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Thymic epithelial tumors are presently staged using a consistent TNM classification developed by the International Association for the Study of Lung Cancer (IASLC) and approved by the Union for International Cancer Control and the American Joint Committee on Cancer. The stage classification is incorporated in the eight edition of the TNM classification of thoracic malignancies. The IASLC Staging and Prognostic Factors Committee (SPFC)-Thymic Domain (TD) is in charge for the next (ninth) edition expected in 2024. The present article represents the midterm report of the SPFC-TD: in particular, it describes the unresolved issues identified by the group in the current stage classification which are worth being addressed and discussed for the ninth edition of the TNM classification on the basis of the available data collected in the central thymic database which will be managed and analyzed by Cancer Research And Biostatistics. These issues are grouped into issues of general importance and those specifically related to T, N, and M categories. Each issue is described in reference to the most recent reports on the subject, and the priority assigned by the IASLC SPFC-TD for the discussion of the ninth edition is provided.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that—in the case of the interdependent tumor cell morphology and adapted immune response—reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

This European Respiratory Society guideline is dedicated to the provision of good quality recommendations in lung cancer care. All the clinical recommendations contained were based on a comprehensive systematic review and evidence syntheses based on eight PICO (Patients, Intervention, Comparison, Outcomes) questions. The evidence was appraised in compliance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence profiles and the GRADE Evidence to Decision frameworks were used to summarise results and to make the decision-making process transparent. A multidisciplinary Task Force panel of lung cancer experts formulated and consented the clinical recommendations following thorough discussions of the systematic review results. In particular, we have made recommendations relating to the following quality improvement measures deemed applicable to routine lung cancer care: 1) avoidance of delay in the diagnostic and therapeutic period, 2) integration of multidisciplinary teams and multidisciplinary consultations, 3) implementation of and adherence to lung cancer guidelines, 4) benefit of higher institutional/individual volume and advanced specialisation in lung cancer surgery and other procedures, 5) need for pathological confirmation of lesions in patients with pulmonary lesions and suspected lung cancer, and histological subtyping and molecular characterisation for actionable targets or response to treatment of confirmed lung cancers, 6) added value of early integration of palliative care teams or specialists, 7) advantage of integrating specific quality improvement measures, and 8) benefit of using patient decision tools. These recommendations should be reconsidered and updated, as appropriate, as new evidence becomes available.

Objective: Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un). Methods: A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact. Results: In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobespecific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for RO, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between RO and R(un) in pN0 cases. Conclusions: R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

International audience; Many neoplasms remain unclassified after histopathological examination, which requires further molecular analysis. To this regard, mesenchymal neoplasms are particularly challenging due to the combination of their rarity and the large number of subtypes, and many entities still lack robust diagnostic hallmarks. RNA transcriptomic profiles have proven to be a reliable basis for the classification of previously unclassified tumors and notably for mesenchymal neoplasms. Using exome-based RNA capture sequencing on more than 5000 samples of archival material (formalin-fixed, paraffin-embedded), the combination of expression profiles analyzes (including several clustering methods), fusion genes, and small nucleotide variations has been developed at the Centre Léon Bérard (CLB) in Lyon for the molecular diagnosis of challenging neoplasms and the discovery of new entities. The molecular basis of the technique, the protocol, and the bioinformatics algorithms used are described herein, as well as its advantages and limitations.

Introduction Very little is known about the characteristics of mesothelial tumours in the paediatric population. In adults with malignant mesothelioma, the pemetrexed-based regimen with cytoreductive surgery (CRS) is a standard of care in limited tumours, but long-term survival is uncommon. Material and methods The European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT) retrospectively reviewed children, adolescents and young adults (≤21 year) diagnosed with mesothelial tumours treated between 1987 and 2018. Results Thirty-three patients were identified, 15 male and 18 female patients. One patient's exposure to asbestos was documented. Primary tumour was mainly in the peritoneum (23 patients). Histology was multicystic mesothelioma of the peritoneum (MCM) (six patients) or malignant mesothelioma (MM) (27 patients). Among MM, the first-line treatment comprised preoperative chemotherapy (14 cases), surgery only (three cases), chemotherapy only (five cases), adjuvant chemotherapy (three cases) or palliative treatment (two cases). The response rate to cisplatin–pemetrexed was 50% (6/12 cases). CRS with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was performed in 19 patients (upfront in three, after neoadjuvant therapy in 12, or after tumour progression in six patients, including three twice). After a median follow-up of 6.7 years (range, 0–20), five-year overall and event-free survivals were 82.3% (95% CI, confidential interval ((CI), 67.8–99.9) and 45.1% (95% CI, 28.4–71.7), respectively. All patients with MCM are alive after surgery (five patients) and CRS-HIPEC (one patient). Conclusions Paediatric mesothelioma is exceptional and seems to be different from its adult counterpart with few asbestos exposures, more peritoneal primary, and a better outcome. The cisplatin–pemetrexed regimen showed promising efficacy. Relapses could be salvaged with active therapy including CRS-HIPEC.

Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

To the Editor,The severe prognosis of Erdheim-Chester disease (ECD) is essentially based on central nervous system involvement and probably on cardiac injuries [1,2]. Recently, treatments blocking ...

Resume La creation et la mise en ligne de materiel pedagogique demandent beaucoup de temps et d’energie, et restent difficile a organiser pour les enseignants d’une seule universite. Sous l’egide du College des pathologistes, nous avons initie la mise en place d’un reseau national inter-universitaire ayant pour objectif de creer et de mutualiser un enseignement en ligne en pathologie, reposant sur des cas anatomocliniques, des tests et d’autres contenus pedagogiques multimedias. Dix-neuf universites francaises sont associees a ce projet initialement soutenu par l’UNF3S ( http://www.unf3s.org/ ). Le contenu pedagogique en ligne repose sur une plate-forme utilisant le logiciel Moodle ( http://virtual-slides.univ-paris7.fr/moodle/ ), contenant du texte, differents medias et des liens vers des lames virtuelles decentralisees. Les enseignants ont appris a maitriser l’interface Moodle a l’aide de conferences Web avec partage d’ecran. A ce jour, 20 cas anatomocliniques ont ete crees, ainsi que plusieurs tests contenant des questions a choix multiples ou a reponses courtes, et des videos de macroscopie. Une enquete realisee aupres de 16 enseignants et etudiants a montre un taux de satisfaction de 94 %, la plupart souhaitant que ce type d’enseignement en ligne se developpe en complement de l’enseignement presentiel. Les developpements du site concerneront l’ensemble des niveaux d’etude, du L2–L3 jusqu’aux internes en pathologie et le developpement professionnel continu, en passant par la preparation aux ECN. En conclusion, ces nouveaux outils offrent de tres interessantes perspectives pour l’enseignement de la pathologie. L’organisation d’un reseau national inter-universitaire est un moyen efficace de creer et de mutualiser des ressources pedagogiques nombreuses et de qualite.

hma.2013.0789 Auteur(s) : Alexandra Audemard1, Xavier Troussard1, Francoise Galateau-Salle2, Margaret Macro1 macro-m@chu-caen.fr 1 Hematologie clinique, 2 Departement de pathologie, CHU de Caen 14000-Caen, Universite de Caen Basse Normandie, UFR de medecine, 14000 Caen, France Tires a part : M. Macro La maladie de Gaucher (MG) est une maladie de surcharge lysosomale (MSL), dont la transmission est autosomique recessive. Elle est secondaire a un deficit en beta-glucocerebrosidase (GBA), qui [...]

