Immunohistochemical negativity of AID and MUM1 identifies a prognostically favorable subgroup of diffuse large B-cell lymphoma/high-grade B-cell lymphoma with double-hit MYC and BCL2 or BCL6 and triple hit, and a gene set and enrichment analysis showed that genes belonged to PI3K-Akt, matrix remodeling and metastasis, cell adhesion and migration, myeloid compartment, and metabolic stress were up-regulated in the AID-negative/MUM1-negative subgroup.

No comparative analysis of the infrequently occurring B-cell neoplasms (BCNs) in the oral cavity has yet been reported in patients with non-immunosuppressiveness or immunosuppressiveness. To identify any differences in clinicopathological findings between patients with non-immunosuppressiveness and those with immunosuppressiveness, we compared the clinicopathological characteristics of oral-cavity BCNs in these patient groups. The clinical characteristics of 39 patients were analyzed from hospital records, including 24 with non-immunosuppressiveness and 15 with immunosuppressiveness. Histological and immunohistochemical evaluation was performed using formalin-fixed paraffin-embedded tissue sections. Comparisons between the two groups were conducted using cross-tabulations and the chi-squared or Fisher exact test. In patients with non-immunosuppressiveness, diffuse large B-cell lymphoma (DLBCL) was the most common type (14/24, 58%), followed by mucosa-associated lymphoid tissue lymphoma (MALT-L, 4/24, 17%). In patients with immunosuppressiveness, EBV-positive mucocutaneous ulcers (EBV-MCU) were the most common type (9/15, 60%), followed by DLBCL (3/15, 20%) and polymorphic/lymphoplasmacytic infiltration (3/15, 20%). Macroscopic findings showed 21 masses (88%) and 3 ulcers (13%) in patients with non-immunosuppressiveness and 11 ulcers (73%) and 4 masses (27%) in patients with immunosuppressiveness. Immunohistochemistry revealed that BCNs in patients with non-immunosuppressiveness expressed EBER in only 1 case (1/22, 5%), whereas those in patients with immunosuppressiveness expressed EBER in all cases (15/15, 100%). Our macroscopic findings and EBV status allowed us to distinguish BCNs between patients with non-immunosuppressiveness and those with immunosuppressiveness.

We report a rare case in which CD5-positive diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS), and CD5-positive intravascular large B-cell lymphoma (IVLBCL) were identified in different samples from the same patient. A 76-year-old man presented with widespread lymphadenopathy and a prostatic mass on imaging. A prostatic biopsy revealed CD5+ DLBCL NOS. Notably, he had undergone transurethral resection of the prostate (TURP) four months prior because of urinary retention. A retrospective histological review of the TURP specimen revealed CD5-positive IVLBCL. This case suggests that DLBCL may initially manifest with an IVLBCL-like growth pattern at an extremely early stage.

Background Polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone (Pola-R-CHP) has become a first-line treatment option for diffuse large B-cell lymphoma (DLBCL), but real-world data remain limited. We retrospectively compared Pola-R-CHP and R-CHOP in patients with newly diagnosed DLBCL. METHODS:We analyzed 127 patients who received first-line Pola-R-CHP (n = 57) or R-CHOP (n = 70) at a single center between January 2021 and August 2025. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events. A 120-day landmark analysis, subgroup analyses, and exploratory analysis for sepsis were also performed. RESULTS:Median age was 75 years in the Pola-R-CHP group and 79.5 years in the R-CHOP group; patients aged >80 years were more frequent in the R-CHOP group (21.1% vs 47.1%, P = 0.003). 1-year PFS was 83.9% with Pola-R-CHP and 76.9% with R-CHOP (P = 0.56). 1-year OS was 89.8% and 91.1%, respectively (P = 0.61). In the 120-day landmark analysis, no significant difference in PFS was observed (HR 0.68, 95% CI 0.29-1.56, P = 0.36). Infection-related treatment discontinuation was more frequent with Pola-R-CHP (12.3% vs 0%, P = 0.003). Sepsis was also more frequent in the Pola-R-CHP group (14.0% vs 4.3%, P = 0.098). CONCLUSIONS:In this single-center retrospective cohort, Pola-R-CHP was not associated with a significant improvement in PFS compared with R-CHOP. Infection-related treatment discontinuation was more frequent in the Pola-R-CHP group. Sepsis was also numerically more frequent, highlighting the importance of careful infection monitoring in clinical practice.

