SMARCB1 Dotaz Zobrazit nápovědu
SMARCB1 (INI1) deficient sinonasal carcinoma is a recently recognized entity with wide histomorphologic spectrum. We present a case of this carcinoma that contained, in addition to a "common" morphology, scattered foci of yolk sac tumor differentiation. The tumor occurred in paranasal sinuses in a 44-year-old woman. Immunohistochemically, it was diffusely negative for INI1, whereas an expression of yolk sac tumor markers (α-fetoprotein, glypican-3, CDX2) was limited to the yolk sac tumor component. For comparison with the present case, we performed INI1 immunostaining on a series of 11 gonadal germ cell tumors with yolk sac tumor differentiation. All of these cases showed strong and diffuse expression of INI1, in contrast with the present sinonasal tumor. Our findings expand the morphologic spectrum of SMARCB1 (INI1) deficient sinonasal carcinoma. In addition, we show preliminarily that gonadal germ cell tumors with yolk sac tumor differentiation are not SMARCB1/INI1-deficient.
- Klíčová slova
- SMARCB1 (INI1) deficient carcinoma, gonadal mixed germ cell tumor, sinonasal carcinoma, yolk sac tumor,
- MeSH
- buněčná diferenciace MeSH
- dospělí MeSH
- gen SMARCB1 analýza biosyntéza MeSH
- germinální a embryonální nádory metabolismus MeSH
- karcinom metabolismus patologie MeSH
- lidé MeSH
- nádor z entodermálního sinusu patologie MeSH
- nádorové biomarkery analýza MeSH
- nádory sinu maxillaris metabolismus patologie MeSH
- nádory vaječníků metabolismus MeSH
- testikulární nádory metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- gen SMARCB1 MeSH
- nádorové biomarkery MeSH
- SMARCB1 protein, human MeSH Prohlížeč
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.
- Klíčová slova
- DNA methylation profiling, SMARCB1/INI1, atypical teratoid/rhabdoid tumor, copy number alterations, tyrosinase,
- MeSH
- dítě MeSH
- gen SMARCB1 nedostatek genetika MeSH
- Kaplanův-Meierův odhad MeSH
- kojenec MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- mutace genetika MeSH
- nádory mozku genetika MeSH
- neparametrická statistika MeSH
- neuroepitelové nádory genetika patologie MeSH
- předškolní dítě MeSH
- rhabdoidní nádor genetika patologie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- gen SMARCB1 MeSH
- SMARCB1 protein, human MeSH Prohlížeč
- MeSH
- dospělí MeSH
- gen SMARCB1 genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA biosyntéza MeSH
- nádorové biomarkery MeSH
- nádory vedlejších dutin nosních genetika patologie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- gen SMARCB1 MeSH
- mikro RNA MeSH
- nádorové biomarkery MeSH
- SMARCB1 protein, human MeSH Prohlížeč
The aim of the study was detailed clinicopathological investigation of SMARCB1/INI1-deficient sinonasal carcinomas, including molecular genetic analysis of mutational status and DNA methylation of selected protooncogenes and tumor suppressor genes by means of next generation sequencing (NGS) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). A total of 4/56 (7%) cases of SMARCB1/INI1-deficient carcinomas were detected among 56 sinonasal carcinomas diagnosed over a 19year period using immunohistochemical screening. The series comprised 3 males and 1 female, aged 27-76 years (median 64 years). All tumors arose in the nasal cavity. Three neoplasms were diagnosed in advanced stage pT4. During the follow-up period (range 14-111 months (median 72 months)), three tumors recurred locally, but none of the patients developed regional or distant metastases. Ultimately, two patients died due to the tumor. Microscopically, all tumors consisted of infiltrating nests of polygonal basaloid cells with a variable component of rhabdoid cells with eosinophilic cytoplasm. Immunohistochemically, there was almost diffuse expression of cytokeratins (CK), p16, p40 and p63 in all cases, while expression of CK5/6, CK7 and vimentin was only focal or absent. The detection of NUT gave negative results. In three cases, the absence of SMARCB1/INI1 expression was due to deletion of SMARCB1/INI1 gene. Methylation of SMARCB1/INI1 gene was not found. One tumor harbored HPV18 E6/E7 mRNA. All 12 genes (BRAF, BRCA1, BRCA2, KIT, EGFR, KRAS, NRAS, PDGFRA, PIK3CA, PTEN, RET, and ROS1) tested for mutations using NGS were wild-type. Regarding DNA methylation, all four SMARCB1/INI1-deficient tumors showed methylation of RASSF1 gene by means of MS-MLPA. There was a statistically significant difference in RASSF1 gene methylation between SMARCB1/INI1-deficient and SMARCB1/INI1-positive tumors (p=0.0095). All other examined genes (ATM, BRCA1, BRCA2, CADM1, CASP8, CD44, CDKN1B, CDKN2A, CDKN2B, CHFR, DAPK1, ESR1, FHIT, GSTP1, HIC1, KLLN, MLH1a, MLH1b, RARB, and VLH) were unmethylated. In summary, we described four cases of SMARCB1/INI1-deficient sinonasal carcinoma with detailed clinicopathological data indicating that these tumors can be regarded as a distinct entity with aggressive behaviour. For the first time, we performed analysis of DNA methylation in SMARCB1/INI1-deficient sinonasal carcinomas, reporting on significantly higher methylation of RASSF1 gene in this neoplasm.
