Neuroendocrine Tumours of Extrahepatic Biliary Tract: Report of Four Cases with Literature Review.

Neuroendocrine tumours (NETs) originating from extrahepatic bile duct are an extremely rare entity. They are typically slow growing tumours with malignant potential. Commonly presenting as obstructive jaundice, preoperative clinico-radiologic differentiation between extrahepatic biliary tract neuroendocrine tumours and cholangiocarcinoma is difficult and the final diagnosis is usually established after surgical histopathology and immunohistochemistry examination. R0 resection offers the only curative option with good long-term outcomes for well-differentiated NETs (grade1, grade2, and grade3) while the aggressive poorly differentiated neuroendocrine carcinoma (NEC) needs multimodality approach. We present our experience of management of four cases including three cases of grade II NET and one case of NEC undergoing surgical resection at a single centre with a short review of available literature.

Hepatic disease control in patients with intrahepatic cholangiocarcinoma correlates with overall survival.

PURPOSE: The role of locoregional therapy compared to systemic chemotherapy (SYS) for unresectable intrahepatic cholangiocarcinoma (IHC) remains controversial. The importance of hepatic disease control, either as initial or salvage therapy, is also unclear. We compared overall survival (OS) in patients treated with resection, hepatic arterial infusion pump (HAIP) chemotherapy, or SYS as it relates to hepatic recurrence or progression. We also evaluated recurrence after resection to determine the efficacy of locoregional salvage therapy. PATIENTS AND METHODS: In this single-institution retrospective analysis, patients with biopsy-proven IHC treated with either curative-intent resection, HAIP (with or without SYS), or SYS alone were analyzed. Propensity score matching (PSM) was used to compare patients with liver-limited, advanced disease treated with HAIP versus SYS. The impact of locoregional salvage therapies in patients with liver-limited recurrence was analyzed in the resection cohort. RESULTS: From 2000 to 2017, 714 patients with IHC were treated, 219 (30.7%) with resectable disease, 316 (44.3%) with locally advanced disease, and 179 (25.1%) with metastatic disease. Resected patients were less likely to recur or progress in the liver (hazard ratio [HR] 0.41, 95% CI 0.34-0.45) versus those that received HAIP or SYS (HR 0.58, 95% CI 0.50-0.65 vs. HR 0.63, 95% CI 0.57-0.69, respectively). In resected patients, 161 (64.4%) recurred, with 65 liver-only recurrences. Thirty of these patients received subsequent locoregional therapy. On multivariable analysis, locoregional therapy was associated with improved OS after isolated liver recurrence (HR 0.46, 95% CI 0.29-0.75; p = 0.002). In patients with locally advanced unresectable or multifocal liver disease (with or without distant organ metastases), PSM demonstrated improved hepatic progression-free survival in patients treated with HAIP versus SYS (HR 0.65; 95% CI 0.46-0.91; p = 0.01), which correlated with improved OS (HR 0.59, 95% CI 0.43-0.80; p < 0.001). CONCLUSION: In patients with liver-limited IHC, hepatic disease control is associated with improved OS, emphasizing the potential importance of liver-directed therapy.

A proposal of drain removal criteria in hepatobiliary resection.

BACKGROUND: Standardized criteria for drain removal in hepatobiliary resection are lacking. Here, we evaluated the outcomes of delayed removal policy in this extended surgery. METHODS: Patients undergoing hepatectomy with biliary reconstruction between 2012 and 2018 were retrospectively reviewed. The drains were removed on postoperative day (POD) 7 when the drainage fluid was grossly serous, biochemically normal, and negative for bacterial contamination as assessed by Gram staining; additionally, no abnormal fluid collection was confirmed by computed tomography. Clinically relevant abdominal complications (CRACs), including biliary leakage, pancreatic fistula or intra-abdominal abscess, served as the primary outcome measure. RESULTS: Among 374 study patients, surgical drains were removed in 166 (44.3%) patients who met the criteria. Of these patients, 16 (9.6%) patients subsequently required additional drainage due to CRAC. Drains were retained and exchanged in 208 (55.6%) patients who did not meet the criteria. Of these, exchanged drains were soon removed in 34 patients due to no signs of CRAC. The diagnostic ability of the criteria revealed 0.916 sensitivity, 0.815 specificity, and 0.866 accuracy. CONCLUSION: The four findings on POD 7 worked well as criteria for drain removal, and these criteria may be helpful in drain management after hepatobiliary resection.

