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AimsCutaneous syncytial myoepithelioma (CSM) is a rare myoepithelioma variant of skin, characterized by intradermal syncytial growth of spindle cells with a distinct immunophenotype of EMA and S100 positivity and infrequent keratin expression. While CSM was first described as a cutaneous tumor, singular non-cutaneous cases have since been reported in bone. We aimed to investigate the clinicopathological features of this variant across all anatomic sites through a large multi-institutional study.Methods and resultsWe complied a total of 24 myoepitheliomas with syncytial growth from our files. The tumors occurred in 12 male and 12 female patients (M:F = 1:1), with a median age of 31 years (range, 9–69 years). While the majority of tumors (75%, n = 18) occurred in skin, a significant subset (25%, n = 6) arose in non-cutaneous sites, including bone (n = 3), bronchus/trachea (n = 2), and interosseous membrane of tibia/fibula (n = 1). Tumor size ranged from 0.4 to 5.9 cm. Clinical follow-up (7 patients; range 14–202 months; median 56.5 months) showed a single local recurrence 8 years after incomplete skin excision but no metastases; all patients were alive at the time of last follow-up without evidence of disease. Histologically, all tumors were pink at low-power and characterized by a syncytial growth of bland ovoid, spindled, or histiocytoid cells with eosinophilic cytoplasm and prominent perivascular lymphoplasmacytic inflammation. One-third displayed adipocytic metaplasia (8/24). Rare cytologic atypia was seen but was not associated with increased mitotic activity. All tumors expressed S100, SMA, and/or EMA. Keratin expression was absent in most cases. Molecular analysis was performed in 16 cases, all showing EWSR1-rearrangments. In total, 15/15 (100%) harbored an EWSR1::PBX3 fusion, whereas 1 case EWSR1 FISH was the only molecular study performed.ConclusionSyncytial myoepithelioma is a rare but recognizable morphologic variant of myoepithelioma which may have a predilection for skin but also occurs in diverse non-cutaneous sites. Our series provides evidence supporting a reappraisal of the term “cutaneous syncytial myoepithelioma,” as 25% of patients in our series presented with non-cutaneous tumors; thus, we propose the term “syncytial myoepithelioma” to aid pathologist recognition and avoidance of potentially confusing terminology when referring to non-cutaneous examples. The behavior of syncytial myoepithelioma, whether it arises in cutaneous or non-cutaneous sites, is indolent and perhaps benign with a small capacity for local recurrence.

Clear Cell odontogenic Carcinomas (CCOC) are rare, aggressive malignant odontogenic tumours which are often misdiagnosed as benign odontogenic tumours due to the non-specific histologic appearance, and benign early clinical presentation. However, due to their propensity to metastasize, the best outcomes are experienced with they are diagnosed early and treated aggressively. In this paper, we present a case of a CCOC misdiagnosed as a clear cell calcifying epithelial odontogenic tumour which was only found to be a CCOC after cervical node metastasis. The original diagnosis was questioned and confirmed to be a CCOC by identification of the chromosomal translocation EWSR1 on fluorescence in situ hybridization. This has recently been described in CCOC and a wide variety of other mesenchymal and epithelial neoplasms. Previous reports have demonstrated EWSR1–ATF1 and EWSR1–CREB1 fusions in CCOC. Next generation sequencing of this case demonstrated the EWSR1–CREM fusion gene which has not been previously reported for CCOC. CREM fusion proteins have only recently been found in several tumour types including the closely associated hyalinizing clear cell carcinoma of salivary glands. This is discussed in this paper, and the role of the discovery of the CREM fusion protein in CCOC adds to your understating of the role of CREM in oncogenesis, and the possible link between CCOCs and hyalinizing clear cell carcinomas.

