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International Journal of Hepatology
Volume 2012 (2012), Article ID 782672, 9 pages
http://dx.doi.org/10.1155/2012/782672
Review Article

Surgical Treatment of Liver Metastases in Neuroendocrine Neoplasms

1Department of Surgical Oncology, Lilavati Hospital & Research Centre, Mumbai 400 050, India
2Department of Surgical Oncology, Dr. L. H. Hiranandani Hospital and Research Centre, Mumbai 400 076, India
3Department of Gastrointestinal Surgical Oncology, Tata Memorial Hospital, Mumbai 400 012, India

Received 15 July 2011; Accepted 7 October 2011

Academic Editor: Wouter de Herder

Copyright © 2012 Palepu Jagannath et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Neuroendocrine neoplasms (NENs) are a distinctive entity, and nearly 10% of patients already have liver metastases at presentation. The management of neuroendocrine liver metastases (NEN-LM) is complex with differing patterns of metastatic presentation. An aggressive approach should be used to resect the primary tumor, to remove regional lymph nodes, and to resect or treat appropriate distant metastases (including liver tumors). Despite having an indolent course, NENs have a significantly reduced survival when liver metastases are untreated. Though a wide range of therapies are now available with a multimodal approach to the treatment, surgical treatment offers the only chance for a significant survival prolongation and/or improvement of symptoms and quality of life. A review of the existing surgical modalities for NEN-LM is discussed in this paper.

1. Introduction

Neuroendocrine tumors (NETs) consist of a group of neoplasms that arise from neuroendocrine cells dispersed throughout the body and show variable clinical course. The World Health Organization (WHO) classifications in 2000 and subsequently in 2004 did not address the diversity of these tumors. A histologic grading system based on Ki-67 labelling index was proposed by the European Neuroendocrine Tumour Society (ENETS) [1, 2]. The ENETS grading system (G1, G2, G3) has thus been incorporated in the new WHO 2010 classification [3]. It is now recognized that all neuroendocrine tumours are potentially malignant and hence characterized as neuroendocrine neoplasms (NENs). Intestinal NENs represent two-thirds [4], while pancreatic NENs represent about one-third of gastroenteropancreatic NENs (GEP-NENs) [5]. Besides regional lymph node involvement, liver is the predominant site of metastases [6]. Up to 75% of patients with small bowel NEN and 30–85% of pancreatic NENs present with liver metastases (NEN-LM) either at initial evaluation or during the course of their disease [79]. An additional 5–10% of NEN patients present with liver metastases with unknown primary tumor site.

In contrast with the traditional opinion that NEN represents an indolent disease, Touzios et al. [10] reported 5-year survivals range from 13–54% in patients with untreated NEN-LM compared to 75–99% in those without liver metastases [1115].

2. Liver Metastases as a Prognostic Factor

Pancreatic NENs have a lower 5-year survival rate (30–60%) compared to intestinal NENs (60–90%) [1618]. Liver metastases, however, are the most important prognosticator of survival in patients with NEN regardless of the primary site [19].

Two large population-based studies [7, 20] with 13715 and 4104 patients, reported that 12.9% of patients already had liver metastases at initial diagnosis regardless of tumor location and 5–10% of patients had metastases with unknown primary. Occasionally a primary neoplasm is not found elsewhere despite extensive investigations, raising the possibility that the hepatic lesion is the primary tumour [21]. This might be due to the low sensitivity of currently available imaging techniques, although this seems increasingly less likely with advances in technology such as helical computed tomography (CT), endoscopic ultrasonography (EUS), and Gallium-68 PET CT.

Histological subtypes have an influence on treatment and survival outcomes. The reported overall survival ranges from 5.2 to 57% with different histological subsets of digestive NETs [7, 20]. A 95% survival at 20 years has been reported for patients with gastrinoma without liver metastases in contrast with 15% 10-year survival in the presence of bilobar hepatic metastases [22]. 5-year survivals of midgut and hindgut NET decrease by 10–20% and 50–60%, respectively, in the presence of liver metastases [2326]. The new WHO classification (2010) emphasizes the importance of grades G1–3. Tumors with <2 mitosis/10 hpf and <3% Ki67 index are well differentiated and are labelled as G1 tumors, while well-differentiated tumors with 2–20 mitosis/10 hpf or 3%–20% Ki67 index are designated as G2. High immunohistochemical expression of Ki67 is a strong marker of poorly differentiated NETs, and tumors with >20 mitoses/10 hpf or a Ki67 >20% are labelled as G3 tumors [3]. Well-differentiated G1 tumors tend to be more indolent and are good candidates for liver-directed therapy, whereas poorly differentiated G3 neuroendocrine carcinomas (with or without liver metastases) are highly aggressive and patients (even with treated metastatic disease) have an expected survival time of 6–18 months [27, 28]. These tumors are not proposed for surgical resection and are usually confined to systemic chemotherapy (commonly Cisplatin and Etoposide combination).

3. Distribution of Hepatic Metastases

The pattern of distribution of liver metastases is an important determinant of prognosis [26, 29, 30]. Three different patterns of NEN-LM are identified that have an impact on the therapeutic approach: Type I: “restricted metastases,” that is, the metastases are confined to one liver lobe or limited to two adjacent segments. This pattern is usually seen in 20–25% of the cases; the metastases are clearly resectable and can be dealt with by a standard anatomical resection; Type II: “dominant lesion with bilobar metastases” in which there is one dominant lesion but with smaller satellites contralaterally. Such bilobar patterns occur in 10–15% of the cases; the metastases may be potentially resectable and can still be approached surgically with a combination of ablative therapy on the contralateral lobe; Type III: “diffuse, multifocal liver metastases” are found in 60–70% of the cases and surgery is not a good option for these tumors [31, 32]. Type III tumors are clearly unresectable, and a cautious option of liver transplant may be considered for these tumors. Thus, the extent of hepatic involvement of metastatic NEN limits the benefit of surgery in a substantial majority of patients and standard resection alone is inadequate [33]. Nevertheless, it is evident that Type I NEN-LM are associated with favourable outcomes compared to the other two types [10, 30].

