Marie-Christine Copin

Bronchioloalveolar carcinoma and congenital cystic adenomatoid malformation

We report on a 42-year-old woman in whom was discovered a symptomless peripheral radiologic excavated lesion of the lung, which actually existed 3 years before. All investigations were negative. A segmentectomy was performed. Histopathologic examination proved a bronchioloalveolar carcinoma in contact with a type I congenital cystic malformation of the lung. Such a malformation can be diagnosed late in adult life. The epithelial cells of the malformation might predispose to slow proliferation and malignancy, enhanced by smoking habits.

Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

Purpose: Despite research efforts to develop more effective diagnostic and therapeutic approaches, malignant pleural mesothelioma (MPM) prognosis remains poor. The assessment of tumor response to therapy can be improved by a deeper phenotypical classification of the tumor, with emphasis on its clinico-biological heterogeneity. The identification of molecular profiles is a powerful approach to better define MPM subclasses and targeted therapies. Experimental Design: Molecular subclasses were defined by transcriptomic microarray on 38 primary MPM cultures. A three-gene predictor, identified by quantitative reverse transcription PCR, was used to classify an independent series of 108 frozen tumor samples. Gene mutations were determined in BAP1, CDKN2A, CDKN2B, NF2, and TP53. Epithelial-to-mesenchymal transition (EMT) markers were studied at the mRNA and protein levels. Results: Unsupervised hierarchical clustering on transcriptomic data defined two robust MPM subgroups (C1 and C2), closely related to prognosis and partly to histologic subtypes. All sarcomatoid/desmoplastic MPM were included in the C2 subgroup. Epithelioid MPM were found in both subgroups, with a worse survival prognosis in the C2 subgroup. This classification and its association with histologic subtypes and survival were validated in our independent series using the three-gene predictor. Similar subgroups were found after classification of other MPM series from transcriptomic public datasets. C1 subgroup exhibited more frequent BAP1 alterations. Pathway analysis revealed that EMT was differentially regulated between MPM subgroups. C2 subgroup is characterized by a mesenchymal phenotype. Conclusions: A robust classification of MPM that defines two subgroups of epithelioid MPM, characterized by different molecular profiles, gene alterations, and survival outcomes, was established. Clin Cancer Res; 20(5); 1323–34. ©2014 AACR.

Thirty Years of Research on Met Receptor to Move a Biomarker from Bench to Bedside

Met receptor tyrosine kinase was discovered in 1984 as an oncogene. Thirty years later, Met and its ligand hepatocyte growth factor/scatter factor are promising targets for the novel therapies developed to fight against cancers, with more than 240 clinical trials currently conducted. In this review, we offer to trace and highlight the most recent findings of the exemplary track record of research on Met receptor, which allowed moving this biomarker from bench to bedside. Indeed, three decades of basic research unravelled the structural basis of the ligand/receptor interaction and their complex downstream signaling network. During this period, animal models highlighted their crucial role in the development and homeostasis of epithelial organs. In parallel, involvement of Met in tumorigenesis was confirmed by the direct association of its deregulation to poor prognosis in numerous cancers. On the basis of these data, pharmaceutical companies developed many Met inhibitors, some of which are in phase III clinical trials. These impressive achievements should not detract from many questions that still remain, such as the precise Met signaling involvement in development or homeostasis of specific epithelial structures. In addition, the processes involving Met in resistance to current therapies or the appearance of resistances to Met-targeted therapies are far from being fully understood.

Mésothéliome : les dispositifs en place en France « le réseau mésothéliome » 1998–2013

Mesothelioma is a rare disease less than 0.3% of cancers in France, very aggressive and resistant to the majority of conventional therapies. Asbestos exposure is nearly the only recognized cause of mesothelioma in men observed in 80% of case. In 1990, the projections based on mortality predicted a raise of incidence in mesothelioma for the next three decades. Nowadays, the diagnosis of this cancer is based on pathology, but the histological presentation frequently heterogeneous, is responsible for numerous pitfalls and major problems of early detection toward effective therapy. Facing such a diagnostic, epidemiological and medico-legal context, a national and international multidisciplinary network has been progressively set up in order to answer to epidemiological survey, translational or academic research questions. Moreover, in response to the action of the French Cancer Program (action 23.1) a network of pathologists was organized for expert pathological second opinion using a standardized procedure of certification for mesothelioma diagnosis. We describe the network organization and show the results during this last 15years period of time from 1998-2013. These results show the major impact on patients management, and confirm the interest of this second opinion to provide accuracy of epidemiological data, quality of medico-legal acknowledgement and accuracy of clinical diagnostic for the benefit of patients. We also show the impact of these collaborative efforts for creating a high quality clinicobiological, epidemiological and therapeutic data collection for improvement of the knowledge of this dramatic disease.

