promotion of NMSC is sirolimus which has been shown, in limited studies, to reduce risk when added to current regimens in renal transplant patients [26].

Summary: HIV/AIDS

•HIV increases the risk of developing NMSC, particularly virally mediated types. HAART therapy may play a role in treating HIV patients with malignancy.

and routine surveillance for HPV associated verrucae performed. Imiquimod has been successfully used to treat HPV and anal intraepithelial neoplasia in these patients and may be used prior to excision of SCC for cosmetically sensitive areas. Excision with or without MMS, depending on histologic subtype, site, and size, are the mainstays of treatment for SCC/BCC. Melanoma tends to follow a more aggressive course in HIV infected patients and immune reconstitution should be considered as adjuvant therapy [33]. Surgical margins will vary based on Breslow depth and the use of sentinel lymph node biopsy should be considered in tumors >1 mm.

9.3HIV/AIDS

Human immunodeficiency affects approximately 1 million people in the United States and is caused by a DNA retrovirus that primarily replicates in CD4+ T helper cells leading to substantial immunocompromise as lymphopenia develops [27]. Patients may ultimately develop Acquired Immunodeficiency Syndrome (AIDS) and have a threeto fivefold increased risk of NMSC [28]. Virally associated neoplasms, including Kaposi Sarcoma (KS) and human papillomavirus (HPV) associated cancers, are particularly prevalent in this population [29]. HPV dysplasia and subsequent development of SCC has been established in cervical, anal, genital, and oropharyngeal lesions. These NMSC tend to present at more advanced stages, be higher grade, and lead to shortened overall survival compared to immunocompetent hosts [29, 30]. Unlike SOTR, the ratio of SCC to BCC in HIV/AIDS patients parallels that seen in the general population at 1:7 with similar risk factors including: fair skin, age, and chronic sun exposure [31]. HIV/AIDS patients also have an increased risk of melanoma (SIR = 1.3), MCC (SIR = 11) and sebaceous carcinoma (SIR = 8.1) [32].

In recent years enormous progress has been made in the treatment of this disease, and like organ transplant recipients, patients are experiencing substantial improvement in overall survival. The advent of highly active antiretroviral therapy (HAART) has resulted in a decreased incidence of KS and melanoma in this population [28]. Treatment recommendations for NMSC and melanoma in the HIV/AIDS population parallel the general population with an emphasis on increased prevention of virally mediated cancers. HAART should be considered for all eligible patients

Summary: Cutaneous Neoplasms

•The most common malignancies in transplant patients are squamous cell carcinomas, followed by basal cell carcinomas. Merkel cell carcinoma, Kaposi sarcoma, and melanoma occur more commonly in the immunosuppressed population.

9.4Cutaneous Neoplasms

9.4.1Actinic Keratoses and Squamous Cell Carcinoma

Actinic keratoses are widespread in the general population with a prevalence of 11–26% and are present in roughly half of all heart/renal transplant patients [34, 35]. They occur on chronically sun exposed skin and share many of the histological features of SCC in situ. Risks for developing AKs parallel those for SCC with skin type, long term UVB exposure, advanced age, and immunosuppression all conferring added risk. While the exact relationship between actinic keratoses and development of squamous cell skin cancer remains controversial, studies have shown a rate of transformation in immunocompetent individuals of approximately 0.1– 0.6% per year [36, 37]. Actinic keratoses are a marker of excessive sun damage and the risk of developing SCC in SOTRs increases with higher numbers of keratotic lesions.

Due to the high risk SCC poses in this patient population prevention is increasingly being recommended

[35, 38]. Limited numbers of AKs may be treated by cryotherapy or curettage but extensive actinic damage should receive field treatments. The options available include topical fluorouracil, photodynamic therapy (PDT), imiquimod, and topical diclofenac. Topical fluorouracil and PDT are the most commonly described modalities and appear to confer a benefit in clearing actinic keratoses. Imiquimod is less well characterized in this population due to the theoretical risk of enhanced immunogenicity from activation of toll like receptor 7 but has been safely used for treating actinic keratosis in OTRs and at least one study looked closely at safety parameters [39]. Guidelines support the role of proactive field treatments in patients with extensive AKs to reduce the risk of SCC [35]. Oral retinoids have also been used in select OTR with promising results [40].

