Malignancies after Transplantation and Posttransplant Lymphoproliferative Disorders

Yolanda Tai Becker

Bryan N. Becker

Division of Transplantation, Department of Surgery and Section of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53792

INTRODUCTION

Cancer is always an important cause of morbidity and mortality, but it poses distinct challenges in immunosuppressed individuals such as transplant recipients. A number of issues have to be considered in this unique patient population, including whether or not to continue immunosuppression; potential recurrence of malignancy after transplantation; and transmission of malignancy from donor organs. The aging of the population in general is certainly reflected in the graying of the donor and recipient populations. This fact alone increases the likelihood that a previously treated cancer is on an individual’s problem list, be it donor or recipient.

Malignancies unfortunately do not dissipate after transplantation. The risk of developing a new malignancy continues to increase even 15 to 20 years after successful kidney transplantation (1). Penn noted a 22% recurrence rate in renal transplant patients with preexisting malignancy (2). Thus, timing of the transplant with respect to the original diagnosis and stage of disease is critical. Worse yet, but nonetheless, a distinct consideration, carcinoma may be a “passenger pathogen” and transmitted from the donor organ.

With the advent of more potent and directed immunosuppression, the risk for posttransplant de novo malignancies is increased. Unfortunately, cancer is now the cause of death for 9% to 12% of all renal transplant recipients (3). The overall risk is increased 3- to 8-fold greater in transplant patients compared to age-matched controls, though this varies widely with cancer type (4). All this suggests that physicians and surgeons must be wary of malignancies in transplant recipients.

RISK FACTORS FOR CANCER AFTER TRANSPLANTATION

Cancer in general appears to occur more frequently in the end-stage renal disease (ESRD) population. Maisonneuve et al (5) compiled a tremendous volume of worldwide registry data from the United States, Europe, Australia and New Zealand (831,804 patients with more than 2,000,000 person-years of follow-up) in an effort to determine rates of malignancy in this group of patients. They noted a standardized incidence rate of 1.18 compared to the general population. A higher risk for cancer was evident in patients greater than 45 years of age, and the risk gradually increased in older individuals. There was a significantly increased risk for renal cancers, bladder carcinoma, thyroid and endocrine malignancies and malignancies putatively associated with viruses.

This is the background upon which cancers after transplantation develop. Not surprisingly, a number of studies have demonstrated that the incidence of cancer after kidney transplantation is higher than in the general population. A review of 10 single-center studies published by Danpanich and Kasiske (1) summarized basic information relating to non-skin malignancies and outcomes. The mean incidence of non-skin malignancies was 5.2% ± 2.6% during an average follow-up of 4.61 ± 2.47 years. This analysis led to a crude annual incident rate of posttransplant non-skin malignancy of 1.48% ± 1.14% per year.

Danpanich and Kasiske went further in their study of 1,500 kidney transplant recipients. They attempted to define risk factors for non-skin malignancies posttransplantation. They noted that, in contrast to the nontransplant ESRD population, age was a strong risk factor for non-skin malignancies after transplantation (relative risk [RR]: 2.00; 95% confidence interval [CI]: 1.21, 3.30, p = 0.0007), similar to other analyses (6, 7, 8). This is not surprising as the incidence of malignancies in general increases with advancing age. Moreover, aging is associated with alterations in immune activity and thus could predispose to an inability to modulate cancer risk over time, especially in the presence of immunosuppressive agents.

Tobacco use was also a risk factor for posttransplant malignancy (RR: 1.12 for each 10 pack-years, 95% CI: 1.02, 1.21, p = 0.015), even in those who had greater than five years of a non-smoking history prior to transplantation. Splenectomy, though largely abandoned now as a pretransplant immunomodulatory therapy, was also associated with an increased risk for posttransplant malignancy (RR: 1.87; 95% CI 1.12, 3.12, p = 0.016). Not surprisingly, a history of invasive cancer prior to transplantation also increased the risk for posttransplant malignancy (RR: 2.38; 95% CI 1.18, 4.83, p = 0.015).

Interestingly, in one of his last manuscripts, Penn addressed the issues surrounding evaluation of transplant candidates with preexisting malignancies (9). He examined data on 1,258 patients with 1,297 different preexisting malignancies. There was a 21% recurrence rate (n = 239) in individuals treated prior to transplantation. Of that group, more than 50% (n = 128) recurred in patients less than 2 years after transplantation. Based on that analysis and previous studies, Penn categorized tumor priors transplant as those with low recurrence rates (1% to 7%); intermediate recurrence rates (11% to 21%) and high recurrence rates (>21%). The highest recurrence rates arose in individuals with a history of breast carcinoma (23%), symptomatic renal cell carcinoma (27%), sarcoma (29%), bladder carcinoma (29%), nonmelanoma skin cancers (53%), and multiple myeloma (67%).

TABLE 24.1. Suggested waiting time prior to transplantation for individuals with previous malignancy

Type of malignancy	Suggested minimum waiting time following treatment before proceeding to transplantation
Symptomatic renal cell carcinoma (small)¹	2 years
Wilms tumor	2 years
Bladder cancer²	2 years
Uterine carcinoma	2 years
Testicular cancer	2 years
Thyroid and other endocrine tumors	2 years
Kaposi and other sarcomas³	2 years
Prostate cancer⁴	2 years
Lymphoma and posttransplant lymphoproliferative disorder	2 years
Leukemias	2 years
Lung cancer	2 years
Cervical carcinoma⁵	2-5 years
Colorectal cancer	5 years
Melanoma	5 years
Renal cell carcinoma (large) or invasive⁶	5 years
Breast cancer	5 years
Anogenital malignancies	Insufficient evidence for recommendation
Multiple myeloma⁷	Insufficient evidence for recommendation
¹Lesions <5 cm ; ²can consider no delay for in situ or noninvasive papillomas; ³patients who have previous Kaposi sarcoma with a previous transplant may wish to forego transplant due to high rate of recurrence; ⁴treatment for localized disease may allow for earlier transplantation; ⁵waiting time following treatment for invasive cervical carcinoma is unclear; ⁶lesions ≥5 cm; ⁷multiple myeloma frequently recurs after transplantation—individuals with active myeloma probably should not be transplanted; monoclonal gammopathy of unknown significance is not a contraindication to transplantation

Basic recommendations for waiting time prior to transplantation have been developed based on these studies by the American Society of Transplantation (10). For most neoplasms, it is acceptable to have a 2-year waiting time between treatment for cancer and transplantation (Table 24.1). For a rare few incidentally discovered isolated small renal cell carcinomas, in situ carcinomas, low-grade bladder cancers, and basal cell skin cancers, it has been suggested that patients do not need to wait at all to proceed with transplantation. Alternatively, waiting time greater than 2 years is recommended for individuals with a history of malignant melanoma, breast carcinoma, and colorectal carcinoma (10). Standard pretransplant evaluation for individuals with a history of malignancy should include history, physical examination and appropriate disease-oriented diagnostic testing. Consultation with an oncologist may be helpful in assessing long-term risk of recurrence posttransplantation.

Even with these recommendations, it is still possible that patients may harbor occult recurrent or de novo
malignancies at the time of transplantation. The group at Pittsburgh published a straightforward analysis of their transplant population, examining individuals who died within 100 days of transplant and were autopsied. While the majority of those individuals received liver allografts, it should be noted that there was a 2.9% frequency of occult malignancy at autopsy (11).

THE ROLE OF IMMUNOSUPPRESSIVE MEDICATIONS

A number of indirect lines of evidence implicate immunosuppressive agents as etiologic factors in the genesis of cancer after transplantation. A reduction in immunosuppression can lead to partial or complete remission of lymphoproliferative disorders and Kaposi sarcoma that arise after transplantation (12). Triple therapy regimens after kidney transplantation are associated with increased rates of malignancy compared to double drug regimens (13). Furthermore, there appears to be a dose-dependent effect of calcineurin inhibition and the likelihood of developing new malignancies after transplantation (14). Finally, data from studies evaluating the use of immunosuppressive drugs in a nontransplant settings, while not definitive, suggest an association between the use of many immunosuppressive drugs and the evolution of new malignancies.

Interestingly, rapamycin, though an immunosuppressive agent, may actually have an anti-neoplastic effect. A growing body of evidence suggests that this drug through one of several mechanisms of action may actually inhibit tumor production. Rapamycin directly inhibits neuroblastoma cell proliferation by attenuating mitogen activiated protein (MAP) kinase activity (15). It also interferes with interleukin (IL)-10 signal transduction to inhibit Epstein-Barr virus (EBV)-related B-cell lymphomas (16); potentiates transforming growth factor (TGF)-β1 induced growth arrest in human cancer cells (17); and actually prolonged the survival of mice inoculated with renal cancer or human bladder cancer cells (18,19). Whether this effect is ultimately clinically present in the context of transplantation remains to be determined.

Despite these observations, there are, as yet, no definitive criteria as to management of immunosuppression in the setting of malignancy after transplantation. A tapering or discontinuation of calcineurin inhibition is often the first step taken with additional immunosuppressive management guided by (a) type of malignancy, (b) type of treatment for the malignancy, and (c) the general function of the transplanted organ over time. Acute rejection certainly can arise as medications are tapered. However, two considerations are significant. Many medications given for malignancies are also immunosuppressive themselves. Their effects have to be accounted for in any decision to further alter immunosuppression. Furthermore, regular monitoring of graft function may obviate drastic changes in immunosuppression by allowing for early interventions to limit the toll of rejection episodes.

DONOR-TRANSMITTED MALIGNANCIES

Donor malignancies transmitted to recipients were acknowledged as the source of the first cases of malignancies reported in transplant patients. The late Dr. Israel Penn, interested in this topic, founded the Denver Transplant Tumor Registry in 1968 to track data regarding malignancies in transplant recipients. This registry subsequently became the Cincinnati Transplant Tumor Registry, and after Dr. Penn’s death, it was renamed the Israel Penn International Transplant Tumor Registry. The Israel Penn International Transplant Tumor Registry and its predecessors have been voluntary registries. Hence, it has always been difficult to define a true rate of transmission of malignancy. To offset this a bit, the United Network for Organ Sharing (UNOS) undertook an expansion of its data collection to include posttransplant malignancy information. This occurred in a two-step process. These efforts in combination with the Israel Penn International Transplant Tumor Registry have afforded us a large gain in our understanding of donor-related malignancies over the last 5 years.

Penn’s last publication on donor cancers described 117 cases of transmission of donor malignancy to recipient (20). There was a 67% mortality rate in the 66 patients who developed disseminated disease with a more variable survival in individuals with localized disease. An updated assessment of UNOS data published in 2002, reported on 34,933 deceased donors and 108,062 recipients (21). Twenty-one donor-related malignancies from 14 deceased and three living donors were identified. Fifteen tumors were described as donor-transmitted (malignancies present in the donor at the time of transplantation). Six tumors were donor-derived (de novo malignancies that develop in transplanted donor hematogenous or lymphoid cells after transplantation). These data yielded a deceased donor-related tumor rate of 0.04%.

Melanoma, breast, neuroendocrine, lung, small cell, prostate, adenocarcinoma, oncocytoma, and a variety of other tumors were among the donor-transmitted malignancies (21, 22, 23, 24, 25). Leukemia, posttransplant lymphoproliferative disorder (PTLD), and adenocarcinoma were the donor-derived malignancies. The overall mortality among patients developing donor-related malignancies was 38% with transmitted tumors being somewhat higher (46%) than derived tumors (33%).

UNOS also reported important data examining transplant outcomes in 1,276 organ transplants from 488 donors with a known past history of cancer (21). Recipients developed a total of 54 posttransplant malignancies but none of these were donor-related.

Several tumor types have high transmission rates and use of organs from these potential donors should be avoided. Thirty patients received organs from a donor with melanoma and 23 developed donor-derived disease (77% transmission rate). Of these 23 patients, 18 (60%) died from metastatic disease. Choriocarcinoma demonstrated a 93% transmission
rate (13/14 patients). Lung cancer also has a high metastatic potential.

More controversial is the use of organs from patients with low-grade breast or colon cancer. As cancer screening rates increase, more in situ cancers are likely to be discovered. With the current average donor rate of 20 per million patients (26), nine additional donor organs would result from the use of organs from patients with stage 0-1 breast or colon cancer. While this may seem a modest number, this would provide organs for 16% of status 1 patients on the liver recipient list. However, based on the aforementioned data, UNOS has recommended against using donors with a history of melanoma, choriocarcinoma, lymphoma, and carcinoma of the lung, breast, kidney, and colon given their risk for transmission (Table 24.2).

Donors with CNS Malignancies

Donors with central nervous system (CNS) malignancies are a bit more unique. Until recently, there was a consensus opinion that the risk of donor-transmitted malignancy was negligible from donors with CNS tumors. An initial summary report from UNOS was unable to note transmission of cancer to any of 1,220 recipients of organs from 397 donors with CNS tumors (21). Case series from Australia and New Zealand as well as the Czech Republic appeared to confirm this low risk (27,28). The only caveat that went in concert with these findings was the recommendation from UNOS to avoid CNS tumors that might have a higher risk for transmission, e.g., glioblastoma multiforme and medulloblastoma (Table 24.3). On the heels of those publications, there was a report to the UNOS registry of transmission of glioblastoma multiforme to recipients of organs from a donor who had this tumor. Further concerns were raised by the study of Buell et al (29). They described 62 recipients of organs from individuals with a history of or active CNS malignancy from the Israel Penn International Transplant Tumor Registry. Eight transmitted tumors were identified in individuals who received organs from a donor with glomerular basement membrane. Seven of those individuals subsequently died as a result of metastatic disease. Three transmitted malignancies were noted in individuals who received organs from donors with medulloblastoma. The authors noted a number of risk factors for transmission from donor to recipient of a CNS malignancy, including compromise of the blood-brain barrier, high-grade tumors, ventriculoperitoneal or ventriculoatrial shunts, prior craniotomy; and systemic chemotherapy.

TABLE 24.2. Malignancies with an increased risk of donor to recipient transmission

Malignant melanoma

Choriocarcinoma

Lymphoma

Carcinoma of the lung

Carcinoma of the breast

Renal cell cancer

Carcinoma of the colon

SOLID TUMORS AFTER TRANSPLANTATION

The incidence of solid tumors after kidney transplantation is variable. Data from the United States Renal Data System (USRDS) 2003 annual data report suggest that gastrointestinal, breast and lung cancer affect 6% to 12% of kidney transplant recipients (3). Risk factors for these malignancies include older age, male gender, and non-Hispanic ethnicity (3). The management of these tumors, including staging and treatment is similar to that undertaken in the nontransplant population with the caveat that a reduction in immunosuppression is part of the treatment approach in many instances. While this maneuver theoretically improves the innate immune response to the malignant cells, it also minimizes some of the untoward effects of too much immunosuppression during treatment for the malignancy, e.g., opportunistic infections, marrow toxicity. As with all such tumors, appropriate consultation with an oncologist is important to gauge the best form of treatment.

Renal Cell Carcinoma

The incidence of renal cell carcinoma has been steadily rising from 2.3% to 4.3% between 1975 and 1995 (30,31) (Fig. 24.1). This rise in incidence is largely attributed to improvements in imaging techniques, and earlier stage renal cell carcinoma is being discovered. Surgical resection remains the cornerstone of therapy and partial nephrectomy is certainly possible in a large number of cases. If a potential donor has a history of a small, resected renal cell carcinoma, can the contralateral kidney or other solid organs be used safely? In several case series (32, 33, 34), small T1-2 N0 M0 (less than 4 cm) tumors had no postoperative recurrences following partial nephrectomy. The risk of asynchronous or bilateral disease is only 2% to 5%. In a study of 70 patients with incidentally discovered renal cell carcinoma, four patients developed renal cell carcinoma in the contralateral kidney 2, 3, 3, and 4 years after the original partial nephrectomy. In the Penn registry, 14 cases are reported in which a small renal cell carcinoma was noted in a single kidney, the contralateral kidney was normal and was used for transplantation. No patient developed donor-related malignancy in up to 153 months of follow-up. In another 14 cases, a small tumor was noted on the donor organ at the time of transplant
(11 cadaver donors, three living donors). At 14 to 200 months follow-up, there has been no recurrence in the recipients.

