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Pulmonary embolism is a major cause of maternal morbidity during pregnancy. Beside the frequently encountered thromboembolism, trophoblastic cell embolism has also been reported in a few case reports. This phenomenon may be symptomless in physiological gestational process but is more pronounced in contexts of preeclampsia or gestational trophoblastic disease. It was exceptionally reported to be associated with death. Here, we report the case of a 15-year-old girl, who experienced dyspnea followed by cardiac arrests and disseminated intravascular coagulation. Echocardiography showed a massive proximal pulmonary embolism. Abdominal sonography revealed that she was 11 weeks pregnant. Autopsy confirmed the presence of multiple clot emboli in the proximal pulmonary arteries. Additionally, the histopathological examination showed a massive syncytiotrophoblastic embolism in the lung microcirculation. Microscopic examination of the uterus revealed an exaggerated placental site reaction. In conclusion, this exhaustive post-mortem study describes a previously unreported association between exaggerated placental site reaction and pulmonary trophoblastic embolism, with fatal issue. Forensic pathologists should be aware that a large sampling of the lungs and uterus and examination of both placenta and fetus are needed to achieve this diagnosis. This case study emphasizes the need for further work elucidating pathways of trophoblast deportation.

The diagnosis of skin wound vitality is currently based on standard histology, but histological findings lack sensitivity in case of a short survival time. New reliable biomarkers of vitality are therefore strongly needed. We assessed the ability of 10 candidate cytokines (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α) to discriminate between vital and early post-mortem wounds. Twenty-four cadavers with a recent open skin wound (

The International Society for the Study of Vascular Anomalies (ISSVA) has defined four vascular lesions in the central nervous system (CNS): arteriovenous malformations, cavernous angiomas (also known as cerebral cavernous malformations), venous malformations, and telangiectasias. From a retrospective central radiological and histopathological review of 202 CNS vascular lesions, we identified three cases of unclassified vascular lesions. Interestingly, they shared the same radiological and histopathological features evoking the cavernous subtype of angioleiomyomas described in the soft tissue. We grouped them together with four additional similar cases from our clinicopathological network and performed combined molecular analyses. In addition, cases were compared with a cohort of 5 soft tissue angioleiomyomas. Three out 6 CNS lesions presented the same p.Gly41Cys GJA4 mutation recently reported in hepatic hemangiomas and cutaneous venous malformations and found in 4/5 soft tissue angioleiomyomas of our cohort with available data. Most DNA methylation profiles were not classifiable using the CNS brain tumor (version 12.5), and sarcoma (version 12.2) classifiers. However, using unsupervised t-SNE analysis and hierarchical clustering analysis, 5 of the 6 lesions grouped together and formed a distinct epigenetic group, separated from the clusters of soft tissue angioleiomyomas, other vascular tumors, inflammatory myofibroblastic tumors and meningiomas. Our extensive literature review identified several cases similar to these lesions, with a wide variety of denominations. Based on radiological and histomolecular findings, we suggest the new terminology of “dural angioleiomyomas” (DALM) to designate these lesions characterized by a distinct DNA methylation pattern and frequent GJA4 mutations.

In the forensic anthropology practice, bone diseases are rarely considered for personal identification. In this paper, we present a forensic skeletonized case with tuberculous bone lesions, for which bone pathology may provide an indicator for positive personal identification. Antemortem hospital records were available. Postmortem CT scans of the pathologically affected bones were performed, and 3D reconstructions with Global Illumination Reconstruction software (GIR) were realized, in order to confront antemortem and postmortem data. As a result, the juxtaposition and superimposition of antemortem and postmortem images evidenced several points of correspondence in the position, anatomical contour, character, and morphological characteristics of the bone lesions, thus demonstrating through a concrete case study the potential of morphological features of bone lesions for the personal identification of unknown deceased.

The diagnosis of anaplastic meningioma (AM) (WHO grade III) is based on the presence of a high mitotic index (MI) and/or overt anaplasia. Only few data exist about the reproducibility and prognostic value of overt anaplasia. Additionally, the prognostic value of H3K27me3 loss in AM has not yet been demonstrated. Our objectives were to evaluate the reproducibility and prognostic value of WHO criteria and H3K27me3 loss in a multicenter series of 66 AM. Interobserver reproducibility was good for the determination of WHO grade (Kappa = 0.671) and MI (intraclass correlation coefficient [ICC] = 0.649), and fair for assessment of overt anaplasia (Kappa = 0.366). Patients with meningiomas showing high MI had significantly shorter overall survival (OS) than patients with meningiomas showing overt anaplasia without high MI (p = 0.009). OS was significantly lower in case of overt anaplasia with low MI (

