Malignancy Following Renal Transplantation

After transplantation, there is an increase in the incidence of a wide variety of malignancies compared to the general population, due to the chronic use of immunosuppressive agents. They appear to have a more aggressive behavior and a worse outcome. As a result, among recipients of renal transplantation, malignancy is the third most common cause of patient death with graft function, after cardiovascular diseases and infections. Since management and outcomes of the cardiovascular and infectious complications are improving, malignancy after transplantation will probably become more important (Briggs, 2001). In this chapter, we will focus on the increased cancer incidence in solid organ transplant recipients, in order to emphasize the clinical importance of this topic in renal transplant patients. Since skin cancer and post-transplantation lymphoproliferative disorder PTLD are most strikingly increased after renal transplantation, we will study them in detail. There is some evidence that individual immunosuppressive agents have a different role in the development of post-transplantation malignancy. The available data on this will be discussed. Finally, based on the currently available international guidelines, we will propose an appropriate prevention and early detection program for patients undergoing renal transplantation.


Introduction
After transplantation, there is an increase in the incidence of a wide variety of malignancies compared to the general population, due to the chronic use of immunosuppressive agents. They appear to have a more aggressive behavior and a worse outcome. As a result, among recipients of renal transplantation, malignancy is the third most common cause of patient death with graft function, after cardiovascular diseases and infections. Since management and outcomes of the cardiovascular and infectious complications are improving, malignancy after transplantation will probably become more important (Briggs, 2001). In this chapter, we will focus on the increased cancer incidence in solid organ transplant recipients, in order to emphasize the clinical importance of this topic in renal transplant patients. Since skin cancer and post-transplantation lymphoproliferative disorder PTLD are most strikingly increased after renal transplantation, we will study them in detail. There is some evidence that individual immunosuppressive agents have a different role in the development of post-transplantation malignancy. The available data on this will be discussed. Finally, based on the currently available international guidelines, we will propose an appropriate prevention and early detection program for patients undergoing renal transplantation.

Epidemiology and risk factors
Cancer risk is a major problem after renal transplantation. There is much data on the incidence of cancer after renal transplantation, mostly derived from large transplant registries. One of the largest is an American report (by the United States Renal Data System USRDS) on more than 35,000 patients who received a first renal transplantation (deceased or living donor). The incidence of malignancies during the first 3 years after transplantation was examined compared with the general US population. Three years after transplantation, a cumulative incidence of 7.5% for non-skin malignancy and 7.4% for skin cancer (excluding melanoma) was noted. Compared to the general population, there was especially an important increase in the incidence of Kaposi's sarcoma, non-Hodgkin's lymphoma and nonmelanoma skin cancers (more than 20-fold) and kidney cancer (approximately 15-fold). By contrast, the more common solid cancers in the general population (e. g. breast, lung, prostate, colorectal, uterine and ovarian cancer) were only slightly increased in incidence in transplant recipients (roughly twofold higher). Since cancer appears to be more common among haemodialysis patients (because of the correlation between uremia and abnormalities in the immune system), an additional comparison between the population of

Skin cancer
Skin cancer is the most common cancer type following renal transplantation in Caucasian transplant recipients, occurring in more than 50% of patients in high incidence areas (such as Australia) after 20 years of renal transplantation. The incidence increases with the duration of immunosuppressive therapy. They occur at younger age (10 to 15 years younger than in the general population) and in multiple sites. Moreover, they are more aggressive and more likely to recur after resection. For that reason, they can cause serious morbidity and may have a life-threatening course. As in the immunocompetent population, sun exposure (UV radiation, causing genetic mutations in epidermal keratinocytes that affect cell cycle regulation) is the major risk factor of developing skin cancer. In transplant patients, an additional important risk factor is the duration and intensity of immunosuppression. For that reason, skin cancer is 2 to 3 times more common after heart transplantation (requiring higher levels of immunosuppression), compared to kidney transplantation. It has been suggested that certain immunosuppressive medications (like azathioprine AZA and cyclosporine CsA) are associated with greater risk of skin cancer due to photosensitizing and mutagenic effects and that others (like mTOR inhibitors) may have antiproliferative effects (Kovach & Stasko, 2009). We will discuss this in detail in below (see '5. Immunosuppressive drugs and the risk of malignancy after transplantation').

