Journal of Hepatology
Volume 47, Issue 4 , Pages 460-466, October 2007

Neuroendocrine tumors metastatic to the liver: How to select patients for liver transplantation?☆

Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Istituto Nazionale Tumori Fondazione IRCCS, Via Venezian 1, Milan 20133, Italy

published online 02 August 2007.

Article Outline

Abbreviations: NET, neuroendocrine tumor, WHO, World Health Organization, OLT, orthotopic liver transplantation, TACE, trans-arterial chemo-embolization, RFA, radiofrequency ablation, CgA, chromogranin A, MIBG, metaiodo-benzylguanidine, MEN1, multiple endocrine neoplasia type 1

 

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1. Introduction 

Neuroendocrine tumors (NET), which originate from different parts of the widespread neuroendocrine system [1], are very rare and originate in about 85% of cases in the gastrointestinal tract (2 cases per 100.000 inhabitants/year with a slight female predominance) and in the pancreas (1–1.5 cases per 100.000 inhabitants/year) [1], [2], [3]. Although the large majority of NET arise sporadically, a small group of patients are affected by inherited multiple endocrine neoplasia type 1 (MEN-1) which are at risk of developing neuroendocrine malignancies in 30% of the cases.

In general, NET which originate in the gastrointestinal tract are slow-growing tumors often discovered in the metastatic phase (40–80% of patients present at diagnosis with metastases), being the liver the most involved organ (40–93%) followed by bone (12–20%) and lung (8–10%). The clinical deterioration of patients affected by NET in advanced stages is almost invariably related to massive liver involvement with hepatomegaly, discomfort and poor quality of life. However, metastases of NET remain usually confined to the liver for a long time, leading to a 5-year survival of 30%, even in untreated patients [4].

Many therapeutic strategies have been attempted over the years for patients with NET. Loco-regional therapies such as hepatic artery embolization and trans-arterial chemo-embolization (TACE), radiofrequency thermal ablation (RFA) and cryoablation are the most commonly used, together with somatostatin analogues and chemotherapy in the effort to reduce the tumor bulk or the metabolic activity in unresectable cases. Surgery is considered as a bare palliation in patients with large tumor bulk and severe symptoms. However, recent progressive adjustments in patient selection and clinical-pathological definition of stages contributed to a re-definition of the role of surgical therapies for metastatic NET. In particular, orthotopic liver transplantation (OLT) is increasingly proposed as an alternative for cure in patients with limited tumor bulk and long expected survival, either because of young age or because of favorable biological behaviour of the tumor itself. Indeed, the current reappraisal of OLT for NET metastatic to the liver also takes into account the many lessons learnt from patients affected by the same disease treated in the last three decades with liver resection.

Nowadays, more precise prognostic information, based on tumor characteristics and clinical features, are favoring OLT as a potentially curative strategy for selected cases; as a consequence of this, hepatic metastases from NET are the only accepted indication to liver replacement in case of a metastatic cancer.

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2. Surgical rationale for treating liver metastases from NET: from resection to transplantation 

Recent adjustments of the histological classification reported in Table 1 [1] and new markers such as chromogranin A (CgA) can better predict different pattern of disease growth and dissemination. One characteristic of NET’s malignancy is that often the primary tumor site cannot be detected for years, and during this period further spreading to distant organs [1], [2], [3], [4] is likely to occur.

Table 1. WHO classification of neuroendocrine tumors (NET) of the Gastrointestinal Tract with portal venous drainage (adapted from Solcia E. et al.: Ref. 1)
Stomach, ileum, colonPancreas
Well-differentiated Endocrine Tumor (Carcinoid)Well-differentiated Endocrine Tumor
(1) Benign behaviour(1) Benign behaviour
Non-functioning Confined to the pancreas, non-angioinvasive
Confined to mucosa-submucosa, non-angioinvasiveSize: <2cm
Size: ⩽1cm (stomach and small intestine) or ⩽2cm (colon) Mitoses: ⩽2
Ki67 positive cells/10 HPF: ⩽2%
(2) Uncertain behaviour(2) Uncertain behaviour
Non-functioning Confined to the pancreas
Confined to mucosa-submucosa, angioinvasive Size: ⩾2cm
Size: >1cm (stomach or small intestine) or >2cm (colon) Mitoses: >2, or angioinvasive
Ki67 positive cells/10 HPF: >2%
Well-differentiated Endocrine Carcinoma (Malignant Carcinoid)Well-differentiated Endocrine Carcinoma
Low-grade malignant tumor Functioning or non-functioning
Deeply invasive (muscularis propria or beyond) or with metastases (liver) Low-grade malignant tumor with gross local invasion and/or metastases (liver)
Ki67 positive cells/10 HPF: >5%
Poorly-differentiated Endocrine CarcinomaPoorly-differentiated Endocrine Carcinoma
Small-cell carcinoma Small-cell carcinoma
High-grade malignant tumor High-grade malignant tumor
Ki67 positive cells/10 HPF: >15%
Mixed Endocrine/Exocrine Carcinoma
Moderate to high-grade malignant tumor

In case of metastatic NET limited to the liver, surgery is thought to be the most rationale approach. However, only 10–25% of liver metastases from NET can be removed curatively, i.e. clear margins and no microscopic residue (R0 resection). Patients with unilobar or single metastatic spread without evidence of extra-hepatic disease have a tumor 5-year recurrence of about 80% (Table 2) [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17].

Table 2. Results of hepatic resections for liver metastases from neuroendocrine tumors: literature review
AuthorPeriod (years)No. of patientsHistologySurgeryPeri-operative mortalityPatient survivalDisease-free survival
CARNCARCurativePalliative
Martin [5]–55–41046 mo (median)NR
Danforth [6]1957–19821–1100––
Norton [7]1975–19855–541080% at 30 moNR
Makridis [8]1979–198966––6030 mo (median)NR
McEntee [9]1970–198937241317202.7%85% at 20 moNR
Søreide [10]1960–198944–13–139 mo (median)NR
Carty [11]1982–199117–17134079% at 5 year22% at 5 year
Que [4]1984–199274502428462.773% at 4 year36% at 4 year
Dousset [12]1986–1994171071255.946% at 5 year36% at 5 year
Chen [13]1984–19951551015–073% at 5 year25% at 2 yeara
Chamberlain [14]1992–199834142015196%76% at 5 yearNR
Jaeck [15]1986–1998135813–068% at 6 year69% at 3 year
Sarmiento [16]1977–19981701205075951.2%35% at 10 year16% at 5 year
Yao [17]1992–2000168816–073% at 5 year42% at 5 year
INT Milano1987–20063630636–085% at 5 year34% at 5 year
59% at 10 year19% at 10 year

CAR, carcinoid; NCAR, non-carcinoid; NR, not reported.

Mean age of the reported patients: 56 years old.

aData calculated from the published curves.

At the opposite end of the surgical spectrum, liver resection can be applied with clear palliative intents as in case of multiple mass-forming metastases causing symptoms or a clinically relevant syndrome: the rationale for such a demanding procedure is based on the fact that the removal of more than 90% of the tumor bulk allows a significant clinical improvement otherwise not achievable with alternative non-surgical approaches [4].

Although prospective studies comparing surgical resection with non-surgical therapies are lacking, the benefit in survival observed in patients who undergo surgery appears relevant if compared to the expected outcome of patients treated with medical treatment or palliative support only [18], [19], [20], [21]. Since a R0 resection is rarely achievable, OLT theoretically appears to be an appealing approach.

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3. Liver transplantation for metastatic NET: cure rather than palliation 

Over the last two decades, the established strategy for the management of patients with metastatic NET takes into account the option of OLT as a salvage therapy, with unfortunately disappointing results as a consequence of suboptimal patient selection (Table 3) [19], [22], [23], [24], [25], [26], [27], [28]. As for other tumors amenable to surgical management, a modern approach to the treatment of NET has to consider multimodal approach carried out by a multidisciplinary team, including oncologists, hepatologists, nuclear medicine experts, interventional radiologists, psychologists, etc.

