Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca2+) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, and arterial contractility. Store-operated Ca2+ entry is involved in Ca2+ homeostasis in PASMCs, but its properties in PAH are unclear. METHODS: Using a combination of Ca2+ imaging, molecular biology, in vitro, ex vivo, and in vivo approaches, we investigated the roles of the Orai1 SOC channel in PA remodeling in PAH and determined the consequences of pharmacological Orai1 inhibition in vivo using experimental models of pulmonary hypertension (PH). RESULTS: Store-operated Ca2+ entry and Orai1 mRNA and protein were increased in human PASMCs (hPASMCs) from patients with PAH (PAH-hPASMCs). We found that MEK1/2 (mitogen-activated protein kinase kinase 1/2), NFAT (nuclear factor of activated T cells), and NFκB (nuclear factor-kappa B) contribute to the upregulation of Orai1 expression in PAH-hPASMCs. Using small interfering RNA (siRNA) and Orai1 inhibitors, we found that Orai1 inhibition reduced store-operated Ca2+ entry, mitochondrial Ca2+ uptake, aberrant proliferation, apoptosis resistance, migration, and excessive calcineurin activity in PAH-hPASMCs. Orai1 inhibitors reduced agonist-evoked constriction in human PAs. In experimental rat models of PH evoked by chronic hypoxia, monocrotaline, or Sugen/hypoxia, administration of Orai1 inhibitors (N-{4-[3,5-bis(Trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide [BTP2], 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline [JPIII], or 5J4) protected against PH. CONCLUSIONS: In human PAH and experimental PH, Orai1 expression and activity are increased. Orai1 inhibition normalizes the PAH-hPASMCs phenotype and attenuates PH in rat models. These results suggest that Orai1 should be considered as a relevant therapeutic target for PAH.

SUR1 As a New Therapeutic Target for Pulmonary Arterial Hypertension.

Mutations in ABCC8 have been identified in pulmonary arterial hypertension (PAH). ABCC8 encodes SUR1, a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. However, the pathophysiological role of the SUR1/Kir6.2 channel in PAH is unknown. We hypothesized that activation of SUR1 could be a novel potential target for PAH. We analyzed the expression of SUR1/Kir6.2 in the lungs and pulmonary artery (PA) in human PAH or experimental pulmonary hypertension (PH). The contribution of SUR1 in human or rat PA tone was evaluated, and we measured the consequences of in vivo activation of SUR1 in control and PH rats. SUR1 and Kir6.2 protein expression was not reduced in the lungs or human pulmonary arterial endothelial cells and smooth muscle cells from PAH or experimentally induced PH. We showed that pharmacological activation of SUR1 by three different SUR1 activators (diazoxide, VU0071063, and NN414) leads to PA relaxation. Conversely, the inhibition of SUR1/Kir6.2 channels causes PA constriction. In vivo, long- and short-term activation of SUR1 with diazoxide reversed monocrotaline-induced PH in rats. In addition, in vivo diazoxide application (short protocol) reduced the severity of PH in chronic-hypoxia rats. Moreover, 3 weeks of diazoxide exposure in control rats had no cardiovascular effects. Finally, in vivo, activation of SUR1 with NN414 reduced monocrotaline-induced PH in rats. In PAH and experimental PH, the expression of SUR1/Kir6.2 was still present. In vivo pharmacological SUR1 activation by two different molecules alleviated experimental PH, providing proof of concept that SUR1 activation should be considered for PAH and evaluated more thoroughly.

Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology.

INTRODUCTION: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. METHODS: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). RESULTS: Genomic patterns were heterogeneous ranging from "quiet" to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6-17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating "neuroendocrine carcinoma-like" genetic alterations through progression such as TP53/RB1 alterations. CONCLUSION: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.

Can MRI differentiate surrounding vertebral invasion from reactive inflammatory changes in superior sulcus tumor?

