Search

Resume Le reseau INCa RYTHMIC a pour but la prise en charge clinique de tout patient presentant une tumeur epitheliale thymique. Chaque patient atteint de cette tumeur doit pouvoir beneficier d’une RCP regionale ou nationale, basee sur le diagnostic du pathologiste initial. Toutefois, une relecture nationale est organisee au decours de la RCP pour chaque patient inclus dans le reseau clinique, relecture nationale qui doit etre distinguee du second avis demande de pathologiste a pathologiste pour une tumeur thymique difficile a classer. Cette revue a pour objectif de preciser aux pathologistes francais la methodologie de travail et l’experience acquise du groupe de relecture national qui a beneficie de l’excellente participation des pathologistes sur l’ensemble du territoire, lui permettant d’avoir relu plus de 1000 cas. Cette revue insiste sur l’importance de la prise en charge macroscopique pour faciliter une relecture adaptee, les principales caracteristiques histopathologiques et immunophenotypiques utilisees par le groupe pour faciliter la reproductibilite interobservateur de l’histotype, les diagnostics differentiels et les difficultes persistantes de la classification en stade.

Micronodular thymic carcinoma with lymphoid hyperplasia (MNTCLH) is a rare form of thymic carcinoma. We present the experience of RYTHMIC, the French national network devoted to the treatment of thymic epithelial tumors through multidisciplinary tumor boards with a review of all tumors by pathologists for classification and staging. Six cases of MNTCLH were diagnosed during a review of 1007 thymic epithelial tumors. Histologically, epithelial cells with atypia and mitoses formed micronodules that were surrounded by an abundant lymphoid background with follicles. There was neither obvious fibro-inflammatory stroma nor necrosis. Spindle cells areas were common. Initial diagnosis was micronodular thymoma in two cases, cellular atypia being overlooked, eclipsed by the micronodular pattern. Immunohistochemistry with a panel of five antibodies showed that cytokeratins (AE1-AE3) and p63-positive epithelial cells also expressed CD5 and that there was no TdT-positive cells within the tumors. CD20 highlighted the lymphoid hyperplasia. Additionally epithelial cells also expressed CD117 and diffusely Glut 1. Twenty-seven micronodular thymomas with lymphoid stroma diagnosed during the same period did not show the CD5 and CD117 positivities seen in MNTCLH and contained TdT-positive lymphocytes. Three of the 6 patients with MNTCLH had adjuvant radiotherapy. Three patients with follow-up information were alive without recurrence at 38, 51, and 95 months. Our study shows that immunohistochemistry, such as that used in the RYTHMIC network with a small panel of antibodies, may easily help to confirm the correct diagnosis of MNTCLH, a rare and low-aggressive form of thymic carcinoma, and avoid the misdiagnosis of micronodular thymoma.

Background Classification of thymic epithelial tumours (TETs) is known to be challenging; however, the level of discordances at a nationwide level between initial and expert diagnosis and their clinical consequences are currently unknown. RYTHMIC is a national network dedicated to the management of TET based on initial histological diagnosis, followed by an additional expert review of all cases. Our aim was to evaluate the discordances between initial and expert diagnoses and whether they would have led to different clinical management. Patients and methods We conducted a retrospective analysis of the cohort of patients discussed at RYTHMIC tumour board from January 2012 to December 2016. Assessment of disagreement was made for histological typing and for staging. The discordances were classified as major or minor based on whether they would have changed or not the proposed therapeutic strategy, respectively. Follow-up of the patients with major discordances was conducted until December 2018. Results Four hundred sixty-seven patients were reviewed, and 183 (39%) discordances were identified either related to histological subtype (132) and/or stage (72). Major discordances were identified in 27 patients (6%). They included 16 patients with TET for whom treatment recommendation based on the central review would have been post-operative radiotherapy, whereas it had not been the case. However, follow-up did not show any progression among the 15 patients with high-grade histology and/or stage resected thymomas. On the other hand, among the remaining 11 patients including 7 with a diagnosis other than TET, the overall management or follow-up would have been completely different with the expert diagnosis. Conclusion Our real-life cohort reveals a high level of discordances considering TET diagnosis and supports expert review for optimal clinical management.

BackgroundInflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype.Methods657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing.ResultsWe identified 296 IHCA (45%), 81% of them were mutated in either IL6ST (61%), FRK (8%), STAT3 (5%), GNAS (3%) or JAK1 (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving ROS1, FRK or IL6 genes. ROS1 fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver (PLG, RBP4, APOB) fused with exon 33–35 to 43 of ROS1 including the tyrosine kinase domain. In two cases a truncated ROS1 transcript from exon 36 to 43 was identified. ROS1 rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to ROS1 overexpression. Among the 5 IHCA with FRK rearrangements, 5 different partners were identified (MIA3, MIA2, LMO7, PLEKHA5, SEC16B) fused to a common region in FRK that included exon 3–8. No overexpression of FRK transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2–SH3 domains. In two IHCA, we identified truncated 3’UTR of IL6 associated with overexpression of the transcript.ConclusionRecurrent chromosomal alterations involving ROS1, FRK or IL6 genes lead to activation of the JAK/STAT pathway in IHCAs.

Background Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. Methods The nationwide incidence of sarcoma or TIM (2013–2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. Results Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1–0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p−6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. Conclusions This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (16/year) are less likely to be included in clinical trials.

We read with great interest Poli et al's case report describing a post-Liver Transplantation (LT) Sinusoidal Obstruction Syndrome (SOS) induced by Mycophenolate Mofetil (MMF). This case led us to make two comments.SOS is considered a rare liver disorder in the post-LT setting. Acute rejection, CMV reactivation, advanced age, and underlying vascular disease may be triggers for SOS2 . Finally, immunosuppressive drugs have been implicated, i.e. azathioprine historically and MMF and tacrolimus more recently, even rarely.

