Integrative analysis of a series of 192 rhabdomyosarcomas defines new subgroups

Les rhabdomyosarcome (RMS) sont les sarcomes des tissus mous les plus fréquents chez l'enfant. Selon la dernière classification de l'OMS, ces sarcomes sont subdivisés en 4 groupes : les RMS embryonnaires, le RMS alvéolaires, le RMS pléomorphes et les RMS à cellules fusiformes/sclérosants. Les RMS alvéolaires correspondent à des proliférations de cellules rondes monotones et sont caractérisé par des translocations chromosomiques récurrentes qui sont utilisées en pratique courante comme marqueurs diagnostiques. Cliniquement, le RMS alvéolaire survient chez les enfants plus âgés et suit une évolution agressive. Le RMS embryonnaire n'est pas associé à une anomalie moléculaire spécifique et peut présenter différentes caractéristiques morphologiques ; son diagnostic est souvent basé sur l'absence de translocation. Cliniquement, le RMS embryonnaire est souvent diagnostiqué chez des enfants plus jeunes et a un meilleur pronostic. Ces deux groupes, qui représentent la majorité des cas pédiatriques, sont maintenant divisés en tumeurs à fusion FOXO1 positive et à fusion FOXO1 négative. Le RMS à cellules fusiformes/sclérosant est un groupe hétérogène, comprenant probablement différents types de RMS avec des caractéristiques morphologiques et cliniques différentes. Le RMS pléomorphe est un sarcome au profil génétique complexe survenant principalement chez l'adulte et correspondant histologiquement à une prolifération cellulaire pléomorphe. Récemment, plusieurs études ont décrit deux types de RMS initialement inclus dans le groupe des RMS à cellules fusiformes/sclérosants : Les RMS avec réarrangement des gènes VGLL2 ou TEAD1 et les RMS avec une mutation du gène MYOD1. Les RMS caractérisés par une fusion génique impliquant VGLL2 ou TEAD1 avec NCOA2 ou CITED2 apparaissent pendant la période néonatale et semblent être moins agressifs que les RMS classiques. Les RMS avec des mutations de MYOD1 touchent l'enfant et chez l'adulte et ont un mauvais pronostic. Un nouveau type de RMS lié à une translocation a également été récemment rapporté : le RMS intra osseux avec un gène de fusion EWSR1- ou FUS-TFCP2 (1) et MEIS1-NCOA2. Enfin, un nouveau groupe de tumeurs musculaires squelettiques borderline appelé " tumeur rhabdomyoblastique inflammatoire " a été identifié, les auteurs ajoutant une nouvelle catégorie de malignité intermédiaire dans le groupe des tumeurs musculaires squelettiques. Nous avons rapporté ici une série de 192 RMS avec leurs données cliniques, morphologiques et moléculaires. Nous avons décrit six nouveaux types de RMS : RMS avec réarrangement de SRF, RMS avec fusion BRD4::LEUTX, RMS avec fusion EP300::VGLL3, RMS avec réarrangement de TBL1XR1, RMS épithélioïde avec amplification de MYC-l et RMS avec réarrangement de Kinase. Nous avons décrit une grande série de groupes rares de RMS : RMS avec mutation MYOD1 et tumeurs rhabdomyoblastiques inflammatoires.Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in childhood. According to the latest WHO classification this sarcoma is sub-classified in 4 groups: embryonal RMS, alveolar RMS, pleomorphic RMS and spindle cell/sclerosing RMS. Alveolar RMS is a well-defined tumor, characterized by a round cell proliferation pattern and recurrent chromosomal translocations which are used in routine practice as diagnostic markers. Clinically, alveolar RMS occurs in older children and follows an aggressive course. The embryonal RMS type is not associated with a specific molecular abnormality and can show different morphological features and its diagnosis is often supported by the lack of translocation. Clinically, the embryonal RMS is often diagnosed in younger children and has a better prognosis. These two groups, representing the majority of pediatric cases, are now divided into FOXO1 fusion-positive and FOXO1-fusion negative tumors. Spindle cell/sclerosing RMS is a heterogeneous group, probably including different types of RMS with different morphological and clinical features. Pleomorphic RMS is a sarcoma with a complex genetic profile occurring predominantly in adult and associated microscopically with a pleomorphic cell proliferation. Recently, several studies have described two kinds of RMS initially included into the spindle cell/sclerosing RMS: RMSs with rearrangement of the VGLL2 or TEAD1 genes and RMSs with a mutation in the MYOD1 gene. RMSs characterized by a gene fusion involving VGLL2 or TEAD1 with NCOA2 or CITED2 arise during the neonatal period and seem to be less aggressive than classical RMS. RMSs with MYOD1 mutations occur in child and in adults and have a poor outcome. A novel type of translocation related RMS was also recently reported: intra osseous RMS with a EWSR1- or FUS-TFCP2 (1) and MEIS1-NCOA2 fusion gene. Finally, a new group of borderline skeletal muscle tumors labelled “histiocyte-rich rhabdomyoblastic tumor” was identified, the authors adding a new category of intermediate malignancy in the group of skeletal muscle tumors. Herein we reported a series of 192 RMS with clinical, morphological and molecular data. We described six new kind of RMS: RMS with SRF rearrangement, RMS with fusion BRD4::LEUTX, RMS with fusion EP300::VGLL3, RMS with rearrangement of TBL1XR1, epithelioid RMS with amplification of MYC-l and RMS with Kinase rearrangement. We described large series of rare groups of RMS: RMS with MYOD1 mutation and Inflammatory rhabdomyoblastic tumors

P16 dans les cancers broncho-pulmonaires chez les patients exposés à l'amiante (expression et altérations moléculaires)

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF

[Diagnosis of brain metastases: an update in 2012].

International audienceDiagnosis of brain metastases should aim to identify anatomoclinical entities for which a specific treatment is more accurate. Growing numbers of targeted therapies have shown to be effective against specific cancers. Several studies have reported that targeted therapies are capable of reducing brain metastases in melanoma or non small cell lung cancer (NSCLC), sometimes with a high dramatic response. These results have clearly impacted routine neuropathological practice, leading to multidisciplinary strategy management of brain metastases tissues. In accordance with the recommendations of French National Cancer Institute (INCa), the pathologist develops appropriate strategies for molecular and immunohistochemical analysis, in order to provide results as soon as possible

Infantile Rhabdomyosarcomas With VGLL2 Rearrangement Are Not Always an Indolent Disease: A Study of 4 Aggressive Cases With Clinical, Pathologic, Molecular, and Radiologic Findings.

VGLL2-rearranged rhabdomyosarcomas (RMS) are rare low-grade tumors with only favorable outcomes reported to date. We describe 4 patients with VGLL2-rearranged RMS confirmed by molecular studies, who experienced local progression and distant metastases, including 2 with fatal outcomes. Tumors were diagnosed at birth (n=3) or at 12 months of age (n=1), and were all localized at initial diagnosis, but unresectable and therefore managed with chemotherapy and surveillance. Metastatic progression occurred from 1 to 8 years from diagnosis (median, 3.5 y). Three patients experienced multimetastatic spread and one showed an isolated adrenal metastasis. At initial diagnosis, 3 tumors displaying bland morphology were misdiagnosed as fibromatosis or infantile fibrosarcoma and initially managed as such, while 1 was a high-grade sarcoma. At relapse, 3 tumors showed high-grade morphology, while 1 retained a low-grade phenotype. Low-grade primary tumors showed only very focal positivity for desmin, myogenin, and/or MyoD1, while high-grade tumors were heterogenously or diffusely positive. Whole-exome sequencing, performed on primary and relapse samples for 3 patients, showed increased genomic instability and additional genomic alterations (eg, TP53, CDKN2A/B, FGFR4) at relapse, but no recurrent events. RNA sequencing confirmed that high-grade tumors retained VGLL2 fusion transcripts and transcriptomic profiles consistent with VGLL2-rearranged RMS. High-grade samples showed a high expression of genes encoding cell cycle proteins, desmin, and some developmental factors. These 4 cases with distinct medical history imply the importance of complete surgical resection, and suggest that RMS-type chemotherapy should be considered in unresectable cases, given the risk of high-grade transformation. They also emphasize the importance of correct initial diagnosis