Effect of modified biopsy forceps on the diagnosis of malignant biliary strictures: A randomized controlled trial

To the Editor: Malignant biliary strictures are typically associated with highly aggressive and diagnostically challenging diseases, including cholangiocarcinoma, pancreatic cancer, gallbladder cancer, liver cancer, and metastatic cancer.[1] Biliary biopsy during endoscopic retrograde cholangiopancreatography (ERCP) is the primary method for diagnosing biliary stricture. Conducting a biopsy through forceps sampling is a technically intricate procedure that involves maneuvering the biopsy forceps through the duodenal papilla to access the biliary area. Additionally, inadequate sampling leads to a reduced biopsy positivity rate.[2] ERCP for biliary biopsy is usually performed with pediatric gastroscopy biopsy forceps. We aimed to modify the pediatric gastroscopy biopsy forceps to allow easier access to the biliary tract and reduce operational difficulty. The main objective of this study was to evaluate the accuracy and complication rate of the modified biopsy forceps for diagnosing biliary strictures during ERCP. This was a single-center, prospective, patient-blinded, randomized controlled trial. The study was conducted at the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. Patients with suspected bile duct malignancy by computed tomography or magnetic resonance imaging were randomized into a conventional and modified biopsy forceps group. All procedures were performed following the Declaration of Helsinki, and the study was approved by the Ethics Committee of the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology (No. 2020-0523). All patients signed the informed consent forms. From January 2021 to June 2022, patients with suspected bile duct malignancy undergoing ERCP for obstructive jaundice at Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, were included in this study. All patients underwent ERCP for the first time. A total of 72 consecutive patients underwent eligibility assessment, among whom eight were excluded (five met exclusion criteria and three declined to participate). The 64 eligible patients were enrolled and randomly allocated into the modified biopsy forceps group (n = 32) or control group (n = 32) [Supplementary Figure 1, https://links.lww.com/CM9/C99]. Exclusion criteria were age under 18 years, upper gastrointestinal postoperative changes, tumors located in the intrahepatic bile duct, malignant pancreatic tumors, and tumors in the ampulla of Vater. We utilized a stratified permuted block randomization approach. Based on a computer-generated list of numbers, patients were randomly (1:1) divided into two groups and biopsied with modified and conventional biopsy forceps, respectively. An investigator not involved in data collection and analysis prepared the opaque sealed envelope containing the computer-generated random number list. The randomization key was locked until data collection was completed. Only one investigator collected all the data. An independent statistician performed the final statistical analysis. All patients, pathologists, and outcome assessors were blinded to the assignments. The endoscopist performing the ERCP could not be blinded. All ERCP procedures were performed by experienced endoscopists who had performed more than 1000 ERCP procedures. ERCP was performed using a JF260V duodenoscope (Olympus, Tokyo, Japan). After successful bile duct intubation, cholangiography was performed to confirm the location of the stricture. A small incision of the duodenal papillary muscle was made, the guide wire was retained, and biopsy forceps were inserted. The conventional biopsy forceps are disposable pediatric upper endoscope biopsy forceps (JiuHong, Changzhou, China). We modified the biopsy forceps by bending the biopsy forceps approximately 40°–45°, 1.2–1.5 cm away from the tip of the biopsy forceps, as shown in Supplementary Figure 2, https://links.lww.com/CM9/C99. This improvement could be achieved by hand, bending the front end of the biopsy forceps without affecting their use. After repeated testing, the tip of the modified biopsy forceps always faces the direction of the duodenal papilla. The X-ray image is shown in Supplementary Figure 3, https://links.lww.com/CM9/C99, where the biopsy forceps with the bent tip at the front end made it easier to locate the stricture of the bile duct. Specimens described as “carcinoma,” “suspected carcinoma,” and “high-grade intraepithelial neoplasia” on the histological examination were considered to be malignant. Patients with histologically undiagnosed malignancy after at least 6 months of follow-up, with disease progression or distant metastasis, are clinically diagnosed with malignant biliary stricture. The benign biliary stricture was defined as a pathologically benign diagnosis with no progression or improvement in radiographic lesions reviewed during at least 6 months of follow-up. The study’s primary outcome was the sensitivity and accuracy of pathological diagnosis of ERCP biliary biopsy, and the secondary outcome was the incidence of complications after ERCP. We compared other indices of biliary biopsy in both groups; the number of biopsy samples, biopsy time, and National Aeronautics and Space Administration Task Load Index (NASA-TLX) score. The site of biliary stricture was divided into the hilar and distal bile ducts. Biopsy time was defined as the time between the first contact of the biopsy forceps with the duodenal papilla and the completion of the last biopsy. Post-ERCP complications were defined according to the guidelines. Previous studies reported a sensitivity of 48.1% for biliary biopsy using conventional biopsy forceps and 81.0% for modified biopsy via dilation catheter-guided mini-forceps biopsy. Combining literature reports and our own experience, we estimated the sensitivity of modified biopsy forceps to be 83% and that of conventional biopsy forceps to be 50%. The required sample size was 32 patients for each group with a two-sided α-value of 0.05, a power of 80%, and a 10% dropout rate. SPSS 23.0 (IBM, Armonk, NY, USA) and MedCalc 20.1.0 (MedCalc Software, Ostend, Belgium) statistical software were used to analyze the data. The measurement data with a normal distribution were presented as mean±standard deviation, and the t-test of two independent samples was used for comparisons between groups. The measurement data that did not conform to the normal distribution were presented as median (Q1, Q3), and the Mann–Whitney U test was used for comparisons between groups. Count data were presented as frequency (%). The chi-square and Fisher’s exact tests were used to compare groups. P <0.05 was considered to indicate significance statistically. The main characteristics of the patients are shown in Supplementary Table 1, https://links.lww.com/CM9/C99. The two groups had no statistically significant differences regarding age, sex, stenosis location, stenosis length, total bilirubin (TBIL), or alanine transaminase (ALT). The comparison of the biopsy process between the two groups is shown in Supplementary Table 2, https://links.lww.com/CM9/C99. The median number of biopsies in the modified group was 3 (3, 4), and the number of biopsies in the conventional group was also 3 (3, 3) (P = 0.264). There was no statistical difference in the number of biopsies. The biopsy time of the modified group was 223.6 ± 72.7 s, and that of the control group was 304.6 ± 94.2 s (P <0.001). The biopsy time of the modified group was significantly less than that of the conventional group. The NASA-TLX score was used to evaluate the procedure’s difficulty. The results showed that the surgeon’s mental demand, physical burden, time demand, effort, and dissatisfaction in the modified group were significantly reduced (P <0.001). In the modified group, 25 patients were pathologically diagnosed with cholangiocarcinoma, two with intraductal papillary neoplasm of the bile duct (IPNB) canceration, three with malignancy during follow-up, and two with benign stenosis during follow-up. In the conventional group, 20 were pathologically diagnosed with cholangiocarcinoma, one with IPNB canceration, one with metastatic cancer, eight with malignant diseases, and two with benign stenosis at follow-up [Supplementary Table 3, https://links.lww.com/CM9/C99]. As shown in Table 1, the diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the modified group were 84.4% (95% confidence interval [CI]: 67.2–94.7%), 83.3% (95% CI: 65.3–94.4%), 100% (95% CI: 15.8–100%), 100%, and 28.6% (95% CI: 15.2–47.1%), respectively. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the conventional group were 53.1% (95% CI: 34.7–70.9%), 50.0% (95% CI: 31.3–68.7%), 100% (95% CI: 15.8–100%), 100%, and 11.8% (95% CI: 8.5–16.0%). The modified group’s diagnostic accuracy (P = 0.003) and sensitivity (P = 0.006) were statistically significantly higher than those of the conventional group. The two groups had no significant difference in the incidence of surgery-related adverse events. Postoperative pancreatitis occurred in one patient (3%) in the modified group and two patients (6%) in the conventional group (P >0.999). All of them suffered mild pancreatitis and were cured through conservative management. Table 1 - Primary clinical outcomes of patients with suspected bile duct malignancy undergoing ERCP for obstructive jaundice in the modified and conventional groups. Variables Modified group (n = 32) Conventional group (n = 32) Overall (n = 64) P-value Accuracy, % (95% CI) 84.4 (67.2–94.7) 53.1 (34.7–70.9) 67.8 (54.9–78.9) 0.003 Sensitivity, % (95% CI) 83.3 (65.3–94.4) 50.0 (31.3–68.7) 66.1 (52.6–77.9) 0.006 Specificity, % (95% CI) 100 (15.8–100) 100 (15.8–100) 100 (47.8–100) PPV, % (95% CI) 100 100 100 NPV, % (95% CI) 28.6 (15.2–47.1) 11.8 (8.5–16.0) 20 (14.9–26.3) Complications, n (%) 1 (3) 2 (6) 3 (5) >0.999 Pancreatitis, n 1 2 3 Bleeding, n 0 0 0 Perforation, n 0 0 0 CI: Confidence interval; NPV: Negative predictive value; PPV: Positive predictive value. In the present study, we evaluated the diagnostic performance of the modified pediatric gastroscopy biopsy forceps in biliary tract biopsy. The findings showed that the diagnostic accuracy and sensitivity of the modified biopsy forceps were greatly improved, with no significant differences in complications. The modified biopsy forceps had the following advantages; they could enter the bile duct quickly without guidewire guidance, making the procedure less difficult and allowing more biopsy specimens to be taken. Patients with biliary strictures undergoing ERCP increased difficulty in cannulation. A meta-analysis revealed that transpancreatic sphincterotomy improved the success rate of bile duct cannulation.[3] We also applied this method in cases of difficult cannulation. A retrospective study by Inoue et al[4] showed that the sensitivity and accuracy of the biopsy forceps with an adjustable curvature at the front end, similar to the design of the cutting knife bow, were 60% and 72%, respectively. The relatively low sensitivity may be related to the smaller diameter of the biopsy forceps after opening, in which case further improvement is required. A meta-analysis demonstrated that the sensitivity and specificity of visual diagnosis of bile duct cancer using peroral cholangioscopy were 94% and 95%, respectively, recommending routine utilization in indeterminate biliary strictures.[5] Our results show that modified biopsy forceps can safely perform biliary biopsies without serious adverse events compared with conventional biopsy forceps. Due to the lower sensitivity of peroral cholangioscopy-guided biopsies, it is advisable to employ modified biopsy forceps concurrently with peroral cholangioscopy. Modified biopsy forceps reduce the difficulty faced during biliary biopsies, have a good safety profile, and improve the accuracy and sensitivity of diagnosis. However, this study had some limitations. First, the modified biopsy forceps did not have guide wire guidance, and it was difficult to biopsy intrahepatic bile duct lesions, which needs further improvement in design. Secondly, this was a single-center study with a small sample size. In conclusion, compared with conventional biopsy forceps, the modified biopsy forceps in this study could be better manipulated, improved the accuracy and sensitivity of biliary biopsy, and were a safe and effective tool for biliary stricture tissue biopsy. Acknowledgment The authors wish to acknowledge all participants in this study and everybody involved in the set-up and implementation of the study. Funding This study was supported in part by grants from the National Natural Science Foundation of China (Nos. 82070667, 82170571, and 81974068). Conflicts of interest None.