCCN guidelines recommend consideration of radiation therapy in the following situations[10] :

• Primary disease: As definitive therapy for melanoma in situ (MIS), lentigo maligna (LM) type in inoperable patients; as adjuvant treatment in selected patients with risk factors that include deep desmoplastic melanoma with narrow margins, extensive neurotropism, or locally recurrent disease
• Regional disease: As definitive or palliative treatment for unresectable disease; as adjuvant treatment following resection of nodes, with LDH < 1.5 times the upper limit of normal, and extranodal tumor extension ^{[50, 51]}
• Metastatic disease: As either adjuvant or primary treatment for brain metastases

ESMO recommends considering stereotactic radiation of regional or single distant metastatic disease. Adjuvant radiation therapy can also be considered for high-risk patients where regional control is a major issue and/or where systemic therapy is not possible.[36]

Systemic therapy for advanced melanoma

NCCN recommendations for systemic treatment of melanoma stage IV disease with distant metastasis include the following[10]

• Treatment depends on whether melanoma is limited (resectable) or disseminated (unresectable).
• In limited disease, resection is recommended; alternatively, systemic therapy may be chosen and observation is not recommended. 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[10] :

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

If the tumor contains a BRAF V600 activating mutation, category 1 recommendations for first-line therapy are as follows[10] :

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

Second-line or subsequent therapy recommendations are as follows[10] :

• Anti PD-1 monotherapy: Pembrolizumab or nivolumab
• Nivolumab plus 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[49] :

• 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[49] :

• 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 V600E/K mutation, an alternative to immunotherapy is first-line therapy with BRAF/MEK inhibitors.
• Chemotherapy should be considered only if resistance to immunotherapy and targeted therapies is present.

The joint European guidelines include the following recommendations for brain metastases[49] :

• 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.
• The preferred systemic therapy for brain metastases is combined immunotherapy; targeted therapy is an alternative in patients with BRAF V600E/K mutations.

Toxicities of Novel Melanoma Drugs

Reported adverse effects of novel melanoma drugs—such as those that target the MAPK pathway (BRAF inhibitors and mitogen-activated protein kinase inhibitors) and immune checkpoint inhibitors (eg, monoclonal antibodies against CTLA-4, PD-1, and its ligand programmed death ligand 1 [PD-L1])—include the following:

• Cutaneous toxicity
• Gastrointestinal toxicity (eg, diarrhea/colitis)
• Hepatoxicity
• Pneumonitis
• Endocrine toxicities (eg, autoimmune thyroid disease, hypophysitis, adrenal insufficiency, type 1 diabetes mellitus)

The American Academy of Dermatology (AAD) provides the following guidance regarding cutaneous toxicities of such novel melanoma drugs[16] :

• Dermatologists should collaborate with oncologists for management of cutaneous toxicity during BRAF/MEK kinase or immune checkpoint inhibitor therapy, because appropriate recognition and control of skin adverse effects may improve the quality of life of patients with melanoma and avoid unnecessary interruption of medication.
• The frequency of dermatologic assessment for cutaneous toxicity diagnosis and management depends on the agent(s) being used, age of the patient, underlying skin cancer risk factors (eg, history of actinic damage and/or skin cancer), and/or potential role of skin findings as a biomarker for response.

The AAD recommends the following dermatologic assessment schedules:

• For patients with numerous squamoproliferative neoplasms on BRAF inhibitor monotherapy, dermatologic assessment is recommended every 2-4 weeks for the first 3 months,.
• For patients on immune checkpoint inhibitors, dermatologic assessment should occur within the first month of therapy and continue as needed for management of cutaneous toxicity.
• Patients with atopic dermatitis, psoriasis, or other autoimmune dermatoses should be seen before initiation of therapy by a dermatologist for pre-emptive counseling and treatment.