Types of skin cancer
Skin cancer includes squamous cell carcinoma SCC, basal cell carcinoma BCC, malignant melanomas, Merkel cell carcinoma and Kaposi's sarcoma. In contrast to the general population, there is a predominance of SCC over BCC in renal transplant recipients, with a ratio of SCC to BCC of 4:1.

Squamous cell carcinoma SCC
Squamous cell carcinoma SCC arises from atypical keratinocytes of the epidermis. It occurs most commonly in sun exposed areas and is usually associated with precursor lesions like actinic keratoses, Bowen's disease (SCC in situ), viral warts and/or keratoacanthomas. The risk of SCC is 60 to 100 times greater than in the general population. The lesions appear as small red, keratotic, hard nodules that occasionally ulcerate. The pathogenesis is multifactorial, with cumulative sun exposure as most important factor. Also infection with human papillomavirus (HPV, particularly oncogenic HPV 5 and 8 strains) plays an important role in the development of SCC, with HPV being detected in 65 to 90% of SCC of transplant recipients. Other risk factors are fair skin, age, the level of immunosuppression, duration of pretransplantion dialysis, ionizing radiation, chronic inflamed skin (like scars or chronic ulcers) and possibly smoking. SCC is more aggressive in transplant recipients than in the general populations, resulting in higher risk of local recurrence (14% of patients), regional and distant metastasis (6-9% of patients) and mortality. In patients with metastases, disease-specific survival is approximately 50%. Treatment consists of complete local excision and lymphadenectomy if necessary. In immunocompromised patients with the initial presentation of aggressive SCCs, Mohs micrographic surgery should be administered in order to minimize the risk of recurrence and tissue loss. Mohs micrographic surgery includes removal of the tumour followed by immediate frozen section histopathologic examination of margins with subsequent re-excision of tumour-positive areas and final closure of the defect. When more than one lymph node is affected or when there is extracapsular spread, adjuvant radiotherapy should be considered. Systemic chemotherapy can be used for metastatic SCC (Kovach & Stasko, 2009).

Basal cell carcinoma BCC
Basal cell carcinoma BCC arises from the basal layer of the epidermis and its appendages. It occurs on sun-exposed skin, most commonly on the face or head (up to 70%). Common sites are eyelid margins, nose folds, lips and around and behind the ears. The incidence of BCC is increased by a factor 10 to 16 in transplant recipients, compared to the general population. Intense intermittent sun exposure is important in the pathogenesis of BCC, in contrast with SCC were the cumulative sun exposure plays an important role. Other risk factors for developing BCC are similar as for SCC. According to the clinical presentation, BCC can be divided in three sub-groups: nodular BCC (a pink or flesh-colored papule, often with a translucent, 'pearly' appearance and a teleangiectatic vessel, sometimes with central erosion), superficial BCC (a slightly scaly, light red papule or plaque) and morpheaform BCC (smooth, flesh-colored, or very lightly erythematous papules or plaques, frequently atrophic). As for SCC, treatment of BCC consists of local excision (Mohs surgery) with or without lymphadenectomy. Metastases of BCC are very rare even in immunosuppressed patients. However, BCC can cause serious local destruction, necessitating surgery and resulting in significant cosmetic deformity (Kovach & Stasko, 2009).