Squamous cell carcinomas (SCC) are the second most common neoplasm in the United States, with an annual incidence of at least 200,000, but are the most common malignancy in SOTR [41]. They occur most commonly on sun exposed areas, including the head and neck. SCC is 65 times more common in organ transplant patients than the general population, with increased risk conferred by cardiac transplantation and increasing number of immunosuppressant medications [7]. High risk SCC accounts for the vast majority of the 8,000 nodal metastases and 3,000 annual deaths attributed to SCC [42, 43].

SCCs in SOTR tend to behave more aggressively, with increased rates of growth, local recurrence, and metastases. Immunosuppressed patients have a 13% risk of metastatic disease compared to 6% for the general population [42]. In one case series of SOTR, 15% of patients who developed SCCs died from metastatic disease within 10 years of diagnosis [16]. The 3-year survival rate is only 48% once regional metastases occur, and distant metastases confer a 1-year survival of only 39% [45].

Other high risk clinical features include tumors greater than 2 cm in diameter and invasion of subcutaneous fat, fascia, muscle, or bone [46]. Histologically, poorly differentiated disease has a 33% risk of metastasis [42]. Tumors in SOTR are more likely to demonstrate increased proliferation rates and perineural invasion. In patients who have involvement of nerves greater than 0.1 mm in size there is a 32% risk of disease specific death [47]. Lip and ear involvement also occurs more frequently in this population and has a higher frequency of metastasis [42].

All patients with SCC should receive regional lymph node exam, and any enlarged nodes evaluated histologically [41]. Lymphadenectomy is preferred for lymph node positive disease with radiotherapy appearing to confer an additional survival benefit when appropriate [48]. Controlled studies regarding the role of radiological imaging and sentinel lymph node examination have not been performed to date for cutaneous SCC.

Low-risk SCC can be managed with standard surgical excision with 4-mm margins in tumors less than 2 cm in size producing cure in 95% of cases. Shave excision plus electrodessication and curettage has also been shown to be effective for low-risk SCC. Features of low-risk SCC are outlined in Fig. 9.1. If patients have clinically or histologically high-risk SCC based on criteria in Fig. 9.1, they should be treated with excision of at least 6-mm margins with histopathological clear margins or, preferably, Mohs micrographic surgery. If perineural invasion remains, deep structures such as bone are involved, or if clearance cannot be obtained, then adjuvant therapy should be considered. Imaging studies to assess for extension and localized radiation should be considered. Reducing immunosuppression levels should also be discussed with the patient’s transplant team and, if feasible, has been shown to decrease new SCC formation and improve outcomes [49].

9.4.2Basal Cell Carcinoma

Basal cell carcinomas are the second most common neoplasm in SOTR and occur at a rate up to ten times higher than the general population. Histologically, they are indistinguishable from those found in immunocompetent patients and tend to follow a similarly indolent course [50]. Risk factors for their development include pretransplant NMSC, duration of immunosuppression, and increasing age of recipient.

There are no standardized recommendations regarding treatment of BCC in the SOTR. While increased surveillance is suggested due to elevated risk in this population, the type of treatment modality chosen will parallel that seen in the general population. Histologic subtype, tumor size, and tumor location are the primary considerations when choosing a therapy. Superficial BCCs may be treated with a wide variety of methods based on patient/physician preference

Size:

*Low risk

<0.6 cm - face (excluding cheeks, forehead, neck and scalp), ears, genitals, hands and feet

<1.0 cm - cheeks, forehead, neck and scalp

<2.0 cm - trunk and extremities

**High risk

>0.6 cm - face (excluding cheeks, forehead, neck and scalp), ears, genitals, hands and feet

