Basal cell carcinoma (BCC) is a neoplasm of nonkera- tinizing cells from the basal ..... acterized by infection with multiple HPV types and de- velopment of SCC.
24 Basal Cell and Squamous Cell Skin Cancer 䡵 䡵 䡵
John A. Carucci Darrell S. Rigel Robert J. Friedman
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ONMELANOMA SKIN CANCER (BASAL AND squamous cell carcinoma) represents a major public health burden. Estimates predict that approximately 1.3 million new nonmelanoma skin cancers will be diagnosed this year in the United States, rendering the incidence of this type of neoplasm nearly equal in magnitude to the sum of all other cancers combined [1]. At current rates, one in five Americans will develop a skin cancer during their lifetime, with more than 97% of these being nonmelanoma skin cancer [2]. Some studies suggest a correlation between development of nonmelanoma skin cancer and risk for internal malignancy, although the precise nature of this relationship is yet to be defined [3, 4]. What should be noted is that nonmelanoma skin cancer is a preventable disease. Primary prevention behaviors include application of sunscreen, use of protective clothing, limit of sun exposure during peak hours, and avoidance of artificial sources of ultraviolet irradiation [5]. Secondary prevention behaviors include regular screening for skin cancer to promote early detection [6]. A recent study indicated that sun awareness education programs may inspire and support prevention behavior in children [7].
BASAL CELL CARCINOMA Definition Basal cell carcinoma (BCC) is a neoplasm of nonkeratinizing cells from the basal cell layer of the epidermis. Metastases are rare. However, BCC may result in extensive local damage if left untreated.
Epidemiologic Characteristics BCC is the most common cancer in humans, accounting for 75% of all nonmelanoma skin cancers and almost
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25% of all cancers diagnosed in the United States [8]. It occurs primarily on sun-exposed skin and rarely develops in dark-skinned persons [9, 10]. Currently, BCC affects men only slightly more often than women [8]. Once infrequent before the age of 40, BCC is becoming more common in younger individuals. Probably this is due to changes in fashion and lifestyle, leading to increased sun exposure and possibly coupled with depletion of the ozone layer [11].
Pathogenesis Factors implicated in the development of BCC include exposure to ultraviolet light (UVL), mutations in tumor suppressor and regulatory genes, exposure to ionizing radiation, alterations in immunosurveillance, and selected inherited conditions. The factor implicated most frequently in the pathogenesis of BCC is exposure of the skin to UVL. The most damaging irradiation lies in the 290- to 320-nm (ultraviolet B [UVB]) range. Individuals at greatest risk of developing skin cancer are those living near the equator or in ozone-depleted areas [11,12]. Cumulative exposure to UVL over many years is necessary for the development of skin cancer. Therefore, individuals with outdoor professions or hobbies are at risk for developing BCC [13]. Light-skinned people who tend to burn easily are at increased risk for developing BCC. One study correlates heavy freckling or moles with a diameter of more than 5 cm in children with a tendency to develop BCC in adulthood [14]. The risk of BCC is decreased substantially in dark-skinned people and those who tan rather than burn [15]. Mutations in tumor suppressor genes and genes that regulate developmental pathways may be involved in the pathogenesis of BCC. Recent studies indicate that mutations in the tumor suppressor gene p53 are present in 50% of BCC cases [16]. UVL may be involved in mutation of p53; Ananthaswamy et al. [17] demonstrated that application of sunscreen prevented development of mutations of tumor suppressor gene p53 in mice exposed to UVL. This finding supports the potential protective role for sunscreens in skin cancer development. Other studies indicate that the human patched gene is mutated in both sporadic and hereditary BCC. Inactivation of this gene may be a necessary step in the pathogenesis of BCC [18]. Ionizing radiation is an etiologic factor in BCC with a long latency period [19]. Davis et al. [19] stated that the latency period of skin cancer varies inversely with the dose of radiation. As with carcinomas caused by UVL, damage to DNA probably plays a critical role [20,
21]. Chemical factors associated with the development of BCC may include arsenic [22]. Immunosurveillance plays an unclear role in the pathogenesis of skin cancer. Marked increases in the incidence of squamous cell carcinoma (SCC) but only a slight variation in BCC development [23–25] are noted in immunosuppressed patients with lymphoma or leukemia and patients who have undergone transplantations. A potential link between UVL and immunosurveillance has been suggested by Gitierrez-Steil et al. [26], who demonstrated that UVL-induced BCC tumor cells express the Fas ligand (CD95L). These authors further showed that these cells were associated with CD95-bearing T cells undergoing apoptosis. In patients with depressed cellular immunity secondary to human immunodeficiency virus (HIV) infection, a higher frequency of more aggressive, infiltrative BCC has been demonstrated [27]. Inherited conditions associated with BCC include the basal cell nevus syndrome [28]. Alterations of the patched gene have been implicated in the basal cell nevus syndrome, which presents with frontal bossing, mental deficiency, odontogenic cysts, hyperkeratotic palmar pits, and numerous BCCs [29].
