Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with EWSR1/FUS-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations. Since 2018, 3 cases of URCS with a novel CRTC1::SS18 gene fusion have been reported in the literature. Herein, we report 3 additional cases of CRTC1::SS18 sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range, 12-42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round-to-epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor. Immunohistochemical results were nonspecific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed CRTC1::SS18 gene fusions in all cases, involving exons 1 to 2 of CRTC1 (the 5\' partner gene) on chromosome 19 and either exon 2 or exon 4 of SS18 (the 3\' partner gene) on chromosome 18. The clinical course was variable. Although 1 previously reported case demonstrated aggressive behavior with a fatal outcome, 2 others had a relatively indolent course with gradual growth for 6 to 7 years prior to resection. Two cases developed metastatic disease, including 1 case with bilateral lung metastasis and 1 with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aimed to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.

We report a case of small gastric synovial sarcoma (SS) finally diagnosed after laparoscopic-endoscopic cooperative surgery (LECS). A 50 year-old male underwent medical examination for a chief complaint of epigastric pain. Endoscopic examination showed a 20 mm submucosal tumor (SMT) located in the anterior wall which extended to the lesser curvature of the middle stomach. The biopsy tissue did not yield a definitive diagnosis. During 6 months of follow-up for this lesion suspected to be an inflammatory tumor, neither the shape nor the size of the tumor changed. We performed LECS for both diagnosis and treatment. Histologically, the tumor was composed of fascicles of spindle cells. Immunohistochemically, the tumor cells were focally positive for epithelial membrane antigen, cytokeratin (AE1/AE3) and S100 protein, while being negative for desmin, α-smooth muscle actin, CD34, c-kit and DOG1. The expression of INI1 was reduced. Fluorescence in situ hybridization (FISH) detected SS18 rearrangement. The SMT was diagnosed as primary SS. A SMT measuring < 20 mm might be malignant potential tumor such as SS even if there are no typical malignant findings by endoscopy. Surgical resection should be considered for SMT measuring < 20 mm with atypical findings even in the absence of definitive high-risk features.

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UNASSIGNED: Synovial sarcomas (SS) are enigmatic soft tissue tumors, which are yet to have a defined cell of origin. SS have a variety of differential diagnosis depending upon the age of the patient and the site of presentation. This makes diagnosis cumbersome unless the specific fusion SS18:SSX is identified by reverse transcription-polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH). Immunohistochemistry is a useful tool in resource-poor settings in helping to narrow the differentials and help diagnose this tumor. This study set about assessing possible candidate immunohistochemical markers in their utility to recognize SS.
UNASSIGNED: Forty cases of SS, proven by FISH were included. A tissue microarray (TMA) was constructed, and immunohistochemistry was done using antibodies - TLE1 (OTI1F5), β-catenin (14), INI1 (MRQ-27), CK7 (OV-TL), CK19 (polyclonal), SS18 (polyclonal), calponin (CALP), and claudin1 (Polyclonal). The expression was analyzed to arrive at sensitivity and specificity.
UNASSIGNED: TLE1 had a sensitivity of 92.5% and a specificity of 100%; β-Catenin had a sensitivity of 17.5% and specificity of 100%; Calponin had a sensitivity of 97.5% and a specificity of 81.25%; SS18 had a sensitivity of 95% and specificity of 100%; INI1 had a sensitivity of 95% and specificity of 100%; CK7 had a sensitivity of 90% and specificity of 87.5%; CK19 had a sensitivity of 90% and a specificity of 59.38%; and Claudin had a sensitivity of 85% and a specificity of 78.12%.
UNASSIGNED: The study showed both TLE1 and SS18 are robust diagnostic markers of synovial sarcoma with a sensitivity of 92% and 95%, respectively. INI1 can be used to discriminate SS from nonepithelioid and nonrhabdoid differentials. Calponin expression is helpful to differentiate poorly differentiated SS from its mimics. CK7 is a better marker than CK19 and can be used as a replacement for EMA in the initial screening panel. The use of claudin1 was restricted to delineating the epithelial component. β-Catenin had poor sensitivity, restricting its utility in SS.

A novel SS18-POU5F1 fusion gene was recently reported in soft tissue sarcoma occurring in three adolescent and young adult patients. Herein, we firstly reported the treatment response of SS18-POU5F1 sarcoma to immune checkpoint inhibitor, angiogenesis inhibitor, chemotherapy and radiotherapy. Our patient demonstrated no response to various systemic therapies including immune checkpoint inhibitor, angiogenesis inhibitor and chemotherapy. However, we noted that the SS18-POU5F1 sarcoma had a quick, robust but transient clinical response to radiotherapy. Further studies are needed to elucidate the mechanism underlying the different tumor response to radiotherapy and systemic therapy in this kind of tumor.