4. Diagnostic Work up for Neuroendocrine Liver Metastases

Combined anatomic and functional imaging studies provide tumor localization and assessment of posttreatment outcomes. Our current practice of evaluation is a Triphasic Triplanar CT scan with 1-2 mm slice thickness. A typical contrast enhancement in the arterial phase of the scans is characteristic due to the hypervascular nature of these tumors. However, depending on the tumor type, size, and location, the portal and parenchymal phases of contrast enhancement may also be important for improved detection [3437].

Magnetic resonance (MR) imaging is complimentary and especially helpful in patients unable to receive iodinated contrast agents. One study [38] showed that MR imaging can detect more liver lesions, and a T2-weighted imaging may detect most lesions when contrast agents cannot be given.

Somatostatin receptor scintigraphy (SRS) has rapidly evolved as the gold-standard imaging procedure for NEN expressing somatostatin receptor subtype 2. Indium-labelled somatostatin analogues have been replaced by Gallium-labelled analogues that in combination with a PET-CT (68 Ga-DOTATOC PET/CT) increase the diagnostic sensitivity up to 30% higher than the conventional scanning. Moreover, SRS has resulted in a change in the clinical management in 33–77% of NEN patients in various studies [31, 39].

Beside the advantage of total-body imaging with the potential of simultaneous visualization of the primary tumour and metastatic deposits, SRS can possibly identify those patients who might be candidates for somatostatin receptor-based radiotherapy [3941].

Plasma chromogranin A (CgA) is a widely accepted tumour marker with respect to diagnosis, prognosis, and monitoring of the treatment [4245]. Though the sensitivity of CgA depends upon the NEN type and tumour burden, patients with NEN-LM tend to have significantly higher CgA concentrations than those without metastases [46]. Additional assessment of insulin, C-peptide, gastrin, pancreatic polypeptide, vasoactive intestinal peptide, glucagon, calcitonin, and somatostatin should be useful depending on the tumor functional status, clinical symptoms, and histological features.

A core needle biopsy and a histological examination with immunohistochemistry (IHC), Ki-67, and mitotic index of the primary/metastasis is essential for planning treatment. Tumour staging predicts the prognosis and tailors the therapeutic strategy [32, 47] particularly in patients who are not candidates for complete resection.

5. Liver-Directed Therapy

No optimal therapeutic strategies exist for treatment of liver metastases from GEP-NEN, and best strategy for treatment of NEN-LM is still poorly defined [48, 49]. Moreover, there is no randomized trial comparing surgery with nonsurgical treatments like RFA (radiofrequency ablation), TACE (transarterial chemoembolization), and medical treatment. In view of the infrequency of these tumours, multicentre clinical trials are needed in addressing the role of surgery.

5.1. Resection
5.1.1. Does Resection Benefit?

Surgery is generally proposed to all patients with operable well-differentiated metastases from digestive NENs regardless of the site of origin [32]. However, most NENs are detected after extensive liver metastases are present, and, consequently, only 10% to 20% of patients with NEN-LM are eligible for resection [50, 51].

The benefits of surgical resection for NEN-LM have been demonstrated in terms of overall survival and quality of life. Overall survival after hepatic resection has been reported in 46–86% at 5 years and 35–79% at 10 years in various series [52]. Complete resection (R0/R1) for both mid- and hindgut tumors is associated with better long-term survival [30, 5356]. In many reported series of patients in whom hepatic resection was feasible, a median survival time was not reached during a followup of 27 months [56] up to 78 months [57] compared with 27 months [56] and 17 months [57] in those with unresectable tumours.

A recent multicenter study evaluating 339 patients who underwent surgical management of NEN-LM from 1985 to 2009 identified those who are likely to benefit the most by liver-directed surgery. It was observed that patients with hormonally functional NEN who had R0/R1 resection benefited the most from surgery [58]. Another large study [59] observed that R1 resections, unlike many other cancers, were not associated with a worse overall survival after liver resection for NEN-LM.

Resection is associated with a low mortality rate (0–5%) and an acceptable morbidity (close to 30%), and up to 95% of patients have shown symptom improvement in one large surgical series of 170 patients [56].

R0 resection rates have been reportedly between 20 and 57% in various series [31, 55, 56, 6062]; however, among patients undergoing complete resection, long-term disease-free survival is reported in up to only 20 percent of patients [53, 63].

Such variability of clinical outcomes demands a meticulous case selection, and certain prerequisites should be considered prior to a resectional surgery [32, 52, 64]: (i) resectable primary tumor (previously resected or considered resectable synchronously), (ii) well-differentiated NEN-LM, (iii) possibility of R0 resection, (iv) exclusion of nonresectable extrahepatic disease, (v) reasonable performance status, and (vi) corrected or optimised carcinoid heart disease prior to aggressive liver surgery.

The presence of local recurrence including abdominal lymph node involvement is not an absolute contraindication for surgery if the removal of liver metastases and lymph nodes and/or the recurrence site(s) is planned [32].

In all cases in which the patients have carcinoid syndrome, specific perioperative treatments with somatostatin analogues are indicated to prevent intra- and postoperative carcinoid crisis [65, 66].

5.1.2. Recurrence after Resection and Impact of R0 Resection

Recurrence after an R0 resection is not uncommon, and 5-year local recurrence rates of up to 97% have been reported even when complete resection has been achieved [53, 55, 67, 68]. Recurrence depends mainly on the initial completeness of liver resection, and a thorough pre- and intraoperative assessment of small liver metastases is essential.

In a large series of 170 surgically treated patients, 5- and 10-year recurrence rate was 84% and 94%, respectively, with a median time to recurrence of 21 months. Only 44% of patients had a complete tumour resection in this series with a 5-year recurrence rate of 76% and a median time to recurrence of 30 months. In comparison patients who did not undergo a complete resection showed a 5-year recurrence rate of 91% with a median time to recurrence of only 16 months [53].

The prognostic relevance of R0 resection has been pointed out by Gomez et al. in their report of 18 resected patients who showed an overall 5-year recurrence rate of 34%. The five-year recurrence was only 10% in patients with tumour-free resection margins, in contrast to 75% when resection margins were involved [68]. Thus, an aggressive surgical approach does benefit irrespective of completeness or R0 status and has an impact on prognosis.

