Comparative dosimetric study of spot-scanning proton therapy versus volumetric-modulated radiation therapy for extrahepatic bile duct cancer.

This study aimed to compare the dose distributions and clarify the dosimetric characteristics of spot-scanning proton therapy (SSPT) and photon volumetric modulated arc therapy (VMAT) for extrahepatic bile duct cancer (EBDC). This retrospective study included 10 patients with EBDC treated with real-time image-gated SSPT. Using the simultaneous integrated boost technique, the 2 prescription dose levels for planning target volumes were 72.6 and 44 Gy, delivered in 22 fractions. Plan quality comparisons were conducted by analyzing various parameters, including homogeneity, conformity, dose to organs at risk, and normal tissue complication probability (NTCP) for radiation-induced liver damage (RILD). The target dose distributions using SSPT were almost equivalent to those achieved using photon VMAT. There was a significant reduction in all liver dose parameters, the NTCP value for RILD, and kidney dose (mean, V12 Gy, and V18 Gy) in SSPT than in photon VMAT. No significant differences were observed in the intestinal doses in the high-dose area. Thus, compared with photon VMAT, SSPT for EBDC significantly reduced radiation doses to the liver and kidneys and has shown potential clinical benefits of reduced radiation-induced toxicity.

Risk Factors for Distant Metastasis in Extrahepatic Bile Duct Cancer after Curative Resection (KROG 1814).

PURPOSE: Risk factors predicting distant metastasis (DM) in extrahepatic bile duct cancer (EHBDC) patients treated with curative resection were investigated. MATERIALS AND METHODS: Medical records of 1,418 EHBDC patients undergoing curative resection between Jan 2000 and Dec 2015 from 14 institutions were reviewed. After resection, 924 patients (67.6%) were surveilled without adjuvant therapy, 297 (21.7%) were treated with concurrent chemoradiotherapy (CCRT) and 148 (10.8%) with CCRT followed by chemotherapy. To exclude the treatment effect from innate confounders, patients not treated with adjuvant therapy were evaluated. RESULTS: After a median follow-up of 36.7 months (range, 2.7 to 213.2 months), the 5-year distant metastasis-free survival (DMFS) rate was 57.7%. On multivariate analysis, perihilar or diffuse tumor (hazard ratio [HR], 1.391; p=0.004), poorly differentiated histology (HR, 2.014; p < 0.001), presence of perineural invasion (HR, 1.768; p < 0.001), positive nodal metastasis (HR, 2.670; p < 0.001) and preoperative carbohydrate antigen (CA) 19-9 ≥ 37 U/mL (HR, 1.353; p < 0.001) were significantly associated with inferior DMFS. The DMFS rates significantly differed according to the number of these risk factors. For validation, patients who underwent adjuvant therapy were evaluated. In patients with ≥ 3 factors, additional chemotherapy after CCRT resulted in a superior DMFS compared with CCRT alone (5-year rate, 47.6% vs. 27.7%; p=0.001), but the benefit of additional chemotherapy was not observed in patients with 0-2 risk factors. CONCLUSION: Tumor location, histologic differentiation, perineural invasion, lymph node metastasis, and preoperative CA 19-9 level predicted DM risk in resected EHBDC. These risk factors might help identifying a subset of patients who could benefit from additional chemotherapy after resection.

Proton beam therapy for extrahepatic biliary tract cancer: Analysis with prospective multi-institutional patients' registration database, Proton-Net.

Background and purpose: To examine the role of proton beam therapy (PBT) in the treatment of extrahepatic biliary tract cancer (EBC). Methods and materials: We analyzed the data accumulated in the Proton-Net database, which prospectively registered all individual patient data treated with PBT in all Japanese proton institutions from May 2016 to June 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS), and toxicity. Results: Ninety-three patients with unresectable and/or recurrent EBC were treated with PBT using a median prescribed dose of 67.5 Gy (RBE) (range, 50-72.6 Gy) in 25 (22-30 fractions). With a median follow-up of 16.3 months, the median survival time was 20.1 months and the 2-year OS was 37.8%. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Poor liver function (Child-Pugh B, C), a narrower distance between the tumor and digestive tract (2 cm >), and a larger tumor diameter (2 cm <) were identified as poor prognostic factors for OS. PBT-related grade 3 ≤ acute and late adverse events occurred in 5.4% and 4.3% of patients, respectively, including one gastrointestinal late toxicity (duodenal ulcer). Conclusions: This is the largest prospectively accumulated series of PBT for EBC, and PBT showed favorable outcomes with acceptable toxicity profiles.

