Clinical Guidelines for the Staging, Diagnosis, and Management of Cutaneous Malignant Melanoma

Function

American Joint Committee on Cancer, AJCC, eighth edition, TNM staging of cutaneous malignant melanoma:

Cutaneous malignant melanoma is currently staged using the eighth edition of the AJCC staging system, which was implemented in the United States in January 2018. The staging is based on Tumor(T), Nodes (N), and metastases (M) classification and grouping criteria.[7][8]

The tumor category is determined based on Breslow tumor thickness and the presence or absence of ulceration. Measurement of Breslow tumor thickness to 0.1mm is recommended, round down to those ending in decimal places 1 to 4 and round up to decimal places ending from 5 to 9. Ulceration is determined based on histopathological examination and is defined as the full-thickness absence of epidermis above any portion of the primary tumor. The absence of the epidermis due to biopsy-related trauma should not be designated as ulceration. There may be an associated host reaction to ulceration; when there is doubt if the origin of ulceration is tumor-related versus iatrogenic, then the tumor is staged as ulcerated. Mitotic rate is no longer a T category criterion even though it is thought to have prognostic significance, and assessment of mitotic rate is recommended. Table 1 below describes the T category classification.

Table 1: T Category Classification for Cutaneous Malignant Melanoma

Node (N) category identifies metastases to regional lymph nodes and non-nodal regional sites, including in-transit, micro-satellite, satellite, and subcutaneous metastases. Regional lymph nodes detected clinically or radiographically are designated as “clinically apparent,” while nodes detected only on sentinel lymph node biopsy are labeled “clinically occult.” No size threshold is set for sentinel lymph node; if melanoma cells are identified adjacent to or within the lymphatic channel of a lymph node, it is considered involved. The extracapsular extension (ECE) is not considered for N category classification; however, it is recommended that the ECE status be assessed and recorded for the potential prognostic value of this parameter.

Satellite metastases include clinically evident cutaneous or subcutaneous metastases occurring discontinuous from and less than 2cm from the primary tumor, whereas micro-satellite and satellite metastases refer to similar lesions but clinically non-evident and only detected microscopically. In-transit metastases include metastases discontinuous from and more than 2cm from the primary tumor. Two or more nodes adherent to one another detected are classified as matted nodes.  N categories are further subcategorized using descriptors for clinically occult (N1a, N2a, N3a), clinically apparent (N1b, N2b, N3b), and non-nodal locoregional metastases (N1c, N2c, N3c). Table 2 below describes the N category classification.

Table 2: N Category Classification for Cutaneous Malignant Melanoma

M category, which designates distant metastases, is further stratified based on the site of metastases. At the same time, lactate dehydrogenase (LDH) level is indicated as a descriptor for each M category for its prognostic value. Table 3 below describes the M category classification.

Table 3: M Category Classification for Cutaneous Malignant Melanoma

Using the information from T, N, and M classification, cutaneous malignant melanoma is further grouped into clinical and pathological prognostic stages. Clinical staging includes information obtained through clinical and radiological assessment, including from tumor biopsy. Information from a further pathological assessment such as wide local tumor excision, sentinel lymph node biopsy, and completion lymph node dissection is used for pathological staging. Stage grouping provides prognostic information with an estimated five-year survival of stage I, II, III as 97 to 99%,75 to 88%,24 to 88%, respectively. Tables 4 and 5 lists the pathological and clinical prognostic staging of the cutaneous malignant melanoma per AJCC eighth edition.

Table 4: Pathological Prognostic Grouping of Cutaneous Malignant Melanoma as Per American Joint Committee on Cancer 8 Edition

Table 5: Clinical Prognostic Grouping of Cutaneous Malignant Melanoma as Per American Joint Committee on Cancer 8 Edition

Diagnostic Assessment for Cutaneous Melanoma

Cutaneous pigmented lesions characterized by dynamic changes in the shape, color, diameter, and borders (ABCD rule) are suspicious for melanoma[9]. Dermoscopy can be used as a diagnostic aid to improve the accuracy of the tissue sampling and is endorsed by all the clinical practice guidelines. Full-thickness excision biopsy is recommended for diagnosis; AAD and NCCN recommend a negative margin of around 1-3mm, while CCA recommends a margin of 2mm and upper subcutis. ESMO does not specify the margin distance while recommending minimal margins with the full-thickness biopsy. A partial-thickness biopsy is acceptable for locations such as the face or acral surfaces. AAD advises that superficial shave biopsy be avoided except biopsy of a macular lesion suspicious for melanoma in-situ lentigo melanoma sub-type.