The RYTHMIC network, supported by the French National Cancer Institute is dedicated to the management of patients with thymic epithelial tumors through regional and national multidisciplinary tumor boards. Tumor board decisions are based on the initial pathology diagnoses. However, following clinical inclusion in the network, a central pathology review is organized, implicating a panel of pathologists, for histotype and stage classification, which is different from a classical second opinion from pathologist to pathologist for a difficult case. Thanks to the participation of all French pathologists, more than 1000 cases have been reviewed by the panel. The aim of this review is to share with the French pathology community, the experience of the group. It underlines the importance of macroscopy and surgeon-pathologist involvement to allow a good central review, the main histopathological and immunophenotypical patterns of the most frequent thymomas and thymic carcinoma types, the differential diagnoses, as well as the difficulties for the panel to reproducibly assess on slides, stage, for some cases.

International audience; Phaeohyphomycosis is a chronic infectious disease caused by dematiaceous fungi. It is characterized by the presence of pigmented septate mycelia within tissues. In the case of superficial infection, the lesion(s) chronically evolve(s) toward painless pseudo-tumor(s) of the soft parts. We report herein the original case of a heart transplanted man who exhibited phaeohyphomycosis of the left hand, with no mention of travels in endemic areas. Trematosphaeria grisea was identified as the causative agent, which is quite innovative since this species has been rather described in mycetoma. The antifungal treatment initially based on isavuconazole alone was not sufficient to cure the patient. In contrast, its association with local terbinafine ointment allowed total clinical improvement. This finding is unusual as diagnosis of phaeohyphomycosis caused by T. grisea is uncommon in nontropical countries, and as the outcome appeared successful by the means of add-on therapeutic strategy with terbinafine.

Background: Since 2010, presentation to a designated sarcoma tumor board and pathological review by an expert network are mandatory for sarcoma patients in France. NETSARC+ (merging the 3 initial RREPS, RESOS & NETSARC) collected prospectively all cases of reviewed sarcomas and tumors of intermediate malignancy (TIM) nationwide. We report on the incidence of subtypes according to WHO classification from 2013 to 2016. Methods: Sarcoma or TIM confirmed by review of expert sarcoma pathologists were all prospectively integrated in the database; the results using the latest WHO classification are presented for the years 2013 to 2016, including yearly variations. Correlation of the incidence of each histotype with dedicated published clinical trials was conducted. Results: 139 different histological subtypes are reported among the 25172 patients with sarcomas (n = 18710, 64%) or TIM (n = 6460, 36%), respectively n = 5838, n = 6153, n = 6654, and n = 6527 yearly from 2013 to 2016. Over these 4 years, the observed yearly incidence of sarcomas, TIM, and both was therefore 79.7, 24.9 and 95.1/106/year, above that previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of all sarcomas. Only GIST, as a single entity exceeded a yearly incidence above 10/million per year. There were respectively 30, 63 and 66 different histological subtypes of sarcomas or TIM (single entities or lumped together, e.g. MPNST, or vascular sarcomas...) with an incidence ranging from 10 to 1/106/year, 1-0.1/106 per year, or < 0.1/106/year respectively. The 2 later “incidence groups” included 21% of the patients. The incidence of 8 histotypes varied significantly over this 4 years. Patients with tumors with an incidence above 1/106 per year have significantly higher numbers of dedicated published phase III and phase II clinical trials (p < 10-6). Conclusions: This nationwide registry of sarcoma patients with an histology reviewed by sarcoma experts shows that the incidence of sarcoma and TIM is higher than previously reported, may vary over years for some histotypes, and that tumors with an incidence < 10e6 have a much lower access to clinical trials. Funding Statement: NetSARC (INCA & DGOS) and RREPS (INCA & DGOS), RESOS (INCA & DGOS) and LYRICAN (INCA-DGOSINSERM 12563), Institut Convergence PLASCAN (17-CONV-0002), Association DAM’s, Ensemble contre Le GIST, Eurosarc (FP7-278742), la Fondation ARC, Infosarcome, InterSARC (INCA), LabEx DEvweCAN (ANR-10-LABX-0061), Ligue de L’Ain contre le Cancer, La Ligue contre le Cancer, EURACAN (EC 739521) funded this study. Declaration of Interests: The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

International audience; Background & aims: Liver adenomatosis (LA) is characterized by the presence of at least 10 hepatocellular adenomas (HCAs), but the natural history of this rare liver disorder remains unclear. Thus, we aimed to reappraise the natural history and the risk of complications in a cohort of patients with at least 10 HCAs.Methods: We analyzed the natural history of 40 patients with LA, excluding glycogen storage disorders, in a monocentric cohort. Pathological examination was performed, with immunostaining and molecular biology carried out on surgical specimens or liver biopsies.Results: Forty patients (36 female) were included with a median follow-up of 10.6 (1.9-26.1) years. Six (15%) patients had familial LA, all with germline HNF1A mutations. Median age at diagnosis was 39 (9-55) years. Thirty-three (94%) women had a history of oral contraception, and 29 (81%) women had a pregnancy before LA diagnosis. Overall, thirty-seven (93%) patients underwent surgery at diagnosis. Classification of HCAs showed 46% of patients with HNF1A-mutated HCA, 31% with inflammatory HCA, 3% with sonic hedgehog HCA, 8% with unclassified HCA. Only 15% of the patients demonstrated a "mixed LA" with different HCA subtypes. Hepatic complications were identified in 7 patients: 1 patient (3%) died from recurrent hepatocellular carcinoma after liver transplantation; 6 (15%) had hemorrhages, of which 5 occurred at diagnosis, with 1 fatal case during pregnancy, and 2 occurred in male patients with familial LA. Four patients (10%) had repeated liver resections. Finally, 4 (10%) patients developed extrahepatic malignancies during follow-up.Conclusions: The diversity in HCA subtypes, as well as the occurrence of bleeding and malignant transformation during long-term follow-up, underline the heterogeneous nature of LA, justifying close and specific management. In patients with germline HNF1A mutation, familial LA occurred equally frequently in males and females, with a higher rate of bleeding in male patients.Lay summary: Liver adenomatosis is a rare disease characterized by the presence of 10 or more hepatocellular adenomas that may rarely be of genetic origin. Patients with liver adenomatosis have multiple adenomas of different subtypes, with a risk of bleeding and malignant transformation that justify a specific management and follow-up.