OBJECTIVES: Vertebral invasion is a key prognostic factor and a critical aspect of surgical planning for superior sulcus tumors. This study aims to further evaluate MRI features of vertebral invasion in order to distinguish it from reactive inflammatory changes. METHODS: Between 2000 and 2016, a retrospective study was performed at a single institution. All patients with superior sulcus tumors undergoing surgery, including at least two partial vertebrectomies, were included. An expert radiologist evaluated qualitative and quantitative MRI signal intensity characteristics (contrast-to-noise ratio [CNR]) of suspected involved and non-involved vertebrae. A comparison of CNR of invaded and sane vertebrae was performed using non-parametric tests. Imaging data were correlated with pathological findings. RESULTS: A total of 92 surgical samples of vertebrectomy were analyzed. The most specific sequences for invasion were T1 and T2 weighted (92% and 97%, respectively). The most sensitive sequences were contrast enhanced T1 weighted fat suppressed and T2 weighted fat suppressed (100% and 80%). Loss of extrapleural paravertebral fat on the T1-weighted sequence was highly sensitive (100%) but not specific (63%). Using quantitative analysis, the optimum cut-off (p < 0.05) to distinguish invasion from reactive inflammatory changes was CNR > 11 for the T2-weighted fat-sat sequence (sensitivity 100%), CNR > 9 for contrast-enhanced T1-weighted fat-suppressed sequence (sensitivity 100%), and CNR < - 30 for the T1-weighted sequence (specificity 97%). Combining these criteria, 23 partial vertebrectomies could have been avoided in our cohort. CONCLUSION: Qualitative and quantitative MRI analyses are useful to discriminate vertebral invasion from reactive inflammatory changes. KEY POINTS: • Abnormal signal intensity in a vertebral body adjacent to a superior sulcus tumor may be secondary to direct invasion or reactive inflammatory changes. • Accurate differentiation between invasion and reactive inflammatory changes significantly impacts surgical planning. T1w and T2w are the best sequences to differentiate malignant versus benign bone marrow changes. The use of quantitative analysis improves MRI specificity. • Using contrast media improves the sensitivity for the detection of tumor invasion.

[Thymoma and squamous thymic carcinoma diagnosis; experience from the RYTHMIC network]. / Diagnostic des thymomes et carcinomes thymiques malpighiens ; expérience du réseau RYTHMIC.

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.

Risk factors associated with myasthenia gravis in thymoma patients: The potential role of thymic germinal centers.

Thymomas are associated with a very high risk of developing Myasthenia Gravis (MG). Our objectives were to identify histological and biological parameters to allow early diagnosis of thymoma patients susceptible to developing MG. We conducted a detailed retrospective analysis from a patient database, searching for differences between patients with thymoma-associated MG (MGT, n = 409) and thymoma without MG (TOMA, n = 111) in comparison with nonthymomatous MG patients (MG, n = 1246). We also performed multiplex and single molecule arrays to measure the serum levels of cytokines in these groups of patients and controls (n = 14-22). We identified a set of parameters associated with MG development in thymoma patients: 1) detection of anti-acetylcholine receptor (AChR) antibodies, 2) development of B1 or B2 thymoma subtypes, 3) presence of ectopic thymic germinal centers (GCs), 4) local invasiveness of thymoma, and 5) being a woman under 50 years old. Among these parameters, 58.8% of MGT patients displayed GCs with a positive correlation between the number of GCs and anti-AChR titers. By immunohistochemistry, we found thymic GCs in the adjacent tissues of thymomas encircled by high endothelial venules (HEVs) that could favor peripheral cell recruitment. We also clearly associated MG symptoms with higher IFN-γ, IL-1ß and sCD40L serum levels, specifically in MGT patients compared to TOMA patients. Altogether, these analyses allowed the clear identification of histological, in particular the presence of GCs, and biological parameters that would facilitate the evaluation of the probability of the MG outcome postoperatively in thymoma patients.

Non-small cell lung carcinomas with CTNNB1 (beta-catenin) mutations: A clinicopathological study of 26 cases.

