Int J Gastrointest Interv 2021; 10(3): 114-119
Published online July 31, 2021 https://doi.org/10.18528/ijgii210037
Copyright © International Journal of Gastrointestinal Intervention.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Soon Chun Hyang University, Seoul, Korea
Correspondence to:*Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soon Chun Hyang University Seoul Hospital, 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea.
E-mail address: firstname.lastname@example.org (S.-W. Cha).
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Patients with indeterminate biliary stricture frequently pose a challenge in the clinical management. Discrimination between benign and malignant biliary strictures is important to prevent the morbidity and mortality associated with incorrect diagnoses. Traditional tissue sampling using endoscopic retrograde cholangiography does not always produce a definitive diagnosis, with a considerable proportion of cases remaining as indeterminate biliary strictures. Recent advances in endoscopic and molecular techniques have the potential to improve the diagnostic and prognostic accuracy of biliary strictures. This article reviews various etiologies of biliary strictures and discusses the recent advances of diagnostic approaches for indeterminate biliary tract obstruction.
Keywords: Cholangioscopy, Confocal laser endomicroscopy, Endoscopic retrograde cholangiopancreatography, Endoscopic ultrasound, Indeterminate biliary stricture
Biliary stricture is often a diagnostic dilemma in which the underlying cause cannot be determined even after extensive evaluation. Such biliary stricture is referred to as “indeterminate biliary strictures” and presents a therapeutic dilemma for clinicians involved in management. Various differential diagnoses exist for indeterminate biliary tract obstruction, including benign or malignant lesions. Diagnosis of indeterminate biliary tract obstruction includes physical examination, laboratory tests, imaging techniques, and endoscopic procedures. Despite advances in less invasive imaging techniques such as transabdominal ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI), endoscopy plays an essential role in accurate diagnosis, including histological diagnosis. Imaging findings and brush cytology and/or forceps biopsy fluoroscopic guidance with endoscopic retrograde cholangiopancreatography (ERCP) is widely used as a standard for diagnosing biliary strictures. However, ERCP cannot provide an intraluminal view of biliary tract lesions and the results are unsatisfactory. Recently, oral cholangioscopy, confocal laser endoscopy, endoscopic ultrasound (EUS), and EUS-guided fine-needle aspiration (FNA) and/or biopsy were reported to be useful for indeterminate biliary strictures. The appropriate endoscopic method should be selected according to the patient’s condition, lesion, and endoscopist. The discovery of recent advanced endoscopic modalities, and multimodal evaluations could improve diagnostic yields. Although the majority of indeterminate biliary strictures have a malignant origin, 20% of indeterminate biliary strictures are benign.1,2 In addition, up to 25% of initially classified malignant strictures were found to be benign after surgical resection.3,4 High diagnostic accuracy is the goal in order not to delay correct treatment or to avoid unnecessary surgery.
A broad differential diagnosis exists between benign and malignant conditions (Table 1). The etiology of benign biliary strictures is diverse. Benign biliary strictures are caused by primary sclerosing cholangitis (PSC), immunoglobulin G4-related cholangitis, bile duct stones, infection, ischemia related to surgical interventions, or iatrogenic injury. The most frequent benign causes are iatrogenic and secondary to biliary injury after cholecystectomy or liver transplantation.1 In contrast to the variety of benign causes that can lead to biliary strictures, the two primary causes of malignant biliary strictures are cholangiocarcinoma and pancreatic adenocarcinoma. Pancreatic adenocarcinoma should be suspected in patients with distal common bile duct strictures regardless of whether a mass is identifiable on cross-sectional imaging. By contrast, cholangiocarcinoma is more likely in patients with mid and proximal bile duct strictures than those with distal strictures. Rare causes include metastatic cancer, hepatocellular carcinoma and extrinsic compression by large periportal lymph nodes or extension of gallbladder and ampullary tumors into the biliary tree.
Table 1 . Etiology of Biliary Strictures.
|Primary sclerosing cholangitis (PSC)|
|Immunoglobulin G4-related cholangitis|
|Sarcoidosis, Eosinophilic cholangitis, Mast cell cholangitis, Histiocytosis X|
|Choledocholithiasis (Mirizzi syndrome)|
|Infectious (tuberculosis, viral, parasitic, HIV cholangiopathy)|
|Vascular (vasculitis, ischemic cholangiopathy)|
|Others (trauma, chemotherapy, post radiation therapy)|
|Malignant cause||Pancreatic adenocarcinoma|
Various endoscopic methods are available for the diagnosis and evaluation of indeterminate biliary tract strictures are described below.
ERCP is still the most widely used diagnostic method for the evaluation of biliary strictures. When performing ERCP, interpretation of cholangiographic results is the first step. It allows precise differentiation of benign and malignant biliary strictures by accurately defining the location, extent, and morphology of biliary strictures.5 Malignant strictures are suggested when the cholangiography shows strictures that are longer than 10 mm, asymmetric, and irregular. Benign strictures are suggested when cholangiography shows short, regular, and symmetric strictures. Using these criteria, the diagnostic sensitivity and specificity for cholangiography findings were reported to be 74% and 70%, respectively.6 After cholangiography, intraductal ultrasound (IDUS) is performed to evaluate the main lesion. This technique makes use of a wire-guided thin ultrasound probe that can be inserted into the biliary tract without sphincterotomy. Mechanical rotation of the probe permits a cross-sectional view of the bile duct. When inserting the IDUS probe into the bile duct, some cases are difficult due to the tension in the sphincter of Oddi. In such cases, endoscopic sphincterotomy may be performed. When inserting the IDUS catheter over the stricture, balloon dilation may be performed to pass the stricture. However, it should be limited for mandatory cases where investigation of proximal superficial extension is required because it might damage the main lesion. IDUS can be used to identify superficial expansions from major lesions or vascular invasion.7,8 In a large retrospective study, a sensitivity of 93.2%, a specificity of 89.5%, and an accuracy of 91.4% for the assessment of malignant strictures were reported.9 Malignant suggestive features include the presence of a sessile tumor, an interrupted wall structure, and a tumor size > 10 mm.7 IDUS was diagnostically superior to endoscopic transpapillary biopsies, EUS, and CT in detecting malignant biliary strictures. The sensitivity and specificity of IDUS in this study were determined to be 93% and 89%, respectively.10 A major limitation of earlier IDUS was the inability to obtain biopsies for pathologic diagnosis. More recently, transpapillary biopsies have been performed under IDUS guidance. Kim et al11 performed a prospective comparative study that showed that IDUS-guided transpapillary biopsy has a higher diagnostic accuracy than fluoroscopic-guided transpapillary biopsy for the diagnosis of malignant biliary strictures (90.8% vs 76.9%;
EUS can differentiate between benign and malignant strictures by allowing sonographic visualization of the biliary tract along with the surrounding viscera including the pancreas. EUS is an ultrasound technique in which a high-frequency transducer is mounted at the end of an endoscope. Regarding detection of malignant biliary stricture, EUS without FNA was found to provide a sensitivity of 78% and specificity of 84%.15 Another study proved that EUS was superior for the detection of malignancies compared to CT and MRI (94%, 30%, and 42%, respectively).16
Regarding adverse events, EUS, especially for observation purposes, can avoid pancreatitis, which is mainly problematic for ERCP. EUS-FNA is the established diagnostic modality to obtain specimens, particularly of pancreatic tumors.17 EUS-FNA enables the acquisition of histological evidence of cancer when chemotherapy is being considered to distinguish benign or malignant tumors when deciding whether surgery or follow-up is needed, and assessment of the degree of progression of malignant tumors when unexplained lymph node swelling is detected. A recent meta-analysis established the pooled sensitivity and specificity of EUS-guided FNA in the diagnosis of malignant biliary strictures to be 80% and 97%, respectively. When the location of the biliary stricture was taken into consideration, EUS-guided FNA of distal strictures had a higher sensitivity (83%) than that of proximal strictures (76%); however, there was no difference in specificity.18 At present, the most frequently used needle sizes are 22 gauge and 25 gauge. In a recent meta-analysis, it was reported that the mean sensitivities