Perihilar Biliary Neuroendocrine Carcinoma Treated With Perioperative Chemotherapy and Radical Liver Surgery: A Thought-Provoking Case

Introduction

Biliary neuroendocrine neoplasm (NEN) arising from the extrahepatic bile duct is extremely rare, with an incidence of 0.2% among gastroentero-hepatopancreatobiliary NEN cases [1,2]. The incidence of primary lesions in the extrahepatic bile duct is in the following order: distal bile duct (Bd) >common hepatic duct (Bp/CHD) >gallbladder and cystic duct (GB/C) >perihilar bile duct (Bp/Hilar), with Bp/Hilar reported in less than 10% [1,3]. Biliary NENs include biliary neuroendocrine tumors (NET) and biliary neuroendocrine carcinomas (NEC), with highly malignant biliary NET-G3 and biliary NEC being the least frequently reported. Even if resectable, biliary NEC recurs frequently, and in a small number of case series, the 5-year survival rate has been reported to be very low, at 17% to 19% [4,5]. Therefore, biliary NEC requires multidisciplinary treatment, including surgery, chemotherapy, and radiotherapy [1]. However, there have been only a few reports on the combined therapy for biliary NEC. Herein, we report a case of Bp/Hilar NEC that underwent multidisciplinary treatment combining perioperative chemotherapy and extended hepatectomy with vascular resection.

Case Report

A 74-year-old Japanese man was referred to our hospital with the chief concern of jaundice. His initial symptoms also included general discomfort and fatigability for a few months. His medical history included hypertension and dyslipidemia. He had no known food or drug allergies. He did not smoke or consume alcohol and had no history of substance abuse. Physical examination revealed systemic jaundice but no abdominal tenderness. Laboratory tests at the first visit showed elevated liver enzymes and bilirubin levels (aspartate aminotransferase, 93 IU/L; alanine aminotransferase, 160 IU/L; total bilirubin 13.8 mg/dL, direct bilirubin 9.8 mg/dL), which was suspected to be obstructive jaundice. Tumor markers showed high carbohydrate 19-9 (CA19-9 421.0 U/mL) and pro-gastrin-releasing peptide (ProGRP 161.2 pg/mL). The indocyanine green retention test (ICG-r15) showed poor liver function (ICG-r15, 42.0%) even after the jaundice improved. All other laboratory data were unremarkable and within normal limits. Contrast-enhanced computed tomography (CECT) revealed a 25-mm hypovascular tumor in the hepatic hilar area with bilateral intrahepatic biliary dilation, consistent with a biliary malignant neoplasm. The tumor was located away from the portal bifurcation and was closely attached to the right hepatic artery (RHA), without apparent vascular invasion (Figure 1). Endoscopic retrograde cholangiopancreatography revealed perihilar biliary obstruction and severe occlusion of the left hepatic duct. Endoscopic retrograde biliary drainage was performed using a plastic tube placed in the right hepatic duct. Endoscopic biliary biopsy of the tumor revealed poorly differentiated cells with characteristic nuclear molding and extensive crush artifacts, consistent with NEC. Other biliary mapping biopsies showed no evidence of malignancy (Figure 2). Contrast-enhanced magnetic resonance imaging revealed that T1-weighed and T2-weighed images showed non-specific signals in the tumor, and there was no signal change between opposed-phase and in-phase images. Diffusion-weighted imaging showed that the apparent diffusion coefficient was measured at 0.79×10−3 mm2/s, demonstrating pronounced diffusion restriction. These findings were highly suggestive of a small round cell tumor, including NEN or lymphoma. Fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed very high FDG uptake in the primary tumor (Standardized Uptake Value Maximum 11.1) and ruled out distant metastasis. Based on these findings, the patient was diagnosed with a rare biliary NEC localized to the hepatic hilar area.

However, there are no consensus guidelines for biliary NEC. As NEC is a highly aggressive malignancy, we selected a multidisciplinary approach for tumor management. Because his liver function was insufficient for major hepatectomy, we decided to administer systemic chemotherapy. We selected etoposide and cisplatin (EP regimen) as the first-line therapy. In every course of the EP regimen, he had severe neutropenia and thrombocytopenia and required antibiotics and endoscopic therapies for refractory recurrent cholangitis. We assessed the tumor status every 2 courses of the EP regimen by CECT and tumor markers. After 4 courses of the EP regimen, CECT revealed regression of the tumor size (from 25 to 15 mm) without any distant metastasis (Figure 3). Tumor markers showed a stable status (CA19-9 291.9 U/mL, ProGRP 147.7 pg/mL). Furthermore, his liver function unexpectedly improved (ICG-r15, 24.1%), probably because of cholestasis improvement by several biliary stent exchanges. The patient was then considered a candidate for radical liver surgery.

