Search

INTRODUCTION: Fluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2, or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies. METHODS: We describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens. RESULTS: FISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement. DISCUSSION: FISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2, or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing.

AbstractDouble-hit lymphoma (DHL) is a high-risk subtype of large B-cell lymphoma, defined by concurrent rearrangements MYC and BCL2. The diagnosis is confirmed through histologic and immunophenotypic examination and fluorescence in situ hybridization (FISH) to demonstrate the rearrangements. DHL morphology ranges from DLBCL to high-grade B-cell lymphoma which can resemble Burkitt lymphoma and is almost always germinal center B-cell like (GCB). Prognosis is influenced by elevated lactate dehydrogenase (LDH), advanced stage, and extranodal involvement, among other factors. Treatment outcomes vary, but intensive chemotherapy regimens such as dose-adjusted EPOCH-R have shown the most promising results, though low-risk cases do occur and may do well with less intensive treatments. Recent therapeutic advances such as CAR-T cells and bispecific antibodies offer promise for patients with relapsed/refractory disease. This review synthesizes data from recent literature to provide a comprehensive analysis of the molecular underpinnings, diagnostic criteria, prognostic factors, and therapeutic strategies for DHL. [ABSTRACT FROM AUTHOR]

Abstract High-grade B-cell lymphoma with 11q aberration (HGBL-11q) is a distinct lymphoma entity according to the 5th edition of the WHO classification of hematolymphoid tumors. It lacks MYC translocation but carries proximal gains and/or telomeric losses of chromosome 11q. This rare type of B-cell lymphoma is less frequently reported in people living with HIV (PLWH), and its exact frequency remains unclear. Our goal was to retrospectively analyze its frequency in a cohort of aggressive B-cell lymphomas in PLWH, including Burkitt lymphoma (BL, n = 35), diffuse large B-cell lymphoma (DLBCL, n = 48), high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS, n = 13), which was diagnosed as AIDS-related lymphoma (ARL) at our institution. In total, 10/96 (10.4%) cases harbored the typical 11q aberration pattern, predominantly those that had been classified as BL (6/35, 17.1%), DLBCL (2/48, 4.2%), and HGBL, NOS (2/13, 15.4%). We also evaluated 7 cases of AIDS-related HGBL-11q (AR-HGBL-11q) reported in the literature. The median age of our cohort was 35 years, and all the patients were male. Most cases (70%) had a history of HIV infection for over 1 year, and all were involved in lymph nodes (100%), frequently involved extranodal sites (60%), and Ann Arbor stage III/IV. In histomorphology, the cases exhibited diverse cytological features, reminiscent of BL (6 cases), DLBCL (2 cases), and HGBL (2 cases). A comparison of the combined cohort of 17 AR-HGBL-11q cases with 11 ARL cases that lacked both MYC rearrangement and 11q aberration at our institution showed that HGBL-11q cases were characterized by strikingly coarse apoptotic debris (P

High-grade B-cell lymphoma with 11q aberration (HGBL-11q) is a distinct lymphoma entity according to the 5th edition of the WHO classification of hematolymphoid tumors. It lacks MYC translocation but carries proximal gains and/or telomeric losses of chromosome 11q. This rare type of B-cell lymphoma is less frequently reported in people living with HIV (PLWH), and its exact frequency remains unclear. Our goal was to retrospectively analyze its frequency in a cohort of aggressive B-cell lymphomas in PLWH, including Burkitt lymphoma (BL, n = 35), diffuse large B-cell lymphoma (DLBCL, n = 48), high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS, n = 13), which was diagnosed as AIDS-related lymphoma (ARL) at our institution. In total, 10/96 (10.4%) cases harbored the typical 11q aberration pattern, predominantly those that had been classified as BL (6/35, 17.1%), DLBCL (2/48, 4.2%), and HGBL, NOS (2/13, 15.4%). We also evaluated 7 cases of AIDS-related HGBL-11q (AR-HGBL-11q) reported in the literature. The median age of our cohort was 35 years, and all the patients were male. Most cases (70%) had a history of HIV infection for over 1 year, and all were involved in lymph nodes (100%), frequently involved extranodal sites (60%), and Ann Arbor stage III/IV. In histomorphology, the cases exhibited diverse cytological features, reminiscent of BL (6 cases), DLBCL (2 cases), and HGBL (2 cases). A comparison of the combined cohort of 17 AR-HGBL-11q cases with 11 ARL cases that lacked both MYC rearrangement and 11q aberration at our institution showed that HGBL-11q cases were characterized by strikingly coarse apoptotic debris (P < 0.001), background rich in eosinophils (P = 0.002), higher expression of the germinal centre marker LMO2 (P = 0.080), lower expression of MUM1 (P = 0.004), BCL2 (P = 0.007), and LEF1 (P = 0.080), and lower positivity for EBER in situ hybridisation (P = 0.027). Notably, one case in our series was EBV-positive, a finding not previously reported in the literature. Furthermore, comparing the prognosis between these two groups, AR-HGBL-11q showed a relatively favorable prognosis (P = 0.15), although the difference was not statistically significant. We analyzed this rare lymphoma entity in the HIV setting and highlighted the importance of integrating histomorphological and immunophenotypic features in its diagnosis and classification. [ABSTRACT FROM AUTHOR]

Abstract High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual dysregulation of MYC and BCL2 is one of the important pathogenic mechanisms. Thus, combined targeting of MYC and BCL2 appears to be a promising strategy. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme for the de novo biosynthesis of pyrimidine. It has been shown to be a potential therapeutic target for multiple diseases. In this study, the DHODH inhibitor brequinar exhibited growth inhibition, cell cycle blockade, and apoptosis promotion in HGBCL cell lines with MYC and BCL2 rearrangements. The combination of brequinar and BCL2 inhibitors venetoclax had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Venetoclax could upregulate MCL-1 and MYC expression, which has been reported as a resistance mechanism of BCL2 inhibitors. Brequinar downregulated MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in HGBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its anti-tumor effects. In vivo studies demonstrated synergetic tumor growth inhibition in xenograft models with brequinar and venetoclax combination treatment. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in HGBCL with abnormal MYC and BCL2.

