Bile Duct Margin Research Articles

Clinicopathologic and Prognostic Significance of Gallbladder and Cystic Duct Invasion in Distal Bile Duct Carcinoma.

The roles of the gallbladder and cystic duct (CD) invasions in distal bile duct carcinoma (DBDC) have not been well elucidated. To define the characteristics and prognostic significance of gallbladder or CD invasions in patients with DBDC. Organ invasion patterns with clinicopathologic features were assessed in 258 resected DBDCs. CD invasions (N = 31) were associated with frequent concomitant pancreatic and/or duodenal invasions (23 of 31, 74%) and showed stromal infiltration (16 of 31, 52%) and intraductal cancerization (15 of 31, 48%) patterns. In only 2 cases, invasions with intraductal cancerization were observed in the gallbladder neck. Conversely, all pancreatic (N = 175) and duodenal (83) invasions developed through stromal infiltration. CD invasions were associated with larger tumor size (P = .001), bile duct margin positivity (P = .001), perineural invasions (P = .04), and higher N categories (P = .007). Patients with pancreatic or duodenal invasions had significantly lower survival rates than those without pancreatic (median, 31.0 versus 93.9 months) or duodenal (27.5 versus 56.8 months, P < .001, both) invasions. However, those with gallbladder or CD invasions did not have different survival times (P = .13). Patients with concomitant gallbladder/CD and pancreatic/duodenal invasions demonstrated significantly lower survival rates than those without organ invasions (P < .001). Gallbladder invasions were rare in DBDCs as neck invasions with intraductal cancerization. CD invasions occurred by stromal infiltrations and intraductal cancerization, whereas all pancreatic and duodenal invasions had stromal infiltration patterns. Gallbladder and/or CD invasions did not affect survival rates of patients with DBDC, while pancreatic and duodenal invasions affected survival rates. Therefore, these differences in survival rates may originate from the different invasive patterns of DBDCs.

Hybrid Laparoscopic and Robotic Hepatopancreaticoduodenectomy for Cholangiocarcinoma

IntroductionCombined hepatic resection and pancreaticoduodenectomy is the treatment of choice for patient with extensive horizontal-spreading cholangiocarcinoma involving both the perihilar bile duct and the intrapancreatic distal bile duct.1-3 This surgical procedure is extremely complex, and incurs a high risk of postoperative morbidity and mortality.4 However, in recent years, this complicated high-risk operation can be safely performed in well-selected patients.5 However, as we know, none of these operations have been reported as minimally invasive surgery. Patient and MethodsA 73-year-old female presented with jaundice and was diagnosed with cholangiocarcinoma. The preoperative image studies revealed a 4.3-cm-long diffuse, infiltrative cholangiocarcinoma from the hilar bile duct to the intrapancreatic bile duct without major vascular invasion. The patient was scheduled to undergo left hepatectomy with caudate lobectomy and pancreaticoduodenectomy to obtain a free resection margin. In order to maximize the efficiency of each surgical modality, we designed a hybrid method of laparoscopic resection and robotic reconstruction for this complicated surgery with a long operation time. A 12-mm port was placed at the subxiphoid area, which was utilized for laparoscopic CUSA during the liver resection. Three 12-mm ports around the umbilicus and an 8-mm robotic port at the right flank were placed. In the resection phase, pancreaticoduodenectomy was performed first, followed by hilar dissection and liver resection in en bloc manner. Here, a hanging maneuver was helpful for the complete resection of the caudate lobe in environment with the large specimen attached. In reconstruction phase, the right flank 8-mm port and the left side 12-mm port (using the double docking technique) were used for docking of two robotic working arms. ResultsThe total operation time was 510 min, and the estimated blood loss was 350 mL without transfusion. The patient’s postoperative recovery was smooth, except for a mild fever due to cystitis, and she was discharged on the 16th postoperative day. Permanent pathologic examination revealed a disease-free proximal bile duct margin, but a metastasis was discovered in one regional lymph node metastasis from 18 retrieved lymph nodes. The patient is receiving adjuvant gemcitabine chemotherapy and regular surveillance. We performed two consecutive cases and the perioperative outcomes were summarized in the attached video. ConclusionHepatopancreaticoduodenectomy has a long operative time, involves complicated anatomical structures and difficulty of R0 resection, and it is a remaining frontier of minimally invasive surgery. However, we expect that highly selected patients can carefully undergo minimally invasive surgery if the advantages of the currently available surgical methods are well utilized.