Histone methyltransferase EZH2 is essential for germinal center formation, and gain-of-function mutations of EZH2 occur in approximately 20% of follicular lymphomas (FLs). Although EZH2 inhibitors are used for relapsed/refractory EZH2-mutated (EZH2mut) FLs, their clinicopathological characteristics remain incompletely understood. We assessed the EZH2 Y646 mutation by Sanger sequencing in 301 FLs and identified mutations in 17% (50/301). Compared with EZH2 wild-type (EZH2wt), EZH2mut FL showed a significantly higher proportion aged > 60 years (p = 0.033). Pathologically, EZH2mut FL more frequently exhibited clear neoplastic follicles (p < 0.0001) and grater interfollicular tumor cell distributions highlighted by CD20 immunohistochemistry (p < 0.0001). These cases also more often showed the typical FL immunophenotype (CD10+, BCL2+, BCL6+) (p = 0.027) and BCL2 rearrangement (p = 0.0060). Gene expression profiling revealed enrichment of TNF-α/NF-κB signaling in EZH2wt FL, whereas EZH2mut FL showed upregulation of cell-cycle programs, particularly the G2/M checkpoint. Concordance of EZH2 mutation status between primary and relapsed lesions was 94% (33/35). Even at relapse, EZH2mut FL retained its characteristic pathological features, including clear follicles and high interfollicular spread of tumor cells. In conclusion, EZH2mut FL exhibits distinctive clinicopathological and molecular features that may help identify patients most likely to benefit from EZH2-targeted therapy.

INTRODUCTION:TP53 mutations play a central role in the carcinogenesis of oral squamous cell carcinoma (OSCC). However, due to the diversity of variant patterns of TP53 genetic alterations, the clinical significance of TP53 mutations in OSCC remains poorly understood. Thus, we set out to analyze all exons of the TP53 gene to characterize the TP53 mutation landscape in OSCC and to investigate its associations with clinical outcomes. METHODS:Treatment-naïve surgical specimens from 124 patients with OSCC were comprehensively analyzed for TP53 mutations using next-generation sequencing. Pathogenicity for each mutation was defined by referring to genomic databases, OncoKB and ClinVar. Multivariable Cox regression analysis was performed to assess the association between the presence of TP53 pathogenic mutations and cancer-specific survival. RESULTS:TP53 pathogenic mutations were detected in 81/124 (65%) OSCC cases, comprising 75 different variant patterns. OSCC patients harboring TP53 pathogenic mutations showed shorter cancer-specific survival compared to those without pathogenic mutations (multivariable hazard ratio, 3.70; 95% confidence interval, 1.08-12.61). Moreover, cases with truncating and/or splice mutations showed worse outcomes than other mutation types. Among OSCC patients with stage III/IV, the presence of TP53 pathogenic mutations was significantly associated with shorter survival (P = 0.001), whereas no such association was observed in stage I/II patients (P = 0.89). CONCLUSIONS:TP53 pathogenic mutations in OSCC have been associated with shorter cancer-specific survival, especially for advanced diseases. Our findings likely attest to the importance of TP53-based molecular classification, leading to the development of novel precision strategies against OSCC.

