Search

Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid tumors (n = 11), HB with SCU component (n = 41), and HB with low AFP (n = 14). Seven were excluded for erroneously low AFP levels. Overall survival was 0% for patients with rhabdoid tumors, 76% for patients with HB with SCU component, and 64% for patients with HB with AFP less than 100 ng/mL. Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors. When rhabdoid tumors are excluded, the presence of SCU component and low AFP at diagnosis were not associated with poor prognosis in patients diagnosed with HB.

While the neural crest cell population gives rise to an extraordinary array of derivatives, including elements of the craniofacial skeleton, skin pigmentation, and peripheral nervous system, it is today increasingly recognized that Schwann cell precursors are also multipotent. Two mammalian paralogs of the SWI/SNF (switch/sucrose nonfermentable) chromatin-remodeling complexes, BAF (Brg1-associated factors) and PBAF (polybromo-associated BAF), are critical for neural crest specification during normal mammalian development. There is increasing evidence that pathogenic variants in components of the BAF and PBAF complexes play central roles in the pathogenesis of neural crest–derived tumors. Transgenic mouse models demonstrate a temporal window early in development where pathogenic variants in Smarcb1 result in the formation of aggressive, poorly differentiated tumors, such as rhabdoid tumors. By contrast, later in development, homozygous inactivation of Smarcb1 requires additional pathogenic variants in tumor suppressor genes to drive the development of differentiated adult neoplasms derived from the neural crest, which have a comparatively good prognosis in humans. [ABSTRACT FROM AUTHOR]

Integrase interactor 1 (INI1)-deficient carcinomas, recently described in several sites including the head and neck, are associated with basaloid or rhabdoid histology and aggressive behavior irrespective of origin. INI1-deficient thyroid carcinoma is extremely rare. We present here the phenotype and genotype of an INI1-deficient thyroid carcinoma and report on the INI1 protein expression in various thyroid lesions. Case report with clinicopathologic and molecular characterization and INI1 assessment in 184 thyroid lesions. A 67-year-old woman presented with globus sensation due to a large thyroid mass with extrathyroid extension, focal necrosis and cervical and mediastinal nodal involvement. Histologically, tumor cells had a solid, alveolar and pseudopapillary architecture in a myxoid stroma, exhibited monomorphic epithelioid and focal rhabdoid/plasmacytoid morphology and lacked glandular, squamous or follicular cell differentiation. Tumor cells were positive for AE1/AE3 and CK18 but negative for TTF1, thyroglobulin and PAX8. INI1 nuclear expression was absent. A frameshift SMARCB1/INI1 mutation was detected. In addition, TET2 and Notch1 mutations were present but alterations of BRAF, RET, PAX8/PPAR8 or RAS were not identified. Patient death occurred 14 months after diagnosis from post-therapeutic complications. None of the 184 benign and malignant thyroid lesions tested, including 12 poorly and undifferentiated thyroid carcinomas, were INI1-deficient. INI1-deficient thyroid carcinoma shares the phenotype, genotype and biology of other INI1-deficient tumors. Epithelioid and plasmacytoid/rhabdoid changes are most frequent whereas basaloid morphology is not reported, in contrast with sinonasal tumors. Poorly differentiated and undifferentiated thyroid tumors with epithelioid or rhabdoid morphology should be tested for INI1 protein expression to better characterize these aggressive neoplasms and identify patients eligible for targeted therapy. [ABSTRACT FROM AUTHOR]

The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The SMARCB1/INI1 gene was first discovered in the mid-1990s, and since then it has been revealed that loss of function mutations in this gene result in aggressive rhabdoid tumors. Recently, the term “rhabdoid tumor” has become synonymous with decreased SMARCB1/INI1 expression. When genetic aberrations in the SMARCB1/INI1 gene occur, the result can cause complete loss of expression, decreased expression, and mosaic expression. Although SMARCB1/INI1-deficient tumors are predominantly sarcomas, this is a diverse group of tumors with mixed phenotypes, which can often make the diagnosis challenging. Prognosis for these aggressive tumors is often poor. Moreover, refractory and relapsing progressive disease is common. As a result, accurate and timely diagnosis is imperative. Despite the SMARCB1/INI1 gene itself and its implications in tumorigenesis being discovered over two decades ago, there is a paucity of rhabdoid tumor cases reported in the literature that detail SMARCB1/INI1 expression. Much work remains if we hope to provide additional therapeutic strategies for patients with aggressive SMARCB1/INI1-deficient tumors.