Malignant melanoma
Malignant melanomas arise from melanocytes. To detect a malignant melanoma, new or changing pigmented lesions should be examined with special attention for A, assymmetry; B, border irregularity; C, color variation/dark black color; D, diameter more than 6 mm; and E, evolution or change. Malignant melanomas can be classified into lentigo malignant melanomas (arising on sun-exposed skin of older individuals), superficial spreading malignant melanomas (most common, occurring in 70%, especially in Caucasian people), nodular malignant melanomas, acral lentiginous melanomas (arising on palms, soles and nail beds, commonly in more darkly pigmented persons), malignant melanomas on mucous membranes and miscellaneous forms. The risk of developing melanoma is 3.6 times greater in renal transplant recipients than in the general population. Risk factors for the development of posttransplant malignant melanomas are the presence of atypical nevi, history of blistering sunburns, immunosuppression, fair skin, a personal or family history of malignant melanomas, older age at the time of transplantation and the use of depleting anti-lymphocyte antibodies. While SCC and BCC are rarely lethal, melanoma is a potentially fatal malignancy. The most prognostic factor is tumour thickness (Breslow depth). Patients diagnosed with malignant melanoma with a tumour thickness of less than 1 mm have an excellent outcome. However, if there is lymph node involvement or distant metastasis, survival rate is low with a 5-year survival of respectively 30% and less than 10% in immunocompetent persons. Outcome for posttransplant lesions with < 2 mm thickness is similar to the general population, while for lesions > 2 mm thickness prognosis is significantly worse (Matin et al., 2008). Treatment of melanoma consists of surgical excision, with reexcision of margins according to the thickness of the tumour. Sentinel node biopsy is recommended for patients with clinically negative nodes if Breslow depth is more than 1 mm. Reduction or change of the immunosuppressive regimen should be considered, balancing the prognosis of the tumour and the risk of graft rejection (Zwald FO et al., 2010).

Kaposi's sarcoma
Kaposi's sarcoma KS is a vascular neoplasm, characterized by reddish-brown or purple-blue plaques or nodules on cutaneous or mucosal surfaces, including the skin, lungs, gastrointestinal tract and lymphoid tissue. KS has been associated with the reactivation of latent human herpes virus 8 (HHV-8) infection or donor-to-recipient transfer of HHV-8infected progenitor cells. The incidence of KS is 20 times increased in renal transplant recipients. It occurs frequently early after renal transplantation, with an average time to development after transplantation of 13 to 21 months. It is more common in male transplant recipients, with a male to female ratio ranging from 2:1 to 4:1. Most cases occurs in patients from Mediterranean, Jewish, Arabic, Caribbean or African ethnic groups. The treatment of Kaposi's sarcoma in renal transplant patients primarily consists of a reduction or discontinuation of the immunosuppressive medication, and possibly a conversion to alternative immunosuppressive agents like mTOR inhibitors (as will be discussed below) (Antman & Chuang, 2000;.