Abstract Background Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL. Results We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β

High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual dysregulation of MYC and BCL2 is one of the important pathogenic mechanisms. Thus, combined targeting of MYC and BCL2 appears to be a promising strategy. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme for the de novo biosynthesis of pyrimidine. It has been shown to be a potential therapeutic target for multiple diseases. In this study, the DHODH inhibitor brequinar exhibited growth inhibition, cell cycle blockade, and apoptosis promotion in HGBCL cell lines with MYC and BCL2 rearrangements. The combination of brequinar and BCL2 inhibitors venetoclax had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Venetoclax could upregulate MCL-1 and MYC expression, which has been reported as a resistance mechanism of BCL2 inhibitors. Brequinar downregulated MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in HGBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its anti-tumor effects. In vivo studies demonstrated synergetic tumor growth inhibition in xenograft models with brequinar and venetoclax combination treatment. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in HGBCL with abnormal MYC and BCL2. [ABSTRACT FROM AUTHOR]

Introduction: Fluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2, or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies. Methods: We describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens. Results: FISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement. Discussion: FISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2, or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL. Results: We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499–31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286–18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239–21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319–27.397) and PFS (HR 4.689, 95% CI 1.102–19.963) in LBCL treated with R-CHOP-like regimens. Conclusion: We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs. [ABSTRACT FROM AUTHOR]

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine. [ABSTRACT FROM AUTHOR]

Aggressive B-cell non-Hodgkin lymphomas are a heterogeneous group of diseases and our concepts are evolving as we learn more about their clinical, pathologic, molecular genetic features. Session IV of the 2020 EAHP Workshop covered aggressive, predominantly high-grade B-cell lymphomas, many that were difficult to classify. In this manuscript, we summarize the features of the submitted cases and highlight differential diagnostic difficulties. We specifically review issues related to high-grade B-cell lymphomas (HGBCLs) with MYC and BCL2 and/or BCL6 rearrangements including TdT expression in these cases, HGBCL, not otherwise specified, large B-cell lymphomas with IRF4 rearrangement, high-grade/large B-cell lymphomas with 11q aberration, Burkitt lymphoma, and pleomorphic mantle cell lymphoma. Since the workshop, the 5th edition of the WHO Classification for Haematolymphoid Tumours (WHO-HAEM5) and International Consensus Classification (ICC) 2022 were published. We endeavor to use the updated terminology. [ABSTRACT FROM AUTHOR]

IntroductionFluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2, or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies.MethodsWe describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens.ResultsFISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement.DiscussionFISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2, or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing.

This case report discusses a 95-year-old man diagnosed with two types of lymphomas. He was hospitalized for erysipelas in September 2018. The lymph node revealed high-grade B-cell lymphoma with Myc and Bcl-2 rearrangement. Bone marrow biopsy revealed hairy cell leukemia, a rare type of indolent B-cell lymphoma. We found that the bone marrow and left inguinal lymph node were non-homologous. There are no known reports of super-aged patients with two types of lymphoma simultaneously. The toxicity of R-CHOP in elderly people limited its usage, so we first chose rituximab. However, this approach was not successful. We then considered the Bruton tyrosine kinase (BTK) inhibitor, but its use was limited due to high blood pressure. Finally, we administered venetoclax, which the patient took for 2 years. The results of the routine blood examination were close to normal and no enlarged superficial or abdominal lymph nodes were observed.This is the oldest reported patient with two types of malignant lymphatic diseases. Additionally, this rare case suggests that targeted therapy can be more effective and safe for super-aged individuals. To summarize, a 95-year-old man diagnosed with two types of lymphomas, high-grade B-cell lymphoma and hairy cell leukemia, was successfully treated with venetoclax after other treatments failed. This case suggests that targeted therapy can be effective and safe for super-aged patients with multiple malignant lymphatic system diseases.

Gastric high-grade B-cell lymphoma (HGBL) with adrenal gland invasion is a rare clinical entity with few cases reported in the literature. Patients usually present with nonspecific symptoms that lead to delays in the diagnosis, initiation of treatment, and prognosis. In this report, we present a case of a middle-aged woman in her 60s who presented with shortness of breath, dysphagia, early satiety, and melena. Further investigations confirmed the presence of an ulcerated gastric mass with invasion to the left adrenal gland, and histopathological and molecular studies of the gastric mass confirmed the diagnosis of B-Cell Lymphoma with MYC and BCL-6 rearrangements, a rare aggressive lymphoma subtype known as HGBL. Consequently, she was started on R-CHOP-21 chemotherapy protocol with good outcomes and resolution of the mass on repeat imaging; the current report aimed to emphasize the importance of recognizing unusual presentations of HGBL, especially gastric HGBL, which will help in early recognition, treatment, and prognosis. [ABSTRACT FROM AUTHOR]

