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(Malignant Melanoma)

by Gregory L. Wells, MD

Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or CNS). Metastasis is correlated with depth of dermal invasion. With spread, prognosis is poor. Diagnosis is by biopsy. Wide surgical excision is the rule for operable tumors. Metastatic disease requires systemic therapy but is difficult to cure.

About 76,250 new cases of melanoma occur yearly in the US, causing about 9,180 deaths. Lifetime risk is about 1 to 2%. Incidence has remained steady over the last 8 yr (it had previously been increasing at a faster rate than any other malignant tumor). Melanoma accounts for < 5% of total skin cancers diagnosed in the US but causes most skin cancer deaths. On average, one person in the US dies of melanoma every hour.

Melanomas occur mainly on the skin but also on the mucosa of the oral, genital, and rectal regions and conjunctiva. Melanomas may also develop in the choroid layer of the eye, in the leptomeninges (pia or arachnoid mater), and in the nail beds. Melanomas vary in size, shape, and color (usually pigmented) and in their propensity to invade and metastasize. Metastasis occurs via lymphatics and blood vessels. Local metastasis results in the formation of nearby satellite papules or nodules that may or may not be pigmented. Metastasis to skin or internal organs may occur, and, occasionally, metastatic nodules or enlarged lymph nodes are discovered before the primary lesion is identified.


Risk factors for melanoma include

  • Sun exposure, particularly repeated blistering sunburns

  • Repeated tanning with ultraviolet A (UVA) or psoralen plus UVA (PUVA) treatments

  • Nonmelanoma skin cancer

  • Family and personal history

  • Fair skin, freckling

  • Atypical moles, particularly > 10

  • Increased numbers of melanocytic nevi (particularly > 20, depending on family history)

  • Immunosuppression

  • Occurrence of lentigo maligna

  • Congenital melanocytic nevus > 20 cm (giant congenital nevi)

  • Atypical mole syndrome (dysplastic nevus syndrome)

  • Familial atypical mole–melanoma syndrome

Patients with a personal history of melanoma have an increased risk of additional melanomas. People who have one or more 1st-degree relatives with a history of melanoma have an increased risk (up to 6 or 8 times) over those without a family history.

Atypical mole syndrome is the presence of > 50 moles, at least one of which is atypical and at least one of which is > 8 mm in diameter.

Familial atypical mole–melanoma syndrome is the presence of multiple atypical moles and melanoma in ≥ 2 1st-degree relatives; such people are at markedly increased risk (25 times) of melanoma.

Melanoma is less common among people with darker pigmentation; when it occurs, the nail beds, palms, and soles are more often affected.

About 30% of melanomas develop from pigmented moles (about half each from typical and atypical moles); almost all the rest arise from melanocytes in normal skin. Atypical moles (dysplastic nevi) may be precursors to melanoma. The very rare melanomas of childhood almost always arise in the leptomeninges or from giant congenital nevi present at birth. Although melanomas occur during pregnancy, pregnancy does not increase the likelihood that a mole will become a melanoma; moles frequently change in size and darken uniformly during pregnancy. However, the following signs of malignant transformation should be carefully sought:

  • Change in size

  • Change in shape, including irregular or indistinct borders

  • Irregular change in color, especially spread of red, white, and blue pigmentation to surrounding normal skin

  • Change in surface characteristics or consistency

  • Signs of inflammation in surrounding skin, with possible bleeding, ulceration, itching, or tenderness

Recent enlargement, darkening, ulceration, or bleeding usually indicates that the melanoma has invaded the skin deeply. Patients at risk can be taught self-examination to detect changes in existing moles and to recognize features suggesting melanoma (see Diagnosis).


There are 4 main types of melanoma.

Superficial spreading melanoma

This type accounts for 70% of melanomas. Typically asymptomatic, it occurs most commonly on women’s legs and men’s torsos. The lesion is usually a plaque with irregular, raised, indurated, and tan or brown areas, which often have red, white, black, and blue spots or small, sometimes protuberant blue-black nodules. Small notchlike indentations of the margins may be noted, along with enlargement or color change. Histologically, atypical melanocytes characteristically invade the dermis and epidermis. This type of melanoma most commonly has activating mutations in the BRAF gene at V600.

Nodular melanoma

This type accounts for 15 to 30% of melanomas. It may occur anywhere on the body as a dark, protuberant papule or a plaque that varies from pearl to gray to black. Occasionally, a lesion contains little if any pigment or may look like a vascular tumor. Unless it ulcerates, nodular melanoma is asymptomatic, but patients usually seek advice because the lesion enlarges rapidly.

Lentigo maligna melanoma

This type accounts for 5% of melanomas. It tends to arise in older patients. It arises from lentigo maligna (Hutchinson freckle or malignant melanoma in situ—a frecklelike tan or brown macule). It usually occurs on the face or other areas of chronic sun exposure as an asymptomatic, flat, tan or brown, irregularly shaped macule or patch with darker brown or black spots scattered irregularly on its surface. In lentigo maligna, both normal and malignant melanocytes are confined to the epidermis. When malignant melanocytes invade the dermis, the lesion is called lentigo maligna melanoma, and the cancer may metastasize. This type of melanoma most commonly has mutations in the C-kit gene.

