A rare case of hypervirulent Klebsiella pneumoniae liver abscess and bacterial endophthalmitis associated with distal bile duct cancer.

We report a case of a patient with distal bile duct cancer who presented with ocular pain and eye redness due to a liver abscess. The patient developed a liver abscess while waiting for surgery. Since Klebsiella pneumoniae with high viscosity was identified and imaging studies showed systemic infection, a diagnosis of klebsiella invasive syndrome was made. In addition, infectious intraocular inflammation was also observed at the same time. In addition to antibiotic therapy, vitrectomy and percutaneous transhepatic abscess drainage successfully normalized the inflammatory response and negative blood cultures were obtained. Thirty-four days after the start of treatment, surgery was performed and the postoperative course was uneventful, and the patient was discharged from the hospital on the 39th postoperative day. Forty-six months after that surgery, there has been no evidence of recurrence of cholangiocarcinoma or recurrence of infection, but unfortunately, vision loss in the right eye remains. Some Klebsiella pneumoniae are highly pathogenic and are often reported from Southeast Asia, and ocular pain and hyperemic symptoms are important physical findings.

Middle and distal bile duct carcinoma, retrospective analysis & short-term and long-term outcomes of surgical therapy.

INTRODUCTION: The prognosis of extrahepatic cholangiocarcinoma is dismal and the only way to achieve long-term survival is surgical resection. While pancreatoduodenectomy (PD) is the standard procedure for distal cholangiocarcinoma (distal bile duct cancer; DBDC), bile duct segmental resection (BDR) can be used as an alternative approach for middle bile duct cholangiocarcinoma (middle bile duct cancer; MBDC). The aim of the study was to calculate the short-term and long-term outcomes of curative-intent surgery in distal bile duct cholangiocarcinoma patients. METHODS: A retrospective cohort study of consecutive patients treated for MBDC and DBDC with PD or BDR between 1/2009-12/2019. The patients were divided according to the type of surgical resection (PD and BDR group). Demographic, clinicopathological and histopathological data and overall survival (OS) were evaluated in both groups. OS was estimated using the Kaplan-Meier analysis. RESULTS: The study comprised a total of 62 patients - 45 patients (72.6%) in the PD group and 17 (27.4%) in the BDR group. Patients undergoing BDR were significantly older than those receiving PD (p=0.048). Men predominated in the PD group (N=34/45; 75.6%) while more women were included in the BDR group (N=10/17; 58.8%). Median age was higher in the BDR group (p=0.048). Serious morbidity (Clavien-Dindo III-V) (33.3% vs 11.8%), 30-day and 90-day mortality (4.4% vs 0.0% and 8.9% vs 5.9%, respectively) predominated in the PD group although the differences were not statistically significant, as well as a longer hospital stay (16.0 days vs 11.0 days; p=0.002). Pathological assessments revealed comparable numbers of positive lymph nodes in both groups, but a significantly higher number of total resected lymph nodes in the PD group (p.

Surgical resection of mixed neuroendocrine-non-neuroendocrine neoplasm in the biliary system: a report of two cases.