Purpose Sinusoidal obstruction syndrome (SOS) is a likely side effect of colorectal liver metastases (CRLM) chemotherapy. This study aimed to assess computed tomography scan (CT-scan) performance for SOS diagnosis for patients receiving neoadjuvant chemotherapy (NC) prior to CRLM surgery, comparing obtained results with pathological gold standard. Methods Preoperative CT-scans of 67 patients who had received a NC prior to liver resection for CRLM from 2011 to 2016 were retrospectively analysed. Positive diagnosis and severity of SOS were established after consensual review of the slides by three pathologists. Preoperative CT-scans were separately interpreted by two radiologists and evocative signs of SOS were sought, defined according to a literature review and operators experience. In order to identify SOS predictors, univariate analysis and multivariate logistic regression were used to study CT-scan signs and pathological results correlation. Results Twenty-nine patient (43%) had an SOS, 22 (33%) were low-grade and 7 (10%) were high-grade. All patient had received a median of 6 cures (3–27) containing Oxaliplatin for 53 (79%) of them. In univariate analysis, hepatic heterogeneity (p Conclusion CT-scan can detect suggestive signs of SOS in patients receiving chemotherapy for CRLM. By integrating clinical and biological information into CT-scan data, it may be fruitful to create a positive diagnostic and severity score for chemotherapy-induced SOS.

International audience; Iatrogenic Kaposi sarcoma (KS) has previously been reported in patients with bullous pemphigoid (BP), in relation to systemic steroids. Objectives: To report three cases of previously unreported cutaneous KS during treatment with superpotent topical steroids (STS) and methotrexate (MTX). Patients and Methods: All patients were elderly men with BP treated with STS for 2 to 32 months (cumulative doses: 2,700-9,150 g) before MTX was introduced (dosage: 10-12.5 mg/week). Results: KS occurred one to nine months after the combined therapy. In one case, KS rapidly resolved after withdrawal of MTX. In two cases, vinblastine and/or radiotherapy were required to achieve regression of KS. Human herpes virus 8 (HHV8) latency-associated nuclear antigen was not expressed in BP lesions biopsied prior to development of KS (n = 3), but HHV8 DNA was detected in BP lesions from the patient with the most aggressive KS. Conclusion: Several predisposing factors were identified, including sex and age, high cumulative doses of STS, combination with MTX, and impaired immune status. In such cases, serum antibodies against HHV8 infection may be investigated in BP patients before introduction of MTX in order to guide clinical monitoring.

Aim Hepatocellular carcinoma (HCC) is a common outcome of chronic hepatitis C virus (HCV) infection and constitutes the main burden of this disease. The molecular mechanisms underlying the development of HCC are multiple and might involve certain microRNA (miR). Since discordant results have been reported concerning the detection of expression of miR-152 and miR-122 in HCC, our aim was to measure the levels of both miRs in serum and liver samples. Methods We analyzed miR-152 and miR-122 expression by RT-qPCR in a serum cohort from 14 HCV-infected patients who developed HCC, 20 HCV+ patients without HCC and 19 control patients. We also studied miR-152 and miR-122 in an independent tissue cohort from 11 normal livers, and from paired HCC and non-tumor adjacent livers of 11 HCV-infected patients and 12 non-infected patients. Results In serum samples, higher levels of miR-122 were found in non-HCC HCV+ compared to HCC HCV+ and control groups whereas miR-152 was detectable in a lower range in HCC HCV+ compared to non-HCC HCV+ and control groups. We found higher signals for miR-122 and miR-152 in non-tumor liver and HCC tissues compared to control tissues. HCC etiology had no detectable influence on miR-122 expression whereas miR-152 was increased in HCV+ tissue samples. Conclusions Detection of low values of circulating miR-152 is a potentially interesting marker of hepatocarcinogenesis in HCV+ patients, in contrast to miR-122, which varies according to hepatocyte damage.

Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype.657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing.We identified 296 IHCA (45%), 81% of them were mutated in eitherRecurrent chromosomal alterations involving

Background Immunotherapy is currently under investigation in B3 Thymoma (TB3) and Thymic Carcinoma (TC). PD-L1 expression has been evaluated on a limited number of patients with selected antibodies. We aimed to analyze cohort of TB3 and TC with a panel of antibodies to assess the prevalence of PD-L1 expression, its prognostic value and to set up a reproducible test. Methods We retrospectively studied 103 patients samples of FFPE histologically confirmed TB3 (n = 53) and TC (n = 50) by expert pathologists within the RYTHMIC national network. We compared PD-L1, PD1, CD8 and PD-L2 expression and performed correlation with tumor types and patients outcomes. Four PD-L1 antibodies were tested, three of them validated as companion tests in lung cancer, one tested on two automates on whole section of tumors. We evaluated the percentage and intensity of both epithelial and immune stained cells. Results TB3 epithelial cells had a higher and more diffuse expression of PD-L1 than TC regardless the antibodies tested (p Conclusion Frequent PD-L1 expression, particularly in TB3, paves the way for immunotherapy in TET (Thymic Epithelial Tumor). Otherwise, we have set up three reproducible LDT (laboratory-developed test) for four PD-L1 antibodies.