5.1.3. Resection Strategies in Synchronous and Metachronous Tumors

Unlike most malignancies, resection of the primary is beneficial for patients with NENs and should be considered in patients who have resectable metastatic disease [69, 70]. However, resection of a small asymptomatic (relatively stable) primary in the presence of unresectable metastatic disease is not indicated [69].

In synchronous disease, liver surgery can be performed either as a one-step or a two-step procedure [32, 55, 71]. NEN-LM may be resected at the same time as the primary tumor with little additional risk if the metastases are unilobar [54, 55]. The main consideration however should be to perform a complete resection with acceptable morbidity rate. If major or complex liver resection is required, a two-stage surgery may be preferable in order to reduce the operative risk especially in patients with Type II metastases. A two-step surgery may involve at the first step a resection of metastases of the one lobe in addition to a resection of the primary and lymph nodes. Contralateral liver volume enhancement by portal venous embolization is an option with an aim to induce left liver hypertrophy followed by right hepatectomy or Lobectomy as a second step. Such an approach can in selected patients avoid or delay indications for liver transplantation [71]. For patients with unresectable liver metastases, a cholecystectomy is recommended to prevent ischemic complications of the gallbladder subsequent to chemoembolization and possible gallstones formation during somatostatin analogue therapy [54].

For metachronous liver metastases, a one-step procedure can be recommended as a low-risk approach to unilobar disease (<30% morbidity). For bilobar or diffuse liver metastases, a sequential approach including resection with or without ablative techniques, preoperative portal embolization, percutaneous treatments, or intra-arterial chemoembolization may be adopted [32, 72].

Overall, the effectiveness of the resection of unilobar and bilobar liver metastases depends on the operative techniques employed as well as the competence of the hepatobiliary surgeon. Intraoperative ultrasonography is essential in defining the extent of any known lesions and to detect any additional smaller lesions missed during a preoperative diagnosis. Resectional surgery should be the first option before patient is considered for liver transplantation due to standard priority in listing.

5.1.4. Does Debulking Benefit?

Several retrospective series have suggested that selected patients who undergo aggressive “debulking” of NEN-LM, in which the majority but not all of the disease is resected, have better quality of life and longer survival relative to those who do not undergo surgery [10, 30, 7377]. Soreide et al. [78] found that patients with NEN hepatic metastases who underwent surgical debulking (planned repeat operations included) had a three- to fourfold longer median survival time compared with those who did not. However, complication and mortality rates were high (33% and 9%, resp.), and the duration of symptom relief in most cases was 6–24 months.

Incomplete debulking surgery (R2) has limited indications, yet it can improve the quality of life in selected patients for whom medical treatment has failed. However, in order to be efficient, the removal of at least 90% of the tumor volume is required [54, 56, 79, 80].

Thus, when complete resection of NEN-LM is not feasible or in the presence of unresectable extrahepatic disease, a tumor debulking strategy should be considered especially in patients with functional NENs with hormonal symptoms refractory to other treatments. Debulking can be a strategy for nonfunctioning NENs with local effects such as abutting the hepatic hilum (resulting in biliary obstruction) or obstructing the colon/duodenum [47, 81].

A combination of techniques, namely, resection and ablation or resection combined with other liver-directed therapy should be used to achieve complete tumor response when all liver disease cannot be resected.

5.2. Local Ablative Techniques

Radiofrequency ablation (RFA) has become the preferred local-ablative therapy in most centres, and its use has been shown to be effective in both relieving the symptoms of NEN-LM and achieving local control of the metastases [32, 82, 83].

Mazzaglia and colleagues reported the largest experience of ablation in patients with NEN-LM, encompassing a total of 452 lesions in 63 patients via 80 laparoscopic RFA sessions. Thirty-six patients were symptomatic from disease, and 94% experienced symptom relief after ablation for a median duration of 11 ± 2.3 months after RFA. The procedure-associated morbidity was 5%, and there was no 30-day mortality. Median survival was 3.9 years calculated from the first RFA session with a 2-year survival of 77% [84].

In yet another study of patients with 234 NEN metastases, 34 were treated with RFA. 80% of the patients reported a complete or significant relief from their symptoms, lasting for an average of 10 months and 41% of the treated patients showed no evidence of progression [85].

Tumor size poses a significant limit on the effectiveness of RFA. Though ablation may be used repeatedly within the same metastasis, it is difficult to fully eradicate with certainty tumors that are >3 cm in diameter, and a tumor >5 cm in diameter is considered to be unsuitable for RFA [86].

RFA has been shown to be a relatively low-risk procedure for treating liver tumors [87], and while the safety of RFA makes it an attractive method of treatment, the rate of tumor recurrence after therapy limits its effectiveness as a single therapy [86]. A recent study reported progressive liver disease in 80% of patients with NEN liver metastases treated with RFA [84].

5.3. Combination Techniques of Resection and Other Modalities
5.3.1. Resection Combined with Cryoablation

While liver resection for NEN-LMs provides the best chance of long-term survival, it is unfortunately not feasible in the majority of patients given the often widespread presentation of liver disease. Combining resection with local ablation can potentially expand the resection criteria and thus help improve survival [88]. In a recent study, forty patients with NEN-LMs underwent concomitant hepatic resection and cryoablation between 1992 and 2010 with a median followup of 61 months (for alive patients). The median progression-free survival and overall survival after hepatic resection were 22 and 95 months, respectively. Five-year and 10-year overall survival rate was 61% and 40%, respectively. While histologic grade was an independent factor associated with overall survival, presence of extrahepatic disease was associated with progression-free survival.

It thus appears that concomitant hepatic resection and cryoablation to achieve tumor debulking is associated with good survival outcomes in well-selected patients. This recent report suggested that such an approach may increase the number of patients with borderline resectable disease undergoing surgical management of advanced NEN-LMs [88].

5.3.2. Resection and Radiofrequency Ablation

Therapy with RFA alone is associated with higher recurrence rates compared to RFA plus resection, and in patients whose metastases are otherwise unresectable or difficult to access, the combination of resection and RFA provides the opportunity to achieve complete tumor removal [8991].

