Search Results (466)

Background: Diffuse large B cell lymphoma is an aggressive, heterogeneous yet treatable disease. Primary bone lymphoma is a lymphoma involving a single or multiple osseous sites with or without regional nodal involvement. It is exceedingly rare, representing <1% of new non-Hodgkin lymphoma cases per year. Most cases of primary bone lymphoma are diffuse large B cell lymphoma. They infrequently involve the craniofacial bones and mandible; its rarity can lead to delays in diagnosis. Case Series Presentation: Two 64-year-old male patients initially presented to local dentists with concerns of tooth pain and numbness. Both underwent extensive dental procedures including extraction and debridement, with an initial diagnosis of osteomyelitis. They were placed on long-term antibiotics. After months without improvement, further testing was pursued, including imaging and repeat biopsies. The patients were finally diagnosed with primary bone diffuse large B cell lymphoma. From the initial treatment of osteomyelitis, a median time of 8.5 months passed before diagnosis of lymphoma. Treatment with cytotoxic chemotherapy was initiated and both patients achieved remission. Conclusions: As in the two cases presented here, the initial point of entry into the medical system may be a visit to the local dentist. When patients present with periodontal complaints, it is imperative to maintain a broad differential, including lymphoma. This is especially crucial when the patient’s clinical course does not respond to initial treatment. This results in delays of diagnosis and initiation of therapy for a treatable cancer. Full article

BTK (Bruton’s tyrosine kinase) has become a key therapeutic target across several hematologic diseases, beginning with its original use in CLL/SLL. As a central mediator of B-cell receptor signaling and microenvironment interactions, BTK supports survival, proliferation, and trafficking in multiple mature B-cell malignancies (mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and other indolent/aggressive lymphomas) and in selected immune-mediated conditions such as chronic graft-versus-host disease. Covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) irreversibly bind the C481 residue and have produced high response rates and durable disease control, often replacing chemoimmunotherapy in the relapsed setting and, for some entities, even in the first line. Differences in kinase selectivity lead to different safety profiles: second-generation covalent agents generally maintain efficacy while reducing significant off-target toxicities, especially atrial fibrillation and hypertension. Resistance to covalent BTK inhibitors most commonly develops through BTK C481 substitutions and activating PLCG2 mutations, with other kinase-domain variants increasingly recognized. Non-covalent BTK inhibitors (e.g., pirtobrutinib) bind BTK independently of C481, can overcome classic C481-mediated resistance, and extend BTK pathway targeting into later lines of therapy. Overall, BTK inhibition has evolved into a versatile platform enabling long-term, often chemo-free management strategies. Full article

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy caused by persistent infection with human T-cell leukemia virus type 1 (HTLV-1). ATLL remains difficult to treat despite intensive chemotherapy, antiviral therapy, and hematopoietic stem cell transplantation. The limited durability of current treatment strategies highlights the need for mechanism-based therapeutic approaches. Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that regulates transcription, RNA splicing, DNA damage responses, and immune signaling through symmetric dimethylation of histone and non-histone substrates. PRMT5 is frequently overexpressed across hematologic and solid tumors. Preclinical studies indicate that PRMT5 expression is elevated during HTLV-1-mediated T-cell transformation and that pharmacologic inhibition of PRMT5 selectively impairs the survival and transformation of infected T cells in vitro and in vivo. In this review, we highlight the current understanding of PRMT5 biology in cancer, summarize preclinical studies supporting PRMT5 as a therapeutic target in ATLL, and discuss key challenges to future clinical translation. We also discuss emerging approaches such as rational combination therapies and tumor-selective PRMT5 inhibitors as potential paths toward treatment for ATLL. Full article