Biological Behavior The behavior of BCC, including the potential to invade locally and metastasize, depends on stromal and angiogenic factors, growth characteristics, and propensity for the tumor to follow the anatomic path of least resistance. The stroma is critical for both initiating and maintaining the development of BCC. Usually, transplants of BCC devoid of stroma are unsuccessful [8]. In one study, Hernandez et al. [30] demonstrated that cultured BCC tumor cells stimulated collagenase production by fibroblasts. Many studies indicate that collagenase may contribute to the spread of BCC [31]. Tumor development also depends on a sufficient blood supply. BCC can elicit angiogenic factors, which may account also for the characteristic telangiectases. Often, large BCCs have necrotic centers, owing to an extreme radial distance from its blood supply [8, 32]. Generally, the growth rate of BCC is slow, the result of opposing forces of growth and tumor regression. The dominant phase dictates the rate at which the tumor enlarges [33]. BCCs are locally invasive and destructive. They follow the path of least resistance, a tendency that explains why invasion of bone, cartilage, and muscle is a late event. When an invasive BCC reaches these areas, it tends to migrate along the perichondrium, the perios-
Basal Cell and Squamous Cell Skin Cancer teum, the fascia, or the tarsal plate [34–36]. This proclivity may contribute to high recurrence rates on the eyelid, nose, and scalp [34, 37–39]. Embryonic fusion planes offer little resistance and can lead to deep invasion and tumor spread, with extraordinarily high rates of recurrence after therapy. Susceptible areas include the inner canthus, the philtrum, the middle to lower chin, the nasolabial groove, the preauricular area, and the retroauricular sulcus [34–36, 40]. Usually, BCCs do not penetrate the subcutis because of an insufficient vascular supply. Perineural spread is uncommon and usually is seen with recurrent, aggressive lesions [41]. In one series, Niazi and Lamberty [42] noted perineural invasion in 0.178% of BCC cases. In all cases, perineural extension was associated with recurrent tumors that most often were located at the periauricular and malar areas. Perineural invasion may manifest with paresthesia, pain, weakness, or paralysis. Metastatic BCC is rare, with incidence rates varying from 0.0028% to 0.1%, and rarely is noted in nonimmunosuppressed patients [8, 43]. Most commonly, this form of BCC occurs via lymphatic spread to regional nodes and hematogenous spread to long bones and lungs. When metastasis is present, usually the primary lesion is located on the head and neck area and has been long-standing. BCC may invade both the vasculature and the periosteum. Although the adenoid and basosquamous (metatypical) variants of BCC metastasize most often, all histologic subtypes may do so.
Clinical Manifestations Variants of BCC include nodular, superficial, morpheaform, cystic, and basosquamous (BSCC), and fibroepithelioma of Pinkus [8–10]. Nodular (noduloulcerative) BCC is the most common type of primary lesion. Usually, it presents as a flesh-colored or pink translucent nodule with superimposed telangiectases. Ulceration may accompany growth of the tumor (Color Plate 24.1). The occasional presence of melanin accounts for the variable amount of visible pigment and may cause the lesion to appear black, resembling a melanocytic neoplasm (Color Plate 24.2) This melanin is produced by benign melanocytes and is taken up by macrophages found adjacent to nests of BCC. Over many years, these tumors can grow and invade deeply, destroying an eyelid, nose, or ear (Color Plate 24.3). The destruction may be so extensive that the ulcer’s primary cause is not easily discernible. Close inspection of the ulcer’s periphery, however, often reveals a pearly, telangiectatic rolled border.
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Most often, the superficial multicentric variant of BCC is found on the trunk and extremities, although it may occur also in the head and neck region. Usually, the lesion is an erythematous, slightly scaly patch that typically has a rolled, translucent border. Atrophy and pigmentary alterations appear in areas in which regression has occurred. Lesions vary in size and may be single or multiple. Their appearance may resemble such benign inflammatory processes as nummular dermatitis and psoriasis. Early radial growth is responsible for the large size of these tumors; however, they also can penetrate vertically, forming nodules and ulceration. A high recurrence rate after surgical removal is caused by persistent subclinical centrifugal extension of the lesions. The morpheaform BCC presents as an indurated sclerotic plaque of varying size, with occasional telangiectases, resembling a lesion of morphea (Color Plate 24.4). Clinically and histologically, this form also can mimic metastatic carcinoma. Morpheaform BCC infiltrates aggressively and subclinically, tending to recur after seemingly adequate treatment. Cystic BCC is characterized by clear, blue cystic lesions containing a clear fluid that can be expressed with manipulation. When present on the face, the lesions resemble hidrocystomas. Occasionally, the cystic changes that can be seen histologically are fairly subtle clinically, thus giving the tumor the appearance of a common nodular BCC. Basosquamous cell carcinoma (BSCC) is a histologic classification, although it is clinically more aggressive than are other BCCs. Some believe that its characteristics are more like those of SCC, with an increased incidence of metastasis and postoperative recurrences [44, 45]. The estimated incidence of metastasis for this type of BCC is 9.7% [44]. Histologic studies confirmed that BSCC shows staining patterns similar to those of both SCC and BCC. The presence of a transition zone supports the concept that BSCC represents a phenomenon of differentiation rather than of collision [46]. The fibroepithelioma of Pinkus is a rare variant of BCC usually found on the lower back. The lesion, a firm smooth nodule that is classically pedunculated, resembles a fibroma. It may represent spread of BCC via eccrine ducts [47].
Staging The American Joint Committee on Cancer defines a TNM (tumor, node, metastasis) staging system that applies to both BCC and SCC, with instructions for clinical and pathologic staging of the disease (Tables 24.1, 24.2)
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Table 24.1 TNM Staging for Basal Cell and Squamous Cell Carcinoma of the Skin
Table 24.2 AJCC Stage Grouping for Basal Cell and Squamous Cell Carcinoma of the Skin
Classification
Stage 0 Stage I Stage II
Definition
Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor ⱕ 2 cm in greatest dimension T2 Tumor ⬎ 2 cm in greatest dimension but ⱕ 5 cm in greatest dimension T3 Tumor ⬎ 5 cm in greatest dimension T4 Tumor invading deep extradermal structures (e.g., cartilage, skeletal muscle, or bone) Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Histopathologic grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated G4 Undifferentiated Notes: Staging excludes eyelid, vulva, and penis. In the case of multiple simultaneous tumors, the tumor with the highest T category will be classified, and the number of separate tumors will be indicated in parentheses [e.g., T2(5)]. Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. Reprinted from ID Fleming, JS Cooper, DE Henson, et al. (eds), AJCC Cancer Staging Manual (5th ed). Philadelphia: Lippincott-Raven, 1997:157–161.
[48]. Clinical staging is based on physical examination of the lesion and lymph nodes. With fixed lesions, underlying bony structures should be imaged, especially if these lesions occur on the scalp. Pathologic staging requires resection of the entire site and confirmation of any lymph node involvement. For both clinical and pathologic staging, complete excision of the site and microscopical verification is necessary to determine the histologic type.
Treatment Overview Common treatment options for BCC include destruction by electrodesiccation and curettage, cryosurgery, excision by either traditional or Mohs’ technique, and
Stage III Stage IV
Tis T1 T2 T3 T4 Any T Any T
N0 N0 N0 N0 N0 N1 Any N
M0 M0 M0 M0 M0 M0 M1
AJCC ⫽ American Joint Committee on Cancer. Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. Reprinted from ID Fleming, JS Cooper, DE Henson, et al. (eds), AJCC Cancer Staging Manual (5th ed). Philadelphia: Lippincott-Raven, 1997:157–61.
radiotherapy. Selection of the most appropriate therapy requires consideration of anatomic location, knowledge of histologic characteristics of the lesion, understanding of the potential for invasion and recurrence, and familiarity with the various treatment options. The primary goal in managing patients with BCC is complete removal of the lesion. Also important are the need for conservation of normal structure and function and for an optimal cosmetic result. Mohs’ micrographic surgery provides superior cure rates while allowing for maximal conservation of normal tissue [49]. The anatomic location should be considered in selecting the appropriate treatment. Certain high-risk areas, including the inner canthus, philtrum, middle to lower chin, nasolabial groove, preauricular area, and the retroauricular sulcus, may be at increased risk for recurrence. Some anatomic structures, including the temporal branch of the facial nerve and the temporal artery, may be at increased risk for intraoperative injury. Adequate treatment of BCC requires knowledge of the pathologic pattern of the neoplasm and of its varying modes of extension. Though some BCCs are small and superficial and behave in essentially a “biologically benign” manner as long as they are removed conservatively, others behave more aggressively and thus require more aggressive treatment. BCCs having infiltrative (morpheaform) features and those that invade deeper structures (e.g., cartilage or bone) require wider, deeper, and generally more extensive surgical extirpation. Although BCCs enlarge slowly and seldom metastasize, their potential for aggressive local growth should not be underestimated in determining a treatment approach. The decision to perform repeated desiccation and curettage rather than surgical removal of a recurrent BCC eventually could result in extensive tissue destruction if the tumor depth is not appreciated sufficiently. On diagnosis of BCC, optimal therapy may require
Basal Cell and Squamous Cell Skin Cancer referral to an appropriately skilled expert. When multiple treatment options are suitable, clinicians should select the modality with which they have the most experience. CURETTAGE AND ELECTRODESICCATION Curettage and electrodesiccation is the method used most commonly by dermatologists in treating BCC [50, 51]. Less-than-optimal depth of curettage will lead to recurrence, and deeper treatment than is required to eradicate the tumor will merely contribute to poor cosmesis. Cure rates using curettage and electrodesiccation have been reported to be as high as 95% [52], but only certain lesions are amenable to this form of therapy. Curettage and electrodesiccation should not be considered in most cases for BCC arising in areas characterized by a high rate of recurrence (e.g., eyelids, nose, lips, ears, scalp, temple, and embryonic fusion planes), because there is no confirmation of tumor destruction. Silverman et al. [53] stated that BCCs less than 6 mm in diameter, regardless of anatomic site, are treated effectively by curettage and electrodesiccation. Alternative forms of treatment should be considered for lesions greater than 1 cm in diameter, because curettage and electrodesiccation fail to remove tumor completely in the majority of primary BCCs greater than 1 cm and in recurrent BCC [34, 52]. Potential complications include hypertrophic scar, pigmentary alterations, and local recurrence. Some dermatologists have omitted electrodesiccation to optimize the cosmetic result and have achieved cure rates only slightly lower than those achieved by the combination of curettage and electrodesiccation [53]. Although the omission decreases the incidence of hypertrophic scarring, it does not prevent postinflammatory pigmentary alterations. EXCISION Surgical excision provides a specimen that can be histologically evaluated. If performed skillfully, excision can provide adequate cosmesis. Theoretically, excision is appropriate for most BCC, but it requires more time and experience than is involved in electrodesiccation and curettage. Normal tissue is sacrificed with traditional excisional surgery. The cure rates are inferior to those for Mohs’ surgery in the treatment of recurrent BCC, morpheaform BCC, some large superficial multicentric BCCs, and BCC in high-risk areas [54–57]. Wolf and Zitelli [58] have shown that for nonmorpheaform BCC
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with a distinct border and a diameter of less than 2 cm, 4-mm clear margins were necessary to eliminate 98% of the lesions. These authors reported that the subclinical extension of the neoplasms was not uniform in all directions; in BCCs greater than 2 cm in diameter, subclinical spread was so irregular that the investigators could not offer advice regarding an appropriate margin. The question as to the proper depth of the excision remains unanswered. For small primary BCCs, excision into fat generally is appropriate, because spread into the subcutis is rare. However, large recurrent or highrisk BCCs may infiltrate deeper into the subcutaneous tissue. Potential complications of traditional excisional surgery include postoperative infection, bleeding, and recurrence. MOHS’ MICROGRAPHIC SURGERY Mohs’ micrographic surgery permits superior histologic verification of complete removal, allows maximum conservation of tissue, and remains cost-effective as compared to traditional excisional surgery for nonmelanoma skin cancers [39, 59, 60]. It is the preferred treatment for large penetrating tumors; for morpheaform and recurrent, poorly delineated, high-risk, and incompletely removed BCC; and for those sites in which tissue conservation is imperative [59]. With the Mohs’ technique, the tumor is removed in stages and is fully evaluated histologically, thus allowing maximal tissue conservation with superior margin control. Mohs’ surgery is more time-consuming than is routine surgery and is not always as easily accessible. As this technique may be applied to the most aggressive BCC, other surgical specialists may be consulted for removal of a deeply invasive tumor or for repair of the resulting surgical defect [61]. Potential complications include postoperative infection and bleeding, as with any excisional surgery. High cure rates for high-risk and recurrent tumors are obtainable; one study showed an overall five-year cure rate of more than 96% [62]. RADIOTHERAPY Radiotherapy is helpful in the treatment of some BCCs. Its major advantage is that normal tissue is spared, obviating the need for complicated surgical procedures. Often, it is preferred for BCC of the nose, ear, and periocular area, as reconstructive surgery is not required and functional integrity is not compromised [63]. Radiotherapy has been used also for palliation in inoperable BCC. However, it should not be used in young patients because of potential late irradiation sequelae.
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Although one dose of radiation can treat a small BCC (⬍ 1 cm) adequately, usually appropriate treatment consists of fractionated doses administered over several sessions to maximize cure and cosmesis. The skin of the head and neck endures the effects of radiotherapy better than does that of the trunk and extremities. The five-year cure rate for primary BCC treated with irradiation is 90% to 95%. Cure rates for recurrent BCC are poorer than those for primary lesions, an outcome probably owing to the subclinical spread of the neoplasm. Potential complications of radiotherapy include scarring, cutaneous necrosis, and chronic irradiation dermatitis. Though surgical scars improve with time, cosmesis deteriorates after radiotherapy. At 9 to 12 years, only 50% of patients maintain satisfactory cosmetic results. CRYOSURGERY Cryosurgery may be used to treat BCC. A liquid nitrogen spray unit is required; cotton-tipped swabs in liquid nitrogen are not acceptable. A double freeze-thaw cycle to a tissue temperature of –50°C is required to destroy the tumor sufficiently. A margin of normal-appearing skin also should be frozen to ensure eradication of subclinical disease [64, 65]. Cryosurgery is recommended for BCC of the eyelid because the procedure preserves normal tissue and obviates the need for reconstructive surgery. In fractional cryosurgery, treatment is performed in stages until tumor size is reduced to less than 1 cm, at which point the final stage is performed. The advantage of this variation is that the final scar corresponds to the size of the final stage rather than to the size of the original tumor. In this anatomic area, cure rates as high as 97% have been reported for BCC less than 1 cm in diameter; the cure rate decreases with larger and recurrent lesions. Cure rates for cryosurgery of BCC in other areas are excellent (97–98%) for tumors less than 2 cm in diameter. Larger tumors and morpheaform, recurrent, and high-risk BCCs are more likely to recur after therapy. Cryosurgery is not advised for BCC of the scalp. Lesions on the lower legs treated with cryosurgery heal slowly and often yield poor cosmetic results. Patients with blood dyscrasias, dysglobulinemia, cold intolerance, or autoimmune disease and those who are receiving immunosuppressive therapy may not be candidates for cryosurgery. Potential complications include hypertrophic scarring and postinflammatory pigmentary changes. The occurrence of pain early during the thaw can be avoided by preoperative infiltration of the treatment
area with a local anesthetic. Blistering, crusting, and swelling also can develop, but usually these effects resolve within a few weeks. LASERS The CO2 laser has been used in the treatment of BCC and offers several advantages over conventional surgery. The sealing of small blood vessels and nerves provides a relatively bloodless surgical field and reduced postoperative pain. In a recent study, Humphreys et al. [66] reported ablation of primary superficial BCC with the high-energy pulsed CO2 laser. INTERFERON Interferon has been used as an alternative therapy for noduloulcerative and superficial BCC. A study of 172 patients receiving intralesional injections of interferon␣2b resulted in an 81% cure rate after a follow-up period of 1 year [67]. Single doses of 1.5 million IU were administered three times per week for 3 weeks, resulting in a total dose of 13.5 million IU. Attempts using lower doses were unsuccessful. Side effects from this therapy include fever, malaise, myalgias, chills, transient leukopenia, and injection site reactions. RETINOIDS Experience with the use of retinoids is limited; the process is used most often in patients with the basal cell nevus syndrome [68]. Partial regression of BCC has resulted from the use of 4.5 mg/kg/day of isotretinoin and 1 mg/kg/day of etretinate. Potential side effects limit the use of these agents for prolonged periods, and discontinuation of therapy can lead to relapse. CHEMOTHERAPY Chemotherapy is appropriate for locally aggressive or metastatic tumors. Otherwise, disseminated disease is associated with a poor prognosis, with an average survival of 10 to 20 months [45]. A complete systemic workup is required in evaluating affected patients for metastasis. Included are a thorough medical history, physical examination, complete blood counts, liver profile, chest roentgenography, bone and liver scans, and computed tomographic scans, when appropriate. Platinum-based cytotoxic therapy may be indicated when local therapy is inadequate or in cases of metastatic disease. Moeholt et al. [69] reviewed 53 cases of
