Publications by authors named "Anne de Muret"

64 Publications

Micronodular thymic carcinoma with lymphoid hyperplasia: relevance of immunohistochemistry with a small panel of antibodies for diagnosis-a RYTHMIC study.

Virchows Arch 2021 Feb 24. Epub 2021 Feb 24.

Department of Pathology, AP-HP.5, University of Paris, Paris, France.

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.
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http://dx.doi.org/10.1007/s00428-021-03044-2DOI Listing
February 2021

Impact of expert pathologic review of thymic epithelial tumours on diagnosis and management in a real-life setting: A RYTHMIC study.

Eur J Cancer 2021 Jan 11;143:158-167. Epub 2020 Dec 11.

Department of Cancer Medicine, Gustave Roussy, Villejuif, France.

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.
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http://dx.doi.org/10.1016/j.ejca.2020.11.011DOI Listing
January 2021

[Thymoma and squamous thymic carcinoma diagnosis; experience from the RYTHMIC network].

Ann Pathol 2020 Dec 10. Epub 2020 Dec 10.

Inserm U1163, service d'anatomie pathologique, institut imagine, université de Paris, hôpital universitaire Necker-Enfants malades, AP-HP centre, 149, rue de Sèvres, 75015 Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.annpat.2020.11.002DOI Listing
December 2020

Letter to the Editor: Post-Liver Transplantation Sinusoidal Obstruction Syndrome and immunosuppressive drugs: causality of MMF or tacrolimus?

Hepatology 2020 Nov 13. Epub 2020 Nov 13.

Department of Digestive Surgery and Liver Transplantation, Trousseau University Hospital, Avenue de la République, 37170, Chambray-lès-Tours, France.

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 SOS . Finally, immunosuppressive drugs have been implicated, i.e. azathioprine historically and MMF and tacrolimus more recently, even rarely.
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http://dx.doi.org/10.1002/hep.31633DOI Listing
November 2020

Desquamative interstitial pneumonia induced by metal exposure. A case report and literature review.

Sarcoidosis Vasc Diffuse Lung Dis 2020 15;37(1):79-84. Epub 2020 Mar 15.

Service de Pneumologie et d'explorations fonctionnelles respiratoires, CHU Bretonneau, Tours, France.

Background: Forms of interstitial pneumonia secondary to exposure to an air-contaminant are varied and so far, insufficiently described.

Objectives/methods: We report here a case of a 57-year-old patient managed in our department for the exploration of MRC grade 2 dyspnoea and interstitial pneumonia. He mentioned multiple occupational and domestic exposures such as hens' excrements, asbestos and metal particles; he also had a previous history of smoking.

Results: High-resolution computed tomography showed ground glass opacities predominating in posterior territories and surrounding cystic lesions or emphysematous destruction. The entire etiological assessment revealed only macrophagic alveolitis with giant multinucleated cells on the bronchoalveolar lavage. A surgical lung biopsy allowed us to refine the diagnosis with evidence of desquamative interstitial pneumonia and pulmonary granulomatosis. Finally, the analysis of the mineral particles in the biopsy revealed abnormally high rates of Zirconium and Aluminium. We were therefore able to conclude to a desquamative interstitial pneumonia associated with pulmonary granulomatosis linked to metal exposure (Aluminium and Zirconium). The clinical, functional and radiological evolution was favorable after a systemic corticosteroid treatment with progressive decay over one year.

Conclusion: This presentation reports the first case to our knowledge of desquamative interstitial pneumonitis related to exposure to Zirconium and the third one in the context of Aluminium exposure. The detailed analysis of the mineral particles present on the surgical lung biopsy allows for the identification of the relevant particle to refine the etiological diagnosis, to guide the therapeutic management and to give access to recognition as an occupational disease. .
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http://dx.doi.org/10.36141/svdld.v37i1.9103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569535PMC
November 2020

Successful Terbinafine Treatment for Cutaneous Phaeohyphomycosis Caused by Trematosphaeria grisea in a Heart Transplanted Man: Case Report and Literature Review.

