Orthotopic liver transplantation (OLT) represents a generally accepted albeit somewhat controversially discussed therapeutic strategy in highly selected patients with non-resectable hepatic metastases from neuroendocrine tumours (NET). Whilst there are some exclusion criteria, these are not universally followed, and the optimal set of inclusion parameters for deeming patients eligible has not yet been elucidated. This is due to heterogeneity in the study populations, as well differing approaches employed and also divergences in selection criteria between centres. Recent data have suggested that OLT may represent the most efficacious approach in terms of overall and disease-free survival to the management of NET metastatic to the liver when conducted in accordance with the modified Milan criteria. Therefore, a consensus set of selection criteria requires definition to facilitate stringent and fair allocation of deceased-donor organs, as well as consideration for living-donor organs. In the context of classically non-resectable metastatic tumour bulk, multivisceral transplantation with or without the liver may also be indicated, yet experience is very limited. In this review, we discuss the diagnostic work-up of patients in whom the aforementioned transplantation approaches are being considered, critically analyse the published experience and also anticipate future developments in this field, including a discussion of immediate and longer-term research priorities.

Representing an increasingly prevalent class of neoplasms, neuroendocrine tumours (NET) display protean clinical manifestations, and those arising from the lung, pancreas and bowel possess a particular proclivity for metastasis to the liver. Up to 90% of small bowel NET display evidence of at least nodal metastasis at initial diagnosis[1], and the incidences of liver metastases (LM) in small bowel and pancreatic NET treated at specialist centres range between 67%-91% and 28.3%-77%, respectively[2,3]. The liver is the sole location of distant oligo-metastatic disease in approximately half of all NET[4] and their presence has markedly detrimental impact on the long-term survival of NET patients, thus conferring great significance on the management of neuroendocrine liver metastases (NELM)[5-7].

Therapeutic strategies for NELM may incorporate surgical approaches, i.e., resection with curative or palliative intention, peptide receptor radionuclide therapy, liver-directed trans-arterial or percutaneous treatments and medical therapies[8]. Hepatic surgery is the only approach offering potential cure, and resection of liver deposits if attainable has classically been held as the first-line modality conferring the best survival outcomes[8]. However, cure is rarely realised even with complete elimination of the hepatic tumour burden as patients almost invariably develop recurrent disease, and resection should be regarded in most to be a palliative endeavour. Under the premises of complete resection of the primary tumour and loco-regional lymph node metastases , the radical approach of total extirpation of the liver with unresectable NELM in the context of orthotopic liver transplantation (OLT) has re-gained attention as outcomes continue to improve. In fact, stringently selected patients undergoing OLT may actually attain the most favourable survival outcomes, based on recent data from Mazzaferro and his group following the modified Milan (‘Milan NET’) criteria[9]. However, there is great divergence in the selection criteria followed at different centres, and a recent systematic review of retrospective case series calculated a median overall survival at 1-, 3-, and 5-years of 89%, 69% and 63%, respectively[10].

Multivisceral transplantation (MVT) with or without the liver (i.e., modified [M]MVT)[11] is a seldom utilised approach for highly selected patients with extensive metastatic burden, either in those with pancreatic head tumours and LM[12], or potentially some patients with no LM but extensive mesenteric lymph node metastases threatening vascular supply to the gut by encasement of mesenteric vessels[13,14]. Again, recent data suggest improving outcomes over time with such approaches involving intestinal allografts[15] and therefore these could be more widely utilised in the near future.

In this review, we provide an overview of the diagnostic work-up of patients with NELM being considered for transplantation, specifically the power of both functional and morphological imaging in patient selection. Thereafter, we provide a critical analysis of the reported outcomes from OLT and MVT/MMVT and conclude with discussion of future perspectives in this burgeoning field.