Elias et al. [92] reported an overall survival rate of 84% at 3 years by incorporating a one-step combined approach of hepatectomy (for large or contiguous NEN-LMs) along with intraoperative use of multiple RFAs (for remnant metastases <2.5 cm). A mean of 15 ± 9 NEN-LMs per patient were surgically removed, and a mean of 12 ± 8 (median of 10) NEN-LMs per patient were RF ablated.

A combination of RFA along with parenchyma preserving liver resections seems to be the way forward while dealing with multiple bilobar liver metastases that are unlikely to be completely resected by surgery alone.

5.3.3. Resection and Chemoembolization

Chemoembolization is indicated for nonresectable multiple bilobar metastases, and in various studies 55%–100% of patients with malignant NENs treated by hepatic arterial embolization (HAE)/transarterial chemoembolization (TACE) have symptomatic improvement and 20%–80% have an objective response with tumor shrinkage. The mean duration of response ranges from 6 to 42 months [9396].

Advances in major liver resectional surgery has resulted in further development of multimodal approaches for NELMs where surgeons and interventional radiologists have tried to work in multidisciplinary settings to evaluate whether TACE and surgery can have a synergistic action on overall outcomes of NELMs. Hepatic resection may be possible after cytoreduction of the tumor following TACE and other therapies [97]; however, the data on this subject is sparse.

5.4. Liver Transplantation

In patients with diffuse unresectable liver metastases or who suffer from life-threatening hormonal disturbances refractory to medical therapy, liver transplantation may be an option for carefully selected patients [32].

Primary tumor location has an impact on outcomes of liver transplantation. While the 5-year survival rate was 68% in patients with limited hepatic disease and non-duodenopancreatic tumours, it dropped to 12% in the case of hepatomegaly and primary tumour localized within the duodenum or pancreas [98, 99].

Majority of patients undergoing orthotopic liver transplantation (OLT) ultimately develop recurrent disease and reported 5-year recurrence-free survival ranges from 24 to 45% with an overall survival range of 36–57% [100105].

Mazzaferro et al. could achieve a 90% overall survival and a 77% recurrence-free survival at 5 years by defining specific criteria for indication of liver transplant in the setting of NLM: (a) well-differentiated NENs (low-grade functioning or nonfunctioning), (b) a prior curatively resected primary tumor drained by the portal system, (c) ≤50% metastatic involvement of the liver, (d) good response or stable disease for a minimum of 6 months prior to transplantation, and (e) age ≤ 50 years [106].

An early disease recurrence, a considerable postoperative mortality, the absence of extensive experience, and lack of universal indications have precluded orthotopic liver transplantation as a good option for most patients with unresectable NEN-LMs [107]. Moreover, limited availability of donor organs in many regions has been a barrier to the widespread use of liver transplantation in general. Thus, the potential benefit of liver transplantation in patients with malignant NENs needs to be weighed against issues of perioperative morbidity and the ethical distribution of donor organs [32].

A modified algorithm for the treatment of patients with metastatic NETs based on ENETS consensus guidelines [32] is shown in Figure 1.

782672.fig.001
Figure 1: Suggested treatment algorithm for patients with NEN-LM. NEN: neuroendocrine neoplasm; LM: liver metastasis; RFA: radiofrequency ablation; TACE: transcatheter arterial chemoembolization; TAE: transcatheter arterial embolization; PVE: portal vein embolization; PVL: portal vein ligation.

6. Summary

Surgical resection remains the gold standard especially in the treatment of well-differentiated NEN-LMs for symptom relief and long-term survival. In both synchronous and metachronous tumors, one- and two-step procedures may be undertaken, depending upon whether the liver disease is unilobar or complex.

Debulking resections are justified in functioning NEN and selective nonfunctioning NENs; however, removal of at least 90% of the tumor volume is necessary.

RFA can be used effectively as antitumor treatment and as a sole therapy for relieving symptoms in patients with NEN-LMs, but when combined with resection a better outcome is anticipated.

Liver transplantation needs to be carefully considered in specific liver alone bilobar metastases especially in (low-grade) well-differentiated NENs.

Surgical options are complimented by ablative techniques (RFA/cryoablation), nonsurgical liver-directed therapies (HAE/TACE/Transarterial radioembolization—TARE), and systemic treatment modalities (peptide receptor radiotherapy, cytotoxic chemotherapy, somatostatin analogues, and newer molecular-targeted treatments). A multidisciplinary team approach is necessary to customize therapy for each patient with NEN-LM.

