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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

The incidence of de novo malignancies is increased in organ transplant recipients, and patients with hepatic carcinomas are at high risk for tumor recurrence after liver transplantation. Data about recurrent cancer after orthotopic liver transplantation (OLT) in patients with a history of nonhepatic malignancy are very limited. We retrospectively analyzed data from 606 adult OLT recipients and identified 37 patients (6.1%) with a preexisting extrahepatic malignancy. In the same group, 43 patients (7.0%) developed de novo cancer. Preexisting malignancies included 26 solid tumors and 11 hematological malignancies, including 7 patients with Budd-Chiari syndrome due to myeloproliferative disorders (MPDs). Patients had been selected for OLT because of the expected good prognosis of their preexisting malignancy. Except for 3 patients, recipients were tumor-free at OLT. The median interval from tumor diagnosis to OLT was 44 months (range, <1-321). After a median follow-up of 66 months post transplantation (range, 4-131), all but 1 recipient with incidental colon carcinoma were free of recurrence. No patient with MPD showed leukemic transformation, whereas a patient with neurofibromatosis experienced growth of skin fibromas. Our data and an included review of published OLT recipients with preexisting malignancies have enabled us to show that recurrence rates are comparable for nontransplanted patients and renal-transplant recipients. In conclusion, cancer recurrence is low if OLT recipients are carefully selected. Therefore, previous extrahepatic malignancy should not be considered a contraindication for OLT per se, but the oncologic/hematologic prognosis should be considered, particularly with respect to the current 5-year survival rate of OLT. Liver Transpl, 2008. © 2008 AASLD

The incidence of extrahepatic de novo malignancies following orthotopic liver transplantation (OLT), including solid tumors and hematological malignancies, ranges from 4.7% to 15.7%, and the underlying mechanisms and management of these malignancies have attracted substantial interest in the past decade.1, 2 Also, transplantation for treatment of liver neoplasms, such as hepatocellular carcinoma (HCC) or cholangiocellular carcinoma, can lead to accelerated growth and dissemination of residual malignant cells, and the outcome of patients transplanted for HCC has been extensively analyzed and subsequently improved.3, 4 In contrast, data concerning the outcome of patients with a history of extrahepatic malignancies before OLT are very limited, and no distinct guidelines exist for such patients presenting for evaluation. Surveillance and elimination of tumor cells through various mechanisms represent an important challenge for the immune system, which can be impeded by immunosuppressive therapy in multiple ways, including attenuation of cytotoxic T-cell and natural killer cell functions and disturbance of humoral interaction with macrophages.5, 6 Therefore, transplant recipients may be at increased risk for growth of dormant malignant cells and, eventually, for tumor recurrence. Data analysis from more than 1000 renal-transplant recipients with previous malignancies, generated by Israel Penn and colleagues7–9 from the Cincinnati Transplant Tumor Registry, showed a recurrence rate of 22% and led to recommendations to postpone transplantation for 2 to 5 years, depending on the type of tumor. However, although renal transplantation can be protracted through hemodialysis, the medical condition of OLT candidates with decompensated cirrhosis does usually not allow postponement of transplantation. Therefore, in 1996, after analysis of 44 OLT recipients with previous malignancies, Penn7 recommended that transplantation may be undertaken “if the malignancy would have been totally eradicated, and the stage of the neoplasm is not associated with a poor prognosis.” To add further insight to this debatable issue, we report our transplant center's experience 1 decade after the publication of these recommendations and review the scarce existing literature.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Between 1996 and 2006, 606 OLTs in adult patients were performed at the Hamburg University Transplant Center. We identified 37 patients (12 male, 25 female) with a history of extrahepatic malignancy who had been in close medical surveillance through their oncology specialists or surgeons after tumor remission and on whom an update restaging was performed during evaluation for OLT. Only candidates with a previous low tumor stage or with a highly curable disease despite an advanced tumor stage and a long interval from tumor treatment had been accepted for OLT. Therefore, the selection of candidates included a hematology/oncology consultation: if the oncological probability of survival over 5 years was considered to be at least 50%-60%—immunosuppression disregarded—this led to final acceptance for OLT by an interdisciplinary team including hepatologists, oncologists, and transplant surgeons. For this retrospective study, all patients were seen at the outpatient clinic at the time of data collection or were telephone-interviewed to ensure that a recent visit at their specialist verified that they were still in remission. Informed written consent was obtained from each patient.