International audience; no abstract

Objectives Glucose-transporter-1 (Glut-1) may be a useful marker for differentiating B3 thymomas and thymic carcinomas. Since the literature is limited, we undertook a study to evaluate its diagnostic value in a series of thymic epithelial tumors. Materials and methods Glut-1 expression was studied by the group of pathologists linked to the French national oncological network RYTHMIC. Immunostaining was performed on a whole section of one paraffin block in a series of 92 successive surgical specimens. Patterns (focal, zonal, diffuse) and intensity of Glut-1 expression were assessed and compared with WHO histological subtypes. Results Expression was mainly restricted to epithelial cells. Immature T-lymphocytes were negative. A diffuse, moderate or strong staining was observed in most thymic carcinomas (15/16). In B3 thymomas (10/11) and in B3 thymomas borderline to thymic carcinomas (5/6), a moderate to strong zonal staining was observed at distance from vessels and fibrous septa. This pattern sometimes created the aspect of an anastomosing network in large cellular lobules. In B1 thymomas, immunostaining highlighted foci of medullary differentiation (7/8). B2 thymomas (n = 25) were heterogeneous, with a spectrum of patterns ranging between those of B1 and B3 thymomas. Type A thymomas (n = 5) mostly presented a weak positivity but one aggressive case showed zonal moderate/strong positivity. Most AB thymomas (15/17) showed weak to moderate immunostaining in spindle cell areas. In micronodular thymomas (n = 3), epithelial cells and B-lymphocytes were weakly positive while follicular dendritic cells were strongly highlighted. One metaplastic thymoma displayed diffuse and moderate positivity. Conclusion Glut-1 expression globally depended on histological subtypes and the staining patterns (diffuse or zonal) were different between thymic carcinomas and type B3 thymomas. A comparative study of Glut-1 expression in atypical versus conventional type A thymomas appears warranted. Otherwise, restriction to epithelial cells makes likely a correlation with clinical assessment of glucose uptake in lymphocyte-poor tumors.

International audience

Resume Introduction A partir de notre etude retrospective portant sur 2760 lymphoproliferations cutanees incluses dans les reseaux LYMPHOPATH et GFELC, nous avons analyse les cas douteux et discordants entre pathologiste expert et non expert, et l’apport diagnostique d’une confrontation anatomoclinique. Materiel et methodes Nous avons extrait les principales difficultes diagnostiques posees par les lymphoproliferations cutanees et avons concu et teste sur 20 cas tires au sort et grâce a 20 pathologistes, des algorithmes destines a tout pathologiste non specialiste en dermatopathologie. Resultats Les problematiques les plus frequentes sont les suivantes : MF ou dermatose reactionnelle ; lymphome sans autre precision ou infiltrat reactionnel ; lymphoproliferation B a petites cellules : lymphome ou reactionnel ; lymphoproliferation B a grandes cellules : phenotypage. Nous avons egalement etudie d’autres problematiques sur ou sous-diagnostiquees. Le test sur les 20 cas tires au sort a objective 72 % de reussite. L’utilisation de plusieurs algorithmes pour un meme cas est possible. Discussion Notre travail montre que la seconde lecture d’expert a un interet dans le domaine des lymphoproliferations cutanees. La relecture est utile pour distinguer un lymphome B a petites cellules d’un infiltrat reactionnel et dans l’aboutissement a un diagnostic apres envoi pour « doute entre lymphome et entite reactionnelle ». Nous montrons cependant que, pour la problematique MF ou dermatose reactionnelle, la confrontation anatomoclinique apporte plus de resultats, en premiere intention, que la seconde lecture. Conclusion Ceci est la premiere etude concernant les lymphoproliferations cutanees qui, sans exclure les infiltrats reactionnels, s’appuie sur les diagnostics douteux et discordants entre pathologistes non experts et experts pour aboutir a des algorithmes diagnostiques testes.

To evaluate the diagnostic value of MDM2 status in craniofacial fibro-osseous lesions, we investigated MDM2 expression by immunohistochemistry and analyzed MDM2 amplification by qPCR in 30 cases of ossifying fibroma (including 13 cases of the juvenile variant) and 17 cases of fibrous dysplasia. Two cases of uncommon extragnathic psammomatoid fibrous dysplasia and a mixed control group of 15 cases of low-grade osteosarcoma and 15 cases of well-differentiated/dedifferentiated liposarcoma were included. MDM2 amplification was found in 33% of ossifying fibromas (peak of 69% for the juvenile variant) and in 12% of fibrous dysplasia, in none of which was MDM2 overexpressed. All control cases exhibited MDM2 amplification and overexpression. To investigate possible polysomy of chromosome 12, we studied RASAL1 amplification, a gene telomeric to MDM2 on the long arm of chromosome 12. RASAL1 amplification was reported in all benign fibro-osseous lesions exhibiting MDM2 amplification but not in controls. Simultaneous amplification of these two genes was significantly higher in juvenile ossifying fibromas compared with fibrous dysplasia (P=0.004), non-juvenile ossifying fibromas (P=0.001), and all other benign craniofacial fibro-osseous lesions combined (P=0.0001). Of the nine cases of juvenile ossifying fibroma exhibiting amplification, three were locally invasive and four were recurrent, suggesting aggressive disease. The two cases of extragnathic psammomatoid fibrous dysplasia also showed MDM2 and RASAL1 amplification with no MDM2 overexpression. This large chromosome 12 rearrangement, spanning MDM2 and RASAL1, is the first recurrent molecular abnormality to be reported in juvenile ossifying fibroma. It may represent both a molecular diagnostic marker and a characteristic of more aggressive forms with a higher risk of recurrence. Finally, the presence of this rearrangement in extragnathic psammomatoid fibro-osseous lesions mimicking ossifying fibromas might reflect a common molecular pathway in their pathogenesis and calls into question the classification of such lesions within fibrous dysplasia.

Background: The link between organizing pneumonia (OP) and gastroesophageal reflux disease (GERD) is not well known. There is little evidence in the literature to establish a causal link between GERD and OP. Objectives: The aim of the study was to assess the hypothesis that OP is more severe when it is associated with GERD and that it leads to more frequent relapses. Methods: In a retrospective study on 44 patients suffering from OP, we compared the clinical, radiological and histological characteristics of 2 groups, 1 composed of patients with GERD (n = 20) and the other of patients without GERD (n = 24). Results: The GERD group was distinguished by a higher number of patients with migratory alveolar opacities on chest radiography and thoracic computerized tomography (14/20 vs. 9/24; p = 0.03 and 18/20 vs. 13/24; p = 0.01), greater hypoxemia [60 (42-80) vs. 70 (51-112) mm Hg; p = 0.03], greater bronchoalveolar lavage cellularity [0.255 (0.1-1.8) vs. 0.150 (0.05-0.4) g/l; p = 0.035] and more frequent relapses (14/20 vs. 9/24; p = 0.03). Conclusions: OP associated with GERD is more severe and results in more frequent relapses. Microinhalation of gastric secretions might induce lung inflammation leading to OP and relapse. We suggest that typical symptoms of GERD such as pyrosis should be investigated in OP.

