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Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas
Schwannomatosis is characterized by the onset of multiple intracranial, spinal, or peripheral schwannomas, without involvement of the vestibular nerve, which is instead pathognomonic of neurofibromatosis type 2 (NF2). Recently, a schwannomatosis family with a germline mutation of the SMARCB1 gene on chromosome 22 has been described. We report on the molecular analysis of the SMARCB1 and NF2 genes in a series of 21 patients with schwannomatosis and in eight schwannomatosis-associated tumors from four different patients. A novel germline SMARCB1 mutation was found in one patient; inactivating somatic mutations of NF2, associated with loss of heterozygosity (LOH) of 22q, were found in two schwannomas of this patient. This is the second report of a germline SMARCB1 mutation in patients affected by schwannomatosis and the first report of SMARCB1 mutations associated with somatic NF2 mutations in schwannomatosis-associated tumors. The latter observation suggests that a four-hit mechanism involving the SMARCB1 and NF2 genes may be implicated in schwannomatosis-related tumorigenesis. 相似文献
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Malignant rhabdoid tumor (MRT) is a rare and aggressive tumor associated with deletion or mutation of a tumor suppressor gene SMARCB1/INI1, a member of the SWI/SNF chromatin-remodeling complex. Reported herein is a case of pancreatic mucinous carcinoma accompanying rhabdoid features with immunohistochemical and ultrastructural studies as well as analysis of the SMARCB1/INI1 gene. A 65-year-old woman presented with a 2 month history of abdominal and chest pain. A well-defined grayish tan fish-flesh mass (11 x 9 x 7 cm) with focal mucinous area was present in the pancreatic tail. Microscopically, the tumor had a biphasic growth pattern: a mucinous carcinoma component and a poorly differentiated carcinoma component with rhabdoid features showing loosely cohesive cells with abundant eosinophilic cytoplasm, displaced nuclei, and prominent nucleoli. The rhabdoid component coexpressed vimentin and cytokeratin. Sequencing analysis of the DNA extracted from the mucinous and rhabdoid components showed a missense mutation CCC to ACC in codon 116 of the SMARCB1/INI1 gene. Being aware of rhabdoid features would help diagnose this rare and aggressive malignant tumor and may provide an opportunity for further evaluation of SMARCB1/INI1 gene alteration and determination of its prognostic significance. 相似文献
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《Pathology, research and practice》2020,216(4):152830
BackgroundBiallelic 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.Case presentationWe 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.ConclusionAwareness of this novel entity is essential to avoid misdiagnosis, and for appropriate management, especially in an era of increased feasibility of targeted therapy. 相似文献
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The purpose of this study was to evaluate and validate immunohistochemical (IHC) expression of INI1/SMARCB1 in various musculoskeletal tumors in the light of the established literature. 相似文献
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Schwannomatosis is a third major form of neurofibromatosis that has recently been linked to mutations in the SMARCB1 (hSnf5/INI1) tumor suppressor gene. We analyzed the coding region of SMARCB1 by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) in genomic DNA from 19 schwannomatosis kindreds. Microsatellite markers in the SMARCB1 region were developed to determine loss of heterozygosity (LOH) in associated tumors. We detected four alterations in conserved splice acceptor or donor sequences of exons 3, 4 and 6. Two alterations that likely affect splicing were seen in introns 4 and 5. An additional four alterations of unclear pathogenicity were found to segregate on the affected allele in eight families including two non-conservative missense alterations in three families. No constitutional deletions or duplications were detected by MLPA. Nine of 13 tumors examined showed partial LOH of the SMARCB1 region consistent with 'second hits.' Alterations were detected in tumors both with and without somatic NF2 gene changes. These findings support the hypothesis that SMARCB1 is a tumor suppressor for schwannomas in the context of familial disease. Further work is needed to determine its role in other multiple and single tumor syndromes. 相似文献
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Kohashi K Izumi T Oda Y Yamamoto H Tamiya S Taguchi T Iwamoto Y Hasegawa T Tsuneyoshi M 《Human pathology》2009,40(3):349-532
