The etiology of cancer posttransplantation is multifactorial. It involves a combination of impaired defense mechanism against viruses, impaired immune surveillance against tumor cells, DNA damage or interference with DNA repair by the immunosuppressive agents, exposure to carcinogenic agents like ultra violet (UV) light, genetic predisposition, and upregulation of cytokines such as TGF-β and vascular endothelial growth factor (VEGF) which may promote tumor progression. Cancers that are related to viral infections, such as non-Hodgkin’s lymphoma, KS, etc. have a particularly increased risk of malignancy [9, 10].

The role of immunosuppressive agents in cancer following transplantation is highlighted by the fact that there is a two to fourfold higher incidence of cancer in patients with heart transplant compared to kidney transplant [11, 12]. This is presumed to be due to the higher level of immunosuppression needed. Similarly, patients who have had pretransplant immunosuppressive therapy have a higher incidence of cancer posttransplant compared to those who have not. Immunosuppressive agents may predispose to malignancy from impairing the ability to eliminate tumor cells. In experimental and animal models, the role of T lymphocytes, natural killer (NK) cells, and cytokines in protection of the host from tumors has been demonstrated [13]. Immunosuppressive agents like azathioprine and cyclosporine sensitize DNA to UV light and predispose to mutations and skin cancers. They can impair DNA repair mechanisms and apoptosis, while at the same time enhancing angiogenesis and tumor growth [14, 15]. In addition, they have been shown to promote clonal proliferation of cells with p53 gene mutations resulting in skin malignancies [16]. Immunosuppressants may also act by impairing antiviral activity, predisposing to infection with oncogenic viruses, and eventual malignant transformation. It has been noted that patients who are naïve to viruses like Epstein–Barr virus (EBV) and human herpes virus (HHV) are more likely to develop malignancies posttransplantation and reduction or withdrawal of immunosuppression often results in regression of the malignancy [17, 18]. These virus associated tumors may be more responsive to reduction in immunosuppression, presumably due to increased recognition of nonself through presentation of viral peptides, compared to chemical and environmental carcinogens [19]. Cytokines such as IL-6, IL-10, and latent membrane protein-1 (LMP-1) have also been implicated in tumor genesis. IL-6 acts as an autocrine and paracrine growth factor. Its production is known to be enhanced by cyclosporine and OKT3. IL-10 prevents antigen presentation, interferes with antitumor cytokine production and cytotoxic T lymphocyte response, and prevents programmed cell death. IL-10 transcripts have been seen in squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) lesions. High-production genotype of IL-10 has been found to be more frequent in these malignancies. Posttransplant lymphoma or posttransplant lymphoproliferative disease (PTLD) , is often related to EBV viral infection of B cells. In such cases, IL-10 production is induced by viral LMP-1 gene, and serves as an autocrine growth pathway. Other factors involved in tumor genesis include VEGF and TGF-β. VEGF is critical in angiogenesis, and necessary for tumor growth, progression, invasion, and metastasis [20]. Dysregulation of TGF-β is known to promote tumor genesis. TGF-β can also promote angiogenesis and lead to metastasis [21]. Cyclosporine is known to induce IL-6 and TGF-β production. Tacrolimus has also been shown to promote TGF-β production [22].

Last, the chronic inflammation and activation of the immune system due to the alloreactivity or viral infection can predispose to tumor genesis. Mechanisms include infiltration with T regulatory cells, immature dendritic cells, expression of negative costimulatory pathways, and production of tumor growth factors [19].

On the contrary, mammalian target of rapamycin (mTOR) inhibitors have been used to treat cancer, and may have a protective effect in transplantation. Rapamycin has been shown to block the growth of tumors, and this has been consistently shown in several clinical studies [23]. Mechanisms include, its ability to reduce TGF-β production [23] and inhibit IL-10 production [24–29].

