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

Authors


Abstract

Liver transplantation for gastroenteropancreatic neuroendocrine cancer (GEP) is controversial. The aim of this study was to assess patient outcomes after liver transplantation for hepatic metastases from GEP. Medical records of patients who underwent liver transplantation for GEP were reviewed. Immunohistochemistry for assessing the Ki67 proliferation index was performed on explanted liver tissue. Nineteen patients who underwent liver transplantation had a mean follow-up of 22 months with a range of 0 to 84 months. There was 1 intraoperative death, and 3 patients had disease recurrence after liver transplantation 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%. Three of 11 patients with pancreatic islet cell GEP developed disease recurrence, whereas all 8 patients with carcinoid GEP remain free of disease. Analysis of the Ki67 proliferation index in 18 patients did not differentiate those with recurrence from those without disease recurrence. In conclusion, liver transplantation for patients with hepatic metastases from GEP is a viable therapeutic option in highly selected patients. Liver Transpl 12:448–456, 2006. © 2006 AASLD.

Neuroendocrine cancers form a diverse group of tumors, frequently arising from neuroendocrine cells within the gastrointestinal tract and pancreas. Gastroenteropancreatic neuroendocrine cancer (GEP) has an incidence of 1 or 2 cases per 100,000 people per year.1 Most GEPs are characterized by slow growth despite frequent presentation with advanced stage of disease and metastases. These malignancies have the capacity to produce hormones with specific syndromes (e.g., the carcinoid syndrome), or they can be nonfunctioning. GEPs preferentially metastasize to the liver, and metastases can be limited to the liver for protracted periods of time.2 Many patients are asymptomatic. Others have hormonal syndromes that can be controlled with long-acting somatostatin analogues. Once disease becomes progressive, with bilobar hepatic metastases, survival is limited, with an average 5-year survival of only 30%.3

Current therapeutic approaches for patients with advanced GEP, metastatic to the liver, are palliative and include hepatic arterial embolization and chemoembolization, debulking surgery, and administration of somatostatin analogues and cytotoxic chemotherapy. Although all of these approaches are associated with favorable response rates,4, 5 metastatic GEP is ultimately a fatal disease. Because metastases may be limited to the liver for extended periods, orthotopic liver transplantation (OLT) has been advocated as a potentially curative therapy for selected patients.4 Our experience at the Mayo Clinic with hepatic debulking surgery also suggests that liver transplantation may have a potential palliative effect by “debulking” disease, even if it's not curative. In the past, liver transplantation was reserved for patients with aggressive disease who had failed palliative therapies and remained extremely symptomatic. Indeed, in an early report on liver transplantation for 30 patients with metastatic GEP, 1-year survival was only 52%.6 However, a later review of 103 patients reported a 2-year survival rate of 60% and a 5-year survival rate of 47%7—a substantial improvement over the earlier report. In 2002, the largest single-center study of liver transplantation for GEP was reported (n = 19) with a 5-year survival of 80%,8 which is comparable to that after liver transplantation for cirrhosis.9 These data suggest that liver transplantation is emerging as a viable option for selected patients with unresectable hepatic metastases from GEP.

Reliable liver transplantation selection criteria for patients with GEP remain unknown. Current data suggest that age under 50 years, prior resection of the primary GEP and other extrahepatic disease, and GEP with a low Ki67 proliferation index are favorable prognostic factors for outcome with liver transplantation.7, 8, 10–12 It has also been suggested that carcinoid GEP from the small intestine may have a better outcome than GEP arising from the pancreas.10–13 However, these and other clinical and pathological factors are not widely validated yet as selection factors because of the small number of patients, the limited duration of follow-up, and the inconsistent pathologic evaluation of GEP reported to date.

