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

Rhabdoid tumors are aggressive tumors that may arise in the kidney, soft tissue, central nervous system, or other organs. They are defined by SMARCB1 (INI1) or SMARCA4 alterations. Often, very young children are affected, and the prognosis is dismal. Four patients with primary atypical teratoid rhabdoid tumor (AT/RT, a rhabdoid tumor in the central nervous system) were treated by resection and high dose chemotherapy. Tazemetostat was introduced after completion of chemotherapy. Three patients have achieved an event free survival of 32, 34, and 30 months respectively. One progressed and died. His overall survival was 20 months. One patient was treated for a relapsed atypical teratoid rhabdoid tumor. The treatment combined metronomic therapy, radiotherapy, tazemetostat and immunotherapy. This patient died of disease progression, with an overall survival of 37 months. One patient was treated for a rhabdoid tumor of the ovary. Tazemetostat was given as maintenance after resection, chemotherapy, and radiotherapy, concomitantly with immunotherapy. Her event free survival is 44 months. Only approximately 40% of patients with rhabdoid tumors achieve long-term survival. Nearly all relapses occur within two years from diagnosis. The event free survival of four of the six patients in our cohort has exceeded this timepoint. Tazemetostat has been mostly tested as a single agent in the relapsed setting. We present promising results when applied as maintenance or add on in the first line treatment.

• MeSH
• dítě MeSH
• DNA-helikasy MeSH
• gen SMARCB1 MeSH
• jaderné proteiny MeSH
• kojenec MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• nádory centrálního nervového systému * patologie   MeSH
• předškolní dítě MeSH
• rhabdoidní nádor * farmakoterapie   patologie   MeSH
• teratom * patologie   MeSH
• transkripční faktory MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA-helikasy MeSH
• gen SMARCB1 MeSH
• jaderné proteiny MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• tazemetostat MeSH Prohlížeč
• transkripční faktory MeSH

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials.

• Klíčová slova
• ASCL1, Atypical teratoid/rhabdoid tumor, DNA methylation profiling, GFAP, Gene expression, Neuroradiology, OLIG2, Overall survival, Prognosis, Sonic hedgehog,
• MeSH
• gen SMARCB1 genetika   metabolismus   MeSH
• lidé MeSH
• metylace DNA MeSH
• nádory centrálního nervového systému * genetika   MeSH
• neuroepitelové nádory * genetika   MeSH
• prognóza MeSH
• proteiny hedgehog genetika   metabolismus   MeSH
• rhabdoidní nádor * genetika   MeSH
• teratom * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• gen SMARCB1 MeSH
• proteiny hedgehog MeSH
• SHH 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

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not been described. Here, we report 3 malignant central nervous system tumors in children (10, 13, and 18 y old). All tumors were located in the temporal lobe. In 2 cases, there was no history of a low-grade precursor lesion; in 1 case anaplastic PXA had been diagnosed 3 months earlier. Histopathologically, all tumors were composed of RT cells and showed frank signs of malignancy as well as loss of nuclear SMARCB1/INI1 protein expression. Two cases displayed homozygous deletions of the SMARCB1 region while the third case showed an exon 7 mutation (c.849_850delGT; p.Met283Ilefs*77). Of note, DNA methylation profiles did not group with AT/RT or other tumor entities using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-distributed stochastic neighbor embedding analysis and hierarchical clustering analysis, however, all tumors clearly grouped with PXA. Genome-wide copy number analysis revealed homozygous CDNK2A/B deletions and gains of whole chromosome 7. BRAF V600E mutations could be demonstrated in all cases. In conclusion, the possibility of AT/RT with molecular features of PXA needs to be taken into account and warrants molecular characterization of AT/RT especially in older children. Since treatments targeting mutated BRAF are available, identification of such cases may also have therapeutic consequences.

• MeSH
• astrocytom genetika   MeSH
• dítě MeSH
• gen SMARCB1 genetika   MeSH
• lidé MeSH
• mladiství MeSH
• mutace MeSH
• nádory mozku genetika   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• rhabdoidní nádor genetika   MeSH
• teratom genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• gen SMARCB1 MeSH
• protoonkogenní proteiny B-Raf MeSH
• SMARCB1 protein, human MeSH Prohlížeč

