Diagnosis Of High-grade B-cell Lymphoma Research Articles

Molecular characterization of a rare case of high-grade B-cell lymphoma with MYC, BCL2, BCL6, and CCND1 rearrangements

Quadruple-hit lymphomas are extremely rare non-Hodgkin lymphomas with a reported dismal prognosis in the few reported cases. A “quadruple hit” has been defined by the presence of concurrent MYC, BCL2, BCL6, and CCND1 chromosomal rearrangements. We report a new case of a quadruple hit lymphoma in a 73-year-old Hispanic man who presented with an enlarging left-sided neck mass. Computed tomography showed a 1.9-cm mass in left the tonsil with bulky cervical lymphadenopathy. The presence of all four chromosomal rearrangements can reportedly occur with disease progression in both diffuse large B-cell lymphomas and mantle cell lymphomas. Further characterization of the tumor by next-generation sequencing may be of benefit to delineate between these two possibilities. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing were used to confirm and classify the diagnosis. Histologic sections of the cervical lymph node demonstrated an atypical lymphoid infiltrate with large and pleomorphic cells, which were positive for CD20, CD10, BCL1 (Cyclin D1), BCL2, BCL6, and cMYC and negative for CD5 and SOX11 on immunohistochemistry with a Ki-67 proliferative index of 70%. FISH demonstrated MYC, BCL2, BCL6, and CCND1 rearrangements and the diagnosis of high-grade B-cell lymphoma with MYC, BCL2, BCL6, and CCND1 was rendered. Our patient was treated with dose adjusted etoposide, doxorubicin, cyclophosphamide, prednisone, and rituximab chemotherapy and has been in remission for 20 months.

High-grade B-cell lymphoma with a quadruple-hit genetic profile including concurrent MYC, BCL2, BCL6, and CCND1 gene rearrangements.

Several reports of concurrent MYC, BCL2, BCL6, and CCND1 rearrangements in high-grade B-cell lymphoma (HGBL) have been recently described. Herein, we aimed to delineate the scope of this entity through a review of HGBL with a "quadruple-hit" genetic profile identified at our institution. We performed a retrospective review (2015-2023) at our institution of B-cell lymphoma (BCL) cases that were evaluated with concurrent MYC, BCL2, and BCL6 break-apart and IGH::MYC and IGH::CCND1 dual-color dual-fusion fluorescence in situ hybridization studies. Of 203 cases meeting inclusion criteria, 2 (1%) with a quadruple-hit genetic profile were identified. Case 1 represented a 59-year-old female with widespread lymphadenopathy and a diagnosis of HGBL who exhibited primary refractoriness to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) chemotherapy. Case 2 represented a 58-year-old male with mediastinal and abdominal lymphadenopathy and a diagnosis of large BCL who died from disease after 1 cycle of DA-EPOCH-R chemotherapy. Similarly, a literature review of 7 previously reported cases of HGBL with a quadruple-hit profile also demonstrated aggressive disease behavior. Our study adds 2 new cases to the rarely encountered quadruple-hit HGBL, and a brief meta-analysis of the 9 available cases indicates aggressive disease behavior conferred by this constellation of genetic events.

False positive PET scan in patients with treated malignancy following COVID-19 vaccination.

e18698 Background: The COVID-19 pandemic led to mass vaccination across the globe and resulted in several unintended consequences, one of which being reactive lymphadenopathy mimicking malignancy. A large study reported hypermetabolic lymphadenopathy (HLN) in over 45% of patients after receiving at least one dose of COVID-19 vaccine. A study on breast cancer patients noted a near-400% increase in lymphadenopathy on MRI and ultrasonography over the two years prior to mass vaccination. These findings present a dilemma in patients with treated malignancy while under surveillance. As vaccination became more commonplace, a case series reported on patients with PET-detected lymphadenopathy, with biopsies confirming VRLN. These investigations contributed to general recommendations on the importance of clinical context in patient care after COVID-19 vaccination. We present a unique study that evaluates patients with treated solid and hematological malignancies that presented with HLN after COVID-19 vaccination which emphasizes the importance of clinical acumen in the management of oncological patients in the pandemic era. Methods: We identified 6 patients aged 39-95 with prior malignancy. 5 were diagnosed with metastatic melanoma, and one had a diagnosis of high-grade B-cell lymphoma. Patients were managed with chemotherapy, immunotherapy, surgery, radiotherapy, or a combination of modalities, and were in complete radiological remission. All patients received at least two doses of a COVID-19 vaccine, with one dose at least three weeks prior to a routine surveillance PET-CT. Each patient exhibited HLN. Results: Of six patients, three underwent biopsy. There was no evidence of malignancy in any biopsy, and VRLN was confirmed. The remaining patients were followed with surveillance, and all had resolution of HLN without intervention. Time between COVID-19 vaccination and PET evidence of HLN ranged from 19 to 232 days. Time between first positive and first resolved PET ranged from 92 to 463 days. All patients were alive at the time of abstract submission. Conclusions: Our study emphasizes the importance of a focused history when suspecting recurrent malignancy, especially after sustained remission in our vulnerable populations. Acknowledging that COVID-19 vaccination can lead to HLN is becoming more common, and we show that this can occur, persist, and resolve even months after vaccination. While high suspicion for recurrence should be maintained, all efforts should be taken to protect patients and prevent unnecessary procedures. Records of recent vaccinations should be available and reviewed prior to radiological studies and clinical decisions, which can reduce avoidable interventions and harm. Surveillance of our patients proved to be an appropriate approach, and our study shows that similar patient presentations can have different paths of care depending on the awareness of treating physicians.