of ERCP and EUS-FNA for the diagnosis of malignant biliary strictures were 49% and 75% while specificities were 96% and 100%, respectively.19 EUS-FNA might offer a safer alternative to ERCP. With the recent progress of needles, the fine-needle biopsy (FNB) device, which was designed primarily to obtain core tissue samples, was introduced to overcome the FNA sampling material limitation.20 A recent randomized cross-over trial demonstrated that EUS-guided FNB had considerably higher diagnostic yield and specimen adequacy than FNA.21 In a recent meta-analysis comparing FNA with FNB needles, FNB provided a higher pooled diagnostic accuracy, tissue core rate, and allowed diagnosis with fewer passes in both pancreatic and nonpancreatic lesions.22 Although there were no reports using FNB needles regarding the biliary tract, FNB needles have the potential to increase the diagnostic accuracy. Hence, studies regarding EUS-FNB use for the biliary tract are warranted. Recently, increasing case reports of needle tract seeding following EUS-FNA/FNB are emerging. In a recent review regarding needle tract seeding following EUS-FNA/FNB, 33 patients (27, pancreatic cancer; 6, others) with needle tract seeding following EUS-FNA/FNB have been reported up to January 2020.23 Although there were no reports regarding the biliary tract, needle tract seeding could be caused. Thus, EUS-FNA should not be performed when it does not guide treatment selection.
As described above, ERCP is the gold standard for diagnosing biliary strictures. However, ERCP does not provide an intraluminal view of biliary strictures. Direct visualization of the bile duct can be achieved using peroral cholangioscopy (POCS). Moreover, it can perform targeted biopsies of the site of interest. The traditional “mother–baby” POCS requires two endoscopists, with one operating the cholangioscope, while the second endoscopist controls the duodenoscope. The limitations of this system are the need for two operators, baby scope fragility, and time consumption. The development of single-operator cholangioscopy (SOC) has recently led to a resurgence of interest in the use of this technique. Over the past decade, SOC (SpyGlassTM Direct Visualization System; Boston Scientific, Marlborough, MA, USA) has been widely utilized with disposable fiberoptic technology.24 The setup of SOC is easy; only one operator is needed, four-way tip deflection is allowed, and targeted biopsies and therapeutic procedures such as lithotripsy can be performed. Nowadays, the new digital SOC with high-resolution digital technology (SpyGlass DSTM Direct Visualization System) provides improved image quality and maneuverability of the catheter tip.25 The system consists of a 10.8-Fr catheter. The POCS is generally advanced over a guidewire into the bile duct through the working channel of a duodenoscope. Before insertion, sphincterotomy is generally performed. The working channel (1.2-mm diameter in SOC) allows the passage of accessory devices and aspiration. POCS findings are defined as either malignant or benign according to the previous reports.26–29 Malignant findings include: (i) irregular thick tortuous vessels, (ii) oozing, (iii) irregular papillogranular surface, and (iv) a nodular elevated surface such as a submucosal tumor. Benign findings include: (i) a fine network of thin vessels and a flat surface with or without shallow pseudodiverticula; (ii) a lower homogeneous papillogranular surface without primary masses, suggesting hyperplasia; (iii) a bumpy surface with or without pseudodiverticula, suggesting inflammation; and (iv) a white surface with a convergence of folds, suggesting scarring. Cholangioscopic inspection of the epithelium may provide macroscopic clues pertaining to malignancy. Any intraductal masses, nodules, or ulcerations should prompt direct biopsies from the region. The presence of a “tumor vessel,” an irregular, dilated, and tortuous vessel, is considered a reliable feature of biliary malignancy.29 A meta-analysis performed by Sun et al30 demonstrated that visual inspection alone using cholangioscopy is useful for detecting biliary malignancy, with pooled sensitivity and specificity of 90% and 87%, respectively. However, confirmation using cholangioscopic-directed biopsies is still needed, which has an overall sensitivity and specificity of 69% and 98%, respectively. Despite good outcomes, the visual criteria for malignancy are not yet fully established, and there is significant inter observer variation in interpretation of POCS visualization. These variations can be misleading and may result in false-positive malignant diagnoses. Therefore, definite pathological confirmation is important for a definitive diagnosis of indeterminate biliary strictures.
