Rhabdomyosarcomas (RMS) constitute a heterogeneous spectrum of tumors with respect to clinical behavior and tumor morphology. The paternal uniparental disomy (pUPD) of 11p15.5 is a molecular change described mainly in embryonal RMS. In addition to LOH, UPD, the MLPA technique (ME030kit) also determines copy number variants and methylation of H19 and KCNQ1OT1 genes, which have not been systematically investigated in RMS. All 127 RMS tumors were divided by histology and PAX status into four groups, pleomorphic histology (n = 2); alveolar RMS PAX fusion-positive (PAX+; n = 39); embryonal RMS (n = 70) and fusion-negative RMS with alveolar pattern (PAX-RMS-AP; n = 16). The following changes were detected; negative (n = 21), pUPD (n = 75), gain of paternal allele (n = 9), loss of maternal allele (n = 9), hypermethylation of H19 (n = 6), hypomethylation of KCNQ1OT1 (n = 6), and deletion of CDKN1C (n = 1). We have shown no difference in the frequency of pUPD 11p15.5 in all groups. Thus, we have proven that changes in the 11p15.5 are not only specific to the embryonal RMS (ERMS), but are often also present in alveolar RMS (ARMS). We have found changes that have not yet been described in RMS. We also demonstrated new potential diagnostic markers for ERMS (paternal duplication and UPD of whole chromosome 11) and for ARMS PAX+ (hypomethylation KCNQ1OT1).
V kazuistike popisujeme raritný prípad embryonálneho rabdomyosarkómu v dospelosti u 39-ročného muža. Marec 2016 amputácia pravej hornej končatiny v polovici ramena pre malígny tumor – histológia mezenchiálny tumor s črtami v. s. fibrózneho monofázického synoviálneho sarkómu. Dva roky po operácii došlo u pacienta k rozvoju srdcového zlyhávania. Echokardiograficky bol v popredí nálezu tumor okolo voľnej steny ľavej komory (ĽK) nasadajúci na stenu ĽK a utláčujúci voľnú stenu ĽK. Nález bol potvrdený aj magnetickou rezonanciou srdca. Po zhodnotení nálezu heart tímom bol pacient indikovaní na kardiochirurgickú operáciu-extirpáciu tumoru. Táto bola úspešne zrealizovaná. U pacienta však došlo vo včasnom pooperačnom období k rozvoju závažného srdcové zlyhávania a následne multiorgánovému zlyhaniu a piaty poopečný deň exitoval. Na základe komplexného histomorfologického, imunohistochemického a molekulovo-genetického vyšetrenia ide o embryonálny rabdomyosarkóm (vretenobunkový podtyp high – grade).
The case report describes a rare case of embryonal rhabdomyosarcoma in adult a 39-year-old male. March 2016 right upper limb amputation in mid-arm for malignant tumor – histology mesenchial tumor with traits v.s. fibrous monophasic synovial sarcoma. Subsequently, two years after the operation, the patient developed heart failure. Echocardiographically a tumor was found around the free wall of the left ventricle (LV) deploying on the LV wall and oppressing the free wall of LV. The finding was also confirmed by the magnetic resonance of the heart. After evaluating the heart team the patient was indicated for cardiac surgery-tumor extirpation. This has been successfully implemented. However, the patient developed severe heart failure in the early post-operative period followed by multiorgan failure and fifth post-operative day patient died. On the basis of complex histomorphological, immunohistochemical and molecular-genetic examination it is embryonal rhabdomyosarcoma (spindle cell subtype high – grade).
- MeSH
- amputace MeSH
- dospělí MeSH
- embryonální rhabdomyosarkom chirurgie diagnostické zobrazování imunologie patologie MeSH
- horní končetina chirurgie patologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- multiorgánové selhání etiologie mortalita MeSH
- myogenin izolace a purifikace krev MeSH
- nádory srdce * chirurgie diagnostické zobrazování mortalita MeSH
- nádory z fibrózní tkáně chirurgie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma. METHODS: RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m2 on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m2, on days 1-28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing. FINDINGS: Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4-89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6-83·2) with maintenance chemotherapy versus 69·8% (62·2-76·2) without maintenance chemotherapy (hazard ratio [HR] 0·68 [95% CI 0·45-1·02]; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2-90·9) with maintenance chemotherapy versus 73·7% (65·8-80·1) without (HR 0·52 [95% CI 0·32-0·86]; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3-4 leucopenia, 148 (82%) had grade 3-4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved. INTERPRETATION: Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials. FUNDING: Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK.