The underlying liver diseases in these recipients were as follows (Table 1): hepatitis C virus cirrhosis (HCV; n = 7, including 2 with HCC), hepatitis B virus cirrhosis (HBV; n = 2), HCV plus HBV (n = 2), autoimmune hepatitis–related cirrhosis (n = 4), primary sclerosing cholangitis (n = 2), acute liver failure (n = 3), alcoholic cirrhosis (n = 5), primary biliary cirrhosis (n = 3), secondary biliary cirrhosis (n = 1), alpha-1 antitrypsin deficiency (n = 1), and Budd-Chiari syndrome (BCS; n = 7). For data analysis of preexisting malignancies, all hepatic tumors that led to liver transplantation were excluded (HCC, cholangiocellular carcinoma, and liver metastases).

Table 1. Basic Clinical Data for OLT Recipients with a Tumor History
Patient No.SexMalignancyLiver DiseaseAge at TumorAge at OLTCurrent AgeRejection Episodes
  • Abbreviations: AAT, alpha-1 antitrypsin deficiency; AIH, autoimmune hepatitis–related cirrhosis; ALC, alcoholic cirrhosis; ALF, acute liver failure; ALM, acral lentiginous melanoma; AML, acute myeloid leukemia; BCS, Budd-Chiari syndrome; FAB, French-American-British classification; HBV, hepatitis B virus cirrhosis; HCV, hepatitis C virus cirrhosis; m, man; NF, neurofibromatosis; OLT, orthotopic liver transplantation; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SBC, secondary biliary cirrhosis; SSM, superficial spreading melanoma; w, woman.

  • *

    This patient was transplanted twice because of chronic graft failure. Tumor developed after first OLT.

  • Patients who died.

  • Both patients with PSC and colon carcinoma had underlying ulcerative colitis.

  • §

    All criteria of neurofibromatosis fulfilled.

1mNon-Hodgkin's lymphomaALF5959640
2mNon-Hodgkin's lymphomaHCV5461650
3wNon-Hodgkin's lymphomaPBC6667690
4mAML (FAB M2)HCV466768†1
5wEssential thrombocythemiaBCS3232430
6wEssential thrombocythemiaBCS2323281
7wEssential thrombocythemiaBCS4559600
8wEssential thrombocythemiaBCS2829380
9wEssential thrombocythemiaBCS4647551
10wEssential thrombocythemiaBCS2020292
11wPolycythemia veraBCS4952570
12wFallopian tube leiomyosarcomaHCV3648520
13wOvarian cancerSBC4265710
14wCervix carcinomaALC4243532
15wCervix carcinomaALF344455Chronic
16wVulva carcinoma (squamous)HBV + HCV2526260
17wEndometrial carcinomaAAT6266703
18wBreast cancerAIH5760671
19wBreast cancerALC4758598
20wOral squamous carcinomaALC5253600
21wMalignant melanoma, choroideaHCV5659640
22mMalignant melanoma (SSM)HCV5168692
23wMalignant melanoma (ALM)HCV3440510
24wBasal cell carcinomaALF*6363651
25wBasal cell carcinomaPBC6567690
26mTesticular cancer (seminoma)ALC2450572
27mTesticular cancer (malignant teratoma)AIH2440501
28mProstate cancerHCV6769720
29wRenal cell carcinomaAIH4852540
30wColon carcinomaPBC6161620
31mColon carcinomaPSC3840432
32mColon carcinomaPSC5859592
33wRectum carcinomaHBV5463690
34mOsteoclastomaALC5157640
35wDesmoid tumorAIH5154571
36mOligodendrogliomaHBV4751610
37mNeurofibromas (NF type I)HBV + HCV20§44501

Where applicable and available, the following patient data were retrospectively recorded: patient follow-up after OLT, exact (sub)type of tumor, age at tumor diagnosis, tumor stage and grading, tumor treatment modalities, treatment outcome, interval between tumor diagnosis and OLT, tumor recurrence, interval between OLT and tumor recurrence, patient survival, immunosuppressive regimen, and number of rejection episodes.

Estimates and standard errors of actuarial probabilities of tumor recurrence and de novo tumor development were obtained with the Kaplan-Meier method with SPSS software, version 15.0 (SPSS, Munich, Germany). Patients with posttransplant lymphoproliferative disorders without progression to lymphoma were not included in the de novo tumor group.

