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Liver transplantation in patients with liver metastases from neuroendocrine tumors: A systematic review

      Background

      Liver transplantation to treat neuroendocrine tumors, especially in the setting of diffuse liver involvement not amenable to operative resection remains controversial. We sought to perform a systematic review of the current literature to summarize data on patients undergoing liver transplantation with neuroendocrine tumors liver metastases as the indication.

      Methods

      A systematic review was conducted in accordance to the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. Eligible studies were identified using 3 distinct databases through March 2017: Medline (PubMed), ClinicalTrials.gov, and Cochrane library, Cochrane Central Register of Controlled Trials using a search algorithm: “(neuroendocrine or NET) and transplantation and liver.”

      Results

      From the 1,216 records retrieved, 64 studies were eligible. Overall, 4 studies presented data from registries, namely the European Liver Transplant Registry and the United Network for Organ Transplantation/Organ Procurement and Transplantation Network databases, 3 were multicenter studies. The largest cohort of data on patients undergoing liver transplantation for neuroendocrine tumors liver metastasis indication were from single center studies comprising a total of 279 patients. Pancreas was the primary tumor site for most patients followed by the ileum. Several studies reported that more than half of patients presented with synchronous disease (55.9% and 57.7%); in contrast, metachronous neuroendocrine tumors liver metastasis ranged from 17.7% to 38.7%. Overall, recurrence after liver transplantation ranged from 31.3% to 56.8%. Reported 1-, 3-, and 5-year overall survival was 89%, 69%, and 63%, respectively. Several prognostic factors associated with worse long-term survival including transplantation >50% liver tumor involvement, high Ki67, as well as a pancreatic neuroendocrine tumors versus gastrointestinal neuroendocrine tumors tumor location.

      Conclusion

      Liver transplantation may provide a survival benefit among patients with diffuse neuroendocrine tumors metastases to the liver. However, due to high recurrence rates, strict selection of patients is critical. Due to the scarcity of available grafts and the lack of level 1 evidence, the recommendations to endorse liver transplantation for extensive liver neuroendocrine tumors metastases warrants ongoing deliberations.
      Neuroendocrine tumors (NET) are rare neoplasms that arise from cells of the neuroendocrine system. The biologic behavior of these tumors can be heterogenous with clinical presentation varying from an incidental diagnosis in an asymptomatic patient to extensive metastatic disease and refractory carcinoid syndrome.
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      For patients with metastatic disease, the liver is one of the most common sites of NET metastases, with up to 50% of patients developing liver metastasis.
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      Numerous treatment options for cure and disease control have been investigated. The optimal management of hepatic NET metastases remains, however, a topic of debate. Operative resection with curative intent (R0 or R1) is associated with long-term survival, despite a high incidence of recurrence after operation.
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      Unfortunately at diagnosis, >80% of patients present with multifocal or bilobar hepatic metastatic disease that may exclude them from operative cure.
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      In general, palliative treatments for NET aim to relieve symptoms induced by excess serotonin, in the case of functional tumors, or to relieve symptoms caused by the hepatic tumor burden itself.
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      Many nonoperative palliative treatment modalities also have been used for patients with extensive NET liver disease. These liver-directed therapies for NET liver metastases have included ablative techniques, as well as transarterial chemoembolization or radionuclide therapy (111 indium-pentetreotide, Ytrium DOTATOC, Lutetium DOTA or meta-iodobenzylguanidine). These locoregional therapies can be effective in slowing tumor progression and palliating symptoms.
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      Although these therapies may provide some therapeutic benefit, current locoregional and systemic treatment options do not, however, provide a chance for cure.
      Although some of the first cases of liver transplantation (LT) reported in the literature were performed for metastatic liver tumors, contemporary LT largely has been restricted to hepatocellular carcinoma and, in select settings, hilar cholangiocarcinoma.
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      More recently, some investigators have advocated that LT may be an option to treat NET, especially in the setting of diffuse liver involvement not amenable to operative resection.
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      ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary.
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      The role of LT for NET remains, however, controversial. As such, we sought to perform a systematic review of the current literature to summarize data on patients undergoing LT with NET liver metastases as the indication.

      Material and methods

      Search strategy, data sources, and eligibility criteria

      A systematic review was conducted in accordance to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines (Supplemental Table I).
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      A study protocol, agreed beforehand, was strictly followed by all authors. Eligible studies were identified using 3 distinct databases through March 2017; Medline (PubMed), ClinicalTrials.gov, and Cochrane library, Cochrane Central Register of Controlled Trials (CENTRAL). The following algorithm was applied: “(neuroendocrine or NET) and transplantation and liver.” Two independent reviewers (D.I.T., I.N.S.) screened all articles retrieved by the aforementioned algorithm. Reference lists of eligible studies were assessed manually so that no relevant article was missed.
      Eligible studies were considered if data were report on patients undergoing LT with NET liver metastasis as the indication. Exclusion criteria included: 1) animal studies, 2) studies reporting on LT for an indication other than NET, 3) studies involving both NET and another primary cancer without referring specifically to the NET cohort, 4) reviews and meta-analyses, 5) editorials and letters to the editors, and 6) overlapping studies. Regarding any overlapping reports, only the most recent or most informative study for a single center was included in the analyses. There were no study restrictions with regards to language or study sample size.

      Data extraction and tabulation

      After reviewing the full-texts of eligible studies, 2 independent authors (D.I.T., I.N.S.) performed the data extraction and cross-checked all results. Extracted variables included: general study characteristics (eg, author, year of publication, country of enrollment, study design, number of patients), patient demographics (eg, age, sex), primary tumor site, history of hormone therapy and chemotherapy, tumor status (functional, nonfunctional), indications for LT, concomitant multivisceral transplantation, donor classification, immunosuppressive therapy, adjuvant chemotherapy, 1-, 3-, and 5-year overall survival (OS), 1-, 3-, and 5- disease-free survival (DFS), recurrence, mortality (eg, overall and disease-related) and patient status at the end of follow-up. When coding the data, any disagreements were adjudicated by a third reviewer (D.M.).
      Data were tabulated and cumulative analysis was performed when possible. Categorical variables were extracted as numbers and reported as proportions. Regarding continuous variables, the method proposed by Hozo et al was utilized when data were presented as medians with a range to estimate the respective means and standard deviations.
      • Hozo S.P.
      • Djulbegovic B.
      • Hozo I.
      Estimating the mean and variance from the median, range, and the size of a sample.
      DFS was defined as the time from liver transplantation to metastatic or locoregional disease recurrence or occurrence of a new NET tumor. OS was defined as the time from liver transplantation to death or last follow-up. Finally, “absolute survival” rates were estimated to calculate OS and DFS at 1-, 3-, and 5-years after LT.