High-Grade B-Cell Lymphoma with Effusion as the Initial presentation

Abstract Introduction/Objective Malignant effusion is usually caused by metastatic carcinoma. Lymphoma is often not included in the differential diagnoses. Here, we describe two cases of young females with no significant past medical history, presenting with fluid overload. Methods/Case Report The first case is a 41-year-old female with abdominal ascites and pleural effusion. Microscopic examination of the ascitic fluid showed intermediate to large lymphoid cells with irregular nuclear contours and fine chromatin. Flow cytometry showed CD10-positive lambda restricted B-cells. She had retropectoral mass biopsy showing sheets of intermediate to large-sized lymphoma cells with abundant apoptotic bodies and necrosis. The lymphoma cells are positive for CD20, CD10, BCL-2, BCL-6, and C-MYC (~50%,) while negative for TdT and cyclin D1. Proliferative index by Ki-67 stain is ~80%). Fluorescence in situ hybridization (FISH) analysis demonstrated rearrangements of BCL2/18q (80%) and MYC/8q (82%). The patient had a diagnosis of high-grade B-cell lymphoma with MYC and BCL-2 gene rearrangements. The second case is a 43-year-old woman with abdominal pain. She was diagnosed with acute cholecystitis and underwent cholecystectomy. Peritoneal fluid showed numerous neoplastic cells with irregular nuclei, prominent nucleoli, and cytoplasmic vacuoles. Flow cytometry demonstrated CD10-positive B-cells with lambda restriction. The cells were positive for CD10, CD20, BCL-2, BCL-6, and PAX5, and negative for CD34, cyclin D1, HHV-8, and TDT. EBER ISH was negative. The proliferation index by Ki67 stain was >90%. FISH studies showed MYC, BCL2 and BCL6 gene arrangements. Cytogenetic analysis revealed a complex karyotype. A diagnosis of HGBL with triple-hit rearrangements was rendered. Despite receiving aggressive chemotherapy, the patient expired 8.5 months after the diagnosis. Results (if a Case Study enter NA) NA. Conclusion HGBL is an aggressive and often stage IV disease. It should be considered in the differential diagnoses of malignant effusions. Flow cytometry and FISH analysis of the body fluid specimen are essential to reach an accurate diagnosis in a timely manner.

A Combined Biomarker of Bright CD38 and MYC ≥55% Is Highly Predictive of Double-/Triple-Hit High-Grade B-Cell Lymphoma.

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. We compared features of 40 cases of DTHL and 39 cases of diffuse LBCL (DLBCL) without MYC rearrangement. 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. 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.

A Rare Case of Primary B Cell Lymphoma of the Spine

Spinal non-Hodgkin’s lymphomas are rare and often present late when the disease is in an advanced stage. We describe a case of primary B cell lymphoma diagnosed in a 74-year-old male, who presented with worsening back pain and unilateral leg weakness. Radiological imaging identified an abnormality within the T6 vertebral body, but analysis of initial vertebral body biopsies showed no clear evidence of malignancy. The diagnosis of high-grade B-cell lymphoma was only made following repeated bone biopsies and subsequent histopathological analysis. The patient’s care has since been transferred to Haematology and is currently undergoing intensive chemotherapy.