>1.0 cm - cheeks, forehead, neck and scalp

including: electrodessication and curettage, cryotherapy, topical chemotherapeutic agents (5-fluorouracil), topical immunomodulators (imiquimod), and photodynamic therapy [51–53]. Infiltrative and nodular basal cell carcinomas are more likely to require surgical excision, with or without micrographic margin control, for complete and sustained clearance. Cosmetically sensitive locations, such as the face, and embryonic fusion planes should generally be managed with Mohs micrographic surgery for best cosmetic outcome and lowest recurrence risk.

9.4.3Melanoma

The incidence of melanoma is increasing at a faster rate than any other cancer in the United States with over 44,200 cases documented annually [8, 54]. Lifetime risk of developing a melanoma is now estimated at 1 in 63 [54]. Studies comparing risk of melanoma in immunocompetent patients to SOTR have yielded conflicting results, with some studies demonstrating a greater than 3.5–8-fold increased risk in renal transplant patients and others showing no appreciable increase [4, 55]. Further studies are needed to clarify risks and prognostic factors for SOTR.

Risk of melanoma recurrence after transplantation is also not well characterized. One study showed 6 of 31 patients who were in remission for an average of 2 years prior to transplant developed a recurrence, and all 6 died from metastatic melanoma [56]. Melanoma may also rarely be transmitted through transplantation itself and is associated with exceedingly poor outcomes [57].

There are no formal guidelines dictating management of melanoma in the SOTR, but similar outcomes to immunocompetent controls have been reported for thin melanoma (<1 mm) when utilizing standard therapeutic practices, with excision as the mainstay of treatment. Wide local excision should be performed with surgical margins dependent on Breslow depth. A sentinel lymph node biopsy should be considered in patients with tumors >1 mm in Breslow depth, but data regarding impact on outcome and overall survival are lacking in the SOTR. The International Transplant Skin Cancer Collaborative (ITSCC) and the Skin Care in Organ Transplant Patients Europe (SCOPE) have recently published guidelines advising decreasing immunosuppressive regimen as an adjuvant management strategy.

Data is limited on the impact of this approach, but it should be considered in all patients with stage IV melanoma.

9.4.4Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer primarily occurring in the elderly and immunosuppressed. HIV/AIDS patients and SOTR have a greater than 13-fold increased risk of developing MCC compared to the general population. The mean age of those affected is 70 years old with a male predominance. In one study, MCC developed an average of 91 months after transplantation, with over 70% of patients developing metastases and 50% dying from their disease [58]. The recent discovery of a novel polyomavirus, Merkel cell polyomavirus, in 70–80% of MCC cases has begun to shed light on the possible etiology of this rare tumor [59].

There is no formal consensus on the treatment of MCC in the immunosuppressed patients, but given the aggressive nature of this tumor, wide local excision is the preferred initial treatment modality. If this is not feasible, due to anatomic location, the use of Mohs micrographic surgery may be considered. In the immunocompetent patient, MMS has been used successfully with high cure rates [60]. Sentinel lymph node biopsy has been proposed as a useful staging tool and prognostic indicator [61]. Adjuvant radiation with 3–5-cm margins should be considered after tumor removal and some centers consider radiation to the draining lymph node basin. Clinically apparent lymph node involvement and disseminated disease may require further surgical intervention, radiation therapy, or chemotherapy. All patients should have routine follow-up and close monitoring.

9.4.5Kaposi Sarcoma

Kaposi sarcoma is a rare endothelial tumor caused by human herpesvirus 8 (HHV-8) that is primarily seen in immunosuppressed patients. Homosexual men with acquired immunodeficiency syndrome are disproportionately affected, and increased rates of lymphopenia directly correlate with disease severity. Incidence of the disease in SOTR directly correlates with the prevalence of the disease and HHV-8 infection. In patients