Liver transplantation for gastroenteropancreatic neuroendocrine cancers: Defining selection criteria to improve survival

ORIGINAL ARTICLE

Liver Transplantation for GastroenteropancreaticNeuroendocrine Cancers: Defining SelectionCriteria to Improve SurvivalFrederike G.I. van Vilsteren,1,2 Edwina S. Baskin-Bey,1 David M. Nagorney,1 Schuyler O. Sanderson,1

Walter K. Kremers,1 Charles B. Rosen,1 Gregory J. Gores,1 and Timothy J. Hobday,11Mayo Clinic College of Medicine, Rochester, MN, and 2International School of Hepatology and TropicalMedicine GISH-T, Groningen, Netherlands

Liver transplantation for gastroenteropancreatic neuroendocrine cancer (GEP) is controversial. The aim of this study was toassess patient outcomes after liver transplantation for hepatic metastases from GEP. Medical records of patients whounderwent liver transplantation for GEP were reviewed. Immunohistochemistry for assessing the Ki67 proliferation index wasperformed on explanted liver tissue. Nineteen patients who underwent liver transplantation had a mean follow-up of 22 monthswith a range of 0 to 84 months. There was 1 intraoperative death, and 3 patients had disease recurrence after livertransplantation leading to death in 1 patient. Overall estimated 1-year survival for 17 patients included in the treatment protocol(mean follow-up, 15 months) was 87% with an estimated 1-year recurrence-free rate (conditional on survival) of 77%. Threeof 11 patients with pancreatic islet cell GEP developed disease recurrence, whereas all 8 patients with carcinoid GEP remainfree of disease. Analysis of the Ki67 proliferation index in 18 patients did not differentiate those with recurrence from thosewithout disease recurrence. In conclusion, liver transplantation for patients with hepatic metastases from GEP is a viabletherapeutic option in highly selected patients. Liver Transpl 12:448-456, 2006. © 2006 AASLD.

Received July 16, 2005; accepted August 29, 2005.

Neuroendocrine cancers form a diverse group of tu-mors, frequently arising from neuroendocrine cellswithin the gastrointestinal tract and pancreas. Gastro-enteropancreatic neuroendocrine cancer (GEP) has anincidence of 1 or 2 cases per 100,000 people per year.1

Most GEPs are characterized by slow growth despitefrequent presentation with advanced stage of diseaseand metastases. These malignancies have the capacityto produce hormones with specific syndromes (e.g., thecarcinoid syndrome), or they can be nonfunctioning.GEPs preferentially metastasize to the liver, and metas-tases can be limited to the liver for protracted periods oftime.2 Many patients are asymptomatic. Others havehormonal syndromes that can be controlled with long-acting somatostatin analogues. Once disease becomesprogressive, with bilobar hepatic metastases, survivalis limited, with an average 5-year survival of only 30%.3

Current therapeutic approaches for patients with ad-vanced GEP, metastatic to the liver, are palliative andinclude hepatic arterial embolization and chemoembo-lization, debulking surgery, and administration of so-matostatin analogues and cytotoxic chemotherapy. Al-though all of these approaches are associated withfavorable response rates,4,5 metastatic GEP is ulti-mately a fatal disease. Because metastases may be lim-ited to the liver for extended periods, orthotopic livertransplantation (OLT) has been advocated as a poten-tially curative therapy for selected patients.4 Our expe-rience at the Mayo Clinic with hepatic debulking sur-gery also suggests that liver transplantation may have apotential palliative effect by “debulking” disease, even ifit’s not curative. In the past, liver transplantation wasreserved for patients with aggressive disease who hadfailed palliative therapies and remained extremely

Abbreviations: GEP, gastroenteropancreatic neuroendocrine cancer; OLT, orthotopic liver transplantation.Supported by NIH grants DK59427 (G.J.G.), the Palumbo and Mayo Foundation,. and Koningin Wilhelmina Fonds Kanker Bestrijding(F.G.I.V.V.), Marco Polo Fonds (F.G.I.V.V.), Jan Kornelis de Cock Stichting (F.G.I.V.V.), and Groninger Universiteits Fonds (F.G.I.V.V.).Address reprint requests to Gregory J. Gores, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905. Telephone: 507-284-0686;FAX: 507-284-0762; E-mail: [email protected]

DOI 10.1002/lt.20702Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 12:448-456, 2006

© 2006 American Association for the Study of Liver Diseases.

symptomatic. Indeed, in an early report on liver trans-plantation for 30 patients with metastatic GEP, 1-yearsurvival was only 52%.6 However, a later review of 103patients reported a 2-year survival rate of 60% and a5-year survival rate of 47%7—a substantial improve-ment over the earlier report. In 2002, the largest single-center study of liver transplantation for GEP was re-ported (n � 19) with a 5-year survival of 80%,8 which iscomparable to that after liver transplantation for cir-rhosis.9 These data suggest that liver transplantation isemerging as a viable option for selected patients withunresectable hepatic metastases from GEP.