ABCL-241: Comparing Efficacy of Intrathecal Chemotherapy versus High-Dose Methotrexate for Central Nervous System Prophylaxis in High-Grade B-Cell Lymphomas

Context Outcomes of patients with high-grade B-cell lymphomas have improved with chemoimmunotherapy. However, some patients are at an increased risk of developing secondary central nervous system (CNS) relapse, associated with increased morbidity. Objective The objective of this study was to analyze the efficacy of intrathecal chemotherapy versus high-dose methotrexate for the prevention of secondary CNS relapse in high-grade B-cell lymphoma patients. Design This was a single-institution, retrospective cohort study. A report was created via electronic health records to identify patients that received CNS prophylaxis with a confirmed diagnosis of high-grade B-cell lymphoma from January 2017 to September 2020. Setting This study took place at a general community hospital. Patients or Other Participants Inclusion criteria included age > 18 years, histologically confirmed high-grade B-cell lymphoma, either R-CHOP or DA-R-EPOCH as the primary chemoimmunotherapy regimen, and no CNS involvement at the time of diagnosis. Interventions Arm A included 11 patients that received intrathecal chemotherapy, and arm B included 11 patients that received intravenous high-dose methotrexate for prophylaxis. Main Outcome Measures The primary outcome of this retrospective study was to assess rates of CNS relapse, with a median follow-up of 1 year since diagnosis. Secondary outcomes included progression-free survival (PFS), overall survival (OS), toxicity, cost of care, and delays in therapy between both arms. Results Development of secondary CNS relapse occurred in 2 (18.2%) of the patients in arm A and 2 (18.2%) in arm B, which was not statistically significant by Chi-square analysis with Yates correction (p=.58042). PFS was consistent between both arms at 72.7%. One-year OS for each arm was 90.9% vs 72.7%, (p=.0887). Toxicity developed in 36% of high-dose methotrexate patients. Two patients needed a dose reduction of high-dose methotrexate, and two had delays in further cycles of primary chemoimmunotherapy regimen. High-dose methotrexate was associated with a significantly higher cost on average per cycle. Conclusions There was no statistically significant difference in the development of secondary CNS relapse between intrathecal chemotherapy and high-dose methotrexate. Further prospective, randomized studies are needed to assess if CNS prophylaxis improves outcomes and which method of prophylaxis is more efficacious.

Complete response in a frail patient with high-grade B-cell lymphoma to only one cycle of R-CHOP or to prolonged COVID-19?

BackgroundCOVID-19 infection increases mortality in hematological malignancies. In a large meta-analysis, patients aged 60 years and older had a significantly higher risk of death than patients under 60 years of age [1]. Furthermore, a high risk of death and reduced survival in patients receiving B cell depletion therapy with prolonged COVID-19 infection was reported in a recent study [2]. High-grade B-cell lymphomas are classified as morphologically aggressive lymphomas with the presence of a high mitotic index and Ki-67 proliferation rates. They demonstrate aggressive behavior clinically as well as morphologically, and COVID-19 infection is an important factor that increases mortality in these patients. Herein, we present an elderly patient with a diagnosis of high-grade B-cell lymphoma, in whom a complete response was observed after prolonged COVID-19 infection. Case summaryAn 81-year-old female patient received her first cycle of R-CHOP (rituximab, cyclophosphamide, vincristine, and prednisolone) treatment after being diagnosed with high- grade B-cell lymphoma. After being discharged from the hospital, the patient was referred to the emergency department with complaints of fever and fatigue when she came for the second cycle of chemotherapy. Her COVID-19 PCR test was found positive. She was admitted to the infectious diseases service and favipiravir treatment was started. On the 24th day of hospitalization, it was decided to perform interim FDG-PET/CT (Fluorodeoxyglucose - Positron Emission Tomography/Computed Tomography) scan at a time that her PCR (Polymerase Chain Reaction) test was still positive. A complete metabolic response was detected in her imaging. On the 26th day, the PCR test became negative and the patient was transferred to the oncology service and received the second cycle of R-CHOP treatment. ConclusionOur case emphasizes that antitumor effect could be seen in a patient with SARS-CoV-2 infection and a hematologic malignancy. It also highlights being alert to prolonged COVID-19 infection in patients receiving B-cell depletion therapy.