Mycopathologia 2020 Aug 19;185(4):709-716. Epub 2020 Jun 19.

Parasitologie - Mycologie et Médecine Tropicale, Hôpital Bretonneau, CHU de Tours, 2 Boulevard Tonnellé, 37044, Tours, France.

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.
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http://dx.doi.org/10.1007/s11046-020-00467-4DOI Listing
August 2020

Recurrent chromosomal rearrangements of , and activating JAK/STAT pathway in inflammatory hepatocellular adenomas.

Gut 2020 Sep 6;69(9):1667-1676. Epub 2020 Jan 6.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm,Université de Paris, Université Paris 13, Functional Genomics of Solid Tumors laboratory, F-75006 Paris, France

Background: 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.

Methods: 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.

Results: We identified 296 IHCA (45%), 81% of them were mutated in either (61%), (8%), (5%), (3%) or (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving or genes. fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver (, , ) fused with exon 33-35 to 43 of including the tyrosine kinase domain. In two cases a truncated transcript from exon 36 to 43 was identified. rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to overexpression. Among the 5 IHCA with rearrangements, 5 different partners were identified (, , , ) fused to a common region in that included exon 3-8. No overexpression of transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2-SH3 domains. In two IHCA, we identified truncated 3'UTR of associated with overexpression of the transcript.

Conclusion: Recurrent chromosomal alterations involving , or genes lead to activation of the JAK/STAT pathway in IHCAs.
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http://dx.doi.org/10.1136/gutjnl-2019-319790DOI Listing
September 2020

Immune biomarkers in thymic epithelial tumors: expression patterns, prognostic value and comparison of diagnostic tests for PD-L1.

Biomark Res 2019 4;7:28. Epub 2019 Dec 4.

11Hôpital Larrey, Centre Hospitalier Universitaire de Toulouse, 24 Chemin de Pouvourville, 31059 Toulouse, France.

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 ( = 53) and TC ( = 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 ( < 0.0001). Three out of four antibodies targeting PD-L1 tested on the DAKO autostainer gave similar staining. Concordance between antibodies was lower for PD-L1 staining on immune cells with no significant difference between TB3 and TC except on E1L3N antibody. PD-L2 antibody stained no tumor epithelial cells. High PD-L1 expression was correlated with a better overall survival for TB3 and was not correlated with tumor staging.

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.
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http://dx.doi.org/10.1186/s40364-019-0177-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894111PMC
December 2019

Natural history of liver adenomatosis: A long-term observational study.

J Hepatol 2019 12 13;71(6):1184-1192. Epub 2019 Aug 13.

Department of Hepatology and Gastroenterology, University Hospital of Tours, Tours, France.

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.
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http://dx.doi.org/10.1016/j.jhep.2019.08.004DOI Listing
December 2019

Primary cutaneous large B-cell lymphomas: relevance of the 2017 World Health Organization classification: clinicopathological and molecular analyses of 64 cases.

Histopathology 2019 Jun 25;74(7):1067-1080. Epub 2019 Apr 25.

Pathology Department, University Hospital of Bordeaux, Hôpital Haut-Lévêque, Bordeaux, France.

Aims: We applied the 2017 World Health Organization (WHO) classification criteria to categorise a series of 64 primary cutaneous large B-cell lymphomas (PCLBCLs), containing a majority (≥80%) of large cells and a proliferative rate of ≥40%, raising the problem of the differential diagnosis between PCLBCL, leg type (PCLBCL-LT) and primary cutaneous follicle centre lymphoma, large cell (PCFCL-LC). The aims were to determine the reproducibility and prognostic relevance of the 2017 WHO criteria.