Adenosquamous Carcinoma of the Extrahepatic Bile Duct.

Background: Most malignant tumors arising from the biliary tract are adenocarcinomas. Adenosquamous carcinoma is an uncommon variant of extrahepatic bile duct cancer that is associated with more aggressive behavior than adenocarcinoma. Case Report: A 58-year-old male presented with complaints of obstructive jaundice and dull aching pain in the abdomen. At his initial evaluation in another hospital, ultrasound of the abdomen and magnetic resonance cholangiopancreatography revealed common bile duct dilatation with an ill-defined lesion in the periampullary region. Endoscopic retrograde cholangiopancreatography showed infiltration of the ampulla. Biopsy specimen taken during stenting of the common bile duct suggested dysplasia. Because of recurrent jaundice, the patient was referred to our institution, and contrast-enhanced computed tomography (CT) of the abdomen showed a hypoenhancing lesion with ill-defined margins in the head of the pancreas. The patient underwent a Whipple procedure. Microscopic examination of the pancreaticoduodenectomy specimen showed an invasive adenosquamous tumor arising from the distal part of the common bile duct that infiltrated the body and head of the pancreas, involved the wall of the duodenum, and reached the duodenal mucosa. Morphologic diagnosis was supported by immunohistochemistry profile. Postoperative contrast-enhanced CT of the abdomen showed multiple enlarged mesenteric lymph nodes and multiple lesions in both lobes of the liver, suggestive of metastasis. The patient died 1 week after surgery. Conclusion: Because the clinical, pathologic, and prognostic characteristics of adenosquamous carcinoma are poorly known, early diagnosis of this rare entity is warranted for patient management.

Synchronous double primary malignancies of the pancreatic body and extrahepatic bile duct treated with pancreatoduodenectomy and splenic artery resection following neoadjuvant chemotherapy with gemcitabine plus nab-paclitaxel: a case report.

BACKGROUND: Primary pancreatic cancer with synchronous primary tumors in other organs is a rare condition, and its treatment largely depends on the progression of pancreatic cancer. Here, we describe a rare case of double primary malignancies involving borderline resectable pancreatic body and extrahepatic bile duct cancers that were successfully resected after neoadjuvant chemotherapy (NAC), subsequently avoiding total pancreatectomy. CASE PRESENTATION: A 61-year-old Japanese male was referred to our hospital by his general practitioner after presenting with elevated liver enzymes during a routine check-up for type 2 diabetes mellitus. He was diagnosed with synchronous borderline resectable pancreatic cancer in the body of the pancreas and lower extrahepatic bile duct cancer with obstructive jaundice. Abdominal computed tomography (CT) confirmed a hypovascular mass in the pancreatic body with partial encasement of the common hepatic artery, left gastric artery, celiac artery, and splenic artery and invasion of the splenic vein. Endoscopic retrograde cholangiopancreatography and bile duct biopsy confirmed lower bile duct cancer. Following multidisciplinary discussion, endoscopic retrograde biliary drainage was performed, and neoadjuvant chemotherapy comprising gemcitabine plus nanoparticle albumin-bound paclitaxel (GEM + nab-PTX) was administered. After a total of seven cycles of chemotherapy, follow-up CT showed that the size of the pancreatic lesion reduced, following which the patient underwent pancreatoduodenectomy with splenic artery resection. The postoperative course was uneventful without any surgical complications or intensive hypoglycemic treatment. The pathological diagnosis was pancreatic ductal adenocarcinoma (ypT3N1aM0 ypStage IIB/UICC 8th) with synchronous extrahepatic cholangiocarcinoma (ypT2N1M0 ypStage IIB/UICC 8th). R0 pancreatic resection was performed with an Evans grade III response to neoadjuvant chemotherapy. The patient was followed up and had no tumor recurrence at 22 months after surgery with adjuvant S-1 chemotherapy, however, died after 32 months after surgery due to multiple liver metastasis and para-aortic lymph node metastasis despite salvage GEM + nab-PTX chemotherapy. CONCLUSION: In our case, neoadjuvant chemotherapy for borderline resectable pancreatic cancer and function-preserving pancreatoduodenectomy (R0 resection) for double primary malignancies achieved balanced patient survival and postoperative quality of life.