The SMARCB1/INI1 gene was first discovered in the mid-1990’s, and since then it has been revealed that loss of function mutations in this gene result in aggressive rhabdoid tumors. Recently, the term “rhabdoid tumor” has become synonymous with decreased SMARCB1/INI1 expression. When genetic aberrations in the SMARCB1/INI1 gene occur, the result can cause reduced, complete loss, and mosaic expression. Although SMARCB1/INI1-deficient tumors are predominantly sarcomas, this is a diverse group of tumors with mixed phenotypes, which can often make the diagnosis challenging. Prognosis for these aggressive tumors is often poor. Moreover, refractory and relapsing progressive disease is common. As a result, accurate and timely diagnosis is imperative. Despite the SMARCB1/INI1 gene itself and its implications in tumorigenesis being discovered over two decades ago, there is a paucity of rhabdoid tumor cases reported in the literature that detail SMARCB1/INI1 expression. Much work remains if we hope to provide additional therapeutic strategies for patients with aggressive SMARCB1/INI1-deficient tumors.

Epithelioid cell features mimicking carcinomas characterize a variety of histogenetically, phenotypically, and molecularly distinct subsets of mesenchymal neoplasms. In a pathogenetic sense, epithelioid soft tissue tumors basically fall into three main genetic categories: (1) switch/sucrose non-fermenting (SWI/SNF) complex-deficient tumors (with epithelioid sarcoma as their prototype); (2) epithelioid neoplasms driven by specific rare gene fusions (such as sclerosing epithelioid fibrosarcoma with EWSR1 fusions and GLI1-related malignant epithelioid soft tissue neoplasms); and (3) a heterogeneous group encompassing epithelioid variants of diverse other entities. Notably, lesions in the first and third groups may display variable, occasionally prominent, rhabdoid cell morphology, thus further complicating their differential diagnosis. This review summarizes the main clinicopathological, phenotypic, and genotypic features of these diseases and discusses their pertinent differential diagnostic considerations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The role of the switch/sucrose nonfermenting chromatin remodeling complex in the initiation and progression of cancer is emerging. In the female genital tract, only ovarian small cell carcinoma, hypercalcemic type harbors recurrent inactivating SMARCA4 mutations. Otherwise, only rare case reports documented SMARCB1 involvement in endometrial cancer. We analyzed 24 grade 3 uterine endometrioid adenocarcinomas and 2 undifferentiated carcinomas for immunohistochemical expression of SMARCB1 and SMARCA4. All tumors showed high-grade nuclear features with a predominance of solid growth pattern. All cases showed intact nuclear SMARCB1 expression in all tumor cells. However, 1 case of a 78-year-old woman showed complete loss of SMARCA4 in 90% of the tumor with retained expression in 10% of the tumor. The SMARCA4-intact component was a moderate-to-poorly differentiated endometrioid adenocarcinoma. The SMARCA4-deficient dominating component showed solid growth of highly anaplastic undifferentiated large cells with prominent rhabdoid features. None of the 25 SMARCA4-intact cases showed rhabdoid cell morphology. To our knowledge, this is the first systematic study of SMARCB1 and SMARCA4 expression in endometrioid adenocarcinoma of uterus and the first description of a novel SMARCA4-deficient variant of dedifferentiated/undifferentiated endometrial carcinoma. The presence of a differentiated SMARCA4-intact endometrioid component points to a novel pathway of dedifferentiation in endometrioid adenocarcinoma as a consequence of a “second hit.” This case further underlines the close link between the “rhabdoid phenotype” and the SWI/SNF pathway. [ABSTRACT FROM AUTHOR]

