Squamous cell carcinoma

Squamous Cell Carcinoma Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer in whites. Despite the fact that these tumors are largely preventable, the incidence of SCC is rising every year, and shows no signs of abating. While ultraviolet radiation is the most common cause of this type of cancer, other factors including ionizing radiation, human papillomavirus, chemical agents, immunosuppression, and chronically injured or inflamed skin also predispose to SCC development. Invasive SCC may arise from a precursor lesion such as actinic keratosis, or from SCC in situ, and may exhibit a wide spectrum of clinical features. Similarly, the histopathology of SCC may be viewed as a spectrum of squamous intraepithelial neoplasia, within which a variety of common and more unusual variants have been identified. Since invasive SCC has the potential to recur and metastasize, it is important to recognize those factors placing individual lesions at a higher risk for recurrence or metastasis. These include size >2 cm, location on the ear, lip, and other specific sites on the head and neck, as well as acral and genital regions, degree of histologic differentiation, perineural invasion, immunosuppression, and history of previous treatment. Treatment of primary cutaneous SCC is essential both to mitigate locally destructive growth and to minimize the risk of metastatic spread. While low risk lesions may be treated effectively with electrodesiccation and curettage, excision, cryosurgery, radiation therapy, or photodynamic therapy, high risk SCCs may require Mohs micrographic surgery or excision with wider margins to minimize their risk of recurrence. Adjunctive treatment with radiotherapy, lymph node dissection, systemic chemotherapy or biologic response modifiers may be required for the treatment of regional or distant metastatic disease. Screening via total body skin examination is the only test available to detect cutaneous SCC. Patients at risk for developing SCC should be identified early, and patients with a previous history of skin cancer should be monitored for the development of new and recurrent skin lesions. The role of prevention through sun avoidance and protection from sunlight, beginning in childhood, cannot be underestimated. Physicians should emphasize to their patients that these prophylactic measures will help to minimize their risk of developing this potentially life-threatening cancer, and that prompt detection of early disease will maximize their chance of complete treatment with a high rate of cure. (Curr Probl Dermatol 2003;15:85-134.)

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Squamous Cell Carcinoma Introduction Cutaneous squamous cell carcinoma (SCC) is a malignant tumor of epithelial keratinocytes that represents a growing public health problem. It is the second most common skin cancer in whites, with approximately 250,000 cases expected in the United States in 2002. Although most cutaneous SCCs are easily treated with a high rate of cure, a substantial minority of lesions may recur or metastasize. Those lesions that metastasize are responsible for most of the 1300 to 2300 nonmelanoma skin cancer–associated deaths per year in the United States.1 This article summarizes the current state of the literature regarding the incidence, causation, clinical and histologic presentation, prognosis, treatment, follow-up, and prevention of cutaneous SCC.

Incidence In 1994, the lifetime risk of SCC in the United States was estimated to be 9% to 14% in men and 4% to 9% in women.2,3 About 200,000 cases of SCC occur annually in the United States. Because SCCs are more common in the elderly, these tumors can be expected to contribute more to the morbidity and mortality burden than melanoma.4,5

Measurement Problems The incidence and associated mortality burden of SCC defy precise characterization. The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute does not collect incidence or survival data for SCC, except for SCC of the genitalia.6 Existing population-based studies are imperfect, with the most convincing data available from circumscribed populations in the United States, Australia, and Scandinavia.7,8 One problem with informal and mandated tumor registries is underregistration of tumors. A critical evaluation of the West of Scotland Cancer Registry found that 44% of tumors that should have been recorded were not.9 In addition, other potential

Curr Probl Dermatol 2003;15:85-134. Copyright © 2003 by Mosby, Inc. 1040-0486/2003/$30.00 ⫹ 0 doi:10.1016/S1040-0486(03)00005-X

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selection biases may impair the integrity of the data that are collected. For example, it has been suggested that people with lighter skin more prone to sunburns may eschew long-term outdoor occupations, thus artifactually depressing the presumed linkage between sun exposure and cancer incidence.10

Current Estimates and Recent Trends: US Data Examination of the data reveals that a sharp rise in the incidence rate of SCC has been clearly documented over the past 2 decades.11 Longitudinal studies from the United States and Canada indicate that the incidence rate of cutaneous SCC has grown by 50% to 200% over the last 10 to 30 years.2-14 In the geographically isolated population served by the Mayo Clinic and affiliated hospitals in Rochester, Minnesota, age-adjusted incidence rates per 100,000 women for biopsy-proven SCC grew from 46.5 in the period from 1984 to 1986 to 99.6 for the period 1990 to 1992; the corresponding rates for men were 125.9 and 191.0, respectively.13 Although the preponderance of data indicate an increase in SCC incidence over time, some notable exceptions exist. Review of data from the Southeastern Skin Cancer Registry showed a plateau in incidence from 1985 to 1996, even though the overall incidence rate in this sun-drenched area remained much higher than the national average.15 The absolute incidence rate of SCC among whites varies by up to 50-fold by geographic region, with the lowest reported incidence rates from northern Europe and the highest from Australia. These differences may be partly explained by geographic variation in the level of sun exposure. In the United States, the age-adjusted incidence rate per 100,000 whites has been found to be as follows: in Kauai, Hawaii, a relatively high-risk area, from 1983 to 1987, 174 for men and 115 for women; in southeastern Arizona, another sun-intense region, in 1996, 271 and 112, respectively; and in the United States overall, in Weinstock3 and colleagues’ 1994 extrapolations of age-specific population-based incidence figures from registries maintained in British Columbia, Canada, and by Kaiser-Permanente in Oregon, 81 to 136 for men and 26 to 59 for women.3,11,12,14-17 Regions of high ultraviolet exposure have uniformly higher incidence rates, as in the 3 to 6 times higher rate in Arizona compared with more northern areas.15 Similarly, data from the nurse’s health study indicate a greater risk of

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SCC among women living in California (relative risk [RR] ⫽ 1.8) and Florida (RR ⫽ 2.1) compared with those residing in the Northeast.18 Incidence data must be interpreted carefully because no widely recognized protocol exists for its collection. Much of the available information derives from small case-control studies, and severe underreporting is the norm. In numerous cases, SCCs may be misclassified when physicians fail to obtain histopathologic verification. When more biopsies are performed, the ratio of basal cell carcinomas (BCCs) to SCCs falls. In recent decades, the incidence rate of SCCs has been rising sharply in most areas, and this must be considered when computing current incidence rates. For instance, in New Hampshire, the incidence rate increased by 235% for men and 350% for women between 1979 and 1980 to 1993 and 1994 and incidence rates approximately doubled in Rochester, Minnesota, between 1984 and 1986 and 1990 and 1992.13,19 Finally, age-adjusted incidence rate must be distinguished from the age-specific incidence rate, given that the latter increases sharply with age. For instance, in Albuquerque, New Mexico, the age-adjusted incidence rate per 100,000 for whites in 1992 was 180 to 214 for men and 50 to 63 for women, but the age-specific rate for men over 80 years was 3689. In Kauai (1983 to 1987), the age-specific rate for men ages 75 to 84 years was 1567 and in Rochester, Minnesota (1990 to 1992), the age-specific rate for men ages 75 to 84 years was 1057.3,6,13,16,17,20

Current Estimates and Recent Trends: International Data Statistics from outside North America report similar incidence rates and also note a rise in these levels over time.21-27 In Australia, the overall incidence rate is approximately 1% to 2% (1000 to 2000/105 people ⫻ year).21,28 This high level has been confirmed in population-based longitudinal studies in which physical examinations were prospectively conducted.29 Analysis of 39,805 tumors registered with the Swedish Cancer Registry from 1961 to 1995 indicated an increase in age-standardized incidence rate of 425% in men and 146% in women over this period.27 Both older and younger patients showed this growth in incidence rate. From 1966 to 1995, a study of 11,662 patients in Norway indicated a 3-fold to 4-fold increase in SCC incidence rate. Men were much more likely to be affected.30 At Kings College in the United

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Kingdom, a 10-fold increased incidence rate was seen in SCCs from 1970 to 1992.31 The age-specific incidence rate for 75-year-old to 79-year-old men in Queensland, Australia, in 1984 was 12,616.21-26 In summary, the age-adjusted incidence rate of cutaneous SCC among whites is about 100 to 150 per 100,000 individuals per year, and the age-specific incidence rate for persons over age 75 years is approximately 10 times greater.1,3,13,17,20

Death Studies Incidence data have also been captured from studies of deaths attributed to cutaneous SCC. This information is unreliable as a marker of overall incidence rate because SCC is not routinely reported as a cause of death by medical examiners, but the inferred conclusions provide useful demographic information. Review of all the cancer-related death certificates issued in Victoria, Australia, from 1988 to 1990 found 115 deaths from SCC. Of these, 64% were in men with a mean age of 74 years and 36% were in women aged 81 years. Multiple errors in death designation, with misclassification of deaths induced by other skin cancers and non–skin cancers as SCC-related deaths, suggested that many deaths truly caused by SCC were likewise misclassified and missed with this chart review.32

Differences in Incidence due to Risk Factors The incidence rate of invasive SCC is higher in subpopulations that are unusually susceptible to known risk factors for skin cancer. Psoriasis patients treated with psoralens and ultraviolet A light (PUVA) have been shown to have an increased risk of SCC that is associated with the number of treatments and the intensity of therapy. Long-term follow-up studies of psoriasis patients who undergo treatment with high doses of PUVA show a RR of 4 to 6 compared with individuals not exposed to such treatments.33-35 Patients receiving so-called low-dose PUVA, fewer than 100 treatments or 1000 J/cm2, had 1/14 the SCC incidence rate after 5-year follow-up of those receiving more than 200 treatments or 1000 J/cm2.36 Prospective 20-year follow-up data indicated that in PUVA patients with an SCC, the risk of a second SCC was 26% at 1 year and 62% at 5 years.37 High levels of PUVA exposure before the development of the first

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SCC were associated with a 3.32 times increased risk of second SCC as compared with low initial PUVA levels, and greater numbers of PUVA treatments before the first SCC were associated with an incidence hazard ratio of 1.72 (for each 10 treatments per year for patients with low prefirst SCC PUVA levels). Genital SCCs, rare in the general population, are much more frequent in PUVA patients, who are more than 50 times as likely to have penile and scrotal SCC develop, with high-intensity PUVA receivers having an additional incidence risk ratio of 4.5 compared with those undergoing lower intensity treatment.38

Ionizing Radiation For assessment of the effect on incidence of previous therapeutic ionizing radiation, a population-based case-control study was conducted in New Hampshire with a statewide surveillance system to identify SCC patients and investigate their radiation treatment records.39 An elevated incidence rate of SCC was noted only at the site of radiation exposure. The mean odds ratio of 2.94 was greater yet in the subset who had undergone radiation for acne treatment.

Laser Procedures: A Questionable Effect A similar physician-induced risk may be posed by newer cosmetic dermatologic interventions, but the concern remains mostly theoretic in the absence of significant evidence. A single case report does document the induction of nonmelanoma skin cancer after ablative laser resurfacing.40 The proliferation of socalled nonablative laser treatments (alternatively, subsurface resurfacing or photorejuvenation) has not generated any similar reports about this procedure. However, because a subset of patients are beginning to receive nonablative resurfacing treatments on a routine, usually monthly, and indefinite basis, the concern has been raised of cumulative photodamage manifesting in basal cell and squamous cell cancer formation.41 Of note is that the wavelengths used in nonablative laser therapies do not include any part of the ultraviolet A or ultraviolet B spectrum.

Organ Transplantation: A Skin Cancer Crisis The incidence rate of cutaneous SCC is increased in organ transplant recipients.42 Patients with transplants

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are at a 3-fold to 4-fold increased risk of systemic and cutaneous cancers compared with other patients, with SCC being one of the most common malignant diseases, along with other skin cancers, lymphoma, cervical carcinoma, and Kaposi’s and other sarcomas.43-45 In nations populated primarily by fairskinned whites, cutaneous SCC is the most common posttransplantation cancer.46 The magnitude of the incremental risk of SCC in transplant patients is great. A Norwegian study of kidney and heart transplant recipients documented a 65-fold risk compared with the control sample.47 Ten years after transplantation, approximately 45% of patients in Australian studies were found to have a skin cancer, most often SCC; in Holland, England, and Italy, this risk was reported as 10% to 15%; and in Oregon, the figure was found to be 35%.48-52 The ratio of SCC to BCC was approximately 3:1 to 4:1, or essentially reversed from the ratio observed in the general population.53 Japanese transplant patients had SCC develop at much lower rates.54,55 An increased incidence rate of SCC after transplantation is associated with time after transplantation, decreasing latitude, and older age as well as childhood, duration of immunosuppression, intensity of immunosuppression, and history of skin cancer before transplantation.47,48,56-64 Although most organ transplant patients with cutaneous SCCs will have 1 or a few lesions, in some cases so-called “catastrophic carcinogenesis” can occur. Instances of a single individual with more than 100 SCCs annually are not uncommon.42 Differences appear to exist between the incidence of SCC and general skin cancer incidence related to the type of organ transplanted. Liver transplant patients may at be lowest risk, followed by kidney transplant patients and then heart transplant patients, who may have the highest risk.47,50,64-69 Whether the differences in risk would remain as significant if recipients were matched for age and degree of immunosuppression is unclear.

Distribution of Lesions By Anatomic Region. The anatomic location of cutaneous SCC is primarily on sun-exposed areas, and hence, overall incidence rate is greater in geographic regions receiving more ambient solar radiation.70,71 In a study of patients dying of SCC, only 3.5% of primary tumors were on routinely covered areas of the trunk and the remainder were on exposed areas easily

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viewed during physical examination.32 Scandanavian studies have verified that the highest incidence rates per unit surface area are on chronically sun-exposed head-neck sites, particularly the ears.27,30,72 The next most at-risk area is the extremities.16 Some disagreement exists regarding exactly which parts of the head and neck are most at risk: Australian data suggest that the so-called “less-exposed face” (area within the orbit and nasolabial fold) may be a more common site for SCC (incidence rate of 5843 per 100,000 body units) than the “more-exposed face” (ears, nose, and cheeks; incidence rate of 4200 per 100,000 body units).24 By Skin Type and Ethnicity. The incidence rates for darker-skinned individuals remain relatively low compared with those for the lighter-skinned. Recent data indicate that non-Hispanic whites have an 11 times greater rate of SCC development than Hispanics.15 Likewise, in the nurse’s health study, red (RR ⫽ 2.0) and light brown (RR ⫽ 1.7) hair was associated with an higher risk of SCC than dark brown hair; women who tended to burn after 2 or more hours of sun exposure in childhood also displayed a slightly higher risk (RR ⫽ 1.5) of SCC.18 In other studies, the RR of SCC has been found to be about 3 times higher among people born in geographic areas receiving high amounts of ultraviolet irradiation than in residents who moved to the high irradiation regions only in adulthood; 2 to 5 times higher in those with very light skin color, hazel or blue eyes, and blonde or red hair; 5 times higher in individuals with exclusively outdoor occupations as opposed to those with all-indoors work; and 3 to 8 times higher in people with severe as versus no solar elastosis, freckling, and facial telangiectasias.22,73 Although fair-skinned whites, especially men in their 60s and 70s, are at highest risk for cutaneous SCC, other racial and ethnic types with intermediate skin types may be susceptible given predisposing environmental conditions. For instance, a recent chart review notes that SCC is not rare on the legs of elderly African-American women.74 Moreover, a dramatic rise has been observed in SCC incidence rate among Japanese-Americans residing in the sun-intensive milieu of Hawaii.75 Even within the indigenous Japanese population, a rise in the incidence rate of actinic keratoses (AKs) has been documented over the past 3 decades, with this change possibly associated with increased foreign travel by lighter-skinned Japanese.76,77 Migration patterns, coupled with depletion of the ozone layer, may continue to modify risk profiles of populations traditionally considered to be largely protected from SCC.

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Unanswered Questions Many questions remain regarding SCC incidence. Specifically, we still do not know the pattern of sun exposure that most predisposes to cancer risk. The relative contribution to SCC emergence of sun exposure parameters, such as age at exposure, sunburn or severity during a given exposure, cumulative exposure, and time between exposures, has not been quantitatively described. Indeed, we do not even know whether there is a plateau beyond which sun exposure has minimal additional carcinogenic effect and whether sun exposure close to the time of tumor emergence is contributory at all. Because solar irradiance appears to be the primary environmental factor associated with SCC incidence, further information about the specific impact of sunlight will likely be of help in counseling patients.78

Actinic Keratoses Current Estimates: Wide Disparities. Now widely considered an incipient form of SCC in situ, AKs are a precursor lesion for invasive SCC.79,80 Aggregate prevalence of numerous AKs on a given individual is the most important risk factor for SCC.1 Unfortunately, the extent to which specific AKs transform into SCC has eluded precise characterization because of the difficulty inherent in tracking individual lesions over a span of many decades. A review of 5 studies from the period 1988 to 1998 revealed mean rates of conversion of AKs to invasive SCCs varying from 0.025% to 16% per lesion per year, with a mean of approximately 8%.81-86 Historically, earlier studies have found rates of conversion per AK lesion per year of 0.1% to 10%.1,82,84,87 Early studies by Marks and colleagues82,87 indicated rates of conversion of less than 1%, but these examined a younger sample population, considered only a 1-year duration, and did not evaluate the risk of multiple AKs. More realistically, the presence of multiple AKs over a 10-year period is associated with a lifetime risk of progression to SCC of 6% to 10%.84 In Arizona, patients with more than 10 AKs had a 14% cumulative 5-year risk of SCC.88 So-called “proliferative AKs,” which manifest histologically as a multilayered sheet of anaplastic cells along the undersurface of the epidermis extending down hair follicles and present over a large area, may be associated with a greater tendency to develop into invasive SCC than other AKs.89

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Measurement Problems: Minimization of Squamous Cell Carcinoma Incidence. Research on the likelihood of degeneration of AKs into SCC is hampered by practical considerations. Most significantly, few clinically diagnosed AKs are biopsied for histologic verification, and so, it is not clear whether the lesions visually tracked as AKs for the purpose of epidemiologic study are in fact true AKs. In addition, given the number of AKs on severely afflicted individuals and the impetus for prophylactic treatment, a longitudinal, prospective trial would be cumbersome and probably unethical. Visual counts of AKs are notoriously inconsistent between different raters, even if these are experienced dermatologists.90 When AKs have been exhaustively histologically examined, they have been frequently found to be proximal to frank SCC. In 1 study, step sectioning of AKs revealed additional diagnostic findings in a third of specimens, with 13% of these meeting criteria for SCC in situ and 3% for invasive SCC.91 Because the likelihood of a specific AK evolving into SCC is difficult to measure, treatment of all clinically identified AKs is indicated to reduce cumulative risk. Significantly, although studies examining AKs have offered annual rates of progression per lesion ranging from 0.025% to 20%, the cumulative risk depends on the number of lesions and the overall duration. In western Australia from 1987 to 1994, the number of AKs was found to be the risk factor most correlated with SCC emergence.10,13,21-26,29 In 1 study, patients with 1 to 5 AKs had a RR for SCC of 1.7, compared with a risk of 4.2 for 6 to 20 lesions and 11.0 for greater than 20 lesions.

Causation Ultraviolet Radiation Table I summarizes the risk factors for development of cutaneous SCC, with exposure to sunlight in the form of ultraviolet radiation being the most common cause of this type of cancer.92-95 Ultraviolet B radiation (280 to 315 nm) has been primarily implicated in carcinogenesis, with some contribution from ultraviolet A (315 to 400 nm). Proposed mechanisms include both direct genotoxicity and damage from reactive oxygen species, depending on the wavelength of radiation involved. Both ultraviolet B and ultraviolet C

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TABLE 1. Risk Factors for Development of Cutaneous SCC Exposure to ultraviolet radiation Ultraviolet A Ultraviolet B Therapy with methoxsalen and ultraviolet A radiation (PUVA) Exposure to ionizing radiation Genodermatoses Oculocutaneous albinism Xeroderma pigmentosum Infection with HPV-, especially 5, 6, 11, 16, 18 Exposure to chemical carcinogens Arsenic Polycyclic aromatic hydrocarbons Immunosuppression and immunosuppressive medications Organ transplantation HIV infection Leukemia and lymphoma Chronically injured or diseased skin Ulcers, sinus tracts, and osteomyelitis Radiation dermatitis Certain chronic inflammatory disorders, such as dystrophic epidermolysis bullosa Precursor lesions AKs Arsenical keratoses Radiation-induced keratoses Bowen’s disease (squamous cell carcinoma in situ) Erythroplasia of Queyrat (squamous cell carcinoma in situ of penis)

(190 to 280 nm) radiation are directly genotoxic, dimerizing pyrimidines in DNA at dipyrimidine sites.96 Ultraviolet C waves are absorbed in the outer atmosphere forming ozone and do not normally reach the earth. Ultraviolet B radiation, however, produces specific mutations at these sites in human DNA and thereby leaves a distinctive signature. Mutations are predominantly C to T transitions, including CC to TT base changes, which are only known to occur from ultraviolet radiation. Such mutations occur in the p53 tumor suppressor gene in human cutaneous SCCs, positively identifying ultraviolet B radiation as a carcinogen.97 Human SCC biopsies have also been shown to exhibit acute upregulation of cycloocygenase-2 protein with ultraviolet B irradiation compared with normal non–sun-exposed control skin, suggesting that cycloocygenase-2 may play a key role in mediating skin cancer development.98 Ultraviolet A radiation causes cell and DNA injury via the formation of reactive oxygen species, such as hydrogen peroxides and hydroxyl radicals.99 These molecules are formed after ultraviolet A radiation is directly absorbed by endogenous intracellular photosensitizers, such as porphyrins and NADH. Ultraviolet radiation also downregulates host immune function,

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most notably by upregulating the action of suppressor T cells.100-102 In the context of this decreased immunoregulation, ultraviolet-induced damage to keratinocyte DNA may continue undetected until significant irreversible damage has been done. In normal cells, 1 ultraviolet-induced mutation in p53 will lead to apoptosis and cell death, as long as the second p53 gene remains intact and functional. In cells with 1 dysfunctional p53, an additional mutation (eg, as a result of irradiation) prevents apoptosis from occurring and instead leads to clonal expansion of the defective cells. If this proliferation continues in an uncontrolled fashion, the stage has been set for the development of in situ SCC, which may later evolve into invasive disease. Over the past 50 years, lifestyle changes and recreational preferences have led to increased exposure to sunlight. Frequent exposure to sunlight during childhood and a history of sunburns at a young age may be among the most important behavioral risk factors in the development of SCC.103 As mentioned previously, fair-skinned individuals (ie, Fitzpatrick skin types I and II) are at highest risk; those with light skin, hazel or blue eyes, and blonde or red hair have 2 to 5 times the RR of darker individuals.92 Occupational exposure to sunlight and ultraviolet radiation has also been identified as a significant risk factor.104 Individuals with outdoor occupations have 5 times the RR of those who work indoors, and those born in areas that receive high amounts of ultraviolet radiation have 3 times the risk of those who move to such areas during adulthood. The incidence rate of cutaneous SCC increases rapidly with age. Depending on geographic location, the risk for individuals 55 to 75 years of age may be 4 to 8 times that of individuals 20 years younger.94 The use of tanning devices may contribute to the risk of developing nonmelanoma skin cancer.105 The combination of oral methoxsalen and ultraviolet A radiation, commonly known as PUVA therapy and used frequently in the treatment of severe psoriasis, has been identified as a significant independent risk factor in the development of SCC. PUVA effects appear to be dose-related, and although lesions may occur as early as 5 years after therapy, the strongest correlation is seen in the second decade after therapy completion. Patients in whom SCC develops after the start of PUVA therapy are at increased risk of subsequent SCCs.37 There is also a significant increase in risk if the

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patient has received high-dose methotrexate in addition to or preceding PUVA treatment.35 As mentioned previously, patients receiving PUVA therapy, and particularly those with high-dose exposures to topical tar and ultraviolet B, also have an increased risk of genital SCCs.38 Peritz and Gasparro106 found an unexpected series of mutations associated with SCCs in PUVA patients, specifically frequent C to T transitions, usually seen with exposure to ultraviolet B radiation, and very few T to A transitions, which would be expected if damage was simply from ultraviolet A–induced photoadduct formation. These authors concluded that a different mechanism beside direct ultraviolet A injury must be involved in the development of PUVA-associated SCC. Ultraviolet A radiation possibly acts as a potent immunosuppressive agent, allowing other carcinogenic events to ensue without triggering a protective immune response. Individuals with genetic susceptibility to ultraviolet radiation are at similarly increased risk of SCC. Patients with oculocutaneous albinism have insufficient pigment protection from ultraviolet radiation and thus are at increased risk for ultraviolet-associated mutagenesis and carcinogenesis.107 Individuals with the rare condition xeroderma pigmentosum also have insufficient genetic mechanisms to repair ultravioletinduced DNA damage and have multiple cutaneous cancers develop, including SCCs, at an unusually early age from cumulative ultraviolet exposure.108,109

Ionizing Radiation Ionizing radiation, frequently used in the 1940 to 1950s to treat numerous dermatologic conditions, including acne, dermatitis, tinea, and hemangiomas, has been implicated as a risk factor for SCC.110 Individuals exposed to ionizing radiation, particularly radiographs, in the workplace are also at increased risk. The risk of cancer is directly related to cumulative radiation exposure and may be augmented by ␥ and grenz rays. The sun-reactive skin type of patients exposed to ionizing radiation or with significant chronic radiation dermatitis may predict risk of tumor formation if the cumulative radiation dose is unknown.110 It is thought that ionizing radiation acts as an initiator for malignant disease and that subsequent exposure to ultraviolet radiation may promote tumor formation.

