Chapter 34: 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 are usually benign. Cutaneous melanoma can occur in adults of all ages, even young individuals, and people of all colors; its location on the skin and its distinct clinical features make it detectable at a time when complete surgical excision is possible. Examples of malignant and benign pigmented lesions are shown in Fig. 34-1.

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. Cutaneous melanoma 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. In 2014, more than 76,000 individuals in the United States were expected to develop melanoma, and approximately 9700 were expected to die. There will be nearly 50,000 annual deaths worldwide as a result of melanoma. Data from the Connecticut Tumor Registry support an unremitting increase in the incidence and mortality of melanoma. In the past 60 years, there have been 17-fold and 9-fold increases in incidence for men and women, respectively. In the same six decades, there has been a tripling of mortality rates for men and doubling for women. Mortality rates begin to rise at age 55, with the greatest increase in men age >65 years. Of particular concern is the increase in rates among women <40 years of age. Much of this increase is believed to be associated with a greater emphasis on tanned skin as a marker of beauty, the increased availability and use of indoor tanning beds, and exposure to intense ultraviolet (UV) light in childhood. These statistics highlight the need to promote prevention and early detection.

RISK FACTORS

Presence of nevi

The risk of developing melanoma is related to genetic, environmental, and host factors (Table 34-1). The strongest risk factors for melanoma are the presence of multiple benign or atypical nevi and a family or personal history of melanoma. The presence of melanocytic nevi, common or dysplastic, is a marker for 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. 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 patients whose disease is 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, a rare malformation that affects 1 in 30,000–100,000 individuals. Since the lifetime risk of melanoma development is estimated to be as high as 6%, 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

Once diagnosed, patients with melanoma require a lifetime of surveillance because their risk of developing another melanoma 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 germline mutations in the cell cycle regulatory gene cyclin-dependent kinase inhibitor 2A (CDKN2A). In fact, 70% of all cutaneous melanomas have 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. A second high-risk locus for melanoma susceptibility, CDK4, is located on chromosome 12q13 and encodes the kinase inhibited by p16. CDK4 mutations, which also inactivate the RB pathway, are much rarer than CDKN2A mutations. Germline mutations in the melanoma lineage-specific oncogene microphthalmia-associated transcription factor (MITF) predispose to both familial and sporadic melanomas.

The melanocortin-1 receptor (MC1R) gene is a moderate-risk 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 red/yellow pheomelanins, which are not sun-protective and produce red hair, rather than brown/black eumelanins that are photoprotective. This red hair color (RHC) phenotype is associated with fair skin, red hair, freckles, increased sun sensitivity, and increased risk of melanoma. In addition to its weak UV shielding capacity relative to eumelanin, increased pheomelanin production in patients with inactivating polymorphisms of MC1R also provides a UV-independent carcinogenic contribution to melanomagenesis via oxidative damage.

A number of other more common, low-penetrance polymorphisms that have small effects on melanoma susceptibility include other genes related to pigmentation, nevus count, immune responses, DNA repair, metabolism, and the vitamin D receptor.

PREVENTION AND EARLY DETECTION

Primary prevention of melanoma and nonmelanoma skin cancer (NMSC) is based on protection from the sun. Public health initiatives, such as the SunSmart program that started in Australia and now is operative in Europe and the United States, have demonstrated that behavioral change can decrease the incidence of NMSC and melanoma. Preventive measures should start early in life because damage from UV light begins early despite the fact that cancers develop years later. Biological factors are increasingly being understood, such as tanning addiction, which is postulated to involve stimulation of reward centers in the brain involving dopamine pathways, and cutaneous secretion of β-endorphins after UV exposure, and may represent another area for preventive intervention. Regular use of broad-spectrum sunscreens that block UVA and UVB with a sun protection factor (SPF) of at least 30 and protective clothing should be encouraged. Avoidance of tanning beds and midday (10:00 a.m. to 2:00 p.m.) sun exposure is recommended.

