CHAPTER 33: CANCER OF THE SKIN

Pigmented lesions are among the most common findings on skin examination. The challenge is to distinguish cutaneous melanomas, which account for the overwhelming majority of deaths resulting from skin cancer, from the remainder, which with rare exceptions are benign. Cutaneous melanoma can occur in adults of all ages, even young individuals, and people of all colors; it is located on the skin, where it is visible; and it has distinct clinical features that make it detectable at a time when complete surgical excision is possible. Examples of malignant and benign pigmented lesions are shown in Fig. 33-1.

EPIDEMIOLOGY

Melanoma is an aggressive malignancy of melanocytes: pigment-producing cells that originate from the neural crest and migrate to the skin, meninges, mucous membranes, upper esophagus, and eyes. Melanocytes in each of these locations have the potential for malignant transformation. In the United States, nearly 69,000 individuals were expected to develop melanoma and approximately 9000 were expected to die in 2010. Although the overall incidence and mortality have increased over the past decades, the mortality rates for younger patients have flattened, but those rates for individuals older than age 65 years have continued to increase. It is predominantly a malignancy of white-skinned people (98% of cases), and the incidence correlates with latitude of residence, providing strong evidence for the role of sun exposure. Men are affected slightly more than women (1.3:1), and the median age at diagnosis is the late fifties. Dark-skinned populations (such as those of India and Puerto Rico), blacks, and East Asians also develop melanoma, albeit at rates 10–20 times lower than those in whites. Cutaneous melanomas in these populations are diagnosed more often at a higher stage, and patients tend to have worse outcomes. Furthermore, in nonwhite populations, there is a much higher frequency of acral (subungual, plantar, palmar) and mucosal melanomas.

RISK FACTORS

The strongest risk factors for melanoma are the presence of multiple benign or atypical nevi and a family or personal history of melanoma (Table 33-1). The presence of melanocytic nevi, common or dysplastic, is a marker for an increased risk of melanoma. Nevi have been referred to as precursor lesions because they can transform into melanomas; however, the actual risk for any specific nevus is exceedingly low. About one-quarter of melanomas are histologically associated with nevi, but the majority arise de novo. Table 33-2 lists the characteristic features of clinically atypical moles and the features that differentiate them from benign acquired nevi. The number of clinically atypical moles may vary from one to several hundred, and they usually differ from one another in appearance. The borders are often hazy and indistinct, and the pigment pattern is more highly varied than that in benign acquired nevi. Individuals with clinically atypical moles and a strong family history of melanoma have been reported to have a >50% lifetime risk for developing melanoma and warrant close follow-up with a dermatologist. Of the 90% of melanoma patients whose disease is regarded as sporadic (i.e., who lack a family history of melanoma), ~40% have clinically atypical moles compared with an estimated 5–10% of the population at large.

Congenital melanocytic nevi, which are classified as small (≤1.5 cm), medium (1.5–20 cm), and giant (>20 cm), can be precursors for melanoma. The risk is highest for the giant melanocytic nevus, also called the bathing trunk nevus, which is a rare malformation that affects 1 in 30,000–100,000 individuals, with a lifetime risk of melanoma development estimated to be as high as 6%. At present, there are no uniform management guidelines for giant congenital nevi, but because of the potential for malignancy, prophylactic excision early in life is prudent. This usually requires staged removal with coverage by split-thickness skin grafts. Surgery cannot remove all at-risk nevus cells, as some may penetrate into the muscles or central nervous system (CNS) below the nevus. Small- to medium-size congenital melanocytic nevi affect approximately 1% of persons; the risk of melanoma developing in these lesions is not known but appears to be relatively low. The management of small- to medium-size congenital melanocytic nevi remains controversial.

Personal and family history

Perhaps the single greatest risk factor for melanoma is a personal history of melanoma. Once diagnosed, patients with melanoma require a lifetime of surveillance because their risk is 10 times that of the general population. First-degree relatives have a higher risk of developing melanoma than do individuals without a family history, but only 5–10% of all melanomas are truly familial. In familial melanoma, patients tend to be younger at first diagnosis, lesions are thinner, survival is improved, and multiple primary melanomas are common.