Reliable liver transplantation selection criteria for pa-tients with GEP remain unknown. Current data suggestthat age under 50 years, prior resection of the primaryGEP and other extrahepatic disease, and GEP with alow Ki67 proliferation index are favorable prognosticfactors for outcome with liver transplantation.7,8,10-12 Ithas also been suggested that carcinoid GEP from thesmall intestine may have a better outcome than GEParising from the pancreas.10-13 However, these andother clinical and pathological factors are not widelyvalidated yet as selection factors because of the smallnumber of patients, the limited duration of follow-up,and the inconsistent pathologic evaluation of GEP re-ported to date.

The overall aim of this study was to report our expe-rience with liver transplantation for GEP. Specifically,we sought to correlate patient and tumor features withsurvival to better define selection criteria for liver trans-plantation in patients with metastatic GEP. The Ki67labeling index was examined because the proliferationindex is relevant to clinical proliferation category andclassification of GEP, and it has previously shown to bea promising selection criterion.8,14-17 The results sug-gest that liver transplantation for GEP is an effectivetherapeutic option for selected patients, and that theKi67 labeling index in hepatic metastases from GEP isnot a reliable prognostic factor for survival and diseaserecurrence in individual patients.

PATIENTS AND METHODS

Clinical Data Collection

Since March of 1998, 24 patients with GEP metastaticto the liver were registered for liver transplantation withthe United Network of Organ Sharing. Two patientswere transplanted before February of 2002, at whichpoint a formal practice guideline was developed to de-fine eligibility criteria for considering patients with met-astatic GEP for liver transplantation (vide infra). For all24 patients, clinical data concerning staging were re-viewed. Clinical data concerning histopathology, preop-erative treatment, liver transplantation procedure, andfollow-up data were obtained for the 19 patients whounderwent liver transplantation at the Mayo Clinic,Rochester. Informed consent was obtained from all 24patients enrolled to the protocol.

Practice Guidelines for Liver Transplantationof Patients With Metastatic GEP

A written clinical management protocol was developed,after an initial favorable experience with 2 patients,defining selection criteria as follows: (1) histologic con-firmation of a GEP metastatic to the liver or histologicconfirmation of a primary GEP with clinical evidence ofmetastatic disease; (2) bilobar, unresectable, progres-sive hepatic metastases as determined by an experi-enced hepatobiliary surgeon; (3) complete resection ofthe primary GEP prior to liver transplantation (patientswith unknown primary GEP should be excluded afterstaging, unless a single dominant hepatic lesion isidentified and the GEP is thought to be a primary liverlesion); (4) absence of extrahepatic disease, with excep-tion of regional lymph node metastases from the pri-mary GEP that were considered completely resectableprior to liver transplantation, and/or perihepatic lymphnode metastases considered resectable as part of thestandard liver transplantation procedure; (5) the pa-tient is deemed a candidate for liver transplantation bya transplant team, and listed with the United Networkfor Organ Sharing. Exclusion criteria were (1) otherknown cancers except nonmelanoma skin cancers, un-less there was a 5-year disease-free interval from resec-tion of that cancer until liver transplantation; (2) severecomorbid disease or active infection; (3) prior nonselec-tive hepatic artery embolization unless the angiogramwas reviewed and approved by a transplant surgeon(applied only to patients undergoing evaluation for liv-ing donor liver transplantation); (4) rectal carcinoid asprimary tumor; (5) anaplastic carcinoid or poorly differ-entiated neuroendocrine (grade 3 or 4) tumor histology;(6) right atrial pressure �15 mm Hg with or withoutvalvular signs of carcinoid heart disease; and (7) knownpregnancy.

According to these practice guidelines, each patientidentified as a potential liver transplant candidate wasassessed independently by physicians from the divi-sions of medical oncology, surgical oncology, trans-plantation surgery, and hepatology. Patients were ini-tially screened for locally recurrent and extrahepaticmetastatic disease with chest, abdomen, and pelviccomputed tomography scans, bone scan, and soma-tostatin receptor scintigraphy (octreotide scan) within60 days of preliminary registration for transplantation.Patient reevaluation for metastatic disease prior to livertransplantation was performed every 4 months, includ-ing laboratory tests, tumor marker assays, hepatic ul-trasonography, and abdominal and pelvic computedtomography scans. To exclude peritoneal metastases,staging laparoscopy or laparotomy was performed priorto liver transplantation. Patients in whom the primarydisease had not been resected underwent resection ofthe primary GEP at this time. After resection of theprimary GEP, patients were observed for an additional6 months to exclude extrahepatic disease progression.Prior somatostatin analogue therapy, chemotherapy,interferon, hepatic artery embolization/chemoemboli-zation, radiotherapy, radiofrequency ablation, targeted

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radioisotope therapy, and hepatic resection were al-lowed if prior therapy did not technically precludetransplantation.

