Figure - available from: Virchows Archiv
This content is subject to copyright. Terms and conditions apply.
Burkitt lymphoma, EBV + , associated with granulomas in parotid biopsy (CD20 + , CD10 + , BCL2-, FISH studies showed IGH::MYC but no BCL2 or BCL6 rearrangement). (A) There is a diffuse lymphoid infiltrate associated with scattered granulomas. (B) At higher magnification note the relatively uniform intermediate-sized cells associated with mitotic figures and tingible body macrophages. The granulomatous areas also included smaller T-cells. (C) The tumor is EBER positive (A H&E, 100 × , B H&E, 1000 × oil, C EBER in situ hybridization with hematoxylin counterstain, 400 ×)
Source publication
Since the 2016 WHO update, progress has been made in understanding the biology of Burkitt lymphoma (BL) and the concept of high-grade B-cell lymphomas (HGBCL) that allows some degree of refinement. The summary presented here reviews in detail the discussions of the Clinical Advisory Committee and expands upon the newly published 2022 International...
Citations
... However, cellof-origin classification can also be achieved using immunohistochemistry combining the assessment of CD10, BCL6, and MUM-1 (IRF4) [1]. Recently, the lymphoma classification has been updated with the incorporation of additional molecular features [2][3][4][69][70][71][72][73][74][75][76]. ...
Background: Artificial intelligence in medicine is a field that is rapidly evolving. Machine learning and deep learning are used to improve disease identification and diagnosis, personalize disease treatment, analyze medical images, evaluate clinical trials, and speed drug development. Methods: First, relevant aspects of AI are revised in a comprehensive manner, including the classification of hematopoietic neoplasms, types of AI, applications in medicine and hematological neoplasia, generative pre-trained transformers (GPTs), and the architecture and interpretation of feedforward neural net-works (multilayer perceptron). Second, a series of 233 diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab-CHOP from the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) was analyzed. Results: Using conventional statistics, the high expression of MYC and BCL2 was associated with poor survival, but high BCL6 was associated with a favorable overall survival of the patients. Then, a neural network predicted MYC, BCL2, and BCL6 with high accuracy using a pan-cancer panel of 758 genes of immuno-oncology and translational research that includes clinically relevant actionable genes and pathways. A comparable analysis was performed using gene set enrichment analysis (GSEA). Conclusions: The mathematical way in which neural networks reach conclusions has been considered a black box, but a careful understanding and evaluation of the architectural design allows us to interpret the results logically. In diffuse large B-cell lymphoma, neural networks are a plausible data analysis approach.
... In contrast, DHL was identified in 13% of YA patients in our study. YA DHL is predominantly HGBCL-DH-BCL6 (15/17 DHL cases, 88%), contrasting the figures documented in adult populations in whom HGBCL-DH-BCL2 prevail, accounting for 80-90% of DH/TH lymphomas [30]. ...
... Data is limited, but some studies do suggest benefit from more aggressive therapy regimens in patients with HGBCL-DH-BCL6, arguing that more data is needed before elimination of this category [24,26,[32][33][34][35]. Additionally, in up to 30% of cases of HGBCL-DH-BCL6, MYC-R involve the BCL6 gene as the rearrangement partner [30,36]. This profile has been described as "pseudo-double hit" [37]. ...
MYC-rearranged B-cell lymphoma (BCL) in the pediatric/young adult (YA) age group differs substantially in disease composition from adult cohorts. However, data regarding the partner genes, concurrent rearrangements, and ultimate diagnoses in these patients is scarce compared to that in adult cohorts. We aimed to characterize the spectrum of MYC-rearranged (MYC-R) mature, aggressive BCL in the pediatric/YA population. A retrospective study of morphologic, immunophenotypic, and fluorescence in situ hybridization (FISH) results of patients age ≤ 30 years with suspected Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL), and a MYC-R by FISH between 2013–2022 was performed. Two-hundred fifty-eight cases (129 (50%) pediatric (< 18 years) and 129 (50%) YA (18–30 years)) were included. Most MYC-R BCL in pediatric (89%) and YA (66%) cases were BL. While double-hit (DH) cytogenetics (MYC with BCL2 and/or BCL6-R, HGBCL-DH) was rare in the pediatric population (2/129, 2%), HGBCL-DH increased with age and was identified in 17/129 (13%) of YA cases. Most HGBCL-DH had MYC and BCL6-R, while BCL2-R were rare in both groups (3/258, 1%). MYC-R without an IG partner was more common in the YA group (14/116 (12%) vs 2/128 (2%), p = 0.001). The pediatric to YA transition is characterized by decreasing frequency in BL and increasing genetic heterogeneity of MYC-R BCL, with emergence of DH-BCL with MYC and BCL6-R. FISH to evaluate for BCL2 and BCL6 rearrangements is likely not warranted in the pediatric population but should continue to be applied in YA BCL.
