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      Rapidly fatal SMARCA4-deficient undifferentiated sarcoma originating from hybrid hemosiderotic fibrolipomatous tumor/pleomorphic hyalinizing angiectatic tumor of the foot

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          Abstract

          Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft parts and hemosiderotic fibrolipomatous tumor (HFLT) are two rare low-grade locally recurring neoplasms with predilection for the foot/ankle. Recent studies support a close link between the two entities, and origin of PHAT from HFLT and occurrence of hybrid HFLT/PHAT have been documented. Both lesions often harbor TGFBR3 or MGEA5 rearrangements. Rare sarcomas originating from HFLT/PHAT have been reported, typically resembling myxofibrosarcoma or myxoinflammatory fibroblastic sarcoma. We describe a novel SMARCA4-deficient undifferentiated sarcoma with rhabdoid features originating from hybrid HFLT/PHAT in the foot of a 54-year-old male. The tumor pursued a highly aggressive course with rapid regrowth after resection and multiple metastases resulting in patient’s death within 5 months, despite systemic chemotherapy. Immunohistochemistry revealed SMARCA4 loss in the undifferentiated sarcoma, but not in the HFLT/PHAT. Molecular testing confirmed TGFBR3/MGEA5 rearrangements. This report expands the phenotypes of sarcomas developing from pre-existing PHAT/HFLT.

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          SMARCA4-Deficient Thoracic Sarcomatoid Tumors Represent Primarily Smoking-Related Undifferentiated Carcinomas Rather Than Primary Thoracic Sarcomas

          Introduction: Highly aggressive thoracic neoplasms characterized by SMARCA4 (BRG1) deficiency and undifferentiated round cell or rhabdoid morphology have been recently described and proposed to represent thoracic sarcomas. However, it remains unclear whether such tumors may instead represent sarcomatoid carcinomas, and how their clinicopathologic characteristics compare with those of nonsarcomatoid SMARCA4-deficient non–small cell lung carcinomas (SD-NSCC). Methods: We identified 22 SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) with round cell and/or rhabdoid morphology and 45 SD-NSCCs, and comprehensively analyzed their clinicopathologic, immunohistochemical, and genomic characteristics using 341–468 gene next-generation sequencing and other molecular platforms. Results: The relationship of SD-TSTs with NSCC was supported by (1) the presence of NSCC components juxtaposed with sarcomatoid areas in five cases, (2) focal expression of NSCC lineage markers TTF1 or p40 in four additional cases, (3) smoking history in all except one patient (mean = 51 pack-years), accompanied by genomic smoking signature, and (4) high tumor mutation burden (mean = 14.2 mutations per megabase) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-TSTs exhibited considerably larger primary tumor size (p < 0.0001), worse survival (p = 0.004), and more frequent presentation at younger age (30–50 years) despite heavier smoking history. Distinctive pathologic features of SD-TSTs included consistent lack of adhesion molecule claudin-4, SMARCA2 (BRM) codeficiency, and frequent expression of stem cell markers. Conclusions: SD-TSTs represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. Despite their histogenetic relationship with NSCC, these tumors have unique clinicopathologic characteristics, supporting their recognition as a distinct entity. Further studies are warranted to determine therapeutic approaches to this novel class of exceptionally aggressive thoracic tumors.
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            SWI/SNF Complex-deficient Undifferentiated/Rhabdoid Carcinomas of the Gastrointestinal Tract: A Series of 13 Cases Highlighting Mutually Exclusive Loss of SMARCA4 and SMARCA2 and Frequent Co-inactivation of SMARCB1 and SMARCA2.

            Undifferentiated gastrointestinal tract carcinomas are rare highly aggressive neoplasms with frequent but not obligatory rhabdoid features. Recent studies showed loss of SMARCB1 (INI1), a core subunit of the SWI/SNF chromatin remodeling complex, in 50% of tested cases. However, the molecular pathways underlying histologically similar but SMARCB1-intact cases are unknown. We herein analyzed 13 cases for expression of 4 SWI/SNF complex subunits SMARCB1, SMARCA2, SMARCA4, and ARID1A and the mismatch-repair proteins MLH1, MSH2, MSH6, and PMS2 by immunohistochemistry. Patients included 12 men and 1 woman aged 32 to 81 years (median, 57 y). Site of origin was colon (5), small bowel (2), stomach (3), small+large intestine (1), small intestine+ampulla of Vater (1), and esophagogastric junction (1). All tumors showed anaplastic large to medium-sized cells with variable rhabdoid features, pleomorphic giant cells, and, rarely, spindle cell foci. Abortive gland formation was seen in 3 cases and bona fide glandular component in 1 case. Most cases strongly expressed vimentin and variably pancytokeratin. In total, 12/13 cases (92%) showed loss of at least 1 SWI/SNF component. Loss of SMARCB1 (5/13), SMARCA2 (10/13), SMARCA4 (2/13), and ARID1A (2/13) was observed either in combination or isolated. SMARCA2 loss was isolated in 5 cases and coexisted with lost SMARCB1 in 5 cases (all 5 SMARCB1-deficient tumors showed loss of SMARCA2 as well). Co-inactivation of SMARCB1 and SMARCA4 or of SMARCA2 and SMARCA4 was not observed. Two mismatch-repair-deficient cases (MLH1/PMS2) showed concurrent loss of SMARCB1, SMARCA2, and (one of them) ARID1A. This study illustrates for the first time loss of different components of the SWI/SNF complex other than SMARCB1 in undifferentiated gastrointestinal carcinomas including novel SMARCA4-deficient and SMARCA2-deficient cases. Our results underline the close link between SWI/SNF deficiency and the aggressive rhabdoid phenotype. Frequent loss of SMARCA2 possibly points to fragility/vulnerability of the SWI/SNF complex as a consequence of lost core subunit SMARCB1. The exact molecular mechanisms underlying co-inactivation of different SWI/SNF subunits merit further investigations.
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              SMARCA4-deficient Sinonasal Carcinoma :
              A Series of 10 Cases Expanding the Genetic Spectrum of SWI/SNF-driven Sinonasal Malignancies