Liver Transplantation: Procedure andImmunosuppression

Patients undergoing deceased donor liver transplanta-tion had a caval-sparing hepatectomy (n � 12), exceptwhen extrahepatic disease required a venovenous by-pass procedure with caval interposition (n � 2) or whencaval-sparing hepatectomy was not yet performed (n �1). Living donor liver transplantation (n � 4) was per-formed as previously described.18,19 During liver trans-plantation, regional lymphadenectomy was performed,excising all lymphatic tissue along the common hepaticand replaced hepatic arteries to the level of the celiactrunk. Postoperatively, patients received standard im-munosuppression used at the Mayo Clinic that con-sisted initially of tacrolimus, mycophenolic acid, andprednisone. The target blood levels of tacrolimus were10-15 ng/mL in the first 2 weeks and 5-10 ng/mL there-after. Mycophenolic acid was given as a dose of 2 g/dayand discontinued at 4 months after liver transplantation.The dose of prednisone was tapered and discontinuedcompletely by 4 months after transplantation.

Patient Follow-up

Patients were hospitalized for 1 to 2 weeks followingliver transplantation, and then followed in the outpa-tient clinic for approximately 2 to 4 weeks.20 Patientswere evaluated at the Mayo Clinic every 4 months for 1year, then every 6 months for 2 years, and annually upto 5 years after transplantation. Routine laboratorytests, hepatic ultrasonography, and abdominal and pel-vic computed tomography scans were obtained at eachfollow-up visit. If elevated prior to liver transplantation,specific serum hormonal markers were monitored afterliver transplantation to monitor for recurrent disease.Follow-up for the purposes of this study was assessedas of April 14, 2005.

Review of Histopathology

The histopathology was reviewed systematically by ahepatobiliary pathologist. The specimens were diag-nosed and graded as metastatic neuroendocrine canceraccording to the World Health Organization criteria.21

Immunohistochemistry Staining for Ki67

Representative sections were available from the ex-planted livers, including adjacent liver tissue. Un-stained slides of tissue specimens were deparaffinizedand hydrated. Antigen retrieval was performed usingethylenediaminetetraacetic acid (1 mmol/L, pH 8.0);slides were placed in a vegetable steamer for 40 min-utes at 97°C followed by a cooling-off period of 20 min-utes. Thereafter, the catalyzed signal amplification sys-tem (DakoCytomation, Carpinteria, CA) was used for

Ki67 staining according to the manufacturer’s instruc-tions. The primary antibody utilized was the murinemonoclonal Ki67 antibody (1:500, clone 35, BD Trans-duction Laboratories, Pharmingen, San Diego, CA).Surrounding liver parenchyma served as internal pos-itive control.

To examine Ki67 expression, slides were viewed undermicroscopy (Axioplan 2, Carl Zeiss, Inc. Oberkochen,Germany). Digital pictures were captured through avideo archival system using a digital TV camera sys-tem (Axiocam High Resolution color, Carl Zeiss, Inc.,Oberkochen, Germany). With an automated softwareanalysis program (KS400, Carl Zeiss, Inc., Oberkochen,Germany), the percentage of Ki67 stain (Dako Cytoma-tion, Carpinteria, CA) (red color in area/field area �100) from the digital photomicrographs was quantified.A minimum of 5 digital photomicrographs were evalu-ated to calculate the mean percentage of positive sig-nals in the total picture surface. Ki67 expression wasexamined without observers’ knowledge of clinical data.

Statistics

Patient survival and recurrence rates were calculatedusing Kaplan-Meier estimates with log-rank testing forsignificance. To assess the influence of possible prog-nostic factors on survival and recurrence, Kaplan-Meierestimates and Fisher exact, Mann-Whitney U, Pearson,and Spearman tests were used. Differences in survivalrates were considered significant if P � 0.05.

RESULTS

Patient Population

Of 24 patients with GEP metastatic to the liver, regis-tered for liver transplantation with the United Networkfor Organ Sharing, 19 patients underwent liver trans-plantation, including one patient who died during thetransplantation procedure prior to implantation (Table1). The mean time interval from protocol enrollment totransplantation was 10 months (range, 2-32 months).Four patients initially registered were excluded fromour protocol: 2 patients underwent transplantationelsewhere, 1 patient ultimately declined liver trans-plantation, and 1 patient developed extrahepatic me-tastases precluding liver transplantation. One patientis still awaiting transplantation.

The patient population included 15 men and 4women. The median age of the 19 patients at the time oftransplantation was 47.0 years (range, 22-64 years).Eight patients had a carcinoid GEP, with a small bowelprimary in 7 patients. One other patient had a primaryhepatic carcinoid tumor. Except for the patient withprimary hepatic carcinoid GEP, all patients with carci-noid GEP had elevated urinary levels of 5-hydroxyin-doleacetic acid. Eleven patients had primary pancreaticGEP or islet cell cancers, including gastrinoma (n � 3),glucagonoma (n � 1), vasoactive intestinal peptide se-creting GEP (n � 1), and nonfunctioning GEP (n � 6).

In the pretransplant period, the carcinoid syndrome(flushing and diarrhea) was present in 6 of 8 carcinoid

450 VAN VILSTEREN ET AL.


patients. Additional symptoms included abdominalpain (n � 6), weight loss (n � 4), wheezing (n � 2),nausea and vomiting (n � 1), carcinoid heart disease(n � 1), and tumor fevers (n � 1). Patients with pancre-atic GEP had abdominal pain (n � 4), diarrhea (n � 4)(including 1 patient with a vasoactive intestinal peptidesecreting GEP and another with a gastrinoma), severeacid reflux (n � 4: 2 gastrinoma patients and a glu-cagonoma patient, whose tumor also produced gastrin),nausea (n � 3), vomiting (n � 2), weight loss (n � 2), andjaundice (n � 1), early satiety (n � 1), and migratorynecrolytic erythema (n � 1) (glucagonoma). One patientwith nonfunctioning GEP was asymptomatic.

Histopathological proof of GEP preceded liver trans-plantation by a mean of 3 years (range, 7 months to 6years). The mean time interval between histopathologicalor image-based diagnosis of hepatic metastases and livertransplantation was 2.3 years (range, 7 months to 6.5years). There was a significant difference (P � 0.03) in themean time interval from diagnosis of hepatic metastasesto liver transplantation between carcinoid patients (16months) and pancreatic GEP (45 months).

Surgical Management Prior to LiverTransplantation

All 19 patients underwent surgical or radiological inter-vention prior to liver transplantation (Table 2). Surgical

resection of the primary GEP was performed prior toliver transplantation in 17 patients. One patient had aprimary ileal carcinoid that was resected during OLT,and 1 patient had a primary unresectable hepatic car-cinoid GEP. Six patients with primary small bowel car-cinoid underwent partial small bowel resection com-bined with cholecystectomy and hepatic artery ligation(n � 1), appendectomy (n � 1), resection of a mesentericmass (n � 1), and excision of hepatic metastases andhemicolectomy (n � 1). All 11 patients with pancreaticGEP underwent partial pancreatic resections. Three pa-tients had a pancreaticoduodenectomy, and 8 patientshad a distal pancreatectomy and splenectomy. Addi-tionally, patients with pancreatic GEP underwent thefollowing procedures prior to transplantation: partialsplenectomy (n � 1), cholecystectomy (n � 3), partialgastrectomy (n � 1), adrenalectomy (n � 1), partialadrenalectomy and partial colectomy (n � 1), and righthepatectomy (n � 1). Regional lymphadenectomy com-bined with resection of the primary GEP was performedwhen indicated. Lymph node metastases were con-firmed pathologically in 14 patients (n � 8 pancreaticGEP, n � 6 carcinoid GEPs) during surgical explorationprior to OLT.

After initial resection of the primary GEP, 5 patientshad additional operations for resection of GEP prior toliver transplantation. One patient had a second pancre-

TABLE 1. Demographic and Histologic Data, Tumor Recurrence, Current Status, and Follow-up in 19 Patients

Transplanted for Metastatic Gastroenteropancreatic Neuroendocrine Cancer

Patient Age Sex

Primary

Tumor Site

Clinical

Classification

Tumor

Markers

Recurrent

Disease Status

Follow-up

(months)

1 53 M Ileum Carcinoid 5-HIAA No Alive 182 57 M Pancreas Islet cell cancer;

gastrinomaGastrin No Alive 18

3 36 F Liver Carcinoid N/F No Alive 274 54 M Pancreas Islet cell cancer N/F No Alive 135 41 M Pancreas Islet cell cancer N/F No Alive 306 22 M Small bowel Carcinoid 5-HIAA No Alive 247 33 M Ileum Carcinoid 5-HIAA,

serotoninNo Alive 20

8 45 M Ileum Carcinoid 5-HIAA No Alive 289 38 M Pancreas Islet cell cancer;

glucagonomaGlucagon,

gastrinYes Alive 17

10 56 M Pancreas Islet cell cancer;gastrinoma

Gastrin Yes Dead 9

11 27 M Pancreas Islet cell cancer N/F No Alive 1312 56 M Ileum Carcinoid 5-HIAA No Alive 1113 47 M Pancreas Islet cell cancer N/F No Alive 414 45 M Pancreas Islet cell cancer N/F No Alive 515 64 F Small bowel Carcinoid 5-HIAA No Alive 416 56 M Pancreas Islet cell cancer;

gastrinomaGastrin Yes Alive, tumor

free10

17 62 F Pancreas Islet cell cancer;VIPoma

VIP No Alive 73

18 48 M Ileum Carcinoid 5-HIAA No Alive 8419 42 F Pancreas Islet cell cancer N/F - Dead 0

Abbreviations: M, male; 5-HIAA, 5-hydroxyindoleacetic acid; F, female; N/F, nonfunctioning; VIP, vasoactive intestinalpeptide.

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atectomy. One patient had a second partial small bowelresection and cholecystectomy followed by a third par-tial small bowel resection. Another patient underwent asecond small bowel resection followed by 3 operationsto excise liver metastases (with cholecystectomy, cryo-surgery, and radiofrequency ablation) and a partial pul-monectomy for bronchoalveolar carcinoma. Two otherpatients underwent operations to excise liver metasta-ses combined with intraoperative radiofrequency abla-tion in both patients and electrocautery ablation in onepatient. Altogether, surgical excision of hepatic metas-tases was performed in 5 of 19 patients, plus radiofre-quency ablation in 3 patients.

Medical Therapy Prior to LiverTransplantation

Medical treatment was given to patients when neces-sary to control symptoms and limit tumor progressionon the waiting list. Systemic chemotherapy was given topatients with somatostatin-receptor-negative tumors orwhose tumor was otherwise not responsive to soma-tostatin therapy. Hepatic embolization was used whenhepatic metastases caused symptoms due to progres-sive intrahepatic disease. Sixteen patients were treatedwith somatostatin analogues (octreotide). Systemicchemotherapy (dacarbazine, gefitinib, and combinedadriamycin and streptozotocin) was used in 3 patientsand interferon in 2 patients. One patient underwentradiolabeled monoclonal antibody therapy (Cotara),

and another was treated with yttrium-labeled oct-reotide. Six patients underwent repeated hepatic arteryembolization. Three patients did not receive any medi-cal therapy prior to OLT.

Staging Procedure

Staging laparoscopy or laparotomy was performed priorto registration for liver transplantation in 24 patients.There was no evidence for extrahepatic disease in 21patients. Three patients had extrahepatic disease dur-ing staging. One patient with carcinoid hepatic metas-tases underwent ileal resection and regional lymphad-enectomy for the primary GEP. After an extrahepaticrecurrence-free interval of 3 years, liver transplantationwas performed. Two patients with hepatic metastasesfrom pancreatic GEP had extrahepatic disease, sug-gested by cross-sectional imaging and confirmed byendoscopic ultrasound guided biopsy. An incompleteresection of the primary tumor required repeat resec-tion with distal pancreatectomy and regional lymphad-enectomy in one patient. Liver transplantation was at-tempted 7 months later, but the patient died during theprocedure. The other patient had recurrent GEP in thehead of the pancreas and was therefore excluded fromliver transplantation.

Liver Transplantation and Complications

Fifteen of 19 patients underwent deceased donor livertransplantation, and 4 patients underwent living donor

TABLE 2. Pretransplant Operative Treatment in 19 Patients With Gastroenteropancreatic Neuroendocrine Cancer

Patient Surgical Procedures

1 Small bowel resection/cholecystectomy/hepatic artery ligation2 Distal pancreatectomy/splenectomy/lymphadenectomy3 HAE 2�4 Pylorus preserving Whipple procedure/cholecystectomy; excision liver metastases/RFA/

electrocautery ablation5 Whipple procedure; Wedge resection liver/RFA6 Small bowel resection 2�; excision liver

metastases/cholecystectomy/cryosurgery/lymphadenectomy; Wedge resection liver;cryoablation; partial pulmonectomy; liver resection/RFA; RFA; HEA;chemoembolization Yttrium; biliary sphincterotomy/stenting

7 Small bowel resection; partial ileum resection/cholecystectomy; HAE 2�; excisionileum/lymphadenectomy

8 HAE 4�; tricuspid and pulmonary valve replacement9 Distal pancreatectomy/splenectomy/partial stomach resection/lymphadenectomy10 Distal pancreatectomy/partial splenectomy; HEA 5�11 Distal pancreatectomy/splenectomy/adrenalectomy/cholecystectomy/lymphadenectomy12 Partial ileal resection/appendectomy; HAE 2�13 Distal pancreatectomy/splenectomy14 Whipple procedure15 Partial small bowel resection/resection mesenteric mass16 Distal pancreatectomy/splenectomy/partial adrenalectomy/partial colectomy17 Distal pancreatectomy/right hepatectomy/splenectomy18 Ileal resection/hemicolectomy/ileotransverse colostomy/excision liver metastases19 Distal pancreatectomy/splenectomy/cholecystectomy; distal

pancreatectomy/lymphadenectomy

Abbreviations: HEA, hepatic artery embolization; RFA, radiofrequency ablation.



liver transplantation. All patients underwent regionallymphadenectomy, and 8 patients had metastatic dis-ease involving 1 to 5 lymph nodes in the hepatoduode-nal ligament. One patient had an ileal resection duringOLT because the patient was too ill to have the primarytumor resected prior to OLT.

Major complications within the first week posttrans-plant were as follows: portal vein thrombosis requiringsurgery with thrombectomy and conversion of the arte-rial anastomosis to the infrarenal abdominal aorta; he-patic artery thrombosis with bile leakage requiring sur-gical revision of the arterial anastomosis andoversewing of the bile leak; bile leak and stricture forwhich a Roux-en-Y choledochojejunostomy was per-formed; jejunal perforation, which was oversewn; dis-placed bile catheter (lying free within the peritonealcavity), which had to be surgically removed; and partialcolectomy for diverticulitis. Other major complicationsoccurred within 6 months after transplantation: 1 pa-tient suffered from early portal vein thrombosis requir-ing thrombectomy, a pelvic abscess that resolved withantibiotics, and a hepatic artery stenosis requiringstent placement; other single patients showed hepaticvein stenosis requiring dilation, wound dehiscence re-quiring surgery, and a bile leak for which a biliarysphincterotomy with pancreatic stent placement wasperformed. Nine patients underwent treatment foracute cellular rejection, which was steroid responsive.

Pathology of the Explanted Liver

GEP was confirmed microscopically as well-differenti-ated neuroendocrine carcinoma (grades 1 and 2) in theliver explants of 18 patients. The Ki67 proliferation in-dex was assessed in 18 explanted livers. Ki67 indices intumor specimens varied from 0.06% to 2.35% with anaverage of 0.69%.

Analysis of the relation between the survival or recur-rence and the Ki67 index (low: Ki67 � 2%, n � 15; high:Ki67 � 2%, n � 3) showed a significant correlationbetween Ki67 labeling index and survival (r � �0.54;P � 0.02) when using the Pearson and Spearman tests.No significant correlation was found between recur-rence and low or high Ki67 labeling indices (r � 0.20;P � 0.43). However, Fischer’s exact test did not showsignificant differences in survival and recurrence be-tween patients with low or high Ki67 labeling indices(P � 0.19 and P � 0.49, respectively). Although meanKi67 percentage was observed to be greater in patientswith pancreatic GEP than in those with carcinoid GEP(0.81% vs. 0.57%) and greater for nonfunctioning GEPthan for functioning GEP (0.82% vs. 0.64%), these dif-ferences were not statistically significant.

Outcomes

The mean follow-up for 17 patients (exclusion of 2 pa-tients transplanted before development of the treat-ment protocol) is 15 months (range, 0-30 months). Themean follow-up for all 19 patients was 22 months(range, 0-84 months). After ending follow-up, there

were 2 deaths, and 17 patients were alive, including 1patient with recurrent disease. One patient died duringliver transplantation, and another patient died 9months posttransplant from metastatic disease, dis-covered after 5 months. Two additional patients haddisease recurrence after 11 and 5 months, respectively:1 is alive with bone metastases and porto-caval andaortocaval lymphadenopathy, and 1 is alive withoutevidence of disease after resection of recurrent meta-static lymph nodes. This patient had an initial resectionof positive regional lymph nodes during liver transplan-tation. All 3 patients with disease recurrence after livertransplantation have had previous pancreatic GEP.

Estimated 1-year patient survival was 87% for 17patients transplanted after development of the treat-ment protocol. Ten of 17 patients were at risk of dying at1 year after transplantation, 4 patients were at risk ofdying at 2 years, and no patients were at risk of dyingmore than 3 years after transplantation (Fig. 1). Esti-mated 1-year patient survival was 88% for all 19 trans-planted patients. Estimated 1-year survival was notstatistically different between patients with carcinoid(n � 7) and pancreatic GEP (n � 10) (100% vs. 77%, P �0.2). Estimated 1-year recurrence-free rate (conditionalon survival) was 77% for 17 patients transplanted afterdevelopment of the treatment protocol and 80% for all19 transplanted patients (Fig. 2A). Estimated 1-yearrecurrence-free rates (conditional on survival) did notdiffer among tumor types (100% vs. 60%, P � 0.1) (Fig.

Figure 1. Kaplan Meier estimates of overall survival in 17patients after liver transplantation for metastatic gastroen-teropancreatic neuroendocrine cancer. Numbers above curveindicate the number of patients still at risk as a function oftime.

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2B). Similarly, recurrence-free rates between function-ing (n � 10) and nonfunctioning (n � 7) GEP were notstatistically different at 1 year (65% vs. 100%, P � 0.2).No correlations were found between following possibleprognostic factors and survival and recurrence: age�50 years (r � 0.08, P � 0.75 and r � 0.14, P � 0.58),lymph nodes at OLT (r � 0.02, P � 0.94 and r � 0.12,

P � 0.62), carcinoid/pancreatic GEP (r � 0.29, P � 0.22and r � 0.37, P � 0.12), and nonfunctioning/function-ing GEP (r � 0.09, P � 0.70 and r � 0.33, P � 0.17).

DISCUSSION

The principal findings of our experience with livertransplantation for GEP metastatic to the liver demon-strate that (1) despite extensive prior surgery, livertransplantation in these patients can be accomplishedwith excellent estimated 1-year and 2-year survival(87%), and (2) estimated disease recurrence in the first2 years is acceptable (23%). These results support con-tinued evaluation of liver transplantation for highly se-lected patients with GEP.

The early overall survival of patients after liver trans-plantation for hepatic metastases from GEP is similarto liver transplantation for other indications.8,13,14 In-deed, recent overall 1- and 2-year survival after livertransplantation at the Mayo Clinic, Rochester, are 92%and 89%, respectively, compared to an estimated 1-and 2-year survival of 87% for patients undergoing livertransplantation for hepatic metastases from GEP. Theabsence of portal hypertension in patients with meta-static GEP is a factor that simplifies the liver transplantprocedure technically despite prior abdominal opera-tions. The effect of immunosuppression on progressionof potential micrometastatic disease after transplanta-tion as a potential concern also was not observed in ourexperience. Thus, from a technical and clinical perspec-tive, liver transplantation can be accomplished in thesepatients with excellent early survival.

A large single-center study on long-term follow-upafter liver transplantation for GEP (n � 19; mean follow-up, 59 months) reported 1-year and 5-year survivalrates of 89% and 80%, respectively.8 Less favorableresults on long-term follow-up were observed in a re-cent study (n � 11; mean follow-up, 34 months) with 1-and 5-year survival of 73% and 36%, respectively.22 It isimportant is to note that in these 2 prior studies, ex-tensive surgery to remove extrahepatic disease was per-formed at the time of OLT in many patients, which haspreviously been shown to be a predictor of disease re-currence.7 Our estimated survival rates are likely favor-able as compared to these prior studies due to thespecific evaluation protocol and patient selection crite-ria. Indeed, to exclude extrahepatic disease at the timeof liver transplantation, a thorough staging protocolwith frequent patient reevaluation for metastatic dis-ease was performed, including a staging laparotomy orlaparoscopy when technically permitted. In addition,the implementation of somatostatin receptor scintigra-phy (octreotide scan) has increased detection rates forGEP4,23 and was also used to exclude patients as livertransplant candidates. Only patients with unresectablemetastases without extrahepatic disease were selectedfor the treatment protocol. Additionally, the time inter-val between resection of the primary GEP and livertransplantation has been suggested as a critical factorin patient selection.14 Candidacy at our center requiredan initial resection of the primary GEP followed by clin-

Figure 2. (A) Kaplan-Meier estimates of the probability ofbeing recurrence-free (conditional on survival) in 17 patientsafter liver transplantation for metastatic gastroenteropancre-atic neuroendocrine cancer. Numbers above curve indicate thenumber of patients still at risk as a function of time. (B)Kaplan-Meier estimates of the probability of being recur-rence-free (conditional on survival) in 17 patients after livertransplantation for metastatic gastroenteropancreatic neu-roendocrine cancer. Comparison between carcinoid and pan-creatic gastroenteropancreatic neuroendocrine cancer groupsdid not show significant differences although patients withpancreatic gastroenteropancreatic neuroendocrine cancerwere observed to have greater recurrence-free probability.Numbers above curve indicate the number of patients still atrisk for the two groups together as a function of time.



ical restaging after a minimal interval of 6 months toexclude extrahepatic disease progression. This ap-proach assured disease stability over a 6-month inter-val and may also have improved outcomes.