As per AAD and NCCN, it is recommended that pathology report include clinical information of the patient, location of the lesion, size of the specimen, Breslow tumor thickness to nearest 0.1mm, ulceration status (Level I/ II, Grade A), dermal mitotic rate (number of mitoses/mm2, Level I/ II, Grade A), peripheral and deep margins and microsatellites. Information on lymphovascular invasion, peri-neural invasion, Clark Level, vertical growth face, tumor-infiltrating lymphocytes, and regression are optional. ESMO recommends describing tumor thickness to the closest 0.1mm while rounding up at 0.05 mm, presence of ulceration and margin status, anatomic location (Level II, Grade A). Mitotic rate and regression status are recommended. Describing histological sub-type is optional as per AAD and NCCN but necessary as per ESMO.

AAD recommends evaluating actionable mutations such as BRAFV600E only for metastatic disease (Level III, Grade C), while NCCN and CCA recommend testing for BRAFV600E and other less common BRAF mutations for a patient with stage III disease who might be a candidate for BRAF-directed therapies. Mutational testing for actionable targets is recommended for high-risk resected IIC, stage III, and stage IV disease per ESMO (Level I, Grade A). Further, if initial testing for BRAFV600E is negative, sequential testing for less common BRAF, NRAS, and c-kit mutations are recommended. (Level II, Grade B). Immunohistochemistry or next-generation sequencing may be used for such molecular testing. NCCN advises that comprehensive genomic hybridization or fluorescent in-situ hybridization may be useful for identifying molecular alteration in histologically equivocal cases such as melanocytic or Spitz tumors and aid in their diagnosis. Programmed death ligand-1 (PDL-1) testing may be considered but should not be used for guiding treatment decisions.

Laboratory and Imaging Investigations

No baseline investigations are recommended for patients with stage 0-II cutaneous melanoma as per AAD and stage 0 to IIIB as per NCCN. Serum LDH has prognostic value in metastatic disease, and testing for LDH is recommended in patients with metastatic melanoma across all guidelines. ESMO and NCCN recommend whole-body positron emission tomography (PET) and magnetic resonance imaging (MRI) of the brain for patients with stage III and higher disease. ESMO recommends PET and MRI of the brain for any patients with tumor pT3b and higher. Additionally, as per NCCN, PET and MRI brain should be considered for patients with early-stage disease and signs and symptoms of metastatic disease and patients with the high-risk disease for patients such as those who present with positive sentinel lymph node or microscopic satellite or in-transit metastatic lesions on pathology or with clinically palpable lymph nodes. However, CCA does not recommend imaging for patients with positive sentinel lymph nodes (Grade B) while recommending PET and MRI brain imaging for palpable lymph nodes (Grade B).

Surgical Management of Cutaneous Malignant Melanoma

Sentinel Lymph Node Biopsy

Recommendations for sentinel lymph node biopsy and management of positive sentinel lymph nodes are uniform across society guidelines and are described as follows. 

Sentinel lymph node biopsy (SLNB) is recommended for patients with tumor thickness more than 0.8mm.  For pT1a (tumor thickness less than 0.8mm without ulceration), SLNB is not recommended by all the guidelines. Therefore, consideration for SLNB for less than 0.8mm with ulceration and tumors 0.8mm to 1mm in thickness is recommended. SLNB should be considered for pT1a without ulceration in the presence of other high-risk factors for lymph node involvement such as young age, high mitotic rate, lymphovascular invasion, positive margins on biopsy.

