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International audience; Primary central nervous system diffuse large B cell lymphoma (PCNS-DLBCL) is a rare and aggressive entity of diffuse large B cell lymphoma (DLBCL). Elements of the tumour microenvironment (TME) including tumour-infiltrating lymphocytes (TILs) and tumour-associated macrophages (TAMs) have been associated with survival in DLBCL but their composition and prognostic impact in PCNS-DLBCL are unknown. Programmed cell death-1 (PD1)/programmed death-ligand 1 (PD-L1) immune checkpoint may represent a therapeutic option. Here, we aimed to characterise PD1/PDL1 immune checkpoints and the composition of the TME in PCNS-DLBCL. We collected tumour tissue and clinical data from 57 PCNS-DLBCL and used immunohistochemistry to examine TAMs (CD68, CD163), TILs (CD3, CD4, CD8, PD1) and tumour B cells (PAX5/PDL1 double stains, PDL1). The PDL1 gene was evaluated by fluorescence in situ hybridization (FISH). PAX5/PDL1 identified PDL1 expression by tumour B cells in 10/57 cases (17.5%). PDL1 gene translocation was a recurrent cytogenetic alteration in PNCS-DLBCL (8/47.17%) and was correlated with PDL1 positive expression in tumour B cells. The TME consisted predominantly of CD163 (+) M2 TAMs and CD8 (+) TILs. Most TAMs expressed PDL1 and most TILs expressed PD1. The density of TAMs and TILs did not associate with outcome. We showed that expression of PD1 on TILs and PDL1 on TAMs, but not the expression of PDL1 on tumour B cells was correlated with better prognosis. These findings support a significant role of TME composition and PD1/PDL1 crosstalk in PCNS-DLBCL pathogenesis and bring new insights to the targeted therapy of this aggressive lymphoma.

e16558 Background: Voided urinary cytology is a non-invasive test, but it suffers from a lack of sensitivity (Se), particularly in low-grade urothelial lesions, and it remains pathologist-dependent. In order to improve the performance of urinary cytopathology, the VitaDX company (France) developed a medical device which uses whole-slide digitalization and artificial intelligence algorithms to identify tumor cells. The device allows complete analysis of morphological characters of voided urothelial cells, such as the shape, size and color of the nuclei. Methods: VISIOCYT1 is a prospective, multicenter clinical trial involving 319 patients divided into two groups: 1) patients with non-muscle invasive bladder tumors (NMIBC) confirmed by histology, and 2) control patients with negative urinary cytology and cystoscopy. The primary objective of the study was to evaluate the Se of the VisioCyt test. Specificity (Sp) and comparison of Se and Sp of conventional urinary cytology vs. the VisioCyt test were also calculated. Results: A total of 319 patients were included (170 in the NIMBC group vs. 149 controls). Overall Se was 80.9% and 45.9% for VisioCyt test and conventional urinary cytology, respectively (p = .002). Negative cytology being an inclusion criterion, a 100% Sp was attributed to the control group. It was calculated at 61.8% for the VisioCyt test. Concerning grade, the VisioCyt test allowed higher Se to be obtained in the low grade tumor category (66.7% vs. 26.1% for conventional urinary cytology, Mc Nemar test, p < .0001). A higher Se was also observed in high grade tumors: 93.7% vs. 62.8% (p < .0001). Conclusions: The VisioCyt test greatly improves the performance of urinary cytopathology in the diagnosis of urothelial bladder tumors, particularly in low grade, pTa lesions. Its implementation could dramatically reduce the need for cystoscopy in patients followed after conservative treatment of bladder cancer. Clinical trial information: NCT02966691. [Table: see text]

International audience; In clinical laboratories, the diagnosis of parasite diseases can sometimes be challenging for non-expert microbiologists. Indeed, in spite of the advent of the molecular biology, macroscopic and microscopic examinations still remain essential. Nonetheless, it is usually not automated and requires great skills to complete the correct diagnosis. It is not infrequent that inert elements mislead to erroneous diagnoses. Through three different concrete examples, this article aims at underscoring the actual risk of parasite misidentification and at highlighting the systematic approach to be conducted in order to enable reliable diagnosis.