Introduction La maladie d’Erdheim–Chester (MEC) est une histiocytose non langerhansienne rare. Du fait de l’implication des interleukines 1 et 6 dans sa physiopathologie, l’anakinra a la dose empirique de 100 mg/j a ete utilise avec une efficacite et une tolerance satisfaisantes. Neanmoins, certains cas de reponses partielles ou d’echec ont ete publies avec cette posologie. Nous rapportons une serie de 4 patients atteints de MEC traites par anakinra double dose. Patients et methodes Sur une cohorte de 10 patients atteints de MEC traite par anakinra a simple dose (100 mg/j), 6 ont atteint une reponse complete. Les 4 patients qui n’ont pas atteint une reponse complete ont ete traite par anakinra a double dose (200 mg/j). Cette etude retrospective rapporte l’evolution sous anakinra a double dose de ces 4 patients. Le diagnostic de MEC etait base sur les resultats histologiques et un tableau clinique et radiologique compatible. L’evolution clinique etait evaluee comme etant complete en cas de disparition des symptomes, partielle en cas d’amelioration partielle des symptomes, stable en cas d’absence de modification de la symptomatologie et progressive en cas d’aggravation de la symptomatologie. La reponse radiologique etait evaluee selon les criteres RECIST 1.1. Resultats Parmi les 4 patients (1 femme, âge moyen au diagnostic de 59,8 ans), 2 etaient porteurs d’une mutation BRAF V600E, 1 d’une mutation NRAS et il n’a pas ete retrouve de mutation chez le dernier. L’anakinra a simple dose etait prescrit en 2e ou 3e ligne apres echec de l’interferon (n = 3) ou en premiere ligne (n = 1), et permettait d’atteindre une reponse partielle chez 3 patients, avec une progression de la maladie chez le dernier. Sous anakinra a double dose, 2 patients ont atteint une reponse complete, 1 etait en reponse partielle soutenue avec une diminution de la symptomatologie par rapport a l’anakinra simple dose, et le dernier n’a eu qu’une reponse partielle temporaire (2 mois) avec une progression de la maladie sous forme d’une pleuropericardite. Devant la decouverte de la mutation BRAF V600E dans une minorite des cellules tumorales, ce patient a ete traite et a obtenu une reponse complete sous l’association d’anakinra a simple dose et de vemurafenib (dont la posologie a ete secondairement diminuee de moitie du fait de la survenue d’un syndrome d’erythrodysesthesie palmoplantaire). L’anakinra a double dose a permis l’obtention ou le maintien d’une reponse complete concernant les masses atriales droites (n = 3/3), les xanthelasmas (n = 2/2), l’atteinte intraperitoneale (panniculite mesenterique, epanchement et nodules peritoneaux) (n = 2/2), et l’atteinte radiologique (n = 2/2). La reponse etait partielle en ce qui concernait l’atteinte pleuropericardique (n = 2/2), avec une reponse transitoire pour un patient. En revanche, il n’a pas eu d’efficacite sur le diabete insipide, considere comme sequellaire (n = 2). Concernant la tolerance de l’anakinra a double dose, les effets secondaires etaient identiques a l’anakinra a simple dose, avec des reactions aux points d’injection et/ou des rash cutanes transitoires (n = 4). Deux patients ont eu une neutropenie moderee et transitoire. Conclusion L’anakinra a double dose ameliore la reponse a l’anakinra et a permis l’obtention de 2 reponses completes et d’une reponse partielle chez 3/4 patients atteints de MEC, avec des effets secondaires mineurs et comparables a ceux de la dose simple. Les echecs etaient secondaires a des serites massives. La reponse semble independante du statut mutationnel BRAF.

Objectives. In Erdheim-Chester disease (ECD), the empirical single dose (SD, 100 mg/day) anakinra sometimes induces only partial responses. Since SD is usually well tolerated, doubling the dose might improve response while maintaining an acceptable safety profile. Methods. A retrospective analysis was performed of outcomes under double-dose (DD) of anakinra in 4 ECD patients who did not exhibit a complete response (CR) under SD treatment. Bone, retroperitoneal, neurologic/orbital, peritoneal, pericardial, right atrium, and pleural involvements were recorded. CR, partial response (PR), stable disease, progressive disease (PD) and tolerance of DD were assessed. Results. SD treatment was a second or third line treatment in three patients after interferon-therapy failure. Two patients, including one with a BRAF mutation, achieved a CR and one patient with a NRAS mutation achieved a PR with DD treatment. The fourth patient, wild-type for both genes, did not respond to a first DD treatment, but then achieved CR under SD associated with a reduced dose of vemurafenib (960 mg/d). Bone and retroperitoneal lesions partially improved on imaging with SD in all patients, but were further improved under DD with two patients achieving CR. With SD treatment, two patients with right atrial masses showed sustained CR. Under DD treatment, two patients with massive serositis refractory to SD, showed PR. Conclusion. DD improved the response to anakinra and lead to two CRs and a PR in three out of four ECD patients, with minor and comparable side-effects to those of SD, while failures were essentially related to massive serositis.

Noninfectious ascending aortitis is a very rare cause of ascending aortic aneurysm. We report a case of the truly fortuitous finding of this rare condition in a 67-year-old man operated on for an ascending aortic aneurysm associated with dystrophic aortic valve regurgitation. Intraoperative inspection revealed dissection of the aorta just above the left main coronary artery. A modified Bentall operation was performed. The pathological diagnosis was giant cell arteritis.