KS is an angioproliferative disorder, caused by HHV-8. The SIR for this cancer is more than 60, and has one of the greatest increases in incidence compared to all other cancers in transplant patients [7]. KS is three times more likely to occur in transplanted men than women. It is more common in patients of Jewish, Mediterranean, Caribbean, and African origins, and the affected patients are usually in their 40s. This disease is believed to be caused by an infection of the endothelium with HHV-8 [30, 31]. The incidence of KS has been found to be higher among those with preexisting anti-HHV antibodies [32]. Other risk factors for developing KS include the use of calcineurin inhibitors (CNI), induction therapy with rabbit anti-thymocyte globulin, multiple sexual partners, and genetic predisposition [33].

HHV-8 can have a transformative effect on endothelial cells. Most of the cells within the KS lesions reveal latent infection with HHV-8, while a small proportion of cells express lytic cycle genes. Transition to the lytic phase is mediated by several cytokines and growth factors. During the lytic phase, the production of viral gene products leads to replication. The viral genome also harbors several oncogenes which interfere with apoptosis and cell cycle regulation, leading to tumor genesis. There is a noted increase in G protein cellular receptor (GPCR) expression, which causes the cell to enter the replicative stage [36]. Other chemokines and growth factors, such as IL-6, IL-8, CXCR 3,4, and CCR1,5 are implicated in angiogenesis and cell migration [33–36]. HHV-8 encodes K3 and K5 membrane proteins which downregulate major histocompatibility complex (MHC) antigen presentation and help the virus evade the hosts cytotoxic response [37].

Skin involvement is the most common manifestation of KS. It usually appears as red to purple maculopapular or nodular cutaneous lesions. Patients with KS may have lower extremity lymphedema due to dermal lymphatic involvement or dermal infiltration. KS can also involve the viscera such as the gastrointestinal tract, lungs, and lymphoid tissue. Pleural or pulmonary involvement is seen in advanced stages of the disease [33]. Isolated visceral involvement occurs in around 10 % of cases, and portends a poor prognosis [30].

KS is also clinically staged as follows:

The most prudent step in treating KS is to reduce the immunosuppressive therapy to the lowest possible level while maintaining allograft function. This reduction in immunosuppressive therapy restores the anti-HHV T cell response and can lead to resolution of the KS lesions [38]. One strategy which has been very successful is switching to sirolimus-based immunosuppressive regimen. In an Italian study of 15 patients with KS, clinical and histological resolution of skin lesions, while preserving graft function, was achieved by changing immunosuppression to Mammalian target of rapamycin inhibitor-based therapy [39]. Mammalian target of rapamycin inhibitors impair VEGF production, and limit angiogenesis and tumor progression. Additionally, it has been shown that genesis of KS involves stimulation of tuberin phosphorylation by vGPCR and activation of mTOR. This suggests a role for mTOR inhibitors in preventing sarcoma genesis [40, 41].

Localized therapy such has radiation, laser, surgical excision, and topical antivirals have been occasionally reported to be successful [33, 42, 43]. In some cases of KS with visceral involvement, systemic chemotherapy may be required [44]. This is particularly true in patients that have failed to respond to reduction in immunosuppression alone. Paclitaxel and docetaxel have been used successfully, and other agents like pegylated liposomal doxorubicin, vinca-alkaloids, etoposide, gemcitabine, bleomycin, interferon α-2, and thalidomide have also been used [43, 45]. The studies are diverse, lack consistency, and the overall evidence does not allow a recommendation for a specific chemotherapy.

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) account for more than 90 % of all nonmelanoma skin cancers in transplant patients. Cancer registries are not required to report these tumors, but their incidence is known to be significantly increased after solid organ transplantation. Skin cancers are known to develop in more than 50 % of all recipients and account for up to 40 % of all malignancies post-solid organ transplantation [46, 47]. The incidence of SCC can be increased 65–250 times compared to the general population, while that of BCC is increased ten times [48]. These cancers appear to be age dependent and occur sooner in older patients following transplantation [46, 47]. Proposed risk factors for posttransplant skin cancer include geography (Australia has the highest incidence) [49], UV light exposure, and pre- and posttransplant history of actinic keratosis (AK), SCC, or BCC [50, 51]. The risk of nonmelanoma skin cancer has been found to be greater in heart, lung, and combined kidney and pancreas transplants when compared to kidney or liver transplants alone [52]. This may be related to a greater intensity of immunosuppression in specific types of organ transplants [53]. Other risk factors include polymorphisms in the folate pathway [54], and infection with human papilloma virus (HPV) [55].