Rosette-forming glioneuronal tumour (RGNT) is a rare central nervous system (CNS) World Health Organization (WHO) grade 1 brain neoplasm. According to the WHO 2021, essential diagnostic criteria are a 'biphasic histomorphology with neurocytic and a glial component, and uniform neurocytes forming rosettes and/or perivascular pseudorosettes associated with synaptophysin expression' and/or DNA methylation profile of RGNT whereas 'FGFR1 mutation with co-occurring PIK3CA and/or NF1 mutation' are desirable criteria.We report a series of 46 cases fulfilling the essential pathological diagnostic criteria for RGNT. FGFR1 and PIK3CA hotspot mutations were searched for by multiplexed digital PCR in all cases, whereas DNA methylation profiling and/or PIK3R1 and NF1 alterations were analysed in a subset of cases.Three groups were observed. The first one included 21 intracranial midline tumours demonstrating FGFR1 mutation associated with PIK3CA or PIK3R1 (n = 19) or NF1 (n = 1) or PIK3CA and NF1 (n = 1) mutation. By DNA methylation profiling, eight cases were classified as RGNT (they demonstrated FGFR1 and PIK3CA or PIK3R1 mutations). Group 2 comprised 11 cases associated with one single FGFR1 mutation. Group 3 included six cases classified as low-grade glioma (LGG) other than RGNT (one-sixth showed FGFR1 mutation and one a FGFR1 and NF1 mutation) and eight cases without FGFR1 mutation. Groups 2 and 3 were enriched in lateral and spinal cases.We suggest adding FGFR1 mutation and intracranial midline location as essential diagnostic criteria. When DNA methylation profiling is not available, a RGNT diagnosis remains certain in cases demonstrating characteristic pathological features and FGFR1 mutation associated with either PIK3CA or PIK3R1 mutation.

Pediatric bithalamic gliomas encompass several histomolecular tumoral types from benign to malignant and underlines the central role of a comprehensive neuropathological review, including immunohistochemistry, genetic, and epigenetic analyses, to achieve an accurate diagnosis.

International audience; Introduction : L’application PELICAN (« Partager efficacement en laboratoire les informations des comptes rendus anatomopathologiques ») est un outil permettant de générer des comptes rendus standardisés et de renseigner automatiquement une base de données, utilisée au CHRU de Nancy depuis 2014 en neuropathologie tumorale. L’objectif de cet article était d’illustrer l’utilisation de cette application pour les méningiomes, avec une première exploitation statistique.Matériels et méthodes : L’étude inclut les cas de méningiomes enregistrés dans l’application PELICAN jusqu’en juillet 2018. L’application PELICAN est un fichier Microsoft Excel comportant un logiciel écrit en Visual Basic pour Applications, utilisé par le pathologiste pour élaborer le compte rendu. Les principales données cliniques ont été recueillies à partir de la fiche de recensement du Registre de l’Hérault. Le suivi était renseigné de façon systématique pour les méningiomes atypiques.Résultats : Deux cent quatre-vingt-quinze méningiomes ont été analysés dont 250 méningiomes de grade I, 42 méningiomes de grade II et 3 méningiomes de grade III. Dans les méningiomes de grade II, on constatait une proportion significativement plus élevée d’hommes (p = 0,002) et d’infiltration de la dure-mère (p < 0,001), une augmentation significative de l’indice Ki-67 (p < 0,0001) et une diminution significative de l’expression des récepteurs à la progestérone (p < 0,001). Dans les méningiomes atypiques, un indice Ki-67 de plus de 20 % était corrélé significativement à une survie sans progression plus courte (p = 0,032).Conclusion : L’application PELICAN est un outil d’utilisation simple, permettant de générer des comptes rendus standardisés tout en alimentant une base de données, ouvrant de très intéressantes perspectives d’un point de vue épidémiologique et scientifique.

Current histoprognostic parameters and prognostic scores used in paragangliomas and pheochromocytomas do not adequately predict the risk of metastastic progression and survival. Here, using a series of 147 cases of paraganglioma and pheochromocytoma, we designed and evaluated the potential of a new score, the COPPS (COmposite Pheochromocytoma/paraganglioma Prognostic Score), by taking into consideration three clinico-pathological features (including tumor size, necrosis, and vascular invasion), and the losses of PS100 and SDHB immunostain to predict the risk of metastasis. We compared also the performance of the COPPS with several presently used histoprognostic parameters in risk assessment of these tumors. A PASS score (Pheochromocytoma of the Adrenal gland Scaled Score) ≥ 6 was significantly associated with the occurrence of metastases (P

The coronavirus disease 2019 (COVID-19), due to SARS-CoV-2, is primarily a respiratory disease, causing in most severe cases life-threatening acute respiratory distress syndrome (ARDS). Cardiovascular involvement can also occur, such as thrombosis or myocarditis, generally associated with pulmonary lesions. Little is known about SARS-CoV-2-induced myocarditis. We report the case of a 69-year-old man suffering from a refractory cardiogenic shock, without significant lung involvement. Prior to death, several nasopharyngeal swabs and distal bronchoalveolar lavage were sampled in order to perform RT-PCR analyses for SARS-CoV-2-RNA, which all gave negative results. Autopsy showed coronary atherosclerosis, without acute complication. Microscopic examination of the heart revealed the existence of an intense multifocal inflammatory infiltration, in both ventricles and septum, composed in its majority of macrophages and CD8+ cytotoxic T lymphocytes (CD4/CD8 ratio: 0.11). Immunohistochemistry for anti-SARS nucleocapsid protein antibody was strongly positive in myocardial cells, but not in lung tissue. RT-PCR was realized on formalin-fixed paraffin-embedded lung and heart tissue blocks: only heart tissue was positive for SARS-CoV-2 RNA. In conclusion, this exhaustive post-mortem pathological case study of fulminant myocarditis demonstrates the presence of SARS-CoV-2 RNA in heart tissue, without significant lung involvement. Immunohistochemistry showed that the virus was specifically localized in cardiomyocytes and induced a strong cytotoxic T cells inflammatory response. This case report thus gives new insight in the pathogenesis of SARS-CoV-2-induced myocarditis and emphasizes on the importance and reliability of post-mortem analyses in order to better understand the physiopathology of this worldwide spreading new viral disease.