Acral-lentiginous melanoma

This type accounts for only 2 to 10% of melanomas. Incidence is probably the same regardless of skin pigmentation, but because people with darkly pigmented skin infrequently develop other forms of melanoma, acral-lentiginous melanoma is the most common type among them. It arises on palmar, plantar, and subungual skin and has a characteristic histologic picture similar to that of lentigo maligna melanoma. This type of melanoma often has mutations in the C-kit gene.


  • Biopsy

Differential diagnosis includes basal cell carcinomas and squamous cell carcinomas, seborrheic keratoses, atypical moles, blue nevi, dermatofibromas, moles, hematomas (especially on the hands or feet), venous lakes, pyogenic granulomas, and warts with focal thromboses.

If doubt exists, biopsy should include the full depth of the dermis and extend slightly beyond the edges of the lesion. Biopsy should be excisional for most lesions except those on anatomically sensitive or cosmetically important areas; in these cases, a broad shave biopsy can be done. By doing step sections, the pathologist can determine the maximal thickness of the melanoma. Definitive radical surgery should not precede histologic diagnosis.

Pigmented lesions with the following features should be excised or biopsied:

  • Recent enlargement

  • Darkening

  • Bleeding

  • Ulceration

However, these features usually indicate that the melanoma has already invaded the skin deeply. Earlier diagnosis of melanoma is possible if biopsy specimens can be obtained from lesions having variegated colors (eg, brown or black with shades of red, gray, or blue), irregular elevations that are visible or palpable, and borders with angular indentations or notches. Polarized light and immersion contact dermoscopy, which is used to examine pigmented lesions, may be useful for distinguishing melanomas from benign lesions. Because earlier diagnosis can be lifesaving and features of melanoma can be variable, even slightly suspect lesions should be biopsied.

Tumors are tested genetically for mutations.


The staging of melanoma is based on clinical and pathologic criteria and closely corresponds to the traditional tumor-node-metastasis (TNM) classification system. The staging system classifies melanomas based on local, regional, or distant disease.

  • Stages I and II: Localized primary melanoma

  • Stage III: Metastasis to regional lymph nodes

  • Stage IV: Distant metastatic disease

Stage strongly correlates with survival. A minimally invasive microstaging technique, the so-called sentinel lymph node biopsy (SLNB), is a major advance in the ability to stage cancers more accurately. Recommended staging studies depend on the Breslow depth (how deeply tumor cells have invaded) and histologic characteristics of the melanoma; dermal mitoses and ulceration indicate higher risk in melanomas that are < 1 mm Breslow depth (see Table: Staging of Melanoma Based on Thickness and Ulceration). Staging studies may include SLNB, laboratory tests (eg, CBC, LDH, liver function tests), chest x-ray, CT, and PET and are done by a coordinated team that includes dermatologists, oncologists, general surgeons, plastic surgeons, and dermatopathologists.


Melanoma may spread rapidly, causing death within months of its recognition, yet the 5-yr cure rate of early, very superficial lesions is very high. Thus, cure depends on early diagnosis and early treatment.

For tumors of cutaneous origin (not CNS and subungual melanomas) that have not metastasized, the survival rate varies depending on the thickness of the tumor at the time of diagnosis. The 5-yr survival rates range from 97% for patients with stage IA melanomas to 53% for patients with stage IIC melanomas; 10-yr survival rates range from 93% for patients with stage IA melanomas to 39% for patients with stage IIC melanomas.

Mucosal melanomas (especially anorectal melanomas), which are more common among nonwhites, have a poor prognosis, although they often seem quite limited when discovered.

Once melanoma has metastasized to the lymph nodes, 5-yr survival ranges from 25 to 70% depending on the degree of ulceration and number of nodes involved. Once melanoma has metastasized to distant sites, 5-yr survival is about 10%.

Staging of Melanoma Based on Thickness and Ulceration




Intraepithelial or in situ melanoma


1 mm with no ulceration and dermal mitoses < 1/mm 2


1 mm with ulceration and/or at least 1 dermal mitoses/mm 2

1.01–2 mm with no ulceration


1.01–2 mm with ulceration

2.01–4 mm with no ulceration


2.01–4 mm with ulceration

4 mm with no ulceration


> 4 mm with ulceration

Adapted from Edge SB, Byrd DR, Compton CC, et al: AJCC Cancer Staging Manual, ed. 7. New York, Springer (2010).

Degree of lymphocytic infiltration, which represents reaction by the patient’s immunologic defense system, may correlate with the level of invasion and prognosis. Chances of cure are maximal when lymphocytic infiltration is limited to the most superficial lesions and decrease with deeper levels of tumor cell invasion, ulceration, and vascular or lymphatic invasion.

