Patients with neuroendocrine tumors with unresec-table liver involvement can benefit from liver transplant. There is a specific set of guidelines for neuroendocrine tumors with liver metastasis that involve less than 50% of the liver. However, beyond those guidelines, there are reports of exceptional criteria patients who benefited from liver transplant. Here, we present 2 unusual cases of patients with exceptional circumstances and with neuroendocrine tumors who underwent liver transplant. The first case describes a patient with an extremely rare neuroen-docrine tumor of the proximal common bile duct that caused liver biliary cirrhosis. The patient underwent tumor resection and liver transplant concurrently. The second case describes a patient with a neuroendocrine tumor of unknown primary origin with more than 50% hepatic involvement who received a liver transplant after downstaging. In our center, patients with unresectable hepatic metastases from neuroendoc-rine tumors are currently selected for liver transplant based on well-established criteria. However, these 2 cases did not meet the criteria for consideration of liver transplant; thus, multidisciplinary team sessions were held to discuss these 2 cases. After a period of nonsurgical treatment and evaluation of the tumor behavior, we selected the patients as candidates for liver transplant based on the favorable tumor behavior and favorable response to treatment. For both patients, we did not observe any signs of tumor recurrence during follow-up. The outcomes were acceptable, and the patients tolerated treatment well. Considering the favorable tumor pathology (G1 phase and low Ki67 index), we suggest that more studies should be conducted to evaluate the outcomes of patients with low-grade tumors and that the criteria for patients with low-grade tumors could be extended based on such future data.

Key words : Biliary cirrhosis, Common bile duct, Liver metastasis, Neuroendocrine disease

Introduction

Approximately 5% of all malignant tumors of the gastroenteropancreatic system are neuroendocrine tumors (NET).¹ The incidence of NET has increased to more than 5 cases per 100 000 population per year over the past decade.¹ These tumors can be classified as pancreatic NET and carcinoid tumors, and the biologic characteristics can vary from indolent well-differentiated tumors to undifferentiated malignan-cies with poor prognosis.¹ Approximately 12% to 27% of all patients with NET have distant metastasis at initial diagnosis, which increases to more than 40% during the follow-up period.² The most frequent site of distant metastasis is the liver.^3,4 In most cases, the metastases are multiple and involve the liver bilaterally before symptoms arise.⁵ These tumors grow slowly and are confined to the liver for long periods.⁶ Metastatic disease has a negative impact on survival, and patients who present with distant metastasis are 4 times more likely to die versus patients with localized disease.⁴

There are several treatment options for metastatic liver NET, but the best option remains a subject for debate.⁷ Surgery (hepatic resection), liver-directed therapies, and systemic therapies are 3 categories of therapeutic options.² Generally, surgery is the treatment of choice for patients with NET with hepatic metastasis.^8,9 However, approximately 20% of patients are eligible for curative hepatic resection because, in most cases, the liver involvement is diffuse and multilobar.^10,11 Other therapeutic options are pharmacologic therapy (eg, somatostatin analogues, interferon), chemoembolization, hepatic-artery embolization, radiofrequency ablation, and cryosurgery.¹² Nonoperative management has a low response rate and does not appear to increase survival. On the other hand, surgery is the only chance for extended survival and enhanced quality of life.⁶

Although surgery with curative purpose is considered the best treatment choice for eligible patients, as indicated in international guidelines, liver transplant for unresectable liver metastases is advocated as an alternative treatment option; however, its impact and role remain controversial.² Patients with diffuse liver metastases for whom the primary tumor has been removed could be candidates for liver transplant.¹³ Due to the limited number of published reports of liver transplants for patients with NET with liver metastases, as well as the lack of perspective and randomized trials, the selection criteria and timing for transplant remain uncertain.⁷

In this article, we present 2 unusual cases of patients with NET who underwent liver transplant with exceptional circumstances. The first case describes a patient with an extremely rare NET of the proximal common bile duct that caused liver biliary cirrhosis. The patient underwent tumor resection and liver transplant concurrently. The second case describes a patient with NET of unknown primary origin with more than 50% hepatic involvement who received liver transplant after downstaging.

Case Report

Case 1

A 37-year-old female patient presented with itching, jaundice, and cholangitis at the age of 31 years. The initial assessment was by ultrasonography, which showed a mass in the liver hilum. Endosonography revealed a mass in the hilar region that extended to the right and left secondary orders of bile ducts. The results of an endoscopic ultrasonographic fine-needle aspiration biopsy were in favor of a low-grade NET of the bile duct (NET grade 1; tumor cells positive for Ki67 nuclear antigen [Ki67 index] = 2%). The initial computed tomography (CT) scan showed signs of portal hypertension and splenomegaly (Figure 1a). A liver biopsy confirmed chronic bile duct obstruction along with liver fibrosis. Therefore, surgical resection was excluded as a treatment option because of liver fibrosis and the tumor extent. Endoscopic retrograde cholangiopancreatography with biliary stenting was conducted to address the bile duct obstruction; thus, additional workups were performed (Figure 1b). A gallium Ga-68 dotatate radiopharmaceutical positron emission tomography (PET)-CT scan showed the previously identified tumor in the hilum of the liver, with no additional uptake around the body.

The results of other evaluations, including upper gastrointestinal endoscopy, colonoscopy, and whole-body scans, were all unremarkable. Therefore, the patient was considered as a candidate for liver transplant. Unfortunately, she could not find any relatives for living liver donation, so she was registered on the wait list for a deceased donor liver transplant (Model for End-Stage Liver Disease [MELD] score 8, Child score 5). Table 1 and Table 2 show pretransplant liver function and laboratory data. According to the organ allocation policy of Iran, the patient was not on the priority list for transplant for 2 years. Meanwhile, the patient received octreotide long-acting repeatable (LAR) treatment and was evaluated for any progression in the disease every 3 months. The evaluation immediately before transplant revealed no new lesions, no progression in disease, and no lymphadenopathy. The transplant was conducted without any complications during surgery. On the posttransplant day 7, the patient experienced severe acute cellular rejection (biopsy proven) and was successfully treated by modification of the immunosuppressive drug regimen (Table 3). Two years after the transplant, she became pregnant and gave birth to a healthy baby through cesarean section. Three years after the transplant, she was diagnosed with COVID-19 infection and fortunately recovered. At the time of this writing, 4 years and 3 months after the transplant, she remains healthy and in good condition.

Case 2

A 54-year-old woman (Table 1) presented with crampy, vague abdominal pain and moderate weight loss. She did not mention any complaints in favor of carcinoid syndrome.

The evaluations began with abdominal ultraso-nography and revealed several liver masses. The CT scan confirmed liver lesions with typical NET features with more than 50% involvement of the liver volume, but no primary tumor was located (Figure 2a). Liver mass biopsy showed low-grade NET (NET grade 1; Ki67 = 1.5%). A PET-CT scan revealed multiple foci of increased radiotracer uptake in the liver, but no uptake outside liver. According to the patient’s liver involvement, which was greater than 50% of the whole liver, she was not considered an eligible candidate for liver transplant or any surgical treatment, at first. Thus, she received LAR treatment in combination with lutetium Lu-177 dotatate. She underwent transarterial chemoembolization (TACE) of the liver at 3- to 6-month intervals, as recommended by a multidisciplinary team (MDT) meeting. Two years after the initial diagnosis, after 6 TACE sessions, the evaluations showed disease regression that included a 60% reduction in size in the largest mass, with less than 50% metastatic involvement of the liver (Figure 2b). As a result of acceptable downstaging, the patient was considered a candidate for liver transplant, subsequent to approval at a second MDT meeting (Table 2). Also, it was recommended to continue LAR and Lu-177 dotatate therapy until the time of liver transplant. This patient could not find any relatives for living liver donation; therefore, she was listed with MELD exception for transplant from a deceased donor with brain death, which was not available for the next 1.5 years (according to the regulations of the Iranian Society of Liver Transplantation and Liver Allocation unit).