      Results

      Search results and study characteristics

      The results yielded by the initial algorithm and the successive steps of the selection process are depicted in Fig. Twenty studies were excluded as obvious overlaps or duplications (Supplemental Table II). From the 1,216 records retrieved, 64 studies were finally considered eligible. Due to possible overlap of cohort populations among the studies, registry analyses and multicenter studies were described in a narrative fashion, while single center studies were described cumulatively. Overall, 4 studies presented data from registries, namely the European Liver Transplant Registry (ELTR)
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      and the United Network for Organ Transplantation (UNOS)/Organ Procurement and Transplantation Network databases.
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      Neuroendocrine liver metastases and orthotopic liver transplantation: the US experience.
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      Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database.
      • Nobel Y.R.
      • Goldberg D.S.
      Variable use of model for end-stage liver disease exception points in patients with neuroendocrine tumors metastatic to the liver and its impact on patient outcomes.
      Three were multicenter studies,
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      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
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      Long term results of hepatic resection or orthotopic liver transplantation in patients with liver metastases from gastrointestinal neuroendocrine tumors.
      • Sher L.S.
      • Levi D.M.
      • Wecsler J.S.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumors: outcomes and prognostic variables.
      while the majority of studies were single center reports (57 out of 64).
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      Presence of cytokeratin 19-expressing cholangiocarcinoma-like tumour in a liver metastatic lesion of rectal neuroendocrine tumour.
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      The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors.
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      Gastrointestinal neuroendocrine tumor with unresectable liver metastases: an example of multimodal therapeutic approach.
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      Living donor liver transplantation: a life-saving option in emergency situations for diffuse hepatic neuroendocrine tumor metastasis.
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      Outcomes following liver transplantation for metastatic neuroendocrine tumors.
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      Liver transplantation for hepatic metastatic pancreatic insulinoma with a survival over five years.
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      Liver transplantation for symptomatic liver metastases of neuroendocrine tumours.
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      Liver transplantation for patients with metastatic endocrine tumors: single-center experience with 15 patients.
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      Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival.
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      Liver transplantation for metastatic neuroendocrine tumor: a case report and review of the literature.
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      Liver transplantation for neuroendocrine tumors.
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      Primary and secondary liver endocrine tumors: clinical presentation, surgical approach and outcome.
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      Multimodality treatment for gastric carcinoid tumor with liver metastases.
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      Diagnosis and management of metastatic gastrinoma by multimodality treatment including liver transplantation: report of a case.
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      Living-related liver transplantation for multiple liver metastases from rectal carcinoid tumor: a case report.
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      Orthotopic liver transplantation for carcinoid tumour metastatic to the liver: anesthetic management.
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      Metastatic pancreatic VIPoma: deteriorating clinical course and successful treatment by liver transplantation.
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      Intrahepatic arterial chemoembolization for hepatocellular carcinoma and metastatic neuroendocrine tumors in the era of liver transplantation.
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      Metastatic endocrine tumors: medical treatment, surgical resection, or liver transplantation.
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      Orthotopic liver transplantation in the treatment of metastatic neuroendocrine tumors of the liver.
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      • et al.
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      Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas.
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      Orthotopic liver transplantation for secondary malignancies of the liver.
      In turn, the largest cohort of data on patients undergoing LT for NET liver metastasis indication were from single center studies comprising a total of 279 patients (Supplemental Table III).