A new commercially available test of gene expression (DecisionDx TM -Melanoma) helps determine whether patients who have stage I or II melanomas are at high or low risk of metastases.


  • Surgical excision

  • Possibly adjuvant radiation therapy, imiquimod, or cryotherapy

  • For metastatic or unresectable melanoma, immunotherapy (eg, pembrolizumab, nivolumab), targeted therapy (eg, ipilimumab, vemurafenib, dabrafenib), and radiation therapy

Treatment of melanoma is primarily by surgical excision (wide local excision). Although the width of margins is debated, most experts agree that a 1-cm lateral tumor-free margin is adequate for lesions < 1 mm thick. In tumors < 1 mm thick, but with ulceration or at least 1 dermal mitoses/mm2, SLNB can be considered. Thicker lesions may deserve larger margins, more radical surgery, and SLNB.

Lentigo maligna melanoma and lentigo maligna are usually treated with wide local excision and, if necessary, skin grafting. Intensive radiation therapy is much less effective. The ideal treatment of melanoma in situ is surgical excision. Sometimes this can be accomplished with staged excisions or Mohs micrographic surgery. If patients decline or are not candidates for surgical therapy (eg, because of comorbidities or involvement of cosmetically important areas), imiquimod and cryotherapy can be considered. Most other treatment methods usually do not penetrate deeply enough into involved follicles, which must be removed.

Spreading or nodular melanomas are usually treated with wide local excision extending down to the fascia. Lymph node dissection may be recommended when nodes are involved. (See also the American Academy of Dermatology Association’s guidelines of care for the management of primary cutaneous melanoma .)

Metastatic disease

Treatment of metastatic melanoma typically includes

  • Immunotherapy

  • Molecular targeted therapy

  • Radiation therapy

  • Rarely surgical resection

All of these treatments should be considered for all patients who have metastatic melanoma. Final decisions are generally individualized by an oncologist and may depend on availability.

Metastatic disease is generally inoperable, but in certain cases, localized and regional metastases can be excised to help eliminate residual disease.

Immunotherapy with anti-programmed death (PD-1) antibodies (pembrolizumab and nivolumab) lengthens survival. They inhibit the PD-1 receptor that attenuates T-cell effector responses against cancers.

Ipilimumab (a monoclonal antibody to cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) is another form of immunotherapy that can also lengthen survival. It works by preventing anergy of T cells, thus freeing the immune system to attack tumor cells.

Molecular targeted therapy includes use of vemurafenib and dabrafenib, which function by inhibiting BRAF activity, resulting in slowing or stopping of tumor cell proliferation. These drugs have lengthened survival in patients with metastases; adding mitogen-activated protein kinase (MEK) inhibitor enzymes MEK1 and MEK2 (via trametinib) lengthens survival even more.

Cytotoxic chemotherapy has not been shown to improve survival in patients with metastatic disease and is normally reserved for patients who do not have other options.

Adjuvant therapy with recombinant biologic response modifiers (particularly interferon alfa) to suppress clinically inapparent micrometastases may also be used for inoperable metastatic melanoma.

Radiation therapy may be used to palliate brain metastases, but the response is poor.

The following are under study:

  • Infusion of lymphokine-activated killer cells or antibodies (for advanced-stage disease)

  • Vaccine therapy


Because melanoma seems to be related to ultraviolet (UV) exposure, a number of measures are recommended to limit exposure.

  • Sun avoidance: Seeking shade, minimizing outdoor activities between 10 am and 4 pm (when sun's rays are strongest), and avoiding sunbathing and the use of tanning beds

  • Use of protective clothing: Long-sleeved shirts, pants, and broad-brimmed hats

  • Use of sunscreen: At least sun protection factor (SPF) 30 with broad-spectrum UVA/UVB protection, used as directed (ie, reapplied every 2 h and after swimming or sweating); should not be used to prolong sun exposure

Current evidence is inadequate to determine whether these measures reduce incidence or mortality of melanoma; in nonmelanoma skin cancers ( basal cell carcinoma and squamous cell carcinoma), sun protection does decrease the incidence of new cancers.

Key Points

  • Melanoma accounts for < 5% of total skin cancers diagnosed in the US but causes most skin cancer deaths.

  • Melanoma can develop in the skin, mucosa, conjunctiva, choroid layer of the eye, leptomeninges, and nail beds.

  • Although melanoma can develop from a typical or atypical mole, most do not.

  • Physicians (and patients) should monitor moles for changes in size, shape, borders, color, or surface characteristics and for bleeding, ulceration, itching, and tenderness.

  • Biopsy even slightly suspect lesions.

  • Excise melanomas whenever feasible, particularly when melanomas have not metastasized.

  • Consider immunotherapy (eg, pembrolizumab, nivolumab), targeted therapies (eg, ipilimumab, vemurafenib), radiation therapy, and excision if melanoma is unresectable or metastatic.

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