Hairy cell proliferations represent very different entities. They include hairy cell leukemia in its classic form (HCL), a well-defined entity, but also the variant form of HCL (LT-V ou HCL-V), whose presentation is far from HCL and whose prognosis is poorer. Other hairy cell proliferations include splenic red pulp lymphoma (SDRPL) and splenic marginal zone lymphomas (SMZL) with circulating villous cells. In this article, we emphasize the novelties concerning the different recent biological aspects of HCL, including the unusual clinical presentations but also the importance for the diagnosis of the detection of the BRAFV600E mutation, a molecular marker of the disease, and the presence of other non-canonical mutations that should be identified because of the contraindication to the use of BRAF inhibitors. Finally, the presence of a non-mutated profile of immunoglobulin heavy chains (IGHV), observed in 20% of cases, is associated with a poor prognosis. We also provide guidance in characterizing other hairy cell proliferations when examining the blood smear. The first-line treatment of HCL has recently changed and immunochemotherapy combining cladribine plus rituximab has become the gold standard. In relapsed or refractory forms, other treatments should be discussed in a multidisciplinary consultation meeting and combine BRAF inhibitors with anti-CD20 antibodies, BTK inhibitors or Bcl-2 inhibitors. The choices should be discussed according to the patient's profile but also their biological profile.

Alterations in DNA methylation profiles are typically found in cancer cells, combining genome-wide hypomethylation with hypermethylation of specific regions, such as CpG islands, which are normally unmethylated. Driving effects in cancer development have been associated with alteration of DNA methylation in certain regions, inducing, for example, the repression of tumor suppressor genes or the activation of oncogenes and retrotransposons. These alterations represent prime candidates for the development of specific markers for the detection, diagnosis and prognosis of cancer. In particular, these markers, distributed along the genome, provide a wealth of information that offers potential for innovation in the field of liquid biopsy, in particular thanks to the emergence of artificial intelligence for diagnostic purposes. This could overcome the limitations related to sensitivities and specificities, which remain too low for the most difficult applications in oncology: the detection of cancers at an early stage, the monitoring of residual disease and the analysis of brain tumors. In addition, targeting the enzymatic processes that control the epigenome offers new therapeutic strategies that could reverse the regulatory anomalies of these altered epigenomes.

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumour, with a poor prognosis, ranking third for cancer mortality worldwide. HCC is a morphologically and molecularly heterogeneous tumour. This update aims to address this heterogeneity by describing the different histological and molecular subtypes of HCC. Morphologically, eight subtypes have been described according to the WHO classification: steatohepatitic, macrotrabecular massive (MTM), clear cell, chromophobe, scirrhous, fibrolamellar, lymphocyte-rich and neutrophil-rich. Other HCCs are classified as non-specific (not otherwise specified or NOS). These subtypes may be associated with a different prognosis, particularly the MTM, which displays a poorer survival than the other subtypes. Genomically, most HCCs present mutations in the TERT promoter, while other mutations occured later in carcinogenesis, such as TP53 and CTNNB1. TP53 mutated HCCs are associated with a poor prognosis and the MTM subtype. From a transcriptomic standpoint, two classifications are particularly noteworthy, as they are associated with both prognosis (proliferative vs. non-proliferative classification) and clinical, morphological and genomic tumour characteristics (G1-G6 classification). In conclusion, the morphological heterogeneity of HCC, directly linked to molecular heterogeneity, is associated with prognosis. This strongly supports the specification of the different HCC subtypes in our reports.

Since the last FIGO classification in 2009, numerous studies and recommendations have contributed to improving the management of endometrial cancer. The introduction of molecular classification (including POLE, MMR, and P53 status) has enabled better categorization of these cancers by defining specific patient groups, thus allowing for more tailored surgical management and adjuvant treatment. The data and analyses on molecular and histological classification developed in the 2021 guidelines from the European Societies of Gynecologic Oncology (ESGO), Radiation Therapy and Oncology (ESTRO), and Anatomical Pathology (ESP) have been utilized to develop the new 2023 FIGO classification for endometrial cancer. We are witnessing an evolution of the FIGO classification, shifting from a purely anatomical classification to a risk-based classification. It is important in pathology reports to specify the histological type of the tumor, the grade for endometrioid tumors, the presence or absence of lymphovascular space invasion, and the extent of the tumor (myometrial invasion, involvement of the serosa, cervix, vagina, adnexa, or neighboring organs). These essential points are included in the 2023 FIGO classification and will enable precise staging of the tumor. This article aims to clarify and simplify the classification of patients according to the new 2023 FIGO classification for endometrial cancer.

