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.

Primitive cutaneous T-cell lymphomas are lymphomas clinically restricted to skin at diagnosis in opposite to skin localizations of systemic lymphomas. Cutaneous T-cell lymphomas are the most frequent. Beside mycosis fungoides and related forms, CD30+ lymphoproliferations (lymphomatoid papulosis, anaplastic large cell primitive cutaneous T-cell lymphomas) and erythrodermic T-cell lymphomas which constitute the main entities, other rare lymphomas are described: panniculitis like alpha/beta lymphoma, gamma/delta lymphoma, epidermotropic CD8+ aggressive lymphoma, small to medium T-cell lymphomas and acral CD8+ lymphoproliferations. Clinical skin examination and skin biopsy examination are crucial for diagnosis but recent advances in molecular genetics bring promising tools for diagnostic. Thanks to international cooperative groups, treatment of mycosis fungoides, CD30+ lymphoproliferations and erythrodermic lymphomas is now well established which is not the case for the other entities. Treatments may be classified in five categories: skin directed therapies, systemic non-chemotherapeutic treatments, immunomodulators, targeted immunotherapies and chemotherapies.

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.

LATEST DEVELOPMENTS IN ANAPLASTIC THYROID CARCINOMA MANAGEMENT IN 2024: Anaplastic thyroid carcinomas (ATCs) represent a rare and undifferentiated form of thyroid cancer with a poor prognosis, typically marked by a median overall survival of four to ten months. However, recent advances have shown improvements due to the more systematic application of molecular testing, targeted therapies, and immunotherapy, alongside the establishment of rapid specialized care protocols in expert centers. Clinically, ATCs often present as a rapidly enlarging cervical mass originating from the thyroid, causing neck, pain and tenderness, dyspnea and dys-phagia, and associated lymphadenopathy, typically in elderly patients. Diagnostic confirmation requires an urgent biopsy, reviewed by a pathologist within the TUTHYREF-path network, with a mandatory search for BRAFV600E molecular alterations. Following diagnosis, care coordination is expedited within an expert center of the ENDOCAN-TUTHYREF network whenever feasible. Initial surgery is rarely an option due to frequent loco-regional cervical invasion. A multimodal treatment approach is essential: BRAF/MEK inhibitors (dabrafenib/trametinib) in cases of BRAFV600E mutation, or chemotherapy in the absence of a molecular target, combined with radiotherapy and, potentially, surgery if the disease becomes resectable following induction therapy. PD-1/PD-L1 targeted immunotherapy, either alone or in combination with targeted therapies, has shown potential to extend survival in some patients; however, predictive biomarkers and the optimal sequencing of immunotherapy (whether as induction and/or maintenance) require further clarification and may vary depending on the clinical context.

TREATING RADIO-IODINE REFRACTORY DIFFERENTIATED THYROID CANCER IN 2024: About 5 to 10% of patients with differentiated thyroid cancer (DTC) have advanced tumors at presentation or recurrence, with invasive cervical disease and/or distant metastases that cannot be effectively treated by conventional treatment, i.e. thyroid surgery and radioactive iodine. These DTC cases are defined as refractory to radioiodine (RAIR) and require expert multidisciplinary management. In France, patients are referred to centers of the ENDOCAN-TUTHYREF Network. This review summarizes current management of RAIR DTC patients and therapeutic options available in 2024. We discuss following topics : epidemiological data, modalities of local ablative treatment for selected metastatic lesions, molecular tests to be performed, optimum timing for initiating systemic therapy, choice of first-line treatment among validated tyrosine kinase inhibitors (TKIs), alternative targeted treatments (including selective TKIs adapted to the molecular profile, some of which can redifferentiate and restore radioactive iodine uptake), proactive management of TKI side effects, and finally give an overview of systemic strategies. Management of RAIR DTC is still challenging but substantial progress has been made over the last decade that has significantly improved outcome for these more aggressive thyroid cancer.

The incidence of follicular-derived thyroid cancers has increased worldwide in recent decades, mainly papillary thyroid cancers at low recurrence risk. A process of de-escalation in the initial management and follow-up of these patients has therefore been implemented in parallel. This article provides the best practice recommendations made by the French learned societies (Société française d'endocrinologie, Société française de médecine nucléaire, Association française de chirurgie endocrine, Société française d'oto-rhino-laryngologie et de chirurgie de la face et du cou), european and international learned societies (European Society for Medical Oncology and the American Thyroid Association), in the management of follicular-derived thyroid cancer without distant metastases. The extent of thyroid surgery and lymph node dissection, strategies of radioiodine ablation, follow-up protocols and the management of excellent prognosis papillary cancers ≤ 10 mm will be addressed.

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.

Superficial leiomyosarcoma is a rare malignant soft tissue tumor arising from smooth muscle cells, accounting for 2-3% of superficial sarcomas, with limited literature available on the subject. It is typically observed in patients aged 50-60 years and affects both men and women equally in the subcutaneous subtype, whereas the cutaneous subtype predominantly affects men.

Ovarian cancers are gynecological cancers with a poor prognosis. Most ovarian cancers are high-grade serous carcinomas. It is now accepted that they are very often tubal in origin. Their management has undergone major advances in recent years. Their clinical manifestations are not very specific, and no screening test has yet -proved its worth, which explains why they are often diagnosed late. The diagnostic phase is essentially based on ultrasound and abdomino-pelvic CT scans, for reasons of ease of access. Other -examination modalities, such as MRI and above all PET-Ct, are playing an increasingly important role in the initial management of extension or thera-peutic follow-up. Even with notable advances in diagnosis and treatment, the overall prognosis remains poor.