The overall aim of this study was to report our experience with liver transplantation for GEP. Specifically, we sought to correlate patient and tumor features with survival to better define selection criteria for liver transplantation in patients with metastatic GEP. The Ki67 labeling index was examined because the proliferation index is relevant to clinical proliferation category and classification of GEP, and it has previously shown to be a promising selection criterion.8, 14–17 The results suggest that liver transplantation for GEP is an effective therapeutic option for selected patients, and that the Ki67 labeling index in hepatic metastases from GEP is not a reliable prognostic factor for survival and disease recurrence in individual patients.

Abbreviations

GEP, gastroenteropancreatic neuroendocrine cancer; OLT, orthotopic liver transplantation.

PATIENTS AND METHODS

Clinical Data Collection

Since March of 1998, 24 patients with GEP metastatic to the liver were registered for liver transplantation with the United Network of Organ Sharing. Two patients were transplanted before February of 2002, at which point a formal practice guideline was developed to define eligibility criteria for considering patients with metastatic GEP for liver transplantation (vide infra). For all 24 patients, clinical data concerning staging were reviewed. Clinical data concerning histopathology, preoperative treatment, liver transplantation procedure, and follow-up data were obtained for the 19 patients who underwent liver transplantation at the Mayo Clinic, Rochester. Informed consent was obtained from all 24 patients enrolled to the protocol.

Practice Guidelines for Liver Transplantation of 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 confirmation of a GEP metastatic to the liver or histologic confirmation of a primary GEP with clinical evidence of metastatic disease; (2) bilobar, unresectable, progressive hepatic metastases as determined by an experienced hepatobiliary surgeon; (3) complete resection of the primary GEP prior to liver transplantation (patients with unknown primary GEP should be excluded after staging, unless a single dominant hepatic lesion is identified and the GEP is thought to be a primary liver lesion); (4) absence of extrahepatic disease, with exception of regional lymph node metastases from the primary GEP that were considered completely resectable prior to liver transplantation, and/or perihepatic lymph node metastases considered resectable as part of the standard liver transplantation procedure; (5) the patient is deemed a candidate for liver transplantation by a transplant team, and listed with the United Network for Organ Sharing. Exclusion criteria were (1) other known cancers except nonmelanoma skin cancers, unless there was a 5-year disease-free interval from resection of that cancer until liver transplantation; (2) severe comorbid disease or active infection; (3) prior nonselective hepatic artery embolization unless the angiogram was reviewed and approved by a transplant surgeon (applied only to patients undergoing evaluation for living donor liver transplantation); (4) rectal carcinoid as primary tumor; (5) anaplastic carcinoid or poorly differentiated neuroendocrine (grade 3 or 4) tumor histology; (6) right atrial pressure >15 mm Hg with or without valvular signs of carcinoid heart disease; and (7) known pregnancy.

According to these practice guidelines, each patient identified as a potential liver transplant candidate was assessed independently by physicians from the divisions of medical oncology, surgical oncology, transplantation surgery, and hepatology. Patients were initially screened for locally recurrent and extrahepatic metastatic disease with chest, abdomen, and pelvic computed tomography scans, bone scan, and somatostatin receptor scintigraphy (octreotide scan) within 60 days of preliminary registration for transplantation. Patient reevaluation for metastatic disease prior to liver transplantation was performed every 4 months, including laboratory tests, tumor marker assays, hepatic ultrasonography, and abdominal and pelvic computed tomography scans. To exclude peritoneal metastases, staging laparoscopy or laparotomy was performed prior to liver transplantation. Patients in whom the primary disease had not been resected underwent resection of the primary GEP at this time. After resection of the primary GEP, patients were observed for an additional 6 months to exclude extrahepatic disease progression. Prior somatostatin analogue therapy, chemotherapy, interferon, hepatic artery embolization/chemoembolization, radiotherapy, radiofrequency ablation, targeted radioisotope therapy, and hepatic resection were allowed if prior therapy did not technically preclude transplantation.

Liver Transplantation: Procedure and Immunosuppression

Patients undergoing deceased donor liver transplantation had a caval-sparing hepatectomy (n = 12), except when extrahepatic disease required a venovenous bypass procedure with caval interposition (n = 2) or when caval-sparing hepatectomy was not yet performed (n = 1). Living donor liver transplantation (n = 4) was performed as previously described.18, 19 During liver transplantation, regional lymphadenectomy was performed, excising all lymphatic tissue along the common hepatic and replaced hepatic arteries to the level of the celiac trunk. Postoperatively, patients received standard immunosuppression used at the Mayo Clinic that consisted initially of tacrolimus, mycophenolic acid, and prednisone. The target blood levels of tacrolimus were 10-15 ng/mL in the first 2 weeks and 5-10 ng/mL thereafter. Mycophenolic acid was given as a dose of 2 g/day and discontinued at 4 months after liver transplantation. The dose of prednisone was tapered and discontinued completely by 4 months after transplantation.

Patient Follow-up

Patients were hospitalized for 1 to 2 weeks following liver transplantation, and then followed in the outpatient clinic for approximately 2 to 4 weeks.20 Patients were evaluated at the Mayo Clinic every 4 months for 1 year, then every 6 months for 2 years, and annually up to 5 years after transplantation. Routine laboratory tests, hepatic ultrasonography, and abdominal and pelvic computed tomography scans were obtained at each follow-up visit. If elevated prior to liver transplantation, specific serum hormonal markers were monitored after liver transplantation to monitor for recurrent disease. Follow-up for the purposes of this study was assessed as of April 14, 2005.

Review of Histopathology

The histopathology was reviewed systematically by a hepatobiliary pathologist. The specimens were diagnosed and graded as metastatic neuroendocrine cancer according to the World Health Organization criteria.21

Immunohistochemistry Staining for Ki67

Representative sections were available from the explanted livers, including adjacent liver tissue. Unstained slides of tissue specimens were deparaffinized and hydrated. Antigen retrieval was performed using ethylenediaminetetraacetic acid (1 mmol/L, pH 8.0); slides were placed in a vegetable steamer for 40 minutes at 97°C followed by a cooling-off period of 20 minutes. Thereafter, the catalyzed signal amplification system (DakoCytomation, Carpinteria, CA) was used for Ki67 staining according to the manufacturer's instructions. The primary antibody utilized was the murine monoclonal Ki67 antibody (1:500, clone 35, BD Transduction Laboratories, Pharmingen, San Diego, CA). Surrounding liver parenchyma served as internal positive control.

To examine Ki67 expression, slides were viewed under microscopy (Axioplan 2, Carl Zeiss, Inc. Oberkochen, Germany). Digital pictures were captured through a video archival system using a digital TV camera system (Axiocam High Resolution color, Carl Zeiss, Inc., Oberkochen, Germany). With an automated software analysis program (KS400, Carl Zeiss, Inc., Oberkochen, Germany), the percentage of Ki67 stain (Dako Cytomation, Carpinteria, CA) (red color in area/field area × 100) from the digital photomicrographs was quantified. A minimum of 5 digital photomicrographs were evaluated to calculate the mean percentage of positive signals in the total picture surface. Ki67 expression was examined without observers' knowledge of clinical data.

Statistics

Patient survival and recurrence rates were calculated using Kaplan-Meier estimates with log-rank testing for significance. To assess the influence of possible prognostic factors on survival and recurrence, Kaplan-Meier estimates and Fisher exact, Mann-Whitney U, Pearson, and Spearman tests were used. Differences in survival rates were considered significant if P ≤ 0.05.

RESULTS

Patient Population

Of 24 patients with GEP metastatic to the liver, registered for liver transplantation with the United Network for Organ Sharing, 19 patients underwent liver transplantation, including one patient who died during the transplantation procedure prior to implantation (Table 1). The mean time interval from protocol enrollment to transplantation was 10 months (range, 2-32 months). Four patients initially registered were excluded from our protocol: 2 patients underwent transplantation elsewhere, 1 patient ultimately declined liver transplantation, and 1 patient developed extrahepatic metastases precluding liver transplantation. One patient is still awaiting transplantation.

Table 1. Demographic and Histologic Data, Tumor Recurrence, Current Status, and Follow-up in 19 Patients Transplanted for Metastatic Gastroenteropancreatic Neuroendocrine Cancer
PatientAgeSexPrimary Tumor SiteClinical ClassificationTumor MarkersRecurrent DiseaseStatusFollow-up (months)
  1. Abbreviations: M, male; 5-HIAA, 5-hydroxyindoleacetic acid; F, female; N/F, nonfunctioning; VIP, vasoactive intestinal peptide.

153MIleumCarcinoid5-HIAANoAlive18
257MPancreasIslet cell cancer; gastrinomaGastrinNoAlive18
336FLiverCarcinoidN/FNoAlive27
454MPancreasIslet cell cancerN/FNoAlive13
541MPancreasIslet cell cancerN/FNoAlive30
622MSmall bowelCarcinoid5-HIAANoAlive24
733MIleumCarcinoid5-HIAA, serotoninNoAlive20
845MIleumCarcinoid5-HIAANoAlive28
938MPancreasIslet cell cancer; glucagonomaGlucagon, gastrinYesAlive17
1056MPancreasIslet cell cancer; gastrinomaGastrinYesDead9
1127MPancreasIslet cell cancerN/FNoAlive13
1256MIleumCarcinoid5-HIAANoAlive11
1347MPancreasIslet cell cancerN/FNoAlive4
1445MPancreasIslet cell cancerN/FNoAlive5
1564FSmall bowelCarcinoid5-HIAANoAlive4
1656MPancreasIslet cell cancer; gastrinomaGastrinYesAlive, tumor free10
1762FPancreasIslet cell cancer; VIPomaVIPNoAlive73
1848MIleumCarcinoid5-HIAANoAlive84
1942FPancreasIslet cell cancerN/F-Dead0

The patient population included 15 men and 4 women. The median age of the 19 patients at the time of transplantation was 47.0 years (range, 22-64 years). Eight patients had a carcinoid GEP, with a small bowel primary in 7 patients. One other patient had a primary hepatic carcinoid tumor. Except for the patient with primary hepatic carcinoid GEP, all patients with carcinoid GEP had elevated urinary levels of 5-hydroxyindoleacetic acid. Eleven patients had primary pancreatic GEP or islet cell cancers, including gastrinoma (n = 3), glucagonoma (n = 1), vasoactive intestinal peptide secreting 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 patients. Additional symptoms included abdominal pain (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 pancreatic GEP had abdominal pain (n = 4), diarrhea (n = 4) (including 1 patient with a vasoactive intestinal peptide secreting GEP and another with a gastrinoma), severe acid reflux (n = 4: 2 gastrinoma patients and a glucagonoma patient, whose tumor also produced gastrin), nausea (n = 3), vomiting (n = 2), weight loss (n = 2), and jaundice (n = 1), early satiety (n = 1), and migratory necrolytic erythema (n = 1) (glucagonoma). One patient with nonfunctioning GEP was asymptomatic.

