Belisario A. Arango, MD
The skin is the most extensive organ in the body, and its role as a protective barrier constantly exposes it to a broad range of toxic insults such as chemicals and sun radiation. The incidence of melanoma has dramatically risen over the past several decades, and an estimated 79,000 new cases with close to 10,000 deaths are expected yearly in the United States. Famous people diagnosed with melanoma include Bob Marley, Diane Keaton, Anderson Cooper, Brooke Shields, Melanie Griffith, Ewan McGregor, John McCain, Laura Bush, Troy Aikman, Hugh Jackman, James Rebhorn, amongst others. As a result, melanoma is now the fifth most common malignancy in the United States.
Risk factors for melanoma include light complexion, poorly tanning skin, and blonde or red hair. Intense intermittent sun exposure and a history of blistering sunburn appear to confer a greater risk than lower-level, continuous sunlight exposure. Both ultraviolet A and ultraviolet B radiation have been implicated in the pathogenesis of melanoma. Exposure to ultraviolet radiation via tanning booths is associated with an increase in the risk of melanoma. Individuals with many common nevi and large congenital nevi are associated with an increased risk for the development of melanoma. The dysplastic nevus syndrome is characterized by numerous atypical nevi and the development of melanoma at an early age approaches 100%.
Skin melanomas can be detected by close observation for the ugly duckling sign of some skin lesions. The majority of melanomas display one of the following ABCDEs. Asymmetry, Border irregularity, Color variation, Diameter greater than 6 millimeters, and Enlargement or Evolution. Melanoma is highly curable by surgical excision when detected at an early stage. The efficacy of topical sunscreens in the primary prevention of melanoma has not been rigorously demonstrated.
The likelihood of recurrence and death from melanoma is directly correlated with tumor thickness. Superficial spreading on the skin is not as important as the depth of invasion of the tumor into the skin layers. Ulceration is also a powerful adverse prognostic feature. The presence of lymphatic and lymph node involvement is associated with an increased risk of recurrence and metastatic spread of disease. Stage-for-stage, advanced age, and male sex are associated with a worse prognosis in melanoma.
When a cutaneous lesion is suspected to be a melanoma an excisional biopsy or punch biopsy will provide the examining pathologist the most information. In particular the ability to assess the thickness and depth of invasion. Ablative procedures such as cryotherapy should be avoided as these specific tumor characteristics along with the mitotic index will be prohibitive to evaluate. Once the diagnosis of melanoma is established, a wide local excision with healthy skin margins of 2cm is the treatment of choice. The procedure of sentinel lymph node mapping and selective lymphadenectomy is highly sensitive for the detection of microscopic metastatic disease. Definitive surgical excision remains the mainstay therapeutic modality for early stage localized melanoma. Radiation therapy, chemotherapy or immunotherapy should not be used as the sole therapeutic modality for early stage melanoma.
When surgical excision reveals the presence of lymph node metastasis treatment with high-dose interferon alfa-2b should be considered. Treatment with high-dose interferon in this setting has demonstrated a survival benefit by decreasing the risk of recurrence and the development of a distant metastatic disease. Isolated limb perfusion with melphalan and moderate hyperthermia are an effective treatment for recurrent or unresectable in-transit metastasis of an extremity. High concentrations of chemotherapy to the limb can be achieved without excessive systemic exposure by isolation of the circulation.
The prognosis for patients with metastatic melanoma is poor. Melanoma can spread to the liver, lungs, bones, and brain. However, melanomas are notorious for being tumors that can metastasize to the most unusual surfaces like the heart, intestines, urogenital tract, than any other tumor. Lastly, melanomas have a predictably unpredictable behavior meaning that they can remain indolent and quiescent for many years and have the recurrent disease even decades after the primary tumor had been diagnosed.
Among medical oncology, there is no other single solid tumor that has benefited from the development of new discoveries in the biology and treatment modalities than melanomas. The understanding of these tumors at a molecular level has permitted the development of targeted treatments that exploit certain tumor pathways that allow cancer to grow, proliferate, and metastasize. These novel therapeutic modalities have allowed cancer specialists to treat the patient’s tumor while sparing the remainder of the healthy organs.
For over two decades we have recognized the importance that the immune system plays in combating melanoma. Treatment with high-dose interleukin-2, an immune-mediated cytokine, was the only treatment that had demonstrated long-term disease survival in patients with metastatic disease. The discovery of the activity of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and a second immune checkpoint programmed death 1/programmed death one ligand (PD-1/PD-L1) has emerged as a target for monoclonal antibodies against these tumor pathways. These novel agents have changed the landscape in the management of melanoma and have offered a more promising outlook for a patient who is afflicted with metastatic melanoma.