The patient was regularly followed for disease progression. During these years, the disease remained stable. Eventually (5 years after initial presentation), the patient received priority status for liver transplant. Immediate evaluations pretrans-plant revealed no evidence of progression, and liver involvement was less than 50%. Table 3 shows the laboratory findings of the patient before transplant. The patient underwent orthotopic liver transplant and was discharged without any complications (Table 3). At 2 months after transplant, the Ga-68 dotatate PET-CT scan showed no uptake. The patient has been followed up for 3 consecutive years after transplant. She has been doing well without any tumor recurrence up until the time of this writing.

Discussion

The incidence of gastroenteropancreatic NET has been increasing in recent years. Recently, there have been considerable breakthroughs in the successful treatment of patients with NET. Published reports have indicated that a change to the current management of NET could be warranted.¹ Despite a previous Cochrane study by Gurusamy and colleagues, which indicated that surgery is not superior to nonsurgical treatment for neuroendocrine patients with liver metastasis,¹⁴ further research has demonstrated that surgery is associated with better survival rates.¹⁵ Current guidelines continue to recommend surgical resection as the preferred treatment for both locoregional and metastatic NET, despite recent advances in nonsurgical treatments.¹ According to the findings of Yuan and colleagues, a meta-analysis of liver resection showed statistical associations with a greater rate of symptom relief, a longer median survival time, higher 2- or 3-year survival rates, and a higher 5-year survival rate.¹⁶ In another study, Mayo and colleagues compared intra-arterial treatment with surgery and reported results consistent with previous studies.¹⁷

According to our review of the literature, Makowka and colleagues introduced orthotopic liver transplant as a therapeutic option for treatment of gastrointestinal NET with liver metastases for the first time in 1989.¹⁸ Subsequently, several reports of liver transplant for treatment of NET were published. Table 4 shows the summary results of the selected studies.

According to Valvi and colleagues (from 2021), younger age is associated with higher survival in patients undergoing liver transplant for metastatic NET. They revealed that patients who waited less than 6 months for a transplant had a greater rate of tumor recurrence than those who waited longer than 6 months.¹⁹ Higher Ki67 index and pancreas origin were also found to indicate higher recurrence rates.²⁰ Rosenau and colleagues also suggested Ki67 and E-cadherin as prognostic factors in patients with metastatic neuroendocrine disease undergoing liver transplant.²¹ However, in another study, the analysis of the Ki67 proliferation index did not differentiate patients with disease recurrence from those without disease recurrence.²² Olausson and colleagues included a higher proliferation rate and a larger tumor burden as well as a higher age, than described in previously defined criteria. The results showed that graft and patient survival were comparable to previously published results. The study proposed liver transplantation as a therapeutic option in individual patients for symptom relief and long disease-free intervals despite the inclusion of high-risk patients.²³ Gedaly and colleagues compared the outcomes of patients with carcinoid and noncar-cinoid tumors, metastatic NET, and hepatocellular carcinoma in a large series of 87 280 liver transplants (150 liver transplants for metastatic NET), and their results showed no difference in survival between patients with carcinoid tumors and those with noncarcinoid tumors. They also indicated no difference between patients with metastatic NET and those with hepatocellular carcinoma. They demonstrated that longer wait times (greater than 2 months) resulted in better outcomes. So, they suggested that patients should wait for the disease to stabilize before proceeding with transplant.²⁴

