SENOSI Confocal Microscopy: A New and Innovating Way to Detect Positive Margins in Non-Palpable Breast Cancer?

In Switzerland, breast cancer is the leading cancer among women, with breast-conserving surgery (BCS) being the preferred treatment for small tumors. The margin status post-surgery is a critical predictor of local recurrence. Achieving negative margins remains a challenge, leading to re-excision in 20-30% of cases. Traditional methods like intraoperative examination palpation and radiography have limitations in assessing excised margins. This study introduces the Histolog® Scanner, a confocal microscopy tool, as a potential solution. It provides real-time images of tissue architecture, allowing for rapid and accurate assessment of excised margins. Our research compared the Histolog® Scanner with standard per-operative radiography in patients with non palpable breast cancer. Preliminary results indicate that the Histolog® Scanner offers a reliable and time-efficient method for margin assessment, suggesting its potential for clinical integration.

Follicular Lymphoma Presenting With Symptomatic Bone Involvement: A Clinicopathologic and Molecular Analysis of 16 Cases.

Primary bone lymphoma (PBL) is rare and mostly represented by diffuse large B-cell lymphomas (DLBCL). Follicular lymphoma (FL), albeit commonly disseminating to the bone marrow, rarely presents primarily as bone lesions. Here, we studied 16 patients (12 men:4 women, median age 60 years) who presented with bone pain and/or skeletal radiologic abnormalities revealing bone FL. Lesions were multifocal in 11 patients (spine ± appendicular skeleton), and unifocal in 5 patients (femoral, tibial, or vertebral). An infiltrate of centrocytes and centroblasts (CD20+ CD5- CD10+ BCL2+ BCL6+) with abundant reactive T cells and an increased reticulin fibrosis massively replaced the marrow spaces between preserved bone trabeculae. The pattern was diffuse ± nodular, often with paratrabecular reinforcement and/or peripheral paratrabecular extension. Ki-67 was usually <15%. Two cases had necrosis. BCL2 rearrangement was demonstrated in 14 of 14 evaluable cases (with concomitant BCL6 rearrangement in one). High-throughput sequencing revealed BCL2, KMT2D, and TNFRSF14 to be the most frequently mutated genes. After staging, 5 qualified for PBL (3 limited stage) and 11 had stage IV systemic FL. All patients received rituximab ± polychemotherapy as firstline treatment, and 7 received local therapy (6 radiotherapy and 2 surgery). Three patients experienced transformation to DLBCL. At the last follow-up (15/16, median 48 months), 11 patients achieved complete remission, including all cases with PBL and most patients with limited extraosseous disease (3-year progression-free survival 71%). One patient died of unrelated cause (3-year overall survival 91%). FL may manifest as a localized or polyostotic bone disease. A minority represent PBL, whereas most reveal systemic disease.

CIC-DUX4 Chromatin Profiling Reveals New Epigenetic Dependencies and Actionable Therapeutic Targets in CIC-Rearranged Sarcomas.

CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor that occurs most frequently in young adults. The key oncogenic driver of this disease is the expression of the CIC-DUX4 fusion protein as a result of chromosomal rearrangements. CIC-DUX4 displays chromatin binding properties, and is therefore believed to function as an aberrant transcription factor. However, the chromatin remodeling events induced by CIC-DUX4 are not well understood, limiting our ability to identify new mechanism-based therapeutic strategies for these patients. Here, we generated a genome-wide profile of CIC-DUX4 DNA occupancy and associated chromatin states in human CDS cell models and primary tumors. Combining chromatin profiling, proximity ligation assays, as well as genetic and pharmacological perturbations, we show that CIC-DUX4 operates as a potent transcriptional activator at its binding sites. This property is in contrast with the repressive function of the wild-type CIC protein, and is mainly mediated through the direct interaction of CIC-DUX4 with the acetyltransferase p300. In keeping with this, we show p300 to be essential for CDS tumor cell proliferation; additionally, we find its pharmacological inhibition to significantly impact tumor growth in vitro and in vivo. Taken together, our study elucidates the mechanisms underpinning CIC-DUX4-mediated transcriptional regulation.

[Diagnosis and management of tenosynovial giant cell tumor]. / Diagnostic et prise en charge de la tumeur à cellules géantes ténosynoviale.

Tenosynovial giant cell tumor is a benign condition that originates from synovial cells within joints, tendon sheaths, or bursae and may present either in localized (benign) or diffuse (locally aggressive) forms. Currently, the primary treatment approach is surgical, yielding satisfactory results with low recurrence rates in the localized forms, whereas the diffuse type displays high recurrence rates. In parallel, clinical trials are underway to explore pharmaceutical treatment options for the advanced diffuse type. This article aims at consolidating current knowledge about diagnosis and management of this rare tumor, additionally proposing a brief overview of novel therapeutic approaches.

La tumeur à cellules géantes ténosynoviale, bénigne, prend son origine dans les cellules synoviales des articulations, des gaines tendineuses ou des bourses et se présente dans une forme soit localisée (bénigne), soit diffuse (localement agressive). Le traitement principal est chirurgical, offrant des résultats satisfaisants à long terme, avec un faible risque de récidive dans la forme localisée, alors que le taux de récidives est élevé dans la forme diffuse. Parallèlement, des essais cliniques sont en cours pour explorer des options de traitement systémique pour les formes diffuses sévères. Cet article rappelle les connaissances actuelles pour le diagnostic et la prise en charge de cette tumeur rare. De plus, nous proposons un aperçu succinct des nouvelles approches thérapeutiques.

Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity.

Cell fate transitions observed in embryonic development involve changes in three-dimensional genomic organization that provide proper lineage specification. Whether similar events occur within tumor cells and contribute to cancer evolution remains largely unexplored. We modeled this process in the pediatric cancer Ewing sarcoma and investigated high-resolution looping and large-scale nuclear conformation changes associated with the oncogenic fusion protein EWS-FLI1. We show that chromatin interactions in tumor cells are dominated by highly connected looping hubs centered on EWS-FLI1 binding sites, which directly control the activity of linked enhancers and promoters to establish oncogenic expression programs. Conversely, EWS-FLI1 depletion led to the disassembly of these looping networks and a widespread nuclear reorganization through the establishment of new looping patterns and large-scale compartment configuration matching those observed in mesenchymal stem cells, a candidate Ewing sarcoma progenitor. Our data demonstrate that major architectural features of nuclear organization in cancer cells can depend on single oncogenes and are readily reversed to reestablish latent differentiation programs.

Assessment of RANK/RANK-L prevalence and clinical significance in NSCLC European Thoracic Oncology Platform Lungscape cohort and SPLENDOUR randomized clinical trial.

BACKGROUND: The primary objective of this study is to evaluate the clinical significance of RANK/L expression, in both a retrospective cohort of surgically resected stage I-III NSCLC (Lungscape) and a randomized clinical trial-cohort (SPLENDOUR) of advanced NSCLC treated with chemotherapy alone or in combination with denosumab. METHODS: RANK-L expression was assessed on tissue microarrays (TMAs) in Lungscape and whole sections in SPLENDOUR, using immunohistochemistry, with H-scores values > 0 indicating positivity. Prevalence of RANK positivity and its association with clinicopathological characteristics, and patient outcome was explored in a subset of the ETOP Lungscape cohort and in SPLENDOUR. Also investigated were the prevalence of RANK overexpression (proportion of positive cancer cells ≥ 50%) in the Lungscape cohort, and RANK-L in the SPLENDOUR trial. RESULTS: In the Lungscape cohort, RANK expression was assessed at a median follow-up of 46 months (N = 488 patients; 4 centers); 35% were female, 44/49/6% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 48/27/25% with stage I/II/III. Median RFS/TTR/OS were 58/Not reached/74 months. Prevalence of RANK expression was 31% (95%CI:27%-35%); significantly higher in AC: 50% (95%CI:43%-57%) vs SCC: 12% (95%CI:8%-16%) (p < 0.001); more frequent in females (42% vs 25%, p < 0.001) and tumors ≤ 4 cm (35.3% vs 23.3%, p = 0.0065). No association with outcome was found. In the SPLENDOUR trial (463 patients), the prevalence of membranous and cytoplasmic RANK positivity was 34% (95%CI:30%-38%) and 9% (95%CI:7%-12%), respectively, while prevalence for RANK-L was 5% (95%CI:3%-7%) and 36% (95%CI:31%-40%), respectively. Cytoplasmic RANK-L positivity was more common among females (47% vs 31%, p = 0.001) and in non-SCC histology (45% vs 10%, p < 0.0001). At the pre-specified 1% significance level, no prognostic or predictive effect was found. CONCLUSIONS: Both cohorts indicate that RANK expression is more common in adenocarcinoma/non-squamous NSCLC and in female patients. No prognostic effect is found, and in the clinical trial involving addition of denosumab to chemotherapy no predictive effect is detected.

The first comprehensive genomic characterization of rectal squamous cell carcinoma.

BACKGROUND: Rectal cancers represent 35% of colorectal cancers; 90% are adenocarcinomas, while squamous cell carcinoma accounts for 0.3% of them. Given its rarity, little is known concerning its pathogenesis, molecular profile and therapeutic management. The current treatment trend is to treat rectal squamous cell carcinoma by analogy to anal squamous cell carcinoma with definitive chemo-radiotherapy, setting aside surgery in case of local recurrence. METHODS: We performed an in-depth genomic analysis (next-generation sequencing, copy number variation, and human papilloma virus characterization) on 10 rectal squamous cell carcinoma samples and compared them in silico to those of anal squamous cell carcinoma and rectal adenocarcinoma. RESULTS: Rectal squamous cell carcinoma shows 100% HPV positivity. It has a mutational (PIK3CA, PTEN, TP53, ATM, BCL6, SOX2) and copy number variation profile (3p, 10p, 10q, 16q deletion and 1q, 3q, 5p, 8q, 20p gain) similar to anal squamous cell carcinoma. PI3K/Akt/mTOR is the most commonly affected signaling pathway similarly to anal squamous cell carcinoma. Most commonly gained or lost genes seen in rectal adenocarcinoma (FLT3, CDX2, GNAS, BCL2, SMAD4, MALT1) are not found in rectal squamous cell carcinoma. CONCLUSION: This study presents the first comprehensive genomic characterization of rectal squamous cell carcinoma. We confirm the existence of this rare histology and its molecular similarity with anal squamous cell carcinoma. This molecular proximity confirms the adequacy of therapeutic management based on histology and not localization, suggesting that rectal squamous cell carcinoma should be treated like anal squamous cell carcinoma and not as a rectal adenocarcinoma.

EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma.

Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

Immunopathogenesis and proposed clinical score for identifying Kelch-like protein-11 encephalitis.