Loss of SMARCB1/INI1 protein expression is considered useful for confirming a histologic diagnosis of malignant rhabdoid tumor. However, loss of SMARCB1/INI1 protein expression has recently been reported in other tumors as well, including a few cases of epithelioid sarcoma. In addition, the histopathologic differences between proximal-type epithelioid sarcoma and malignant rhabdoid tumor have not been conclusively defined. We analyzed SMARCB1/INI1 protein expression in 54 epithelioid sarcoma (proximal-type, 25; distal-type, 29) and examined alterations of the SMARCB1/INI1 gene in the cases lacking protein expression. We found that 19 (76.0%) proximal-type epithelioid sarcoma and 27 (93.1%) distal-type epithelioid sarcoma showed loss of SMARCB1/INI1 protein expression. Analysis of 39 cases with loss of protein expression revealed 4 cases (10.3%) with SMARCB1/INI1 gene alterations at the DNA level (homozygous deletion, 2; 1- or 2-bp deletion, 2) that could have induced the loss of gene products, and all 4 of these were proximal-type epithelioid sarcoma. Epithelioid sarcoma was thus associated with a high frequency of loss of SMARCB1/INI1 protein expression similar to that in malignant rhabdoid tumor. However, the frequency of SMARCB1/INI1 gene alteration at the DNA level in proximal-type epithelioid sarcoma was significantly lower than that in malignant rhabdoid tumor. In addition, the prognosis of patients with malignant rhabdoid tumor is significantly worse than that of patients with proximal-type epithelioid sarcoma (P = .001). Therefore, proximal-type epithelioid sarcoma and malignant rhabdoid tumor are suggested to be distinctive tumors with respect to the mechanism of the loss of SMARCB1/INI1 protein expression. Analysis of alterations in the SMARCB1/INI1 gene may thus be a useful diagnostic tool to distinguish proximal-type epithelioid sarcoma from malignant rhabdoid tumor. 相似文献
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Spectrum of cytopathologic features of epithelioid sarcoma in a series of 7 uncommon cases with immunohistochemical results,including loss of INI1/SMARCB1 in two test cases
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Diagnosis of an epithelioid sarcoma (ES) is challenging on fine needle aspiration cytology (FNAC) smears. There are few documented series describing cytopathologic features and immunostaining results of ESs. The present study describes cytopathologic features of seven cases of ES. All seven tumors occurred in males within age‐range of 22–61 years; in sites, such as forearm (n = 3), hand (n = 2), thigh (n = 1), and inguinal region (n = 1). FNAC was performed for metastatic lesions (n = 5), recurrent lesions (n = 4), as well as for a primary diagnosis (n = 1). FNAC smears in most cases were moderate to hypercellular, composed of polygonal cells(seven cases) and spindle cells(three cases), arranged in loosely cohesive groups, non‐overlapping clusters, and scattered singly, containing moderate to abundant cytoplasm, defined cell borders, vesicular nuclei, and discernible nucleoli. Variable cytopathologic features identified in certain cases were “rhabdoid‐like” intracytoplasmic inclusions (n = 5), giant cells (n = 3), and interspersed scanty, metachromatic stroma (n = 4). Histopathologic examination revealed two cases of conventional‐type ES, three of proximal/large cell‐type ES, and two cases of mixed‐type ES, displaying features of conventional and proximal subtypes. By immunohistochemistry (IHC), tumor cells were positive for cytokeratin (CK)(4/5), epithelial membrane antigen (EMA) (6/6), panCK (1/1), vimentin (3/3), and CD34 (7/7). Tumor cells were completely negative for INI1/SMARCB1 (0/2) and CD31 (0/5). In our settings, FNAC was mostly performed in recurrent and/or metastatic cases of ES, and rarely for a primary diagnosis of ES. Important cytopathologic features of ESs include loosely cohesive, non‐overlapping clusters of polygonal cells with variable “rhabdoid‐like” and spindle cells. Optimal diagnostic IHC markers in such cases include CK, EMA, AE1AE3, CD34, and INI1/SMARCB1. Clinical correlation is imperative in all cases. Diagn. Cytopathol. 2016;44:636–642. © 2016 Wiley Periodicals, Inc. 相似文献
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Utility of characteristic ‘Weak to Absent’ INI1/SMARCB1/BAF47 expression in diagnosis of synovial sarcomas
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Bharat Rekhi Ulrich Vogel 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2015,123(7):618-628
Recently, very few studies have shown value of immunohistochemical (IHC) expression of INI1/SMARCB1 in diagnosis of synovial sarcomas (SSs). This study was aimed at testing reproducibility and utility of this finding. Sixty‐eight SSs and 147 other tumours, in the form of various biopsies, were tested for IHC expression of INI1. Twenty‐six SSs were further confirmed with positive SS18 rearrangement. Forty monophasic spindle cell type (58.8%), 13 biphasic (19.1%), 12 poorly differentiated (17.6%) and three calcifying SSs (4.4%) were positive for epithelial membrane antigen (EMA) (46/62) (74.1%), pan cytokeratin (AE1/AE3) (31/47) (65.9%), cytokeratin (CK7) (20/31) (64.5%), BCL2 (62/66) (93.9%), MIC2 (61/63) (96.8%), transducin‐like enhancer of split 1 (TLE1) (29/31) (93.5%) and CK19 (14/24) (58.3%). INI1 expression was ‘weak to absent’ in 60/68 (88.2%) SSs; in 1/3 atypical ossifying fibromyxoid tumours (AOFMTs) and in 3/10 (30%) malignant peripheral nerve sheath tumours (MPNSTs) of various types. INI1 was completely absent in 10/10 (100%) epithelioid sarcomas (ESs), 4/4 (100%) malignant rhabdoid tumours, single paediatric undifferentiated sarcoma, 5/19 (26.3%) myoepithelial carcinomas and in 2/4 (50%) epithelioid‐subtype of MPNSTs. Remaining 100 tumours, including 12 Ewing sarcomas, 15 carcinomas, eight solitary fibrous tumours (SFT), seven extraskeletal myxoid chondrosarcomas, three fibrosarcomas and other tumours retained INI1 expression. A unique ‘weak to absent’ IHC expression of INI1 is highly sensitive (88.2%) and specific (97.3%) for a SS, irrespective of its subtypes and types of biopsies. This can be considered useful in diagnosing SSs, especially in settings lacking molecular and/or cytogenetic analysis. A similar INI1 expression is shared by certain AOFMTs and MPNSTs. 相似文献
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目的探讨儿童颅底SMARCB1/INI1缺失性差分化脊索瘤(poorly differentiated chordoma, PDC)的临床病理特点及鉴别诊断。方法整理2017年3月至2021年3月首都医科大学三博脑科医院诊断的脊索瘤139例, 其中5例诊断为SMARCB1/INI1缺失性的PDC, 收集此5例患者的临床影像学资料, 进行HE和免疫组织化学染色、DNA甲基化测序检测, 并复习相关文献。结果 5例PDC均发生在中颅底斜坡, 平均年龄6.4岁(3~16岁);3例女性, 2例男性。形态学上, 缺乏脊索瘤的典型形态学特征, 表现为成片或巢片状分布的上皮样或梭形肿瘤细胞, 核分裂象活跃, 均见坏死, 可见肿瘤浸润周围组织。免疫表型特征上, 表达脊索瘤常见免疫标志物广谱细胞角蛋白(CKpan)、上皮细胞膜抗原(EMA)、波形蛋白及brachyury, 同时SMARCB1/INI1核表达缺失。2例S-100蛋白阳性, Ki-67阳性指数高(20%~50%), 均存在p53过表达。需要与儿童颅底发生的SMARCB1/INI1缺失性肿瘤或具有上皮样和梭形细胞形态学特征的肿瘤进行鉴别。其中3... 相似文献
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Bharat Rekhi Kemal Kosemehmetoglu Gaye Guler Tezel Sergulen Dervisoglu 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2017,125(8):679-689
Epithelioid malignant peripheral nerve sheath tumor (MPNST) is a rare, relatively less chemosensitive sarcoma. We report clinicopathologic features of 11 epithelioid MPNSTs, including rare forms, along with INI1 immunostaining and BRAF V600E mutation results. BRAF V600E mutation was tested by Real‐time polymerase chain reaction (PCR) technique. Eleven tumors occurred in six men and five women (M:F ratio = 0.85:1) within an age range of 5–73 years (average = 44), mostly in lower limbs (five), followed by upper limbs (four). Tumor size (n = 6), varied from 3.1 to 15 cm (average = 8.3). Histopathologically, most tumors were multilobular, characterized by epithelioid to round‐shaped, malignant cells, along with spindle cells (three cases), “rhabdoid‐like” cells (seven cases) and pleomorphic giant cells (single case). By immunohistochemistry, tumor cells were positive for S100 protein (11/11) (100%), EMA (3/7) (42.8%), pan CK(2/7) (28.5%), and HMB45 (1/11) (9%), while these were negative for Melan A (0/11) and INI1 (3/11), including a single tumor, displaying HMB45 positivity. BRAF V600E mutation was positive in 1/8 cases, that lacked melanocytic marker expression. All patients (n = 5) were treated by surgical resection. During follow‐up (n = 8, median duration = 23 months), four patients developed tumor recurrences and four developed metastasis, mostly to lymph nodes (3). Finally, four patients were alive with disease, two were alive with no evidence of disease, and two patients died of disease. Epithelioid MPNSTs have a diverse histopathologic spectrum. Loss of INI1 is useful, including in identifying rare forms of epithelioid MPNST, displaying melanocytic differentiation. Most tumors are treated by surgical resection. Loss of INI1 and the presence of BRAF V600E mutation in some cases raises future possibility of exploring targeted therapy in those, rare epithelioid MPNSTs. 相似文献
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Qiu Rao Qiu-Yuan Xia Qin Shen Shan-Shan Shi Pin Tu Qun-Li Shi Xiao-Jun Zhou 《International journal of clinical and experimental pathology》2014,7(4):1782-1787