Methods And Results: Morphology and phenotype identified 32 PCLBCLs-LT and 25 PCFCLs-LC; seven cases (11%) remained unclassified. Morphology was less reproducible than immunophenotype. Pertinent markers for the differential diagnosis were MUM1, FOXP1, CD10, and IgM. bcl-2 and bcl-6 were expressed by both PCFCLs-LC and PCLBCLs-LT at substantial levels. Neither Ki67 expression nor p63 expression was of diagnostic value. MYD88 was found to be mutated only in PCLBCLs-LT (n = 22, 69%). According to Hans/Hans modified algorithms, 23 of 25 PCFCLs-LC had germinal centre (GC) status, and the 32 PCLBCLs-LT had non-GC status. Overall survival was poorer for PCLBCLs-LT than PCFCLs-LC (P = 0.0002). Non-GC cases had poorer overall survival than GC cases (P = 0.0007). In PCLBCLs-LT, MYC expression was associated with cutaneous relapses (P = 0.014). When GC/non-GC status was applied to unclassified cases, only a single case remained discordant.

Conclusions: Our results support the 2017 WHO classification criteria for PCLBCL diagnosis. The Hans modified algorithm using CD10 and MUM1 distinguished PCFCLs-LC from PCLBCLs-LT with optimal diagnostic value without requiring bcl-6 immunolabelling (poorly reproducible). Rare unclassified cases may constitute a provisionally heterogeneous subgroup for which GC/non-GC status (relevant for prognosis) may guide therapeutic decisions.
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http://dx.doi.org/10.1111/his.13832DOI Listing
June 2019

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Syndrome Treated With Sirolimus.

Ann Intern Med 2018 08 10;169(3):197-198. Epub 2018 Apr 10.

Université François Rabelais, Tours, France (L.P., S.M.).

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http://dx.doi.org/10.7326/L17-0634DOI Listing
August 2018

Diagnostic performance of contrast-enhanced CT-scan in sinusoidal obstruction syndrome induced by chemotherapy of colorectal liver metastases: Radio-pathological correlation.

Eur J Radiol 2017 Sep 3;94:180-190. Epub 2017 Jul 3.

University Hospital center of Tours, General Radiology Department, Trousseau Hospital, Tours, France. Electronic address:

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<0.001), puddle-like or micronodular appearance (p<0.001), peripheral distribution of heterogeneity (p=0.085), clover-like sign (p=0.02), splenomegaly (p=0.0026), spleen volume increase ≥30% (p=0.04) or splenic length increase ≥15% (p=0.04), as well as the subjective impression of the observer (P<0.001) were significantly associated with SOS diagnosis. In multivariate analysis, clover-like sign (OR 1.87, 95% CI 1.18-2.95, p=0.0081), increase in spleen volume ≥30% (OR 1.29, 95% CI 1.01-1.64, p=0.04), and the peripheral distribution of heterogeneity (OR 1.53, 95% CI 1.21-1.94, p<0.001) were independent SOS predictors. The area under the ROC curve was 0.804. The inter-observer agreement for SOS diagnosis was moderate (Kappa=0.546).

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.
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http://dx.doi.org/10.1016/j.ejrad.2017.06.025DOI Listing
September 2017

Cutaneous Kaposi sarcoma during treatment with superpotent topical steroids and methotrexate for bullous pemphigoid: three cases.

Eur J Dermatol 2017 Aug;27(4):369-374

University François Rabelais, Boulevard Tonnelé, 37044 Tours Cedex 9, France, Department of Dermatology, Hospital of Tours, Avenue de la République, 37044 Tours Cedex 9, France, Laboratory "Biologie des Infections à Polyomavirus", ISP 1282, INRA-University François, Rabelais, Tours, France.

Iatrogenic Kaposi sarcoma (KS) has previously been reported in patients with bullous pemphigoid (BP), in relation to systemic steroids. To report three cases of previously unreported cutaneous KS during treatment with superpotent topical steroids (STS) and methotrexate (MTX). 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). 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. 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.
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http://dx.doi.org/10.1684/ejd.2017.3027DOI Listing
August 2017

Interest of variations in microRNA-152 and -122 in a series of hepatocellular carcinomas related to hepatitis C virus infection.

Hepatol Res 2018 Jun 28;48(7):566-573. Epub 2017 Jun 28.

Université François-Rabelais de Tours, PRES Centre-Val de Loire Université, Tours, France.

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). 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.

Methods: 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.