In the 2020 5th edition of the World Health Organization classification of soft tissue and bone tumours a major reorganization of Undifferentiated Small Round Cell Sarcomas (USRCS) took place based on the underlying molecular features. The classification now recognizes Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusions, CIC-rearranged sarcoma and sarcoma with BCOR alterations. The focus on these genetic alterations highlights the importance of molecular techniques in the diagnosis of these entities. Knowledge of these features can drastically reduce the time to diagnosis and avoid potential misdiagnosis. Molecular diagnostic capabilities should not be limited to an overall small number of centres worldwide as is reflected by the WHO's recognition of 'essential' and 'desirable' diagnostic criteria. A good knowledge of the usual histomorphology, uncommon variants and diagnostic pitfalls remains essential even in centres with access to a full molecular testing arsenal. This review aims to give an overview of the current classification of USRCS not by going over each entity, but instead going over the molecular, morphological, immunophenotypic and clinical features step by step to allow easy comparison of these features between the separate entities.

Triple negative breast cancer (TNBC) is defined by the absence of expression of estrogen and progesterone receptors, as well as the absence of overexpression of HER2. Accounting for 10 to 15% of breast cancers, it remains characterized by an aggressive phenotype with an increased risk of early recurrence and overall survival less favorable compared to other subtypes. The challenges in management and therapeutic evolution are likely related to the demonstrated high biological heterogeneity of this subtype. Regarding therapeutic management, chemotherapy remains the cornerstone of TNBC treatment. In the early stage, the neoadjuvant strategy is the standard, allowing adaptation of the adjuvant sequence depending on whether a complete histological response is achieved or not. Dose-dense chemotherapy regimens and the addition of carboplatin have been associated with an improvement in these response rates. Furthermore, immunotherapy, particularly pembrolizumab, has shown significant benefits in terms of recurrence-free survival. In the metastatic setting, the role of theranostic markers is now established, allowing access to immunotherapy (pembrolizumab if CPS PD-L1>10%) or PARP inhibitors (in case of constitutional BRCA mutation). Antibody-drug conjugates are gradually moving up the lines, offering promising prospects in these complex situations. In conclusion, despite recent progress, TNBC remains a major clinical challenge. A better understanding of its biology and a personalized therapeutic approach are essential to improve clinical outcomes for patients with this aggressive form of breast cancer.

MANAGING MEDULLARY THYROID CARCINOMA IN 2024: Medullary thyroid carcinoma is a rare neuroendocrine thyroid cancer with a heterogeneous prognosis which has the particularity of being associated with a RET gene mutation, germline in 20-25% of cases in the context of multiple endocrine neoplasia type 2 (NEM2), and somatic in 70% of sporadic cases. It is often diagnosed on a thyroid nodule or in the context of genetic screening. Calcitonin is a biological marker, used for diagnosis, monitoring of therapeutic response and prognostic evaluation. The only curative treatment is surgery for localized disease. The extent must be carefully assessed, particularly in terms of calcitonin levels and imaging, and carried out by an expert surgeon. The prognosis of locally advanced or metastatic disease is highly heterogeneous. Histological factors, such as high grade, or biological factors, such as calcitonin doubling time, can help assess prognosis. The development of multi-kinase inhibitors cabonzantinib and vandetanib, and RET-targeted inhibitors selpercatinib, has completely changed the therapeutic arsenal for advanced disease, but their prescription is reserved to progressive disease with high tumor volume or to symptomatic disease inaccessible to local treatment in expert centers from the ENDOCAN-TUTHYREF network. Active surveillance is the alternative of choice for slowly progressing disease.

WHO CLASSIFICATION 2022, BETHESDA SYSTEM 2023, MOLECULAR BIOLOGY AND MOLECULAR TESTING: Thyroid pathology has experienced significant advances with the publication of the 5th edition of the World Health Organization classification of endocrine tumors in 2022 and the third edition of the Bethesda system for thyroid cytopathology in 2023. At the same time, the availability of next-generation sequencing data coupled with numerous translational research projects have considerably increased our knowledge of the genomics and mechanics of thyroid cancers, enabling us to refine prognosis and propose new targeted therapies. In this review, we will take up the main new features of the WHO 2022 and Bethesda 2023 classifications, as well as molecular biology findings, with an emphasis on the practical implications for clinicians.

Non-small cell lung cancers (NSCLC) are the most common lung cancers, withpeak incidence at 65years of age. These cancers rarely occur before the age of 40.