In the 2022, World Health Organisation classification of odontogenic tumours, the clear cell odontogenic carcinoma is designated as a malignant odontogenic tumour with high recurrence and aggressive behaviour. Deceptive behaviour in the context of a wide range of differentials presents a significant diagnostic problem. It is the fifth most commom type of malignant odontogenic tumor. A systematic assessment of published cases, case series, and retrospective investigations of diagnostic significance of EWSR1 gene in clear cell odontogenic carcinoma is presented to determine trends in presentation, diagnostic characteristics, treatment, and patient outcome. To locate papers reporting clear cell odontogenic carcinoma and EWSR1, extensive database searches were carried out. Demographics, tumour location, immunohistochemical and molecular tests, treatment, follow-up, and recurrence were the variables. 34 cases were detected; 52.9% (n = 18) of the cases were females. The average age was 62.5 years, with a range of 43–82 years. The average size ranged from 3.4 to 8 cm. The mandibular body was the most common location, followed by the maxilla. Maximum immunohistochemistry positivity revealed by CK 19, CKAE1/3, EMA and p63. Most common gene fusion detected was EWSR1-ATF1 in 62.4% of cases contributing to its diagnostic attributes. Surgical treatment was used in 97% of cases. The average follow-up period was 30.3 months, and recurrence was reported in 52.4% of the cases. CCOC can metastasize, and the prognosis is fair. This is first systematic review, where we have attempted to consolidate the mutational expression of EWSR1 in Clear cell odontogenic carcinoma. It is difficult to identify from other clear cell tumours of the head and neck region. It is crucial to distinguish it from other clear cell lesions because of its aggressiveness.

Primary renal myoepithelial carcinoma is an exceedingly rare neoplasm with an aggressive phenotype and Ewing sarcoma breakpoint region 1 (EWSR1) rearrangement in a small fraction of cases. In addition to its rarity, the diagnosis can be challenging for the pathologist due to morphologic heterogeneity, particularly on the biopsy specimen. At times, immunohistochemistry may be indecisive; therefore, molecular studies should be undertaken for clinching the diagnosis. We aim to illustrate a case of primary myoepithelial carcinoma of the kidney with EWSR1-rearrangement in a 67-year-old male patient who presented with right supraclavicular mass, which was clinically diagnosed as carcinoma of an unknown primary. An elaborate immunohistochemical work-up aided by fluorescent in-situ hybridization allowed us to reach a conclusive diagnosis. This unusual case report advocates that one should be aware of the histological mimickers and begin with broad differential diagnoses alongside sporadic ones and then narrow them down with appropriate ancillary studies.

Ewing sarcomas (ES) are rare small round cell sarcomas often affecting children and characterized by gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors (usually FLI1 or ERG). The detection of EWSR1 rearrangements has important diagnostic value. Here, we conducted a retrospective review of 218 consecutive pediatric ES at diagnosis and found eight patients having data from chromosome analysis, FISH/microarray, and gene-fusion assay. Three of these eight ES had novel complex/cryptic EWSR1 rearrangements/fusions by chromosome analysis. One case had a t(9;11;22)(q22;q24;q12) three-way translocation involving EWSR1::FLI1 fusion and 1q jumping translocation. Two cases had cryptic EWSR1 rearrangements/fusions, including one case with a cryptic t(4;11;22)(q35;q24;q12) three-way translocation involving EWSR1::FLI1 fusion, and the other had a cryptic EWSR1::ERG rearrangement/fusion on an abnormal chromosome 22. All patients in this study had various aneuploidies with a gain of chromosome 8 (75%), the most common, followed by a gain of chromosomes 20 (50%) and 4 (37.5%), respectively. Recognition of complex and/or cryptic EWSR1 gene rearrangements/fusions and other chromosome abnormalities (such as jumping translocation and aneuploidies) using a combination of various genetic methods is important for accurate diagnosis, prognosis, and treatment outcomes of pediatric ES.

Pulmonary myxoid sarcoma is an rare and poorly understood malignant neoplasm that primarily arises within the pulmonary tissue. Characterized by its distinctive histological features of myxoid stroma and spindle-shaped cells, this neoplasm poses significant diagnostic and therapeutic challenges due to its rarity and the non-specific nature of its clinical presentation. Current knowledge regarding the pathogenesis, optimal therapeutic strategies and prognostic factors for pulmonary myxoid sarcoma remains limited, primarily due to the scarcity of reported cases and comprehensive studies. The present study reports a case of pulmonary myxoid sarcoma. A 41-year-old male was admitted to the Jeonbuk National University Hospital due to a pulmonary mass in the left lower lobe discovered during a routine health check-up. A CT scan performed at our hospital revealed a nodule ~1 cm in size in the mediobasal segment of the left lower lobe, with relatively well-defined margins and significant enhancement. A wedge resection was performed for diagnosis and treatment, and frozen section examination showed a high likelihood of pleomorphic adenoma. The histological findings of the permanent section examination revealed an abundant myxoid matrix with embedded spindle, stellate and rounded/epithelioid cells arranged in a reticular pattern. The tumor cells exhibited mild to moderate cellular atypia, with rare mitotic figures. Immunohistochemistry showed positive staining for vimentin and negative findings for myoepithelial cell markers such as calponin, high-molecular weight cytokeratin and p63. The presence of the EWSR1-CREB1 fusion was confirmed through fluorescence in situ hybridization and reverse transcription-PCR analyses. Based on these findings, the nodule was diagnosed as pulmonary myxoid sarcoma.