Major resection in addition to liver transplant, poor tumor differentiation, and hepatomegaly were discovered to be poor prognostic indicators in a retrospective multicenter investigation of 213 patients from 35 European hospitals.²⁵ Nobel and colleagues evaluated 120 wait list patients who had NET with liver metastases and obtained MELD exception points. Serum total bilirubin may act as a predictor of poor posttransplant survival and may aid in the risk stratification of individuals who apply for MELD exception points.²⁶ Research conducted by Sher and colleagues in 2015 showed that large vascular invasion and the extent of extrahepatic resection during liver transplant were predictors of lower overall survival in patients who received liver transplants for metastatic NET.²⁷ Mazzaferro and colleagues evaluated the long-term benefit of liver transplant for patients with hepatic metastases from NET versus the benefit of liver resection. They demonstrated that the transplant group had a significant advantage versus patients treated with nontransplant strategies at 5 and 10 years of survival (97.2% and 88.8% vs 50.9% and 22.4%, respectively; P < .001) and time-to-progression duration (13.1% and 13.1% vs 83.5% and 89%, respectively; P < .001).²⁸

According to our literature search, 3 systematic reviews directly addressed the subject of liver transplant in patients with NET. Mathe and colleagues published the first systematic review (in 2011) to assess the survival of neuroendocrine patients who underwent liver transplant due to hepatic metastases, which encompassed all data published until June 2010. They enrolled 89 transplant patients in more than 20 studies. The calculated mean survival time was 54.45 ± 6.31 months, with cumulative 1-year, 3-year, and 5-year survival rates of 71%, 55%, and 44%, respectively. Patients with vasoactive intestinal peptide-secreting tumor had the best overall survival. The 1-year, 2-year, and 5-year recurrence-free survival rates were 84%, 47%, and 47%, respectively. In both univariate and multivariate Cox proportional hazard models, recipient age ≥55 years and concurrent pancreatic resection during transplant were poor survival predictors.²⁹

Another systematic review on liver transplant for patients with metastatic NET was published by Moris and colleagues in 2017. Their review of 64 studies showed a recurrence rate ranging from 31.3% to 56.8% and 1-year, 3-year, and 5-year overall survival rates of 89%, 69%, and 63%, respectively. More than 50% liver tumor involvement and high Ki67 index, as well as a pancreatic NET versus gastrointestinal NET, were prognostic factors associated with long-term survival.³⁰ Fan and colleagues examined 46 relevant publications (including 706 liver transplants for NET liver metastasis) and concluded that patients with NET who only had liver metastases and no poorly differentiated disease were favorable candidates for liver transplants. The authors questioned the inclusion criteria of a delay (>6 months) to evaluate tumor progression before transplant.³¹ In the most recent systematic review, Duchateau and colleagues evaluated the reported experience on combined liver-intestine and multivisceral transplants for NET. Overall, patient survival was 51.2% and recurrence was 35%. The recurrence rate was comparable to recurrence after liver transplant for NET. They discovered that patients with NET with a diffuse abdominal presentation, which is typically a contraindication, could benefit from radical resection and multivisceral transplant.³²

There are 3 well-known criteria for selecting patients who undergo liver transplant for NET with liver metastasis: the European Neuroendocrine Tumor Society guidelines, the Milan criteria, and the United Network for Organ Sharing guidelines.^33,34 Liver involvement of more than 50% is typically not recommended for liver transplant according to the aforementioned criteria. In the second case of our study, the liver involvement was more than 50% at the time of diagnosis, but after downstaging through TACE and medical treatment, it was less than 50%.

