Utility of combining OLIG2 and SOX10 IHC expression in CNS tumours: promising biomarkers for subtyping paediatric- and adult-type gliomas.

AIMS: The SOX10 transcription factor is important for the maturation of oligodendrocytes involved in central nervous system (CNS) myelination. Currently, very little information exists about its expression and potential use in CNS tumour diagnoses. The aim of our study was to characterize the expression of SOX10 in a large cohort of CNS tumours and to evaluate its potential use as a biomarker. METHODS: We performed immunohistochemistry (IHC) for SOX10 and OLIG2 in a series of 683 cases of adult- and paediatric-type CNS tumours from different subtypes. The nuclear immunostaining results for SOX10 and OLIG2 were scored as positive (≥10% positive tumour cells) or negative. RESULTS: OLIG2 and SOX10 were positive in diffuse midline gliomas (DMG), H3-mutant, and EZHIP-overexpressed. However, in all DMG, EGFR-mutant, SOX10 was constantly negative. In diffuse paediatric-type high-grade gliomas (HGG), all RTK1 cases were positive for both OLIG2 and SOX10. RTK2 cases were all negative for both OLIG2 and SOX10. MYCN cases variably expressed OLIG2 and were all immunonegative for SOX10. In glioblastoma, IDH-wildtype, OLIG2 was mostly positive, but SOX10 was variably expressed, depending on the epigenetic subtype. All circumscribed astrocytic gliomas were positive for both OLIG2 and SOX10 except pleomorphic xanthoastrocytomas, astroblastomas, MN1-altered, and subependymal giant cell astrocytomas. SOX10 was negative in ependymomas, meningiomas, pinealoblastomas, choroid plexus tumours, intracranial Ewing sarcomas, and embryonal tumours except neuroblastoma, FOXR2-activated. CONCLUSION: To conclude, SOX10 can be incorporated into the IHC panel routinely used by neuropathologists in the diagnostic algorithm of embryonal tumours and for the subtyping of paediatric and adult-type HGG.

B Cell-activating factor (BAFF): A promising trans-nosographic biomarker of inflammation and autoimmunity in bipolar disorder and schizophrenia.

Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3'UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3'UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF.

NTRK-rearranged spindle cell neoplasms are ubiquitous tumours of myofibroblastic lineage with a distinct methylation class.

AIMS: NTRK gene fusions have been described in a wide variety of central nervous system (CNS) and soft tissue tumours, including the provisional tumour type 'spindle cell neoplasm, NTRK-rearranged' (SCN-NTRK), added to the 2020 World Health Organisation Classification of Soft Tissue Tumours. Because of histopathological and molecular overlaps with other soft tissue entities, controversy remains concerning the lineage and terminology of SCN-NTRK. METHODS AND RESULTS: This study included 16 mesenchymal tumours displaying kinase gene fusions (NTRK fusions and one MET fusion) initially diagnosed as infantile fibrosarcomas (IFS), SCN-NTRK and adult-type fibrosarcomas from the soft tissue, viscera and CNS. We used immunohistochemistry, DNA methylation profiling, whole RNA-sequencing and ultrastructural analysis to characterise them. Unsupervised t-distributed stochastic neighbour embedding analysis showed that 11 cases (two CNS tumours and nine extra-CNS) formed a unique and new methylation cluster, while all tumours but one, initially diagnosed as IFS, clustered in a distinct methylation class. All the tumours except one formed a single cluster within the hierarchical clustering of whole RNA-sequencing data. Tumours from the novel methylation class co-expressed CD34 and S100, had variable histopathological grades and frequently displayed a CDKN2A deletion. Ultrastructural analyses evidenced a myofibroblastic differentiation. CONCLUSIONS: Our findings confirm that SCN-NTRK share similar features in adults and children and in all locations combine an infiltrative pattern, distinct epigenetic and transcriptomic profiles, and ultrastructural evidence of a myofibroblastic lineage. Further studies may support the use of new terminology to better describe their myofibroblastic nature.

[The use of immunohistochemical slides for performing FISH as a useful method of conserving tissue samples]. / Ré-utilisation de lames d'immunohistochimie pour la réalisation de FISH : une solution pertinente d'épargne tissulaire.

Diagnostic updates, an increased precision of tumor sub-type classification and the development of new diagnostic biomarkers (immunohistochemistry (IHC), Fluorescence in situ hybridization (FISH) and other molecular pathology techniques), have a significant impact on pathologists' management of tissue samples. The objective of this work was to test and validate the FISH technique on detached IHC slides. An IHC technique was first performed on 30 tissue samples. After detachment of the lamella, a FISH technique was then performed according to the usual protocol with a centromeric probe. A validation cohort (n=10) with duplicate testing using a traditional FISH technique and an IHC slide with a detached lamella was then carried out. Finally, a cohort of 20 "old" cases (IHC carried out over 2years ago) was also tested. Different types of probes (specific locus, break apart) have been used. All the slides were interpreted by a technician and a pathologist. Evaluation criteria were: the general interpretability of the slide ; the percentage of labeled nuclei; intensity of the signal and the presence or absence of autofluorescence. FISH was interpretable in 100% of recently treated cases and 90% of "old" cases with a satisfactory intensity and a high percentage of labeled nuclei, without autofluorescence. The results of our study show that the reuse of IHC slides for performing FISH is a powerful means of economizing tissue samples, especially for small samples and in the absence of archived representative material.

[Contributions and limitations of FISH analysis for the diagnosis of central nervous system tumors according to the 2021 WHO classification: Feedback from Sainte-Anne Hospital's Department of Neuropathology]. / Apports et limites de la FISH dans le diagnostic des tumeurs du système nerveux central selon la classification de l'OMS de 2021 : retour d'expérience du service de neuropathologie de l'hôpital Sainte-Anne.

The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System has identified many new tumor types and has established, for the first time, essential and desirable diagnostic criteria for each of them. Among these, genetic alterations play an important role associated with morphology. For the first time, epigenetic data can also constitute essential and/or desirable criteria. These genetic abnormalities can be fusions, deletions or gains/amplifications and can thus be detected by fluorescence in situ hybridization techniques. The purpose of this article is to present the advantages and limitations of this technique in reference to its specific use within neuro-oncopathology in light of the 2021 WHO classification.

[A pulmonary tumor that racks our brains!] / Une tumeur pulmonaire à se creuser les méninges !

We report the case of a 74-year-old woman who, as part of the follow-up for two breast cancers, presented a 2cm long lung nodule. A microscopic examination of the biopsy under a scanner showed a proliferation of epithelial appearance but whose immunophenotypic profile did not permit a precise diagnosis (negativity of CK7, GATA3, TTF1, negative estrogen receptors but positive progesterone receptors). Wedge resection surgery was performed. Extemporaneous and definitive microscopic examination showed a well-defined lesion made up of lobules of cohesive-looking cells, frequently forming coils. The tumor cells showed some intranuclear inclusions and a few psammomas while the immunohistochemical study showed diffuse expression of EMA, SSTR2A and progesterone receptor markers and a low proliferation index. A diagnosis of a pulmonary localization of a meningioma was proposed. The radiological assessment of the entire neuraxis did not show any other lesion leading to the final diagnosis of primary intra-pulmonary meningioma. This is an exceptional tumor with a difficult histopathological diagnosis of biopsy material, which must familiar to the pathologists. It is associated with an excellent prognosis. Our observation aims to illustrate the macroscopic and microscopic aspects and to present the data from the recent literature review.