International audience; A 62-year-old man, who was a heavy drinker, presented with deep asthenia, isolated fever, inflammatory syndrome (CRP 120 mg/l) and cytopenias (Hb 6.5 g/dl, platelet count 100 G/l). A whole-body CT scan found dysmorphic hepatomegaly and splenomegaly. Endoscopy revealed bleeding gastrointestinal angiodysplasia and non-bleeding oesophageal varices. After coagulation for angiodysplasia and blood transfusions, the Hb level remained around 8.5 g/dl. To investigate blood malignancy, a bone marrow biopsy revealed small-vessel vasculitis (Fig. 1A, 2), fibrinoid necrosis affecting the small vessel walls (Fig. 1A, 3), multinucleated giant cells (Fig. 1A, 1) constituting microgranulomas (Fig. 1A, 4) and...

Purpose To evaluate the feasibility of prostatic artery embolization in patients with low-risk prostate cancer (PC) under active surveillance (AS). Methods This monocentric prospective pilot study, running from June 2018 to June 2019, included 10 patients with low-risk PC under AS, median age 72 years (range, 62–77 years), with a unilateral focal lesion visible on magnetic resonance (MR) imaging, with Prostate Imaging Reporting and Data System v2 score ≥3/5 confirmed by multiparametric MR imaging-targeted biopsy and Gleason score 6. The patients underwent unilateral prostatic artery embolization with 300–500 μm Embospheres in the affected prostatic lobe. The primary endpoint was technical feasibility (prostate and no off-target ischemia in the imaging). The secondary endpoints included safety, negative biopsies/MR imaging response/functional outcomes at 6 months, and oncologic efficacy at 1 year. Results Embolization was successfully achieved in all patients; prostate ischemia was confirmed on multiparametric MR imaging, and no off-target ischemia was reported. No major complications were reported. Four patients (40%) presented with both negative targeted and systematic biopsies at 6 months. No lesions were seen on the MR imaging in 30% of patients. The mean International Prostate Symptom Score and International Index of Erectile Function score were 7 and 19 and 5 and 20 at baseline and 6 months, respectively, with no significant difference. Nine patients (90%) were still under AS at 1 year. One patient (10%) had PC progression outside the target lesion and was switched over to curative radiotherapy. Conclusions Prostatic artery embolization is feasible and appears safe for prostate cancer patients under AS, with no impact on erectile function or continence status. These results justify the pursuit of further studies.

International audience; Despite distinct clinical presentation and outcome, systemic, primary cutaneous, and breast implant-associated anaplastic large cell lymphomas (S-, PC-, BI-ALCL) ALK-negative (ALK-) show similar histopathological features including the presence of the "hallmark" cells with horseshoe-shaped nuclei and CD30 protein expression. The purpose was to better characterize these three entities using immunohistochemistry and FISH (Fluorescent in situ hybridization) to identify biomarkers differently expressed and that might be involved in their pathogenesis. Twenty-two S-ALCL ALK-, 13 PC-ALCL, and 2 BI-ALCL were included. Cases were tested for P53, P63, MUM1, MYC, GATA3, p-STAT3, PD1, and PDL1 protein expression and DUP22, TP53, TP63, MYC, and PDL1 chromosomal aberrations. As expected, S-ALCL ALK- patients had adverse outcome compare to PC and BI-ALCL. No difference was observed between the three groups concerning protein expression except for MUM1 that was significantly more frequently expressed in S-ALCL ALK- compared to PC-ALCL. In particular, constitutive activation of the STAT3 pathway and PDL1/PD1 immune-checkpoint expression was present in the three entities. TP53 deletion and PDL1 gene amplification were the commonest cytogenetic alterations and were present in the three entities. None of the studied biological parameters was associated with prognosis. Despite distinct clinical behavior, S-ALCL ALK-, PC-ALCL, and BI-ALCL share similar biological features. Larger series should be investigated with the current approach to determine more precisely the activity and the prognostic value of these biomarkers and pathways in each group.