Basal Cell and Squamous Cell Skin Cancer advanced BCC treated with platinum-based chemotherapy and showed an overall response rate of 83%, with complete remission observed in 37% of cases. OTHER THERAPEUTIC MODALITIES Other options for treating BCC include photodynamic therapy, intralesional 5-fluorouracil–epinephrine injectable gel, and electrochemotherapy with bleomycin [70–72].
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ity, and a predisposition to sunburn, are at increased risk for developing SCC. Some have suggested that psoriasis patients treated with oral psoralens and ultraviolet A (UVA) irradiation are at increased risk for development of SCC [76, 77]. The lamps in most commercial tanning booths emit light that is primarily in the UVA spectrum [78]. In a study by Van Weelden et al. [79], UVA was shown to be carcinogenic in mice. Whether the incidence of SCC in tanning booth patrons will increase remains to be seen. Another risk factor for development of SCC is exposure to arsenic [80].
Follow-Up Regularly examining patients with BCC is imperative. Although most recurrences appear within 5 years, many can develop later. Subsequent new primary BCCs also can appear; 20% to 30% develop within 1 year of treatment of the original lesion [73]. Equally important is advising patients to avoid excessive sun exposure and to apply at regular intervals a sunscreen with a sunprotective factor of 15 whenever they are exposed to direct or reflected sunlight.
SQUAMOUS CELL CARCINOMA Definition SCC is a neoplasm of keratinizing cells that shows malignant characteristics including anaplasia, rapid growth, local invasion, and metastatic potential. If left untreated, SCC may metastasize to regional lymph nodes and distant sites.
Epidemiologic Characteristics Nearly 200,000 cases of SCC are diagnosed in the United States each year, rendering it the second most common human cancer. The risk of occurrence increases with age and affected men tend to outnumber affected women [74]. In a large retrospective study, the mean ages at diagnosis of SCC were 68.1 and 72.7 years for men and women, respectively [75]. Many studies suggest that SCC depends on the total accumulated dose of solar irradiation (Color Plate 24.5) [76–79]. The relative risk of SCC for individuals with a history of excessive sun exposure is increased three to five and one-half times. Clearly, skin pigmentation protects against the induction of skin cancer. People of Celtic descent, with fair complexions, poor tanning abil-
Pathogenesis The factors that initiate or promote the development of SCC are similar to those involved in BCC. They include exposure to ultraviolet radiation or chemicals, mutations in tumor suppressor genes, and alterations in immune response. In addition, chronic inflammation, viral transformation, and defective DNA repair are risk factors. The evidence for an association with sunlight (i.e., UVL) is even stronger for SCC than for BCC. Actinic damage leads to actinic keratoses, which may undergo malignant transformation to invasive SCC [81]. The rate at which solar keratoses undergo invasive progression has been estimated to be as high as 20%. However, the risk of progression of a single actinic keratosis is likely to be much less [81]. The p53 gene product acts as a tumor suppressor, and mutations in p53 are associated with SCC. Recent studies have demonstrated that UVL may introduce mutations into tumor suppressor gene p53. Thus, UVL may be acting as both tumor initiator and tumor promoter [82]. Immunosuppression also may play a role in pathogenesis. Patients receiving immunosuppressive therapy and renal, cardiac, and bone marrow transplant recipients are prone to SCC [18, 19]. Skin cancers in such patients appear primarily on sun-exposed skin. This correlation suggests that immunosuppression and UVL act as cofactors in the development of SCC. HIV-infected patients tend to experience higher rates of SCC [83–88]. However, the exact correlation between HIV and the incidence of SCC has not yet been determined. UVL may be involved with immunosuppression. Exposure to UVB appears to interfere with the density and antigenprocessing capability of Langerhans cells and may suppress production of T-helper 1 (Th1) cytokines interleukin-2 and interferon-␥ through a mechanism involving
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the Th2 cytokine interleukin-4 [87]. It may be that UVB exposure contributes to a state of immune tolerance with regard to tumors, through alteration of these and other cellular and cytokine networks. SCC has a tendency to develop in areas of chronic inflammation. It has been reported in lesions of discoid lupus erythematosus, chronic osteomyelitis, acne conglobata, lupus vulgaris, hidradenitis suppurativa, pilonidal sinus, thermal burns, and leg ulcers [88, 89]. The potential role of human papillomavirus (HPV) in the development of SCC has been studied. Eliezri et al. [90] demonstrated a correlation between the venereal spread of HPV-16 and the initiation of SCC. Epidermodysplasia verruciformis is a rare inherited disorder characterized by infection with multiple HPV types and development of SCC. It has been associated with HPV types 5 and 8 and, most recently, with types 20, 23, 38, DL40, and DL267 [91]. Xeroderma pigmentosum is a rare genetic disorder characterized by defective DNA excision repair and increased susceptibility to skin cancer [92]. Patients with xeroderma pigmentosum are unable to repair damage induced by UVL and show markedly increased incidence of both nonmelanoma skin cancer and melanoma.
Biological Behavior The metastatic potential of SCC depends on a number of variables, including depth and degree of differentiation, presence of chronic inflammation at the site of the primary tumor, the anatomic location, and the presence of perineural invasion. SCC restricted to the epidermis is called SCC in situ, whereas invasive SCC is defined by dermal penetration. SCC in situ may arise also in association with preexisting actinic or arsenical keratosis. These lesions may be considered “biologically benign,” without competence for metastasis if removed completely or otherwise destroyed. Invasive SCCs that penetrate to the reticular dermis and subcutis tend to recur [93]. Immerman et al. [94] observed a 20% incidence of recurrence in 86 patients with invasive SCC. Patients with moderately or poorly differentiated neoplasms had a greater degree of recurrence. Invasive SCC can metastasize. The most common type arises on sun-damaged skin, often associated with actinic keratosis and solar elastosis. The incidence of metastasis of such lesions is low (3–5%). A higher incidence (10–30%) is associated with SCC arising on mucosal surfaces (lip, genitalia) and on sites of prior injury (scars, chronic ulcers) [95–97]. Approximately 10% to 40% of SCC cases develop
at sites of preexisting inflammatory conditions. Tumors arising in areas of chronic inflammation are prone to metastasis. SCCs developing at burn scar sites reportedly have a metastatic rate of 18%, those developing in conjunction with chronic osteomyelitis a rate of 31%, and those arising in discoid lupus erythematosus a 30% metastatic rate [88, 98]. Although tumors are more likely to disseminate to regional lymph nodes than to organs, intravascular metastases to viscera have appeared in as many as 5% to 10% of all metastatic cases [89]. The incidence of metastasis from SCC arising in noninflamed, actinically damaged skin varies from 0.05% to 16.0% [98]. Although actinically induced tumors behave in a more biologically benign fashion than de novo SCC, all lesions have the potential to become invasive locally and to metastasize to draining lymph nodes. Friedman et al. [99] demonstrated that all trunk and extremity primary SCCs that later developed local or nodal recurrence were at least 4 mm deep and penetrated into the reticular dermis or subcutis. Every fatal lesion was at least 10 mm deep and invaded the subcutis. SCCs arising in nonglabrous mucocutaneous sites (lip, vulva, penis, perianal area) are more likely to metastasize than are those involving glabrous areas of the skin. The incidence of metastasis for SCC varies from 0.5% for patients with primary cutaneous SCC to 11% for patients with mucocutaneous labial lesions. Distant metastases may occur also with perineural involvement. In one study [100], 14% of SCCs showed perineural spread, whereas rates as high as 36% have been found by other investigators [101]. Regional lymph node metastases and distant metastases were increased in patients with perineural involvement. SCC of the head and neck may metastasize to cervical lymph nodes and distantly to the central nervous system, the latter either hematogenously or via the perineural space, which directly connects to the subarachnoid space. High-risk areas include the midface, lip, and areas involving the mandibular branch of the trigeminal nerve. Although patients thus afflicted generally are asymptomatic, they show a lower 10-year survival (23% versus 88%) and a higher local recurrence rate (47% versus 7.3%) than do those without neural involvement. Despite poor prognosis, Mohs’ micrographic surgery occasionally can achieve successful treatment in such patients [102].