The EWSR1::CREM rearranged intra-abdominal malignant epithelioid neoplasm is an emerging tumor, with only a few publications describing it to date. Here, we report two new cases of this highly aggressive tumor, primarily involving the peritoneal surface. The tumors presented as a widespread diffuse peritoneal lesion associated with a 4-cm pelvic mass in a 28-year-old woman (Case 1) and as a 10-cm intra-abdominal mass infiltrating the stomach with multiple hepatic metastases in a 53-year-old woman (Case 2). The tumors shared predominant epithelioid morphology with minimal nuclear polymorphism. One of them additionally harbored spindle and rhabdoid cell populations. Both tumors displayed immunoreactivity for pan-cytokeratins, EMA, and CD99, and variable positivity for MUC4, progesterone and estrogen receptors, pan-NTRK, and synaptophysin. This misleading histology and immunophenotype give rise to a wide spectrum of differential diagnoses and highlight the crucial role of RNA sequencing in diagnostic accuracy and thus in appropriate therapeutic approaches.

Purpose This review primarily aims to review the epidemiology, clinical characteristics, imaging, pathology, immunohistochemistry, diagnosis, differential diagnosis, treatment, and prognosis of Primary pulmonary myxoid sarcoma (PPMS) with EWS RNA binding protein 1::cAMP response element binding protein 1 (EWSR1::CREB1) fusion. It provides reference for the diagnosis and treatment of this disease. Methods Retrospectively collected the literature about PPMS with EWSR1::CREB1 fusion, its clinical, radiology, histology, molecular characteristics and current treatment strategies were collated and analyzed. This review provides a detailed differential diagnosis of the disease. Results PPMS is an exceptionally rare, low-grade malignant tumor of the lung. This tumor commonly infiltrates lung tissue and develops within bronchial passages. It is identified by a genetic rearrangement involving the EWSR1 gene and a distinct chromosomal translocation t(2; 22)(q33; q12). Variants include EWSR1::CREB1 fusion and EWS RNA binding protein 1::activating transcription factors (EWSR1::ATF1) fusion. PPMS with EWSR1::CREB1 fusion is more prevalent among middle-aged individuals and affects both sexes almost equally. Clinical symptoms are relatively non-specific, primarily including cough, hemoptysis, and weight loss. Most patients undergo surgery and experience a favorable prognosis. Further research is required to validate the effectiveness of alternative treatments for PPMS with EWSR1::CREB1 fusion. Conclusion EWSR1 rearrangement and EWSR1::CREB1 fusion are crucial genetic features of PPMS and serve as important diagnostic markers. Immunohistochemically, PPMS tests positive for EMA. In terms of treatment, surgery has been the primary approach in recent years. Therefore, the efficacy of other treatments still requires further investigation.

EWSR1::NFATC2 sarcoma, a rare round cell sarcoma constituting the majority of EWSR1::non-ETS sarcomas, has recently been defined in the latest WHO classification. To date, the cytological findings of EWSR1::NFATC2 sarcoma remain undocumented. We present the case of a 25-year-old man with a history of polyostotic fibrous dysplasia in the right leg, referred to our hospital with left thigh pain. Cytological findings included metachromasia, minimally pleomorphic round cells, and eosinophilic infiltration. There was no precursor fibrous dysplasia and the initial diagnosis was undifferentiated pleomorphic sarcoma. Following histologic review, we successfully performed immunocytochemistry and fluorescence in situ hybridization (FISH) on archival cytology specimens. The tumor cells were positive for NKX2-2, NKX3-1, and PAX7 and showed amplified 5ʹ single signals of EWSR1 gene. Reverse transcriptase-polymerase chain reaction revealed an in-frame fusion of EWSR1 and NFATC2. This report describes the cytological features of EWSR1::NFATC2 sarcoma and highlights the diagnostic utility of archival cytology specimens.