This review focuses on uterine mesenchymal tumors that are defined on a molecular level by a single and unique genetic alteration, that is somehow necessary and sufficient to allow tumor growth and progression. Although diverse from a clinical, morphological and immunohistochemical point of view, the different entities we are going to talk about share both a simple genomic profile with a low number of chromosomal alterations observed by CGH Array (few deletions, gains or amplifications...) and a low mutational burden observed by sequencing technics. Some of these entities are already well known and described in the literature when found outside of the uterus and gynecological tract. It remains intriguing that uterine mesenchymal pathology has been lagging behind when compared to its extrauterine counterpart. How can we explain that when it comes to inflammatory myofibroblastic tumors, abundant numbers of articles have been published since the 70's, but it was only in the early 2000s that the first relevant descriptions of this tumor in the uterus emerged? Certainly, the increased accuracy, availability, and use of molecular biology technics and in particular RNA sequencing in the area of uterine pathology can partly explain the reduction of the gap between soft tissue and uterine pathology we currently observe. Other reasons explaining this gap may be the high prevalence of smooth muscle tumors in the uterus and the abounding diversity of their morphological aspects, which may have partly eclipsed the array of differential diagnoses. Last but not least, one can hypothesize that the relative "simplicity" of hysterectomy procedures, referring to their safety and accessibility, has cured most of the lesions and partly clouded our knowledge regarding the biological potential and natural history of these newly described entities. As a consequence of this situation, our reader will often encounter the wording "uncertain malignant potential", as for some of these rare entities, evidence to establish reliable prognostic variables is still insufficient. We hope this review to be a useful tool to guide pathologists through the diversity and complexity of uterine mesenchymal tumors. As a scientific and medical community, sharing this knowledge will help us to collectively raise our vigilance and awareness by expanding the array of our differential diagnoses. We hope this will lead to more cases being accurately diagnosed, and ultimately, to a deeper knowledge regarding the biological potential and clinical evolution of these tumors. From a therapeutical point of view, the consequences of an accurate diagnosis for the patient are already appreciable through the use of targeted therapy. Examples include: ALK inhibitors in inflammatory myofibroblastic tumor, tyrosine-kinase inhibitors in COL1A::PDGFB rearranged sarcomas or mTOR inhibitors in PEComa.

The prognostic of certain cancers improved significantly in recent years thanks not only to the launch of innovative treatments but also to progress made in the diagnostic field. Thus, next-generation sequencing (NGS) became paramount to help characterizing tumors and selecting the most pertinent treatments. The survey conducted by a multi stakeholder committee, at the end of 2022, with 103 actors of the management of cancer patients (public and private centers, labs, prescribers, biologists, pathologists, direction) confirmed the heterogeneity of use of NGS tests across France due to, mainly, the lack of systematic reimbursement of related costs. Référentiel des actes innovants hors nomenclature de biologie (RIHN) covers, in a delayed and partial way, only half of costs engaged by centers. Only those with a critical mass of patients or with a sufficient funding capacity can guarantee an access to large panels. Postponing the initiation of a required treatment represents a risk of loss of opportunity for patients who cannot benefit of this technology. NGS large panels tests, an efficiency lever for cancer treatment, must be part of the care toolbox. Those with a demonstration of value created should nowadays be fully reimbursed by collectivity after HAS' evaluation, for a fair access throughout the territory. Precision diagnostic can open the way to a more personalized and efficient medicine.

Molecular profiling has become essential in the management of patients with biliary tract cancer (BTC). The aim of this study was to evaluate the practices of French genetics platforms in the management of BTCs.

In 2019, the 5th edition of the WHO classification of digestive tumours has retained the terminology "goblet cell adenocarcinoma" (GCA) to designate a tumour whose amphicrine nature owed it more than ten denominations since its initial description among which the most tenacious "goblet cell carcinoid" is no longer recommended today. This rare tumour represents 15-19% of appendicular tumours. Its incidence is rising. The positive diagnosis is based on morphological examination and mandatory identification of a low-grade component of glands comprising goblet cells stained by PAS and Alcian blue. The appendix must be entirely examined. Global tumour grade (low, intermediate, high) is based on the proportions of low-grade and high-grade components. This tumour's immunohistochemical profile is particular because of expression of CK20 and often CK7 as well as neuroendocrine markers. It is often an incidental finding on a surgical specimen, among individuals aged 50 or more years, presenting with a locally advanced stage with vascular and perineural invasion. Lymph node metastases are present in a third of cases. Non-specific mutations of ARID1A and genes of the Wnt pathway may be identified. GCA is not associated with microsatellite instability or Lynch syndrome. Its prognosis is intermediate. Surgery is the reference therapy based on the stage. The main differential diagnoses are colorectal adenocarcinoma NOS, mucinous adenocarcinoma and signet ring cell adenocarcinoma. Patients are referred to the RENAPE expert network.