SUN-327 Hypercalcemia and Hypoglycemia Due To EBV-Associated Lymphoma

Background: Hypercalcemia is uncommon in HIV infection but can occur in the setting of lymphoma. We describe a patient with HIV with hypercalcemia and hypoglycemia due to an initially undetected EBV-associated lymphoma. Clinical Case: A 32-year old Caucasian male with recent diagnosis of HIV was admitted for HIV arthropathy and sepsis, and found to have hypercalcemia (Ca 10.7mg/dL, n 8.9-10.2mg/dL; ionized Ca 6.1mg/dL, n 4.6-5.7mg/dL). PTH was suppressed (<10pg/mL, n 12-72pg/mL). PTH-independent causes of hypercalcemia were unremarkable for humoral hypercalcemia of malignancy (PTHrP 0.2pmol/L, n <2.0pmol/L), vitamin D toxicity (24-hydroxyvitamin D 41ng/mL, n 30-80ng/mL), granulomatous disorders (1,25-dihydroxyvitamin D 24.8pg/mL, n 19.9-79.3pg/mL; quantiferon negative), hyperthyroidism, and adrenal insufficiency. Renal function was normal and there was no thiazide, lithium, calcium, or vitamin A use. Serum protein electrophoresis (PEP) showed hypogammaglobinemia consistent with immunodeficiency. Urine PEP was negative for immunoglobulin light chains. Hypercalcemia was initially attributed to HIV with immobilization and calcium level was expected to normalize with antiretroviral therapy. Workup for infectious etiology was negative, his arthralgia and overall clinical status improved, and he was discharged. Three days later, he was readmitted for altered mental status and anemia. He was hypoglycemic, which was new on readmission, and required dextrose-containing IV fluids in addition to tube feeds to keep his serum glucose within normal range. Work up was negative for insulinoma (C peptide 0.48ng/mL, n 0.81-5.3ng/mL; glucose 31mg/dL) but IGF-2 to IGF-1 ratio was elevated at 4.57 which was suggestive of IGF-2-mediated tumor-associated hypoglycemia. Persistent leukocytosis and type B lactic acidosis also suggested an underlying malignancy. Bronchoscopy, bone marrow biopsy, and CSF cytology were negative for malignancy. CSF was positive for EBV (77,100 copies/mL). CT imaging showed liver lesions and biopsy led to the diagnosis of high-grade B-cell lymphoma. He was started on chemotherapy. Hypoglycemia resolved 10 days later, as did the lactic acidosis. Hypercalcemia was treated with pamidronate with return to normal levels. Conclusion: Hypercalcemia in an HIV patient warrants diligent workup. Hypercalcemia in lymphomas are often attributed to elevated 1,25-dihydroxyvitamin D. A possible explanation for normal 1,25-dihydroxyvitamin D observed in our patient is the effect of antiretroviral therapy on accelerated catabolism of vitamin D. Hypoglycemia may be due to IGF-2 production by tumor and malignancy-related glucose consumption via glycolytic pathway with lactic acid production. Literature on concurrent hypercalcemia and hypoglycemia with B-cell lymphoma is sparse and, to our knowledge, occurrence in the setting of HIV has not been reported.

Najważniejsze zmiany w diagnostyce agresywnych chłoniaków z komórek B według klasyfikacji Światowej Organizacji Zdrowia z 2017

In 2017, the revised 4 th edition of the classification of tumors of hematopoietic and lymphoid tissues developed by the World Health Organization was introduced. Some of the significant changes concern the updating of data covering biology, pathomorphology, genetics and clinical features of aggressive lymphomas from mature B cells. New entities have been introduced (high grade B-cell lymphoma and Burkitt-like lymphoma with 11q aberration), some of existing ones have beenmodified (EBV-positive diffuse large B-cell lymphoma, not otherwise specified) and some provisional ddefinitions (unclassified B-cell lymphoma, with intermediate features between diffuse B-cell lymphoma and classic Hodgkin’s lymphoma) have been retained. Significant progress in the field of molecular biology techniques and genetics translates into their practical use in the routine diagnosis of lymphomas. Currently, the correct diagnosis of high-grade B-cell lymphoma in addition to pathomorphological and immunohistochemical diagnosis requires the determination of status C-MYC , BCL2 and BCL6 genes. This is a significant challenge for the reorganization of routine diagnostics. This is influenced by limited availability of standardized molecular/genetic techniques and determination of funding for these studies. The most important factor still remaining is the involvement of a specialized team of doctors and technicians ensuring adequate collection, protection of biological material and its development by various techniques, which translates into the possibility of issuing a full result including proper diagnosis.