In this study, we analyzed the immunohistochemical and molecular profiles of an unusual RCC showed coexistent absence of INI1 and BRG1 expression, rhabdoid morphology, and poor prognosis. Histologically, the tumor had rhabdoid features, which were demonstrated by large round to polygonal cells with eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm varying from abundant to scanty. Immunohistochemically, the tumor were positive for BRM, PBRM1, ARID1A, CD10, CKpan, Vimentin, carbonic anhydrase IX (CA-IX), and P504S (AMACR) but negative for INI1, BRG1, HMB45, melan A, CK7, CD117, Ksp-cadherin, TFEB, TFE3, and Cathepsin K. We detected all three exons status of the VHL gene of the tumor and observed 1 somatic mutations in 1st exon. Chromosome 3p deletion, coupled with polysomy of chromosome 3 was also found. Based on these findings, it is further indicated that in some cases, rhabdoid RCC may arise from clear cell RCC. SWI/SNF chromatin remodeling complex may be an attractive candidate for being the “second hit” in RCCs and may play an important role during tumor progression. The role of SWI/SNF complex in rhabdoid RCC should be further studied on a larger number of cases. 相似文献
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Shogo Tajima Yusuke Takahasi Michi Hikoaki Rei Goto 《International journal of clinical and experimental pathology》2015,8(6):7526-7532
In the vulvar region, epithelioid sarcoma (ES) is the most frequent SMARCB1-deficient neoplasm, followed by myoepithelial carcinoma (MC). Previous studies have demonstrated that some SMARCB1-deficient vulvar neoplasms cannot be classified as either ES or MC. Herein, we report of a 42-year-old woman with a SMARCB1-deficient neoplasm with prominent myxoid stroma in the vulva. It contained both epithelioid and spindled tumor cells, both of which showed vimentin and EMA expression. Although other markers useful for the differential diagnosis among SMARCB1-deficient tumors were negative, this tumor displayed characteristic expression of ERG and FLI1. As there are no reliable data regarding expression of ERG and FLI1 in MC, which are demonstrated to be often expressed in ES, further classification of cases such as the one reported here requires reliable data regarding their expression status in MC. 相似文献
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Bourdeaut F Fréneaux P Thuille B Lellouch-Tubiana A Nicolas A Couturier J Pierron G Sainte-Rose C Bergeron C Bouvier R Rialland X Laurence V Michon J Sastre-Garau X Delattre O 《The Journal of pathology》2007,211(3):323-330
Rhabdoid tumours (RTs) are rare but highly aggressive tumours of childhood. Their rarity and their miscellaneous locations make the diagnosis particularly challenging for pathologists. Central nervous system and peripheral RTs have been associated with biallelic inactivation of the hSNF5/INI1/SMARCB1 (hSNF5/INI1) tumour suppressor gene. Immunohistochemistry (IHC) with a monoclonal anti-hSNF5/INI1 antibody has recently been proposed as an efficient diagnostic tool for RTs. We have conducted a retrospective study of 55 tumours referred to our institution with a suspicion of RT. This analysis included pathological review, IHC with anti-hSNF5/INI1 antibody, and molecular investigation using quantitative DNA fluorescent analysis and sequencing of the nine exons of hSNF5/INI1. The molecular lesion could be detected in 37 of the 39 cases exhibiting negative staining for hSNF5/INI1. In the two discrepant cases, the lack of detection of genetic abnormality was probably owing to the presence of a high number of non-tumour cells in the samples. This indicates that hSNF5/INI1 IHC is very sensitive and highly specific for the detection of hSNF5/INI1 loss-of-function. Among the 38 cases with typical RT histological features, six failed to exhibit hSNF5/INI1 mutation and stained positive for hSNF5/INI1. This strongly supports the evidence of a second genetic locus, distinct from hSNF5/INI1, associated with RT. Conversely, seven tumours with histological features poorly compatible with RT stained negative for hSNF5/INI1; they nevertheless exhibited an age of onset and a clinical behaviour similar to RT. This suggests that hSNF5/INI1 inactivation is not strictly limited to typical RT but characterizes a wider family of hSNF5/INI1-deficient tumours. Consequently, we believe that anti-hSNF5/INI1 IHC should be performed widely, even when the pathological characteristics are not typical. The molecular investigation should be performed in infants when a rhabdoid predisposition syndrome is suspected. 相似文献
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Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1‐deficient non‐rhabdoid tumor with favorable long‐term outcome
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Pascal D. Johann Volker Hovestadt Christian Thomas Astrid Jeibmann Katharina Heß Susanne Bens Florian Oyen Cynthia Hawkins Christopher R. Pierson Kenneth Aldape Sang‐Pyo Kim Eva Widing David Sumerauer Péter Hauser Frank van Landeghem Marina Ryzhova Andrey Korshunov David Capper David T.W. Jones Stefan M. Pfister Reinhard Schneppenheim Reiner Siebert Werner Paulus Michael C. Frühwald Martin Hasselblatt 《Brain pathology (Zurich, Switzerland)》2017,27(4):411-418
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. 相似文献