... The differential diagnosis for both cases included the following entities: BL, DLBCL-NOS (encompassing DLBCL with MYC rearrangement), and HGBCL-NOS, the latter of which was not supported due to the "large cell" cytology. 8,9 While BCL2 expression is traditionally thought to preclude a diagnosis of BL in pediatric/adolescent patients, a few studies including considerable numbers of BLs with variable degrees of BCL2 expression have challenged this assumption. 10,11 Furthermore, a Ki-67 proliferation index >95% and strong C-MYC positivity is generally not seen in DLBCL. ...
We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as “DLBCL-NOS with MYC rearrangement” using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA).
... It originates from Blymphocytes of the germinal centers, or from the post-germinal center region. The molecular pathogenesis is complex, heterogeneous, and follows a multistep process [104][105][106][107][108][109][110][111][112]. The best characterized pathogenic changes include BCL6 aberrant expression, TP53 downregulation, BCL2 overexpression, MYC overexpression, immune evasion, abnormal lymphocyte trafficking, and an aberrant somatic hypermutation [113]. ...
... The gene expression of DLBCL has been extensively analyzed using gene expression microarray technology and immunohistochemistry. Based on the cell of origin, the cases can be classified into Germinal center B cell-like (GCB) that has a gene expression profile similar to the normal germinal center B cells; Activated B cell-like (ABC) that has a profile like the post-germinal center-activated B cells; and an Unclassified Type III heterogeneous group [104][105][106][107][108][109][110][111][112][113]. ...
Diffuse large B-cell lymphoma is one of the most frequent mature B-cell hematological neoplasms and non-Hodgkin lymphomas. Despite advances in diagnosis and treatment, clinical evolution is unfavorable in a subset of patients. Using molecular techniques, several pathogenic models have been proposed, including cell-of-origin molecular classification; Hans’ classification and derivates; and the Schmitz, Chapuy, Lacy, Reddy, and Sha models. This study introduced different machine learning techniques and their classification. Later, several machine learning techniques and artificial neural networks were used to predict the DLBCL subtypes with high accuracy (100–95%), including Germinal center B-cell like (GCB), Activated B-cell like (ABC), Molecular high-grade (MHG), and Unclassified (UNC), in the context of the data released by the REMoDL-B trial. In order of accuracy (MHG vs. others), the techniques were XGBoost tree (100%); random trees (99.9%); random forest (99.5%); and C5, Bayesian network, SVM, logistic regression, KNN algorithm, neural networks, LSVM, discriminant analysis, CHAID, C&R tree, tree-AS, Quest, and XGBoost linear (99.4–91.1%). The inputs (predictors) were all the genes of the array and a set of 28 genes related to DLBCL-Burkitt differential expression. In summary, artificial intelligence (AI) is a useful tool for predictive analytics using gene expression data.
... Historically, three epidemiologic variants of BL have been described: endemic, sporadic (non-endemic), and immunodeficiency-associated [5]. However, this differentiation is somewhat confounded by the frequency of EBV positivity across all subtypes [6], and the current classification systems recommend distinguishing EBV-negative from EBV-positive cases [7] [8]. The patient described in this case had sporadic BL, which accounts for 1% -2% of adult lymphomas [9] and has a trimodal age-specific incidence, with peaks at 10 years (most frequent), 40 years (especially in males, who are affected three-to-four times more frequently than females), and 75 years [10]. ...
Adult intussusception is rare, highly associated with a malignant lead point, and often requires emergent surgical management. We report the case of a 44-year-old male who presented with generalized abdominal pain and was found to have early ileocolic intussusception secondary to a large ileocecal mass. Biopsies of the mass and an enlarged cardiophrenic lymph node, as well as pleural fluid cytology were all consistent with Burkitt lymphoma (BL). Curiously, the patient’s abdominal exam was reassuring, and the intussusception and malignant bowel obstruction resolved over 36 hours with conservative management alone. With a Burkitt lymphoma international prognostic index (BL-IPI) score of 2, the patient proceeded to treatment with combination chemoimmunotherapy and attained a complete response after four cycles. There was no bowel perforation or recurrent intussusception throughout treatment. Thus, this report marks the first reported case of adult BL-associated intussusception to resolve with non-invasive management and establishes a precedent for conservative management in select patients.
... Burkitt lymphoma (BL) belongs to the group of non-Hodgkin lymphomas (NHL) and is the most aggressive malignancy, doubling its cell population every 24-48 hours [7]. BL is characterised by hyperinvasiveness and high lethality [8]. ...
The capabilities of molecular modelling and docking allow for the discovery of new potential drug agents to improve the treatment of diseases, which is a current concern. The objective of this study was to conduct in silico screening for antibody mimetics to B-cell membrane proteins for the treatment of Burkitt lymphoma through virtual screening. In this work, a standard protocol for structure-based virtual screening was employed, with the distinction that pharmacophores for screening were built not based on small-molecule ligands but on selected amino acid residues of antibodies. Based on literature data and the presence of a mechanism of direct cytotoxic action, as well as the availability of 3D structures of complexes, three monoclonal antibodies were selected: obinutuzumab, epratuzumab, and atezolizumab. The identification of biological targets was carried out by searching for 3D structures of selected complexes with target proteins in the Protein Data Bank. For virtual screening, the web service Pharmit was chosen. Using the Molecular Operating Environment program, pharmacophore models were constructed for three complexes: CD20 and obinutuzumab, CD22 and epratuzumab, and PD-L1 and atezolizumab. Docking with the CD20, CD22, and PD-L1 proteins was conducted at the binding sites recognised by the original antibody. Through in silico virtual screening using the Molecular Operating Environment software, a search for antibody mimetics to B-cell membrane proteins for Burkitt lymphoma treatment was conducted, resulting in the selection of 5 potential anti-lymphoma agents: CHEMBL505179 for the CD20 receptor, an antagonist of the melanocortin receptor for CD20 (PubChem-44406884), an inhibitor of blood clotting Factor Xa for CD22 (PubChem-136510605), and a blocker of epithelial Na+ channels for CD22 (PubChem-126761430), and an agonist of the melanocortin receptor for PD-L1 (PubChem-25078192). The obtained results can be applied in the pharmaceutical industry and oncological practice to enhance therapeutic outcomes in the treatment of patients with Burkitt lymphoma
... One of the two originally designated entities of high-grade B-cell lymphoma (HGBL) was one with MYC and BCL2 and/or BCL6 translocations, which was also termed double-hit (DH) or triple-hit (TH) lymphoma. However, this has subsequently been split into two distinct categories (1) HGBL with MYC and BCL2 rearrangements, which account for 80-90% of such cases; and (2) HGBL with MYC and BCL6 rearrangements, which account for 10-20% of such cases, with substantial evidence allowing the former to be retained as a bona fide entity, while the latter seems to be more heterogeneous and has been relegated, by the ICC but not WHO, to a provisional entity [41]. Virtually all of the MYC+BCL2 HGBLs are of GCB origin, whereas only around 50% of the MYC+BCL6 HGBLs are. ...
... The possibility of a large B-cell lymphomas with 11q aberrations should be considered particularly with a Burkitt-like morphologic appearance but with coarse apoptotic material in the tingible body macrophages and lack of a MYC R. Some cases, however, will more closely resemble a DLBCL. DLBCL, diffuse large B-cell lymphoma; R, rearrangement; HGBL: high-grade B-cell lymphoma; DH, double hit (modified according to [41]) ...
With the explosion in knowledge about the molecular landscape of lymphoid malignancies and the increasing availability of high throughput techniques, molecular diagnostics in hematopathology has moved from isolated marker studies to a more comprehensive approach, integrating results of multiple genes analyzed with a variety of techniques on the DNA and RNA level. Although diagnosis of lymphoma still relies on the careful integration of clinical, morphological, phenotypic, and, if necessary molecular features, and only few entities are defined strictly by genetic features, genetic profiling has contributed profoundly to our current understanding of lymphomas and shaped the two current lymphoma classifications, the International Consensus Classification and the fifth edition of the WHO classification of lymphoid malignancies. In this review, the current state of the art of molecular diagnostics in lymphoproliferations is summarized, including clonality analysis, mutational studies, and gene expression profiling, with a focus on practical applications for diagnosis and prognostication. With consideration for differences in accessibility of high throughput techniques and cost limitations, we tried to distinguish between diagnostically relevant and in part disease-defining molecular features and optional, more extensive genetic profiling, which is usually restricted to clinical studies, patients with relapsed or refractory disease or specific therapeutic decisions. Although molecular diagnostics in lymphomas currently is primarily done for diagnosis and subclassification, prognostic stratification and predictive markers will gain importance in the near future.
... Its definition relies on morphologic 16 features, including the Burkitt-like and blastoid variants, but after exclusion of the double-hit 17 lymphoma it is not defined by cytogenetic or molecular markers. 14 Categorical variables were compared using Fisher's exact test, and continuous variables using 2 rank-sum test. Survival analysis was conducted using the Kaplan-Meier method. ...
In this multi-institutional retrospective study, we examined characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS). This rare lymphoma category is defined by high-grade morphologic features, most commonly Burkitt-like, and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements (so-called double-hit). Our results show that HGBL-NOS tumors are heterogeneous: 83% had a germinal center B-cell immunophenotype, 37% a dual expressor immunophenotype (MYC and BCL2 expression), 28% (single-hit) MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage 4 disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included DA-EPOCH-R (43%), R-CHOP (33%), or other intensive chemotherapy programs (11%). We found no significant differences in the rates of complete response (CR, P=0.32), progression-free (PFS, P=0.82), or overall survival (OS, P=0.60) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% (95%CI, 46.9-62.7), and OS was 68.1% (95%CI, 59.7-75.0). In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3x upper limit of normal, and a dual expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS (13% at 2 years). Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R versus R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.
... These transformed tumors may have the morphology of DLBCL or HGBL and include the entity "diffuse large B cell lymphoma/high grade B-cell lymphoma with rearrangements of MYC and BCL2" (DLBCL/HGBL-MYC/BCL2) (WHO-HAEM5) or "high-grade B-cell lymphoma with MYC and BCL2 rearrangements" (2022 International Consensus Classification [ICC]). 2, [8][9][10] These cytogenetically defined aggressive lymphomas are often colloquially referred to as "double hit" (DH; MYC and BCL2 rearrangements) or "triple hit" (TH; MYC, BLC6, and BCL2 rearrangements) lymphomas. Although many of these DH and TH lymphomas arise de novo, approximately 20% to 35% are thought to arise from an antecedent or concurrent FL. ...
Objectives:
The 2021 Society for Hematopathology and European Association for Haematopathology Workshop addressed the molecular and cytogenetic underpinnings of transformation and transdifferentiation in lymphoid neoplasms.
Methods:
Session 4, "Transformations of Follicular Lymphoma," and session 5, "Transformations of Other B-Cell Lymphomas," included 45 cases. Gene alteration analysis and expression profiling were performed on cases with submitted formalin-fixed, paraffin embedded tissue.
Results:
The findings from session 4 suggest that "diffuse large B-cell lymphoma/high-grade B-cell lymphoma with rearrangements of MYC and BCL2" is a distinct category arising from the constraints of a preexisting BCL2 translocation. TdT expression in aggressive B-cell lymphomas is associated with MYC rearrangements, immunophenotypic immaturity, and a dismal prognosis but must be differentiated from lymphoblastic -lymphoma. Cases in session 5 illustrated unusual morphologic and immunophenotypic patterns of transformation. Additionally, the findings support the role of cytogenetic abnormalities-specifically, MYC and NOTCH1 rearrangements-as well as single gene alterations, including TP53, in transformation.
Conclusions:
Together, these unique cases and their accompanying molecular and cytogenetic data suggest potential mechanisms for and unusual patterns of transformation in B-cell lymphomas and indicate numerous opportunities for further study.
... Novel genomic perspectives are updated with emphasis on alterations that may be of clinical interest in the near future. The spectrum of entities recognized under the term of "follicular lymphoma" (FL) has expanded in recent years, particularly with the identification of several entities that contrary to conventional FL do not carry the t (14,18). Laurent and colleagues [15] review issues related to grading FL, provide a comprehensive perspective of FLs negative for BCL2 rearrangement, and highlight the relevance of molecular studies in the differential diagnosis of these entities and other related lymphomas. ...
... Although still not considered ready for clinical use, they open new perspectives that most likely will influence our practice in the coming years. High-grade B-cell lymphomas are a challenging group of neoplasms thoroughly reviewed by King et al. [18] The paradigm of these tumors is the well characterized Burkitt lymphoma in which recent genomic studies are distinguishing EBV positive and negative tumors. The manuscript provides the rationale for the new definition of these tumors based on the presence of MYC, BCL2, and BCL6 rearrangements and the new consideration of occasional TdT expression in these tumors. ...