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Human Papillomavirus A strong association between infection with human papillomavirus (HPV) and SCC has also been elucidated. HPV, an encapsulated, double-stranded DNA virus that infects epithelial cells, is found in common warts and condyloma acuminatum. At least 86 distinct HPV types have been identified and fully sequenced, with at least 130 more awaiting sequencing.111 HPV types 5, 16, and 18 have been positively associated with SCC development.112 HPV types 16 and 18 have been shown to produce cell line immortalization and tumor development in vitro.113 Other viral types have shown less oncogenicity in vitro and differing levels of deactiviation of p53, which suggests that p53 is probably not involved in the development of HPVasssociated cutaneous SCCs.114 Although the exact relationship between HPV and carcinogenesis remains to be defined, HPV infection produces specific viral proteins encoded by the E6 and E7 genes, which bind and alter tumor suppressor genes p53 and pRB, respectively, shutting off normal regulatory and apoptotic activities. A more recent study has shown the absence of a tumor suppressor protein, Bak, a proapoptotic protein that is induced by ultraviolet radiation and broken down by E6 protein, in SCCs with associated HPV infection.115 It appears that, in most cases, viral infection alone does not lead to tumor formation and that there may be a requirement for cocarcinogens to lead to the formation of cancers. For example, most HPV-associated SCCs are found in sun-exposed or irradiated areas of the body, suggesting that ultraviolet or ionizing radiation may serve as cocarcinogens. HPV has been shown in lesions of nongenital Bowen’s disease with in situ DNA hybridization, lending support to this hypothesis.116 Another possibility is that viral infection, in the context of immunosuppression, allows for cell transformation and carcinogenesis. This has been shown in immunosuppressed patients on organ transplant regimens who have a significantly increased risk of cutaneous warts and SCC.117 Certain HPV types, particularly types 5 and 8, are associated with the rare inherited condition epidermodysplasia verruciformis (EV), which predisposes affected individuals to unusual cutaneous warts and multiple skin cancers. Although the exact mechanism is unknown, it is thought that the basis of this disorder lies in alteration of viral regulatory pathways at the keratinocyte level. This alteration, possibly in combination with immunosuppression or ultraviolet radiation, may

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lead to tumor formation at a relatively early age.118,119 In addition, SCCs in EV can be more invasive and more likely to metastasize.

Chemical Agents Historically, certain chemical agents have been strongly associated with the development of cutaneous SCC. In 1775, Percival Pott recognized that scrotal cancer in chimney sweeps was caused by exposure to soot. Arsenic, formerly commonly prescribed for various medicinal purposes, has also been shown to induce tumor formation. In this day, contaminated wine and unprocessed well water, especially in developing countries, are significant sources of arsenic; metal-ore workers and those with substantial exposure to insecticide are also at risk. Exposure to arsenic typically produces arsenical keratoses and carcinoma in situ and invasive tumors of the skin, particularly on the palms and soles. The carcinogenic effects of arsenic seem to be dose-dependent and in addition, may indicate internal malignant disease, especially if the skin tumor is in a non–sun-exposed area. Interestingly, an individual’s genetically determined ability to process arsenic may be important in determining the later development of skin cancers.120 Polycyclic aromatic hydrocarbons, created in the production of coal tar, cutting oils, and pitch, also carry a significant risk of inducing cutaneous SCC of the scrotum. Changes in industrial practices have fortunately made these once-common cancers quite rare.

Immunosuppression As discussed previously, organ-transplant recipients are at significantly increased risk for cutaneous SCC and other cutaneous lesions, such as AKs and warts, probably from the use of immunosuppressive medications.42,47,121-126 Many groups have described this association in renal transplant patients, but individuals receiving heart transplants may be at even greater risk because of the increased doses in their standard immunosuppressive regimens.92,127,128 Cutaneous SCC is up to 65 times more likely to develop in transplant recipients than in age-matched controls.117 Lesions appear 2 to 4 years after transplantation, on average, and increase in frequency over time after transplantation, making duration of immunosuppression the primary risk factor in these patients. Transplant recipients have SCCs develop approximately 3

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times more often than BCCs, a reversal of the ratio seen in the general population.53 Lesions generally appear in sun-exposed areas, leading many to believe that immunosuppression allows the effects of ultraviolet radiation–induced damage to be potentiated in keratinocyte DNA. There has also been speculation that renal transplant patients’ development of SCC may, in part, be the result of infection with HPV because viral DNA is often present in their lesions.129 Transplant recipients with widespread HPV infection may in fact resemble EV patients clinically. One study, however, showed the equal prevalence of EVtype HPV DNA in benign skin lesions of renal transplant patients with and without a history of SCC, making the exact role of HPV in cutaneous oncogenesis unclear.130 High-level exposure to the immunomodulatory agent methotrexate has also been shown to increase the risk of SCC by 2-fold.35 Individuals with other immunosuppressive conditions may also have a higher risk of SCC. Persons infected with HIV may have a slightly higher incidence rate of cutaneous SCC at relatively earlier ages than nonimmunosuppressed individuals, although this finding has not yet been definitively confirmed.131,132 HIV-infected individuals with fair skin, significant amounts of sun exposure, or outdoor occupations have, however, been shown to have an increased risk of SCC.133,134 Furthermore, patients infected with HIV may have aggressive, rapidly growing cutaneous SCCs develop, with a high risk of local recurrence and metastasis.132 An increased incidence rate of skin cancer has also been documented in patients with chronic lymphocytic leukemia.135 Similarly, cutaneous T-cell lymphoma patients, particularly those with Se´ zary syndrome, have an approximately 25% risk of secondary neoplasms, of which half are cutaneous SCCs.136 Just as the progressive depletion and dysfunction of T-cells associated with HIV seem likely to explain this increased incidence rate of neoplasia, T-cell and B-cell dysregulation resulting in functional T-cell deficits may explain the increased neoplasia seen in patients with chronic lymphocytic leukemia and cutaneous T-cell lymphoma.123

Chronically Injured or Inflamed Skin Squamous cell carcinoma is more likely to develop in chronically injured, inflamed, or diseased skin than in normal skin. Individuals with longstanding ulcers, sinus tracts, osteomyelitis, radiation

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dermatitis, or burn scars are at increased risk.92,110,137 Tumors in these areas may be neglected for long periods of time and may therefore carry substantial risk for invasiveness and metastasis when finally diagnosed, either because of their long-standing duration or because of intrinsically invasive behavior. Some chronic inflammatory and infectious disorders may also predispose to SCC development, including lichen sclerosus et atrophicus, lichen planus, and lupus vulgaris.138 Oral lichen planus, in a large series, was associated with only a 0.8% risk of oral SCC.139 Such cancer emergence occurred at sites previously diagnosed with clinical examination as erosive or erythematous lichen planus. Chronic discoid lupus erythematosus is also associated with SCC, which may behave more aggressively in African-American individuals.140,141 Finally, dystrophic (dermolytic) epidermolysis bullosa, including both dominantly and recessively inherited types, is associated with increased risk of cutaneous SCC development.142,143 In this group of autosomally inherited diseases, blistering occurs beneath the basal lamina with both chronic tissue stress and decreased immunoregulation. Individuals with this condition are more likely to have multiple invasive and metastatic SCCs develop at much younger ages than the general population. In contrast to ultraviolet-induced skin cancer, the tumors in epidermolysis bullosa tend to develop on distal extremities at sites of chronic wound healing.144 Some studies indicate that more than two thirds of affected individuals die of SCC metastases, with poor response to standard treatment.145,146

Clinical Presentation Actinic Keratoses Actinic keratoses are both precursors of cutaneous SCC and markers of increased risk for nonmelanoma skin cancer, as they are sensitive indicators of cumulative ultraviolet radiation exposure.94,147,148 Clinically, they arise as rough, scaly patches, on average 2 to 6 mm in diameter, on sun-exposed areas of the body. They are often more easily felt than seen and can be skin-colored, pink, or brown. Surrounding areas may also show solar damage, with telangiectases, yellowish discoloration from solar elastosis

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Fig 1. Multiple AKs on scalp, consisting of scaly patches and keratotic papules and plaques. Largest plaque was biopsied and found to be SCC in situ.

and patchy hypopigmentation or hyperpigmentation. AKs can be solitary, but most affected individuals have multiple lesions. The most common sites of AKs are those of greatest ultraviolet radiation exposure: the nose, cheeks, hands, and forehead and, in men, the dorsal aspects of the ears.147 AKs are more likely to occur on the upper limbs, particular the dorsal hands and forearms, than the head and neck.1 This is the opposite of the anatomic distribution of invasive SCCs, which exhibit a predilection for the face compared with the extremities. AKs can be discrete, with sharply defined borders, or they may be diffuse and confluent. Although they are usually asymptomatic, mild tenderness, pruritus, or burning sensations are occasionally reported. These symptoms do not distinguish AK from SCC.149 Over time, the erythematous scaly patches of early AKS can evolve into hyperkeratotic, hypertrophic lesions, which may be difficult to distinguish clinically from early SCC (Fig 1). Clinical variants of AK include the cutaneous horn, with a conical hyperkeratotic projection, the lichen planus-like keratosis, and the pigmented AK, which may resemble a lentigo with scale.150 The anatomic distributions of AKs and SCCs are similar but not exactly the same. Specifically, AKs are found most often on the upper limbs, particularly the dorsal hands and forearms, with the head and neck being the next most likely location.1 Conversely, SCCs occur most often on the head and neck. This mismatch remains mysterious, especially in view of the prevailing belief

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that SCCs may arise from AKs. Apart from this discrepancy, the SCC and AK share common body area distribution patterns, mostly preferring regions of sustained and intense sun exposure.1,22,73,151,152 Some AKs involute spontaneously, especially if the individual avoids sun exposure or uses sunscreen regularly for an extended period of time.153 More specifically, it has been reported that up to 25% of AKs will regress without treatment, leading some to advocate a conservative approach of observation if lesions are not symptomatic.87 Most lesions persist, however, and although the actual annual rate of conversion to SCC is unknown and debated, with estimates of conversion ranging from 0.025% to 20%,81,82,84,154 it may be most accurate to estimate the conversion of one AK per thousand per year.82 Because most affected individuals have multiple lesions (on average, 7 to 10), their cumulative lifetime risk of progression to SCC becomes substantial, approximately 6% to 10%.1,155 Unfortunately, because of the tendency of some AKs to involute, and the fact that their treatment with destructive means precludes follow-up, accurate determinations of lesional progression are difficult to ascertain. Furthermore, it would be ethically questionable to require patients with clinically diagnosed AKs to go untreated in an effort to determine which lesions would regress and which would develop into carcinoma. One study has reported that AKs of the hypertrophic, hyperkeratotic variety are significantly more likely to undergo malignant transformation than other subtypes.103 Future studies will undoubtedly produce better evidence-based guidelines for the evaluation and management of this widespread problem. Epidermodysplasia verruciformis, as discussed in the section on Causation, is also considered a precancerous condition for cutaneous SCC. Radiation keratoses and arsenical keratoses should also be considered precancerous lesions and should be monitored closely for clinical change. Currently, it is believed that although it may not be cost effective or practical to treat each specific keratotic lesion, individuals with multiple AKs should be followed closely, so that changing or evolving SCCs can be detected early and managed in an appropriate manner.150,156 Treatment options include liquid nitrogen cryosurgery, electrodesiccation and curettage, topical fluorouracil cream, dermabrasion, and laser resurfacing. Recently, studies have shown the therapeutic effect of imiquimod, an immunomodulatory

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Fig 2. Bowen’s disease of posterior neck. This erythematous plaque with overlying fine scale was asymptomatic and had been present for years.

agent applied topically as a 5% cream, in the treatment of AKs.157-161 Follow-up for patients with multiple AKs is recommended at 6-month to 12-month intervals, unless lesions become newly symptomatic, in which case earlier evaluation may be warranted.147

Squamous Cell Carcinoma in Situ Clinically, cutaneous SCC in situ can present in a variety of ways, ranging from ill-defined rough pink patches similar to AKs, to verrucous papules or plaques, to the well-recognized subset known as Bowen’s disease, originally described in 1912.162 Bowen’s disease, or SCC in situ, typically presents as a slow-growing, well-demarcated erythematous plaque, with irregular borders and surface crusting, scaling, or velvety features (Fig 2).163 It may be associated with all of the previously discussed risk factors, including exposure to ultraviolet radiation, arsenic, immunosuppression, HPV, ionizing radiation, and chronic dermatoses.164 It is most commonly found on sun-exposed sites, including the head, neck, extremities, and ears.165 It may also present within the nail unit and in the periungual region (Fig 3).166 Although Bowen’s disease was previously thought to be associated with internal malignant disease, current studies no longer support this relationship.167-169 When SCC in situ manifests in a genital distribution, it is referred to as erythroplasia of Queyrat (penile intraepithelial neoplasia) or bowenoid papulosis. Bowenoid papulosis is

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Fig 3. Squamous cell carcinoma in situ of proximal nailfold. This lesion was recurrent after Mohs’ micrographic surgery 5 years previously, and viral typing revealed positivity for HPV 16.

more specifically associated with HPV types 16 and 18 and has a slight female predominance, presenting with hyperpigmented papules with histologic features identical to those of Bowen’s disease. Although it does not evolve into carcinoma in most cases, it may cause extensive lesions and is considered precancerous.164 Erythroplasia of Queyrat, on the other hand, occurs primarily on the glans penis of uncircumcised men as red, smooth plaques. All types of SCC in situ may progress to invasive cancer if not treated, with the risk of Bowen’s disease undergoing malignant transformation estimated to be on the order of 3%.170 In contrast, the risk of invasion of erythroplasia of Queyrat is thought to be approximately 10%,171 and progression of bowenoid papulosis is extremely rare.172 Therapeutic options for in situ SCC include all of the methods described for the treatment of AK, including cryotherapy, 5-fluorouracil, electrodesiccation and curettage, laser, and photodynamic therapy (PDT). Isotretinoin and interferon ␣ have also been proposed for patients with multiple lesions.173 The immune-modulator imiquimod, available as a 5% cream, is also a viable option for the treatment of Bowen’s disease.174-176 Excision with frozen section margin evaluation or Mohs’ micrographic surgery may be indicated for optimal tissue sparing when lesions are large or recurrent or involve the face, digits, subungual areas, or the penis.164

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Fig 4. Invasive SCC arising within AK on medial cheek.

Fig 6. Squamous cell carcinoma of cutaneous lower lip. This friable nodule bled easily when traumatized and grew rapidly over period of 1 to 2 months.

Fig 5. Invasive SCC on cheek of heart transplant patient. This lesion grew rapidly over period of 6 weeks and was clinically and histologically similar to keratoacanthoma.

Invasive Squamous Cell Carcinoma Most invasive cutaneous SCCs occur on sun-exposed areas of the body (Fig 4). Approximately 80% develop on the arms, head, and neck,92 followed by the trunk. Lesions typically appear as firm papules, plaques, or nodules, which may be smooth or hyperkeratotic and are skin-colored or pink. They usually have elevated borders and indistinct margins and may have a central ulceration (Fig 5). Invasive SCCs can be symptomatic: patients may have pruritus or describe a painful, nonhealing wound that bleeds when traumatized (Figs 6 and 7). Atypically, pain may precede

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Fig 7. Squamous cell carcinoma of third finger in patient with long history of psoriasis treated with PUVA and ultraviolet B. This nonhealing erosion arose within an erythematous plaque that was clinically similar to patient’s psoriasis. Note psoriatic patches and plaques diffusely distributed over hand and fingers.

physical signs of the tumor.177 Invasive SCC can also develop an overlying cutaneous horn of keratinized material; these conical protrusions often have a wide base or low height-to-base ratio when associated with malignant lesions (Fig 8).178 Most lesions are approximately 0.5 cm to 1.5 cm on initial presentation, but lesions that have been neglected for long periods of

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Fig 8. Recurrent SCC of upper forehead. Prominent cutaneous horn is present overlying this invasive lesion.

Fig 9. This rapidly growing exophytic nodular SCC measured 4.5 ⫻ 4.5 cm in diameter on initial presentation. Although no clinical evidence of metastasis was seen, patient underwent radical neck dissection and superficial parotidectomy after surgical removal of tumor because of aggressive clinical and histologic features of this lesion.

time may be significantly larger (Fig 9).162 These larger lesions may present with synchronous lymph node metastasis, especially if over 2 cm in diameter.179 In black patients, SCCs may present in non–sunexposed areas, including the perianal region and lower legs, and may exhibit prominent pigmentary changes.74,180 Clinically, these tumors may present as nonhealing ulcers or as erythematous, papules, or plaques with varying degrees of scale, resulting in

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Fig 10. Sqamous cell carcinoma of left lower leg in AfricanAmerican woman. Ulcerated nodule overlies this pigmented plaque. Hypopigmented macules are diffusely present surrounding this lesion.

confusion with other dermatoses, including psoriasis, eczema, infections, and trauma.181 Hyperpigmented, hyperkeratotic papules and plaques, often accompanied by multiple hypopigmented and hyperpigmented macules, have been described on the lower legs of black patients, especially elderly African-American women (Fig 10).74 The atypical appearance of these tumors and their occurrence in darkly pigmented individuals is characteristic, and the clinician must be alert to the possibility of squamous dysplasia when this distinctive combination of clinical features is seen. An uncommon variant of invasive SCC is the slowgrowing, exophytic verrucous carcinoma. This variant tends to grow in sites of chronic irritation or inflammation182 and may be difficult to distinguish clinically from verruca vulgaris.183 Verrucous carcinoma tends to occur in 3 major areas: the oral cavity (oral florid papillomatosis), the anogenital area (giant condyloma of Buschke-Lowenstein), and the plantar aspects of the hands and feet (carcinoma cuniculatum).92,184 HPV types 6 and 11 have been detected in oral verrucous carcinomas, and HPV types 16 and 18 in laryngeal carcinomas, suggesting that the HPV virus contributes to carcinogenesis in these areas and in the anogenital area.185 Although it grows slowly and may resemble warts clinically in its earlier stages, verrucous carcinoma may exhibit deep, aggressive invasion if left untreated (Fig 11). A deep biopsy is therefore critical to differentiate verrucous carcinoma from benign le-

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Fig 11. Verrucous carcinoma of left index finger. Note destruction of nail plate and involvement of nailbed.

Fig 12. Keratoacanthoma of wrist, consisting of well-defined erythematous nodule with central keratotic plug.

sions. After histologic confirmation of the diagnosis is obtained, treatment with wide excision or Mohs’ micrographic surgery is recommended, combined with frequent follow-up to detect any evidence of recurrence.186 Irradiation is not currently recommended for treatment of verrucous carcinoma because these lesions can undergo anaplastic transformation after radiation therapy.183 Local recurrences of these lesions are common; regional lymph node metastases have occasionally been reported and metastases are rare.185 Carcinoma, including SCC, arising in scar tissue is commonly referred to as Marjolin’s ulcer. Usually associated with burn scars, Marjolin’s ulcers can arise in any area of chronic injury, such as venous ulcers, pressure ulcers, chronic sinuses of osteomyelitis, and discoid lupus erythematosus, among others. The average latency period for malignant transformation is approxiamately 30 years.187 In this context, SCCs tend to develop around the perimeter of the scar, in areas of epidermal regeneration.188 They usually appear as nodular proliferations and may also be secondarily infected on presentation. Keratoacanthoma may appear clinically similar to SCC. The classic keratoacanthoma arises as a single lesion in sun-exposed areas of fair middle-aged to elderly individuals, approximately 0.5 cm to 2.0 cm in size.182 Keratoacanthomas typically present as rapidly growing, red dome-shaped papules or nodules that subsequently develop a central crater filled with a keratinous plug (Fig 12). They also tend to regress spontaneously without treatment within 6 to 9 months. On histologic examination, keratoacanthomas may

resemble well-differentiated SCC. Experienced dermatopathologists are able to make the correct diagnosis in approximately 85% of cases.189 Atypical or difficult cases should be considered and treated as SCCs.

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Histology The histopathology of sqamous cell carcinoma has been characterized as a spectrum of squamous intraepithelial neoplasia analogous to that of evolving carcinoma of the cervix.79,190 Partial thickness intraepidermal atypia has traditionally been termed AK and distinguished from full thickness epidermal atypia, which is termed SCC in situ, and from invasive SCC. AKs, if untreated, have the potential to progress to invade deeper tissues and ultimately to metastasize. For this reason, some authors recommend use of the term keratinocytic intraepidermal neoplasia to denote that AKs, regardless of the extent of their epidermal involvement, are evolving SCCs of the skin.79,190

Actinic Keratoses The microscopic changes seen in AKs may be confined to foci of crowded atypical keratinocytes at the basal layer of the epidermis or may extend upward into the stratum spinosum and stratum granulosum. Irregular acanthosis, hyperkeratosis, and parakeratosis may be present. Cytologically, the atypical cells of AK and SCC are indistinguishable, exhibiting loss of polarity, nuclear pleomorphism, disorderly matura-

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tion, and increased numbers of mitoses. Severe solar elastosis is frequently seen in the dermis. Multiple histologic subtypes of AK exist, including acantholytic, bowenoid, pigmented, atrophic, and hypertrophic, analogous to the multiple histologic subtypes of SCC. Lesions initially diagnosed as AK may also reveal histologic features consistent with skin cancer on step sectioning, including SCC in situ and invasive SCC, confirming the importance of AK as a precursor to fully evolved malignant neoplasms.91,155,191 Similarly, invasive SCC has been shown to exhibit in situ changes at the periphery or within the confines of the lesion in over 97% of cases, with malignant changes evolving from the lower epidermis into the upper epidermis and dermis, confirming that invasive lesions may originate as AK.192 Progression from AK to SCC may be associated with an inflammatory response, with an increase in T lymphocytes and Langerhans’ cells; the number of inflammatory cells seen histologically subsides as malignant conversion with progression to SCC occurs.193

Fig 13. Recurrent, deeply invasive, well-differentiated SCC of frontal scalp. Lobules of atypical keratinocytes (shown with arrow) extend beneath frontalis muscle into galea. This lesion ultimately metastasized to regional nodes and to distant sites. Magnification, ⫻100.

Squamous Cell Carcinoma Subtypes The histologic subtypes of SCC include the following: conventional, otherwise known as generic or simplex, acantholytic, bowenoid, spindle cell/pleomorphic, and verrucous.194-196 Most SCCs fall into the conventional, or simplex, group.196 These lesions are characterized by lobules and cords of atypical keratinocytes originating in the epidermis and invading the dermis in large and small islands or infiltrating tumor strands. A mononuclear inflammatory infiltrate of varying degrees of intensity may be seen within or surrounding the tumor. Solar elastosis is frequently seen in the dermis. Well-differentiated SCCS are often characterized by keratin pearl formation and individual cell keratinization, with minimal cellular atypia. Superficial epithelial loss or ulceration may occur; alternatively, the tumor surface may be extremely hyperkeratotic. On high-power magnification, intercellular bridges between the atypical keratinocytes may be seen. More poorly differentiated lesions may have less obvious keratinization, more prominent cellular atypia, numerous mitotic figures, and occasional multinucleated keratinocytes. With progression of the tumor, deeper invasion into the subcutaneous fat, fascia, or muscle may occur (Fig 13). Perineural invasion is uncommon but has been reported to occur in 2.4% to 7.4% of SCCs.197,198

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Fig 14. Acantholytic SCC. Loss of cohesion between tumor cells results in formation of clefts within tumor. Prominent dyskeratosis is seen.

Acantholytic tumors, also known as adenoid or lobular SCCS, exhibit a conventional SCC pattern with squamous differentiation, associated with acantholysis, which leads to a pseudoglandular appearance histologically. Loss of cohesion between tumor cells results in the formation of clefts within the tumor, with a cohesive layer of cells surrounding the acantholytic cells (Fig 14). Tubular or alveolar nests and cords of tumor cells are characteristically seen, with freefloating atypical keratinocytes within their lumina. Individual atypical cells may be large, multinucleated, or bizarre in appearance, and mitotic figures may be present. The histologic differential diagnosis of these

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tumors includes eccrine adenocarcinoma, metastatic adenocarcinoma, and epithelioid angiosarcoma. Reactivity with cytokeratins, and lack of reactivity with endothelial and glandular cell markers, distinguishes acantholytic SCC from vascular and sweat gland tumors. This subtype is regarded by some authors as more malignant than other histologic subtypes, but there is as yet an insufficient amount of evidence in the literature to make this assertion unequivocally.194,196,199-202 In 1 recent review of prognostic factors for metastasis in SCC of the skin, a higher rate of metastasis was noted in those tumors exhibiting acantholysis, single cells, and small nests and infiltrating strands of tumor.197 Interestingly, certain cell adhesion molecules, which are expressed primarily on the surface of adult epithelial cells and act in concert to stabilize the epithelium, show decreased expression in acantholytic SCC. Bayer-Garner, Sanderson, and Smoller203 have shown decreased immunoreactivity of E-cadherin and syndecan-1 with decreasing cellular differentiation in invasive SCC and increased cytosolic staining rather than cell membrane staining in acantholytic areas. These authors suggest that the loss or decreased expression of these adhesion molecules, which leads to acantholysis, is associated with malignant transformation into SCC. Bowenoid SCC is characterized by architectural disorder of the full thickness of epidermis, with loss of polarity and absence of orderly keratinocyte maturation, resulting in a “windblown” appearance.204 In situ disease is characterized by an intact dermoepidermal junction. When neoplastic keratinocytes invade the dermis, invasive bowenoid SCC results. Hyperkeratosis, parakeratosis, and acanthosis are characteristically seen in bowenoid SCC. Keratinocyte atypia, with mitoses, nuclear enlargement and hyperchromatism, multinucleated cells, and vacuolated cells, is also characteristic. The atypical keratinocytes of bowenoid SCC may extend downward along the follicular epithelium to the level of the sebacous glands. A mononuclear inflammatory infiltrate is frequently present in the upper dermis, consisting of lymphocytes, dermal dendrocytes, and occasional plasma cells. Spindle cell SCC is a relatively uncommon variant of SCC (Fig 15). This poorly differentiated subtype is characterized by a proliferation of pleomorphic spindle cells that infiltrate the underlying connective tissue. These atypical cells may be arranged in a whorled pattern and may infiltrate the dermis as single

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Fig 15. Moderately differentiated SCC. Well-differentiated lobules and cords of atypical keratinocytes are present on left, and more poorly differentiated spindle cells are present on right. Scattered mitotic figures are present. Note cellular anaplasia and nuclear atypia. Magnification, ⫻100.

cells, often without connection to the overlying epidermis. Deep extension into the subcutaneous fat and fascia is common. Numerous mitotic figures and multinucleated pleomorphic giant cells may be seen. Histologic evidence of keratinization may be infrequently seen or absent. For this reason, spindle cell SCC may be difficult to distinguish from other spindle cell tumors, including atypical fibroxanthoma, malignant fibrous histiocytoma, spindle cell melanoma, and dermatofibrosarcoma protuberans, making immunhistochemical studies essential to reach an accurate diagnosis. Verrucous carcinomas are well-differentiated SCCs, with thickened, bulbous, often papillomatous rete pegs, composed of well-differentiated keratinocytes, that push into, or bulldoze into, the underlying dermis.194,205 Tumor strands may extend deeply into the dermis and subcutaneous fat and may form keratinfilled sinus tracts that connect with the surface of the skin. Both endophytic and exophytic growth patterns may be seen. On high-power magnification, large atypical keratinocytes may at times be present, which may exhibit mitotic figures, nuclear enlargement, and hyperchromasia. A dense mononuclear inflammatory infiltrate may also be present. A superficial biopsy of verrucous carcinoma frequently exhibits relatively bland features, without significant atypia, making a deep incisional biopsy essential to make an accurate diagnosis. Keratoacanthoma is a subtype of SCC that may be difficult to distinguish clinically and histologically

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from well-differentiated SCC but that, unlike SCC, is capable of spontaneous regression.206 Histologically, these tumors appear as well-circumscribed, keratinfilled invaginations of the epidermis with buttresses of normal epidemis.206 The lining of the invagination is formed by well-differentiated squamous epithelium, composed of cells with a pale eosinophilic, or “glassy,” cytoplasm. Lobules and strands of keratinocytes may extend into the dermis. Mitotic figures and nuclear atypia may be seen, as well as a mixed, dense inflammatory infiltrate. Perineural invasion is uncommon but may occur; recurrence and metastases do not appear to be attributable to this histologic finding, highlighting the behavioral differences between keratoacanthoma and SCC.207 Importantly, malignant transformation of keratoacanthoma has been identified histologically as a focal event in as many as one quarter of cases, more frequently in older patients and in photoexposed areas, affirming that keratoacanthomas must be completely excised and studied in serial paraffin blocks to reveal any foci of malignant transformation.208 Because keratoacanthoma is so difficult to distinguish histologically from SCC, multiple histologic and immunohistochemical studies have been performed to find ways of separating these 2 distinct entities. In 1 study of 296 cases, the 5 most relevant criteria helpful in distinguishing keratoacanthoma from SCC included: epithelial lip and sharp outline between tumor and stroma in favor of keratoacanthoma and ulceration, numerous mitoses, and marked pleomorphism/ anaplasia in favor of SCC.189 Nevertheless, in difficult cases, even these criteria did not significantly increase the specificity or sensitivity of the histologic diagnosis, such that atypical or difficult cases still need to be considered and treated as SCC. Use of monoclonal antibodies to show differential expression of desmosomal glycoproteins in keratoacanthomas and SCCs may be helpful in distinguishing these tumors immunohistochemically because there is a strong negative correlation between desmoglein expression and degree of dysplasia in SCCs.209,210 Desmogleins have been found to be reduced or absent in SCC but preserved in keratoacanthoma.209 Furthermore, the bcl-2 protooncogene has been shown to be present diffusely in SCC, in contrast with keratoacanthomas in the proliferative phase of growth, in which bcl-2 positivity is limited to the basal cell area.211 The small cell variant of SCC is a histologic simulant of Merkel cell carcinoma, carcinoid, and oat cell

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carcinoma of the lung.196 Small cell SCC is usually associated with more charactistic histologic findings of cutaneous SCC, including overlying in situ disease and an adjacent inflammatory response. Nuclear molding is typically absent, although it is generally present in Merkel cell carcinoma and other neuroendocrine tumors. More unusual histologic variants of SCC include clear cell SCC, papillary SCC, signet ring SCC, pigmented SCC, and desmoplastic SCC.194,212 Clear cell SCC may be mistaken histologically for a variety of clear cell neoplasms, including sebaceous and adipose neoplasms, because of the presence of clear tumor cells with peripherally displaced nuclei.213 Keratinizing, nonkeratinizing, and pleomorphic variants have been described. Papillary SCC is a highly unusual variant characterized by large papillary fronds with fibrovascular cores.214 Signet ring SCC has only been reported in 2 cases and shows nuclear displacement and compression by cytoplasmic contents as in other signet ring tumors.215,216 Pigmented SCCs show accumulation of melanin within keratinocytes and melanophages in the upper dermis, with a differential diagnosis that includes pigmented BCC, malignant melanoma with pseudoepitheliomatous hyperplasia, and pilomatrixoma.212,217 Desmoplastic SCC has a marked desmoplastic stromal reaction surrounding cords and mironodular formations of atypical cell and is thought to have an increased risk of recurrence and metastasis.218 Occasionally, SCC has been reported to be associated with other cutaneous tumors, including BCC and Merkel cell carcinoma.219,220 The common etiologic role of ultraviolet radiation in these tumors, coupled with the intimate association of antigenically different populations of neoplastic cells in these reported cases, has led some authors to postulate that Merkel cell carcinoma and SCC may arise from a pluripotent epidermal stem cell.220

Immunohistochemistry Squamous cell carcinomas characteristically show diffuse positive cytoplasmic staining for high–molecular weight cytokeratins and also stain positively for epithelial membrane antigen.221 Vimentin antibody immunoreactivity may be present in poorly differentiated tumors, although this is a relatively nonspecific marker that stains mesenchymal lesions, such as atypical fibroxanthoma222,223 SCCs, regardless of histologic subtype, consistently stain negatively for S-100,

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HMB-45, amylase, carcinoembryonic antigen, and CD34, helping to distinguish them from melanoma, sweat gland carcinomas, and angiosarcoma. Cytokeratin 20 may be useful in distingushing small cell SCCs from Merkel cell carcinoma because this marker is limited to Merkel cells. If the immunohistochemical results are difficult to interpret, tonofilaments, keratohyaline granules, and desmosomes will be visible on electron microscopy, confirming the epithelial origin of the tumor.

Grading and Microstaging of Squamous Cell Carcinomas The Broders’ classification is the classic grading system for SCC that takes into consideration the degree of cellular differentiation of the tumor to determine the histologic grade of the lesion. Broders’ grade I lesions are less than 75% keratinized, and grade II, III, and IV lesions are 50% to 75%, 25% to 50%, and less than 25%, respectively. Poorly differentiated lesions have been found to be 3 times as likely to metastasize as well-differentiated lesions.224 Although the histopathologic grade of differentiation is important and useful for SCC staging, other factors must be taken into consideration as well.185 Tumor thickness and depth of invasion are the most important of these, with tumors greater than 5 mm in depth at highest risk of metastasis, corresponding in most cases with invasion to or below the reticular dermis (Clark level IV or V).191,199,225-228 If desmoplasia is present, the risk of metastasis may be further increased.185,199,218 Perineural invasion may represent another poor prognostic feature, carrying an increased risk of recurrence and metastasis.198,229

Prognosis, Recurrence, and Metastasis Invasive SCC has the potential to recur and metastasize. The overall 5-year rate of recurrence of primary cutaneous lesions is 8%, and the 5-year rate of metastasis is 5%.224,230,231 However, tumor-specific and patient-specific characteristics result in substantial differences in RR for recurrence and metastasis, as summarized in Table II. The most comprehensive analysis of recurrence and metastatic risk was compiled by Rowe, Carroll, and Day,224 who reviewed all relevant studies from 1940 to 1992 on the prognosis of SCC of the skin, lip, and ear.

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TABLE 2. Factors predisposing to recurrence and metastasis of cutaneous SCC Approximate RRs*

Clinical factors Rapid growth Size ⬎2 cm Site: lip Site: ear Immunosuppression History of irradiation Previously treated Histologic factors Tumor depth ⬎4 mm or to Clark level IV or V Poorly differentiated histology Infiltrative deep or peripheral margins Spindle cell histology Acantholytic histology Perineural invasion

Of recurrence

Of metastasis

– 2 2 2 2 – 3

– 3 3 3 – – 4

2

5

2

3

– – – 5

– – – 5

*1 is defined as RR of recurrence or metastasis of small primary SCC.

When cutaneous SCC metastasizes, the most common sites of spread are local lymph nodes, particularly the level I neck nodes.232 There does seem to be agreement regarding the magnitude of overall metastatic risk. The 5-year metastatic rate for primary SCCs of the skin is 5.2%, according to the review of Rowe, Carroll, and Day.224 Joseph, Zulueta, and Kennedy233 found a similar metastatic rate of 4.9% for SCCs of the trunk and limbs. A prospective study begun in south Australia during the period from 1988 to 1989 followed patients for 3 years and found a 5.8% metastatic rate for SCCs.230 A chart review (1944 to 1976) at MD Anderson revealed a metastatic rate for SCC of the extremity of 1.4%.1-3 The American Academy of Dermatology’s Statement on Actinic Keratoses (1997) is a review of the literature and offers an overall metastatic rate for SCC of 2% to 6%.234

Risk Factors for Metastasis Size, Location, and Growth Rate. Chief among the factors that affect metastatic risk are the size and location of the tumor and, to a lesser extent, rapid rate of growth.199,228 Large lesions (⬎2 cm in diameter) metastasize at a rate of 30%, 3 times that of smaller lesions.224 Lesions deeper than 4 mm display similar behavior. Rapidly growing lesions on the eyelid or ear

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may metastasize in up to one third of cases.235 Metastatic rates are particularly high for the ear (11.0%) and lip (13.7%), and the 5-year survival rate after metastasis from these primaries ranges from 25% to 40%. Other sites associated with a high-risk metastasis are the scalp, forehead, temple, eyelid, nose, mucous membranes, dorsal surface of the hands, penis, scrotum, and anus.92,104,236,237 Primary SCCs on the trunk and limb have been associated with a metastatic rate of 4.9% in a series that may be biased towards larger lesions.233 SCCs arising in injured or chronically diseased skin are associated with a risk of metastasis that approaches 40%.224,238 Although risk estimates are derived by averaging conclusions from multiple studies, it should be noted that many of these studies are methodologically dissimilar and the numbers of tumors examined is not always large. Degree of Histologic Differentiation. Degree of histologic differentiation is shown in many studies to be correlated with metastatic rates in cutaneous SCCs, but differentiation may be a less reliable prognostic marker than tumor size and thickness.233 Histologic features predictive of metastasis include a depth of more than 4 mm, involvement of the reticular dermis or subcutaneous fat, or penetration into fascia, muscle, bone, or cartilage. In the study by Rowe, Carroll, and Day,224 poorly differentiated lesions (Broders’ grades 3 and 4) were found to metastasize at a rate of 32.8%, 3 times as often as well-differentiated tumors (Broders’ grades 1 and 2). A more recent study also found that risk of metastasis was linked to the degree of differentiation, presence of small tumor nests, infiltrative tumor strands, and single-cell infiltration.197 However, because of the relative ubiquity of well-differentiated lesions, over 60% of metastatic SCCs exhibit high levels of differentiation. In addition, some individual studies have not found an association between the degree of histologic differentiation of the initial tumor and likelihood of later metastasis.228,233 The expectation of diminished aggressiveness of SCCs found to be histologically contiguous with AKs, and hence, presumably arising from these AKs, has not been verified with empiric analysis. In 1 series of metastatic SCC, AKs abutted 44% of the original SCC lesions that metastasized.191 The average primary was over 6 mm thick, and two thirds were moderately or well differentiated; apparently, as with other SCCs, tumor size and depth were more indicative of metastatic potential than other factors.

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Perineural Invasion. Perineural invasion, about equally likely in primary or recurrent SCC, is also an ominous finding indicative of a grave prognosis.239 Neurotropic spread results from contiguous movement of tumor cells along nerve fibers. Although years ago, perineural infiltration was thought to be a type of locoregional tumor growth along small lymphatics parallel to nerve branches, it has since been shown that the perineurium is a true subarachnoid space formed by the cleavage plane between the nerve and nerve sheath. Extension along this cavity represents a path of least resistance for neoplastic growth.227,240-247 One theory suggests that traumatic neuromas may develop at the sites of surgical scars and the proliferating nerves of such neuromas may provide a path for perineural extension.248 SCC involvement of extremely thin nerves in the reticular dermis is routine and does not bear the same dire prognosis as the infiltration of larger nerves, which is generally considered the threshold for diagnosis of perineural invasion.229,249 When real invasion of the perineural cavity does occur, it may not be clinically or histologically apparent until the tumor has spread extensively.92,236 Discontinuous metastatic skip lesions are characteristic of perineural infiltration; these may develop in the cranial cavity as well.250 Intracranial extension tends to be via large nerves that traverse bone channels into the brain, with the possible contemporaneous induction of the underrecognized complication of meningeal carcinomatosis.251,252 Transorbital spread is especially frequent among lesions originating on the forehead or eyebrow. Magnetic resonance imaging may be of use in delineating such pervasive involvement. Although early reports suggested that most perineural spread was within 1 cm of the initial tumor, more recent data confirm nerve extension of up to 14 cm.198,246,247,251,253-258 Typically, cases of perineural SCC are asymptomatic, with 60% to 70% of patients reporting no discomfort.251,257 When symptoms do occur, their character is contingent on whether sensory or motor nerves are affected. Impingement on the sensory innervation can result in numbness, paresthesias, tingling, progressive pain, “shooting pain,” diplopia, and blurred vision.229,247,251,253,255,259-261 Orbital perineural invasion is associated with loss of sensation and ophthalmoplegia in most patients, with a smaller percentage afflicted with pain and involvement of the local branches of the facial nerve.262 Motor impairments can include ptosis, ophthalmoplegia, facial

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muscle weakness, progressive muscle weakness that is more generalized, and overt paresis. Numbness, a near pathognomonic finding, may result from direct invasion of the nerve itself, and motor symptoms may be caused by external compression by tumor at points of vulnerability, like foramina. Just as symptoms of perineural invasion are rare, so too are abnormal radiologic findings, which generally show the presence of late stage disease.246,251,253 Overall, perineural spread occurs in 2.4% to 16% of cases of SCC, with the range of statistics in published reports likely a consequence of case selection.198,241,249 Male gender, tumor size greater than 2 cm, forehead location, and previous therapy are associated with a higher risk of this phenomenon.239 The risk of further metastasis after perineural tumor spread is almost 50%, even after aggressive initial extirpation with surgical excision.92,236 Two thirds of patients die of the disease within 5 years after presentation. Lymph Node Involvement. Histologically confirmed regional lymph node metastases from primary cutaneous SCC of the head and neck are also associated with a poor prognosis. Patients with such metastases are more likely than control patients to have had primary lesions more than 2 cm in diameter and greater than 4 mm deep. Clinical staging of the neck may be a useful prognostic intervention (P ⬍ .01), but the 5-year survival remains a dismal 20%.179 Immunosuppression and Organ Transplantation. Immunosuppression, particularly in transplant patients, greatly worsens the prognosis of cutaneous SCC. Not only do transplant patients have a higher incidence of SCC, but they also tend to have more aggressive individual lesions, larger numbers of tumors per patient, and onset at younger ages. In transplant recipients with long-term immunosuppression, tumors develop 2 to 3 decades earlier than in immunocompetent patients; in the former group, the overall rate of metastasis per patient can exceed 10%. Transplant-associated SCCs are biologically aggressive and are associated with a higher risk of local recurrence, regional and distant spread, and increased mortality.44-53,127,263-267 According to 1 populationbased registry, the risk of metastastic SCC in posttransplant patients is about 7%, and the risk of mortality is 5%.46 In another study, 11% of heart or lung transplant patients had malignant disease develop within 2 years of their transplants; 41% of these cases were SCC or melanoma (55% poorly differentiated SCC, 30% melanoma), and of these, half died, with a

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mean time to mortality of 20 months.264 Approximately one quarter of deaths after the fourth year after heart transplantation can be attributed to skin cancer, mostly SCC.53 In another study of heart or lung transplant patients, over the course of 9 years, the average patient had 4.6 malignant diseases develop, of which 40% were cutaneous SCC of the head and neck; 13% of these behaved aggressively, necessitating radical surgery, radiation, or chemotherapy, but prognosis remained dismal, with a more than 50% overall cancer-related mortality rate.266 Pediatric patients are at particularly high risk for morbidity and mortality from SCC after solid organ transplantation. Among those receiving organs at or before the age of 18 years, high-risk SCCs of the lip comprise a disproportionate 23% of all skin cancers.61 Short-term risk of skin cancer mortality in the pediatric population approaches 8%, with a 9% likelihood of lymph node mestastasis. Moreover, as has been noted by Berg and Otley,42 the many decades of normal lifespan ahead of these young people suggest an alarmingly high cumulative long-term risk of morbidity and mortality from aggressive SCC. As discussed previously, patients with HIV also have an increased risk of aggressive SCCs, with diameters larger than 1.5 cm, rapid growth rate, local recurrence, or evidence of metastasis.132 Such SCCs can develop and progress at an early age in this population, with high rates of morbidity and mortality. Significantly, those with more advanced HIV disease and greater levels of immunosuppression do not appear to have outcomes any worse than those of other patients with HIV.

Notable Manifestations of Squamous Cell Carcinoma Metastasis Parotid Gland Involvement. Parotid gland and neck metastases are not uncommon in metastatic cutaneous SCC originating from the head and neck. These nearby metastases may be deep and difficult to clear with Mohs’ surgery and may necessitate referral to otolaryngology or other appropriate specialty services. In 1 series of 75 patients with parotid and neck metastases, resection required total loss of the facial nerve in fewer than 10% of patients but at least some damage to the facial nerve damage in 20%.268 Approximately half of patients had recurrence develop within a year after surgical management of their metastatic disease, with positive surgical margins at

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the end of the procedure associated with greater risk of recurrence (P ⬍ .05). Significantly, postoperative radiotherapy was not associated with improved disease management or prolonged survival.268 Zosteriform and Sporotrichoid Spread. Recently, several reports have been seen of cutaneous SCC metastasizing in a zosteriform or sporotrichoid pattern.56,269,270 After excision of a primary SCC, painful and erythematous papules, some with vesicles and crusts, may present in a zosteriform distribution along dermatomes or in a pattern indicative of epidermotropic growth along lymphatic channels. The extremities and trunk may be the most common site for this presentation, which has also been noted to occur after extracorporeal photophoresis for cutaneous T-cell lymphoma and in association with organ transplantation.56,269,270 Treatment Method and Metastatic Spread. Another factor impacting the rate of metastasis is the choice of initial treatment method.224 Excisional techniques provide greater assurance of margin control than in vivo destructive methods that assume gross injury to the visible tumor is sufficient to eliminate all malignant cells. Mohs’ micrographic surgery, which offers not only microscopic margin control to maximize chance of cure but also tissue sparing to facilitate aesthetic reconstruction, is generally considered the treatment of choice for invasive squamous cell of the head and neck. At other anatomic sites, high-risk lesions, including large, recurrent, poorly defined, and histologically aggressive SCCs may also be best treated with Mohs’. Average cure rates for primary SCCs less than 2 cm in diameter are 83.5% with non-Mohs’ methods, compared with 98.1% with Mohs’; for larger lesions, the rates are 58.3% and 74.8%, respectively.224 Welldifferentiated SCCs are cured with other treatments 81.0% of the time, compared with 97.0% of the time with Mohs’ surgery; for poorly differentiated lesions, the cure rates are 46.4% and 67.4%, respectively.224 For neurotropic SCC of the skin, treatment with Mohs’ micrographic surgery is associated with a metastatic rate of 8.3%, compared with a rate of 47.3% with simple excision. Even in advanced cases, more than 75% of neurotropic SCCs may be successfully treated with Mohs’ surgery, possibly in association with adjuvant irradiation.224 Penetration of the skull base suggests a poor prognosis, and neither Mohs’ surgery nor any other treatment has been shown to be effective in these extensive cases.

