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SWI/SNF chromatin remodeling complex BAF subunit (SMARCB1)-deficient lung carcinoma is rare and may be suitable for immunotherapy. This article presents the case of an elderly male who presented with "a persistent dry cough for 3 months without obvious inducement", and was initially diagnosed with non-small cell lung carcinoma following bronchoscopic biopsy. Immunohistochemical staining for SMARCB1 (-), SMARCA4 (+), PD-L1(22C3) (tumor proportion score is 60%), Ki-67 (+) with a positive index of 60%. The final diagnosis is SMARCB1-deficient lung carcinoma. He was subsequently treated once with a combination of chemotherapy and immunotherapy, and has been followed up for 34 months. Currently, the patient continues to survive with tumor.

We report the case of a 14 year-old teenager who has SC hemoglobinosis and presented with a tumor syndrome with a retro-peritoneal mass, a supraclavicular lymph node and a mid-renal lesion. The microscopic examination revealed an undifferentiated tumor proliferation infiltrating the lymph node parenchyma. This tumor proliferation was INI1/SMARCB1-deficient, and expressed cytokeratins. Given the fact that the histopathological data showed an undifferentiated INI1-deficient carcinoma and that the patient has a kidney lesion and a sickle cell trait, the final diagnosis was lymph node metastasis of SMARCB1-deficient renal medullary carcinoma (OMS 2022)., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Molecularly defined neoplasms are increasingly recognized, given the broader application and performance of molecular studies. These studies allow us to better characterize these neoplasms and learn about their pathogenesis. In the thorax, molecularly defined neoplasms include tumors such as NUT carcinoma, SMARCA4-deficient undifferentiated tumor (DUT), primary pulmonary myxoid sarcoma with EWSR1::CREB1 fusion, hyalinizing clear cell carcinoma, and SMARCB1-deficient neoplasms. Overall, these tumors are rare but are now more often recognized given more widely available immunostains such as NUT (NUT carcinoma), BRG1 (SMARCA4-DUT), and INI-1 (SMARCB1-deficient neoplasm). Furthermore, cytogenetic studies for EWSR1 to support a hyalinizing clear cell carcinoma or primary pulmonary myxoid sarcoma are, in general, easily accessible. This enables pathologists to recognize and diagnose these tumors. The diagnosis of these tumors is important for clinical management and treatment. For instance, clinical trials are available for patients with NUT carcinoma, SMARCA4-DUT, and SMACRB1-deficient neoplasms. Herein, our current knowledge of clinical, morphologic, immunophenotypic, and molecular features of NUT carcinomas, SMARCA4-DUT, primary pulmonary myxoid sarcomas, hyalinizing clear cell carcinoma, and SMARCB1-deficient neoplasms will be reviewed., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Pathogenic variants (mutations) and other molecular events involving subunits of the SWItch/Sucrose Non-Fermentable chromatin remodelling complex are common in a wide variety of malignancies. Many of these neoplasms are characterized by undifferentiated morphology. They arise at a variety of sites in the female genital tract but have rarely been reported in the uterine cervix. We report 2 primary cervical neoplasms arising in young women (ages 28 and 29 yr) exhibiting loss of nuclear immunoreactivity with SMARCB1 (INI1). In one case, which had a mixture of epithelioid and spindle cells, molecular studies revealed no SMARCB1 pathogenic variant, but showed a SPECCL1::NTRK 3 fusion, in keeping with an NTRK fusion sarcoma. The second case exhibited rhabdoid morphology and molecular testing confirmed a SMARCB1 pathogenic variant (c.425 T>G:p.(Leu142Ter) which, interpreted in conjunction with the morphology and immunohistochemistry, resulted in classification as a proximal-type epithelioid sarcoma. To our knowledge, this is the first reported cervical neoplasm exhibiting a SMARCB1 pathogenic variant and the first NTRK fusion sarcoma showing SMARCB1 protein loss. We discuss the diagnostic challenges and complexities of the molecular findings., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Undifferentiated carcinomas are highly aggressive tumors with a dismal prognosis. A subset of these tumors has been associated with inactivation or mutations of the Switch/Sucrose Nonfermenting (SWI/SNF) remodeling complex. Our understanding of the relationship between the clinicopathological features and molecular profiling of SWI/SNF-deficient undifferentiated carcinoma is still evolving due to its rarity. We herein present a rare tumor of undifferentiated carcinoma with SMARCB1/ INI1 deficiency arising from the colon. The histology revealed a tumor composed of sheets of discohesive, high-grade epithelioid cells with rhabdoid morphology along with anaplastic giant cells. Additionally, there was a significant infiltration of inflammatory cells in the background. Immunohistochemical (IHC) analysis supported the diagnosis of carcinoma with loss of INI1 expression, the tumor was mismatch repair protein proficient. Molecular analysis demonstrated an oncogenic KRAS mutation (p.G12D), whereas it was wild-type BRAF , and wild-type NRAS . The diagnosis of SWI/SNF-deficient undifferentiated carcinoma can be challenging. Correlation with clinical findings, in conjunction with IHC work-up and molecular analysis, is of utmost importance to arrive at the appropriate diagnosis and exclude potential mimics., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

SMARCB1-deficient sinonasal adenocarcinoma is a rare variant of SWI/SNF-deficient malignancies with SMARCB1 loss and adenocarcinoma features. More than 200 high-grade epithelial sinonasal malignancies were retrieved. A total of 14 cases exhibited complete SMARCB1 (INI1) loss and glandular differentiation. SMARCA2 and SMARCA4 were normal, except for one case with a loss of SMARCA2. Next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) revealed an alteration in the SMARCB1 gene in 9/13 cases, while 2/13 were negative. Two tumors harbored SMARCB1 mutations in c.157C > T p.(Arg53Ter) and c.842G > A p.(Trp281Ter). One harbored ARID1B mutations in c.1469G > A p.(Trp490Ter) and MGA c.3724C > T p.(Arg1242Ter). Seven tumors had a SMARCB1 deletion. One carried an ESR1 mutation in c.644-2A > T, and another carried a POLE mutation in c.352_374del p.(Ser118GlyfsTer78). One case had a PAX3 mutation in c.44del p.(Gly15AlafsTer95). Histomorphology of SMARCB1-deficient adenocarcinoma was oncocytoid/rhabdoid and glandular, solid, or trabecular in 9/14 cases. Two had basaloid/blue cytoplasm and one showed focal signet ring cells. Yolk sac tumor-like differentiation with Schiller-Duval-like bodies was seen in 6/14 cases, with 2 cases showing exclusively reticular-microcystic yolk sac pattern. Follow-up of a maximum of 26 months (median 10 months) was available for 8/14 patients. Distant metastasis to the lung, liver, mediastinum, bone, and/or retroperitoneum was seen in 4/8 cases. Locoregional failure was seen in 75% of patients, with 6/8 local recurrences and 3 cervical lymph node metastases. At the last follow-up, 5 of 8 (62%) patients had died of their disease 2 to 20 months after diagnosis (median 8.2 months), and 3 were alive with the disease. The original diagnosis was usually high-grade non-intestinal-type adenocarcinoma or high-grade myoepithelial carcinoma. A correct diagnosis of these aggressive tumors could lead to improved targeted therapies with potentially better overall disease-specific survival., (© 2023. The Author(s).)

SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor has aggressive nature with a poor prognosis. Patients with this disease were diagnosed by immunohistochemistry or next-generation sequencing. Those who were able to receive a surgery tended to be cured, while the others treated with chemotherapy, radiation therapy, or immune checkpoint inhibitor were often insensitive to these therapies. However, one having CD274 (PD-L1) amplification showed the response to immune checkpoint inhibitor and a good prognosis. We believed that this report could provide promising information for determining the optimal treatment option.