Beta-catenin, encoded by the CTNNB1 gene, plays an important role in cell proliferation. Mutations of CTNNB1 are oncogenic in several tumor types and are often associated with a nuclear abnormal expression. However, such mutations have only rarely been reported in non-small cell lung carcinomas and their clinical signification is not well described. Our study was conducted on 26 CTNNB1-mutated non-small cell lung carcinomas. Tumors were routinely tested by next generation sequencing for mutations in exon 3 of CTNNB1 gene. Twenty three cases were from a series of 925 tumors (2.48%). The hospital files and pathological data, from surgical samples (n = 16), small biopsies (n = 5) and trans-bronchial fine needle aspirations (n = 5), were reviewed. Immunohistochemistry was performed with an anti-beta-catenin antibody. There were 10 female and 16 male patients aged 52 to 83. Eleven of 25 patients were no-smoking or light smokers. Three cases were diagnosed while under treatment with EGFR tyrosine kinase inhibitor. There were 25 adenocarcinomas and 1 squamous cell carcinoma. Most adenocarcinomas had a papillary component and were TTF1-positive. One case was a well-differentiated fetal adenocarcinoma. Eleven cases (42%) with CTNNB1 mutations showed associated EGFR mutations. The frequency of CTNNB1 mutations was higher among EGFR mutated carcinomas. Immunohistochemistry showed heterogeneous nuclear or cytoplasmic abnormal expression. Our study shows that CTNNB1 mutations mostly occur in TTF1-positive adenocarcinomas with a papillary pattern. These mutations are often associated with EGFR mutations and possibly interfer in the mechanism of resistance to tyrosine kinase inhibitors. Our experience suggests that immuno-histochemistry cannot be used for screening.

CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages.

Radiation-induced lung fibrosis (RIF) is a delayed side-effect of chest radiotherapy, frequently associated with macrophage infiltration.We aimed to characterise the role of pulmonary macrophages in RIF using human lung biopsies from patients receiving radiotherapy for thorax malignancies and a RIF model developed in C57BL/6 mice after 16-Gy thorax irradiation.High numbers of macrophages (both interstitial and alveolar) were detected in clinical and preclinical RIF. In the preclinical model, upregulation of T-helper (Th)2 cytokines was measured, whereas Th1 cytokines were downregulated in RIF tissue lysate. Bronchoalveolar lavage demonstrated upregulation of both types of cytokines. At steady state, tissue-infiltrating macrophages (IMs) expressed 10-fold more arginase (Arg)-1 than alveolar macrophages (AMs), and a 40-fold upregulation of Arg-1 was found in IMs isolated from RIF. IMs, but not AMs, were able to induce myofibroblast activation in vitro In addition, whereas depletion of AMs using Clodrosome didn't affect RIF score, depletion of IMs using a clinically available colony-stimulating factor receptor-1 (CSF1R) neutralising antibody was antifibrotic.These findings suggest differential contributions of alveolar versus interstitial macrophages in RIF, highlighting the fibrogenic role of IMs. The CSF1/CSF1R pathway was identified as a new therapeutic target to inhibit RIF.

Natural History of Localized and Locally Advanced Atypical Lung Carcinoids after Complete Resection: A Joined French-Italian Retrospective Multicenter Study.