Direct carcinogenic effects of agents like UV light exposure and immunosuppressants, such as cyclosporine, tacrolimus, and azathioprine, along with impaired tumor surveillance facilitate development of skin cancers. Oncogenic viruses like HPV may impair DNA repair mechanisms while proliferating themselves, and can augment the oncogenic response [56].

The kidney disease improving global outcomes (KDIGO) guidelines recommend that transplant patients have annual skin and lip cancer screening performed by a qualified physician [57]. UV exposure is a major risk factor for development of nonmelanoma-based skin cancers, and the use of sunscreen has been found to reduce the incidence of skin cancer in transplant recipients [58]. Reduction in immunosuppression and use of agents such as the mTOR inhibitor Rapamycin has also been somewhat effective in reducing the incidence and mitigating the aggressiveness of skin cancers [59–61]. Similarly systemic retinoids, like acitretin, have been shown to reduce the incidence of AK and SCC [62].

Below we discuss treatments for the common skin cancers seen in transplant patients.

The risk for cancers of the anogenital region is increased almost 100-fold in the posttransplant period and can account for 2–3 % of all malignancies posttransplant. These include cancers of the anus, vulva, vagina, cervix, penis, and scrotum. They are more frequent in women (2:1) and tend to occur late posttransplant [89]. They are strongly associated with HPV infection, particularly the high-risk subtypes (16 and 18) [90]. Other risk factors include HIV, cigarette smoking, prior HPV related anogenital malignancy , and history of infection with genital herpes. The median age at presentation is in the fifth decade, and they tend to be multiple extensive maculopapular lesions. They may resemble genital warts and can be localized or invasive [89]. For local noninvasive lesions, treatment options include topical fluorouracil, laser, electrocautery, topical imiquimod along with reduction in immunosuppression . For invasive tumors, treatment involves wide excision, lymphadenectomy, and adjuvant chemo and/or radiation therapy [91]. Screening strategies, such as annual gynecological exams including a cervical smear, have been shown to be beneficial and cost effective posttransplantation. Similarly, anal cytology and high-resolution anoscopy may be beneficial in select patients [92–94]. The HPV vaccines are recommended in the female transplant population between the ages of 9–26, although the immune response is not clearly delineated [95].

RCC has a somewhat unique relationship to ESKD and transplantation, as there is not only an increased risk associated with ESKD and transplantation but it can also be a cause of ESKD [7, 8]. When compared to the general population, the SIR of RCC is significantly greater in kidney transplant recipients. However, it is very similar to patients with chronic kidney disease and those on dialysis [7, 8]. RCC is more common in the native kidneys than in the transplanted kidneys. RRC can also rarely be transmitted from the donor kidney. The increased risk of RCC is believed to be due to acquired cystic kidney disease (ACKD), and this is borne out by the fact that the SIR is maximally increased after kidney transplant compared to other organ transplants [7, 96, 98]. Indeed, after lung transplant there is no notable increase in SIR for RCC, and the increase after lung and liver transplant is small [7].

The presence of ACKD is associated with dialysis vintage [99]. Posttransplant RCC is usually incidental in nature. An ultrasound or a computed tomography (CT) scan may reveal a complex cyst or mass. Once a mass is found, biopsies are generally not performed. Staging is completed with a CT scan and a chest X-ray. Screening for RCC after transplantation is controversial. Cytology is not reliable posttransplantation. It is challenging to use iodinated contrast with CT scans, due to its potential deleterious effects on renal function, and gadolinium-based magnetic resonance imaging (MRI) imaging imparts a risk of nephrogenic systemic fibrosis. Ultrasound has been shown in one French study to have good sensitivity and specificity in identifying RCC in the native kidneys posttransplant [100]. The authors recommended obtaining a baseline ultrasound at the time of transplant and repeat ultrasounds after every 3 years. Authors of a more recent German study recommend annual screening in kidney transplant patients regardless of ACKD. They went on to recommend further imaging with a combination of CT and ultrasound based on Bosniak scores. RCC was more likely to occur in patients with Bosniak category 2F or more, accounting for more than 58 % of all cases [97]. Despite these studies, there is no good data that mortality is reduced by screening transplant patients for RCC. The American Society of Transplant Guidelines do not recommend routine screening [101]. However, patients with a higher risk for RCC and those with a longer than average life expectancy, may benefit. This includes young patients with known cystic renal disease, those with prior RCC, and those with a history of analgesic nephropathy or tuberous sclerosis. RCC arising from ACKD have a greater percentage of the papillary type histology although clear cell histology is the most prevalent, and is frequently bilateral in comparison to sporadic RCC [97].