Number of positive lymph nodes and lymphatic invasion are significant prognostic factors after pancreaticoduodenectomy for distal cholangiocarcinoma.

Background: Early recurrence of distal cholangiocarcinoma (DCC) may result in a poorer prognosis. This study aimed to evaluate the clinicopathological factors that predict survival and recurrence in patients with DCC.Methods: Fifty-five patients with DCC who underwent pancreaticoduodenectomy between 2005 and 2015 were studied retrospectively. The following clinicopathological parameters were analyzed as predictors of disease-free survival (DFS) and overall survival (OS): sex, age, body mass index, presence of biliary tract decompression, macroscopic type, histological type, tumor size, TNM classification, lymph node metastasis ratio, number of positive lymph nodes (PLNs), lymphatic invasion, venous invasion, perineural invasion, proximal bile duct margin, dissected margin, portal system invasion, arterial system invasion, stage, and residual tumor.Results: Univariate analysis showed that contiguous extension of the primary tumor, PLN, lymphatic invasion, venous invasion, perineural invasion, and stage were significant prognostic factors for DFS and OS. Multivariate analysis revealed that PLN and lymphatic invasion were prognostic for DFS and OS (P<0.001). Significant differences in OS and DFS were found in analyses stratified by PLN (0, 1, 2 vs ≥3) and lymphatic invasion (0 vs 1, 2, 3).Conclusion: Among the clinicopathological parameters analyzed, PLN and lymphatic invasion were confirmed as prognostic factors for DCC.

Surgery for cholangiocarcinoma.

Surgical resection is the only potentially curative treatment for patients with cholangiocarcinoma. For both perihilar cholangiocarcinoma (pCCA) and intrahepatic cholangiocarcinoma (iCCA), 5‐year overall survival of about 30% has been reported in large series. This review addresses several challenges in surgical management of cholangiocarcinoma. The first challenge is diagnosis: a biopsy is typically avoided because of the risk of seeding metastases and the low yield of a brush of the bile duct. However, about 15% of patients with suspected pCCA are found to have a benign diagnosis after resection. The second challenge is staging; even with the best preoperative imaging, a substantial percentage of patients has occult metastatic disease detected at staging laparoscopy or early recurrence after resection. The third challenge is an adequate volume and function of the future liver remnant, which may require preoperative biliary drainage and portal vein embolization. The fourth challenge is a complete resection: a positive bile duct margin is not uncommon because the microscopic biliary extent of disease may be more extensive than perceived on imaging. The fifth challenge is the high post‐operative mortality that has decreased in very high volume Asian centres, but remains about 10% in many Western referral centres. The sixth challenge is that even after a complete resection most patients develop recurrent disease. Recent randomized controlled trials found conflicting results regarding the benefit of adjuvant chemotherapy. The final challenge is to determine which patients with cholangiocarcinoma should undergo liver transplantation rather than resection.

The clinical significance of biliary intraepithelial neoplasia-3 in proximal resection margin of bile duct in perihilar cholangiocarcinoma

The clinical significance of biliary intraepithelial neoplasia-3 in proximal resection margin of bile duct in perihilar cholangiocarcinoma

Number of positive lymph nodes and lymphatic invasion are significant prognostic factors for distal cholangiocarcinoma

Introduction: Early recurrence of distal cholangiocarcinoma (DCC) may Result in a poorer prognosis. This study aimed to evaluate the clinicopathological factors that predict survival and recurrence in patients with DCC. Method: Fifty-five patients with DCC who underwent pancreaticoduodenectomy between 2005 and 2015 were studied retrospectively. The following clinicopathological parameters were analyzed as predictors of disease-free survival (DFS) and overall survival (OS): sex, age, body mass index, presence of biliary tract decompression, macroscopic type, histological type, tumor size, TNM classification, lymph node metastasis ratio, number of positive lymph nodes (PLN), lymphatic invasion, venous invasion, perineural invasion, proximal bile duct margin, dissected margin, portal system invasion, arterial system invasion, stage, and residual tumor. Result: Univariate analysis showed that contiguous extension of the primary tumor, PLN, lymphatic invasion, venous invasion, perineural invasion, and stage were significant prognostic factors for DFS and OS. Multivariate analysis revealed that PLN and lymphatic invasion were prognostic for DFS and OS (p<0.001). Significant differences in OS and DFS were found in analyses stratified by PLN (0, 1, 2 vs. ≥3) and lymphatic invasion (0 vs. 1, 2, 3). Conclusion: Among the clinicopathological parameters analyzed, PLN, and lymphatic invasion were confirmed as prognostic factors for DCC.

Surgical outcomes of left trisectionectomy combined with vascular reconstruction for perihilar cholangiocarcinoma

Introduction: Left risectionectomy for perihilar cholangiocarcinoma (PHC) is a complicated and extensive surgical procedure with high morbidity and mortality rates. Hence thorough regional extirpation including combined resection of adjacent vasculature is often required for curative surgical treatment of PHC. In the present study, we elucidate whether left trisectionectomy is efficacious in surgery for PHC. Method: Between April 1992 and December 2017, our department surgically treated 252 cases of PHC. These included 19 cases for which we performed left trisectionectomy (Tri) and 71 cases that underwent left hemihepatectomy (Hemi). Curative resection rates, incidences of Clavien-Dindo grade III or higher complications, in-hospital mortality rates, and long-term results were analyzed. Result: Preoperative patients’ background of the two group is almost similar except Bismuth type (Bismuth type IV; 94.7% in Tri, 22.5% in Hemi, p<0.001). Although PD was added 11.2% (8/71) in Hemi and only one patient in Tri (5.2%: 1/19) (p=0.730). Hepatic artery reconstruction was performed 39.4% (28/71) in Hemi and 73.6% (14/19) in Tri (p=0.007). Curative resection rates were almost same in both groups: 73.6% (14/19) in Tri and 80.2% (57/71) in Hemi (p=0.531). No Tri cases showed a positive bile duct surgical margin. Incidences of complications were similar in both groups, at 73.6% in Tri, and 54.9% in Hemi (p=0.140). In-hospital mortality rates in Tri were statistically higher than those in Hemi (26.3% (5/19) vs 8.4% (6/71), p=0.034). Five-year survival rates were 30.1% in Tri and 34.9% in Hemi. In Tri, the resection afforded good long-term results even with advanced cancers. Conclusion: Left trisectionectomy proved useful in securing the bile duct margin. However, as left trisectionectomy remains a challenging procedure with high in-hospital mortality rates, surgeons need to pay close attention to anatomical variations in order to perform left trisectionectomy safely and successfully.

ASO Author Reflections: Re-resection of Positive Bile Duct Margin for Hilar Cholangiocarcinoma.

ASO Author Reflections: Re-resection of Positive Bile Duct Margin for Hilar Cholangiocarcinoma.

Effect of mapping biopsy on surgical management of cholangiocarcinoma.

The effect of endoscopic transpapillary mapping biopsy (MB) on decision-making of surgical indications, selecting surgical procedures, or operative outcomes remains unclear. Two-hundred and thirty-four patients with cholangiocarcinoma who were evaluated for surgical resection from 2007 to 2017 were reviewed. MB was performed in 80 patients who underwent tumor resection. We examined how MB affected operative indications or modified surgical procedures. Operative curability was compared between patients with and without preoperative MB. MB resulted in avoidance of noncurative resections in eight patients (14%, 8/57) of abandoned laparotomies. Based on the MB, surgical procedures were modified in nine patients (11.3%, 9/80), and this was justified by pathological examinations in eight patients (88.9%, 8/9). The MB group had an improved negative margin rate (83.8% vs 67.5%, P = 0.017) and a lower incidence of carcinoma in situ (8.8% vs 20.0%, P = 0.043) at the first cut than the non-MB group. The incidence of bile leakage was significantly lower in the MB group in both anastomotic site (5.0% vs 16.3%, P = 0.018) and parenchymal surface (2.5% vs 10.0%, P = 0.043). MB is helpful for selecting optimal surgical procedure for cholangiocarcinoma and it contributes for safe surgery by securing negative bile duct margin on the first cut.