BACKGROUND: The natural history and the best modality of follow-up of atypical lung carcinoids (AC) remain ill defined. The aim of this study was to analyze recurrence-free survival (RFS) after complete resection (R0) of stage I-III pulmonary AC. Secondary objectives were prognostic parameters, the location of recurrences, and the modality of follow-up. METHODS: A retrospective review of 540 charts of AC patients treated between 1998 and 2008 at 10 French and Italian centers with experience in lung neuroendocrine tumor management was undertaken. The exclusion criteria were MEN1-related tumor, history of another cancer, referral after tumor relapse, and being lost to follow-up. A central pathological review was performed in each country. RESULTS: Sixty-two patients were included. After a median follow-up time of 91 months (mean 85, range 6-165), 35% of the patients experienced recurrence: 16% were regional recurrences and 19% were distant metastases. Median RFS was not reached. The 1-, 3-, and 5-year RFS rate was 90, 79, and 68%, respectively. In univariate analysis, lymph node involvement (p = 0.0001), stage (p = 0.0001), mitotic count (p = 0.004), and type of surgery (p = 0.043) were significantly associated with RFS. In multivariate analysis, lymph node involvement was significantly associated with RFS (HR 95% CI: 0.000-0.151; p = 0.004). During follow-up, somatostatin receptor scintigraphy, fibroscopy, and abdominal examination results were available for 22, 12, and 25 patients, respectively. The median time interval for imaging follow-up was 10 months. CONCLUSIONS: After complete resection of AC, recurrences were observed mostly within the first 5 years of follow-up, within bronchi, mediastinal nodes, the liver, and bones. In R0 patients, lymph node involvement could help to stratify follow-up intervals. Suboptimal imaging is evidenced.

Diagnostic yield of a biopsy performed immediately after lung radiofrequency ablation.

OBJECTIVES: To evaluate the diagnostic performance of lung biopsies performed immediately after radiofrequency ablation (RFA). METHODS: Twenty consecutive patients were treated with lung RFA. A biopsy was performed immediately after RFA, through the cannula used to insert the RFA probe to avoid hampering the RFA probe placement. Biopsies were analysed for diagnostic of malignancy and tumour morphological characteristics. Recurrence of RFA and procedure-related complications are reported. RESULTS: Mean tumour size was 17.3 mm (±6.2 mm). Ninety per cent (18/20) of biopsies were able to help diagnose malignancy. Cancer subtype and origin were determined in 70 % (14/20) of tumours, including 12 metastases and two primary lung cancers. During a median follow-up of 24 months, one tumour demonstrated local progression (5 %). The overall survival, lung disease-free survival and progression-free survival rates at 12 months were 100 %, 75 % and 65 %, respectively. Adverse events of the procedure including RFA and biopsy were five pneumothoraces requiring chest tube placement (25 %), seven minor pneumothoraces (35 %) and one subsegmental intrapulmonary haemorrhage (5 %) not requiring any treatment. CONCLUSIONS: A biopsy performed immediately after lung RFA allowed diagnosis of malignancy in 90 % of cases. This diagnosis is obtained without the need for additional puncture and does not hamper the accuracy of the initial RF probe placement. KEY POINTS: • Treatment and biopsy are feasible during the same procedure, avoiding multiple punctures. • The best puncture path can be preserved to treat the lung tumour. • Malignancy can be determined on a post-RFA biopsy in 90 % of cases. • Cancer classification can be assessed in 70 % of cases after lung RFA.

CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients.

We had previously demonstrated the role of CD103 integrin on lung tumor-infiltrating lymphocyte (TIL) clones in promoting specific TCR-mediated epithelial tumor cell cytotoxicity. However, the contribution of CD103 on intratumoral T cell distribution and functions and the prognosis significance of TIL subpopulations in non-small cell lung carcinoma (NSCLC) have thus far not been systematically addressed. In this study, we show that an enhanced CD103(+) TIL subset correlates with improved early stage NSCLC patient survival and increased intraepithelial lymphocyte infiltration. Moreover, our results indicate that CD8(+)CD103(+) TIL, freshly isolated from NSCLC specimens, display transcriptomic and phenotypic signatures characteristic of tissue-resident memory T cells and frequently express PD-1 and Tim-3 checkpoint receptors. This TIL subset also displays increased activation-induced cell death and mediates specific cytolytic activity toward autologous tumor cells upon blockade of the PD-1-PD-L1 interaction. These findings emphasize the role of CD8(+)CD103(+) tissue-resident memory T cells in promoting intratumoral CTL responses and support the rationale for using anti-PD-1 blocking Ab to reverse tumor-induced T cell exhaustion in NSCLC patients.

BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension.

The impact of bone morphogenetic protein receptor 2 (BMPR2) gene mutations on vascular remodelling in pulmonary arterial hypertension (PAH) is unknown. We sought to identify a histological profile of BMPR2 mutation carriers.Clinical data and lung histology from 44 PAH patients were subjected to systematic analysis and morphometry.Bronchial artery hypertrophy/dilatation and bronchial angiogenesis, as well as muscular remodelling of septal veins were significantly increased in PAH lungs carrying BMPR2 mutations. We found that patients displaying increased bronchial artery remodelling and bronchial microvessel density, irrespective of the mutation status, were more likely to suffer from severe haemoptysis. History of substantial haemoptysis (>50 mL) was significantly more frequent in BMPR2 mutation carriers. 43.5% of BMPR2 mutation carriers, as opposed to 9.5% of noncarriers, displayed singular large fibrovascular lesions, which appear to be closely related to the systemic lung vasculature.Our analysis provides evidence for the involvement of the pulmonary systemic circulation in BMPR2 mutation-related PAH. We show that BMPR2 mutation carriers are more prone to haemoptysis and that haemoptysis is closely correlated to bronchial arterial remodelling and angiogenesis; in turn, pronounced changes in the systemic vasculature correlate with increased pulmonary venous remodelling, creating a distinctive profile in PAH patients harbouring a BMPR2 mutation.

Osteopontin and thrombospondin-1 play opposite roles in promoting tumor aggressiveness of primary resected non-small cell lung cancer.

BACKGROUND: Osteopontin (OPN) and thrombospondin-1 (TSP-1) are extracellular matrix proteins secreted by stromal and tumor cells. These proteins appear to have a key role in the tumor microenvironment for cancer development and metastasis. There is little information regarding the prognostic value of the combination of these two proteins in human cancers. Our aim was to clarify clinical significance and prognostic value of each circulating protein and their combination in primary resected non-small cell lung cancer (NSCLC) patients. METHODS: We retrospectively reviewed 171 patients with NSCLC following curative intent surgery from January to December of 2012. Preoperative serums, demographics, clinical and pathological data and molecular profiling were analyzed. Pre-treatment OPN and TSP-1 serum levels were measured by ELISA. Tissue protein expression in primary tumor samples was determined by immunohistochemical analysis. RESULTS: OPN and TSP-1 serum levels were inversely correlated with survival rates. For each 50 units increment of serum OPN, an increased risk of metastasis by 69 % (unadjusted HR 1.69, 95 % CI 1.12-2.56, p = 0.01) and an increased risk of death by 95 % (unadjusted HR 1.95, 95 % CI 1.15-3.32, p = 0.01) were observed. Conversely, for each 10 units increment in TSP-1, the risk of death was decreased by 85 % (unadjusted HR 0.15, 95 % CI 0.03-0.89; p = 0.04). No statistically significant correlation was found between TSP-1 serum level and distant metastasis-free survival (p = 0.2). On multivariate analysis, OPN and TSP-1 serum levels were independent prognostic factors of overall survival (HR 1.71, 95 % CI 1.04-2.82, p = 0.04 for an increase of 50 ng/mL in OPN; HR 0.18, 95 % CI 0.04-0.87, p = 0.03 for an increase of 10 ng/mL in TSP-1). In addition, the combination of OPN and TSP-1 serum levels remained an independent prognostic factor for overall survival (HR 1.31, 95 % CI 1.03-1.67, p = 0.03 for an increase of 6 ng/mL in OPN/TSP-1 ratio). CONCLUSIONS: Our results show that pre-treatment OPN and TSP-1 serum levels may reflect the aggressiveness of the tumor and might serve as prognostic markers in patients with primary resected NSCLC.

Lymphoproliferative Disorders after Lung Transplantation: Clinicopathological Characterization of 16 Cases with Identification of Very-Late-Onset Forms.