Clinical Manifestations SCC includes SCC in situ, invasive SCC, and verrucous carcinoma. SCC in situ may occur in a preexisting ther-
Basal Cell and Squamous Cell Skin Cancer mal, hydrocarbon, or arsenical keratosis. Invasive SCC is characterized by the potential to metastasize. Verrucous carcinoma is a low-grade lesion, and differentiating it from the common wart may be difficult. Morphologic variants of SCC in situ include Bowen’s disease, bowenoid papulosis, and erythroplasia of Queyrat. Usually, an intraepidermal carcinoma or a premalignant lesion precedes invasive SCC clinically. Most lesions consist of patches or plaques that may be covered with scale, crust, or ulceration (Color Plate 24.6). Usually, the lesions lack the pearly rolled border and superficial telangiectases found in BCC. Although most are red, hyperkeratotic SCCs or those that occur on mucocutaneous surfaces may be white. The clinical differential diagnosis includes other tumors (BCC, keratoacanthoma, adnexal neoplasm); precancerous lesions (actinic keratosis, Bowen’s disease); and inflammatory disorders (psoriasis, eczema). SCC may appear anywhere on the body. Though SCC on the trunk usually does not present a therapeutic challenge, SCC occurring on the nose, lip, nail bed, or penis may be troublesome. Small SCCs appearing on the trunk and extremities are treated easily, although advanced lesions may be aggressive. Factors associated with a poor prognosis included a low degree of histologic differentiation, location on the sacrum or perineum, and degree of lymphatic metastasis. SCC of the trunk and extremities may spread to the axillary and inguinal lymph nodes, whereas hand and foot tumors may metastasize to epitrochlear and popliteal nodes, respectively. SCC of the nose was studied by Binder et al. [103], who found that 21 of 114 patients had involvement of underlying cartilage and bone. In 77% of these 21 individuals, lesions were more than 3 cm in diameter, and symptoms had been present for more than one year. The incidence of nodal metastasis in this study was 8%. In every patient who developed metastases, the cervical lymph nodes were involved (ipsilateral in six cases, bilateral in two, and contralateral in one), as was cartilage or bone, and all experienced symptoms for at least one year. Most had a primary lesion greater than 3 cm in diameter. Only one patient developed distant metastases. The majority of SCCs on the lip arise from the lower lip in an area of chronic actinic cheilitis. The reported risk of metastasis from SCC of the lip has ranged from 5% to 37% [102]. SCC can occur also on the nail bed, nail folds, and matrix (Color Plate 24.7) [104]. If the nail matrix is affected, atrophy or loss of the nail plate can result. The differential diagnosis of these lesions includes
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paronychia, pyogenic granuloma, verrucae, nail dystrophies, and such tumors as glomus, keratoacanthoma, and melanoma. SCC of the penis is rare in the Western hemisphere [105]. On the penis, it may develop within lesions of leukoplakia, erythroplasia of Queyrat, and balanitis xerotica obliterans. Verrucous carcinoma of the penis (Buschke-Lowenstein tumor) is histologically well differentiated, with features of a wart. However, it behaves clinically like an aggressive SCC; it may undergo malignant transformation and may metastasize [105–107]. Usually, penile SCC occurs between the ages of 40 and 60. It may present with a penile nodule, ulceration, discharge, edema, or inguinal adenopathy. The most common site of involvement is the glans. However, it can develop anywhere along the shaft. Metastasis to inguinal lymph nodes has been reported in 33% to 50% and is associated with poor prognosis [107]. Verrucous carcinoma, a subtype of low-grade SCC, can affect the cutaneous and mucosal surfaces [108]. Most often, this lesion occurs in middle-aged and elderly men. It is characterized by a warty exophytic neoplasm containing sinuses, with a greasy, malodorous discharge.
Staging As previously noted, the American Joint Committee on Cancer includes a TNM staging system that applies to both SCC and BCC (see Table 24.1) [48]. Clinical staging is based on size of the primary lesion and on examination of lymph nodes. Pathologic staging requires resection and confirmation of lymph node involvement.
Treatment Overview Many of the treatments for BCC are appropriate for SCC. The type of therapy should be selected on the basis of size of the lesion, anatomic location, depth of invasion, degree of cellular differentiation, and history of previous treatment. Essentially, treatment of SCC can follow any of three approaches: (1) destruction by curettage and electrodesiccation or cryosurgery; (2) removal by traditional excisional surgery or by Mohs’ micrographic surgery; and (3) radiotherapy. Curettage and electrodesiccation can be used for small lesions arising in sun-damaged skin. Excisional surgery is indicated for larger, ill-defined lesions and for more extensive lesions that have invaded deeper structures. Rarely, regional
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lymph node dissection may be required in SCCs that have metastasized there. Radiotherapy is indicated for head and neck SCC in the absence of spread to bone or cartilage and of evidence of metastasis.
