Neuroendocrine Differentiation in Synovial Sarcoma—An Immunohistochemical Study of 357 Tumors With 4 Markers: Chromogranin A, Synaptophysin, Insulinoma-associated Protein 1 and Insulin Gene Enhancer Protein ISL-1

Expression of neuroendocrine differentiation (NE) markers in synovial sarcoma may result in misdiagnosis as a neuroendocrine tumor. This investigation evaluated 357 synovial sarcomas to determine the presence of NE markers-chromogranin A (CgA), synaptophysin (SYP), insulinoma-associated protein 1 (INSM1), and insulin gene enhancer protein ISL-1 (ISLET1)-using immunohistochemistry. The cohort included 248 primary tumors, 28 metastases, 4 recurrences, and 77 undetermined lesions. The female-to-male ratio was equal (128/124), and patient ages ranged from 7 to 80 years (median=32). Lower (n=107) and upper (n=50) limbs represented the most frequent sites for primary tumors, while the lung (n=18) was the main site of metastasis. Tumors were classified as monophasic (n=289), biphasic (n=57), and poorly differentiated (n=11). Immunostainings were categorized as diffuse, patchy (≥10% and <75%), or focal (<10%). A diffuse staining pattern for SYP, INSM1, and ISLET1 was observed in 30 (8.4%), 1, and 3 tumors, respectively. Likewise, patchy immunoreactivity was detected in 30, 2, and 7 (2%) cases. In 2 tumors, only patchy CgA staining was noted. Strong, moderate-to-strong, moderate, and weak-to-moderate immunoreactivity for CgA, SYP, INSM1, and ISLET1 was observed in 1.4%, 18%, 2%, and 4% of cases, respectively. Nine tumors (2.5%) co-expressed 2 (n=6) or 3 markers. NE proteins were more commonly expressed in biphasic (~70%) than monophasic (~16%) tumors; the difference was statistically significant. One of 11 (9%) poorly differentiated synovial sarcomas showed ISLET1 immunoreactivity. Also, SSX2-fusion compared with SSX1-fusion tumors more frequently expressed NE markers (56.7% vs. 31.7%), but the difference was not statistically significant. In summary, the presence of NE differentiation proteins in certain synovial sarcomas can make diagnosis more difficult, particularly when assessing small biopsy samples where synovial sarcoma is not initially included in the differential diagnosis.