      Patient and primary tumor characteristics

      The demographic and clinical data of patients who underwent LT for NET liver metastases between 1974 and 2016 are summarized in Table I. Among the included studies, mean patient age ranged from 44.9 to 48.7 (age range, 11 to 75) with more male versus female patients. Pancreas was the primary tumor site for most patients followed by the ileum. Specifically, in analyzing the ELTR database, Le Treut et al reported 44.1% (94/213) and 22.5% (48/213) of primary tumors originated from the pancreas and the ileum, respectively.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      Sher et al described pancreas/duodenum as the primary tumor site in 49.4% (42/85) of cases,
      • Sher L.S.
      • Levi D.M.
      • Wecsler J.S.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumors: outcomes and prognostic variables.
      which was similar to another study by Le Treut et al that analyzed the records from 17 French centers (48.2%).
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      In addition, cumulative analysis from single center studies demonstrated the pancreas to be the most common site of primary tumor origin (53.4%, 149/279) followed by the ileum (23%, (64/279).
      Table IFeatures and demographics of eligible studies
      PMIDFirst author (year of publication)Years of enrollmentCountry/databaseStudy designNo. of patientsMale: FemaleAge (y)
      Mean (SD)Range
      Registry databases25989503Nobel (2015)2002–2014UNOS databaseRetrospective120NRNRNR
      23532105Le Treut (2013)1982–2009ELTR databaseRetrospective213114:9946 (11)16–71
      22254141Nguyen (2011)1988–2011UNOS databaseRetrospective184100:8444.9 (NR)11–69
      21844436Gedaly (2011)1988–2008UNOS databaseRetrospective15084:6645.1 (SE:12.5)11–69
      Multicenter experience27900037Pasqual (2016)1990–2012ItalyRetrospective40:448.75 (11.84)N/R
      26171686Sher (2015)1988–2012USARetrospective8551:3446.75 (17)16–75
      18444921Le Treut (2008)1989–2005FranceRetrospective8546:3945 (11)18–64
      Single center experience
      Details on single center experience are provided in Supplemental Table III.
      Details on single center experience are provided in Supplemental Table III.
      1974–2016
      Details on single center experience are provided in Supplemental Table III.
      Details on single center experience are provided in Supplemental Table III.
      279147:11542 (10)13–67
      Details on single center experience are provided in Supplemental Table III.
      Only 3 studies provided details on the histologic type of primary tumors.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      • Gedaly R.
      • Daily M.F.
      • Davenport D.
      • et al.
      Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      Among functional tumors, carcinoid was the most common subtype, whereas the incidence of nonfunctional tumors ranged from 30.3% (single center analysis) to 52.6%.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      With regard to liver involvement, NET metastases seemed to occupy <60% of liver parenchyma in most cases (Table II).
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      Table IIPrimary tumor characteristics
      Author (year of publication)Registry databasesMulticenter experienceSingle center experience
      Nobel (2015)Le Treut (2013)Nguyen (2011)Gedaly (2011)Pasqual (2016)Sher (2015)Le Treut (2008)
      Primary tumor site
       Bronchial treeNR16 (10 carcinoids, 6NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      005 (3 carcinoids, 2 NF)14
       StomachNR8 (1carcinoid, 7NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      003 (3 NF)7
       DuodenumNR3 (2 gastrinomas, 1NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      041 (13 gastrinomas, 2 VIPomas, 2 glucagonomas, 2 insulinomas, 1 carcinoid, 1 polymorph, 20 NF)20
       PancreasNR94 (18 gastrinomas, 6 insulinomas, 6 VIPomas, 4 polymorphs, 3 glucagonomas, 3 carcinoids, 54NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      142149
       JejunumNR16 (2 carcinoids, 1 GFRHoma, 1 VIPoma,1 gastrinoma, 11NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      006 (2 carcinoids, 1 VIPoma, 3 NF)21
       IleumNR48 (38 carcinoids, 10NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      3016 (14 carcinoids, 2 NF)64
       Right colonNR4 (4NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      0008
       Sigmoid colonNR1 (1NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      004 (4 NF)6
       RectumNR5 (5NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      006
       Common bile ductNR1 (1 carcinoid)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      0000
       UndetectedNR17 (3 carcinoids, 1 gastrinoma, 13NF)NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      01610 (2 carcinoids, 8 NF)13
       OtherNR0NRNR
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      024 digestive tract, 1 lung, 1 both pancreas and bowel, 1 choledochal cyst07
      Functional status of the tumor, n (%)
       FunctionalNR101 (47.4)NRNR2 (50)NR43 (50.6)136 (69.7)
       NonfunctionalNR112 (52.6)NRNR2 (50)NR42 (49.4)59 (30.3)
      Extent of liver involvement (%)
       <60NR113NRNRNRNR61<50: 50
       >608524>50: 46
      51 carcinoids, 6 insulinomas, 3 glucagonomas, 11 gastrinomas, 9 VIP-secreting tumors, and 70 unspecified NETs.
      Several studies reported that more than half of patients presented with synchronous disease (55.9% and 57.7%); in contrast, metachronous NET liver metastasis ranged from 17.7% to 38.7%.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      Of note, diagnosis of liver metastases before the identification of the primary tumor was reported as 20.6%
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      and 24.6%
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      in 2 multicenter studies and 18.7% in the cumulative single center analysis.
      • Ishii N.
      • Araki K.
      • Yokobori T.
      • et al.
      Presence of cytokeratin 19-expressing cholangiocarcinoma-like tumour in a liver metastatic lesion of rectal neuroendocrine tumour.
      • Mazzaferro V.
      • Sposito C.
      • Coppa J.
      • et al.
      The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors.
      • Rao B.
      • Segovia M.C.
      • Kazimi M.
      • et al.
      Use of everolimus after multivisceral transplantation: a report of two cases.
      • Ismail H.
      • Broniszczak D.
      • Markiewicz-Kijewska M.
      • et al.
      Metastases of pancreatic neuroendocrine tumor to the liver as extremely rare indication for liver transplantation in children. Case report and review of the literature.
      • Martinez J.
      • Besa S.
      • Arab J.P.
      • et al.
      Gastrointestinal neuroendocrine tumor with unresectable liver metastases: an example of multimodal therapeutic approach.
      • Yankol Y.
      • Mecit N.
      • Kanmaz T.
      • et al.
      Living donor liver transplantation: a life-saving option in emergency situations for diffuse hepatic neuroendocrine tumor metastasis.
      • Grat M.
      • Remiszewski P.
      • Smoter P.
      • et al.
      Outcomes following liver transplantation for metastatic neuroendocrine tumors.
      • Ortiz J.
      • Balasubramanian M.
      • Brown T.
      • et al.
      Liver transplant for neuroendocrine tumor metastatic to the liver: literature review and report of extirpation at 16-year recurrence.
