liver transplantation for treatment of metastatic neuroendocrine tumors
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Ann. N.Y. Acad. Sci. 1014: 265–269 (2004). © 2004 New York Academy of Sciences.doi: 10.1196/annals.1294.029
Liver Transplantation for Treatment of Metastatic Neuroendocrine Tumors
HÅKAN AHLMAN, STYRBJÖRN FRIMAN, CHRISTIAN CAHLIN, OLA NILSSON, SVANTE JANSSON, BO WÄNGBERG, AND MICHAEL OLAUSSON
Department of Surgery and Department of Pathology, Göteborg University,Sahlgrenska University Hospital, Göteborg, Sweden
ABSTRACT: Liver transplantation can be considered a therapeutic option forpatients with neuroendocrine tumors only metastatic to the liver. Importantselection criteria are well-differentiated tumors and a low proliferation rate(Ki67 <10%). In this series, orthopic liver transplantation offered good reliefof symptoms and long disease-free intervals with initial survival of grafts andpatients as in benign disease. The experience with multivisceral transplanta-tion is still limited.
KEYWORDS: liver transplantation; carcinoids; endocrine pancreatic tumors
INTRODUCTION
Metastases from neuroendocrine tumors, that is, carcinoids and endocrine pan-creatic tumors (EPTs), can be limited to the liver for long periods and show slowgrowth. Liver transplantation (Tx) may be considered in selected patients if thetumors are not accessible for curative, or cytoreductive, surgery, are associated withlife-threatening hormone secretion (e.g., insulin or histamine), or do not respond tomedical treatment or other interventional procedures (e.g., local ablation or hepaticarterial embolization).1
In 1994 Bechstein and Neuhaus2 reviewed the world literature on liver transplan-tation (30 patients, half of whom had EPTs). The 1-year survival was 52% withtransplantation-associated deaths in half the patients within 8 months. Four yearslater, more favorable survival figures were reported. The actuarial 5-year survivalfrom Hannover was 80%; 1 of 12 patients with orthopic liver transplantation (OLT)died from recurrent tumor.3 Similar figures were indicated for patients with carci-noid tumors in contrast to poor survival rates for those with EPTs in a Frenchmulticenter series that included 31 patients.4 Relatively few multivisceral transplan-tations (MVTx) have been performed in patients with neuroendocrine tumors, butthe prognosis seems to surpass that of other tumor diagnoses (sarcoma, hepatocellu-lar carcinoma, or cholangiocarcinoma) with a 5-year survival of about 60%.5
Address for correspondence: Dr. Hakan Ahlman, Department of Surgery and Department ofPathology, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
266 ANNALS NEW YORK ACADEMY OF SCIENCES
PATIENTS AND METHODS
Since 1997, we have performed transplantation with curative intent in 12 patients(median age 50 years, range 38–60) with well-differentiated endocrine carcinomaand limited proliferation (Ki67 ≤ 10%). Tumor types were eight EPTs (two with ex-cess secretion of insulin) and four carcinoids (two with excess secretion of serotoninand one with histamine) (FIG. 1). All patients with carcinoids and tail-located EPTsfirst underwent excision of the primary tumor followed by OLT at intervals ofbetween 3 months and 10 years. One of the symptomatic carcinoid patients (no. 10)was treated for 10 years with repeated embolizations, octreotide, and interferon andwas finally therapy resistant. Four patients with EPT of the head of the pancreasunderwent tumor excision and MVTx in one surgical setting; these patients had alarge tumor burden (exceeding 50% of the liver volume). All patients were investi-gated preoperatively by octreotide scintigraphy + SPECT and by spiral CT/MRT todetermine if the tumor disease was confined to the liver. They were also screened forgeneral (chromogranin A) and tumor-specific peptide hormones in plasma and forthe main serotonin/histamine metabolites in urine (5-HIAA/MeImAA). Coarseneedle liver biopsies were examined by the same pathologist and were classified aswell-differentiated endocrine carcinoma according to the WHO 2000 criteria. Theproliferation index, indicated by Ki67 immunostaining, did not exceed 10% in anyof the tumor specimens (TABLE 1).
TABLE 1. Clinical details of Tx patientsa
aABBREVIATIONS: Tx, liver transplantation; MVTx, multivisceral transplantation; OLT, ortho-pic liver transplantation; EPT, endocrine pancreatic tumor; FC, foregut carcinoid; MC, midgutcarcinoid; HC, hindgut carcinoid.
Type of Tx
Patient no. Gender
Tumor type Ki67
Hormonal symptoms
Age (yr) at Tx
Tumor surgery after Tx
MVTx 1 M EPTb
b Tumors in the head of the pancreas.
10% No 38MVTx 2 M EPTb 10% No 56MVTx 3 F EPTb 6% No 58MVTx 4 M EPTb 10% No 43OLT 5 M EPT 8% Insulinoma 60OLT 6 F MC 1% Carcinoid
syndrome41
OLT 7 M FC 1% Atypicalcarcinoidsyndrome
54
OLT 8 M EPT 10% Insulinoma 52 Liver resectionOLT 9 M HC 1% No 59OLT 10 M MC 1% Carcinoid
syndrome41 Lu177-octreo-
tate × 3OLT 11 F EPT 1% No 49 Tumor resectionOLT 12 M EPT 1% No 40 Abdominal ln.
met. × 2Neck met. × 1
267AHLMAN et al.: LIVER TRANSPLANTATION IN NE TUMORS
Postoperatively at 3-month intervals the patients were followed up by tumormarkers and at 6-month intervals with octreotide scintigraphy + SPECT and spiralCT. With discrepant findings, MRT was also performed.
RESULTS
The mean follow-up of the entire series was 30 ± 22 months (range 1–66). All 8OLT patients (nos. 5–12) are today alive. One EPT patient (no. 12) was operated onfor three recurrences, but also had two negative neck explorations due to false-positive octreotide scintigraphies (normal tumor markers and radiological findings).Two EPT patients (nos. 8 and 11) were operated on for one recurrence each firstdiagnosed by scintigraphy (borderline elevated tumor markers). The carcinoidpatient (no. 10) with a very long interval between primary surgery and OLT devel-oped multiple lymph node metastases 9 months after OLT and was therefore treatedwith 177Lu-DOTA-Tyr3-octreotate (7-7.5 GBq i.v. × 4). This resulted in long-lastingpalliation and more than 50% reduction of tumor markers to almost normal levels.Currently, five of eight OLT patients demonstrate no clinical evidence of tumordisease (FIG. 1).
Two of four EPT patients (nos. 1 and 2) with MVTx died 4 months after surgeryof transplantation-associated causes (posttransplant lymphoproliferative disease andarteritis, respectively). One patient (no. 3) has been followed up for 8 months with-out recurrence. The other patient (no. 4) underwent exploration for suspicion of arecurrent tumor in the mesenteric root after 36 months, but had negative tumor find-ings. A small infected aneurysm had probably caused the positive scintigraphic find-ings and was resected.
FIGURE 1. Observation periods before and after transplantation (Tx) in 12 consecutivepatients subjected to either multivisceral transplantation (MVTx) or orthopic liver trans-plantation (OLT) due to neuroendocrine tumors.
268 ANNALS NEW YORK ACADEMY OF SCIENCES
DISCUSSION
Lehnert6 in 1998 reviewed the first 103 reported cases of patients given trans-plants for metastatic neuroendocrine tumors. In this heterogeneous series, the 5-yearoverall and disease-free survival were 47% and 24%, respectively. Tumor recurrencewas frequent, but 39 patients were alive and disease free after a median follow-up of23 months. Survival seemed to be favorably influenced by young age (<50 years),certain tumor types (lung and bowel carcinoids), less extensive upper abdominalprimary surgery, and octreotide treatment prior to transplantation. The latter findingmay reflect more differentiated tumors with maintained hormone production, requir-ing medical treatment of hormonal symptoms.
This series differs from previous ones in several aspects. Patients up to 60 yearsand patients with a large tumor burden were included. Most patients were treated fortheir primary tumors at our center. Patients with carcinoids, or tail-located EPTs,were treated in two steps: histologically proven radical removal of the primary andregional metastases followed by careful work-up to exclude extrahepatic lesionsprior to OLT. Patients with EPTs that were located in the head required extensiveupper abdominal surgery, and we chose to treat them with MVTx. In general, thesepatients had higher Ki67 indices and a larger tumor burden than did OLT patientsand most likely represent a negative selection bias.
Ki67 is a nuclear protein expressed in all proliferating cells correlating with theclinical course of tumor diseases.7 For pancreatic neuroendocrine tumors, a cut-offvalue of more than 5% identified patients with a shorter survival.7 With our cut-offlevel of 10%, all well-differentiated endocrine carcinomas presented to the Trans-plantation Board (1997–2003) could be included. In a retrospective study of 19 OLTpatients with neuroendocrine tumors and long follow-up, low Ki67 levels and regu-lar expression of the adhesion molecule E-cadherin were associated with better prog-nosis, while analysis of p53 expression did not improve the prognostic accuracy.8 Tofind the optimal histopathologic criteria to predict clinical outcome of transplanta-tion, larger series are clearly needed.
We conclude that OLT for metastatic well-differentiated neuroendocrine tumorsoffers good relief of hormonal symptoms and long disease-free intervals. The initialsurvival of grafts and patients is comparable to those of OLT for benign disease. Theexperience with MVTx is still too limited for evaluation.
ACKNOWLEDGMENTS
This work was supported by the Swedish MRC and the Swedish Cancer Society.
REFERENCES
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