BACKGROUND: Mixed neuroendocrine-non-neuroendocrine neoplasm (MINEN) is a rare disease and there is scarce literature on its diagnosis, treatment, and prognosis. We encountered two unusual cases of MINEN in the biliary tract, one in the ampulla of Vater and the other in the distal bile duct. In this report, we describe the clinical course of these two cases in detail. CASE PRESENTATION: Case 1: A 69-year-old woman presented with a chief complaint of epigastric pain. When endoscopic sphincterotomy and retrograde biliary drainage were performed for gallstone pancreatitis, an ulcerated lesion was found in the ampulla of the Vater. Based on the biopsy results, the lesion was diagnosed as the ampulla of Vater carcinoma and subtotal stomach-preserving pancreatoduodenectomy (SSPPD) was performed. Postoperative histopathological examination revealed the coexistence of adenocarcinoma and neuroendocrine carcinoma components, consistent with the diagnosis of MINEN. In addition, lymph node metastasis was found on the dorsal side of the pancreas and the metastatic component was adenocarcinoma. Adjuvant chemotherapy with etoposide and cisplatin was administered for 6 months, and presently the patient is alive without recurrence 64 months after surgery. Case 2: A 79-year-old man presented with a chief complaint of anorexia. Cholangiography showed severe stenosis of the distal bile duct. A biopsy was conducted from the stenotic lesion and it revealed the lesion to be adenocarcinoma. A diagnosis of distal bile duct carcinoma was made, and SSPPD was performed. Histopathological examination revealed the coexistence of adenocarcinoma and neuroendocrine carcinoma components, and the tumor was confirmed as MINEN of the distal bile duct. No adjuvant chemotherapy was administered due to the poor performance status. 7 months later, the patient was found to have a liver metastasis. CONCLUSION: We experienced two valuable cases of biliary MINEN. To identify better treatments, it is important to consider the diversity of individual cases and to continue sharing a variety of cases with different presentations.

The Diagnostic Value of the CA19-9 and Bilirubin Ratio in Patients with Pancreatic Cancer, Distal Bile Duct Cancer and Benign Periampullary Diseases, a Novel Approach.

Distinction of pancreatic ductal adenocarcinoma (PDAC) in the head of the pancreas, distal cholangiocarcinoma (dCCA), and benign periampullary conditions, is complex as they often share similar clinical symptoms. However, these diseases require specific management strategies, urging improvement of non-invasive tools for accurate diagnosis. Recent evidence has shown that the ratio between CA19-9 and bilirubin levels supports diagnostic distinction of benign or malignant hepatopancreaticobiliary diseases. Here, we investigate the diagnostic value of this ratio in PDAC, dCCA and benign diseases of the periampullary region in a novel fashion. To address this aim, we enrolled 265 patients with hepatopancreaticobiliary diseases and constructed four logistic regression models on a subset of patients (n = 232) based on CA19-9, bilirubin and the ratio of both values: CA19-9/(bilirubin-1). Non-linearity was investigated using restricted cubic splines and a final model, the 'Model Ratio', based on these three variables was fitted using multivariable fractional polynomials. The performance of this model was consistently superior in terms of discrimination and calibration compared to models based on CA19-9 combined with bilirubin and CA19-9 or bilirubin alone. The 'Model Ratio' accurately distinguished between malignant and benign disease (AUC [95% CI], 0.91 [0.86-0.95]), PDAC and benign disease (AUC 0.91 [0.87-0.96]) and PDAC and dCCA (AUC 0.83 [0.74-0.92]) which was confirmed by internal validation using 1000 bootstrap replicates. These findings provide a foundation to improve minimally-invasive diagnostic procedures, ultimately ameliorating effective therapy for PDAC and dCCA.

Recognition and pathological features of periampullary region adenocarcinoma with an indeterminable origin.

Determination of the primary tumor in periampullary region carcinomas can be difficult, and the pathological assessment and clinicopathological characteristics remain elusive. In this study, we investigated the current recognition and practices for periampullary region adenocarcinoma with an indeterminable origin among expert pathologists through a cognitive survey. Simultaneously, we analyzed a prospective collection of cases with an indeterminable primary tumor diagnosed from 2008 to 2018 to elucidate their clinicopathological features. All cases with pathological indeterminable primary tumors were reported and discussed in a clinicopathological conference to elucidate if it was possible to distinguish the primary tumor clinically and pathologically. From the cognitive survey, over 85% of the pathologists had experienced cases with indeterminable primary tumors; however, 70% of the cases was reported as pancreatic cancer without definitive grounds. Interpretation of the main tumor mass varied, and no standardized method was developed to determine the primary tumor. During a prospective study, 42 of the 392 periampullary carcinoma cases (10.7%) were considered as tumors with a pathological indeterminable origin. After the clinicopathological conferences, 21 (5.4%) remained indeterminable and were considered final indeterminable cases. Histological studies showed that the tumors spread along both the bile duct and main pancreatic duct; this was the most representative finding of the final indeterminable cases. This study is the first to elucidate and recognize the current clinicopathological features of periampullary region adenocarcinomas with an indeterminable origin. Adequate assessment of primary tumors in periampullary region carcinomas will help to optimize epidemiological data of pancreatic and bile duct cancer.