Steroids in combination with cyclosporine (with or without induction therapy with polyclonal antibodies) were used for primary immunosuppression in 24 of the 37 patients (65%), and steroids combined with tacrolimus were used in the remaining 13 patients; this reflected a distribution similar to that of the overall OLT group during the quoted period. A change of immunosuppressive regimen was indicated in 12 patients (32%) because of rejection or adverse reactions. Mycophenolate mofetil was added in 16 patients (43%) in order to reduce calcineurin inhibitor dosage, and azathioprine or sirolimus was added in 1 patient each. All rejections were histologically confirmed. Treatment of acute rejection consisted of steroid-bolus therapy for 3 consecutive days as well as dose adjustment or change of immunosuppressive therapy, if necessary. Monoclonal antibodies (for example, OKT3) were not applied to our patient population.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

The 37 OLT recipients with a history of previous malignancy represented 6.1% of the OLT recipients at our transplant center during the observation period. For comparison, we assessed the number of patients without preexisting malignancies receiving OLT within the same period; in this control group, 43 patients developed a de novo malignancy (7.0%). No patient with a preexisting tumor had more than 1 malignancy. The tumors consisted of 11 hematological malignancies, 22 solid malignant tumors, and 4 semimalignant tumors (Tables 2–4). The latter were included as they were known to have a high recurrence or growth rate regardless of immunosuppressive therapy.

Table 2. Outcome of Patients with a History of Hematological Malignancy
Patient No.MalignancyClinical Stage or TypeTreatmentOutcomeInterval to OLT (Months)Follow-Up post OLT (Months)Tumor RecurrenceSurvival
  1. Abbreviations: B-NHL, B-cell non-Hodgkin's lymphoma; CHOEP, cyclophosphamide, hydroxydaunorubicin, Oncovorin (vincristine), etoposide, prednisolone; CR, complete remission; FAB, French-American-British classification; OLT, orthotopic liver transplantation.

1B-NHL (centroblastic lymphoma)IIaChemotherapy CHOEP, rituximabCR555NoYes
2B-NHL (follicular lymphoma grade 2)IIaLymphadenectomy radiationCR9646NoYes
3B-NHL (nodal marginal zone B-lymphoma)IIIaSteroids624No progressionYes
4Acute myeloid leukemiaFAB M2PolychemotherapyCR2594NoNo
5Essential thrombocythemiaHydroxyurea, anticoagulation<1131Stable plateletsYes
6Essential thrombocythemiaHydroxyurea, anticoagulation660Stable plateletsYes
7Essential thrombocythemiaHydroxyurea, anticoagulation16815Stable plateletsYes
8Essential thrombocythemiaAnagrelide, anticoagulation20106Stable plateletsYes
9Essential thrombocythemiaAnticoagulation<199Stable plateletsYes
10Essential thrombocythemiaHyroxyurea, anticoagulation<1120Stable plateletsYes
11Polycythemia veraPhlebotomy3962Progressive cytopeniaYes
Table 3. Outcome of Patients with a History of Solid Malignancies
Patient No.MalignancyClinical Stage, Size, Etc.TNM Stage (Grade)TreatmentOutcomeInterval to OLT (Months)Follow-Up post OLT (Months)Tumor RecurrenceSurvival
  1. Abbreviations: AJCC, American Joint Committee on Cancer; CR, complete remission; FIGO, Federation Internationale de Gynecologie et d'Obstetrique; LNR, lymph node resection; n.a., not available; OLT, orthotopic liver transplantation.