The grading of glial tumors is based on morphological and sometimes on molecular features. Many markers have been assessed in order to grade the glial tumours without a real consensus. Some authors reported that SRSF1, a spiling factor, presents an expression correlated to the tumours grades.

Castration-resistant metastatic prostate cancer remains lethal and a therapeutic challenge. Current strategies are geared towards the personalization of treatments based on the identification of relevant molecular targets, including genomic alterations involved in tumoral processes. Among these novel targeted therapies, poly-ADP-ribose polymerase inhibitors (PARPi), by blocking the action of enzymes involved in deoxyribonucleic acid (DNA) repair, induce the destruction of cells carrying defects in homologous recombination repair, often associated with alterations in genes involved in this mechanism. Thus, determining the presence of a molecular anomaly, particularly alterations in the BRCA1/2 genes, is a prerequisite for initiating PARPi monotherapy. In patients with metastatic castration-resistant prostate cancer , around 20-30 % carry this type of mutation. In this population, single-agent studies have demonstrated PARPi ability to prolong overall survival, and to improve symptom control, including pain. Other studies are underway to assess their effectiveness in combination with other therapies, and it already appears that association with new-generation hormone therapy can further prolong radiological progression-free survival, regardless of the mutation status of the genes involved in DNA repair, indicating a synergistic action between PARPi and new-generation hormone therapy.

RUNX1 is essential during human hematopoiesis. Numerous RUNX1 deregulations have been described, including translocations and germline or somatic mutations. Recurrent de novo RUNX1 mutations in acute myeloid leukemias (AML) prompted the creation of a provisional entity of AML with mutated RUNX1 in the 2016 WHO. In addition, recent genomic studies underlined rare AML patients with plasmacytoid dendritic cell (pDC) expansion and high RUNX1 mutations frequency. To better characterized AML with RUNX1 mutations, we retrospectively investigated a cohort of 32 patients diagnosed at Strasbourg University Hospital. Detailed clinical and biological features were aggregated. The presence of a pDC contingent was assessed by cytology and flow cytometry. In our cohort, no common features were identified either in term of cytology, stage of leukemia arrest or mutational features. Based on our observations, mutated RUNX1 AMLs do not appear to be a distinct AML entity. The new 2022 WHO classification includes AML with mutated RUNX1 within AML myelodysplasia-related category. We also identified within our cohort a patient whose AML fulfilled AML-pDC criteria, a rare and newly included entity in the last WHO classification.

The rising global incidence of cancer makes it the second leading cause of death worldwide. Over the past decades, significant progress has been made in both basic knowledge and the discovery of new therapeutic approaches. However, the complexity of mechanisms related to tumor development requires the use of sophisticated and adapted research tools. Among these, the fruitfly Drosophila melanogaster represents a powerful genetic model with numerous practical and conceptual advantages. Indeed, the conservation of genes implicated in cancer between this insect and mammals places Drosophila as a crucial genetic tool for understanding the fundamental mechanisms governing tumorigenesis and identifying new therapeutic targets. This review aims to describe this original model and demonstrate its relevance for studying cancer biology.

Treatment of pediatric high-risk acute myeloid leukemia (AML), defined either on molecular or cytogenetic features, relies on bone marrow transplant after cytologic remission. However, relapse remains the first post-transplant cause of mortality. In this 13th session of practice harmonization of the francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), our group worked on recommendations regarding the management of post-transplant relapse in AML pediatric patients based on international literature, national survey and expert opinion. Overall, immunomodulation strategy relying on both measurable residual disease (MRD) and chimerism evaluation should be used for high-risk AML. In very high-risk (VHR) AML with a 5-year overall survival ≤30 %, a post-transplant maintenance should be proposed using either hypomethylating agents, combined with DLI whenever possible, or FLT3 tyrosine kinase inhibitors if this target is present on leukemia cells. In the pre-emptive or early relapse settings (< 6 months post-transplant), treatments combining DLI, Azacytidine and Venetoclax should be considered. Access to phase I/II trails for targeted therapies (menin, IDH or JAK inhibitors) should be discussed in each patient according to the underlying molecular abnormalities of the disease.