There are scarce data published that have descri-bed the improvement of posttransplant outcomes for patients with NET by downstaging disease. According to a previously published analysis of 35 000 patients, somatostatin analogues showed survival benefits.³⁵ It is reasonable to expect similar advantages of downstaging through medical and targeted therapy before transplant. This problem would be addressed by well-designed studies.³¹ According to a European Liver Transplant Registry Study of 213 cases, patients with more than 50% liver involvement had a significantly lower 5-year survival rate. However, in multivariate analysis, it was not an independent predictor of poor prognosis.²⁵ The univariate analyses from Le Treut and colleagues (from 2008) showed that, when patients were divided by a liver involvement cutoff criterion of 40%, the difference of survival was significant, but the overall percentage of liver involvement was not a discriminating factor.³⁶ In a similar study, which included 15 liver transplants for patients with NET and liver metastases, 12 of 15 patients had tumor burdens that exceeded 50% of the volume of the liver; nonetheless, this had no discernible effect on tumor recurrence.²³ Makowka and colleagues evaluated liver transplants in 5 patients with metastatic NET when the tumor had already occupied 70% or more of the hepatic parenchyma. The findings of the investigation were favorable. One patient died shortly after complications from transplant, and another died from a cholangiocarcinoma recurrence that was unexpectedly detected during orthotopic liver transplant for a carcinoid tumor. However, the other 3 patients remained alive and showed no signs of tumor recurrence (over follow-up of 7-34 months).¹⁸ Therefore, although promising results with liver transplant have been shown in patients with greater than 50% hepatic involvement, to achieve even better outcomes, we advocate a focus to downstage patients before transplant.

The hepatic bile tract (including the gallbladder) is the rarest primary site for NET.³⁷ Extrahepatic biliary NET cases account for 0.2% to 2% of all gastrointestinal NET.³⁸ Neuroendocrine tumors are frequently derived from endoderm chromaffin and Kulchitsky cells, and the common bile duct has none of these cells, which explains the rarity of bile duct NET.³⁹ The majority of extrahepatic biliary NET cases (19.2%) involve the distal common bile duct. The cystic duct and the middle of the common bile duct each account for 17.9% and 16.7% of the cases, respectively. The proximal common bile duct has the lowest rate (11.5%),³⁸ and surgery is the main treatment option for choledochal NET. The surgical approach for proximal common bile duct NET is extrahepatic biliary excision with portal lympha-denectomy and Roux-en-Y biliary reconstruction with or without partial hepatectomy.⁴⁰

Our first case was a patient with NET located in the proximal portion of the common bile duct in the liver hilum that resulted in liver fibrosis and cholangitis due to biliary obstruction. Because of the location of the tumor, partial liver resection was indicated; however, liver dysfunction prevented such a procedure. Therefore, liver transplant has been performed for this case as an exceptional indication. Turrion and colleagues reported a similar case of a patient with a common bile duct NET treated with liver transplant. In their case, the diagnosis before transplant was Klatskin tumor.⁴¹ Another case of common bile duct carcinoid tumor was reported by Hao and colleagues, which was discovered after liver transplant for decompensated cirrhosis and was nonobstructive and had no metastases.⁴² Our present study describes the first experience, to our knowledge, of liver transplant for treatment of a previously known NET of the common bile duct. Our patient tolerated the procedure well and had a promising outcome. At 4 years and 3 months after transplant, she remained in good health with no sign of recurrence.

We believe that 2 important reasons for favorable outcomes in our cases were the G1 phase status and low Ki67 index. In a recent multicenter study conducted by Eshmuminov and colleagues, G2 phase status and liver transplant outside Milan criteria were negative prognostic factors in transplant recipients. In addition, the survival benefit of liver transplant over liver resection was lost for transp-lants performed outside the Milan criteria.⁴³ In our center, patients with unresectable hepatic metastases from NET are currently selected for liver transplant based on well-established criteria. However, these 2 cases did not meet the criteria for considering liver transplant, so MDT sessions were held to discuss the patients. After a period of nonsurgical treatment and evaluation of the tumor characteristics, we selected them as candidates for liver transplant based upon the favorable tumor characteristics and favorable response to treatment. For both patients, we did not observe any signs of tumor recurrence during follow-up. The outcomes were acceptable, and both patients tolerated treatment well. Considering the favorable tumor pathology (G1 phase and low Ki67 index), we suggest that more studies should be conducted to evaluate the outcomes in patients with low-grade tumors and that the criteria for patients with low-grade tumors could be extended based on such future data.

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