12Fallopian tube leiomyosarcomaAJCC IT1bN0M0 (G1)Hysterectomy, adnectomy, LNRCR11550NoYes
13Ovarian cancerFIGO IBT1N0M0Hysterectomy, adnectomy, LNRCR27871NoYes
14Cervix carcinomaFIGO. IAT1a1N0M0HysterectomyCR168116NoYes
15Cervix carcinomaFIGO IBT1b1N0M0Hysterectomy, LNR (Meigs)CR122131NoYes
16Vulva carcinoma (squamous)FIGO 0TisN0M0Local excisionCR611NoYes
17Endometrial carcinomaFIGO IBT1b2N0M0Hysterectomy, adnectomy, radiationCR4442NoYes
18Breast cancer (ductal)AJCC IT1N0M0 (G1)Resection, radiation, tamoxifenCR3486NoYes
19Breast cancer (ductal)AJCC IT2N0M0Resection, radiationCR20412NoYes
20Oral squamous carcinomaAJCC IT1N0M0ResectionCR288NoYes
21Malignant melanoma (choroidea)smallLocal irradiation (cobalt-60 plaques)CR4164NoYes
22Malignant melanomaClark IT1bN0M0Local excisionCR1929NoYes
23Malignant melanoman.a.n.a.Local excisionCR78130NoYes
24Basal cell carcinomaAJCC I (5 mm)T1N0M0ExcisionCR520NoYes
25Basal cell carcinomaAJCC II (2 cm)T2N0M0ExcisionCR2423NoYes
26Testicular cancer (seminoma)AJCC 1BT2N0M0OrchiectomyCR32187NoYes
27Testicular cancer (malignant teratoma)AJCC IIIAT2N1M1Orchiectomy, LNR chemotherapyCR149125NoYes
28Prostate cancerAJCC IIT2bN0M0 (G1)Prostatectomy, radiationCR2432NoYes
29Renal cell adenocarcinomaAJCC IT1N0M0 (G2)NephrectomyCR4818NoYes
30Colon carcinoma (incidental)AJCC IIICT4N2M0Hemicolectomy, LNR, chemotherapyR0?<112YesNo
31Colon carcinomaAJCC 0TisN0M0Hemicolectomy, LNRCR1040NoYes
32Colon carcinomaAJCC IT2N0M0 (G1)Total colectomy, LNRCR135NoYes
33Rectum carcinomaAJCC IT1N0M0 (G1)Transanal endoscopic surgeryCR10878NoYes
Table 4. Outcome of Patients with Semimalignant Tumors with High Recurrence Risk
Patient No.MalignancyClinical Stage, Size, Etc.TNM Stage (Grade)TreatmentOutcomeInterval to OLT (Months)Follow-Up post OLT (Months)Tumor RecurrenceSurvival
  1. Abbreviations: CR; complete remission; OLT, orthotopic liver transplantation.

34Osteoclastoma (tibia)4 cmResection, ostheosynthesisCR7290NoNo
35Desmoid tumor (abdominal wall)4 cmResectionCR28833NoYes
36Oligodendroglioma3 cm— (G1)None48113Stable sizeYes
37Neurofibromas (multiple)2–6 mmNone69GrowthYes

Basic clinical data are summarized in Table 1. The median age of patients at the time of tumor diagnosis was 48 (range, 20-67) years. The median age at OLT was 54 (range, 20-69) years. The median interval between tumor diagnosis and OLT was 43 (range, <1-321) months. Most patients with myeloproliferative malignancies presented with acute BCS and were therefore diagnosed shortly before OLT, whereas of the other 30 patients, 8 (27%) were diagnosed or treated for their malignancy less than 2 years before OLT, 8 (27%) were diagnosed or treated between 2 and 5 years before OLT, and the remaining 14 patients (47%) were treated more than 5 years before OLT. One tumor was incidentally identified during transplantation (discussed later). In 1 patient (no. 24) who underwent transplantation twice because of chronic rejection, a skin tumor (basal cell carcinoma) developed and was resected before the second transplantation. The median current age of patients alive is 59 (range, 26-72) years, with an overall median follow-up period from OLT to the present or patient's death of 66 (range, 4-131) months.

Of the 11 patients with hematological malignancies, none experienced recurrence or transformation of disease during a follow-up ranging from 4 to 131 months (Table 2). One patient with acute myeloid leukemia was in complete remission already 20 years prior to OLT, and his death 4 months following OLT was related to cardiovascular complications. Of 2 patients with aggressive non-Hodgkin's lymphoma, 1 had developed acute liver failure through HBV recurrence during chemotherapy. At this time, she had received 5 cycles of polychemotherapy and rituximab and was already in complete remission, which is still ongoing more than 2 years after OLT. Seven patients suffered from acute or chronic BCS due to underlying myeloproliferative disorder (MPD; essential thrombocythemia, n = 6; polycythemia vera, n = 1). After OLT, none of these patients showed transformation into leukemia, and platelet or hematocrit levels remained stable under continued hydroxyurea or anagrelide therapy. The patient with polycythemia vera (no. 11) showed progressive leukopenia and thrombocytopenia in a recent blood count, but bone marrow biopsy did not reveal leukemia or aplasia.

