© Borgis - Postępy Nauk Medycznych 2/2014, s. 95-103
*Renata Wieczorek-Godlewska, Magdalena Durlik
Nawrót choroby nowotworowej o dramatycznym przebiegu u pacjentki po przeszczepieniu nerki – analiza problemu nawrotu nowotworu po transplantacji i opis przypadku
Dramatic recurrence of cancer in a patient who underwent kidney transplant – an analysis of post-transplant cancer recurrence and case report
Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw
Head of Department: prof. Magdalena Durlik, MD, PhD
Choroby nowotworowe są obok chorób układu sercowo-naczyniowego i zakażeń główną przyczyną zgonów pacjentów po przeszczepieniu narządu unaczynionego. Po transplantacji najczęściej rozwijają się nowotwory de novo, znacznie rzadziej jest to nawrót choroby nowotworowej rozpoznanej i leczonej przed przeszczepieniem; wyjątkowo zdarza się przeniesienie nowotworu z narządem dawcy. O ile epidemiologia i przebieg choroby nowotworowej powstającej de novo po przeszczepieniu są stosunkowo dobrze zbadane, to problem nawrotu nowotworu sprzed transplantacji, jako znacznie rzadszy i wykazujący bardziej indywidualny, trudny do wcześniejszego przewidzenia przebieg, jest wyzwaniem dla współczesnej transplantologii.
Praca jest opisem nadspodziewanie szybkiego nawrotu rzadkiego nowotworu, mięsaka podścieliskowego macicy, który wystąpił w krótkim czasie po przeszczepieniu nerki od dawcy zmarłego, u pacjentki po leczeniu onkologicznym zakończonym 7 lat przed transplantacją. Dramatyczny przebieg choroby, powikłany nawracającą masywną zakrzepicą żyły głównej dolnej, jam prawego serca i zatorowością płucną oraz ciężkim powikłaniami infekcyjnymi, jest przykładem trudności w kwalifikowaniu pacjentów z wywiadem onkologicznym do transplantacji. Skala problemu będzie prawdopodobnie narastała w związku z akceptacją na listach oczekujących na przeszczepienie biorców w starszym wieku oraz coraz skuteczniejszym leczeniem chorób nowotworowych.
Autorzy pracy na kanwie opisywanego przypadku i analizy piśmiennictwa próbują znaleźć odpowiedź na pytanie o ryzyko nawrotu nowotworu u pacjenta poddanego leczeniu immunosupresyjnemu oraz określić możliwości jego minimalizowania. Odpowiedź na te pytania jest szczególnie istotna w sytuacji znacznie bardziej agresywnego przebiegu nawrotu nowotworów, ograniczonych możliwości leczenia onkologicznego oraz gorszego rokowania u pacjentów nieimmunokompetentnych.
Beside cardiovascular diseases and infections, cancers are the main cause of death in patients after transplantation of a vascularised organ. After transplantation, usually de novo cancers develop. Recurrence of cancers which had been diagnosed and treated before transplantation is much rarer. In exceptional cases, cancer is transferred with the donor’s organ. The epidemiology and the course of post-transplant de novo neoplasia is relatively well known. However, the issue of recurrence of pre-transplant cancer, which is significantly rarer and its course more individualised and difficult to predict, poses a challenge to contemporary transplantation.
This paper presents an unexpectedly rapid recurrence of rare cancer – endometrial stromal sarcoma – which occurred shortly after transplantation of a kidney from a deceased donor to a patient who had undergone cancer treatment 7 years earlier. The dramatic course of the disease, complicated with recurrent massive thrombosis of the inferior vena cava and the right cardiac cavities as well as pulmonary embolism and serious infectious complications illustrate the difficulties related to qualifying patients with a history of malignancy for transplantation. The scale of the problem will most likely increase as older recipients are being put on transplant waiting lists and cancer treatment is becoming more effective.
The authors of this paper, based on the case report presented and the review of literature, attempt to find an answer to the question about the risk of cancer recurrence in patients receiving immunosuppressive therapy and find out how it can be minimized. Answering these questions is particularly important if the recurrent cancer is substantially more aggressive, cancer treatment options are limited and the prognosis is poor due to lack of immunocompetence.
Beside cardiovascular diseases and infections, cancers are one of the three main causes of death after renal transplantation. At present, the risk of death from cancer developing after transplantation of a vascularised organ is estimated at 7-12%, and in recent years it is systematically increasing (1). It results from the fact that mortality from other causes, i.e. cardiovascular diseases and infections, is decreasing. Increasingly better knowledge of risk factors for cardiovascular diseases, prevention programmes and availability of effective treatment modalities, as well as quick and usually effective treatment of infections, result in cancers being an increasingly more common cause of death in patients with an active graft. Equally important are older age of transplant recipients, longer survival of post-transplant patients and increasingly more effective immunosuppressive drugs, which at the same time interfere with the recipients’ immune system to a greater extent. It is estimated that within the next 20 years cancers will become the main cause of death after transplantation (2). This results from not so well defined risk factors for neoplasia, frequently ineffective screening programmes and considerably more limited cancer treatment options compared with non-transplant patients.