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

Surgical Management Prior to Liver Transplantation

All 19 patients underwent surgical or radiological intervention prior to liver transplantation (Table 2). Surgical resection of the primary GEP was performed prior to liver transplantation in 17 patients. One patient had a primary ileal carcinoid that was resected during OLT, and 1 patient had a primary unresectable hepatic carcinoid GEP. Six patients with primary small bowel carcinoid underwent partial small bowel resection combined with cholecystectomy and hepatic artery ligation (n = 1), appendectomy (n = 1), resection of a mesenteric mass (n = 1), and excision of hepatic metastases and hemicolectomy (n = 1). All 11 patients with pancreatic GEP underwent partial pancreatic resections. Three patients had a pancreaticoduodenectomy, and 8 patients had a distal pancreatectomy and splenectomy. Additionally, patients with pancreatic GEP underwent the following procedures prior to transplantation: partial splenectomy (n = 1), cholecystectomy (n = 3), partial gastrectomy (n = 1), adrenalectomy (n = 1), partial adrenalectomy and partial colectomy (n = 1), and right hepatectomy (n = 1). Regional lymphadenectomy combined with resection of the primary GEP was performed when indicated. Lymph node metastases were confirmed pathologically in 14 patients (n = 8 pancreatic GEP, n = 6 carcinoid GEPs) during surgical exploration prior to OLT.

Table 2. Pretransplant Operative Treatment in 19 Patients With Gastroenteropancreatic Neuroendocrine Cancer
PatientSurgical Procedures
  1. Abbreviations: HEA, hepatic artery embolization; RFA, radiofrequency ablation.

1Small bowel resection/cholecystectomy/hepatic artery ligation
2Distal pancreatectomy/splenectomy/lymphadenectomy
3HAE 2×
4Pylorus preserving Whipple procedure/cholecystectomy; excision liver metastases/RFA/electrocautery ablation
5Whipple procedure; Wedge resection liver/RFA
6Small 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
7Small bowel resection; partial ileum resection/cholecystectomy; HAE 2×; excision ileum/lymphadenectomy
8HAE 4×; tricuspid and pulmonary valve replacement
9Distal pancreatectomy/splenectomy/partial stomach resection/lymphadenectomy
10Distal pancreatectomy/partial splenectomy; HEA 5×
11Distal pancreatectomy/splenectomy/adrenalectomy/cholecystectomy/lymphadenectomy
12Partial ileal resection/appendectomy; HAE 2×
13Distal pancreatectomy/splenectomy
14Whipple procedure
15Partial small bowel resection/resection mesenteric mass
16Distal pancreatectomy/splenectomy/partial adrenalectomy/partial colectomy
17Distal pancreatectomy/right hepatectomy/splenectomy
18Ileal resection/hemicolectomy/ileotransverse colostomy/excision liver metastases
19Distal pancreatectomy/splenectomy/cholecystectomy; distal pancreatectomy/lymphadenectomy

After initial resection of the primary GEP, 5 patients had additional operations for resection of GEP prior to liver transplantation. One patient had a second pancreatectomy. One patient had a second partial small bowel resection and cholecystectomy followed by a third partial small bowel resection. Another patient underwent a second small bowel resection followed by 3 operations to excise liver metastases (with cholecystectomy, cryosurgery, and radiofrequency ablation) and a partial pulmonectomy for bronchoalveolar carcinoma. Two other patients underwent operations to excise liver metastases combined with intraoperative radiofrequency ablation in both patients and electrocautery ablation in one patient. Altogether, surgical excision of hepatic metastases was performed in 5 of 19 patients, plus radiofrequency ablation in 3 patients.

Medical Therapy Prior to Liver Transplantation

Medical treatment was given to patients when necessary to control symptoms and limit tumor progression on the waiting list. Systemic chemotherapy was given to patients with somatostatin-receptor-negative tumors or whose tumor was otherwise not responsive to somatostatin therapy. Hepatic embolization was used when hepatic metastases caused symptoms due to progressive intrahepatic disease. Sixteen patients were treated with somatostatin analogues (octreotide). Systemic chemotherapy (dacarbazine, gefitinib, and combined adriamycin and streptozotocin) was used in 3 patients and interferon in 2 patients. One patient underwent radiolabeled monoclonal antibody therapy (Cotara), and another was treated with yttrium-labeled octreotide. Six patients underwent repeated hepatic artery embolization. Three patients did not receive any medical therapy prior to OLT.