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. Hepatocellular carcinoma 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.
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http://dx.doi.org/10.1111/hepr.12915DOI Listing
June 2018

Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation.

Gastroenterology 2017 03 7;152(4):880-894.e6. Epub 2016 Dec 7.

Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département d'Oncologie, Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1053/j.gastro.2016.11.042DOI Listing
March 2017

MYD88 Somatic Mutation Is a Diagnostic Criterion in Primary Cutaneous Large B-Cell Lymphoma.

J Invest Dermatol 2016 08 14;136(8):1741-1744. Epub 2016 May 14.

INSERM U1053, Université Bordeaux, Bordeaux, France; Department of Pathology, Centre Hospitalier Universitaire de Bordeaux, Pessac, France.

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http://dx.doi.org/10.1016/j.jid.2016.04.018DOI Listing
August 2016

Glut-1 intensity and pattern of expression in thymic epithelial tumors are predictive of WHO subtypes.

Pathol Res Pract 2015 Dec 19;211(12):996-1002. Epub 2015 Oct 19.

Université Paris Descartes, Sorbonne Paris Cité, Service de Pathologie, AP-HP Hôpital Necker Enfants Malades, Paris, France.

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.
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http://dx.doi.org/10.1016/j.prp.2015.10.005DOI Listing
December 2015

Comments on Carter et al's "activating GNAS mutations in parosteal osteosarcoma".

Am J Surg Pathol 2015 Jul;39(7):1010-3

*Service de Pathologie †Laboratoire de Biochimie et Biologie Moléculaire, Hôpital Universitaire et Université François Rabelais de Tours ††Université François Rabelais de Tours INSERM, U966, Tours ‡Service de Pathologie, Université Paris Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Paris §Service de Pathologie, Hôpital Universitaire, La Timone, Marseille ∥Service de Pathologie, Hôpital Universitaire Rangueil, Toulouse ¶Institut de Pathologie, Centre de Biologie Pathologie, Hôpital Universitaire de Lille Lille #Service de Pathologie, Hôpital René-Huguenin, Institut Curie, Saint Cloud **Centre de Biopathologie Léon Bérard Lyon ‡‡Université de Nantes, INSERM, UMR 957, Nantes, France.

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http://dx.doi.org/10.1097/PAS.0000000000000461DOI Listing
July 2015

[Cutaneous lymphoproliferations: proposal for the use of diagnostic algorithms based on 2760 cases of cutaneous lymphoproliferations taken from the INCa networks (LYMPHOPATH and GFELC) over a two-year period].

Ann Pathol 2015 Apr 13;35(2):131-47. Epub 2015 Mar 13.

Service de pathologie, hôpital Haut-Lévêque, CHU de Bordeaux, avenue de Magellan, 33604 Pessac cedex, France.

Introduction: Taking as a base our retrospective study of 2760 cases of cutaneous lymphoproliferations from the LYMPHOPATH and GFELC networks, we analyzed the doubtful and discordant cases between non-expert and expert pathologists, and the interest of clinicopathological confrontation.

Material And Methods: We defined the main diagnostic difficulties presented by cutaneous lymphoproliferations. We then designed and tested the algorithms on 20 random cases with 20 pathologists, in order to be used by any pathologist (not necessarily specialised in dermatopathology).

Results: The problematic differential diagnoses most frequently encountered are the following: MF or reactive dermatose; lymphoma without any other precision or reactive infiltrate; small B cell lymphoproliferation: lymphoma or reactive infiltrate; phenotyping of large B cell lymphoproliferation. We also analyzed less common problematic differential diagnoses, on the grounds that they are over- or under- diagnosed. Our test had a 72% success rate among the 20 randomly tested cases. The use of several algorithms for the same case is possible.

Discussion: Our study shows that an expert second-opinion is of interest in the area of cutaneous lymphoproliferations. A second opinion is useful for distinguishing a small B cell lymphoma from a HLR, and for defining a final diagnosis when the first pathologist doubts between lymphoma and reactive infiltrate. However, we demonstrate that for the problem MF or reactive dermatose, an initial clinicopathological confrontation produces more results than a second-opinion pathology review.

Conclusion: This is the first study of cutaneous lymphoproliferations that, without excluding reactionary infiltrates, concentrates on doubtful and discordant diagnoses between non expert and expert pathologists, and which has produced tested diagnostic algorithms.
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http://dx.doi.org/10.1016/j.annpat.2015.02.001DOI Listing
April 2015

Gastroesophageal reflux disease is a risk factor for severity of organizing pneumonia.

Respiration 2015 28;89(2):119-26. Epub 2015 Jan 28.

Services de Pneumologie et explorations fonctionnelles respiratoires, Tours, France.

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.
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http://dx.doi.org/10.1159/000369470DOI Listing
December 2015

Subcutaneous phaeohyphomycosis due to Phialemoniopsis ocularis successfully treated by voriconazole.

Med Mycol Case Rep 2014 Jul 10;5:4-8. Epub 2014 May 10.

CHU Tours, Service de Parasitologie-Mycologie-Médecine tropicale, 2 Boulevard Tonnellé, Tours 37044, France ; Université François Rabelais, CEPR - UMR INSERM U1100/EA 6305, Faculté de Médecine, 10 Boulevard Tonnellé, Tours 37032, France.

We report a case of subcutaneous infection in a 67 year-old Cambodian man who presented with a 5-month history of swelling of the right foot. Histopathology was compatible with phaeohyphomycosis and the hyphomycete Phialemoniopsis ocularis was identified by the means of morphological and molecular techniques. The patient responded well to a 6-month oral treatment with voriconazole alone.
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http://dx.doi.org/10.1016/j.mmcr.2014.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052356PMC
July 2014

Chromosome 12 long arm rearrangement covering MDM2 and RASAL1 is associated with aggressive craniofacial juvenile ossifying fibroma and extracranial psammomatoid fibro-osseous lesions.

Mod Pathol 2015 Jan 13;28(1):48-56. Epub 2014 Jun 13.

1] Department of Pathology, University Hospital of Tours and University François Rabelais, Tours, France [2] INSERM, UMR 957, Laboratory for Bone Resorption Physiopathology and Primary Bone Tumour Therapy, Faculty of Medicine, University of Nantes, Nantes, France.

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.
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http://dx.doi.org/10.1038/modpathol.2014.80DOI Listing
January 2015

Sirolimus-induced inflammatory lymphoedema of the breast resolved after switching to cyclosporine.

Acta Derm Venereol 2015 Jan;95(1):108-9

Department of Dermatology, CHRU de Tours, FR-37044 Tours, France.

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http://dx.doi.org/10.2340/00015555-1889DOI Listing
January 2015

Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation.

Cancer Cell 2014 Apr;25(4):428-41

INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, 75015 Paris, France. Electronic address:

Hepatocellular 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.
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http://dx.doi.org/10.1016/j.ccr.2014.03.005DOI Listing
April 2014

[Rythmic-pathology: the French national pathology network for thymic epithelial tumours].

Ann Pathol 2014 Feb 21;34(1):87-91. Epub 2014 Feb 21.

Service d'anatomie pathologique, AP-HP, hôpital universitaire Necker-Enfants-Malades, université Paris Descartes, Sorbonne Paris Cité, 149, rue de Sèvres, 75015 Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.annpat.2014.01.010DOI Listing
February 2014

Blastic plasmacytoid dendritic cell neoplasms: clinico-immunohistochemical correlations in a series of 91 patients.

Am J Surg Pathol 2014 May;38(5):673-80

Departments of *Dermatology ‡Pathology, hôpital Lyon Sud, Claude Bernard Lyon 1 University, Hospices Civils de Lyon, Lyon †Department of Statistics, Université claude bernard lyon I, Villeurbanne §Department of Pathology, Hôpital Haut-Lévêque, CHU, Bordeaux ∥Department of Pathology, Hôpital Henri Mondor, APHP, Créteil ¶Department of Pathology, Hôpital Saint-Louis ¶¶Department of Pathology, Hôpital Cochin ***Department of Pathology, Hôpital Necker-Enfants Malades, APHP, Paris #Department of Pathology, Centre hospitalo-universitaire, Montpellier **Department of Pathology, Hôpital Purpan, CHU, Toulouse ††Department of Dermatologie, Hôpital du Bocage §§§Department of Pathology, PTB, CHU ∥∥∥Centre de Pathologie, Dijon ‡‡Department of Pathology, Centre hospitalo-universitaire, Lille §§Department of Pathology, Hôpital Estaing, CHU, Clermont-Ferrand ∥∥Department of Pathology, Hôpital Ch. Nicolle, CHU, Rouen ##Department of Pathology, Hôpital Trousseau, CHU, Tours †††Department of Pathology, Hôpital Avicennes, APHP, Bobigny, France ‡‡‡Department of Pathology, Hôpital Maisonneuve Rosemont, Montréal, QC, Canada.

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.
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http://dx.doi.org/10.1097/PAS.0000000000000156DOI Listing
May 2014

Diffuse panbronchiolitis and IgA nephropathy.

Am J Respir Crit Care Med 2014 Jan;189(1):106-9

1 CHRU Tours, Service de Pneumologie Tours, France.

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http://dx.doi.org/10.1164/rccm.201307-1381LEDOI Listing
January 2014

CD20 antigen may be expressed by reactive or lymphomatous cells of transformed mycosis fungoides: diagnostic and prognostic impact.

Am J Surg Pathol 2013 Dec;37(12):1845-54

*Department of Pathology, the Tumor Bank and Tumor Biology Laboratory, the departments of Statistics and Dermatology, University Hospital of Bordeaux †Departments of Pathology and Dermatology, University Hospital of Paris-Est Créteil ‡Departments of Pathology and Dermatology, University Hospital of Montpellier §Departments of Pathology and Dermatology, University Hospital of Paris, APHP ∥Departments of Pathology and Dermatology, University Hospital of Tours ¶Departments of Pathology and Dermatology, University Hospital of Lyon #Departments of Pathology and Dermatology, University Hospital of Clermont-Ferrand, France.

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 was <10% for 54 cases (38%), 10% to 49% for 71 cases (81%), and >50% for 17 cases (19%). We focused the study on 23 cases that contained >50% 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 of >50% CD20 cells and of a nodular perifollicular pattern of this component.
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http://dx.doi.org/10.1097/PAS.0000000000000091DOI Listing
December 2013

Cutaneous epithelioid clear cells angiosarcoma in a young woman with congenital lymphedema.

Case Rep Pathol 2013 3;2013:931973. Epub 2013 Sep 3.

Department of Pathology, Tours University Hospital, 37044 Tours, France.

Angiosarcomas are rare aggressive neoplasms that can occur secondary to chronic lymphedema (Stewart-Treves syndrome). Although secondary angiosarcomas are commonly described after-mastectomy and/or after-radiotherapy, few cases have been reported in association with chronic lymphedema of congenital origin. We report the clinical, pathological, and cytogenetic findings in a case of cutaneous epithelioid clear cells angiosarcoma that occurred in a 21-year-old woman with hemibody congenital lymphedema. Surgical biopsies of the tumor mass revealed diffuse epithelioid proliferation of clear atypical cells, for which immunophenotyping highlighted the vascular differentiation. Despite en bloc resection of the tumor, the patient died of metastatic disease three months after diagnosis. This case illustrates the clinical and pathology characteristics of angiosarcoma that is a rare entity secondary to chronic lymphedema. It is the first reported case for which the c-MYC amplification status was assessed. The diagnostic value of this amplification should be further evaluated in this specific context.
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http://dx.doi.org/10.1155/2013/931973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776547PMC
September 2013

Complete and rapid regression of primary cutaneous follicular lymphoma with repeated oral administration of acitretin for palmoplantar psoriasis.

J Am Acad Dermatol 2013 Oct;69(4):e176-7

Department of Dermatology, CHU Tours and Université François Rabelais de Tours, Tours, France.

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http://dx.doi.org/10.1016/j.jaad.2013.04.006DOI Listing
October 2013