A 20-year-old man, with a recent diagnosis of relapsing polychondritis, was hospitalized for crescendo angina pectoris. Relapsing polychondritis, an auto immune multi-system disease characterized by recurrent inflammation and destruction of different cartilaginous structures, was clinically diagnosed after nasal chondritis ( Panel A ), left cochlear–vestibular …

OBJECTIVES: To analyse statistical aspects of mortality, morbidity and survival after bilobectomy (BT), an operation rarely studied in the literature. METHODS: One hundred and ten cases were studied, comprising 58 upper-middle bilobectomies and 52 lower-middle bilobectomies performed between 1999 and 2010. Indications were of 9 benign diseases, 12 carcinoid tumours, 5 metastases and 84 non-small cell lung cancers (2 stage 0; 34 stage I; 22 stage II; 25 stage III and 1 stage IV). RESULTS: Mortality was nil. Twenty-six percent of patients experienced significant morbidity, influenced in multivariate analysis by the presence of three or more comorbidities (P = 0.03) and by a forced expiratory volume in 1 s of

Light-chain (AL) amyloidosis may present with features suggesting vasculitis, including giant-cell arteritis (GCA). We describe a case of an 80-year-old man, who initially presented with bilateral jaw claudication, bi-temporal headache and arthralgia, however a temporal-artery biopsy then revealed AL amyloidosis. A diagnosis of AL amyloidosis complicating multiple myelome simulates GCA and polymyalgia rheumatica was established. The patient was successfully treated with melphalan and dexamethasone: the free kappa light chains decreased, the patient's jaw claudication and headache disappeared. Then we discuss similarities between GCA and AL amyloidosis and potential confusion in diagnosis. We suggest that, in patients with clinical features of GCA without any temporal-artery typical findings, specimens are stained with Congo red, which then results in a different diagnosis and treatment.

Erdheim–Chester disease (ECD) pathophysiology remains largely unknown. Its treatment is not codified and usually disappointing. Interferon (IFN)-α therapy lacks efficacy for some life-threatening manifestations and has a poor tolerance profile. Because interleukin (IL)-1Ra synthesis is naturally induced after stimulation by IFN-α, we hypothesized that recombinant IL-1Ra (anakinra) might have some efficacy in ECD. We treated 2 patients who had poor tolerance or contraindication to IFN-α with anakinra as a rescue therapy and measured their serum C-reactive protein, IL-1β, IL-6, and monocytic membranous IL-1α (mIL-1α) levels before, under, and after therapy. Another untreated ECD patient and 5 healthy subjects were enrolled as controls. After treatment, fever and bone pains rapidly disappeared in both patients, as well as eyelid involvement in one patient. In addition, retroperitoneal fibrosis completely or partially regressed, and C-reactive protein, IL-6, and mIL-1α levels decreased to within the normal and control range. Beside injection-site reactions, no adverse event was reported. Therefore, our results support a central role of the IL-1 network, which seemed to be overstimulated in ECD. Its specific blockade using anakinra thereby opens new pathophysiology and therapeutic perspectives in ECD.

Summary Background Although the role of asbestos in the genesis of mesothelioma and primary bronchopulmonary cancers has been established, results from studies focusing on the relationship between occupational exposure to asbestos and digestive cancer remain contradictory. Aim To determine whether occupational asbestos exposure increases the incidence of digestive cancers. Methods Our study was a retrospective morbidity study based on 2024 subjects occupationally exposed to asbestos. The incidence of digestive cancer was calculated from 1st January 1978 to 31st December 2004 and compared with levels among the local general population using Standardized Incidence Ratios. Asbestos exposure was assessed using the company’s job exposure matrix. Results Eighty-five cases of digestive cancer were observed within our cohort, for an expected number of 66.90 (SIR = 1.27 [1.01; 1.57]). A significantly elevated incidence, particularly notable among women, was observed for peritoneal mesothelioma, independently of exposure levels. A significantly elevated incidence was also noted among men for cancer of small intestine and oesophagus, for cumulative exposure indexes for asbestos above 80 fibres/mL × years. A significantly elevated incidence of cancer of the small intestine was also observed among men having been exposed to asbestos for periods in excess of 25 years and for mean exposure levels in excess of 4 fibres/mL. Conclusions This study suggests the existence of a relationship between exposure to asbestos and cancer of the small intestine and of the oesophagus in men.