The recently introduced, highly sensitive and specific SS18-SSX immunohistochemistry (IHC) is an attractive alternative to SS18 fluorescence in situ hybridization (FISH) testing in synovial sarcoma (SS). However, little is known about how SS18-SSX IHC correlates with SS18 FISH. We correlated the SS18 FISH results of SS from 36 patients with SS18-SSX IHC. Twenty-six tumours had a classic break-apart FISH pattern (1 fused, 1 red and 1 green signal) and all stained positive for the IHC. Ten had an atypical (non-classic) FISH pattern of which 5 stained positive for the IHC. Four of these (including two with novel atypical SS18 FISH patterns) were confirmed to harbour the SS18-SSX fusion on targeted RNA sequencing, while one had classic features of a biphasic SS. The remaining 5 tumours stained negative for the IHC. One had a TPM3-NTRK1 fusion, and one had no fusion, while the remaining three had insufficient tissue/RNA for sequencing. The sensitivity of the IHC was 91% (after excluding the 2 cases with confirmed absence of SS18-SSX fusion). Twenty histologic mimics of SS also stained negative for the IHC (100% specificity). Our study shows that the SS18-SSX IHC is more specific than SS18 FISH in diagnosing SS, especially in cases with atypical FISH patterns. It correlates well with RNA sequencing result and has the potential to replace SS18 FISH testing. A positive IHC result supports the diagnosis of SS, while a tumour with atypical FISH pattern and negative IHC result should undergo further molecular testing.

We report a case of microsecretory adenocarcinoma of the hard palate. The patient is a 37-year-old woman with a 15 mm submucosal tumor, which was incidentally found by her primary care dentist, in her hard palate. Preoperative magnetic resonance imaging revealed a tumor exhibiting high signal on T2-weighted image, which was gradually enhanced on dynamic study. Histologically, the tumor border was ill-defined without fibrous capsule and adjoined minor salivary gland with permeative infiltration at the tumor periphery. The tumor comprised intercalated duct-like cells with polygonal narrow eosinophilic to clear cytoplasm and small, uniform oval nuclei. These cells formed small infiltrative microcysts, tubules and fascicular cords collecting pale basophilic secretions and small vacuoles setting in an abundant fibromyxoid stroma. The tumor cells were positive for CK AE1+AE3, S-100 protein, and p63, while are completely negative for p40, alpha-SMA, and calponin. The MEF2C-SS18 fusion was identified by reverse transcriptase-polymerase chain reaction followed by Sanger sequencing. The combination of characteristic histology, immunophenotype, and presence of MEF2C-SS18 fusion indicated the diagnosis of microsecretory adenocarcinoma of the hard palate, an entity described only recently. Post-operative course was uneventful and there was no evidence of disease at 4 months after surgery.

YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity of the C\'-terminal fusion partner. The YAP activity of the different YAP1 fusions is resistant to negative Hippo pathway regulation due to constitutive nuclear localization and resistance to degradation of the YAP1 fusion proteins. Genetic disruption of the TEAD-binding domain of these oncogenic YAP1 fusions is sufficient to inhibit tumor formation in vivo, while pharmacological inhibition of the YAP1-TEAD interaction inhibits the growth of YAP1 fusion-expressing cell lines in vitro. These results highlight TEAD-dependent YAP activity found in these gene fusions as critical for oncogenesis and implicate these YAP functions as potential therapeutic targets in YAP1 fusion-positive tumors.

Despite significant recent advances in characterizing the molecular pathogenesis of undifferentiated round cell neoplasms, rare cases remain unclassified. Here, we report two distinctive undifferentiated round cell tumors occurring in young adults. One tumor presented intrabdominally and the other arose within the abdominal wall. One patient died of disease following local and distance recurrence, despite aggressive chemotherapy and radiotherapy. Morphologically, both tumors were similarly composed of primitive round to epithelioid cells arranged in nests, sheets, and trabecular patterns. The cytoplasm was scant and amphophilic, while the nuclei were round and uniform with brisk mitotic activity. Focal necrosis was present. Immunohistochemically, both tumors were variably positive for S100 and EMA, and one case focally expressed cytokeratin and TLE1. Targeted RNA sequencing revealed in both an identical SS18-POU5F1 fusion gene. Fluorescence in situ hybridization was performed which confirmed SS18 and POU5F1 gene rearrangements. Expression data, relative to over 200 other mesenchymal neoplasms that had undergone targeted RNA sequencing on the same platform, suggested the SS18-POU5F1 tumors cluster with EWSR1/FUS-POU5F1-positive myoepithelial tumors. In view of our limited sample size, additional studies are needed to characterize the breadth of clinical and pathologic findings in these neoplasms. In addition, further investigation is necessary to determine whether this entity represents a clinically aggressive and phenotypically undifferentiated variant of myoepithelial tumors, or perhaps an altogether novel category of undifferentiated round cell sarcoma.

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