Of the 22 patients with solid malignancies, only 1 had recurrent disease. This patient (no. 30) had a stage IIIC colon carcinoma, which was incidentally detected during transplantation. Because the donor liver was no longer transferable to another center, the patient was transplanted and received colectomy and lymph node resection 3 weeks later. Six months following the operation, the patient developed diffuse pleural and lymph node metastases and died rapidly from tumor progression despite palliative chemotherapy. Except for a patient (no. 27) with metastasized malignant teratoma of the testis, including lymph node and late organ metastases (American Joint Committee on Cancer stage IIIA), most of the other OLT recipients had a low TNM stage of their malignancy (Table 3). Testicular cancer, even in this stage, is considered to be a highly curable disease, and given the fact that he was tumor-free more than 12 years before OLT, his prognosis was considered to be excellent. Only 5 patients with a tumor-to-OLT interval of less than 1 year underwent transplantation: the aforementioned colon carcinoma patient (no. 30), 2 patients with the in situ stage (American Joint Committee on Cancer stage 0) of a colon carcinoma (no. 31) or vulva carcinoma (no. 16), patient no. 20 with completely resected T1 stage oral squamous carcinoma, and patient no. 24 with T1 basal cell carcinoma. None of these patients had metastases, and all have remained tumor-free until present. Fallopian tube leiomyosarcoma is a very rare tumor (17 published cases) with a usually poor prognosis.10 However, our patient (no. 12) had a stage I, grade 1 tumor and was free of recurrence following resection for more than 9 years before OLT. She is alive and in good condition 2 years after transplantation.

The 4 semimalignant tumors with a high general risk of recurrence (Table 4) included a resected grade 1 osteoclastoma of the tibia as well as a desmoid tumor, neither of which recurred or caused symptoms after OLT. The patient with grade 1 oligodendroglioma of the brain (no. 36) did not receive therapy because neurosurgery was considered too dangerous on account of the localization of the tumor. This patient never had neurological symptoms until OLT but developed progressive seizures 3 years thereafter. However, multiple imaging scans did not reveal growth of the glioma. The patient with neurofibromatosis type I (no. 37) had multiple skin neurofibromas between 2 and 6 mm in size. He experienced no change in tumor diameter or thickness until OLT, but in the 5 years thereafter, many neurofibromas began to grow slowly, now up to double their original size. This patient received cyclosporine and mycophenolate mofetil as immunosuppressive therapy. He had no acute rejections and, therefore, no steroid-bolus treatments.

Taken together, the 5- and 10-year actuarial probability of tumor recurrence/transformation in our group was 2.9% ± 2.8%, and the actuarial risk of de novo neoplasia was 6.8% ± 1.2% (5 years) and 14.6% ± 2.4% (10 years; Fig. 1). These data along with a review of previous studies reporting OLT recipients with a history of extrahepatic malignancy enabled us to compare recurrence/transformation rates following OLT with those in nontransplanted cancer patients as well as recurrence rates following renal transplantation (Tables 5 and 6).

thumbnail image

Figure 1. Kaplan-Meier estimate of the actuarial probability of recurrence of extrahepatic malignancy after liver transplantation in 37 patients (gray, dotted) and de novo neoplasia after 606 OLTs (black).

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Table 5. Published Cases of OLT Recipients with a History of Tumor or Myeloproliferative Disorder
Author (Year)Number of PatientsOverall Rate of Recurrence/TransformationTumor-OLT Interval (Months)Follow-Up (Months)
MedianMeanRangeMedianMeanRange
  • Abbreviation: OLT, orthotopic liver transplantation.

  • *

    Solid tumors, 1/12 (3.8%); myeloproliferative disorders, 1/6 (16.7%).

Dousset et al.23 (1995)50%24310–48485115–102
Penn7 (1996)4424%266–4111161–67
Kelly et al.11 (1998)2913.8%1046–420291–83
Saigal et al.12 (2001)1811%*12350–24071621–19
Current report372.7%44851–32166694–131
Table 6. Most Frequent Malignancies Before Orthotopic Liver Transplantation, Their Recurrence Rate (Summarized from Refs.7,11,12, and 23 and the Current Report), and Comparison with Renal-Transplanted and Nontransplanted Patients
MalignancyNumber of Published CasesPercentage of Recurrence/TransformationRecurrence Rate in Renal-Transplant RecipientsRecurrence Rate in Nontransplanted Patients
  • NOTE: For a more comprehensive list including additional preexisting malignancies and more cases from other publications, please refer to the online supplementary table.