Enhanced Recovery After Surgery (ERAS) is a series of measures designed to promote early recovery after surgery. Application of this approach has led to significantly decreased morbi-mortality and reduced length of hospital stay. The aim of our study was to determine whether non-completion of the ERAS protocol following robotic-assisted mini-invasive lobectomy could be the cause of prolonged hospital stay (exceeding 6 days). We conducted a longitudinal retrospective analysis of 34 patients (17 men and 17 women) having undergone robotic-assisted lobectomy for early-stage primary lung carcinoma from January 1, 2022 to December 31, 2022. The study population was divided into two groups based on length of hospital stay: group 1 with length of stay not exceeding 6 days and group 2 with a stay of 7 days or more. Comparative analysis showed no significant difference in ERAS completion score between the two groups, whatever the preoperative (P=0.15), perioperative (P=0.73) or postoperative (P=0.97) time. That said, prolonged air leak (P=0.01) was the main difference among the analyzed variables, followed by Charlson score (P=0.01), grade of complications (P=0.03) and smoking status (P=0.01). Incorporation of complementary measures in our ERAS protocol strategy would in all probability optimize air leak management and further reduce length of hospital stay.

Current events in radiotherapy oncology are marked by the results of strategic trials, particularly for esophageal and rectal cancers. For resectable esophageal adenocarcinoma, results of the ESOPEC study showed a benefit in overall survival from the perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin and docetaxel compared to chemoradiotherapy (41.4Gy radiotherapy and carboplatin/paclitaxel chemotherapy). In definitive setting, the CONCORDE study did not show any benefit from dose escalation and the standard dose remains 50Gy. For resectable pancreatic cancer, the NRG/RTOG0848 study that compared adjuvant chemotherapy with or without chemoradiotherapy found a significant increase of the 5-year disease-free survival rate in the subgroup of node-negative patients. For rectal cancers, the 7-year update of PRODIGE 23 study confirmed the benefit in disease-free- and overall survival of neoadjuvant folinic acid, fluorouracil, irinotecan and oxaliplatin chemotherapy before chemoradiotherapy of T3, T4 or N+ adenocarcinoma, while the update of the RAPIDO study revealed an unacceptable local recurrence rate in the experimental arm. The update of the OPRA study shows a significantly higher 5-year organ preservation rate in favor of the chemoradiotherapy arm followed by consolidation chemotherapy compared to induction chemotherapy followed by CRT. A phase 2 study, including 41 patients with mismatch repair deficient, locally advanced rectal cancer reported that exclusive treatment with anti-PDL1 immunotherapy (dostarlimab) for 6 months resulted in complete clinical response without the need of additional treatment (neither radiotherapy nor surgery). For anal carcinoma, the analysis of survival and toxicity profiles of patients treated for a small stage T1 or T2 tumor were compared depending on whether they received exclusive radiotherapy or chemoradiotherapy. The addition of chemotherapy to radiotherapy did not show any survival benefit but significantly increased toxicity and the risk of radiotherapy disruption.

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 three most common varieties of systemic amyloidosis are transthyretin amyloidosis (ATTR), immunoglobulin amyloidosis (AL) and inflammatory amyloidosis (AA). There are two forms of transthyretin amyloidosis: the wild type, the most common, represents approximately 15% of heart diseases and the genetic, or "mutated" form, which is a rare disease and manifests mainly by peripheral neuropathy and heart disease. Major therapeutic advances have been made in recent years thanks to molecules that stabilize transthyretin and/or prevent its translation by destroying messenger RNA. Immunoglobulin amyloidosis (AL) is a hematological disease whose severity is due to the toxicity of immunoglobulin light chains forming amyloid deposits that are toxic to tissues, particularly the heart and kidneys. Treatments for immunoglobulin amyloidosis are increasingly effective, and target the plasma cell, leading to an overall improvement in the prognosis, with cardiac involvement being the most worrying condition. Inflammatory amyloidosis (AA) complicates chronic inflammatory diseases less often due to the effectiveness of anti-inflammatory biotherapies in inflammatory rheumatism, chronic inflammatory bowel diseases and genetic auto-inflammatory diseases. The causes of inflammatory amyloidosis are now more diverse with an increase in cases of unknown cause associated or not with obesity.

Herein, we provide a non-exhaustive selection of the main clinical trials presented in 2023-2024 related to radiation-oncology used in the treatment of urological cancers including prostate cancer (radiotherapy of localized prostate cancer, post-prostatectomy irradiation, reirradiation, biochemical recurrence following local treatment, radiotherapy for metastatic cancer), muscle invasive bladder cancer and primary kidney cancer.

Myeloid sarcoma (MS) is a rare extra-medullary manifestation of acute myeloid leukaemia (AML) in the form of a first manifestation, progression or recurrence. Mostly located in the bones, it has the particularity of reaching the ENT sphere by mimicking common patho-logies, leading to a delay in diagnosis and treatment. The -mastoid involvement that we have encountered in our clinical -practice (clinical vignette) shows the complexity of identifying this pathology, with very few cases reported in the literature. The anamnesis, including a -history of AML, and the clinical examination help to guide the investigations. Targeted imaging, in this case CT/MRI combined with a biopsy of the lesion and a marrow puncture, is used to make the -diagnosis. Treatment with chemotherapy is indicated and rapidly initiated.

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.

The aim of our study was to assess the proportion of high-grade histological lesions, according to HPV type, in patients referred for colposcopy involving a positive HPV-HR test and ASC-US cytology.