Prevention
As for immunocompetent individuals, prior exposure to solar ultraviolet radiation (UVR) is the predominant risk factor for development of cutaneous malignancies. In patients at highrisk, primary prevention including the avoidance of sun exposure (especially during peak hours of radiation), use of protective clothing and use of an effective sunscreen (protection factor >15) for unclothed body parts (head, neck, hands and arms) is very important. Early detection of skin cancer is essential to reduce disfiguring surgery and to prevent mortality from advanced or metastatic lesions. For this reason, patients should be aware of the increased risk of skin cancer and perform regular self-screening. Annual skin examination by a dermatologist is recommended, especially in high-risk patients (e.g. patients with a history of skin cancer, fair-skin, living in high sun-exposure climates, having occupations with sun exposure or having had significant sun exposure as a child). Treatment of premalignant lesions (actinic keratoses, viral warts) is advised in order to prevent progression to SCC. This can be done with liquid nitrogen cryosurgery, excision, and curettage or with topical therapies such as 5-fluorouracil (which interferes with DNA synthesis and cell proliferation) or imiquimod 5% cream (a topical imidazoquinolone immunomodulator stimulating local cell-mediated immune response directed against tumoral and viral antigens). When actinic keratoses or viral warts persist with these therapies, biopsy is required to rule out progression to SCC (Kovach & Stasko, 2009). There are several studies suggesting that retinoids (vitamin A derivates, available in topical and oral preparations) may be beneficial to the treatment and/or prevention of non-melanoma skin tumours after solid organ transplantation. They are said to influence a broad spectrum of cellular functions through interactions with nuclear receptors. Topical retinoids are used to control actinic keratoses and to diminish SCC recurrence. Oral retinoids (most common acitretin) has been advised for patients with multiple and/or recurrent skin cancers. Chen et al. reviewed three small randomized controlled clinical trials on the use of oral retinoids as preventive agents in the development of skin cancer. The first trial was a cross-over trial with 23 high-risk patients. Compared to the acitretin period (25 mg daily), a 42% increase in the incidence of SCC was seen in the drug-free period. In the second trial, 44 high-risk patients were randomized to receive acitretin 30 mg daily or placebo. After 6 months of follow-up, 18 new skin cancers developed in the placebo group, whereas only 2 new skin cancers developed in the acitretin group. The last trial compared two different dose regimens (0.2 mg/kg/day versus 0.4 mg/kg/day) in 26 renal transplant recipients and did not find a significant difference in development of skin cancers between the two groups. While the first two trials included only high-risk patients, the last included any stable renal transplant recipient, which could explain the lack of benefit (Chen et al., 2005). After cessation of therapy, rebound phenomena with development of large numbers of cutaneous malignancies are reported. For that reason, oral retinoids should always be given as long-term maintenance therapy. The major factor, however, limiting the use of oral retinoids in the prevention of skin cancer is the poor tolerance associated with it. Adverse effects include headaches, mucocutaneous side effects, musculoskeletal symptoms and hyperlipidaemia. Cheilitis has been reported in 70 to 100% of patients. In conclusion, in recipients with multiple and/or recurrent skin cancers, the use of systemic retinoids, such as low-dose acitretin (dose between 0.2 and 0.4 mg/kg/day), could be advised for months/years, if well tolerated. Gradual dose escalation to an effective dose in combination with monitoring of symptoms and laboratory findings and proactive management of adverse effects rather than discontinuation of therapy is recommended (Kovach et al, 2006;Otley et al., 2006). solid-organ transplantation or bone marrow allograft. It is the second most frequent cancer after transplantation after skin cancer, with an overall incidence of 1 to 2% after kidney transplantation (30 to 50 times higher than in the general population). PTLD frequently arises from B lymphocytes, but can rarely also originate from T-cell proliferation. It is the most frequent malignancy during the first post-transplantation year, when the level of immunosuppression is the highest. There is a strong association with Epstein-Barr virus (EBV) infection, with 98% of cases associated with latent EBV infection. An increase in the EBV viral load in peripheral blood is often detected before development of PTLD. This EBV infection leads to B cell proliferation in the setting of decreased T-cell immune surveillance due to immunosuppressive treatment. Only 10 of almost 100 viral genes in the EBV