  • Abbreviations: B-NHL, B-cell non-Hodgkin's lymphoma; n.a., not available; NHL, non-Hodgkin's lymphoma.

  • *

    Including 8 cases of basalioma, 1 squamous cell carcinoma, and 8 not further specified.

  • Lymphoma type (NHL versus Hodgkin's) missing in 9 cases; recurrence in 1 NHL (subtype missing).

  • In retrospect, all 3 cases should not have been transplanted because of advanced stage (see ref.7).

  • §

    For 31 additional cases of patients with myeloproliferative disorders (refs.24–26), please refer to the online supplementary table [total rate of transformation to acute myeloid leukemia: 3 out of 45 patients (6.7%)].

  • These data were taken from refs.7–9.

  • For references, please refer to the online supplementary material.

Lymphoma (all subtypes)185.9%10%Highly variable, ranging from 6% for Hodgkin's stage I to >50% for B-NHL stage IV
Nonmelanoma skin cancer*17*23.5%60%1–18% per 5 years for basal cell carcinoma
Colorectal cancer1618.8%20%Ranging from 3% for rectal cancer stage I to 40% for colon carcinoma stage II and III
Myeloproliferative disorder§147.1%n.a.Refer to the discussion in the main text
Breast cancer1233.3%24%20–40%, depending on stage
Renal cancer70%0% (incidental), 30% (symptomatic)6–70%, depending on stage
Oral squamous carcinoma633.3%n.a.25 to >90%, depending on stage
Malignant melanoma60%29%0.1–50%, depending on stage (only for nonmetastasized carcinomas)
Cervix carcinoma50%5%10–40%, depending on stage
Endometrial cancer50%15%4% (stage I) to >60% (IV)
Thyroid carcinoma425.0%7%5–50% for papillary and follicular carcinomas (anaplastic excluded)

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

These data indicate that tumor recurrence in OLT recipients is low if patients are accurately selected, and survival seems to be not inferior compared to that of patients without extrahepatic malignancy. Despite the yet small number of reported liver transplant recipients with a history of malignant disease, these findings will be relevant for consideration of such patients for transplantation.

The advances in transplantation medicine have led to improved outcome of liver transplantation, increasing age limits, and widening of indications. Therefore, the number of patients with a history of previous malignancy presented to liver transplant units for OLT evaluation is growing. Previously, these patients were selected or rejected on the basis of individual clinical decisions, and in contrast to renal-transplant recipients, no distinct data can predict their outcome. The influence of Cincinnati Transplant Tumor Registry data for renal-transplant recipients as well as the aforementioned recommendations for selection of OLT candidates with a tumor history, composed in the pioneering works of Penn7 and Kelly et al.11 in the 1990s, has led to a reduction of tumor recurrence in a more recent study by Saigal et al.12 in 2001 (Table 5). Of their reported 12 patients with a solid malignancy, only 1 experienced tumor recurrence, and 1 out of 6 patients with MPD suffered from disease progression and transformation to leukemia.

The complete absence of tumor recurrence in our patient population—excluding the patient with incidentally detected advanced stage colon carcinoma during OLT—is probably related to a careful selection of patients. Taking into account the general life expectancy 5 years after OLT at the beginning of our observation period, only candidates with an oncologically estimated 5-year survival of at least 50%-60% were accepted, so our findings are in contrast to the data reported by Penn with a recurrence rate of 24% in 44 patients. In fact, retrospective analysis of recipients who had tumor recurrence led to the conclusion that several of these patients had an advanced tumor stage or a too short interval between therapy and OLT and should not have undergone transplantation.7 We had the privilege of using this early information for our more recent patient acquisition, and this may explain the good results. Additionally, implementation of lower calcineurin inhibitor levels used in OLT recipients during the past decade, the availability of modern immunosuppressive agents, and omitting monoclonal antibodies for treatment of acute rejections may have contributed to the better outcome in this study compared with previous ones. In accordance, the implementation of a low-dose cyclosporine regimen has led to lower incidence of de novo malignancies following renal transplantation in comparison with a high-dose regimen,13 and this demonstrates a possible dose-dependent effect of immunosuppressive therapy on tumor surveillance.

A significant portion of published patients developed recurrence during the first 2 years following transplantation, pointing to a possible role of dormant bone marrow micrometastases, which seem to play a role in a number of tumor types.14, 15 However, the few patients of our study who were at higher risk are still in complete remission. Similarly, Saigal et al.12 reported 4 patients with high-risk carcinomas detected during OLT who did not experience tumor recurrence during follow-up. Therefore, it is of importance to prospectively study the possible underlying biological mechanisms of tumor recurrence, such as bone marrow micrometastasis, which may help us to predict outcome following transplantation in the future.

Information about immunocompromised patients or organ transplant recipients with highly recurrent semimalignant tumors is available only from a limited series of case reports, so the comparability of clinical courses is restricted.16–19 Concerns have been raised that transplant recipients with neurofibromatosis might be at increased risk of tumor growth or development of malignant tumors from neurofibromas, and even a case of late onset neurofibromatosis has occurred following liver transplantation.20-22 Our patient with neurofibromatosis type I also experienced growth of skin fibromas after OLT, and this underlines the importance of close medical attendance of patients after organ transplantation and alludes to the possible role of immunosuppression in patients with this disease.

For patients with MPDs, which are the main underlying cause of BCS, Saigal et al.12 and Dousset et al.23 reported a total of 7 OLT recipients with polycythemia vera or essential thrombocythemia, of whom 1 developed acute leukemia many years after transplantation.12 This was in accordance with 2 other studies, which described 1 out of 11 patients and 1 out of 8 patients with BCS and MPD who developed acute leukemia, respectively.24, 25 Likewise, none of our 7 patients and none of 12 patients with MPD from another study experienced leukemic transformation during a median follow-up of 101 and 65 months after OLT, respectively.26 In comparison, in a nontransplanted patient population, the general transformation rate has been reported to be approximately 5% in 7 years for patients with essential thrombocythemia and 1.3% per year in a 2.7-year follow-up for polycythemia vera.27, 28 This underlines the safety of OLT for patients with BCS and underlying MPD with respect to transformation to acute leukemia.

The total number of published OLT recipients with a history of malignancy prior to OLT is still low, and groups are too inhomogeneous to make a statistically solid statement for patient selection (Table 5). Therefore, it appears useful to sort the currently published patients derived from our report and the previous 4 studies according to their tumor type in order to get an impression of the possible recurrence rates, as shown in Table 6. To add even further information, we compared these data, although unmatched for tumor stage, with the general recurrence rates in nontransplanted patients and with those in renal-transplant recipients, which showed that the risk of cancer recurrence following OLT appears not to be increased compared with that of these patient populations (Table 6). However, such a summary can be of clinical value for decision making of transplant centers only if all relevant data are provided: accurate tumor subtype, stage, grade, tumor therapy, interval to OLT, and follow-up period. For example, the various non-Hodgkin's lymphoma subtypes of our study (Table 2) exhibit extremely variable biological behavior, ranging from indolent to very aggressive. Despite the shortcoming of pioneering studies, providing such data only for some OLT recipients who experienced tumor recurrence, we made an attempt to list each case published to date and sort it by tumor type, also including publications focusing on a single preexisting tumor type. This information can be viewed online (as a supplementary table) at the Liver Transplantation Web site.

If we take into account data from renal-transplant recipients with a previous malignancy, the particularly different clinical course of end-stage liver disease, and the limited yet growing experience from OLT recipients, what is a reasonable approach for the selection of candidates with a tumor history? It is already accepted that a previous malignancy should not be considered a contraindication for OLT in general. However, we believe that the previous recommendation for patient selection—“if the tumor does not have a poor prognosis”—is unspecific for most cases. Instead, the prognosis of each malignancy in terms of 5-year survival rates should be defined in particular, and it should not fall below the general 5-year life expectancy after liver transplantation, which is currently above 70%. However, definite intervals to OLT following tumor treatment cannot be specified from the available data. To improve the prognostic benefit of retrospective data, we recommend the implementation of an open-access database at international transplantation networks recording oncological details of every OLT recipient with a tumor history as well as online use of the Israel Penn International Transplant Tumor Registry. The value of pretransplant bone marrow immunocytology for the detection of dormant tumor cells should be examined in a clinical trial if the interval from tumor treatment to OLT is short. Immunosuppressive therapy based on mammalian target of rapamycin inhibitors, which exhibit antiproliferative effects and have improved outcomes in patients who undergo transplantation for HCC,29, 30 should likewise be studied in OLT recipients with a previous extrahepatic malignancy.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

This article contains Supplementary Material available at http://www.mrw.interscience.wiley.com/suppmat/1527-6465/suppmat

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