Secondary prevention comprises education, screening, and early detection. Patients should be educated in the clinical features of melanoma (ABCDEs; see following “Diagnosis” section) 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 exam seems to be a simple, practical way to approach reducing the mortality rate for skin cancer. Depending on the presence or absence of risk factors, strategies for early detection can be individualized. This is particularly true for patients with clinically atypical moles (dysplastic nevi) and those with a personal history of melanoma. For these individuals, surveillance should be performed by the dermatologist and include total-body photography and dermoscopy where appropriate. 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. 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.

DIAGNOSIS

The main goal is to identify a melanoma before tumor invasion and life-threatening metastases have occurred. Early detection 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); and evolving (any change in size, shape, color, or elevation or new symptoms such as bleeding, itching, and crusting). 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. 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 skin 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. An excisional biopsy with 1- to 3-mm margins is suggested. This facilitates pathologic assessment of the lesion, permits accurate measurement of thickness if the lesion is melanoma, and constitutes definitive treatment if the lesion is benign. For lesions that are large or 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 are an acceptable alternative, particularly if the suspicion of malignancy is low, but they should be deep and include underlying fat; cauterization should be avoided. The biopsy should be read by a pathologist experienced in pigmented lesions, and 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 and comparative genome hybridization (CGH) can be helpful.

CLINICAL CLASSIFICATION

Four major types of cutaneous melanoma have been recognized (Table 34-2). 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 sites 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 microscopically after biopsy of a new or a changing skin nodule. Melanomas can also arise in the mucosa of the head and neck (nasal cavity, paranasal sinuses and oral cavity), the gastrointestinal tract, the CNS, the female genital tract (vulva, vagina), and the uveal tract of the eye.

Although cutaneous melanoma subtypes are clinically and histopathologically distinct, this classification does not have independent prognostic value. Histologic subtype is not part of American Joint Committee on Cancer (AJCC) staging, although the College of American Pathologists (CAP) recommends inclusion in the pathology report. Newer classifications will increasingly emphasize molecular features of each melanoma (see below). The molecular analysis of individual melanomas will provide a basis for distinguishing benign nevi from melanomas, and determination of the mutational status of the tumor will help elucidate the molecular mechanisms of tumorigenesis and be used to identify targets that will guide therapy.

PATHOGENESIS AND MOLECULAR CLASSIFICATION

Considerable evidence from epidemiologic and molecular studies suggests that cutaneous melanomas arise via multiple causal 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 below). 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 would not only help classify patients but also would contribute to the understanding of etiology and aid the development of new therapeutic options. A genome-wide 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 cutaneous melanomas on skin without chronic sun-induced damage, cutaneous melanomas with chronic sun-induced damage, mucosal melanomas, and acral melanomas. Distinct patterns of DNA alterations were noted that varied with the site of origin and were independent of the histologic subtype of the tumor. Thus, although the genetic changes are diverse, the overall pattern of mutation, amplification, and loss of cancer genes indicates they have convergent effects on key biochemical pathways involved in proliferation, senescence, and apoptosis. The p16 mutation that affects 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. 34-2).

RAS 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 and thereby generate potential therapeutic targets. 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; thus, they often are accompanied by other mutations. The BRAF mutation is most commonly 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); they are more common in younger patients and are present in most melanomas that arise on sites with intermittent sun exposure and are less common in melanomas from chronically sun-damaged skin.

Melanomas also harbor 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 both prolong cell 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. A loss-of-function mutation in NF1, which can affect both MAP kinase and PI3K/AKT pathways, has been described in 10–15% of melanomas. In melanoma, these two signaling pathways (MAP kinase and PI3K/AKT) enhance tumorigenesis, chemoresistance, migration, and cell cycle dysregulation. Targeted agents that inhibit these pathways have been developed, and some are available for clinical use (see below). Optimal treatment of patients with melanoma may require simultaneous inhibition of both MAPK and PI3K pathways as well as promotion of immune eradication of malignancy.