References

  1. G. Rindi, G. Klöppel, H. Alhman et al., “TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system,” Virchows Archiv, vol. 449, no. 4, pp. 395–401, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. G. Rindi, G. Klöppel, A. Couvelard et al., “TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system,” Virchows Archiv, vol. 451, no. 4, pp. 757–762, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. F. Bosman, F. Carneiro, R. Hruban, et al., WHO Classification of Tumors of the Digestive System, IARC Press, Lyon, France, 2010.
  4. M. S. Talamonti, K. Stuart, and J. C. Yao, “Neuroendocrine tumors of the gastrointestinal tract: how aggressive should we be?” in American Society of Clinical Oncology 2004 Education Book, M. Perry, Ed., pp. 206–215, American Society of Clinical Oncology, Alexandria, Egypt, 2004.
  5. M. A. Kouvaraki, J. A. Ajani, P. Hoff et al., “Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas,” Journal of Clinical Oncology, vol. 22, no. 23, pp. 4762–4771, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. A. P. Venook, “Embolization and chemoembolization therapy for neuroendocrine tumors,” Current Opinion in Oncology, vol. 11, no. 1, pp. 38–41, 1999. View at Publisher · View at Google Scholar · View at Scopus
  7. I. M. Modlin, K. D. Lye, and M. Kidd, “A 5-decade analysis of 13,715 carcinoid tumors,” Cancer, vol. 97, no. 4, pp. 934–959, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. F. R. Norheim, K. Oberg, and E. Theodorsson-Norheim, “Malignant carcinoid tumors. An analysis of 103 patients with regard to tumor localization, hormone production, and survival,” Annals of Surgery, vol. 206, no. 2, pp. 115–125, 1987. View at Scopus
  9. K. Oberg and B. Eriksson, “Endocrine tumors of pancreas,” Best Practice & Research Clinical Gastroenterology, vol. 19, pp. 753–781, 2005.
  10. J. G. Touzios, J. M. Kiely, S. C. Pitt et al., “Neuroendocrine hepatic metastases: does aggressive management improve survival?” Annals of Surgery, vol. 241, no. 5, pp. 776–785, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. L. F. Starker and T. Carling, “Molecular genetics of gastroenteropancreatic neuroendocrine tumors,” Current Opinion in Oncology, vol. 21, no. 1, pp. 29–33, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. E. W. M. McDermott, B. Guduric, and M. F. Brennan, “Prognostic variables in patients with gastrointestinal carcinoid tumours,” British Journal of Surgery, vol. 81, no. 7, pp. 1007–1009, 1994. View at Publisher · View at Google Scholar · View at Scopus
  13. C. G. Moertel, W. G. Sauer, M. B. Dockerty, and A. H. Baggenstoss, “Life history of the carcinoid tumor of the small intestine,” Cancer, vol. 14, pp. 901–912, 1961.
  14. G. B. Thompson, J. A. van Heerden, C. S. Grant, J. A. Carney, and D. M. Ilstrup, “Islet cell carcinomas of the pancreas: a twenty-year experience,” Surgery, vol. 104, no. 6, pp. 1011–1017, 1988. View at Scopus
  15. J. Zeitels, K. Naunheim, E. L. Kaplan, and F. Straus, “Carcinoid tumors. A 37-year experience,” Archives of Surgery, vol. 117, no. 5, pp. 732–737, 1982. View at Scopus
  16. F. Panzuto, S. Nasoni, M. Falconi et al., “Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization,” Endocrine-Related Cancer, vol. 12, no. 4, pp. 1083–1092, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. I. Madeira, B. Terris, M. Voss et al., “Prognostic factors in patients with endocrine tumours of the duodenopancreatic area,” Gut, vol. 43, no. 3, pp. 422–427, 1998. View at Scopus
  18. P. Tomassetti, D. Campana, L. Piscitelli et al., “Endocrine pancreatic tumors: factors correlated with survival,” Annals of Oncology, vol. 16, no. 11, pp. 1806–1810, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. G. Rindi, T. D'Adda, E. Froio, G. Fellegara, and C. Bordi, “Prognostic factors in gastrointestinal endocrine tumors,” Endocrine Pathology, vol. 18, no. 3, pp. 145–149, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. C. Lepage, B. Rachet, and M. P. Coleman, “Survival from maliganant digestive neuroendocrine tumors in England and Wales: a population-based study,” Gatroenterology, vol. 132, pp. 899–904, 2007.
  21. F. Maire, A. Couvelard, M. P. Vullierme et al., “Primary endocrine tumours of the liver,” British Journal of Surgery, vol. 92, no. 10, pp. 1255–1260, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. D. C. Madoff, S. Gupta, K. Ahrar, R. Murthy, and J. C. Yao, “Update on the management of neuroendocrine hepatic metastases,” Journal of Vascular and Interventional Radiology, vol. 17, no. 8, pp. 1235–1250, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. O. Nilsson, E. Van Cutsem, G. Delle Fave, et al., “Consensus conference; European neuroendocrine tumor society: poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic),” Neuroendocrinology, vol. 84, no. 3, pp. 212–215, 2006. View at Publisher · View at Google Scholar · View at PubMed
  24. J. A. Norton and R. T. Jensen, “Resolved and unresolved controversies in the surgical management of patients with Zollinger-Ellison syndrome,” Annals of Surgery, vol. 240, no. 5, pp. 757–773, 2004. View at Publisher · View at Google Scholar · View at Scopus
  25. E. W. M. McDermott, B. Guduric, and M. F. Brennan, “Prognostic variables in patients with gastrointestinal carcinoid tumours,” British Journal of Surgery, vol. 81, no. 7, pp. 1007–1009, 1994. View at Publisher · View at Google Scholar · View at Scopus
  26. A. P. Burke, R. M. Thomas, A. M. Elsayed, and L. H. Sobin, “Carcinoids of the jejunum and ileum: an immunohistochemical and clinicopathologic study of 167 cases,” Cancer, vol. 79, no. 6, pp. 1086–1093, 1997. View at Publisher · View at Google Scholar · View at Scopus
  27. J. Soga, “Statistical evaluation of 2001 carcinoid cases with metastases, collected from literature: a comparative study between ordinary carcinoids and atypical varieties,” Journal of Experimental and Clinical Cancer Research, vol. 17, no. 1, pp. 3–12, 1998. View at Scopus
  28. E. T. Janson, L. Holmberg, M. Stridsberg et al., “Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center,” Annals of Oncology, vol. 8, no. 7, pp. 685–690, 1997. View at Publisher · View at Google Scholar · View at Scopus
  29. J. A. Norton, “Endocrine tumours of the gastrointestinal tract. Surgical treatment of neuroendocrine metastases,” Best Practice & Research Clinical Gastroenterology, vol. 19, pp. 577–583, 2005.
