HIV and Skin Cancer

Dermatol Clin 24 (2006) 521–530

HIV and Skin Cancer Kord S. Honda, MD Division of Dermatology, Box 356524, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA

AIDS produces profound alterations in normal immunity. In addition to opportunistic infections, HIV infection predisposes patients to a range of neoplastic disorders. Fortunately, highly active antiretroviral therapy (HAART) has mitigated the prognosis of this disease by reducing opportunistic infections. A similar substantial effect of HAART on the development of non–AIDS-defining cancers has yet to be established clearly. Impaired cellular immunity permits new tumor formation as evidenced by the solidorgan transplant literature. The weakened cellular immune system of HIV-infected patients resembles in some ways the iatrogenic immunosuppression in solid-organ transplant recipients. Although numerous studies clearly establish an exaggerated risk of squamous cell carcinoma (SCC) among solid-organ transplant recipients, fewer studies have evaluated the risk of skin cancer in HIV, and most show a modest increase in nonmelanoma skin cancer among HIV-infected individuals. This article briefly summarizes what is known about skin cancer in the solid-organ transplant population and reviews how the immunodysregulation of HIV infection compares with the iatrogenic immunosuppression following solid-organ transplantation. The article then focuses on the literature exploring the association of HIV and skin cancer and concludes with an assessment of skin cancer treatment modalities for HIV-infected patients.

This article was supported by a grant from the National Institutes of Health. E-mail address: [email protected]

Skin cancers in organ transplant recipients With an estimated 1 million new cases in the United States each year, the incidence of skin cancer surpasses that of any other cancer. In immunocompetent individuals, basal cell carcinoma (BCC) accounts for the majority of these cancers, with a 3:1 ratio of incidence compared with squamous cell carcinoma (SCC). Despite this higher incidence, BCC generally causes less morbidity and mortality than SCC. An increasing incidence of these tumors, collectively called ‘‘nonmelanoma skin cancer,’’ currently accompanies an earlier onset. Many fewer patients develop melanoma (an estimated 59,580 cases in the United States in 2004), but its incidence continues to increase without a reduction in mortality. Despite its lower representation, the mortality from melanoma surpasses the combined mortality of nonmelanoma skin cancers [1]. The incidence of all skin cancers increases with age and cumulative sun exposure and disproportionately affects individuals who have lighter skin types. In addition to the impact of sun exposure, immune regulation plays a significant role in the containment and development of skin cancers. Clinical evidence supports the theory that patients who have altered immune systems acquire skin cancers more frequently than persons who have normal immunity. Skin cancers behave more aggressively and occur with a much higher incidence in patients who have iatrogenically suppressed cellular immune systems after solid-organ transplantation [2–7]. Other natural and iatrogenic immunodeficient states also may predispose patients to increased risk of skin cancer, albeit to a much lesser degree. One study has shown that cyclosporine, especially when coadministered with psoralen-ultraviolet A

