Key Points

  • The therapy of malignant melanoma is determined by the histopathologic features (primarily tumor thickness, ulceration, regression, and mitotic index), by the location of the tumor, by the presence of regional or distant metastases and by the patient characteristics (age, medical co-morbidities).
  • Increased tumor thickness is associated with significant morbidity and mortality.
  • Evidence clarifying which patients should have elective regional lymph node dissection remains somewhat controversial. In questionable cases, referral to regional centers or consultation with regional experts is recommended.
  • New therapies for metastatic melanoma that are immunomodulatory or target melanoma signaling pathways (anti-CTLA4, anti-PD1, BRAF inhibitors) have significantly changed the management of metastatic melanoma and extend survival for affected patients.

Introduction

Melanoma is a malignant tumor of melanocytes residing in skin, mucosal sites, eye, and meninges. In the United States, the incidence is 10-25 per 100,000 persons, with approximately 76,100 new cases of melanoma and 9,710 melanoma-related deaths reported in 2014. New cases may arise de novo or from preexisting pigmented skin lesions which have evolved. The expansion in size, change in pigmentation, ulceration or bleeding, and development of irregularity within the border are all possible signs of melanoma and warrant further evaluation and/or biopsy. Risk factors for melanoma include family history, atypical nevi, numerous nevi, genetic factors and UV exposure. The variation in size, depth (of invasion), color, and secondary changes, such as erosions or ulcerations, produce a large spectrum of clinical lesions, some of which are very difficult to diagnose correctly. Clinical phenotypes of melanoma include lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, amelanotic melanoma, mucosal melanoma, and ocular melanoma.

Prognosis is largely determined by histologic features of the primary melanoma (depth of invasion and/or the degree to which the tumor has invaded the skin) as well as presence of ulceration and mitotic index seen on biopsy. The major independent risk factor is tumor thickness measured in millimeters (Breslow depth). Depth of invasion is also determined by Clark’s level (depth based on histologic location). Histological, genetic or molecular features, anatomic location, spread to regional lymph nodes, and clinical features may also influence clinical outcome. Clinical staging is predicated on whether the tumor has spread to regional lymph nodes or distant sites; the American Joint Committee on Cancer (AJCC) designates melanoma staging by standard TNM classification (2009). Thus, accurate biopsy interpretation and staging is critical to the proper management of the patient.
Table 1. TNM Staging Categories for Cutaneous Melanoma [Balch CM et al (2009) Final version of the 2009 AJCC melanoma staging and classification, JCO, 27:6199-6206.]

Classification Thickness (mm) Ulceration Status/Mitoses
T
Tis NA NA
T1 < 1.00 a: Without ulceration and mitosis < 1/mm2
b: With ulceration or mitoses ≥ 1/mm2
T2 1.01-2.00 a: Without ulceration
b: With ulceration
T3 2.01-4.00 a: Without ulceration
b: With ulceration
T4 > 4.00 a: Without ulceration
b: With ulceration
N No. of Metastatic Nodes Nodal Metastatic Burden
N0 0 NA
N1 1 a: Micrometastasis*
b: Macrometastasis†
N2 2-3 a: Micrometastasis*
b: Macrometastasis†
c: In transit metastases/satellites without metastatic nodes
N3 4+ metastatic nodes, or matted nodes, or in transit metastases/satellites with metastatic nodes
M Site Serum LDH
M0 No distant metastases NA
M1a Distant skin, subcutaneous, or nodal metastases Normal
M1b Lung metastases Normal
M1c All other visceral metastases Normal
Any distant metastases Elevated

Abbreviations: NA, not applicable; LDH, lactate dehydrogenase. *Micrometastases are diagnosed after sentinel lymph node biopsy.†Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically.

Table 2. Depth of melanoma invasion based on histopathologic level (Clark’s level)

Clark’s Level Level of invasion
I Lesion involves only epidermis (in situ)
II Invasion of papillary dermis only without involvement of the papillary-reticular dermal interface
III Invasion to the papillary dermis without extension into the reticular dermis
IV Invasion into the reticular dermis without involvement of subcutaneous tissue
V Invasion into subcutaneous tissue

In this chapter, only treatment of primary lesions is discussed. Treatment of melanoma is mainly surgical. Although occasional patients with local recurrence or metastasis may elect to undergo additional surgery, chemotherapy, radiotherapy, vaccination, or immunomodulatory therapy, the primary focus must be to adequately excise the primary lesion at the time of initial definitive diagnosis.

Clinical variants of melanoma:

  • Superficial spreading melanoma (SSM) is the most common form of melanoma, and typically presents with irregular borders, highly uneven pigmentation and/or unusual pigmentation (i.e., blue, pink, red, purple).
  • Nodular melanoma (NMM) typically presents as a solitary nodule that arises from a preexisting nevus or de novo. It may grow rapidly in thickness without radial spread (extension along the surface of the skin).
  • Lentigo maligna melanoma (LMM) presents as a highly asymmetric pigmented lesion with evolution of darker or lighter areas of pigmentation within a lentigo on the face.
  • Acral lentiginous melanoma (ALM) presents as a symmetric pigmented macule, plaque or nodule on the fingers with extension under the nail plate.
  • Mucosal melanoma presents as a pigmented macule growing on the mucosal surfaces (oral, genital, intestinal etc.).
  • Ocular melanoma.

Initial Evaluation

Melanoma frequently presents as an asymmetric pigmented lesion with an irregular scalloped border and uneven pigmentation. Some of the lesions are marked by hypopigmented areas (signifying areas of regression) or more darkly pigmented raised areas (where the melanoma is arising).

Malignant melanoma, metastatic

Differential Diagnosis

Melanocytic nevi

Basal cell carcinoma, especially pigmented variants of basal cell carcinoma. Amelanotic (non-pigmented) melanoma may also clinically mimic basal cell carcinoma.

Squamous cell carcinoma

Keratoacanthoma

Treatment

Initial therapy

First-line therapy: Surgical excision

  • For diagnosis, complete excisional biopsy with minimal margins, pathologically evaluated at multiple levels to determine the tumor thickness, as well as to determine presence of ulceration, mitotic index, evidence of regression, perineural or perivascular invasion and maximum depth, is highly recommended. For large lesions that cannot be excised without a major surgical procedure or significant cosmetic deformity, an incisional biopsy of the clinically thickest appearing area is reasonable.
  • Once histologic features are determined, wide local excision with margins is recommended. Recommended excision margins vary; no international standards yet exist.

Table 3. Recommended excision margins based on tumor thickness

Tumor thickness Recommended excision margins: United States Recommended excision margins: European (Leiter U, et al. 2010)
Melanoma in situ 0.5 cm 0.5 cm
Breslow < 1 mm thickness 1 cm
Breslow 1-2 mm 1-2 cm
Breslow < 2 mm thickness 1 cm
Breslow > 2 mm thickness 2 cm (at least) 2 cm
  • Melanoma in situ should be excised to the depth of the subcutaneous fat; melanoma should be excised to the depth of the underlying fascia. The appropriate margin for excision is highly controversial, and standard treatment options based on current evidence are suggested. Surgical margins will reduce the risk of local relapse, but will not influence overall survival.
  • Obtain a baseline history and full body skin exam plus physical examination (especially noting any enlarged lymph nodes). Depending on the histology, blood tests (CBC, LDH, ALT), ultrasonography of the regional lymph nodes, abdominal ultrasound, a chest x-ray, or CT scan +/- PET scan might be recommended.
  • Patients with higher risk lesions (over 1 mm thick or < 1 mm with aggressive features such as ulceration or mitotic index >1 per mm2) should be considered for more extensive baseline evaluation such as sentinel lymph node biopsy and/or searching for metastases (CT or MRI of the brain, chest, abdomen or pelvis, or PET CT).

Ancillary therapy

The decision to pursue regional sentinel lymph node dissection is controversial, and consultation and/or referral to a dermatologist with expertise in cutaneous oncology or an oncologist specializing in melanoma is highly recommended. Patients with higher risk lesions (over 1 mm thick or < 1 mm with aggressive features such as ulceration or mitotic index >1 per mm2) should be considered for sentinel lymph node biopsy (Balch CM, et al. AJCC, 2009). Adjuvant treatment after surgery with interferon-alpha-2b has proven a disease free survival benefit, and further clinical trials are necessary to find adjuvant therapies with benefit on overall survival.

For unresectable Stage III, Stage IV, and recurrent melanoma, there are new chemotherapeutic agents that either serve as immunotherapy (anti-CTLA-4, such as ipilimumab; anti-PD-1/ PD-L1; high dose interleukin-2, or combination therapy) or signal transduction inhibitors (BRAF inhibitors, such as vemurafenib, dabrafenib; MEK inhibitors, such as trametinib; or combination therapy; c-Kit inhibitors). These agents – especially combination therapy using signal transduction inhibitors – extend overall survival. Selection of these agents should be guided by specific (FDA approved) genetic testing of the tumor to determine whether the melanoma tumor carries mutations in the targeted pathway, i.e., dabrafenib and trametinib in combination is indicated for patients who carry specific BRAF mutations (V600E or V600K). Referral to a dermatologist with expertise in cutaneous oncology or an oncologist specializing in melanoma is highly recommended for both management of the chemotherapy and adverse effect management.