Pediatric chordomas are rare malignant neoplasms, and few data are available for optimizing therapeutic strategies and outcome. This study aimed at evaluating how best to manage them and to identify prognostic factors. This multicentric retrospective study included 40 children diagnosed with chordomas between 1966 and 2012. Clinical, radiological, and histopathological data, treatment modalities, and outcomes were reviewed. The median age was 12 years old. Most chordomas were histologically classical forms (45.5%) and were mostly located at the skull base (72.5%). The overall survival (OS) was 66.6% and 58.6%, and progression-free survival (PFS) was 55.7% and 52% at 5 and 10 years, respectively. Total resection was correlated with a better outcome (p = 0.04 for OS and PFS, log-rank). A histopathological/immunohistochemical grading system recently crafted for adults was applied. In a multivariate analysis, it significantly correlated with outcome (PFS and OS, p = 0.004), and the loss of BAF47 immunoexpression appeared to be a significant independent prognostic factor (PFS, p = 0.033). We also identified clinical and histopathological parameters that correlated with prognosis. A new grading system combined with the quality of surgical resection could help classify patients to postpone radiotherapy in case of low risk. Targeted therapy and reirradiation at recurrence may be considered as potential therapeutic strategies.

Minichromosome maintenance complex component 6 (MCM6) is involved in initiating DNA replication and is upregulated during licensed G0 phase of the cell cycle. This early expression permits its labeling of more proliferating cells than those by Ki-67. Here using a cohort of 89 endometrioid adenocarcinoma, we report findings made on the prognostic value of MCM6 based on immunohistochemical labeling index (LI) of the protein in comparison with that of Ki67 as no such information is currently available. Additionally, we examined the prognostic values of these markers based on their mRNA expression using a cohort of uterine corpus endometrial carcinoma (UCEC, n = 307) taken from The Cancer Genome Atlas (TCGA) database. Our evidence indicated the presence of a positive correlation between the LI of MCM6 and the histological grade of endometrioid endometrial adenocarcinoma (grade I, 66.7%; grade II, 75.3%; grade III, 81.4%; p

HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro-oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti-proliferative effects of HuR knockdown in two meningioma cell lines (IOMM-Lee and Ben-Men-1) and conducted transcriptome-wide analyses (IOMM-Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade (p = 1.2 × 10-8 ) and negatively with progression-free and overall survival (p = 0.01) time in human meningioma tissues. In vitro, siHuR-induced HuR knockdown was shown to reduce the growth of both Ben-Men-1 (p = 2 × 10-8 ) and IOMM-Lee (p = 4 × 10-9 ) cells. Transcriptome analyses revealed HuR knockdown in IOMM-Lee cells to deregulate the HIF1A signalling pathway (p = 1.5 × 10-6 ) and to up-regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide-excision repair, poly(A)-specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [p(FDR)

The differential diagnosis between meningioma and others tumors can be challenging. This study aimed to evaluate different immunohistochemical markers for the differential diagnosis between meningioma and their morphological mimics. Immunohistochemistry was performed on tissue microarray with antiepithelial membrane antigen (EMA), progesterone receptor, somatostatin receptor 2A (SSTR2A), CD34, STAT6, S100, SOX10, HMB45, MelanA, GFAP, inhibin, and BCL2 antibodies. One hundred and twenty-seven meningiomas, 26 solitary fibrous tumor/hemangiopericytomas (SFT/HPC), 39 schwannomas, 17 hemangioblastomas, 21 melanomas, 9 gliosarcomas, 5 neurofibromas, 9 peripheral primitive neuroectodermal tumors, 7 synovial sarcomas, and 5 malignant peripheral nerve sheath tumors were included in the microarray. SSTR2A was the most sensitive (95.2%) and specific (92%) marker of meningiomas. In combination, SSTR2A and/or EMA positivity reached maximal sensitivity (100%). Coexpression of SSTR2A and EMA was the most specific (94.8%) for the diagnosis of meningioma, regardless of the grade or subtype, with the exception of the differential diagnosis with synovial sarcoma. All synovial sarcomas were EMA-positive and 6/7 SSTR2A-positive. STAT6 showed optimum sensitivity and specificity (100%) for SFT/HPC. SOX10 was the most sensitive (94.3%) and specific (100%) marker to discriminate meningiomas from schwannomas. In conclusion, SSTR2A, STAT6, and SOX10 were the most sensitive and specific markers to distinguish meningiomas from their morphological mimics.

International audience

Denosumab, an antibody directed against receptor activator of nuclear factor-κB ligand (RANKL), has recently been introduced in the treatment strategy of giant cell tumor of bone. In this study, we assessed the tumor changes induced by denosumab in a national multicentric series of 35 cases (French Bone Pathology Group network-ResOs). Tissue specimens collected before and after denosumab treatment were investigated for RANKL, H3.3 G34W, p63, and Ki-67 expression, and for H3F3A mutation. These parameters were put in correspondance with clinical and radiologic presentation to identify prognostic factors, and more specifically, predictive markers of an optimal histologic response to denosumab, identified as a ≥50% loss in giant cells with fibrosis and ossification. The main changes in posttreatment specimens showed an induction of ossification (P=2.10), an increased fibrosis (P=3.10), and a major decrease in giant cells (P=6.10). No significant change in mononuclear tumor cell density and in patterns of expression of RANKL (P=0.061) and H3.3 G34W was observed (P=0.061). An optimal histologic response to denosumab treatment was associated with an enhanced progression-free survival (P=0.010 in univariate analyses; P=0.040 in multivariate analyses). The initial number of giant cells was predictive of the histologic response to treatment (P=0.016). In summary, denosumab treatment induced radical changes in the tumor. The histologic response, despite the absence of objective regression of the mononuclear cells, was associated with an enhanced progression-free survival. Greater numbers of giant cells represented the only predictive indication of an optimal histologic response to denosumab treatment.

International audience; Anaplastic oligodendroglioma (AO), IDH‐mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high‐grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki‐67, in a large series of IDHmut+/1p19qcodel AO included in the POLA (“Prise en charge des Oligodendrogliomes Anaplasiques”) French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labelling indices (LI) of MCM6 and Ki‐67 were obtained via computer‐assisted color image analyses on immunostained AO tissues of the cohort (n=220). Furthermore, a subgroup of AO (n=68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki‐67 (≥ 15%) correlated with shorter overall survival, both in univariate (P=0.013 and P=0.004, respectively) and multivariate analyses (P=0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki‐67). MCM6 and Ki‐67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro‐neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta‐amyloid binding, and postsynaptic specialization.In conclusion, the overexpression of MCM6 and/or Ki‐67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy‐to‐use and cost‐effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down‐regulated immune response and lower microglial cells activation, and bears pro‐neural phenotype.

Resume Introduction L’application PELICAN (« partager efficacement en laboratoire les informations des comptes rendus anatomopathologiques ») est un outil permettant de generer des comptes rendus standardises et de creer des bases de donnees utilisables a visee scientifique. Cette application est utilisee dans notre laboratoire depuis 2014 en neuropathologie tumorale. L’objectif de ce travail etait de l’etendre a un autre type de tumeur, le cancer du poumon. Materiel et methodes Le contenu des comptes rendus etait au prealable defini a l’aide de divers referentiels (Societe francaise de pathologie, institut national du cancer, classification OMS 2015, …). Une double codification SNOMED et ADICAP etait utilisee. L’application PELICAN est un fichier Microsoft Excel comportant un logiciel specifiquement developpe pour les laboratoires, ecrit en Visual Basic pour Applications, et respectant la norme CDA-R2. Resultats Apres etablissement du cahier des charges, une beta-version a ete installee en fevrier 2018. Diverses mises a jour ont ensuite ete realisees, la version 3.19 ayant ete installee en juillet 2018. La quasi-totalite des pieces d’exerese fait ainsi aujourd’hui l’objet d’un compte-rendu genere par l’application PELICAN. Un total de 56 comptes-rendus a ete valide au moment de la redaction de cet article. Par rapport aux comptes rendus classiques, le temps medical de generation du compte rendu est globalement le meme, voire diminue, le temps de secretariat etant quant a lui fortement diminue. Conclusion L’application PELICAN est un outil simple, d’utilisation facile, permettant de generer des comptes rendus standardises en pathologie pulmonaire, alimentant une base de donnees facilement exploitable sur le plan statistique.

Microvascular proliferation (MVP) is a hallmark of glioblastoma. Endothelial cell hypertrophy (ECH), also known as endothelial hyperplasia, is correlated with a shorter survival of patients with gliomas. However, the prognostic value of these 2 morphological features has not been studied in meningiomas. The aim of this study was to evaluate the prognostic value of angiogenesis in meningiomas, most notably ECH, MVP, and microvascular density, which were evaluated using immunohistochemistry with antibodies against CD34 and CD105 (a marker of neovascularization) in a series of 139 meningiomas. ECH, MVP, and CD105 immunoreactivity were significantly correlated with higher histological grades (p

In this daily practice, the forensic pathologist is rarely confronted with postmortem hyperthermia associated with the rapid onset of rigor mortis. We report 2 similar cases where the rectal temperature value taken during the on-scene investigations by the forensic pathologist was greater than 40°C (104°F) in both cases, and rigor mortis was complete within less than 6 hours postmortem. The first case was due to a deadly intoxication by ecstasy and the second one to the deadly association of methadone and a possible neuroleptic malignant syndrome. Infection-related deaths were eliminated. Thus, the association of postmortem hyperthermia and rapid-onset rigor mortis would suggest in the first hypothesis a toxic death, particularly 3,4-methylenedioxymethamphetamine. However, an autopsy and toxicological analysis are necessary to confirm the cause of death.

International audience; Few studies on oncogenesis of chondrosarcoma (CS) are available in the literature. Our previously published experimental evidence suggests that while the C-propeptide of procollagen I alpha 1 (PC1CP), a component of cartilage, favors tumor progression, the C-propeptide of procollagen II alpha 1 (PC2CP) exerts antitumor properties. In this study, we analyzed expression of PC1CP and PC2CP by immunohistochemistry in a series of enchondromas and CS. Our retrospective series consisted of 88 cases, including 43 CSs, 34 enchondromas and 11 nontumor samples. Immunohistochemical staining for PC1CP and PC2CP was evaluated in the cytoplasm and in the extracellular matrix (ECM). Diffuse staining for PC1CP in ECM was significantly more frequent in tumor than in nontumor samples (32 % vs. 0 %; p = 0.03), and in CSs than in enchondromas (44 vs. 18 %; p = 0.02). ECM semiquantitative score was higher in tumors than in nontumor samples (p < 0.005) and higher in CSs than in enchondromas (p = 0.05). Staining for PC2CP in ECM was more frequently found in enchondromas than in CSs (59 vs. 33 %; p = 0.02). ECM semiquantitative score was higher in enchondromas than in CSs (p = 0.02). Diffuse staining for PC1CP in combination with absence of staining for PC2CP had 94 % specificity for CS but with a sensitivity of only 35 %. Expression of neither PC1CP nor PC2CP correlated with recurrence-free survival or occurrence of metastases. In conclusion, we show that the expression of PC1CP is higher and that of PC2CP lower in malignant cartilaginous tumors. These results support an oncogenic role of PC1CP and anti-oncogenic property of PC2CP in cartilaginous tumors.