Mutations in the SMARCB1 gene are involved in several human tumor-predisposing syndromes. They were established as an underlying cause of the tumor suppressor syndrome schwannomatosis in 2008. There is a much higher rate of mutation detection in familial disease than in sporadic disease. We have performed extensive genetic testing on a cohort of familial and sporadic patients who fulfilled clinical diagnostic criteria for schwannomatosis. In our updated cohort, we identified novel mutations within the SMARCB1 gene as well as several recurrent mutations. Of the schwannomatosis screens reported to date, including those in our updated cohort, SMARCB1 mutations have been found in 45% of familial probands and 9% of sporadic patients. The exon 1 mutation, c.41C>A p.Pro14His (10% in our series), and the 3′ untranslated region mutation, c.*82C>T (27%), are the most common changes reported in patients with schwannomatosis to date, indicating the presence of mutation hot spots at both 5′ and 3′ portions of the gene. Comparison with germline SMARCB1 mutations in patients with rhabdoid tumors showed that the schwannomatosis mutations were significantly more likely to occur at either end of the gene and be nontruncating mutations ( P < 0.0001). SMARCB1 mutations are found in a significant proportion of schwannomatosis patients, and an even higher proportion of rhabdoid patients. Whereas SMARCB1 alone seems to account for rhabdoid disease, there is likely to be substantial heterogeneity in schwannomatosis even for familial disease. There is a clear genotype–phenotype correlation, with germline rhabdoid mutations being significantly more likely to be centrally placed, involve multiple exon deletions, and be truncating mutations. [ABSTRACT FROM AUTHOR]

Malignant rhabdoid tumors (MRTs) of the central nervous system (atypical teratoid, rhabdoid tumor (AT/RT)), kidney (rhabdoid tumor of the kidney (RTK)), and soft tissues all share an aggressive clinical behavior and dismal prognosis. The burden of the intensive treatment required to cure patients is a matter of great concern given the young median age at diagnosis, regardless of tumor location. Thus, a greater understanding of the oncogenic properties of SMARCB1 and the SWI/SNF complex, as well as the clinical aspects of malignant rhabdoid tumors is necessary. Towards this aim, the first international SMARCB1 and rhabdoid tumor symposium was held in Paris, France in December 2013, organized by the collaborative efforts of the Dana-Farber Cancer Institute (Susan Chi), Swabian Children's Cancer Center/EU-RHAB Center (Michael Frühwald) and Curie Institute (Franck Bourdeaut). This workshop of physicians and other scientists fostered the integration of biologic insights towards clinical application in rhabdoid tumors, and other SWI/SNF-related cancers. The following report is a synopsis of the highlights of this meeting. [ABSTRACT FROM AUTHOR]

Malignant rhabdoid tumors (MRTs) are rare pediatric malignancies characterized by clinically aggressive lesions that typically show loss of SMARCB1 expression. We herein describe a case of a malignant rhabdoid tumor of the bladder in a 14-year-old male with an autism spectrum disorder and a de novo 3 Mb germline deletion in chromosome band 22q11.2 that included the SMARCB1 gene. The malignancy developed in the setting of chronic hematuria (>2 years) following the occurrence of two other lesions: a central nervous system ganglioglioma and an intraoral dermoid cyst. MRTs of the bladder are exceedingly rare, and this patient is the oldest child reported with this tumor to date. This case adds to the growing body of literature regarding the recently described, phenotypically diverse, distal 22q11.2 syndrome. Furthermore, this is the first reported case in which an MRT of the bladder appears to have developed from a pre-existing bladder lesion. Finally, this case further supports a rhabdoid tumorigenesis model in which heterozygous loss of SMARCB1 predisposes to initial tumor formation with intact SMARCB1 expression, with subsequent inactivation of the other SMARCB1 allele, which results in transformation into more malignant lesions. [ABSTRACT FROM AUTHOR]

Extraordinary advancements in sequencing technology have made what was once a decade-long multi-institutional endeavor into a methodology with the potential for practical use in a clinical setting.We therefore set out to examine the clinical value of next-generation sequencing by enrolling patients with incurable or ambiguous tumors into the Personalized Onco- Genomics initiative at the British Columbia Cancer Agency where by whole genome and transcriptome analyses of tumor/ normal tissue pairs are completed with the ultimate goal of directing therapeutics. First, we established that the sequencing, analysis, and communication with oncologists could be completed in less than 5 weeks. Second, we found that cancer diagnostics is an area that can greatly benefit from the comprehensiveness of a whole genome analysis. Here, we present a scenario in which a metastasized sphenoid mass, which was initially thought of as an undifferentiated squamous cell carcinoma, was rediagnosed as an SMARCB1-negative rhabdoid tumor based on the newly acquired finding of homozygous SMARCB1 deletion. The new diagnosis led to a change in chemotherapy and a complete nodal response in the patient. This study also provides additional insight into the mutational landscapeofanadultSMARCB1-negativetumorthat has not been explored at a whole genome and transcriptome level. [ABSTRACT FROM AUTHOR]

Aims Rhabdoid morphology resembling that of the aggressive paediatric rhabdoid tumours occurs in various malignancies usually lacking characteristic SMARCB1 ( INI1) loss. Little is known about the clinicopathological and molecular characteristics of the rhabdoid phenotype in gastrointestinal stromal tumours ( GISTs). Methods and results Six gastric rhabdoid GISTs were examined by immunohistochemistry, KIT and platelet-derived growth factor receptor-α gene ( PDGFRA) mutation analysis, and comparative genomic hybridization ( CGH). All tumours expressed KIT, PDGFRA, DOG-1, and SMARCB1 (two of six with a mosaic pattern). Five of six tumours harboured PDGFRA mutations (D842V in four; N659K in one), and one case was wild type for KIT/ PDGFRA and succinate dehydrogenase ( SDH) A-negative and SDHB-negative by immunohistochemistry. CGH revealed aberrations typical of GISTs (−1p, −14, and −22q in three, five, and three cases, respectively), with a mean of 1.7 aberrations in the epithelioid component and 2.7 in the rhabdoid component. None showed progression (mean follow-up of 25 months). Conclusions Rhabdoid gastric GISTs are associated with epithelioid morphology and PDGFRA mutations. They harbour CGH aberrations that are typical of ordinary GISTs in both tumour components. The presence of additional genetic alterations in the rhabdoid areas indicates evolution from the epithelioid components, and possible genetic and biological progression. On the basis of our series and previous reports, rhabdoid morphology in GISTs presumably does not imply aggressiveness. [ABSTRACT FROM AUTHOR]

The discovery of biallelic, inactivating SMARCB1 mutations in rhabdoid tumors (RTs) over a decade ago represented the first recognized link between chromatin remodeling and tumor suppression. SMARCB1 is a core subunit of the SWI/ SNF chromatin remodeling complex, and the recent emergence of frequent mutations in genes that encode subunits of this complex across a wide variety of cancers suggests that perturbation of this chromatin remodeling complex constitutes a key driver of cancer formation. Despite the highly aggressive nature of RTs, they are genetically simple cancers that appear to lack chromosomal instability and contain very few mutations. Indeed, the mutation rate in RTs is among the lowest of all cancers sequenced, with loss of SMARCB1 as essentially the sole recurrent event. Given the genetic simplicity of this disease, understanding the chromatin dysregulation caused by SMARCB1 loss may provide more general insight into how epigenetic alterations can contribute to oncogenic transformation and may reveal opportunities for targeted therapy not only of RT but also the variety of other SWI/ SNF mutant cancers. [ABSTRACT FROM AUTHOR]

Biallelic loss of SMARCB1 /INI1 is associated with highly aggressive malignancies, namely renal and extra-renal malignant rhabdoid tumors, and atypical teratoid/ rhabdoid tumor. Increasing availability of molecular testing and immunohistochemical stains acting as surrogate tools to genetic analysis has led to an increasing recognition of SMARCB1 loss in a variety of neoplasms. Interestingly, many of these lack the typical rhabdoid features ascribed to this group of tumors, making their identification difficult. We describe the cytological, histological, immunohistochemical and molecular features of the first case of primary SMARCB1 (INI1)-deficient carcinoma of the thyroid gland in literature. The tumor was unique in various aspects; apart from never having been documented at this location, it showed extensive glandular differentiation, mimicking metastatic adenocarcinoma. Awareness of this novel entity is essential to avoid misdiagnosis, and for appropriate management, especially in an era of increased feasibility of targeted therapy. [ABSTRACT FROM AUTHOR]