Role of adjuvant radiotherapy in extrahepatic bile duct cancer: A multicenter retrospective study (Korean Radiation Oncology Group 18-14).

PURPOSE: To evaluate the role of adjuvant radiotherapy (RT) after curative resection in patients with extrahepatic bile duct (EHBD) cancer. METHODS: Between January 2000 and December 2015, 1475 patients with EHBD cancer who underwent curative resection were accrued from 14 institutions in Korea. Among these, 959 patients did not receive any adjuvant therapy (RT(-) group), while 516 underwent postoperative RT with or without chemotherapy (RT(+) group). RESULTS: The median age was 67 years. Nodal involvement was present in 482 patients (32.7%), and resection margin was involved in 293 patients (19.9%). RT(+) group had more patients with proximal tumours, advanced tumours, nodal involvement, perineural invasion, and involved resection margin than RT(-) group (all p < 0.001). With a median follow-up of 36 months, there were 211 locoregional recurrences, 307 distant metastases and 322 combined locoregional and distant failures. On multivariate analysis incorporating age, tumour location, differentiation, pT classification, pN classification, perineural invasion and resection margin, adjuvant RT was associated with improved overall survival (hazard ratio, 0.74; 95% confidence interval, 0.63-0.86; p < 0.001). When RT(+) group was separated into RT alone, concurrent chemoradiotherapy (CCRT) and CCRT followed by chemotherapy, the greatest benefit was observed in patients treated with CCRT followed by chemotherapy (hazard ratio, 0.52; 95% confidence interval, 0.41-0.68). CONCLUSIONS: Adjuvant RT combined with chemotherapy improved survival outcomes of resected EHBD cancer patients. Considering the greatest benefit observed in patients receiving CCRT followed by chemotherapy, a randomised controlled trial comparing chemotherapy alone and CCRT followed by chemotherapy is urgently needed.

Radiologic Evaluation and Structured Reporting Form for Extrahepatic Bile Duct Cancer: 2019 Consensus Recommendations from the Korean Society of Abdominal Radiology.

Radiologic imaging is important for evaluating extrahepatic bile duct (EHD) cancers; it is used for staging tumors and evaluating the suitability of surgical resection, as surgery may be contraindicated in some cases regardless of tumor stage. However, the published general recommendations for EHD cancer and recommendations guided by the perspectives of radiologists are limited. The Korean Society of Abdominal Radiology (KSAR) study group for EHD cancer developed key questions and corresponding recommendations for the radiologic evaluation of EHD cancer and organized them into 4 sections: nomenclature and definition, imaging technique, cancer evaluation, and tumor response. A structured reporting form was also developed to allow the progressive accumulation of standardized data, which will facilitate multicenter studies and contribute more evidence for the development of recommendations.

Histological evaluation of tumor differentiation score and prognosis of extrahepatic bile duct cancer: A proposal for a new histological grading system.

Extrahepatic bile duct (EHBD) cancer is a devastating cancer, and more common in Asian countries than in Western countries. Histological grading continues to be a highly relevant factor in prognosis and management of many kinds of cancer, however no uniform histological grading system exists for EHBD cancer. Histological heterogeneity within tumors is a problem in the evaluation of EHBD cancer. We developed an EHBD histological grading scheme to evaluate tumor differentiation pattern, and statistically analyzed its relationship with prognosis. In the present study, 257 surgically resected EHBD cancers were reviewed and their histological glandular differentiation (HGD) pattern was scored, and then we summed up the most and second most predominant scores. These scores were statistically analyzed for their relationship with patient prognosis. Patients showed a trend of shortening recurrence-free survival (RFS) and overall survival (OS) in association with higher HGD scores. In multivariate analyses, HGD score was determined to be an influential factor in RFS (P = 0.00041) and OS (P < 0.0001). In addition, combining HGD score and lymph node status correctly stratified patient prognosis in RFS. In conclusion, this new HGD scoring system is highly practical and has powerful prognostic value for EHBD cancer.