  30. R. S. Chamberlain, D. Canes, K. T. Brown et al., “Hepatic neuroendocrine metastases: does intervention alter outcomes?” Journal of the American College of Surgeons, vol. 190, no. 4, pp. 432–445, 2000. View at Publisher · View at Google Scholar · View at Scopus
  31. A. Frilling, J. Li, E. Malamutmann, K. W. Schmid, A. Bockisch, and C. E. Broelsch, “Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease,” British Journal of Surgery, vol. 96, no. 2, pp. 175–184, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. T. Steinmüller, R. Kianmanesh, M. Falconi et al., “Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary,” Neuroendocrinology, vol. 87, no. 1, pp. 47–62, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. I. Ihse, B. Persson, and S. Tibblin, “Neuroendocrine metastases of the liver,” World Journal of Surgery, vol. 19, no. 1, pp. 76–82, 1995. View at Publisher · View at Google Scholar · View at Scopus
  34. J. L. Fidler, J. G. Fletcher, C. C. Reading et al., “Preoperative detection of pancreatic insulinomas on multiphasic helical CT,” American Journal of Roentgenology, vol. 181, no. 3, pp. 775–780, 2003. View at Scopus
  35. A. D. King, G. T. C. Ko, V. T. F. Yeung, C. C. Chow, J. Griffith, and C. S. Cockram, “Dual phase spiral CT in the detection of small insulinomas of the pancreas,” British Journal of Radiology, vol. 71, pp. 20–23, 1998. View at Scopus
  36. T. Ichikawa, M. S. Peterson, M. P. Federle et al., “Islet cell tumor of the pancreas: biphasic CT versus MR imaging in tumor detection,” Radiology, vol. 216, no. 1, pp. 163–171, 2000. View at Scopus
  37. L. Van Hoe, S. Gryspeerdt, G. Marchal, A. L. Baert, and L. Mertens, “Helical CT for the preoperative localization of islet cell tumors of the pancreas: value of arterial and parenchymal phase images,” American Journal of Roentgenology, vol. 165, no. 6, pp. 1437–1439, 1995. View at Scopus
  38. C. Dromain, T. De Baere, J. Lumbroso et al., “Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging,” Journal of Clinical Oncology, vol. 23, no. 1, pp. 70–78, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. E. P. Krenning, D. J. Kwekkeboom, W. H. Bakker et al., “Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients,” European Journal of Nuclear Medicine, vol. 20, no. 8, pp. 716–731, 1993. View at Scopus
  40. F. Gibril, J. C. Reynolds, J. L. Doppman et al., “Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas—a prospective study,” Annals of Internal Medicine, vol. 125, no. 1, pp. 26–34, 1996. View at Scopus
  41. D. J. Kwekkeboom, E. P. Krenning, K. Scheidhauer et al., “ENETS consensus guidelines for the standards of care in neuroendocrine tumors: somatostatin receptor imaging with 111In-pentetreotide,” Neuroendocrinology, vol. 90, no. 2, pp. 184–189, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. D. T. O'Connor and L. J. Deftos, “Secretion of chromogranin A by peptide-producing endocrine neoplasms,” New England Journal of Medicine, vol. 314, no. 18, pp. 1145–1151, 1986. View at Scopus
  43. K. Öberg and M. Stridsberg, “Chromogranins as diagnostic and prognostic markers in neuroendocrine tumours,” Advances in Experimental Medicine and Biology, vol. 482, pp. 329–337, 2000. View at Scopus
  44. E. Baudin, J. M. Bidart, A. Bachelot et al., “Impact of chromogranin A measurement in the work-up of neuroendocrine tumors,” Annals of Oncology, vol. 12, supplement 2, pp. S79–S82, 2001. View at Scopus
  45. P. Tomassetti, M. Migliori, P. Simoni et al., “Diagnostic value of plasma chromogranin A in neuroendocrine tumours,” European Journal of Gastroenterology and Hepatology, vol. 13, no. 1, pp. 55–58, 2001. View at Publisher · View at Google Scholar · View at Scopus
  46. M. C. Zatelli, M. Torta, A. Leon et al., “Chromogranin A as a marker of neuroendocrine neoplasia: an Italian Multicenter Study,” Endocrine-Related Cancer, vol. 14, no. 2, pp. 473–482, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. R. Sutcliffe, D. Maguire, J. Ramage, M. Rela, and N. Heaton, “Management of neuroendocrine liver metastases,” American Journal of Surgery, vol. 187, no. 1, pp. 39–46, 2004. View at Publisher · View at Google Scholar · View at Scopus
  48. K. S. Gurusamy, V. Pamecha, D. Sharma, and B. R. Davidson, “Techniques for liver parenchymal transection in liver resection,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD006880, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. K. S. Gurusamy, V. Pamecha, D. Sharma, and B. R. Davidson, “Palliative cytoreductive surgery versus other palliative treatments in patients with unresectable liver metastases from gastro-entero-pancreatic neuroendocrine tumours,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD007118, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. T. J. Vogl, N. N. N. Naguib, S. Zangos, K. Eichler, A. Hedayati, and N. E. A. Nour-Eldin, “Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and thermal ablation,” European Journal of Radiology, vol. 72, no. 3, pp. 517–528, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. I. Ihse, B. Persson, and S. Tibblin, “Neuroendocrine metastases of the liver,” World Journal of Surgery, vol. 19, no. 1, pp. 76–82, 1995. View at Publisher · View at Google Scholar · View at Scopus
  52. A. Frilling, G. C. Sotiropoulos, J. Li, O. Kornasiewicz, and U. Plöckinger, “Multimodal management of neuroendocrine liver metastases,” International Hepato-Pancreato-Biliary Association, vol. 12, no. 6, pp. 361–379, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. J. M. Sarmiento, G. Heywood, J. Rubin, D. M. Ilstrup, D. M. Nagorney, and F. G. Que, “Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival,” Journal of the American College of Surgeons, vol. 197, no. 1, pp. 29–37, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. J. M. Sarmiento and F. G. Que, “Hepatic surgery for metastases from neuroendocrine tumors,” Surgical Oncology Clinics of North America, vol. 12, no. 1, pp. 231–242, 2003. View at Publisher · View at Google Scholar · View at Scopus
  55. D. Elias, P. Lasser, M. Ducreux et al., “Liver resection (and associated extrahepatic resections) for metastatic well-differentiated endocrine tumors: a 15-year single center prospective study,” Surgery, vol. 133, no. 4, pp. 375–382, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. H. Chen, J. M. Hardacre, A. Uzar, J. L. Cameron, and M. A. Choti, “Isolated liver metastases from neuroendocrine tumors: does resection prolong survival?” Journal of the American College of Surgeons, vol. 187, no. 1, pp. 88–93, 1998. View at Publisher · View at Google Scholar · View at Scopus