Prolyl hydroxylase domain (PHD) proteins play a major role in regulating the hypoxia-inducible factor (HIF) that induces expression of genes involved in angiogenesis, erythropoiesis, and cell metabolism, proliferation, and survival. Germ-line mutations in the prolyl hydroxylase domain 2 gene (PHD2) have been reported in patients with familial erythrocytosis but not in association with tumors. We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation. This mutation affects PHD2 function and stabilizes HIF-alpha proteins. In addition, we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene.

Malignant mesothelioma (MM) is an aggressive neoplasm caused by exposure to asbestos fibers in 80% of cases.1,2 Although asbestos has been banned in most developed countries, the incidence of mesothelioma is still rising because of the long latency period from the time of exposure to development of the disease (20–40 years). Asbestos fibers interact with the mesothelial cells from which these tumors arise in several different ways and generate reactive oxygen species (see Chapter 44), cytokines, and growth factors secondary to inflammatory responses from the host, resulting in DNA damage. Protooncogenes may be activated, leading to cell proliferation and susceptibility to mutations. Over time, structural alterations and numerical losses and gains to chromosomes occur, producing genomic instability and alteration of the role of tumor suppressor genes. These complex cytogenetic and molecular events in MM development attest to the multistep process from a benign proliferation to a malignant neoplasm.

Concerns remain over the risk of cancer following differentiated thyroid carcinoma and its causes. Iodine-131 ((131)I) and external irradiation are known to have potential carcinogenic effects. Thyroid carcinoma is a polygenic disease which may be associated with other malignancies. We investigated the incidence of second cancer and its aetiology in a cohort of 875 patients (146 men, 729 women) with differentiated thyroid carcinoma originating from Basse-Normandie, France. Cancer incidence was compared with that of the general population of the Département du Calvados matched for age, gender and period. The cumulative proportion of second cancer was estimated using the life-table method. Factors that correlated with the risk of second cancer were studied using the Cox model. After a median follow-up of 8 years, 58 second cancers had been observed. Compared with general population incidence rates, there was an overall increased risk of second cancer in women [standardised incidence ratio (SIR)=1.52; P0.01], but not in men (SIR=1.27; P0.20). Increased risk related to cancers of the genitourinary tract (SIR=3.31; P0.001), and particularly to cancer of the kidney (SIR=7.02; P0.01). Multivariate analysis showed that age above 40 years (P0.01) and a history of previous primary cancer (P0.001) correlated with risk. In contrast, neither cervical irradiation nor cumulative activity of (131)I was related to the risk. These data confirm that women with differentiated thyroid carcinoma are at risk of developing a second cancer of the genitourinary tract and kidney. Only age and medical history of primary cancer before thyroid carcinoma are risk factors for second cancer. Common environmental or genetic factors as well as long-term carcinogenic effects of primary cancer therapy should be considered.

While the role of exposure to asbestos in the development of several cancers such as mesotheliomas and bronchopulmonary cancers is now well established, the possible relationship between digestive cancers, other than peritoneal mesotheliomas, and occupational exposure to asbestos is still controversial. The great majority of the studies are based on mortality data. The aim of the study was to analyse the relationship between digestive cancer incidence and occupational exposure to asbestos in a population of subjects for whom precise occupational exposure data and precise incidence data were available. The population consisted of salaried and retired workers from a company using asbestos to manufacture fireproof textiles and friction materials. There were 1454 men (79.9%) and 366 women (20.1%). A cumulative exposure index and a mean exposure concentration in fibres/ml for each subject were calculated with the aid of an in-house job-exposure matrix. The number of cases of digestive cancer observed was compared with the expected and Standardized Incidence Ratio (SIR) was estimated. Precise occupational exposure data allowed us to study the dose-response relationship between asbestos exposure and risk of digestive cancer using Cox model. Fifty-six digestive cancers occurred in the study population over the 18-year follow-up period for 48.4 expected (SIR = 1.16 [0.87-1.50]). Comparing with incidence in the county, SIR was not significant for any of the digestive localization, but for peritoneum. However, even after taking into account the potential confounders via the Cox model, there was a significant dose-response relationship between the occurrence of digestive cancers and the mean exposure concentration, even after exclusion of peritoneum cancers. Our study provides initial evidence suggesting a relationship between occupational exposure to asbestos and the risk of digestive cancer: first, it is a study of incidence although the risk evidenced is not significant; secondly, a dose-effect relationship is demonstrated in the whole population. However, these preliminary results require confirmation by more powerful studies focusing on larger series.