T-cell large granular lymphocyte (T-LGL) leukemia is a lymphoproliferative disease classically defined by an excess of circulating clonal T-LGL (> 0.4 G/L), evidence of abnormal CD3+, CD8+, CD57+ m...

pT1G3 bladder tumors have a high tendency to recur and progress. We evaluated the prognostic values of the depth of submucosal invasion and immunostaining with survivin and p53 in 30 pT1G3 urothelial carcinomas at the first endoscopic resection. The depth of invasion was evaluated toward the muscularis mucosa and measured using a micrometer. Survivin and p53 immunostaining were performed using an automated immunostainer. Of the patients, 19 (63%) had tumor recurrence, 11 (37%) had tumor progression, 10 (33%) had metastatic spread, and 10 (33%) died of the disease. Infiltration of deep lamina propria (pT1b) and a micrometric measure of 1.5 mm or more were associated with an increased risk of tumor local and/or metastatic progression (P = .03 and P = .02, respectively). A combined high expression of survivin (≥ 20%) and p53 (≥50%) was associated with an increased risk of tumor local progression (P = .0007). We showed that combined p53 and survivin immunostaining could be helpful in distinguishing patients with a high risk of tumor progression. Bladder carcinoma is the seventh most common cancer worldwide, representing 3.2% of all adult cancers. 1 At initial diagnosis, approximately 70% of the tumors are noninvasive papillary urothelial carcinomas. However 10% of these tumors manifest with a high cytologic grade, G3 according to the 1973 World Health Organization (WHO) classification or high-grade according to the 2004 WHO/International Society of Urological Pathology (ISUP) classification, and with infiltration of the lamina propria (pT1 stage). 2 pT1G3 tumors are considered by urologists as “superficial tumors” that are treated with a conservative approach. But the risk of recurrence is high (50%-80%), and the risk of progression to muscular invasion is about 40% to 50%. Death related to this disease is about 36% after 5 years. 3

Invasive urothelial carcinoma may present with many deceptive morphologic variants. We report the clinicopathologic and immunohistochemical features of 5 cases of the so-called lipid-cell variant of urothelial carcinoma. The tumors occurred in 4 men and 1 women aged from 56 to 80 years. Four cases were developed in the bladder and 1 case in the renal pelvis. All cases were revealed by a macroscopic hematuria. The tumors were composed of sheets and nests of large epithelial cells with an abundant clear multivacuolated cytoplasm mimicking lipoblasts. Nuclei were irregular, hyperchromatic, eccentric, and frequently indented by cytoplasmic vacuoles. Mucin stains (PAS, Alcian Blue) were negative. Tumor cells were strongly stained with cytokeratin 7, cytokeratin 20, and EMA but were negative with S-100 protein. In all cases, a usual high-grade urothelial carcinoma component was admixed with lipoid tumor cells. Two tumors infiltrated the bladder muscle, 2 cases invaded the bladder submucosa, and 1 case invaded the renal parenchyma. In the follow-up, despite appropriate surgical treatment, 4 patients died of the disease and 1 patient is alive without recurrence. Because of its rarity and the tumor cells' appearance, the lipoid-cell variant may be misdiagnosed and must be distinguished from liposarcoma or signet-ring cell carcinoma. In the present series, the lipoid-cell variant of urothelial carcinoma was associated with an aggressive behavior and a poor prognosis.

International audience; CONTEXT: Empirical evidence suggests that autocrine human GH (hGH) may possess a proliferative and oncogenic role in human mammary carcinoma. However, this concept is largely derived from studies using cultured human mammary carcinoma cell (HMCC) lines. OBJECTIVE: We investigated the expression and functionality of hGH and the hGH receptor in isolated cultures of primary HMCC. Design: Epithelial cell adhesion molecule-positive primary HMCC were isolated from surgical biopsies of patients with mammary carcinoma and cultured in vitro. Expression of hGH and hGH receptor was determined by RT-PCR, immunofluorescence microscopy, and ELISA. The proliferative response of the cultured primary HMCC to hGH stimulation or hGH inhibition with a hGH antagonist was determined. RESULTS: One hundred percent of cultured primary HMCC expressed the hGH receptor, and 52% expressed hGH at the mRNA level. hGH-positive primary HMCC produced hGH protein within the cell and secreted hGH to the media. Both hGH-negative and hGH-positive HMCC responded to hGH stimulation with large increases in cell number. hGH-positive HMCC responded to inhibition of hGH by a hGH antagonist with a decrease in cell number, whereas hGH-negative HMCC did not. CONCLUSION: Primary HMCC proliferate in response to hGH, and the proliferation of hGH-positive HMCC is inhibited by hGH antagonism. Inhibition of hGH in patients with mammary carcinoma may therefore limit tumor growth.