Objectives Large B-cell lymphomas (LBCLs) are a heterogeneous group of lymphoid neoplasms whose molecular and cytogenetic profile has predictive and prognostic implications. The concept of double-hit lymphomas (DHLs) was recently updated in the fifth edition of the World Health Organization classification, with the exclusion of MYC and BCL6 rearranged tumors from the group. Now, DHLs are referred to as diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements. Fluorescence in situ hybridization (FISH) is the current gold standard for detecting rearrangements in LBCLs, but comprehensive genomic profiling (CGP) has recently been suggested to be at least as accurate as FISH in classifying these neoplasms and providing additional genetic information. Methods We analyzed a cohort of 131 patients in whom FISH and CGP studies were performed as part of our normal clinical workflow and compared the effectiveness of FISH and CGP in detecting these clinically relevant rearrangements. Results Our findings are in agreement with our previously published study, which analyzed a cohort of 69 patients, supporting our hypothesis that the best approach to maximize detection of DHLs while limiting waste seems to be a combination of CGP and MYC break-apart FISH testing, the latter to capture the presence of non– IGH::MYC events. Conclusions Our study supports the combined use of FISH and GCP rather than either method alone to better detect MYC and BCL2 (and BCL6) gene rearrangements. [ABSTRACT FROM AUTHOR]

In this study, we reported a seldom case of pediatric high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS) with loss of B-cell markers (CD19, CD20, CD22, CD79a, CD38, Pax5, OCT2, and BOB1) and CD45, which bring great challenges to exclude a non-lymphomatous neoplasm. However, no evidence was found to support the diagnosis of sarcoma and carcinoma. Thus, due to the patient's prior history of Burkitt's lymphoma treated by rituximab-containing therapies, we carefully searched for any indication of B-cell differentiation. Eventually, NGS results revealed the monoclonal rearrangement of IGH (IGHD2-8-IGHJ6 and IGHV4-30–2-IGHJ4) in both pre-treatment and present tumors, confirming the same B-cell lineage. Moreover, both tumors exhibited the same IGHA1-MYC translocation and somatic mutations of c-MYC, TP53, ID3, and CCND3. Therefore, in addition to strong expression of BCL2 in the present tumor, we finally arrived at a diagnosis of pediatric HGBL, NOS with loss of B-cell lineage markers and CD45. [ABSTRACT FROM AUTHOR]

Gastric high-grade B-cell lymphoma (HGBL) with adrenal gland invasion is a rare clinical entity with few cases reported in the literature. Patients usually present with nonspecific symptoms that lead to delays in the diagnosis, initiation of treatment, and prognosis. In this report, we present a case of a middle-aged woman in her 60s who presented with shortness of breath, dysphagia, early satiety, and melena. Further investigations confirmed the presence of an ulcerated gastric mass with invasion to the left adrenal gland, and histopathological and molecular studies of the gastric mass confirmed the diagnosis of B-Cell Lymphoma with MYC and BCL-6 rearrangements, a rare aggressive lymphoma subtype known as HGBL. Consequently, she was started on R-CHOP-21 chemotherapy protocol with good outcomes and resolution of the mass on repeat imaging; the current report aimed to emphasize the importance of recognizing unusual presentations of HGBL, especially gastric HGBL, which will help in early recognition, treatment, and prognosis.

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. [ABSTRACT FROM AUTHOR]

Objectives Malignant effusion is usually caused by metastatic carcinoma. Malignant lymphoma is often not included as a top differential diagnosis of malignant effusion. Here, we describe 3 cases of young female patients with no significant past medical history who presented with fluid overload and were diagnosed with high-grade B-cell lymphoma (HGBL). Methods We conducted histopathologic examination and immunophenotypic and cytogenetic analyses on three cases using immunohistochemistry, flow cytometry, fluorescence in situ hybridization (FISH), and karyotyping. We also included patients' clinical and radiological findings in our case reports. Results Histologic examination of the effusion samples showed numerous intermediate to large lymphoma cells with irregular nuclear contours and fine chromatin. The lymphoma cells were positive for CD10, CD20, BCL2, BCL6, and PAX5 and negative for CD34, cyclin D1, HHV-8, and TdT. In situ hybridization for Epstein-Barr virus (EBV)–encoded small RNAs was negative. The proliferation index by Ki-67 stain was more than 80%. Flow cytometry showed CD10-positive B cells with monotypic immunoglobulin light chain expression. Fluorescence in situ hybridization analysis demonstrated MYC , BCL2 , or BCL6 rearrangements. These 3 patients were diagnosed as having HGBL with double-/triple-hit rearrangements. Despite receiving aggressive chemotherapy, all 3 patients had a dismal clinical course, with 2 patients dying less than 2 years after initial diagnosis. Conclusions High-grade B-cell lymphoma should be considered in the differential diagnoses of malignant effusions. Flow cytometric and FISH analyses of the body fluid specimens are essential to reach an accurate and timely diagnosis. [ABSTRACT FROM AUTHOR]

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 Consensus Classification for lymphoid malignancies (Campo et al. Blood, 2022). BL remains the prototypic HGBCL and diagnostic criteria are largely unchanged. HGBCL with MYC and BCL2 and HGBCL with MYC and BCL6 rearrangements are now separated to reflect biologic and pathologic differences. HGBCL, NOS remains a diagnosis of exclusion that should be used only in rare cases. FISH strategies for diffuse large B-cell lymphoma (DLBCL) and HGBCL are discussed in detail for these diseases. Advances in integrative analysis of mutations, structural abnormalities, copy number, and gene expression signatures allow a more nuanced view of the heterogeneity of DLBCL, NOS as well as definitions of HGBCL and point to where the future may be headed for classification of these diseases. [ABSTRACT FROM AUTHOR]