Since the first description of sinonasal undifferentiated carcinoma (SNUC) as a distinctive highly aggressive sinonasal neoplasm with probable origin from the sinonasal mucosa (Schneiderian epithelium), SNUC has been the subject of ongoing study and controversy. In particular, the SNUC category gradually became a "wastebasket" for any undifferentiated or unclassifiable sinonasal malignancy of definite or probable epithelial origin. However, with the availability of more specific and sensitive immunohistochemical antibodies and increasing implementation of novel genetic tools, the historical SNUC category became the subject of progressive subdivision leading to recognition of specific genetically defined, reproducible subtypes. These recently recognized entities are characterized by distinctive genetic aberrations including NUTM1-rearranged carcinoma (NUT carcinoma) and carcinomas associated with inactivation of different members of the SWI/SNF chromatin-remodeling gene complex such as SMARCB1-deficient and less frequently SMARCA4-deficient carcinoma. The ring became almost closed, with recent studies highlighting frequent oncogenic IDH2 mutations in the vast majority of histologically defined SNUCs, with a frequency of 82%. A review of these cases suggests the possibility that "true SNUC" probably represents a distinctive neoplastic disease entity, morphologically, phenotypically, and genetically. This review addresses this topic from a historical perspective, with a focus on recently recognized genetically defined subsets within the SNUC spectrum.

• MeSH
• DNA-helikasy genetika   MeSH
• gen SMARCB1 genetika   MeSH
• jaderné proteiny genetika   MeSH
• karcinom diagnóza   epidemiologie   genetika   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory sinu maxillaris diagnóza   epidemiologie   genetika   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• DNA-helikasy MeSH
• gen SMARCB1 MeSH
• jaderné proteiny MeSH
• nádorové biomarkery MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• SMARCB1 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

BACKGROUND: Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT. METHODS: Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3). RESULTS: Median observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation. CONCLUSIONS: Long-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.

• Klíčová slova
• brain tumors, neuro-oncology, pediatric oncology, teratoid/rhabdoid tumors,
• MeSH
• dítě MeSH
• DNA-helikasy genetika   MeSH
• gen SMARCB1 genetika   MeSH
• jaderné proteiny genetika   MeSH
• kojenec MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• míra přežití MeSH
• nádorové biomarkery genetika   MeSH
• nádory míchy genetika   mortalita   patologie   terapie   MeSH
• následné studie MeSH
• předškolní dítě MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• rhabdoidní nádor genetika   mortalita   patologie   terapie   MeSH
• teratom genetika   mortalita   patologie   terapie   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA-helikasy MeSH
• gen SMARCB1 MeSH
• jaderné proteiny MeSH
• nádorové biomarkery MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• SMARCB1 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

Dedifferentiated liposarcoma is one of the most common sarcoma types in adults with a predilection for the retroperitoneum. We have recently encountered 6 cases of DDL composed predominantly of rounded, rhabdoid or epithelioid cells mimicking rhabdoid melanoma, epithelioid rhabdomyosarcoma or undifferentiated carcinoma. Patients were 5 males and one female aged 64 to 81 years (median, 68). Tumors originated in the retroperitoneum (n=5; 3 in the psoas muscle) and deep soft tissue of the thigh (n=1). All 3 patients with follow-up died of metastatic disease within 4 to 8 months. Preoperative biopsy diagnoses never suggested dedifferentiated liposarcoma as a possibility; instead carcinoma, rhabdomyosarcoma and lymphoma were on top of suggestions. Five resected tumors were composed predominantly (70%-100%) of anaplastic rounded to oval rhabdoid cells with prominent central nucleoli and paranuclear rhabdoid inclusions. Bi- and multinucleation was a constant feature. The background stroma showed variable myxoid changes and minor mixed inflammatory cells. Two cases showed homologous dedifferentiation and another had sclerosing spindle cell nodule but a well-differentiated lipomatous component was not seen in any. One biopsied case showed solely monotonous small round blue cells with scattered rhabdoid cells. Immunohistochemistry showed expression of MDM2 (6/6), CDK4 (5/6), pancytokeratin AE/1AE3 (4/6) and diffusely desmin and myogenin (2/6). All cases showed high-level co-amplification of MDM2/CDK4 by in situ hybridization. The SWI/SNF complex components (SMARCB1, SMARCA2, SMARCA4, ARID1A and PBRM1) were intact in all cases. This highly aggressive liposarcoma variant needs to be distinguished from a variety of neoplasms including undifferentiated carcinoma, melanoma, lymphoma, rhabdomyosarcoma and others.

• Klíčová slova
• Dedifferentiated liposarcoma, Epithelioid, Melanoma, Retroperitoneum, Rhabdoid, Rhabdomyosarcoma, SWI/SNF,
• MeSH
• diferenciální diagnóza MeSH
• DNA-helikasy metabolismus   MeSH
• epiteloidní buňky patologie   MeSH
• gen SMARCB1 metabolismus   MeSH
• imunohistochemie metody   MeSH
• jaderné proteiny metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• liposarkom diagnóza   patologie   MeSH
• nádorové biomarkery analýza   MeSH
• nádory měkkých tkání diagnóza   patologie   MeSH
• rhabdoidní nádor diagnóza   metabolismus   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktory metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA-helikasy MeSH
• gen SMARCB1 MeSH
• jaderné proteiny MeSH
• nádorové biomarkery MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• SMARCB1 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

• 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

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