The effect of preoperative serum CA 19-9 and the length of proximal resection margin of bile duct on resected hilar cholangiocarcinoma

Introduction: This study was to clarify the survival benefits of R0 resection of hilar cholangiocarcinoma (HCCA) following different length between gross tumor and proximal ductal resection margin (LPM) under different level of preoperative CA 19-9. Methods: All patients who underwent hepatectomy for HCCA from 2000 to 2017 were analyzed. Surgical variables, the LPM, prognostic factors, and survival were evaluated. Results: A total of 228 patients were enrolled for comparative analysis. The LPM of 44 patients were ≤ 5 mm (group A), 58 patients were 5 mm < LPM ≤ 10 mm (group B), 88 patients were 10 mm < LPM ≤ 20 mm (group C), 38 patients were 20 mm < LPM (group D). When preCA19-9≤150.0U/ml, the overall survival (OS) of group A was significantly worse than that of group C and D, but not significantly differ from that of R1 resection (P>0.05). The OS of group B, C, and D were significantly better than R1 resection (P< 0.05). When preCA19-9>150.0 U/ml, the OS of group D was significantly better than group A, B, C and R1 resection (P< 0.05). Conclusion: The LPM is associated with the survival of HCCA in different level of preCA19-9. When preCA 19-9≤150.0 U/ml, the proximal margin wider than 10 mm potentially achieve a higher R0 resection rate and better survival benefits; When preCA 19-9>150.0U/L, the LPM wider than 20 mm may achieve a significant better survival benefit.

Effectiveness of additional resection of the invasive cancer-positive proximal bile duct margin in cases of hilar cholangiocarcinoma

Introduction: There is still debate concerning the survival benefits of additional resection of the positive proximal ductal margin in cases of hilar cholangiocarcinoma (HCCA). This retrospective study was to investigate the effectiveness of additional resection of the invasive cancer positive proximal ductal margin (PM) under different level of preoperative CA19-9. Methods: Patients who underwent hepatectomy for HCCA from 2000 to 2017 were analyzed. Surgical variables, resection margin status and length of the PM (LPM), prognostic factors, and survival were evaluated. Results: A total of 228 patients were enrolled: 175 PM(-) without additional resection (group A), 21 PM(-) resulted by additional resection (group B), and 32 final positive proximal ductal margin: PM(+) (group C). The median survival of group B (20.99 months) was not significantly different with that of group A (23.00 months; P=0.16), and both of them were significantly better than that of group C (11.60 months) even in different subgroup of pr-CA 19-9 (P< 0.05). The survival of patients with LPM>10mm was significantly better than that of patients with LPM≤10mm especially when pr-CA 19-9>150U/ml (P< 0.05). Only when LPM>10mm, the survival of group B could be comparable with group A (P>0.05). Conclusion: HCCA patients could get survive benefit from the negative PM resulted by additional resection. The survival could be comparable with that of negative PM without additional resection in HCCA patients. The LPM>10 mm is potentially more associated with the survival rather than whether additional resection of the positive PM is performed under different level of pre-CA 19-9.

Tumour origin and R1 rates in pancreatic resections: towards consilience in pathology reporting.

To evaluate differences in the R1 rates of ampullary (AC), pancreatic (PC), and distal bile duct (DBD) cancers in pancreatoduodenectomies (PD) using standardised pathology assessment. Data of PD (2010-2011) analysed in accordance with the Royal College of Pathologists (UK) protocol, were retrieved. Clinicopathologic features, including frequency, topography, and mode of margin involvement in AC (n = 87), PC (n = 18), and DBD (n = 5) cancers were evaluated. The R1 rate was 7%, 67%, and 20% in the AC, PC, and DBD cancers (p < 0.001). Within the PC cohort, R1 rate was heterogeneous (chemo-naïve, 77%; post-neoadjuvant, 40%). Commonest involved margins were as follows: posterior in overall PD (35%), AC (43%), overall PC (33%), and post-neoadjuvant PC (100%); superior mesenteric artery margin in chemo-naïve PC (38%) and common bile duct margin in DBD (100%) cancers. In AC, majority (66%) of R1 were signet ring cell type. Indirect margin involvement due to tumour within lymph node, perineural sheath or lymphovascular space was observed in 26% cases, and altered R1 rate in AC, PC, and DBD cohorts by 1%, 12%, and 0%, respectively. Although not statistically significant, patients with R1 had lower disease-free survival than those with R0 (mean, 25.4months versus 44.4months). Tumour origin impacts R1 data in PD necessitating its accurate classification by pathologists. Indirect involvement, histology, and neoadjuvant therapy influence the R1 rate, albeit in a minority of cases. Generating cogent R1 data based on standardised pathology reporting is the foremost need of the hour.