- Klíčová slova
- DNA methylation, RASSF1, Rhabdoid, SMARCB1/INI1, Sinonasal tract, Squamous cell carcinoma,
- MeSH
- dospělí MeSH
- gen SMARCB1 genetika metabolismus MeSH
- imunohistochemie MeSH
- karcinom genetika metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA * MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádorové supresorové proteiny genetika metabolismus MeSH
- nádory sinu maxillaris genetika metabolismus patologie MeSH
- senioři MeSH
- staging nádorů MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- gen SMARCB1 MeSH
- nádorové biomarkery MeSH
- nádorové supresorové proteiny MeSH
- RASSF1 protein, human MeSH Prohlížeč
Poorly differentiated chordoma is a newly recognized entity in the recent World Health Organization (WHO) classification of tumors of soft tissue and bone. Slightly over 60 such cases have been documented. Herein, we present a clinicopathological profile, including radiological features, of nine cases, which occurred in five males and four females, with age varying from 1 to 29 years (median = 43), in the cervical spine (n = 2), skull base (n = 2), clivus (n = 2), thoracic spine (n = 1) lumbar spine (n = 1) and coccyx (n = 1) Average tumor size was 4.8 cm. None of the 6-referral cases was diagnosed as a poorly differentiated chordoma at the referring laboratory. Histopathologically, all cases displayed a cellular tumor comprising polygonal cells (n = 9) displaying moderate to marked nuclear pleomorphism with prominent nucleoli (n = 7), eosinophilic (n = 9) to vacuolated cytoplasm (n = 7), rhabdoid morphology (n = 4), interspersed mitotic figures (n = 5), focal necrosis (n = 6) and inflammatory cells (n = 9). A single tumor displayed areas resembling classic chordoma, transitioning into poorly differentiated areas. There were multinucleate giant cells and physaliphorous cells in two tumors, each, respectively. Immunohistochemically, tumor cells were positive for AE1/AE3 (7/7), EMA (7/7), cytokeratin (CK) MNF116 (1/1), OSCAR (1/1), brachyury (9/9, diffusely), S100P (4/7, mostly focally), and glypican 3(2/4). SMARCB1/INI1 was completely lost in all nine tumors. A single case tested by FISH showed homozygous deletion of the SMARCB1 gene. Therapeutically (n = 7), all patients were treated with surgical resection (invariably incomplete) (n = 5), followed by adjuvant radiation therapy (n = 4) and chemotherapy (n = 4). While a single patient partially responded to treatment and another patient is alive with no evidence of disease after 23 years, three patients died of disease, six, eight, and 11 months post-diagnosis, despite adjuvant treatments. A single patient presented with a metastatic lung nodule, while another developed widespread metastasis. Poorly differentiated chordomas display a spectrum of features, are associated with a lower index of suspicion for a diagnosis, and display aggressive outcomes. Critical analysis of radiological and histopathological features, including necessary immunostains (brachyury and SMARCB1/INI1), is necessary for their timely diagnosis. These tumors show loss of SMARCB1/INI1 immunostaining and homozygous deletion of INI1/SMARCB1 gene.