been controversial because of the potential for anaplastic transformation or a high rate of metastasis (or both) [113]. CRYOTHERAPY
CURETTAGE AND ELECTRODESICCATION SCCs greater than 2 cm in diameter are amenable to this form of therapy. Honeycutt and Jansen [109] reported a 99% cure rate for 281 SCCs after a four-year follow-up. Two recurrences were noted in lesions larger than 2 cm in diameter. Others have reported five-year cure rates of greater than 95% [110]. EXCISION Surgical excision is another well-accepted treatment modality. Lesions larger than 3 cm in diameter on the scalp, forehead, and distal extremities are best treated by excision because of the poor healing qualities of the thin layers of subcutaneous tissue overlying bone. Usually, carcinomas of the eyelid and lip commissures are excised, because function and cosmesis can be better preserved. Carcinomas of the penis, vulva, and anus usually are treated by excision because of the frequent need for lymph node dissection and because of poor tolerance of these areas to irradiation. Surgical excision is the treatment of choice for verrucous carcinoma [111]. MOHS’ MICROGRAPHIC SURGERY Mohs’ surgery is useful for SCCs that fall into one of the following groups: (1) recurrent SCC; (2) clinically illdefined SCC; (3) SCC invading bone or cartilage; (4) carcinoma arising in late irradiation dermatitis; and (5) other SCC arising in areas at high risk for recurrence. This modality allows conservation of the maximum amount of tissue with preservation of function and enhanced cosmesis and is superior with regard to local recurrence [112]. RADIOTHERAPY As with BCC, radiotherapy is excellent for elderly patients who have SCC and are unwilling to undergo surgery. It is especially suitable for lesions of the nose, lip, eyelid, and canthal region. Radiotherapy in a fractionated dose schedule is associated with a better cosmetic result and probably an enhanced therapeutic effect. The use of radiotherapy for verrucous carcinoma has
Cryotherapy for SCC is useful in selected patients. Lesions having a diameter between 0.5 and 2.0 cm and well-defined borders are amenable to this modality. This technique boasts exceptional cosmetic results and has achieved five-year cure rates as high as 96.1% [114]. OTHER THERAPEUTIC MODALITIES Other treatment options have included the neodymium–yttrium aluminum garnet laser, photodynamic therapy, retinoids, 5-fluorouracil given either topically or systemically, and a combination of cisplatin and 5fluorouracil [115–117]. Humphreys et al. [66] found that high-energy pulsed CO2 was not sufficient to treat superficial SCC.
Follow-Up Invasive SCC can be a potentially lethal neoplasm and warrants close follow-up with yearly total-body skin examinations. In one study, approximately 30% of patients with SCC developed a subsequent SCC; 54% of these recurrences were seen within the first year of follow-up [118]. The association between solar irradiation and the development of SCC is established firmly. Thus, an important step in follow-up is to advise patients to avoid excessive sun exposure and to apply sun block with a sun-protective factor of higher than 15.
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Color Plate 24.1 Ulcerated basal cell carcinoma characterized by a central ulceration and a rolled border.
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Color Plate 24.2 Pigmented basal cell carcinoma on the scalp. This pigmented lesion is difficult to distinguish from a melanocytic neoplasm.
Color Plate 24.3 Large fungating, ulcerated basal cell carcinoma. This advanced neoplasm has been present for many years and has replaced a large portion of the nose.
The editors are deeply indebted to Dr. Carl Washington (Department of Dermatology, Emory University School of Medicine) for graciously allowing us to use the color plates cited in this chapter.
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Color Plate 24.4 Morpheaform basal cell carcinoma. This depressed lesion (arrow) was present for many years on the chest of a middle-aged man. The elevation adjacent to the basal cell carcinoma is an implanted cardiac pacemaker.
Color Plate 24.5 Multiple squamous cell carcinomas on markedly sun-damaged skin in an elderly man.
Color Plate 24.6 In situ squamous cell carcinoma. This scaly, slightly elevated plaque has been present for many years.
Color Plate 24.7 Squamous cell carcinoma of the periungual region.
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Additional Images Chapter 24 Instructions: Click on each figure legend below to bring up a composite image (thumbnail image or images and the figure legend combined). When the composite appears on the screen, click on each thumbnail to see a full screen image. Close each full screen image to return to the composite. Close the composite to return to this screen. See the “How To Use This CD-ROM” file for more information. CD image 24.01. Cohen, MD.)
Basal cell carcinoma of upper lip. (Image provided by Cynthia
CD image 24.02. Basal cell carcinoma. (A) At low magnification, the nodular dermal growth pattern is apparent. (B) Intermediate magnification shows nests of small, basophilic cells with peripheral palisading and stromal retraction. (C) A higher magnification view reveals moderately atypical, basaloid cells, small pools of mucin, and peripheral palisading. (Images provided by Hunter T. Hardy, MD.) CD image 24.03. Squamous cell carcinoma on the sole of the foot. (Image provided by Cynthia Cohen, MD.) CD image 24.04 Squamous cell carcinoma. (A) Low magnification shows a hyperkeratotic lesion with invasive islands of squamous epithelium present within the dermis. (Image provided by Hunter T. Hardy, MD.) (B) The nuclear atypia of neoplastic keratinocytes is apparent at higher magnification. Note the features of squamous differentiation: prominent cytoplasmic borders and keratin pearl formation. (Images provided by Cynthia Cohen, MD.) CD image 24.05 Merkel cell carcinoma. (A) Low magnification shows a large, expansile nodule composed of hyperchromatic “small, round, blue cells.” (B) Higher magnification demonstrates that the cells are relatively uniform in size with little cytoplasm. (Images provided by Hunter T. Hardy, MD.) CD image 24.06 Cutaneous angiosarcoma. The lesion is superficial and composed of irregular vascular spaces containing red blood cells. The infiltrative nature of the lesion and cytologic atypia characterize this vascular lesion as malignant. (Image provided by Hunter T. Hardy, MD.)
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