Effectiveness of additional resection of the invasive cancer-positive proximal bile duct margin in cases of hilar cholangiocarcinoma.

The survival benefits of additional resection of the positive proximal ductal margin (PM) in hilar cholangiocarcinoma (HCCA) remains controversial. This retrospective study investigated the effectiveness of additional resection of the invasive cancer PM under different levels of preoperative carbohydrate antigen 19-9 (CA19-9). Patients who underwent hepatectomy for HCCA from 2000 to 2017 were analyzed. Surgical variables, resection margin status, length of the PM (LPM), prognostic factors, and survival were evaluated. A total of 228 patients were enrolled: 175 PM(-) without additional resection patients (group A), 21 PM(-) after additional resection (group B), 16 PM(+) without additional resection (group C), and 16 PM(+) after additional resection (group D). The median survival of group B (20.99 months) was similar to that of group A (23.00 months; P=0.16), and both were significantly better than those of group C (11.60 months) and D (9.50 months), especially when preoperative CA19-9>150 U/mL (P<0.05). The survival of patients with an LPM >10 mm was significantly better compared with those with an LPM ≤10 mm, especially when preoperative CA19-9 was >150 U/mL (P<0.05). Only in the LPM >10 mm group, the survival of group B was comparable with that of group A (P>0.05). HCCA patients could get a survival benefit from a negative PM resulting from additional resection. Survival could be comparable with that of negative PM without additional resection among HCCA patients. An LPM >10 mm is possibly more associated with better survival compared with whether additional resection of the positive PM is performed under different levels of preoperative CA19-9.

Intraoperative frozen section diagnosis of bile duct margin for extrahepatic cholangiocarcinoma

AIMTo evaluate the usefulness of frozen section diagnosis (FSD) of bile duct margins during surgery for extrahepatic cholangiocarcinoma (CCA).METHODSWe retrospectively analyzed 74 consecutive patients who underwent surgery for extrahepatic CCA from 2012 to 2017, during which FSD of bile duct margins was performed. They consisted of 40 distant and 34 perihilar CCAs (45 and 55 bile duct margins, respectively). The diagnosis was classified into three categories: negative, borderline (biliary intraepithelial neoplasia-1 and 2, and indefinite for neoplasia), or positive. FSD in the epithelial layer, subepithelial layer, and total layer was compared with corresponding permanent section diagnosis (PSD) postoperatively. Then, association between FSD and local recurrence was analyzed with special reference to borderline.RESULTSAnalysis of 100 duct margins revealed that concordance rate between FSD and PSD was 68.0% in the total layer, 69.0% in the epithelial layer, and 98.0% in the subepithelial layer. The extent of remaining biliary epithelium was comparable between FSD and PSD, and more than half of the margins lost > 50% of the entire epithelium, suggesting low quality of the samples. In FSD, the rate of negative margins decreased and that of borderline and positive margins increased according to the extent of the remaining epithelium. Diagnostic discordance between FSD and PSD was observed in 31 epithelial layers and two subepithelial layers. Alteration from borderline to negative was the most frequent (20 of the 31 epithelial layers). Patients with positive margin in the total and epithelial layers by FSD demonstrated a significantly worse local recurrence-free survival (RFS) compared with patients with borderline and negative margins, which revealed comparable local RFS. Patients with borderline and negative margins in the epithelial layer by PSD also revealed comparable local RFS. These results suggested that epithelial borderline might be regarded substantially as negative. When classifying the status of the epithelial layer either as negative or positive, concordance rates between FSD and PSD in the total, epithelial, and subepithelial layers were 95.0%, 93.0%, and 98.0%, respectively.CONCLUSIONDuring intraoperative assessment of bile duct margin, borderline in the epithelial layer can be substantially regarded as negative, under which condition FSD is comparable to PSD.

The Impact of Intraoperative Re-Resection of a Positive Bile Duct Margin on Clinical Outcomes for Hilar Cholangiocarcinoma.

The impact of re-resection of a positive intraoperative bile duct margin on clinical outcomes for resectable hilar cholangiocarcinoma (HCCA) remains controversial. We sought to define the impact of re-resection of an initially positive frozen-section bile duct margin on outcomes of patients undergoing surgery for HCCA. Patients who underwent curative-intent resection for HCCA between 2000 and 2014 were identified at 10 hepatobiliary centers. Short- and long-term outcomes were analyzed among patients stratified by margin status. Among 215 (83.7%) patients who underwent frozen-section evaluation of the bile duct, 80 (37.2%) patients had a positive (R1) ductal margin, 58 (72.5%) underwent re-resection, and 29 ultimately had a secondary negative margin (secondary R0). There was no difference in morbidity, 30-day mortality, and length of stay among patients who had primary R0, secondary R0, and R1 resection (all p>0.10). Median and 5-year survival were 22.3 months and 23.3%, respectively, among patients who had a primary R0 resection compared with 18.5months and 7.9%, respectively, for patients with an R1 resection (p=0.08). In contrast, among patients who had a secondary R0 margin with re-resection of the bile duct margin, median and 5-year survival were 30.6 months and 44.3%, respectively, which was comparable to patients with a primary R0 margin (p=0.804). On multivariable analysis, R1 margin resection was associated with decreased survival (R1: hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.0-1.7; p=0.027), but secondary R0 resection was associated with comparable long-term outcomes as primary R0 resection (HR 0.9, 95% CI 0.4-2.3; p=0.829). Additional resection of a positive frozen-section ductal margin to achieve R0 resection was associated with improved long-term outcomes following curative-intent resection of HCCA.

Expanding Role of Radiofrequency Ablation in the Treatment of Intraductal Papillary Neoplasms of the Bile Duct (IPNB)

Introduction: Intraductal papillary neoplasms of the bile duct (IPNB) are relatively rare neoplasms with high malignancy potential. Total surgical resection has been the main curative treatment, but is many times limited by the location and extent of the lesion. Endoscopic retrograde cholangiopancreatography (ERCP) guided radiofrequency ablation (RFA) is a newly immerging therapy primarily used in palliation of pancreaticobiliary malignancies. We present a case using ERCP-guided RFA as an adjuvant curative treatment after incomplete surgical resection of cholangiocarcinoma arising from an IPNB. Case: 59 year old male with no significant past medical history presented forpainless jaundice. Initial bloodwork was consistent with obstructive jaundice, and MRI of abdomen demonstrated marked intrahepatic ductal dilation to the portal confluence. ERCP with Spyglass was performed. Cholangiography showed a single diffuse stenosis 20 mm in length in common hepatic duct, correlating with a frond-like/villous mass in the upper third of the bile duct seen with direct visualization and biopsied. Pathology returned as IPNB with high grade dysplasia (HGD). He underwent an exploratory laparotomy with bile duct resection, but negative margins could not be achieved. Surgical pathology demonstrated cholangiocarcinoma arising from an IPNB, without lymphovascular invasion. HGD was still present at the margin of the intra-pancreatic common bile duct (CBD) remnant. Repeat ERCP was performed one month later. ERCP-guided RFA was successfully performed on the intra-pancreatic CBD remnant, and repeat cholangioscopy demonstrating circumferential whitish mucosa indicative of ablated mucosa. The patient recovered well with initiation of chemotherapy and radiation planned in the future.Figure: IPNB seen on cholangiogram as 2cm stricture.Discussion: IPNB is a term encompassing a large spectrum of neoplasms affecting the biliary system, first categorized by WHO in 2010. Multiple histological subtypes exist, but in general carry a high risk of malignancy. Approximately 75% of IPNBs have features of invasive carcinoma, and pathology within a single IPNB lesion is usually heterogeneous warranting treatment. Ideally total surgical resection should be performed, but as this case demonstrates, may not always be possible. The role of ERCP-guided RFA for the treatment of pancreaticobiliary neoplasms is evolving. Here we demonstrate its utility as an adjuvant therapy in the curative treatment of an IPNB.Figure: Cholangioscopy of hepatic duct mass.Figure: Cholangioscopy after RFA.

Redefining the Positive Margin in Pancreatic Cancer: Impact on Patterns of Failure, Long-Term Survival and Adjuvant Therapy.

There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA. We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5-1, >1-2, or >2mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS). Among all margins, PM clearance up to 2mm was prognostic of DFS (p=0.01) and OS (p=0.01). Dichotomizing the PM at 2mm revealed it to be an independent predictor of local recurrence-free survival [hazard ratio HR] 0.20, 95% confidence interval [CI] 0.048-0.881, p=0.033), DFS (HR 0.46, 95% CI 0.22-0.96, p=0.03), and OS (HR 0.31, 95% CI 0.14-0.74, p=0.008). A margin status of >2mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11-0.89, p=0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10-1.58, p=0.19). These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2mm.

Biliary intraductal papillary neoplasm with metachronous multiple tumors - true multicentric tumors or intrabiliary dissemination: A case report and review of the literature.

Intraductal papillary neoplasms of the bile duct (IPNBs) are recognized as a distinct type of biliary tumor. We herein discuss the possible mechanisms underlying the development of multiple tumors in patients with IPNBs through a case presentation and literature review. A 64-year-old woman initially underwent extended right hepatectomy for IPNB in the right hepatic duct. Although the surgical margin of the common bile duct was tumor-free, recurrence was detected in the intrapancreatic bile duct 26 months later. Both tumors had similar histopathological characteristics (intestinal-type IPNB with high-grade dysplasia, but no invasive cancer). A literature review identified 9 additional cases of multiple IPNBs. Unlike conventional IPNBs, which typically affect the intrahepatic or hilar bile duct, 80% of recurrent multiple tumors developed in the extrahepatic bile duct. Although multicentric tumors have been suggested in such cases, the intrabiliary dissemination of tumor cells appears to be more likely, as the majority of recurrent tumors develop in more distal parts of the bile duct compared with the primary tumor.

A long survivor with local relapse of hilar cholangiocarcinoma after R1 surgery treated with chemoradiotherapy: a case report and literature review.

The treatment outcome of extrahepatic cholangiocarcinoma remains insufficient because it is difficult to obtain accurate diagnosis of tumor spreading and effective treatment agent is quite limited in spite of substantial current efforts, all of which have been unsuccessful except for gemcitabine plus cisplatin. The patient was a 60-year-old female who had developed hilar cholangiocarcinoma and underwent extrahepatic bile duct resection. Although it was conceivable that it would be the R1 resection, the patient wanted to receive limited resection to avoid postoperative complication mainly because she was depressed. In histology, interstitial spreading of tumor was appreciated at the surgical margin of bile duct. The patient did not accept to receive the additional treatment after the surgery and hardly visited the hospital to take the periodical test for monitoring the residual cancer cells. As expected, the local relapse of tumor was appreciated 1 year after the R1 surgery. She chose radiotherapy and agreed with subsequent S-1 treatment for 26 months. Consequently, elevated CA19-9 was decreased, and local relapse has been successfully controlled for more than 7 years after the relapse of tumor. Here, we report quite a rare case in terms of long survivor after chemoradiotherapy on locally relapsed unresectable hilar cholangiocarcinoma.

Intraoperative frozen section analysis of the proximal bile ducts in hilar cholangiocarcinoma is of limited value.

Frozen section analysis (FS) during cancer surgery is widely used to assess resection margins. However, in hilar cholangiocarcinoma (HCCA), FS may be less reliable because of the specific growth characteristics of the tumor. The aim of this study was to determine the accuracy and consequences of intraoperative FS of the proximal bile duct margins in HCCA. Between 1990 and 2014, 67 patients underwent combined extrahepatic bile duct resection and partial liver resection for HCCA with the use of FS. Sensitivity and specificity of FS was 68% and 97%, respectively. Seventeen of 67 patients (25%) displayed a positive bile duct margin at FS. The false‐negative rate was 16% (eight patients). Ten patients (15%) with a positive bile duct margin underwent an additional resection in an attempt to achieve negative margins, which succeeded in three patients (4%). However, only one of these three patients did not have concomitant lymph node metastases, which are associated with a poor prognosis by itself. The use of FS of the proximal bile duct is of limited clinical value because of the relatively low sensitivity, high risk of false‐negative results, and the low rate of secondary obtained tumor‐free resection margins. Supported by the literature, a new approach to the use of FS in HCCA should be adopted, reserving the technique only for cases in which a substantial additional resection is possible.