Treatment depends on the extent of the disease and the comorbidities of the patient. Localized lesions are managed with radical nephrectomy. Five year survival in such patients is approximately 80 %. Treatment may be accompanied by changes in immunosuppression, such as conversion of a CNI to an mTOR inhibitor, reduction in CNI or antimetabolite. Tumors in the transplanted kidneys are difficult to treat, due to the fact that there is a need to preserve renal function. For small peripheral tumors (< 4 cm) nephron sparing surgeries such as partial nephrectomy, cryoablation, or radio frequency ablation may be possible. Metastatic disease has been reported, and prognosis is generally poor. Radical nephrectomy with immune therapy using IL-2 and interferon-α have been reported, but are fraught with danger of precipitating rejection. Drugs such as sunitinib, sorafenib, temsirolimus, and everolimus (an mTOR inhibitor) can be used in metastatic disease. The mTOR inhibitors are particularly attractive because of the immunosuppressive properties in addition to the antitumor effects. Choosing the option of no treatment is also a reasonable palliative option in this case, due to the dismal prognosis [102, 103]. A detailed chapter on medical and surgical treatment of RCC is discussed elsewhere in this book.

Bladder and other urinary tract malignancies, including bladder cancer, are increased after transplantation, particularly among patients with exposure to cyclophosphamide, aristolochic acid (Chinese herb), or with a history of analgesic nephropathy [102–104]. The presentation is most commonly painless hematuria. Other presenting features are dysuria, flank pain, and urinary obstruction. Diagnostic tests include imaging of the upper urinary tract with an ultrasound or CT scan, urine cytology, and cystoscopy [102]. Treatment depends on the TNM stage and is similar to transplant naïve patients. Superficial tumors can be managed with transurethral bladder resection. Invasive tumors require more aggressive surgical therapies, including radical cystectomy with creation of an ileal conduit or an ileal neobladder. It must be noted that many of these procedures are more complicated due to the proximity of the kidney transplant graft. Nephroureterectomy is beneficial to prevent recurrent disease, and may be useful in multifocal disease [102, 105]. For patients with a high risk of recurrence, intravesical Bacillus Calmette-Guerin (BCG) or mitomycin is used in the general population. BCG is usually not recommended in a transplant setting, as it is a live attenuated bacteria; however, it has been used with variable success [106]. For metastatic disease, methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) has been used. Other regimes used include cisplatin, methotrexate, vinblastine, or gemcitabine with cisplatin. Traditional immunosuppressive agents like tacrolimus and mycophenolate are usually reduced during chemotherapy [102, 107]. Our standard practice has been to stop the antimetabolite (either mycophenolate or azathioprine) during chemotherapy, although this approach requires careful monitoring for rejection.

In addition to the risk factors above, BK virus (BKV) has been examined as a potential risk factor for urinary tract malignancy. Case reports suggest an association between BKV infection and the development of renal and bladder cancers in renal transplant recipients [108]. In the tumor cells, it is sometimes possible to detect fragments of the BK viral genome that could alter the control mechanisms of the cell cycle and DNA repair. An oncogenic potential of BKV has been observed in vitro and in animal models [109]. In humans, however, the implication of BKV in tumor development is still unclear.