In a meta-analysis regarding POCS procedures, overall and serious adverse event rates of 7% and 1%, respectively, were reported.31 When performing POCS, we must be mindful that cholangitis could be caused by an increase in intraductal pressure due to water irrigation during the procedure. Therefore, it is necessary to use antibiotic prophylaxis and perform biliary drainage to prevent cholangitis. Cholangioscopy has been assessed by many studies to be a safe procedure even in elderly and comorbid patients.32,33 Despite its diagnostic utility, the uptake of cholangioscopy has been relatively limited in many endoscopy centers. Many endoscopists perceive the procedure to be technically difficult, as it requires mastery in ERCP while concurrently operating the cholangioscope through the working channel. Nonetheless, studies have demonstrated a relatively quick learning curve with reportedly only 10 procedures needed to gain proficiency.34,35 Further research and development in cholangioscopy may increase the uptake of this technique in the future.
In addition to the direct or indirect methods to evaluate the bile duct changes already mentioned above, confocal laser endomicroscopy (CLE) is a real-time microscopy providing histopathological diagnoses of biliary diseases. CLE is an endoscopic imaging technique that can provide
A promising technology is the next-generation sequencing (NGS) with the detection of cholangiocarcinoma-associated mutations from bile duct biopsies and brush cytology. It allows for the rapid and simultaneous sequencing of genetic material on a single medium or surface.47,48 This method can potentially increase the sensitivity of the histology or cytology and thus represents a good and technically simple addition. In a recently published study with 252 patients, the combination of NGS and histology achieved a sensitivity of 83% with a specificity of 99%.48 Due to the increasingly broader and more cost-effective application of panel sequencing, implementation in routine diagnostics appears possible in the future. Although further studies are required, it has the potential to diagnose biliary strictures and identify targetable genomic alterations.
We discussed the diagnostic process using endoscopy for indeterminate biliary strictures. Various modalities using endoscopy for the diagnosis of biliary strictures have been reported, and their capabilities have improved. We propose the diagnostic algorithm (Fig. 1). First of all, noninvasive evaluation such as taking the patient’s history, examining the patient’s symptoms, hepatobiliary enzymes, and tumor markers should be performed. Second, cross-sectional imaging such as US, CT, and MRI (magnetic resonance cholangiopancreatography, MRCP) should be performed. EUS imaging is also useful at the same time. Third, an ERCP-related procedure should be performed. As we showed, POCS findings and POCS guided biopsy/CLE provide better outcomes than ERCP under fluoroscopic guidance. However, as POCS and CLE are too expensive to use in the first instance, ERCP (IDUS) with brush cytology and forceps biopsy should be performed first. If the ERCP with brush cytology and forceps biopsy is positive, surgery should be performed. If the stricture remains indeterminate, ERCP with POCS (POCS-guided biopsy)/CLE should be performed. Although EUS-FNA may be performed at this time, we must take into consideration that seeding could be caused. If the stricture remains indeterminate, repeat consideration should be made for repeat ERCP with brushings, POCS with biopsies, and pCLE. If the stricture remains indeterminate even though repeat procedures were performed and suspicion for malignancy remains high, close follow-up or surgery might be considered. Although progress has been made regarding endoscopic procedures, further improvement is needed.
Despite recent advances in endoscopic techniques, the assessment of biliary strictures is still difficult. The diagnosis of biliary strictures may be aided by advances in cytopathological staining and imaging practices. Therefore, a multidisciplinary approach involving endoscopists, surgeons, pathologists and radiologists is necessary to provide a holistic direction for diagnosis. To accurately distinguish indeterminate biliary strictures, clinicians must adjust their decisions based on the clinical condition of the individual patient. In addition, an appropriate endoscopic method is selected according to the patient’s condition, lesion, and endoscopist.
No potential conflict of interest relevant to this article was reported.
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