Patients diagnosed with melanoma during pregnancy have a similar prognosis than those who are not pregnant.[52]  Regarding cutaneous melanoma management, the American Academy of Dermatology (AAD) provides the following guidance[16] :

• A tailored, multidisciplinary approach to care that involves the obstetrician and melanoma specialists is recommended. Work-up and treatment must take the safety of the fetus into consideration.
• For those with a prior history of a melanoma, a prolonged waiting period before a potential subsequent pregnancy is not recommended. 
• The approach to melanocytic nevi in pregnancy should be identical to that in the nonpregnant patient. Any changing nevus during pregnancy should be evaluated and subjected to biopsy if clinically and/or dermoscopically concerning.
• Exogenous hormones (eg, oral contraceptives and hormone-containing contraceptive devices/implants, postmenopausal hormone replacement therapy, or hormones associated with assisted reproductive technology) may be used in pregnant patients with a diagnosis of cutaneous melanoma.

Broadly, there are four clinical scenarios that may warrant genetic counseling and/or testing:

• Melanoma diagnosed at earlier than expected ages
• Multiple relatives with melanoma
• Individuals with multiple primary melanomas
• Other types of cancer in the family. 

American Academy of Dermatology (AAD)

The AAD recommends cancer risk counselling for the following patients with cutaneous melanoma[16] :

• Those with a family history of invasive melanoma or pancreatic cancer (≥3 affected members on 1 side of the family)
• Those with multiple primary invasive melanoma (≥3), including 1 early-onset tumor (at age < 45 y)
• ≥1 melanocytic BAP1-mutated atypical intradermal tumor (MBAIT) and a family history of mesothelioma, meningioma, and/or uveal melanoma
• ≥2 MBAITs

National Comprehensive Cancer Network (NCCN)

With regards to genetic counseling and testing, the NCCN provides the following recommendations:16

• Genetic counseling for patients with a strong family history of invasive melanoma with or without pancreatic cancer. 
• p16/ CDKN2A mutation testing in the presence of 3 or more invasive cutaneous melanomas, or a mix of invasive melanoma, pancreatic cancer, and/or astrocytoma diagnoses in an individual or family. 
• Multigene panel testing that includes  CDKN2A for patients with invasive cutaneous melanoma who have a first-degree relative diagnosed with pancreatic cancer  

Follow-up guidelines from the National Comprehensive Cancer Network (NCCN) for all patients with melanoma are as follows[10] :

• History and physical examination (H&P), with emphasis on nodes and skin, at least annually, depending on stage (see below). In patients with high mole count and/or presence of clinically atypical nevi, pre-diagnostic clinical modalities (ie, total-body photography and sequential digital dermoscopy), and other imaging modalities (eg, reflectance confocal microscopy, electrical impedance spectroscopy) may enhance early detection of new primary melanoma. Pre-diagnostic noninvasive patch testing may also be helpful to guide biopsy decisions.
• Patient education in regular skin and lymph node self-examination. 
• Patient education in principles of sun safety, including sun avoidance during peak hours, use of sun-protective clothing/hat/eyewear, and regular application of broad-spectrum sunscreen to exposed skin when outdoors, particularly in individuals with sun sensitivity/light complexion.
• In patients with an equivocal lymph node exam, short-term follow-up and/or additional imaging (US [preferred] or CT) should be considered, with imaging-directed biopsy as warranted. 
• Regional lymph node US in patients with a positive SLNB who did not undergo CLND is generally preferred where expertise is available. The MSLT-II and DeCOG trials recommend conducting clinical examinations and US surveillance every 4 months during the first 2 years, then every 6 months during years 3 through 5.

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

• H&P (with emphasis on skin), at least annually for life
• 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:

• H&P (with emphasis on nodes and skin), every 6-12 months for 5 years, then annually for life as clinically indicated
• 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 IIB-IV (patients with no evidence of disease) is as follows:

• H&P (with emphasis on nodes and skin) every 3-6 months for 2 years, then every 3-12 months for 3 years, 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 months for 2 years, then every 6–12 months for another 3 years (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 3-5 years, depending on the risk of relapse.