Evaluation of positive sentinel lymph node with regional nodal ultrasound surveillance is preferred over complete lymph node dissection (Level III, Grade C). This is based on the results from MSLT-II and DeCOG-SLT trials.[10][11][12] In these randomized controlled trials, no improvement in overall survival was observed with complete lymph node dissection compared to periodic ultrasound-based surveillance every 3 months. However, patients that develop nodal relapse on ultrasound-based surveillance should be evaluated for complete lymph node dissection. Patients that present with palpable nodal disease should undergo evaluation for lymph node involvement. If lymph nodes are found to contain malignant cells, they should be offered complete lymph node dissection.[13]

Excision of the Primary Malignant Tumor

Definite excision of the tumor is recommended as the primary treatment for cutaneous malignant melanoma. Wide local excision with a negative margin of 1cm for tumors less than 1mm thick (Level I/II, Grade A), 1-2 cm for tumors 1 to 2 mm thick (Level I, Grade A), and 2 cm margin for tumors more than 2 mm in thickness (Level I, Grade A) whereas a margin of 0.5 to 1 cm is acceptable for melanoma in-situ including lentigo maligna (Level II/III, Grade A) as per the AAD and NCCN. ESMO recommends a margin of 0.5 cm for melanoma in-situ, a margin of 1cm for tumors less than 2 mm thick, and a margin of 2 cm for tumors more than 2 mm in thickness. As per CAA, a margin of 1.01 to 2 cm for tumors 1.01 to 2 mm thick, a margin of 1.01 to 2 cm for tumors 2.01 to 4 mm thick, and a margin of 2 cm for tumors more than 4 mm in thickness are recommended (Grade B). Deep margins to the muscle fascia are desirable. Additionally, as per NCCN and AAD, Microscopic Moh's surgery is not recommended for routine surgical management of cutaneous melanoma. It might be appropriate for patients with cutaneous melanoma of the face, acral structures of lentigo maligna (Level II/III, Grade B).

Melanoma with Unresectable In-transit Metastases

Systemic therapies such as immune checkpoint inhibitors and molecular targeted therapies are preferred over local therapy options such as wide local excision for patients with unresectable in-transit metastatic disease as per both NCCN and ESMO. If local therapies are feasible, Tlimogene (T-vec) is recommended over other options (NCCN Category I). Other options include local radiation therapy (NCCN Category 2B) and isolated limb infusion with melphalan. ESMO and CCA also consider isolated limb perfusion with melphalan as an option for such patients. CCA does not have recommendations regarding T-vec or systemic therapies for such patients.

Systemic Therapy for Cutaneous Malignant Melanoma

All clinical guidelines have uniform recommendations for adjuvant therapy and include radiation therapy and systemic therapy with immune checkpoint inhibitors and molecular targeted therapies as options. As per NCCN, ESMO, and CCA, adjuvant radiation therapy may be considered for patients with desmoplastic cutaneous melanoma after wide local excision and high-risk features such as tumor thickness of more than 4mm, peri-neural invasion, head and neck location, and narrow deep margin of resection.

Systemic therapy is recommended for stage III cutaneous melanoma following wide local excision with or without sentinel lymph node biopsy and lymph node dissection. Options include anti-PDL-1 (programmed death ligand-1) inhibitors and BRAF/MEK inhibitors (for patients with BRAF mutated tumors) for 12 months. Additionally, for patients with stage IIC with high-risk features such as tumor ulceration, adjuvant interferon may be considered. Patients with stage IIIA and sentinel lymph node involvement of <1mm or tumors <2mm in thickness risk versus benefit of adjuvant therapy should be discussed.

All major clinical guidelines have uniform recommendations for systemic therapy for stage IV cutaneous melanoma. For limited involvement, resectable metastatic disease local resection followed by adjuvant systemic therapy with either BRAF/MEK inhibitors for BRAF mutated tumors, anti-PDL-1 inhibitors for 12 months is recommended. For patients previously treated with these agents and progression within 3 months of the completion of adjuvant treatment, checkpoint inhibitors are an option. For asymptomatic and limited or small (<3 cm) number of brain metastases upfront, systemic therapy rather than stereotactic radiosurgery is an option. For patients with bulky brain metastatic disease or those with symptoms, upfront brain-directed therapy such as stereotactic radiosurgery is the preferred option. For unresectable disseminated disease options include systemic therapy, local therapies with T-vec (for limited unresectable disease, category I), and palliative radiation therapy. 