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Given the high absolute incidence rate of SCC, and the high risk of mortality associated with metastatic spread, even modest metastatic rates translate into significant numbers of lives lost. Approximately 2000 people are estimated to die of SCCs in the United States every year.92,224 Age-adjusted nonmelanoma skin cancer mortality rate has been computed to be 0.44/105, with 59% of these cases from SCC. As previously noted, these cumulative figures are probably underestimated, given the lack of comprehensive reporting of SCCs and the fact that many lesions may be missed or never biopsied for histologic confirmation.

Recurrence Risk Factors for Recurrence The risk factors for recurrence of primary SCC are similar to those for metastatic spread. As with metastatic rates, the summary recurrence rate of approximately 8% (RR ⫽ 1) for primary cutaneous SCC is modified by various factors, as detailed subsequently.92,224 Size, Location, and Growth Rate. Size, rapid growth, and anatomic location are the most important factors predisposing to higher recurrence rates.271 For large tumors (⬎2 cm), the RR of recurrence is approximately 2, with an absolute rate of about 15%. More deeply invasive tumors behave in like fashion. Elevated recurrence rates are also seen in tumors of high-risk areas, such as lip and ear, which recur in 10.5% and 18.7% of cases, respectively.224 Scarring. SCC arising in preexisting scars is likely to be aggressive, recurrent, and associated with a poor prognosis. In part, suboptimal outcomes may be ascribed to delayed diagnosis or only partial initial resection of such lesions. For example, cutaneous SCC in patients with dystrophic epidermolysis bullosa may be identified so late as to necessitate radical treatment. In 1 case series of such patients, the size at initial diagnosis of SCC lesions within scarred skin ranged from 2 to 28 cm.272 Forty percent of the lesions affecting limbs were only manageable with limb amputation. The development of SCC in patients with epidermolysis bullosa is not confined to the dystrophic forms. Multiple tumors, probably from the chronic wounding associated with recurrent blistering, have also been reported in a pair of siblings with generalized atrophic benign epidermolysis bullosa.273

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Perineural Invasion. Perineural growth of tumor and poor histologic differentiation also increase the likelihood of recurrence.271 Lesions with perineural spread recur locally at a rate (approximately 33% to 50%) similar to the metastatic rate of such lesions.224,274 Treatment of perineural spread with aggressive radiation therapy or radiation therapy coupled with surgical resection is at best associated with a 50% rate of cure, which is virtually indistinguishable from the rate of cure after surgery alone.275 Mohs’ micrographic surgery offers a much enhanced cure rate of almost 90% for perineural tumors, and this must consequently be considered the standard of care for such lesions.198,239 Less histologically differentiated SCCs recur about 30% of the time, or about 4 times as often as cutaneous SCCs in general. Treatment Method and Rate of Recurrence. As with the rate of metastasis, the rate of recurrence is impacted by the type of treatment. Long-term (⬎5year) follow-up indicates that ear SCCs are about one third as likely to recur (5.3% versus 18.7%) if Mohs’ surgery is used instead of other methods.224 For lip tumors, Mohs’ surgery decreases the recurrence rate to one fourth that of other methods (2.3% versus 10.5%). For primary cutaneous SCCs in general, Mohs’ surgery reduces the recurrence risk from approximately 8% to 3%. Logistic regression analysis of a sample of more than 1000 patients with SCC revealed a statistically significant correlation between tumor treatment method and likelihood of recurrence (P ⬍ .01).271 When SCCs recur and are retreated, the likelihood of subsequent recurrence is greater than for primary lesions.224 Local rerecurrence of tumors after treatment is about 25%, and the metastatic rate for these lesions may be closer to 50%. Mohs’ surgery is indicated for locally recurrent tumors, which may only rerecur 10% of the times as a result.

Risk of New Tumors Second Primary Squamous Cell Carcinoma. A 30% risk of a second primary SCC exists within 5 years of treatment for the first SCC.276 The corresponding 3-year risk is 18%, which is in itself 10 times the likelihood of an SCC in the general population.2 The highest risk of a second primary SCC is in men who are less than 60 years old, who are most likely to have such a lesion in the first year after diagnosis of the initial primary cancer.277 Smokers and former smokers are up to 2 times more likely to have new

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SCCs.278 Because about 90% of recurrences and metastases occur within 5 years of surgical treatment, screening for 5 years after the last SCC may be adequate.32,279,280 Evidence also suggests that organ transplant recipients should be regularly screened for SCC after transplantation regardless of any history of SCC.281 Transplant patients have a RR for SCC much greater than that of the general elderly population, and these tumors tend to be particularly fast growing and prone to metastasize. Other Primary Malignant Diseases. The incremental risk of other tumors after development of SCC has also been studied. The risk of a BCC in patients with a prior SCC is about equal to that risk among patients with a prior BCC.2 Swedish studies have suggested that incidence patterns of subsequent melanoma, nonmelanoma, and internal cancers are not different in patients with prior in situ versus invasive SCC.282 If a second primary SCC is excluded, the RR of a second cancer in a person with an earlier cutaneous SCC is reduced to 1.3 times the baseline rate.277 Subsequent skin cancer risk is, however, markedly elevated (RR ⫽ 15), with a 3-fold rise in the risk for malignant melanoma. Significantly increased risks have also been found for other squamous epithelium-associated cancers, including cancers of the lip (RR ⫽ 5), respiratory organs (RR ⫽ 1.7), esophagus (RR ⫽ 1.5), uterine cervix (RR ⫽ 2.2), and vulva (RR ⫽ 2.3). In addition, the risks of cancers of the salivary glands have been shown to grow (RR ⫽ 5), and more modest rises in the likelihood of hematopoietic/lymphoproliferative (RR ⫽ 2) and digestive tissue (RR ⫽ 1 to 2) cancers have also been observed. Danish studies have indicated that prior Bowen’s disease does not predispose patients to elevated general cancer risk but does raise the likelihood of several specific cancers, including nonmelanoma skin cancer (RR ⫽ 4.3), lip carcinoma (RR ⫽ 8.2), and leukemia among men (RR ⫽ 3.2).283 After an SCC of the lower lip, an approximately 18% 5-year risk of development of new primary cancers (excluding skin cancers) exists; these cancers are most often within the respiratory and upper digestive tract.284

Summary In summary, the mean rate of metastasis for primary SCCs is approximately 5% (RR ⫽ 1). For lesions associated with the ear, lip, or immunosuppression, the RR for metastasis is 2 to 3. Furthermore, SCCs arising

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in scars, associated with perineural spread, and growing very large in size have a RR of metastasis of 5 or greater. Although SCCs with very high RRs (eg, ⬎5) for recurrence or metastasis are relatively unusual, they are mentioned to alert practitioners to the grim prognoses associated with these. In the anecdotal experience of many surgeons, large, neglected SCCs are associated with a dismal prognosis that usually culminates in severe morbidity or mortality.

Treatment Rationale for Intervention Treatment of primary cutaneous SCC is necessary for 2 reasons: 1, mitigation of locally destructive growth; and 2, elimination of the risk of metastatic spread.162 Although SCCs of the skin grow slowly, this growth can include not only peripheral enlargement but also vertical growth deep to the lesion. Impingement on subcutaneous structures, such as muscle and cartilage, and even compression of bony regions, can occur. On the face, occlusion or damage of vital sensory organs including the eyes, ears, or nose is possible. Beyond the ensuing loss of functionality is the added problem of disfigurement in cosmetically sensitive areas. As tumors enlarge, the risk of locoregional recurrence and regional lymph node or distant metastases increases. Because metastatic SCC bears a dismal prognosis, there is an incentive to treat lesions definitively when they are small, thus both simplifying the technical challenge of the surgery and forestalling severe morbidity and mortality. Actinic keratoses and SCC in situ (Bowen’s disease) can be treated with topical medications and PDT, methods that are less efficacious for invasive SCC. Treatment options for localized invasive cutaneous SCC include electrodesiccation and curettage, excision, or cryosurgery.285-287 Appropriate use of these methods can cure up to 90% of low-risk tumors, defined as small (⬍1 cm), well-defined primary lesions on the neck, trunk, or extremities.92 Cryosurgery and electrodesiccation and curettage are relatively inexpensive to perform. Surgical excision and Mohs’ surgery are more costly but can offer significantly lower rates of recurrence and metastasis for high-risk tumors.

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Therapeutic Methods for Low-risk to Moderate-risk Lesions Topical Medications. Actinic keratoses can be treated with various methods in addition to the routine approach of liquid nitrogen cryotherapy. A monthlong course of topical 5-fluorouracil once a day can successfully improve skin areas with severe diffuse actinic damage and clusters of AKs. Even if newer low-concentration 5-fluorouracil cream is used (0.5%, as versus the previously available 5% concentration), significant discomfort and irritation are inevitable and residual erythema at the site of application may persist for months, as acknowledged in the package insert of Carac 0.5% fluorouracil cream (Dermik Laboratories, Berwyn, Penn).288 Topical diclofenac sodium gel has recently been approved for the treatment of AKs. Twice-a-day application for 60 to 90 days may similarly clear actinic damage, with the longer course potentially offset by a lesser degree of cutaneous irritation.289 When treatment of actinic damage is attempted with topical medications, success is difficult to measure because before and after biopsy verification is seldom available. Instead, improvement in the appearance of the skin is used as a proxy for apparent resolution of early in situ SCC lesions. Imiquimod 5% cream, a topical immune response modifier that acts by upregulating interferon and other cytokines involved in the cell-mediated immune response, has become increasingly popular for the treatment of superficial BCC, and even more recently, for treatment of SCC in situ. Case reports document success in the treatment of SCC in situ of the glans penis and perianal SCC.174,290,291 Use of this method for genital SCC appears particularly reasonable given the association with of SCC in this area with HPV infection, against which imiquimod is known to have therapeutic activity. Three times weekly treatment with imiquimod for 4 to 6 weeks also appears to be effective in the treatment of actinic cheilitis.292 Local unwanted reactions during treatment include increased erythema, induration, and erosions or ulcerations.292 Studies continue to confirm the utility of imiquimod in clearing AKs.158,159 Overall, imiquimod may be most effective at treating AKs and borderline in situ SCC rather than invasive SCC. Some practitioners are concerned that the ease of use of this therapy may result in its enthusiastic overprescription for lesions that are not clearly superficial; the result may be inadequate treatment of primary invasive SCC, lead-

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ing to subsequent recurrence or spread, a preventable morbidity. Photodynamic Therapy. Photodynamic therapy is a treatment methods that uses 3 elements, a photosensitizing drug, light, and oxygen, to induce targeted cell death of neoplastic or abnormal tissue.293,294 Specifically, sensitization of the target tissue is selective and occurs via the topically or systemically administered photosensitizing agent. After administration, the photosensitizer is activated by light and reacts with oxygen and other metabolites to produce highly reactive oxygen intermediates and free radicals that result in destruction of targeted tissue.295 The introduction of a new photosensitizer prodrug 5-aminolevulinic acid (5-ALA) presented a novel approach for induction of photosensitization because this substance penetrates the stratum corneum to reach the deep stroma of skin tumors, where it is transformed into the highly photoactive endogenous protoporphyrin IX.296 Actinic keratoses represent 1 of the most successful indications for ALA-PDT in dermatology.297,298 A number of studies report response rates of 71% to 100% for facial AKs after a single treatment.299-302 For the treatment of AKs, a variety of noncoherent and coherent light sources have been used with wavelengths ranging from 417 to 630 nm and light doses and dose rates ranging from 10 to 540 J/cm2 and 10 to 300 mW/cm2, respectively. Most studies of ALA-PDT for AKs are limited by lack of histologic confirmation and have short follow-up periods ranging from 3 to 20 months. Nonfacial hyperkeratotic lesions respond poorly to ALA-based PDT and have weighted clearance rates of 44%, compared with 91% for facial lesions.302-306 Response rates of ALA-PDT appear to be comparable with those of topical 5-fluorouracil (5-FU) and cryotherapy.302,307-309 Although most studies on AKs have used red light sources, blue light (DUSA BLU-417, DUSA Pharmaceuticals, Toronto, Ontario) has also received US Food and Drug Administration approval for the treatment of nonhyperkeratotic AKs of the face and scalp with the topical 5-ALA formulation Levulan Kerastick (DUSA Pharmaceuticals, Toronto, Ontario). ALA-PDT for darker-skinned Asian patients is hampered by melanin absorption of light, but Itoh et al305 report results in Asian patients comparable with those seen in white patients, notwithstanding the fact that up to 6 treatment sessions were necessary to achieve a clearance rate of 82%. Lesions not completely resolved after PDT may be treated a second time after 8 weeks. Patients should avoid

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excessive sun exposure in the interim, and before and after treatment. Thus far, the procedural complexity and posttreatment photosensitivity associated with PDT has limited its popularity among physicians and patients. Indeed, although the recent literature abounds in reports and trials of PDT for AKs and Bowen’s disease, this inevitable bias in the medical literature towards new technology should not obscure the fact that this treatment is currently used for only a small minority of patients.310 Electrodesiccation and Curettage. Electrodesiccation and curettage destroys the tumor and a surrounding margin of clinically unaffected tissue via cauterization and scraping of the area with a curette.236 The process is repeated several times to maximize the probability of complete tumor extirpation. A disadvantage of this method is that no specimen is sent for margin evaluation. Nevertheless, 5-year cure rates for small primary SCC with electrodesiccation and curettage may be as high as 96%.92,224,271,311-318 Several technique variations are in common usage and may account for reported differences in efficacy.319 Selection bias may account for the fact that overall cure rates with electrodessication and curettage rival the likelihood of cure with such methods as surgical excision: a greater proportion of small SCCs are treated with curettage and electrodessication than other techniques. Cure rates for high-risk tumors treated with electrodesiccation and curettage are much lower, although no well-controlled prospective studies have been done.320 Curettage has also been advocated as a preliminary intervention that enhances the cure rate after subsequent surgical excision. However, although such “preexcisional curettage” has been shown to decrease the surgical failure rate for BCC, no therapeutic advantage has been shown for SCC.321 Curettage alone as a treatment method for SCC is not recommended because the extension of cells down hair follicles and eccrine structures may render this intervention ineffective, thus increasing the risk of subsequent metastatic disease.322,323 Studies of Bowen’s disease treated with curettage only reveal a 10% to 40% rate of recurrence.324-326 Cryotherapy. Cryotherapy uses liquid nitrogen to cool small SCCs to tumoricidal temperatures.236,327 Patients with bleeding disorders or contraindications for surgery may be candidates for cryotherapy. Graham and Clark328 reported a cure rate of 97.3% for 563 primary SCCs, most of which were between 0.5 cm and 1.2 cm in diameter. Recurrences generally

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become evident within 2 years. There is substantial variation in cryotherapy technique, and this renders difficult any comparison of the results of cryotherapy trials.164,310,329 Simple Excision. Low-risk primary tumors can be locally excised. Surgical excision offers the advantages of histologic verification of tumor margins, rapid healing, and improved cosmesis. Disadvantages of excision include the risks of hematoma, seroma, infection, and wound dehiscence. It is important to note that surgical excision uses the traditional bread-loafing method of histopathologic processing, which provides a view of less than 1% of the complete margin of the surgical specimen.330 For this reason, cure rates for SCC after excision do not differ significantly from cure rates after electrodesiccation and curettage, and excision may even be somewhat less efficacious, with aggregate 5-year cure rates of primary SCC of only 92%.224 For well-differentiated tumors less than 2 cm in diameter, not occurring on the scalp, ears, eyelids, lips, or nose and not involving the subcutaneous fat, a margin of 4 mm around the clinical borders of the lesion has been recommended to achieve a 95% clearance rate.331 For tumors in high-risk sites or greater than 2 cm in size, a 6-mm margin is recommended.331 Recurrence rates after excision of low-risk lesions range from 5% to 8%.224 High-risk tumors, however, have an increased risk of recurrence, with tumors greater than 2 cm in size recurring at a rate of 15.7% after excision and tumors less than 2 cm in size recurring at a rate of 5.8%.224 Poorly differentiated lesions recur at a rate of 25% after excision, as opposed to well-differentiated lesions, which recur at a rate of 11.8%.224 Other Approaches. Numerous other treatment methods have been used for treatment of SCC. Anecdotal reports and small case series delineating the success of a variety of less common therapies appear in the literature. For example, in situ SCC and invasive SCC have been treated with intralesional injections of low-dose recombinant interferon ␣-2b, and separately with interferon ␣-2c, with only invasive lesions occasionally remaining after 3-week to 6-week treatment courses.332-334 Interferon may additionally be therapeutic for SCCs arising in patients with EV.335 Erbium:yttrium aluminum garnet (YAG) and pulsed carbon dioxide lasers have been used to ablate AKs, but even multiple passes of carbon dioxide laser may not be sufficient to eliminate all tumor cells of SCC in situ,

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although Bowen’s disease of the digits has been eradicated with this method without potentiation of scar contracture or loss of function.336-340 Dermabrasion, another skin resurfacing method, has also been used to treat severe actinic damage, including that caused by xeroderma pigmentosum.341,342 Nonablative lasers, such as the vascular-selective Neodymium: yttrium aluminum garnet (Nd:YAG), may also have some efficacy against Bowen’s disease.69,343 Hyperthemia has also been used to destroy Bowen’s disease, with 1 of the more interesting approaches entailing the adaptation of disposable chemical pocket warmers to function as the heat-inducing source.344 Extensive and diffuse facial SCCs have been treated with minimal excision combined with perfusion of 5-fluorouracil, and widespread Bowen’s disease from arsenic ingestion has responded to topical 5-fluorouracil combined with topical dinitrochlorobenzene.345,346 Better and more selective immune response modifiers are being developed to target SCC, and these may possibly eventually function as a long-term “silver bullet,” providing protective immunity against initial tumors.347 Radiotherapy. Fractionated radiation treatment may be preferred for patients who are unable to tolerate surgery or have inoperable tumors and may provide favorable functional and cosmetic results.92,236 Radiation may also be used in combination with other therapies to treat aggressive or recurrent lesions.33,236 Disadvantages of radiotherapy include its cost and the need for multiple office visits per week for several weeks.92,348 Furthermore, tumors recurring after radiotherapy are likely to be highly aggressive.92 Healing of wounds may be delayed after radiotherapy. Consequently, particularly on the lower legs, tumors wider than 4 cm that are minimally invasive should be treated with staged cryotherapy or surgical excision, methods that are less associated with failure to heal.349

Therapeutic Methods for High-risk Lesions High-risk tumors, including those that are large, situated in risky anatomic locations, histologically poorly differentiated, recurrent, or within immunocompromised hosts, must be treated definitively to maximize the chance of cure. If local excision is used, a 6-mm margin of surrounding normal tissue should be removed to achieve a 95% cure rate.331 Patients with

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high-risk tumors may be considered for prophylactic postoperative regional lymph node irradiation.236 Mohs’ Micrographic Surgery. The treatment with the highest cure rates for high-risk primary and recurrent SCC is Mohs’ micrographic surgery.104,239,350-359 Modern Mohs’ surgery is performed in stages on a single operative day, and the Mohs’ technique of horizontal frozen sectioning provides a view of 100% of the peripheral and deep margins of each specimen, making incomplete excision much less likely than with standard pathologic processing.330 Lesions to be removed with Mohs’ surgery are mapped before removal and the excised specimens are processed so that orientation relative to the operative site is maintained; in the event of subtotal removal of the tumor after excision of the first stage, prior mapping permits the surgeon to return to the operative site and remove only the tissue along the margins deemed to remain positive. Consequently, Mohs’ surgery offers both microscopic margin control and tissue sparing, thus facilitating small, minimally disfiguring reconstructions of the resulting defects. Mohs’ surgery affords a 5-year local cure rate of 96.9% for primary cutaneous SCCs at all sites, except for lip and ear, in contrast to a 5-year local cure rate of 92.1% for non-Mohs’ methods.224 Mohs’ surgery is associated with 5-year cure rates of 90% to 93.3% for recurrent SCC, in contrast to recurrence rates of 23.3% for recurrent tumors treated with standard excision.224 For SCCs associated with perineural invasion, Mohs’ offers a cure rate of approximately 90%, compared with a rate of only 50% for wide surgical excision.239 Mohs’ surgery is also the treatment of choice for nail unit SCCs because of the technique’s tissue-sparing properties and the concurrent need to limit damage to the nail matrix.166,360,361 When the visible borders of SCC are indistinct, or masked by hypertrophic tissue as in rhinophyma, Mohs’ surgery may also be appropriately selected.362 Genital SCC, including SCC of the glans penis or the penile shaft, is another potential indication for Mohs’ surgery.363,364 Although Mohs’ surgery is a definitive procedure, its performance with local anesthesia in an outpatient setting makes it a safe intervention for the vast majority of eligible patients, including patients who are elderly or those with multiple morbidities.365,366 When used as indicated, Mohs’ surgery is a cost-effective method because it markedly reduces recurrence and the need for retreatment, and the outpatient setting minimizes hospital-related overhead costs.348 Mohs’ surgery continues to evolve, with the

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incorporation of new tissue-staining techniques to identify small foci of high-risk tumors.367 In vivo techniques, such as confocal microscopy, are being investigated to reduce the amount of tissue that must be removed with Mohs’ through precise identification of the tumor margins before the first cut is made.368 However, at present, the reliability of in vivo microscopy remains far inferior to frozen section technique. Although tumor cure is the primary goal of Mohs’ surgery and other treatment methods for cutaneous SCC, preservation of anatomic structures and minimization of disfigurement are also imperative, especially in cosmetically sensitive areas on younger, more active patients. Mohs’ surgeons receive training in reconstructive surgery, including skin grafts and local flaps.369 According to Medicare reimbursement data, dermatologic surgeons perform more flaps for skin cancer reconstruction than any other surgical subspecialty. In some cases when tumor is extensive or deep, radical surgical procedures may be indicated. Primary or metastatic SCC deriving from chronic osteomyelitis are often amenable to Mohs’ surgery as a limb-sparing procedure, but certain cases may necessitate limb amputation.369,373 Similarly, if SCC lesions invade deep into muscular, glandular, or bony structures or if they involve the viscera, Mohs’ surgery may be relegated to obtaining clearance of peripheral skin margins, with other surgical services enlisted to clear the deep margins. After excision of massive or highrisk cutaneous SCC with Mohs’ surgery, some practitioners counsel adjuvant radiotherapy, but this has not been shown to improve survival or decrease morbidity.374 Indeed, in the absence of any data to support the efficacy of adjuvant radiotherapy for locally invasive disease, the associated morbidity from such radiotherapy may be in itself a contraindication. Sentinel lymphadenectomy has been recommended by some in combination with Mohs’ micrographic surgery for the treatment of high-risk SCCs.375 As an experimental therapeutic intervention, sentinel lymphadenectomy may help identify regionally metastates that may subsequently be extirpated in a timely manner. Adjuvant Treatment. Treatment of nodal disease may involve radiation, lymph node dissection, or both. Regional disease can be treated with these 2 methods in combination, with a 5-year cure rate of 30% to 40%.224 Radical neck dissections and modified neck dissections may be necessary to debulk metastatic cervical disease, with the less aggressive latter proce-

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dure preserving, when possible, structures such as the spinal accessory nerve, the internal jugular vein, and the sternocleidomastoid muscle.376-379 Advances in radiotherapy have yielded more precisely directed methods that limit subcutaneous fibrosis and mobility impairments at functional sites like the hand and wrist: for instance, in brachytherapy, sealed radioactive sources are used to deliver radiation at a short distance and surface-mold therapy uses principles of geometry to localize radiation specifically onto skin tumors.380-382 Treatment of metastatic SCC may include systemic chemotherapy or treatment with biologic response modifiers, but the efficacy of these methods in treatment of distant metastatic disease has not been well established.383-385 Before treatment for metastatic disease is begun, magnetic resonance imaging and fine needle aspiration (FNA) may be performed to confirm and delineate the extent of spread, but FNA should be reconfirmed with frozen section biopsy at the onset of the definitive surgery.319,386 Coordination of treatment for metastatic disease may best occur under the auspices of a multidisciplinary tumor board comprised of dermatologists, pathologists, diagnostic and therapeutic radiologists, medical oncologists, head and neck surgeons, and plastic surgeons.

Management of Posttransplant Tumors The treatment of aggressive posttransplant SCCs is a daunting challenge. In general, the recommended treatment methods are those routinely used for aggressive SCC, but these should be implemented with even greater timeliness and thoroughness. Prevention should be a mainstay of treatment, with patients trained to self examine and routine professional dermatologic follow-up, preferably in the context of a dedicated transplant skin cancer clinic.387 Chemoprophylaxis with retinoids is indicated, as is management of early cutaneous carcinogenesis manifesting as AKs and in situ SCC with prophylactic medications, like 5-fluorouracil cream and topical imiquimod, or other destructive methods, such as cryotherapy, PDT, or electrocautery.125,388,389 If possible, lowering the doses of immunosuppressive medications should be considered to decrease the rate of emergence of new lesions. When invasive SCCs do develop in transplant patients, treatment should be prompt and comprehensive. Mohs’ micrographic surgery is indicated for aggressive tumors, including those in high-risk anatomic

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locations (eg, lip) and those of very large size. However, to minimize overall operative time for the patient, it may be concurrently imperative to debulk less clinically worrisome SCCs with less definitive means. Hyperkeratotic SCCs, and other ubiquitous lesions of similar provenance on the trunk and limbs, may be removed many at a time with deep saucerization with a broad blade, simple excision, electrodessication and curettage, or extremely intense cryotherapy. A typical patient visit to a skin cancer surgeon may thus entail Mohs’ surgery on 2 or 3 lesions, destruction or excision of 10 or more lesser lesions, and a careful physical examination and reminder to continue riskminimizing behaviors and prophylactic medications. Especially for patients with catastrophic cutaneous carcinogenesis, timely and repeated follow-up care of this nature may be imperative to forestall mortality directed related to metastatic cutaneous SCC.

Management of Perineural Invasion The treatment of choice for perineural SCC is Mohs’ micrographic surgery, possibly in concert with wide surgical excision and adjuvant radiotherapy.198 The need for rapid, optimal treatment is imperative given the high likelihood of metastasis and mortality if cure is not effected. Cure rates for SCC with perineural invasion without Mohs’ surgery are 20% to 30%, but the Mohs’ technique coupled with radiotherapy offers dramatically improved rates of 80% to 90%.198,229,245,251,257 Unfortunately, no convincing assessments of the incremental value of radiotherapy are available, with at least 1 small study indicating diminished recurrence rate after radiotherapy and 1 showing no benefit.198,257 In practice, most patients do receive radiotherapy, and some are also referred for chemotherapy.

Guidelines for Care Guidelines for the management of cutaneous SCC have been promulgated and disseminated by various national and international professional organizations. The British Association of Dermatologists, in their guidelines for management of Bowen’s disease, note that the risk of progression from in situ to invasive SCC is approximately 3%, although the risk for in situ SCC of the neck and genitalia appears to be about 10%.164,170-172,326,390,391 With regard to treatment, it is suggested that slowly progressive thin lesions on the

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lower legs of elderly patients be observed rather than treated if slow healing is a concern. Common treatment options for Bowen’s disease are said to include cryotherapy, curettage with cautery, excision, laser, PDT, and topical 5-fluorouracil, and the strength of evidence is noted to be strongest for cryotherapy, curettage and cautery, excision, and PDT. Radiotherapy and cryotherapy, although efficacious, may result in protracted healing. Indeed, a prospective study shows that curettage and cautery is associated with significantly shorter healing time, less pain, fewer complications, and lower recurrence rate than cryotherapy.392 In the United States, the National Comprehensive Cancer Network (NCCN), a consortium of 17 institutions, has published detailed guidelines of care for nonmelanoma skin cancer.393 The consensus guidelines for cutaneous SCC are summarized in a flowchart. Anatomic site-specific risk is stratified with the modifiers “L” (low risk for recurrence: trunk, extremities), “M” (middle risk for recurrence: cheeks, forehead, neck, scalp), and “H” (high risk for recurrence: “mask” areas of face: central face, eyelids, eyebrows, periorbital, nose, lips, chin, mandible, preauricular and postauricular, temple, ear). For primary disease that is low risk, treatment options include: 1, curettage and electrodesiccation in non– hair bearing areas, with surgical excision required if fat is reached; 2, excision with postoperative margin assessment if the lesion can be excised with 6-mm margins and a primary repair performed (margin positivity should lead to retreatment with Mohs’ surgery or radiotherapy, with the former preferred for cosmesis and preservation of function); 3, radiotherapy if the patient is older than 55 years, even if there is involvement of area “M” or area “H,” excluding the genitalia (eg, verrucous carcinoma), hands, or feet; and 4, PDT per clinical protocols. For primary disease that is high risk, NCCN suggests: 1, excision with postoperative margin assessment if the lesion is greater than or equal in diameter to 20 mm in area “L” with no other high-risk factors and can be excised with 10-mm margins and primary repair (margin positivity should lead to retreatment with Mohs’ or radiotherapy, with the former preferred for cosmesis and preservation of function); 2, Mohs’ resection with intraoperative frozen sections (if margins are negative after Mohs’ but perineural involvement is extensive, adjuvant radiotherapy should be considered, and if margins are positive after Mohs’, multidisciplinary consultation and enrollment in clinical trials should be sought); and 3, radiotherapy for patients older

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than 55 years without verrucous carcinoma who have tumors less than 15 mm in diameter in area “H” (excluding genitalia, hands, and feet) or less than 20 mm in area “M” if there are no other high-risk factors. For palpable regional lymph nodes, NCCN recommends FNA, which if positive should trigger regional lymph node dissection followed by adjuvant radiotherapy, with the latter not essential if there is only 1 involved node of less than 3-cm diameter and no evidence of extracapsular spread. A negative FNA should lead to an open biopsy with frozen section, and if the biopsy indicates positivity, the tumor should be treated as if a positive FNA were obtained. Palpable intraparotid masses should trigger superficial parotidectomy, followed by adjuvant radiotherapy. The American Academy of Dermatology has also developed guidelines of care for cutaneous SCC.236 Treatment options are divided into surgical and nonsurgical categories. Surgical approaches include: 1, curettage and electrosurgery, which is deemed less effective for recurrent lesions or those that invade subcutis; 2, cryosurgery, judged especially useful in patients with bleeding disorders and in whom surgery is contraindicated; 3, excision, described as useful in both primary and recurrent tumors, the margins of which can be verified with pathology; 4, Mohs’ micrographic surgery, for recurrent tumors and primary lesions displaying 1 or more factors associated with biologic aggressiveness; and 5, laser surgery, which may be used for excision or destruction and may have the added benefit of assuring hemostasis. Nonsurgical methods include: 1, ionizing radiation, which may be useful for primary lesions and some selected recurrent lesions and for palliation of inoperable tumors; aggressive lesions may require concurrent treatment with another method, and there is some evidence to suggest that radiotherapy increases the metastatic potential of verrucous carcinoma; 2, evolving therapies, such as PDT, intralesional and interferon-related therapies, and oral and topical retinoids; and 3, palliation and observation, which is based on the notion that the benefit of any intervention must be weighed against the risks to general health and wellbeing. The current American Academy of Dermatology guidelines were compiled in 1993 and hence, are less instructive regarding the appropriate use of newer topical medications and PDT. More recently, the British Association of Dermatologists, the British Association of Plastic Surgeons, and the Faculty of Clinical Oncology of the Royal College

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of Radiologists have jointly authored multiprofessional guidelines for the management of the patient with cutaneous SCC.394 In this document, surgical excision is regarded as the treatment of choice for most cutaneous SCC. A major benefit of excision is the ability to confirm the histology of the removed tissue and the absence of tumor cells at the margin. Excision is defined broadly, with higher risk tumors necessitating either wider simple excisions or excision with Mohs’ micrographic surgery. Significantly, the guidelines include the observation that the concept of tumor and excision margins is predicated on the existence of a clinically well-defined boundary. Around high-risk primary cutaneous SCC, microscopic metastases may be found. When this is suspected, a wide surgical margin may result in a higher cure rate; because Mohs’ surgery removes tumor in continuity and cannot identify in-transit metastases, an additional stage may be taken after histologic margin clearance with Mohs’ in such high-risk lesions to increase the likelihood of true clearance. The guidelines note the potential for missed tumor associated with typical “bread loaf” histology technique and note the benefits of the Mohs’ technique for visualizing tumor margins but also note that on occasion SCC may be difficult to track on frozen sections and formalinfixed analysis may be indicated. Other treatment methods for SCC are also considered: 1, curettage and cautery, a highly efficacious approach for small welldifferentiated primary lesions but not an appropriate treatment for locally recurrent disease; selection bias may underly the high reported cure rates with this technique; 2, cryosurgery, a method with many variations, that may be used cautiously for primary but not recurrent lesions; 3, radiotherapy, which has comparable cure rates with other methods, that may be useful for maintaining cosmesis and functionality as particular anatomic locations or for treating advanced tumors where surgery is impractical; 4, elective prophylactic lymph node dissection, proposed for SCC on the lip greater than 6 mm in depth and cutaneous SCC greater than 8 mm in depth; this is seldom practiced and the evidence for benefit is weak; and 5, multiprofessional oncology teams, comprised of dermatologists, pathologists, plastic or maxillofacial surgeons, clinical oncologists, and clinical nurse specialists in skin cancer, that may manage advanced tumors that are not surgically respectable in coordination with the patient and, when appropriate, a multiprofessional palliative care team.226,227,395,396

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Screening, Follow-up, and Prevention A thorough history and physical examination are necessary in evaluation of a patient for SCC. Pertinent information includes the patient’s history of sun exposure beginning in early childhood, occupational exposure to ultraviolet light or carcinogenic chemicals including arsenic and polycyclic hydrocarbons, previous radiation therapy for cancer, psoriasis, or other dermatologic disorders, potential causes of immunosuppression, including medications and underlying medical conditions, and any other history of chronically diseased or ulcerated skin. If the patient has a history of skin cancer, the type, location, method, and time of treatment should be elicited. For screening purposes, a total-body examination of the skin is the only test available to detect cutaneous SCC. Although the US Preventive Services Task Force determined that there is insufficient evidence for or against the efficacy of routine screening for skin cancer in the general population,397 there is reason to believe that total-body screening examinations benefit those judged to be at high risk for cutaneous SCC.398,399 Although the efficacy of screening has not been formally shown, screening itself is noninvasive, and the diagnostic test, the skin biopsy, is associated with low morbidity.400 Thus, individuals with risk factors listed previously, and the elderly, in whom SCC becomes much more common, should be routinely screened. Because early disease is highly and effectively curable, whereas metastatic disease carries a grim prognosis, identification of SCC early in its course is essential to maximize treatment benefit. Prompt detection by a trained healthcare provider may vastly improve a patient’s quality of life and is potentially lifesaving. Most dermatologists believe that patients, and especially those with risk factors, should be routinely screened and provided with counseling about sun exposure and cancer preventive strategies.401 Primary care physicians should be advised to refer high-risk patients for screening by a dermatologist and to refer other patients as well if diagnosis of skin lesions is uncomforable. Recommendation of screening is essential to patients with a history of skin cancer, both to monitor for persistence and recurrence of tumor and for the development of new skin lesions.2 Fewer than 10% of cutaneous SCCs recur; the risk of recurrence is associated with location, size, depth of tumor, histologic pattern, type of previous treatment, and additional

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patient factors such as immunosuppression.402 Between 30% and 50% of patients with a history of nonmelanoma skin cancer will have a new skin cancer within 5 years, and the risk is highest within the first year after treatment of the primary lesion.276 Risk factors for development of subsequent skin cancer include: skin that burns easily, a high cumulative exposure to ultraviolet radiation, male gender, and history of multiple nonmelanoma skin cancers.278 Because about 90% of recurrences are within the first 5 years after treatment, screening during this period may constitute adequate surveillance.280 Organ-transplant recipients should be screened regularly regardless of their skin cancer history because their high risk of multiple tumors.281 Rigorous cost-effectiveness information regarding the need for screening patients for SCC is not available. The American Academy of Dermatology guidelines for cutaneous SCC note that long-term follow-up is essential because of the risks of recurrence, metastasis, and new lesions, but the duration of follow-up is dependent on the particular case.236 Koh et al403 note that screening may be appropriate for SCCs because the lesions are common and associated with significant morbidity and mortality, the screening tool (full body skin examination) is safe and inexpensive, and early diagnosis can decrease morbidity. Particularly among patients with prior SCCs, screening may be appropriate to monitor for recurrence, persistence, or new lesions. Evidence suggests that screening for 5 years after the last SCC may be adequate. In Victoria, Australia, where 115 SCC-associated deaths were recorded during the period from 1988 to 1990, 83% of metastases were found to occur within 4 years of diagnosis.23 Similarly, Rowe, Carroll, and Day224 found that 96% of metastases and 95% of disease recurrence occurred within 5 years of surgical treatment. Evidence also exists to suggest that organ transplant recipients should be screened for SCC regardless of any history of SCC. Skin malignant diseases are the most common type of malignant disease in transplant patients, and these tumors tend to be particularly fast-growing and aggressive. In a Dutch population, transplant recipients were found to have a 250-fold higher risk of SCC than the general population.7 Unfortunately, a recent US study revealed that after kidney transplantation, only 27% of patients had a dermatologist and only 14% were followed regularly by a dermatologist.281

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Most experts agree that patients with a history of nonmelanoma skin cancer or who are otherwise at high risk should be screened at least once or twice yearly. In a patient with a history of SCC when metastasis is suspected, biopsy specimens from palpable lymph nodes should be obtained and examined histologically. Imaging studies and laboratory studies may also be indicated. Appropriate imaging and laboratory studies should be performed as needed to detect the presence of distant metastases. Patients at lower risk may be screened every 18 to 24 months. Individuals should be educated in regard to the need for protection against ultraviolet radiation and the benefits of performing self-examinations on a regular basis; this is especially true in organ-transplant recipients.53 Patient performance of self-examination is directly correlated with self-perceived risk of the development of cancer and discussions with healthcare providers.404 Patients should therefore be advised appropriately according to their level of risk. Currently, most counseling on prevention strategies occurs during dermatologic visits; fewer than half of patients at high risk receive counseling at primary care visits.405 Even in dermatologic settings, however, there continues to be wide variation in how often cancer preventive services are actually provided.401 Because cumulative exposure to ultraviolet radiation is believed to be the most important risk factor, prevention of exposure beginning in childhood should show a considerable lowering in the incidence of tumor development. Sunscreen application, even after significant exposure during childhood and young adulthood, may reduce the incidence of AKs, precursors to SCC,406,407 and SCC tumor development or recurrence.408 Use of a broad-spectrum sunscreen has recently been shown to be effective in preventing ultraviolet B–induced thymine dimer formation in human subjects.409 These results strongly support the concept that regular sunscreen use reduces the risk of skin cancer. However, many adults, and especially the elderly, have already received significant and irreversible exposure to ultraviolet radiation. An agent that could arrest or reverse carcinogenesis regardless of existing risk factors could greatly benefit such individuals.410 Recently, several agents have been evaluated for their possible role in prevention of cutaneous SCC. An ideal agent would have little or no side effects, high efficacy, oral administration, a known mechanism of action, low cost, and human acceptance. ␤-Carotene is one such agent, thought to possess Curr Probl Dermatol, May/June 2003

chemopreventive properties from stimulation of the immune system, enhancement of cell-cell communication, and effects on cell proliferation and differentiation.411,412 Although studies of ␤-carotene and cancer prevention in experimental animals have been promising, large-scale, randomized trials in humans have not shown any effect on the development of nonmelanoma skin cancer.413 Other substances that have shown promise in animal studies include green tea and polyphenols.414 Diets low in fat and high in fruits and vegetables, including ␤-carotene, vitamins E and C, and selenium may also help prevent nonmelanoma skin cancer, although recommendations to prevent cancer have not been more specific thus far.415 Retinoids, a class of compounds structurally related to vitamin A, have shown excellent promise in the prevention and treatment of cutaneous SCC. The mechanism of action is through modulation and inhibition of cell proliferation and induction of cellular differentiation in the skin via nuclear retinoid receptors.416 Topical and oral retinoids have been shown to have effects on all 3 stages of prevention (ie, primary prevention in healthy individuals at risk, secondary treatment in patients with precancerous lesions, and tertiary prevention of additional tumors in patients with a history of nonmelanoma skin cancer).417 Topical retinoids used as monotherapy have been shown to decrease numbers of AKs in patients with multiple lesions and have also been used successfully in combination with low-dose systemic retinoids in transplant recipients.418,419 Treatment with high-dose (2 mg/kg) isotretinoin was shown in 1 early study to decrease the incidence of skin cancer in patients with xeroderma pigmentosum.420 Toxicity associated with high doses of this medication made it difficult for patients to comply with treatment, with reappearance of tumors after cessation of therapy.421 More recent studies suggest a possible role for retinoids in chemoprophylaxis against skin cancer in transplant recipients.388,389 One small randomized trial of acitretin in renal transplant recipients over 6 montbs showed a significant reduction in new SCCs with no evidence of adverse effects on renal function.388 A more recent retrospective review of a similar population of transplant patients taking acitretin also suggested a reduction in new skin cancers, without significant side effects from this medication.389 Experimental applications of retinoids include oral vitamin A supplementation, highdose isotretinoin, and combination retinoid/interferon

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therapy. Clearly, the full potential of retinoid application has not been explored, but future use in patients at risk for cutaneous SCC appears likely. The role of cycloocygenase inhibitors in skin cancer prevention has recently been investigated.422 These agents exert an anticarcinogenic effect by inhibiting prostaglandins, which are themselves pathogenetically linked to carcinogenesis through their influence on cell proliferation, tumor growth, and immune responsiveness.422 Recent studies in the hairless mouse model have shown celecoxib, a cycloocygenase-2 inhibitor, to be an effective and safe chemopreventive agent to ultraviolet carcinogenesis at doses equivalent to those prescribed in humans, as it produced increases in the tumor latency period and reduction in tumor multiplicity in treated animals versus controls.422,423 Human studies are also underway, looking at the usefulness of a selective cycloocygenase-2 inhibitor as a preventive treatment for AK and as a chemopreventive agent in patients with basal cell nevus syndrome.424 Ultimately, cycloocygenase-2 inhibitors may prove to be a possible approach for prevention of ultraviolet-induced SCCs in patients at high risk, although much depends on the results of the studies underway to determine which patients would benefit from these agents for skin cancer chemoprevention.

Conclusion Cutaneous SCC is a significant public health problem, whose incidence, morbidity, mortality, and associated costs increase steadily with every passing year. Although many of these tumors should be preventable with sun avoidance and effective sun protection, changing leisure habits involving greater exposure to sunlight have resulted in the epidemic increase in this and other nonmelanoma skin cancers. The importance of early detection of SCC cannot be overemphasized because small low-risk lesions are largely curable if caught early. A complete history and a total body skin examination will help to identify tumors at high risk for recurrence and metastasis and those that may be more easily treated. Because the prognosis is poor for tumors with regional or distant spread, lesions at high risk for metastasis should be treated promptly, with close follow-up subsequently and consideration given to adjunctive therapies as deemed appropriate.263,265,267,335

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REFERENCES 1. Salasche S. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000;42 (1 Pt 2):4-7. 2. Marcil I, Stern R. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and metaanalysis. Arch Dermatol 2000;136:1524-30. 3. Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol 1994;30(5 Pt 1):774-8. 4. Weinstock MA. Death from skin cancer among the elderly: epidemiological patterns. Arch Dermatol 1997;133:1207-9. 5. Weinstock M, Bogaars H, Ashley M, Litle V, Bilodeau E, Kimmel S. Nonmelanoma skin cancer mortality. A population-based study. Arch Dermatol 1991;127:1194-7. 6. Cohn BA. Squamous cell carcinoma: could it be the most common skin cancer [letter]? J Am Acad Dermatol 1998;39: 134-6. 7. Coebergh JW, Neumann HA, Vrints LW, van der Heijden L, Meijer WJ, Verhagen-Teulings MT. Trends in the incidence of non-melanoma skin cancer in the SE Netherlands 19751988: a registry-based study. Br J Dermatol 1991;125:353-9. 8. Kaldor J, Shugg D, Young B, Dwyer T, Wang YG. Nonmelanoma skin cancer: ten years of cancer-registry-based surveillance. Int J Cancer 1993;53:886-91. 9. Lucke TW, Hole DJ, Mackie RM. An audit of the completeness of non-melanoma skin cancer registration in Greater Glasgow. Br J Dermatol 1997;137:761-3. 10. Green A, Battistutta D, Hart V, Leslie D, Weedon D. Skin cancer in a subtropical Australian population: incidence and lack of association with occupation. The Nambour Study Group. Am J Epidemiol 1996;144:1034-40. 11. Gallagher RP, Hill GB, Bajdik CD, Coldman AJ, Fincham S, McLean DI, et al. Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer. II. Squamous cell carcinoma. Arch Dermatol 1995;131:164-9. 12. Gallagher RP, Ma B, McLean DI, Yang CP, Ho V, Carruthers JA, et al. Trends in basal cell carcinoma, squamous cell carcinoma, and melanoma of the skin from 1973 through 1987. J Am Acad Dermatol 1990;23(3 Pt 1):413-21. 13. Gray DT, Suman VJ, Su WP, Clay RP, Harmsen WS, Roenigk RK. Trends in the population-based incidence of squamous cell carcinoma of the skin first diagnosed between 1984 and 1992. Arch Dermatol 1997;133:735-40. 14. Glass AG, Hoover RN. The emerging epidemic of melanoma and squamous cell skin cancer [see comments]. JAMA 1989;262):2097-100. 15. Harris RB, Griffith K, Moon TE. Trends in the incidence of nonmelanoma skin cancers in southeastern Arizona, 19851996. J Am Acad Dermatol 2001;45:528-36. 16. Chuang TY, Reizner GT, Elpern DJ, Stone JL, Farmer ER. Squamous cell carcinoma in Kauai, Hawaii. Int J Dermatol 1995;34:393-7. 17. Reizner G, Chuang T, Elpern D, Stone J, Farmer E. Bowen’s disease (squamous cell carcinoma in situ) in Kauai, Hawaii. A population-based incidence report. J Am Acad Dermatol 1994;31:596-600. 18. Grodstein F, Speizer FE, Hunter DJ. A prospective study of

122

19.

20.

21. 22.

23. 24.

25.

26.

27.

28. 29.

30.

31.

32.

33.

34.

35.

36.

37.

incident squamous cell carcinoma of the skin in the nurses’ health study. J Natl Cancer Inst 1995;87:1061-6. Karagas MR, Greenberg ER, Spencer SK, Stukel TA, Mott LA. Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. New Hampshire Skin Cancer Study Group. Int J Cancer 1999;81:555-9. Hoy W. Nonmelanoma skin carcinoma in Albuquerque, New Mexico: experience of a major health care provider. Cancer 1996;77:2489-95. Buettner PG, Raasch BA. Incidence rates of skin cancer in Townsville, Australia. Int J Cancer 1998;78:587-93. Green A, Battistutta D. Incidence and determinants of skin cancer in a high-risk Australian population. Int J Cancer 1990;46:356-61. Harrigan P. Skin cancer in Australia. Lancet 1995; 345(8961):1360. Raasch B, Maclennan R, Wronski I, Robertson I. Body site specific incidence of basal and squamous cell carcinoma in an exposed population, Townsville, Australia. Mutat Res 1998;422:101-6. Stenbeck KD, Balanda KP, Williams MJ, Ring IT, MacLennan R, Chick JE, et al. Patterns of treated non-melanoma skin cancer in Queensland: the region with the highest incidence rates in the world. Med J Aust 1990;153:511-5. Green A, Beardmore G, Hart V, Leslie D, Marks R, Staines D. Skin cancer in a Queensland population. J Am Acad Dermatol 1988;19:1045-52. Wassberg C, Thorn M, Johansson AM, Bergstrom R, Berne B, Ringborg U. Increasing incidence rates of squamous cell carcinoma of the skin in Sweden. Acta Derm Venereol 2001;81:268-72. Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol 2002;146(Suppl 61):1-6. English DR, Kricker A, Heenan PJ, Randell PL, Winter MG, Armstrong BK. Incidence of non-melanocytic skin cancer in Geraldton, Western Australia. Int J Cancer 1997;73:629-33. Iversen T, Tretli S. Trends for invasive squamous cell neoplasia of the skin in Norway. Br J Cancer 1999;81:52831. Hughes JR, Higgins EM, Smith J, Du Vivier AW. Increase in non-melanoma skin cancer: the King’s College Hospital experience (1970-92). Clin Exp Dermatol 1995;20:304-7. Rosenblatt L, Marks R. Deaths due to squamous cell carcinoma in Australia: is there a case for a public health intervention? Australas J Dermatol 1996;37:26-9. Lindelof B, Sigurgeirsson B, Tegner E, Larko O, Johannesson A, Berne B, et al. PUVA and cancer risk: the Swedish follow-up study. Br J Dermatol 1999;141:108-12. Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med 1984;310:1156-61. Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Photochemotherapy Follow-up Study. Cancer 1994;73:2759-64. Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A radiation (PUVA). A meta-analysis. Arch Dermatol 1998;134:1582-5. Katz KA, Marcil I, Stern RS. Incidence and risk factors associated with a second squamous cell carcinoma or basal

Curr Probl Dermatol, May/June 2003

38.

39.

40.

41. 42.

43.

44. 45. 46.

47.

48.

49.

50.

51.

52.

53.

54.

cell carcinoma in psoralen ⫹ ultraviolet a light-treated psoriasis patients. J Invest Dermatol 2002;118:1038-43. Stern RS, Bagheri S, Nichols K. The persistent risk of genital tumors among men treated with psoralen plus ultraviolet A (PUVA) for psoriasis. J Am Acad Dermatol 2002;47:33-9. Lichter MD, Karagas MR, Mott LA, Spencer SK, Stukel TA, Greenberg ER. Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group. Arch Dermatol 2000;136:1007-11. Stratigos AJ, Tahan S, Dover JS. Rapid development of nonmelanoma skin cancer after CO2 laser resurfacing. Arch Dermatol 2002;138:696-7. Chan HH. Photorejuvenation or photoaging: where does one draw the fine line? J Am Acad Dermatol 2002;47:321-2. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-20. Sheil AG. Development of malignancy following renal transplantation in Australia and New Zealand. Transplant Proc 1992;24:1275-9. Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf 2000;23:101-13. Penn I. Cancers in renal transplant recipients. Adv Ren Replace Ther 2000;7:147-56. Sheil AG, Disney AP, Mathew TH, Amiss N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc 1993;25(1 Pt 2):1383-4. Jensen P, Hansen S, Moller B, Leivestad T, Pfeffer P, Geiran O, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999;40(2 Pt 1):177-86. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, O’Sullivan B, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation 1996;61:715-21. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 1990;49: 506-9. Naldi L, Fortina AB, Lovati S, Barba A, Gotti E, Tessari G, et al. Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study. Transplantation 2000;70:1479-84. London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP. Risk of neoplasia in renal transplant patients. Lancet 1995; 346(8972):403-6. Lampros TD, Cobanoglu A, Parker F, Ratkovec R, Norman DJ, Hershberger R. Squamous and basal cell carcinoma in heart transplant recipients. J Heart Lung Transplant 1998;17: 586-91. Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol 1999;40:27-34. Marubayashi S, Tashiro H, Watanabe H, Fudaba Y, Hayamizu K, Ohdan H, et al. Study on eight patients with malignant tumors after renal transplantation. Hiroshima J Med Sci 2000;49:117-20.

Curr Probl Dermatol, May/June 2003

55. Kishikawa H, Ichikawa Y, Yazawa K, Hanafusa T, Fukunishi T, Ebisui C, et al. Malignant neoplasm in kidney transplantation. Int J Urol 1998;5:521-5. 56. Kato N, Aoyagi S, Sugawara H, Mayuzumi M. Zosteriform and epidermotropic metastatic primary cutaneous squamous cell carcinoma. Am J Dermatopathol 2001;23:216-20. 57. Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN. Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients. Am J Kidney Dis 2000;36:167-76. 58. Webb MC, Compton F, Andrews PA, Koffman CG. Skin tumours posttransplantation: a retrospective analysis of 28 years’ experience at a single centre. Transplant Proc 1997; 29:828-30. 59. Dyall-Smith D, Ross JB. Cutaneous malignancies in renal transplant recipients from Nova Scotia, Canada. Australas J Dermatol 1995;36:79-82. 60. Sheil AG, Disney AP, Mathew TG, Amiss N, Excell L. Malignancy following renal transplantation. Transplant Proc 1992;24:1946-7. 61. Penn I. Posttransplant malignancies in pediatric organ transplant recipients. Transplant Proc 1994;26:2763-5. 62. Jensen P, Hansen S, Moller B, Leivestad T, Pfeffer P, Fauchald P. Are renal transplant recipients on CsA-based immunosuppressive regimens more likely to develop skin cancer than those on azathioprine and prednisolone? Transplant Proc 1999;31:1120. 63. Penn I. Malignant melanoma in organ allograft recipients. Transplantation 1996;61:274-8. 64. Penn I. The effect of immunosuppression on pre-existing cancers. Transplantation 1993;55:742-7. 65. Frezza EE, Fung JJ, van Thiel DH. Non-lymphoid cancer after liver transplantation. Hepatogastroenterology 1997;44: 1172-81. 66. Kelly DM, Emre S, Guy SR, Miller CM, Schwartz ME, Sheiner PA. Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors. Cancer 1998;83: 1237-43. 67. Euvrard S, Kanitakis J, Pouteil-Noble C, Dureau G, Touraine JL, Faure M, et al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol 1995;33(2 Pt 1):222-9. 68. Gjersvik P, Hansen S, Moller B, Leivestad T, Geiran O, Simonsen S, et al. Are heart transplant recipients more likely to develop skin cancer than kidney transplant recipients? Transpl Int 2000;13(Suppl 1):S380-1. 69. Fortina AB, Caforio AL, Piaserico S, Alaibac M, Tona F, Feltrin G, et al. Skin cancer in heart transplant recipients: frequency and risk factor analysis. J Heart Lung Transplant 2000;19:249-55. 70. Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Photochem Photobiol B 2001;63:8-18. 71. Stern RS. The mysteries of geographic variability in nonmelanoma skin cancer incidence. Arch Dermatol 1999;135: 843-4. 72. Koskinen A, Oikarinen A. Nonmelanoma skin cancer in northern Finland. Int J Dermatol 1996;35:700-3. 73. English D, Armstrong B, Kricker A, Winter M, Heenan P,

123

74. 75.

76.

77.

78. 79.

80.

81. 82.

83.

84.

85. 86.

87.

88.

89. 90.

91.

124

Randell P. Demographic characteristics, pigmentary and cutaneous risk factors for squamous cell carcinoma of the skin: a case-control study. Int J Cancer 1998;76:628-34. McCall CO, Chen SC. Squamous cell carcinoma of the legs in African Americans. J Am Acad Dermatol 2002;47:524-9. Woodhead AD, Setlow RB, Tanaka M. Environmental factors in nonmelanoma and melanoma skin cancer. J Epidemiol 1999;9(Suppl 6):S102-14. Ichihashi M, Naruse K, Harada S, Nagano T, Nakamura T, Suzuki T, et al. Trends in nonmelanoma skin cancer in Japan. Recent Results Cancer Res 1995;139:263-73. Takemiya M, Ohtsuka H, Miki Y. The relationship between solar keratoses and squamous cell carcinomas among Japanese. J Dermatol 1990;17:342-6. Armstrong BK, Kricker A, English DR. Sun exposure and skin cancer. Australas J Dermatol 1997;38(Suppl 1):S1-6. Cockerell C. Histopathology of incipient intraepidermal squamous cell carcinoma (“actinic keratosis”). J Am Acad Dermatol 2000;42(1 Pt 2):11-7. Brand D, Ackerman AB. Squamous cell carcinoma, not basal cell carcinoma, is the most common cancer in humans. J Am Acad Dermatol 2000;42:523-6. Glogau R. The risk of progression to invasive disease. J Am Acad Dermatol 2000;42(1 Pt 2):23-4. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988;1(8589):795-7. Marks R, Rennie G, Selwood T. The relationship of basal cell carcinomas and squamous cell carcinomas to solar keratoses. Arch Dermatol 1988;124:1039-42. Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic keratoses and the controversy over treatment. A patient-oriented perspective. Arch Dermatol 1991;127:1029-31. Graham JH. Precancerous lesions of the skin. Primary Care 1976;2:699-716. Graham JH. Solar keratosis with squamous cell carcinoma-a 40 year perspective: results of a study. Presented at the American Academy of Dermatology Meeting, March 3, 1998, Orlando, FL. Marks R, Foley P, Goodman G, Hage BH, Selwood TS. Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 1986;115:649-55. Moon TE, Levine N, Cartmel B, Bangert JL, Rodney S, Dong Q, et al. Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, doubleblind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiol Biomarkers Prev 1997;6: 949-56. Goldberg LH, Joseph AK, Tschen JA. Proliferative actinic keratosis. Int J Dermatol 1994;33:341-5. Weinstock MA, Bingham SF, Cole GW, Eilers D, Naylor MF, Kalivas J, et al. Reliability of counting actinic keratoses before and after brief consensus discussion: the VA topical tretinoin chemoprevention (VATTC) trial. Arch Dermatol 2001;137:1055-8. Carag HR, Prieto VG, Yballe LS, Shea CR. Utility of step sections: demonstration of additional pathological findings in

92.

93. 94. 95. 96. 97.

98.

99.

100.

101. 102. 103.

104.

105.

106.

107. 108.

109.

110.

111.

biopsy samples initially diagnosed as actinic keratosis. Arch Dermatol 2000;136:471-5. Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol 1992;26(3 Pt 2):467-84. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001;344:975-83. Preston DS, Stern RS. Nonmelanoma cancers of the skin. N Engl J Med 1992;327:1649-62. Ortonne JP. From actinic keratosis to squamous cell carcinoma. Br J Dermatol 2002;146(Suppl 61):20-3. de Gruijl FR. Photocarcinogenesis: UVA vs UVB. Methods Enzymol 2000;319:359-66. Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, et al. A role for sunlight in skin cancer: UVinduced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A 1991;88:10124-8. Buckman S, Gresham A, Hale P, Hruza G, Anast J, Masferrer J, et al. COX-2 expression is induced by UVB exposure in human skin: implications for the development of skin cancer. Carcinogenesis 1998;19:723-9. Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer: new understanding. Arch Dermatol 1997;133:1263-70. Fisher MS, Kripke ML. Suppressor T lymphocytes control the development of primary skin cancers in ultravioletirradiated mice. Science 1982;216(4550):1133-4. Kripke ML, Morison WL. Modulation of immune function by UV radiation. J Invest Dermatol 1985;85(1 Suppl):62s-6s. Streilein JW. Photoimmunology of non-melanoma skin cancer. Cancer Surv 1996;26:207-17. Suchniak JM, Baer S, Goldberg LH. High rate of malignant transformation in hyperkeratotic actinic keratoses. J Am Acad Dermatol 1997;37(3 Pt 1):392-4. Kwa RE, Campana K, Moy RL. Biology of cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;26:126. Karagas MR, Stannard VA, Mott LA, Slattery MJ, Spencer SK, Weinstock MA. Use of tanning devices and risk of basal cell and squamous cell skin cancers. J Natl Cancer Inst 2002;94:224-6. Peritz AE, Gasparro FP. Psoriasis, PUVA, and skin cancer: molecular epidemiology: the curious question of T3 A transversions. J Investig Dermatol Symp Proc 1999;4:11-6. Kromberg JG, Castle D, Zwane EM, Jenkins T. Albinism and skin cancer in Southern Africa. Clin Genet 1989;36:43-52. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987;123:241-50. Dumaz N, Drougard C, Sarasin A, Daya-Grosjean L. Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA—repair-deficient xeroderma pigmentosum patients. Proc Natl Acad Sci U S A 1993;90:10529-33. Davis MM, Hanke CW, Zollinger TW, Montebello JF, Hornback NB, Norins AL. Skin cancer in patients with chronic radiation dermatitis. J Am Acad Dermatol 1989;20: 608-16. Harwood CA, Proby CM. Human papillomaviruses and

Curr Probl Dermatol, May/June 2003

112.

113.

114.

115.

116.

117. 118.

119.

120.

121.

122.

123.

124.

125. 126.

127.

128.

129.

non-melanoma skin cancer. Curr Opin Infect Dis 2002;15: 101-14. Drolet BA, Neuburg M, Sanger J. Role of human papillomavirus in cutaneous oncogenesis. Ann Plast Surg 1994;33:33947. Woodworth CD, Doniger J, DiPaolo JA. Immortalization of human foreskin keratinocytes by various human papillomavirus DNAs corresponds to their association with cervical carcinoma. J Virol 1989;63:159-64. de Villiers EM, Ruhland A, Sekaric P. Human papillomaviruses in non-melanoma skin cancer. Semin Cancer Biol 1999;9:413-22. Jackson S, Harwood C, Thomas M, Banks L, Storey A. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 2000;14:3065-73. Kettler AH, Rutledge M, Tschen JA, Buffone G. Detection of human papillomavirus in nongenital Bowen’s disease by in situ DNA hybridization. Arch Dermatol 1990;126:777-81. Marshall V. Premalignant and malignant skin tumours in immunosuppressed patients. Transplantation 1974;17:272-5. Harwood CA, McGregor JM, Proby CM, Breuer J. Human papillomavirus and the development of non-melanoma skin cancer. J Clin Pathol 1999;52:249-53. Kaspar TA, Wagner RF Jr, Jablonska S, Niimura M, Tyring SK. Prognosis and treatment of advanced squamous cell carcinoma secondary to epidermodysplasia verruciformis: a worldwide analysis of 11 patients. J Dermatol Surg Oncol 1991;17:237-40. Yu RC, Hsu KH, Chen CJ, Froines JR. Arsenic methylation capacity and skin cancer. Cancer Epidemiol Biomarkers Prev 2000;9:1259-62. Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens [see comments]. Lancet 1998;351(9103):623-8. Espana A, Redondo P, Fernandez AL, Zabala M, Herreros J, Llorens R, et al. Skin cancer in heart transplant recipients. J Am Acad Dermatol 1995;32:458-65. Otley CC. Immunosuppression and skin cancer: pathogenetic insights, therapeutic challenges, and opportunities for innovation. Arch Dermatol 2002;138:827-8. DiGiovanna JJ. Posttransplantation skin cancer: scope of the problem, management, and role for systemic retinoid chemoprevention. Transplant Proc 1998;30:2771-8. DiGiovanna JJ. Retinoid chemoprevention in the high-risk patient. J Am Acad Dermatol 1998;39(2 Pt 3):S82-5. Preciado DA, Matas A, Adams GL. Squamous cell carcinoma of the head and neck in solid organ transplant recipients. Head Neck 2002;24:319-25. Euvrard S, Kanitakis J, Pouteil-Noble C, Disant F, Dureau G, Finaz de Villaine J, et al. Aggressive squamous cell carcinomas in organ transplant recipients. Transplant Proc 1995; 27:1767-8. Caforio AL, Fortina AB, Piaserico S, Alaibac M, Tona F, Feltrin G, et al. Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy. Circulation 2000;102(19 Suppl 3):III222-7. Shamanin V, zur Hausen H, Lavergne D, Proby CM, Leigh

Curr Probl Dermatol, May/June 2003

130.

131.

132.

133.

134.

135. 136.

137.

138.

139.

140.

141.

142.

143.

IM, Neumann C, et al. Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients. J Natl Cancer Inst 1996; 88:802-11. de Jong-Tieben LM, Berkhout RJ, ter Schegget J, Vermeer BJ, de Fijter JW, Bruijn JA, et al. The prevalence of human papillomavirus DNA in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer. Transplantation 2000; 69:44-9. Smith KJ, Skelton HG, Yeager J, Ledsky R, McCarthy W, Baxter D, et al. Cutaneous findings in HIV-1-positive patients: a 42-month prospective study. Military Medical Consortium for the Advancement of Retroviral Research (MMCARR). J Am Acad Dermatol 1994;31(5 Pt 1):746-54. Nguyen P, Vin-Christian K, Ming ME, Berger T. Aggressive squamous cell carcinomas in persons infected with the human immunodeficiency virus. Arch Dermatol 2002;138: 758-63. Lobo DV, Chu P, Grekin RC, Berger TG. Nonmelanoma skin cancers and infection with the human immunodeficiency virus. Arch Dermatol 1992;128:623-7. Maurer TA, Christian KV, Kerschmann RL, Berzin B, Palefsky JM, Payne D, et al. Cutaneous squamous cell carcinoma in human immunodeficiency virus-infected patients. A study of epidemiologic risk factors, human papillomavirus, and p. Arch Dermatol 1997;133:577-83. Manusow D, Weinerman BH. Subsequent neoplasia in chronic lymphocytic leukemia. JAMA 1975;232:267-9. Scarisbrick JJ, Child FJ, Evans AV, Fraser-Andrews EA, Spittle M, Russell-Jones R. Secondary malignant neoplasms in 71 patients with Sezary syndrome. Arch Dermatol 1999; 135):1381-5. Kontochristopoulos G, Kyriakis K, Symeonidou S, Katsiboulas V, Aroni K, Panteleos D, et al. Squamous cell carcinoma in chronic trophic ulcers of leprosy patients. J Eur Acad Dermatol Venereol 2000;14:230-1. Kanwar AJ, Thami GP, Kaur S, Mohan H, Attri AK, Kaur C. Squamous cell carcinoma in long-standing untreated lichen sclerosus et atrophicus of the penis. Urol Int 2002;68:291-4. Eisen D. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol 2002;46:207-14. Dabski K, Stoll HL Jr, Milgrom H. Squamous cell carcinoma complicating late chronic discoid lupus erythematosus. J Surg Oncol 1986;32:233-7. Caruso WR, Stewart ML, Nanda VK, Quismorio FP Jr. Squamous cell carcinoma of the skin in black patients with discoid lupus erythematosus. J Rheumatol 1987;14:156-9. Newman C, Wagner RF Jr, Tyring SK, Spigel GT. Squamous cell carcinoma secondary to recessive dystrophic epidermolysis bullosa. A report of 4 patients with 17 primary cutaneous malignancies. J Dermatol Surg Oncol 1992;18: 301-5. Schwartz RA, Birnkrant AP, Rubenstein DJ, Kim U, Burgess GH, Stoll HL Jr, et al. Squamous cell carcinoma in dominant type epidermolysis bullosa dystrophica. Cancer 1981;47: 615-20.

125

144. Weber F, Bauer J, Sepp N, Hogler W, Salmhofer W, Hintner H, et al. Squamous cell carcinoma in junctional and dystrophic epidermolysis bullosa. Acta Derm Venereol 2001;81: 189-92. 145. Reed WB, College J Jr, Francis MJ, Zachariae H, Mohs F, Sher MA, et al. Epidermolysis bullosa dystrophica with epidermal neoplasms. Arch Dermatol 1974;110:894-902. 146. Keefe M, Wakeel RA, Dick DC. Death from metastatic, cutaneous, squamous cell carcinoma in autosomal recessive dystrophic epidermolysis bullosa despite permanent inpatient care. Dermatologica 1988;177:180-4. 147. Sober AJ, Burstein JM. Precursors to skin cancer. Cancer 1995;75(Suppl 2):645-50. 148. Marks R, Selwood TS. Solar keratoses. The association with erythemal ultraviolet radiation in Australia. Cancer 1985;56: 2332-6. 149. Schwartz RA. The actinic keratosis. A perspective and update. Dermatol Surg 1997;23:1009-21. 150. Moy R. Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000;42(1 Pt 2):8-10. 151. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol 1994;131:455-64. 152. Franceschi S, Levi F, Randimbison L, La Vecchia C. Site distribution of different types of skin cancer: new aetiological clues. Int J Cancer 1996;67:24-8. 153. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993;329: 1147-51. 154. Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol 1997;36:650-3. 155. Mittelbronn M, Mullins D, Ramos-Caro F, Flowers F. Frequency of pre-existing actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol 1998;37:677-81. 156. Hurwitz RM, Monger LE. Solar keratosis: an evolving squamous cell carcinoma. Benign or malignant [letter]? Dermatol Surg 1995;21:184. 157. Stockfleth E, Ulrich C, Meyer T, Arndt R, Christophers E. Skin diseases following organ transplantation: risk factors and new therapeutic approaches. Transplant Proc 2001;33: 1848-53. 158. Persaud AN, Shamuelova E, Sherer D, Lou W, Singer G, Cervera C, et al. Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis. J Am Acad Dermatol 2002;47:553-6. 159. Persaud A, Lebwohl M. Imiquimod cream in the treatment of actinic keratoses. J Am Acad Dermatol 2002;47(Suppl 4): S236-9. 160. Salasche SJ, Levine N, Morrison L. Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: an open-label trial. J Am Acad Dermatol 2002;47: 571-7. 161. Stockfleth E, Meyer T, Benninghoff B, Salasche S, Papadopoulos L, Ulrich C, et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 2002;138:1498-502. 162. Goldman GD. Squamous cell cancer: a practical approach. Semin Cutan Med Surg 1998;17:80-95.