DNA are expressed in latently infected B cells, including two oncogenes latent membrane protein type 1 LMP-1 and type 2 LMP-2. The number of expressed viral genes is reduced to diminish the recognition of cytotoxic T cells. PTLD can be divided in three distinct morphologic groups, according to the World Health Organization classification, each containing some subtypes: -Early disease (55% of cases), characterized by diffuse B cell hyperplasia of polyclonal nature, with no signs of malignant transformation. This has a good prognosis after reduction of immunosuppression. -Polymorphic PTLD (30%), usually polyclonal B cell proliferation with evidence of early malignant transformation, such as clonal cytogenetic abnormalities and immunoglobulin gene rearrangements. -Monomorphic PTLD (15%), characterized by monoclonal B cell proliferation with malignant cytogenetic abnormalities and immunoglobulin rearrangements. This includes high-grade invasive lymphoma of B or T lymphocyte centroblasts. It is associated with the worst outcome. In table 2, the clinical and pathological features and the management of the different groups is summarized (Magee et al., 2008). The clinical manifestations from PTLD are extremely variable and it often presents in a nonspecific way. Early PTLD (first year after transplantation) presents often with an infectious mononucleosis-like presentation, with prominent B-cell symptoms (fever, night sweats and weight loss) and rapid enlargement of the tonsils and cervical nodes. Late PTLD (more than 1 year after transplantation) has often a more gradual clinical course and fewer systemic symptoms. In half of the patients, extra-nodal disease is present, with involvement of gastrointestinal tract (stomach, intestine), lungs, skin, liver, central nervous system or frequently the allograft itself. It is of major importance to recognize early clinical signs and symptoms of PTLD. PTLD is often associated with elevated serum markers such as lactate dehydrogenase LDH. For an accurate diagnosis of PTLD, tissue biopsy is required. Fluorodeoxyglucose (FDG)-positron emission tomography (PET/CT) is an important tool in the diagnosis, staging and post-treatment evaluation. Prognosis of PTLD varies according to clonality and extent of disease. However, in general, PTLD has a poor prognosis with a 1-year mortality of approximately 40%. The most important risk factors for PTLD are the type, length and intensity of immunosuppressive drug therapies. There is an increased risk of PTLD in patients who received potent T-cell depleting antibodies (like OTK3 or anti-thymocyte globulin ATG) for induction therapy or for treatment of rejection. There would be a twofold higher risk for development of PTLD in patients receiving tacrolimus in comparison to cyclosporine. A special category of patients at particular risk for PTLD development are seronegative patients at the time of transplantation, receiving an organ from an EBV-seropositive donor (inducing a primary EBV infection after transplantation). An age effect on the development of PTLD is present, with the incidence highest among children < 10 years of age and adults > 60 years of age (Opelz & Henderson, 1993;Opelz & Döhler, 2003).
In the prevention of PTLD, monitoring of EBV viral load in high-risk patients (who received large dose of immunosuppressive drugs for induction or allograft rejection) is recommended since reduction of immunosuppressive treatment can be considered if high viral loads are detected. Use of antiviral therapy as profylaxis for PTLD in high-risk patients is controversial. Treatment of PTLD consists in the first place of reduction or discontinuation of the immunosuppressive therapy (especially cyclosporine CsA, tacrolimus and mycophenolate mofetil MMF) to reestablish host defense mechanisms. Concomitantly, prednisone can be increased to prevent allograft rejection. This can lead to complete and durable resolution of some lymphomas, especially of early and polymorphic PTLD (sometimes in combination with antiviral therapy such as acyclovir and ganciclovir). Evidence for the treatment of PTLD with antiviral therapy is lacking and it is not used in monomorphic PTLD. For monomorphic PTLD, besides reduction or discontinuation of immunosuppressive therapy, other therapeutic strategies must be considered. In localized disease, surgical resection can be an option, for example transplant nephrectomy when PTLD is restricted to the renal graft. The use of rituximab RTX as first-line therapy is increasing, because of its low toxicity and high specificity. RTX is a chimeric monoclonal antibody against the B-cell-specific CD 20 antigen (widely expressed on B lymphocytes). Treatment consists of doses of 375 mg/m 2 intravenously weekly for a total of 4 weeks. In case of diffuse lymphomas, lack of response to RTX or CD20 negative lymphoma, chemotherapy (e.g. CHOP cyclophosphamide, doxorubicin, vincristine and prednisone) can be considered (Andreone et al., 2003;Bakker et al., 2007).

