Clinical Utility of Cytology with Ancillary Testing in the Management of Patients with Pancreaticobiliary Lesions

Background: The cytological diagnosis of pancreaticobiliary (PB) lesions is fraught with challenges. Diagnostic specificity is high, but sensitivity suffers from a high threshold for a definitive diagnosis of malignancy. Ancillary testing using immunohistochemical stains, biochemical analysis, and genetic testing have greatly improved diagnostic accuracy of cytology and small biopsy samples of PB lesions. Summary: This review of the cytomorphology and helpful ancillary tests for the diagnosis of the commonly encountered PB lesions offers a practical approach for the practicing pathologist. Key Messages: The differential diagnosis of pancreatic lesions is initially divided into two groups based on imaging: solid versus cystic. Solid masses are the most common lesion, and pancreatic ductal carcinoma is the most common malignancy. Although most cases of adenocarcinoma can be diagnosed on morphology alone, ancillary tests such as immunohistochemical stains of p53, SMAD4/DPC4, and p16 can add support for challenging cases. The clinical questions for the evaluation of a pancreatic cyst are twofold: is the cyst mucinous, and if so, is it high risk for malignancy? Biochemical and molecular testing are ancillary tests that help answer these questions. Bile duct strictures are evaluated with brushing cytology to assess for malignancy. Molecular analysis is an important ancillary test to assist in overcoming the low sensitivity of cytology given the high threshold for the cytological diagnosis of malignancy. A multimodal approach using clinical and imaging information, cytomorphology, and ancillary testing is the key to accurate diagnosis in all three scenarios.