BACKGROUND: The incidence of posttransplant lymphoproliferative disorders (PTLD) has recently declined, but late cases are increasingly reported in lung transplant recipients. OBJECTIVES: We present our experience with PTLD after lung transplantation, attempting to examine the distinguishing characteristics of early versus late cases. METHODS: We have reviewed clinical and pathological data of all cases occurring in our institution between 2001 and 2014. RESULTS: Patients, aged 15-63 years, were mostly (12/16) Epstein-Barr virus (EBV) seropositive at the time of transplantation. Eleven early cases, occurring 9.4 ± 5.2 months after transplantation and mostly (9/11) prior to 2010, had EBV+ diffuse large B-cell lymphomas. Lungs and/or thoracic lymph nodes were often involved (n = 8). Treatments included reduction of immune suppression (n = 11), rituximab (n = 8) and chemotherapy (n = 7). Two patients are in complete remission at 26 and 216 months. Nine patients died 8.0 ± 6.5 months after PTLD diagnosis. Of the 5 cases with late PTLD occurring 4-23 years (mean ± SD: 10.4 ± 7.7) after transplantation (and 3/5 after 2009), 1 had pulmonary lymphomatoid granulomatosis (only endothoracic case), 1 cutaneous large T-cell lymphoma, 2 had anaplastic large cell lymphomas, and 1 Hodgkin's disease. Two of the 5 cases were EBV-, including one followed by a second EBV+ PTLD after 8 years of complete remission. Two patients were alive and well (follow-up: 44 and 151 months), one having suffered from EBV-related cholestatic hepatitis 6 years after the PTLD. CONCLUSION: Our small experience shows a trend toward (very) late occurrence, associated with more unusual clinicopathologic features, but not with a worse prognosis.

Thoracic endometriosis: clinicopathologic updates and issues about 18 cases from a tertiary referring center.

Thoracic endometriosis is defined as the ectopic presence of endometrial glands and stroma in lung or pleura and constitutes an uncommon cause of spontaneous pneumothorax in nonsmoker women in childbearing age. From 2000 to 2014, 18 (7.3%) women of 246 had a histologically proven endometriosis-related pneumothorax. The examination of thoracic samples was performed on formalin-fixed, paraffin-embedded hematoxylin and eosin-stained slides. Immunohistochemistry was carried out on all samples. The pathologic findings included endometriosis foci appearing as a triad of endometrial glands, stroma, and hemosiderin-laden macrophages in 8 patients. In the remaining 10 patients, minute nests of endometrial stroma were recognized at histologic examination and immunohistochemistry. One patient displayed diaphragmatic endometriosis and pulmonary lymphangioleiomyomatosis. Thoracic endometriosis is an uncommon cause of recurrent pneumothorax necessitating histologic confirmation. The histologic diagnosis of endometriosis may be challenging on small pleural or lung biopsies because endometriosis mostly appears as minute nests of endometrial stromal cells. Here, we present our experience on thoracic endometriosis: considering frequent interpretation difficulties of biopsy samples, we propose a multidisciplinary diagnostic algorithm.

Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature.

Limited numbers of operated patients with chronic thromboembolic pulmonary hypertension (CTEPH) are refractory to pulmonary endarterectomy (PEA) and experience persistent pulmonary hypertension (PH). We retrospectively assessed lung histology available from nine patients with persistent PH (ineffective PEA (inPEA) group) and from eight patients transplanted for distal CTEPH inaccessible by PEA (noPEA group). Microscopically observed peculiarities were compared with the histology of a recently developed CTEPH model in piglets. Pre-interventional clinical/haemodynamic data and medical history of patients from the inPEA and noPEA groups were collected and analysed. Conspicuous remodelling of small pulmonary arteries/arterioles, septal veins and pre-septal venules, including focal capillary haemangiomatosis, as well as pronounced hypertrophy and enlargement of bronchial systemic vessels, were the predominant pattern in histology from both groups. Most findings were reproduced in our porcine CTEPH model. Ink injection experiments unmasked abundant venular involvement in so-called small vessel or microvascular disease, as well as post-capillary bronchopulmonary shunting in human and experimental CTEPH. Microvascular disease is partly due to post-capillary remodelling in human and experimental CTEPH and appears to be related to bronchial-to-pulmonary venous shunting. Further studies are needed to clinically assess the functional importance of this finding.