Immunosuppressive drugs and the risk of malignancy after transplantation
The principal factor influencing the risk of posttransplant malignancy is the overall level of immunosuppressive treatment. Indeed, in a prospective, randomised trial comparing lowdose cyclosporine CsA (trough blood concentrations 75-125 ng/mL) versus high-dose CsA (trough blood concentrations 150-250 ng/mL) both in combination with azathioprine AZA, a clear correlation between high-dose regimen and more secondary malignant disorders was demonstrated (Dantal et al., 1998). This may also explain why the incidence of posttransplantation malignancy is more frequent in heart transplant recipients (which usually receive more intense immunosuppression) than in renal transplant recipients. In transplant patients with cancer, a significant reduction or even cessation of the immunosuppressive therapy is advised. There is some evidence that also the type of immunosuppressive agent would matter. However, since in most cases combinations of several immunosuppressive drugs are used, clear data concerning individual therapies are lacking and sometimes conflicting. The purine analogue azathioprine AZA has been associated with increased risk of skin cancer, possibly as a result of increased photosensitivity to ultraviolet A light (Perrett et al., 2008). In 1999, one study suggested that the calcineurin inhibitor cyclosporine CsA could promote cancer progression in vitro and in vivo in an immunodeficient mouse model by a direct cellular effect, independent of any effect on the host immune system. This would be mediated by stimulation of transforming growth factor β TGF-β production, which may lead to development of morphological transformation of cells from a non-invasive phenotype to an invasive phenotype and which may promote tumor invasiveness and metastasic spread (Hojo et al., 1999). Similar results were seen with tacrolimus, with increase in the number of pulmonary metastases and TGF-β overexpression in mouse renal cell carcinoma receiving tacrolimus (Maluccio et al., 2003). In contrast, there is growing data suggesting that inhibitors of the mammalian target of rapamycin mTOR ( sirolimus and everolimus) have antioncogenic properties and are therefore associated with a reduced risk for some malignancies and longer times for malignancies to develop. This can be explained by the fact that mTOR inhibitors repress several enzymes along the intracellular signaling pathways that play a role in the development and progression of different cancers (like p70 S6K, IL-10, and cyclins), resulting in deceleration or inhibition of cell-cycle progression, increased sensitivity to apoptosis and reduced angiogenesis. There are several clinical trials linking the use of mTOR inhibitors to reduced incidence of malignancies. In 2004, Mathew et al. reviewed 5 multicenter studies, comparing the cancer risk for different immunosuppressive regimens. Two studies containing 1295 patients randomized to receive CsA in combination with sirolimus, AZA or placebo. After 2 years, they saw a significant lower incidence of skin cancer in the sirolimus-group (2% in a low-dose group, 2.8% in a high-dose group) compared to the placebo-group (6.9%). Compared to the AZA-group (4.3%), the difference was not statistically significant. Two other trials (161 patients) compared maintenance therapy based on sirolimus or CsA (both in combination with steroids and AZA or mycophenolate mofetil MMF). In the CsA based-group, 5% of patients had some form of malignancy after 2 years, compared to 0% in the sirolimus-based group. In the fifth trial (525 patients), CsA withdrawal 3 months after renal transplantation in combination with steroids and increased sirolimus trough levels (20 to 30 ng/ml during year 1, 15 to 25 ng/ml thereafter) was compared with a continuous regimen of CsA, steroids and sirolimus (trough levels 5 to 15 ng/ml). After 2 years, the incidence of overall malignancies was significant lower in the CsA-elimination group (4.2% compared to 9.8%) (Mathew et al., 2004). The long-term results of this last trial are incorporated in the Rapamune Maintenance Trial (430 patients). Similarly, after 5 years follow-up, patients in the CsA withdrawal group had a reduced incidence of both skin and nonskin malignancies. What's more, the median time to first skin carcinoma was significantly shorter in the CsA group (491 days) compared to the withdrawal group (1,126 days) (Campistol et al., 2006). A large registry (United Network for Organ Sharing database) reporting 33,249 renal transplant patients whose maintenance immunosuppression contained an mTOR-inhibitor, an mTOR-inhibitor in combination with a calcineurin inhibitor CNI or a CNI alone, showed reduction in the overall incidence of de novo malignancy in patients receiving an mTORinhibitor. After a mean follow-up of 2.3 years, an incidence of 0.6% was seen in the mTORinhibitor alone or the mTOR-inhibitor plus CNI group versus 1.8% in the CNI alone group (Kauffman et al., 2005). Similar results turned up in the Sirolimus Convert Trial where 830 renal allograft recipients receiving CNI-based immunosuppression were randomly assigned to convert to sirolimus or to continue CNI. The overall malignancy rates after 24 months were significantly lower in the sirolimus group (3.8%) versus the CNI group (11%). However, the number of adverse effects in the sirolimus group was higher than in the CNI group (Schena et al., 2009). There is some evidence that sirolimus does not only prevent the occurrence of cancer, as described above, but is also promising in treating existing tumors. There would be some benefit of basing immunosuppression in patients with new-onset malignancy after transplantation on these drugs (especially for Kaposi's sarcoma). In 15 renal transplant recipients with biopsy-proven cutaneous Kaposi's sarcoma, cyclosporine and mycophenolate mofetil were stopped and sirolimus was started. After six months, all patients had complete clinical and histological regression of Kaposi's sarcoma lesions (Stallone et al., 2005). Gutierrez-Dalmau et al. reported similar results in 7 renal transplant patients after conversion of CNI to sirolimus (Gutierrez-Dalmau, 2005).
In patients with established malignancy after transplantation, some therapeutic options should be considered. It is clear that reduction of the total amount of immunosuppressive medication is very important. This should however be balanced against the risk of graft rejection and the quality of life with and without a functioning graft. The most serious effect of a reduction or cessation of therapy can be expected from malignancies with a greater increase in incidence after renal transplantation (like non-melanoma skin cancer, PTLD and Kaposi's sarcoma). Whether CNI should be converted into an mTOR-inhibitor is somewhat questionable. It is certainly advised for Kaposi's sarcoma. However, when considering switching CNI to mTOR inhibitors for other malignancies, it should be balanced against its frequent side effects, including increase in serum lipids, myelotoxicity, proteinuria, pneumopathy (hypersensitivity-like interstitial pneumonitis), dermatological manifestations, some degree of oedema and aphtae. Up to one-third of patients starting sirolimus will stop because of side effects. When patients still need surgical intervention for the malignancy, potential wound healing complications attributed to mTOR-inhibitors should also be taken into account Cravedi P et al., 2009; Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group, 2009).