Preoperative diagnosis of intraductal papillary neoplasm of the bile duct with endoscopic ultrasound.

Intraductal papillary mucinous neoplasm of the bile duct is a rare tumour only recently classified as a distinct pathological entity. These neoplasms, rarely encountered in clinical practice in the UK, are now considered to be important precursors for the development of cholangiocarcinoma. We present a histologically confirmed case of intraductal papillary neoplasm of the bile duct in a male patient and discuss the main radiographic manifestations of this rare condition across multiple imaging modalities, with an emphasis on the imaging features of endoscopic ultrasonography and its role in establishing the diagnosis.

Minimally invasive surgical treatment of intrahepatic cholangiocarcinoma: A systematic review.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and is characterized by an aggressive behavior and a dismal prognosis. Radical surgical resection represents the only potentially curative treatment. Despite the increasing acceptance of laparoscopic liver resection for surgical treatment of malignant liver diseases, its use for ICC is not commonly performed. In fact, to achieve surgical free margins a major resection and/or vascular and/or biliary reconstructions is often needed, as well as an associated lymph node dissection. AIM: To review and summarize the current evidences on the minimally invasive resection of ICC. METHODS: A systematic review of the literature based on the criteria predetermined by the investigators was performed from the 1st of January 2009 up to the 1st of January 2021 in 4 databases (PubMed, Scopus, Google Scholar, and Cochrane databases). All retrospective and prospective studies reporting on the comparative outcomes of open vs minimally invasive treatment of ICC were included. An evaluation of manuscripts quality was achieved using Methodological Index for Non-Randomized Studies criteria and Newcastle-Ottawa Scale. RESULTS: After a systematic search 9 studies fulfilled the inclusion criteria. Among the all 3012 included patients, 2450 were operated by an open approach and 562 by a minimally invasive (laparoscopic) approach. Baseline characteristics, tumor characteristics, surgical outcomes and oncological outcomes were collected and analyzed, highlighting values with a statistical significant difference between patients treated with open or laparoscopic approach. Shorter hospital stay and lower intraoperative blood losses were reported by some Authors in minimally invasive surgery, on the contrary, in the open group there was a higher number of lymphadenectomies and a higher percentage of major hepatectomies. CONCLUSION: Minimally invasive resection of ICC has some short-term benefits and it is safe and feasible only in selected centers with a high experience in laparoscopic approach for liver surgery. Minimally invasive surgery, actually, was considered mainly in patients with a tumor with a diameter < 5 cm, without invasion of main biliary duct or main vessel and no vascular or biliary reconstructions were planned. Further studies are needed to elucidate its impact on long term oncologic outcomes.

Role of Leptin in Neoplastic and Biliary Tree Disease.

BACKGROUND/AIM: Leptin is a small hormone of protein nature, it is strongly involved in the regulation of lipid metabolism and its functioning mechanism is not yet well known or whether or not it is actually secreted by cholangiocytes, nor if the biliary tree expresses its receptors. In the past, various studies have tried to correlate leptin levels with certain neoplasms. The aim of this study was to demonstrate that serum leptin values can become a new sensitive and specific serum marker for cholangiocarcinoma. MATERIALS AND METHODS: Seventy-two patients with gallbladder stones, hepatolithiasis with benign biliary stenosis, cholangiocarcinoma, and a group of patients without hepato-biliary diseases were enrolled in the study. In all cases blood and bile samples were collected for evaluation of leptin levels and liver biopsies were performed to confirm diagnosis. In all patients, both ultrasound and cholangio-magnetic resonance imaging (MRI) were performed to complete the diagnostic procedure. RESULTS: Twenty-two patients were affected by cholangiocarcinoma, 50 by benign biliary disease (35 cholelithiasis and 6 hepatolithiasis and 9 by inflammatory biliary stenosis). The mean values of serum leptin in patients with cholangiocarcinoma were 19.28±8.76 ng/ml, significantly higher than those observed in non-neoplastic biliary diseases. CONCLUSION: Serum leptin levels might be a useful marker to differentiate patients with cholangiocarcinoma from those with biliary lithiasis and inflammatory stenosis.

Predictive performance of Blumgart T staging for perihilar cholangiocarcinoma in a Japanese center.