      • Chen Y.
      • Sreenivasan G.M.
      • Shojania K.
      • et al.
      Cryofibrinogenemia after a liver transplant: first reported case posttransplant and a case-based review of the nontransplant literature.
      • Nikeghbalian S.
      • Aliakbarian M.
      • Shamsaeefar A.
      • et al.
      Multivisceral transplantation for the treatment of intra-abdominal tumors.
      • Varkey J.
      • Simren M.
      • Bosaeus I.
      • et al.
      Survival of patients evaluated for intestinal and multivisceral transplantation—the Scandinavian experience.
      • Massaro S.A.
      • Emre S.H.
      Metastatic gastrinoma in a pediatric patient with Zollinger-Ellison syndrome.
      • Chen X.B.
      • Yang J.
      • Xu M.Q.
      • et al.
      Liver transplantation for hepatic metastatic pancreatic insulinoma with a survival over five years.
      • Chan G.
      • Kocha W.
      • Reid R.
      • et al.
      Liver transplantation for symptomatic liver metastases of neuroendocrine tumours.
      • Quinonez E.
      • Capitanich P.
      • Anders M.
      • et al.
      • Kleine M.
      • Schrem H.
      • Vondran F.W.
      • et al.
      Extended surgery for advanced pancreatic endocrine tumours.
      • Bonaccorsi-Riani E.
      • Apestegui C.
      • Jouret-Mourin A.
      • et al.
      Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review.
      • Stauffer J.A.
      • Steers J.L.
      • Bonatti H.
      • et al.
      Liver transplantation and pancreatic resection: a single-center experience and a review of the literature.
      • Dhupar R.
      • de Vera M.E.
      • Marsh J.W.
      • et al.
      Simultaneous pancreatectomy and liver transplantation: a single-institution experience.
      • Johnston P.C.
      • Ardill J.E.
      • Johnston B.T.
      • et al.
      Vasoactive intestinal polypeptide secreting pancreatic tumour with hepatic metastases: long term survival after orthotopic liver transplantation.
      • Adham M.
      • Giunippero A.
      • Hervieu V.
      • et al.
      Central pancreatectomy: single-center experience of 50 cases.
      • Marin C.
      • Robles R.
      • Fernandez J.A.
      • et al.
      Role of liver transplantation in the management of unresectable neuroendocrine liver metastases.
      • Olausson M.
      • Friman S.
      • Herlenius G.
      • et al.
      Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors.
      • Frilling A.
      • Malago M.
      • Weber F.
      • et al.
      Liver transplantation for patients with metastatic endocrine tumors: single-center experience with 15 patients.
      • van Vilsteren F.G.
      • Baskin-Bey E.S.
      • Nagorney D.M.
      • et al.
      Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival.
      • Blonski W.C.
      • Reddy K.R.
      • Shaked A.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumor: a case report and review of the literature.
      • Fernandez J.A.
      • Robles R.
      • Marin C.
      • et al.
      • Florman S.
      • Toure B.
      • Kim L.
      • et al.
      Liver transplantation for neuroendocrine tumors.
      • el Rassi Z.S.
      • Ferdinand L.
      • Mohsine R.M.
      • et al.
      Primary and secondary liver endocrine tumors: clinical presentation, surgical approach and outcome.
      • Rosenau J.
      • Bahr M.J.
      • von Wasielewski R.
      • et al.
      Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors.
      • Coppa J.
      • Pulvirenti A.
      • Schiavo M.
      • et al.
      Resection versus transplantation for liver metastases from neuroendocrine tumors.
      • Pascher A.
      • Steinmuller T.
      • Radke C.
      • et al.
      Primary and secondary hepatic manifestation of neuroendocrine tumors.
      • Caplin M.E.
      • Hodgson H.J.
      • Dhillon A.P.
      • et al.
      Multimodality treatment for gastric carcinoid tumor with liver metastases.
      • Savelli G.
      • Chiti A.
      • Spinelli A.
      • et al.
      Bone lesion in a patient with transplanted liver for a metastatic carcinoid. The role of somatostatin receptor scintigraphy.
      • Gottwald T.
      • Koveker G.
      • Busing M.
      • et al.
      Diagnosis and management of metastatic gastrinoma by multimodality treatment including liver transplantation: report of a case.
      • Nakajima Y.
      • Takagi H.
      • Sohara N.
      • et al.
      Living-related liver transplantation for multiple liver metastases from rectal carcinoid tumor: a case report.
      • Claure R.E.
      • Drover D.D.
      • Haddow G.R.
      • et al.
      Orthotopic liver transplantation for carcinoid tumour metastatic to the liver: anesthetic management.
      • Hengst K.
      • Nashan B.
      • Avenhaus W.
      • et al.
      Metastatic pancreatic VIPoma: deteriorating clinical course and successful treatment by liver transplantation.
      • Inturri P.
      • Galligioni A.
      • Halmos O.
      • et al.
      • Martin M.
      • Tarara D.
      • Wu Y.M.
      • et al.
      Intrahepatic arterial chemoembolization for hepatocellular carcinoma and metastatic neuroendocrine tumors in the era of liver transplantation.
      • Dousset B.
      • Saint-Marc O.
      • Pitre J.
      • et al.
      Metastatic endocrine tumors: medical treatment, surgical resection, or liver transplantation.
      • Anthuber M.
      • Jauch K.W.
      • Briegel J.
      • et al.
      Results of liver transplantation for gastroenteropancreatic tumor metastases.
      • Amikura K.
      • Alexander H.R.
      • Norton J.A.
      • et al.
      Role of surgery in management of adrenocorticotropic hormone-producing islet cell tumors of the pancreas.
      • Routley D.
      • Ramage J.K.
      • McPeake J.
      • et al.
      Orthotopic liver transplantation in the treatment of metastatic neuroendocrine tumors of the liver.
      • Curtiss S.I.
      • Mor E.
      • Schwartz M.E.
      • et al.
      A rational approach to the use of hepatic transplantation in the treatment of metastatic neuroendocrine tumors.
      • Socci C.
      • Mazzaferro V.
      • Regalia E.
      • et al.
      Insulin independence after islet-liver transplantation for metastatic neuroendocrine pancreatic tumor.
      • Farmer D.G.
      • Shaked A.
      • Colonna 2nd, J.O.
      • et al.
      Radical resection combined with liver transplantation for foregut tumors.
      • Schweizer R.T.
      • Alsina A.E.
      • Rosson R.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumors.
      • Haerty W.
      • Schraudolph M.
      • Nerlich A.
      • Lobe T.E.
      • Vera S.R.
      • Bowman L.C.
      • et al.
      Hepaticopancreaticogastroduodenectomy with transplantation for metastatic islet cell carcinoma in childhood.
      • Wenisch H.J.
      • Markus B.H.
      • Herrmann G.H.
      • et al.
      • Le Hello C.
      • Auvray S.
      • Letellier P.
      • et al.
      • Bramley P.N.
      • Lodge J.P.
      • Losowsky M.S.
      • et al.
      Treatment of metastatic Vipoma by liver transplantation.
      • Benhamou G.
      • Marmuse J.P.
      • Le Goff J.Y.
      • et al.
      • Bizouarn P.
      • Villalon L.
      • Campion J.P.
      • et al.
      • Makowka L.
      • Tzakis A.G.
      • Mazzaferro V.
      • et al.
      Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas.
      • Muhlbacher F.
      • Piza F.
      Orthotopic liver transplantation for secondary malignancies of the liver.