Genetic Counseling Recommendations

According to AAD and NCCN guidelines, genetic counseling referral for evaluating mutations in CKDNK2, CDK4, TERT, BAP-1, and other potential genes is recommended for patients with the following: (Level III, Grade C).

1. 1) Family history of cutaneous melanoma or pancreatic cancer in three or more individuals on the same side of the family
2. 2) Personal history of multiple primary cutaneous invasive melanomas, including one at the young age of onset (<45 years of age)
3. 3) One or more melanocytic BAP-1 mutated atypical intradermal tumor and family history of mesothelioma, meningioma, or uveal melanoma
4. 4) Two or more melanocytic BAP-1 mutated atypical intradermal tumor
5. ESMO does not make recommendations on genetic counseling for melanoma. At the same time, CCA recommends genetic referral for CDKN2A mutation testing for patients with a strong family history of melanoma (3 or more cases in first or second-degree relatives) and personal history of early-onset cutaneous melanoma, multiple primary cutaneous melanomas, or history of pancreatic cancer (Grade C).

Surveillance After Definitive Treatment and No Evidence of Disease

As per AAD and NCCN, patients with stages 0, I, and IIA should undergo a comprehensive physical exam, complete skin examination every 6-12 months for the first 1 to 2 years, then annually. Imaging modalities are not recommended for surveillance of stage 0 to IIA except for patients with signs and symptoms concerning the recurrent metastatic disease. For patients with stage IIB and above comprehensive physical exam and complete skin check every 3 to 6 months for the first 2 years, then every 6 to 12 months from year 3 to 5 annually is suggested. Imaging consideration including brain imaging every 3 to 12 months for the first 2 years then every 6 to 12 months from year 3 to 5 is suggested for stage IIB and above. Additionally, NCCN recommends more frequent MRI brain for patients with a history of brain metastases and those with high risk for brain metastases, such as patients with stage IIIC and above disease. ESMO provides no consensus on the optimal schedule for follow-up and imaging. For post-treatment surveillance, CCA recommends self-skin exams and periodic routine physical exams, and complete skin exams per patient's preferred medical practitioner are recommended. Periodic radiographic imaging every 3 to 12 months for the first 3 years after completing definitive treatment is also recommended (Grade C).

Issues of Concern

Accurate staging of cutaneous malignant melanoma depends on the availability of full-thickness biopsy specimens. Sentinel lymph node biopsy, if accessible, should be performed for patients with node-negative disease and tumors at least 0.8 mm thick or for tumors with high-risk features and less than 0.8 mm thick. Evaluation for potential hereditary syndrome and appropriate genetic referral should be considered.

Clinical Significance

Cutaneous malignant melanoma is one of the most common skin malignancies. Understanding AJCC TNM classification for staging is pivotal for the assessment and management of patients with this disease. Guidelines from professional societies such as  ESMO, NCCN, and Cancer Council of Australia professional societies on cutaneous malignant melanoma are used by clinicians for managing the disease. This summary of the guidelines will provide a quick reference for a clinician when dealing with issues in the various steps of management.

Enhancing Healthcare Team Outcomes

Multidisciplinary care of patients with cutaneous melanoma involving dermatologists, pathologists, genetic counselors, social workers, radiation oncology, medical oncology, and patients general practitioner is recommended for optimizing the available care resources for its management. The role of various specialists in the prevention and detection of recurrent disease is significant. Multidisciplinary tumor board review for patients with extensive nodal or disseminated disease is recommended per the NCCN guidelines. Similarly, the Cancer Council of Australia recommends multidisciplinary care for all patients with stage III and IV cutaneous melanoma. [Level-5]