PROGNOSTIC FACTORS

The prognostic factors of greatest importance to a newly diagnosed patient are included in the staging classification (Table 34-3). 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 has minimal influence on treatment decisions. The anatomic site of the primary is also prognostic; 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 effect of age is not straightforward. Older individuals, especially men over 60, 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. Other important adverse factors recognized via the staging classification include high mitotic rate, presence of ulceration, microsatellite lesions and/or in-transit metastases, evidence of nodal involvement, elevated serum lactate dehydrogenase (LDH), and presence and site of distant metastases.

STAGING

Once the diagnosis of melanoma has been made, the tumor must be staged to determine the prognosis and treatment. Staging helps determine prognosis and aids in treatment selection. The current melanoma staging criteria and estimated 15-year survival by stage are depicted in Table 34-3. The clinical stage of the patient is determined after the pathologic evaluation of the melanoma skin lesion and clinical/radiologic assessment for metastatic disease. Pathologic staging also includes the microscopic evaluation of the regional lymph nodes obtained at sentinel lymph node biopsy or completion lymphadenectomy as indicated. All patients should have a complete history, with attention to symptoms that may represent metastatic disease such as malaise, weight loss, headaches, visual changes, and pain, and physical examination 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, and to the regional draining lymph nodes, CNS, liver, and lungs. A complete blood count (CBC), complete metabolic panel, and LDH should be performed. Although these are low-yield tests for uncovering occult 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 computed tomography (CT) scan or possibly a positron emission tomography (PET) (or CT/PET combined) scan. If signs or symptoms of metastatic disease are present, 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 exam, in which case imaging is not indicated.

TREATMENT

TREATMENT

FOLLOW-UP

Skin examination and surveillance at least once a year are recommended for all patients with melanoma. The National Comprehensive Cancer Network (NCCN) guidelines for patients with stage IA–IIA melanoma recommend a comprehensive history and physical examination every 6–12 months for 5 years, and then annually 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 x-ray are recommended at the physician’s discretion, but are ineffective tools for the detection of occult metastases. Routine imaging for metastatic disease is not recommended at this time. For patients with higher stage disease (IIB–IV), imaging (chest x-ray, CT, and/or PET/CT scans) every 4–12 months can be considered. Because no discernible survival benefit has been demonstrated for routine surveillance, it is reasonable to perform scans only if clinically indicated.

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States. Although tumor registries do not routinely gather data on the incidence of basal cell and squamous cell skin cancers, it is estimated that the annual incidence is 1.5–2 million cases in the United States. Basal cell carcinomas (BCCs) account for 70–80% of NMSCs. Squamous cell carcinomas (SCCs), which comprise ~20% of NMSCs, are more significant because of their ability to metastasize and account for 2400 NMSC deaths annually. There has also been an increase in the incidence of nonepithelial skin cancer, especially Merkel cell carcinoma, with nearly 5000 new diagnoses and 3000 deaths annually.

PATHOPHYSIOLOGY AND ETIOLOGY

The most significant cause of BCC and SCC is UV exposure, whether through direct exposure to sunlight or by artificial UV light sources (tanning beds). Both UVA and UVB can induce DNA damage through free radical formation (UVA) or induction of pyrimidine dimers (UVB). The sun emits energy across the UV spectrum, whereas tanning bed equipment typically emits 97% UVA and 3% UVB. DNA damage induced by UV irradiation can result in cell death or repair of damaged DNA by nucleotide excision repair (NER). Inherited disorders of NER, such as xeroderma pigmentosum, are associated with a greatly increased incidence of skin cancer and help to establish the link between UV-induced DNA damage, inadequate DNA repair, and skin cancer. The genes damaged most commonly by UV in BCC involve the Hedgehog pathway (Hh). In SCC, p53 and N-RAS are commonly affected. There is a dose-response relationship between tanning bed use and the incidence of skin cancer. As few as four tanning bed visits per year confers a 15% increase in BCC and an 11% increase in SCC and melanoma. Tanning bed use as a teenager or young adult confers greater risk than comparable exposure in older individuals. Other associations include blond or red hair, blue or green eyes, a tendency to sunburn easily, and an outdoor occupation. The incidence of NMSC increases with decreasing latitude. Most tumors develop on sun-exposed areas of the head and neck. The risk of lip or oral SCC is increased with cigarette smoking. Human papillomaviruses and UV radiation may act as cocarcinogens.