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for psoriasis, multiplies the risk of squamous cell carcinoma sevenfold above the risk associated with psoralen-ultraviolet A alone [8]. Cyclosporine alone modestly increases the risk of nonmelanoma skin cancer when used in the treatment of psoriasis [9]. Three studies have linked prolonged use of prednisone with an increased risk of nonmelanoma skin cancer with a hazard ratio of 2 [10–12]. Finally, the immunosuppressive effect of certain medical diseases, rather than their treatments, also may influence skin cancer rates. Small studies have shown that chronic lymphocytic leukemia may predispose patients to nonmelanoma skin cancer and recurrence following Mohs micrographic surgery [13–18]. The magnitude of skin cancer rates among solid-organ transplant recipients dwarfs that of any other immunosuppressive state reported to date, however. Although the incidence of melanoma, Merkel cell carcinoma, Kaposi’s sarcoma, BCC, SCC, and non-Hodgkin’s lymphoma are all increased in solid-organ transplant recipients [2–4,19,20], SCC carries the highest risk of occurrence in these patients, with a relative risk of 20 to 50 compared with immunocompetent patients [2–5]. This relative risk of SCC contrasts sharply with that of other cutaneous cancers, for which the relative risks generally are less than 10. The percentage of patients developing SCC increases with time: by 5 years after transplantation, 29.1% of patients have had an SCC; at 20 years, that number increases to 82.1% [3]. This increased risk inverts the normal ratio of BCC to SCC found in immunocompetent patients [3,5,21]. These SCC cause significant morbidity and mortality in transplant recipients [7], with onset at a younger age and more frequent metastases [6]. Clinically, these SCC can be difficult to differentiate from warts and keratoses [22], in part because of the large number of these growths. Investigators have identified specific immunerelated correlates of skin cancer risk in organ transplant recipients. The risk of skin cancer correlates with the level of immunosuppression and inversely with the CD4 lymphocyte count [21,23,24]. One randomized study showed that when the trough cyclosporine dose was titrated to 75 to 125 ng/mL rather than 150 to 250 ng/ mL, fewer kidney transplant recipients developed skin cancers [23]. Renal transplant recipients who developed skin cancers had an average CD4 cell count of 234 to 330 cells/mL, whereas their counterparts who did not develop skin cancer had higher mean CD4 cell counts of 503 to

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543 cells/mL [25,26]. Ceasing the use of immunosuppressant medications can reduce the number of subsequent carcinomas [27]. Clinical studies most frequently implicate azathioprine and the calcineuriun inhibitors cyclosporine and tacrolimus as contributing to carcinogenesis in solid-organ transplant recipients [28]. The potential role of human papilloma virus in tumor formation in transplant recipients [29–34] bolsters the importance of the immune system in cancer prevention. Despite the prominent role of the immune system in the development of these cancers, increased skin cancer afflicts whites almost exclusively [35]. In summary, one learns from the solid-organ transplant experience that SCC occurs commonly in this population and behaves more aggressively; its risk of occurrence correlates with duration and intensity of immunosuppression, older age, and lighter skin type [28].

Overview of skin cancer in HIV-infected patients The well-documented experience of the impact of iatrogenically impaired cellular immunity on the rate and behavior of skin cancer suggests that patients who have AIDS could be expected to have an increased incidence of skin cancers with a more aggressive course. The correlation of skin cancers with HIV infection is less well defined, however. The immunosuppression of HIV undoubtedly predisposes patients to cancer development, with Kaposi’s sarcoma, some lymphomas, and cervical carcinoma classified as AIDS-defining diseases. Other factors specific to HIV may encourage carcinogenesis. HIV-1 Tat protein has antiapoptotic and angiogenic properties in vitro [36–38]. In vitro investigations have shown that the combination of zidovudine and didanosine can induce genetic mutations [39]. Kaposi’s sarcoma is the most common cancer presenting in the skin of HIV-positive individuals [40]. The data on the relative risk of melanoma and nonmelanoma skin cancer in these patients are conflicting, however, and studies note a much smaller relative risk, with maintenance of the normal ratio of BCC to SCC. The immunologic differences between HIVinfected patients and solid-organ transplant recipients may explain these disparate findings. First, the two conditions represent distinctly different mechanisms of immunosuppression. Cyclosporine and azathioprine may promote the development of skin cancer through mechanisms