International audience; The promalignant effects of neurotensin (NTS) are sustained in many solid tumors, including hormone-dependent cancers. As the endometrium is also subjected to hormonal regulation, we evaluated the contribution of NTS to endometrial carcinogenesis. Neurotensin receptor 1 (NTSR1) expression and NTSR1 promoter methylation (HM450) were analyzed in 385 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Additionally, from a series of 100 endometrial carcinomas, and 66 benign endometrium samples, NTS and NTSR1 labeling was evaluated by immunohistochemistry. Using TCGA series, NTSR1 messenger RNA (mRNA) level was negatively correlated with overall survival (OS) and progression-free survival (PFS) (p = 0.0012 and p = 0.0116, respectively), and positively correlated with the grade (p = 0.0008). When including only endometrioid carcinomas, NTSR1 mRNA level continued to be negatively correlated with OS (log-rank: p < 0.0001) and PFS (log-rank: p = 0.002). A higher NTSR1 mRNA level was significantly associated with a loss of NTSR1 promoter methylation. Immunohistochemical expression of NTS and NTSR1 was significantly increased in adenocarcinoma (n = 100), as compared to benign endometrium (p < 0.001). NTSR1 expression was positively correlated with grade (p = 0.004). High immunohistochemical expression of cytoplasmic NTSR1 was significantly correlated with a shorter OS and PFS (p < 0.001 and p = 0.001, respectively). This correlation remained significant when excluding non-endometrioid subtypes (p = 0.04 and p = 0.02, respectively). In multivariate analysis, the expression of NTSR1 was an independent prognostic factor (p = 0.004). NTSR1 overexpression is a poor prognostic factor in endometrial cancer, highlighting the contribution of NTS in endometrial cancer progression and its uses as a prognostic marker, and as a potential therapeutic target.

The timing of skin wounds is one of the most challenging problems in forensic pathology. In the first minutes or hours after infliction, histological examination fails to determine whether a wound was sustained before or after death. The aim of this study was to evaluate the use of three immunohistochemical markers (FVIIIra, CD15, and tryptase) for the interpretation of the timing of cutaneous stab wounds. We evaluated these markers in intravital wounds from autopsy cases (n = 12) and surgical specimens (n = 58). As controls, we used normal skin samples from autopsies (n = 8) and an original ex vivo surgical human model of recent postmortem wounds (n = 24). We found overexpression of FVIIIra in 100 % of vital wounds, but also in 53 % of the controls. The number of CD15-positive cells was higher in wound margins than in internal controls (p < 0.0001) and was significantly correlated with the time interval between incision and devascularization (p = 0.0005; minimal time for positivity, 9 min). Using the anti-tryptase antibody, we found that the mast cell degranulation rate was higher in wound margins (p < 0.0001) and correlated with the time interval (minimal time, 1 min). The sensitivity and specificity for the diagnosis of vitality were respectively 100 and 47 % for FVIIIra, 47 and 100 % for CD15, and 60 and 100 % for tryptase. The inter-observer agreement coefficients were 0.68 for FVIIIra, 0.90 for CD15, and 0.46 for tryptase. Finally, we demonstrated that these markers were not reliable in putrefied or desiccated specimens. In conclusion, CD15 and tryptase, but not FVIIIra, may be useful markers for differentiating recent antemortem from postmortem injuries.

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

Retinoid receptors (RRs) play a key role in cell proliferation and differentiation. We characterized the expression of RA receptors and retinoid X receptors (RARs and RXRs) in a series of 111 thyroid tumors and investigated the mechanisms responsible for their deregulation: hypermethylation of the RARB2 promoter, loss of heterozygosity (LOH) in the regions of RARB and RXRA, and altered expression of CRBP1 and enzymes involved in RA biosynthesis (RDH10 and RALDH2). Expression of RALDH2 and RDH10 was conserved in 100 % of adenomas and in 90 and 98 %, respectively, of carcinomas, whereas staining for CRBP1 was decreased in 9 % of FAs and 28 % of carcinomas, mainly anaplastic carcinomas (55 %). We found an abnormal expression of RARA, RARB, RXRA, and RXRB in 67, 69, 66, and 73 %, respectively, of thyroid carcinomas (n = 78) and in 9, 9, 9, and 33 % of follicular adenomas (n = 33) (p < 0.001). An abnormal staining pattern of at least two of these markers had 90 % sensitivity and 91 % specificity for a diagnosis of malignancy. Promoter hypermethylation of RARB2 was observed in some anaplastic carcinomas (14 %). LOH was found to be common at the RARB locus (3p24–3p25) and the RXRA locus (9q34), respectively, in 44 and 55 % of carcinomas and in 27 and 43 % of adenomas. In conclusion, immunohistochemical staining for RARs and RXRs may help in the differential diagnosis between well-differentiated carcinoma and follicular adenoma. Further investigation should be carried out to determine whether the characterization of RR expression might identify patients who could benefit from therapy with RA derivatives.