- Klíčová slova
- Brachyury, INI1, Notochordal tumors, Poorly differentiated chordoma, Rare bone tumors, SAMRCB1,
- MeSH
- chordom * diagnóza diagnostické zobrazování genetika patologie MeSH
- dítě MeSH
- dospělí MeSH
- gen SMARCB1 * analýza genetika MeSH
- imunohistochemie MeSH
- kojenec MeSH
- lidé MeSH
- metastázy nádorů patologie MeSH
- mladiství MeSH
- nádorové biomarkery analýza genetika MeSH
- předškolní dítě MeSH
- sekvenční delece MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- gen SMARCB1 * MeSH
- nádorové biomarkery MeSH
- MeSH
- analýza přežití MeSH
- chordom diagnóza genetika metabolismus patologie MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- gen SMARCB1 nedostatek genetika MeSH
- kojenec MeSH
- lidé MeSH
- metylace DNA * MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádory mozku diagnóza genetika metabolismus patologie MeSH
- předškolní dítě MeSH
- prognóza MeSH
- rhabdoidní nádor diagnóza genetika metabolismus patologie MeSH
- shluková analýza MeSH
- teratom diagnóza genetika metabolismus patologie MeSH
- variabilita počtu kopií segmentů DNA MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
- Názvy látek
- gen SMARCB1 MeSH
- nádorové biomarkery MeSH
- SMARCB1 protein, human MeSH Prohlížeč
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.
- Klíčová slova
- Head and neck, Next-generation sequencing, Rhabdoid, SMARCB1-deficient adenocarcinoma, SWI/SNF complex, Sinonasal, Yolk sac-like,
- Publikační typ
- časopisecké články MeSH
Rhabdoid tumors are rare but highly aggressive malignancies of infancy and early childhood with a generally unfavorable prognosis. Despite a wide variety of anatomic locations rhabdoid tumors share mutational inactivation of the SWI/SNF (SWItch/Sucrose NonFermentable) core component gene SMARCB1 (also known as INI1, hSNF5 or BAF47) in chromosome 22. As this inactivation usually results in loss of SMARCB1 expression, detectable by an antibody against the SMARCB1 protein, the accurate diagnosis of a rhabdoid tumor may be more distinctly and frequently made. Several reports on rhabdoid tumors presenting in various anatomic sites outside the kidneys and CNS are on record. We report two cases of rhabdoid tumors originating in the heart (cardiac tissue), which were entered into the European Rhabdoid Registry (EU-RHAB). The first case presented with intracardial and -cranial lesions as well as malignant ascites, while the second patient demonstrated an isolated cardiac tumor. This induced a different therapeutic approach and subsequently different clinical course (death 7 weeks after diagnosis in patient 1). Patient 2 presented with a bifocal intracardial tumor without metastases and remains in complete remission for 46 months since diagnosis following multimodal therapy. The second case demonstrates that even in a potentially futile clinical situation early and accurate diagnosis followed by prompt and intensive multimodal therapy may offer prolonged survival, potential cure and improved quality of life.