Genetic susceptibility

Approximately 20–40% of cases of hereditary melanoma (0.2–2% of all melanomas) are due to germ-line mutations in the cell cycle regulatory gene cyclin-dependent kinase inhibitor 2A (CDKN2A). In fact, 70% of all cutaneous melanomas have somatic mutations or deletions affecting the CDKN2A locus on chromosome 9p21. This locus encodes two distinct tumor suppressor proteins from alternate reading frames: p16 and ARF (p14^ARF). The p16 protein inhibits CDK4/6-mediated phosphorylation and inactivation of the retinoblastoma (RB) protein, whereas ARF inhibits MDM2 ubiquitin-mediated degradation of p53. The end result of the loss of CDKN2A is inactivation of two critical tumor suppressor pathways, RB and p53, which control entry of cells into the cell cycle. Several studies have shown an increased risk of pancreatic cancer among melanoma-prone families with CDKN2A mutations.

The melanocortin-1 receptor (MC1R) gene is also an inherited melanoma susceptibility factor. Solar radiation stimulates the production of melanocortin (α-melanocyte-stimulating hormone [α-MSH]), the ligand for MC1R, which is a G-protein–coupled receptor that signals via cyclic AMP and regulates the amount and type of pigment produced. MC1R is highly polymorphic, and among its 80 variants are those that result in partial loss of signaling and lead to the production of pheomelanin, which is not sun-protective and produces red hair. This red hair color (RHC) phenotype is associated with fair skin, red hair, freckles, increased sun sensitivity, and increased risk of melanoma.

CLINICAL CLASSIFICATION

Traditionally, four major types of cutaneous melanoma have been recognized (Table 33-3). In three of these types—superficial spreading melanoma, lentigo maligna melanoma, and acral lentiginous melanoma—the lesion has a period of superficial (so-called radial) growth during which it increases in size but does not penetrate deeply. It is during this period that the melanoma is most capable of being cured by surgical excision. The fourth type—nodular melanoma—does not have a recognizable radial growth phase and usually presents as a deeply invasive lesion that is capable of early metastasis. When tumors begin to penetrate deeply into the skin, they are in the so-called vertical growth phase. Melanomas with a radial growth phase are characterized by irregular and sometimes notched borders, variation in pigment pattern, and variation in color. An increase in size or change in color is noted by the patient in 70% of early lesions. Bleeding, ulceration, and pain are late signs and are of little help in early recognition. Superficial spreading melanoma is the most common variant observed in the white population. The back is the most common site for melanoma in men. In women, the back and the lower leg (from knee to ankle) are common sites. Nodular melanomas are dark brown-black to blue-black nodules. Lentigo maligna melanoma usually is confined to chronically sun-damaged, sun-exposed sites (face, neck, back of hands) in older individuals. Acral lentiginous melanoma occurs on the palms, soles, nail beds, and mucous membranes. Although this type occurs in whites, it occurs most frequently (along with nodular melanoma) in blacks and East Asians. A fifth type of melanoma, desmoplastic melanoma, is associated with a fibrotic response, neural invasion, and a greater tendency for local recurrence. Occasionally, melanomas appear clinically to be amelanotic, in which case the diagnosis is established histologically after biopsy of a new or a changing skin nodule or because of suspicion of a basal cell carcinoma.

Although melanoma subtypes are clinically and histopathologically distinct, this classification does not have independent prognostic value and has fallen out of favor. Histologic subtype is not part of American Joint Committee on Cancer (AJCC) staging and often is not identified in current pathology reports. Future classification schemes will be based on molecular features of each melanoma (see later discussion). The molecular analysis of individual melanomas will provide a basis for distinguishing benign nevi from melanomas, identify distinct subclasses of melanoma on the basis of the anatomic site, indicate the extent of ultraviolet (UV) exposure, and determine the mutational status of the tumor, which will help elucidate the molecular mechanisms of tumorigenesis and identify targets that will serve as a basis for selection of therapy.