BACKGROUND: The Blumgart system has been used for local tumor assessment in perihilar cholangiocarcinoma to predict resectability and survival, and T3 tumors are considered unresectable disease. The aim was to validate the predictive performance of this system using a Japanese cohort. METHODS: Medical records of consecutive patients with perihilar cholangiocarcinoma between 2006 and 2016 were retrospectively reviewed. Resectability, surgical procedure, R0 resection rate, and survival were compared among T stages. RESULTS: Among 729 study patients, 191 patients had T1 tumors, 94 patients had T2 tumors, and 444 (60.9%) patients had T3 tumors according to the Blumgart T stage. Resection was performed in 513 (70.4%) patients; resectability rate decreased with the progression of T stage: 89.0% in T1, 79.8% in T2, and 60.4% in T3 tumors (P < 0.001). The incidences of left hepatic trisectionectomy and portal vein resection were 44.0% and 54.1%, respectively, in patients with T3 tumors, which were significantly greater than those of T1/2 tumors (P = 0.001 and P < 0.001). R0 resection reduced with advanced T stage: 92.4% in T1, 81.3% in T2, and 70.9% in T3 tumors (P < 0.001). The 5-year survival rate was 53.4%, 38.4%, and 19.7% in T1, T2, and T3 tumors, respectively (P < 0.001); that was 59.6%, 48.6%, and 30.7%, respectively, in the resected cohort (P < 0.001). CONCLUSION: Blumgart T stage was closely associated with the resectability rate, surgical procedures, R0 resection rate, and survival time, suggesting that the T stage works as well as a presurgical staging system. However, the unresectable classification of T3 tumors should be revised.

The interobserver agreement of optical features used to differentiate benign from neoplastic biliary lesions assessed at balloon-assisted cholangioscopy.

BACKGROUND AND AIM: Balloon-assisted cholangioscopy allows mucosal assessment of the biliary tree with pediatric endoscopes. No validated optical criteria exist to differentiate benign from neoplastic biliary lesions. We aimed to identify, validate, and revalidate optical features differentiating benign from neoplastic biliary lesions. Furthermore, we aimed to determine whether cholangioscopic appearance allows endoscopists to accurately differentiate benign from neoplastic biliary lesions. METHODS: Baseline: from 44 de-identified balloon-assisted cholangioscopy videos, a blinded investigator analyzed potential optical features distinguishing benign from neoplastic biliary lesions. VALIDATION: during the initial "teaching phase," 20 endoscopists viewed video clips of 11 optical features identified in the baseline study. At the subsequent "test phase," 20 further video clips were assessed by the endoscopists blinded to clinical details and questionnaires completed for the presence or absence of optical features, favored diagnosis and diagnostic confidence. Revalidation: The six identified optical features from the validation study with at least moderate agreement were revalidated the same way 12 months later assessing 20 new lesions. RESULTS: Baseline: 11 optical features were found to differentiate benign from neoplastic biliary lesions. Validation and revalidation: six optical features demonstrated at least moderate interobserver agreement (irregular margin, dark mucosa, adherent mucous, papillary projections, tubular, or branched/disorganized surface structures). Endoscopists correctly diagnosed lesions as benign in 89% and neoplastic in 83%. When highly confident, endoscopists correctly diagnosed 96% of benign and 87% neoplastic lesions. CONCLUSIONS: Six features were validated and revalidated to differentiate benign from neoplastic biliary lesions. When highly confident with a diagnosis, endoscopists usually differentiate benign from neoplastic biliary lesions.

Congested bile can predict the outcomes of endoscopic stenting for hilar biliary malignancies.

OBJECTIVE: Endoscopic management of malignant hilar biliary obstruction (MHBO) remains challenging, with relatively poor jaundice control and high infectious risk. The factors that affect the outcome of endoscopic therapy are still unclear. This retrospective cohort study aimed to investigate predictive factors for the outcomes of biliary stenting in patients with MHBO. METHODS: Between June 2015 and June 2016, consecutive patients with MHBO who received primary endoscopic stenting and completed follow-up at our institution were identified and evaluated. All patients received full aspiration of congested bile followed by plastic or metal stent(s) placement. Clinical success was achieved in patients whose total serum bilirubin decreased by over two-thirds in a month. RESULTS: A total of 64 patients were included. Among them, 28 received a single stent placement and 36 received multiple stent placements. Altogether 53 (82.8%) patients attained clinical success and 48 (75.0%) underwent re-interventions within 6 months. Multivariate analyses showed that only a total bile volume of ≥30 mL aspirated from the intrahepatic ducts predicted clinical success (OR 6.83, 95% CI 1.2-38.4, P = 0.029), absence of early post-endoscopic retrograde cholangiopancreatography cholangitis (OR 0.03, 95% CI 0.004-0.36, P = 0.001), and lack of re-intervention within 6 months (HR 0.10, 95% CI 0.05-0.22, P < 0.001) after initial endoscopic stenting. CONCLUSION: The volume of congested bile may effectively predict treatment outcomes of endoscopic stenting for MHBO and guide the therapeutic strategy.

Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency.

The pathology of biliary carcinomas is diverse with different gross and histological features in tumors arising in the different segments of the biliary system. Various epidemiological risk factors, varied genetic makeup, and tissue microenvironment are contributory factors. As biliary tumors have been shown to be a part of the Lynch syndrome tumor spectrum, it is plausible to speculate that DNA mismatch repair (MMR) deficiency plays a role in biliary tumors. Literature data suggest that DNA MMR deficiency indeed occurs in these tumors, albeit infrequently with the reported frequencies (weighted for sample size) of high level microsatellite instability (MSI) being 5% each for gallbladder carcinoma and carcinoma of extra-hepatic bile ducts, and 10% each for intrahepatic cholangiocarcinoma and ampullary carcinoma. Importantly, the presence of MMR deficiency in these tumors has been shown to have different implications with regard to its association with Lynch syndrome, tumor histological features, and other clinical characteristics, when compared with non-biliary tumors or among the biliary tumors from the different segments of the biliary system. Ongoing and future efforts that utilize large scale sequencing techniques and aim at detecting actionable molecular targets should emphasize a multidisciplinary approach that integrates genomic discoveries with not only functional studies but also studies of tumor pathology and the tumor's clinical and biological behavior.

Incidence of underlying biliary neoplasm in patients after major hepatectomy for preoperative benign hepatolithiasis.

BACKGROUNDS/AIMS: Despite hepatolithiasis being a risk factor for biliary neoplasm including cholangiocarcinoma, the incidence of underlying biliary neoplasm is unknown in patients with preoperative benign hepatolithiasis. The aim of this study was to evaluate the incidence of underlying biliary neoplasm in patients who underwent major hepatectomy for preoperative benign hepatolithiasis. METHODS: Between March 2005 and December 2015, 73 patients who underwent major hepatectomy for preoperative benign hepatolithiasis were enrolled in this study. The incidence and pathological differentiation of concomitant biliary neoplasm were retrospectively determined by review of medical records. Postoperative complications after major hepatectomy were evaluated. RESULTS: Concomitant biliary neoplasm was pathologically confirmed in 20 patients (27.4%). Biliary intraepithelial neoplasia (BIN) was detected in 12 patients (16.4%), and 1 patient (1.4%) had intraductal papillary mucinous neoplasm (IPMN), as the premalignant lesion. Cholangiocarcinoma was pathologically confirmed in 7 patients (9.6%). Preoperative imaging of the 73 patients revealed biliary stricture at the first branch of bile duct in 31 patients (42.5%), and at the second branch of bile duct in 39 patients (53.4%). Postoperative complications developed in 14 patients (19.1%). Almost all patients recovered from complications, including intra-abdominal abscess (9.6%), bile leakage (4.1%), pleural effusion (2.7%), and wound infection (1.4%). Only 1 patient (1.4%) died from aspiration pneumonia. CONCLUSIONS: The incidence of underlying biliary neoplasm was not negligible in the patients with hepatolithiasis, despite meticulous preoperative evaluations.

Multicystic biliary hamartoma: A report of a rare entity and a review of the literature.