Solid organ transplant recipients on chronic immunosuppression have a 65-fold increase in SCC and a 10-fold increase in BCC. The frequency of skin cancer is proportional to the level and duration of immunosuppression and the extent of sun exposure before and after transplantation. SCCs in this population also demonstrate higher rates of local recurrence, metastasis, and mortality. There is increasing use of tumor necrosis factor (TNF) antagonists to treat inflammatory bowel disease and autoimmune disorders such as rheumatoid and psoriatic arthritis. TNF antagonists may also confer an increased risk of NMSC. BRAF-targeted therapy can induce SCCs including keratoacanthoma-type SCCs in keratinocytes, with preexisting H-RAS overexpression present in approximately 60% of patients.

Other risk factors include HIV infection, ionizing radiation, thermal burn scars, and chronic ulcerations. Albinism, xeroderma pigmentosum, Muir-Torre syndrome, Rombo’s syndrome, Bazex-Dupré-Christol syndrome, dyskeratosis congenita, and basal cell nevus syndrome (Gorlin syndrome) also increase the incidence of NMSC. Mutations in Hh genes encoding the tumor-suppressor patched homolog 1 (PTCH1) and smoothened homolog (SMO) occur in BCC. Aberrant PTCH1 signaling is propagated by the nuclear transcription factors Gli1 and Gli2, which are salient in the development of BCC and have led to the FDA approval of an oral SMO inhibitor, vismodegib, to treat advanced inoperable or metastatic BCC (Fig. 34-4). Vismodegib also reduces the incidence of BCC in patients with basal cell nevus syndrome who have PTCH1 mutations, affirming the importance of Hh in the onset of BCC.

CLINICAL PRESENTATION

Basal cell carcinoma

BCC arises from epidermal basal cells. The least invasive of BCC subtypes, superficial BCC, consists of often subtle, erythematous scaling plaques that slowly enlarge and are most commonly seen on the trunk and proximal extremities (Fig. 34-5). 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 tortuous telangiectatic vessels on its surface, rolled borders, and a central crust (nodular BCC). The occasional presence of melanin in this variant of nodular BCC (pigmented BCC) may lead to confusion with melanoma. Morpheaform (fibrosing), infiltrative, and micronodular BCC, the most invasive and potentially aggressive subtypes, manifest as solitary, flat or slightly depressed, indurated whitish, yellowish, or pink scar-like plaques. Borders are typically indistinct, and lesions can be subtle; thus, delay in treatment is common, and tumors can be more extensive than expected clinically.

Squamous cell carcinoma

Primary cutaneous SCC is a malignant neoplasm of keratinizing epidermal cells. SCC has a variable clinical course, ranging from indolent to rapid growth kinetics, with the potential for metastasis to regional and distant sites. Commonly, SCC appears as an ulcerated erythematous nodule or superficial erosion on sun-exposed skin of the head, neck, trunk, and extremities (Fig. 34-5). It may also appear as a banal, firm, dome-shaped papule or rough-textured plaque. It is commonly mistaken for a wart or callous when the inflammatory response to the lesion is minimal. Clinically visible overlying telangiectasias are uncommon, although dotted or coiled vessels are a hallmark of SCC when viewed through a dermatoscope. The margins of this tumor may be ill defined, and fixation to underlying structures may occur (“tethering”).

A very rapidly growing but low-grade form of SCC, called keratoacanthoma (KA), typically appears as a large dome-shaped papule with a central keratotic crater. Some KAs regress spontaneously without therapy, but because progression to metastatic SCC has been documented, KAs should be treated in the same manner as other types of cutaneous SCC. KAs are also associated with medications that target BRAF mutations and occur in 15–25% of patients receiving these medications.

