Navigating the landscape of liver transplantation in neuroendocrine tumors: A comprehensive scoping review

Abstract

BACKGROUND

Neuroendocrine tumors (NET) are rare neoplasms with heterogeneous biological behavior. Although in these scenarios surgical resection can result in favorable outcomes, a considerable proportion of patients are not candidates for this modality due to extensive liver involvement. In these scenarios, liver transplantation (LT) may be a therapeutic alternative for these patients.

AIM

To map the main evidence for the role of LT in NET. Analyze evidence and other possible therapies.

METHODS

A review of LT for hepatic metastatic NET. MEDLINE-PubMed, Lilacs, and Cochrane Library were searched. For MEDLINE-PubMed MESH-terms used were [“Neuroendocrine Tumors” (MeSH Terms)] OR “Neuroendocrine Tumors” (All Fields)] AND [“Liver Transplantation” (MeSH Terms) OR “Liver Transplantation” (All Fields)]. Cochrane Library search: (“neuroendocrine tumors” AND “liver transplantation”). Lilacs search: (neuroendocrine tumor) AND (liver transplantation). Articles were selected based on the person-centred care framework. Two independent reviewers (Oliveira EC, Zanini LK) performed selection and quality assessment, with a third (Nacif LS) resolving disagreements.

RESULTS

After applying the inclusion and exclusion criteria based on the acronym person-centred care. A total of 73 articles out of 513 articles: 498 in MEDLINE, 12 in Cochrane, and 3 in LILACS. The last search was conducted in February 2025. No randomized controlled clinical trials or systematic reviews based on clinical trials were identified. We identified 14 reports or case series, 3 commentaries or letters to the editor, 22 retrospective cohorts, 29 narrative reviews, and 5 systematic reviews with diverse populations and based on observational studies.

CONCLUSION

LT may represent a significant benefit in overall survival for adult patients with liver metastases from NET who are not candidates for curative resection.

Key Words: Neuroendocrine tumors; Liver transplantation; Liver neoplasms; Neoplasm metastasis; Hepatectomy

Core Tip: Liver transplantation is an established but uncommon treatment for patients with unresectable liver metastases from neuroendocrine tumors. This scoping review mapped the available evidence, identifying 73 studies (case series, retrospective cohorts, and reviews). Reported outcomes suggest improved overall survival in selected patients compared to non-transplant strategies, although data heterogeneity and the lack of high-level evidence limit definitive conclusions. Our findings highlight the need for prospective, multicenter studies and standardized selection criteria to optimize patient outcomes and better define the role of transplantation in this setting.

INTRODUCTION

Neuroendocrine tumors (NET) are rare neoplasms with uncertain biological behavior, whose most common site of metastasis is the liver[1]. Hepatic metastatic involvement often presents diffusely, making resection impossible[1,2]. This leads to a worsening of patients’ quality of life due to endocrine syndromes and decreased survival[2-4]. In this context, liver transplantation (LT) has emerged as a potential treatment modality for selected patients with unresectable liver metastases[1]. LT offers the possibility of cure or substantial improvement of symptoms, especially for those with difficult-to-control hormonal syndromes[5,6]. However, the exact role of LT and the ideal timing for its performance remain controversial topics in the literature. The scarcity of robust data, the heterogeneity of cases, and the high rates of post-transplant recurrence contribute to this uncertainty[7,8]. Unlike a systematic review, which would have a more specific focus, such as evaluating the effectiveness of the intervention, this scoping review aims to discuss and critically analyze the experience and results of LT for NET metastases, based on the current literature. We seek to clarify the role of LT as a therapeutic option in a multimodal treatment setting, highlighting the need for rigorous patient selection to maximize benefits and justify the use of limited resources, especially donor organs.

MATERIALS AND METHODS

A scoping review on neuroendocrine tumors and LT was performed. MEDLINE-PubMed, Lilacs, and Cochrane Library databases were searched electronically.