      Pretransplant treatment history

      Le Treut et al reported that 161 out of 213 (76%) patients in the ELTR database had a history of hormone therapy or chemotherapy prior to LT.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      Similarly, in a separate study, 70 out of 85 (82%) patients were noted to have received hormone therapy or chemotherapy in the French multicenter analysis.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      Data from our cumulative single center analysis noted that 137 out of 184 (74.4%) patients received such pre-LT therapy.
      • Ishii N.
      • Araki K.
      • Yokobori T.
      • et al.
      Presence of cytokeratin 19-expressing cholangiocarcinoma-like tumour in a liver metastatic lesion of rectal neuroendocrine tumour.
      • Mazzaferro V.
      • Sposito C.
      • Coppa J.
      • et al.
      The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors.
      • Rao B.
      • Segovia M.C.
      • Kazimi M.
      • et al.
      Use of everolimus after multivisceral transplantation: a report of two cases.
      • Ismail H.
      • Broniszczak D.
      • Markiewicz-Kijewska M.
      • et al.
      Metastases of pancreatic neuroendocrine tumor to the liver as extremely rare indication for liver transplantation in children. Case report and review of the literature.
      • Martinez J.
      • Besa S.
      • Arab J.P.
      • et al.
      Gastrointestinal neuroendocrine tumor with unresectable liver metastases: an example of multimodal therapeutic approach.
      • Yankol Y.
      • Mecit N.
      • Kanmaz T.
      • et al.
      Living donor liver transplantation: a life-saving option in emergency situations for diffuse hepatic neuroendocrine tumor metastasis.
      • Grat M.
      • Remiszewski P.
      • Smoter P.
      • et al.
      Outcomes following liver transplantation for metastatic neuroendocrine tumors.
      • Ortiz J.
      • Balasubramanian M.
      • Brown T.
      • et al.
      Liver transplant for neuroendocrine tumor metastatic to the liver: literature review and report of extirpation at 16-year recurrence.
      • Chen Y.
      • Sreenivasan G.M.
      • Shojania K.
      • et al.
      Cryofibrinogenemia after a liver transplant: first reported case posttransplant and a case-based review of the nontransplant literature.
      • Nikeghbalian S.
      • Aliakbarian M.
      • Shamsaeefar A.
      • et al.
      Multivisceral transplantation for the treatment of intra-abdominal tumors.
      • Varkey J.
      • Simren M.
      • Bosaeus I.
      • et al.
      Survival of patients evaluated for intestinal and multivisceral transplantation—the Scandinavian experience.
      • Massaro S.A.
      • Emre S.H.
      Metastatic gastrinoma in a pediatric patient with Zollinger-Ellison syndrome.
      • Chen X.B.
      • Yang J.
      • Xu M.Q.
      • et al.
      Liver transplantation for hepatic metastatic pancreatic insulinoma with a survival over five years.
      • Chan G.
      • Kocha W.
      • Reid R.
      • et al.
      Liver transplantation for symptomatic liver metastases of neuroendocrine tumours.
      • Quinonez E.
      • Capitanich P.
      • Anders M.
      • et al.
      • Kleine M.
      • Schrem H.
      • Vondran F.W.
      • et al.
      Extended surgery for advanced pancreatic endocrine tumours.
      • Bonaccorsi-Riani E.
      • Apestegui C.
      • Jouret-Mourin A.
      • et al.
      Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review.
      • Stauffer J.A.
      • Steers J.L.
      • Bonatti H.
      • et al.
      Liver transplantation and pancreatic resection: a single-center experience and a review of the literature.
      • Dhupar R.
      • de Vera M.E.
      • Marsh J.W.
      • et al.
      Simultaneous pancreatectomy and liver transplantation: a single-institution experience.
      • Johnston P.C.
      • Ardill J.E.
      • Johnston B.T.
      • et al.
      Vasoactive intestinal polypeptide secreting pancreatic tumour with hepatic metastases: long term survival after orthotopic liver transplantation.
      • Adham M.
      • Giunippero A.
      • Hervieu V.
      • et al.
      Central pancreatectomy: single-center experience of 50 cases.
      • Marin C.
      • Robles R.
      • Fernandez J.A.
      • et al.
      Role of liver transplantation in the management of unresectable neuroendocrine liver metastases.
      • Olausson M.
      • Friman S.
      • Herlenius G.
      • et al.
      Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors.
      • Frilling A.
      • Malago M.
      • Weber F.
      • et al.
      Liver transplantation for patients with metastatic endocrine tumors: single-center experience with 15 patients.
      • van Vilsteren F.G.
      • Baskin-Bey E.S.
      • Nagorney D.M.
      • et al.
      Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival.
      • Blonski W.C.
      • Reddy K.R.
      • Shaked A.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumor: a case report and review of the literature.
      • Fernandez J.A.
      • Robles R.
      • Marin C.
      • et al.
      • Florman S.
      • Toure B.
      • Kim L.
      • et al.
      Liver transplantation for neuroendocrine tumors.
      • el Rassi Z.S.
      • Ferdinand L.
      • Mohsine R.M.
      • et al.
      Primary and secondary liver endocrine tumors: clinical presentation, surgical approach and outcome.
      • Rosenau J.
      • Bahr M.J.
      • von Wasielewski R.
      • et al.
      Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors.
      • Coppa J.
      • Pulvirenti A.
      • Schiavo M.
      • et al.
      Resection versus transplantation for liver metastases from neuroendocrine tumors.
      • Pascher A.
      • Steinmuller T.
      • Radke C.
      • et al.
      Primary and secondary hepatic manifestation of neuroendocrine tumors.
      • Caplin M.E.
      • Hodgson H.J.
      • Dhillon A.P.
      • et al.
      Multimodality treatment for gastric carcinoid tumor with liver metastases.
      • Savelli G.
      • Chiti A.
      • Spinelli A.
      • et al.
      Bone lesion in a patient with transplanted liver for a metastatic carcinoid. The role of somatostatin receptor scintigraphy.
      • Gottwald T.
      • Koveker G.
      • Busing M.
      • et al.
      Diagnosis and management of metastatic gastrinoma by multimodality treatment including liver transplantation: report of a case.
      • Nakajima Y.
      • Takagi H.
      • Sohara N.
      • et al.
      Living-related liver transplantation for multiple liver metastases from rectal carcinoid tumor: a case report.
      • Claure R.E.
      • Drover D.D.
      • Haddow G.R.
      • et al.
      Orthotopic liver transplantation for carcinoid tumour metastatic to the liver: anesthetic management.
      • Hengst K.
      • Nashan B.
      • Avenhaus W.
      • et al.
      Metastatic pancreatic VIPoma: deteriorating clinical course and successful treatment by liver transplantation.
      • Inturri P.
      • Galligioni A.
      • Halmos O.
      • et al.
      • Martin M.
      • Tarara D.
      • Wu Y.M.
      • et al.
      Intrahepatic arterial chemoembolization for hepatocellular carcinoma and metastatic neuroendocrine tumors in the era of liver transplantation.
      • Dousset B.
      • Saint-Marc O.
      • Pitre J.
      • et al.
      Metastatic endocrine tumors: medical treatment, surgical resection, or liver transplantation.
      • Anthuber M.
      • Jauch K.W.
      • Briegel J.
      • et al.
      Results of liver transplantation for gastroenteropancreatic tumor metastases.
      • Amikura K.
      • Alexander H.R.
      • Norton J.A.
      • et al.
      Role of surgery in management of adrenocorticotropic hormone-producing islet cell tumors of the pancreas.
      • Routley D.
      • Ramage J.K.
      • McPeake J.
      • et al.
      Orthotopic liver transplantation in the treatment of metastatic neuroendocrine tumors of the liver.
      • Curtiss S.I.
      • Mor E.
      • Schwartz M.E.
      • et al.
      A rational approach to the use of hepatic transplantation in the treatment of metastatic neuroendocrine tumors.
      • Socci C.
      • Mazzaferro V.
      • Regalia E.
      • et al.
      Insulin independence after islet-liver transplantation for metastatic neuroendocrine pancreatic tumor.
      • Farmer D.G.
      • Shaked A.
      • Colonna 2nd, J.O.
      • et al.
      Radical resection combined with liver transplantation for foregut tumors.
      • Schweizer R.T.
      • Alsina A.E.
      • Rosson R.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumors.
      • Haerty W.
      • Schraudolph M.
      • Nerlich A.
      • Lobe T.E.
      • Vera S.R.
      • Bowman L.C.
      • et al.
      Hepaticopancreaticogastroduodenectomy with transplantation for metastatic islet cell carcinoma in childhood.
      • Wenisch H.J.
      • Markus B.H.
      • Herrmann G.H.
      • et al.
      • Le Hello C.
      • Auvray S.
      • Letellier P.
      • et al.
      • Bramley P.N.
      • Lodge J.P.
      • Losowsky M.S.
      • et al.
      Treatment of metastatic Vipoma by liver transplantation.
      • Benhamou G.
      • Marmuse J.P.
      • Le Goff J.Y.
      • et al.
      • Bizouarn P.
      • Villalon L.
      • Campion J.P.
      • et al.
      • Makowka L.
      • Tzakis A.G.
      • Mazzaferro V.
      • et al.
      Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas.
      • Muhlbacher F.
      • Piza F.
      Orthotopic liver transplantation for secondary malignancies of the liver.
      In another study, pre-LT treatment included operative resection of the primary tumor in 74.2% (158/213) of patients, resection of NET liver metastasis in 26.3% (56/213), while 5.6% (12 patients) had no therapy used before LT.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      In a different multicenter study, the proportion of patients treated with these different pre-LT options were 64.7%, 33% and 8%, respectively.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      When considering aggregate data from single center studies, 77.8% (179/230) of patients had pre-LT resection of the primary tumor, whereas 5.6% (13/230) did not receive any treatment preoperatively.