International audience; BACKGROUND & AIMS: Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications.METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation.RESULTS: Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively.CONCLUSIONS: Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.

Blastic plasmacytoid dendritic cell neoplasm is a rare clinicopathologic entity, characterized by strong skin tropism and a poor prognosis. The diagnosis is generally made by skin biopsy with appropriate immunohistochemical studies. To identify potential biological prognostic factors for blastic plasmacytoid dendritic cell neoplasm, we performed an extended clinico-immunohistochemical study on a series of 91 well-documented cases collected since 1995 by the French Study Group on Cutaneous Lymphomas. Skin biopsies were analyzed using a panel of 12 immunohistochemical markers (CD4, CD56, CD123, CD303, TCL1, CD68, CD2, CD7, TdT, Ki-67, S100, and MX-1). The results were correlated with survival. The 5 most characteristic markers of this entity (CD4, CD56, CD123, CD303, and TCL1) were expressed simultaneously in only 46% of patients. However, when 4 markers were expressed the diagnosis could still be reliably made without resorting to any additional stains. Expression of TdT and/or S100 correlated with varying degrees of maturation. Statistical survival analyses showed that CD303 expression and high proliferative index (Ki-67) were significantly associated with longer survival.

SummaryHepatocellular adenomas (HCA) are benign liver tumors predominantly developed in women using oral contraceptives. Here, exome sequencing identified recurrent somatic FRK mutations that induce constitutive kinase activity, STAT3 activation, and cell proliferation sensitive to Src inhibitors. We also found uncommon recurrent mutations activating JAK1, gp130, or β-catenin. Chromosome copy number and methylation profiling revealed patterns that correlated with specific gene mutations and tumor phenotypes. Finally, integrative analysis of HCAs transformed to hepatocellular carcinoma revealed β-catenin mutation as an early alteration and TERT promoter mutations as associated with the last step of the adenoma-carcinoma transition. In conclusion, we identified the genomic diversity in benign hepatocyte proliferation, several therapeutic targets, and the key genomic determinants of the adenoma-carcinoma transformation sequence.

Resume Les tumeurs epitheliales thymiques sont des tumeurs rares et parfois de classification difficile. Depuis fin 2010, l’Institut national du cancer a finance la mise en place d’un reseau clinique de prise en charge de ces tumeurs rares, denomme Rythmic, avec des reunions de concertation pluridisciplinaires (RCP) nationales et regionales. Les tumeurs des patients presentes et traites dans le reseau doivent faire l’objet secondairement d’une relecture nationale par le groupe de pathologistes Rythmic-Pathologie. Cet article a pour but de presenter le reseau Rythmic et notamment les modalites de fonctionnement de la relecture pour la classification des tumeurs et du stade.

Chronic infections of respiratory tracts are suspected to promote the development of IgA nephropathy. From the study of one case, we discuss the hypothesis that infections by pseudomonas aeruginosa might promote an increased bronchial production of IgA1, which could pass in the serum and settle into immune complexes in the kidney. A 67 years old woman presented simultaneously IgA nephropathy and diffuse panbronchiolitis. The evolution was marked by repeated infections by pseudomonas aeruginosa. The study of lung biopsy by immunohistochemistry showed intense expression of IgA1 in bronchioles, increased when compared to large bronchi. In contrast, expression of the transport receptor (pIgR) was decreased in inflamed bronchioles and preserved in bronchi. The BAL during an infection by pseudomonas aeruginosa showed increased secretory (S-) IgA with predominance of S-IgA1 (28.6 µg/mL versus S-IgA2 8.4µg/mL). In the sera collected during two infectious episodes and compared with an inter-critical sample, we found an increased IgA1 (776 and 549µg/mL versus 455µg/mL), associated with increased polymeric IgA (estimated at 40-50%, versus normally  10%). The increased expression of IgA1 in bronchiolar tissue, BAL and serum in the case of our patient further suggests a putative link between IgA nephropathy and diffuse panbronchiolitis, through exuberant production of IgA1 induced by pseudomonas aeruginosa infections.

Mycosis fungoides (MF), the most common primitive cutaneous T-cell lymphoma, can undergo transformation in about 10% of cases. Transformed mycosis fungoides (T-MF) is often associated with the appearance of a CD20 component. The aim of this study was to analyze whether such cells are reactive or lymphomatous and to evaluate their prognostic impact. Among 311 T-MFs from the French Cutaneous Lymphoma Study Group registry, we studied 148 cases. CD20 was expressed in 88 cases (59%). The proportion of CD20 cells among T-MF lesions was10% for 54 cases (38%), 10% to 49% for 71 cases (81%), and50% for 17 cases (19%). We focused the study on 23 cases that contained50% CD20 cells. To evaluate the nature of the CD20 component, we used immunohistochemistry (2 anti-CD20 antibodies, L26 and 7D1 clones, and 2 other anti-B-cell antigen antibodies, CD22 and PAX5) and a double-stain immunofluorescence technique (anti-CD20 and anti-CD3 antibodies). The clonality of B cells was studied by polymerase chain reaction. Three profiles were observed. In 15 of the 23 cases, the CD20 cells were reactive. In 6 cases, CD20 protein was aberrantly expressed in T-MF lesions. Lastly, there were 2 composite lymphomas (T-MF infiltrate with a B-cell follicular lymphoma). In view of this series, we propose a simple algorithm to help pathologists evaluate the nature of the CD20 component associated with T-MF. Although statistically not significant, there was a trend toward a worse prognosis in the presence of50% CD20 cells and of a nodular perifollicular pattern of this component.