Table 3. Liver transplantation (OLT) for metastatic neuroendocrine tumors (literature review: 1970–2006)
AuthorNo. of patientsHistologyPatients with symptomsVenous drainage primary tumorChemo pre-OLTMedian interval between diagnosis and OLT (months)Patient survivalRecurrence-free survival
CARNCARPortalSystemic
Lehnerta[22]103366742% 38%NR47% at 5 year24% at 5 year
Le Treut [23]31151655%84%16%84%1936% at 5 year17% at 5 year
Olausson [24]94544%100% 02–12088% at 3 year44% at 3 year
Fernandez [25]52333%100% 100%1180% at 2 year40% at 2 year
Rosenau [26]1961090%100% NRNR80% at 5 year21% at 5 year
Cahlin [27]104640%89%20%0NR80% at 1 year50% at 3 year
Florman [28]1138100%91%9%NRNR36% at 5 year9% at 5 year
V.Vilsteren [19]1981132%100% 47%NR87% at 1 year77% at 1 year
INT Milanob2424–10%100% 55%1890% at 5 year77% at 5 year

CAR, carcinoid; NCAR, non-carcinoid; CT, chemotherapy; NR, not reported; OLT, orthotopic liver transplantation.

Mean age of the reported patients: 48 years old. Median follow-up of the reported series: from 5 to 103 months.

aLehnert is a review of the previous literature on 103 cases collected between 1981 and 1997

bINT Milano is a prospective series collected in accordance to the criteria reported in Table 4.

The entire transplantation field is limited by the worldwide donor scarcity, public awareness on controversial issues such as organ assignment, cost/effectiveness of different medical procedures and consequence on quality of life and life expectancy. Thus, only patients with tumors presenting with biologically favorable features, limited bulk and absence of systemic disease are potential candidates for OLT.

Similarly to other types of cancer (i.e. hepatocellular carcinoma), eligibility to OLT in case of metastatic NET is hardly accepted as a bare palliation for advanced stages. Rather transplantation for metastatic NET must generate a sustained response and a 5-year recurrence-free survival higher than 50%.

The following are practical guidelines for a better definition of transplant candidacy in patients with NET metastatic to the liver. They are the result of cumulative experiences on both a multicentric (summarized in Table 3) and institutional basis. The variegate elements leading to liver transplantation candidacy (Milan Criteria in case of NET) are summarized in Table 4.

Table 4. Milan criteria for indication to liver transplantation in patients with hepatic metastasis
Inclusion criteria
1.Confirmed histology of carcinoid tumor (low-grade neuroendocrine tumors) with or without syndrome
2.Primary tumor drained by the portal system (pancreas and intermediate gut: from distal stomach to sigmoid colon) removed with a curative resection (pre-transplant removal of all extra-hepatic tumor deposits) through surgical procedures different and separate from transplantation
3.Metastatic diffusion to liver parenchyma ⩽ 50%
4.Good response or stable disease for at least 6 months during the pre-transplantation period
5.Age ⩽55 years
Exclusion criteria
1.Small-cell carcinoma and high-grade neuroendocrine carcinomas (non-carcinoid tumors)
2.Other medical/surgical conditions contraindicating liver transplantation, including previous tumors
3.Non-gastrointestinal carcinoids or tumors not-drained by the portal system

3.1. Tumor histology and behavior 

As summarized in Table 1 and Fig. 1 the last WHO classification [1] system of NET combines anatomic location, histological features of malignancies and hormone production. Candidates for OLT must have histologic confirmation of NET on both primary and metastatic sites, and only well-differentiated low-grade tumors should be considered for OLT. More aggressive carcinomas are associated with poor outcome after OLT [18], [23], [26], [28].

  • View full-size image.
  • Fig. 1. 

    Proliferation index (grading) of gastrointestinal NET as assessed by Ki67 immunocytochemistry in biopsies of liver metastases. Arrows indicate positive cells. (a) Well-differentiated carcinoid (Ki67: none or <2% cells/10 HPF); (b) low-grade malignant carcinoid (Ki67: 2–5% cells/10 HPF); (c) poorly-differentiated endocrine carcinoma (Ki67: >10% cells/10 HPF).

NET may show a variety of architectural patterns such as glandular, insular, trabecular, solid or mixed, and cell morphology can vary from well-differentiated to undifferentiated, resembling microcitoma cells [1]. In case of functional carcinoids, pre-emptive diagnosis is feasible by evaluation of hormonal compounds (i.e. gastrin, insulin, glucagone, VIP, etc.) found to be in the serum of the affected patients either elevated at baseline or increased after provocation tests. A useful marker of non-functioning NET is chromogranin A (CgA), a protein normally present in neuroendocrine granules involved in pro-hormone processing: its increase in serum is helpful in diagnosis and evaluation of response to therapy in most of the cases.

The numbers of mitoses and/or the proliferation index (as assessed by Ki67 staining) are other surrogates of cells’ malignancy. In particular Ki67 expression at immunostaining has been proposed as a prognostic factor of risk of recurrence [26]. A Ki67 proliferation index of <10% is a characteristic of well-differentiated tumor, which we have adopted as a cut-off value to consider patients for possible OLT.

3.2. Primary tumor site and treatment strategy of the extra-hepatic disease 

Only NET with portal drainage can be considered to have the liver as the “first station” colonized during the hematogenous spread of malignant cells from the primary site. According to general principles of surgical oncology the complete removal of the primary tumor and of the metastatic load (whenever limited to one organ) seems not only rationale but associated to a significantly improved patient outcome [15], [18], [19], [22].

It should be remembered that portal venous drainage is assured only for the embryological-derived midgut (distal stomach, duodenum, small bowel, right colon) and for part of the pancreas. Consequently, NET originated in other portions of the gastrointestinal tract (i.e. esophagus, lower rectum) or in other systems (i.e. lungs, thyroid, adrenals, etc.) should be currently excluded from OLT candidacy.

The primary tumor site should therefore be resected by experienced teams with a precise curative intent including loco-regional and distant lymph node dissection (R0). Extended surgical procedures with particular reference to pancreatic resection adversely affect patient outcome when performed at the same surgical time of OLT [15], [18], [19], [22]. Multi-step resections rather than complex removal of the primary tumor at the time of transplantation seem also appropriate for a better staging of the extra-hepatic disease, because it gives enough time to observe both the natural progression of the metastatic disease and response to medical therapies.

Not differently from staged bowel and liver resection associated with chemotherapy for metastatic colorectal cancer, a multi-step surgical approach to the NET of the gastrointestinal tract, even though going against the surgical principle of “en-bloc resection” of the tumor, results in the reduction of peri-operative mortality and improvement of patient selection.

3.3. Staging of liver metastases 

Tumor bulk (palliative) removal affects prognosis after any kind of surgical resection, a solid principle which has been previously confirmed by the early results of OLT with unselected cases of advanced metastatic NET (Table 3). Laparoscopy or laparotomy is rarely necessary for assessing the stage of metastatic deposits and imaging techniques (CT-scan, NMR, octreoscan and PET) currently replace more invasive diagnosis.

Metastatic involvement should not be more than 50% of the functional liver parenchyma is a pragmatic factor for excluding OLT in patients with too advanced disease otherwise amenable to palliation (Fig. 2). The limit of 50% has not been confirmed in other series; however in our experience it has been applied in combination with other criteria, as it gives with a simple CT or NMR scan an immediate idea of the general extension of the disease. A macroscopic cut-off for considering eligibility to surgery (resection vs. transplantation) also leads to a more extensive application of down-staging procedures such as hepatic artery embolization, chemo-embolization, radiofrequency ablation and cryosurgery for reducing tumor deposits and possibly reconsiders OLT at a later time.

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  • Fig. 2. 