The 5th WHO classification of thoracic tumours includes thoracic SMARCA4-deficient undifferentiated tumour (SMARCA4-UT) among the "other epithelial tumours of the lung" chapter. Herein, we present a case of undifferentiated thoracic neoplasm with retention of SMARCA4 expression, lack of NUT fusion protein and loss of SMARCB1/INI1 expression. After presenting the clinical and pathological features of the tumour, we carried out a review of the literature on the same topic. Albeit very rare, we believe this entity should be included in the heterogeneous group of undifferentiated neoplasms of the thorax., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project 1-3 . We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

So-called primary yolk sac tumors of the vulva are very rare and often have an aggressive disease course. Their molecular features have not been previously characterized. There is also a well-documented group of SMARCB1 (INI-1)-deficient vulvar neoplasms, which includes proximal-type epithelioid sarcoma and myoepithelial carcinoma. Until now, "vulvar yolk sac tumors" and SMARCB1-deficient neoplasms were considered unrelated diseases. After reviewing an index case of a vulvar yolk sac tumor with loss of SMARCB1 by immunohistochemistry, we retrospectively identified 2 additional cases diagnosed as vulvar yolk sac tumors. Patient ages were 34, 32, and 25 years old, and 2 tumors were associated with a pregnancy. All 3 cases showed morphology typical of a yolk sac tumor, and by immunohistochemistry all were positive for SALL4, glypican-3, keratins, and lacked CD34 positivity. All tumors also demonstrated loss of SMARCB1 in tumor cells. Targeted molecular profiling was performed in 2 cases and identified 2 copy deletion of SMARCB1, without genomic alterations typically seen in gonadal yolk sac tumors. In the third case, isochromosome 12p was not identified by fluorescence in situ hybridization. All 3 patients had either local recurrences or distant metastases, and 2 died of disease. One patient had progressive disease while receiving the enhancer of zeste homolog 2 inhibitor tazemetostat. Overall, these findings suggest that vulvar tumors with pure yolk sac-like morphology may represent morphologic variants of SMARCB1-deficient tumors and not veritable germ cell neoplasia. This potential reclassification may have both prognostic and treatment implications and warrants study of additional extragonadal yolk sac tumors., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Mimickers of neuroendocrine neoplasms (NEN) include a number of important pitfall tumors. Here, we describe our experience with mesenchymal mimics of NENs to illustrate their spectrum and draw the attention particularly to a group of mesenchymal/non-epithelial neoplasms (MN) that combine epithelioid histology with neuroendocrine (NE-) features and peculiar genetic abnormalities. In a consultation series of 4498 cases collected between 2009 and 2021, 2099 neoplasms expressing synaptophysin and/or chromograninA were reviewed and analyzed. A total of 364 (18%) were diagnosed as non-NENs, while the remaining tumors were NEN. The group of mesenchymal/non-epithelial neoplasms with NE-features (MN-NE) included 31/364 (8%) cases. These mostly malignant neoplasms showed an epithelioid morphology. While all but one tumor expressed synaptophysin, mostly patchy, only 10/29 (34%) co-expressed chromograninA. A total of 13/31 (42%) of the MN-NE showed EWSR1-related gene fusions (6 Ewing sarcomas, 5 clear cell sarcomas, and 1 desmoplastic small round cell tumor, 1 neoplasm with FUS-CREM gene fusion) and 7 (23%) were SWI/SNF (SMARCB1 or SMARCA4)-deficient neoplasms. The remaining MN-NE included synovial sarcoma, sclerosing epithelioid mesenchymal neoplasm, melanoma, alveolar soft part sarcoma, solitary fibrous tumor, and chordoma. A total of 27/31 MN-NE were from the last 8 years, and 6 of them were located in the pancreas. Eleven MN-NE were initially diagnosed as neuroendocrine carcinomas (NECs). MN-NE with epithelioid features play an increasing role as mimickers of NECs. They mostly belong to tumors with gene fusions involving the EWSR1 gene, or with SWI/SNF complex deficiency. Synaptophysin expression is mostly patchy and chromograninA expression is infrequent in MN-NE of this series and data extracted from literature., (© 2021. The Author(s).)

Aims: Complete loss of SMARCB1/INI1 in soft-tissue tumours such as malignant rhabdoid tumour, epithelioid sarcoma, myoepithelial tumour of soft tissue and extraskeletal myxoid chondrosarcoma is often associated with high-grade malignancy and poor prognosis. The diagnosis is sometimes challenging, owing to histological similarities, so careful differential diagnosis is required. Therefore, soft-tissue tumours with complete SMARCB1/INI1 loss could potentially include an unknown entity., Methods and Results: We analysed 160 cases of SMARCB1/INI1-deficient soft-tissue tumour, and found 14 cases that were not classifiable into already existing categories and had common clinical and histological features. These involved two male and 12 female patients, ranging in age from 20 years to 61 years. The tumours were located in the the puboinguinal region (n = 13) and pelvic cavity (n = 1). Histologically, the tumours showed relatively uniform epithelioid to spindle-shaped cells with myxoid stroma. All tumours showed immunoreactivity for brachyury, epithelial membrane antigen, and progesterone receptor, and 12 of 14 cases did so for oestrogen receptor. Variable positive staining for α-smooth muscle actin, S100 and glial fibrillary acidic protein (GFAP) was seen. NR4A3 and EWSR1 gene rearrangements were not detected in 13 and 11 examined cases, respectively. Clinical follow-up data for the 14 patients showed that 13 were alive without disease and one had been lost to follow-up; four patients developed local recurrence and/or metastases., Conclusion: The designation 'myxoepithelioid tumour with choroid features' (METC) was proposed as a tumour with intermediate malignancy controllable with appropriate treatment, including the entity of myoepithelioma-like tumour of the vulvar region. METC represents a novel and independent subset that is histologically, biologically and clinically distinct from already existing SMARCB1/INI1-deficient soft-tissue tumours., (© 2021 John Wiley & Sons Ltd.)

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRT SMARCB1 ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRT SMARCA4 ) instead of SMARCB1. However, very few ECRT SMARCA4 cases have been published to date, and a systematic characterization of ECRT SMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRT SMARCA4 and show that they are comparable to those of ECRT SMARCB1. We also assess whether ECRT SMARCB1 , ECRT SMARCA4 , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRT SMARCA4 display molecular features intermediate between SCCOHT and ECRT SMARCB1 ; however, ECRT SMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRT SMARCB1 , potentially supporting their continuous separate classification. Lastly, we show that ECRT SMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: SMARCB1-deficient malignancies can arise in various sites. We describe a novel primary SMARCB1-deficient carcinoma of skin (SDCS) and characterize SMARCB1 mutations in non-melanoma skin cancers (NMSC)., Methods: Cases underwent immunophenotyping and targeted exome sequencing (MSK-IMPACT) assay interrogating somatic mutations in 468 cancer-related genes. The MSK-IMPACT database from 2014 to 2020 encompassing 55, 000 cases was searched for NMSC with SMARCB1 mutations., Results: SDCS arose on the scalp of an 18-year-old woman showing homozygous SMARCB1 deletion with a LATS2 G963E variant. Another case arose on the temple of a 76-year-old man harboring a SMARCB1 W206* mutation associated with loss of heterozygosity (LOH), 59 concurrent mutations, and a UV mutation signature (UV-MS). Both tumors exhibited INI1 loss, positive CK5/6, p40, p63, and claudin-4 with negative CD34. Of 378 NMSC cases, including 370 carcinomas, 7 SMARCB1-mutated tumors were identified: 3 squamous cell, 3 Merkel cell, and one basal cell carcinoma. Six showed UV-MS. Five INI1-interrogated cases retained protein expression suggesting they were SMARCB1-proficient., Conclusions: SDCS can be clinically aggressive, harbor SMARCB1 homozygous deletions or truncating SMARCB1 mutations associated with LOH, and can occur with or without UV-MS. Overall, SMARCB1 mutations in NMSC are rare with most being of undetermined significance and associated with retained INI1 and UV-MS., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: Genomic inactivation of ARID1B in ARID1A-inactivated tumour and genomic inactivation of SMARCB1 represent two recurrent mechanisms, core SWItch/sucrose non-fermentable (SWI/SNF) complex inactivation, that are associated with de-differentiation in endometrial carcinoma. Approximately one-third of dedifferentiated/undifferentiated endometrial carcinomas (DDEC/UEC) show loss of ARID1B expression with a minor subset showing loss of SMARCB1 expression, but little is known regarding the specificity of ARID1B or SMARCB1 loss in gynaecological tract tumours in general. The aim of this study was to examine the frequency of ARID1B and SMARCB1 loss by immunohistochemistry in a series of gynaecological tract epithelial/mesenchymal neoplasms., Methods and Results: We evaluated 1849 tumours that included 748 endometrial carcinomas, 101 uterine carcinosarcomas/adenosarcomas, 64 uterine sarcomas, 221 cervical carcinomas and 715 ovarian carcinomas/borderline tumours by tissue microarrays (TMA). We observed ARID1B loss in 35 of 86 (41%) and SMARCB1 loss in three of 86 (3%) DDEC/UEC, but not in any other uterine tumour types examined. ARID1B-deficient DDEC/UEC also showed concurrent loss of ARID1A expression. All SMARCB1-deficient tumours showed loss of MLH1 and PMS2, while 29 of 35 ARID1B-deficient tumours showed loss of MLH1 and PMS2 or loss of MSH6. All ovarian carcinomas/borderline tumours and cervical carcinomas showed intact expression of ARID1B and SMARCB1., Conclusion: Our findings indicate that the loss of expression of ARID1B or SMARCB1 by immunohistochemistry is highly specific for undifferentiated carcinoma among tumours of the upper gynaecological tract and cervix, and therefore can be used to identify these highly aggressive malignant tumours., (© 2021 John Wiley & Sons Ltd.)

Objectives: The SWI/SNF complex core subunit SMARCB1 is inactivated in a variety of neoplasms that share characteristic "rhabdoid" cytomorphology. The aim of this study was to evaluate SMARCB1-deficient soft tissue neoplasms on cytology to identify diagnostic clues., Methods: Eleven SMARCB1-deficient tumors, including six epithelioid sarcomas, three malignant rhabdoid tumors, one epithelioid malignant peripheral nerve sheath tumor (MPNST), and one poorly differentiated chordoma with fine-needle aspiration (FNA), serous effusion, or touch prep (TP) from two institutions, were included. Targeted next-generation sequencing (NGS) was performed in two cases., Results: Evaluation of FNA (n = 4), effusion (n = 4), and TP (n = 3) in nine adult and two pediatric patients demonstrated cellular samples (n = 11), epithelioid cells with rhabdoid morphology (n = 9), eccentrically located nuclei with prominent nucleoli (n = 7), and cytoplasmic bodies (n = 4); two patients were diagnosed on FNA with cell block. Immunohistochemistry (IHC) demonstrated SMARCB1 loss in all cases and keratin and/or EMA expression in all but the epithelioid MPNST; NGS identified SMARCB1 inactivation in both cases., Conclusions: SMARCB1-deficient soft tissue neoplasms comprise a variety of tumors with epithelioid morphology and frequent expression of keratin and/or EMA. Recognition of characteristic rhabdoid morphology on cytology can prompt IHC and/or NGS testing for SMARCB1 deficiency and help establish the diagnosis., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Atypical Teratoid Rhabdoid Tumor (AT/RT) is a rare pediatric central nervous system cancer often characterized by deletion or mutation of SMARCB1, a tumor suppressor gene. In this study, we found that SMARCB1 regulates Human Endogenous Retrovirus K (HERV-K, subtype HML-2) expression. HML-2 is a repetitive element scattered throughout the human genome, encoding several intact viral proteins that have been associated with stem cell maintenance and tumorigenesis. We found HML-2 env expression in both the intracellular and extracellular compartments in all AT/RT cell lines (n = 4) and in 95% of AT/RT patient tissues (n = 37) evaluated. SMARCB1 knock-down in neural stem cells (NSCs) led to an upregulation of HML-2 transcription. We found that SMARCB1 binds adjacent to the HML-2 promoter, repressing its transcription via chromatin immunoprecipitation; restoration of SMARCB1 expression in AT/RT cell lines significantly downregulated HML-2 expression. Further, targeted downregulation of HML-2 transcription via CRISPR-dCas9 coupled with suppressor proteins led to cellular dispersion, decreased proliferation, and cell death in vitro. HML-2 knock-down with shRNA, siRNA, and CRISPR-dCas9 significantly decreased Ras expression as measured by qRT-PCR, suggesting that HML-2 modulates MAPK/ERK signaling in AT/RT cells. Overexpression of NRAS was sufficient to restore cellular proliferation, and MYC, a transcription factor downstream of NRAS, was bound to the HERV-K LTR significantly more in the absence of SMARCB1 expression in AT/RT cells. We show a mechanism by which these undifferentiated tumors remain pluripotent, and we demonstrate that their formation is aided by aberrant HML-2 activation, which is dependent on SMARCB1 and its interaction with MYC.

Loss of SMARCB1 protein expression has recently been identified in a variety of tumor types such as poorly differentiated chordoma (PCh) and malignant rhabdoid tumor (MRT) including atypical teratoid/rhabdoid tumor (AT/RT). PCh is characterized by poorly differentiated epithelioid tumor cells, sheet arrangement, and coexpression of nonepithelial and epithelial markers. Rhabdoid cells are sometimes present. Therefore, the differentiation of these tumors is often difficult. Brachyury is a transcription factor within the T-box family typically expressed in notochord tissue and chordomas. Some studies have reported high specificity and sensitivity of brachyury expression in chordomas. In the present study, we analyzed immunohistochemical brachyury expression in SMARCB1-deficient tumors and discuss important clinicopathological and diagnostic points, especially in cases of intracranial SMARCB1-deficient tumors with brachyury expression. Brachyury and cytokeratin immunoexpression status was examined in 42 formalin-fixed paraffin-embedded SMARCB1-deficient tumor specimens (PCh, 6 cases; extra-central nervous system [CNS] MRT, 26 cases; AT/RT, 10 cases) and 25 cases of conventional chordoma (CCh). All cases of PCh and CCh showed diffuse immunopositivities for cytokeratin 8, pan-cytokeratin, and brachyury. Brachyury immunoexpression was present in 2 extra-CNS MRT (8%) and 5 AT/RT (50%) cases, but immunopositivity was focal not diffuse. Indeed, in almost all cases of AT/RT (cytokeratin 8, 7/10 cases; pan-cytokeratin, 7/10 cases) and extra-CNS MRT (cytokeratin 8, 23/26 cases; pan-cytokeratin, 25/26 cases), fewer than 50% of cells showed immunoreactivity. Although the histological and clinical features of PCh resemble those of AT/RT, semiquantitative evaluations of the degree of brachyury and cytokeratin immunoexpressivity may help to distinguish PCh from AT/RT., (Copyright © 2021 Elsevier Inc. All rights reserved.)

SMARCB1/INI1 deficient sinonasal carcinoma is a variant of sinonasal undifferentiated carcinoma (SNUC). There is a paucity of literature describing the histomorphological features of this relatively new entity. Herein we describe the histomorphological features of three such cases and review the literature. We retrospectively reviewed the cases of SNUC diagnosed in our institute in the last 6 years. Immunohistochemistry for INI1, NUT & p16 were performed on these cases. Three cases showed loss of INI1. The histomorphology and clinicopathological features of these cases were studied and compared with non INI1 deficient SNUC. A total of 9 cases of SNUC were identified. Three of these cases showed loss of INI1. These three cases had presented with large sinonasal mass and with intracranial extension. Histopathology of these cases showed a diffuse infiltrative pattern, nest, and islands of predominantly basaloid cells with focal rhabdoid morphology. Additional features like small cell carcinoma like pattern, pseudoalveolar and pseudoglandular patterns, clear vacuoles and pseudopapillary appearance were also noted. We conclude that in presence of a mixed pattern of cells with a predominance of basaloid morphology, the possibility of SMARCB1/INI1 deficient sinonasal carcinoma must be strongly suspected and immunohistochemistry for INI1 must be performed.

Our knowledge regarding the role of genes encoding the chromatin remodeling switch/sucrose non-fermenting (SWI/SNF) complex in the initiation and progression of gynecologic malignancies continues to evolve. This review focuses on gynecologic tumors in which the sole or primary genetic alteration is in SMARCA4 or SMARCB1, two members of the SWI/SNF chromatin remodeling complex. In this review, we present a brief overview of the classical example of such tumors, ovarian small cell carcinoma of hypercalcemic type, and then a detailed review and update of SMARCB1-deficient and SMARCA4-deficient tumors of the uterus and vulva., (© 2020 Wiley Periodicals LLC.)

Evolution of poorly differentiated chordoma from conventional chordoma has not been previously reported. We encountered a case of a poorly differentiated chordoma with evidence of whole-genome doubling arising from a SMARCB1-deficient conventional chordoma. The tumor presented as a destructive sacral mass in a 43-year-old man and was comprised of a highly cellular poorly differentiated chordoma with small, morphologically distinct nodules of conventional chordoma accounting for <5% of the total tumor volume. Immunohistochemistry (IHC) revealed both components were strongly reactive for brachyury and lacked normal staining for INI1. Single nucleotide polymorphism (SNP) array analysis identified multiple genomic imbalances in the conventional component, including deletions of 1p, 3p, and 22q (involving SMARCB1) and loss of chromosomes 5 and 15, while the poorly differentiated component exhibited the same aberrations at a more profound level with additional loss of chromosome 4, low level focal deletion of 17p (involving TP53), and tetraploidy. Homozygous deletion of SMARCB1 was present in both components. Fluorescence in situ hybridization (FISH) analysis confirmed the relevant deletions in both components as well as genome doubling in the poorly differentiated tumor. This case suggests that SMARCB1 loss is an early event in rare conventional chordomas that could potentially evolve into poorly differentiated chordoma through additional genomic aberrations such as genome doubling. Further studies with additional patients will be needed to determine if genome doubling is a consistent pathway for evolution of poorly differentiated chordoma., (© 2020 Wiley Periodicals LLC.)

Switch/sucrose nonfermenting complex subunits, such as BRG1, INI1, and ARID1B, are inactivated in a subset of endometrial undifferentiated carcinoma and dedifferentiated carcinoma (DC). Limited information is currently available on their prevalence in other subtypes or the nosological status of endometrial carcinoma with their deficiencies. This study immunohistochemically examined the expression status of BRG1, INI1, and ARID1B using 570 archived cases of endometrial carcinoma and carcinosarcoma resected at a single institution. We identified 1 BRG1-deficient undifferentiated carcinoma, 8 BRG1/INI1/ARID1B-deficient DC, and 3 BRG1-deficient clear-cell carcinomas. None of the cases of endometrioid and serous carcinomas or carcinosarcoma showed deficiencies of these subunits. We then compared 8 BRG1/INI1/ARID1B-deficient DC with 6 BRG1/INI1/ARID1B-intact DC and 28 carcinosarcomas, the latter of which was often confused with DC. Histologically, BRG1/INI1/ARID1B-intact and BRG1/INI1/ARID1B-deficient DC shared a monotonous solid appearance with rhabdoid and epithelioid cells and a myxoid stroma; however, abrupt keratinization and cell spindling was absent in BRG1/INI1/ARID1B-deficient tumors. The median overall survival of patients with BRG1/INI1/ARID1B-deficient DC was 3.8 months, which was worse than those with BRG1/INI1/ARID1B-intact DC (P=0.008) and with carcinosarcoma (P=0.004). BRG1/INI1/ARID1B-deficient DC may be a separate entity with an aggressive behavior to be distinguished from BRG1/INI1/ARID1B-intact DC and carcinosarcoma. Regarding clear-cell carcinoma (n=12), BRG1 deficiency appeared to be mutually exclusive with abnormal ARID1A, BRM, and p53 expression. Further studies are needed to clarify whether BRG1 deficiency plays a role in the pathogenesis of clear-cell carcinoma.

Introduction: SMARCB1 encodes for a component of the SWI/SNF complex and is widely implicated in carcinogenesis. In the head and neck, SMARCB1-deficient carcinomas typically arise in the sinonasal tract but can be found at other sites. EZH2 inhibitors have emerged as potential targeted therapy against SWI/SNF-deficient tumors. We sought to characterize the cytomorphology of head and neck carcinomas with SMARCB1 deficiencies to identify potential candidates for targeted therapy., Materials and Methods: Head and neck carcinomas with SMARCB1 mutations were retrospectively identified and confirmed to be SMARCB1-deficient by both molecular (fluorescent in-situ hybridization or next generation sequencing) and immunohistochemical means. Cases with positive cytology were reviewed and their cytologic features cataloged., Results: A total of 19 specimens from 13 patients were reviewed, including 8 specimens from 7 sinonasal carcinomas, 4 specimens from 3 thyroid carcinomas, 3 specimens from 2 skin carcinomas, and 4 specimens from 1 carcinoma of unknown primary origin. High-grade features were common, including mitoses (11 of 19) necrosis (13 of 19) and multinucleation (16 of 19). Tumors showed either dense cytoplasm with distinct cell borders (10 of 19) or delicate cytoplasm with indistinct cell borders (9 of 19). Most tumors showed no distinct epithelial differentiation (12 of 19), while some (7 of 19) showed glandular or signet ring features. A minor cohort demonstrated rhabdoid cells (4 of 19)., Conclusions: Head and neck carcinomas with SMARCB1 deficiencies have a wide array of morphologies and tend to demonstrate high-grade features. Only a minor cohort demonstrate rhabdoid-type cells. Evaluation of SMARCB1 deficiency for potential targeted therapy should not be limited to tumors with rhabdoid morphology., (Copyright © 2020. Published by Elsevier Inc.)

SMARCB1-deficient sinonasal carcinoma (SNC) is an aggressive malignancy characterized by INI1 loss mostly owing to homozygous SMARCB1 deletion. With the exception of a few reported cases, these tumors have not been thoroughly studied by massive parallel sequencing (MPS). A retrospective cohort of 22 SMARCB1-deficient SNCs were studied by light microscopy, immunohistochemistry, fluorescence in situ hybridization (n = 9), targeted exome MPS (n = 12), and Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) (n = 10), a bioinformatics pipeline for copy number/zygosity assessment. SMARCB1-deficient SNC was found in 13 (59%) men and 9 (41%) women. Most common growth patterns were the basaloid pattern (59%), occurring mostly in men (77%), and plasmacytoid/eosinophilic/rhabdoid pattern (23%), arising mostly in women (80%). The former group was significantly younger (median age = 46 years, range = 24-54, vs 79 years, range = 66-95, p < 0.0001). Clear cell, pseudoglandular, glandular, spindle cell, and sarcomatoid features were variably present. SMARCB1-deficient SNC expressed cytokeratin (100%), p63 (72%), neuroendocrine markers (52%), CDX-2 (44%), S-100 (25%), CEA (4/4 cases), Hepatocyte (2/2 cases), and aberrant nuclear β-catenin (1/1 case). SMARCB1 showed homozygous deletion (68%), hemizygous deletion (16%), or truncating mutations associated with copy neutral loss of heterozygosity (11%). Coexisting genetic alterations were 22q loss including loss of NF2 and CHEK2 (50%), chromosome 7 gain (25%), and TP53 V157F, CDKN2A W110∗, and CTNNB1 S45F mutations. At 2 years and 5 years, the disease-specific survival and disease-free survival were 70% and 35% and 13% and 0%, respectively. SMARCB1-deficient SNCs are phenotypically and genetically diverse, and these distinctions warrant further investigation for their biological and clinical significance., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Several aggressive pediatric cancers harbor alterations in SMARCB1 , including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between SMARCB1 genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors., Experimental Design: We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or SMARCB1 genomic alterations on prior somatic sequencing., Results: SMARCB1 two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of SMARCB1 was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a SMARCB1 alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors., Conclusions: A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers., (©2020 American Association for Cancer Research.)

The classification of sinonasal adenocarcinoma (SNAC) is complex. The high-grade, non-intestinal SNAC group is particularly heterogeneous, with tumors showing widely variable morphology. SMARCB1 (INI-1)-deficient sinonasal carcinoma is a newly described, aggressive tumor that usually resembles sinonasal undifferentiated carcinoma (SNUC) or non-keratinizing squamous cell carcinoma; however, glandular differentiation has been rarely reported and this feature may be under-recognized. We present a dedicated series of 12 SMARCB1-deficient SNACs. All tumors had an oncocytoid/plasmacytoid cytomorphology with variable degrees of glandular differentiation consisting of tubules and cribriform structures with foci of intracellular or intraluminal mucin. Three of 12 tumors exhibited foci of yolk sac tumor-like histologic features. The tumors were uniformly high-grade, with nuclear pleomorphism, elevated mitotic rates and frequent necrosis. By immunohistochemistry, all tumors were entirely SMARCB1-deficient, and 10 of 12 were CK7-positive. Occasional expression of CDX2 (4 of 12), CK20 (3 of 12), and p40 (3 of 10) was seen. Expression of yolk sac markers was variably present in tumors that harbored yolk sac-like areas but also tumors that did not: glypican-3 (10 of 11), SALL4 (6 of 11), HepPar-1 (4 of 11), PLAP (1 of 10), and AFP (1 of 11). SMARCB1-deficient sinonasal carcinoma, particularly the oncocytoid/plasmacytoid form, can demonstrate variable degrees of glandular differentiation. This unexpected morphology combined with variable immunohistochemical results may lead to misdiagnoses of high-grade intestinal or non-intestinal SNAC, myoepithelial carcinoma, or even yolk sac tumor or metastatic hepatocellular carcinoma.

Introduction: To describe the current state of literature involving SMARCB1/INI-1 deficient sinonasal carcinoma (SDSC) and examine a case at our institution., Methods: A systematic search was performed using the Population, Intervention, Comparator, Outcome, and Study Design approach. Search criteria included all occurrences in the title or abstract of the terms: "integrase interactor 1 deficient," "INI1 deficient," or "SMARCB1 deficient" and "sinonasal carcinoma." The main outcomes were disease-free survival, all-cause mortality, rates of recurrence, or metastases., Results: Systematic search yielded 13 studies for final review. All studies were either case series or case reports with 82 cases of SDSC published since 2014. Age on presentation ranged from 19 to 75 years, with the majority of patients being male. Surgical resection was the primary modality of treatment with adjuvant radiation or chemoradiation therapy. Overall, the prognosis was poor, with most tumors presenting at advanced stages with an overall median (range) survival of 22 (12-44) months with an average (standard deviation) of 45.3% (33.1%) of patients dying of the disease. An average (standard deviation) of 38.2% (34.0%) of patients had no evidence of disease at follow-up. Studies comparing sinonasal undifferentiated carcinoma to SDSC reported worse prognosis for SDSC and increased risk for locoregional recurrence in the latter cohort., Conclusions: SDSC represents a highly aggressive tumor presenting at advanced stage with propensity of metastasis. More research is necessary to determine the optimal treatment modality and management., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Undifferentiated and dedifferentiated endometrial carcinomas (UDEC) are aggressive uterine tumors which may show loss of expression of SMARCA4 (BRG1) or SMARCB1 (INI-1). The recently described SMARCA4-deficient undifferentiated uterine sarcoma (SDUS) has a morphology which overlaps with UDEC. In this study, we compared clinical, morphologic, immunohistochemical, and molecular characteristics to identify features which differentiate SDUS from UDEC. Cases of SDUS (n=12) were compared with cases of UDEC (n=84, 55 of which were previously published). Immunohistochemistry was performed for p53, mismatch repair proteins, claudin-4, SMARCA4, and SMARCB1. Targeted molecular profiling was performed on 15 cases. Patients with SDUS were significantly younger than those with UDEC (mean 35.8 vs. 61.2 y, P=0.0001). UDEC and SDUS showed morphologic overlap; however, phyllodiform architecture favored a diagnosis of SDUS (36% vs. 0%, P=0.005), while prominent nuclear pleomorphism was only seen in some cases of UDEC (0% vs. 24%, P=0.15). Compared with SDUS, UDEC more frequently showed TP53 mutations (0% vs. 34%, P=0.03), microsatellite instability (0% vs. 44%, P=0.006), and intact SMARCA4 and SMARCB1 (0% vs. 80%); a panel combining these immunohistochemical markers had a sensitivity of 100% and specificity of 92% in distinguishing SDUS and UDEC. Cases of UDEC had mutations in genes associated with endometrial adenocarcinomas (eg, TP53, PTEN, PIK3CA) and occasionally SMARCA4, while SDUS was characterized solely by inactivating mutations in SMARCA4. Disease-specific survival was shorter in SDUS than UDEC (median survival 9 and 36 mo, P=0.01). In conclusion, SDUS occurs in younger patients than UDEC, has a worse prognosis, and in most cases has a distinct molecular and immunohistochemical profile.

SMARCB1 is a tumor suppressor gene, which is part of SWI/SNF complex involved in transcriptional regulation. Recently, loss of SMARCB1 expression has been reported in gastrointestinal carcinomas. Our purpose was to evaluate the incidence and prognostic value of SMARCB1 loss in colon carcinoma (CC). Patients with stage III CC (n= 1695), and a second cohort of 23 patients with poorly differentiated CC were analyzed. Immunohistochemistry for SMARCB1 was performed on tissue microarrays, and cases with loss of expression were controlled on whole sections. Loss of SMARCB1 was compared with the clinico-pathological and molecular characteristics, and the prognostic value was evaluated. Loss of SMARCB1 was identified in 12 of 1695 (0.7%) patients with stage III CC. Whole section controls showed a complete loss in only one of these cases, corresponding to a medullary carcinoma. SMARCB1 loss was not associated with histological grade, tumor size nor survival. In the cohort of poorly differentiated CC, we detected 2/23 (8.7%) cases with loss of SMARCB1; one was rhabdoid while the other had medullary and mucinous histology. These 2 cases were deficient for MisMatched Repair (dMMR) and mutated for BRAF. SMARCB1 loss is rare in stage III CC, but appears more frequent in poorly differentiated CC.

