The importance of an intact immune system in preventing the formation of de novo malignancies was discussed by Burnett in 1970 [3]. He theorized that immune cells played a crucial role in recognizing “self” and eliminating those cells that escaped homeostatic controls. Histologic correlation of this phenomenon is evident in tumors with infiltrating cytotoxic lymphocytes [4]. This view is further supported by studies of patients with impaired immunity, namely, HIV/AIDS and solid organ transplant recipients (SOTR) on chronic immunosuppression, who have an increased risk of NMSC, – up to 250-fold higher than the general population [5–7]. Understanding the role of a compromised immune system on the development of neoplasms is critical when designing therapeutic strategies aimed at prevention and treatment in this patient population.

Summary: Solid Organ Transplant Recipients

•Solid organ transplant patients are at a higher risk of developing NMSC than the general population. Heart transplant patients are at the highest risk, followed by renal and liver transplant recipients. Some immunosuppressant medications appear to play both an indirect and direct role in promoting carcinogenesis.

Occurring in excess of 1–2 million cases annually in the United States alone, NMSC is by far the most common human malignancy worldwide [9]. While generally considered somewhat indolent neoplasms in most immunocompetent individuals, NMSC in the solid organ transplant patient may have devastating effects [10–12]. Consequences range from frequent painful procedures, such as extensive cryotherapy, to severe disfigurement and disease-associated mortality.

Risk Factors for NMSC in SOTR

•Duration and type of immunosuppression

•History of chronic sun exposure

•Fitzpatrick skin type I–III

•Male sex

•Age at transplantation

•Number of actinic keratoses

•Exposure to human papillomavirus

•CD4 lymphopenia

In addition to the risk factors outlined above, risk

of NMSC appears to vary by transplant type. Renal transplantation, the first to be performed successfully and the most common type of solid organ transplantation occurring today, with greater than 16,000 transplants annually [1], is second only to heart transplant patients in terms of increased NMSC incidence [13]. While it varies by country, the reported incidence of SCC and BCC 20 years post-renal transplant is extraordinarily high: 41% in the Netherlands [14], 48% in the United States [15], 54.4% in New Zealand [16], and 82% in Australia [17]. The majority of these skin can-

The first successful solid organ transplant took place in 1954 between identical twins, but frequent graft rejection and high mortality rates, outside such settings, limited its use [8]. The subsequent introduction of immunosuppressant medications, such as azathioprine and cyclosporine, substantially improved graft survival and ushered in the era of modern transplantation. New combinations of immunosuppressants and the use of targeted therapies have resulted in ever improving survival and a paradigm shift from traditional causes of mortality in this patient population (surgical complications, rejection, and acute infection) to long-term causes (diabetes, cardiovascular disease, chronic infection, and malignancies including NMSC.)

of 3:1 to basal cell carcinoma [16], opposite of the observed frequency of 1:4 typically seen in immunocompetent individuals.

Heart transplantation, which first took place in 1967 [7], has the highest risk of NMSC. Historically cardiac transplantation has been associated with an increased risk of graft rejection compared with other organs which is theorized to result from an inherent increased immunogenicity of the myocardium. As a result, patients are usually placed on higher immunosuppression doses than other SOTR which has led to the inference that the higher cumulative immunosuppressive dose may play a role in promoting NMSC [13]. This is further supported by studies of liver transplant patients, typically the least immunosuppressed of all SOTR due

to a lower risk of graft rejection, who have the lowest rate of NMSC. Several studies appear to support the notion that total amount of immunosuppression, rather than the type, is the most important determinant of future NMSC development [7, 18, 19].

Lung transplantation is much less commonly performed, with only 1,660 performed in 2009 [1], and the overall risk of NMSC is less well characterized in this subset of patients. Incidence appears to be most similar to renal transplant patients with approximately 0.7–6.4% of all patients studied developing SCC within 1 year of lung transplant and a similar ratio of SCC to BCC as in other SOTR of 4:1 [20–22]. The use of voriconazole in this patient population is a unique exposure not generally seen in other transplant recipients. Utilized as a prophylactic antifungal medication to prevent respiratory fungal infections, voriconazole is known to increase risk of photosensitivity [23]. Its use has been identified as an independent risk factor for SCC development in lung transplant patients [20]

and may be related to the enhanced UV sensitivity which has previously been identified as a risk factor for SCC development.

In addition to voriconazole, multiple immunosuppressant medications have been proposed as playing a role in promoting NMSC. Cyclosporine A has been shown to directly increase the invasive potential of murine model cells by promoting increased TGF-B levels and inducing phenotypic alterations, independent of direct immunosuppression [24]. Whether this effect holds true in SOTR is less clear. A study comparing types of immunosuppression demonstrated that azathioprine had the highest risk of cutaneous carcinogenesis in a mouse model, followed by cyclophosphamide, cyclosporine, and lastly prednisolone [25]. Due to confounding variables it is difficult to quantify the exact role varying immunosuppressive regimens play in promoting NMSC but a general estimation of effect based on the available literature is shown in Table 9.1. A notable exception to immunosuppressant agent