Liver transplantation may be offered to patients with metastases of low- or intermediate grade (G1/2) NET (Ki67 of < 20%[16]) confined to the liver without extra-hepatic metastases, unless these are themselves resectable[8]. Up to 80% of NELM display diffuse multifocal and bilobar spread, and are therefore not amenable for standard resections with curative attempt[17]. In patients with non-miliary metastases but nevertheless conventionally non-resectable hepatic disease, advanced surgical procedures such as ALPPS may be considered to offer chance of resection via a two-stage approach[18,19]. Accordingly, meticulous selection of patients with advanced NET for transplantation approaches relies on the use of high quality imaging strategies to accurately depict disease burden, with emphasis both on the distribution of disease within the liver, but especially also possible extra-hepatic deposits as these could render a patient ineligible for transplantation (Figure 1A-C). Morphological and functional imaging modalities have important roles in the evaluation of NET and their metastases.

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Figure 1 Multimodality imaging in a patient with neuroendocrine liver metastases considered for transplantation. A: Magnetic resonance imaging of the liver in a patient with hepatic metastases from a small bowel neuroendocrine tumour. This patient underwent resection of the primary tumour, and then a left hepatectomy. Following post-hepatectomy lanreotide, peptide receptor radiotherapy and also selective internal radiotherapy for recurrent hepatic metastases, this patient was considered for orthotopic liver transplantation. There was no extra-hepatic disease on conventional cross-sectional imaging. B: ⁶⁸Ga-DOTATATE PET/CT in the same patient. Multiple foci of increased avidity are demonstrated within the liver that were not appreciated on magnetic resonance imaging. C: Radiotracer uptake corresponding to one of multiple bone metastases. According to standard criteria, these would exclude this patient from orthotopic liver transplantation.

As most NELM are hypervascular, computed tomography (CT) imaging must include hepatic arterial phases[20]. Furthermore, diffusion-weighted magnetic resonance imaging (DW-MRI) should be systematically performed in any evaluation of NELM as it possesses the highest specificity of all MRI phases, even in tumours < 1 cm in size[21].

Functional imaging with positron emission tomography (PET) using 68-gallium radiolabelled DOTA peptides combined with CT (e.g., ⁶⁸Ga-DOTATATE or ⁶⁸Ga-DOTATOC PET/CT) represents the gold standard approach in G1/G2 NET as it may detect lesions that morphological imaging modalities cannot, as well as those not identified by somatostatin-receptor scintigraphy with ¹¹¹In-conjugated radiopharmaceuticals[21-23]. Imaging with ⁶⁸Ga-DOTA PET/CT detects NELM with a sensitivity between 82%-100%, a specificity of 67%-100%, and also detects extra-hepatic disease with a sensitivity of 85%-100% and a specificity of 67%-90%[23]. In fact, a major proportion of the power of ⁶⁸Ga-DOTA PET/CT in terms of surgical selection is in its ability to identify extra-hepatic disease that is capable of altering clinical strategies[24,25], which is especially relevant when considering visceral transplantation.

Novel radiotracers for PET/CT, such as those using 64-copper have shown promising results comparable to ⁶⁸Ga-DOTA , although they are not in wide circulation as of yet[26]. The archetypal oncological radiotracer ¹⁸F-FDG is widely used in the imaging of adenocarcinomas, and there is increasing evidence to support its implementation in the radiological work-up of NET patients alongside ⁶⁸Ga-DOTA PET to assess the metabolic activity of tumours which correlates with disease aggressiveness and prognosis[27]. However, one may argue that there is limited (if any) role of ¹⁸F-FDG PET/CT in NET patients as part of pre-transplant work-up as lower-grade disease is the sine qua non for consideration of this approach. Additional radiotracers have also been assessed in cohorts of NET patients, especially in European centres, specifically ¹⁸F-DOPA and ¹¹C-5-hydroxytryptophan[28,29]. However, experience with these tracers is limited, and can at present only be recommended as part of investigative studies, or as an adjunct to lessen radiological uncertainty when there are inconclusive findings with ‘standard’ functional imaging.