In this study, we report the clinical features of Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome, design and validate a clinical score to facilitate the identification of patients that should be tested for Kelch-like protein 11 antibodies, and examine in detail the nature of the immune response in both the brain and the tumour samples for a better characterization of the immunopathogenesis of this condition. The presence of Kelch-like protein 11 antibodies was retrospectively assessed in patients referred to the French Reference Center for paraneoplastic neurological syndrome and autoimmune encephalitis with (i) antibody-negative paraneoplastic neurological syndrome [limbic encephalitis (n = 105), cerebellar degeneration (n = 33)] and (ii) antibody-positive paraneoplastic neurological syndrome [Ma2-Ab encephalitis (n = 34), antibodies targeting N-methyl-D-aspartate receptor encephalitis with teratoma (n = 49)]. Additionally, since 1 January 2020, patients were prospectively screened for Kelch-like protein 11 antibodies as new usual clinical practice. Overall, Kelch-like protein 11 antibodies were detected in 11 patients [11/11, 100% were male; their median (range) age was 44 (35-79) years], 9 of them from the antibody-negative paraneoplastic neurological syndrome cohort, 1 from the antibody-positive (Ma2-Ab) cohort and 1 additional prospectively detected patient. All patients manifested a cerebellar syndrome, either isolated (4/11, 36%) or part of a multi-system neurological disorder (7/11, 64%). Additional core syndromes were limbic encephalitis (5/11, 45%) and myelitis (2/11, 18%). Severe weight loss (7/11, 64%) and hearing loss/tinnitus (5/11, 45%) were common. Rarer neurologic manifestations included hypersomnia and seizures (2/11, 18%). Two patients presented phenotypes resembling primary neurodegenerative disorders (progressive supranuclear palsy and flail arm syndrome, respectively). An associated cancer was found in 9/11 (82%) patients; it was most commonly (7/9, 78%) a spontaneously regressed ('burned-out') testicular germ cell tumour. A newly designed clinical score (MATCH score: male, ataxia, testicular cancer, hearing alterations) with a cut-off ≥4 successfully identified patients with Kelch-like protein 11 antibodies (sensitivity 78%, specificity 99%). Pathological findings (three testicular tumours, three lymph node metastases of testicular tumours, one brain biopsy) showed the presence of a T-cell inflammation with resulting anti-tumour immunity in the testis and one chronic, exhausted immune response-demonstrated by immune checkpoint expression-in the metastases and the brain. In conclusion, these findings suggest that Kelch-like protein 11 antibody paraneoplastic neurological syndrome is a homogeneous clinical syndrome and its detection can be facilitated using the MATCH score. The pathogenesis is probably T-cell mediated, but the stages of inflammation are different in the testis, metastases and the brain.

A live single-cell reporter assay links intratumor heterogeneity to metastatic proclivity in Ewing sarcoma.

Targeting of the most aggressive tumor cell subpopulations is key for effective management of most solid malignancies. However, the metastable nature of tumor heterogeneity, which allows cells to transition between strong and weak tumorigenic phenotypes, and the lack of reliable markers of tumor-promoting properties hamper identification of the most relevant cells. To overcome these obstacles, we designed a functional microRNA (miR)-based live-cell reporter assay to identify highly tumorigenic cells in xenotransplants of primary Ewing sarcoma (EwS) 3D cultures. Leveraging the inverse relationship between cell pluripotency and miR-145 expression, we successfully separated highly tumorigenic, metastasis-prone (miR-145low) cells from poorly tumorigenic, nonmetastatic (miR-145high) counterparts. Gene expression and functional studies of the two cell populations identified the EPHB2 receptor as a prognostic biomarker in patients with EwS and a major promoter of metastasis. Our study provides a simple and powerful means to identify and isolate tumor cells that display aggressive behavior.

Pelvic Chondrosarcoma Treated by En Bloc Resection with Patient-Specific Osteotomy Guides and Reimplantation of the Extracorporeally Irradiated Bone as an Osseocartilaginous Structural Orthotopic Autograft: A Report of Two Cases with Description of the Surgical Technique.

Primary tumors of the pelvis are considered difficult to treat due to the complex anatomy and the proximity of important neurovascular structures. The surgical armamentarium for the treatment of these tumors has evolved with the help of cutting-edge technology from debilitating hemipelvectomies to solutions such as precise resections guided by patient-specific instruments or computer navigation and reconstruction by modular prostheses, 3D-printed custom-made implants, or orthotopic autograft reimplantation after extracorporeal irradiation. Different combinations of these techniques have been described in the literature with various rates of success. We present two cases of pelvic chondrosarcomas successfully treated by a combination of periacetabular resection with patient-specific osteotomy guides and orthotopic reimplantation of the extracorporeally irradiated autograft resulting in retention of the native hip.

Abscopal effect in a patient with malignant pleural mesothelioma treated with palliative radiotherapy and pembrolizumab.

The abscopal effect describes the ability of locally administered radiotherapy to induce systemic antitumor effects. Although mentioned for the first time in the 1950s, records of abscopal effects, considered to be immune-mediated, are scarce with radiotherapy alone. However, with the continued development and use of immunotherapy, reports on the abscopal effect have become increasingly frequent during the last decade. Here, we report a patient with advanced malignant pleural mesothelioma who had progressive disease while on the anti-PDL1 inhibitor pembrolizumab and showed an abscopal response after palliative radiotherapy.

Nongenetic Evolution Drives Lung Adenocarcinoma Spatial Heterogeneity and Progression.

Cancer evolution determines molecular and morphologic intratumor heterogeneity and challenges the design of effective treatments. In lung adenocarcinoma, disease progression and prognosis are associated with the appearance of morphologically diverse tumor regions, termed histologic patterns. However, the link between molecular and histologic features remains elusive. Here, we generated multiomics and spatially resolved molecular profiles of histologic patterns from primary lung adenocarcinoma, which we integrated with molecular data from >2,000 patients. The transition from indolent to aggressive patterns was not driven by genetic alterations but by epigenetic and transcriptional reprogramming reshaping cancer cell identity. A signature quantifying this transition was an independent predictor of patient prognosis in multiple human cohorts. Within individual tumors, highly multiplexed protein spatial profiling revealed coexistence of immune desert, inflamed, and excluded regions, which matched histologic pattern composition. Our results provide a detailed molecular map of lung adenocarcinoma intratumor spatial heterogeneity, tracing nongenetic routes of cancer evolution. SIGNIFICANCE: Lung adenocarcinomas are classified based on histologic pattern prevalence. However, individual tumors exhibit multiple patterns with unknown molecular features. We characterized nongenetic mechanisms underlying intratumor patterns and molecular markers predicting patient prognosis. Intratumor patterns determined diverse immune microenvironments, warranting their study in the context of current immunotherapies.This article is highlighted in the In This Issue feature, p. 1307.

Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma.

Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.

The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies.

Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene SS18 to one of three SSX genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose polycomb repressor complex (PRC) 2 activity, while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and are associated with vulnerability to USP7 loss, a core member of ncPRC1.1. Using the power of primary tumor organoids, our work helps define the mechanisms of epigenetic dysregulation on which SyS cells are dependent.

Differentiation of Crystals Associated With Arthropathies by Spectral Photon-Counting Radiography: A Proof-of-Concept Study.

OBJECTIVES: The aims of this study were to test whether spectral photon-counting radiography (SPCR) is able to identify and distinguish different crystals associated with arthropathies in vitro and to validate findings in a gouty human third toe ex vivo. MATERIALS AND METHODS: Industry-standard calibration rods of calcium pyrophosphate, calcium hydroxyapatite (HA), and monosodium urate (MSU) were scanned with SPCR in an experimental setup. Each material was available at 3 different concentrations, and a dedicated photon-counting detector was used for SPCR, whereas validation scans were obtained on a clinical dual-energy computed tomography (DECT) scanner. Regions of interest were placed on SPCR images and consecutive DECT images to measure x-ray attenuation characteristics, including effective atomic numbers (Zeff). Statistical tests were performed for differentiation of Zeff between concentrations, materials, and imaging modalities. In addition, a third toe from a patient with chronic gouty arthritis was scanned with SPCR and DECT for differentiation of MSU from HA. RESULTS: In both SPCR and DECT, significant differences in attenuation and Zeff values were found for different concentrations among (P < 0.001) and between different materials (P < 0.001). Overall, quantitative measurements of Zeff did not differ significantly between SPCR- and DECT-derived measurements (P = 0.054-0.412). In the human cadaver toe, gouty bone erosions were visible on standard grayscale radiographic images; however, spectral image decomposition revealed the nature and extent of MSU deposits and was able to separate it from bone HA by Zeff. CONCLUSIONS: Identification and differentiation of different crystals related to arthropathies are possible with SPCR at comparable diagnostic accuracy to DECT. Further research is needed to assess diagnostic accuracy and clinical usability in vivo.

Distal-type epitheloid sarcoma mimicking a wart in a child: A diagnosis not to be missed.

Epithelioid sarcoma is a rare soft-tissue tumor that occurs mainly in children and young adults. It typically presents as a subcutaneous or deep dermal mass in distal extremities. Due to its benign-appearing clinical presentation, infrequent occurrence, and histologic similarities with other pathologies, the diagnosis of epithelioid sarcoma in its early stages can be extremely difficult and can be easily confused with benign lesions such as warts or foreign body granuloma. In this paper, we report the case of a 12-year-old boy with a distal-type epithelioid sarcoma of the hand and wish to emphasize the difficulties of diagnosing this potentially lethal tumor both clinically and histologically.

Image-guided percutaneous cryoablation of unresectable sacrococcygeal chordoma: Feasibility and outcome in a selected group of patients with long term follow-up.

BACKGROUND: Chordoma is a rare malignant tumor of the axial skeleton. Percutaneous cryoablation (PCA) is a minimally invasive technique that allows freezing of tumors under imaging control. The purpose of our retrospective study was to investigate the outcome of PCA in a selected cohort of patients with sacrococcygeal chordoma, with a minimum of 5 years follow-up. MATERIALS AND METHODS: Four patients were treated in 10 sessions. The mean follow-up was 57.3 months. We evaluated the feasibility, the procedure-related complications, the impact on pain control and oncological outcomes. RESULTS: Freezing of 100% of the tumor volume was possible in 60%. Pain control was not reliably evaluable. Local recurrence occurred in 90% of the treated lesions; the mean time to progression was 8.1 months (range 1.5-16). At last follow-up, one patient had died of the disease, one of another cause and one was receiving the best supportive care. The only patient alive without the disease had received additional carbon-ion radiotherapy. The 5-year survival rate after index PCA was 50%. CONCLUSION: Complete freezing of the tumor was technically challenging, mainly due to the complex local anatomy. Recurrence occurred in 90% of the lesions treated. PCA should be considered with caution in the curative management of sacrococcygeal chordoma.

Imaging features and differential diagnoses of non-neoplastic diffuse mediastinal diseases.

Acute or chronic non-neoplastic diffuse mediastinal diseases have multiple causes, degrees of severity, and a wide range of management. Some situations require emergency care while others do not need specific treatment. Although the diagnosis may be suspected on chest X-ray, it is mainly based on CT. A delayed recognition is not uncommonly observed. Some findings may prompt the radiologist to look for specific associated injuries or lesions.This pictorial review will successively describe the various non-neoplastic causes of diffuse mediastinal diseases with their typical findings and major differentials.First, pneumomediastinum that can be provoked by extra- or intra-thoracic triggers requires the knowledge of patient's history or recent occurrences. Absence of any usual etiological factor should raise suspicion of cocaine inhalation in young individuals.Next, acute mediastinitis may be related to post-operative complications, esophageal perforation, or contiguous spread of odontogenic or retropharyngeal infections. The former diagnosis is not an easy task in the early stage, owing to the similarities of imaging findings with those of normal post-operative appearance during the first 2-3 weeks.Finally, fibrosing mediastinitis that is linked to an excessive fibrotic reaction in the mediastinum with variable compromise of mediastinal structures, in particular vascular and airway ones. Differential diagnosis includes tumoral and inflammatory infiltrations of the mediastinum.