PATHOGENESIS AND MOLECULAR CLASSIFICATION

Considerable evidence from epidemiologic and molecular studies suggests that cutaneous melanomas arise via multiple pathways. There are both environmental and genetic components. Uv solar radiation causes genetic changes in the skin, impairs cutaneous immune function, increases the production of growth factors, and induces the formation of DNA-damaging reactive oxygen species that affect keratinocytes and melanocytes. A comprehensive catalog of somatic mutations from a human melanoma revealed more than 33,000 base mutations with damage to almost 300 protein-coding segments compared with normal cells from the same patient. The dominant mutational signature reflected DNA damage due to UV light exposure. The melanoma also contained previously described driver mutations (i.e., mutations that confer selective clonal growth advantage and are implicated in oncogenesis). These driver mutations affect pathways that promote cell proliferation and inhibit normal pathways of apoptosis in response to DNA repair (see later discussion). The altered melanocytes accumulate DNA damage, and selection occurs for all the attributes that constitute the malignant phenotype: invasion, metastasis, and angiogenesis.

An understanding of the molecular changes that occur during the transformation of normal melanocytes into malignant melanoma not only would help classify patients in similar prognostic groups but also would contribute to the understanding of etiology and help identify new therapeutic options. A genomewide assessment of melanomas classified into four groups based on their location and degree of exposure to the sun has confirmed that there are distinct genetic pathways in the development of melanoma. The four groups were melanomas on skin without chronic sun-induced damage, melanomas on skin with chronic sun-induced damage, mucosal melanomas, and acral melanomas. Remarkably, distinct patterns of DNA alterations were noted that varied with the site of origin and were independent of the histologic subtype of the tumor. What that work and research done by others have shown is that the overall pattern of mutation, amplification, and loss of cancer genes indicate that although the genetic changes are diverse, they have convergent effects on key biochemical pathways involved in proliferation, senescence, and apoptosis. The p16 mutation that leads to cell cycle arrest and the ARF mutation that results in defective apoptotic responses to genotoxic damage were described earlier. The proliferative pathways affected were the mitogen-activated protein (MAP) kinase and phosphatidylinositol 3′ kinase/AKT pathways (Fig. 33-2).

The RAS family and BRAF, members of the MAP kinase pathway, which classically mediates the transcription of genes involved in cell proliferation and survival, undergo somatic mutation in melanoma. N-RAS is mutated in approximately 20% of melanomas, and somatic activating BRAF mutations are found in most benign nevi and 40–60% of melanomas. Neither mutation by itself appears to be sufficient to cause melanoma; they often are accompanied by other mutations, (e.g., CDKN2A) or phosphatidylinositol 3′ kinase pathway (e.g., loss of PTEN). The BRAF mutation is almost always a point mutation (T→A nucleotide change) that results in a valine-to-glutamate amino acid substitution (V600E). V600E BRAF mutations do not have the standard UV signature mutation (pyrimidine dimer) but are present in most melanomas that arise on sites with intermittent sun exposure and are absent in melanomas from chronically sun-damaged skin.

Melanomas also contain mutations in AKT (primarily in AKT3) and PTEN (phosphatase and tensin homolog). AKT can be amplified, and PTEN may be deleted or undergo epigenetic silencing that leads to constitutive activation of the PI3K/AKT pathway and enhanced cell survival by antagonizing the intrinsic pathway of apoptosis. Loss of PTEN, which dysregulates AKT activity, and mutation of AKT3 prolong survival through inactivation of BAD, Bc12-antagonist of cell death, and activation of the forkhead transcription factor FOXO1, which leads to synthesis of prosurvival genes. In melanoma, these two signaling pathways enhance tumorigenesis, chemoresistance, migration, and cell cycle dysregulation. Targeted agents are being employed that inhibit each pathway, but it is likely that effective antimelanoma therapy will require simultaneous inhibition of both MAPK and PI3K.

DIAGNOSIS

The main goal is to diagnose melanoma early in its natural history, before tumor invasion and life-threatening metastases have occurred. Early detection of melanoma may be facilitated by applying the ABCDEs: asymmetry (benign lesions are usually symmetric), border irregularity (most nevi have clear-cut borders), color variegation (benign lesions usually have uniform light or dark pigment), diameter >6 mm (the size of a pencil eraser); evolving (any change in size, shape, color, or elevation or new symptoms such as bleeding, itching, and crusting). The aim of differential diagnosis is to distinguish benign pigmented lesions from melanoma and its precursor. If melanoma is a consideration, biopsy is appropriate. Some benign look-alikes may be removed in the process of trying to detect melanoma. Several factors may help distinguish benign nevi from atypical moles:

1. Size: Benign nevi usually are <6 mm in diameter; atypical moles usually are >6 mm in diameter.

2. Shape: Benign nevi usually are round with distinct borders and may be flat or elevated; atypical moles usually have irregular borders with pigment fading off at the edge.

3. Color: Benign nevi usually are uniformly brown or tan; atypical moles usually have variable mixtures of brown, tan, black, and reddish pigment and differ from one another.

4. Location: Benign nevi usually appear on sun-exposed skin above the waist, rarely involving the scalp, breasts, or buttocks; atypical moles usually appear on sun-exposed skin, most often on the back, but can involve the scalp, breasts, or buttocks.

5. Number: Benign nevi are present in 85% of adults, with 10–40 moles scattered over the body; atypical nevi can be present in the hundreds.

The entire cutaneous surface, including the scalp and mucous membranes, as well as the nails should be examined in each patient. Bright room illumination is important, and a hand lens is helpful for evaluating variation in pigment pattern. Any suspicious lesions should be biopsied, evaluated by a specialist, or recorded by chart and/or photography for follow-up. A focused method for examining individual lesions, dermoscopy, employs low-level magnification of the epidermis and may allow a more precise visualization of patterns of pigmentation than is possible with the naked eye. Complete physical examination with attention to the regional lymph nodes is part of the initial evaluation in a patient with suspected melanoma. The patient should be advised to have other family members screened if either melanoma or clinically atypical moles (dysplastic nevi) are present. Patients who fit into high-risk groups should be instructed to perform monthly self-examinations.

Biopsy

Any pigmented cutaneous lesion that has changed in size or shape or has other features suggestive of malignant melanoma is a candidate for biopsy. The recommended technique is an excisional biopsy, which facilitates pathologic assessment of the lesion, permits accurate measurement of thickness if the lesion is melanoma, and constitutes treatment if the lesion is benign. For large lesions or lesions on anatomic sites where excisional biopsy may not be feasible (such as the face, hands, and feet), an incisional biopsy through the most nodular or darkest area of the lesion is acceptable; this should include the vertical growth phase of the primary tumor, if present. Incisional biopsy does not appear to facilitate the spread of melanoma. For suspicious lesions, every attempt should be made to preserve the ability to assess the deep and peripheral margins and to perform immunohistochemistry. Shave biopsies and cauterization should be avoided. The biopsy should be read by a pathologist experienced in pigmented lesions, and the minimal elements of the report should include Breslow thickness, mitoses per square millimeter for lesions ≤1 mm, presence or absence of ulceration, and peripheral and deep margin status. Breslow thickness is the greatest thickness of a primary cutaneous melanoma measured on the slide from the top of the epidermal granular layer, or from the ulcer base, to the bottom of the tumor. To distinguish melanomas from benign nevi in cases with challenging histology, fluorescence in situ hybridization (FISH) with multiple probes can be helpful.

PROGNOSTIC FACTORS

The prognostic factors of greatest importance to a newly diagnosed patient are included in the staging classification (Table 33-4). The best predictor of metastatic risk is the lesion's Breslow thickness. The Clark level, which defines melanomas on the basis of the layer of skin to which a melanoma has invaded, does not add significant prognostic information and no longer is used. Other important factors recognized via the staging classification include the presence of ulceration, evidence of nodal involvement, serum lactate dehydrogenase (LDH) level, and presence and site of distant metastases. The effects of these important prognostic factors on survival can be seen in Fig. 33-3, where survival is depicted according to stage (Table 33-4). Another determinant is anatomic site; favorable sites are the forearm and leg (excluding the feet), and unfavorable sites include the scalp, hands, feet, and mucous membranes. In general, women with stage I or II disease have better survival than men, perhaps in part because of earlier diagnosis; women frequently have melanomas on the lower leg, where self-recognition is more likely and the prognosis is better. The impact of age is not straightforward. Older individuals, especially men older than age 60 years, have worse prognoses, a finding that has been explained in part by a tendency toward later diagnosis (and thus thicker tumors) and in part by a higher proportion of acral melanomas in men. However, there is a greater risk of lymph node metastasis in young patients.

STAGING

Once the diagnosis of melanoma has been made, the tumor must be staged to determine the prognosis and treatment. The 2009 AJCC revised melanoma staging and classification are depicted in Table 33-4. The clinical stage of the patient is determined after the pathologic evaluation of the melanoma skin lesion and any clinical or radiologic assessment for metastatic disease. Pathologic staging also includes the pathologic evaluation of the regional lymph nodes obtained at sentinel lymph node biopsy or complete lymphadenectomy. All patients with melanoma should have a complete history and physical examination with attention to symptoms that may represent metastatic disease such as malaise, weight loss, headaches, visual difficulty, and pain. The physical examination should be directed to the site of the primary melanoma, looking for persistent disease or for dermal or subcutaneous nodules that could represent satellite or in-transit metastases. Physical examination also should include the regional draining lymph nodes, CNS, liver, and lungs. A complete blood count (CBC), complete metabolic panel, and LDH level should be performed. Although these are low-yield tests for uncovering metastatic disease, a microcytic anemia would raise the possibility of bowel metastases, particularly in the small bowel, and an unexplained elevated LDH should prompt a more extensive evaluation, including CT scan or possibly a positron emission tomography (PET) (or CT and PET combined) scan. If signs or symptoms of metastatic disease are uncovered, appropriate diagnostic imaging should be performed. At initial presentation, more than 80% of patients will have disease confined to the skin and a negative history and physical examination, in which case imaging generally is not indicated.

FOLLOW-UP

Skin examination and surveillance at least once a year is recommended for all patients with melanoma. The National Cancer Comprehensive Network (NCCN) guidelines for patients with stage IB–IV melanoma recommend a comprehensive history and physical examination every 3–6 months for 2 years, then every 3–12 months for 3 years, and annually thereafter, as clinically indicated. Particular attention should be paid to the draining lymph nodes in stage I–III patients as resection of lymph node recurrences may still be curative. A CBC, LDH, and chest radiography are recommended at the physician's discretion. Routine imaging for metastatic disease is not recommended at this time because there is no discernible survival benefit to the early detection of metastatic disease.

PREVENTION

Primary melanoma prevention is based on protection from the sun, which includes wearing protective clothing, avoiding intense midday UV exposure and tanning booths, and routine application of a broad-spectrum ultraviolet-A/ultraviolet-B (UV-A/UV-B) sunblock with sun protection factor ≥15. This includes use of protective clothing and avoidance of intense midday UV exposure. Secondary prevention consists of education and screening. Patients should be educated in the clinical features of melanoma (ABCDEs) and advised to report any growth or other change in a pigmented lesion. Brochures are available from the American Cancer Society, the American Academy of Dermatology, the National Cancer Institute, and the Skin Cancer Foundation. Self-examination at 6- to 8-week intervals may enhance the likelihood of detecting change. Although the U.S. Preventive Services Task Force states that evidence is insufficient to recommend for or against skin cancer screening, a full-body skin cancer screening seems to be a simple, practical way to approach reducing the mortality rate for skin cancer. This is particularly true for patients with clinically atypical moles (dysplastic nevi) and those with a personal history of melanoma. Individuals with three or more primary melanomas and families with at least one invasive melanoma and two or more cases of melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family may benefit from genetic testing.

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, with an estimated annual incidence of 1.5–2 million cases. Basal cell carcinomas (BCCs) account for 70–80% of NMSCs. Squamous cell carcinomas (SCCs), though representing only ~20% of NMSCs, are more significant because of their ability to metastasize (Fig. 33-4). They account for most of the 2400 deaths annually. Incidence rates have risen dramatically over the past decade.

ETIOLOGY

The causes of BCC and SCC are multifactorial. Cumulative exposure to sunlight, principally the UV-B spectrum, is the most significant factor. Other factors associated with a higher incidence of skin cancer are male sex, older age, Celtic descent, a fair complexion, blond or red hair, blue or green eyes, a tendency to sunburn easily, and an outdoor occupation. The incidence of these tumors increases with decreasing latitude. Most tumors develop on sun-exposed areas of the head and neck. Tumors are more common on the left side of the body in the United States but on the right side in England, presumably owing to asymmetric exposure during driving. As the earth's protective ozone shield continues to thin, further increases in the incidence of skin cancer can be anticipated. In certain geographic areas, exposure to arsenic in well water or from industrial sources may increase the risk of BCC and SCC significantly. Skin cancer in affected individuals may be seen with or without other cutaneous markers of chronic arsenism (e.g., arsenical keratoses). Less common is exposure to the cyclic aromatic hydrocarbons in tar, soot, or shale. The risk of lip or oral SCC is increased with cigarette smoking. Human papillomaviruses and UV radiation may act as cocarcinogens.

Host factors associated with a higher risk of skin cancer include immunosuppression induced by disease or drugs. Solid-organ transplant recipients on chronic immunosuppressive therapy have a dramatically higher incidence of NMSCs. SCCs are most common, with a 65-fold increase in incidence, whereas BCCs have a tenfold increase in incidence. The frequency of skin cancer is proportional to the level and duration of immunosuppression as well as the extent of sun exposure both before and after transplantation. SCCs in this population also demonstrate more aggressive behavior with higher rates of local recurrence, metastasis, and mortality.

Skin cancer is not uncommon in patients infected with HIV, and tumors may be more aggressive in this setting. Other factors include ionizing radiation, thermal burn scars, and chronic ulcerations. Several heritable conditions are associated with skin cancer (e.g., albinism, xeroderma pigmentosum, Rombo's syndrome, Bazex-Dupré-Christol syndrome, and basal cell nevus syndrome). Background mutations in hedgehog pathway genes, primarily genes encoding patched homolog 1 (PTCH1) and smoothened homolog (SMO), occur in BCC. In fact, an oral hedgehog inhibitor has shown promise in clinical trials treating advanced inoperable or metastatic BCC.

CLINICAL PRESENTATION

NMSCs are often asymptomatic, but nonhealing ulceration, bleeding, or pain can occur in advanced lesions.

Basal cell carcinoma

BCC is a malignancy arising from epidermal basal cells. The least invasive of BCC subtypes, superficial BCC, classically consists of truncal erythematous scaling plaques that slowly enlarge. This BCC subtype may be confused with benign inflammatory dermatoses, especially nummular eczema and psoriasis. BCC also can present as a small, slowly growing pearly nodule, often with small telangiectatic vessels on its surface (nodular BCC). The occasional presence of melanin in this variant of nodular BCC (pigmented BCC) may lead to confusion clinically with melanoma. Morpheaform (fibrosing) and micronodular BCC, the most invasive subtypes, manifest as solitary, flat or slightly depressed, indurated whitish or yellowish plaques. Borders are typically indistinct, a feature associated with a greater potential for extensive subclinical spread.

Squamous cell carcinoma

Primary cutaneous SCC is a malignant neoplasm of keratinizing epidermal cells. SCC can grow rapidly and metastasize. The clinical features of SCC vary widely. Commonly, SCC appears as an ulcerated erythematous nodule or superficial erosion on the skin or lower lip, but it may present as a verrucous papule or plaque. Overlying telangiectasias are uncommon. The margins of this tumor may be ill defined, and fixation to underlying structures may occur. Cutaneous SCC may develop anywhere on the body but usually arises on sun-damaged skin. A related neoplasm, keratoacanthoma, typically appears as a dome-shaped papule with a central keratotic crater, expands rapidly, and commonly regresses without therapy. This lesion can be difficult to differentiate from SCC.

Actinic keratoses and cheilitis, both premalignant forms of SCC, present as hyperkeratotic papules on sun-exposed areas. The potential for malignant degeneration in untreated lesions ranges from 0.25 to 20%. Bowen's disease, the in situ form of SCC, presents as a scaling, erythematous plaque. Treatment of premalignant and in situ lesions reduces the subsequent risk of invasive disease.

NATURAL HISTORY

Basal cell carcinoma

The natural history of BCC is that of a slowly enlarging, locally invasive neoplasm. The degree of local destruction and risk of recurrence vary with the size, duration, location, and histologic subtype of the tumor; presence of recurrent disease; and various patient characteristics. Location on the central face, ears, or scalp may portend a higher risk. Small nodular, pigmented, cystic, or superficial BCCs respond well to most treatments. Large lesions and micronodular and morpheaform subtypes may be more aggressive. The metastatic potential of BCC has been estimated to be 0.0028–0.1%. Persons with either BCC or SCC have an increased risk of developing subsequent skin cancers that is estimated to be up to 40% in 5 years.

Squamous cell carcinoma

The natural history of SCC depends on both tumor and host characteristics. Tumors arising on sun-damaged skin have a lower metastatic potential than do those on protected surfaces. Cutaneous SCC metastasizes in 0.3–5.2% of individuals, most frequently to regional draining lymph nodes. Tumors occurring on the lower lip and ear have metastatic potentials approaching 13 and 11%, respectively. The metastatic potential of SCC arising in scars, chronic ulcerations, and genital or mucosal surfaces is higher. The overall metastatic rate for recurrent tumors may approach 30%. Large, poorly differentiated, deep tumors with perineural or lymphatic invasion often behave aggressively. Multiple tumors with rapid growth and aggressive behavior can be a therapeutic challenge in immunosuppressed patients.

PREVENTION

As the vast majority of skin cancers are related to chronic UV radiation exposure, patient and physician education could reduce their incidence dramatically. Emphasis should be placed on preventive measures that begin early in life. Patients must understand that damage from UV-B begins early despite the fact that cancers develop years later. Regular use of sunscreens and protective clothing should be encouraged. Avoidance of tanning salons and midday (10 A.M. to 2 P.M.) sun exposure is recommended. Precancerous and in situ lesions should be treated early. Early detection of small tumors allows the use of simpler treatment modalities with higher cure rates and lower morbidity rates. In patients with a history of skin cancer, long-term follow-up for the detection of recurrence, metastasis, and new skin cancers should be emphasized. Chemoprophylaxis using synthetic retinoids as well as immunosuppression reduction in transplant patients may be useful in controlling new lesions in those with multiple tumors.

OTHER NONMELANOMA CUTANEOUS MALIGNANCIES

Neoplasms of cutaneous adnexa and sarcomas of fibrous, mesenchymal, fatty, and vascular tissues make up the remaining 1–2% of NMSCs (Table 33-1) Merkel cell carcinoma is a neural crest–derived (cytokeratin-20-positive), highly aggressive malignancy that exhibits mortality rates of about 33% at 3 years. Recent studies have implicated a novel oncogenic Merkel cell polyomavirus that is present in 80% of tumors. Prognosis largely depends on extent of disease: 90% survival with local disease, 52% with nodal involvement, and 10% with distant disease at 3 years. Incidence tripled from 1986 to 2001 with a current estimate of 1200 cases per year in the United States. It typically presents as an asymptomatic rapidly expanding red/pink tumor on sun-exposed skin of older white patients. Treatment is surgical excision with or without sentinel lymph node biopsy, often followed by adjuvant radiation.

Extramammary Paget's disease is an uncommon apocrine malignancy arising from stem cells of the epidermis that are characterized histologically by the presence of Paget cells. These tumors present as moist erythematous patches on anogenital or, less commonly, axillary skin of the elderly. Treatment may be challenging as these tumors characteristically extend far beyond clinical margins; surgical excision with MMS has the highest cure rates. Similarly, MMS is the treatment of choice in other rare cutaneous tumors with extensive subclinical extension such as dermatofibromasarcoma protuberans.

Kaposi's sarcoma (KS) is a soft tissue sarcoma of vascular origin that is induced by the human herpes virus 8. The incidence of KS was rare before the AIDS epidemic. AIDS-associated KS has decreased 10-fold with the institution of highly active antiretroviral therapy.

ACKNOWLEDGMENT

Hensin Tsao, MD, and Arthur J. Sober, MD, contributed to this chapter in the 17th edition of Harrison's Principles of Internal Medicine, and material from that chapter is included here.