Actinic keratoses and cheilitis (actinic keratoses occurring on the lip), 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%. SCC in situ, also called Bowen’s disease, is the intraepidermal form of SCC and usually presents as a scaling, erythematous plaque. As with invasive SCC, SCC in situ most commonly arises on sun-damaged skin, but can occur anywhere on the body. Bowen’s disease forming secondary to infection with human papillomavirus (HPV) can arise on skin with minimal or no prior sun exposure, such as the buttock or posterior thigh. 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. 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, infiltrative, and morpheaform subtypes may be more aggressive. The metastatic potential of BCC is low (0.0028–0.1% in immunocompetent patients), but the risk of recurrence or a new primary NMSC is about 40% over 5 years.

Squamous cell carcinoma

The natural history of SCC depends on tumor and host characteristics. Tumors arising on sun-damaged skin have a lower metastatic potential than do those on non-sun-exposed areas. Cutaneous SCC metastasizes in 0.3–5.2% of individuals, most frequently to regional lymph nodes. Tumors occurring on the lower lip and ear develop regional metastases in 13 and 11% of patients, respectively, whereas the metastatic potential of SCC arising in scars, chronic ulcerations, and genital or mucosal surfaces is higher. Recurrent SCC has a much higher potential for metastatic disease, approaching 30%. Large, poorly differentiated, deep tumors with perineural or lymphatic invasion, multifocal tumors, and those arising in immunosuppressed patients often behave aggressively.

TREATMENT

PREVENTION

The general principles for prevention are those described for melanoma earlier. Unique strategies for NMSC include active surveillance for patients on immunosuppressive medications or BRAF-targeted therapy. Chemoprophylaxis using synthetic retinoids and immunosuppression reduction when possible may be useful in controlling new lesions and managing patients with multiple tumors.

OTHER NONMELANOMA CUTANEOUS MALIGNANCIES

Neoplasms of cutaneous adnexae and sarcomas of fibrous, mesenchymal, fatty, and vascular tissues make up the remaining 1–2% of NMSCs.

Merkel cell carcinoma (MCC) is a neural crest–derived highly aggressive malignancy with mortality rates approaching 33% at 3 years. An oncogenic Merkel cell polyomavirus is present in 80% of tumors. Many patients have detectable cellular or humoral immune responses to polyoma viral proteins, although this immune response is insufficient to eradicate the malignancy. Survival depends on extent of disease: 90% survive with local disease, 52% with nodal involvement, and only 10% with distant disease at 3 years. MCC incidence tripled over the last 20 years with an estimated 1600 cases per year in the United States. Immunosuppression can increase incidence and diminish prognosis. MCC lesions typically present as an asymptomatic rapidly expanding bluish-red/violaceous tumor on sun-exposed skin of older white patients. Treatment is surgical excision with sentinel lymph node biopsy for accurate staging in patients with localized disease, often followed by adjuvant RT. Patients with extensive disease can be offered systemic chemotherapy; however, there is no convincing survival benefit. Whenever possible a clinical trial should be considered for this rare but aggressive NMSC, especially in light of the potential for new treatments directed at the oncogenic virus that causes this malignancy.

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 axillary skin of the elderly. Outcomes are generally good with site-directed surgery, and 5-year disease specific survival is approximately 95% with localized disease. Advanced age and extensive disease at presentation are factors that confer diminished prognosis. RT or topical imiquimod can be considered for more extensive disease. Local management may be challenging because these tumors often 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 herpesvirus 8. The incidence of KS increased dramatically during the AIDS epidemic, but has now decreased tenfold with the institution of highly active antiretroviral therapy.

Acknowledgment

Carl V. Washington, MD, and Hari Nadiminti, MD, contributed to this chapter in the 18th edition of Harrison’s Principles of Internal Medicine, and material from that chapter is included here. Claudia Taylor, MD, and Steven Kolker, MD, provided valued feedback and suggested many improvements to this chapter.