Although our survival rates mirror those of some pre-vious studies, the estimated 1-year recurrence-free rateof 77% is excellent in comparison with 3 large studiesshowing estimated 1-year recurrence-free survivalrates of 45%,11 60%,7 and 56%.8 In these studies therates of lymph node metastases at the time of livertransplantation (13/23, 37/42, and 10/19, respec-tively) were slightly higher than the rate in our study(8/19). Perhaps patients in our study had more com-plete resections prior and during liver transplantationbecause of better detection of tumor tissue and positivelymph nodes after implementation of somatostatin re-ceptor scintigraphy.

Similar to others, we observed a possible influence ofthe primary tumor site on disease recurrence followingliver transplantation.11,13 In our study, a trend towardbetter outcome, as demonstrated by lower recurrencerate, was observed in patients with hepatic metastasesfrom carcinoid GEP than in patients with metastaticpancreatic GEP. Indeed, all 3 recurrences were found inpatients with functioning pancreatic GEP (1 glu-cagonoma and 2 gastrinomas). In accordance with ourresults, a higher recurrence rate after liver transplan-tation for pancreatic GEP was also observed in a studyof 10 patients showing 5 patients with disease recur-rence after liver transplantation, including 4 patientswith pancreatic GEP.13 Another study also observedsignificant adverse survival outcomes in patients withpancreatic GEP vs. intestinal carcinoids after livertransplantation.11 A third study observed excellent 1-and 5-year survival of 100% and 70%, respectively, bytransplanting only patients with hepatic metastasesfrom carcinoid GEP.10 Larger patient numbers will benecessary to substantiate these observations, as thecurrent experience is too limited to alter selection cri-teria based on origin of tumor.

Several studies have observed that patients whosetumors demonstrate a low proportion of Ki67 positivecells have a better outcome.8,13,17 Others achieved goodresults by selecting only patients with well-differenti-ated GEP and low Ki67 proliferation index (�10%) fortransplantation.14-16 The Ki67 labeling indices in thisstudy appear to be low in comparison to other studies.Possible explanations are that (1) all the patients in thisstudy had well-differentiated neuroendocrine tumorhistology, and (2) in contrast to others, we used a com-puted quantification technique. Although a significantcorrelation between survival and Ki67 labeling indexwas found, there were only 3 patients with recurrenceand 2 patients who died, making the data too limited torelate survival and recurrence to the Ki67 labeling in-dex. However, our patient with the highest absoluteKi67 labeling index developed early disease recurrenceand death from metastases. Larger numbers of patientswith recurrent disease and a high Ki67 labeling indexare required to determine the prognostic value of theKi67 labeling index.

Currently, liver transplantation for metastatic GEP iscontroversial, and patients with metastatic GEP do notreceive prioritization in the model for end-stage liverdisease allocation system.24 The results of our studydemonstrate that liver transplantation for GEP is asso-ciated with early outcomes comparable to patients un-dergoing liver transplantation for cirrhosis. In contrast,reported 5-year survival for patients with bilobar, un-resectable hepatic metastases is only 30%.3 In the past,analogous situations existed for hepatocellular carci-noma. For example, results of liver transplantation forhepatocellular carcinoma before 1995 were disappoint-ing, with overall 2-year survival rates of 30% or less. In1996 a prospective trial using highly selective tumorcriteria demonstrated excellent results, resulting in ac-ceptance of selected patients with hepatocellular carci-noma for liver transplantation.25,26 Nevertheless, forpatients with metastatic GEP, model for end-stage liverdisease scores with upgrades could be considered, es-pecially if subsequent studies better define those pa-tients who have a better survival after liver transplan-tation. We suggest that deceased donor livertransplantation, especially for patients with carcinoidGEP metastatic to the liver,8,10,11,13 be reevaluated forconsideration of model for end-stage liver disease as-signment.

ACKNOWLEDGMENTSThe authors thank Erin Bungum for superb secretarialservices and Jim Tarara for the excellent help in thedetailed computer analysis of the Ki67 immunohisto-chemistry.

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Liver transplantation for gastroenteropancreatic neuroendocrine cancers: Defining selection criteria to improve survival