Malignancies After Transplantation and Posttransplant Lymphoproliferative Disorder

Modifiable risk factors

1. Smoking

2. Sun exposure

3. Geographical location

4. Immunosuppressive drug therapy

Nonmodifiable risk factors

1. Age

2. Male gender

3. White ethnicity

4. Genetic disposition

5. Oncogenic viruses

6. Chronic renal disease/dialysis duration

7. Posttransplant life span

8. Presence of cystic kidney disease

9. History of previous malignancy

Table 25.2
Incidence of infection-related malignancies after transplantation [2, 3, 60, 127]

Cancer site


SIR (95 % CI)

P value

Non-Hodgkin’s lymphoma


7.54 (7.17–7.93)



Hepatitis C and hepatitis B

11.56 (10.83–12.33)



H. pylori

1.67 (1.42–1.96)


Kaposi sarcoma


61.46 (50.96–73.49)


Oropharynx including tonsil






5.84 (4.70–7.18)


Hodgkin’s lymphoma


3.58 (2.86–4.43)




7.60 (5.77–9.83)




1.03 (0.75–1.38)




4.13 (2.59–6.26)




0.96 (0.42–1.90)




2.35 (0.94–4.84)


2.10 (2.06–2.14)


Immunosuppression: A critical and obvious risk factor in this patient population is the use of immunosuppression. This includes not only the maintenance therapies but also induction strategies such as T cell depletion that add to the overall suppressive burden. Indeed, the level and intensity of immunosuppression have been correlated to higher rates of cancer in solid organ transplant recipients that have greater exposures [8]. Immunosuppression may also have untoward effects on innate and adaptive immunity in the context of tumor surveillance [9, 10]. Additionally, the class of agent also has specific impact on cancer development. Depletional induction therapies have been associated with EBV-mediated PTLD [11]. The use of belatacept, the costimulatory inhibitor, is also associated with a higher risk of PTLD, particularly in EBV-naïve recipients who received EBV-seropositive organs. Calcineurin inhibitors, both cyclosporine A and tacrolimus, may promote cancer formation by stimulating transforming growth factor beta (TGFβ) with enhanced small vessel growth [12, 13]. Clinical evidence is not conclusive, however, of a direct relationship between CNI use and higher rates of malignancy [14, 15].

The antimetabolite azathioprine is known to sensitize skin to UV light-mediated damage. However, the mycophenolate mofetil may lower cancer development [16, 17] through its primary inhibition of inosine monophosphate dehydrogenase, an enzyme elevated in a number of malignancies [18, 19]. There are insufficient data, however, to support this notion as a preventive therapy.

Of significant interest this decade has been the growing number of reports using inhibitors of mammalian target of rapamycin (mTORi). This class of agents has antiproliferative and inhibitory properties for a variety of other solid tumors [20] through inhibition of VEGF. In kidney transplant recipients converted to mTORi [21] or on mTORi-based maintenance therapy [22], the incidence of cancers was reduced compared to CNI-based regimens, particularly NMSC, although these are retrospective studies and with limited follow-up. More recent prospective studies converting to mTORi have shown slower rates of skin cancer growth and prevention of further recurrences as demonstrated in a recent clinical trial [23]. The use of mTORi for maintenance immunosuppression in recipients with prior cancer and for those in whom cancer develops has been advocated by some in the field [24]. However, the relative lack of prospective, well-controlled studies using mTORi for prevention of all malignancies makes this strategy difficult to recommend in all situations.

Preexisting cancer: A critical risk to posttransplant disease is cancer prior to transplantation. Recurrence risk is dependent on the type of tumor, stage [25], management, and the interval between treatment of the tumor and a subsequent renal transplant. High rates of recurrence have been observed with multiple myeloma [26], suggesting a critical treatment plan prior to considering transplantation. Consequently, malignancy-free waiting periods are recommended for each cancer type in order to alleviate the morbidity of cancer recurrence after transplantation (Table 25.3) [27, 28].

