SPN is an uncommon tumor accounting for less than 3% of all exocrine pancreatic tumors. Most patients are younger women. SPN often occurs in the pancreatic body and tail. These are tumors of low malignant potential with a recurrence rate of 10 to 15%, so complete resection is the recommended therapy. Currently, there are no proven morphologic features that indicate which tumors will recur or metastasize. According to the Papanicolaou Society of Cytopathology System for Reporting Pancreatobiliary Cytology, SPN are classified as “Neoplastic: Other” as they represent a low grade malignancy with potential to recur.

By CT scan and endoscopic ultrasound, these tumors are well demarcated and may show both solid and cystic components. Endoscopic ultrasound guided fine needle aspiration is an effective way to make the diagnosis of SPN prior to resection. Even though the cytomorphology of these tumors can be fairly characteristic (loosely cohesive bland cells with monotonous grooved nuclei, fine and even chromatin, pseudopapillary structures with myxoid or hyalinized stroma), immunocytochemistry can be very helpful to make a solid diagnosis and exclude mimics.
Immunochemical stains can be performed on smears or on cell block sections. SPN has nuclear and cytoplasmic staining for beta catenin. PR, vimentin, alpha one antitrypsin, and CD56 are also positive. CD10 has membranous staining. ER and chromogranin are negative. E-cadherin lacks membranous staining pattern (as seen in neuroendocrine tumors). Synaptophysin and pancytokeratin are typically negative, but weak and focal staining may be seen. A recent paper by Foo and colleagues reports utility of immunocytochemistry using SOX-11 and TFE3 to aid in the diagnosis of SPN. Of the two markers, SOX-11 is more sensitive and specific for SPN.

Well differentiated pancreatic neuroendocrine tumor (NET) can be considered in the differential diagnosis as it is composed of small loosely cohesive cells with eccentrically placed nuclei. Typically, NETs will have coarser, stippled chromatin. NETs should be strongly and diffusely positive for pancytokeratin with staining for chromogranin and synaptophysin. NETs also have membranous staining for E-cadherin, which is not a feature of SPN. If using E-cadherin in this scenario, remember that interloping gastrointestinal epithelium will have membranous staining. SPN are typically negative for pancytokeratin, chromogranin, and synaptophysin, although focal weak staining for pancytokeratin and synaptophysin may be seen. Both NET and SPN can be positive for CD56.