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Background. The advances of minimally invasive endoscopy-guided procedures that usually yield limited diagnostic material changed pancreaticobiliary cytopathology into one of the most challenging areas of Cytopathology given the abundance of differential diagnoses to be considered when dealing with limited specimens. Summary. We describes a few challenging, examples of potential pitfalls in pancreatobiliary cytopathology evaluation collected from a busy academic hospital (tertiary) center. Case 1 illustrates the challenges in handling paucicellular specimens from pancreatic solid lesions in which, differential diagnoses may include acinar cell carcinoma, neuroendocrine tumors, adenocarcinoma, or even benign pancreatic tissue, among others. Case 2 illustrates the pitfalls in evaluating limited specimens from patients with chronic pancreatitis specially when distinguishing exuberant reactive atypia from dysplastic changes is mandatory. Case 3 illustrates pitfalls in distinguishing malignancy from reactive changes in biliary brushing specimens from patients with Primary Sclerosing Cholangitis. Finally, cases 4 and 5 highlight the importance of including the possibility of pancreatic metastasis in the differential diagnoses of some pancreatic lesions. Key messages. Over time, there has been an increasing demand for pathologists to render diagnoses on limited specimens obtained through minimally invasive procedures which can be frequently challenging even for the most experienced professionals. In many difficult cases, salvaging additional material for a cell block can turn out to be extremely helpful given the possibility of utilizing additional ancillary tests for diagnostic confirmation.

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