Background. The study of genetic predictors of non-Hodgkin’s lymphomas prognosis is one of the most relevant areas of oncohematology. It is extremely interesting to search for integral markers that reflect the most important stages of tumor pathogenesis. DNA repair system plays one of the key roles in genomic instability. Aberrations of microsatellite repeats such as microsatellite instability (MSI), in particular elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is characteristic for mismatch repair system and loss of heterozygosity (LOH) is an integral feature of genomic instability.Objective. Analysis of MSI, EMAST, LOH significance in follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and high-grade B-cell lymphoma (HGBL) patients.Materials and methods. The study was performed by multiplex PCR and fragment analysis with diagnostic panels COrDIS Plus and COrDIS MSI in 85 FL patients, 32 DLBCL patients, and 37 HGBL patients.Results. The frequency of LOH in the general FL group was 40/81 (49.4 %), MSI – 10/82 (12.2 %), EMAST – 15/81 (18.5 %). The frequency of LOH in the HGBL group was 21/31 (67.8 %), MSI – 11/37 (29.7 %), EMAST – 13/31 (41.9 %). The frequency of LOH in the DLBCL group was 18/29 (62.0 %), MSI – 5/32 (15.6 %), EMAST – 14/32 (43.8 %). When considering the morphological types of FL, it was noted that a higher frequency of genetic aberrations was characteristic of lymphomas with a more aggressive morphology (p

High-grade B-cell lymphoma (HGBL) with c-MYC and BCL2 and/or BCL6 rearrangements, also known as a double-hit and triple-hit lymphoma, is an aggressive non-Hodgkin lymphoma affecting older adults. After formal recognition of this entity in the 2017 revision of the World Health Organization Classification of lymphoid neoplasms, only two well-documented cases of triple-hit lymphoma of the orbit appear in the literature. Herein, we describe a 70-year-old man with progressive diplopia, ophthalmoplegia, and rapidly enlarging temporal mass. Biopsy revealed a tumor morphologically consistent with HGBL, coexpressing CD20, CD10, BCL6, BCL2, and c-MYC on immunohistochemical analysis. Fluorescence in-situ hybridization showed rearrangements in c-MYC and BCL-2 genes, confirming double-hit HGBL. Systemic workup revealed Ann Arbor stage IV disease. This report reviews the existing literature on ocular adnexal double-hit and triple-hit lymphoma and provides an update on the diagnostic ancillary studies, prognostic implications, and latest management for this aggressive hematolymphoid malignancy. [ABSTRACT FROM AUTHOR]

ObjectiveHigh-grade B-cell lymphoma (HGBL) is highly aggressive and has a poor prognosis.MethodsThe clinical data of 76 patients with High-grade B-cell lymphoma treated in our lymphoma center from July 2016 to April 2020 were analyzed retrospectively. The clinical features, treatment and prognosis of patients with two types of high-grade B-cell lymphoma were compared and analyzed.ResultsAmong 76 patients with high-grade B-cell lymphoma, 44 cases (57.9%) were high-grade B-cell lymphoma, accompanied by MYC and Bcl-2 and/or Bcl-6 rearrangement (HGBLR) patients, and 32 cases (42.1%) were HGBL, NOS patients. The bone marrow infiltration, IPI (international prognostic index), Ann Arbor stage (III/IV), extranodal disease are more likely to occur in HGBLR group (P

Objectives: Diagnosis of high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements (double-/triple-hit lymphoma [DTHL]) appears to mandate fluorescence in situ hybridization (FISH) testing for all large B-cell lymphoma (LBCL). Given the low incidence of DTHL, we aimed to identify flow cytometry (FC) and immunohistochemistry (IHC) features of DTHL that could be used to develop an optimal screening strategy. This combined FC-IHC approach has not yet been studied.Methods: We compared features of 40 cases of DTHL and 39 cases of diffuse LBCL (DLBCL) without MYC rearrangement.Results: Bright CD38 expression (CD38bright) by FC, high MYC expression (≥55%), and double-expressor phenotype by IHC were significantly associated with DTHL. The biomarker combining FC and IHC, CD38bright and/or MYC ≥55%, was superior to FC and IHC markers alone in predicting DTHL. Restricting FISH testing to approximately 25% of LBCL based on CD38brightand/or MYC ≥55% would detect approximately 95% of DTHL-BCL2 and approximately 75% of DHL-BCL6.Conclusions: Our study demonstrated that the novel biomarker of CD38bright and/or MYC ≥55% is highly predictive of DTHL. Awareness of the advantages and limitations of this screening strategy would facilitate development of a rational diagnostic workflow to provide high-quality patient care. [ABSTRACT FROM AUTHOR]

Purpose of Review: This article reviews the current data and future directions in the management of Burkitt lymphoma (BL) and high-grade B-cell lymphoma (HGBL). Recent Findings: BL is a rare, mature B-cell lymphoma molecularly defined by translocation of the proto-oncogene MYC. Multiple intensive combination chemoimmunotherapy regimens have demonstrated excellent efficacy in this disease, although treatment toxicity remains a challenge in many patients. Double-hit lymphoma (DHL) represents HGBL with translocations of the oncogene MYC along with either BCL2 or BCL6, or both. In 2016, the World Health Organization update of this classification was revised to a new entity defined by cytogenetics: HGBL with MYC and BCL2 and/or BCL6 rearrangements. Recent prospective data using dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab has demonstrated encouraging treatment efficacy in these patients. HGBL, not otherwise specified (NOS) is a heterogeneous, aggressive, mature B-cell lymphoma that does not meet criteria for BL, DHL, or diffuse large B-cell lymphoma NOS. Therapy for this entity is not well established. Summary: The aggressive B-cell lymphomas BL, DHL, and HGBL, NOS are unique diseases with specific pathogenesis and biology. Insights into the molecular biology of these diseases have enabled new classifications and personalization of therapy. [ABSTRACT FROM AUTHOR]