Clinical anatomy of the anterior and posterior hepatic plexuses, including relations with the pancreatic plexus: A cadaver study.

The poor prognosis after surgery for pancreatic cancer or extrahepatic bile duct cancer has mainly been attributed to early lymph node metastasis, as well as a high frequency of perineural invasion along the peripancreatic neural plexuses or extrahepatic bile duct plexus. However, there has been no detailed morphological description of the anterior and posterior hepatic plexuses (AHP and PHP). In addition, the concepts of the pancreatic plexus and PHP are confused by surgeons. To assess the relations of the pancreatic plexus and hepatic plexuses from the morphological, developmental, and clinical perspectives, these plexuses were dissected in 24 cadavers. The PHP was found to be completely independent of the AHP. The PHP ran behind the portal vein, with most nerve fibers ascending along the bile duct to the gallbladder and the liver or descending to the distal common bile duct and duodenal papilla. Some branches of the PHP contributed to the pancreatic plexus, corresponding to pancreatic head plexus I as defined by the Japan Pancreas Society. The differences between the PHP and pancreatic head plexus I should be understood, even though liver function is not obviously affected after PHP excision for pancreatic head cancer. Further study is needed to determine whether there are functional differences between the AHP and PHP. Clin. Anat., 33:630-636, 2020. © 2019 Wiley Periodicals, Inc.

Radiation therapy for extrahepatic bile duct cancer: Current evidences and future perspectives.

Extrahepatic bile duct cancer (EBDC) is a rare malignancy that involves neoplastic changes extending from both hepatic ducts to the common bile duct. The treatment of choice is surgical resection, but the predominant pattern of initial treatment failure is locoregional recurrence. Accordingly, adjuvant radiotherapy has been administered after surgical resection based on these rationales. At this time, there is minimal evidence supporting adjuvant radiotherapy, because there have been no phase III trials evaluating its benefit. Relatively small retrospective studies have tried to compare outcomes associated with EBDC treated with or without radiotherapy. We aimed to review studies investigating adjuvant radiotherapy for resected EBDC. Because less than one-third of EBDC cases are amenable to curative resection at diagnosis, other locoregional treatment modalities need to be considered, including radiotherapy. The next aim of this review was to summarize reports of definitive radiotherapy for unresectable EBDC. Patients with advanced EBDC often experience biliary obstruction, which can lead to jaundice and progress to death. Biliary stent insertion is an important palliative procedure, but stents are prone to occlusion after subsequent ingrowth of the EBDC. Radiotherapy can be effective for maintaining the patency of inserted stents. We also reviewed the benefit of palliative radiotherapy combined with the biliary stent insertion. Lastly, we discuss the existing gaps in the evidence supporting radiotherapy in the management of EBDC.

The Comparison of Inflammation-Based Prognostic Scores in Patients With Extrahepatic Bile Duct Cancer After Pancreaticoduodenectomy.

BACKGROUND: Inflammation-based prognostic scores are associated with tumor recurrence and survival in various cancers. The aim of this study was to identify the significance of inflammation-based prognostic scores and to detect the most useful score in patients with distal extrahepatic bile duct cancer after pancreaticoduodenectomy. METHODS: Between 2000 and 2015, 121 patients were enrolled in this retrospective study. The relationship between clinicopathological variables including various prognostic scores and disease-free (DFS) as well as overall (OS) survival was investigated by univariate analysis. The area under the receiver operating characteristics curve was calculated to compare the predictive ability of each scoring system. Multivariate analysis was performed to identify the clinicopathological variables associated. RESULTS: In univariate analysis, Glasgow prognostic score (GPS), mGPS, C-reactive protein/Alb ratio score, prognostic index, and preoperative monocyte count were significant risk factors for both DFS and OS. The area under the receiver operating characteristics curve of GPS is consistently larger in comparison with other four scores in both DFS as well as OS. In multivariate analysis, GPS was an independent risk factor of both tumor recurrence and poor prognosis. CONCLUSIONS: GPS score is an independent tumor recurrence and prognostic factor in patients with distal extrahepatic bile duct cancer and is superior to the other prognostic scores.

Overexpression of matriptase in tumor stroma is a poor prognostic indicator of extrahepatic bile duct cancer.