Table 25.3
Proposed waiting times for kidney transplant after malignancy [27]


Recommended pre-transplant waiting time (year)


• Carcinoma in situ


• Cancer


Lung cancer


Colon cancer

• Stage 1


• Stage 2 or greater


Renal cell cancer

• Small, low grade


• Large, high grade





Not recommended

Multiple myeloma

Not recommended



• CNS lymphoma HIV

Not recommended



Skin cancer

• Malignant melanoma (in situ)


• Squamous cell


• Basal cell

No wait






• Noninvasive


• Noninvasive


Kaposi’s sarcoma

• Limited


• Diffuse, disseminated in HIV

Not recommended

Donorderived transmitted tumors: Prior to 2000, cancer transmission from deceased donor organs was thought to be relatively uncommon with a rate of 0.017 % [29], but a relatively high mortality when they occur. These rates, however, were based on registry data that were incomplete [30]. Further reports from the IPTTR suggested that transmission rates for donors with malignancy were substantially higher at 42 %, with the highest rate of transmission from known cancer-bearing donors to be in renal transplant recipients [31]. CNS tumors were the most commonly identified in donors, and the highest transmission rates were for choriocarcinoma and melanoma. These data support the need for better assessment of donor malignancy history and risk of transmission. Recognizing the limitations of this voluntary registry, analysis of donor OPTN/UNOS data from 2000 to 2005 indicated that only 2 % of deceased donor organs came from donors with history of malignancy [32]. In this series, nonmelanoma squamous cell cancers of the skin, CNS tumors, and uterine cancer were the most common cancers noted in donors. Recently, a malignancy subcommittee for the OPTN/UNOS Disease Transmission Advisory Committee analyzed current literature and created levels of risk from 0 (no risk) to 4 (high risk) and also a category for unknown risk [33]. Additionally, all possible cancers were classified by this scheme based on clinical behavior of the tumor, cure probability, and time to metastasize (Table 25.4). These guidelines provide a basis to the donor surgeon in terms of appropriate utilization of donor organs and allow the informed risk assessment to the recipient who may succumb to their end-stage disease prior to transplantation.

Table 25.4
Donor transmission risk categorization for specific tumors after transplantation [33]

Risk category (% transmission)


No significant risk

• Benign tumors

Minimal risk (<0.1 %)

• Basal cell skin cancer

• Squamous cell skin cancer without metastases

• Carcinoma in situ, skin

• In situ cervical carcinoma

• In situ vocal cord carcinoma

• Superficial papillary carcinoma of the bladder

• Solitary papillary thyroid carcinoma, ≤0.5 cm

• Minimally invasive follicular thyroid carcinoma (≤1.0 cm)

• Resected solitary renal cell carcinoma ≤1.0 cm, well differentiated (Fuhrman 1–2)

Low risk (0.1–1 %)

• Resected solitary renal cell carcinoma ≥1.0 cm ≤2.5 cm, well differentiated (Fuhrman 1–2)

• Low-grade CNS tumor (WHO grade I or II)

• Primary CNS teratoma

• Solitary papillary thyroid carcinoma 0.5–2.0 cm

• Minimally invasive follicular carcinoma thyroid 1.0–2.0 cm

• History of treated non-CNS malignancy (≥5 years prior) with >99 % probability of cure

Intermediate risk (1–10 %)

• Breast carcinoma in situ (Stage 0)

• Colon carcinoma in situ (Stage 0)

• History of treated non-CNS malignancy (≥5 years prior) with probability of cure 90–99 %

• Resected solitary renal cell carcinoma T1b (4–7 cm), well differentiated (Fuhrman 1–2) stage 1

High risk (>10 %)

• Malignant melanoma

• Breast carcinoma > stage 0 (active)

• Colon carcinoma > stage 0 (active)

• Choriocarcinoma

• CNS tumor (any) with ventriculoperitoneal or atrial shunt, surgery, irradiation or extra-CNS manifestations

• CNS tumor WHO grade III or IV

• Leukemia or lymphoma

• History of melanoma, leukemia, lymphoma, small cell lung/neuroendocrine carcinoma

• Any other history of treated non-CNS malignancy either (a) insufficient follow-up to predict behavior, (b) considered incurable, or (c) with probability of cure <90 %

• Metastatic carcinoma

• Sarcoma

• Lung cancer (stages I–IV)

• Renal cell carcinoma >7 cm or stage II–IV

• Small cell/neuroendocrine carcinoma, any site of origin

• Active cancer not listed elsewhere

Cancer After Renal Transplantation: De Novo Cancers

The relative incidences of cancers after kidney transplantation have already been defined above. We will now explore the key common posttransplant malignancies, their management, and outcomes.

Skin cancer: NMSC is the most commonly occurring post kidney transplant cancer. Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) account for 95 % of posttransplant NMSC [34]. Interestingly, compared to the general public, SCC is far more frequent than BCC at an incidence of 4:1 [35]. The incidence of NMSC increases steadily with time post transplantation with an incidence of 5 % at 2 years, 10–27 % at 10 years, and up to 60 % at 20 years in the United States and western Europe [3638] and a mean time of development of 8–10 years post transplantation. These are aggressive tumors, recurring locally in 13 % of patients with metastases in 5–8 %. Moreover, and the presence of one is predictive of multiple subsequent lesions and these recipients have frequent second primary cancers.

Disease results from both skin exposure and reduced immune surveillance in the context of the overall burden of immunosuppression. A lower incidence of skin cancer has been seen in living donor transplant recipients who require less overall immunosuppression. Azathioprine has been associated with higher rates of skin cancer by sensitization to UVA-induced skin damage [39]. Several studies have shown patients on three-drug immunosuppressive regimens had a threefold increased risk of NMSC compared to patients taking two-drug regimens [3, 21, 40, 41]. Note, however, that low-dose cyclosporine has been shown to confer a lower risk of NMSC than standard-dose cyclosporine [42]. As previously discussed, recent studies with mTORi demonstrate beneficial effects on slowing growth rates and the development of new lesions [23].

Other risk factors for NMSC include male gender and age, such that patients who received their transplant after the age of 55 have a 12-fold higher risk for development of skin cancer compared to patients who received grafts before the age of 34 [43]. In renal transplant recipients, HPV 8 DNA has been detected in 80 % of precancerous lesions such as Bowen’s disease compared with only 30 % of the general population, again supporting the notion that viral-related mechanisms are important in NMSC development post transplantation [44, 45].

Treatment of transplant-related skin cancer requires a multidisciplinary effort particularly in the context of multiple lesions, their size, and location. Annual evaluation by a dermatologist is recommended, with more frequent visits for high-risk patients. Education before and after transplantation covering skin cancer prevention, detection, and treatment is essential. This includes discussion of avoidance of sun exposure, the use of protective clothing, and the appropriate application of UVB-retarding sunscreen. Compliance in this area can be difficult, as this is not covered by insurance or Medicare. Lesions such as actinic keratoses, keratoacanthomas, and Bowen’s disease (SCC in situ) should be followed closely and treated as those lesions are associated with potential for SCC development [46].

With suspected or proven squamous cell lesions, surgical excision with clear margins is the standard of care. Superficial lesions may be managed with cryotherapy or electrocautery and curettage. Invasive squamous cell cancers require more aggressive management due to the higher risk of recurrence and metastasis. Local regional lymph node may be curable by lymphadenectomy alone, but may require adjuvant treatment with chemotherapy or radiation. BCC generally do not metastasize and do not require care beyond the standard used for the general public, but the treatment of specific lesions, however, does not prevent recurrence or the development of new cancers.

For larger treatment areas, additional therapy may include topical imiquimod, 5-fluorouracil, photodynamic therapy, and 3 % diclofenac gel. Systemic retinoids have been shown to slow the development of new lesions, and topical retinoids reduce actinic keratoses. Clearly, immunosuppressive modification is needed, but there is no consensus on specific agent reduction or approach. As already noted, the use of mTORi shows promise as an alternative strategy both to avoid rejection and limit disease progression.

Melanoma is a less frequent cause of skin cancer, but with a fourfold higher incidence than in the general population [3]. Disease may be due to donor transmission or from prior disease or developed de novo post transplantation. Posttransplant outcomes, as demonstrated by a recent retrospective analysis of European transplant centers, showed a 27 % mortality rate. However, recipients with T1 and T2 lesions have similar results to otherwise age- and sex-matched individuals with melanomas [47]. However, with more advanced disease (T3 and T4), the hazard ratio for death was 11.49 (p < 0.001) compared to non-transplanted individuals. Thus, treatment of melanoma requires an aggressive management plan, with wide local excision and/or sentinel lymphadenectomy. Reduction in immunosuppression is recommended but there are insufficient data with regard to specific strategies in this group [48].

Kaposi’s sarcoma: As in other skin cancers, this vascular tumor is markedly more frequent in posttransplant recipients compared to non-immunosuppressed individuals [49]. Presenting as a dark red or blue nodular or maculopapular cutaneous lesion, it more commonly affects the skin of the lower limbs, although the trunk and arms may be affected [50]. It is more frequently seen in men than women [51]. Visceral organs may be affected in 10 % of cases and carry a more severe prognosis. Notably, allograft involvement is extremely rare [52]. HHV 8 infection at time of transplantation is a critical risk factor; incidence rate varies from 5 % in Mediterranean and African descent population to 0.5 % in western and northern countries reflecting specific geographic distribution [51, 53]. Hence, donor screening for HHV 8 virus may be useful in areas with considerable rate of infection to avoid posttransplant transmission. This of course has to be weighed into the need and benefit for transplantation compared to dialysis and the opportunity for available organs. A key management strategy is to reduce or discontinue immunosuppression and typically the lesions will regress [54]. The introduction of mTORi has been associated with dramatic reduction in lesions [55] and a reduction in recipient mortality after disease diagnosis [56].

Renal cell and genitourinary tract cancers: The incidence of renal cell carcinoma is nearly 100 times greater in end-stage renal disease and transplant patients than the general population [3, 57]. Disease presentation is often aggressive with median survival of 17 months post diagnosis [58]. Most cancers arise in the native kidneys rather than the renal allograft and are more aggressive than in non-immunocompromised hosts. There are no recommended guidelines for use of urinalysis or urine cytology. Routine ultrasonographic surveillance of the native kidneys is not recommended and there are no prospective data to determine if such a screening strategy is cost-effective. In general, patients with or without ADPKD who have Bosniak I (simple benign cysts) or II cysts (one or two septations, fine-wall calcifications, non-enhancing hyper dense cysts) should undergo renal ultrasonography twice yearly, followed by CT or MRI for suspicious lesions. Bosniak IIF patients should have ultrasound every 3 months and annual CT or MRI. Nephrectomy is indicated for progressive lesions or Bosniak III or IV lesions [59]. The presence of unexplained hematuria should prompt evaluation to exclude renal or bladder lesions. There is an increased risk of developing neoplasms of the native urinary tract especially in patients with a history of analgesic nephropathy, prolonged exposure to cyclophosphamide, and those with a history of Chinese Herb exposure [60]. Urine cytology is not a reliable diagnostic tool. In addition to radiologic imaging as recommended above, serum BK and adenovirus PCR [61] and PSA are recommended. Patients with non-glomerular hematuria should also undergo cystoscopy.

Colon cancer: Though a common tumor in the non-immunosuppressed population, colorectal cancer is not seen at a higher frequency post kidney transplantation [62, 63]. However, in a recent study of age 50 and older kidney transplant recipients screened with fecal occult blood testing and colonoscopy, advanced colorectal disease was found in 13 % [64], and such data support the need for the standard use of screening colonoscopy.

Anogenital cancer: While these cancers occur in about 2–3 % of recipients, this is significantly more frequent than in the general population. The association with HPV has been identified over the last decade and is nearly uniform in anogenital cancers [65]. This association, especially with HPV 16 and 18, has provided additional incentive to vaccinate the pre-transplant patient, although recipients already infected may make vaccination futile [66]. The role of vaccination post transplantation is more controversial as it may be ineffective due to a delayed antibody response, with lower seroconversion rate and more rapid decline of antibody level compared to the general population [4]. Disease may be multifocal, and gynecologic exams should be performed regularly.

Cervical cancer: There is a marked increase risk of cervical cancer in the posttransplant patient population compared to the general population, although many of these lesions are in situ [67]. Standard treatment applies in this population as well. Screening through Pap smear has been extremely effective in the general population, and again, there is no justification to alter this screening post transplantation [4]. While the role of colposcopy has been debated, there is a lack of evidence to suggest employing this in kidney transplant recipients [68]. The strong association with HPV has been discussed above, supporting appropriate screening post transplantation. The effective role of vaccination remains to be fully determined [69].

Breast cancer: Compared to the general population, the incidence of breast cancer is not increased in the post kidney transplant recipient [3]. Mortality in this disease is high in the general population, based on stage of disease. In transplant recipients, outcomes are comparable to the general population although survival is worse with more advanced disease [70]. Standard management includes surgery, chemotherapy, and/or radiation. Screening reduces mortality in the general population and there are no data to suggest additional screening is necessary in the kidney transplant population [4]. A further discussion regarding appropriate cancer prevention screening is given below.

Hepatobiliary cancer: Hepatocellular cancer is primarily associated with hepatitis B and C infections and incidence varies depending on the prevalence of these infections which varies with geography. However, the risk of cancer is significantly higher in this population with an SIR of 11.56 [2]. Disease prevalence in this population is such that it argues for appropriate antiviral treatment prior to transplantation [71]. Most recipients have advanced disease when they present, making effective therapy less likely. The role of screening for all transplant recipients is questionable and may not be cost-effective [4, 69]. However, in high-risk recipients, the use of hepatic ultrasound as a sensitive tool to detect small hepatocellular cancers is meaningful and is recommended to occur at 6-month intervals in those with long-standing liver disease and hepatitis [72].

Lung cancer: While lung cancer is more common in posttransplant recipients, the difference is not as dramatic as that of other tumors with an SIR of 1.46 [2]. Cigarette use clearly increases the risk of cancer in the renal transplant recipient [73], and hence cessation should be encouraged and emphasized. Outcomes are similar to the general population. There are no supportive data to engage in routine screening using radiography or sputum sampling [69]. The use of chest CT for high-risk patients that smoke following transplantation is similarly unknown.

Prostate cancer: The risk of this cancer is not elevated post transplantation, but it is a prevalent cancer in the older population [2]. Survival rates are relatively better than other cancers due to the slow growing nature and local spread of disease, followed by metastasis to bone. Regular screening methods have been advocated using digital rectal exam and prostate-specific antigen testing [74], although this is not uniformly accepted as the magnitude of benefit of screening is estimated as smaller in the kidney transplant recipient [74]. While the incidence is low, the aging recipient population may result in a higher than expected frequency of cases over time.

Posttransplant Lymphoproliferative Disorder

PTLD is a major cause of morbidity and mortality after solid organ transplantation [75]. The incidence of PTLD differs according to the type of the transplanted organ, being lowest among renal transplant recipients at 1–2 % [76] and highest for intestinal transplant recipients ranging from 19 to 30 % [77, 78]. The risk in renal transplant recipients should not be understated and represents a 20–50-fold higher risk of lymphoma compared to the general population [2]. Most PTLDs are B cell, large non-Hodgkin’s lymphomas but those of T cell in origin confer a more dismal prognosis. Greater than 50 % of PTLDs present in extra-nodal sites and involve the gastrointestinal tract, lungs, liver, mucosal tissue, skin, and CNS. In the renal allograft recipient, PTLD is more likely to develop in the renal allograft, while in heart transplant recipients, lymphoma typically presents in the heart allograft. This predilection of the transplanted organ for subsequent development of PTLD may be attributed to local immune response to foreign tissue. Presentation may be bimodal in fashion with prevalence in the early posttransplant period at 1–2 years and another peak at 4–5 years after transplantation [77].

Pathogenesis: More than 90 % of recipients have been previously infected with EBV and are lifelong carriers of the virus [78]. Among immunocompetent hosts, control of virally infected B cell proliferation is maintained by the development of host antiviral immune response. In a persistent infection, EBV antigen-specific T cells are maintained at a frequency of 1–5 % of peripheral blood T cells that eliminate reactivating and proliferating infected B cells. In contrast, in transplant recipients, 60–70 % of PTLD cases are associated with EBV infection due to unrestrained growth of EBV-infected B cells [79]. The transformation of EBV-infected memory B cells into malignant tissue involves the production of latent viral proteins related to EBV nuclear antigen 2 (EBNA-2). Activation of this transcription factor initiates B cell proliferation. B cells containing these viral particles are normally recognized and destroyed by cytotoxic T cells. In immunosuppressed patients, when T cell functions are impaired, uncontrolled proliferation of EBV-infected B cells will lead to the development of PTLD [80].

EBV-negative PTLD incidence is estimated at 30–40 % [81] and typically presents later within 3–5 years after transplantation with monomorphic pathology and carries worse prognosis [82, 83]. The mechanism of EBV-negative PTLD development is not clear. Some reports suggest a role of HHV8 [84], or possible chronic antigenic stimulation of the immune system [85]. The existence of EBV-unrelated PTLD strengthens the theory of multifactorial pathogenic process involving the interaction between viral oncogenes, impaired immunity, genetic actors, and chronic antigen stimulation [86].

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Mar 5, 2017 | Posted by in NEPHROLOGY | Comments Off on Malignancies After Transplantation and Posttransplant Lymphoproliferative Disorder

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