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

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

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

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

We present a rare case of malignant rhabdoid tumor (ovarian small cell carcinoma of hypercalcemic type) in a 24-year-old female with fulminant course. Clinically, hypercalcemia was not found at the time of primary diagnosis. However, it appeared later during the course of tumor progression. Histologically, the tumor showed classical features of small cell carcinoma of hypercalcemic type. Therapy included radical surgery with adjuvant chemotherapy. Despite this intensive therapy, the disease recurred and the patient died 10 months after the diagnosis. We discuss the diagnosis and therapy of this tumor, as well as its recent classification as malignant rhabdoid tumor.

• Klíčová slova
• Chemotherapy, Immunohistochemistry, Malignant rhabdoid tumor, Ovarian cancer, Small cell carcinoma of hypercalcemic type,
• Publikační typ
• kazuistiky MeSH

We report a case of an aldosterone producing adrenocortical adenoma with rhabdoid features in a 16-year-old girl. Grossly, the tumor measured 30 mm in diameter and weighed 24 g. Histologically, the tumor was composed of approximately equal parts of tumor cells with rhabdoid features arranged in a solid and trabecular pattern and cells characterized by compact eosinophilic cytoplasm, solid growth with focal necroses, and increased mitotic activity. The lipid-rich tumor cells with ample clear vacuolized cytoplasm represent a minor component. Immunohistochemically, all the tumor cells showed the same results and were positive for vimentin, synaptophysin, Melan A, and alpha-inhibin. Cytokeratin CAM 5.2 was positive only focally. Chromogranin A, actin, alpha-actin, S100 protein, EMA, and cytokeratin AE1/AE3 were negative. Rhabdoid features have been described in many tumors of variable histogenesis; however, to the best of our knowledge, the presence of rhabdoid phenotype has never been described in either adrenocortical adenoma or carcinoma.

• MeSH
• adenom kůry nadledvin patologie   chirurgie   MeSH
• adrenalektomie MeSH
• adrenokortikální nádory metabolismus   patologie   MeSH
• aldosteron metabolismus   MeSH
• lidé MeSH
• mladiství MeSH
• nádorové biomarkery analýza   MeSH
• následné studie MeSH
• rhabdoidní nádor metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldosteron MeSH
• nádorové biomarkery MeSH

A 3.0 × 2.5 cm rhabdoid myomelanocytic tumor was incidentally found in the left ovary of a 43-year-old black woman. The tumor cells were cytologically bland with minimal proliferation rate, multifocally weakly or moderately expressed TFE3, strongly expressed smooth muscle markers and SMARCB1/INI1, and focally expressed HMB45. They contained numerous paranuclear whorls of intermediate filaments that were verified by ultrastructure. No other lines of differentiation were detected within the tumor. Neither translocation nor increased number of copies of the TFE3 gene at Xp11.22 was detected by fluorescence in situ hybridization. The patient remains well, free of tumor, 7 years after surgery. A rhabdoid variant of myomelanocytic tumor is a rarity, with only a single case described previously.

• Klíčová slova
• TFE3-positive tumors, ovarian myomelanocytic tumors, perivascular epithelioid cell tumors, rhabdoid tumors,
• MeSH
• dospělí MeSH
• imunohistochemie MeSH
• lidé MeSH
• nádorové biomarkery analýza   MeSH
• nádory vaječníků diagnóza   patologie   MeSH
• nádory z perivaskulárních epiteloidních buněk diagnóza   patologie   MeSH
• následné studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• nádorové biomarkery MeSH

BACKGROUND: Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated in the management of hematologic malignancies in adults, safety in children has also been demonstrated repeatedly. MATERIALS AND METHODS: A retrospective series of patients who received decitabine upon relapse or progression following therapy according to the EU-RHAB regimen is presented. Due to the retrospective nature of analyses, response was defined as measurable regression of at least one lesion on imaging. 850k methylation profiling was done whenever tumor tissue was available. RESULTS: A total of 22 patients with RT of any anatomical localization were included. Most patients (19/22) presented with metastases. All received low-dose decitabine with or preceding conventional chemotherapy. Patients received a median of two (1-6) courses of decitabine; 27.3% (6/22) demonstrated a radiological response. Molecular analyses revealed increased methylation levels in tumors from responders. No excessive toxicity was observed. Clinical benefits for responders included eligibility for early phase trials or local therapy. Responders showed prolonged time to progression and overall survival. Due to small sample size, statistical correction for survivorship bias demonstrated no significant effect on survival for responders. CONCLUSIONS: Patients with RT demonstrate promising signs of antitumor activity after multiagent relapse therapy including decitabine. Analyses of methylation data suggest a specific effect on an epigenetic level. We propose to consider decitabine and other epigenetic drugs as candidates for further clinical investigations in RT.

• Klíčová slova
• ATRT, decitabine, malignant rhabdoid tumor, relapsed and refractory rhabdoid tumors,
• MeSH
• azacytidin terapeutické užití   MeSH
• decitabin terapeutické užití   MeSH
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   genetika   MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• retrospektivní studie MeSH
• rhabdoidní nádor * farmakoterapie   genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• azacytidin MeSH
• decitabin 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

BACKGROUND: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. METHODS: Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors. RESULTS: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ± 8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ± 12.2%). CONCLUSIONS: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.

• Klíčová slova
• ATRT, DNA methylation profiling, European Rhabdoid Tumor Registry, SMARCB1, prognosis,
• MeSH
• dítě MeSH
• dospělí MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• metylace DNA MeSH
• mladiství MeSH
• mladý dospělý MeSH
• rhabdoidní nádor * genetika   terapie   MeSH
• rizikové faktory MeSH
• teratom * genetika   terapie   MeSH
• věkové rozložení MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH