Wen-Jie Ma

Prognostic factors and long-term outcomes of hilar cholangiocarcinoma: A single-institution experience in China

AIM To evaluate the prognostic factors of hilar cholangiocarcinoma in a large series of patients in a single institution. METHODS Eight hundred and fourteen patients with a diagnosis of hilar cholangiocarcinoma that were evaluated and treated between 1990 and 2014, of which 381 patients underwent curative surgery, were included in this study. Potential factors associated with overall survival (OS) and disease-free survival (DFS) were evaluated by univariate and multivariate analyses. RESULTS Curative surgery provided the best long-term survival with a median OS of 26.3 mo. The median DFS was 18.1 mo. Multivariate analysis showed that patients with tumor size > 3 cm [hazard ratio (HR) = 1.482, 95%CI: 1.127-1.949; P = 0.005], positive nodal disease (HR = 1.701, 95%CI: 1.346-2.149; P < 0.001), poor differentiation (HR = 2.535, 95%CI: 1.839-3.493; P < 0.001), vascular invasion (HR = 1.542, 95%CI: 1.082-2.197; P = 0.017), and positive margins (HR = 1.798, 95%CI: 1.314-2.461; P < 0.001) had poor OS outcome. The independent factors for DFS were positive nodal disease (HR = 3.383, 95%CI: 2.633-4.348; P < 0.001), poor differentiation (HR = 2.774, 95%CI: 2.012-3.823; P < 0.001), vascular invasion (HR = 2.136, 95%CI: 1.658-3.236; P < 0.001), and positive margins (HR = 1.835, 95%CI: 1.256-2.679; P < 0.001). Multiple logistic regression analysis showed that caudate lobectomy [odds ratio (OR) = 9.771, 95%CI: 4.672-20.433; P < 0.001], tumor diameter (OR = 3.772, 95%CI: 1.914-7.434; P < 0.001), surgical procedures (OR = 10.236, 95%CI: 4.738-22.116; P < 0.001), American Joint Committee On Cancer T stage (OR = 2.010, 95%CI: 1.043-3.870; P = 0.037), and vascular invasion (OR = 2.278, 95%CI: 0.997-5.207; P = 0.051) were independently associated with tumor-free margin, and surgical procedures could indirectly affect survival outcome by influencing the tumor resection margin. CONCLUSION Tumor margin, tumor differentiation, vascular invasion, and lymph node status were independent factors for OS and DFS. Surgical procedures can indirectly affect survival outcome by influencing the tumor resection margin.

Xanthogranulomatous cholecystitis mimicking gallbladder carcinoma: An analysis of 42 cases

AIM To review and evaluate the diagnostic dilemma of xanthogranulomatous cholecystitis (XGC) clinically. METHODS From July 2008 to June 2014, a total of 142 cases of pathologically diagnosed XGC were reviewed at our hospital, among which 42 were misdiagnosed as gallbladder carcinoma (GBC) based on preoperative radiographs and/or intra-operative findings. The clinical characteristics, preoperative imaging, intra-operative findings, frozen section (FS) analysis and surgical procedure data of these patients were collected and analyzed. RESULTS The most common clinical syndrome in these 42 patients was chronic cholecystitis, followed by acute cholecystitis. Seven (17%) cases presented with mild jaundice without choledocholithiasis. Thirty-five (83%) cases presented with heterogeneous enhancement within thickened gallbladder walls on imaging, and 29 (69%) cases presented with abnormal enhancement in hepatic parenchyma neighboring the gallbladder, which indicated hepatic infiltration. Intra-operatively, adhesions to adjacent organs were observed in 40 (95.2%) cases, including the duodenum, colon and stomach. Thirty cases underwent FS analysis and the remainder did not. The accuracy rate of FS was 93%, and that of surgeons macroscopic diagnosis was 50%. Six cases were misidentified as GBC by surgeons macroscopic examination and underwent aggressive surgical treatment. No statistical difference was encountered in the incidence of postoperative complications between total cholecystectomy and subtotal cholecystectomy groups (21% vs 20%, P > 0.05). CONCLUSION Neither clinical manifestations and laboratory tests nor radiological methods provide a practical and effective standard in the differential diagnosis between XGC and GBC.

Coexisting cancers: a mixture of neuroendocrine carcinoma and adenocarcinoma in the gallbladder: A case report.

Background:Neuroendocrine carcinoma is rare with a proportion of less than 2% in gallbladder malignancies, cases of gallbladder neuroendocrine cell carcinoma coexisting with adenocarcinoma are exceptionally rare, and the prognosis is dismal. Methods:Herein, we presented an unusual case of poorly differentiated gallbladder neuroendocrine cell carcinoma coexisting with poorly differentiated adenocarcinoma who survived 20 months after the multimodal treatment (MT) of extended surgery and postoperative chemotherapy. Results:Our result indicated that for advanced gallbladder neuroendocrine cell carcinoma coexisting with adenocarcinoma, MT including extended surgical approach combined with postoperative chemotherapy may contribute to a relatively good survival outcome. Conclusion:MT may contribute to a relatively good survival outcome for advanced gallbladder neuroendocrine cell carcinoma coexisting with gallbladder adenocarcinoma.