Staging Procedure

Staging laparoscopy or laparotomy was performed prior to registration for liver transplantation in 24 patients. There was no evidence for extrahepatic disease in 21 patients. Three patients had extrahepatic disease during staging. One patient with carcinoid hepatic metastases underwent ileal resection and regional lymphadenectomy for the primary GEP. After an extrahepatic recurrence-free interval of 3 years, liver transplantation was performed. Two patients with hepatic metastases from pancreatic GEP had extrahepatic disease, suggested by cross-sectional imaging and confirmed by endoscopic ultrasound guided biopsy. An incomplete resection of the primary tumor required repeat resection with distal pancreatectomy and regional lymphadenectomy in one patient. Liver transplantation was attempted 7 months later, but the patient died during the procedure. The other patient had recurrent GEP in the head of the pancreas and was therefore excluded from liver transplantation.

Liver Transplantation and Complications

Fifteen of 19 patients underwent deceased donor liver transplantation, and 4 patients underwent living donor liver transplantation. All patients underwent regional lymphadenectomy, and 8 patients had metastatic disease involving 1 to 5 lymph nodes in the hepatoduodenal ligament. One patient had an ileal resection during OLT because the patient was too ill to have the primary tumor resected prior to OLT.

Major complications within the first week posttransplant were as follows: portal vein thrombosis requiring surgery with thrombectomy and conversion of the arterial anastomosis to the infrarenal abdominal aorta; hepatic artery thrombosis with bile leakage requiring surgical revision of the arterial anastomosis and oversewing of the bile leak; bile leak and stricture for which a Roux-en-Y choledochojejunostomy was performed; jejunal perforation, which was oversewn; displaced bile catheter (lying free within the peritoneal cavity), which had to be surgically removed; and partial colectomy for diverticulitis. Other major complications occurred within 6 months after transplantation: 1 patient suffered from early portal vein thrombosis requiring thrombectomy, a pelvic abscess that resolved with antibiotics, and a hepatic artery stenosis requiring stent placement; other single patients showed hepatic vein stenosis requiring dilation, wound dehiscence requiring surgery, and a bile leak for which a biliary sphincterotomy with pancreatic stent placement was performed. Nine patients underwent treatment for acute cellular rejection, which was steroid responsive.

Pathology of the Explanted Liver

GEP was confirmed microscopically as well-differentiated neuroendocrine carcinoma (grades 1 and 2) in the liver explants of 18 patients. The Ki67 proliferation index was assessed in 18 explanted livers. Ki67 indices in tumor specimens varied from 0.06% to 2.35% with an average of 0.69%.

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

Outcomes

The mean follow-up for 17 patients (exclusion of 2 patients transplanted before development of the treatment protocol) is 15 months (range, 0-30 months). The mean 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 1 patient with recurrent disease. One patient died during liver transplantation, and another patient died 9 months posttransplant from metastatic disease, discovered after 5 months. Two additional patients had disease recurrence after 11 and 5 months, respectively: 1 is alive with bone metastases and porto-caval and aortocaval lymphadenopathy, and 1 is alive without evidence of disease after resection of recurrent metastatic lymph nodes. This patient had an initial resection of positive regional lymph nodes during liver transplantation. All 3 patients with disease recurrence after liver transplantation have had previous pancreatic GEP.

Estimated 1-year patient survival was 87% for 17 patients transplanted after development of the treatment protocol. Ten of 17 patients were at risk of dying at 1 year after transplantation, 4 patients were at risk of dying at 2 years, and no patients were at risk of dying more than 3 years after transplantation (Fig. 1). Estimated 1-year patient survival was 88% for all 19 transplanted patients. Estimated 1-year survival was not statistically different between patients with carcinoid (n = 7) and pancreatic GEP (n = 10) (100% vs. 77%, P = 0.2). Estimated 1-year recurrence-free rate (conditional on survival) was 77% for 17 patients transplanted after development of the treatment protocol and 80% for all 19 transplanted patients (Fig. 2A). Estimated 1-year recurrence-free rates (conditional on survival) did not differ among tumor types (100% vs. 60%, P = 0.1) (Fig. 2B). Similarly, recurrence-free rates between functioning (n = 10) and nonfunctioning (n = 7) GEP were not statistically different at 1 year (65% vs. 100%, P = 0.2). No correlations were found between following possible prognostic 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 = 0.22 and r = 0.37, P = 0.12), and nonfunctioning/functioning GEP (r = 0.09, P = 0.70 and r = 0.33, P = 0.17).

Figure 1.

Kaplan Meier estimates of overall survival in 17 patients after liver transplantation for metastatic gastroenteropancreatic neuroendocrine cancer. Numbers above curve indicate the number of patients still at risk as a function of time.

Figure 2.

(A) Kaplan-Meier estimates of the probability of being recurrence-free (conditional on survival) in 17 patients after liver transplantation for metastatic gastroenteropancreatic neuroendocrine cancer. Numbers above curve indicate the number of patients still at risk as a function of time. (B) Kaplan-Meier estimates of the probability of being recurrence-free (conditional on survival) in 17 patients after liver transplantation for metastatic gastroenteropancreatic neuroendocrine cancer. Comparison between carcinoid and pancreatic gastroenteropancreatic neuroendocrine cancer groups did not show significant differences although patients with pancreatic gastroenteropancreatic neuroendocrine cancer were observed to have greater recurrence-free probability. Numbers above curve indicate the number of patients still at risk for the two groups together as a function of time.

DISCUSSION

The principal findings of our experience with liver transplantation for GEP metastatic to the liver demonstrate that (1) despite extensive prior surgery, liver transplantation in these patients can be accomplished with excellent estimated 1-year and 2-year survival (87%), and (2) estimated disease recurrence in the first 2 years is acceptable (23%). These results support continued evaluation of liver transplantation for highly selected patients with GEP.

The early overall survival of patients after liver transplantation for hepatic metastases from GEP is similar to liver transplantation for other indications.8, 13, 14 Indeed, recent overall 1- and 2-year survival after liver transplantation at the Mayo Clinic, Rochester, are 92% and 89%, respectively, compared to an estimated 1- and 2-year survival of 87% for patients undergoing liver transplantation for hepatic metastases from GEP. The absence of portal hypertension in patients with metastatic GEP is a factor that simplifies the liver transplant procedure technically despite prior abdominal operations. The effect of immunosuppression on progression of potential micrometastatic disease after transplantation as a potential concern also was not observed in our experience. Thus, from a technical and clinical perspective, liver transplantation can be accomplished in these patients with excellent early survival.

A large single-center study on long-term follow-up after liver transplantation for GEP (n = 19; mean follow-up, 59 months) reported 1-year and 5-year survival rates of 89% and 80%, respectively.8 Less favorable results on long-term follow-up were observed in a recent study (n = 11; mean follow-up, 34 months) with 1- and 5-year survival of 73% and 36%, respectively.22 It is important is to note that in these 2 prior studies, extensive surgery to remove extrahepatic disease was performed at the time of OLT in many patients, which has previously been shown to be a predictor of disease recurrence.7 Our estimated survival rates are likely favorable as compared to these prior studies due to the specific evaluation protocol and patient selection criteria. Indeed, to exclude extrahepatic disease at the time of liver transplantation, a thorough staging protocol with frequent patient reevaluation for metastatic disease was performed, including a staging laparotomy or laparoscopy when technically permitted. In addition, the implementation of somatostatin receptor scintigraphy (octreotide scan) has increased detection rates for GEP4, 23 and was also used to exclude patients as liver transplant candidates. Only patients with unresectable metastases without extrahepatic disease were selected for the treatment protocol. Additionally, the time interval between resection of the primary GEP and liver transplantation has been suggested as a critical factor in patient selection.14 Candidacy at our center required an initial resection of the primary GEP followed by clinical restaging after a minimal interval of 6 months to exclude extrahepatic disease progression. This approach assured disease stability over a 6-month interval and may also have improved outcomes.

Although our survival rates mirror those of some previous studies, the estimated 1-year recurrence-free rate of 77% is excellent in comparison with 3 large studies showing estimated 1-year recurrence-free survival rates of 45%,11 60%,7 and 56%.8 In these studies the rates of lymph node metastases at the time of liver transplantation (13/23, 37/42, and 10/19, respectively) were slightly higher than the rate in our study (8/19). Perhaps patients in our study had more complete resections prior and during liver transplantation because of better detection of tumor tissue and positive lymph nodes after implementation of somatostatin receptor scintigraphy.

Similar to others, we observed a possible influence of the primary tumor site on disease recurrence following liver transplantation.11, 13 In our study, a trend toward better outcome, as demonstrated by lower recurrence rate, was observed in patients with hepatic metastases from carcinoid GEP than in patients with metastatic pancreatic GEP. Indeed, all 3 recurrences were found in patients with functioning pancreatic GEP (1 glucagonoma and 2 gastrinomas). In accordance with our results, a higher recurrence rate after liver transplantation for pancreatic GEP was also observed in a study of 10 patients showing 5 patients with disease recurrence after liver transplantation, including 4 patients with pancreatic GEP.13 Another study also observed significant adverse survival outcomes in patients with pancreatic GEP vs. intestinal carcinoids after liver transplantation.11 A third study observed excellent 1- and 5-year survival of 100% and 70%, respectively, by transplanting only patients with hepatic metastases from carcinoid GEP.10 Larger patient numbers will be necessary to substantiate these observations, as the current experience is too limited to alter selection criteria based on origin of tumor.

Several studies have observed that patients whose tumors demonstrate a low proportion of Ki67 positive cells have a better outcome.8, 13, 17 Others achieved good results by selecting only patients with well-differentiated GEP and low Ki67 proliferation index (<10%) for transplantation.14–16 The Ki67 labeling indices in this study appear to be low in comparison to other studies. Possible explanations are that (1) all the patients in this study had well-differentiated neuroendocrine tumor histology, and (2) in contrast to others, we used a computed quantification technique. Although a significant correlation between survival and Ki67 labeling index was found, there were only 3 patients with recurrence and 2 patients who died, making the data too limited to relate survival and recurrence to the Ki67 labeling index. However, our patient with the highest absolute Ki67 labeling index developed early disease recurrence and death from metastases. Larger numbers of patients with recurrent disease and a high Ki67 labeling index are required to determine the prognostic value of the Ki67 labeling index.

Currently, liver transplantation for metastatic GEP is controversial, and patients with metastatic GEP do not receive prioritization in the model for end-stage liver disease allocation system.24 The results of our study demonstrate that liver transplantation for GEP is associated with early outcomes comparable to patients undergoing liver transplantation for cirrhosis. In contrast, reported 5-year survival for patients with bilobar, unresectable hepatic metastases is only 30%.3 In the past, analogous situations existed for hepatocellular carcinoma. For example, results of liver transplantation for hepatocellular carcinoma before 1995 were disappointing, with overall 2-year survival rates of 30% or less. In 1996 a prospective trial using highly selective tumor criteria demonstrated excellent results, resulting in acceptance of selected patients with hepatocellular carcinoma for liver transplantation.25, 26 Nevertheless, for patients with metastatic GEP, model for end-stage liver disease scores with upgrades could be considered, especially if subsequent studies better define those patients who have a better survival after liver transplantation. We suggest that deceased donor liver transplantation, especially for patients with carcinoid GEP metastatic to the liver,8, 10, 11, 13 be reevaluated for consideration of model for end-stage liver disease assignment.

Acknowledgements

The authors thank Erin Bungum for superb secretarial services and Jim Tarara for the excellent help in the detailed computer analysis of the Ki67 immunohistochemistry.

Ancillary