  57. M. G. House, J. L. Cameron, K. D. Lillemoe et al., “Differences in survival for patients with resectable versus unresectable metastases from pancreatic islet cell cancer,” Journal of Gastrointestinal Surgery, vol. 10, no. 1, pp. 138–145, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. S. C. Mayo, M. C. de Jong, C. Pulitano et al., “Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis,” Annals of Surgical Oncology, vol. 17, pp. 3129–3136, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. E. S. Glazer, J. F. Tseng, W. Al-Refaie et al., “Long-term survival after surgical management of neuroendocrine hepatic metastases,” International Hepato-Pancreato-Biliary Association, vol. 12, no. 6, pp. 427–433, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. K. A. Yao, M. S. Talamonti, A. Nemcek et al., “Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors,” Surgery, vol. 130, no. 4, pp. 677–685, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. S. Musunuru, H. Chen, S. Rajpal et al., “Metastatic neuroendocrine hepatic tumors: resection improves survival,” Archives of Surgery, vol. 141, no. 10, pp. 1000–1005, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. G. L. Grazi, M. Cescon, F. Pierangeli et al., “Highly aggressive policy of hepatic resections for neuroendocrine liver metastases,” Hepato-Gastroenterology, vol. 47, no. 32, pp. 481–486, 2000. View at Scopus
  63. C. S. Cho, D. M. Labow, L. Tang et al., “Histologic grade is correlated with outcome after resection of hepatic neuroendocrine neoplasms,” Cancer, vol. 113, no. 1, pp. 126–134, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. J. C. Yao and J. N. Vauthey, “Primary and metastatic hepatic carcinoid: is there an algorithm?” Annals of Surgical Oncology, vol. 10, no. 10, pp. 1133–1135, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. K. Öberg, L. Kvols, M. Caplin et al., “Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system,” Annals of Oncology, vol. 15, no. 6, pp. 966–973, 2004. View at Publisher · View at Google Scholar · View at Scopus
  66. P. A. Farling and A. K. Durairaju, “Remifentanil and anaesthesia for carcinoid syndrome,” British Journal of Anaesthesia, vol. 92, no. 6, pp. 893–895, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. S. Scigliano, R. Lebtahi, F. Maire et al., “Clinical and imaging follow-up after exhaustive liver resection of endocrine metastases: a 15-year monocentric experience,” Endocrine-Related Cancer, vol. 16, no. 3, pp. 977–990, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. D. Gomez, H. Z. Malik, A. Al-Mukthar et al., “Hepatic resection for metastatic gastrointestinal and pancreatic neuroendocrine tumours: outcome and prognostic predictors,” International Hepato-Pancreato-Biliary Association, vol. 9, no. 5, pp. 345–351, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. National Comprehensive Cancer Network (NCCN), 2011, http://www.nccn.org/index.asp.
  70. S. A. Gulec, T. S. Mountcastle, D. Frey et al., “Cytoreductive surgery in patients with advanced-stage carcinoid tumors,” American Surgeon, vol. 68, no. 8, pp. 667–671, 2002. View at Scopus
  71. R. Kianmanesh, A. Sauvanet, O. Hentic et al., “Two-step surgery for synchronous bilobar liver metastases from digestive endocrine tumors: a safe approach for radical resection,” Annals of Surgery, vol. 247, no. 4, pp. 659–665, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. D. Jaeck, E. Oussoultzoglou, P. Bachellier et al., “Hepatic metastases of gastroenteropancreatic neuroendocrine tumors: safe hepatic surgery,” World Journal of Surgery, vol. 25, no. 6, pp. 689–692, 2001. View at Publisher · View at Google Scholar · View at Scopus
  73. C. S. Landry, C. R. Scoggins, K. M. Mcmasters, and R. C. G. Martin, “Management of hepatic metastasis of gastrointestinal carcinoid tumors,” Journal of Surgical Oncology, vol. 97, no. 3, pp. 253–258, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. D. A. Osborne, E. E. Zervos, J. Strosberg et al., “Improved outcome with cytoreduction versus embolization for symptomatic hepatic metastases of carcinoid and neuroendocrine tumors,” Annals of Surgical Oncology, vol. 13, no. 4, pp. 572–581, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  75. S. Musunuru, H. Chen, S. Rajpal et al., “Metastatic neuroendocrine hepatic tumors: resection improves survival,” Archives of Surgery, vol. 141, no. 10, pp. 1000–1004, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. C. D. Knox, I. D. Feurer, P. E. Wise et al., “Survival and functional quality of life after resection for hepatic carcinoid metastasis,” Journal of Gastrointestinal Surgery, vol. 8, no. 6, pp. 653–659, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  77. B. Givi, S. J. Pommier, A. K. Thompson, B. S. Diggs, and R. F. Pommier, “Operative resection of primary carcinoid neoplasms in patients with liver metastases yields significantly better survival,” Surgery, vol. 140, no. 6, pp. 891–898, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  78. O. Soreide, T. Berstad, A. Bakka et al., “Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors,” Surgery, vol. 111, no. 1, pp. 48–54, 1992. View at Scopus
  79. H. Ahlman, B. Wängberg, S. Jansson et al., “Interventional treatment of gastrointestinal neuroendocrine tumours,” Digestion, vol. 62, supplement 1, pp. 59–68, 2000. View at Scopus
  80. F. G. Que, D. M. Nagorney, K. P. Batts, L. J. Linz, and L. K. Kvols, “Hepatic resection for metastatic neuroendocrine carcinomas,” American Journal of Surgery, vol. 169, no. 1, pp. 36–43, 1995. View at Publisher · View at Google Scholar · View at Scopus
  81. B. Clary, “Treatment of isolated neuroendocrine liver metastases,” Journal of Gastrointestinal Surgery, vol. 10, no. 3, pp. 332–334, 2006. View at Publisher · View at Google Scholar · View at Scopus
  82. A. E. Siperstein, S. J. Rogers, P. D. Hansen, and A. Gitomirsky, “Laparoscopic thermal ablation of hepatic neuroendocrine tumor metastases,” Surgery, vol. 122, no. 6, pp. 1147–1155, 1997. View at Publisher · View at Google Scholar · View at Scopus