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supplemental to their immunosuppressive properties. In addition to immunosuppression, investigators demonstrated that cyclosporine inhibits DNA repair in vitro following ultraviolet B irradiation through the loss of p53 expression [41,42]. Azathioprine use might favor carcinogenesis by generating reactive oxygen species and creating genetic mutations [43]. Donor cells have been found in recipients’ skin cancers, suggesting a possible role of donor stem cells in the development of skin cancer in solid-organ transplant recipients [44]. HIV would lack a similar correlate. Second, the relentless progression of HIV’s immunosuppression early in the disease’s history contrasts sharply with the static to decreasing immunosuppression involved in transplantation. The accompanying poor prognosis of AIDS with death from comorbid opportunistic infections early in the disease’s history might have prematurely precluded the development of skin cancers. HIV ravages the immune system: only 12% of patients have a CD4 cell count greater than 500 cells/mL, and half had a CD4 cell count below 200 cells/mL [45]. The median CD4 cell count of solid-organ transplant recipients who developed SCC was 330 cells/mL [46]. In contrast to the 85% of kidney transplant and 70% of heart transplant recipients who survive 5 years [47], only 55% of HIV-infected patients who have CD4 cell counts below 385 cells/mL survive 5 years [46]. Survival of HIV-infected patients has improved with the advent of HAART [48]. This finding may affect future studies in diametrically opposed ways. HAART’s immune reconstitution may restore cancer surveillance, eliminating any potential increased risk. Alternatively, HAART could decrease death from opportunistic infections so that it unmasks the effect of HIV infection on skin cancer. Finally, the demographics of HIV infection differ significantly from that of organ transplant recipients. The baseline lower risk of skin cancer related to skin type and younger age in HIV-infected patients complicates comparison with the general population. African Americans comprise 17% of solid-organ transplant recipients in the United States to date [47], whereas they account for 33% of patients in a larger study of HIV-positive patients [45]. Patients undergoing solid-organ transplants also are older. The median age of individuals undergoing solid-organ transplantation in the United States is between 35 and 49 years; the age group receiving the most transplants is 50 to 64 years, accounting for 33% of patients. In contrast only 11% of patients

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who have HIV are older than 50 years; 54% are 35 to 49 years old, and 34% are 18 to 34 years old. These differences in cumulative sun exposure and baseline risk for UV radiation–induced skin cancers may account for a portion of the discrepancy in skin cancer rates between these two populations.

Nonmelanoma skin cancer in HIV-infected patients Similar risk factors predispose the development of nonmelanoma skin cancer in HIV-infected patients and seronegative individuals. The risk factors include fairer skin, blue eyes, and increased sun exposure [49,50]. Skin cancers comprise the largest group of non–AIDS-defining cancers. Although not specific to skin cancer, risk factors identified for the development of non– AIDS-defining cancers include duration of HIV infection, age greater than 40 years, and a history of opportunistic infection [51]. Despite increased photosensitivity, patients who have HIV have the same minimal erythema dose as seronegative individuals, suggesting that HIV does not lower the phototoxicity threshold [52]. Studies have not clearly linked the status of immunosuppression with the risk of non–AIDS-defining cancer. The use of HAART may protect against non– AIDS-defining cancer [51,53], although another study did not reveal a similar protective benefit [53]. The nadir CD4 cell count has not been correlated with an increased risk of non–AIDS-defining cancer [51]. In contrast to the literature linking human papilloma virus with SCC in solid-organ transplant recipients and with HIV-related cervical and anal carcinoma, the association of human papilloma virus and cutaneous SCC in HIV-infected patients has been reported only rarely [54]. With an incidence second to Kaposi’s sarcoma, studies clearly establish nonmelanoma skin cancer as the most common non–AIDS-defining cancer [40,51]. Most larger database linkage studies group BCC and SCC as nonmelanoma skin cancer and do not report rates differentially. The relative risk of nonmelanoma skin cancer in HIVinfected individuals compared with non–HIV-infected individuals has ranged from 2 to 7 in four studies [51,55–57]. One study, however, did not find an increased relative risk of nonmelanoma skin cancer for HIV-infected patients [58]. Another database inquiry evaluating a range of cancers, including melanoma but not nonmelanoma

