Melanoma is a malignant tumor of melanocytes cells which produce the pigment melanin. Although most melanomas arise in the skin, they may also arise from mucosal surfaces (oral and genital) in the eyes, ears, gastrointestinal tract and brain (leptomeninges). Melanoma occurs predominantly in adults, and more than 50% of cases arise in apparently normal areas of the skin. Melanoma accounts for only 4% of all skin cancers; however, it causes the greatest number of skin cancer–related deaths worldwide. Early detection of thin cutaneous melanoma is the best means of reducing mortality.

ABCDE of Melanoma

Early signs that would suggest malignant change include:

• Asymmetry: Half the lesion does not match the other half.
• Border irregularity: The edges are ragged, notched, or blurred.
• Color variegation: Pigmentation is not uniform and may display shades of tan, brown, or black; white, reddish, or blue discoloration.
• Diameter: A diameter greater than 6 mm (greater than pencil eraser) is characteristic, although some melanomas may have smaller diameters; any growth in an existing nevus warrants an evaluation.
• Evolving: Changes in the lesion over time; changes include an increase in size, itching, or the development of satellites. Ulceration and/or bleeding are later signs.

Primary risk factors and clinical warning signs for melanoma include:

• • Changing mole (most important clinical warning sign)
  • Clinical atypical (dysplastic) nevi (particularly if more than 5-10)
  • Large numbers of common nevi (over 100)
  • Large (giant) congenital nevi (over 20 cm diameter in an adult)
  • History of previous melanoma
  • Sun sensitivity, history of excessive sun exposure including blistering sunburns in childhood and adolescence
  • Melanoma in first-degree relative(s)
  • Prior non-melanoma skin cancer (basal cell (BCC) and squamous cell carcinoma (SCC))
  • Male gender
  • Over 50 years of age
  • Presence of xeroderma pigmentosum or familial atypical mole melanoma syndrome
  • A fair-skin phenotype (blue/green eyes, blond or red hair, light complexion, sun sensitivity)

Melanoma in women occurs more commonly on the extremities and in men on the trunk or head and neck, but it can arise from any site on the skin surface.

Overall prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, mitotic index, presence of tumor infiltrating lymphocytes, number of regional lymph nodes involved, and ulceration or bleeding at the primary site affect the prognosis.

Favorable prognostic factors include:

• Younger age
• Female gender
• Location of melanoma on the extremities

Clinical subtypes of malignant melanoma are:

• Superficial spreading
• Nodular
• Lentigo maligna
• Acral lentiginous (palmar/plantar and subungual)
• Miscellaneous unusual types:
  • Mucosal lentiginous (oral and genital)
  • Verrucous

Individual subtypes do not have independent prognostic or therapeutic significance.

Melanoma Staging (AJCC 2002 Revised)

Clinical staging of melanoma is based on whether the tumor has spread to regional lymph nodes or distant sites. In cases where disease is clinically confined to the primary site, the greater the thickness and depth of local invasion of the melanoma, the higher the chance of lymph node or systemic metastases and the worse the prognosis.

Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites. The risk of relapse decreases substantially over time, though late relapses are not uncommon.

*Met = metastasis.

The seventh edition of the AJCC Cancer Staging manual (published in 2009) has recommended no major changes for TNM categories and stage groupings, with the exception of removing Clark level and instead incorporating mitotic rate of greater than or equal to 1/mm² to upstage T1a to T1b melanomas.

TREATMENT

Thin melanomas which have not spread beyond the site at which they developed are highly curable. The treatment of localized melanoma is surgical excision with margins proportional to the microscopic stage of the primary lesion.  For most lesions 2 mm or less in Breslow thickness 1-2 cm radial, re-excision margins is recommended.

Melanomas with a Breslow thickness of 2 mm or more are still curable in a significant proportion of patients, but the risk of lymph node and/or systemic metastasis increases with increasing thickness.  The local treatment for these melanomas is surgical excision with margins based on Breslow thickness and anatomic location.  For most melanomas 2 mm to 4 mm in thickness 2 cm to 3 cm radial excision margins are recommended and sentinel lymph node (SLN) biopsy may be required.   Sentinel node biopsy should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Patients with melanomas that have a Breslow thickness more than 4 mm should be considered for adjuvant therapy with high-dose interferon.

Some melanomas that have spread to regional lymph nodes may be curable with wide local excision of the primary tumor and removal of the involved regional lymph nodes.  Adjuvant high-dose interferon was shown to increase relapse-free survival but not overall survival when compared to observation

Melanoma that has spread to distant sites is rarely curable with standard therapy, though high-dose interleukin-2 (IL-2) has been reported to produce durable responses in a small number of patients.  In patients with systemic metastasis confined to one anatomic site, long-term survival is occasionally achieved by complete resection of all metastatic disease.  All patients with distant metastasis are appropriately considered candidates for clinical trials exploring new forms of treatment, including a combination of chemotherapy, biological response modifiers (such as specific monoclonal antibodies, interferons, IL-2, or tumor necrosis factor-alpha), vaccine immunotherapy, or biochemotherapy (chemoimmunotherapy).

Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%.

SENTINEL LYMPH NODE BIOPSY/DISSECTION

Lymphatic mapping and sentinel lymph node biopsy (SLNB) may be recommended in patients with thicker melanomas (greater than 1 mm in depth) and in those of less than 1 mm depth but with specific histologic features (eg, ulceration, lymphovascular invasion, mitotic rate 1 mm²).

SLNB for cutaneous melanoma was developed in the early 1990s to allow a selective approach to identifying occult regional nodal metastasis through localization of the first-draining, or sentinel, node. The success of the technique is based on the concept that cutaneous lymphatic flow is well-delineated in melanoma and that the histology of the sentinel node is characteristic of the entire lymph node basin (ie, a negative sentinel node obviates the need for further lymph node dissection).

Pre-operative radiographic mapping (lymphoscintigraphy) and vital blue dye injection around the primary melanoma or biopsy scar (at the time of wide local excision/re-excision) is performed to identify and remove the initial draining regional node(s).

The sentinel node is examined for the presence of micrometastasis using both routine histology and immunohistochemistry; if present, a therapeutic or completion lymph node dissection (CLND) is performed. A negative sentinel node biopsy result prevents the morbidity associated with an unnecessary lymphadenectomy.

Sentinel node status (positive or negative) is the most important prognostic factor for recurrence and is the most powerful predictor of survival in melanoma patients. Current AJCC melanoma staging and National Comprehensive Cancer Network clinical practice guidelines advocate pathologic staging of the regional lymph nodes for cutaneous melanoma of greater than 1 mm depth along with microstaging of the primary melanoma as the most complete means of staging.  However, the impact of SLN assessment on overall survival has yet to be determined.