Diffuse large B-cell lymphoma (DLBCL) is the most common and clinically aggressive subtype of non-Hodgkin lymphoma (NHL). While novel therapies such as rituximab and polatuzumab vedotin have led to improved outcomes, approximately 35% of patients eventually develop relapsed or refractory disease. MicroRNAs (miRNAs), a class of endogenous single-stranded RNAs approximately 22 nucleotides in length, play a pivotal role in the regulation of gene expression at the post-transcriptional level through interactions with complementary target RNAs and contribute significantly to the development, progression, and treatment response of DLBCL. Oncogenic miRNAs, such as miR-155, miR-21, and the miR-17–92 cluster, promote proliferation, survival, immune evasion, and therapy resistance by modulating pathways including PI3K/AKT, NF-κB, and MYC. Conversely, tumor-suppressive miRNAs such as miR-34a, miR-144, miR-181a, and miR-124-3p inhibit oncogene activity and enhance apoptosis, with their loss often associated with adverse outcomes. Among these, miR-155 and miR-21 are particularly well studied, playing central roles in both tumor progression and remodeling of the tumor microenvironment. This review summarizes current evidence on the biological and clinical relevance of miRNAs in DLBCL, emphasizing their diagnostic and prognostic potential. Full article

Background/Objectives: Advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS) are aggressive forms of cutaneous T-cell lymphoma (CTCL) for which treatment options are limited and prognosis is poor. Brentuximab vedotin (BV), an anti-CD30 antibody–drug conjugate, has demonstrated high response rates in patients with CD30 expression ≥ 10%. However, data on its efficacy in cases with low CD30 expression (<10%) remain scarce. Methods: This retrospective analysis evaluated the real-world efficacy of BV in patients with advanced-stage MF/SS and low CD30 expression. A retrospective analysis was conducted on 32 patients across 11 German CTCL expert centers. All patients had advanced-stage MF or SS with CD30 expression < 10% and received BV at the standard dose. Treatment response was assessed using EORTC-ISCL criteria. Results: All patients had received prior systemic therapies (median: 3) with 36% having undergone prior mono- or polychemotherapy. The study population included 30 MF (stage IIB) and two SS cases. The overall response rate (ORR) in this population was 53.1% (17/32). A complete response (CR) was achieved in 12.5% (4/32), a partial response (PR) was achieved in 40.6% (13/32), stable disease (SD) was seen in 18.8% (6/32), and progressive disease (PD) was seen in 28.1% (9/32). The median progression-free survival (PFS) was 4.0 months (arithmetic mean: 6.38; range: 0.5–15.5), and the median time to next treatment (TTNT) was 7.25 months (arithmetic mean: 7.30; range: 2.00–15.5). Conclusions: BV demonstrated encouraging activity in heavily pretreated advanced MF/SS with low CD30 expression, achieving an ORR comparable to that observed in patients with higher CD30 levels. While response rates were similar, PFS was shorter. These findings suggest that BV remains a potential therapeutic option in this patient population and merits further prospective investigation. Full article

Background and clinical significance: Primary cardiac diffuse large B-cell lymphoma (DLBCL) arising in bioprosthetic valves is exceedingly rare. Most patients present with localized disease often masquerading as suspected thrombi or vegetations. Imaging studies are inconclusive and due to the rarity of the disease, treatment and follow-up data are very limited. Case presentation: We present one such case developing 9 years after aortic valve replacement in an otherwise immunocompetent patient, who presented with minor symptoms despite significant disease burden. This tumor contained Epstein–Barr virus (EBV), was confined to the site of origin, and has behaved non-aggressively after excision with a follow-up of 59 months. Conclusions: This unique disease is classified as Fibrin-associated large B-cell lymphoma (FA-LBCL) in view of its distinct clinical-pathological features. This report also addresses the unique features of this type of lymphoma. Full article

Background: Mantle Cell Lymphoma (MCL) is an aggressive malignancy with variable clinical behavior, largely reflecting the underlying molecular heterogeneity. The genomic landscape of MCL encompasses gene mutations with strong prognostic implications and secondary genetic events, which are also implicated in the pathogenesis and prognosis of the disease. Methods: We evaluated the diagnostic samples of 73 patients with relapsed/refractory MCL that were enrolled in the Fondazione Italiana Linfomi Mantle First-BIO study. All patients had available data for correlating CNVs with the presence of TP53 mutation. Time to first relapse or progression of disease (POD) was used as the primary outcome measure. Results: We identified CNVs associated with MCL, with Del 9p21.3 (CDKN2A) being the strongest predictor of shorter time to POD (p = 0.01), independently of TP53 mutation in multivariable analysis. Unsupervised clustering identified molecularly defined clusters that were associated with significantly different times to POD (p = 0.01). Pairwise log-rank tests confirmed TP53 mutated vs. wild-type (WT) as the strongest prognostic factor, with cluster assessment improving the prognostic predictivity among patients: clusters TP53-mut vs. TP53-WT, p = 0.001, HR = 3.92; and p = 0.014, HR = 2.23, respectively. In conclusion, CNV-based molecular clusters might represent a novel approach to identify patients at higher risk of treatment failure, further contributing to the prognostic predictivity of TP53 mutation. Full article

Background: Malignant lymphomas are among the most common hematological neoplasms and include a heterogeneous group of entities characterized by distinct morphology, immunophenotype, genetics, and clinical features. Recent advances in molecular diagnostics have significantly improved our understanding of the genetic lesions and mechanisms underlying lymphomagenesis. Methods: This review summarizes key developments in molecular pathology relevant to B-cell lymphomas, including updates from the World Health Organization classification and recent progress in genomic, immunophenotypic, and clinical assessment. We highlight findings from next-generation sequencing studies and other molecular approaches used in routine and research settings. Results: Many molecular alterations are now routinely incorporated into diagnostic criteria and influence risk stratification, prognosis, and treatment selection. Although not all lesions are evaluated in everyday clinical practice, several changes have demonstrated prognostic significance and therapeutic relevance. Molecular subclassification has refined our ability to predict clinical behavior and response to targeted therapies. Conclusions: Advances in molecular diagnostics continue to reshape the clinical approach to lymphomas. Improved classification, better identification of therapeutic targets, and more accurate prognostic tools collectively enhance personalized treatment strategies. As a result, molecular tools increasingly guide clinical decision-making and contribute to improved outcomes in patients with B-cell lymphomas. Full article

Background/Objectives: The multitude of histological and genetic features of salivary gland malignancies (SGMs) hampers the ability of the doctors’ board to make a clear and quick decision on how aggressively treatment should be initiated. Despite treatment guidelines, it is difficult to determine the appropriate extent and invasiveness of surgery based on preliminary patient data. The aim of this study is to define the factors that have a significant impact on the oncological outcome of SGM treatment and to create an algorithm for finding the combinations of predictors with a particularly unfavorable impact on survival. Methods: A multicenter retrospective analysis was conducted on 2653 patients with salivary gland tumors (SGTs), including 229 with SGMs (parotid 204/229 = 89.1%; submandibular 25/229 = 10.9%), treated at seven Polish university departments from 2015 to 2022. All patients, except those with malignant lymphoma, underwent surgery followed by radiotherapy. Seventeen potential survival-impacting variables were analyzed: thirteen preoperative and four surgical specimens. The preoperative group aids in deciding surgical aggressiveness, while the postoperative group supports decisions on adjuvant treatment escalation. The main outcome measures were disease-free survival (DFS) and overall survival (OS). Results: SGMs constituted 8.63% of all SGTs, with 204 (89%) in the parotid and 25 (11%) in the submandibular glands. The average age was 63.38 years, with a male predominance (54%). Clinical and radiological signs of malignancy were reported in 45.4% and 54.6% of patients, respectively, with facial nerve palsy reported in 13%. Postoperative specimens revealed 23 histological types, and R0 resections were achieved in 168/229 cases (73%). Fifty-six patients (24.5%) died of cancer within five years. Significant survival factors included gender, urban residence, previous chemical and radiation exposure, clinical malignancy symptoms, pT-stage, pN-stage, clinical stage, and resection margins. Conclusions: The prognosis for SGM remains unsatisfactory, which would suggest more aggressive treatment; thus, carefully collected clinical data could support the decision-making process. Significantly worse survival has been demonstrated in the presence of unfavorable clinical factors, so defining new elements of medical history may be a step towards improving treatment outcomes. Full article

Indolent lymphoproliferative diseases or disorders (LPDs) derived from T cells or Natural Killer (NK) cells may be neoplastic or non-neoplastic, which are often difficult to distinguish from each other and from their aggressive counterparts. The etiology and pathogenesis are mostly nebulous and may be related to infections or immune dysfunction. Indolent lymphomas differ from the high-grade aggressive counterparts by a prolonged clinical course of persistent or relapsing disease, histology, immunophenotype, and genetics. In recent decades, indolent lymphomas or LPD of T or NK cell derivation have been increasingly recognized, causing diagnostic and nosologic confusion. The issue is particularly challenging in the arena of indolent intestinal lymphomas and LPD, as evidenced by the myriad of names given to the indolent intestinal T- and NK-cell lymphomas and LPD. Confounding the picture are also reports of Epstein–Barr virus (EBV) positivity in various indolent non-intestinal LPD and, rarely, even in indolent intestinal T-cell lymphoma, which have been widely accepted to be typically EBV-negative. This review aims to curate current information and understanding of these diseases with the goal of resolving these issues. The recently described indolent T-lymphoblastic proliferation (iTLBP) and the re-classified indolent primary cutaneous CD4-positive small or medium T-cell LPDs and primary cutaneous acral CD8-positive T-cell LPDs also require greater awareness and recognition. It is important to diagnose these indolent entities in order to avoid over-treatment and unnecessary therapeutic intervention and to provide for accurate prognostic prediction and appropriate follow-up. Full article

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) whose clinical course is largely shaped by molecular and biological features. Among the most impactful prognostic markers, TP53 mutations have emerged as critical determinants of treatment resistance since their first identification in MCL in 1996. Regardless of the detection method, TP53 mutations have been consistently associated with primary refractoriness to chemoimmunotherapy and significantly reduced overall survival. In this perspective, we explored recent advances in applying integrated-omics approaches to assess TP53 status. Despite its prognostic value, routine testing for TP53 at diagnosis remains uncommon, hindered by the lack of standardized protocols and costs for Next-Generation Sequencing (NGS), and the suboptimal reliability of immunohistochemistry (IHC) as a surrogate. This gap between research evidence and clinical practice represents a critical barrier to risk-adapted therapy. The broad implementation of standardized and accessible genomic techniques is essential to identify patients who deserve a personalized therapeutic approach. Several clinical trials have recently explored alternative chemo-free or targeted regimens specifically tailored to TP53-mutated patients (i.e., NCT03824483, NCT03567876), with promising results. This risk-adapted approach reflects a paradigm shift in MCL management, emphasizing the need for early molecular risk assessment to guide treatment decisions. In this scenario, TP53 mutations are no longer supporting actors, but a game-changer for the prognosis and treatment of patients with MCL. Full article

Clarifying the function of approximately 20,000 proteins encoded by the human genome is a key challenge in the fields of medicine and biology. However, many proteins remain uncharacterized. In this review, we introduce a challenge that uses adult T-cell leukemia/lymphoma (ATL) and proteomics to study human proteins of unknown function (PUFs). The characteristic properties of ATL cells are as follows: ATL cells (1) are infected with virus, (2) are derived from CD4⁺ T cells, (3) are generated via multi-stage carcinogenesis, (4) have flower-like nuclei, and (5) are highly infiltrative in the aggressive type. Given that ATL cells have contributed to impressive basic research, such as the discovery of HTLV-1 as a human cancer virus and interleukin-2 (IL-2) receptor α chain (IL-2Rα)/CD25, which is used for identifying regulatory T (Treg) cells, ATL cell lines could still be considered an attractive research tool. Furthermore, the “Unknome database” is useful for examining function-unknown degrees of proteins of interest using known scores based on Gene Ontology (GO) annotations and protein analysis through evolutionary relationships (PANTHER). Combining ATL proteomic data obtained by us with the “Unknome database” is expected to contribute not only to investigating the pathogenetic mechanism of ATL but also to clarifying the functions of PUFs. Full article

Fibroblast activation protein (FAP), a transmembrane serine protease expressed primarily in pathological conditions, plays a pivotal role in tumor progression. Despite extensive studies on FAP in solid tumors, its role in hematologic cancers, particularly lymphoid malignancies, remains underexplored. This study aimed to investigate the level and activity of soluble FAP (sFAP) in pre-therapeutic serum samples from 120 lymphoma patients. We measured sFAP serum levels using time-resolved immunofluorometric assay and sFAP activity with Förster resonance energy transfer assay. In addition, immunohistochemistry was used to analyze intratumoral FAP expression in tissue biopsies from a subset of B-cell lymphoma patients (n = 34). Notably, the results revealed significantly reduced circulating sFAP levels (p = 0.002) and activity (p < 0.001) in aggressive disease subtypes compared with indolent subtypes and healthy individuals. At the time of diagnosis, low sFAP activity correlated with inferior overall survival (both p < 0.001) in patients with the aggressive entities, suggesting altered FAP functionality in these tumors. Interestingly, measuring intratumoral FAP levels revealed an inverse pattern, with diffuse large B-cell lymphoma showing higher tissue FAP localization compared with follicular lymphoma (p < 0.001). These findings provide new insights into the biological and clinical significance of FAP in lymphoid malignancies, particularly highlighting the importance of sFAP activity as a potential prognostic marker in aggressive lymphoid malignancies. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) exhibits pronounced racial disparities in incidence and outcomes, yet the molecular basis remains poorly understood. Here, we examined racial differences in gene rearrangements (MYC, BCL2, BCL6), fusions (IGH::MYC, IGH::BCL2), and their interactions among White, Black, Asian, and Other-race groups in patients with DLBCL to uncover genetic drivers of disparities. Methods: We analyzed 919 DLBCL cases (2006–2023) from Johns Hopkins Hospital using fluorescence in situ hybridization to detect gene abnormalities. We used logistic regression and proportional odds models, adjusted for age and sex, to evaluate racial differences in five gene abnormalities and 10 gene–gene interaction pairs. Pearson’s Chi-squared and Goodman–Kruskal’s gamma tests assessed prevalence and interaction severity across racial groups. Results: MYC rearrangements and the MYC*IGH::MYC interaction were marginally more frequent in the White group than in Black and Other groups (p = 0.092, p = 0.098, respectively). IGH::BCL2 fusions were more prevalent in the Asian group than in the White group (p = 0.095), and the BCL2*IGH::BCL2 interaction was significantly higher in the Asian group (p = 0.049) than in the White group. Although high-grade B-cell lymphoma (HGBCL) prevalence showed no significant racial differences (p = 0.16), the Asian group exhibited a higher proportion of aggressive HGBCL with concurrent IGH::MYC and IGH::BCL2 fusions compared with the White group (p = 0.076). Age significantly influenced all gene abnormalities and interactions (p < 0.001–0.052), except for MYC rearrangements and specific pairs. Sex and sex–race interactions showed no significant effects. Conclusions: This study highlights molecular contributions to the racial differences in DLBCL disease. Further research collecting ancestry-specific biomarkers, treatment regimens, and clinical variables and outcomes is needed to advance personalized treatment strategies. Full article

Background and Objectives: Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous neoplasms. CD79B and MYD88 mutations are associated with the activated B-cell-like (ABC) subtype of DLBCL and often co-occur and lead to constitutive activation of the NF-κB pathway. Several different genetic classifications to date have recognized CD79B- and MYD88-mutated DLBCLs as a unique subtype with poor response to therapy and unfavorable survival. However, little is known about gene expression in DLBCLs with mutated CD79B (and MYD88) in comparison to their wild type counterparts. The objective of this study was to compare the gene expression in DLBCLs according to their CD79B mutational status. Methods: A total of 48 primary, treatment-naïve DLBCLs (CD79B-mutated: 35%/n = 17, CD79B-wild type: 65%/n = 31) were investigated using RNA expression profiling (770 genes), followed by immunohistochemical analysis of the up-regulated genes and survival analysis. Results: The gene expression analysis revealed that downstream of CD79B CARD11 and the NF-κB targets NFKBIZ, IL10, IL12A, PIM1 and BCL2A1 were up-regulated in CD79B-mutated DLBCLs. The strongest up-regulation was detected for ARNT2 and WNT11. Other up-regulated genes included the apoptosis-related BID and granzyme B, as well as genes of cell cycle regulation such as RUNX1, RUNX1T1 and RASGRF1. Up-regulation was also found for IL7, STAT3, MLLT4, CD14 and the HSP90B1 subunit. TP53 mutation showed an association with poorer overall survival in a secondary analysis, consistent with prior reports, while survival by CD79B/MYD88 mutation status and the differentially expressed genes showed no significant differences in this cohort. Conclusions: In conclusion, the current study identified novel up-regulated genes in CD79B-mutated DLBCLs beyond NF-κB pathway signaling, which may contribute to a better definition of potential therapeutic targets and further improves the characterization of this distinct and aggressive DLBCL subgroup. Full article