Relationship of tumor size with pathological and prognostic factors for hilar cholangiocarcinoma

Objective To determine the correlation of different tumor-size cutoffs with prognostic factors and survival outcomes to provide a reference for the modification of the T-stage classification in the DeOliveira staging system for hilar cholangiocarcinoma (HCCA). Materials and Methods We retrospectively analyzed 216 patients who underwent curative surgery for HCCA (mean tumor diameter, 2.8 cm) between 2000 and 2013. Univariate and multivariate logistic regression were used to assess the correlation of tumor-size cutoffs with various factors. Results Tumor differentiation (odds ratio [OR]: 1.649, 95% confidence interval [CI]: 1.065–2.555, P = 0.025), node status (OR: 1.971, 95% CI: 1.060–3.664, P = 0.032), resection margin (OR: 2.465, 95% CI: 1.024–5.937, P = 0.044), and hepatectomy (OR: 2.373, 95% CI: 1.226–4.593, P = 0.01) were independently correlated with the 2-cm cutoff, while tumor differentiation (OR: 1.755, 95% CI: 1.062–2.091, P = 0.028), node status (OR: 2.166, 95% CI: 1.054–4.452, P = 0.035), and tumor margin (OR: 2.539, 95% CI: 1.089–5.919, P = 0.031) were independently associated with the 3-cm cutoff. Conclusions The 2-cm and 3-cm cutoffs were strongly correlated with resection margin, node status, tumor differentiation and survival. The 2-cm cutoff may be added to the DeOliveira staging system.

Can preoperative and postoperative CA19-9 levels predict survival and early recurrence in patients with resectable hilar cholangiocarcinoma?

Background To investigate the predictive values of preoperative and postoperative serum CA19-9 levels on survival and other prognostic factors including early recurrence in patients with resectable hilar cholangiocarcinoma. Results In univariate analysis, increased preoperative and postoperative CA19-9 levels in the light of different cut-off points (37, 100, 150, 200, 400, 1000 U/ml) were significantly associated with poor survival outcomes, of which the cut-off point of 150 U/ml showed the strongest predictive value (both P < 0.001). Preoperative to postoperative increase in CA19-9 level was also correlated with poor survival outcome (P < 0.001). In multivariate analysis, preoperative CA19-9 level > 150 U/ml was significantly associated with lymph node metastasis (OR = 3.471, 95% CI 1.216–9.905; P = 0.020) and early recurrence (OR = 8.280, 95% CI 2.391–28.674; P = 0.001). Meanwhile, postoperative CA19-9 level > 150 U/ml was also correlated with early recurrence (OR = 4.006, 95% CI 1.107–14.459; P = 0.034). Materials and Methods Ninety-eight patients who had undergone curative surgery for hilar cholangiocarcinoma between 1995 and 2014 in our institution were selected for the study. The correlations of preoperative and postoperative serum CA19-9 levels on the basis of different cut-off points with survival and various tumor factors were retrospectively analyzed with univariate and multivariate methods. Conclusions In patients with resectable hilar cholangiocarcinoma, serum CA19-9 predict survival and early recurrence. Patients with increased preoperative and postoperative CA19-9 levels have poor survival outcomes and higher tendency of early recurrence.

The puzzle and challenge in treating hepatolithiasis.

