Skin Cancer Update

What are the gross characteristics and risk factors that should raise suspicion of malignant melanoma as opposed to squamous or basal cell carcinoma? Two dermatologists review these and other essential points of diagnosis, prognosis, and treatment that primary care physicians need to know about the three predominant forms of skin cancer.

By Stephen M. Schleicher, MD, and Richard F. Cordova, DO

Dr. Schleicher is director of the DermDx Centers for Dermatology of Northeastern Pennsylvania and clinical instructor of dermatology at the Philadelphia College of Osteopathic Medicine, Kings College in Wilkes-Barre, and Arcadia University in Glenside, Pennsylvania. He is also a member of the Emergency Medicine editorial board. Dr. Cordova is an associate dermatologist at the DermDx Centers.

Skin cancer accounts for more than 40% of all malignancies in the United States. Since 1950, the incidence of the disease has skyrocketed by a factor of 15. This is believed to be due to increased sun exposure, coupled with depletion of the earth's protective ozone layer.

Most skin cancers are basal or squamous cell carcinomas, which together account for nearly one million cases a year. These tumors are locally aggressive; squamous cell carcinomas may disseminate. Malignant melanoma is currently the eighth leading cause of cancer in the United States; there were 50,000 cases in the year 2000. This tumor is capable of metastasizing to the regional lymph nodes, lungs, and liver. On average, one American dies from malignant melanoma every hour.

In this article, we will review the three major types of skin cancer and the variants associated with each neoplasm. We will also discuss current treatment options.

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Malignant Melanoma

The incidence of malignant melanoma in the United States has increased dramatically in the last 30 years. Currently, the lifetime risk for acquiring this neoplasm is 1 in 75. Although it only accounts for 4% of all skin cancers, malignant melanoma is responsible for 75% of skin cancer-related mortality, killing 7500 people in 2000.

Melanoma is the most common cancer affecting Americans between ages 25 and 30. This year, some 50,000 cases of invasive melanoma and up to 40,000 cases of melanoma in situ will be newly diagnosed in the United States. These statistics demonstrate the importance of periodic skin evaluations and a comprehensive full- body examination every year, as recommended by the American Academy of Dermatology.

Multiple risk factors have been associated with the development of malignant melanoma (see box below). These include a history of intense sun exposure during childhood and early adult years, a positive family history, and the presence of so-called atypical or dysplastic nevi (see photo below).

Atypical or dysplastic nevi. Individuals with these lesions are at increased risk of developing melanoma.

The evaluation of moles for possible malignant transformation is important because 30% of all melanomas develop from pre-existing nevi. Applying the ABCDEs of melanoma recognition to individual nevi is helpful (see box below). Additional signs and symptoms associated with malignant transformation include itching and bleeding.

Because a definitive diagnosis of malignant melanoma can only be made by histopathologic examination, biopsy of any suspicious lesion is warranted.

Four distinct subtypes of malignant melanoma have been identified based on clinical and histologic findings. The superficial spreading variant (see photo below) accounts for 75% to 80% of all cases. It is most commonly found on the upper trunk in men and on the legs in women. These lesions are typically more than 6 mm in diameter, with ill-defined borders and variable pigment. They may exhibit radial growth (a horizontal pattern of proliferation confined to the epidermis) for many years before invading the dermis (vertical growth) and undergoing distant metastasis.

Superficial spreading melanoma. Note the irregular border and uneven pigmentation. The majority of these lesions arise de novo.

Nodular melanoma (see photo below) accounts for 10% to 15% of all melanomas. These are usually dark blue or black, dome-shaped nodules that are most commonly found on the legs and back. Because these lesions may resemble benign growths such as hemangiomas and pyogenic granulomas, they must be differentiated histologically. Unlike the superficial spreading variant, nodular melanomas exhibit a vertical growth pattern at an earlier stage of development and may therefore undergo earlier metastatic spread.

Rapidly enlarging, deeply pigmented nodular melanoma. The risk of dissemination is considerable with this lesion.

