Liver transplantation for gastroenteropancreatic neuroendocrine liver metastasis: optimal patient selection and perioperative management in the era of multimodal treatments

Abstract

Gastroenteropancreatic neuroendocrine tumors (NET) often metastasize to the liver. Although curative liver resection provides a favorable prognosis for patients with neuroendocrine liver metastasis (NELM), with a 5-year survival rate of 70-80%, recurrence is almost inevitable, mainly in the remnant liver. In Western countries, liver transplantation (LT) has been performed in patients with NELM, with the objective of complete removal of macro- and micro-NELMs. However, prognosis had been unsatisfactory, with 5-year overall survival and recurrence-free survival rates of approximately 50 and 30%, respectively. In 2007, the Milan criteria were proposed as indications for LT for NELM. The criteria included: (1) confirmed histology of NET-G1 or G2; (2) a primary tumor drained by the portal system and all extrahepatic diseases removed with curative resection before LT; (3) liver involvement ≤50%; (4) good response or stable disease for at least 6 months before LT; (5) age ≤ 55 years. A subsequent report demonstrated outstanding LT outcomes for NELM within the Milan criteria, with 5-year overall survival and recurrence rates of 97 and 13%, respectively. In Japan, living donor LT (LDLT) for NELM has been performed sporadically in only 16 patients by 2021 in Japan; however, no consensus has been reached on the indications or perioperative management of LDLT. This article presents the outcomes of these 16 patients who underwent LDLT in Japan and reviews the literature to clarify optimal indications and perioperative management of LDLT for NELM in the era of novel multimodal treatments.

Keywords: Living donor liver transplantation; Multimodal treatment; Neuroendocrine liver metastasis; Peptide receptor radionuclide therapy.

Fig. 1

LDLT for NELM in Japan. a Annual number of LDLT cases. b Kaplan–Meier OS curve after LDLT for NELM. c Timing of mortality, their potential cause, and their improvement. CI confidence interval, LDLT living donor liver transplantation, MST median survival time, NELM neuroendocrine liver metastasis, OS overall survival

Fig. 2

Screening for LT based on the Milan criteria. *High-grade manifestations include Ki-67 index ≥10% of the primary tumor, discrepantly rapid progression of NELM for the Ki-67 index of the primary tumor, decreased avidity of somatostatin receptor imaging, and increased avidity of ¹⁸F-fludeoxyglucose positron emission tomography. **Extrahepatic metastasis should be ruled out by ⁶⁸Ga-DOTA positron emission tomography. CTA cytotoxic agent, LM liver metastasis, LT liver transplantation, MTA molecular targeted agent, PRRT peptide receptor radionuclide therapy, SSA somatostatin analogue, TACE transcatheter arterial chemoembolization

Fig. 3

Bridging therapy to LT. *CTA is indicated only for pancreatic neuroendocrine neoplasm. CTA cytotoxic agent, LI liver involvement, LT liver transplantation, MTA molecular targeted agent, PD progressive disease, PRRT peptide receptor radionuclide therapy, SD stable disease, SSA somatostatin analogue