      Indication for LT

      Indications for LT were categorized according to the study by Le Treut et al into 3 distinct groups: “hormonal syndrome” including patients with life-threatening or debilitating hormone-related symptoms, “tumor bulk” including patients with pain or debility associated with enlargement of the liver, and “oncological” including patients with low-grade symptoms.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      Two studies provided details on the indications for LT. One study noted that LT was performed for hormonal syndrome in 12%, tumor bulk in 24%, and oncologic reasons in 54%,
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      whereas in another study, the proportion of patients that met each indication were 23.5%, 27.1% and 42.4%, respectively.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      Analysis of aggregate data from single center reports demonstrated that the indications for LT were presentation of symptoms, either debilitating or low-grade, related to the underlying NET in 66.1% (129/195) followed by tumor bulk in 33.8% (66/195).

      Liver transplantation

      Apart from liver only transplantation, multivisceral transplantation (MVT) was used in cases of widespread disease and involvement of more organs. In general, the utilization of MVT was <20%. Most cases of MVT were reported by Sher et al (17 out of 85)
      • Sher L.S.
      • Levi D.M.
      • Wecsler J.S.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumors: outcomes and prognostic variables.
      and Gedaly et al (13 out of 150),
      • Gedaly R.
      • Daily M.F.
      • Davenport D.
      • et al.
      Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database.
      whereas 2 studies mentioned no MVTs.
      • Nguyen N.T.
      • Harring T.R.
      • Goss J.A.
      • et al.
      Neuroendocrine liver metastases and orthotopic liver transplantation: the US experience.
      • Pasqual E.M.
      • Bertozzi S.
      • Londero A.P.
      • et al.
      Long term results of hepatic resection or orthotopic liver transplantation in patients with liver metastases from gastrointestinal neuroendocrine tumors.
      Analysis of single center studies revealed 16 out of 279 (5.7%) cases of MVT.
      Most cases of retransplantation (24 cases) were reported by Le Treut et al, of which 10 were performed due to hepatic artery thrombosis, 6 for primary nonfunction of the graft, 2 for portal/hepatic vein thrombosis, 1 for each of biliary complication, recurrent hepatitis C and chronic rejection as well as 3 undetermined causes.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      Nguyen et al,
      • Nguyen N.T.
      • Harring T.R.
      • Goss J.A.
      • et al.
      Neuroendocrine liver metastases and orthotopic liver transplantation: the US experience.
      as well as single center studies
      • Ortiz J.
      • Balasubramanian M.
      • Brown T.
      • et al.
      Liver transplant for neuroendocrine tumor metastatic to the liver: literature review and report of extirpation at 16-year recurrence.
      • Chen Y.
      • Sreenivasan G.M.
      • Shojania K.
      • et al.
      Cryofibrinogenemia after a liver transplant: first reported case posttransplant and a case-based review of the nontransplant literature.
      • Chan G.
      • Kocha W.
      • Reid R.
      • et al.
      Liver transplantation for symptomatic liver metastases of neuroendocrine tumours.
      • Bonaccorsi-Riani E.
      • Apestegui C.
      • Jouret-Mourin A.
      • et al.
      Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review.
      • Florman S.
      • Toure B.
      • Kim L.
      • et al.
      Liver transplantation for neuroendocrine tumors.
      • Dousset B.
      • Saint-Marc O.
      • Pitre J.
      • et al.
      Metastatic endocrine tumors: medical treatment, surgical resection, or liver transplantation.
      • Curtiss S.I.
      • Mor E.
      • Schwartz M.E.
      • et al.
      A rational approach to the use of hepatic transplantation in the treatment of metastatic neuroendocrine tumors.
      • Socci C.
      • Mazzaferro V.
      • Regalia E.
      • et al.
      Insulin independence after islet-liver transplantation for metastatic neuroendocrine pancreatic tumor.
      • Wenisch H.J.
      • Markus B.H.
      • Herrmann G.H.
      • et al.
      • Makowka L.
      • Tzakis A.G.
      • Mazzaferro V.
      • et al.
      Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas.
      reported a total of 14 cases of retransplantation (Table III). Of note, one patient described by Ortiz et al underwent 3 liver transplantations due to consecutive events of primary graft non-function. This patient was alive at 16 years of follow-up.
      • Ortiz J.
      • Balasubramanian M.
      • Brown T.
      • et al.
      Liver transplant for neuroendocrine tumor metastatic to the liver: literature review and report of extirpation at 16-year recurrence.
      Table IIILiver transplantation and outcomes
      PMIDFirst author (year of publication)No. of patientsNo. of retransplantationsNo. of MVTOS, %DFS, %
      1-year OS3-year OS5-year OS1-year DFS3-year DFS5-year DFS
      Registry databases25989503Nobel (2015)120NANA87 (95% CI, 79–92)69 (95% CI, 59–77)63 (95% CI, 53–72)NRNRNR
      23532105Le Treut (2013)213246816552654030
      22254141Nguyen (2011)18414079.5 (Post-MELD: 84.7)61.4 (Post-MELD: 65)49.2 (Post-MELD: 57.8)NRNRNR
      21844436Gedaly (2011)15001380644877
      As described by the authors, DFS rates were estimated for the 83 patients for whom recurrence information was available.
      50
      As described by the authors, DFS rates were estimated for the 83 patients for whom recurrence information was available.
      32
      As described by the authors, DFS rates were estimated for the 83 patients for whom recurrence information was available.
      Multicenter experience27900037Pasqual (2016)400100
      Not clearly written in the text but obviously extracted from Fig, D of the same study.
      50
      Not clearly written in the text but obviously extracted from Fig, D of the same study.
      50 (95% CI, 12.5–100)NRNRNR
      26171686Sher (2015)85NR17836052NRNRNR
      18444921Le Treut (2008)8573725947563720
      Single center experience
      Details on single center experience are provided in Supplemental Table III.
      Details on single center experience are provided in Supplemental Table III.
      279141681.464.970.7
      5-year survival seems greater than 3-year survival due to the study by Mazzaferro et al32 that did not provide details on 1- and 3-year survival rates but contributed with a 5-year OS of 97.2%.
      59.54126.3
      NA, Not applicable; NR, not reported; MELD, model for end-stage liver disease score.
      Details on single center experience are provided in Supplemental Table III.
      As described by the authors, DFS rates were estimated for the 83 patients for whom recurrence information was available.
      Not clearly written in the text but obviously extracted from Fig, D of the same study.
      § 5-year survival seems greater than 3-year survival due to the study by Mazzaferro et al
      • Mazzaferro V.
      • Sposito C.
      • Coppa J.
      • et al.
      The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors.
      that did not provide details on 1- and 3-year survival rates but contributed with a 5-year OS of 97.2%.
      Among those studies that provided details on donor classification, the use of deceased donor grafts was about 90% with only a small minority of grafts derived from living donors.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      • Gedaly R.
      • Daily M.F.
      • Davenport D.
      • et al.
      Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      In analyzing the ELTR database, Le Treut et al reported a domino procedure in 7 cases,
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      while 2 were reported in the French multicenter analysis.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      Only a few studies provided transplantation-related perioperative data. For example, mean operative time was 7.8 ± 3.1 hours in the ELTR database,
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      whereas mean length of stay was 23 days (range, 15–52) in one report
      • Nguyen N.T.
      • Harring T.R.
      • Goss J.A.
      • et al.
      Neuroendocrine liver metastases and orthotopic liver transplantation: the US experience.
      and 22.2 days (range, 3–160) in another,
      • Gedaly R.
      • Daily M.F.
      • Davenport D.
      • et al.
      Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database.
      both derived from the UNOS database. The amount of blood loss during operation, as well as the need for blood transfusion was not reported in any study.

      Immunosuppressive therapy

      None of the large cohort studies reported on the immunosuppressive therapy used. Mazzaferro et al did report on 41 patients with LT for NET liver metastases and described the use of tapering of steroids within the third posttransplant month with initiation of calcineurin inhibitor monotherapy (tacrolimus and cyclosporine in 81% and 19% of patients, respectively).
      • Mazzaferro V.
      • Sposito C.
      • Coppa J.
      • et al.
      The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors.
      Tacrolimus-based immunosuppression, along with the use of additional regimens such as cyclosporine and steroids, was applied in other single center studies.
      • Chan G.
      • Kocha W.
      • Reid R.
      • et al.
      Liver transplantation for symptomatic liver metastases of neuroendocrine tumours.
      • Bonaccorsi-Riani E.
      • Apestegui C.
      • Jouret-Mourin A.
      • et al.
      Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review.
      • Stauffer J.A.
      • Steers J.L.
      • Bonatti H.
      • et al.
      Liver transplantation and pancreatic resection: a single-center experience and a review of the literature.
      • Olausson M.
      • Friman S.
      • Herlenius G.
      • et al.
      Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors.
      • Frilling A.
      • Malago M.
      • Weber F.
      • et al.
      Liver transplantation for patients with metastatic endocrine tumors: single-center experience with 15 patients.
      • van Vilsteren F.G.
      • Baskin-Bey E.S.
      • Nagorney D.M.
      • et al.
      Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival.
      In the case of calcineurin inhibitors intolerance, use of sirolimus was also reported.
      • Stauffer J.A.
      • Steers J.L.
      • Bonatti H.
      • et al.
      Liver transplantation and pancreatic resection: a single-center experience and a review of the literature.
      Finally, use of adjuvant chemotherapy after LT was not described except in 4 cases: combination of cisplatin, doxorubicin, 5-flurouracil, and vincristine for a metastatic gastrinoma,
      • Massaro S.A.
      • Emre S.H.
      Metastatic gastrinoma in a pediatric patient with Zollinger-Ellison syndrome.
      leukovorin and 5-FU for a metastatic islet cell carcinoma,
      • Lobe T.E.
      • Vera S.R.
      • Bowman L.C.
      • et al.
      Hepaticopancreaticogastroduodenectomy with transplantation for metastatic islet cell carcinoma in childhood.
      adriamycin for a metastatic glucagonoma
      • Makowka L.
      • Tzakis A.G.
      • Mazzaferro V.
      • et al.
      Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas.
      and 5-FU for a mixed carcinoid tumor-cholangiocarcinoma.
      • Makowka L.
      • Tzakis A.G.
      • Mazzaferro V.
      • et al.
      Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas.