INTRODUCTION: Multicystic biliary hamartoma is a rare liver tumor that was first described in 2005. Only nine cases are reported in the literature and all of them originate from Eastern patient populations, specifically Japan and Korea. PRESENTATION OF CASE: Herein we report the occurrence of the tenth multicystic biliary hamartoma reported to date, arising in a Caucasian American woman initially presenting with abdominal pain. At 4.7cm this is the second largest tumor reported to date and the only one arising in a Western patient population. DISCUSSION: The patient underwent multimodality imaging and the tumor was biopsied preoperatively, but the diagnosis remained unclear. An extended right hepatectomy was performed for resection of her tumor, and the tumor was definitively diagnosed based on the surgically resected specimen. As all nine of the previously reported cases also underwent resection, the natural history of this lesion remains unknown. The lack of both recurrence and tumor spread in the previously reported cases indicates that this may be a benign lesion not requiring surgical resection unless symptomatic. CONCLUSION: Multicystic biliary hamartoma is an extremely rare tumor. Increased awareness of the radiologic and pathologic features will likely lead to the diagnoses of further cases in both Western and Eastern populations and could potentially assist with preoperative diagnosis. The natural history and optimal management of this tumor remain uncertain.

Hilar cholangiocarcinoma: diagnosis, treatment options, and management.

Hilar cholangiocarcinoma (HC) is a rare disease with a poor prognosis which typically presents in the 6(th) decade of life. Of the 3,000 cases seen annually in the United States, less than one half of these tumors are resectable. A variety of risk factors have been associated with HC, most notably primary sclerosing cholangitis (PSC), biliary stone disease and parasitic liver disease. Patients typically present with abdominal pain, pruritis, weight loss, and jaundice. Computed topography (CT), magnetic resonance imaging (MRI), and ultrasound (US) are used to characterize biliary lesions. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) assess local ductal extent of the tumor while allowing for therapeutic biliary drainage. MRCP has demonstrated similar efficacies to PTC and ERCP in identifying anatomic extension of tumors with less complications. Treatment consists of surgery, radiation, chemotherapy and photodynamic therapy. Biliary drainage of the future liver remnant should be performed to decrease bilirubin levels thereby facilitating future liver hypertrophy. Standard therapy consists of surgical margin-negative (R0) resection with extrahepatic bile duct resection, hepatectomy and en bloc lymphadenectomy. Local resection should not be undertaken. Lymph node invasion, tumor grade and negative margins are important prognostic indicators. In instances where curative resection is not possible, liver transplantation has demonstrated acceptable outcomes in highly selected patients. Despite the limited data, chemotherapy is indicated for patients with unresectable tumors and adequate functional status. Five-year survival after surgical resection of HC ranges from 10% to 40% however, recurrence can be as high as 50-70% even after R0 resection. Due to the complexity of this disease, a multi-disciplinary approach with multimodal treatment is recommended for this complex disease.

Intraductal neoplasm of the intrahepatic bile duct: clinicopathological study of 24 cases.

AIM: To investigate the clinicopathological features of intraductal neoplasm of the intrahepatic bile duct (INihB). METHODS: Clinicopathological features of 24 cases of INihB, which were previously diagnosed as biliary papillomatosis or intraductal growth of intrahepatic biliary neoplasm, were reviewed. Mucin immunohistochemistry was performed for mucin (MUC)1, MUC2, MUC5AC and MUC6. Ki-67, P53 and ß-catenin immunoreactivity were also examined. We categorized each tumor as adenoma (low grade), borderline (intermediate grade), and malignant (carcinoma in situ, high grade including tumors with microinvasion). RESULTS: Among 24 cases of INihB, we identified 24 tumors. Twenty of 24 tumors (83%) were composed of a papillary structure; the same feature observed in intraductal papillary neoplasm of the bile duct (IPNB). In contrast, the remaining four tumors (17%) showed both tubular and papillary structures. In three of the four tumors (75%), macroscopic mucin secretion was limited but microscopic intracellular mucin was evident. Histologically, 16 tumors (67%) were malignant, three (12%) were borderline, and five (21%) were adenoma. Microinvasion was found in four cases (17%). Immunohistochemical analysis revealed that MUC1 was not expressed in the borderline/adenoma group but was expressed only in malignant lesions (P = 0.0095). Ki-67 labeling index (LI) was significantly higher in the malignant group than in the borderline/adenoma group (22.2 ± 15.5 vs 7.5 ± 6.3, P < 0.01). In the 16 malignant cases, expression of MUC5AC showed borderline significant association with high Ki-67 LI (P = 0.0622). Nuclear expression of ß-catenin was observed in two (8%) of the 24 tumors, and these two tumors also showed MUC1 expression. P53 was negative in all tumors. CONCLUSION: Some cases of INihB have a tubular structure, and are subcategorized as IPNB with tubular structure. MUC1 expression in INihB correlates positively with degree of malignancy.