High-grade B-cell lymphoma (HGBL) is a newly introduced category of rare and heterogeneous invasive B-cell lymphoma (BCL), which is diagnosed depending on fluorescence in situ hybridization (FISH), an expensive and laborious analysis. In order to identify HGBL with minimal workup and costs, a total of 187 newly diagnosed BCL patients were enrolled in a cohort study. As a result, the overall survival (OS) and progression-free survival (PFS) of the HGBL group were inferior to those of the non-HGBL group. HGBL (n = 35) was more likely to have a high-grade histomorphology appearance, extranodal involvement, bone marrow involvement, and whole-body maximum standardized uptake (SUVmax). The machine learning classification models indicated that histomorphology appearance, Ann Arbor stage, lactate dehydrogenase (LDH), and International Prognostic Index (IPI) risk group were independent risk factors for diagnosing HGBL. Patients in the high IPI risk group, who are CD10 positive, and who have extranodal involvement, high LDH, high white blood cell (WBC), bone marrow involvement, old age, advanced Ann Arbor stage, and high SUVmax had a higher risk of death within 1 year. In addition, these models prompt the clinical features with which the patients should be recommended to undergo a FISH test. Furthermore, this study supports that first-line treatment with R-CHOP has dismal efficacy in HGBL. A novel induction therapeutic regimen is still urgently needed to ameliorate the poor outcome of HGBL patients. [ABSTRACT FROM AUTHOR]

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or both, commonly called double-hit lymphoma (DHL), is an aggressive B-cell lymphoma that is molecularly distinct from diffuse large B-cell lymphoma (DLBCL) and is associated with poor outcomes. Recent advances in the molecular classification of DLBCL have identified distinct subsets, including genetic signatures which correlate with DHL and survival. DHL with concomitant TP53 mutation appears to be associated with a very poor prognosis. Standard chemo-immunotherapy is not an effective treatment for these patients and personalized, innovative strategies are needed. In this review, we summarize recent advances in the subclassification of DLBCL, with a focus on DHL. We also incorporate early, promising clinical trial data using CAR T and targeted therapies. Rationally designed clinical trials for DLBCL are needed to advance the care of patients with DHL and other adverse risk DLBCL subgroups. [ABSTRACT FROM AUTHOR]

Abstract Tyrosine kinase inhibitor (TKI) can help to increase the survival time in chronic myeloid leukemia (CML) patients; however, the risk of secondary malignancies due to TKIs is a growing concern. Only few reports showed clinical course of patients who developed lymphoma during TKI therapies. Herein, we report a case of high‐grade B‐cell lymphoma diagnosed in the course of CML treatment with bosutinib. The 75‐year‐old male patient had been diagnosed with CML 25 years ago. After receiving TKIs (imatinib, nilotinib, and bosutinib), he achieved a major molecular response. Over 3 years after starting bosutinib, he was diagnosed with a high‐grade B‐cell lymphoma. A total of six courses of DA‐EPOCH‐R therapy brought complete remission of the lymphoma. Moreover, BCR‐ABL1 transcript copies remained undetectable by RT‐PCR, 8 months after stopping bosutinib. The risk of secondary malignancy due to TKI has been controversial. It is reported that TKI induces irreversible chromosomal abnormalities or chromosome aberrations and inhibits the proliferation or function of T cells, B cells, and NK cells. These mechanisms of TKI may contribute to the development of secondary malignancy. There remains no consensus on the management of secondary lymphoma during TKI therapies. At present, the only alternative is to observe patients receiving TKI treatment cautiously and to treat secondary lymphoma in the same manner as de novo lymphoma.

High-grade B-cell lymphoma (HGBL) is a newly introduced category of rare and heterogeneous invasive B-cell lymphoma (BCL), which is diagnosed depending on fluorescence in situ hybridization (FISH), an expensive and laborious analysis. In order to identify HGBL with minimal workup and costs, a total of 187 newly diagnosed BCL patients were enrolled in a cohort study. As a result, the overall survival (OS) and progression-free survival (PFS) of the HGBL group were inferior to those of the non-HGBL group. HGBL (n = 35) was more likely to have a high-grade histomorphology appearance, extranodal involvement, bone marrow involvement, and whole-body maximum standardized uptake (SUVmax). The machine learning classification models indicated that histomorphology appearance, Ann Arbor stage, lactate dehydrogenase (LDH), and International Prognostic Index (IPI) risk group were independent risk factors for diagnosing HGBL. Patients in the high IPI risk group, who are CD10 positive, and who have extranodal involvement, high LDH, high white blood cell (WBC), bone marrow involvement, old age, advanced Ann Arbor stage, and high SUVmax had a higher risk of death within 1 year. In addition, these models prompt the clinical features with which the patients should be recommended to undergo a FISH test. Furthermore, this study supports that first-line treatment with R-CHOP has dismal efficacy in HGBL. A novel induction therapeutic regimen is still urgently needed to ameliorate the poor outcome of HGBL patients.