Lung carcinomas are heterogeneous in composition. The malignant cells are surrounded by a specialized connective tissue called stroma, consisting of an extracellular matrix (ECM) and a cellular compartment made of fibroblasts, inflammatory cells and endothelial cells. The ability of carcinoma cells to induce a stroma is a phenotypic trait that is maintained at metastatic sites. Stromal tissue is qualitatively distinct from the connective tissue which develops in inflammatory conditions: for instance, stromal inflammatory and mesenchymal cells have distinct phenotypic characteristics, and specific spliced variants of ECM components, such as fibronectin and tenascin, have been reported in carcinomas. Blood vessels are another essential component of the stroma. A vascular supply is necessary for tumor growth over 2 mm3. This is achieved by the complex multistep process of angiogenesis (see chapter by Castronovo et al., this volume). Moreover, the stroma, as opposed to normal connective tissue, is an unstable structure, remodelled throughout tumor development. This plasticity, controlled in part by the neoplastic cells themselves, is the result of a spatially and temporally changing imbalance between the agonist and antagonist stromal mechanisms that control tumor progression.

Background: Immunofluorescence assay (IFA) of viral antigens in nasal aspirates is largely used for the diagnosis of respiratory syncytial virus (RSV), parainfluenzavirus (PIV) type 3 and adenovirus (AdV) infections, whilst rhinovirus (RV) are detected by virus isolation technique (VIT) only. Using the two techniques, IFA and VIT, a significant number of specimens remain negative in spite of clinical and epidemiological presumptions of viral infection. Objectives and study design: The polymerase chain reaction (PCR) should improve the sensitivity of viral detection in clinical specimens. From October 1995 to March 1996, 277 nasal aspirates from hospitalized infants were tested simultaneously by IFA, VIT, polymerase chain reaction and hybridization with a DNA enzyme immunoassay (PCR-EIA) for RSV, PIV-3, AdV and RV. Results: RSV were detected in 177 (64%) samples, PIV-3 in 23 (8%), RV in 40 (14%), and AdV in 30 (10%). PCR-EIA detected RSV in more samples 173 (62%) than IFAVIT: 109 (39%) (P < 10−7). In most cases (79%), RSV-infected infants had lower respiratory tract disease, and routine and PCR techniques were positive. Out of the 23 PIV-3 infections, 12 were IFAVIT- and PCR-EIA-positive, and 11 IFAVIT-negative and PCR-EIA-positive. For RV, 35 (87%) specimens were PCR EIA-positive and 11 (27%) culture-positive; for AdV 30 samples were PCR-EIA-positive and four were culture-positive. Simultaneous viral infections were revealed in a significantly higher proportion than in conventional techniques: 18% (50277) versus 2.5% (7277); P < 10−7. One RSV infection in four was associated with the presence of another virus, mainly PIV-3 (16 cases) and AdV (13 cases). Conclusions: PCR-EIA detects more positive-specimens than IFAVIT, 1.5 times more for RSV, 1.9 for PIV-3, 4 for RV and 10 for AdV, respectively. This increased sensitivity of viral detection by PCR-EIA compared to the IFAVIT could suggest that samples containing low levels of virus are missed by routine methods IFAVIT, and consequently, RSV or PIV-3, and above all RV or AdV are overlooked as agents of respiratory diseases. However, apart from the fact that the economic and convenient aspects of virus diagnostic cannot be missed, it is difficult to answer the following questions: what is the meaning of the detection of a viral sequences in nasal aspirates of infants. or may PCR have detected virus in patients who would not developed disease?