    Diffuse hepatic metastases by low-grade malignant carcinoid limited to less than 50% of the hepatic parenchyma. The specimen belongs to a young girl with primary tumor removed in the terminal ileum; she is alive and well with no sign of recurrence 15 years after liver transplantation.

3.4. Pre-transplant medical treatment, evaluation of response and timing for transplantation 

Systemic chemotherapy using various drug combinations of streptozotocin, doxorubicin, 5-FU, and alpha-interferon is used in patients with unresectable metastatic NET, with an unproven benefit in survival especially in slow-growing tumors such as those worth evaluating for future OLT (i.e. well-differentiated metastatic NET).

Somatostatin analogues such as octreotide and lanreotide show in non-functioning carcinoids [20] a proven effect on relief of symptomatic patients and on reduction of serum levels of CgA. Even if the impact of treatment remains poorly defined, long-acting somatostatin analogues are often employed in patients eligible for liver transplantation in whom extra-hepatic disease has been removed in presence of positive prognostic factors such as histology, extent of tumor bulk and portal drainage [11], [12], [18], [22], [23], [24], [25]. The main purpose of this treatment includes alleviation of hormonal syndromes and eventually control of tumor growth, since somatostatin analogues induce apoptosis and decrease expression of tumor vascular endothelial growth factor as well as level of insulin-like growth factor-1 [29]. In previous experiences the use of somatostatin analogues has proved to be successful in controlling symptoms and tumor progression in patients on the waiting list for OLT [23]. Adjuvant somatostatin has also been given after OLT in individuals treated with the analogues in the pre-transplant period [22].

In approximately 50% of patients whose tumor express receptors for MIBG (metaiodo-benzylguanidine) the therapeutic use of I131-MIBG can be attempted, since such an approach has achieved, in advanced stages, symptomatic relief and disease stability.

Hepatic artery embolization TACE can also be applied in combination to both chemotherapy and somatostatin analogues, and has been used in the pre-liver-resection setting with reported efficacy in tumor bulk reduction. However, there are no data supporting their routine use especially in patients awaiting OLT. Intra-arterial treatment may cause damage to the hepatic artery wall resulting in intra-operative difficulties in preparing vascular anastomosis at the time of OLT. Additionally, massive tumor necrosis can occur after TACE in some highly-vascularized large tumor deposits, with a mortality rate reported as high as 6% [10], [11], [12], [22], [23], [24], [25], [26], [27], [28].

Whatever medical/interventional approach is chosen, the rate and duration of response are good surrogates of tumor behavior and of the natural history of the disease, with particular reference to possible extra-hepatic recurrences from residues not previously removed at the time of primary tumor surgery. In particular, a tumor shrinkage or a steady disease for at least 6 months seems to be a reasonable time span to be observed prior to OLT.

3.5. Transplantation procedure and follow-up 

At the time of liver disease removal, complete lymphadenectomy of the hepatic pedicle and hepato-duodenal ligament should be performed. Post-transplant immunosuppression with low levels of calcineurin inhibitors and early steroid withdrawal should be pursued in all cases. After transplantation, chemotherapy or long-acting somatostatin analogues should not be continued, unless recurrence is detected. Tumor re-staging should be scheduled at least 4 times/year for the first 2 years and continued thereafter with progressively longer follow-up intervals.

Due to frequent CgA modification related to biliary damage/inflammation and cholestasis [30], careful judgment on such a marker during the post-transplant period should be made in relationship to the possible presence of tumor recurrence. In transplanted patients CgA-levels as a marker of NET recurrence is a tricky parameter that should always be interpreted in the context of other diagnostic tests.

In conclusion, the growing body of clinical evidence summarized in Table 1, Table 2 confirms the effectiveness of the surgical approach to liver metastases from NET with particular reference to those originating in the gastrointestinal tract.

In the last decade, conventional selection criteria based on clinical presentation have been integrated with a proper histologic classification and diagnostic techniques. As a result of this effort, surgical intervention (resection or OLT) has been reconsidered not only as a bare palliation but also as a therapy with high potential of not just prolonging survival but of pursuing a curative intent.

Resection of hepatic metastases from NET is rarely a definitive treatment, while transplantation in selected cases has shown a 5-year recurrence-rate as low as 30%. Taking into consideration ethical issues related to organ allocation to patients with a metastatic cancer as well as the natural history of the disease, response to therapy and cost/effectiveness of demanding procedures such as transplantation, the proposal of liver replacement sounds reasonable only for patients with an expected survival ⩾70% and a recurrence-rate not lower than 50% both at 5 years.

The Milan Criteria (Table 4) is a useful guideline for transplant candidacy in our hands. In such criteria, both anatomical and imaging factors are taken into consideration (portal drainage, extent of metastatic liver involvement) as well as prognostic implications (histology and grading), and a test of time is also applied to the natural history of disease (duration of response). Such a proposed model still awaits multi-institutional validation before transplantation for NET can be accepted outside clinical trials.

Although OLT extends the conventional limits of tumor removal, the general principle of complete resection of both primary and secondary tumor has to be respected. With this aim, staged surgical procedures are allowed, as long as all extra-hepatic tumor sites are eliminated before transplantation.

Use of living donation could increase the number of potential candidates with NET tumor for OLT. However, the upcoming years should first witness the validation of reproducible selection criteria and consolidate optimal post-transplant immunosuppressive regimens. Rather than a rescue treatment for patients with no other alternatives, the practice of OLT for metastatic NET should bring to a prospective, valuable set of individuals to be treated with innovative approaches. Besides optimal patient outcome, the ultimate goal of such co-operative effort should focus on the large population of NET-patients still waiting for effective therapeutic alternatives.

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Acknowledgements 

This work has been supported by AIRC (Italian Association for Cancer Research). The authors thank Paola Collini MD, Salvatore Andreola MD and Sherrie Bhoori MD for advice and revision. The editorial assistance of Daniela Guarneri is also acknowledged.