Drug-induced aortic valve stenosis: An under recognized entity

BACKGROUNDnWe have been intrigued by the observation that aortic stenosis (AS) may be associated with characteristic features of mitral drug-induced valvular heart disease (DI-VHD) in patients exposed to valvulopathic drugs, thus suggesting that beyond restrictive heart valve regurgitation, valvulopathic drugs may be involved in the pathogenesis of AS.nnnMETHODSnHerein are reported echocardiographic features, and pathological findings encountered in a series of patients suffering from both AS (mean gradient >15mmHg) and mitral DI-VHD after valvulopathic drugs exposure. History of rheumatic fever, chest radiation therapy, systemic disease or bicuspid aortic valve disease were exclusion criteria.nnnRESULTSnTwenty-five (19 females, mean age 62years) patients having both AS and typical features of mitral DI-VHD were identified. Mean transaortic pressure gradient was 32+/-13mmHg. Aortic regurgitation was ≥ mild in 24 (96%) but trivial in one. Known history of aortic valve regurgitation following drug initiation prior the development of AS was previously diagnosed in 17 patients (68%). Six patients underwent aortic valve replacement and 3 both aortic and mitral valve replacement. In the 9 patients with pathology analysis, aortic valvular endocardium was markedly thickened by dense non-inflammatory fibrosis, a characteristic feature of DI-VHD.nnnCONCLUSIONnThe association between AS and typical mitral DI-VHD after valvulopathic drug exposure may not be fortuitous. Aortic regurgitation was usually associated to AS and preceded AS in most cases but may be lacking. Pathology demonstrated the potential role of valvulopathic drugs in the development of AS.

Hematological manifestations of human T lymphotropic virus type 1 infection: a possible association with autoimmune myelofibrosis

It is estimated that the human T lymphotropic virus type 1 (HTLV-1) infects approximately 20 million people worldwide. Associated diseases, however, manifest only in 5–10% of infected individuals.1 Studies have shown that HTLV-1 is endemic in Southern Japan, the Caribbean, South America, Melanesian islands, Papua New Guinea, the Middle East and Central and Southern Africa. In Brazil, HTLV-1 infection is considered a public health concern as the country figures among the endemic areas in the world with prevalence rates from 1% to 5%.1 Since the discovery of HTLV-1 in 1979, it has been clearly associated with hematologic disorders, specifically with adult T-cell leukemia/lymphoma (ATL), an aggressive neoplasm

Carcinome à grandes cellules, carcinome lymphoepithelioma-like, carcinome NUT

The diagnosis of large cell carcinoma can only be made on a sampled resected tumor and should not be applied to biopsies or cytology. In the 2015 WHO classification, the definition of large cell carcinoma is restricted to carcinomas both lacking morphological signs of glandular, squamous or neuroendocrine differentiation and exhibiting a null or unclear phenotype (TTF1-/p40 ou p63 ou CK5/6+ focally). These carcinomas have an adenocarcinoma molecular profile because they harbor a significant number of KRAS and BRAF mutations, a profile that is more similar to adenocarcinoma than squamous cell carcinoma. They also have a worse prognosis than the other types of non-small cell lung carcinoma. Many large cell carcinomas previously classified on morphological data alone are now reclassified in the adenocarcinoma and squamous cell carcinoma types, including immunohistochemical features. The other large cell carcinoma subtypes from the 2004 WHO classification, i.e. large cell neuroendocrine carcinoma and basaloid carcinoma, are grouped respectively with the other neuroendocrine tumors and squamous cell carcinomas. Clear cell and rhabdoid features are now considered as cytological variants that can occur in any histopathological subtype and not as distinct subtypes. Lymphoepithelioma-like carcinoma is moved to the group of other and unclassified carcinomas as NUT carcinoma.