Study identification and selection

For MEDLINE-PubMed MESH-terms used were [“Neuroendocrine Tumors” (MeSH) Terms] OR “Neuroendocrine Tumors” (All Fields)] AND [“Liver Transplantation" (MeSH Terms) OR “Liver Transplantation” (All Fields)]. Cochrane Library search: (“neuroendocrine tumors” AND “liver transplantation”). Lilacs search: (neuroendocrine tumor) AND (liver transplantation). Two independent researchers (Oliveira EC, Zanini LK) were responsible for the selection. In case of disagreement, a third reviewer decided on the inclusion, exclusion, and quality rating of the articles (Nacif LS). The Rayyan tool[9] was used to select articles, allowing for the identification of duplicate articles and blinded selection.

PCC - inclusion and exclusion criteria

Articles were selected based on the PCC framework (Table 1).

Table 1 Person-centred care structure.

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Population	Adult patients with confirmed hepatic metastatic neuroendocrine tumors from portal vein drainage sites
Concept	Liver transplantation, evaluating overall survival and tumor recurrence
Context	Any clinical or geographical setting, comparing transplantation to conventional treatments or no intervention

Population: Adult patients with confirmed hepatic metastatic neuroendocrine tumors from portal vein drainage sites. Neuroendocrine tumors of portal drainage without restrictions were considered and included: Tumors of the small intestine, cecal appendix, colon, upper rectal portion, stomach, pancreas, and duodenum. Other rarer tumor entities were also accepted, such as neuroendocrine tumors of the gallbladder, neuroendocrine cholangiocarcinoma, and neuroendocrine tumors of the spleen or mesentery.

Concept: LT, evaluating overall survival (OS) and tumor recurrence.

Context: Any clinical or geographical setting, comparing transplantation to conventional treatments or no intervention. The comparative approaches were broad, ranging from surgical to pharmacological approaches, such as hepatectomy, somatostatin analogs, molecular targeted therapies (everolimus, sunitinib), peptide receptor radionuclide therapy (PRRT), and regional therapies (ablation, chemoembolization, and radioembolization).

Articles on the pediatric population were excluded, accepting only patients aged 18 years or older. A narrative synthesis of the information was performed based on the articles selected. Articles were included without language or study design restrictions. Articles that were not compatible with the PCC proposed for this study were excluded. The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist was followed[10].

RESULTS

The search resulted in 73 articles selected out of 513 articles: 498 in MEDLINE, 12 in Cochrane, and 3 in LILACS. The last search was conducted in February 2025. No randomized controlled clinical trials or systematic reviews based on clinical trials were identified. We identified 14 reports or case series (19,1%), 3 commentaries or letters to the editor (4,1%), 22 retrospective cohorts (30,1%), 29 narrative reviews (39,7%), and 5 systematic reviews (6.8%) with diverse populations and based on observational studies. The selection process was represented in a flowchart (Figure 1). The clinical presentations and populations found in the articles were diverse. The systematic reviews[11-15] and the most relevant retrospective cohort studies were represented in a table summarizing the outcomes and populations (Table 2).

Figure 1 Flowchart selection criteria.

Table 2 Systematic reviews identified in the search and the most relevant retrospective cohort studies.

Study design	Ref.	n	Population	Comparison	Outcome
Systematic reviews	Moris et al[11], 2017	279 patients transplanted for NET with liver metastases in the combined series	Patients with NET liver metastases, with unresectable diffuse disease or extensive liver disease	Liver transplantation vs non-surgical treatments; prognostic comparison by histological grade, liver involvement, Ki-67, pancreatic vs gastrointestinal primary	Overall survival at 1, 3, and 5 years: Approximately 89%, 69%, 63%; high recurrence rates (31%-57%) depending on criteria; negative prognostic factors include elevated Ki-67, > 50% liver involvement, pancreatic primary
	Fan et al[12], 2015	706	Adult patients with liver metastases from unresectable NETs undergoing liver transplantation	Liver transplant vs palliative resection or non-surgical treatment	Overall survival (5 years approximately 50%-70%), disease-free survival (30%), prognostic factors (age > 50, pancreatic primary, high Ki-67, poor differentiation, > 50% liver involvement)
	Rossi et al[13], 2014	213	Patients with gastroenteropancreatic NETs with well-differentiated liver metastases, well-defined selection criteria (Ki-67 < 10%, age < 55, stable disease, resected primary tumor, < 50% of the liver involved)	Liver transplantation vs no transplantation; comparison between different selection criteria (location of the primary tumor; degree of differentiation, liver involvement, pre-LT stability)	5-year survival rate up to approximately 90% in well-selected cases; but tumor recurrence remains a problem; beneficiaries are patients with removed primary tumors, low proliferation, and stable disease
	Stump et al[14], 2013	Without a defined n	Adult patients with NET liver metastases (resectable and unresectable)	Liver resection vs non-surgical treatment; LT vs other therapies; resection of the primary tumor vs non-resection	Planned outcomes: Overall survival, progression-free survival, quality of life; establish selection criteria and impact of adjuvant/neoadjuvant therapies
	Máthé et al[15], 2011	89	Patients undergoing liver transplantation for pancreatic neuroendocrine metastases	Various comparators, such as the type of neoplasm and simultaneous resections	Following liver transplantation, the cumulative overall survival rates at 1, 3, and 5 years were 71%, 55%, and 44%, respectively; VIPomas exhibited the highest overall survival. Recurrence-free survival rates at 1, 3, and 5 years were 84%, 47%, and 47%, respectively
Retrospective cohort	Sampaio et al[1], 2023	11 LT due to NET metastasis	Eight patients with NETs of gastrointestinal origin and three with unknown primary sites	No comparison group	LT was favorable in terms of overall survival and disease-free survival in selected patients. Strict patient selection is necessary. The ideal timing for transplant indication remains controversial
	Kuncewicz et al[17], 2023	19 LT of unresectable NET	19 patients undergoing LT from the pancreatic site	No comparison group	Ki-67 index ≥ 5% is a risk factor for worse OS, and RFS recipient age ≥ 55 years for worse RFS; Ki-67 ≥ 5% is a factor for worse OS
	Eshmuminov et al[27], 2023	455 patients included in hepatectomies and LT	225 patients undergoing LT for NET	230 patients undergoing liver resections	Improved OS in LT; this effect depends on the selection criteria (Milan criteria and low-grade tumor)
	Maspero et al[33], 2022	104 patients diagnosed with NET	48 patients in the LT group - only patients meeting the Milan criteria were included	56 patients in the liver resection group	The LT group showed improved survival compared to the liver resection group
	Korda et al[7], 2019	10 LT due to NET metastasis	Patients transplanted due to NET metastasis	No comparison group	Primary pancreatic lesions and elevated Ki67 are associated with higher recurrence rates
	Mazzaferro et al[25], 2016	88 patients with NET meeting the Milan criteria for liver transplantation	42 patients undergoing LT	44 non-surgical treatment options	LT in patients with NET metastasis, in patients with established criteria show excellent OS
	Grąt et al[32], 2014	12 patients with NET metastasis undergoing LT	Patients undergoing LT due to unresectable NET	No comparison group	Excellent long-term OS survival rate in unresectable NET
	Le Treut et al[23], 2013	213 LT for NET performed in 35 European centers	Patients undergoing LT due to unresectable NET	No comparison group	LT in non-resectable NET showed OS at 5 years between 60%-80%; the appropriate timing for transplantation remains uncertain

NET: Neuroendocrine tumor; LT: Liver transplantation; OS: Overall survival; RFS: Recurrence-free survival.

DISCUSSION

Neuroendocrine tumors are rare and have uncertain biological behavior[1,16]. The liver is the most common site of metastasis, occurring in approximately 50% of patients with metastatic disease[16-18]. In individuals where the disease is restricted to the liver but cannot be resected, LT becomes a potentially curative or symptomatic improvement treatment modality, especially in those with hormonal syndromes resulting from the tumor[3,19]. However, due to the high heterogeneity of publications and lack of systematic reviews with a high level of evidence, the indication for LT in these individuals remains controversial in the literature[1,20].

Liver transplant outcomes

LT for NET metastases can offer good OS and disease-free survival (DFS) results in selected patients[12,14,21]. Five-year OS varies considerably between studies, with rates ranging from 33% to 97%[4]. Large registry studies, such as those from the United Network for Organ Sharing and European Liver Transplant Registry databases, report five-year OS rates ranging from 49% to 52%[22,23]. Some studies also suggest a long-term benefit, with 10-year survival reaching 51% to 93% in selected patients[24]. Despite favorable OS, recurrence of the disease after transplantation is a significant concern and one of the greatest clinical obstacles[21,22]. In Sampaio et al[1], DFS at one year and five years in the present study was 72.7% and 36.3%, respectively. This recurrence rate, although considerable, is lower compared to isolated liver resections[1].