To the Editor: Hepatolithiasis is rare in western countries, but common in Asia-Pacific region, where it is detected in 31% to 50% of patients undergoing surgery for cholelithiasis.1,2 Because of its recalcitrant nature, hepatolithiasis is still considered as an intractable problem in hepatobiliary surgery. Because of the recent use of choledochoscopy, the stone clearance rate has increased. But, even after successful choledochoscopic cholelithotomy, the stones recurrence rate could be as high as 40% as most of the stones accompanied with biliary stricture. If this patient group is only treated by endoscopic cholelithotomy, the recurrence of intrahepatic stones is almost inevitable according to the Asia’s experience.3,4 The management of intrahepatic bile duct stricture is definitely not easy. Even after successful balloon dilatation, the incidence of biliary restenosis still remains as high as 24% to 58%.3,4 Traditional hepatectomy seems to be the best treatment for intrahepatic bile duct stone with intractable bile duct stricture. The use of conventional hepatectomy for treating those stones and biliary strictures localized in 1 segment or in 1 lobe, can achieve a good result in 91.16% of the patients.4 Hepatectomy, however, cannot eliminate the possibility of stone recurrence, and, 16% of the patients undergoing hepatectomy can have a new stone at any other site in the liver. In addition, 40% of hepatolithiasis patients have a whole liver distribution of their stones, and many patients cannot tolerate multiple lobes/ segments resection.3,4 Because of these reasons, application of open hepatectomy is greatly restricted. Patients requiring multiple biliary surgeries for stone recurrences and biliary strictures are commonly encountered in East Asia. Reoperative rates in hepatolithaisis can be as high as 37.1% to 74.4% in 4to 10-year follow-up period.3 The degree of biliary stricture increases as per the increasing frequency of stone recurrences, which directly impacts the overall health condition of patients; thus, leading to an even higher reoperative risk. Currently, long-term effectiveness of available therapeutic methods of hepatolithiasis is far from satisfactory. To date, there are no medications or treatments to prevent stone recurrence or biliary restenosis after choledochoscopic lithotomy. Therefore, new treatment modalities to prevent stone recurrence and biliary restenosis after initial choledochoscopic lithotomy, and to further improve the long-term therapeutic effectiveness in hepatolithiasis is urgently required. Multiple factors for the lithogenesis of pigment stones have brought enormous difficulties to its prevention and treatment. Despite many theories concerning the lithogenesis, it has become more and more evident that 75% to 100% of hepatolithiasis cases in Asia are pathologically characterized by chronic proliferative cholangitis.3–5 In recent years, with a deeper understanding of pathologic changes in hepatolithiasis, more and more attention has been paid to the relationship of chronic proliferative cholangitis with stone recurrence and biliary restenosis. The residual chronic proliferative cholangitis is currently considered as the pathologic basis and major cause for the high recurrence rate of intrahepatic calculi and biliary restenosis. Between intrahepatic calculi and chronic proliferative cholangitis, there exists a vicious cycle, which has been considered as an important reason for the poor prognosis of hepatolithiasis patient. Both the stone itself and its secondary biliary infection can stimulate persistent hyperplasia in the biliary tract wall, leading to the occurrence of chronic proliferative cholangitis and biliary stricture; in contrast, the recurrent attacks of chronic proliferative cholangitis will, in turn, facilitate new stone formation via mucoglycoprotein production or induced biliary stricture and biliary infection.3,4 Thus, even when the stone is completely removed and the biliary tract stenosis is corrected, residual chronic proliferative cholangitis will continue to persist and progress with an underlying threat of postoperative stone recurrence and biliary tract restenosis. In the past, improvement of surgical skills concerning the treatment of hepatolithiasis received great attention while the connection between postoperative residual chronic proliferative cholangitis and stone recurrence went unrecognized. The longterm therapeutic effectiveness on hepatolithiasis is too difficult to be further enhanced by surgery alone. Therefore, the treatment of hepatolithiasis should be directed not only on the clearance of the stone and the correction of biliary stricture, but also on the control of chronic proliferative cholangitis, because chronic proliferative cholangitis is a key linkage in this vicious cycle. Unfortunately, an exact and effective chronic proliferative cholangitis therapy is still yet to be formulated. On the basis of the connection between biliary stricture and chronic proliferative cholangitis, the chemical biliary duct embolization was used to eradicate chronic proliferative cholangitis and thereby prevent the recurrence of intrahepatic calculi. Although chemical biliary duct embolization could effectively eradicate chronic proliferative cholangitis and thereby prevent stone recurrence, the price for the chemical biliary duct embolization was the complete damage to the subsidiary hepatic segment and related bile duct, so this kind of chemical biliary duct embolization technique was restricted to some extent in clinical practice.4 Chemical biliary duct embolization only provides an additional and potential approach for handling hepatolithiasis patients who are not suitable for surgical intervention. And further investigation is still needed to confirm long-term effectiveness of this procedure via multicenter study. On the basis of the hyperplastic behavior of chronic proliferative cholangitis, the antiproliferative treatment seems to be another potential approach for intrahepatic stone. There are some reports in treating chronic proliferative cholangitis with paclitaxel or specific blockage of the proliferation-related gene expression such as E2F decoy, C-myc, or proliferating cell nuclear antigen using antisense gene therapy.3 This antiproliferation treatment could Supported by the National Nature Science Foundation of China (30801111, 30972923) and Science & Technology Support Project of Sichuan Province (No. 14ZC1337, 14ZC1335 and 2014SZ000210). The authors declare no conflicts of interest. LETTER TO THE EDITOR

Histological examination of frozen sections for patients with acute cholecystitis during cholecystectomy