- Klíčová slova
- EU-RHAB, Rhabdoid tumor, SMARCB1, heart, intensive multimodal therapy,
- MeSH
- antitumorózní látky terapeutické užití MeSH
- chromozomální proteiny, nehistonové biosyntéza genetika MeSH
- DNA vazebné proteiny biosyntéza genetika MeSH
- gen SMARCB1 MeSH
- kojenec MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- mutace MeSH
- nádorové supresorové proteiny genetika MeSH
- nádory srdce genetika patologie terapie MeSH
- registrace MeSH
- rhabdoidní nádor genetika patologie terapie MeSH
- transkripční faktory biosyntéza genetika MeSH
- transplantace periferních kmenových buněk * MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- chromozomální proteiny, nehistonové MeSH
- DNA vazebné proteiny MeSH
- gen SMARCB1 MeSH
- nádorové supresorové proteiny MeSH
- SMARCB1 protein, human MeSH Prohlížeč
- SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
- transkripční faktory MeSH
Rhabdoid tumors (RT) are rare highly malignant tumors. They are part of the embryonic types of tumors and therefore occur in early childhood (between ages of 0-2 years). The most common locations are brain and kidney, but RTs arising usually from soft tissues have been reported widely at most anatomical sites in the body. These tumors are composed of rhabdoid cells alone or as a mixture with primitive neuroectodermal cells, mesenchymal cells and/or epithelial cells, commonly denoted as atypical teratoid/rhabdoid tumours (AT/RT). Based on extremely rare incidence and usually non-specific histological picture, molecular genetic studies are extremely helpful in confirming diagnosis of RT. Biallelic inactivation mutation of the SMARCB1 gene plays a crucial role in the pathogenesis of most RT. One third of mutations are germline mutations leading to the designation of the so-called rhabdoid predisposition syndrome. Molecular genetic analysis of the SMARCB1 gene might be beneficial in the establishment of correct diagnosis, genetic counselling and for epidemiologic studies.
- MeSH
- chromozomální proteiny, nehistonové genetika MeSH
- DNA vazebné proteiny genetika MeSH
- gen SMARCB1 MeSH
- genetická predispozice k nemoci MeSH
- lidé MeSH
- rhabdoidní nádor * diagnóza genetika patologie MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chromozomální proteiny, nehistonové MeSH
- DNA vazebné proteiny MeSH
- gen SMARCB1 MeSH
- SMARCB1 protein, human MeSH Prohlížeč
- transkripční faktory MeSH
Chordoma is a rare malignant tumor with notochordal differentiation, usually affecting the axial skeleton of young patients. We report a case of a high-grade epithelioid tumor involving the synovium and soft tissues of the knee in a 74-year-old male patient. The preliminary biopsy was inconclusive, but a diagnosis of metastatic clear-cell carcinoma of unknown origin was suggested. However, imaging studies did not reveal any primary lesions. The resection specimen consisted of nests and sheets of oval to polygonal cells with discernible cell borders, clear or lightly amphophilic cytoplasm, and round to oval nuclei with occasional well-visible eosinophilic nucleoli. Rare atypical mitoses, necrotic areas, and bizarre nuclei were noted. The biopsy and resection specimens underwent a wide molecular genetic analysis which included methylation profiling. The DKFZ sarcoma classifier assigned the methylation class chordoma (dedifferentiated) with a calibrated score of 0.96, and additionally, a loss of SMARCB1 locus was noted in the copy number variation plot. To verify these findings, T-brachyury and SMARCB1 immunostaining was performed afterward, showing diffuse nuclear positivity and complete loss in the tumor cells, respectively. To assess the prevalence of T-brachyury immunopositivity among SWI/SNF-deficient tumors and to evaluate its specificity for poorly differentiated chordoma, we analyzed a series of 23 SMARCB1- or SMARCA4-deficient tumors, all of which were negative. After incorporating all the available data, including the absence of any morphological features of conventional chordoma, the case was diagnosed as poorly differentiated chordoma. As illustrated herein, the utilization of methylation profiling in the diagnostic process of some carefully selected unclassifiable soft tissue neoplasms may lead to an increased detection rate of such extremely rare soft tissue tumors and enable their better characterization.
- Klíčová slova
- Brachyury, Extra-axial chordoma, INI1, Knee, Methylation, Poorly differentiated chordoma, SMARCB1,
- MeSH
- buněčná diferenciace MeSH
- chordom * patologie genetika diagnóza metabolismus MeSH
- fetální proteiny * genetika metabolismus MeSH
- gen SMARCB1 * genetika MeSH
- lidé MeSH
- metylace DNA * MeSH
- nádorové biomarkery * analýza genetika MeSH
- nádory měkkých tkání patologie diagnóza genetika metabolismus MeSH
- proteiny T-boxu * genetika metabolismus MeSH
- senioři MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- Brachyury protein MeSH Prohlížeč
- fetální proteiny * MeSH
- gen SMARCB1 * MeSH
- nádorové biomarkery * MeSH
- proteiny T-boxu * MeSH
- SMARCB1 protein, human MeSH Prohlížeč
- transkripční faktory MeSH