Patient selection criteria

There is a worldwide shortage of organs for transplantation, which implies the need for rational use of this resource. High recurrence rates make it necessary to carefully consider and select patients in order to optimize LT outcomes. Mazzaferro et al[25] proposed criteria for establishing the best use of donated organs, the main ones being described below.

Control of the primary tumor: The primary tumor should be resected, ideally before LT, with the site of origin in the gastrointestinal tract drained by the portal system.

Extent of liver involvement: Less than 50% of the liver volume is involved by the tumor.

Histology and differentiation of the tumor: Well-differentiated tumors (grades G1-G2) are preferable. Grade G3 is generally seen as a contraindication[26].

Disease stability: A minimum period of six months of disease stability (or response to therapies) before LT is recommended for a better understanding of the biological behavior of the tumor.

Patient age: Younger patients, typically < 55, indicate a better prognosis.

Ki-67 proliferation index: A low Ki-67 index is a favorable prognostic factor, with suggested limits of < 5%, < 10%. Some studies have excluded patients with Ki-67 ≥ 10%[27].

Some factors remain controversial or have a less clear association with outcomes, such as recipient age in DFS[28], loss of E-cadherin expression[29], the extent of liver involvement[17], and the location of the primary tumor (the location of the primary tumor in the pancreas has been associated with worse outcomes compared to gastrointestinal origin in some studies, leading some authors to contraindicate LT for pancreatic NET)[23].

LT vs other techniques

In patients with resectable neuroendocrine metastatic lesions, surgical resection is conventionally considered the treatment of choice[30]. This approach is associated with excellent long-term survival outcomes, with good five-year OS rates[31]. However, the main limitation of resection is the high recurrence rate, which can be greater than 90%, occurring predominantly in the remaining liver[1]. This high incidence is attributed to the likely presence of micrometastases undetected by preoperative imaging. In this context, LT emerges as a radical alternative for patients with unresectable disease restricted to the liver, as total hepatectomy removes both macroscopic lesions and micrometastases, offering a “true R0” resection[32]. Retrospective comparative studies suggest that, for patients with similar characteristics who meet the Milan criteria, LT offers an advantage in terms of survival and DFS compared to resection[24,31,33].

When compared to non-surgical therapies, LT also demonstrates a survival advantage for selected patients. Non-surgical therapies, such as somatostatin analogs, molecular targeted therapies (everolimus, sunitinib), PRRT, and regional therapies (ablation, chemoembolization, and radioembolization), are predominantly palliative, aiming to control symptoms and slow disease progression[26,31]. (ablation, chemoembolization, and radioembolization) are predominantly palliative, aiming to control symptoms and slow disease progression[26,31]. Five-year survival with these treatments ranges from 25% to 65%, while untreated patients have a survival rate of 20% to 40%[4]. Although the therapeutic landscape has evolved with the advent of PRRT and targeted agents, which were not available in many of the older transplant series, these modalities are not curative, and LT remains a curative option, especially for young patients[24,31].

Challenges and future directions

Despite the optimism, LT for NET faces several challenges. The shortage of donor organs requires careful consideration of its indication. The absence of randomized controlled trials is a significant limitation, with most data coming from retrospective case series. This makes it difficult to prove the superiority of LT over other non-surgical therapies, such as chemoembolization, somatostatin analog therapy, PRRT, and molecularly targeted agents, which have shown significant advances in the treatment of advanced NET. The need to define the role of downstaging and bridging therapy prior to LT is crucial. In addition, the definition of “unresectable” remains ambiguous. The use of living donor LT may also be an alternative to mitigate organ shortage.

CONCLUSION

LT is a treatment modality with good OS and DFS outcomes in selected patients with unresectable liver metastases from neuroendocrine tumors. However, rigorous patient selection is necessary to obtain better results, and the ideal timing for transplantation remains controversial in the literature. The literature lacks randomized clinical trials aimed at establishing evidence of better quality.