Differential diagnosis includes primary pancreatic tumors versus metastasis in this patient with a history of a brain tumor. In this case, primary pancreatic tumors in the differential with similar cytomorphologic features would include solid pseudopapillary neoplasm (SPN), neuroendocrine tumor (NET), or least likely acinar cell carcinoma (ACC). The defining cytomorphological features and immunohistochemistry of each entity in the differential is listed below. SPN: bland, round to oval nuclei with nuclear grooves and cytoplasmic vacuoles that are arranged around capillaries. Presence of cercariform cells and delicate myxoid clear material surrounding the papillae. IHC: beta-catenin+ (nuclear and cytoplasmic)

NET: hypercellular smear with salt and pepper chromatin pattern, can be plasmacytoid, loosely cohesive, endocrine atypia. IHC: chromogranin+ and synaptophysin+ (cytoplasmic). ACC: eccentrically placed nucleus, prominent nucleolus, granular cytoplasm. IHC: trypsin+ (diffuse granular) Commonly in the tail of the pancreas in young women.

Radiographically, based on the well-circumscribed features without duct dilatation, the differential would include neuroendocrine tumor versus metastasis. The most common metastases to the pancreas include renal, colorectal, melanoma, breast, lung, and sarcoma. This patient did not have any history or imaging findings to support these common metastases to the pancreas.

Of the metastatic tumors from the brain, differential diagnosis includes a glioblastoma multiforme (GBM) or a high grade (grade II-III) solitary fibrous tumor/hemangiopericytoma (SFT/HPC). Extraneural metastases are very rare for GBM (0.2 – 0.5%); the mechanism by which this occurs is not clearly understood.

The cytomorphology and immunohistochemical stains, specifically the STAT6 positivity, support the diagnosis of a solitary fibrous tumor/hemangiopericytoma. Although primary solitary fibrous tumors of the pancreas have been reported (about 16 cases in the literature), this would be less likely given the patient’s history of a brain SFT/HPC that displays similar morphology and immunohistochemistry.

SFT/HPC are considered to exist on a spectrum. SFT is a lower grade neoplasm with a more favorable prognosis while HPC is a higher grade neoplasm with high incidence for recurrence and metastasis. 5-year recurrence rate is reported up to 65% for meningeal based tumors and extracranial metastatic disease after primary resection is reported to be between 13% and 31%. Most common sites for metastasis are bone, liver, and lung. In the CNS, these tumors are normally dural based, rarely parenchymal or intraventricular, and are usually compact and non-infiltrating. Other common primary sites include, but are not limited to, the pleura and soft tissue.

The WHO 2016 classification of tumors of the central nervous system classifies SFT/HPC into three grades:

Grade I: SFT phenotype (benign), alternation of hypo- and hypercellular areas, abundant collagen, mitotic activity < 5/10 HPF, “patternless pattern”, staghorn vasculature

Grade II: HPC phenotype (malignant), hypercellular, mitotic activity < 5/10 HPF

Grade III: HPC phenotype (malignant), mitotic activity > 5/10 HPF
*necrosis is not included in the WHO 2016 grading system.

These tumors show NAB2-STAT6 fusions, which occurs as the result of a genomic inversion at the 12q13 locus that leads to the fusion of the NGFI-A-binding protein 2 (NAB2, nuclear transcription repressor) and STAT6 (signal transducer and activator of transcription 6) genes. Because of this, STAT6 IHC (nuclear staining) has proved to be highly sensitive and specific for the diagnosis. CD34 (membranous), CD99 (cytoplasmic), and bcl-2 (nuclear and cytoplasmic) are also positive, but CD34 can show reduced activity or absent in malignant cases. In addition, they are usually negative for S100, EMA, desmin, most keratins, and claudin. In the central nervous system, EMA is also helpful to distinguish from meningiomas, which will be EMA positive and CD34 negative.