High-grade B-cell Lymphoma Mimicking an Unresectable Pancreatic Carcinoma

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin's lymphoma (NHL). Advances have further subcategorized DLBCL. Although extranodal and extramedullary disease frequently accompanies the initial diagnosis, pancreatic involvement is distinctly uncommon. Case Report: A 58-year-old male presented with the chief complaint of left upper quadrant abdominal pain of 6 weeks duration. An abdominal CT scan revealed a poorly enhancing heterogeneous mass in the tail of the pancreas extending to the splenic hilum. Multiple splenic masses and enlarged upper abdominal lymph nodes were noted suggesting metastatic pancreatic adenocarcinoma. The patient had a longstanding history of cigarette smoking and alcohol use. He denied weight loss, fever or night sweats. He was referred for further management. Endoscopic ultrasound (EUS) demonstrated a 3 cm hypoechoic mass in the pancreatic tail with well-defined margins extending to the splenic hilum, enlarged peripancreatic lymph nodes and multiple discrete hypoechoic splenic lesions. EUS-guided fine needle aspiration and core biopsies of the pancreatic tail mass revealed an atypical lymphocytic infiltrate associated with areas of necrosis suspicious for large B-cell lymphoma. The diagnosis of high-grade B-cell lymphoma, which is similar to DLBCL but cytologically and clinically more aggressive, was subsequently confirmed on a CT-guided core biopsy from enlarged retroperitoneal lymph nodes. The lymphoma lacked a MYC rearrangement by interphase fluorescent in-situ hybridization (FISH) analysis, supporting the diagnosis of high-grade B-cell lymphoma, not otherwise specified, per the 2016 WHO Classification of Lymphoid Neoplasms. Conclusion: Aggressive NHL's such as DLBCL and high-grade B-cell lymphoma should be considered in the differential diagnosis of a pancreatic mass and may be associated with a better prognosis than pancreatic adenocarcinoma. The presence of extensive intra-abdominal lymphadenopathy and concomitant splenic lesions are important diagnostic clues.

B‐cell lymphoma with plasmacytoid differentiation, atypical cytoplasmic inclusions, and secondary leukemia in a dog

A 7-year-old male castrated Jack Russell Terrier was presented to the oncology service at the University of California-Davis Veterinary Medical Teaching Hospital for evaluation of suspected lymphoma. The dog had several enlarged lymph nodes and moderate lymphocytosis. Aspirates of an enlarged inguinal lymph node contained a bimorphic population of large immature lymphocytes and smaller cells with plasmacytoid features. Both cell types often contained a single large cytoplasmic inclusion that varied from clear to pale pink to sky blue. Cytologic changes were interpreted as most consistent with lymphoid neoplasia. Based on the predominantly mature cell morphology and some morphologic heterogeneity, the peripheral lymphocytosis was interpreted as most likely reactive in nature. However, the immunophenotype of the cells (CD20+, CD21+, CD79a+, MUM-1+, and MHCII+) and clonality assays showed that tissue and blood lymphocytes were neoplastic B cells with clonal identity despite their different morphologic appearances. The cytoplasmic inclusions were positive with periodic acid-Schiff and were immunoreactive for IgM and IgG. By transmission electron microscopy, inclusions consisted of aberrant rough endoplasmic reticulum; a few small Russell bodies were also noted. A final diagnosis of high-grade B-cell lymphoma with plasmacytoid differentiation, atypical cytoplasmic inclusions, and secondary leukemia was made. Chemotherapy was initiated, but the dog was euthanized due to severe and uncontrolled seizures 9 months after the initial diagnosis. This case extends the morphologic repertoire of canine plasmacytoid neoplasms and emphasizes their continuum with multicentric lymphoma. This case also demonstrates the need for advanced diagnostic techniques in establishing blood involvement in lymphoma in some instances.

Lymphomas associated with HIV infection

INCE the initial reports of non-Hodgkin’s lymphoma (NHL) in patients with acquired immunodeficiency syndrome (AIDS) in 1982,‘,* it has become increasingly apparent that individuals with human immunodeficiency virus (HIV) infection are at an increased risk of developing aggressive malignant lymphomas.3-5 indeed, a diagnosis of high-grade B-cell lymphoma or primary cranial lymphoma in an HIV-infected patient is now recognized as an indicator disease of AIDS.6 These lymphomas mostly affect young males and are predominantly high- and intermediate-grade histologic type, according to the working formulation.7 Patients often present with advanced disease in extranodal sites, particularly the central nervous system (CNS), bone marrow, and gastrointestinal (GI) tract. 3-5 Response to chemotherapy is poor and the prognosis is dismal, with a median survival of less than 1 year.4 Although Hodgkin’s disease has also been described in association with HIV infection,*-‘* it is currently not included among the diagnostic criteria of AIDS. We review herein the incidence, clinical features, pathology, treatment, prognosis, and pathogenesis of lymphomas associated with HIV infection. [Nursing management of many of the problems associated with lymphomas is discussed by McMahon and Coyne elsewhere in this issue.]