Alongside detailed radiological depiction of disease status, patient functional status and relevant co-morbidities must also be evaluated in the overall assessment of patients being considered for transplantation. Carcinoid heart disease (CHD) manifests as fibrous endocardial thickening involving cardiac valves and sub-valvular apparatus, particularly in the right heart. It has an incompletely elucidated aetiology but is presumed to be linked to excessive circulating vasoactive substances secreted by NET, and exerts considerable morbidity and mortality in NET patients. Transthoracic echocardiography is the gold-standard modality for assessment of cardiac function in patients suspected of having/at risk of CHD[30]. Furthermore, untreated CHD is an accepted contraindication for OLT, and should be treated before OLT, or even any hepatic surgery is planned[30].

Patients with advanced NET considered for transplantation require extensive evaluation. This includes assessment of their anaesthetic risk and co-morbidity profile, including specific emphasis on the presence (and if applicable, treatment of) carcinoid heart disease, which is a contraindication to transplantation. Radiological evaluation of disease should include CT (hepatic arterial phase), MRI (especially DW-MRI) and if available, ⁶⁸Ga-DOTA PET/CT. The latter is essential in patients considered for liver transplantation as it enables the best opportunity for the depiction of extrahepatic disease which could invalidate this form of approach. As it represents the gold-standard imaging modality in NET, ⁶⁸Ga-DOTA PET/CT is also most useful in patients considered for intestinal/multivisceral transplantation.

Curative (R0) resection of NELM may be associated with the most favourable survival outcomes in reported retrospective series however is subject to significant limitations[8,31-33]. First, approximately 80% of patients with NELM will not be eligible for this approach due to the anatomical distribution of hepatic disease burden abrogating the feasibility of radical surgical tumour elimination[17]. Second, to what extent R0 resection is actually associated with favourable outcomes cannot be confidently assessed given that studies are retrospective and thus outside the auspices of randomised trials, and that whilst patients are highly selected, the selection criteria themselves are often very poorly defined, if at all[34]. Essentially, the effects of favourable tumour biology and favourable patient characteristics, such as co-morbidity profiles are impossible to disentangle from the reported outcomes due to this selection bias. Third, even in patients undergoing hepatectomy/other hepatic resection with curative intent, vertiginous rates of recurrence are clearly recognised[8,33], to the extent that disease recurrence should not only be considered, but actively expected. The juxtaposition of favourable overall-survival against starkly poor disease/recurrence-free survival in hepatic resection is attributable to most likely the presence of undetected micro-metastases that given the relative indolence of NET, clinically manifest over a protracted period of time. Current gold-standard imaging modalities understage disease burden by 50% when compared with meticulous pathological examination[35], thus explaining the clinical reality that resection with curative intent is almost always a palliative endeavour, albeit an excellent one in terms of significant improvement in the duration of patient overall survival.

Therefore, OLT represents an attractive paradigm for radical therapy of NELM, insofar as total hepatectomy with subsequent transplantation theoretically offers complete resection of both macro- and micro-metastatic disease burden at a single time-point. This approach is heavily debated and rarely utilised (just over 700 patients)[36], and represents only 0.2%-0.3% of all liver transplants recorded in US/European liver transplant registries[37,38]. Table 1 summarises recent published experience from selected series.

There is growing evidence to support consideration of wider implementation of OLT in NET. However, major obstacles include the already heavy demands on deceased-donor livers for non-malignant conditions and also HCC, as well as the limited use of living-donor liver transplantation (LDLT) outside of Asia, where LDLT accounts for up to 60%-90% of all liver transplant activities in some countries[39]. The use of LDLT of course introduces complex ethical considerations, such as risks of morbidity and perhaps even mortality to the healthy donors.

Intestinal transplantation (IT) has gained acceptance as a standard therapeutic strategy in patients with intestinal failure failing rehabilitation, diffuse portal thrombosis or other intra-abdominal catastrophe, but has also been performed in patients with non-resectable, slow-growing tumours encasing the mesenteric root as this threatens the vascular supply to the gut[15,48,49]. Transplantation of the intestines may be within the context of simultaneous transplantation of the stomach, duodenum, pancreas and small bowel with (multivisceral transplantation, MVT) or without the liver (modified MVT, MMVT)[11]. Experience with this radical approach in neuroendocrine tumours is incredibly limited to either case reports or to small numbers within cohorts composed predominantly of patients undergoing OLT[13,37,38,50]. In this setting, patients either have pancreatic head tumours, and/or bulky metastatic load within the small bowel mesentery.