126

163. Lee MM, Wick MM. Bowen’s disease. CA Cancer J Clin 1990;40:237-42. 164. Cox NH, Eedy DJ, Morton CA. Guidelines for management of Bowen’s disease. British Association of Dermatologists. Br J Dermatol 1999;141:633-41. 165. Kossard S, Rosen R. Cutaneous Bowen’s disease. An analysis of 1001 cases according to age, sex, and site. J Am Acad Dermatol 1992;27:406-10. 166. Zaiac M, Weiss E. Mohs micrographic surgery of the nail unit and squamous cell carcinoma. Dermatol Surg 2001;27: 246-51. 167. Chute CG, Chuang TY, Bergstralh EJ, Su WP. The subsequent risk of internal cancer with Bowen’s disease. A population-based study. JAMA 1991;266:816-9. 168. Reymann F, Ravnborg L, Schou G, Engholm G, Osterlind A, Thestrup-Pedersen K. Bowen’s disease and internal malignant diseases. A study of 581 patients. Arch Dermatol 1988;124:677-9. 169. Lycka BA. Bowen’s disease and internal malignancy. A meta-analysis. Int J Dermatol 1989;28:531-3. 170. Kao GF. Carcinoma arising in Bowen’s disease. Arch Dermatol 1986;122:1124-6. 171. Mikhail GR. Cancers, precancers, and pseudocancers on the male genitalia. A review of clinical appearances, histopathology, and management. J Dermatol Surg Oncol 1980;6:102735. 172. Patterson JW, Kao GF, Graham JH, Helwig EB. Bowenoid papulosis. A clinicopathologic study with ultrastructural observations. Cancer 1986;57:823-36. 173. Gordon KB, Roenigk HH, Gendleman M. Treatment of multiple lesions of Bowen disease with isotretinoin and interferon alfa. Efficacy of combination chemotherapy. Arch Dermatol 1997;133:691-3. 174. Schroeder TL, Sengelmann RD. Squamous cell carcinoma in situ of the penis successfully treated with imiquimod 5% cream. J Am Acad Dermatol 2002;46:545-8. 175. Petrow W, Gerdsen R, Uerlich M, Richter O, Bieber T. Successful topical immunotherapy of bowenoid papulosis with imiquimod. Br J Dermatol 2001;145:1022-3. 176. Smith KJ, Germain M, Skelton H. Bowen’s disease (squamous cell carcinoma in situ) in immunosuppressed patients treated with imiquimod 5% cream and a cox inhibitor, sulindac: potential applications for this combination of immunotherapy. Dermatol Surg 2001;27:143-6. 177. Schroeder T, Mac FD, Goldberg L. Pain as an atypical presentation of squamous cell carcinoma. Dermatol Surg 1998;24:263-6. 178. Yu RC, Pryce DW, Macfarlane AW, Stewart TW. A histopathological study of 643 cutaneous horns. Br J Dermatol 1991;124:449-52. 179. Kraus DH, Carew JF, Harrison LB. Regional lymph node metastasis from cutaneous squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1998;124:582-7. 180. Halder RM, Bridgeman-Shah S. Skin cancer in African Americans. Cancer 1995;75(Suppl 2):667-73. 181. Halder RM, Bang KM. Skin cancer in blacks in the United States. Dermatol Clin 1988;6:397-405. 182. Bernstein S, Lim K, Brodland D, Heidelberg K. The many

Curr Probl Dermatol, May/June 2003

183. 184. 185.

186.

187. 188.

189.

190.

191.

192.

193.

194.

195. 196.

197.

198. 199.

200.

201.

faces of squamous cell carcinoma. Dermatol Surg 1996;22: 243-54. Vandeweyer E, Sales F, Deraemaecker R. Cutaneous verrucous carcinoma. Br J Plast Surg 2001;54:168-70. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol 1994; 30:1-22. Petter G, Haustein UF. Histologic subtyping and malignancy assessment of cutaneous squamous cell carcinoma. Dermatol Surg 2000;26:521-30. Padilla RS, Bailin PL, Howard WR, Dinner MI. Verrucous carcinoma of the skin and its management by Mohs’ surgery. Plast Reconstr Surg 1984;73:442-7. Hahn SB, Kim DJ, Jeon CH. Clinical study of Marjolin’s ulcer. Yonsei Med J 1990;31:234-41. Fleming MD, Hunt JL, Purdue GF, Sandstad J. Marjolin’s ulcer: a review and reevaluation of a difficult problem. J Burn Care Rehabil 1990;11:460-9. Cribier B, Asch P, Grosshans E. Differentiating squamous cell carcinoma from keratoacanthoma using histopathological criteria. Is it possible? A study of 296 cases. Dermatology 1999;199:208-12. Yantsos VA, Conrad N, Zabawski E, Cockerell CJ. Incipient intraepidermal cutaneous squamous cell carcinoma: a proposal for reclassifying and grading solar (actinic) keratoses. Semin Cutan Med Surg 1999;18:3-14. Dinehart SM, Nelson-Adesokan P, Cockerell C, Russell S, Brown R. Metastatic cutaneous squamous cell carcinoma derived from actinic keratosis. Cancer 1997;79:920-3. Guenthner S, Hurwitz R, Buckel L, Gray H. Cutaneous squamous cell carcinomas consistently show histologic evidence of in situ changes: a clinicopathologic correlation. J Am Acad Dermatol 1999;41(3 Pt 1):443-8. Berhane T, Halliday GM, Cooke B, Barnetson RS. Inflammation is associated with progression of actinic keratoses to squamous cell carcinomas in humans. Br J Dermatol 2002; 146:810-5. Rinker M, Fenske N, Scalf L, Glass L. Histologic variants of squamous cell carcinoma of the skin. Cancer Control 2001; 8:354-63. Maguire B, Smith NP. Histopathology of cutaneous squamous cell carcinoma. Clin Dermatol 1995;13:559-68. Lohmann C, Solomon A. Clinicopathologic variants of cutaneous squamous cell carcinoma. Adv Anat Pathol 2001; 8:27-36. Cherpelis BS, Marcusen C, Lang PG. Prognostic factors for metastasis in squamous cell carcinoma of the skin. Dermatol Surg 2002;28:268-73. Cottel WI. Perineural invasion by squamous-cell carcinoma. J Dermatol Surg Oncol 1982;8:589-600. Petter G, Haustein U. Squamous cell carcinoma of the skin: histopathological features and their significance for the clinical outcome. J Eur Acad Dermatol Venereol 1998;11: 37-44. Nappi O, Pettinato G, Wick MR. Adenoid (acantholytic) squamous cell carcinoma of the skin. J Cutan Pathol 1989; 16:114-21. Nappi O, Wick MR, Pettinato G, Ghiselli RW, Swanson PE. Pseudovascular adenoid squamous cell carcinoma of the

Curr Probl Dermatol, May/June 2003

202.

203.

204. 205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215. 216.

217.

218.

skin. A neoplasm that may be mistaken for angiosarcoma. Am J Surg Pathol 1992;16:429-38. Toyama K, Hashimoto-Kumasaka K, Tagami H. Acantholytic squamous cell carcinoma involving the dorsum of the foot of elderly Japanese: clinical and light microscopic observations in five patients. Br J Dermatol 1995;133:141-2. Bayer-Garner I, Sanderson R, Smoller B. Syndecan-1 expression is diminished in acantholytic cutaneous squamous cell carcinoma. J Cutan Pathol 1999;26:386-90. Lee MM, Wick MM. Bowen’s disease. Clin Dermatol 1993;11:43-6. Kao GF, Graham JH, Helwig EB. Carcinoma cuniculatum (verrucous carcinoma of the skin): a clinicopathologic study of 46 cases with ultrastructural observations. Cancer 1982; 49:2395-403. Beham A, Regauer S, Soyer H, Beham-Schmid C. Keratoacanthoma: a clinically distinct variant of well differentiated squamous cell carcinoma. Adv Anat Pathol 1998;5: 269-80. Godbolt AM, Sullivan JJ, Weedon D. Keratoacanthoma with perineural invasion: a report of 40 cases. Australas J Dermatol 2001;42:168-71. Sanchez Yus E, Simon P, Requena L, Ambrojo P, de Eusebio E. Solitary keratoacanthoma: a self-healing proliferation that frequently becomes malignant. Am J Dermatopathol 2000; 22:305-10. Krunic AL, Garrod DR, Smith NP, Orchard GS, Cvijetic OB. Differential expression of desmosomal glycoproteins in keratoacanthoma and squamous cell carcinoma of the skin: an immunohistochemical aid to diagnosis. Acta Derm Venereol 1996;76:394-8. Krunic AL, Garrod DR, Madani S, Buchanan MD, Clark RE. Immunohistochemical staining for desmogleins 1 and 2 in keratinocytic neoplasms with squamous phenotype: actinic keratosis, keratoacanthoma and squamous cell carcinoma of the skin. Br J Cancer 1998;77:1275-9. Sleater JP, Beers BB, Stephens CA, Hendricks JB. Keratoacanthoma: a deficient squamous cell carcinoma? Study of bcl-2 expression. J Cutan Pathol 1994;21:514-9. Morgan MB, Lima-Maribona J, Miller RA, Kilpatrick T, Tannenbaum M. Pigmented squamous cell carcinoma of the skin: morphologic and immunohistochemical study of five cases. J Cutan Pathol 2000;27:381-6. Kuo T. Clear cell carcinoma of the skin. A variant of the squamous cell carcinoma that simulates sebaceous carcinoma. Am J Surg Pathol 1980;4:573-83. Landman G, Taylor RM, Friedman KJ. Cutaneous papillary squamous cell carcinoma. A report of two cases. J Cutan Pathol 1990;17:105-10. Cramer SF, Heggeness LM. Signet-ring squamous cell carcinoma. Am J Clin Pathol 1989;91:488-91. McKinley E, Valles R, Bang R, Bocklage T. Signet-ring squamous cell carcinoma: a case report. J Cutan Pathol 1998;25:176-81. Jurado I, Saez A, Luelmo J, Diaz J, Mendez I, Rey M. Pigmented squamous cell carcinoma of the skin: report of two cases and review of the literature. Am J Dermatopathol 1998;20:578-81. Breuninger H, Schaumburg-Lever G, Holzschuh J, Horny

127

219.

220.

221.

222.

223.

224.

225.

226. 227. 228.

229.

230.

231.

232.

233.

234. 235.

128

HP. Desmoplastic squamous cell carcinoma of skin and vermilion surface: a highly malignant subtype of skin cancer. Cancer 1997;79:915-9. Cerroni L, Kerl H. Primary cutaneous neuroendocrine (Merkel cell) carcinoma in association with squamous- and basal-cell carcinoma. Am J Dermatopathol 1997;19:610-3. Iacocca M, Abernethy J, Stefanato C, Allan A, Bhawan J. Mixed Merkel cell carcinoma and squamous cell carcinoma of the skin. J Am Acad Dermatol 1998;39(5 Pt 2):882-7. Heintz P, White C. Diagnosis: atypical fibroxanthoma or not? Evaluating spindle cell malignancies on sun damaged skin: a practical approach. Semin Cutan Med Surg 1999;18:78-83. Smith KJ, Skelton HG III, Morgan AM, Barrett TL, Lupton GP. Spindle cell neoplasms coexpressing cytokeratin and vimentin (metaplastic squamous cell carcinoma). J Cutan Pathol 1992;19:286-93. Gray Y, Robidoux HJ, Farrell DS, Robinson-Bostom L. Squamous cell carcinoma detected by high-molecular-weight cytokeratin immunostaining mimicking atypical fibroxanthoma. Arch Pathol Lab Med 2001;125:799-802. Rowe D, Carroll R, Day CJ. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection [see comments]. J Am Acad Dermatol 1992;26:976-90. Friedman HI, Cooper PH, Wanebo HJ. Prognostic and therapeutic use of microstaging of cutaneous squamous cell carcinoma of the trunk and extremities. Cancer 1985;56: 1099-105. Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin Pathol 1990;94:624-7. Frierson HF Jr, Cooper PH. Prognostic factors in squamous cell carcinoma of the lower lip. Hum Pathol 1986;17:346-54. Griffiths RW, Feeley K, Suvarna SK. Audit of clinical and histological prognostic factors in primary invasive squamous cell carcinoma of the skin: assessment in a minimum 5 year follow-up study after conventional excisional surgery. Br J Plast Surg 2002;55:287-92. Goepfert H, Dichtel WJ, Medina JE, Lindberg RD, Luna MD. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am J Surg 1984;148:542-7. Czarnecki D, Staples M, Mar A, Giles G, Meehan C. Metastases from squamous cell carcinoma of the skin in southern Australia. Dermatology 1994;189:52-4. Jackson A. Prevention, early detection and team management of skin cancer in primary care: contribution to The health of the nation objectives. Br J Gen Pract 1995;45(391):97-101. Tavin E, Persky M. Metastatic cutaneous squamous cell carcinoma of the head and neck region. Laryngoscope 1996;106(2 Pt 1):156-8. Joseph MG, Zulueta WP, Kennedy PJ. Squamous cell carcinoma of the skin of the trunk and limbs: the incidence of metastases and their outcome. Aust N Z J Surg 1992;62:697701. Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol 1997;36:650-3. Fitzpatrick PJ, Harwood AA. Acute epithelioma: an aggressive squamous cell carcinoma of the skin. Am J Clin Oncol 1985;8:468-71.

236. Guidelines of care for cutaneous squamous cell carcinoma. Committee on Guidelines of Care. Task Force on Cutaneous Squamous Cell Carcinoma. J Am Acad Dermatol 1993;28: 628-31. 237. Brodland DG, Zitelli JA. Mechanisms of metastasis. J Am Acad Dermatol 1992;27:1-8. 238. Novick M, Gard DA, Hardy SB, Spira M. Burn scar carcinoma: a review and analysis of 46 cases. J Trauma 1977;17:809-17. 239. Lawrence N, Cottel WI. Squamous cell carcinoma of skin with perineural invasion. J Am Acad Dermatol 1994;31:30-3. 240. Di Gregorio C, Gebbia V, Florena AM, Franco V, Moschella F. Perineural infiltration by cutaneous squamous cell carcinomas of the head and neck. Anticancer Res 1995;15:110715. 241. Mohs F. Modes of spread of cancer of the skin. Arch Dermatol 1952;66:427-39. 242. Byers RM, O’Brien J, Waxler J. The therapeutic and prognostic implications of nerve invasion in cancer of the lower lip. Int J Radiat Oncol Biol Phys 1978;4:215-7. 243. Conte CC, Ergin MT, Ricci A Jr, Deckers PJ. Clinical and pathologic prognostic variables in oropharyngeal squamous cell carcinoma. Am J Surg 1989;157:582-4. 244. Larsen DL. Perineural lymphatics: myth or fact? Am J Surg 1966;11:488-92. 245. Barrett TL, Greenway HT Jr, Massullo V, Carlson C. Treatment of basal cell carcinoma and squamous cell carcinoma with perineural invasion. Adv Dermatol 1993;8:277305. 246. Dodd GD, Dolan PA, Ballantyne AJ, Ibanez ML, Chau P. The dissemination of tumors of the head and neck via the cranial nerves. Radiol Clin North Am 1970;8:445-61. 247. Hanke CW, Wolf RL, Hochman SA, O’Brian JJ. Chemosurgical reports: perineural spread of basal-cell carcinoma. J Dermatol Surg Oncol 1983;9:742-7. 248. Diaz-Cascajo C. Multiple recurrences of cutaneous carcinomas as a consequence of local tumor spread along nerves of traumatic neuroma. Am J Surg Pathol 2002;26:814-6. 249. McGregor IA. Cancer of the face and mouth. New York: Churchill Livingstone; 1986. p. 102. 250. Kumar PP, Patil AA, Ogren FP, Johansson SL, Reeves MA. Intracranial skip metastasis from parotid and facial skin tumors: mechanism, diagnosis, and treatment. J Natl Med Assoc 1993;85:369-74. 251. Ballantyne AJ. The extension of cancer of the head and neck through peripheral nerves. Am J Surg 1963;106:651-67. 252. Hayat G, Ehsan T, Selhorst JB, Manepali A. Magnetic resonance evidence of perineural metastasis. J Neuroimaging 1995;5:122-5. 253. Smith JB, Bishop VL, Francis IC, Kos S, Kneale KA. Ophthalmic manifestations of perineural spread of facial skin malignancy. Aust N Z J Ophthalmol 1990;18:197-205. 254. Carlson KC, Roenigk RK. Know your anatomy: perineural involvement of basal and squamous cell carcinoma on the face. J Dermatol Surg Oncol 1990;16:827-33. 255. Clouston PD, Sharpe DM, Corbett AJ, Kos S, Kennedy PJ. Perineural spread of cutaneous head and neck cancer. Its orbital and central neurologic complications. Arch Neurol 1990;47:73-7.

Curr Probl Dermatol, May/June 2003

256. Carter RL, Foster CS, Dinsdale EA, Pittam MR. Perineural spread by squamous carcinomas of the head and neck: a morphological study using antiaxonal and antimyelin monoclonal antibodies. J Clin Pathol 1983;36:269-75. 257. Mendenhall WM, Parsons JT, Mendenhall NP, Brant TA, Stringer SP, Cassisi NJ, et al. Carcinoma of the skin of the head and neck with perineural invasion. Head Neck 1989; 11:301-8. 258. Mendenhall WM, Amdur RJ, Williams LS, Mancuso AA, Stringer SP, Price Mendenhall N. Carcinoma of the skin of the head and neck with perineural invasion. Head Neck 2002;24:78-83. 259. Banerjee TK, Gottschalk PG. Unusual manifestations of multiple cranial nerve palsies and mandibular metastasis in a patient with squamous cell carcinoma of the lip. Cancer 1984;53:346-8. 260. Anderson C, Krutchkoff D, Ludwig M. Carcinoma of the lower lip with perineural extension to the middle cranial fossa. Oral Surg Oral Med Oral Pathol 1990;69:614-8. 261. Weimar VM, Ceilley RI, Babin RW. Squamous-cell carcinoma with invasion of the facial nerve and underlying bone and muscle: report of a case. J Dermatol Surg Oncol 1979;5:526-30. 262. McNab A, Francis I, Benger R, Crompton J. Perineural spread of cutaneous squamous cell carcinoma via the orbit. Clinical features and outcome in 21 cases. Ophthalmology 1997;104:1457-62. 263. Penn I, First MR. Merkel’s cell carcinoma in organ recipients: report of 41 cases. Transplantation 1999;68:171721. 264. Veness MJ, Quinn DI, Ong CS, Keogh AM, Macdonald PS, Cooper SG, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer 1999;85:1758-64. 265. Adamson R, Obispo E, Dychter S, Dembitsky W, MorenoCabral R, Jaski B, et al. High incidence and clinical course of aggressive skin cancer in heart transplant patients: a singlecenter study. Transplant Proc 1998;30:1124-6. 266. Pollard JD, Hanasono MM, Mikulec AA, Le QT, Terris DJ. Head and neck cancer in cardiothoracic transplant recipients. Laryngoscope 2000;110:1257-61. 267. Glover MT, Niranjan N, Kwan JT, Leigh IM. Non-melanoma skin cancer in renal transplant recipients: the extent of the problem and a strategy for management. Br J Plast Surg 1994;47:86-9. 268. Khurana VG, Mentis DH, O’Brien CJ, Hurst TL, Stevens GN, Packham NA. Parotid and neck metastases from cutaneous squamous cell carcinoma of the head and neck. Am J Surg 1995;170:446-50. 269. Gmyrek R, Beer R, Elizeri Y, Oster MW, Silvers DN, Schneiderman P, et al. Invasive squamous cell carcinoma with sporotrichoid metastasis in a patient with cutaneous T cell lymphoma treated with chronic extracorporeal photopheresis. Cutis 1999;64:261-4. 270. Shafqat A, Viehman GE, Myers SA. Cutaneous squamous cell carcinoma with zosteriform metastasis in a transplant recipient. J Am Acad Dermatol 1997;37:1008-9. 271. Eroglu A, Berberoglu U, Berreroglu S. Risk factors related to

Curr Probl Dermatol, May/June 2003

272.

273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

283.

284.

285.

286. 287. 288.

locoregional recurrence in squamous cell carcinoma of the skin. J Surg Oncol 1996;61:124-30. Bosch R, Gallardo M, Ruiz dPG, Snchez P, Arce M, Herrera E. Squamous cell carcinoma secondary to recessive dystrophic epidermolysis bullosa: report of eight tumours in four patients. J Eur Acad Dermatol Venereol 1999;13:198-204. Swensson O, Christophers E. Generalized atrophic benign epidermolysis bullosa in 2 siblings complicated by multiple squamous cell carcinomas. Arch Dermatol 1998;134:199203. Ampil FL, Hardin JC, Peskind SP, Stucker FJ. Perineural invasion in skin cancer of the head and neck: a review of nine cases. J Oral Maxillofac Surg 1995;53:34-8. McCord MW, Mendenhall WM, Parsons JT, Amdur RJ, Stringer SP, Cassisi NJ, et al. Skin cancer of the head and neck with clinical perineural invasion. Int J Radiat Oncol Biol Phys 2000;47:89-93. Frankel D, Hanusa B, Zitelli J. New primary nonmelanoma skin cancer in patients with a history of squamous cell carcinoma of the skin. Implications and recommendations for follow-up. J Am Acad Dermatol 1992;26(5 Pt 1):720-6. Wassberg C, Thorn M, Yuen J, Ringborg U, Hakulinen T. Second primary cancers in patients with squamous cell carcinoma of the skin: a population-based study in Sweden. Int J Cancer 1999;80:511-5. Karagas MR, Stukel TA, Greenberg ER, Baron JA, Mott LA, Stern RS. Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. Skin Cancer Prevention Study Group. JAMA 1992;267:3305-10. Hacker S, Flowers F. Squamous cell carcinoma of the skin. Will heightened awareness of risk factors slow its increase? Postgrad Med 1993;93:115-121 125-6. Dzubow LM, Rigel DS, Robins P. Risk factors for local recurrence of primary cutaneous squamous cell carcinomas. Treatment by microscopically controlled excision. Arch Dermatol 1982;118:900-2. Cowen E, Billingsley E. Awareness of skin cancer by kidney transplant patients. J Am Acad Dermatol 1999;40(5 Pt 1):697-701. Hemminki K, Dong C. Subsequent cancers after in situ and invasive squamous cell carcinoma of the skin. Arch Dermatol 2000;136:647-51. Jaeger AB, Gramkow A, Hjalgrim H, Melbye M, Frisch M. Bowen disease and risk of subsequent malignant neoplasms: a population-based cohort study of 1147 patients. Arch Dermatol 1999;135:790-3. van der Tol IG, de Visscher JG, Jovanovic A, van der Waal I. Risk of second primary cancer following treatment of squamous cell carcinoma of the lower lip. Oral Oncol 1999;35:571-4. Fleming ID, Amonette R, Monaghan T, Fleming MD. Principles of management of basal and squamous cell carcinoma of the skin. Cancer 1995;75(Suppl 2):699-704. Geisse JK. Comparison of treatment modalities for squamous cell carcinoma. Clin Dermatol 1995;13:621-6. Nguyen TH, Ho DQ. Nonmelanoma skin cancer. Curr Treat Options Oncol 2002;3:193-203. Carac 0.5% Fluorouracil cream. Package insert. 2002. Manu-

129

289. 290.

291.

292.

293. 294.

295. 296.

297.

298.

299.

300.

301.

302.

303.

304.

305.

306.

