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Abstract Mantle cell lymphoma (MCL) is genetically characterized by the IG::CCND1 translocation mediated by an aberrant V(D)J rearrangement. CCND1 translocations and overexpression have been identified in occasional aggressive B-cell lymphomas with unusual features for MCL. The mechanism generating CCND1 rearrangements in these tumors and their genomic profile are not known. We have reconstructed the IG::CCND1 translocations and the genomic profile of 13 SOX11-negative aggressive B-cell lymphomas using whole genome/exome and target sequencing. The mechanism behind the translocation was an aberrant V(D)J rearrangement in three tumors and by an anomalous IGH class-switch recombination (CSR) or somatic hypermutation (SHM) mechanism in ten. The tumors with a V(D)J-mediated translocation were two blastoid MCL and one high-grade B-cell lymphoma. None of them had a mutational profile suggestive of DLBCL. The ten tumors with CSR/SHM-mediated IGH::CCND1 were mainly large B-cell lymphomas, with mutated genes commonly seen in DLBCL and BCL6 rearrangements in 6. Two cases, which transformed from marginal zone lymphomas, carried mutations in KLF2, TNFAIP3 and KMT2D. These findings expand the spectrum of tumors carrying CCND1 rearrangement that may occur as a secondary event in DLBCL mediated by aberrant CSR/SHM and associated with a mutational profile different from that of MCL.

In depth molecular studies are constantly expanding our understanding and refining the classification of gynecological neoplasms. NTRK rearranged spindle cell neoplasms of the lower genital tract are an emerging entity, of particular interest due to possible targeted treatment with selective kinase inhibitors. Nonetheless, surgery remains the initial treatment of choice. We present the case of a 24-year-old patient suffering from a NTRK rearranged spindle cell neoplasm of the uterine cervix which was treated with a fertility preserving conservative surgical approach.

The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5’ (n=9) and 3’ (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5’ breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3’ breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.

Context.—: Despite their stromal origin, follicular dendritic cells (FDCs) share many functions with hematopoietic system cells. FDC neoplasms are currently classified by the World Health Organization along with those of a histiocytic nature. However, the molecular alterations driving oncogenesis in FDC sarcomas (FDCSs) are beginning to be unveiled and do not seem to concur with those described in histiocytic neoplasms, namely MAPK pathway activation., Objective.—: To identify molecular alterations driving tumorigenesis in FDCS., Design.—: We investigated the role of MYC and TP53 in FDC-derived tumor oncogenesis and assessed comprehensively the status of the MAPK pathway in 16 FDCSs, 6 inflammatory pseudotumor (IPT)-like FDCSs, and 8 IPTs., Results.—: MYC structural alterations (both amplifications and rearrangements) were identified in 5 of 14 FDCSs (35.7%), all associated with MYC overexpression. TP53 mutations were identified in 4 of 14 FDCSs (28.6%), all of which displayed intense and diffuse p53 expression. None of these alterations were identified in any IPT-like FDCSs or in IPT cases. No MAPK pathway gene alterations were identified in any of the cases studied., Conclusions.—: The presence of MYC and TP53 alterations and the lack of association with Epstein-Barr virus segregate classical FDCS from IPT-like FDCS, pointing at different oncogenic mechanisms in both entities. Our results suggest a possible oncogenic role of MYC and TP53 alterations in FDCS. The absence of MAPK pathway alterations confirms the lack of a significant role of this pathway in the oncogenesis of FDC-derived neoplasms., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2023 College of American Pathologists.)

Deficits in movement patterns during cutting while running might place soccer players at risk of injury. The objective was to compare joint angles and intersegment coordination between sexes and ages during an unanticipated side-step cutting task in soccer players. This cross-sectional study recruited 11 male (four adolescents and seven adults) and 10 female (six adolescents and four adults) soccer players. Three-dimensional motion capture was used to measure lower-extremity joint and segment angles as participants performed an unanticipated cutting task. Hierarchical linear models examined relationships between joint angle characteristics with age and sex. Continuous relative phase was used to quantify intersegment coordination amplitude and variability. These values were compared between age and sex groups using analysis of covariance. Adult males had greater hip flexion angle excursions than adolescent males, while adult females had smaller excursions than adolescent females (p = .011). Females had smaller changes in hip flexion angles (p = .045), greater hip adduction angles (p = .043), and greater ankle eversion angles (p = .009) than males. Adolescents had greater hip internal rotation (p = .044) and knee flexion (p = .033) angles than adults, but smaller changes in knee flexion angles at precontact compared with stance/foot off (p < .001). For intersegment coordination, females were more out-of-phase than males in the foot/shank segment in the sagittal plane. There were no differences in intersegment coordination variability between groups. Differences in joint motion during an unanticipated cutting task were present between age groups and sexes. Injury prevention programs or training programs may be able target specific deficits to lower injury risk and improve performance.

The engraftment potential of myeloproliferative neoplasms in immunodeficient mice is low. We hypothesized that the physiological expression of human cytokines (macrophage colony-stimulating factor, interleukin-3, granulocyte-macrophage colony-stimulating factor, and thrombopoietin) combined with human signal regulatory protein α expression in Rag2-/-Il2rγ-/- (MISTRG) mice might provide a supportive microenvironment for the development and maintenance of hematopoietic stem and progenitor cells (HSPC) from patients with primary, post-polycythemia or post-essential thrombocythemia myelofibrosis (MF). We show that MISTRG mice, in contrast to standard immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ and Rag2-/-Il2rγ-/- mice, supported engraftment of all patient samples investigated independent of MF disease stage or risk category. Moreover, MISTRG mice exhibited significantly higher human MF engraftment levels in the bone marrow, peripheral blood, and spleen and supported secondary repopulation. Bone marrow fibrosis development was limited to 3 of 14 patient samples investigated in MISTRG mice. Disease-driving mutations were identified in all xenografts, and targeted sequencing revealed maintenance of the primary patient sample clonal composition in 7 of 8 cases. Treatment of engrafted mice with the current standard-of-care Janus kinase inhibitor ruxolitinib led to a reduction in human chimerism. In conclusion, the established MF patient-derived xenograft model supports robust engraftment of MF HSPCs and maintains the genetic complexity observed in patients. The model is suited for further testing of novel therapeutic agents to expedite their transition into clinical trials., (© 2020 by The American Society of Hematology.)

Background: Bone necrosis of the jaw is a serious condition with a broad differential diagnosis of pathologies such as cutaneous histiocytosis, bone metastases or malignant tumours. In addition to the most common cause, medication related osteonecrosis of the jaw (MRONJ), one must consider a number of other causes, such as histiocytosis. Langerhans cell histiocytosis (LCH) is a histiocytic disorder with a large spectrum of clinical manifestations and with possible involvement of a variety of organs. This case shows the importance of an early detection of this rare disease in order to prevent further spreading. Even if an initial diagnosis in the oral cavity is rare, dentists should be aware of this disease., Case Presentation: The presented case describes a patient who was referred for evaluation and treatment due to exposed bone and extensive osteolysis in the region of the upper and lower jaw. After biopsy and diagnosis of LCH, the patient was treated with systemic therapy, achieved remission and is disease free after a 2 year of follow up., Conclusions: This case report illustrates that when dealing with unclear osteolytic changes of the jawbone, Langerhans cell histiocytosis must be taken into consideration in the differential diagnosis and biopsy must be performed in case of suspicion.

MYC rearrangement can be detected in a subgroup of diffuse large B-cell lymphoma characterized by unfavorable prognosis. In contrast to Burkitt lymphoma, the correlation between MYC rearrangement and MYC protein expression in diffuse large B-cell lymphoma is less clear, as approximately one-third of rearranged cases show negative or low expression by immunohistochemistry. To better understand whether specific characteristics of the MYC rearrangement may influence its protein expression, we investigated 43 de novo diffuse large B-cell lymphoma positive for 8q24 rearrangement by FISH, using 14 Burkitt lymphoma for comparison. Different cell populations (clones), breakpoints (classical vs non-classical FISH patterns), partner genes (IGH vs non-IGH) and immunostaining were detected and analyzed using computerized image systems. In a subgroup of diffuse large B-cell lymphoma, we observed different clones within the same tumor distinguishing the founder clone with MYC rearrangement alone from other subclones, carrying MYC rearrangement coupled with loss/extra copies of derivatives/normal alleles. This picture, which we defined MYC genetic heteroclonality, was found in 42% of cases and correlated to negative MYC expression (P=0.026). Non-classical FISH breakpoints were detected in 16% of diffuse large B-cell lymphoma without affecting expression (P=0.040). Non-IGH gene was the preferential partner of rearrangement in those diffuse large B-cell lymphoma showing MYC heteroclonality (P=0.016) and/or non-classical FISH breakpoints (P=0.058). MYC heteroclonality was not observed in Burkitt lymphoma and all cases had positive MYC expression. Non-classical FISH MYC breakpoint and non-IGH partner were found in 29 and 20% of Burkitt lymphoma, respectively. In conclusion, MYC genetic heteroclonality is a frequent event in diffuse large B-cell lymphoma and may have a relevant role in modulating MYC expression.