The risk for post-transplant cancer increases 3-5 times compared with the general population of the same age and sex (3). After transplantation, usually de novo cancers develop. Recurrence of cancers which had been diagnosed before transplantation is much rarer. Sporadically, cancer is incidentally transferred with the donor’s organ. Epidemiology of de novo post-transplant cancers is relatively well known. The aim of this paper was to analyse the incidence, contributing factors and the feasibility of preventing recurrence of cancers which had been diagnosed and treated before transplantation.
Most information about cancer patients undergoing organ transplant comes from large transplant registers and medical data bases from individual countries. Their review shows that the percentage of patients with a history of malignancy and undergoing kidney transplant compared with all the patients undergoing transplantation is relatively low: in the study by Kauffman et al. (4), based on data from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database, it was 2.1% (1358 of the total of 65 999 patients undergoing renal transplant); in the analysis by Chapman et al. (5), based on the Australia-New Zealand Dialysis and Transplant Registry (ANZDATA), it was 1.8%; and in the study by Brattström et al. (6) it was 4% (210/11 894 and 416/10 448 patients with a pre-transplant history of cancer compared with all the patients undergoing transplant, respectively). However, it should be expected that on the transplant waiting lists the number of patients from this population will grow: accepting older transplant recipients and increasingly more effective cancer treatment must inevitably result in an increased number of patients with a history of cancer becoming candidates for transplantation. Even more than recipients of kidneys, the problem concerns patients who require transplantation of life-saving organs such as the heart, lungs and liver whose irreversible damage paradoxically may result from aggressive treatment of cancer.
The fact that immunosuppressive therapy plays a role in the development of post-transplant cancer is indisputable. It is evidenced by a significant increase in cancer risk in immunosuppressed patients compared not only with the general population but also with patients placed on renal transplant waiting lists, who are at an increased risk of oncogenesis compared with patients who do not develop renal failure. Based on the analysis of the ANZDATA register data, Vajdic et al. (7) have ascertained that the standarized incidence ratio (SIR) for all cancers is 1.35 in the case of dialysed patients and 3.46 in the case of patients after renal transplant. The obvious effect of immunosuppression on oncogenesis is also supported by anecdotal reports of the regression of cancer transferred with a transplanted kidney once the the kidney was removed and the immunosuppressive therapy was discontinued (8, 9).
The effect of immunosuppressive drugs on the process of oncogenesis is complex: it results from the inhibition of inborn mechanisms of immune surveillance over cancer cells, direct anthropogenic effects of the drugs, as well as increased risk of developing viruses with oncogenic potential (Epstein-Barr Virus [EBV], Human Herpes Virus 8 [HHV8], Human Papilloma Virus [HPV], Hepatitis B Virus [HBV] and Hepatitis C Virus [HCV]).
Particularly with respect to calcineurin inhibitors (CNI) – cyclosporin a and tacrolimus, both in vitro and experimental animal studies showed an increased risk of cancerogenesis and angiogenesis as well as tendency to metastasise (10). It was postulated that the influence on oncogenesis might be connected with increased expression of cytokines regulating tumour growth, such as transforming growth factor beta (TGF-β), and tumour growth promotion by increased expression of the vascular endothelial growth factor (VEGF). On the other hand, clinical studies comparing the risk for tumour growth in patients either treated or untreated with CNI did not show significant differences in the long-term assessment (11).
Rather than the effect of individual immunosuppressive agents, the cumulative effect of immunosuppression, dependent on the intensity and duration of immunosuppressive therapy, appears to play a greater role. It is clearly evidenced by the fact that cancer risk increases with the time elapsing from transplantation: according to data from the USRDS (United States Renal Data System) database, in the first year after transplantation the risk for cancer is 3.2%, and after 20 years it reaches 40% (12).
What is also noteworthy is a substantially higher cancer rate in recipients of organs other than kidneys, such as the heart or lung, in whom immunosuppression is usually more potent (13, 14). Gallagher et al. (11) observed an increased cancer risk in patients diagnosed with acute graft rejection within one year of transplantation, who were usually treated with glucocorticosteroid pulses and by way of increasing basic immunosuppression, which meant an increased general “load” of immunosuppression.
