The SMARCB1 (INI1/BAF47/SNF5) gene, located on 22q11.2, is a member of the Switch/sucrose nonfermentable (SWI/SNF) chromatin-remodeling complex and is thought to directly activate and suppress gene expression by displacing DNA from histones, thus allowing transcription [1,2]. SMARCB1 is highly conserved and its gene product SMARCB1/INI1 is ubiquitously expressed in all normal human tissue types and can be readily identified by immunohistochemistry (IHC) [3,4]. Loss of SMARCB1/INI1 protein expression is a consequence of allelic inactivation resulting from deletion, mutation and/or epigenetic silencing involving the SMARCB1 gene locus, which can be seen in a variety of human malignancies [3,[5], [6], [7]]. In bone and soft tissue tumors, complete loss of SMARCB1/INI1 expression is seen in virtually all malignant rhabdoid tumors [8], and most cases of epithelioid sarcoma (both proximal and distal types) [9] and poorly differentiated chordoma [10]. In addition, subsets of soft tissue myoepithelial tumors (30 %) [6,11], extraskeletal myxoid chondrosarcoma (20 %) [12], epithelioid schwannoma (40 %) [13], and epithelioid malignant peripheral nerve sheath tumor (70 %) [14] demonstrate SMARCB1/INI1 loss. With a few exceptions, soft tissue neoplasms with SMARCB1/INI1 loss are unified by the presence of a varying proportion of rhabdoid cells [3,4,8,15]. Most of these tumors pursue an extremely poor prognosis and are difficult to cure.

The advances in molecular genetic testing and widespread use of biomarkers specific for genetic alterations have uncovered a wide phenotype diversity among soft tissue tumors with SMARCB1/INI1 deficiency. Recently, Yoshida et al. [16] described a distinct group of SMARCB1/INI1-deficient epithelioid neoplasms that occurred exclusively in superficial female vulvar region and demonstrated overlapping morphologic features but different immunohistochemical profiles with soft tissue myoepithelial tumors, referred to as myoepithelioma-like tumors of the vulvar region (MELTVRs). Most recently, Kinoshita et al. [17] reported on myxoepithelioid tumors with chordoid features (METCs), which were completely deficient in SMARCB1/INI1 expression and affected predominantly the inguinal region of female patients. METCs showed relatively uniform epithelioid to spindle-shaped cells with myxoid stroma and consistent immunoreactivity for brachyury, epithelial membrane antigen (EMA), and progesterone receptor (PR) and/or oestrogen receptor (ER), features that were equivalent to MELTVRTs [16,17]. It is worth noting that both MELTVRTs and METCs have relatively good prognosis, and studies have shown that almost all patients for whom outcome data were available were alive at the end of follow-up, which contrasts with the generally poor prognosis in patients with SMARCB1/INI1-deficient soft tissue tumors [16,17]. These data suggest that MELTVRTs together with METCs may belong to a distinct clinicopathologic subclass of SMARCB1/INI1-deficient soft tissue tumors, highlighting the importance of accurate diagnosis and classification of these tumors.

Because of their overlapping histologic, immunohistochemical, and molecular genetic features, the diagnosis and classification of soft tissue tumors with loss of SMARCB1/INI1 expression are often challenging without specific findings such as a preferential site, a common age, a panel of differential expression markers, a specific fusion gene, or a gene rearrangement. Not infrequently, even after integrating these characteristics, a subset of cases remains difficult to definitively classify [3,15]. In this study, we report two unique cases of SMARCB1/INI1-deficient soft tissue neoplasm with epithelioid and myxoid features, which occurred in an unusual location (paratesticular region), and harbored SMARCB1 gene deletions by targeted next-generation sequencing (NGS) and fluorescence in-situ hybridization (FISH) analyses. The overall clinicopathologic profiles of the two cases made it difficult to classify them as one of the established categories of SMARCB1/INI1-deficient mesenchymal tumors. Our study further expands the clinicopathologic and molecular spectrum of SMARCB1/INI1-deficient epithelioid neoplasms and highlights the challenges to diagnose these tumors.