MELANOMA
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.