Six months after the first visit, we planned a curative hepatectomy (left and caudate hepatectomy with combined resection and reconstruction of the extrahepatic bile duct). During laparotomy, no peritoneal dissemination was observed, and para-aortic lymph node sampling revealed no malignancy. After the common bile duct was dissected, the distal biliary stump was confirmed to be free of malignancy by intraoperative frozen section. In the hepatic hilar area, the right hepatic artery and right portal vein were secured, and the left hepatic artery, middle hepatic artery, and left portal vein were dissected individually. After dissection of the liver parenchyma, we approached the right hepatic duct, where the RHA was found to have severe adhesion to the bile duct and tumor due to multiple preoperative biliary inflammation or oncological invasion. Therefore, we decided to perform a combined resection of the RHA. Finally, we removed the specimen (Figure 4), and our plastic surgeons reconstructed the RHA by end-to-end anastomosis. The biliary system was reconstructed using hepaticojejunostomy with Roux-en-Y anastomosis. The operative time was 955 min, and the bleeding volume was 892 mL.

The pathological diagnosis was a perihilar neuroendocrine neoplasm, intermediate between NEC and NET-G3. Immunostaining was positive for synaptophysin and chromogranin A, Ki-67 index was 35-80%, Rb1 was negative, somatostatin type-2 receptor was positive, and p53 was positive. These findings have mixed characteristics for NEC and NET-G3. The chemotherapeutic effect was moderate, and the percentage of viable tumor cells was estimated to be 50%. Although the tumor was thought to be mass-forming preoperatively, its histopathological findings showed periductal infiltrating features, and the tumor extent was broader than expected. The carcinoma cells crawled along the wall of the bile duct, and the margin of the right hepatic duct (hepatic side) was positive for malignancy. No tumor invasion was observed in the right hepatic artery (Figure 5). According to the Union for International Cancer Control TNM classification 8th edition for perihilar cholangiocarcinoma, the tumor staging was ypT2b, N1, M0, ypStage IIIB, ypDM0, ypHM1, and R1 resection.

After surgery, although he had post-hepatectomy liver failure (Grade B) and postoperative cholangitis, we overcame these complications with conservative transfusion and antibiotic therapy. The patient was discharged on the 31st postoperative day. Tumor marker levels were within normal limits (CA19-9 36.2 U/mL, ProGRP 68.6 pg/mL).

After discharge, the patient received an EP regimen as adjuvant chemotherapy for 6 months. Ten months after surgery, CECT and FDG-PET revealed multiple recurrences in the liver, lymph nodes, and vertebral bones, with elevated levels of tumor markers (CA19-9 47.8 U/mL, ProGRP 169.6 pg/mL). Although he received multidisciplinary therapies, including re-administration of the EP regimen, somatostatin analogs, and radiation, the progression of the recurrent tumors was severe and refractory to these treatments. Unfortunately, he died of liver failure due to cholangitis and sepsis 12 months after the operation and 18 months after his first consultation.

Discussion

CHARACTERISTICS OF BILIARY NEN:

Several pathophysiological mechanisms have been proposed for the origin of biliary NEC: (a) neuroendocrine differentiation secondary to chronic inflammation and epithelial metaplasia; (b) neoplastic transformation of biliary stem/progenitor cells with multipotential differentiation capacity; (c) divergent differentiation or collision with concurrent adenocarcinoma; and (d) origin from ectopic neuroendocrine or pancreatic tissue deposited during embryogenesis [6,7]. Although there is no consensus on the validity of these hypotheses, the present case supports the second mechanism of biliary multipotent stem cells. This is not only because our patient had no history of biliary inflammation but also because immunohistochemistry revealed that the tumor had unique characteristics between NEC and NET-G3 (negative Rb1, positive somatostatin type-2 receptor, and positive p53).

Biliary NEN is often difficult to diagnose preoperatively; it is difficult to distinguish NENs from biliary tract cancer on imaging because its clinical course is similar to that of the latter. It is also difficult to detect deeply located NEC components using the commonly performed transpapillary examination, which may explain its low accuracy. Biopsies are often false-negative, and the preoperative diagnosis rate is low. Furthermore, it is extremely difficult to predict tumor extension into the biliary tract because biliary NEN can progress by creeping along the subepithelial region [3]. Therefore, a pathological diagnosis or tumor extent may be revealed only after resection.

STANDARD STRATEGY FOR BILIARY NEC:

There are no international consensus guidelines for biliary NEN because of the small number of reports. The treatment of biliary NEN is similar to that of cholangiocarcinoma, and surgery is the main curative treatment. However, the treatment strategies for biliary NET G3 and NEC differ from those for cholangiocarcinoma. They may require multidisciplinary treatments, including surgery, chemotherapy, and radiation, similar to those for GEP NEC [3,4,8]. For example, for resectable GEP NEC, the European Neuroendocrine Tumor Society (ENETS) guidelines recommend surgery plus postoperative adjuvant chemotherapy with platinum-based drug and etoposide (4–6 cycles) [9]. The National Comprehensive Cancer Network (NCCN) guidelines also suggest surgery plus postoperative adjuvant chemotherapy with or without radiation therapy, or preoperative chemotherapy with or without radiation therapy plus surgery [10]. Therefore, it is safe to conclude that the same treatment strategy is applicable to biliary NEC.