GNAS (guanine nucleotide-binding protein/α-subunit) mutations that induce the activation of G-protein α-subunit participate in the pathogenesis of fibrous dysplasia. The aim of this study was to evaluate the sensitivity and specificity of GNAS mutations in fibrous dysplasia and other fibro-osseous lesions, to assess the value of investigating this mutation in the diagnosis of fibro-osseous lesions. We studied 91 cases of fibrous dysplasia. The quality and/or quantity of genomic DNA were suitable for molecular analysis for 51 cases of fibrous dysplasia. GNAS mutations were investigated by three techniques: high-resolution melting (exon 8), allele-specific PCR (exons 8 and 9) and/or direct DNA sequencing (exons 8 and 9). Fibrous dysplasia samples were classified blind to the GNAS mutation status into six histological subtypes as conventional, fibro-involutive, osteosclerosing, cementifying, osteocartilaginous and with prominent aneurysmal cystic changes. We also studied 14 cases of low-grade osteosarcoma, 21 cases of ossifying fibroma, 3 cases of osteofibrous dysplasia, 1 case of osseous dysplasia of the jawbone and 1 post-traumatic lesion of the ribs. Twenty-three cases of fibrous dysplasia (45%) showed mutations of codon 201 (exon 8, p.R201H or p.R201C). No mutation was found on codon 227 (exon 9). GNAS mutations in conventional fibrous dysplasia were detected in the same proportion (47%) as in the other histological subtypes (47%, P=0.96), regardless of sex (P=0.44), age (P=0.90) and location (P=1). GNAS mutations were not detected in any other fibro-osseous lesions. The GNAS mutation was thus specific to fibrous dysplasia in the context of fibro-osseous lesions. The particular mosaicism of mutant and non-mutant cells within the lesion or the existence of other mutations not already described could explain the lack of GNAS mutation in cases of fibrous dysplasia. Investigating this mutation may constitute a valuable complementary diagnostic tool, despite its low sensitivity, particularly in unconventional morphologically different subtypes of fibrous dysplasia.

Hepatocellular carcinoma (HCC) is a common outcome of chronic hepatitis C virus (HCV) infection and constitutes the main burden of this disease. The molecular mechanisms underlying the development of HCC are multiple and might involve certain microRNA (miR). As discordant results have been reported concerning the detection of expression of miR-152 and miR-122 in HCC, our aim was to measure the levels of both miRs in serum and liver samples.We analyzed miR-152 and miR-122 expression by reverse transcription-quantitative polymerase chain reaction in a serum cohort from 14 HCV-infected patients who developed HCC, 20 HCV+ patients without HCC, and 19 control patients. We also studied miR-152 and miR-122 in an independent tissue cohort from 11 normal livers, and from paired HCC and non-tumor adjacent livers of 11 HCV-infected patients and 12 non-infected patients.In serum samples, higher levels of miR-122 were found in non-HCC HCV+ compared to HCC HCV+ and control groups, whereas miR-152 was detectable in a lower range in HCC HCV+ compared to non-HCC HCV+ and control groups. We found higher signals for miR-122 and miR-152 in non-tumor liver and HCC tissues compared to control tissues. Hepatocellular carcinoma etiology had no detectable influence on miR-122 expression, whereas miR-152 was increased in HCV+ tissue samples.Detection of low values of circulating miR-152 is a potentially interesting marker of hepatocarcinogenesis in HCV+ patients, in contrast to miR-122, which varies according to hepatocyte damage.

Angioimmunoblastic T-cell lymphoma (AITL) is frequently associated with skin lesions, but epidermotropic cutaneous involvement has never been described. A 37-year-old man presented with erythematous and pruriginous plaques, clinically suggestive of mycosis fungoides, distributed all over the body, 3 weeks after the last line of a polychemotherapy, given for an AITL diagnosed 1 year earlier on a lymph node biopsy. Skin biopsy showed an epidermotropic CD4(+) T-cell lymphoma, so that a diagnosis of mycosis fungoides was first proposed. Further investigations showed that atypical lymphocytes strongly expressed CD10 and markers of follicular helper T cells (T(FH) ) including PD1, BCL-6 and CXCL13. The diagnosis of an unusual epidermotropic cutaneous localization of the AITL was finally made, supported by the presence of the same T-cell clone in the initial lymph node biopsy and the skin. We therefore recommend performing markers of T(FH) cells in patients with unusual epidermotropic cutaneous T-cell lymphomas, particularly if they have any clinical features suggestive of AITL.

Resume Le pronostic des osteosarcomes et des tumeurs de la famille Ewing a ete ameliore avec l’introduction de la chimiotherapie neoadjuvante. L’efficacite du traitement est evaluee en fonction du grading de Huvos et Rosen, sur l’analyse du pourcentage de cellules necrosees sur la piece de resection chirurgicale. L’evaluation du taux de cellules necrosees est le principal facteur pronostique. Il sert a adapter les protocoles de chimiotherapie. La prise en charge macroscopique et microscopique de la piece de resection chirurgicale est essentielle et fait l’objet d’un protocole specifique. De nombreuses etudes ont ete realisees pour identifier de nouvelles cibles therapeutiques. Les inhibiteurs de mTOR et/ou les regulateurs de la balance RANKL/OPG sont des molecules prometteuses en cours d’essais therapeutiques. L’etude de l’expression de nouveaux facteurs predictifs pourrait etre faite sur la biopsie des patients avant toute therapeutique neoadjuvante, et offrir la possibilite d’utiliser d’autres strategies therapeutiques.

International audience; Primary carcinoid tumor (well-differentiated neuroendocrine tumor) of the bone involving the sacrum is extremely rare. We report the case of a 72-year-old man who presented with a 20-year history of intermittent low back pain and was found to have an intraosseous sacral mass on imaging. A needle biopsy revealed that this lesion was a well-differentiated neuroendocrine tumor. Workup did not show any primary tumor or other metastatic disease. There was no associated tailgut cyst or sacrococcygeal teratoma. The lesion was treated with radiation therapy because a surgical approach was rejected. The patient is free of metastatic disease after 28 years evolution of the lesion, retrospectively seen to be present on a conventional radiography performed in 1980. A review of the literature revealed 20 case reports of neuroendocrine tumors arising from the presacral region (with or without associated tailgut cyst or sacrococcygeal teratoma) and sometimes extending to the sacrum. One additional case was located within the neural canal and involved the sacrum, the presacral region, and the rectal wall. Our case is the only tumor arising primarily from the sacrum. The long evolution of this lesion without any other location makes metastatic disease very improbable and this case appears to be a unique example of primary intraosseous sacral carcinoid tumor.

