Endoscopic and novel approaches for evaluation of indeterminate biliary strictures

Indeterminate biliary strictures are defined as strictures which evade definitive diagnosis after endoscopic retrograde cholangiopancreatography (ERCP)-assisted sampling with brush cytology and/or forceps biopsy and pose significant clinical challenges. While most indeterminate biliary strictures are attributed to malignancies, up to one-third are benign strictures. False-negative and false-positive diagnoses lead to delayed or inappropriate treatment with untoward clinical consequences. Peroral cholangioscopy (POC) and single-operator cholangioscopy (SOC) have demonstrated superior diagnostic accuracy over traditional ERCP-based techniques through enhanced visualization and targeted biopsy. Endoscopic ultrasound (EUS)-guided tissue sampling also achieves superior sensitivity and diagnostic accuracy compared with ERCP-based tissue sampling. The 2025 ESGE guideline proposes an algorithm for optimizing the utilization of ERCP-based and EUS-guided tissue sampling and cholangioscopy with consideration of the stricture location. Furthermore, molecular diagnostic tools such as fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) enable the detection of chromosomal and genetic alterations commonly associated with biliary malignancies, thereby enhancing the sensitivity for malignancy. This review summarizes recent advances in the diagnostic work-up of indeterminate biliary strictures and emerging diagnostic strategies and modalities.