TABLE 24.3. Central nervous system tumor transmission

Tumor type	N	Number of recipients with transmission
Astrocytoma	14	1
Glioblastoma	26	8
Medulloblastoma	7	3

FIG. 24.1. Renal cell carcinoma. Renal cell carcinoma, clear cell type, is characterized by nests of cells with clear cytoplasm separated by a dense vascular network. Magnification 400×.

There have been several reports of use of other organs from donors with renal cell carcinoma (35,36). Sack and colleagues (36) reported transmission of renal cell carcinoma; however, the donor had caval invasion at the time of procurement. A screening chest radiograph in a potential donor should be carefully examined, as 30% of metastatic disease from renal cell carcinoma is discovered in the lungs. While the number of cases is small, given the natural history of early renal cell carcinoma, the data suggest that organs from donors with renal cell carcinoma can be used. Favorable histology (clear or papillary cell rather than sarcomatoid), low grade, and small size are associated with low risk of tumor transmission. Potential recipients must be informed that there is a small risk of transmission, but this must be weighed against the chance of death while on the waiting list. No clear-cut recommendations for follow-up have been established; however, serial imaging and urinalysis is likely warranted.

Renal cell carcinoma is one of the most common tumors in the ESRD population. Denton and colleagues (37) reported on 266 incidental nephrectomies performed at the time of transplant. A 100-fold increase in prevalence of renal cell carcinoma in the dialysis population was noted. Risk factors for development include duration of dialysis and acquired renal cystic disease. In the UNOS database, 1,022 out of 54,901 recipients had previously diagnosed renal cell carcinoma. If the disease was found incidentally, the recurrence rate was only 3%. The peak incidence of recurrence was 2 to 5 years posttransplant. Because of the behavior of renal cell carcinoma, the current recommendations for wait time are for incidentally found disease—no additional disease-free waiting period; tumors less than 5 cm—2 years; and tumors greater than 5 cm—5 years with no evidence of disease (10).

Nonmelanoma Skin Cancers

Skin cancers in transplant recipients have a cumulative incidence of 10% to 15% after 10 years. Moreover, these cancers account for more than 50% of all malignancies in transplant recipients. Squamous cell and basal cell carcinomas account for more than 90% of all skin cancers in transplant recipients (38, 39). Their incidence increases with the duration of immunosuppressive treatment. The cumulative incidence of skin cancer in Queensland, Australia, increases from 7% after 1 year to 82% after 20 years of immunosuppressive treatment.

Squamous cell carcinoma occurs 65 to 250 times more frequently in transplant recipients compared to the general population. Basal cell carcinomas are increased at least 10-fold in the transplant population.

The mean time between transplantation and diagnosis of a tumor is 8 years for patients who received transplants around age 40 but only 3 years for individuals transplanted after the age of 60 (40,41). The severity of these lesions is directly related to their number. Notably, 30% to 50% of patients with squamous cell carcinomas also have basal cell carcinomas. The average time between identification of a first and second skin cancer lesion varies between 13 and 15 months (42).

Carcinomas often arise in conjunction with multiple warts and premalignant keratotic lesions. Keratoacanthomas and Bowen’s disease (intraepidermal carcinoma in situ) are found frequently in transplant recipients and they represent significant risk factors for progression to frank malignant lesions
(Fig. 24.2). The distribution of these lesions appears to be age-related. Transplant recipients <40 years old are more likely to have lesions on the dorsum of their hands, forearms and upper trunk. Older transplant recipients tend to develop lesions on the head.

The tumors themselves are more aggressive in transplant recipients than in non-immunosuppressed individuals. They grow rapidly with a local recurrence rate that approximates 15% even by 6 months postresection (38). Poor prognostic features for such cancers in transplant recipients include multiple tumors, localization to the head, multiple extracutaneous tumors, older age, and increased sun exposure (43,44). Histological features of aggressive tumors in these individuals include poorly differentiated, tumor thickness >5 cm, and invasion of the underlying tissue (44,45).

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