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that is histologically and clinically heterogeneous. Skeletonization is a computer vision technique used in image description, segmentation, and pattern recognition. Objectives: This retrospective observational study analyzed the 2D-topological heterogeneity of DLBCL. Methods: A series of 153 patients, including 110 patients with DLBCL and 43 patients with reactive lymphoid tissue, were analyzed by skeleton analysis using hematoxylin and eosin (H&E) digitized images. The skeletonization variable was correlated with several clinicopathological characteristics of the patients, including cell of origin Hans’ classifier and Lymph2Cx assay, MYC and BCL2 rearrangement by FISH, immunohistochemistry of BCL2, CASP8, cCASP3, CD163, CDK6, cPARP, CSF1R, E2F1, ISY1, Ki69, LMO2, MDM2, MYC, MYO, TNFAIP8, PD-L1, and p53, and gene expression using a pancancer immune profiling panel. Results: In comparison with reactive tissue, DLBCL was characterized by lower skeletonization: 5665.20 ± 1012.82 vs. 6341.16 ± 548.23, respectively (p < 0.001). Within the DLBCL diagnostic category, high skeletonization correlated with poor overall survival (hazard risk = 2.5, p = 0.003). High skeletonization was also correlated with higher Epstein–Barr virus (EBV) EBER positivity, death within the first two years, high histological entropy, and lower CD5, E2F1, BCL2, ISY1, and TNFAIP8 protein levels (all p values < 0.05). Gene expression was available in a representative subset of 30 cases, including 18 cases with high skeletonization and 12 cases with low skeletonization. High skeletonization was characterized by upregulation of 166 immuno-oncology genes, such as CD274 (PD-L1), NFKB1A, CD68, CSF1R, CCR5, ITGAM, and TGFB1, and enrichment of IL6 JAK STAT3 signaling, inflammatory response, TNF, NFKB, KRAS, apoptosis, and macrophage function pathways by gene set enrichment analysis (GSEA). In multivariate COX regression analysis for overall survival, the prediction value of skeletonization was independent of Hans’ classifier, the International Prognostic Index (IPI), and EBER (p = 0.030, hazard risk = 2.2). Conclusions: DLBCL is characterized by lower skeletonization than reactive lymphoid tissue. In DLBCL, high skeletonization is associated with poor prognosis and enrichment of immuno-oncology markers.

Epstein-Barr virus (EBV) is an enveloped, double-stranded DNA virus that selectively infects primates. Periodontitis, a common inflammatory disease characterized by alveolar bone destruction, affects more than half of the global adult population. While EBV has been linked to periodontitis due to its pro-inflammatory effects and presence in the human periodontium, its effects on bone metabolism, particularly alveolar bone resorption, remain unclear. This study demonstrated that EBV infection in humanized mice induced osteoclast differentiation and alveolar bone resorption, resulting in sparse trabecular bone patterns and increased lacunae resorption. Extracellular vesicles (EVs) from EBVinfected cells contained M-CSF, essential for osteoclast differentiation, and increased CTSK and RANKL expression in osteoclast precursor cells after uptake. EBV infection increased the expression of group IIA-secreted phospholipase A 2 (sPLA2-IIA), which hydrolyzed EV membranes to produce lipid mediators such as lysophosphatidic acid (LPA) and arachidonic acid derivatives-both of which induce osteoclast differentiation. Treatment with the sPLA2 inhibitor varespladib reduced CTSK and RANKL expression in vitro and in vivo, confirming the role of sPLA2-IIA in osteoclastogenesis. Furthermore, sPLA2-IIA expression and metabolites were significantly elevated in EVs from the gingival crevicular fluid of EBV-positive patients with periodontitis. These findings suggest that sPLA2-IIA-mediated hydrolysis of EVs from EBV-infected cells contributes to alveolar bone loss, offering insights into-therapeutic strategies targeting EBV and sPLA2-IIA to prevent periodontitis progression.

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma and one of the most common hematological neoplasia. Entropy is a statistical measure of randomness that characterizes the texture of an input image and measures tissue complexity. Methods: Image processing and computer vision analysis were performed on a series of 114 diagnostic DLBCL cases and 44 reactive lymphoid tissues stained with hematoxylin and eosin (H&E). Histological entropy was measured to differentiate between reactive lymphoid tissue and DLBCL and predict clinical evolution. At protein level, immunohistochemistry analyzed Ki67, LMO2, MYC, MDM2, CDK6, E2F1, BCL2, CASP8, MYOB, TP53, cPARP, cCASP3, ISY1, TNFAIP8, CSF1R, CD163, PD-L1 and IL-10 markers. Gene expression analysis using the NanoString nCounter PanCancer Immune Profiling Panel was performed in 29 cases. Results: In comparison with reactive lymphoid tissue, DLBCL was characterized by lower entropy (7.32 ± 0.16 vs. 6.82 ± 0.44, respectively; p < 0.001). Within the DLBCL diagnostic category, higher entropy was associated with poor overall survival and death events within the first 2 years (hazard-risk = 2.4, p = 0.004) and lower entropy with a moderate and more favorable outcome (hazard-risk = 0.4, p = 0.004). High entropy was also correlated with ECOG performance status ≥ 2, lower protein expression of apoptosis markers of cPARP and cCASP3, and upregulation of specific immuno-oncology genes such as STAT3, BTK, CASP8, CD47, VCAM1, and MYD88. The prognostic value of entropy was independent of the international prognostic index (IPI), Epstein-Barr virus (EBER), and cell of origin (Hans). Conclusions: The histological evaluation of entropy is useful for the differential diagnosis of reactive lymphoid tissue and DLBCL and is a predictive factor of DLBCL prognosis.

A 55-year-old man was diagnosed with chronic myeloid leukemia (CML) in the chronic phase and achieved a major molecular response (MMR) 3 months after dasatinib induction. Seven months later, he noticed left cervical lymphadenopathy, and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed marked 18F-FDG uptake at the left cervical and supraclavicular lymph nodes. Left cervical lymph node biopsy showed reactive follicular hyperplasia and increased numbers of large B-cells between the follicles. Based on the clinical course, dasatinib-associated lymphadenopathy (DAL) was diagnosed. The treatment was switched to bosutinib, and lymph node enlargement resolved after 4 weeks. Lymphoproliferative disorder during CML treatment is a rare adverse event of dasatinib and is classified in the category of immune deficiency and dysregulation-associated LPDs (IDD-LPDs) in the WHO Classification of Tumours, 5th Edition. As more new drugs associated with IDD-LPDs are used across various indications, the scope of iatrogenic immune deficiency-related LPDs continues to broaden. Although the pathogenesis of DAL remains unclear, the immune dysregulation mechanisms of dasatinib may contribute. Since spontaneous remission can be expected with dasatinib discontinuation, observation should be considered even when differentiation from de novo lymphoma is difficult, and the decision to initiate chemotherapy should be made carefully.

Aims Diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBCL) with MYC and BCL2 rearrangements (double-hit lymphoma with BCL2, DHL-BCL2) is a mature aggressive B-cell lymphoma that also includes concurrent triple hit with BCL6 translocation (TH). DHL with MYC and BCL6 (DH-BCL6) can also occur. The differences among these three DLBCL/HGBCL subtypes have not yet been definitively determined.Methods and Results This study characterized the clinicopathological features and transcriptomic profiles of a series of 101 cases of DLBCL/HGBCL that were subclassified according to MYC, BCL2 and BCL6 FISH data, including cell-of-origin (COO)-like, molecular high-grade (MHG)-like and double-hit/dark-zone (DHIT/DZsig)-like signatures. DLBCL/HGBCL-DH-BCL2 was characterized by higher HGBCL morphology, CD10 positivity, GCB Hans's, GCB COO and MHG molecular subtype. DLBCL/HGBCL-TH had higher LDH levels and worse overall survival. DLBCL/HGBCL-DH-BCL6 had higher MUM1 expression, non-GCB Hans', ABC/Unclassified COO, non-MHG and low DHIT/DZ signatures. Transcriptomic analysis showed that DLBCL/HGBCL-DH-BCL2 and DLBCL/HGBCL-TH were close but separated from DLBCL/HGBCL-DH-BCL6. Gene set enrichment analysis (GSEA) revealed different levels of enrichment between the subtypes.Conclusions DLBCL/HGBCL-DH-BCL6 differs from the DLBCL/HGBCL-DH-BCL2, and the DLBCL/HGBCL-TH is associated with the worst survival. Analysis of all three genes of MYC, BCL2 and BCL6 is recommended in the context of DLBCL/HGBCL diagnosis.

A 78-year-old man was diagnosed as having a submucosal gastric mass (diameter 4 cm). Preoperative findings from endoscopic ultrasound-guided fine needle aspiration suggested a diagnosis of gastric neuroendocrine neoplasm. Total gastrectomy with excision of a metastatic liver lesion and dissection of gastric lymph nodes was performed. Analysis of frozen sections indicated adenocarcinoma of the peritoneum, which suggested the possibility of a mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), based on the presence of solid tubules, metastatic spread, and lymphovascular invasion. However, the smooth gastric mucosal surface, organoid architecture with rare atypia or necrosis, immunopositivity for neuroendocrine markers, a Ki-67 index of 21%, and the presence of somatostatin receptor 2 expression confirmed a final pathological diagnosis of grade 3 gastric neuroendocrine tumor (NETG3) with glandular formation. NETG3 with glandular formation can be difficult to distinguish from MiNEN because their histological features overlap. However, gastric NETG3 with glandular formation is distinguishable from MiNEN by the presence of a submucosal tumor with a histological organoid pattern without frequent mitoses and/or necrosis, immunopositivity for neuroendocrine markers, and the absence of an adenocarcinoma or neuroendocrine carcinoma component within the tumor, as determined by immunohistochemistry for somatostatin receptor 2 expression, Ki-67, and Rb1.

BACKGROUND:Liposarcoma and lymphoma are very rare tumors, and their combination is extremely rare. Moreover, there have been no reports of liposarcoma and lymphoma occurring in the same region. CASE:A 58-year-old man presented to Kanagawa Cancer Center with a mass in his left thigh and underwent a needle biopsy. Histological analysis showed an increase in the number of small lymphocytes and plasma cells; immunohistochemical analysis showed an increase in CD20-positive cells with Lambda light-chain restriction; therefore, the diagnosis of B-cell malignancy with plasma cell differentiation was made. A bone marrow biopsy specimen showed infiltration of atypical cells of the same phenotype and increased serum IgM-M levels; therefore, a diagnosis of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (LPL) was made. The needle biopsy specimen showed scattered CDK4-positive cells in the background of the lymphoma cells and sporadic MDM2 signal amplification on fluorescence in situ hybridization, suggesting mixed well-differentiated liposarcoma (WDL). Tumor resection was performed. The tumor contained a mixture of WDL and LPL areas. RNA sequencing revealed upregulated expression of chemokine genes, including CCL5, CCL18, and CCL19, in WDL and that of the corresponding chemokine receptor genes CCR4, CCR6, and CCR7 in the lymphoma cells. CONCLUSION:Chemokine-chemokine receptor axes may be involved in the pathogenesis of LPL cell-infiltrating WDL. This is an extremely rare case, and we have reported some considerations regarding the tumorigenesis of LPL cell-infiltrating WDL.

Peripheral T-cell lymphoma (PTCL) exhibits a diverse clinical spectrum, necessitating methods to categorize patients based on genomic abnormalities or tumor microenvironment (TME) profiles. We conducted an integrative multiomics study in 129 PTCL patients, performing whole-exome sequencing and identifying three genetic subtypes: C1, C2, and C3. C2 was characterized by loss of tumor suppressor genes and chromosomal instability, while C1 and C3 shared T follicular helper (TFH)-related genomic alterations, with C3 also showing a high incidence of IDH2 mutations and chromosome 5 gain. Compared to C1, survival was significantly worse in C2 (HR 2.52; 95% CI, 1.37–4.63) and C3 (HR 2.14; 95% CI, 1.17–3.89). We also estimated the proportions of immune cell fractions from the bulk RNA sequencing data using CIBERSORTx and classified TME signatures into the following hierarchical clusters: TME1 (characterized by increased B and TFH cells), TME2 (macrophages), and TME3 (activated mast cells). TME2 was associated with shorter survival (HR 3.4; 95% CI, 1.6–7.5) and was more frequent in C2 (64.3%) than in C1 (7.7%), whereas C1 had more TME3 signatures (80.8% vs. 28.6%). These findings highlight a significant relationship between genetic subtypes and TME signatures in PTCL, with important implications for clinical prognosis.

Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia rarely transforms into diffuse large B-cell lymphoma, and there have been no reports of cases proving clonal identity when presenting as primary central nervous system lymphoma. There are many unclear aspects regarding the mechanism by which lymphoplasmacytic lymphoma/Waldenström macroglobulinemia infiltrates the central nervous system and transforms, as well as the treatment methods for the transformed lymphoma. A 49-year-old Asian Japanese male was emergently transported due to loss of consciousness, revealing a tumorous lesion in the brain. He was diagnosed with primary central nervous system lymphoma following an endoscopic biopsy and treated with immunochemotherapy included high-dose methotrexate. During the second course of immunochemotherapy, a computed tomography scan conducted to investigate bilateral lower leg edema revealed tumorous lesions in both lower legs. A biopsy of the thigh node specimen was diagnosed as lymphoplasmacytic lymphoma. When high-dose methotrexate including immunochemotherapies was finished, the lymphoma lesions in central nervous system had disappeared. However, the symptoms of bilateral lower leg edema were prominent because of remaining the bilateral thigh nodes, so additional immunochemotherapy for lymphoplasmacytic lymphoma/Waldenström macroglobulinemia was administered, resulting in complete remission of the lymphoplasmacytic lymphoma/Waldenström macroglobulinemia as well. primary central nervous system lymphoma, and he has maintained both lymphomas for 4 years. The myeloid differentiation factor 88 (MYD88) gene mutation was detected in primary central nervous system lymphoma and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia lymphoma cells. The same clonal origin of primary central nervous system lymphoma and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia was confirmed according to homology in a region of the immunoglobulin heavy chain V (IGHV) gene. On the basis of the characteristics of primary central nervous system lymphoma and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, we speculated that the lymphoplasmacytic lymphoma/Waldenström macroglobulinemia lymphoma cells had already invaded the central nervous system, a condition called Bing-Neel syndrome, and transformed into primary central nervous system lymphoma cells after a certain period. It was revealed that the lymphoma cells of both lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and primary central nervous system lymphoma derived from a common cell possessing MYD88. The utility of adding chemotherapy for low-grade lymphoma in addition to therapy for primary central nervous system lymphoma is not clear. While lymphoplasmacytic lymphoma is a low-grade lymphoma that does not always require chemotherapy, combining treatment for lymphoplasmacytic lymphoma and primary central nervous system lymphoma may contribute to the effectiveness of both treatments.

Background/Objectives: The major question that confronts a pathologist when evaluating a lymph node biopsy is whether the process is benign or malignant, and the differential diagnosis between follicular lymphoma and reactive lymphoid tissue can be challenging. Methods: This study designed a convolutional neural network based on ResNet architecture to classify a large series of 221 cases, including 177 follicular lymphoma and 44 reactive lymphoid tissue/lymphoid hyperplasia, which were stained with hematoxylin and eosin (H&E). Explainable artificial intelligence (XAI) methods were used for interpretability. Results: The series included 1,004,509 follicular lymphoma and 490,506 reactive lymphoid tissue image-patches at 224 × 244 × 3, and was partitioned into training (70%), validation (10%), and testing (20%) sets. The performance of the training (training and validation sets) had an accuracy of 99.81%. In the testing set, the performance metrics achieved an accuracy of 99.80% at the image-patch level for follicular lymphoma. The other performance parameters were precision (99.8%), recall (99.8%), false positive rate (0.35%), specificity (99.7%), and F1 score (99.9%). Interpretability was analyzed using three methods: grad-CAM, image LIME, and occlusion sensitivity. Additionally, hybrid partitioning was performed to avoid information leakage using a patient-level independent validation set that confirmed high classification performance. Conclusions: Narrow artificial intelligence (AI) can perform differential diagnosis between follicular lymphoma and reactive lymphoma tissue, but it is task-specific and operates within limited constraints. The trained ResNet convolutional neural network (CNN) may be used as transfer learning for larger series of cases and lymphoma diagnoses in the future.