Recipient HLA type has been suggested as a possible risk factor for NMSC in OTRs. Several theories on how HLA type may play a role in increasing the risk of NMSC exist. Studies investigating HLA types and the risk of NMSC in OTR have been done with conflicting results [67]. Two of the largest studies have found HLA-A11 to increase post-transplant risk of NMSC [67, 68]. Of these two studies, one was able to successfully identify a subset of Caucasian renal transplant recipients in a northern climate who were at increased risk at both short and long-term follow up after transplantation. This increased risk associated with HLA-A11 is only conferred in patients with lighter, sun-sensitive skin [67]. This study suggests a role for more aggressive monitoring in patients with HLA-A11 type. There are recurring findings in different studies showing HLA- DR1, HLA- DR4 and HLA- B27 and their association with non-melanoma skin cancer, but no definitive conclusions have been reached [69]. Further studies need to be conducted to confirm these findings and perhaps identify other HLA types which may have significance to OTRs and their risk of NMSC.

Management of OTR as a dermatologist is challenging due to the chronic immunosuppression and progressively increasing risk of NMSC. The American Society of Transplantation (AST) recommends that patients perform monthly skin self-examinations and have their skin examined by a physician annually [70]. A survey that weighed the advantages and disadvantages of various clinical settings of OTR concluded that regardless of the clinical design, certain principles are key to providing the best care [71]. The survey stressed the importance of: close communication with the transplant team, education of other care providers regarding OTRs’ unique dermatologic concerns, patient education as a key to prevention, and close follow-up determined by the risk of skin cancer.

The International Transplant-Skin Cancer Collaborative (ITSCC) has combined data from many studies to develop useful clinical guidelines for the treatment of skin cancer in OTR [72]. Patients should be followed according to their individual risk factors. For low-risk individuals with no history of skin cancer, a yearly follow-up is recommended. For higher-risk individuals with a history of sunburns, fair skin type, or of older age, a 6–12 monthly schedule is advised. If there is any history of NMSCs, AKs or warts, then follow-up should be scheduled at 3–6-month intervals. For both high-risk SCCs and multiple NMSCs, a follow-up should be scheduled for every 3 months. Follow-up can be as frequent as once a month for patients with metastatic SCC [73, 74]. Precancerous lesions such as warts and actinic keratoses should be recognized and treated early to reduce the viral burden and the extent of intraepithelial neoplasia (See Figs. 39.1, 39.2, and 39.3). Treatment of precancerous lesions includes: cryosurgery, topical 5-fluorouracil, topical imiquimod, and electrodesiccation and curettage (ED&C). Photodynamic therapy may be used in OTRs for the treatment of actinic keratoses not responsive to conventional treatments, and superficial NMSC [20]. Topical and systemic retinoids may be used as chemoprevention of skin cancer but are only effective while the retinoid is being used [75, 76]. NSAIDs such as topical diclofenac are being used to treat AKs in those patients that prefer not to use 5-FU [73].

Some emerging treatments include epidermal growth factor (EGFR) inhibitors, ingenol mebutate (IM) and afamelanotide. There is increasing evidence showing amplification and overexpression of EGFR in SCCs. Cetuximab, a monoclonal antibody to the EGFR receptor, has been used primarily in metastatic SCC of the head and neck. Ingenol mebutate (IM) is a new topical medication that has been recently approved by the FDA for treating AKs of the scalp, trunk and extremities. It has the added benefit of requiring fewer applications than 5-fluorouracil, diclofenac and imiquimod. The mechanism of action is not known, but two proposed mechanisms are direct damage to the mitochondrial membrane, leading to rapid cellular necrosis and the release of pro-inflammatory mediators. The other mechanism may involve the maturation of B cells that produce antibodies that lead to neutrophil-mediated, antibody-dependent cellular cytotoxicity. Afamelanotide is a synthetic analog of melanocyte stimulating hormone (α-MSH) that may protect skin from UVB damage [20].

Less aggressive SCC can be managed with destructive modalities such as: ED&C, cryosurgery, Mohs micrographic surgery, or excised with postoperative margin assessment (See Table 39.2).

Aggressive SCCs should be removed completely using excisional techniques including Mohs, excision with intraoperative frozen section control, or excision with postoperative margin assessment. Additional modalities may be useful in some instances. Radiation therapy may be considered as adjunctive therapy or as a primary modality for inoperable tumors (Fig. 39.1). Although not routinely used, small studies are beginning to support the role of sentinel lymph node biopsy (SLNB) in the evaluation of high risk NMSC [77].

Chemoprophylaxis with oral retinoids such as acitretin has been shown to be effective in reducing the rate of development of premalignant and malignant lesions in OTR [76, 78]. This effect is only exhibited while the patient is actively taking the retinoid. After cessation of the drug, the rate of development of lesions returns to baseline or may even exceed the prior rate of development. Retinoids have several side effects which are often very difficult for patients to tolerate on a long-term basis. These side effects include: dry skin, dry lips, significant hair loss, pruritus and arthralgias [76].

Areas of multiple SCC, such as the dorsum of the hand, have been successfully treated with excision and split-thickness skin grafting. Although the grafted area remains lesion-free for an extended period, this procedure has significant morbidity and requires an extensive recovery [79, 80].

In cases of life-threatening skin-cancers, reduction of immunosuppression may be considered. Studies have shown that renal transplant recipients with very aggressive SCC have an improved prognosis following dose reduction compared to those whose immunosuppression was left unchanged [81]. It has also been shown that graft function may continue despite reduction of immunosuppression [82, 83]. It is important when considering reduction of immunosuppressive therapy that it is done in consultation with the transplant physician. If the need to reduce the level of immunosuppression is warranted, transplant physicians often prefer to lower the dose of AZA first as CsA confers better allograft survival [84]. Introducing mTOR inhibitors, or substituting them for a calcineurin inhibitor, may further reduce SCC formation [54].