Skin wounds datation is one of the most challenging problems in forensic pathology. The vitality of a recent wound cannot be affirmed when no inflammatory cell is visible. There are in the literature numerous studies about wound vitality, looking for markers involved in coagulation or inflammation, using various methods such as enzymology, molecular biology or immunohistochemistry. In this update, we first introduce some methodological principles to respect. Then, we review the main studies available in the literature. We insist on immunohistochemistry, which seems to be the more valuable method, given its easiness to perform and the possibility to analyze the localization of the molecules of interest. Some markers are promising, such as TNFα, IL-6, IL-1β, TGFα or TGFβ1. Before using them in daily practice, these first results need to be confirmed with other studies, driven by independent teams and integrating multiple controls. Most notably, the antibodies have to be tested in numerous post-mortem wounds. Indeed, there is a critical risk of overexpression in post-mortem wounds, and some interesting markers have been secondary invalidated because of post-mortem false positivity (e.g. fibronectin, P-selectin). Finally, optimal sensibility and specificity values would be probably reached by combining several markers, validated with large groups of pre- and post-mortem wounds.

Resume Introduction La ponction ganglionnaire mediastinale transbronchique guidee par video echo-endoscopie est une technique peu invasive permettant d’echantillonner des adenopathies mediastinales ou hilaires. La faible abondance du materiel recueilli impose une prise en charge optimale des echantillons. Materiel et methodes A partir d’une serie retrospective de 150 examens, nous evaluons les performances diagnostiques globales et de chacune des techniques utilisees pour analyser le materiel recueilli. Resultats Le rendement diagnostique global est de 64,0 % pour les 50 premiers examens (phase d’apprentissage), de 88,0 % pour les 100 examens suivants. La sensibilite et la valeur predictive negative (VPN) maximales globales sont respectivement de 96,3 % et 92,7 %. Le rendement, la sensibilite et la VPN des etalements sont respectivement de 68,0 %, 75,0 % et 66,0 %, de la cytologie monocouche de 77,8 %, 62,1 % et 50,0 %, et de l’inclusion de 65,8 %, 94,4 % et 86,7 %. La combinaison des differentes techniques permet d’ameliorer le rendement par rapport a l’inclusion ou aux etalements seuls (p = 0,03), et la sensibilite et la VPN par rapport aux etalements (p Conclusion La ponction transbronchique guidee par video echo-endoscopie est une technique fiable et sensible. Le conditionnement en milieu liquide et l’inclusion des microfragments permettent d’ameliorer les performances diagnostiques par rapport aux etalements cytologiques seuls, en particulier pour le diagnostic de sarcoidose.

We report two cases of salivary gland anlage tumor (SGAT), a nasopharyngeal lesion that affects newborns. The first case concerned a male newborn, presenting respiratory distress secondary to a nasopharyngeal mass. The second case was diagnosed in a 6-week-old girl, suffering from respiratory difficulties due to a nasal cavity mass. A magnetic resonance imaging (MRI) in the second case revealed the presence of several small round and linear fluid-like areas. Histologically, both lesions were suggestive of SGAT, characterized by epithelial structures that blended with spindle-cells, drawing highly cellular nodules. Connective tissue between nodules contained squamous cystic nests and ducts.

Resume Introduction Les carcinomes metaplasiques du sein sont rares et forment un groupe heterogene de tumeurs, definies par la presence d’une differenciation epidermoide ou sarcomatoide. Patientes et methodes A partir d’une serie de 23 cas, nous en etudions les principaux elements histopronostiques, le statut hormonal (RO, RP) et HER2, l’expression de CK5/6, CK14, p63, EGFR, β-catenine, MUC1 et E-cadherine, l’expression de ces sept derniers antigenes etant egalement etudiee au niveau des metastases ganglionnaires. Resultats Les metaplasies observees sont a cellules fusiformes (35 %), epidermoides (26 %), heterologues osteo- ou chondrosarcomatoides (13 %), ou mixtes (26 %). Des emboles vasculaires sont presents dans 30 % des lesions, des infiltrations perinerveuses dans 4 %, des metastases ganglionnaires dans 33 %. Les marquages constates pour chaque antigene sont : RO+ : 4 % ; RP+ : 8 % ; HER2+ : 0 % ; p63+ : 74 % ; CK14+ : 83 % ; CK5/6+ : 74 % ; EGFR+ : 100 % ; E-cadherine+ : 70 % ; β-catenine : expression aberrante (cytoplasmique ou membranaire faible superieure a 5 % des cellules) : 74 %, negative : 13 % ; MUC1 : expression aberrante (cytoplasmique ou membranaire complete superieure a 5 %) : 35 %, membranaire partiel pur : 22 %, negative : 43 %. Dans 43 % des cas on constate une augmentation de la proportion d’expression aberrante de MUC1 dans les metastases ganglionnaires par rapport a la tumeur primitive. Conclusion Les carcinomes metaplasiques sont des tumeurs agressives, generalement de phenotype « triple-negatif » et basal. Les expressions de MUC1 et de la β-catenine sont souvent absentes ou perturbees, ce qui pourrait jouer un role dans la dissemination metastatique.

Resume Un patient etait opere a 26 ans d’une tumeur du vermis cerebelleux, puis reopere d’une recidive locale a l’âge de 35 ans. L’examen anatomopathologique de la lesion mettait en evidence une proliferation en nappes densement cellulaires evocatrices de medulloblastome. Sur ce fond etaient dispersees des cellules de grande taille au cytoplasme eosinophile, au noyau arrondi avec un volumineux nucleole. L’etude immuno-histochimique montrait une expression de la proteine du neurofilament et de la synaptophysine par la plupart des cellules neuroblastiques. Les cellules de grande taille exprimaient la desmine, la myogenine et le neurofilament. Cet aspect morphologique, joint au profil immuno-histochimique, est caracteristique du medullomyoblastome. Le patient decedait 11 ans apres la premiere intervention. Le medullomyoblastome est une lesion rare, correspondant a une variante de medulloblastome avec differenciation musculaire, les deux populations tumorales partageant les memes alterations genetiques. Les principaux diagnostics differentiels sont la tumeur rhabdoide et teratoide atypique, le teratome immature, le medulloepitheliome, le rhabdomyosarcome intracerebral primitif et le myoneurocytome.

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Introduction Les chordomes sont des tumeurs malignes rares d’origine notochordale, affectant exceptionnellement les enfants (moins de 5 % de l’ensemble des chordomes) et dont le potentiel evolutif est marque par un risque important de recidives locales. Nous avons etabli un grading mixte immunohistopronostique dans une serie de 287 chordomes de l’adulte. Celui-ci integre des donnees morphologiques (presence d’un contingent peu differencie, necrose, nucleoles proeminents, apoptose et mitoses ≥ 3/10 HPF) et immunohistochimiques (Ki67 ≥ 6 % et p53 ≥ 25 %). Ces criteres sont egalement pronostiques sur une serie de 33 chordomes pediatriques, associes au statut BAF47 (SMARCB1). Objectifs : – analyser par biologie moleculaire les alterations du gene SMARCB1 dans les chordomes BAF47-deficients en immunohistochimie ; – valider, chez l’enfant, le score immunohistopronostique defini chez l’adulte ; – etablir un algorithme pronostique tenant compte du statut SMARCB1 des chordomes. Methodes Etude retrospective multicentrique avec relecture histologique et realisation d’un panel d’immunomarquages comprenant brachyurie, Ki67, p53, E-cadherine, EGFR, VEGF, PTEN, pSTAT3 et BAF47. Analyse par technique MLPA (mulitplex ligation dependent probe amplification assay) et sequencage du gene SMARCB1. Analyse par FISH afin de rechercher une deletion du gene pour les prelevements non contributifs en MLPA. Resultats L’analyse immunohistochimique a revele une expression de STAT3p, VEGF, EGFR et une perte de PTEN significative sans correlation avec le pronostic. Une deletion du gene SMARCB1 a ete mise en evidence par MLPA dans 2 cas (3 cas non contributifs en MLPA et en FISH). De facon significative, nous proposons un algorithme pronostique dans lequel les chordomes BAF47-deficients sont ceux ayant le pronostic le plus pejoratif. Dans les chordomes BAF47-conserves, le score immunohistopronostique defini chez l’adulte s’applique mais permet ici de distinguer, de facon significative, trois grades (bas, intermediaire et haut), correles avec la survie globale et la survie sans progression (p = 0,0007 et Discussion Nos resultats montrent que la perte d’expression de BAF47 est liee a une deletion et non une mutation du gene SMARCB1. L’algorithme propose, utilisable en routine distingue : – les chordomes au pronostic le plus severe (BAF47-deficients), ce qui les rapproche d’autres tumeurs presentant une alteration du complexe SWI/SNF egalement grevees d’un pronostic pejoratif (tumeurs rhabdoides et teratoides atypiques avec alterations de SMARCB1, meningiomes a cellules claires avec alterations de SMARCE1) ; – trois grades pour les chordomes BAF47-conserves. Conclusion Notre serie de chordomes pediatriques permet d’etablir un algorithme pronostique pertinent pouvant modifier la prise en charge et le suivi de ces tumeurs malignes au profil evolutif variable.

The BRAF(V600E) mutation confers worse prognosis to metastatic colorectal cancer (mCRC) patients. In addition, this mutation has a negative predictive value for response to treatment with monoclonal antibodies against EGFR in patients with KRAS wild-type (wt) mCRC. The utility of immunohistochemistry (IHC) as an alternative approach for detection of BRAF(V600E) in the thoracic metastases of sporadic mCRC patients has not been evaluated until now. The purpose of this study was to compare BRAF(V600E) IHC staining with molecular biology methods and to define the diagnostic value of the VE1 antibody for the detection of BRAF(V600E) in this population. BRAF mutations were analysed by two DNA sequencing methods (pyrosequencing and Sanger sequencing) in a Caucasian population of 310 sporadic mCRC with thoracic metastases patients expressing KRAS wt. Detection of the BRAF(V600E) mutation was performed in the corresponding tumours by IHC using the VE1 antibody and compared to results of the DNA-based assays. Thirty-nine out of 310 (13%) of tumours harboured a BRAF mutation, which corresponded to either a BRAF(V600E) in 34 of 310 (11%) cases or a non-BRAF(V600E) mutation in 5 of 310 (2%) cases. IHC with VE1 was strongly positive in 32 of 34 (88%) BRAF(V600E) mutated tumours and negative in non-BRAF(V600E) mutated tumours. IHC using the VE1 clone is a specific and sensitive method for the detection of BRAF(V600E) and may be either a complementary or an alternative method to molecular testing in mCRC patients.