Flow cytometry is the diagnostic tool of choice to study abnormal lymphoid population detected in peripheral blood by morphological analysis. The main diagnosed chronic lymphoproliferative disorder (CLPD) is chronic lymphocytic leukemia (CLL). In a significant number of cases, a B-CLPD non-CLL can be diagnosed. Further molecular and histological examinations are then compulsory to characterize such hematologic malignancies. The objective of this study was to determine the incidence of atypical CLL among all B-CLPD diagnosed by flow cytometry. We retrospectively studied the B-CLPD consecutively diagnosed at the hospital of Caen (Normandy, France) between 2000 and 2013. The diagnosis of B-CLPD was based on the detection by flow cytometry of circulating lymphoid abnormal B cells. Multiparametric flow cytometry included markers CD19, CD20, CD22, CD79b, CD5, CD10, CD23, CD43, FMC7, CD38 and light chains (kappa and lambda) of surface immunoglobulin. The diagnosis of CLL was based on the criteria defined by Hallek et al (Blood 2008). The non-CLL B-CLPD were then explored by molecular analyses driven by the phenotype of B-cells (overexpression of cyclin D1 in case of CD5+/CD10-/CD23- B-CLPD and BCL2-JH rearrangement in case of CD10+ B-CLPD). In addition, histological evidence was necessary to classify the B-CLPD non-CLL. 1819 B-CLPD were detected by flow cytometry. The distribution of B-CLPD was as follows: 1156 cases (64%) of CLL or immunophenotypic equivalent (leukemic phase of small lymphocytic lymphoma (SLL) and monoclonal B-cell lymphocytosis (MBL)), 297 cases (16%) of marginal zone lymphoma (MZL), 84 cases (5%) of mantle cell lymphoma (MCL), 39 cases (2%) of follicular lymphoma (FL), 26 cases (1%) of hairy cell leukemia (HCL), 13 cases ( We particularly studied the 1532 cases (84%) of B-CLPD expressing CD5 (table). CD5+ CD23+ B-CLPD cases accounted for 1293 (84%) with 1153 cases of CLL, 13 cases of MCL and 127 cases of atypical CLL. CD5+ CD23- B-CLPD accounted for 239 cases (16%) with 72 cases of MCL, 158 cases of MZL, 4 cases of FL, 2 cases of WM, 2 cases of CD23- CLL and one case of B-PLL.CD5+ casesCD5+ CD23+ B-CLPDCD5+ CD23- B-CLPDTotalCLL115301153Atypical CLL1272129MCL137285MZL0158158FL044WM022B-PLL011Total12932391532 WHO classification of hematologic malignancies do not include atypical CLL as defined by a clonal proliferation of B-cells expressing CD5+, CD23+, cyclin D1- with no histological evidence of MZL or MCL, and which do not meet all the diagnostic criteria of CLL (Hallek et al, Blood 2008). This concept of atypical CLL, first described by Criel et al (BJH 1997), is particularly interesting, because such B-CLPD seems to have a different outcome as compared with CLL (Oscier et al, BJH 1997) and to have a different biological presentation with atypical morphology of CLL cells (Criel et al, BJH 1997), more frequent trisomy 12 (Matutes et al, BJH 1996) and a stronger intensity of CD20 (Ugo et al, Leuk Lymphoma 2006). Diagnosis of B-CLPD relies on a multidisciplinary approach combining morphological, immunophenotypic, molecular and histological analyses. Despite detailed information of these analyses, there are B-CLPD which remain unclassifiable according WHO classification, especially CD5 positive B-CLPD. The concept of atypical CLL seems to take all its meaning to help define such unclassifiable entities. Disclosures: No relevant conflicts of interest to declare.

Although the presence of nodal disease is prognostic in thymic malignancy, the significance of the extent of nodal disease has yet to be defined. Lymph node dissection has not been routinely performed, and there is currently no node map defined for thymic malignancy. To establish a universal language for reporting as well as characterize the staging of this disease more accurately, an empiric node map is proposed here. This was developed using prior classification systems, series reporting specifics of nodal involvement, anatomical studies of lymphatic drainage, and preexisting node maps of the chest as defined by the International Association for the Study of Lung Cancer and the neck as defined by the American Academy of OtolaryngologyHead and Neck Surgery and the American Society for Head and Neck Surgery. The development of this node map was a joint effort by the International Thymic Malignancy Interest Group and the Thymic Domain of the IASLC Staging and Prognostic Factors Committee. It was reviewed and subsequently approved by the members of ITMIG. This map will be used as an adjunct to define node staging as part of a universal stage classification for thymic malignancy. As more data are gathered using definitions set forth by this node map, a revision may be undertaken in the future.