INSM1 expression and its diagnostic significance in extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma is a rare subtype of sarcoma that affects the soft tissue and bones in middle-aged and elderly adults. Its diagnosis can be challenging, with the differential diagnoses including a wide variety of mesenchymal tumors. The line of differentiation of extraskeletal myxoid chondrosarcoma has been controversial, but recent evidence suggests a neuroendocrine phenotype. INSM1 is a zinc-finger transcription factor that plays a pivotal role in neuroendocrine differentiation, and has been proposed as a promising immunohistochemical marker of neuroendocrine carcinoma. The aim of this study was to determine the prevalence of INSM1 expression in extraskeletal myxoid chondrosarcoma and to understand its significance in sarcoma diagnosis. We immunostained the representative sections of 31 NR4A3-rearranged extraskeletal myxoid chondrosarcomas and 187 histological mimics. Nuclear staining of moderate or higher intensity in at least 5% of tumor cells was considered positive. Twenty-eight of the 31 extraskeletal myxoid chondrosarcomas (90%) were positive for INSM1, providing strong evidence for neuroendocrine differentiation. The staining was diffuse (>50%) in 17 cases, with most immunopositive tumors showing at least focal strong expression. The INSM1 staining extent was not correlated with cytomorphology, synaptophysin expression, or fusion types (EWSR1 vs non-EWSR1). In contrast, INSM1 expression was negative in 94% of the 187 other mesenchymal tumors. INSM1-positive mimics comprised a small subset of chordoma (1 of 10), soft tissue myoepithelioma (1 of 20), ossifying fibromyxoid tumor (3 of 10), and Ewing sarcoma (3 of 10), among other tumor types. The majority of these cases showed labeling in <25% of the tumor cells. Although not entirely sensitive or specific, INSM1 could be a potential marker for the diagnosis of extraskeletal myxoid chondrosarcoma when molecular genetic access is limited.