Respiratory epithelial adenomatoid hamartoma (REAH) is regarded as a rare tumor of the nasal cavity. The mechanisms driving the development of REAH are unknown, and its nature as a benign tumor, hamartoma, or reactive inflammatory process is still open to discussion. A total of 150 consecutive patients operated on for nasal polyposis (NP) were extensively checked for the diagnosis of REAH. The profile of REAH occurring in association with NP was compared with solitary REAH in a series of 19 cases. The possible role of tryptase-producing mast cells (MC) and of metalloproteinases MMP2 and MMP9 in REAH development was investigated by immunohistochemistry. REAH lesions were identified in 35% of patients who had surgery for NP (53/150). The distribution of the lesions suggested that REAH originated in the olfactory cleft. Solitary REAH occurred about 20 times less frequently than those observed in an NP context but shared the same microscopic characteristics. Tryptase-producing MCs were recruited at high density in REAH (135/10 hpf), compared with inflammatory polyps (45/10 hpf; P

Endobronchial ultrasound-guided transbronchial needle aspiration has demonstrated its accuracy in the diagnostic workup of enlarged mediastinal lymph nodes. In addition to conventional smears, the use of liquid-based cytology (LBC) and cell block preparations (CBP) has been introduced more recently. The aim of our study was to determine the performance of each of the different techniques, separately and combined, in terms of diagnostic yield and sensitivity. A total of 290 consecutive patients were included. The pathological examination was based on smear cytology, LBC, and CBP. Adequate sampling was defined by the presence of pathological material or lymphocytes. The global diagnostic yield was 82.7 % and the sensitivity was 89.1 %. The diagnostic yield was 72.8 % for smears, 78.8 % for LBC, and 69.9 % for CBP. The combination of smears with CBP significantly increased diagnostic yield (p = 0.01) and sensitivity (p = 0.006), but not the combination of smears with LBC (yield: p = 0.07; sensitivity: p = 0.13). The combination of the three techniques further increased yield (p = 0.007) and sensitivity (p = 0.006), compared with smears alone. CBP were more sensitive than smears for both diagnoses of carcinoma (p = 0.01) and granulomatous inflammation (p = 0.048). Conversely, LBC was less sensitive than smears for granulomatous inflammation (p = 0.004), but the difference was not significant for carcinoma (p = 0.42). CBP, as a complement to smears, increases diagnostic yield and sensitivity for both diagnoses of carcinoma and granulomatous inflammation. LBC, if used alone, increases the risk of a false-negative result.

Summary Aims The aim of this study was to genotype a series of papillary thyroid carcinomas (PTCs) and anaplastic thyroid carcinomas (ATCs) for BRAF mutation, and to evaluate p53 and SOX2 expression as factors implicated in tumour progression. Methods The study included 17 PTCs and 14 ATCs. Analysis of the exon 15 of BRAF was based on direct sequencing. Immunohistochemistry was used to evaluate p53 and SOX2 expression. Results V600E (c.1799T>A) mutation was observed in 53% (9/17) of PTCs. Two cases of ATCs (2/14; 14%), both with PTC component, harboured BRAF mutation: the classical V600E mutation and an undocumented duplication of codon 599 (c.1795_1797dup; p.Thr599dup). These mutations were present in ATC as well as PTC tumour cells. Overexpression of p53 and SOX2 was depicted respectively in 64% (9/14) and 29% (4/14) of ATCs, and absent in PTCs. Conclusion We confirm that V600E mutation is a frequent and specific event in PTC. BRAF -mutated ATCs are associated with a PTC component displaying the same mutation. We describe a new mutation of BRAF, T599dup, in a case of ATC with tall cell PTC component. Moreover, progression from PTC to ATC could be favoured by further TP53 mutation and SOX2 expression.

Summary Background Hyalinised fibrous nodules have been encountered within the gastrointestinal tract (GIT) and been labelled as reactive nodular fibrous tumours. Several have a history of abdominal surgery and/or sepsis that acts as a precipitating cause for the fibrosis. Recently, much attention has been focused on IgG4 related fibrosing lesions that are typically associated with a high population of IgG4 positive plasma cells and tissue fibrosis. There may be attendant elevated serum IgG4 levels and associated autoimmune disease. Methods We present four patients with well-circumscribed fibrous nodular lesions occurring in the GIT Tissue was formalin fixed after microwave antigen retrieval and H&E stains and immunohistochemistry were performed. IgG4/ IgG ratios were calculated from the three high power fields containing the densest concentration of positive plasma cells. Results The patients were two females (45 and 56 years) and two males (47 and 60 years) who presented with gastric (2 cases), caecal and sigmoid flexure involvement. One case had four lesions while the other three cases were solitary nodules. Two patients had coexistent autoimmune disease. All lesions were nodular and composed of paucicellular, hyalinised fibrous tissue associated with chronic inflammation. In all lesions the plasma cell population was strongly IgG4 positive. Conclusions This paper describes unique, well-circumscribed sclerosing nodules containing IgG4 positive plasma cells within the bowel wall that may cause mucosal polypoid lesions. It is possible that these lesions may be related to the spectrum of IgG4 related sclerosing disease or belong to a separate subset of inflammatory reactive conditions that are rich in IgG4 plasma cells.