BACKGROUND Unexpected gallbladder cancer may present with acute cholecystitis-like manifestations. Some authors recommended that frozen section analysis should be performed during laparoscopic cholecystectomy for all cases of acute cholecystitis. Others advocate selective use of frozen section analysis based on gross examination of the specimen by the surgeon. The aim of the present study was to evaluate whether surgeons could effectively identify suspected gallbladder with macroscopic examination alone. If not, is routine frozen section analysis worth advocating? METHODS A total of 1162 patients with acute cholecystitis who had undergone simple cholecystectomy in our hospital from February 2009 to February 2014 were enrolled in the study. The data of patients with acute cholecystitis especially those with concurrent gallbladder cancer in terms of clinical characteristics, operative records, frozen section diagnosis and histopathology reports were analyzed. RESULTS Thirteen patients with acute cholecystitis were found to have concurrent gallbladder cancer, with an incidence of 1.1% in acute cholecystitis. Forty patients with acute cholecystitis were suspected to have gallbladder cancer by macroscopic examination and specimens were taken for frozen section analysis. Six patients with gallbladder cancer were correctly identified by macroscopic examination alone but 7 patients with gallbladder cancer missed, including 3 patients with advanced cancer (2 T3 and 1 T2). Meanwhile, in 6 gallbladder cancer specimens sent for frozen section analysis, 3 early gallbladder cancers (2 Tis and 1 T1a) were missed by frozen section analysis. However, the remaining 3 patients with advanced gallbladder cancers (2 T3 and 1 T2) were correctly diagnosed. CONCLUSIONS The incidence of comorbidity of gallbladder cancer and acute cholecystitis is higher than that of non-acute cholecystitis. The accurate diagnosis of gallbladder cancer by surgeons is poor and frozen section analysis is necessary.

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

Background 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). Methods 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. Results 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). Conclusions 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.

Comparative analysis of different hepatico-jejunostomy techniques for treating adult type I choledochal cyst

Abstract Objective To compare Roux-en-Y hepatico-jejunostomy with complete resection of the cyst or incomplete resection with 1-cm remnant proximal cyst wall in treating adult type I choledochal cyst (CC). Methods The medical records of 267 adult patients with type I CC from January 1998 to December 2015 were reviewed retrospectively. Among them, 171 underwent Roux-en-Y hepatico-jejunostomy with complete resection (PBD 0-cm group) and 96 underwent Roux-en-Y hepatico-jejunostomy with 1-cm proximal cyst wall left (PBD 1-cm group). The short- and long-term post-operative complications were compared between the two groups. Results No significant difference was observed in operative time or anastomotic diameter between the two groups. The incidence of perioperative complications was significantly higher in the PBD 1-cm group than that in the PBD 0-cm group (28.1% vs 14.0%, p=0.005), especially post-operative cholangitis (7.3% vs 1.2%, p=0.021). The incidence of long-term post-operative complications was not significantly different, including anastomotic stricture, reflux cholangitis, intra-hepatic bile duct stones and bile leak (all p >0.05). Post-operative intra-pancreatic biliary malignancy occurred in one patient in the PBD 0-cm group at 25 months and one patient in the PBD 1-cm group at 5 month, respectively. Anatomical site malignancy was observed in one patient in the PBD 1-cm group at 10 months. Conclusion Ease of performing anastomosis does not justify retaining a segment of choledochal cyst in type I CC due to its higher risk of post-operative complication and malignancy. A complete excision of the CC with anastomosis to the healthy proximal bile duct is necessary in treatment of type I CC.

Effective Treatment of Chronic Proliferative Cholangitis by Local Gentamicin Infusion in Rabbits

Background Hepatolithiasis is highly prevalent in East Asia characterized by the presence of gallstones in the biliary ducts of the liver. Surgical resection is the potentially curative treatment but bears a high risk of stone recurrence and biliary restenosis. This is closely related to the universal presence of chronic proliferative cholangitis (CPC) in the majority of patients. Recent evidence has indicated the association of bacterial infection with the development of CPC in hepatolithiasis. Thus, this study aims to investigate the feasibility and efficacy of local infusion of gentamicin (an antibiotic) for the treatment of CPC in a rabbit model. Methods The rabbit CPC model was established based on previously published protocols. Bile duct samples were collected from gentamicin-treated or control animals for pathological and molecular characterization. Results Histologically, the hyperplasia of biliary epithelium and submucosal glands were inhibited and the thickness of the bile duct wall was significantly decreased after gentamicin therapy. Consistently, the percentage of proliferating cells marked by ki67 was significantly reduced by the treatment. More importantly, this treatment inhibited interleukin 2 production, an essential inflammatory cytokine, and the enzyme activity of endogenous β-Glucuronidase, a key factor in the formation of bile pigment. Conclusions Local gentamicin infusion effectively inhibits the inflammation, cell proliferation, and lithogenesis in a rabbit model of CPC. This approach represents a potential treatment for CPC and thus prevents recurrent hepatolithiasis.