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References 

  1. Solcia E, Capella C, Kloppel G, Heitz PU, Sobin LH, Rosai J. Endocrine tumours of the gastrointestinal tract. In:  Solcia E,  Kloppel G,  Sobin LH editor. Histologic typing of endocrine tumours. WHO international histological classification of tumours. Heidelberg-New York: Springer Verlag; 2000;p. 57–67
  2. Blonski WC, Reddy KR, Shaked A, Siegelman E, Metz DC. Liver transplantation for metastatic neuroendocrine: a case report and review of the literature. World J Gastroenter. 2005;7676–7683
  3. Sutcliffe R, Maguire D, Ramage J, Rela M, Heaton N. Management of neuroendocrine liver metastases. Am J Surg. 2004;187:39–46
  4. Que FG, Nagorney DM, Batts KP, Linz LJ, Kvols LK. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg. 1995;10:36–43
  5. Martin JK, Moertel CG, Adson MA, Schutt AJ. Surgical treatment of functioning metastatic carcinoid tumors. Arch Surg. 1983;118:537–542
  6. Danforth DN, Gorden P, Brennan MF. Metastatic insulin-secreting carcinoma of the pancreas: clinical course and the role of surgery. Surgery. 1984;96:1027–1037
  7. Norton JA, Sugarbaker PH, Doppman JL, Welsey RA, Maton PN, Gardner JD, et al. Aggressive resection of metastatic disease in selected patients with malignant gastrinoma. Ann Surg. 1986;203:353–359
  8. Makridis C, Öberg K, Juhlin C, Rastad J, Johansson H, Lörelius LE, et al. Surgical treatment of mid-gut carcinoid tumors. World J Surg. 1990;14:377–386
  9. McEntee GP, Nagorney DM, Kvols LK, Moertel CG, Grant CS. Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery. 1990;108:1091–1096
  10. Søreide O, Berstad T, Bakka A, Schrumpf E, Hanssen LE, Engh V, et al. Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors. Surgery. 1992;111:48–54
  11. Carty SE, Jensen RT, Norton JA. Prospective study of aggressive resection of metastatic pancreatic endocrine tumors. Surgery. 1992;112:1024–1032
  12. Dousset B, Saint-Marc O, Pitre J, Soubrane O, Houssin D, Chapuis Y. Metastatic endocrine tumors: medical treatment, surgical resection, or liver transplantation. World J Surg. 1996;20:908–915
  13. Chen H, Hardacre JM, Uzar A, Cameron JL, Choti MA. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival?. J Am Coll Surg. 1998;187:88–93
  14. Chamberlain RS, Canes D, Brown KT, Saltz L, Jarnagin W, Fong Y, et al. Hepatic neuroendocrine metastases: does intervention alter outcomes?. J Am Coll Surg. 2000;190:432–445
  15. Jaeck D, Oussoultzoglou E, Bachellier P, Lemarque P, Weber JC, Nakano H, et al. Hepatic metastases of gastropancreatic neuroendocrine tumors: safe hepatic surgery. World J Surg. 2001;25:689–692
  16. Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG. Surgical treatment of neuroendocrine metatstases to the liver: a plea for resection to increase survival. J Am Coll Surg. 2003;197:29–37
  17. Yao KA, Talamonti MS, Nemcek A, Angelos P, Chrisman H, Skarda J, et al. Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. Surgery. 2001;130:677–682
  18. Makowka L, Tzakis A, Mazzaferro V, Teperman L, Demetris AJ, Iwatsuki S, et al. Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas. Surg Gynecol Obstet. 1989;168:107–111
  19. Van Vilsteren FGI, Baskin-Bey ES, Nagorney DM, Sanderson SO, Kremers WK, Rosen CB, et al. Liver transplantation for gastropancreatic neuroendocrine cancers: defining selection criteria to improve survival. Liver Transpl. 2006;12:448–456
  20. Arnold R, Simon B, Wied M. Treatment of neuroendocrine GEP tumors with somatostatin analogues: a review. Digestion. 2000;62:84–91
  21. Öberg K. Neuroendocrine gastrointestinal tumors. A condense overview of diagnoses and treatment. Ann Oncol. 1999;10:S3–S8
  22. Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: an analysis of 103 patients. Transplantation. 1998;27:1307–1312
  23. Le Treut Y, Delpero J, Dousset B, Cherqui D, Segol D, Mantiou G, et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report. Ann Surg. 1997;4:355–364
  24. Olausson M, Friman S, Cahlin C, Nilsson O, Jansson S, Wangberg B, et al. Indications and results of liver transplantation in patients with neuroendocrine tumors. World J Surg. 2002;26:998–1004
  25. Fernandez JA, Robles R, Marin C, Hernandez Q, Sanchez Bueno F, Ramirez P, et al. Role of liver transplantation in the management of metastatic neuroendocrine tumors. Transplant Proc. 2003;35:1832–1833
  26. Rosenau J, Bahr MJ, von Wasielewski R, Mengel M, Schmidt HH, Nashan B, et al. Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors. Transplantation. 2002;15:386–394
  27. Cahlin C, Friman S, Ahlman H, Backman L, Mjornstedt L, Lindner P, et al. Liver transplantation for metastatic neuroendocrine tumor disease. Transplant Proc. 2003;35:809–810
  28. Florman S, Toure B, Kim L, Gondolesi G, Roayaie S, Krieger N, et al. Liver transplantation for neuroendocrine tumors. J Gastrointest Surg. 2004;8:208–212
  29. Arnold R, Trautmann ME, Creutzfeldt W, Benning R, Benning M, Neuhaus C, et al. Somatostatin analogue octreotide and inhibition of tumor growth in metastatic endocrine gastroenteropancreatic tumors. Gut. 1996;38:430–438
  30. Roskams T, van den Oord JJ, De Vos R, Desmet VJ. Neuroendocrine features of reactive bile ductules in cholestatic liver disease. Am J Pathol. 1990;137:1019–1025

☆ The authors declare that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

PII: S0168-8278(07)00399-6

doi:10.1016/j.jhep.2007.07.004

Journal of Hepatology
Volume 47, Issue 4 , Pages 460-466, October 2007

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