  83. A. E. Siperstein and E. Berber, “Cryoablation, percutaneous alcohol injection, and radiofrequency ablation for treatment of neuroendocrine liver metastases,” World Journal of Surgery, vol. 25, no. 6, pp. 693–696, 2001. View at Publisher · View at Google Scholar · View at Scopus
  84. P. J. Mazzaglia, E. Berber, M. Milas, and A. E. Siperstein, “Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival,” Surgery, vol. 142, no. 1, pp. 10–19, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. E. Berber, N. Flesher, and A. E. Siperstein, “Laparoscopic radiofrequency ablation of neuroendocrine liver metastases,” World Journal of Surgery, vol. 26, no. 8, pp. 985–990, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. T. Livraghi, S. N. Goldberg, S. Lazzaroni et al., “Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions,” Radiology, vol. 214, no. 3, pp. 761–768, 2000. View at Scopus
  87. H. Nave, E. Mössinger, H. Feist, H. Lang, and H. R. Raab, “Surgery as primary treatment in patients with liver metastases from carcinoid tumors: a retrospective, unicentric study over 13 years,” Surgery, vol. 129, no. 2, pp. 170–175, 2001. View at Publisher · View at Google Scholar · View at Scopus
  88. A. Saxena, T. C. Chua, F. Chu, et al., “Optimizing the surgical effort in patients with advanced neuroendocrine neoplasm hepatic metastases: a critical analysis of 40 patients treated by hepatic resection and cryoablation,” American Journal of Clinical Oncology. In press.
  89. T. M. Pawlik, F. Izzo, D. S. Cohen, J. S. Morris, and S. A. Curley, “Combined resection and radiofrequency ablation for advanced hepatic malignancies: results in 172 patients,” Annals of Surgical Oncology, vol. 10, no. 9, pp. 1059–1069, 2003. View at Publisher · View at Google Scholar · View at Scopus
  90. S. Evrard, Y. Becouarn, M. Fonck, R. Brunet, S. Mathoulin-Pelissier, and V. Picot, “Surgical treatment of liver metastases by radiofrequency ablation, resection, or in combination,” European Journal of Surgical Oncology, vol. 30, no. 4, pp. 399–406, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. B. Fioole, M. C. Jansen, F. H. van Duijnhoven, R. van Hillegersberg, T. M. van Gulik, and I. H. M. Borel Rinkes, “Combining partial liver resection and local ablation of liver tumours: a preliminary Dutch experience,” World Journal of Surgical Oncology, vol. 4, article 46, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  92. D. Elias, D. Goéré, G. Leroux et al., “Combined liver surgery and RFA for patients with gastroenteropancreatic endocrine tumors presenting with more than 15 metastases to the liver,” European Journal of Surgical Oncology, vol. 35, no. 10, pp. 1092–1097, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  93. D. O'Toole and P. Ruszniewski, “Chemoembolization and other ablative therapies for liver metastases of gastrointestinal endocrine tumours,” Best Practice and Research, vol. 19, no. 4, pp. 585–594, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  94. S. Gupta, M. M. Johnson, R. Murthy et al., “Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival,” Cancer, vol. 104, no. 8, pp. 1590–1602, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. D. A. Osborne, E. E. Zervos, J. Strosberg et al., “Improved outcome with cytoreduction versus embolization for symptomatic hepatic metastases of carcinoid and neuroendocrine tumors,” Annals of Surgical Oncology, vol. 13, no. 4, pp. 572–581, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. A. S. Ho, J. Picus, M. D. Darcy et al., “Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors,” American Journal of Roentgenology, vol. 188, no. 5, pp. 1201–1207, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. C. Proye, “Natural history of liver metastasis of gastroenteropancreatic neuroendocrine tumors: place for chemoembolization,” World Journal of Surgery, vol. 25, no. 6, pp. 685–688, 2001. View at Publisher · View at Google Scholar · View at Scopus
  98. Y. P. Le Treut, E. Grégoire, J. Belghiti et al., “Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report,” American Journal of Transplantation, vol. 8, no. 6, pp. 1205–1213, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  99. F. G. I. van Vilsteren, E. S. Baskin-Bey, D. M. Nagorney et al., “Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival,” Liver Transplantation, vol. 12, no. 3, pp. 448–456, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  100. Y. P. Le Treut, J. R. Delpero, B. Dousset et al., “Results of liver transplantation in the treatment of metastatic neuroendocrine tumors: a 31-case French multicentric report,” Annals of Surgery, vol. 225, no. 4, pp. 355–364, 1997. View at Publisher · View at Google Scholar · View at Scopus
  101. B. Dousset, O. Saint-Marc, J. Pitre, O. Soubrane, D. Houssin, and Y. Chapuis, “Metastatic endocrine tumors: medical treatment, surgical resection, or liver transplantation,” World Journal of Surgery, vol. 20, no. 7, pp. 908–915, 1996. View at Publisher · View at Google Scholar
  102. T. Lehnert, “Liver transplantation for metastatic neuroendocrine carcinoma: an analysis of 103 patients,” Transplantation, vol. 66, no. 10, pp. 1307–1312, 1998. View at Scopus
  103. W. O. Bechstein and P. Neuhaus, “Liver transplantation for hepatic metastases of neuroendocrine tumors,” Annals of the New York Academy of Sciences, vol. 733, pp. 507–514, 1994. View at Publisher · View at Google Scholar · View at Scopus
  104. D. Routley, J. K. Ramage, J. McPeake, K. C. Tan, and R. Williams, “Orthotopic liver transplantation in the treatment of metastatic neuroendocrine tumors of the liver,” Liver Transplantation and Surgery, vol. 1, no. 2, pp. 118–121, 1995. View at Scopus
  105. W. C. Blonski, K. R. Reddy, A. Shaked, E. Siegelman, and D. C. Metz, “Liver transplantation for metastatic neuroendocrine tumor: a case report and review of the literature,” World Journal of Gastroenterology, vol. 11, no. 48, pp. 7676–7683, 2005. View at Scopus
  106. V. Mazzaferro, A. Pulvirenti, and J. Coppa, “Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation?” Journal of Hepatology, vol. 47, no. 4, pp. 460–466, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  107. S. K. Reddy and B. M. Clary, “Neuroendocrine liver metastases,” Surgical Clinics of North America, vol. 90, no. 4, pp. 853–861, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus