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Simple Summary: The present study describes a primary mediastinal large B-cell lymphoma (PMBL) cohort on the morphological, immunohistochemical, and molecular levels, allowing to go deeper in the molecular characterization of PMBL. The mean age at diagnosis was 39 years (21–83), with a sex ratio of 0.88, and a predominance Ann Arbor stage II (67%). Most patients presented a non-germinal center phenotype (non-GC-B) using the Hans algorithm (88%). CD30 was expressed in 88% of cases; with a partial and heterogeneous (67%) or intense and diffuse (20%) expression. CD23 was expressed in 75% of cases with a focal (8%), partial (45%), or diffuse (22%) expression. CIITA breaks were observed in 35% of cases. None of the cases displayed BCL2 rearrangement. The most frequent mutations were: SOCS1 (91%), TNFAIP3 (54.5%), ITPKB (51.5%), GNA13 (48.5%), CD58 (36.4%), B2M (36.4%), STAT6 (33.3%), ARID1A (30.3%), XPO1 (27.3%), CIITA (24%), and NFKBIE (24%). These data also provide pathologists with daily routine tools and reinforce the interest in an integrated histomolecular diagnosis to allow precision diagnosis as early as possible and to adapt the therapeutic strategy. Since the description of primary mediastinal large B-cell lymphoma (PMBL) as a distinct entity from diffuse large B-cell lymphomas (DLBCL), numerous studies have made it possible to improve their definition. Despite this, this differential diagnosis can be challenging in daily practice. However, in some centers, PMBL may be treated according to a particular regimen, distinct from those used in DLBCL, emphasizing the importance of accurate identification at diagnosis. This study aimed to describe the histological and molecular characteristics of PMBL to improve the accuracy of their diagnosis. Forty-nine cases of PMBL were retrospectively retrieved. The mean age at diagnosis was 39 years (21–83), with a sex ratio of 0.88. All cases presented a fibrous background with diffuse growth of intermediate to large cells with an eosinophil (26/49, 53%) or retracted cytoplasm (23/49, 47%). "Hodgkin-like" cells were observed in 65% of cases (32/49, 65%). The phenotype was: BCL6+ (47/49, 96%), MUM1+ (40/49, 82%), CD30+ (43/49, 88%), and CD23+ (37/49, 75%). Genomic DNAs were tested by next generation sequencing of 33 cases using a custom design panel. Pathogenic variants were found in all cases. The most frequent mutations were: SOCS1 (30/33, 91%), TNFAIP3 (18/33, 54.5%), ITPKB (17/33, 51.5%), GNA13 (16/33, 48.5%), CD58 (12/33, 36.4%), B2M (12/33; 36.4%), STAT6 (11/33, 33.3%) as well as ARID1A (10/33, 30.3%), XPO1 (9/33, 27.3%), CIITA (8/33, 24%), and NFKBIE (8/33, 24%). The present study describes a PMBL cohort on morphological, immunohistochemical, and molecular levels to provide pathologists with daily routine tools. These data also reinforce interest in an integrated histomolecular diagnosis to allow a precision diagnosis as early as possible. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome with an overall mortality rate of 40%. A multiple-cause-of-death analysis allows for the characterization of mortality and associated causes over an extended period. Death certificates, collected between 2000 and 2016 by the French Epidemiological Centre for the Medical Causes of Death (CepiDC, Inserm), containing the ICD10 codes for HLH (D76.1/2), were used to calculate HLH-related mortality rates and to compare them with the general population (observed/expected ratios, O/E). HLH was mentioned in 2072 death certificates as the underlying cause of death (UCD, n = 232) or as a non-underlying cause of death (NUCD, n = 1840). The mean age at death was 62.4 years. The age-standardized mortality rate was 1.93/million person-years and increased over the study period. When HLH was an NUCD, the most frequently associated UCDs were hematological diseases (42%), infections (39.4%), and solid tumors (10.4%). As compared to the general population, HLH decedents were more likely to have associated CMV infections or hematological diseases. The increase in mean age at death over the study period indicates progress in diagnostic and therapeutic management. This study suggests that the prognosis of HLH may be at least partially related to coexisting infections and hematological malignancies (either as causes of HLH or as complications). [ABSTRACT FROM AUTHOR]

Simple Summary: Composite/synchronous lymphoma is a rare entity, for which the histopathological diagnosis is difficult due to the co-occurrence of at least two lymphomas, sometimes mixed in the same anatomical site. In the present review, we gathered available data on composite lymphomas associating a classical Hodgkin lymphoma (cHL) with another lymphoma. We report the clinical, histopathological, immunohistochemical, and molecular data for each composite lymphoma. These data reinforce the hypothesis of a common clonal origin and a transdifferentiation phenomenon during lymphomagenesis. One of the greatest challenges for the pathologist is to differentiate real Hodgkin cells of cHL from Hodgkin-like cells associated with a non-Hodgkin lymphoma, in order to individualize both contingents for the diagnosis. In contrast, the clinician's challenge is to optimally treat these rare composite pathologies as a single clinical entity. This review could thus be a useful diagnostic support for pathologists and could help clinicians improve management of these uncommon lymphomas. The co-occurrence of several lymphomas in a patient defines composite/synchronous lymphoma. A common cellular origin has been reported for both contingents of such entities. In the present review, we aimed to gather the available data on composite lymphomas associating a classical Hodgkin lymphoma (cHL) with another lymphoma, to better understand the plasticity of mature B and T-cells. This review highlights that >70% of patients with a composite lymphoma are ≥55 years old, with a male predominance. The most reported associations are cHL with follicular lymphoma or diffuse large B-cell lymphoma, with over 130 cases reported. The cHL contingent is often of mixed cellularity type, with a more frequent focal/weak CD20 expression (30% to 55.6%) compared to de novo cHL, suggesting a particular pathophysiology. Moreover, Hodgkin cells may express specific markers of the associated lymphoma (e.g., BCL2/BCL6 for follicular lymphoma and Cyclin D1 for mantle cell lymphoma), sometimes combined with common BCL2/BCL6 or CCND1 rearrangements, respectively. In addition, both contingents may share similar IgH/IgK rearrangements and identical pathogenic variants, reinforcing the hypothesis of a common clonal origin. Finally, cHL appears to be endowed with a greater plasticity than previously thought, supporting a common clonal origin and a transdifferentiation process during lymphomagenesis of composite lymphomas. [ABSTRACT FROM AUTHOR]

Simple Summary: Classical Hodgkin lymphoma (cHL) is a highly curable disease, with about 80% of patients cured using standard first-line chemotherapy. However, outcomes for relapsed/refractory patients remain unfavorable and there is a critical lack of predictive biomarkers for early identification of these patients who may benefit from new therapeutic strategies. Here we evaluated the dynamic expression of 586 immune-related genes in a cohort of 42 cHL patients using NanoString technology. We identified a 19-gene immune signature predictive of relapse at the time of diagnosis, which was found to be strongly dependent on histological subtype. Moreover, comparative analyses between paired diagnostic/relapsed biopsies of nodular sclerosis cHL showed 118 differentially expressed genes, highlighting an immune contexture shift at relapse not found in mixed-cellularity cases. Overall, these results strongly suggest that the predictive value of immune signature in cHL is influenced by histological subtype, a criterion that should be considered when assessing new immunotherapy strategies. Despite the success of standard front-line chemotherapy, 20% of classical Hodgkin lymphoma (cHL) patients still relapse or have refractory disease (r/r), and a subset of them die due to disease progression. There is a critical lack of predictive factors for early identification of those r/r patients who may benefit from new therapeutic strategies. This study aimed to evaluate the dynamic expression of 586 immune-related genes in a cohort of 42 cHL patients including 30 r/r cHL after first-line chemotherapy. Gene expression profiling (GEP) using NanoString technology identified a 19-gene immune signature at diagnosis predictive of cHL relapse, but dependent on histological subtypes. Genes related to tumor survival were found upregulated while genes related to B-lineage were downregulated at diagnosis in r/r nodular sclerosis cHL. In contrast to the mixed-cellularity subtype, comparative GEP analyses between paired diagnosis/relapse biopsies of nodular sclerosis cHL showed 118 differentially expressed genes, supporting an immune contexture switch at relapse with upregulation of immunosuppressive cytokines, such as LGALS1 and TGFB1, and downregulation of the T-cell co-stimulatory receptor ICOS. These results indicate that the predictive value of immune signature in cHL is strongly influenced by histological subtype which should be considered when assessing new immunotherapy target strategies. [ABSTRACT FROM AUTHOR]

Splenic marginal zone lymphoma (SMZL) is a small B-cell lymphoma, which has been recognized as a distinct pathological entity since the WHO 2008 classification. It classically presents an indolent evolution, but a third of patients progress rapidly and require aggressive treatments, such as immuno-chemotherapy or splenectomy, with all associated side effects. In recent years, advances in the comprehension of SMZL physiopathology have multiplied, thanks to the arrival of new devices in the panel of available molecular biology techniques, allowing the discovery of new molecular findings. In the era of targeted therapies, an update of current knowledge is needed to guide future researches, such as those on epigenetic modifications or the microenvironment of these lymphomas. [ABSTRACT FROM AUTHOR]

Simple Summary: Cachexia is a major cause of mortality in cancer patients and is characterized by a continuous skeletal muscle loss. Muscle depletion assessed by computed tomography (CT) is a predictive marker in solid tumors but has never been assessed in non-Hodgkin's lymphoma. Despite software improvements, its measurement remains highly time-consuming and cannot be performed in clinical practice. We report the development of a CT segmentation algorithm based on convolutional neural networks. It automates the extraction of anthropometric data from pretherapeutic CT to assess precise body composition of young diffuse large B cell lymphoma (DLBCL) patients at the time of diagnosis. In this population, muscle hypodensity appears to be an independent risk factor for mortality, and can be estimated at diagnosis with this new tool. Background. Muscle depletion (MD) assessed by computed tomography (CT) has been shown to be a predictive marker in solid tumors, but has not been assessed in non-Hodgkin's lymphomas. Despite software improvements, MD measurement remains highly time-consuming and cannot be used in clinical practice. Methods. This study reports the development of a Deep-Learning automatic segmentation algorithm (DLASA) to measure MD, and investigate its predictive value in a cohort of 656 diffuse large B cell lymphoma (DLBCL) patients included in the GAINED phase III prospective trial (NCT01659099). Results. After training on a series of 190 patients, the DLASA achieved a Dice coefficient of 0.97 ± 0.03. In the cohort, the median skeletal muscle index was 50.2 cm2/m2 and median muscle attenuation (MA) was 36.1 Hounsfield units (HU). No impact of sarcopenia was found on either progression free survival (PFS) or overall survival (OS). Muscular hypodensity, defined as MA below the tenth percentile according to sex, was associated with a lower OS and PFS, respectively (HR = 2.80 (95% CI 1.58–4.95), p < 0.001, and HR = 2.22 (95% CI 1.43–3.45), p < 0.001). Muscular hypodensity appears to be an independent risk factor for mortality in DLBCL and because of DLASA can be estimated in routine practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute myeloid leukemia refers to a large group of diseases that can be further defined by their genetic modifications. A specific alteration called KMT2A-PTD has been previously found in 5% of newly diagnosed acute myeloid leukemia cases. This work aimed to provide specific insight into outcomes of this specific disease and identify factors that may influence survival. Integrating KMT2A-PTD in ELN classification abrogates its predictive value on survival suggesting that this mutation may overcome other genomic marker effects. In patients receiving intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) significantly improved the outcome compared to non-transplanted patients. In conclusion, our results emphasize that KMT2A-PTD should be considered as a potential adverse prognostic factor. Recently, a new subset of acute myeloid leukemia (AML) presenting a direct partial tandem duplication (PTD) of the KMT2A gene was described. The consequences of this alteration in terms of outcome and response to treatment remain unclear. We analyzed retrospectively a cohort of KMT2A-PTD-mutated patients with newly diagnosed AML. With a median follow-up of 3.6 years, the median overall survival was 12.1 months. KMT2A-PTD-mutated patients were highly enriched in mutations affecting epigenetic actors and the RTK/RAS signaling pathway. Integrating KMT2A-PTD in ELN classification abrogates its predictive value on survival suggesting that this mutation may overcome other genomic marker effects. In patients receiving intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) significantly improved the outcome compared to non-transplanted patients. In the multivariate analysis, only HSCT at any time in complete remission (HR = 2.35; p = 0.034) and FLT3-ITD status (HR = 0.29; p = 0.014) were independent variables associated with overall survival, whereas age was not. In conclusion, our results emphasize that KMT2A-PTD should be considered as a potential adverse prognostic factor. However, as KMT2A-PTD-mutated patients are usually considered an intermediate risk group, upfront HSCT should be considered in first CR due to the high relapse rate observed in this subset of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of acute myeloid leukemia (AML) patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. A 4log reduction of NPM1 MRD was associated with a better outcome. DNMT3A negative patients who achieved a 4log reduction had a superior outcome to those who did not. However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identify a subgroup of patients at high risk of relapse. Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached ≥ 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; p < 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse. [ABSTRACT FROM AUTHOR]

According to the World Health Organization (WHO) classification, the nosology of B-cell neoplasms integrates clinical, morphological, phenotypic, and genetic data. In this retrospective analysis, we identified 18 patients with isolated neoplastic lymphocytosis that could not be accurately classified within the WHO classification. Most of them were asymptomatic at the time of diagnosis and the evolution was relatively indolent, as only five patients required treatment after a median follow-up of 48 months. The neoplastic B-cells expressed CD5 in most cases, but the Royal Marsden Hospital score was strictly below 3. Trisomy 12 was the most frequent cytogenetic abnormality. High-throughput sequencing highlighted mutations found in both chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL). Similarly, the immunoglobulin heavy chain variable region repertoire was distinct from those reported in CLL or MZL. However, as treatment choice is dependent on the correct classification of the lymphoproliferative disorder, a histological diagnosis should be performed in case patients need to be treated. [ABSTRACT FROM AUTHOR]