- MeSH
- alveolární rhabdomyosarkom farmakoterapie mortalita patologie MeSH
- časové faktory MeSH
- cyklofosfamid aplikace a dávkování škodlivé účinky MeSH
- dítě MeSH
- embryonální rhabdomyosarkom farmakoterapie mortalita patologie MeSH
- hodnocení rizik MeSH
- indukce remise MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- přežití bez známek nemoci MeSH
- progrese nemoci MeSH
- protokoly protinádorové kombinované chemoterapie aplikace a dávkování škodlivé účinky MeSH
- rizikové faktory MeSH
- udržovací chemoterapie * škodlivé účinky mortalita MeSH
- vinorelbin aplikace a dávkování škodlivé účinky MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Argentina MeSH
- Brazílie MeSH
- Evropa MeSH
- Izrael MeSH
Rhabdomyosarcomas (RMS) are a heterogeneous group of mesodermal tumors, the most common sub-types are embryonal (eRMS) and alveolar (aRMS) rhabdomyosarcoma. Immunohistochemical analysis revealed c-Myb expression in both eRMS and aRMS. c-Myb has been reported to be often associated with malignant human cancers. We therefore investigated the c-Myb role in RMS using cellular models of RMS. Specific suppression of c-Myb by a lentiviral vector expressing doxycycline (Dox)-inducible c-Myb shRNA inhibited proliferation, colony formation, and migration of the eRMS cell line (RD), but not of the aRMS cell line (RH30). Upon c-Myb knockdown in eRMS cells, cells accumulated in G0/G1 phase, the invasive behaviour of cells was repressed, and elevated levels of myosin heavy chain, marker of muscle differentiation, was detected. Next, we used an RD-based xenograft model to investigate the role of c-Myb in eRMS tumorigenesis in vivo. We found that Dox administration did not result in efficient suppression of c-Myb in growing tumors. However, when c-Myb-deficient RD cells were implanted into SCID mice, we observed inefficient tumor grafting and attenuation of tumor growth during the initial stages of tumor expansion. The presented study suggests that c-Myb could be a therapeutic target in embryonal rhabdomyosarcoma assuming that its expression is ablated.
- MeSH
- embryonální rhabdomyosarkom genetika metabolismus patologie MeSH
- G0 fáze * MeSH
- G1 fáze * MeSH
- genový knockdown MeSH
- karcinogeneze genetika metabolismus patologie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protoonkogenní proteiny c-myb genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Childhood rhabdomyosarcoma (RMS) has two major histological subtypes: alveolar (aRMS) and embryonal. The aim of the study was to monitor minimal disseminated disease (MDD) using real-time quantitative reverse-transcription PCR (RQ-RT-PCR) of the PAX3-FKHR, PAX7-FKHR fusion genes and myoD1 gene. We prepared an assay using RQ-RT-PCR for a quantitative assessment of MDD in aRMS by using hydrolysis probe for quantification of PAX3-FKHR, PAX7-FKHR and myoD1 genes and beta-2-microglobulin housekeeping gene. Primary tumor samples (44), samples of local recurrences (26) from 48 patients with aRMS were examined by nested RT-PCR and RQ-RT-PCR techniques. Additionally, bone marrow samples (115), peripheral blood progenitor cell samples (27), and peripheral blood samples (25) from 33 aRMS patients were tested. PAX3/7-FKHR and myoD1 transcripts proved to be a sensitive tool for detection of MDD in RMS. We were able to identify 15/25 patients with bone marrow (BM) involvement at the time of presentation using RQ-RT-PCR. We analyzed PAX3-FKHR or PAX7-FKHR expression during the course of the disease. The RQ-RT-PCR results correlated well with nested RT-PCR results (p < 0.0001). The presence of metastases is the most adverse prognostic factor in RMS, and bone marrow is a frequent site of the tumor dissemination in RMS, especially in aRMS. Our results detecting the fusion transcripts or myoD1 transcript in the BM or peripheral blood suggest that patients with positive findings are at high risk of the tumor progression.
- MeSH
- alveolární rhabdomyosarkom chemie genetika patologie MeSH
- dítě MeSH
- embryonální rhabdomyosarkom genetika patologie MeSH
- forkhead transkripční faktory analýza MeSH
- kojenec MeSH
- kostní dřeň chemie patologie MeSH
- lidé MeSH
- lokální recidiva nádoru patologie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- MyoD Protein genetika MeSH
- nádorové biomarkery analýza MeSH
- polymerázová řetězová reakce s reverzní transkripcí metody MeSH
- předškolní dítě MeSH
- prognóza MeSH
- rekombinantní fúzní proteiny analýza MeSH
- rhabdomyosarkom chemie genetika mortalita patologie MeSH
- transkripční faktor PAX7 analýza MeSH
- transkripční faktory paired box analýza MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Je popsán případ botryoidního typu rabdomyosarkomu ledvinné pánvičky u 491eté ženy. Nádor způsobil hydronefrózu. V resekátu ledviny byl patrný průsvitný polypoidní útvar na tenké stopce vyrůstající ze stěny ledvinné pánvičky. Ve světelné mikroskopii byl patrný objemný exofytický polypoidní nádor s neporušeným povrchovým epitelem; tento nejevil změny dysplastické ani ve smyslu carcinoma in situ. Pod bazálni mt smyslu carcinoma in situ. Pod bazálni membránou byly nahromaděné epiteloidní až vřetenité buňky tvoricí růstovou (kambiální) vrstvu. Stroma léze bylo myxoidní a edematózní s řídce uspořádanými epiteloidními až vřetenitými bunkami. Jak buňky růstové vrstvy, tak buňky ve stromatu jevily výrazné buněčné atypie s mitózami. Imunohistochemická barvení na cytokeratin. S- 100 a myoglobin byla negativní, barvení na desmin a aktin byla pozitivní. I když byl botryoidní typ embryonálního rabdomyosarkomu popsán v různých oblastech genitálního a dolního močového traktu, toto je - pokud je nám známo - první popsaný případ tohoto nádoru v ledvinné pánvičce. I výskyt v dospělosti je u tohoto nádoru neobvyklý.
A case of botryoid-type embryonal rhabdomyosarcoma of the renal pelvis in a 49-year-old woman IS reported. The tumor led to hydronephrosis. The surgical resection specimen disclosed a translucent, polypoid mass attached to the wall of the renal pelvis by thin stalk. Light-microscopic examination revealed a large exophytic polypoid tumor with intact surface epithelium, which was negative for dysplasia or carcinoma in situ. There was a condensation of epithelioid to spindle cells underneath the basement membrane, forming a cambium layer. The core of the lesion contained interspersed epithelioid to spindle cells with myxoid change and edema. Cells of the cambium layer as well as interspersed cells in the core exhibited marked cytologic atypia with mitotic figures. Immunohistochemical stains for cytokeratin, S- 100 and myoglobin were negative, stains for desmin and actin were positive. Although botryoid-type embryonal rhabdomyosarcomas have been reported to occur at various sites in the genital tract and lower urinary tract, to our knowledge, this is the first reported case of the tumor within the renal pelvis. Also, the occurrence of these tumors in adults is quite rare.
- MeSH
- dospělí MeSH
- embryonální rhabdomyosarkom diagnóza patologie MeSH
- finanční podpora výzkumu jako téma MeSH
- hydronefróza patologie MeSH
- imunohistochemie metody MeSH
- ledvinná pánvička patologie MeSH
- lidé MeSH
- nádory ledvin patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