Melanomas that lack significant coloration (amelanotic melanomas, most of which are nodular) pose an especially difficult diagnostic challenge because they contain little or no clinically apparent pigment. These neoplasms present as nonspecific skin lesions, and a diagnosis is usually not made prior to histopathologic examination.

Lentigo maligna melanoma (see photo below) is seen most frequently in the elderly population on sun-exposed areas of the body. Representing 5% to 10% of all melanomas, the tumor frequently develops very slowly—sometimes over the course of a decade—from its precursor lesion, the lentigo maligna, a large, dark brown or black macular growth with irregular borders. Changes that may suggest malignant transformation include an alteration in pigmentary pattern or focal areas of papular or nodular growth within the precursor lesion, which indicate extension into the dermis.

Invasive lentigo maligna melanoma. Nodularity is indicative of a vertical growth phase and potential for metastatic spread.

Acral lentiginous melanomas (ALM), as the name implies, are commonly found on the palms and soles of the feet. They may also originate in mucous membranes and beneath the nail plates (subungual variant). Although they represent less than 10% of all melanomas, ALM is the most common subtype to appear in the Asian, African American, and Hispanic populations. Like lentigo maligna, the tumor grows slowly and typically affects people over 65. It usually appears as dark brown macular lesions with irregular, slowly expanding borders. When ALM develops beneath the nail plate, the differential diagnosis includes subungual hematoma, and a biopsy may be necessary to distinguish between the two entities.

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Depth of Tumor Invasion

The depth of tumor invasion is the most important prognostic factor in malignant melanoma. Breslow depth, which is a measurement (in millimeters) from the top layer of the epidermis to the deepest point of tumor invasion, is the preferred method of staging (see table, below).

When malignant melanoma is suspected in the office setting, an excisional biopsy that includes 2 to 3 mm of normal surrounding skin extending to the subcutaneous fat should be performed where possible. This allows the pathologist to accurately assess the specimen for involvement of the lateral margins and tumor depth. Incisional or punch biopsy is acceptable when the diagnosis is questionable or when full excision cannot be done immediately, which may be the case with larger lesions.

Treatment options depend on the Breslow staging of the lesion and on whether the tumor has spread to a draining lymph node.

The preponderance of data indicates that elective lymph node dissection has no survival benefit, and it is hoped that more selective and specific sentinel node lymphadenectomy will favorably alter the prognosis. (The sentinel node is the lymph node closest to the initial lesion.) Sentinel lymph node evaluation involves injection of a blue dye with radiologic lymphatic mapping for detection of melanoma metastasis to regional lymph nodes. If the sentinel node tests positive, then lymph node dissection is performed. This procedure is most frequently used in patients whose initial tumor depth is greater than 1 mm, but the actual benefit of sentinel node assay in decreasing patient mortality remains controversial, pending the outcomes of several ongoing studies.

In patients with lymph node involvement and distant metastasis, interferon alpha-2b has been approved as adjuvant therapy and may improve five-year survival rates. Patient response to a number of chemotherapeutic regimens has been uniformly disappointing. Melanoma vaccines are being tested in clinical trials. The National Cancer Institute is currently seeking the referral of patients with metastatic melanoma for the evaluation of a vaccine comprised of cancer-associated antigens.

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Squamous Cell Carcinoma

More than 200,000 cases of squamous cell carcinoma (SCC) are diagnosed each year in the United States, making it the second most common skin cancer. The typical lesion of SCC is found on an elderly patient in an area of the skin that has a history of sun exposure (see photos below), with men affected twice as often as women. In advanced cases, this tumor can destroy local tissue and cause significant morbidity. It can also metastasize to regional lymph nodes and viscera, but this occurs in less than 5% of cases. Squamous cell carcinoma is rare in dark-skinned people; the majority of cases involve Caucasians with fair complexions.

Frank squamous cell carcinoma. This lesion appears on the forehead of a fair-skinned man with a history of sun exposure. Also present are multiple actinic keratoses.

Squamous cell carcinoma of the lower lip. Cigarette and cigar smokers are at high risk for this tumor.

Lifetime exposure to ultraviolet radiation is considered the most important risk factor for SCC. Most patients work outdoors‹as farmers, mailmen, or construction workers, for example. More cases occur in areas near the equator, with Australia having the highest incidence of SCC worldwide. Also, PUVA, a treatment for psoriasis and vitiligo, is associated with an increased risk for SCC.

Squamous cell carcinoma frequently develops in immunocompromised patients and is very common (about 40% of cases) after renal transplantation. In the genital and perianal area, SCC may be associated with concurrent infection with human papilloma virus. Previous radiation therapy for treatment of malignancy can also promote development of SCC. Finally, SCC can develop in areas of chronic inflammation such as a burn or vaccination scar. Ulceration may be the first sign of malignant change in these areas, and a biopsy may be necessary to rule out an underlying carcinoma.

The clinical appearance of SCC can be quite variable and may be influenced by the tumor's location and depth. Intraepithelial lesions such as actinic keratoses are considered precursor lesions of SCC. They appear as crusted, hyperkeratotic, erythematous growths on the face, scalp, ears, arms, and hands.

Squamous cell carcinoma is more likely to develop if these lesions are painful, ulcerative, indurated, or unresponsive to treatment with liquid nitrogen or 5-fluorouracil. Squamous cell carcinoma in situ (also known as Bowen's disease) is a solitary lesion with superficial erythema and fine, scaly, sharply demarcated borders. Because of their coin-sized and coin-shaped appearance, these lesions are often misdiagnosed as areas of psoriasis or nummular eczema. When these scaly patches are found on the penis or vulva, the condition is known as erythroplasia of Queyrat, which is clinically indistinguishable from squamous cell carcinoma in situ that develops elsewhere on the body, although it is associated with an increased risk of metastatic spread. Squamous cell carcinoma in situ can also appear as a whitish plaque on the mucous membranes, a condition known as leukoplakia.

A keratoacanthoma is a rapidly expanding nodule that develops a central, keratotic core (see photo below). Although many keratoacanthomas spontaneously involute, they are often characterized histopathologically as low-grade, well-differentiated SCCs.

Keratoacanthoma. This lesion develops rapidly and manifests as a dome-shaped nodule with a central keratotic core. Most cases occur on sun-exposed areas of elderly individuals.

Invasive SCC may develop from a preexisting actinic keratosis, SCC in situ, or de novo from normal or damaged skin. These lesions are usually indurated, with poorly defined borders, and are more likely to be associated with symptoms such as bleeding or localized tenderness. Slow-growing, firm, papular eruptions with adherent keratotic scales tend to be well-differentiated SCC and have a more favorable prognosis. Poorly differentiated SCC tends to manifest as fleshy, erosive, soft, ulcerative growths that exhibit greater depth of invasion histologically and are therefore more likely to metastasize. Clinical features that suggest SCC will follow an aggressive course include: lesions greater than 2 cm in diameter; lesions located on the lips, ears, penis, or mucous membranes or in a scar or area of ulceration; depth of tumor invasion greater than 5 mm; and histologic findings consistent with poorly differentiated disease.

A skin biopsy is necessary for a definitive diagnosis of SCC. Regardless of which biopsy method is used, the specimen should include tissue to the level of the mid-dermis so that the depth of invasion can be determined.

Many treatments are available. For most actinic keratoses, SCC in situ, and small, well-circumscribed SCC, cryotherapy with liquid nitrogen and curettage with electrodessication are effective treatments with high cure rates. Mohs microsurgery is a useful treatment for lesions that are recurrent or more than 2 cm in diameter or when perineural invasion is suspected. It is also an excellent option for any SCC that develops on the nose, lips, nasolabial folds, or around the eyes. Other treatment options include radiotherapy and standard excision with conventional margins (4 to 5 mm). Regardless of the procedure used to treat SCC, overall prognosis is quite good, with cure rates of more than 90%.

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Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common skin cancer in the United States, with an annual incidence of 900,000 cases. Risk factors for BCC are sun exposure, fair complexion, old age, x-ray radiation, immunosuppression, and arsenic exposure. Basal cell carcinoma has a predilection for the head and neck region (see photo below) and can be locally aggressive, resulting in cosmetic deformity. Fortunately, metastatic spread and mortality from BCC are extremely rare.

Neglected basal cell carcinoma of the ear. These tumors begin as pearly, telangiectatic papules that over time become locally destructive.

The most common presentation for BCC is a slowly enlarging lesion on the face that bleeds easily with minor trauma (shaving or facial washing, for example) and frequently undergoes ulceration. Five different subtypes have been identified. Nodular BCC, the most common variant, is a pearly, translucent papule with raised borders and telangiectasias across its surface. Erosion, crusting, and ulceration are typical findings. Cystic BCC lesions are bluish-white, translucent, cystic nodules that are easily confused with sebaceous cysts. Superficial BCC lesions are scaly, erythematous patches with raised edges and central clearing (see photo below). They mimic several benign skin conditions such as psoriasis, tinea, and eczema; they also are unlikely to be invasive. Unlike other subtypes, superficial BCC lesions are more commonly found on the trunk.

Superficial basal cell carcinoma. Frequently misdiagnosed as a rash, these neoplasms are slow-growing and rarely invasive.

In addition to the features seen in nodular BCC, pigmented BCC lesions have brown or black pigment dispersed in an irregular pattern throughout the lesion (see photo below). Differentiating these lesions from malignant melanoma can be quite difficult. Finally, the sclerosing or morphea-like variant is a more aggressive subtype of BCC that appears as atrophic, white plaques of skin that resemble scar tissue. Crusting or ulceration within these lesions is not commonly seen.

Pigmented basal cell carcinomas. These lesions may resemble malignant melanoma.

A shave or punch biopsy is usually performed to confirm the diagnosis of BCC and identify the histologic subtype. Many different treatments are available for BCC; the choice of therapy is based on the histologic findings, location and size of the tumor, and patient preference. Curettage with electrodessication is frequently used for nodular or superficial subtypes and tumors that are less than 2 cm in diameter. Cure rates approach 95% with this technique. The procedure has two limitations: biopsy specimens cannot be examined for margin control, and healing occurs by granulation, which may be prolonged and may result in white atrophic scars on the face and neck.

Mohs surgery is an effective therapeutic modality for tumors that are more than 2 cm in diameter, more aggressive subtypes such as the sclerosing or morphea-like variant, and recurrent lesions. It is also the preferred surgical approach for tumors that develop in certain sensitive areas of the face, such as the nasolabial folds and around the eyes, and in the auditory canal. With this technique, the lesion and a small, thin zone of skin surrounding it are removed. The tissue removed from the margins is then mapped microscopically; if areas of tumor still exist, the tissue is excised only where the margins are positive, sparing normal tissue. Cure rates are generally better than 95% with Mohs surgery. However, it costs more than the other techniques and takes more time.

Radiation therapy is useful for patients who cannot tolerate or wish to avoid surgery. It is particularly well suited to elderly and debilitated patients. Cryosurgery may be used for smaller, less aggressive lesions; however, blister formation and prolonged healing time are possible unwanted sequelae. Cutting-edge therapies include use of the topical agents imiquimod and tazarotene and intralesional injections of interferon alpha-2b. Initial studies involving all of these agents are quite encouraging, with high rates of tumor resolution.

Overall prognosis with BCC is excellent, with recurrence rates of less than 10% regardless of the treatment used.

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Epidemic Proportions

Skin cancer has reached epidemic proportions in the United States. Minimizing sun exposure, especially in fair-skinned and genetically predisposed individuals, is the best preventive option. Patient education and periodic full-body examinations should positively influence morbidity and mortality. Physicians would do well to familiarize themselves with the many variants of skin cancer and should not hesitate to biopsy any suspicious lesion.