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skin cancer, identified a modestly increased risk of lip cancer [59]. Four larger studies specifically evaluating skin cancers in HIV have confirmed that BCC are more common than SCC and were second only to Kaposi’s sarcoma; one study reported an incidence of 1.8% for BCC and 0.23% for SCC over a 3-year period [40,49,51,57]. Only one study has directly compared a cohort of HIV-positive and HIV-negative individuals. This study examined HIV-positive and HIV-negative hemophiliac patients and found a relative risk of 18.3 for BCC in the HIV-infected group [60]. The impact of HIV on the natural history of skin cancer remains unclear. Case reports and case series form the basis of much of the existing knowledge. No large study has defined the prognosis of HIV-infected patients who have skin cancer. The available data suggest that superficial BCC may be the most common skin cancer and that SCC may behave more aggressively. A casecontrol study found that nonmelanoma skin cancers occurred 17 years earlier in HIV-infected patients than in HIV-negative controls [61]. In a larger study of nonmelanoma skin cancer in a military cohort, 11 of 17 BCC were of the superficial type [40]. There were also two pigmented, two nodular, and two metatypical BCC. This finding contrasts with studies that show infiltrating BCC to be more common in immunocompromised patients [62]. There has been only one report of a metastatic BCC in an HIV-infected individual, an extremely uncommon event in the general population [63]. A recurrence rate of 5.4% for BCC followed for longer than 1 year has been reported [49], which compares with 1% to 10% recurrence after standard excision in immunocompetent patients at 5 years and 3% recurrence at 30 months’ follow-up [64–67]. Multiple BCC and SCC in individuals have rarely been reported [68–70]. One study of 10 patients who had 41 SCC found an increased aggressiveness of this tumor, with a 70% recurrence rate following initial treatment and an overall 75% recurrence with 60% metastases. Half of the patients died of metastatic SCC. They also found that tumors were large (4.1 cm in diameter) and deep (7.2 mm thick), and half had perineural spread [68]. CD4 cell count did not affect survival or metastatic rate in this study. Patients who underwent adjuvant radiation in addition to Mohs surgery or wide local excision plus neck dissection had an improved outcome.

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Melanoma in HIV-infected patients The medical literature documents approximately 47 cases of melanoma reported in HIVinfected patients [71–84]. Database studies linking HIV diagnoses with melanoma diagnoses in registries show mixed results. Two such studies have found an increased relative risk of melanoma from 3 to 6 [51,85], but four studies demonstrated no increased risk [59,86–88]. The relative infrequency of melanoma probably significantly affects the power of many of these studies. One case series of three patients found that the stage of melanoma correlated inversely with the CD4 cell count [76], but another report has not corroborated this finding [82]. Eruptive nevi and dysplastic nevi have been reported in HIV-positive patients [89,90], as have multiple melanomas [71,80]. One small case-control study has shown a tendency toward a poorer prognosis for HIVinfected patients who have melanoma, with decreased disease-free and overall survival [82].

Cutaneous lymphoma in HIV-infected patients HIV infection increases the risk of non-Hodgkin’s lymphoma, which remains an AIDS-defining disease that may present in the skin. Case reports constitute most published examples, however [91–105]. The relative risk of cutaneous lymphoma has not been investigated. The lymphopenia of HIV could result in fewer cases of cutaneous lymphoma by decreasing the pool of potential neoplastic cells [102]. Alternatively, the altered immune regulation of HIV infection might allow the development of cutaneous lymphoma. Although mycosis fungoides is the most common lymphoma of the skin in immunocompetent patients [92,94], nonepidermotropic large T-cell cutaneous lymphomas that are mainly CD30-positive and Bcell diffuse cutaneous lymphoma present more frequently than mycosis fungoides in HIVinfected patients [93,94,106–110]. Based on their review of five patients, one group of investigators recommends viewing cases with mycosis fungoides-like histopathology in HIV-infected patients with caution, because these cases may instead represent a reactive inflammatory condition [103]. CD8-positive cutaneous T-cell lymphoma also has been reported [111], as has plasmablastic lymphoma [112]. The potential role of concomitant viral infections with human T-cell leukemia virus II and Epstein-Barr virus has been detailed in one case each [97,113].