              The molecular pathogenesis of poorly differentiated sinonasal carcinoma received significant attention in recent years. As a consequence, several unclassified carcinomas in the morphologic spectrum of sinonasal undifferentiated carcinoma have been reclassified as distinctive genetically defined variants or entities. Among the latter are NUT-rearranged carcinoma and SMARCB1-deficient carcinomas. In this study, we further characterize a rare variant of sinonasal undifferentiated carcinoma-like tumors characterized by inactivation of the SWItch/Sucrose Nonfermentable chromatin remodeler SMARCA4 (BRG1) detectable by immunohistochemistry. Patients were 7 males and 3 females aged 20 to 67 years (median, 44). Tumors originated in the nasal cavity (6), nose and sinuses (2), or at unspecified site (2). Six tumors were initially misdiagnosed as small cell neuroendocrine carcinoma (SCNEC) or large cell neuroendocrine carcinoma (LCNEC). Histologically, the tumors were composed of small basaloid (3 cases) or large epithelioid (7) cells disposed into nests and solid sheets with extensive areas of necrosis. No glands or other differentiating features were noted. Abortive rosettes were seen in 1 case. Immunohistochemistry showed consistent expression of pankeratin and absence of CK5, p63, p16, and NUT in all tumors tested. Other tested markers were variably positive: CK7 (2/6), synaptophysin (9/10; mostly focal and weak), chromogranin-A (4/10; focal), and CD56 (3/5; focal). All tumors showed total loss of SMARCA4 and retained expression of SMARCB1/INI1. Co-loss of SMARCA2 was seen in 1 of 8 cases. Limited data were available on treatment and follow-up. Two patients received surgery (1 also radiotherapy) and 3 received chemotherapy. Metastases (cervical nodes, liver, bone, and lung/mediastinal) were detected in 3 patients; 2 were alive under palliative chemotherapy at 8 and 9 months while 1 died of progressive lung disease at 7 months. Three patients (1 with brain invasion) died soon after diagnosis (1 to 3 mo). In total, 4 of 6 patients (66%) with follow-up died of disease (median, 3 mo). This series characterizes SMARCA4-deficient sinonasal carcinoma as a genetically distinct aggressive entity in the spectrum of undifferentiated sinonasal carcinomas. These variants add to the spectrum of SWItch/Sucrose Nonfermentable-deficient sinonasal carcinomas, at the same time expanding the topographic distribution of SMARCA4-related malignancies.
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                Author and article information

                Contributors
                abbas.agaimy@uk-erlangen.de
                Journal
                Virchows Arch
                Virchows Arch
                Virchows Archiv
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0945-6317
                1432-2307
                14 August 2021
                14 August 2021
                2022
                : 480
                : 5
                : 1115-1120
                Affiliations
                [1 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Institute of Pathology, , Friedrich-Alexander University Erlangen-Nürnberg (FAU), ; Erlangen, Germany
                [2 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Departments of Internal Medicine 5 (Medical Oncology and Hematology), , Friedrich-Alexander University Erlangen-Nürnberg (FAU), ; Erlangen, Germany
                [3 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Department of Laboratory Medicine and Pathology, , Mayo Clinic, ; Rochester, MN USA
                [4 ]GRID grid.419804.0, ISNI 0000 0004 0390 7708, Institute of Pathology, , Klinikum Bayreuth GmbH, ; Bayreuth, Germany
                [5 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Institute of Radiology, , Friedrich-Alexander University Erlangen-Nürnberg (FAU), ; Erlangen, Germany
                [6 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Department of Surgery, , Friedrich-Alexander University Erlangen-Nürnberg (FAU), ; Erlangen, Germany
                Author information
                http://orcid.org/0000-0002-0445-8161
                Article
                3167
                10.1007/s00428-021-03167-6
                9033724
                34389899
                8ae0c393-62c4-4c84-b93c-7e3367d53cef
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 June 2021
                : 15 July 2021
                : 20 July 2021
                Funding
                Funded by: Friedrich-Alexander-Universität Erlangen-Nürnberg (1041)
                Categories
                Brief Report
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2022

                Pathology
                swi/snf complex,pleomorphic hyalinizing angiectatic tumor,phat,hemosiderotic fibrolipomatous tumor,hflt,smarca4,undifferentiated sarcoma

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