Bile duct cancer is known to contain numerous fibroblasts, and reported to recruit cancer- associated fibroblasts by secreting platelet-derived growth factor-D (PDGF-D) which needs serine proteases, such as matriptase, to behave as a ligand. However, their expression pattern, and prognostic value have not been clarified. In this study, we investigated the clinicopathological significance of PDGF-D and matriptase expression in patients with extrahepatic bile duct cancer. The samples were obtained from 256 patients who underwent the surgical resection between 1991 and 2015, and the expression levels of PDGF-D and matriptase were evaluated immunohistochemically. Staining intensities and distribution were scored, and finally classified into low and high expression groups in cancer cells and stroma respectively. High expression of matriptase in the cancer stroma was detected in 91 tumors (40%). The high stromal matriptase expression was significantly associated with shorter recurrence-free survival (RFS) and overall survival (OS) (P = 0.0027 and 0.0023, respectively). Multivariate analyses also demonstrated that the stromal matriptase expression level was an independent influential factor in RFS (P = 0.0050) and OS (P = 0.0093). Our findings suggest that the high stromal matriptase expression was strongly associated with tumor progression, recurrence and poor outcomes in patients with extrahepatic bile duct cancer.

Cytoplasmic CD133 expression correlates with histologic differentiation and is a significant prognostic factor in extrahepatic bile duct cancer and gallbladder cancer.

Prominin-1 (CD133) is one of the most important stem cell markers among various malignant tumor types, but the clinicopathological significance of CD133 expression in intrahepatic cholangiocarcinoma remains controversial. To the best of our knowledge, there have been no reports on extrahepatic bile duct cancer (EHBDCA) and gallbladder cancer (GBCA). The present study examined the clinicopathological significance of CD133 expression in EHBDCA and GBCA. Immunohistochemistry was used to evaluate CD133 expression in resected specimens obtained from 82 patients with EHBDCA and GBCA, and this expression was compared with the clinicopathological parameters and survival data of the patients. Cytoplasmic CD133 expression was identified in 20 patients, and its incidence was significantly associated with histopathological grade (P=0.035), pT factor (P=0.020) and recurrence (P=0.046). Survival analysis revealed that cytoplasmic CD133 expression in patients was significantly associated with a poorer overall survival (OS) and relapse-free survival (RFS) compared with those without cytoplasmic expression (5-year OS rate, 11.6% vs. 39.1%; 3-year RFS rate, 12.5% vs. 42.0%, respectively). Multivariate analysis revealed that cytoplasmic CD133 expression was an independent prognostic factor for OS and RFS (P=0.0036 and P<0.0001, respectively). To the best of our knowledge, this is the first report demonstrating that cytoplasmic CD133 expression was associated with histologic differentiation, cancer progression, recurrence and poor prognosis in EHBDCA and GBCA. CD133 expression may be a useful marker for clinical prognosis in patients with EHBDCA and GBCA.

Synchronous double primary cancers of the extrahepatic bile duct: A case report and literature review.

BACKGROUND: Double cancers of the biliary tract system are rare. Most of these cancers are synchronous double cancers of the gall bladder and bile duct, associated with pancreaticobiliary maljunction (PBM). Synchronous double cancers of the extrahepatic bile duct without PBM are especially rare, and only 4 cases have been reported. CASE PRESENTATION: A 78-year-old woman was admitted to our hospital for examination of hyperbilirubinemia and liver dysfunction. Contrast-enhanced abdominal computed tomography, Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography revealed 2 stenotic regions in the common bile duct: at its junction with the cystic duct and in the distal bile duct. No findings suggested PBM, such as a markedly long common channel. The diagnosis based on endoscopic brush cytology from both stricture portions was adenocarcinoma. The patient had a pylorus-preserving pancreaticoduodenectomy with regional lymph node resection. Macroscopically, there were 2 stenotic regions at the cystic duct junction and in the distal bile duct. Microscopically, the tumor at the junction of the cystic duct was a well-to-moderately differentiated adenocarcinoma. On the other hand, the tumor of the distal bile duct was a poorly differentiated adenocarcinoma. There was no evidence of communication between these 2 cancers. CONCLUSION: Double cancers of the extrahepatic bile duct without PBM are very rare. Therefore, an accurate diagnosis prior to surgery is necessary. Furthermore, this rare condition seems to be associated with a poor prognosis.