General recommendations for cancer screening after renal transplantation
Cancer should be a major focus in the long-term follow-up of renal transplant recipients. First and foremost, preventive measures should be taken, i.e. avoiding excessive immunosuppression (especially depleting anti-lymphocyte antibodies), screening transplant donors and recipients for cancer and avoiding carcinogenic factors (such as nicotin abuse, high sun exposure, etc.). Secondly, in order to detect malignancies in transplant patients at an early stage, periodic screening examinations are recommended. It is questioned whether guidelines for cancer screening for the general population are also applicable for renal transplant recipients, because the life expectancy of these patients is mostly less. Because of this, an individual approach for each patient is recommended, taking into account the individual prognosis and risk of developing malignancy (Webster et al., 2008). Based on the American (KDIGO Transplant Work Group, 2009) and European (European Best Practice Guidelines EBPG, 2002) transplantation professional guidelines, we can however suggest the following practical screening plan: 1. Annual examination of the skin and lip by a dermatologist (more frequently in highrisk patients, such as patients with a history of skin cancer). 2. Abdominal surveillance ultrasonography at least every three years to detect early stage renal cell carcinoma. Especially in high-risk patients including patients with a history of renal cell carcinoma or the presence of acquired cystic disease, analgesic nephropathy or tuberous sclerosis. 3. Standard cancer surveillance (appropriate for age) for neoplasms commonly seen in the general population: -Colorectal cancer: colonoscopy every 5 years from the age of 50 -Breast cancer: breast exam and screening mammography every year from the age of 50 to 69 (from the age of 40 if mother or sister has had breast cancer) -Cervical cancer: pap smear and pelvic exam every year for women within 3 years of onset of sexual activity or from the age of 21 (whichever comes first) -Prostate cancer: digital rectal exam and PSA testing every year from the age of 50 -Hepatocellular cancer: abdominal ultrasound and alpha-feto protein testing every 6-12 months only in high-risk patients (cirrhosis or chronic viral hepatitis, especially HBV).

Conclusion
As short-term patient and graft survival have improved over the past few decades, longterm complications of kidney transplantation are becoming more important. The incidence of malignancies is considerably higher in renal transplant recipients than in the general population. In fact, malignancy is the third most common cause of patient death after renal transplantation (after cardiovascular events and infection). With longer graft survival and older donors (as well as recipients) and with the introduction of more potent immunosuppressive medication, malignancy is becoming even more common. Both clinicians and patients should be aware of this risk, making primary prevention a major concern. In addition, they should consider a cancer screening plan adapted to the patient's individual risk profile and life expectancy.