Malignant melanoma is one of the few types of cancers that has continued to increase in incidence over the past century. Currently, the incidence of melanoma in the United States is 1 in 75 Caucasians; this is projected to continue to increase over the next few decades. However, the rate of mortality from melanoma has dropped, probably as a result of early detection and surgical intervention. According to cancer registries, melanoma ranks sixth in incidence for men and seventh for women. Melanoma is the most common cancer in women aged 25 to 30 years. Approximately 700,000 cases of melanoma were diagnosed in the United States in 2009, and approximately 9000 people died from complications directly related to melanoma.
Clinical Findings: Melanoma follows a characteristic growth pattern. The tumor arises de novo from previously normal skin in approximately 60% of cases and from preexisting melanocytic nevi in the remaining 40% of cases. Melanoma is uncommon in children, the one exception being melanoma arising from giant congenital nevi. The incidence of melanoma peaks in the third decade of life and remains fairly stable over the next 5 decades. There is no gender predilection. Melanoma is more common in the Caucasian population. There are regional variances in distribution of melanoma. The back is more commonly involved in men and the posterior lower legs in women. However, melanoma has been described to occur in any area of the skin and mucous membranes. Melanoma has also been shown to develop within the retinal melanocytes, causing retinal melanoma. This rare tumor is often found incidentally on routine ophthalmological examination.
Melanoma has been described using the ABCDE mnemonic: asymmetric, irregular border, variation in color, diameter greater than 6 mm, and evolving or changing. These are rough guidelines and are not meant to be used to diagnose melanoma. They are intended to be used by the lay public to increase aware- ness and as a method to screen for melanoma. Some melanomas have all of the ABCDE characteristics, and some have only one or two of them. Some variants of melanoma do not follow the ABCDE rules at all, but these are extremely rare.
There are four main variants of melanoma. The most common one is the superficial spreading type, followed by the nodular type. Lentigo maligna melanoma and acral lentiginous melanoma make up the remaining types. Rare variants are also seen, including the amelanotic type and the nevoid type. Superficial spreading melanoma is the most common variant of melanoma seen in clinical practice. It usually manifests as a slowly enlarging, irregularly shaped macule with variegation in color. If not recognized and removed, the melanoma will continue to enlarge and will eventually develop a vertical component that clinically represents the nodular form of melanoma. Some nodular forms of melanoma can develop de novo without the preceding superficial spreading type of melanoma as a precursor lesion. Nodular lesions are often relatively large at the time of diagnosis. This type of melanoma has entered its vertical growth phase, and it is believed that at this point it has developed the ability to metastasize.
Acral lentiginous melanoma has long been thought to portend a poor prognosis. This is most likely not because of the subtype but because this type of melanoma is often diagnosed later in the course of its development. The lesions are often located on the soles, toes, or hands. Patients are often unaware of their presence, and they can mimic a subungual hematoma or bruise. Notably, this form of melanoma is more commonly seen in the African American population.
Lentigo maligna melanoma is most often seen on the face of patients in their fifth to seventh decades of life, especially in those with a considerable sun exposure history. This type of melanoma can be difficult to treat and has a propensity for local recurrence. The borders of the melanoma are ill defined, and it is difficult to distinguish the background normal sun-damaged melanocytes from the tumor cells.
Amelanotic melanoma is the most difficult of all melanomas to diagnosis. These tumors often appear as slowly enlarging pink patches or plaques with no pigment. They are commonly misdiagnosed as dermatitis or tinea infections, and the diagnosis is often delayed. They can also resemble actinic keratoses. The lack of pigment takes away the clinician’s most important diagnostic clue. These tumors are often biopsied because they have not gone away after being treated for something entirely different or after they have developed a papule or nodule. At that point, they are still most commonly thought to be basal cell carcinomas or squamous cell carcinomas; rarely does the clinician include amelanotic melanoma in the differential diagnosis. Patients with albinism or xeroderma pigmentosum are at a higher risk for development of amelanotic melanoma. These patients need to be screened routinely, and any suspicious lesions should be biopsied.
Pathogenesis: There is no single gene defect that can explain the development of all melanomas. The most plausible theory is that a melanocyte within the epidermis is damaged by some external event, such as chronic ultraviolet exposure, or by some internal event, such as the spontaneous mutation of a key gene in the regulation of cell proliferation or apoptosis. After this event has occurred, the abnormal melanocyte proliferates with the epidermis, starting as an in situ variant of melanoma. After time, the clonal melanoma cells begin to coalesce and form nests of melanoma cells. They then continue to proliferate and enlarge until the clinical features are evident. The tumor enters a radial growth phase at first and eventually develops a vertical growth phase with metastatic potential.
Approximately 10% of melanomas are considered to be an inherited familial form. Although no one gene explains all of these tumors, the p16 gene (TP16) is likely the main susceptibility gene. This gene, when mutated, increases an individual’s risk for melanoma as well as pancreatic carcinoma. TP16 is a tumor suppressor gene that is inherited in an autosomal dominant fashion. Genetic testing for this gene is commercially available.
Histology: The diagnosis by histology of melanoma is based on multiple criteria, including symmetry, melanocyte atypia, mitosis, distribution of the melanocytes within the epidermis, lack of maturation of melanocytes as they extend deeper into the dermis, circumscription, and architectural disorder. Melanoma is believed to begin with an in situ portion, followed by an upward spread of single melanocytes within the epidermis, termed pagetoid spread. If no epidermal component of melanoma is seen, the possibility of a metastatic focus is entertained.
Treatment: When a clinician encounters a pigmented skin lesion that is believed to be a melanoma, the lesion should be biopsied promptly. The best method for biopsy of a pigmented lesion that is suspicious for melanoma is with an excisional biopsy method using a small (1-2 mm) margin of normal surrounding skin. This allows for the diagnosis and an accurate measurement of the Breslow depth. The Breslow depth is the distance from the granular cell layer to the base of the tumor. This depth is considered to be the most important prognostic indicator for melanoma.
Therapy for melanoma is based on the Breslow thickness, the presence of ulceration, and the mitotic rate of the primary tumor. The standard of care is to perform a wide local excision with varying margins of skin based on the criteria described previously. Melanoma in situ is treated surgically by wide local excision with 5-mm margins.
Sentinel lymph node sampling is becoming routinely performed in the care of these patients and aids in staging of the disease. If the patient has a positive sentinel lymph node biopsy for metastatic melanoma, staging is performed based on positron emission tomography/computed tomography (PET/CT) scanning and magnetic resonance imaging (MRI) of the brain. Patients with metastatic disease to local lymph nodes only are offered a localized lymph node dissection and adjunctive therapy with interferon. Those with widespread metastatic disease are given various chemotherapeutic regimens or enrolled into clinical studies. The mortality rate for stage IV melanoma is very poor. Follow-up for melanoma patients is based on the stage of disease. The National Comprehensive Cancer Network/National Cancer Institute (NCCN/NCI has published standardized guidelines for clinicians.