The clinical significance of preoperative C-reactive protein/albumin ratio in patients with resected extrahepatic bile duct cancer.

PURPOSE: The C-reactive protein (CRP)/albumin ratio has been identified as a potential prognostic factor for several malignancies. We, therefore, assessed the prognostic role of the CRP/albumin ratio in resected extrahepatic cholangiocarcinoma (EC). MATERIALS AND METHODS: A total of 235 patients were retrospectively analyzed between March 2005 and December 2017. The correlations among the preoperative CRP/albumin ratio, clinicopathological factors, and clinical outcomes were investigated. RESULTS: There were 143 males (60.8%), and the median age at the diagnosis was 70.1 (range 41.0-85.5) years. Patients were diagnosed with perihilar bile duct cancer (n = 61) and distal bile duct cancer (n = 174). The median recurrence-free survival and overall survival were 32.7 and 38.7 months, respectively. The optimal prognostic cut-off point of the CRP/albumin ratio for the survival was 0.18 (× 103). According to the Kaplan-Meier analysis with a log-rank test, the high CRP/albumin ratio group (≥ 0.18) had a significantly shorter overall survival than the low CRP/albumin ratio group (< 0.18) (29.8 vs. 54.6 months, p = 0.002). A multivariate logistic regression analysis for the overall survival showed that CA19-9 ≥ 37 and a high CRP/albumin ratio were associated with a shorter overall survival. CONCLUSION: A high CRP/albumin ratio appears to be significantly associated with clinically worse outcomes in patients with resected EC.

Low H3K9me3 Expression Is Associated With Poor Prognosis in Patients With Distal Common Bile Duct Cancer.

BACKGROUND/AIM: Histone modification is associated with tumorigenesis and cancer progression. Recent studies have revealed the prognostic value of histone modification; however, its prognostic role in distal bile duct cancer remains unclear. PATIENTS AND METHODS: We analyzed the expression of H3K9me3, H4K20me3, and H3K36me3 and its correlation with survival outcomes in resected samples from 88 patients with distal bile duct cancer. RESULTS: Low expression rates of H3K9me3, H4K20me3, and H3K36me3 were significantly associated with poor overall survival (p=0.003, 0.008, and 0.047, respectively) and event-free survival (p=0.03 for H3K9m3). Additionally, low-expression of H3K9me3 was an independent poor prognostic indicator (p<0.001; HR=7.85; 95% CI=2.693-22.883). CONCLUSION: H3K9me3 was an independent poor prognostic factor in distal common bile duct cancer. Our results suggest that histone markers are potential prognostic markers and provide better management for patients at risk for an aggressive course of disease.

Prognostic effects of histology-based tumour microenvironment scores in resected distal bile duct cancer.

AIMS: Histology-based tumour microenvironment (TME) scores are useful in predicting the prognosis of gastrointestinal cancer. However, their prognostic roles in distal bile duct cancer (DBDC) have not been previously studied. This study aimed to evaluate the prognostic significance of the TME scores using the Klintrup-Mäkinen (KM) grade, tumour stroma percentage (TSP) and the Glasgow microenvironment score (GMS) in resected DBDC. METHODS AND RESULTS: Eighty-one patients with DBDC who underwent curative resection were enrolled. DBDC was graded according to KM grade, TSP and GMS. A high KM grade was found in 19 patients (24%) and a high TSP was found in 47 patients (58%). A high TSP was significantly correlated with a low KM grade (P < 0.001). The distribution of the GMS, which was developed by combining the KM grade and TSP, was as follows: 0 (n = 19, 24%), 1 (n = 19, 24%) and 2 (n = 43, 52%). A low KM grade, high TSP and high GMS were significantly associated with short overall survival (OS) (P < 0.001) and relapse-free survival (RFS) (P < 0.001). Furthermore, multivariate analysis showed that a low KM grade [hazard ratio (HR) = 3.826; confidence interval (CI) = 1.650-8.869; P = 0.014], high TSP (HR = 2.193; CI = 1.173-4.100, P = 0.002) and high GMS (HR = 7.148; CI = 2.811-18.173) were independent prognostic factors for short RFS; a low KM grade (HR = 4.324; CI = 1.594-11.733) and high GMS (HR = 6.332; CI = 2.743-14.594) were independent prognostic factors for short OS. CONCLUSION: Histology-based TME scores, including the KM grade, TSP and GMS, are useful for predicting the survival of patients with resected DBDC.