International audience; OBJECTIVES: To evaluate the diagnostic accuracy of liver fibrosis tests and its influencing factors in a meta-analysis with individual data. DESIGN AND METHODS: Four independent centers provided four blood tests and Metavir staging from 825 patients with chronic hepatitis C. RESULTS: FibroMeter AUROC (0.840) for significant fibrosis was superior to those of Fibrotest (0.803, p=0.049), APRI (0.789, p=0.001) and Hepascore (0.781, p

BACKGROUND: The reliable diagnosis rate of diagnostic tests is provided by their intervals with acceptable accuracy (e.g. >/=90%) where a liver biopsy can be avoided. AIMS: To evaluate the overall accuracy and improve the reliable diagnosis rates of blood tests for significant liver fibrosis. METHODS: Five blood tests were compared with Metavir fibrosis (F) staging in 1056 patients with chronic hepatitis C. RESULTS: Area under the receiver operating characteristics (F0-1 vs. F2-4) were: FibroMeter: 0.853, Fibrotest: 0.811, Fib-4: 0.799, aspartate aminotransferase to platelet ratio index (APRI): 0.786 and Hepascore: 0.784 (P /=90% of negative predictive values (NPV) and positive predictive values (PPV), diagnosing F0/1 and F2/3/4, respectively, were: FibroMeter: 43.5%, APRI: 19.6%, Fibrotest: 17.1%, Hepascore: 3.9%, Fib-4: 1.7% (P

Resume Nous rapportons un cas de PECome de localisation inhabituelle, intra-articulaire chez un jeune garcon de 13 ans. La tumeur, de 4 cm, mal limitee, etait composee de cellules epithelioides et fusiformes, claires ou granuleuses eosinophiles, et d’un contingent de cellules plurinucleees. Des atypies cyto-nucleaires etaient focalement observees. L’index mitotique etait evalue a 2 mitoses/50 champs au fort grandissement. Aucune necrose tumorale n’etait decelee. L’etude immunohistochimique montrait une positivite pour l’HMB45 et l’actine-muscle-lisse (AML). L’etude ultrastructurale montrait l’existence de premelanosomes. De rares cas de PEComes ont ete rapportes dans les tissus mous. Leur diagnostic repose sur la positivite des marqueurs melanocytaires (en particulier l’HMB45) et parfois de l’AML. Les criteres de malignite de ces tumeurs sont mal definis et pourraient inclure la mauvaise limitation, la taille tumorale, la presence d’atypies cytologiques et le compte mitotique. Nous discutons ici les diagnostics differentiels de cette tumeur, notamment le sarcome a cellules claires.

The best delivery of a drug in ventilated neonates is obtained when using a small particle diameter solution administered via a spacer. Lung deposition of hydrofluoroalkane beclomethasone dipropionate (QVAR, 1.3 microm particles), delivered via an Aerochamber-MV15, was measured in piglets under conditions mimicking ventilated severely ill neonates (uncuffed 2.5 mm endotracheal tube; peak pressure 16 cm H2O; respiratory rate 40/min). After determining the mass and particle size distribution of the 99mTc-labeled and unlabeled drug, three lung deposition studies were performed: after 1 h of ventilation (controls, n = 18), after 48 h aggressive ventilation inducing an acute lung injury (nine piglets out of the controls), and after increasing the pressure to 24 cm H2O during drug delivery (five piglets out of the nine with acute lung injury). All piglets were then killed for lung histology. Results (median, range), expressed as a percentage of the delivered dose, were compared using an inferential or the Friedman test. While lung deposition was low, it was greater (p = 0.003) in controls (2.66%, 0.50-7.70) than in piglets with histologically confirmed acute lung injury (0.26%, 0.06-1.28) or under a high-pressure ventilation (1.01%, 0.30-2.15). Lung deposition of QVAR in an animal model of ventilated neonates is low, variable, and dramatically affected by lung injury.

Resume Introduction L’hidradenite eccrine neutrophilique (HEN) est une dermatose neutrophilique rare, caracterisee par l’infiltration et la destruction par des polynucleaires neutrophiles des glandes sudorales eccrines. Cliniquement, on observe une eruption cutanee febrile qui regresse habituellement spontanement en quelques jours ou semaines. La grande majorite des cas survient apres une chimiotherapie d’une hemopathie myeloide. Nous rapportons le cas d’une HEN dont la forme clinique, l’evolution longue et l’absence d’etiologie sont inhabituelles. Observation Une femme de 56 ans, sans antecedents notables, en particulier sans notion de chimiotherapie ou de maladie hematoloqique, avait depuis 3 semaines un visage œdemateux et infiltre, erythematoviolace, douloureux, sans fievre. Les tests biologiques montraient un syndrome inflammatoire, une augmentation des polynucleaires neutrophiles (9 150/mm 3 ). La biopsie cutanee montrait un infiltrat neutrophilique avec destruction des glandes sudorales eccrines permettant le diagnostic d’hidradenite eccrine neutrophilique. Aucune cause n’a ete trouvee. Un traitement par colchicine etait debute, entrainant une amelioration des lesions, il a ete poursuivi pendant 1 an. Il n’y a pas eu de recidive ni de decouverte d’une maladie associee avec un recul de 22 mois par rapport au debut de la maladie. Discussion Ce cas d’HEN est particulier par l’atteinte exclusive du visage, l’apyrexie, l’absence de maladie hematologique ou de toute autre maladie associee, l’absence de chimiotherapie, et l’evolution superieure a 3 semaines. La grande majorite des cas survient en effet chez des patients atteints de leucemie aigue myeloblastique, apres une chimiotherapie. Le role de l’excretion et de la toxicite sudorale des chimiotherapies a ete suspecte. Mais il existe quelques cas comme cette observation ou aucune maladie hematologique n’est associee, et aucun facteur medicamenteux trouve. Dans ces cas, une surveillance clinique est recommandee, car l’HEN peut parfois preceder la decouverte de l’hemopathie associee.

Marchand-Adam, Sylvain Diot, Bruno Magro, Pascal De Muret, Anne Guignabert, Christophe Kannengiesser, Caroline Londono-Vallejo, Arturo Draskovic, Irena Toutain, Annick Diot, Patrice United States Am J Respir Crit Care Med. 2013 Aug 1;188(3):402-4. doi: 10.1164/rccm.201301-0010LE.

Hematodermic CD4/CD56 neoplasm is a recently described entity. This name has been initially proposed by the French Study Group on Cutaneous Lymphomas which established the primary anatomoclinical and pathogenic and cytogenic bases of the disease in 1999. This descriptive and provisional name allowed conceptualizing the entity by its main clinical and phenotypical characteristics. The first case in the literature goes back to 1994. Since that time, several other cases have been published. The expression of CD56 led most of the authors to propose an NK-cell lineage origin. In the last WHO classification of lymphomas, the entity was indexed under the name of "blastic NK-cell lymphoma". However, the authors underlined that there were currently no clues to the etiology of blastic NK-cell lymphoma and that the precise lineage of this disease was still unresolved. At the clinical level the main characteristics of the disease are the skin tropism and the occurrence of a leukemic phase at any time during the course of the disease. The median age is 59 but pediatric cases do exist. At the morphological level skin biopsy shows a monomorphous cell proliferation simulating a pleomorphic T cell cutaneous lymphoma. The diagnosis is based on phenotypic criteria which require frozen tissue. Currently, the main characteristics are the expression of CD4 and CD56 antigens while the main defined lineage specific markers are negative (B-cell, T-cell, NK-cell and myeloid-cell lineages). The origin of the tumor cells still remains uncertain but the plasmacytoid dendritic cell is presently a very serious candidate. The tumor cells share a great phenotypical homology and particularly the expression of the CD123 antigen. Functional homologies have also been demonstrated with tumor cells in vitro. Outcome of CD4/CD56 hematodermic neoplasms is very bad. The median time of survival is 14 months irrespective of the treatment given. Conventional chemotherapies used for the treatment of aggressive lymphomas or acute myeloid leukemias are quickly inefficient.

Resume Nous rapportons le cas d’un homme de 41 ans ayant presente une thrombose des veines hepatiques (syndrome de Budd-Chiari) au cours d’un traitement par infliximab (Remicade®) pour une spondylarthrite ankylosante. L’enquete etiologique systematique revelait une hemoglobinurie paroxystique nocturne. Un an plus tard, le malade toujours traite par le danaparoide sodique (Orgaran®) n’avait pas de symptome hepatique et un important reseau collateral intrahepatique s’etait developpe. Le role de l’infliximab dans la survenue de la thrombose est discute.

Background & Aims: Germline mutations in hepatocyte nuclear factor 1α (TCF1/HNF-1α) are associated with maturity-onset diabetes of the young type 3 (MODY3), and somatic biallelic inactivations of the gene are found in hepatocellular adenomas and liver adenomatosis. This study investigated cosegregation of HNF-1α germline mutations with diabetes and liver adenomatosis in 2 families. Methods: Two unrelated patients with liver adenomatosis and harboring HNF-1α germline and somatic mutations were studied. Subsequently, we screened 9 relatives in the 2 independent families for diabetes, hepatocellular adenomas, and HNF-1α germline mutations. Results: In family A, a father and his son presented with an intraperitoneal hemorrhagic rupture of a liver adenomatosis without diabetes. A heterozygous R229X germline mutation was identified in HNF-1α in the father and his son and also in his second 27-year-old son without hepatocellular adenomas. In family B, a diagnosis of liver adenomatosis was made fortuitously in a 14-year-old girl. A heterozygous G55fsX57 germline mutation in HNF-1α was identified in this patient, her diabetic father, and her 2 sisters. Systematic exploration showed liver adenomatosis in the 2 sisters. Somatic inactivation of the second HNF-1α allele was found in liver tumors in both families. Conclusions: This study describes familial liver adenomatosis and shows the association with germline HNF-1α mutations in adults and children. It also highlights the importance of screening for hepatocellular adenomas, diabetes, and HNF-1α germline mutations in relatives of patients with liver adenomatosis. Finally, prevalence of liver adenomatosis remains to be evaluated in MODY3 subjects.

Epithelial thymic tumours are rare and sometimes difficult to classify. Since 2010, the French National Cancer Institute supports a French national network, called Rythmic, devoted to the treatment of these tumours through regional and national multidisciplinary conferences using the web. All the tumours are secondarily reviewed by a French pathology national network for classification and staging. This review focuses on the presentation of the Rythmic network, and mainly to the Pathology review process.

The t(12;15)(p13;q25) translocation, a recurrent chromosomal abnormality of congenital fibrosarcoma, leads to the expression of a Tel–TrkC fusion transcript. To determine whether detection of the chimeric protein may be helpful for the diagnosis of congenital fibrosarcoma, immunohistochemistry was performed with an anti-TrkC antibody on 26 spindle cell tumours of newborn or young children (n=19) or adults (n=7). Four out of five congenital fibrosarcomas showed TrkC immunoreactivity with cytoplasmic paranuclear staining. However, TrkC immunoreactivity was not restricted to congenital fibrosarcoma and was observed in infantile myofibromatosis, congenital haemangiopericytoma, desmoid tumour, nodular fasciitis, fibrous hamartoma, inflammatory myofibroblastic tumour, and adult fibrosarcoma. RT-PCR analysis was performed on nine cases, including four congenital fibrosarcomas, for which frozen material was available. Tel–TrkC transcripts were detected by RT-PCR in the four congenital fibrosarcomas analysed, but not in the five other spindle cell tumours. Furthermore, several Tel–TrkC transcripts encoding for kinase isoforms of the Tel–TrkC protein were detected in congenital fibrosarcoma and may be involved in oncogenesis. The reciprocal TrkC–Tel transcript was detected in only one congenital fibrosarcoma. While the detection of a Tel–TrkC fusion transcript is a recurrent feature of congenital fibrosarcoma, TrkC immunoreactivity does not appear specific for the diagnosis of fibromatous paediatric tumours. Copyright © 2000 John Wiley & Sons, Ltd.