HIV AND SKIN CANCER

Upon diagnosis of a cutaneous lymphoma, the provider should evaluate the patient for systemic involvement to determine whether the patient has a systemic lymphoma with cutaneous involvement or a primary cutaneous lymphoma. One series reported that mycosis fungoides could have a more indolent course [92], but another study found that HIV-infected patients who had cutaneous lymphoma had significantly decreased CD4 cell counts and a worse prognosis that was attributable to their immunosuppression rather than their lymphoma [94].

Merkel cell carcinoma in HIV-infected patients One study found six patients who had Merkel cell carcinoma among 309,365 HIV-infected patients, for a relative risk of 13.5 compared with immunocompetent population studies [114]. Case reports constitute all other patients reported to date [115–119].

Management of skin cancer in HIV-infected patients Because case reports and case series provide the data on the aggressiveness of skin cancers in HIV-infected patients [68,82], and because the prognosis of skin cancer in these patients has not been defined adequately, it would seem reasonable to manage these tumors with standard treatment modalities, including Mohs surgery, standard excision with appropriate margins, destruction, and radiation therapy [120]. An extensive search for metastases at the time of initial diagnosis of melanoma has been recommended [120]. Providers should evaluate patients who have cutaneous lymphoma for systemic involvement. Despite concerns about its ability to incite an immune reaction in HIV-positive patients, topical imiquimod, an immune modulator, successfully cleared a BCC in one patient [121]. Because of the potential for more malignant behavior, providers can consider adjuvant radiation therapy, chemotherapy, and sentinel lymph node biopsies in addition to wide local excision or Mohs micrographic surgery for HIV-infected patients who have SCC that are large, deeply invasive, or demonstrate perineurial invasion [68]. Consideration of referral to an oncologist familiar with HIV can be considered [120], and more frequent follow-up may be required.

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Although there has been one report of the clinical remission of metastatic Merkel cell carcinoma with HAART [122], the effect of HAART on anal SCC has been conflicting. Two studies have shown an increased risk of anal SCC in HIV-positive patients receiving HAART [123,124], but another study found no increase in anal SCC in HIV-positive patients receiving HAART [125]. Another study found less anal intraepithelial neoplasia in patients receiving HAART [126]. Any evaluation of the impact of HAART on the incidence of skin cancer must account for potential confounding from immunosuppression. The risk of skin cancer imparted by the advanced immunosuppression of individuals taking HAART may overshadow a protective benefit of HAART, if, indeed, it contains such a benefit. Once HIV-infected patients are diagnosed as having anal carcinoma, two studies have found that HAART may improve survival [127,128]. This experience parallels that of renal transplant recipients who had metastatic SCC and who had resolution of their metastases with adjuvant treatment after cessation of immunosuppression because of graft failure [129]. One may reasonably assume that HIV-infected patients who have aggressive cutaneous neoplasms and who are not currently receiving HAART may benefit from its addition.

Summary The true incidence of skin cancers in HIV is unknown. Studies support a modest increase in the risk of nonmelanoma skin cancer on the order of 2 to 6 times relative risk. Most of these cancers are BCC, with the superficial type being most common. This finding corroborates the findings from the transplant literature that immune function is important in preventing skin cancer. The available data, however, suggest that the relative risk does not approach that of solid-organ transplant recipients. Unlike patients who have received solid-organ transplants, who have a clearly increased risk of many types of skin cancer and especially SCC, an increased risk of SCC has not been shown consistently in the HIV-infected population. Large epidemiologic studies will be required to provide information about the prognosis of skin cancer in HIV-infected patients and the most optimal treatment modalities. Limited studies suggest that SCC may behave more aggressively in this setting. Pending further data,

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one should manage skin cancer in HIV-infected individuals in a similar manner to that in immunocompetent hosts. The discovery of the effect of HAART on the risk of skin cancer should shed further light on the relationship of HIV and skin cancer. Pending these studies, the addition of HAART for HIV-infected patients who have aggressive cutaneous malignancies may improve prognosis.

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