Background: SMARCB1-deficient sinonasal carcinoma (SDSC) is an aggressive subtype of head and neck cancers that has a poor prognosis despite multimodal therapy. We present a unique case with next generation sequencing data of a patient who had SDSC with perineural invasion to the trigeminal nerve that progressed to a brain metastasis and eventually leptomeningeal spread., Case Presentation: A 42 year old female presented with facial pain and had resection of a tumor along the V2 division of the trigeminal nerve on the right. She underwent adjuvant stereotactic radiation. She developed further neurological symptoms and imaging demonstrated the tumor had infiltrated into the cavernous sinus as well as intradurally. She had surgical resection for removal of her brain metastasis and decompression of the cavernous sinus. Following her second surgery, she had adjuvant radiation and chemotherapy. Several months later she had quadriparesis and imaging was consistent with leptomeningeal spread. She underwent palliative radiation and ultimately transitioned quickly to comfort care and expired. Overall survival from time of diagnosis was 13 months. Next generation sequencing was carried out on her primary tumor and brain metastasis. The brain metastatic tissue had an increased tumor mutational burden in comparison to the primary., Conclusions: This is the first report of SDSC with perineural invasion progressing to leptomeningeal carcinomatosis. Continued next generation sequencing of the primary and metastatic tissue by clinicians is encouraged toprovide further insights into metastatic progression of rare solid tumors.

Purpose: We sought to determine the mechanism of an exceptional response in a patient diagnosed with a SMARCB1/INI1-negative chordoma treated with tazemetostat, an EZH2 inhibitor, and followed by radiotherapy. Patient and Methods: In an attempt to investigate the mechanism behind this apparent abscopal effect, we interrogated tumor tissues obtained over the clinical course. We utilized next-generation sequencing, standard IHC, and employed a novel methodology of multiplex immunofluorescence analysis., Results: We report an exceptional and durable response (2+ years) in a patient with SMARCB1-deleted, metastatic, poorly differentiated chordoma, a lethal disease with an overall survival of 6 months. The patient was treated for 4 weeks with tazemetostat, an EZH2 inhibitor, in a phase II clinical trial. At the time of progression she underwent radiation to the primary site and unexpectedly had a complete response at distant metastatic sites. We evaluated baseline and on-treatment tumor biopsies and demonstrate that tazemetostat resulted in pharmacodynamic inhibition of EZH2 as seen by decrease in histone trimethylation at H3K27. Tazemetostat resulted in a significant increase in intratumoral and stromal infiltration by proliferative (high Ki-67), CD8 + T cells, FoxP3 + regulatory T cells, and immune cells expressing checkpoint regulators PD-1 and LAG-3. These changes were pronounced in the stroma., Conclusions: These observations are the first demonstration in patient samples confirming that EZH2 inhibition can promote a sustained antitumor response that ultimately leads to T-cell exhaustion and checkpoint activation. This suggests that targeted alteration of the epigenetic landscape may sensitize some tumors to checkpoint inhibitors., (©2019 American Association for Cancer Research.)

Integrase interactor 1 (INI1) is a tumor suppressor gene that is ubiquitously expressed in all nucleated cells. The loss of INI1 protein activity was first demonstrated in aggressive pediatric tumors, including atypical teratoid/rhabdoid (AT/RT) tumor of the central nervous system and malignant rhabdoid tumor of the kidney. Subsequently, INI1 deficiency was discovered in other pediatric and some adult neoplasms. The spectrum of INI1-negative tumors includes a wide variety of neoplasms that occur over a wide age range, are variably aggressive, and have a variable rhabdoid component on histopathologic evaluation. In this report, the authors describe a 27-year-old gravid woman with INI1-deficient carcinoma of the lacrimal gland, previously not described in this location.

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19 ARF -p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Integrase interactor 1 (INI-1)-deficient carcinoma is a rare cancer characterized by the loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene ( SMARCB1 ) and tends to follow an aggressive clinical course. There is no currently available standard therapy option, although a few promising treatment strategies, including enhancer of zeste homolog 2 (EZH2) inhibition, are under active investigation. This report describes a 30-year-old woman with INI-1-deficient carcinoma who progressed on combination chemotherapy and an EZH2 inhibitor. Next-generation-sequencing-based targeted cancer-related gene assay confirmed SMARCB1 loss and revealed other mutations in breast cancer 1 gene and checkpoint kinase 2 gene, which may have impacted her clinical course. After discussion at the molecular tumor board, she was offered alisertib, an aurora A kinase inhibitor, on a single-patient expanded-use program and achieved prolonged disease stabilization. Aurora A kinase inhibition may have an important role in the management of patients with INI-1-deficient tumors, warranting further evaluation in clinical studies. KEY POINTS: Loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene ( SMARCB1 ), which encodes integrase interactor 1 (INI-1), is associated with various mesenchymal malignancies, but a few carcinomas with rhabdoid features have been recently described as a distinct entity.INI-1-deficient carcinoma can be very aggressive, and there is no known treatment option available.There are encouraging preliminary data with an enhancer of zeste homolog 2 inhibitor, tazematostat, in INI-1-deficient malignancies, including INI-1-deficient carcinomas.Loss of INI-1 can activate aurora A kinase (AurkA), and inhibition of AurkA by alisertib could be a viable option and warrants further investigation in this cancer.Clinical genomic profiling can confirm diagnosis of molecularly defined malignancy and provide insights on therapeutic options., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

SMARCB1 (INI-1)-deficient sinonasal carcinoma is a rare entity within the subgroup of poorly differentiated sinonasal tract carcinomas. As there are only two papers describing the cytologic features of this entity, herein we describe the unique cytomorphologic features of a pulmonary metastasis of this tumor and include the differential diagnosis based on tumor location. The patient was a 53-year-old male who initially presented with sinus congestion and vision changes including left-eye proptosis and diplopia. The initial biopsy of the ethmoid-centered sinonasal mass was non-keratinizing squamous cell carcinoma based on strong immunoreactivity with p40 and absence of immunoreactivity for chromogranin, synaptophysin, p16, and EBER. However, the final diagnosis of the surgical resection was amended to SMARCB1 (INI-1)-deficient sinonasal carcinoma after additional immunohistochemical stains were performed. Post-primary resection, follow-up computed tomography imaging revealed significant interval progression of a solitary, initially indeterminate 1-cm lung nodule in the left upper lobe. Endobronchial ultrasound-guided fine-needle aspiration with concomitant core-needle biopsy was performed. Rapid on site evaluation of cytologic smears revealed a hypercellular specimen consisting of sheets of epithelioid cells with very scant to absent cytoplasm, ill-defined cell borders, enlarged fragile nuclei, and areas of nuclear molding. Mitotic figures were present. Other areas showed tumor cells with spindled to elongated nuclei and scant to ill-defined wispy cytoplasm. Both cytology cell block and core-needle biopsy histopathologic material showed the tumor cells to be negative for INI-1 nuclear staining as well as CK5/6, CAM5.2, p40, p63, CK7, AE1/3, and TTF-1. SMARCB1 (INI-1)-deficient sinonasal carcinoma can have a spectrum of morphologies and may mimic "small-round-blue-cell" and spindle-cell tumors on cytology preparations. Given the pulmonary location of the aspirate, familiarity with the cytomorphologic spectrum of SMARCB1 (INI-1)-deficient sinonasal carcinoma, inclusion of this entity within the differential diagnosis, and performance of immunohistochemistry will aid in arriving at the correct diagnosis., (© 2019 S. Karger AG, Basel.)