Background & Aims Eosinophilic gastroenteritis (EGE) is a rare gastrointestinal disorder; little is known about its natural history. We determined the clinical features and long-term outcomes of patients with EGE. Methods We reviewed files from 43 patients diagnosed with EGE who were followed from January 1988 to April 2009. The diagnosis was made according to standard criteria after other eosinophilic gastrointestinal disorders were excluded. We analyzed data on initial clinical presentation and long-term outcomes. Results EGE was classified as mucosal, subserosal, or muscular in 44%, 39%, and 12% of cases, respectively. Disease location was mostly duodenal (62%), ileal (72%), or colonic (88%); it was less frequently esophageal (30%) or gastric (38%). Blood eosinophilia (numbers >500/mm 3 ) was observed in 74% of cases. Spontaneous remission occurred in 40% of patients; the majority of treated patients (74%) received oral corticosteroids, which were effective in most cases. After a median follow-up period of 13 years (0.8–29 years), we identified 3 different courses of disease progression: 18 patients (42%; 9 with subserosal disease) had an initial flare of the disease without relapse, 16 (37%) had multiple flares that were separated by periods of full remission (recurring disease), and 9 (21%) had chronic disease. Conclusions The clinical presentation of EGE is heterogeneous and varies in histologic pattern; about 40% of patients resolve the disease spontaneously, without relapse. Approximately 50% have a more complex disease, which is characterized by unpredictable relapses and a chronic course.

Background: Collagenous sprue (CS) is a very rare cause of severe malabsorption with an enteropathy that is characterized by villous atrophy and a distinctive band of subepithelial collagen deposition. A poor outcome has been reported historically. Aim: To describe the clinical characteristics, treatment, and prognosis in a contemporary cohort of patients with CS. Methods: We included cases with biopsy-proven CS evaluated at the Mayo Clinic Results: 15 patients (80% females) with a median age of 67 years (range, 53-83) were included. The clinical manifestations were diarrhea (100%), loss of weight (93%), and abdominal pain (14%). Hospitalizationwas required because severe diarrhea in 9 (64%) patients. Hypoalbuminemia and anemia were evident in 9 (64%) and 7 (50%) patients, respectively. Humanleukocyte antigen genes DQ2 or DQ8 were present in 12 (80%) patients (DQ2+ single dose [n=8], DQ2+ double dose [n=3], and DQ2+/DQ8+ [n=1]). Celiac antibodies were present in only 1 patient. A prior diagnosis of celiac disease was evident in 7 (47%) patients. Histologically, all cases had both the abnormal collagen deposition and some degree of villous atrophy. Aberrant (clonal) intraepithelial lymphocytes were detected in 1 (of 12) patients tested by both immunostaining and T-cell clonality analysis. Associated disorders were collagenous gastritis (n=4), collagenous colitis (n=4), small-intestine bacterial overgrowth (n=4), lymphocytic colitis (n=2), lymphocytic gastritis (n=1), autoimmune hepatitis (n=1), and hyposplenism (n=1). All patients received treatment with a combination of a strict gluten-free diet and steroids such as budesonide 9mg/day (n=12), prednisone 30-40 mg/day (n=2) and dexamethasone 8 mg/day (n=1). Parenteral nutrition was necessary in 11 (79%) patients. One patient developed enteropathy-type T-cell lymphoma during followup and received a combination of nitrogen mustard and methylprednisolone. Clinical followup after treatment was available in 12 (92%) patients (median time = 16 months; range, 172), disappearance of diarrhea was observed in 11 with complete histologic remission documented in one case. Three patients died during follow-up because of emaciation, enteropathy-type T-cell lymphoma, and aspiration pneumonia, respectively. Conclusions: We report the largest case series of CS. Treatment with a combination of gluten-free diet and steroids (especially budesonide) was useful to control symptoms in most patients; however, length of follow-up was limited so far to a few months in the majority of our patients. CS was associated with collagen deposition in other organs, autoimmune conditions, and lymphoma.