When considering candidates for first-line systemic chemotherapy for biliary NEC, the following 3 regimens are considered effective because they are currently used for GEP NEC: cisplatin plus etoposide (EP regimen), carboplatin plus etoposide (EC regimen), and irinotecan plus cisplatin (IP regimen) [9–12]. Furthermore, especially for biliary NEC, we recommend using the first 2 regimens (EP or EC regimens) and avoiding the IP regimen, since irinotecan and its metabolites are excreted via the biliary route [13]. The IP regimen may be difficult to use constantly because biliary NEC is often associated with obstructive jaundice and cholangitis, requiring endoscopic interventions.

POSTOPERATIVE ADJUVANT CHEMOTHERAPY FOR BILIARY NEC:

Although there is currently no high-level evidence for postoperative adjuvant chemotherapy for biliary NEC, its efficacy has been described in a few case series [5,14,15]. For example, Lee et al analyzed 34 cases of gallbladder NEC and performed multivariate analysis of factors involved in overall survival. They concluded that postoperative adjuvant chemoradiotherapy was the only independent prognostic factor. For postoperative adjuvant chemotherapy regimens, EP or EC regimens are often used [9,10].

PREOPERATIVE NEOADJUVANT CHEMOTHERAPY FOR BILIARY NEC:

There are only a few case reports on the use of preoperative neoadjuvant chemotherapy (NAC) for biliary NEC that achieved good surgical results [16,17]. As the preoperative diagnosis of biliary NEC can be difficult, only patients diagnosed with biliary NEC by initial examinations can benefit from an accurate diagnosis. As for preoperative NAC regimens, the above-mentioned EP or EC regimens would be candidates. Although another candidate regimen may include the IP regimen [11,12], it should be avoided from our perspective, as mentioned above. When administering preoperative NAC, infectious control of cholangitis associated with malignant biliary stricture is also a challenge because both are potent chemotherapy regimens that are prone to blood cell depletion [12].

REPORTED CASES OF BP NEC:

Biliary NEC is rare, and Bp NEC (including MiNEN) occurring in the proximal bile duct is extremely rare [3]. According to the English literature from 1993 to 2023, only 16 cases of Bp NEC have been reported [18–33] (Table 1). Eight of the 16 patients were pathologically diagnosed with MiNEN. As expected, the prognosis of Bp NEC appears poor. Among the 16 patients with follow-up data, 37.5% (6/16) died of the disease within 1 year after surgery [19,21, 23,24,27,29], and only 25% (4/16) had no recurrence at the time of publication [25,30,32,33]. Three of the 4 recurrence-free cases were treated with postoperative adjuvant chemotherapy, suggesting that adjuvant therapy can be useful for Bp NEC. Among the 16 cases, only 5 Bp/Hilar cases with intrahepatic bile duct extension required hepatectomy [21,23,25,28,29]. Surgery around the perihilar biliary area is sometimes highly invasive and involves major hepatectomy with extrahepatic biliary resection and reconstruction, which can affect postoperative tumor recurrence and the introduction of postoperative adjuvant chemotherapy. In fact, 3 of 5 patients relapsed within 3 months after surgery, with poor prognoses [23,28,29]. Postoperative adjuvant chemotherapy was administered in only 1 case [28]. Notably, there were no cases in which the patient underwent surgery after preoperative chemotherapy, as in the present case.

INSIGHTS FROM OUR CASE:

Our patient was fortunately diagnosed with a rare Bp/Hilar NEC preoperatively. Owing to its rapid progression and poor liver function, the tumor was judged to be unresectable at the time of the initial diagnosis. Therefore, the EP regimen was introduced as a first-line chemotherapy. Since the patient showed a partial response to treatment and improvement in liver function, he underwent radical surgery followed by a postoperative adjuvant EP regimen. As progression-free survival of the EP regimen for GEP NEC was reported to be approximately 6 months [12], we decided to perform the operation 6 months after the first visit. Although multiple recurrences were eventually observed, the patient achieved an 18-month survival after the initial diagnosis. Considering that the median overall survival of patients with advanced GEP NEC is about 11 months [9], we consider this case to be one in which multidisciplinary treatment was successful.

According to our experience in the present case and our literature review, it can be clinically proposed that if evidence of Bp/Hilar NEC can be obtained at the time of the initial diagnosis, perioperative chemotherapy (especially EP or EC regimens) should be administered, considering the oncological malignancy and surgical invasive stress. Furthermore, patients undergoing R0 resection in radical surgery can be expected to have a longer survival than the present case.

Conclusions

Biliary NEC requires a multidisciplinary treatment plan because of its aggressive nature. This unique report describes the first case of Bp/Hilar NEC that underwent perioperative chemotherapy and radical liver surgery. We believe that the introduction of perioperative chemotherapy is essential to achieve a better prognosis for Bp/Hilar NEC, given its oncological malignancy and surgical invasive stress. Methods for obtaining an accurate diagnosis of biliary NEC at the initial presentation and protocols as perioperative chemotherapy for biliary NEC should be discussed in the future.