SMARCB1-deficiency has been found in a variety of tumors. Here, we report a SMARCB1-deficient squamous cell carcinoma of a mediastinal cyst. A 53-year-old man was diagnosed with a cyst of the pericardial region in his twenties. As a symptom at this time, he complained of severe pain and dyspnea in the right chest. Following investigation using imaging and histological examination of the biopsy specimen, he was diagnosed with a SMARCB1 deficient malignant neoplasm. As tumor cells showed positive immunostaining for p40 and CK5/6, the immunophenotype of the tumor was consistent with squamous cell carcinoma (SCC). The patient died six months after initial presentation. The autopsy showed the most part of the tumor with anaplastic cytomorphology, loss of SMARCB1, diffusely positive immunostaining for pancytokeratin, and negative immunostaining for p40 and CK5/6. To our knowledge, this is the first report of SMARCB1-deficient SCC of mediastinal cyst., (© 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

SMARCB1 inactivation is a well-established trigger event in atypical teratoid/rhabdoid tumor. Recently, a role for SMARCB1 inactivation has emerged as a mechanism of clonal evolution in other tumor types, including rare brain tumors. We describe an unusual malignant intra-axial SMARCB1-deficient spindle cell desmoplastic neoplasm, occurring in a 6-year-old child with meningioangiomatosis and a long history of seizures. Striking features of the tumor were a storiform pattern and strong CD34 expression. Undifferentiated round cell areas with isolated rhabdoid cells showing high mitotic index and focal necrosis with INI1 expression loss were present. The meningioangiomatosis component showed few chromosomal imbalances, including chromosomal 22 monosomy (where SMARCB1 maps) and gain at 6q14.3. In addition to these abnormalities, the spindle cell desmoplastic neoplasm and its dedifferentiated SMARCB1-deficient component shared several other aberrations, including homozygous deletion at 9p21.3, losses at 1p, 3p, 3q, 10p, and 13q, gains and losses at 5p and 11p. In line with INI1 loss, the dedifferentiated component showed remarkably decreased levels of SMARCB1 transcript. The residual SMARCB1 allele was wildtype. Our findings suggest progression from the meningioangiomatosis to the malignant desmoplastic neoplasm through the occurrence of complex chromosomal abnormalities, and point to functional silencing of SMARCB1 in the dedifferentiation component.

Background: SMARCB1 (INI-1)-deficient sinonasal carcinoma (IDSNC) is a newly described, poorly differentiated carcinoma. Herein, the authors describe the cytopathologic features of IDSNC in fine-needle aspiration (FNA) samples., Methods: The pathology archives of 2 academic institutions were searched for cases of IDSNC with available cytologic materials. All available slides were reviewed and a detailed morphological analysis was performed., Results: Six cases were identified from 6 patients. FNA specimens were obtained from metastatic sites (4 cases), a local disease recurrence (1 case), and a primary lesion extending into the orbit (1 case). The majority of cases had cellular specimens with features of nonkeratinizing squamous cell carcinoma composed of cohesive clusters and sheets of oval to polygonal cells with indistinct cell borders present within a background of necrotic debris. Two cases had single rhabdoid cells with more abundant cytoplasm. The nuclei generally were small and uniform with fine chromatin, small nucleoli, and mild nuclear membrane irregularities; moderate anisonucleosis and multinucleation were noted in one case. Apoptotic bodies were common in 5 of 6 cases, and readily identifiable mitoses in 3 of 6 cases. Immunohistochemistry demonstrated that all cases expressed cytokeratins, 4 of 5 cases expressed p63, and all cases demonstrated loss of INI-1 nuclear expression. All cases were negative for neuroendocrine markers and aberrant p16 staining., Conclusions: A diagnosis of IDSNC can be suspected on FNA specimens from patients with high-grade sinonasal carcinomas that have either a nonkeratinizing squamous cell carcinoma or rhabdoid morphology. Clinical history and the availability of material for immunohistochemistry are key in confirming the diagnosis. Cancer Cytopathol 2018. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

SWI/SNF is an evolutionarily conserved multi-subunit chromatin remodeling complex that regulates epigenetic architecture and cellular identity. Although SWI/SNF genes are altered in approximately 25% of human malignancies, evidences showing their involvement in tumor cell-autonomous chromatin regulation and transcriptional plasticity are limiting. This study demonstrates that human primary acute myeloid leukemia (AML) cells exhibit near complete loss of SMARCB1 (BAF47 or SNF5/INI1) and SMARCD2 (BAF60B) associated with nucleation of SWI/SNF Δ SMARCC1 (BAF155), an intact core component of SWI/SNF Δ , colocalized with H3K27Ac to target oncogenic loci in primary AML cells. Interestingly, gene ontology (GO) term and pathway analysis suggested that SMARCC1 occupancy was enriched on genes regulating Rac GTPase activation, cell trafficking, and AML-associated transcriptional dysregulation. Transcriptome profiling revealed that expression of these genes is upregulated in primary AML blasts, and loss-of-function studies confirmed transcriptional regulation of Rac GTPase guanine nucleotide exchange factors ( GEF ) by SMARCB1. Mechanistically, loss of SMARCB1 increased recruitment of SWI/SNF Δ and associated histone acetyltransferases (HAT) to target loci, thereby promoting H3K27Ac and gene expression. Together, SMARCB1 deficiency induced GEFs for Rac GTPase activation and augmented AML cell migration and survival. Collectively, these findings highlight tumor suppressor role of SMARCB1 and illustrate SWI/SNF Δ function in maintaining an oncogenic gene expression program in AML. Implications: Loss of SMARCB1 in AML associates with SWI/SNF Δ nucleation, which in turn promotes Rac GTPase GEF expression, Rac activation, migration, and survival of AML cells, highlighting SWI/SNF Δ downstream signaling as important molecular regulator in AML. Mol Cancer Res; 16(5); 791-804. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Malignant mesothelioma (MM) with rhabdoid features is an MM variant. Fifteen cases have been reported previously, all of which were combined with other types of MM. Herein, we report an autopsy case of pleural MM with monomorphic rhabdoid features. The patient was a 62-year-old male without a history of asbestos exposure. An autopsy revealed a soft, granular tumor that replaced the entire left pleura and had invaded to the diaphragm and lower lobe of the lung. The tumor cells, which had eosinophilic plump cytoplasm and eccentric nuclei, were loosely cohesive. Immunohistochemistry showed that the cells were diffusely positive for calretinin, D2-40, vimentin, CAM5.2, and AE1/AE3; and negative for WT-1, TTF-1, CK7, CEA, desmin, CD34, BCL-2, S100 protein, and p40. Neither homozygous deletion of p16 nor BAP-1 protein loss was observed. Loss of INI1/BAF47 protein, an indicator of malignant rhabdoid tumor, was observed. Therefore, MM with rhabdoid features was confirmed., (© 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

The SMARCB1 gene ( INI1, BAF47) is a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, involved in the epigenetic regulation of gene transcription. SMARCB1 acts as a tumor suppressor gene, and loss of function of both alleles gives rise to SMARCB1-deficient tumors. The prototypical SMARCB1-deficient tumor is the malignant rhabdoid tumor (MRT) which was first described in the kidney but also occurs in soft tissue, viscera, and the brain (where it is referred to as atypical teratoid rhabdoid tumor or AT/RT). These are overwhelmingly tumors of the very young, and most follow an aggressive and ultimately lethal course. Morphologically, most but not all contain a population of "rhabdoid" cells, which are large cells with abundant cytoplasm, perinuclear spherical inclusions, and eccentric vesicular nuclei with large inclusion-like nucleoli. MRT immunohistochemistry reveals complete loss of SMARCB1 nuclear expression, and molecular analysis confirms biallelic SMARCB1 inactivation in the vast majority. Rare AT/RTs have loss of SMARCA4, another SWI/SNF member, rather than SMARCB1. With the widespread adoption of SMARCB1 immunohistochemistry, an increasing number of SMARCB1-deficient tumors outside of the MRT-AT/RT spectrum have been described. In addition to MRT and AT/RT, pediatric tumors with complete loss of SMARCB1 expression include cribriform neuroepithelial tumor, renal medullary carcinoma, and epithelioid sarcoma. Tumors with variable loss of SMARCB1 expression include subsets of epithelioid malignant peripheral nerve sheath tumor, schwannomas arising in schwannomatosis, subsets of chordomas, myoepithelial carcinomas, and sinonasal carcinomas. Variable and reduced expression of SMARCB1 is characteristic of synovial sarcoma. In this review, the historical background, clinical characteristics, morphology, immunohistochemical features, and molecular genetics most germane to these tumors are summarized. In addition, familial occurrence of these tumors (the rhabdoid tumor predisposition syndrome) is discussed. It is hoped that this review may provide practical guidance to pathologists encountering tumors that have altered expression of SMARCB1.