      Long-term outcomes

      Overall, recurrence after LT ranged from 31.3% to 56.8% (Table IV). In analyzing the ELTR database, Le Treut et al reported that a total of 112 out of 213 (52.6%) patients recurred,
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      whereas analysis of aggregate single center data demonstrated a recurrence in 107 out of 267 (39.8%) patients. At the time of last follow-up, reported overall mortality ranged from 33.1% to 71.8%, whereas disease-related mortality ranged from 21% to 52.6%. In turn, the proportion of patients alive at reported last follow-up ranged from 28.2% to 66.9%, with single center studies reporting higher proportions of patient survival.
      Table IVRecurrence and mortality rates
      PMIDFirst Author (year of publication)No. of patientsRecurrence, n (%)Mortality, n (%)Alive patients, n (%)
      Overall mortalityDisease-relatedWith diseaseDisease-free
      Registry databases25989503Nobel (2015)120NR46 (38.3)20/38 (52.6)
      Cause of death was identified in 38 out of 46 deceased patients.
      74 (61.7)
      23532105Le Treut (2013)213112 (52.6)124 (58.2)87 (40.8)26 (12.2)63 (29.6)
      22254141Nguyen (2011)184NR86 (46.7)46 (25)98 (53.3)
      21844436Gedaly (2011)15026/83 (31.3)
      Tumor recurrence was seen in 26 of 83 patients who underwent LT after 1999, when information about tumor recurrence became available.
      NRNRNRNR
      Multicenter experience27900037Pasqual (2016)4NRNRNRNRNR
      26171686Sher (2015)8546/81 (56.8)40 (47)20 (23.5)45 (53)
      18444921Le Treut (2008)8544 (51.8)61 (71.8)44 (51.8)24 (28.2)
      Single center experience
      Details on single center experience are provided in Supplemental Table III.
      Details on single center experience are provided in Supplemental Table III.
      279107/267 (39.8)90/272 (33.1)57/272 (21)182/272
      45 with disease, 97 disease-free, and 40 alive with no disease status.
      (66.9)
      NR, Not reported.
      Cause of death was identified in 38 out of 46 deceased patients.
      Tumor recurrence was seen in 26 of 83 patients who underwent LT after 1999, when information about tumor recurrence became available.
      Details on single center experience are provided in Supplemental Table III.
      § 45 with disease, 97 disease-free, and 40 alive with no disease status.
      Analyzing the UNOS database from 2002 to 2014, Nobel et al reported a 1-, 3-, and 5-year OS of 89%, 69% and 63%, respectively.
      • Nobel Y.R.
      • Goldberg D.S.
      Variable use of model for end-stage liver disease exception points in patients with neuroendocrine tumors metastatic to the liver and its impact on patient outcomes.
      Survival was much greater than that reported by 2 other studies from the same database that reported a 1-year survival of 79.5% and 80%, a 3-year OS of 61.4% and 64%, and a 5-year OS of 48.0% and 49.2%.
      • Nguyen N.T.
      • Harring T.R.
      • Goss J.A.
      • et al.
      Neuroendocrine liver metastases and orthotopic liver transplantation: the US experience.
      • Gedaly R.
      • Daily M.F.
      • Davenport D.
      • et al.
      Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database.
      These data may relate to more unfavorable outcomes in the early 1990s because the latter 2 studies include patients from 1988.
      • Nguyen N.T.
      • Harring T.R.
      • Goss J.A.
      • et al.
      Neuroendocrine liver metastases and orthotopic liver transplantation: the US experience.
      • Gedaly R.
      • Daily M.F.
      • Davenport D.
      • et al.
      Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database.
      Of note, NET patients transplanted after 2002, with the introduction of the model for end-stage liver disease/pediatric end-stage liver disease scoring systems for organ allocation, were associated with an increase in 5-year survival from 49.2% to 57.8% compared with patients transplanted since 1988 (Table III).
      • Nguyen N.T.
      • Harring T.R.
      • Goss J.A.
      • et al.
      Neuroendocrine liver metastases and orthotopic liver transplantation: the US experience.
      The ELTR database analysis, which incorporated a total of 213 patients, noted a 1-, 3-, and 5-year survival of 81%, 65%, and 52%, respectively.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      In assessing multicenter data, Sher et al reported the results from 28 US centers and noted a 1-, 3-, and 5-year OS of 83%, 60%, and 52%, respectively.
      • Sher L.S.
      • Levi D.M.
      • Wecsler J.S.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumors: outcomes and prognostic variables.
      Survival from this study was more favorable than the data previously report by Le Treut et al that analyzed the results of 17 French centers (1-, 3-, 5-year OS: 72%, 59%, and 47%).
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      In a more recent report by Pasqual et al 5-year OS was 50% (95% CI, 12.5–100).
      • Pasqual E.M.
      • Bertozzi S.
      • Londero A.P.
      • et al.
      Long term results of hepatic resection or orthotopic liver transplantation in patients with liver metastases from gastrointestinal neuroendocrine tumors.
      Aggregate data from 57 single center studies was notable for an estimated cumulative 1-, 3-, and 5-year survival of 81.4%, 64.9%, and 70.7%, respectively. Although the cumulative 5-year survival was greater than noted in the larger cohort studies, this difference was likely related to data from the Mazzfero et al study that reported a 5-year OS of 97.2% among transplanted patients versus only 50.9% among those patients treated with nontransplant strategies.
      • Mazzaferro V.
      • Sposito C.
      • Coppa J.
      • et al.
      The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors.

      Survival according to the primary tumor site

      Among the studies included in the current study, only four reported on outcomes stratified by primary tumor site.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      • van Vilsteren F.G.
      • Baskin-Bey E.S.
      • Nagorney D.M.
      • et al.
      Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival.
      Le Treut et al reported that patients with a pancreatic NET (PNET) had a worse 5-year survival compared with patients who had a gastrointestinal NET (GI NET; 44% vs 62%, P < .05).
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      In addition, a French multicenter study reported a worse 5-year survival LT among patients with a PNET versus patients with a GI NET (27% vs 69%, P = .0008).
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      In another study, while not statistically significant, the data did suggest that 1-year OS (77% vs 100%, P = .2) and 1-year DFS (60% vs 100%, P = .1) were both inferior among PNET versus GI NETs patients.
      • van Vilsteren F.G.
      • Baskin-Bey E.S.
      • Nagorney D.M.
      • et al.
      Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival.
      In a different study, Sher et al reported a comparable 5-year survival among patients with tumors arising from the duodenum/pancreas versus remaining digestive tract (53% vs 51%, P = .83).
      • Sher L.S.
      • Levi D.M.
      • Wecsler J.S.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumors: outcomes and prognostic variables.

      Discussion

      LT was originally conceived as a therapy for advanced liver malignancies as it offered the potential for total tumor removal and elimination of recurrence in the liver remnant compared with standard hepatic resection.
      • Ravaioli M.
      • Ercolani G.
      • Neri F.
      • et al.
      Liver transplantation for hepatic tumors: a systematic review.
      Several attempts to implement an LT strategy for both primary and metastatic tumors led to poor results, and therefore LT was not considered for this indication.
      • Ravaioli M.
      • Ercolani G.
      • Neri F.
      • et al.
      Liver transplantation for hepatic tumors: a systematic review.
      Rather, based on data from Mazzaferro et al in the mid-1990s, LT was restricted largely to patients with early hepatocellular carcinoma who met strict selection criteria.
      • Mazzaferro V.
      • Regalia E.
      • Doci R.
      • et al.
      Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
      In contrast, LT for unresectable metastases to the liver essentially was abandoned. More recently, however, LT has been reconsidered as a possible option for highly selected patients with NET liver metastasis. Many patients with NET will develop liver metastasis during the course of their disease. Although resection of the primary tumor and the liver metastases are sometimes amenable to operative resection, a subset of patients will not be candidates for expiration of their disease.
      • Frilling A.
      • Li J.
      • Malamutmann E.
      • et al.
      Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease.
      While cytoreductive operation aimed at removing the bulk of disease may be a possible therapeutic option, this therapeutic approach does not offer the chance at long-term cure.
      • Fan S.T.
      • Le Treut Y.P.
      • Mazzaferro V.
      • et al.
      Liver transplantation for neuroendocrine tumour liver metastases.
      As such, Mazzaferro et al
      • Mazzaferro V.
      • Pulvirenti A.
      • Coppa J.
      Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation?.
      and others have suggested possible selection criteria for patients with NET (Table V). In particular, it is a prerequisite to exclude the possibility of extrahepatic disease through careful staging using SRI or gallium-68 octreotate PET-CT scan with a specific focus on ruling out bone and lymph node metastases.
      • Frilling A.
      • Li J.
      • Malamutmann E.
      • et al.
      Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease.
      • Pavel M.
      • Baudin E.
      • Couvelard A.
      • et al.
      ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary.
      • Bonaccorsi-Riani E.
      • Apestegui C.
      • Jouret-Mourin A.
      • et al.
      Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review.
      • Frilling A.
      • Malago M.
      • Weber F.
      • et al.
      Liver transplantation for patients with metastatic endocrine tumors: single-center experience with 15 patients.
      • Pascher A.
      • Klupp J.
      • Neuhaus P.
      Endocrine tumours of the gastrointestinal tract. Transplantation in the management of metastatic endocrine tumours.
      • Gregoire E.
      • Le Treut Y.P.
      Liver transplantation for primary or secondary endocrine tumors.
      In addition, at the time of operation, exploratory laparotomy or laparoscopy to detect peritoneal deposits also should be considered.
      • Olausson M.
      • Friman S.
      • Herlenius G.
      • et al.
      Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors.
      • Frilling A.
      • Malago M.
      • Weber F.
      • et al.
      Liver transplantation for patients with metastatic endocrine tumors: single-center experience with 15 patients.
      • van Vilsteren F.G.
      • Baskin-Bey E.S.
      • Nagorney D.M.
      • et al.
      Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival.
      Table VMilan criteria for liver transplantation in patients with hepatic metastases from neuroendocrine tumors
      • Inclusion criteria
        • 1.
          Confirmed histology of low-grade neuroendocrine tumors with or without the presence of syndrome
        • 2.
          Primary tumor drained by the portal system (pancreas and intermediate gut: from distal stomach to sigmoid colon) already removed with a curative resection (removal of all extra-hepatic tumor deposits prior to liver transplantations)
        • 3.
          <50% involvement of liver parenchyma
        • 4.
          Good response or stable disease for at least 6 mo during the pretransplantation period
        • 5.
          Age <55 years
      • Exclusion criteria
        • 1.
          Small-cell carcinoma and high-grade neuroendocrine carcinomas (noncarcinoid tumors)
        • 2.
          Other medical/operative conditions contraindicating liver transplantation, including previous tumors
        • 3.
          Nongastrointestinal carcinoids or tumors not drained by the portal system
      Le Treut et al have published the largest cohort study to date of 213 patients with metastatic liver NET who underwent transplantation throughout a 27-year time interval from the European Liver Transplant Registry.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      In this study, 90-day postoperative mortality was 10%, whereas 5-year OS was 52% yet almost 60% of the patients had disease recurrence.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      One strength of the current study was the analysis of aggregate data amassed from the varied single center studies, which provided one of the largest analytic cohorts of patients to date on the topic of NET LT (n = 279). In assessing these aggregate data, 1- and 3-year survival following LT was similar to that reported by Le Treut et al
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      at 81.4% and 64.9%, respectively. In contrast, 5-year survival derived from the aggregate data was 70.7%, which was indeed greater than the 52% reported in other multicenter studies.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      • Sher L.S.
      • Levi D.M.
      • Wecsler J.S.
      • et al.
      Liver transplantation for metastatic neuroendocrine tumors: outcomes and prognostic variables.
      The difference in reported long-term outcomes was likely due to both differences in data reporting as well as patient selection. Specifically, patients eligible for LT according to the Milan-NET criteria had a more favorable long-term.
      • Mazzaferro V.
      • Sposito C.
      • Coppa J.
      • et al.
      The long-term benefit of liver transplantation for hepatic metastases from neuroendocrine tumors.
      Le Treut et al have identified a number of important prognostic factors associated with worse long-term survival, including resection of the primary tumor during liver transplantation, the presence of hepatomegaly (presumably a surrogate for extensive metastatic disease within the liver), transplantation with <50% liver tumor involvement, and tumor bulk as the primary indication for transplantation. In addition, poorly differentiated tumors, a margin-positive resection, and lymph node-positive disease were all associated with worse long-term outcomes.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      Other factors related to poor prognosis include the association of LT with major resection, especially upper abdominal exenteration, liver enlargement >50% and Ki-67 proliferation index>10%.
      • Pavel M.
      • Baudin E.
      • Couvelard A.
      • et al.
      ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      • Le Treut Y.P.
      • Delpero J.R.
      • Dousset B.
      • et al.
      Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report.
      • de Herder W.W.
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      Multidisciplinary approach for the treatment of neuroendocrine tumors.
      Similarly, the ENETS Consensus guidelines note that LT should only be considered based on criteria including well-differentiated (G1, G2) NET with a Ki-67 index of <10%, stable disease for at least 6 months before LT, age <55 years, absence of extrahepatic disease, a <50% liver involvement or <75% for patients with refractory hormonal symptoms, and primary tumor removed before transplantation (at least 6 months ago).
      • Pavel M.
      • Baudin E.
      • Couvelard A.
      • et al.
      ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary.
      The site of the primary tumor is thought to have an important role since gastrointestinal tumors usually have better outcomes compared with PNETs consistent with data in the current study.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      • Le Treut Y.P.
      • Gregoire E.
      • Belghiti J.
      • et al.
      Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.
      • van Vilsteren F.G.
      • Baskin-Bey E.S.
      • Nagorney D.M.
      • et al.
      Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival.
      • Rossi R.E.
      • Burroughs A.K.
      • Caplin M.E.
      Liver transplantation for unresectable neuroendocrine tumor liver metastases.
      For those patients with an unknown primary tumor, Le Treut et al reported a 59% long-term overall survival.
      • Le Treut Y.P.
      • Gregoire E.
      • Klempnauer J.
      • et al.
      Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.
      Based on the relative good long-term results, LT may indeed be a viable option for selected patients with diffuse hepatic metastases, especially patients meeting the criteria established by Mazzaferro et al.
      • Mazzaferro V.
      • Pulvirenti A.
      • Coppa J.
      Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation?.
      In fact, the Organ Procurement and Transplantation Network has established recommendations for selecting patients in the United States for LT with NET. Selection criteria include recipient age <60 years, limitation of the NET metastases to the liver with a bilobar involvement and not amenable to resection and resection of the primary malignancy without evidence for recurrence for at least 6 months. Only patients with well to moderately differentiated NETs (G1/G2) with a low mitotic rate (<20 per 10 high power fields) and a Ki67 value <20%, which originate from the gastroenteropancreatic system with portal system drainage should undergo LT. Furthermore, the guidelines contain instructions for radiologic workup including time interval, type of diagnostics, and radiographic characteristics.

      Organ Procurement and Transplantation Network (OPTN): Guidance on MELD PELD exception review, June 2, 2015. Available from: http://optn.transplant.hrsa.gov/resources/by-organ/liver-intestine/guidance-on-meld-peld-exception-review/#PSC.

      Patients who do not meet these guidelines should be considered for other liver directed therapies such as yittrium-90 or peptide receptor radionuclide therapy.
      In conclusion, LT seems to provide a survival benefit among patients with diffuse NET metastases to the liver who have no evidence of extrahepatic disease. The total number of liver transplants performed for neuroendocrine liver metastases is, however, small. As such, while the survival data seems favorable, caution should be taken and the benefit of LT for NET should be balanced against the world organ shortage and potential clinical benefit.
      Due to high recurrence rates, strict selection of patients is critical. In addition to a multidisciplinary approach, standardization of patient selection criteria, as well as post-LT immunosuppressive regimens are needed. Due to the scarcity of available grafts and the lack of level 1 evidence, the recommendations to endorse LT for extensive liver NET metastases warrants ongoing deliberations.

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