High expression of MMP-9 is associated with better prognosis in extrahepatic bile duct cancer patients.

PURPOSE: To evaluate the prognostic value of matrix metalloproteinase-9 (MMP-9) in patients with extrahepatic bile duct (EHBD) cancer undergoing surgical resection and adjuvant radiotherapy. METHODS: Between January 2000 and August 2006, patients who underwent complete resection followed by adjuvant radiotherapy for EHBD cancer were enrolled in this study. The expression of MMP-9 was assessed with immunohistochemical staining. The prognostic values of the MMP-9 expression and other clinicopathologic factors were evaluated in univariate and multivariate analyses. RESULTS: Sixty-six patients were included in this study. All received radiotherapy with a median dose of 40 Gy (range, 40-56), and 61 patients received concomitant fluoropyrimidine chemotherapy. MMP-9 was highly expressed in 33 patients (50.0%). MMP-9 expression was significantly associated with locoregional recurrence-free survival (LRRFS) and overall survival (OS) but not with distant metastasis-free survival (DMFS). The 5-year LRRFS and OS rates were 50.8% versus 86.5% (p = .0281), and 23.3% versus 68.1% (p = .0087) in patients with low and high expression of MMP-9, respectively. Among the clinicopathologic factors, tumor location was associated with DMFS and OS (p = .0292 and .0003, respectively). Nodal stage and histologic differentiation showed significant association with DMFS (p = .0277 and .0060, respectively). Based on multivariate analysis for OS, tumor location was the only significant prognostic factor (p = .0021), while MMP-9 expression showed marginal significance (p = .0633). CONCLUSION: MMP-9 expression is a useful prognostic factor for predicting LRRFS and OS in patients with EHBD cancer after surgical resection and adjuvant radiotherapy.

Characterization of Prognostic Factors and the Efficacy of Adjuvant S-1 Chemotherapy in Patients with Post-surgery Extrahepatic Bile Duct Cancer.

BACKGROUND/AIM: There is no clear consensus on the type of adjuvant therapy that should be used for patients with extrahepatic bile duct cancer. PATIENTS AND METHODS: Two hundred and seventy-one patients that had undergone surgical resection for extrahepatic bile duct cancer composed the study cohort. Demographics, treatments, and relationships between the potential prognostic factors and survival rates were analyzed. RESULTS: The overall 3-year and 5-year survival rates for post-surgery extrahepatic bile duct cancer patients were 49.0% and 35.4%, respectively. Multivariate analysis revealed that regional lymph node metastasis was an independent negative prognostic factor. We observed a significant correlation between node-positive extrahepatic bile duct cancer and postoperative local recurrence, liver metastasis, peritoneal dissemination, and post-surgery lymph node metastasis. Adjuvant S-1 chemotherapy showed a favorable hazard ratio in patients with lymph node metastases or positive vascular invasion. CONCLUSION: We recommend the use of adjuvant S-1 therapy in patients with lymph node metastases or microvascular invasion.

Impact of radiation dose in postoperative radiotherapy after R1 resection for extrahepatic bile duct cancer: long term results from a single institution.

PURPOSE: This study was conducted to evaluate the impact of radiation dose after margin involved resection in patients with extrahepatic bile duct cancer. METHODS: Among the 251 patients who underwent curative resection followed by adjuvant chemoradiotherapy, 86 patients had either invasive carcinoma (n = 63) or carcinoma in situ (n = 23) at the resected margin. Among them, 54 patients received conventional radiation dose (40-50.4 Gy) and 32 patients received escalated radiation dose (54-56 Gy). RESULTS: Escalated radiation dose was associated with improved locoregional control (5yr rate, 73.8% vs. 47.1%, p = 0.069), but not disease-free survival (5yr rate, 43.4% vs. 32.6%, p = 0.490) and overall survival (5yr rate, 40.6% vs. 29.6%, p = 0.348). In multivariate analysis for locoregional control, invasive carcinoma at the margin (HR 2.957, p = 0.032) and escalated radiation dose (HR 0.394, p = 0.047) were independent prognostic factors. No additional gastrointestinal toxicity was observed in escalated dose group. CONCLUSIONS: Delivery of radiation dose ≥ 54 Gy was well tolerated and associated with improved locoregional control, but not with overall survival after margin involved resection. Further validation study is warranted.

Prognostic Impact of Extracapsular Lymph Node Invasion and Myofibroblastic Activity in Extrahepatic Bile Duct Cancer.

Extrahepatic bile duct carcinoma is a potentially malignant gastrointestinal lesion. Cancer cells spread via the lymphatic system to regional lymph nodes and help in tumor progression. However, there are no reports on the prognostic impact of extracapsular lymph node invasion and myofibroblastic activity in this cancer. Hence, we classified the histopathologic patterns of lymph nodes into 2 patterns: extracapsular lymph node invasion or not. Based on this, we investigated 32 cases of extrahepatic bile duct cancer with lymph node metastasis and classified 21 cases as positive and 11 cases as negative. The extracapsular lymph node invasion cases were associated with poor disease-free survival and overall survival. The myofibroblast density of the metastatic foci was significantly higher in the extracapsular lymph node invasion cases. This is the first study to demonstrate that extracapsular lymph node invasion cases were associated with poor prognosis and that the myofibroblast distribution contributed to malignancy.

Adjuvant concurrent chemoradiotherapy with low-dose daily cisplatin for extrahepatic bile duct cancer.

PURPOSE: We aimed to present the clinical outcomes of adjuvant concurrent chemoradiotherapy (CCRT) with low-dose daily cisplatin regimen compared to the conventional 5-fluorouracil (5-FU)-based regimen for extrahepatic bile duct cancer (EHBDC). METHODS: From October 1994 to April 2013, 41 patients received adjuvant CCRT with low-dose daily regimen or 5-FU-based regimens. Nineteen patients received low-dose of cisplatin just before every delivery of radiation therapy, and 21 patients received two cycles of 5-FU-based regimen during radiotherapy. We compared the clinical outcomes between two adjuvant CCRT regimens. RESULTS: Adjuvant CCRT with low-dose daily cisplatin showed comparable toxicity profiles compared with that of a 5-FU-based regimen. The median follow-up time was 33 months (range, 5-205), and the 5-year overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 34.2, 50.8, and 49.7%, respectively. Univariable analyses showed no significant differences in OS, LRRFS, and DMFS between the groups with two regimens. In multivariable analyses, chemotherapeutic regimen was a significant prognostic factor for OS, favoring the low-dose daily cisplatin regimen (HR = 2.491, p = 0.036) over 5-FU-based regimen, though not for LRRFS (p = 0.642) and DMFS (p = 0.756). CONCLUSIONS: Adjuvant CCRT with low-dose daily cisplatin regimen showed acceptable toxicities and survivals compared to those of the 5-FU-based regimen. Low-dose daily cisplatin can be one of the feasible regimens for adjuvant CCRT for EHBDC.

Prognostic Impact of CD163+ Macrophages in Tumor Stroma and CD8+ T-Cells in Cancer Cell Nests in Invasive Extrahepatic Bile Duct Cancer.

AIM: The aim of this study was to examine the clinicopathological influence of tumor-infiltrating cluster of differentiation (CD) 163+ macrophages and CD8+ T-cells, and to clarify the prognostic effects of these cells in patients with invasive extrahepatic bile duct cancer (EHBC). MATERIALS AND METHODS: The numbers of CD8+ T-cells in cancer cell nests and CD163+ macrophages in tumor stroma were evaluated using immunohistochemistry in 101 resected EHBC specimens. Correlations with clinicopathological variables and overall survival were analyzed. RESULTS: Perihilar EHBC and perineural invasion were significantly associated with a low number of tumor-infiltrating CD8+ T-cells. Poorly- differentiated histology and nodal metastasis were significantly associated with a high number of tumor-infiltrating CD163+ macrophages. A combination of high number of CD8+ T-cells and low number of CD163+ macrophages was independently related to better overall survival in the whole patient cohort (hazard ratio=0.127, p<0.001) and in patients treated with adjuvant chemotherapy (hazard ratio=0.139, p=0.021). CONCLUSION: Infiltrating CD163+ macrophages in tumor stroma and CD8+ T-cells in cancer cell nests have a prognostic impact in patients with EHBC following resection and also after adjuvant chemotherapy.