The prognostic impact of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) in patients with distal bile duct cancer.

BACKGROUND: A growing body of evidence suggests that inflammatory response markers such as the neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are associated with outcomes of various malignancies. However, no study has reported the prognostic value of NLR and LMR in patients with distal bile duct cancer (DBDC) to date. We investigated the prognostic significance of these inflammatory markers in patients with DBDC who underwent radical resection. METHODS: The study included 40 patients diagnosed with DBDC who underwent pancreaticoduodenectomy at Narita Red Cross Hospital between January 2000 and December 2017. The cutoff values for these markers were determined by receiver operating characteristic curve analysis. Survival curves are estimated for each group in the study considered separately using the Kaplan-Meier method. The association between overall survival (OS) and the NLR, LMR, and other prognostic factors was investigated using log-rank test and multivariate Cox proportional hazards regression analysis. RESULTS: Corresponding to the point with the maximum combined sensitivity and specificity on the ROC curve, the best cutoff value for NLR and LMR was determined to be 3.14 and 4.55, respectively. Most clinicopathological factors were not associated with the NLR and LMR based on these cutoff values. However, serum albumin levels were associated with both the NLR and LMR (P = 0.011 and P = 0.023, respectively), and serum carbohydrate antigen 19-9 (CA 19-9) levels were also associated with the LMR (P = 0.030). Univariate analysis showed that a high NLR (P < 0.001), low LMR (P = 0.002), hypoalbuminemia (P = 0.004), high serum CA 19-9 levels (P = 0.008), and lymph node metastasis (P = 0.033) were significantly associated with poor survival rates. Multivariate analysis showed that a high NLR (hazard ratio 5.799, 95% confidence interval 1.188-28.32, P = 0.030) and a low LMR (hazard ratio 4.837, 95% confidence interval 1.826-2.331, P = 0.025) were independent prognostic factors for OS. CONCLUSION: Both NLR and LMR may serve as significant independent preoperative prognostic indicators of disease in patients with DBDC who undergo radical resection.

Prognostic impact of the number of metastatic lymph nodes in distal bile duct cancer: An analysis of Japanese registration cases by the study group for biliary surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery.

BACKGROUND: Lymph node metastasis is an important prognostic factor for distal bile duct cancer. The number of lymph node metastases was adopted for nodal classification. However, different cutoff values have been proposed, ranging from two to five. METHODS: A total of 1748 cases who underwent curative surgery with pancreatoduodenectomy for distal bile duct cancer registered in the nationwide biliary tract cancer registry in Japan from 2008 to 2013 were included. Univariate Cox regression was performed to assess the effect of prognostic lymph node metastasis counts on mortality and to determine cutoff values. RESULTS: The overall survival rate after resection was 47.4% at 5 years. Univariate and multivariate analysis found prognostic factors to include lymph node metastasis. The cutoff point was set to two lymph node metastases using the Cox model. There were significant differences in pairwise comparisons between three groups by the number of metastatic lymph node (P < .001 for 0 vs 1-2 and P = .003 for 1-2 vs ≥3). CONCLUSION: Our data suggest lymph node classification as N0 (patients without lymph node metastases), N1 (metastasis in 1-2 regional lymph nodes), and N2 (metastases in ≥3 regional lymph nodes).

Validation of the T category for distal cholangiocarcinoma: Measuring the depth of invasion is complex but correlates with survival.

According to the current 8th edition of the American Joint Committee of Cancer (AJCC), the T category of distal cholangiocarcinomas is classified based on the depth of invasion (DOI) (T1, < 5 mm; T2, between 5 and 12 mm; T3, > 12 mm). In consideration of the discrepancies between previous studies about the prognostic significance, we aimed to validate the current AJCC T staging system of distal cholangiocarcinomas. DOI was measured using three different methods: DOI1, DOI2, and DOI3. DOI1 was defined and stratified according to the AJCC 8th edition. DOI2 was measured as the distance from an imaginary curved line approximated along the distorted mucosal surface to the deepest invasive tumor cells. DOI3 was defined as the total tumor thickness. DOI2 and DOI3 were also divided into three categories using the same cut-off points as in the AJCC 8th edition. We compared these three DOI methods to the AJCC 7th edition as well. In contrast with the AJCC 7th edition, all three groups showed a correlation with patients' overall survival. Above all, the DOI2 group demonstrated the best significance in multivariate analysis. However, when the C indices were compared between these groups, differential significance proved to be negligible (DOI1 vs DOI2, p = 0.915; DOI2 vs DOI3, p = 0.057). Therefore, the measurement of DOI does not need to be rigorously and stringently performed. In conclusion, we showed that the current T classification system better correlates with the overall survival of patients with distal cholangiocarcinomas than the previous system.

Robotic choledochoduodenostomy for benign distal common bile duct stricture: how we do it.

Benign bile duct stricture poses a significant challenge for gastroenterologists and general surgeons due to the inherent nature of the disease, difficulty in sustaining long-term solutions and fear of pitfalls in performing biliary tract operations. Operative management with an open biliary bypass is mainly reserved for patients who have failed multiple attempts of endoscopic and percutaneous treatments. However, recent advances in minimally invasive technology, notably in the form of the robotics, have provided a new approach to tackling biliary disease. In this technical report, we describe our standardized method of robotic choledochoduodenostomy in a 59-year-old woman with history of Roux-en-Y gastric bypass who presents with benign distal common bile duct stricture following failure of non-operative management. Key steps in this approach involved adequate duodenal Kocherization, robotic portal dissection and creation of a side-to-side choledochoduodenal anastomosis. The operative time was 200 min with no intraoperative complications and estimated blood loss was less than 50 mL. No abdominal drains were placed. The patient was discharged home on postoperative day 1 tolerating regular diet and able to resume her usual activities within 1 week of her operation. A video is attached to this report.

High-grade precursor lesions can be used as surrogate markers to identify the epicenter of periampullary carcinomas.

Identifying the accurate origin of periampullary cancers is important because different origins may trigger different clinicopathological behaviors. The presence of intraepithelial precursor lesions, including high-grade pancreatic intraepithelial neoplasias (PanINs) and/or high-grade biliary intraepithelial neoplasias (BilINs), may be suggestive of the origin of the periampullary carcinoma in challenging cases. To prove the usefulness of high-grade intraepithelial precursor lesions in identifying the origin of ambiguous periampullary cancers, the status and grades of PanINs and BilINs were evaluated in 256 periampullary carcinomas with a well-defined cancer origin as a test set, including 114 pancreatic cancers, 82 distal bile duct cancers, 54 ampullary cancers, and 6 duodenal cancers. One hundred twelve periampullary carcinomas with clinically equivocal epicenter either by radiologic imaging or by endoscopic finding used as a validation set. High-grade PanINs were found more commonly in pancreatic cancers than in distal bile duct, ampullary, and duodenal cancers both in test (P = .002) and validation sets (P < .001). Similarly, high-grade BilINs were identified more frequently in distal bile duct cancers than in ampullary, pancreatic, and duodenal cancers both in test (P < .001) and validation sets (P = .039). High-grade PanINs were found most commonly in pancreatic cancers, whereas high-grade BilINs were seen most frequently in distal bile duct cancers. In addition, both high-grade PanINs and high-grade BilINs are uncommonly noted in ampullary or duodenal cancers. The recognition of high-grade intraepithelial lesions can help identify the primary origin of periampullary cancers, especially when the epicenter of the periampullary cancer is ambiguous.

Inverse Prognostic Relationships of 18F-FDG PET/CT Metabolic Parameters in Patients with Distal Bile Duct Cancer Undergoing Curative Surgery.

PURPOSE: As there were few previous studies with a small number of subjects, the purpose of this was to evaluate the prognostic significance of 18F-FDG PET/CT in patients with distal bile duct cancer undergoing curative surgery. METHODS: The study included 40 patients (M/F = 24:16; age 68.0 ± 8.0 years) who underwent preoperative 18F-FDG PET/CT followed by curative surgical resection. The participant's age, sex, Eastern Cooperative Oncology Group performance-status score, baseline serum CA 19-9 level, stage, pathologic T and N stages, tumor size, tumor grade, tumor growth pattern, R0 resection, and adjuvant therapy were included as clinicopathological variables for predicting overall survival. The PET variables were maximum standardized uptake value (SUVmax), average SUV (SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the tumor. The Kaplan-Meyer method and Cox proportional hazards model were used for the survival analysis. RESULTS: A total of 15 of 40 patients (37.5%) died during the follow-up period. In univariate analysis, low SUVmax (≤ 2.7, p = 0.0005) and low SUVavg (≤ 2.6, p = 0.0034) were significant predictors of poor overall survival. In multivariate analyses, only low SUVmax (HR = 6.7016, 95% CI 1.9961-22.4993, p = 0.0047) was an independent prognostic factor associated with poor overall survival. CONCLUSION: The SUVmax of the primary tumor measured by 18F-FDG PET/CT was an independent significant prognostic factor for overall survival in patients with distal bile duct cancer. However, different results from a previous study warrant further large sample-sized study.

Relevant prognostic factors influencing outcome of patients after surgical resection of distal cholangiocarcinoma.

BACKGROUND: Distal cholangiocarcinoma (DCC) is a rare but over the last decade increasing malignancy and is associated with poor prognosis. According to the present knowledge curative surgery is the only chance for long term survival. This study was performed to evaluate prognostic factors for the outcome of patients undergoing curative surgery for distal cholangiocarcinoma. METHODS: 75 patients who underwent surgery between January 2000 and December 2014 for DCC in curative intention were analysed retrospectively. Potential prognostic factors for survival were investigated including the extent of surgery using purposeful selection of covariates in multivariable Cox regression modeling. RESULTS: Preoperative biliary stenting (Hazard ratio (HR): 2.530; 95%-CI: 1.146-6.464, p = 0.020), the extent of surgery in case of positive histological venous invasion (HR: 1.209; 95%-CI: 1.017-1.410, p = 0.032), lymph node staging (HR: 2.183; 95%-CI: 1.250-3.841, p = 0.006), perineural invasion (HR: 2.118; 95%-CI: 1.147-4.054, p = 0.016) and postoperative complications graded in points according to Clavien-Dindo (HR: 1.395; 95%-CI: 1.148-1.699, p = 0.001) were indentified as independent significant risk factors for survival. Patients receiving preoperative biliary stenting showed prolonged duration between onset of symptoms and date of operation (p = 0.048). CONCLUSIONS: Preoperative biliary stenting reduces survival possibly due to delayed surgery. The extent of surgery is not an independent risk factor for survival except for patients with concomitant histological venous invasion. Oncological factors and postoperative surgical complications are independent prognostic factors for survival.

Prognostic predictability of the new American Joint Committee on Cancer 8th staging system for distal bile duct cancer: limited usefulness compared with the 7th staging system.

BACKGROUND: The new 8th American Joint Committee on Cancer (AJCC) staging has recently been released and there are major changes in distal bile duct (DBD) cancer staging. However, clinical validation is needed before the changes can be widely implemented. METHODS: This study was performed to evaluate the prognostic predictability of the 8th AJCC staging compared with that of the 7th using C statistics. RESULTS: A total of 293 consecutive patients who had curative-intended surgery were enrolled. There was no significant difference of the 5-year survival rate between 7th T1 and T2 (P = 0.123), but significant difference between T2 and T3 (P = 0.039). There were significant differences in pairwise comparisons between the 8th T stage (T1 vs. T2, P = 0.001; T2 vs. T3, P = 0.014). The number of regional lymph node metastases also showed prognostic predictability. The 8th T and N stage both showed comparable prognostic predictability with the 7th (95% confidential intervals for C; T, -0.043 -0.097, N, -0.001 - 0.008). CONCLUSIONS: The 8th AJCC staging for DBD cancer does not have better prognostic predictability than the 7th stage does. The previous pathologic results would become useless unless they were reviewed entirely. Therefore, introduction of the AJCC 8th staging has to be reconsidered, especially for new T staging.

Mixed adenoneuroendocrine carcinoma of the distal bile duct: A case report.

INTRODUCTION: Mixed adenoneuroendocrine carcinomas (MANECs) of the distal bile duct are extremely rare, and only a few cases have been reported in the English literature. PRESENTATION OF CASE: An 82-year-old man was referred to our hospital for increasing biliary enzymes. Abdominal computed tomography (CT) showed enlargement of the intrahepatic bile ducts and stenosis of the distal bile duct. Endoscopic retrograde cholangiopancreatography showed stenosis of the distal bile duct and a high-density signal at the same site on diffusion weighted imaging. PET-CT showed increased FDG accumulation (SUVmax: 4.5) at the distal bile duct stenosis. Biopsy specimens obtained by endoscopic ultrasonography-guided fine-needle aspiration revealed adenocarcinoma. The patient was diagnosed with adenocarcinoma of the distal bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection. The resected distal bile duct tumor was 18×14×12mm in diameter. Hematoxylin and eosin staining revealed a composite carcinoma with adenocarcinoma and non-adenocarcinoma elements. The non-adenocarcinoma component stained positive for synaptophysin and chromogranin A. The Ki-67 labeling index was 37%. The non-adenocarcinoma component was therefore diagnosed as a neuroendocrine carcinoma. The two composite carcinoma was diagnosed as MANEC of the distal bile duct. The patient was treated with surgery alone and he remained disease-free for 7 months after the surgery. DISCUSSION: The treatment of MANECs of the bile duct remains controversial and the prognosis is poor. CONCLUSIONS: There is no standard treatment for MANECs of the bile duct. Larger studies are required to establish standard treatment regimens.

Survival outcome and prognostic factors after pancreatoduodenectomy for distal bile duct carcinoma: a retrospective multicenter study.

PURPOSE: Pancreatoduodenectomy is the most common operative procedure performed for distal bile duct carcinoma. Data on outcome after surgery for this rare malignancy is scarce, especially from western countries. The purpose of this study is to explore the prognostic factors and outcome after pancreatoduodenectomy for distal bile duct carcinoma. METHODS: Patients receiving pancreatoduodenectomy for distal bile duct carcinoma were identified from institutional databases of five German and one Russian academic centers for pancreatic surgery. Univariable and multivariable general linear model, Kaplan-Meier method, and Cox regression were used to identify prognostic factors for postoperative mortality and overall survival. RESULTS: N = 228 patients operated from 1994 to 2015 were included. Reoperation (OR 5.38, 95%CI 1.51-19.22, p = 0.010), grade B/C postpancreatectomy hemorrhage (OR 3.73, 95%CI 1.13-12.35, p = 0.031), grade B/C postoperative pancreatic fistula (OR 4.29, 95%CI 1.25-14.72, p = 0.038), and advanced age (OR 4.00, 95%CI 1.12-14.03, p = 0.033) were independent risk factors for in-hospital mortality in multivariable analysis. Median survival was 29 months, 5-year survival 27%. Positive resection margin (HR 2.07, 95%CI 1.29-3.33, p = 0.003), high tumor grade (HR 1.71, 95%CI 1.13-2.58, p = 0.010), lymph node (HR 1.68, 95%CI 1.13-2.51, p = 0.011), and distant metastases (HR 2.70, 95%CI 1.21-5.58, p = 0.014), as well as severe non-fatal postoperative complications (HR 1.64, 95%CI 1.04-2.58, p = 0.033) were independent negative prognostic factors for survival in multivariable analysis. CONCLUSION: Distant metastases and positive resection margin are the strongest negative prognostic factors for survival after pancreatoduodenectomy for distal bile duct carcinoma; thus, surgery with curative intent is only warranted in patients with local disease, where R0 resection is feasible.

The Likely Sites of Nodal Metastasis Differs According to the Tumor Extent in Distal Bile Duct Cancer.

BACKGROUND: In the revised Japanese and Worldwide TNM classification of distal bile duct cancer, the lymph node status is defined as N0 or N1 without reference to the tumor location or extent, according to the presence/absence of metastasis to the regional lymph nodes. METHODS: Data of 94 patients with distal bile duct cancer who had undergone pancreaticoduodenectomy were reviewed retrospectively. In formalin-fixed specimens, we measured the longitudinal lengths from the papilla to the lower and upper margins of the tumor, in order to investigate the correlation of the tumor extent with the likely sites of nodal metastasis. RESULTS: The frequencies of metastasis to the posterior pancreaticoduodenal nodes (7.1 %) and superior mesenteric artery nodes (0.0 %) were significantly lower in the cases in which the length from the papilla to the lower margin of the tumor was ≥30 mm. The frequencies of nodal metastasis to the common hepatic artery nodes (0.0 %) and hepatoduodenal ligament nodes (6.7 %) were significantly lower in the cases in which the length from the papilla to the upper margin was <40 mm. CONCLUSION: The likely sites of nodal metastasis differ according to the extent of the tumor in cases of bile duct cancer.

EGFR, COX2, p-AKT expression and PIK3CA mutation in distal extrahepatic bile duct carcinoma.

Distal extrahepatic bile duct (EBD) carcinoma is a rare but highly aggressive malignant neoplasm. Some in vitro studies have shown that EGFR and PI3K-Akt pathway play an important role in the carcinogenesis of bile duct carcinoma. The aim of the present study is to investigate the expression of EGFR, p-AKT, and COX-2 and the mutation of PIK3CA in distal EBD carcinoma and evaluate the association with clinicopathological factors. Ninety cases of distal extrahepatic bile duct (EBD) carcinoma specimens were studied. Immunohistochemistry (IHC) using antibodies against EGFR, p-AKT, and COX-2 was performed on TMA blocks. The PIK3CA mutation was evaluated using the PNAClamp Detection Kit from DNA samples extracted from formalin fixed, paraffin embedded tissue. EGFR expression of distal EBD carcinomas was 61.9%, 26.2%, 6.0% and 6.0% in the negative, weakly positive, moderately positive, and strongly positive groups, respectively. Positive EGFR expression showed significant relationships with high T stage (p = 0.024). In Kaplan-Meier analysis, EGFR expression was associated with shorter cancer-specific overall survival (p = 0.005). Multivariate analysis also showed that moderate or strong (2+ or 3+) EGFR expression was a significant prognostic factor in distal EBD carcinoma: HR 5.286; p = 0.001. Ninety cases of EBD carcinoma tissue were analysed for hotspot mutations (exon 9 and 20) in the PIK3CA gene. Only one mutation was detected: a missense mutation of H1047 at exon 20. The expression levels of p-AKT and COX-2 showed no association with any clinicopathological parameters, including survival rate. Moderate and strong EGFR expressions demonstrate a direct link to poor prognosis. Although further study is warranted to understand the clinicopathological significance, our finding suggests EGFR is a useful prognostic marker of patients with distal EBD carcinoma. A low prevalence of PIK3CA mutation exists in the distal EBD carcinoma of Korean patients, indicating that mutation screening may not be useful in determining prognosis or in formulating a treatment response to targeted inhibition in Korea.