Abstract Background High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 is an aggressive mature B-cell neoplasm, whereas B-lymphoblastic lymphoma is immature cell proliferation, with a frequent positivity for terminal deoxynucleotidyl transferase. The transformation of a low-grade follicular lymphoma into a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase is a very rare event. Case presentation A 55-year-old Caucasian man was followed for a grade 1–2 follicular lymphoma carrying a t(14;18) IGH/BCL2+ and was initially treated with R-CHOP. The follicular lymphoma presented two relapses. In the third relapse, the patient had multiple lymphadenopathy and ascites, which motivated a retroperitoneal biopsy and an ascitic tap. These samples were analyzed by histological, cytological, flow cytometric, cytogenetic, and molecular assessments. The patient died of a multiple organ dysfunction syndrome 2 weeks after his third relapse. The biopsy revealed a diffuse proliferation made up of two types of tumor cells: centroblasts (Bcl-6-positive) and immature cells (terminal deoxynucleotidyl transferase-positive). Flow cytometric analysis confirmed the immature phenotype, with an expression of terminal deoxynucleotidyl transferase, combined with a loss of membrane immunoglobulins. The cytogenetic analysis performed on the ascites revealed a clonal evolution characterized by a t(8;22)(q24;q11) MYC+ translocation not previously detected in follicular lymphoma. Fluorescence in situ hybridization confirmed the double rearrangement of the BCL2 and MYC genes. Polymerase chain reactions and sequencing were used to study the clonal relationship between follicular lymphoma and the secondary tumors. The IGVH gene rearrangement revealed a unique clonal rearrangement involving an IGVH4–59 subset in all three specimens. Conclusion These findings suggest a clonal relationship between the two types of lymphoma cells. Furthermore, they support the transformation of an acute follicular lymphoma into a composite lymphoma combining a high-grade B-cell lymphoma and a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase. This case report highlights the possible transformation of follicular lymphoma into a highly aggressive and immature proliferation.

A double-hit lymphoma is a high-grade B-cell lymphoma (HGBCL) with MYC and BCL2/BCL6 rearrangements. It is characterized by a rapidly progressive advanced disease, high rates of central nervous involvement (CNS), refractoriness to conventional chemotherapy, and poorer clinical outcomes. Carcinomatous meningitis is a condition in which cancer cells metastasize to the meninges without involving the brain parenchyma; this phenomenon has also been reported in the literature by other terms like "leptomeningeal meningitis," "leptomeningeal carcinomatosis," "leptomeningeal metastasis," or "neoplastic meningitis." This form of CNS involvement has been described as an infrequent complication with the trajectory of this aggressive lymphoma. We report an illuminating case of a 63-year-old male diagnosed with double-hit lymphoma, which was complicated by fatal carcinomatous meningitis., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Swaminathan et al.)

Some inflammatory conditions, such as pyoderma gangrenosum, and tumoral conditions, such as lymphoma, may appear as soft tissue infections. Herein, a cutaneous lymphoma patient who was hospitalized with a diagnosis of soft tissue infection and was considered to have pyoderma gangrenosum during follow-up is presented. Immediate histopathological examination should be recommended to diagnose skin soft tissue lesions, especially long-term and unresponsive to treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nurlu Temel et al.)

Lineage switch between myeloid and lymphoid in acute leukemia is well established as a mechanism for leukemic cells to escape chemotherapy. Cross-lineage transformation is also recognized in some solid tumors on targeted therapy, such as adenocarcinomas of the lung and prostate that transforms to neuroendocrine carcinoma on targeted therapy. Now lineage plasticity is increasingly recognized in mature lymphomas, such as small B-cell lymphomas transforming to histiocytic/dendritic cell sarcoma. However, there is no report of aggressive mature B-cell lymphoma switching from one histologic category to another upon targeted therapy. We report here a case of high-grade B-cell lymphoma with MYC and BCL6 rearrangements relapsing as a high-grade plasmablastic neoplasm with MYC and BCL6 rearrangements after R-CHOP and R-EPOCH therapy. Being aware of this rare scenario will help improve our understanding of the underlying mechanisms of therapeutic resistance and progression of lymphoma. [ABSTRACT FROM AUTHOR]

Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Lineage switch between myeloid and lymphoid in acute leukemia is well established as a mechanism for leukemic cells to escape chemotherapy. Cross-lineage transformation is also recognized in some solid tumors on targeted therapy, such as adenocarcinomas of the lung and prostate that transforms to neuroendocrine carcinoma on targeted therapy. Now lineage plasticity is increasingly recognized in mature lymphomas, such as small B-cell lymphomas transforming to histiocytic/dendritic cell sarcoma. However, there is no report of aggressive mature B-cell lymphoma switching from one histologic category to another upon targeted therapy. We report here a case of high-grade B-cell lymphoma with MYC and BCL6 rearrangements relapsing as a high-grade plasmablastic neoplasm with MYC and BCL6 rearrangements after R-CHOP and R-EPOCH therapy. Being aware of this rare scenario will help improve our understanding of the underlying mechanisms of therapeutic resistance and progression of lymphoma.

Introduction: The involvement of the Female Genital Tract (FGT) by lymphoma is extremely rare, with ovaries being most commonly affected. Less than 1% of lymphomas present with ovarian involvement and less than 1.5% of ovarian neoplasms are of lymphoid origin. Secondary involvement of ovary by systemic lymphoma is more common than Primary Ovarian Lymphomas (POL) which is usually Primary Ovarian Non-Hodgkin lymphoma (PONHL) of B-cell lineage. Aim: To understand the clinicopathological and immunomorphological features of Primary Ovarian Non-Hodgkin lymphoma. Materials and Methods: This was a descriptive retrospective study conducted at Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka. India, for a duration of 14 years between July 2006 to June 2020. Eight cases of PONHL were identified from departmental archives and clinicopathological and Immunohistochemistry (IHC) findings of these tumours were analysed. Results: The PONHL constituted 0.4% of all Non-Hodgkin lymphoma (NHL) reported during the study period. The patients age ranged from 13-60 years with a mean age of 34 years. Among eight cases of PONHL, two cases were of Diffuse Large B-Cell Lymphoma (DLBCL), followed by one case each of High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS), Follicular Lymphoma (FL), Burkitt Lymphoma (BL), Plasmablastic Lymphoma (PBL), Precursor B-Lymphoblastic Lymphoma (B-LBL), and precursor T-Lymphoblastic Lymphoma (T-LBL). Seven cases were staged IE (Ann Arbor staging system) while one case was designated as stage IIE. Conclusion: This was probably the first study on PONHL from India. The diagnosis of PONHL is challenging unless there is a high index of suspicion as these patients present with non specific pelvic symptoms and can be misdiagnosed as other epithelial, stromal or germ cell ovarian neoplasm which differs in treatment and prognosis. Histological examination with IHC and molecular testing are essential to establish a diagnosis.

Introduction: The involvement of the Female Genital Tract (FGT) by lymphoma is extremely rare, with ovaries being most commonly affected. Less than 1% of lymphomas present with ovarian involvement and less than 1.5% of ovarian neoplasms are of lymphoid origin. Secondary involvement of ovary by systemic lymphoma is commoner than Primary Ovarian Lymphomas (POL) which is usually Primary Ovarian Non-Hodgkin lymphoma (PONHL) of B-cell lineage. Aim: To understand the clinicopathological and immunomorphological features of Primary Ovarian Non-Hodgkin lymphoma. Materials and Methods: This was a descriptive retrospective study conducted at conducted at Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka. India, for a duration of 14 years between July 2006 to June 2020. Eight cases of PONHL were identified from departmental archives and clinicopathological and Immunohistochemistry (IHC) findings of these tumours were analysed. Results: The PONHL constituted 0.4% of all Non-Hodgkin lymphoma (NHL) reported during the study period. The patients ranged in age from 13-60 years with a mean age of 34 years. Among eight cases of PONHL, two cases were of Diffuse Large B-Cell Lymphoma (DLBCL), followed by one case each of High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS), Follicular Lymphoma (FL), Burkitt Lymphoma (BL), Plasmablastic Lymphoma (PBL), Precursor B-Lymphoblastic Lymphoma (B-LBL), and precursor T-Lymphoblastic Lymphoma (T-LBL). Seven cases were staged IE (Ann Arbor stage) while one case was designated as stage IIE. Conclusion: This was probably the first study on PONHL from India. The diagnosis of PONHL is challenging unless there is a high index of suspicion as these patients present with non specific pelvic symptoms and can be misdiagnosed as other epithelial, stromal or germ cell ovarian neoplasm which differs in treatment and prognosis. Histological examination with IHC and molecular testing are essential to establish a diagnosis. [ABSTRACT FROM AUTHOR]

Opinion Statement: Burkitt lymphoma (BL) is highly curable, and prompt institution of therapy is critical to achieving optimal outcomes. Although current "standard" approaches are very effective in disease eradication, treatment-related toxicity makes optimal delivery of curative therapy a challenge, especially in older and immunocompromised individuals. Reduced intensity approaches with fewer toxic complications have been the focus of some recent studies. A critical question is if they can replace "standard" approaches by maintaining high curability with improved tolerability. Additionally, new molecular insights in BL biology suggest that in the future, "targeted therapy" approaches may be feasible using small molecule inhibitors and novel strategies. Recently, a new category of aggressive lymphoma named "high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 translocations" has been recognized. This category overlaps clinically and biologically with BL and has an inferior prognosis compared to most B-cell lymphomas, and the optimal approach to its management remains, as yet, undefined. In this review, we discuss the current landscape of BL treatment including recent results with low-intensity regimens and also consider current approaches to HGBL. We also explore how recently elucidated novel biological insights in BL biology may shape future therapeutic directions including the use of novel cellular therapy approaches. [ABSTRACT FROM AUTHOR]

Aggressive large B-cell lymphomas (LBCLs) represent a frequent but clinically and molecularly heterogeneous group of tumors. Technological advances over the last decades prompted the development of different classification schemas to either sharpen diagnoses, dissect molecular heterogeneity, predict outcome, or identify rational treatment targets. Despite increased diagnostic precision and a noticeably improved molecular understanding of these lymphomas, clinical perspectives of patients largely remain unchanged. Recently, finished comprehensive genomic studies discovered genetically defined LBCL subtypes that predict outcome, provide insight into lymphomagenesis, and suggest rational therapies with the hope of generating patient-tailored treatments with increased perspective for patients in greatest need. Current and future efforts integrate multiomics studies and/or leverage single-cell technologies and will provide us with an even more fine-grained picture of LBCL biology. Here, we highlight examples of how high-throughput technologies aided in a better molecular understanding of LBCLs and provide examples of how to select rationally designed targeted treatment approaches that might personalize LBCL treatment and eventually improve patients' perspective in the near future. [ABSTRACT FROM AUTHOR]

Cutaneous involvement by a systemic lymphoma via direct extension is a very rare phenomenon, historically described in patients who had advanced‐stage disease with bulky lymphadenopathy. Since its original description, most cases of cutaneous lymphomatous spread via direct extension are attributable to Hodgkin disease. Here, we report the occurrence of direct cutaneous dissemination in the setting of nodal high‐grade B‐cell lymphomas, specifically diffuse large B‐cell lymphoma (DLBCL) and B‐cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (also called gray‐zone lymphoma). Both cases are adequately documented with clinical, histopathologic, and immunophenotypic data, as well as additional cytogenetic analysis. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitor (TKI) can help to increase the survival time in chronic myeloid leukemia (CML) patients; however, the risk of secondary malignancies due to TKIs is a growing concern. Only few reports showed clinical course of patients who developed lymphoma during TKI therapies. Herein, we report a case of high‐grade B‐cell lymphoma diagnosed in the course of CML treatment with bosutinib. The 75‐year‐old male patient had been diagnosed with CML 25 years ago. After receiving TKIs (imatinib, nilotinib, and bosutinib), he achieved a major molecular response. Over 3 years after starting bosutinib, he was diagnosed with a high‐grade B‐cell lymphoma. A total of six courses of DA‐EPOCH‐R therapy brought complete remission of the lymphoma. Moreover, BCR‐ABL1 transcript copies remained undetectable by RT‐PCR, 8 months after stopping bosutinib. The risk of secondary malignancy due to TKI has been controversial. It is reported that TKI induces irreversible chromosomal abnormalities or chromosome aberrations and inhibits the proliferation or function of T cells, B cells, and NK cells. These mechanisms of TKI may contribute to the development of secondary malignancy. There remains no consensus on the management of secondary lymphoma during TKI therapies. At present, the only alternative is to observe patients receiving TKI treatment cautiously and to treat secondary lymphoma in the same manner as de novo lymphoma. [ABSTRACT FROM AUTHOR]

Summary: A few prospective trials in HIV‐positive patients with Burkitt lymphoma (BL) or high‐grade B‐cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose‐dense, short‐term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36‐day polychemotherapy induction followed by high‐dose cytarabine‐based consolidation and response‐tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)‐ conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV‐positive adults (median age 42, range 26–58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double‐hit lymphoma (n = 1) were enrolled. All patients had high‐risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non‐haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41–54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77–100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow‐up of 55 (41–89) months, 14 patients are relapse‐free and 15 are alive, with a five‐year progression‐free survival and an overall survival of 70% (95% CI = 60–80%) and 75% (95% CI = 66–84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability. [ABSTRACT FROM AUTHOR]

Abstract Background We report the first case of composite lymphoma consisting of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL) and high-grade B-cell lymphoma with MYC and BCL2 rearrangements within the same needle biopsy in which a clonal relationship between the FL and high-grade B-cell lymphoma components was demonstrated by molecular cytogenetics. Case presentation An 85-year-old man presented with masses in his neck and right groin. Cutting needle biopsy of the inguinal mass revealed the three lymphoma types which were morphologically, immunophenotypically and topographically distinct. Fluorescence in situ hybridization (FISH) identified an IGH-BCL2 rearrangement in both the FL and high-grade B-cell components while a MYC rearrangement was detected in the high-grade B-cell component alone. Conclusions Our findings suggest that the high-grade lymphoma with MYC and BCL2 translocations evolved through transformation of the FL by a process that entailed acquisition of the MYC translocation. No clonal relationship between the FL and CLL/SLL components was evident since the IGH-BCL2 rearrangement was present in in the former but not the latter. This unique case of co-localized FL, CLL/SLL, and high-grade B-cell lymphoma contributes to our understanding of the clonal relationships that may exist between the components of composite lymphomas.

Objectives: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) and primary breast high-grade B-cell lymphoma (PB-HGBCL) are rare extranodal aggressive B-cell lymphomas with distinct characteristics. Reliable data regarding appropriate treatment of these specific entities are lacking due to their rarity. Methods: We reviewed 36 patients diagnosed at four Chinese medical centres between January 2008 and December 2018. Data regarding clinicopathological features, therapeutic evaluation and central nervous system (CNS) relapse were collected, and overall survival (OS) and progression-free survival (PFS) were calculated. Results: Among the 36 patients, there were 29 PB-DLBCL patients and 7 PB-HGBCL patients. The 5-year OS for PB-DLBCL and PB-HGBCL was 75.9% and 28.6%, respectively. The 5-year PFS for PB-DLBCL and PB-HGBCL was 69.0% and 14.3%, respectively. The R-DAEPOCH regimen was significantly more effective in PB-DLBCL patients than the R-CHOP regimen (5-year OS: 78.9% vs 62.5%, P=0.024; 5-year PFS: 73.7% vs 50.0%, P=0.037) but resulted in more severe myelosuppression (P=0.025). The rate of CNS relapse was 17.2% in PB-DLBCL patients and 28.6% in PB-HGBCL patients; the difference was not significant (P=0.602). The R-DAEPOCH regimen did not predominantly reduce CNS recurrence as expected (P=0.616). The Cox proportional hazards model revealed that risk stratification and triple expression were independent prognostic factors. Conclusion: Current treatments, including more intensive chemotherapy regimens, achieve good control of the disease. Novel drugs combined with cellular immunotherapy initially show promising therapeutic effects, and more clinical trials are required to confirm these effects further. [ABSTRACT FROM AUTHOR]

CAR T-cells have transformed the therapeutic landscape for patients with relapsed/refractory aggressive B-cell lymphomas. Currently, three CAR T-cell products are approved or soon to be approved: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. These products differ in construct, manufacturing, clinical trial design and toxicity profile. Patient selection for CAR T-cells, and the ideal product for a given patient, involves myriad considerations including age, fitness, prior therapies, comorbid diseases, organ function, logistics of administration, turnaround time, and institutional familiarity. This article reviews the proper patient and product selection for the management of patients with relapsed/refractory aggressive B-cell lymphomas. [ABSTRACT FROM AUTHOR]