Less than 20% of all NET patients undergoing liver transplantation also receive additional organs – in the aforementioned systematic review of Moris et al[10] only 5.7% of transplants (16/279) outside the largest registry reports/multicentric series receive a multi-organ allograft. The multicentre series of Sher et al[51] included 17 patients (total 85, 20%) undergoing a multivisceral transplantation and reported overall survival rates at 1-, 3- and 5-years of 81%, 40% and 40%, respectively. These were lower than those undergoing OLT, however not significantly so. Thirteen of the 150 patients reported by Gedaly et al[37] (8.7%) received additional organs alongside the liver, however the survival data specifically for this sub-set of patients was not clearly detailed as the authors merely stated that on inclusion of MVT cases, the cohort OS data did not change significantly. Lastly, the published data from Nordic centres have described a 2-year overall survival of 67% in 6 patients with pancreatic head NET that underwent intestinal transplantation within a multivisceral graft, which was not inferior to the outcomes from those transplanted for intestinal failure[12].

Clearly, reports of IT/MVT/MMVT in NET are limited by: (1) The small numbers of patients transplanted; (2) the inconsistent quality of outcome reporting and selection criteria in publications; and (3) the inclusion of multiple indications in single publications (often including non-malignant indications).

Nevertheless, as outcomes continue to improve for IT/MVT/MMVT, one may anticipate a cautiously managed expansion of the number of patients with advanced NET being considered for and undergoing such procedures. As with OLT, emergent concepts will include the optimisation of patient selection criteria, as well as innovative neoadjuvant/adjuvant concepts to abrogate disease recurrence and monitor for allograft dysfunction. For example, recent case reports have detailed the use of everolimus post-MVT in 2 NET patients in attempts to suppress recurrence whilst avoiding the nephrotoxicity of calcineurin inhibitors[52], as well as the use of PRRT to stabilise disease prior to MMVT which also included simultaneous transplantation of a sentinel skin flap from the organ donor to aid monitoring of rejection and tailoring of immunosuppression regimens[13].

Intestinal/multivisceral/modified multivisceral transplantation has been utilised in a very small number of patients with advanced NET worldwide. Case series tend to be small yet highly heterogeneous in terms of patient inclusion, and outcome reporting is of varying quality. Nevertheless, innovative approaches continue to be described in the setting of such advanced surgical procedures.

For patients with well-controlled, G1/G2 neuroendocrine tumours, transplantation approaches may be valid therapeutic strategies in those with classically non-resectable metastases confined to the liver (OLT) and/or bulky mesenteric tumour load threatening the vascular supply to the gut (IT/MVT/MMVT). It is generally advised that the primary tumour and any attendant locoregional lymph node metastases be resected prior to undergoing OLT, and there is a suggestion that longer wait times/observance period prior to transplant to monitor for disease stability, although this is not based on high-quality evidence[9,36]. It is debatable if small volume bone metastases are necessarily a contra-indication to transplantation given that they may be well-controlled with PRRT.

Patients are stringently selected in accordance with a mixture of criteria that are either well defined, or barely documented. As with the NET clinical arena in general, the majority of data available to inform modern clinical practice is derived from retrospective case series of varying quality in their reporting. Prospective studies and randomised clinical trials of surgical treatment for NET are logistically challenging given their relative rarity and relative indolence requiring prolonged follow-up, even before considering the difficulties in randomisation of surgical therapy. Transplantation approaches in NET are subject to the same difficulties. Decision making such as expanding the criteria/exceptions of transplant co-ordinating institutions to include NELM will rely on sound identification of patients most suitable for receiving donated organs which in turn can expect the best outcomes. This is mandated in the context of limited yet heavily demanded availability of deceased donor organs and also limited use of LDLT outside of Asia. Therefore, at least in the short-to-medium terms, such decision making must be based on analyses of the currently available data which is mostly of a retrospective nature. Collaborations such as registries and inter-institutional initiatives will enable statistical analysis of ever-larger pooled patient cohorts. Going forward, the non-mutually exclusive NET and surgical communities must recognise the shortcomings thus far experienced in data reporting in order to improve current and future data collection for use in novel informative projects.

In order to counteract the previously discussed deficiencies in data reporting and also facilitate inter-centre collaboration in the analysis of larger cohorts, we propose that each of the following be documented at an individual patient level within institutional databases, and be available to collaborators, notwithstanding ethical approval for the secure sharing of such data:

(1) Indication for transplantation and timing – time between diagnosis and transplantation, duration of disease stability prior to OLT/MVT.

There is a need to clearly distinguish at which point during the patient journey that the best outcomes may be attained. Patients undergoing OLT when disease is controlled with therapy are posited to derive true benefit with excellent survival. Whilst it is suspected that patients undergoing OLT/MVT as an ultima ratio approach will have poorer outcomes, i.e. marginal life gains, this needs to be categorically confirmed and also judiciously analysed as a possibly legitimate ‘salvage’ option.

Reports suggest that the observation of tumour behaviour for 6 months to ensure disease control is associated with preferable outcomes in OLT. This needs to be clearly documented in larger numbers. Such data also add to the temporal treatment trajectory of individual patients, which may be complex as transplant patients are often heavily ‘pre-treated’. Clear comparisons will only be valid when results are interpreted in the context of the ‘patient journey’.

(2) Clinicopathological characteristics – especially age at transplantation, Ki67 index, hepatic tumour burden (if applicable), clinical syndromes, grade and differentiation of primary tumour and metastases, disease stage (including other metastatic sites and treatment for these), surgical histopathology results (margin and lympho/vascular invasion) and patient co-morbidities.

Optimised selection criteria in the short-to-medium term will likely be developed by multivariable analyses of individual-level data accrued from disparate centres, and clinicopathological characteristics are often reliable arbiters of tumour behaviour and thus patient outcomes. Therefore, clear documentation of parameters that are potentially predictive/prognostic in nature is essential.

(3) Selection criteria – e.g. compliance with Milan NET criteria, or other institutional protocols; imaging modalities and patient-specific parameters for disease assessment.

As aforementioned, selection criteria for surgical intervention are typically very poorly documented, confounding the collation and interpretation of multi-centric data. Whilst the Milan-NET criteria are clearly followed in its respective centre, whether or not alternative protocols are used versus collective multidisciplinary decision making should be documented.

(4) Use of neoadjuvant/adjuvant concepts: Despite excellent results from one centre that does not appear to have utilised post-operative prophylaxis against disease recurrence, whether or not such strategies have been/should be employed in other centres has not been documented clearly. As previously discussed, medical therapies with anti-proliferative/anti-tumour effects could theoretically be useful in disease stabilisation prior to transplant, or to reduce the risks of post-transplant recurrence. This must be clearly delineated from pre-transplant treatment and treatment for post-transplant recurrence. The use of such concepts may be included in multivariable analyses to examine for associations between their utilisation and outcomes (or lack thereof/thereon).

Lastly, it is becoming increasingly clear that multifactorial assessment of neuroendocrine tumour characteristics have tangible benefits in not only prognostication[53], but also detection of recurrence[54,55] and prediction of response to treatment[56]. Novel markers developed from ‘omics’-based technologies, such as the multi-analyte NETest are able to predict outcomes from PRRT and also disease recurrence, and therefore possibly offer improved selection and impact follow-up decisions[56,57]. Precise molecular definition of patient-specific neuroendocrine tumour biology may also have ramifications on patient selection for surgery or transplantation, as well as monitoring for detection of recurrence possibly before lesions are detectable on imaging. Such techniques should also be investigated within the remit of transplantation for advanced NET.