130

factured for Dermik Laboratories, Inc, Berwyn (PA). Manufactured by Pharmaceutical Manufactureing Research Services, Inc, Horsham (PA): Aventis. Solaraze 3% Diclofenac sodium gel. Package insert. 2002. Bioglan Pharma, Inc. Orengo I, Rosen T, Guill CK. Treatment of squamous cell carcinoma in situ of the penis with 5% imiquimod cream: a case report. J Am Acad Dermatol 2002;47(Suppl 4):S225-8. Pehoushek J, Smith KJ. Imiquimod and 5% fluorouracil therapy for anal and perianal squamous cell carcinoma in situ in an HIV-1-positive man. Arch Dermatol 2001;137:14-6. Smith KJ, Germain M, Yeager J, Skelton H. Topical 5% imiquimod for the therapy of actinic cheilitis. J Am Acad Dermatol 2002;47:497-501. Kurwa HA, Barlow RJ. The role of photodynamic therapy in dermatology. Clin Exp Dermatol 1999;24:143-8. Zeitouni NC, Shieh S, Oseroff AR. Laser and photodynamic therapy in the management of cutaneous malignancies. Clin Dermatol 2001;19:328-38. Fritsch C, Goerz G, Ruzicka T. Photodynamic therapy in dermatology. Arch Dermatol 1998;134:207-14. Cappugi P, Campolmi P, Mavilia L, Prignano F, Rossi R. Topical 5-aminolevulinic acid and photodynamic therapy in dermatology: a minireview. J Chemother 2001;13:494-502. Heinritz H, Benzel W, Sroka R, Iro H. Photodynamic therapy of superficial skin tumors following local application of delta-aminolaevulinic acid. Adv Otorhinolaryngol 1995;49: 48-52. Karrer S, Szeimies RM, Hohenleutner U, Landthaler M. Role of lasers and photodynamic therapy in the treatment of cutaneous malignancy. Am J Clin Dermatol 2001;2:229-37. Calzavara-Pinton PG. Repetitive photodynamic therapy with topical delta-aminolaevulinic acid as an appropriate approach to the routine treatment of superficial non-melanoma skin tumours. J Photochem Photobiol B 1995;29:53-7. Morton CA, Whitehurst C, Moseley H, Moore JV, Mackie RM. Development of an alternative light source to lasers for photodynamic therapy. 1. Clinical evaluation in the treatment of pre-malignant non-melanoma skin cancer. Lasers Med Sci 1995;10:165-71. Fijan S, Honigsmann H, Ortel B. Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine. Br J Dermatol 1995;133:282-8. Szeimies RM, Karrer S, Sauerwald A, Landthaler M. Photodynamic therapy with topical application of 5-aminolevulinic acid in the treatment of actinic keratoses: an initial clinical study. Dermatology 1996;192:246-51. Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa H, et al. Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol 2002;146:552-67. Jeffes EW, McCullough JL, Weinstein GD, Fergin PE, Nelson JS, Shull TF, et al. Photodynamic therapy of actinic keratosis with topical 5-aminolevulinic acid. A pilot doseranging study. Arch Dermatol 1997;133:727-32. Itoh Y, Ninomiya Y, Henta T, Tajima S, Ishibashi A. Topical delta-aminolevulinic acid-based photodynamic therapy for Japanese actinic keratoses. J Dermatol 2000;27:513-8. Fink-Puches R, Hofer A, Smolle J, Kerl H, Wolf P. Primary

307.

308.

309.

310. 311. 312.

313. 314. 315. 316.

317.

318.

319.

320.

321.

322. 323.

324. 325. 326.

clinical response and long-term follow-up of solar keratoses treated with topically applied 5-aminolevulinic acid and irradiation by different wave bands of light. J Photochem Photobiol B 1997;41:145-51. Morton CA, Whitehurst C, Moseley H, McColl JH, Moore JV, Mackie RM. Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen’s disease. Br J Dermatol 1996;135:766-71. Kurwa HA, Yong-Gee SA, Seed PT, Markey AC, Barlow RJ. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 1999;41(3 Pt 1):414-8. Jeffes EW, McCullough JL, Weinstein GD, Kaplan R, Glazer SD, Taylor JR. Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light. J Am Acad Dermatol 2001;45:96-104. Cox NH. Bowen’s disease: where now with therapeutic trials? Br J Dermatol 2000;143:699-700. Whelan CS, Deckers PJ. Electrocoagulation for skin cancer: an old oncologic tool revisited. Cancer 1981;47:2280-7. Chernosky ME. Squamous cell and basal cell carcinomas: preliminary study of 3,817 primary skin cancers. South Med J 1978;71:802-3 806. Honeycutt WM, Jansen GT. Treatment of squamous cell carcinoma of the skin. Arch Dermatol 1973;108:670-2. Sheridan AT, Dawber RP. Curettage, electrosurgery and skin cancer. Australas J Dermatol 2000;41:19-30. Freeman RG, Knox JM, Heaton CL. The treatment of skin cancer. Cancer 1964;17:535-8. Roenigk RK, Roenigk HH Jr. Current surgical management of skin cancer in dermatology. J Dermatol Surg Oncol 1990;16:136-51. Knox JM, Lyles TW, Shapiro EM, Martin RD. Curettage and electrodesiccation in the treatment of skin cancer. Arch Dermatol 1960;1960:197-204. Williamson GS, Jackson R. Treatment of squamous cell carcinoma of the skin by electrodesiccation and curettage. Can Med Assoc J 1964;90:408-13. Bone RC. Evaluation and treatment of metastatic head and neck squamous cancer of cutaneous origin. Adv Dermatol 1993;8:265-276. Grekin RC, Salmon PJM. Surgical management of local disease. In: Miller SJ, Maloney ME, editors. Cutaneous oncology: pathophysiology, diagnosis, and management. Malden (MA): Blackwell Science; 1998:p.506-17. Chiller K, Passaro D, McCalmont T, Vin-Christian K. Efficacy of curettage before excision in clearing surgical margins of nonmelanoma skin cancer. Arch Dermatol 2000; 136:1327-32. Reymann F. Treatment of basal cell carcinoma of the skin with curettage. Arch Dermatol 1971;103:623-7. Reymann F. 15 years’ experience with treatment of basal cell carcinomas of the skin with curettage. Acta Derm Venereol 1985;1985:56-9. Reymann F. Multiple basal cell carcinomas of the skin. Treatment with curettage. Arch Dermatol 1975;111:877-9. McDaniel WE. Surgical therapy for basal cell epitheliomas by curettage only. Arch Dermatol 1978;114:1491-2. Thestrup-Pedersen K, Ravnborg L, Reymann F. [Is skin

Curr Probl Dermatol, May/June 2003

327. 328.

329.

330. 331.

332.

333.

334.

335.

336.

337.

338.

339.

340. 341.

342.

343.

344.

cancer a marker of internal cancer?]. Ugeskr Laeger 1988; 150:161-2. August PJ. Cryotherapy of nonmelanoma skin cancer. Clin Dermatol 1995;13:589-92. Graham G, Clark L. Statistical analysis in cryosurgery of skin cancer. In: EW Breitbart, E Dachow-Siwiec, editors. Clinics in dermatology: advances in cryosurgery. New York: Elsevier; 1990:p.101-7. Ball SB, Dawber RP. Treatment of cutaneous Bowen’s disease with particular emphasis on the problem of lower leg lesions. Australas J Dermatol 1998;39:63-70. Abide JM, Nahai F, Bennett RG. The meaning of surgical margins. Plast Reconstr Surg 1984;73:492-7. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;27(2 Pt 1):241-8. Gross G, Roussaki A, Schopf E, De Villiers EM, Papendick U. Successful treatment of condylomata acuminata and bowenoid papulosis with subcutaneous injections of lowdose recombinant interferon-alpha. Arch Dermatol 1986; 122:749-50. Edwards L, Berman B, Rapini RP, Whiting DA, Tyring S, Greenway HT Jr, et al. Treatment of cutaneous squamous cell carcinomas by intralesional interferon alfa-2b therapy. Arch Dermatol 1992;128:1486-9. Ikic D, Padovan I, Pipic N, Knezevic M, Djakovic N, Rode B, et al. Treatment of squamous cell carcinoma with interferon. Int J Dermatol 1991;30:58-61. Blanchet-Bardon C, Puissant A, Lutzner M, Orth G, Nutini MT, Guesry P. Interferon treatment of skin cancer in patients with epidermodysplasia verruciformis. Lancet 1981;1(8214): 274. Jiang SB, Levine VJ, Nehal KS, Baldassano M, Kamino H, Ashinoff RA. Er: YAG laser for the treatment of actinic keratoses. Dermatol Surg 2000;26:437-40. Cleary RK, Schaldenbrand JD, Fowler JJ, Schuler JM, Lampman RM. Treatment options for perianal Bowen’s disease: survery of American Society of Colon and Rectal Surgeons Members. Am Surg 2000;66:686-8. Humphreys TR, Malhotra R, Scharf MJ, Marcus SM, Starkus L, Calegari K. Treatment of superficial basal cell carcinoma and squamous cell carcinoma in situ with a high-energy pulsed carbon dioxide laser. Arch Dermatol 1998;134:124752. Gordon KB, Garden JM, Robinson JK. Bowen’s disease of the distal digit. Outcome of treatment with carbon dioxide laser vaporization. Dermatol Surg 1996;22:723-8. Tantikun N. Treatment of Bowen’s disease of the digit with carbon dioxide laser. J Am Acad Dermatol 2000;43:1080-3. Benedetto AV, Griffin TD, Benedetto EA, Humeniuk HM. Dermabrasion: therapy and prophylaxis of the photoaged face. J Am Acad Dermatol 1992;27:439-47. Ocampo-Candiani J, Silva-Siwady G, Fernandez-Gutierrez L, Field LM. Dermabrasion in xeroderma pigmentosum. Dermatol Surg 1996;22:575-7. Landthaler M, Haina D, Brunner R, Waidelich W, BraunFalco O. Laser therapy of bowenoid papulosis and Bowen’s disease. J Dermatol Surg Oncol 1986;12:1253-7. Hiruma M, Kawada A. Hyperthermic treatment of Bowen’s

Curr Probl Dermatol, May/June 2003

345.

346.

347. 348. 349.

350.

351.

352. 353.

354. 355.

356.

357.

358.

359. 360. 361. 362.

363.

364.

disease with disposable chemical pocket warmers: a report of 8 cases. J Am Acad Dermatol 2000;43:1070-5. Andrews JM. Extensive malignancies of facial skin treated by perfusion with 5-fluorouracil and conservative excision. Br J Plast Surg 1979;32:253-7. Raaf JH, Krown SE, Pinsky CM, Cunningham-Rundles W, Safai B, Oettgen HF. Treatment of Bowen’s disease with topical dinitrochlorobenzene and 5-fluorouracil. Cancer 1976;37:1633-42. Urosevic M, Dummer R. Immunotherapy for nonmelanoma skin cancer: does it have a future? Cancer 2002;94:477-85. Cook J, Zitelli JA. Mohs micrographic surgery: a cost analysis. J Am Acad Dermatol 1998;39(5 Pt 1):698-703. Cox NH, Dyson P. Wound healing on the lower leg after radiotherapy or cryotherapy of Bowen’s disease and other malignant skin lesions. Br J Dermatol 1995;133:60-5. Holmkvist KA, Roenigk RK. Squamous cell carcinoma of the lip treated with Mohs micrographic surgery: outcome at 5 years. J Am Acad Dermatol 1998;38(6 Pt 1):960-6. Robins P, Dzubow LM, Rigel DS. Squamous-cell carcinoma treated by Mohs’ surgery: an experience with 414 cases in a period of 15 years. J Dermatol Surg Oncol 1981;7:800-1. Leslie DF, Greenway HT. Mohs micrographic surgery for skin cancer. Australas J Dermatol 1991;32:159-64. Turner RJ, Leonard N, Malcolm AJ, Lawrence CM, Dahl MG. A retrospective study of outcome of Mohs’ micrographic surgery for cutaneous squamous cell carcinoma using formalin fixed sections. Br J Dermatol 2000;142: 752-7. Vuyk HD, Lohuis PJ. Mohs micrographic surgery for facial skin cancer. Clin Otolaryngol 2001;26:265-73. Nelson BR, Railan D, Cohen S. Mohs’ micrographic surgery for nonmelanoma skin cancers. Clin Plast Surg 1997;24:70518. Miller PK, Roenigk RK, Brodland DG, Randle HW. Cutaneous micrographic surgery: Mohs procedure. Mayo Clin Proc 1992;67:971-80. Lim JK, Stewart MM, Pennington DG. Microscopically controlled excision of skin cancer. Med J Aust 1992;156: 486-8. Lambert DR, Siegle RJ. Skin cancer: a review with consideration of treatment options including Mohs micrographic surgery. Ohio Med 1990;86:745-7. Hruza GJ. Mohs micrographic surgery. Otolaryngol Clin North Am 1990;23:845-64. Ongenae K, Van De Kerckhove M, Naeyaert JM. Bowen’s disease of the nail. Dermatology 2002;204:348-50. Goldminz D, Bennett RG. Mohs micrographic surgery of the nail unit. J Dermatol Surg Oncol 1992;18:721-6. Tamir G, Murakami C, Berg D. Mohs’ surgery as an approach to treatment of multiple skin cancer in rhinophyma. J Cutan Med Surg 1999;3:169-71. Moritz DL, Lynch WS. Extensive Bowen’s disease of the penile shaft treated with fresh tissue Mohs micrographic surgery in two separate operations. J Dermatol Surg Oncol 1991;17:374-8. Leal-Khouri S, Hruza GJ. Squamous cell carcinoma developing within lichen planus of the penis. Treatment with

131

365.

366.

367.

368.

369.

370.

371.

372.

373.

374.

375.

376.

377.

378.

379. 380.

381.

132

Mohs micrographic surgery. J Dermatol Surg Oncol 1994; 20:272-6. MacFarlane DF, Pustelny BL, Goldberg LH. An assessment of the suitability of Mohs micrographic surgery in patients aged 90 years and older. Dermatol Surg 1997;23:389-393. LeVasseur JG, Kennard CD, Finley EM, Muse RK. Dermatologic electrosurgery in patients with implantable cardioverter-defibrillators and pacemakers. Dermatol Surg 1998; 24:233-40. Mondragon RM, Barrett TL. Current concepts: the use of immunoperoxidase techniques in mohs micrographic surgery. J Am Acad Dermatol 2000;43(1 Pt 1):66-71. Aghassi D, Anderson RR, Gonzalez S. Confocal laser microscopic imaging of actinic keratoses in vivo: a preliminary report. J Am Acad Dermatol 2000;43(1 Pt 1):42-8. Kolenik SA III, Leffell DJ. The use of cryopreserved human skin allografts in wound healing following Mohs surgery. Dermatol Surg 1995;21:615-20. Kirsner RS, Garland LD. Squamous cell carcinoma arising from chronic osteomyelitis treated by Mohs micrographic surgery. J Dermatol Surg Oncol 1994;20:141-3. Chang A, Spencer JM, Kirsner RS. Squamous cell carcinoma arising from a nonhealing wound and osteomyelitis treated with Mohs micrographic surgery: a case study. Ostomy Wound Manage 1998;44:26-30. Kirsner RS, Spencer J, Falanga V, Garland LE, Kerdel FA. Squamous cell carcinoma arising in osteomyelitis and chronic wounds. Treatment with Mohs micrographic surgery vs amputation. Dermatol Surg 1996;22:1015-8. Shiu MH, Chu F, Fortner JG. Treatment of regionally advanced epidermoid carcinoma of the extremity and trunk. Surg Gynecol Obstet 1980;150:558-62. Geohas J, Roholt NS, Robinson JK. Adjuvant radiotherapy after excision of cutaneous squamous cell carcinoma. J Am Acad Dermatol 1994;30:633-6. Weisberg NK, Bertagnolli MM, Becker DS. Combined sentinel lymphadenectomy and mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol 2000;43:483-8. Robbins KT, editor. Pocket guide to neck dissection classification and TNM staging of head and neck cancer. 1991. Head and Neck Surgery Foundation, Inc; Otolaryngology American Academy. Bocca E, Pignataro O, Sasaki CT. Functional neck dissection. A description of operative technique. Arch Otolaryngol 1980;106:524-7. Lingeman RE, Helmus C, Stephens R, Ulm J. Neck dissection: radical or conservative. Ann Otol Rhinol Laryngol 1977;86(6 Pt 1):737-44. Medina JE. A rational classification of neck dissections. Otolaryngol Head Neck Surg 1989;100:169-76. Rudoltz MS, Perkins RS, Luthmann RW, Fracke TD, Green TM, Eaglstein NF, et. al. High-dose-rate brachytherapy with a custom-surface mold to treat recurrent squamous cell carcinomas of the skin of the forearm. J Am Acad Dermatol 1998;38(6 Pt 1):1003-5. Solan MJ, Brady LW, Binnick SA, Fitzpatrick PJ. Skin. In: Perez C, Brady LW, editors. Principles and practice of

382.

383.

384.

385.

386.

387.

388.

389.

390. 391. 392.

393.

394.

395.

396.

397. 398. 399.

radiation oncology, 3rd ed. Philadelphia: Lippincott-Raven; 1998:p.723-44. Khan FM. Brachytherapy. In: Khan FM, editor. The physics of radiation therapy, 2nd ed. Baltimore: Williams and Wilkins; 1994:p.418-73. Denic S. Preoperative treatment of advanced skin carcinoma with cisplatin and bleomycin. Am J Clin Oncol 1999;22: 32-4. Lippman SM, Kalvakolanu DV, Lotan R. Retinoids and interferons in non-melanoma skin cancer. J Investig Dermatol Symp Proc 1996;1:219-22. Merimsky O, Neudorfer M, Spitzer E, Chaitchik S. Salvage cisplatin and adriamycin for advanced or recurrent basal or squamous cell carcinoma of the face. Anticancer Drugs 1992;3:481-4. van den Brekel MW, Castelijns JA, Croll GA, Stel HV, Valk J, van der Waal I, et al. Magnetic resonance imaging vs palpation of cervical lymph node metastasis. Arch Otolaryngol Head Neck Surg 1991;117:663-73. Otley CC. Organization of a specialty clinic to optimize the care of organ transplant recipients at risk for skin cancer. Dermatol Surg 2000;26:709-12. Bavinck JN, Tieben LM, Van der Woude FJ, Tegzess AM, Hermans J, ter Schegget J, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995;13:1933-8. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol 1999;140:656-60. Peterka ES. An association between Bowen’s disease and cancer. Arch Dermatol 1961;84:625-8. Cox NH. Body site distribution of Bowen’s disease. Br J Dermatol 1994;130:714-6. Ahmed I, Berth-Jones J, Charles-Holmes S, O’Callaghan CJ, Ilchyshyn A. Comparison of cryotherapy with curettage in the treatment of Bowen’s disease: a prospective study. Br J Dermatol 2000;143:759-66. Miller SJ. The National Comprehensive Cancer Network (NCCN) guidelines of care for nonmelanoma skin cancers. Dermatol Surg 2000;26:289-92. Motley R, Kersey P, Lawrence C. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Dermatol 2002;146: 18-25. Friedman NR. Prognostic factors for local recurrence, metastases, and survival rates in squamous cell carcinoma of the skin, ear, and lip. J Am Acad Dermatol 1993;28(2 Pt 1):281-2. Afzelius LE, Gunnarsson M, Nordgren H. Guidelines for prophylactic radical lymph node dissection in cases of carcinoma of the external ear. Head Neck Surg 1980;2:361-5. Screening for skin cancer: recommendations and rationale. Am J Prev Med 2001;20(3 Suppl):44-6. Wolfe JT. The role of screening in the management of skin cancer. Curr Opin Oncol 1999;11:123-8. Muglia JJ, Pesce K, McDonald CJ. Skin cancer screening: a growing need. Surg Oncol Clin North Am 1999;8:735-45 viii.

Curr Probl Dermatol, May/June 2003

400. Helfand M, Mahon SM, Eden KB, Frame PS, Orleans CT. Screening for skin cancer. Am J Prev Med 2001;20(Suppl 3):47-58. 401. Polster AM, Lasek RJ, Quinn LM, Chren MM. Reports by patients and dermatologists of skin cancer preventive services provided in dermatology offices. Arch Dermatol 1998; 134:1095-8. 402. Demetrius RW, Randle HW. High-risk nonmelanoma skin cancers. Dermatol Surg 1998;24:1272-94. 403. Koh HK, Geller AC, Miller DR, Lew RA. Can screening for melanoma and skin cancer save lives? Dermatol Clin 1991; 9:795-803. 404. Robinson JK, Rigel DS, Amonette RA. What promotes skin self-examination? J Am Acad Dermatol 1998;38(5 Pt 1):752-7. 405. Feldman SR, Fleischer AB Jr. Skin examinations and skin cancer prevention counseling by US physicians: a long way to go. J Am Acad Dermatol 2000;43(2 Pt 1):234-7. 406. Green A, Williams G, Neale R, Hart V, Leslie D, Parsons P, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999;354(9180):723-9. 407. Ley RD, Reeve VE. Chemoprevention of ultraviolet radiation-induced skin cancer. Environ Health Perspect 1997; 105(Suppl 4):981-4. 408. Naylor MF, Farmer KC. The case for sunscreens. A review of their use in preventing actinic damage and neoplasia. Arch Dermatol 1997;133:1146-54. 409. Mahroos M, Yaar M, Phillips T, Bhawan J, Gilchrest B. Effect of sunscreen application on UV-induced thymine dimers. Arch Dermatol 2002;138:1480-5. 410. Baron JA, Greenberg ER. Prevention of nonmelanoma skin cancer. Arch Dermatol 2000;136:245-6. 411. van Poppel G, Goldbohm RA. Epidemiologic evidence for beta-carotene and cancer prevention. Am J Clin Nutr 1995; 62(6 Suppl):1393S-402S. 412. Bendich A. Biological functions of dietary carotenoids. Ann N Y Acad Sci 1993;691:61-7. 413. Frieling UM, Schaumberg DA, Kupper TS, Muntwyler J,

Curr Probl Dermatol, May/June 2003

414. 415. 416. 417. 418. 419.

420.

421.

422.

423.

424.

Hennekens CH. A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physician’s health study. Arch Dermatol 2000; 136:179-84. Bickers DR, Athar M. Novel approaches to chemoprevention of skin cancer. J Dermatol 2000;27:691-5. Lamberg L. Diet may affect skin cancer prevention. JAMA 1998;279:1427-8. Bollag W, Holdener EE. Retinoids in cancer prevention and therapy. Ann Oncol 1992;3:513-26. de Palo G, Formelli F. Risks and benefits of retinoids in the chemoprevention of cancer. Drug Saf 1995;13:245-56. Odom R. Managing actinic keratoses with retinoids. J Am Acad Dermatol 1998;39(2 Pt 3):S74-8. Rook AH, Jaworsky C, Nguyen T, Grossman RA, Wolfe JT, Witmer WK, et al. Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation 1995; 59:714-9. Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1988;318: 1633-7. Kraemer KH, DiGiovanna JJ, Peck GL. Chemoprevention of skin cancer in xeroderma pigmentosum. J Dermatol 1992; 19:715-8. Orengo IF, Gerguis J, Phillips R, Guevara A, Lewis AT, Black HS. Celecoxib, a cyclooxygenase 2 inhibitor as a potential chemopreventive to UV-induced skin cancer: a study in the hairless mouse model. Arch Dermatol 2002;138: 751-5. Pentland AP, Schoggins JW, Scott GA, Khan KN, Han R. Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition. Carcinogenesis 1999;20:193944. Pentland AP. Cyclooxygenase inhibitors for skin cancer prevention: are they beneficial enough? Arch Dermatol 2002;138:823-4.

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