Pitfalls

  • Failure to accurately diagnose a melanoma.
  • Failure to biopsy a suspicious lesion is the most serious pitfall.
  • An inadequate initial biopsy or pathologic evaluation is a major pitfall that may result in inadequate therapy. Inclusion of at least minimal margins (to show histologic circumscription) and full depth of the lesion are imperative to accurate evaluation. An excisional biopsy is highly recommended when possible. The pathology report must include the excision margins, the tumor thickness, the Clark’s level, presence of ulceration, mitotic index, the presence of regression, growth phase (horizontal and/or vertical), lymphatic, vascular or perineural involvement.
  • Melanoma is unpredictable. Remain constantly suspicious of the possibility of metastasis or recurrence.

Subsequent therapy

Frequency of clinical, laboratory and radiological follow-up depends on the stage of the melanoma; however, no evidence-based, international consensus exists (Leiter U, et al 2010). The check-ups should occur frequently in the first 5 years. Afterwards, they are performed less frequently but at least once a year, especially for clinical examination. Regular radiographic and laboratory examinations are indicated for patients with intermediate and high-risk lesions (lesions that are 1.5 mm thickness or greater or a lesion that is Clark’s level IV with 0.76 mm thickness or greater). Regular clinical examinations of pigmented lesions are necessary in all patients with melanoma. First-degree relatives of persons diagnosed with melanoma should also be advised to seek dermatologic care. In some centers, serum S100 protein and LDH (lactate-dehydrogenase enzyme) are checked regularly in melanoma patients.

When to refer to a dermatologist

  • When the diagnosis of melanoma is not certain.
  • For biopsy of a lesion suspected of being melanoma.
  • For staging of biopsy proven diagnosis of melanoma.
  • For treatment of unresectable (Stage III, IV) or recurrent melanoma.

 

Clinical Cases

Case 1

  • 37-year-old woman with >75 atypical nevi
  • No family history of atypical nevi or melanoma
  • Presents for an evaluation of a “”new mole”” that rapidly developed on the right leg
  • A full-body skin examination is performed and does not identify any other suspicious lesions
  • Biopsy: melanoma, 0.7 mm thickness, Clark’s level II. No ulceration present, and mitotic index <1 per mm2
  • She is diagnosed with Stage 1a melanoma

Follow-up

  • The patient goes for wide local excision with 1 cm margins; there is no residual melanoma in the excision specimen

Subsequent follow-up

  • 3 months for full-body skin examination in the first years
  • Photoprotection recommended
  • First-degree relatives recommended to seek dermatologic consultation

Case 2

  • 64-year-old man with numerous lentigines notes a ““changing mole”” on the right forearm; the lesion has doubled in size over a time period of 6 weeks
  • A full-body skin examination is performed and does not identify any other suspicious lesions
  • Biopsy: melanoma, 2.1 mm thickness

Follow-up

  • The patient undergoes wide local excision with 2 cm margins and elects to have sentinel lymph node mapping and dissection, which reveals 2 of 8 lymph nodes affected
  • Brain, chest, abdominal, and pelvic CT scans reveal evidence of metastatic disease in the lung and liver. Blood work is normal
  • Genetic testing is done, which reveals a BRAF V600E mutation. He is referred to local melanoma oncologist and started on dual therapy with vemurafenib and dabrafenib

Subsequent follow-up

  • Ongoing follow-up for full-body skin examination and oncology evaluation for recurrence
  • Photoprotection recommended
  • First-degree relatives recommended to seek dermatologic consultation

References

Balch CM et al (2009) Final version of the 2009 AJCC Melanoma staging and classification, JCO, 27: 6199-6206.

Chapman PB, Hauschild A, Robert C, et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation, N Engl J Med, 364 (26): 2507-16.

Flaherty KT, Infante JR, Daud A, et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations, N Engl J Med, 367 (18): 1694-703.

Flaherty KT, Robert C, Hersey P et al (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma, N Engl J Med, 367 (2): 107-14.

Leiter, U et al (2010) Excision guidelines and follow-up strategies in cutaneous melanoma: Facts and controversies, Clinics in Dermatology, 28:311-315.

Morton DL et al (2006) Sentinel-node biopsy or nodal observation in melanoma, NEJM, 355:1307-1317.

National Cancer Institute. Melanoma Treatment (PDQ). 7 Nov 2014. Web. http: www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional

Robert C, Thomas L, Bondarenko I, et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma, N Engl J Med 364 (26): 2517-26.

Robert C, Ribas A, Wolchok JD, et al (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial, Lancet, 384 (9948): 1109-17.

Sosman JA, Kim KB, Schuchter L, et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib, N Engl J Med, 366 (8): 707-14.