Perturbations to mammalian SWI/SNF (mSWI/SNF or BAF) complexes contribute to more than 20% of human cancers, with driving roles first identified in malignant rhabdoid tumor, an aggressive pediatric cancer characterized by biallelic inactivation of the core BAF complex subunit SMARCB1 (BAF47). However, the mechanism by which this alteration contributes to tumorigenesis remains poorly understood. We find that BAF47 loss destabilizes BAF complexes on chromatin, absent significant changes in complex assembly or integrity. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in increased genome-wide BAF complex occupancy, facilitating widespread enhancer activation and opposition of Polycomb-mediated repression at bivalent promoters. We demonstrate differential regulation by two distinct mSWI/SNF assemblies, BAF and PBAF complexes, enhancers and promoters, respectively, suggesting that each complex has distinct functions that are perturbed upon BAF47 loss. Our results demonstrate collaborative mechanisms of mSWI/SNF-mediated gene activation, identifying functions that are co-opted or abated to drive human cancers and developmental disorders.

SWI/SNF complex is an evolutionarily well-conserved chromatin-remodeling complex, which is implicated in the nucleosomes removing or sliding, impacting on the DNA repair, replication and genes expression regulation. The SWI/SNF complex consists up to 12 protein subunits. The catalytic subunits are BRG1 or BRM, which are exclusive ATPase subunits. BRG1 has been reported to play an important role in cellular senescence. However, The function of non-catalytic subunits involved in cellular senescence is rarely investigated. Therefore, we focused on the senescence regulation roles of SWI/SNF non-catalytic subunits in cellular senescent model induced by H 2 O 2 . H 2 O 2 treatment was used to induce cellular senescence models in vitro. Screening the candidate subunits involved in this process by comparing the expression levels of SWI/SNF subunits with/without H 2 O 2 treatment. Over-expression and knockdown the candidate subunits were utilized to investigate the functions and mechanism of the subunits involved in senescence regulation. The expressions of BAF57, BAF60a and SNF5 were changed significantly after H 2 O 2 treatment. Overexpression of the three subunits separately induced cell growth arrest in both HaCaT and GLL19 cells, while knockdown of the subunits separately eased the senescence induced by H 2 O 2 treatment. Results further showed that BAF57, BAF60a and SNF5 regulated cellular senescence via both p53/p21 and p16/pRB pathways, and the three subunits all had a directly interaction with p53. These results indicated that BAF57, BAF60a and SNF5 might act as novel pro-senescence factors in both normal and tumor human skin cells. Therefore, inhibiting expression of the three factors might delay the cellular senescence process., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with limited treatment options and poor outcome. A morphological spectrum of 47 sinonasal tumours including 17 (36.2%) SNUCs was analysed at genomic level. Thirty carcinomas (cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACT TM ) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumours (cohort 2) were examined only for the presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in two (20%) poorly-differentiated carcinomas with glandular/acinar differentiation, and in one of two high-grade neuroendocrine carcinomas, large cell type (HGNECs). No IDH2 mutation was detected in any of five olfactory neuroblastomas or in any of five SMARCB1-deficient carcinomas. Among 12 IDH2-mutated cases in cohort 1, five (41.7%) harboured co-existing TP53 mutations, four (33.3%) CDKN2A/2B loss-of-function alterations, four (33.3%) MYC amplification, and three (25%) had concurrent SETD2 mutations. AKT1 E17K and KIT D816V hotspot variants were each detected in one IDH2-mutated SNUC. The vast majority of SNUCs and variable proportions of other poorly-differentiated sinonasal carcinomas may be amenable to IDH2-targeted therapy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Rhabdoid phenotype and loss of SMARCB1 expression in a brain tumor are characteristic features of atypical teratoid/rhabdoid tumors (ATRT). Rare non-rhabdoid brain tumors showing cribriform growth pattern and SMARCB1 loss have been designated cribriform neuroepithelial tumor (CRINET). Small case series suggest that CRINETs may have a relatively favorable prognosis. However, the long-term outcome is unclear and it remains uncertain whether CRINET represents a distinct entity or a variant of ATRT. Therefore, 10 CRINETs were clinically and molecularly characterized and compared with 10 ATRTs of each of three recently described molecular subgroups (i.e. ATRT-TYR, ATRT-SHH and ATRT-MYC) using Illumina Infinium HumanMethylation450 arrays, FISH, MLPA, and sequencing. Furthermore, outcome was compared to a larger cohort of 27 children with ATRT-TYR. Median age of the 6 boys and 4 girls harboring a CRINET was 20 months. On histopathological examination, all CRINETs demonstrated a cribriform growth pattern and distinct tyrosinase staining. On unsupervised cluster analysis of methylation data, all CRINETs examined exclusively clustered within the ATRT-TYR molecular subgroup. As ATRT-TYR, CRINETs mainly showed large heterozygous 22q deletions (9/10) and SMARCB1 mutations of the other allele. In two patients, SMARCB1 mutations were also present in the germline. Estimated mean overall survival in patients with CRINETs was 125 months (95% confidence interval 100-151 months) as compared to only 53 (33-74) months in patients with ATRTs of the ATRT-TYR subgroup (Log-Rank P < 0.05). In conclusion, CRINET represents a SMARCB1-deficient non-rhabdoid tumor, which shares molecular similarities with the ATRT-TYR subgroup but has distinct histopathological features and favorable long-term outcome., (© 2016 International Society of Neuropathology.)

Extra-cranial rhabdoid tumors (RT) are highly aggressive malignancies of infancy, characterized by undifferentiated histological features and loss of SMARCB1 expression. The diagnosis is all the more challenging that other poorly differentiated cancers lose SMARCB1 expression, such as epithelioid sarcomas (ES), renal medullary carcinomas (RMC) or undifferentiated chordomas (UC). Moreover, late cases occurring in adults are now increasingly reported, raising the question of differential diagnoses and emphasizing nosological issues. To address this issue, we have analyzed the expression profiles of a training set of 32 SMARCB1-deficient tumors (SDT), with ascertained diagnosis of RT (n = 16, all < 5 years of age), ES (n = 8, all > 10 years of age), UC (n = 3) and RMC (n = 5). As compared with other SDT, RT are characterized by an embryonic signature, and up-regulation of key-actors of de novo DNA methylation processes. Using this signature, we then analysed the expression profiling of 37 SDT to infer the appropriate diagnosis. Thirteen adult onset tumors showed strong similarity with pediatric RT, in spite of older age; by exome sequencing, these tumors also showed genomic features indistinguishable from pediatric RT. In contrary, 8 tumors were reclassified within carcinoma, ES or UC categories, while the remaining could not be related to any of those entities. Our results demonstrate that embryonic signature is shared by all RT, whatever the age at diagnosis; they also illustrate that many adult-onset SDT of ambiguous histological diagnosis are clearly different from RT. Finally, our study paves the way for the routine use of expression-based signatures to give accurate diagnosis of SDT.