In view of the confirmed impact of immunosuppression on the process of oncogenesis, it is particularly important to define the risk for recurrence of the cancer that had been diagnosed and considered cured before transplantation. Many studies suggest that residual, metabolically inactive, “dormant” cancer cells may get activated in the setting of markedly weakened immune system of the recipient, even many years after transplantation (2, 15-17). Regrettably, the contemporary diagnostic modalities do not allow ruling out latent cancer cells with complete certainty or defining their potential for repeat proliferation.
The analyses of transplantation registers show that the post-transplant recurrence risk is 1-25% and is connected mainly with the cancer type and the “grace period” which elapsed from the moment of diagnosis and treatment to the moment of organ transplantation (4-5, 15-16).
In the first historical analyses carried out by Penn et al. based on the Cincinnati Transplant Tumor Registry (CTTR), the overall incidence of cancer recurrence after transplantation of a vascularised organ was 21% (239 recurrences in 1137 patients with a history of cancer undergoing transplantation) (18). Depending on the recurrence risk, Penn et al. classified cancers into three groups:
– cancers with low recurrence risk: < 10% (incidentally discovered renal cancer, testicular cancer, cervical cancer, cancer of the uterine body, thyroid cancer),
– cancers with medium recurrence risk: 11-25% (colorectal cancer, prostate cancer, Wilms tumour, melanoma),
– cancers with high recurrence risk: > 25% (breast cancer, symptomatic renal cancer, urinary bladder cancer, sarcomas, non-melanoma skin cancers, multiple myeloma).
Vast majority of recurrences occurred within 2 years of transplantation (64%); in 24% of patients, cancer recurrence occurred 2-5 years after transplantation, and in the remaining 11% – over 5 years after transplantation.
The recurrence risk was related to the period which elapsed between the time cancer was diagnosed and the time the kidney was transplanted: 54% of recurrences occurred in patients with the “grace period” shorter than 2 years, 33% – in patients with the grace period of 2-5 years, and 13% – when the period between the end of cancer treatment and kidney transplantation was more than 5 years.
Penn’s studies became a starting point for producing current recommendations on the mandatory grace period for individual cancers – the time that has to elapse from the end of cancer treatment until the patient is qualified for transplantation. Penn has proposed a two-year period for most low and medium risk cancers and a five-year period for high recurrence risk cancers (invasive renal cancer, breast cancer, lymphomas).
More recent analyses of the post-transplant recurrence resulted in some reservations about the first works by Penn et al. What deserves notice in the first place is unacceptably high overall risk of cancer recurrence, which was over 20% in the analysis presented and which gives rise to some doubts as to whether patients with a history of cancer are eligible for transplantation. It should be taken into consideration that in a patient with cancer recurrence who is subjected to immunosuppressive therapy, sooner and more aggressive malignancy can be expected, which – combined with limited possibilities of cancer treatment (compared with immunocompetent patients) – significantly worsens the prognosis and increases cancer mortality rates.
However, more recent works show significantly lower risk of cancer recurrence. In the analysis by Chapman et al., based on ANZDATA (5) register data, the overall incidence of recurrences was estimated at about 5% (11 recurrences in 210 patients with a history of cancer), and in a study by Kauffman et al. (4), based on the OPTN/UNOS registry data, the recurrence risk amounted to the total of 2.4% (47 cancer recurrences in 1919 patients a pre-transplant history of cancer).
On the other hand, Brattström et al., based on data from the Cancer and Cause-of-Death Register (6), assessed not the incidence of recurrence but the risk of death related to cancer recurrence, which was estimated at 9.4% (39 of 416 patients with pre-transplant history of cancer died).
To account for these considerable differences between the reports by Penn et al. and the more recent papers, varying, specific nature of the presented registers was pointed out: The CTTR register (currently referred to as IPITTR – Israel Penn International Transplant Tumor Registry) is based on voluntary reporting; reporting for the ANZDATA and OPTN/UNOS registers is mandatory, which increases their credibility and statistical strength of their reviews. What is also of great importance is that fact that most reports in the CTTR register come from an earlier period of transplantation history (40% of the reports were submitted before 1986), which raises hopes that modern diagnostic modalities used for detecting residual pre-transplant cancers are now much more reliable and that some patients who underwent transplantation at that time now would not have been considered eligible for transplantation if the tumour had not been radically removed.
Differences in the previous papers do not, however, change the basic fact that the overall mortality and the mortality related to cancer recurrence in transplant recipients with a history of cancer are markedly higher. In the current analysis by Brattström et al. (6), all-cause mortality in this group increased by 30% (hazard ratio [HR] 1.3; p < 0.0005), and cancer mortality increased over three times in relation to recipients with no history of cancer (HR 3.6; p < 0.0001). The authors have not observed any differences in cardiovascular mortality or infection-related mortality in either group, which clearly suggests that the overall mortality increase is a direct result of an increased number of cancer-related deaths.