Introduction La gastroenterite a eosinophiles (GEE) est une maladie rare dont l’histoire naturelle est mal connue [1,2]. Le but du travail a ete de rapporter les caracteristiques cliniques et l’evolution a long terme des malades atteints de GEE suivis dans notre centre de 1992 a 2007. Patients et Methodes Dans une etude retrospective sur dossiers, le diagnostic de GEE etait porte sur les criteres habituels [1] apres exclusion des autres causes d’eosinophilie digestive. Les GEE etaient classes en forme muqueuse, musculeuse ou sereuse selon la classification de Klein [2]. Un questionnaire de suivi standardise etait rempli lors d’une consultation ou apres contact avec le medecin traitant et/ou le malade. Resultats Quarante et un malades atteints de GEE ont ete recenses, 27 H et 14 F, d’un âge median de 38 ans (16 - 70) au diagnostic. Des douleurs abdominales, une diarrhee, des nausees et/ou vomissements, une ascite, etaient les symptomes inauguraux les plus frequents : 70, 48, 45 et 39 % des cas respectivement. Les autres symptomes revelateurs etaient plus rarement une dysphagie, une rectorragie et un ictere. Le delai median entre les premiers symptomes et le diagnostic etait de 1,5 ans (0,16 - 27). La GEE etait muqueuse, sereuse et musculeuse dans, 44, 39 et 12 % des cas respectivement. L’atteinte, evaluee par des biopsies digestives etagees, etait le plus souvent duodenale (63 %), ileale (45 %) et colique (66 %) plus rarement œsophagienne (20 %) et gastrique (32 %). Trois malades presentaient une atteinte duodeno-pancreatique se revelant par un tableau de pancreatopathie chronique. Une hyper-eosinophilie sanguine (> 500/mm 3 ) etait presente chez 31 malades (79 %) et une elevation des IgE chez 22 (66 %). Sur 27 malades traites (66 %), plus de la moitie (17) avait recu une corticotherapie (1 mg/kg/j), 4 du chromoglycate et 6 des antihistaminiques. Apres un suivi median de 15 ans (1 - 27) trois profils evolutifs pouvaient etre individualises : 18 malades (44 %), (dont 9 etaient des formes sereuses) presentaient une poussee unique inaugurale sans recidive, 14 (36 %) presentaient des poussees entrecoupees de periodes de remission (formes recurrentes) et 9 (21 %) une forme chronique continue. Trois malades etaient cortico-dependants a une faible dose. Aucune transformation myeloproliferative n’etait observee. Conclusion La GEE se revele par des symptomes digestifs varies en fonction de la forme histologique de la maladie. Elle se caracterise souvent par une evolution benigne sans recidive. Cependant, plus de la moitie des malades presente un profil evolutif plus complexe marque par des recidives imprevisibles, sensibles aux corticoides, et une evolution chronique chez plus d’un malade sur cinq.

Les carcinomes a cellules claires avec composante rhabdoide constituent moins de 5 % des cancers du rein a cellules claires. Nous rapportons une serie de 6 observations survenant chez des adultes d’âge moyen de 53,5 ans. Ces tumeurs mesuraient 11,5 cm en moyenne. Microscopiquement, outre un contingent tumoral classique, elles presentaient un contingent tumoral intrinque focal ou plus diffus d’architecture en plages solides, pseudoglandulaire ou fusiforme plus ou moins intrinques. Les cellules tumorales rhabdoides etaient de grande taille globoide, avec un noyau large vesiculeux excentre muni d’un nucleole proeminent au sein d’un cytoplasme abondant, parfois vacuolise en peripherie, et une inclusion eosinophile intracytoplasmique ronde globuleuse. Le stroma tumoral etait grele bien vascularise sans caractere desmoplasique. Systematiquement, la composante rhabdoide etait associee a un haut grade de Furhman (III-IV). En immunohistochimie, cette composante ne montrait pas de differenciation myogenique. Quatre tumeurs avaient une extension extra-renale en rapport avec cette composante. Le suivi clinique objectivait chez 3 patients une diffusion metastatique precoce et un patient decedait de la maladie 7 mois apres la chirurgie. Cette composante rhabdoide presente des similitudes morphologiques, immunohistochimiques et ultrastructurales avec les tumeurs rhabdoides renales de l’enfant. Elle correspondrait a une evolution clonale agressive du contingent tumoral classique. L’identification et la quantification d’un contingent rhabdoide dans les carcinomes a cellules claires parait importante car elle implique un plus mauvais pronostic avec un risque metastatique accru.