Colon cancer has an increased SIR after kidney transplantation [7]. Often the patients are younger (< 50 years of age), and therefore, do not have screening colonoscopies. Studies from Sweden had reported that in addition to an increased incidence of colorectal cancer, right sided cancers were more common than left sided cancers [110]. Colorectal cancer in the transplant population seems to have a lower mean age of diagnosis (58.7 vs. 72 years) and a reduced 5-year survival (30.7 vs. 63.5 %) [111]. The incidence ratio for transplant patients below 50 years of age compared to the general population of the same age is 3. Median survival is reported to be 2.3 years after diagnosis, with 68 % having metastasis [111]. Reasons for the aggressive course may be related to carcinogenic effects of the immunosuppressive agents. Other genetic factors, geographic factors, as well as premalignant conditions are also believed to have a role in the pathogenesis.Based on current screening guidelines early colon cancer may be missed. Therefore some experts recommend screening colonoscopies beginning 2 years post transplantation, particularly in patients with additional risk factors [111].

The incidence of other solid tumors that have a greater frequency after transplant can be seen in Table 16.1. Risk factors for solid tumors after transplantation are the same as those in non-transplant patients. Most solid tumors are present more frequently after transplantation [7, 8]. In general, screening and treatment guidelines should be the same as for non-transplant patients.

Post transplant lymphoproliferative disease (PTLD) is a significant complication of solid organ transplantation. It includes a spectrum of manifestations, ranging from a benign self limited form to a widely disseminated form [112]. The incidence is particularly high after heart, lung, intestinal, and multiorgan transplant (20–25 %), and is lower following kidney and liver transplantation (1–2 %) [12, 113]. The increase in risk is up to 120 % higher when compared to the general population. Non-Hodgkin’s lymphoma accounts for 70 %, multiple myeloma accounts 14 %, lymphoid leukemia 11 %, and Hodgkin’s lymphoma accounts for 5 % of PTLD [12, 114].

As with other malignancies, immunosuppression is an important risk factor for PTLD. Solid organ transplants that require a greater level of immunosuppression, such as heart, lung, and intestine, have a higher incidence of PTLD (20–25 %). However, specific agents targeting T cells, such as ATG, OKT3, CNI, and recently belatacept, have been found to disproportionately increase risk [115, 116]. Belatacept is especially interesting as rejection episodes are more frequent in belatacept-treated patients, suggesting that PTLD in these patients is not always an effect of net immunosuppression [117, 118]. Besides immunosuppression, EBV infection is another major factor in the development of PTLD. Nearly 50–70 % of all cases of PTLD are associated with EBV infection. This is especially true when the transplant recipient is EBV seronegative. In situations where an EBV seronegative patient receives an organ from an EBV positive donor, the risk of PTLD is increased up to six times [119, 120]. EBV seronegative status is especially problematic when using belatacept. Due to the higher risk of PTLD, especially central nervous system (CNS) PTLD, the use of belatacept is contraindicated in EBV seronegative recipients.

PTLD has been found more likely to occur in patients < 10 years of age and those > 60 years. The older population is at higher risk of malignancy overall, and younger patients may be more likely to be EBV seronegative. There is also emerging data revealing genetic risk factors for developing PTLD. Numerous human leukocyte antigen (HLA) types have been suggested to either predispose to or protect from PTLD . Cytokine gene polymorphisms involving TGF-β, INF-γ, TNF-α, are also reported to have a role in pathogenesis. Caucasian race, pretransplant malignancy , and viral infections such as cytomegalovirus (CMV) and HHV-8 have been proposed as additional risk factors [114, 116, 121, 122].

After EBV infection, a group of latent B cells with downregulated antigen expression arise which escape immune surveillance. These cells, in the presence of waning immunity, can proliferate and lead to lymphoproliferative disease. EBV encoded proteins, such as LMP-1 and LMP-2A, transmit signals that can mediate B cell activation. LMP-1 engages the signaling proteins from the tumor-necrosis-factor receptor-associated factors (traFs) that lead to cell growth and transformation. Proteins like EBNA-2 and EBNA-LP, which are both nuclear proteins, upregulate pro-growth factors such as c-Myc. Together they can transform B cells into immortal lymphoblastoid B cells [123].