The same analysis confirmed that the risk of cancer recurrence and the risk of cancer recurrence-related death depend on the type of cancer; as in the paper by Penn et al., breast cancer, symptomatic cancer of the kidney and the urinary bladder, haematological cancers and gastrointestinal cancers comprised the group of higher risk cancers (over 5-fold increase in the risk of cancer-related death). The group of low risk cancers (less than 5-fold increase in the risk of cancer-related death) comprised prostate cancer, cervical cancer and cancer of the uterine body, thyroid cancer and non-melanoma skin cancer.
Special attention needs to be paid to skin cancer classified in Penn’s analysis as high recurrence risk cancer (53%), and in the paper by Brattström classified as cancer with low risk of cancer-related death. Non-melanoma skin cancers (NMSC) are the most common de novo cancers developed after transplantation; the risk of developing NMSC rises over 100 times compared with the general population (19-20). Also the post-transplant recurrence risk is high: in the analysis by Hanaway et al. (16), the overall incidence of recurrence of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) was 73%; at the same time, there was no death related to cancer recurrence. Although on the whole, in immunosuppressed patients skin cancers are more aggressive and tend to infiltrate and metastasise more, they are relatively easy to detect and respond well to treatment. Thus they are not a contraindication for transplantation and according to some authors, if there are no metastases, no grace period is required before placing a patient on the transplant waiting list.
What is of vital importance in assessing the post-transplant prognosis, apart from cancer type, is its staging at diagnosis. Unfortunately, in most transplant registers based on which the analyses referred to were conducted, cancer staging and its histological type are not taken into account, although they are vital for assessing the risk of recurrence. In the analysis by Kauffman et al. (4), the risk of post-transplant recurrence of the urinary bladder cancer is closely connected with its staging: in situ cancer or non-invasive papilloma rarely recur after transplantation and do not require a grace period; in the case of stage T1-T2 urinary bladder cancer, the recurrence risk is 15%; in the case of cancer in stage T3-T4 at diagnosis, the risk is almost twice as high (27%). Likewise, cervical cancer confined to the cervix has low risk of recurrence (1.3%), while invasive cancer recurs in 62.5%.
The data presented show that in deciding on organ transplantation eligibility in the case of a patient with a history of cancer, many factors need to be taken into consideration: cancer type, staging, histological type and preferably also the course of treatment and response to treatment. Based on these data, international transplantation bodies develop guidelines specifying mandatory grace periods from the moment cancer is considered cured to the moment when the patient is put on a transplant waiting list (21-25).
In the case of most cancers, the grace period is 2 years; in the case of higher recurrence risk cancers it is 2-5 years; and in the case of most invasive cancers it is not less than 5 years.
Unfortunately, due to high individual variability of the course of malignancy, also the recommendations regarding specific types of cancers are not always coherent and clear-cut. In the collation of various guidelines by Chapman et al. (26), early cervical cancer (in situ), according to CARI (Caring for Australasians with renal impairment) guidelines (21) and B&D Bunnapradist and Danowitch (22), does not require any grace period; according to European Best Practise Guidelines (EBPG) (23) and the Canadian Society of Nephrology (CSN) guidelines (24), the grace period should be at least 2 years; and according to the American Society of Transplantation (AST) (25), it should be 2-5 years. This discrepancy renders these uneasy clinical decision even more difficult.
According to the American Society of Transplant Physician Guidelines, the two-year grace period allows avoiding 53% of recurrences, and the 5-year grace period – 87% (27). However, even such long grace periods do not completely eliminate the risk of recurrence. In the analysis by Brattström et al. (6), the risk of death caused by recurrence of cancer from the high risk group, even with a grace period of over 10 years from the diagnosis, was almost four times higher than in transplant patients without a history of malignancy.
On the other hand, a too cautious approach to qualifying patients with a history of cancer for organ donation deprives potential recipients of a chance to receive a transplant, especially if life saving organs such as the heart, lung and liver are needed and long waiting time frequently means death from an underlying disease. Also in the case of patients receiving dialysis, who have other options of renal replacement therapy (apart from transplantation), long participation in the dialysis programme worsens the outcomes of transplantation and frequently renders it altogether impossible due to increasing number of comorbidities. Authors of the guidelines emphasise that the decision on qualifying for transplantation and on the grace period must be made on an individual basis and in consultation with the patient and the patient’s oncologist.
By all means, one should aim at ruling out residual cancer using all available imaging examinations and biochemical tests, and the patient must be made aware of the risk of cancer recurrence which cannot be completely eliminated.
We present a case of cancer recurrence after renal transplantation in a 54-year-old female who was in the care of the Dialysis Unit and the Department of Transplantation Medicine and Nephrology, Transplantation Institute, Warsaw, from January 2007.
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