Angiomatoid fibrous histiocytoma of the pulmonary artery: a multidisciplinary discussion.

AIMS: Angiomatoid fibrous histiocytoma (AFH) is a rare neoplastic disease usually occurring in the dermis or subcutis of the extremities of young adults or children. Although sporadic cases in deep soft tissue and visceral organs have been reported, we present here the first description of AFH developing in a large artery. METHODS AND RESULTS: Paraffin sections of the surgical specimen were stained with haematoxylin and eosin, and immunohistochemistry was performed (CKAE1/AE3, EMA, CD34, p63, CD38, smooth muscle actin, and desmin). In addition, FISH and RT-PCR were applied in order to check for EWRS rearrangement. The histomorphological features, and FISH analysis revealing rearrangement of EWSR, indicated the definitive diagnosis of AFH. RT-PCR confirmed EWSR rearrangement, and detected an EWSR1-ATF1 fusion transcript. CONCLUSIONS: A thoracic location of AFH has not been reported until very recently, and shares a differential diagnosis with diverse neoplasms, including spindle cell carcinoma and low-grade sarcoma. We describe the first reported case of thoracic AFH arising in a large vessel, and highlight distinctive histological and molecular features.

[Rythmic-pathology: the French national pathology network for thymic epithelial tumours]. / Rythmic-Pathologie : le groupe français de relecture des tumeurs épithéliales thymiques du réseau clinique Rythmic.

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.

Micronodular thymic epithelial tumors with lymphoid hyperplasia and mimicking lesions.

Micronodular arrangement of epithelial cells and lymphoid B-cell hyperplasia with follicles are both peculiar histological features in thymic tissue. Such features may especially occur in thymic epithelial tumors. The most common form is called micronodular thymoma with lymphoid stroma. We have recently described some characteristics of thymic micronodular carcinoma with lymphoid hyperplasia, highlighting how this carcinomatous counterpart should not be misdiagnosed as a thymoma. In this review, we discuss these two entities but also other mimics, which may occur in the anterior mediastinum. These mimics include various types of cellular micronodules and lymphoid backgrounds encompassing a wide range of mediastinal lesions. Non-neoplastic lesions, such as thymic nodular epithelial hyperplasia, thymic lymphoid hyperplasia, or sarcoidosis, as well as tumors of very varying aggressiveness, such as micronodular thymic epithelial tumors, low-grade lymphoma, seminoma, or lymphoepithelial carcinoma, are discussed. We show how these lesions may be misleading and we describe how a correct diagnostic may be obtained in current practice.

Comparison of juvenile and adult myasthenia gravis in a French cohort with focus on thymic histology.

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile MG (JMG), we analyzed 85 pre- and 132 post-pubescent JMG (with a cutoff age of 13) compared to 721 adult MG patients under 40 years old using a French database. Clinical data, anti-AChR antibody titers, thymectomy, and thymic histology were analyzed. The proportion of females was higher in each subgroup. No significant difference in the anti-AChR titers was observed. Interestingly, the proportion of AChR+ MG patients was notably lower among adult MG patients aged between 30 and 40 years, at 69.7%, compared to over 82.4% in the other subgroups. Thymic histological data were examined in patients who underwent thymectomy during the year of MG onset. Notably, in pre-JMG, the percentage of thymectomized patients was significantly lower (32.9% compared to more than 42.5% in other subgroups), and the delay to thymectomy was twice as long. We found a positive correlation between anti-AChR antibodies and germinal center grade across patient categories. Additionally, only females, particularly post-JMG patients, exhibited the highest rates of lymphofollicular hyperplasia (95% of cases) and germinal center grade. These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty.