Effusion-based Lymphoma Research Articles

New classifications of B-cell neoplasms: a comparison of 5th WHO and International Consensus classifications.

In 2024, the World Health Organization (WHO) launched a new classification of lymphoid neoplasms, a revision of the previously used Revised 4th Edition of their classification (WHO-4R). However, this means that two classifications are now in simultaneous use: the 5th Edition of the WHO classification (WHO-5) and the International Consensus Classification (ICC). Instead of a comprehensive review of each disease entity, as already described elsewhere, this review focuses on revisions made in both the WHO-5 and ICC from WHO-4R and discrepancies between them regarding B-cell neoplasms. Similarities include cutaneous marginal zone lymphoma, cold agglutinin disease, non-primary effusion lymphoma-type effusion-based lymphoma, and gray zone lymphoma. Differences include plasma cell neoplasms, high-grade B-cell lymphoma (double hit lymphoma), follicular lymphoma, LPD with immune deficiency and dysregulation, extranodal large B-cell lymphoma, transformations of indolent B-cell lymphomas, and diffuse large B-cell lymphoma, not otherwise specified. Understanding the similarities and differences between the two latest classifications will aid daily diagnostic practice and future research on lymphoid neoplasms.

Human herpes virus 8-negative effusion-based lymphoma in a patient with persistent serous effusions.

Diffuse large B-cell lymphoma is the most common histologic diagnosis among the aggressive lymphomas, accounting for 30% of all lymphomas. Human herpes virus 8-negative effusion-based lymphoma (HHV8-negative EBL) is a rare form of lymphoma, under recognized and still not well characterized in the literature. In contrast to primary effusion lymphoma (PEL), HHV8-negative EBL is characterized by malignant effusion in essentially serous body cavity with no detectable contiguous tumor masses and is no associated with human immunodeficiency virus and HHV8 infections. The presence of comorbid medical conditions can hide this type of lymphoma and made diagnosis more challenging. Here, we describe a rare case of an 82-year-old male suffering from peritoneal and pleural effusion and Hepatitis B virus related cirrhosis diagnosed with HHV8-negative EBL.

Primary Effusion Lymphoma: A Timely Review on the Association with HIV, HHV8, and EBV.

Primary effusion lymphoma (PEL) is defined by the WHO classification as a large B-cell neoplasm without detectable tumor masses. It is universally associated with HHV8, with most cases occurring in the setting of immunodeficiency such as HIV infection, and a poor prognosis. Morphologically, the neoplastic cells range from immunoblastic, plasmablastic, to anaplastic; and phenotypically, most cases express plasma cell but not B-cell markers, i.e., plasmablastic. During the past decade, primary HHV8-negative effusion lymphoma has been reported. Such cases were considered in the WHO classification scheme as effusion-based lymphoma. We performed a systemic review of 167 HHV8-negative effusion lymphomas from the literature and found that only 42% were associated with a fluid overload state, and with low rates of HIV (6%) or EBV (21%) infection. Furthermore, most patients are old (or immunosenescent) with underlying medical conditions/comorbidities, most neoplasms are of B-cell phenotype, and the outcome is more favorable than that of HHV8-positive PEL. These distinctive findings supported our prior proposal of designating these HHV8-negative cases as type II PEL, in contrast to the classic or type I PEL as defined by the WHO. Furthermore, we propose an algorithmic approach for the diagnosis of PEL and its mimickers.

Successful treatment of HHV8-negative effusion-based lymphoma with drainage of pleural effusion

Two cases of human herpesvirus 8 (HHV8)-negative effusion-based lymphoma (EBL) involving unilateral pleural effusion that regressed only after drainage are reported. Cases 1 and 2 were 91- and 81-year-old men with right and left pleural effusion, respectively. No chemotherapy was administered to either patient because of their advanced age and the presence of cardiac comorbidities. They completely recovered after effusion drainage alone without relapse till the last observation. Thus, this study suggests that some patients with HHV8-negative EBL can be safely managed with effusion drainage alone.

Human herpesvirus 8-negative effusion-based lymphoma with indolent clinical behavior in an elderly patient: A case report and literature review.

Primary effusion lymphoma (PEL) is a B-cell non-Hodgkin's lymphoma that is usually characterized by lymphomatous effusions in the body cavity without any detectable tumor masses. According to the World Health Organization (WHO) schema for tumor classification, PEL is defined by the presence of human herpesvirus 8 (HHV8) in malignant lymphoid cells. However, a subset of effusion-based B-cell lymphoma is not HHV8-positive and exhibits different clinicopathological characteristics. The 2017 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues does not list HHV8-negative effusion-based lymphoma, which remains an underappreciated B-cell lymphoma, as an individual entity. The present study reports a case of this rare type of lymphoma with indolent clinical behavior in a 75-year-old male patient receiving only symptomatic treatment. Additionally, a review of similar cases reported in the English literature is presented.

RARE CAUSE OF PLEURAL EFFUSION

SESSION TITLE: Fellows Lung Cancer Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Primary pleural lymphomas (PPL) represent 7% of lymphomas. Most are of B cell origin, and related to immunosuppression or chronic inflammation. [1, 2]. Anaplastic large cell lymphoma is a rare CD30 positive T cell lymphoma [3]. CASE PRESENTATION: A 73-year-old patient with a past medical history of end-stage renal disease on peritoneal dialysis presented to the emergency department with complaints of dry cough and shortness of breath of two weeks course. He also reported poor appetite and unintentional weight loss over three months prior to his presentation. Physical exam was significant for tachycardia, tachypenia, and oxygen saturation of 92% on 3 liters nasal cannula. Reduced breath sounds on the right hemithorax. His laboratory tests showed hemoglobin of 10.6 gm/dl, serum creatinine of 11 mg/dl. CT of the chest showed a loculated right hydropneumothorax without pleural thickening. A chest tube was placed, and fluid was sent to for analysis. Pleural fluid analysis showed a PH 7.45, lactate dehydrogenase (LDH) 1580 U/l, albumin 1.9 g/dl, no organism was detected. Flow cytometry from the fluid was normal. A pleural biopsy showed CD 30, CD4, MUM1 positive T cell lymphoma and negative for human herpesvirus-8 (HHV-8), ALK, and Myeloperoxidase (MPO). Further staging CT showed no lymphadenopathy, hepatosplenomegaly or any other masses. A diagnosis of primary effusion anaplastic large cell lymphoma, ALK-negative was made and he was started on Brentuximab Vedotin. DISCUSSION: PPL are very uncommon and classified into two different types: i) Primary effusion lymphoma (PEL) related to HIV infection and HHV-8. ii) Pyothorax-associated lymphoma (2.2% of the cases) mainly related to chronic inflammation as in tuberculosis and asbestosis, they are described as B cell non-Hodgkin lymphoma. Pleural T cell lymphomas are quite rare. Few cases are reported in immune-competent patients in the absence of a prior history of pyothorax. Anaplastic large cell lymphoma (ALCL) is a rare CD 30 positive T cell lymphoma. The 2016 revision of the WHO classification divided ALCL in to three subtypes of a) ALK positive (ALK+) ALCL, b) ALK negative (ALK-) ALCL and c) breast implant-associated ALCL Treatment includes chemotherapy, typically cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and CD30-targeted brentuximab vedotin, as The ECHELON- 2 trial showed the combination of Brentuximab with chemotherapy was found to be superior to CHOP CONCLUSIONS: PPLs are extremely rare. Two distinct sub-types exist: PEL in immunosuppressed patients, and pyothorax associated lymphoma with long standing inflammations as in Tuberculosis. The majority of the cases are of B cell origin, with a few reports reporting instances in T cell lymphoblastic lymphoma of the pleura. Anaplastic large cell lymphoma causing primary pleural effusion has not been described in the literature. Reference #1: 1.Alexanian S, Said J, Lones M, Pullarkat ST. KSHV/HHV8-negative Effusion-based Lymphoma, a Distinct Entity Associated With Fluid Overload States. The American Journal of Surgical Pathology 2013;37:241–9. doi:10.1097/pas.0b013e318267fabc. Reference #2: 2.Sun M-L, Shang B, Gao J-H, Jiang S-J. Rare case of primary pleural lymphoma presenting with pleural effusion. Thoracic Cancer 2015;7:145–50. doi:10.1111/1759-7714.12256. Reference #3: 3.Carbone A, Gloghini A. PEL and HHV8-unrelated effusion lymphomas. Cancer 2008;114:225–7. doi:10.1002/cncr.23597. DISCLOSURES: No relevant relationships by Amani Erra, source=Web Response no disclosure on file for Karim Fahmy; No relevant relationships by Mahmoud Khreis, source=Web Response No relevant relationships by Mohanad Soliman, source=Web Response

Primary human herpesvirus 8–negative effusion-based lymphoma: a large B-cell lymphoma with favorable prognosis

AbstractPrimary effusion-based lymphoma (EBL) presents as a malignant effusion in a body cavity. The clinicopathologic features and prognosis of primary human herpesvirus 8 (HHV8)–negative EBL remain unclear. We therefore conducted a retrospective study of 95 patients with EBL, regardless of HHV8 status, in Japan. Of 69 patients with EBL tested for HHV8, a total of 64 were negative. The median age of patients with primary HHV8-negative EBL at diagnosis was 77 years (range, 57-98 years); all 58 tested patients were negative for HIV. Primary HHV8-negative EBL was most commonly diagnosed in pleural effusion (77%). Expression of at least 1 pan B-cell antigen (CD19, CD20, or CD79a) was observed in all cases. According to the Hans algorithm, 30 of the 38 evaluated patients had nongerminal center B-cell (non-GCB) tumors. Epstein-Barr virus–encoded small RNA was positive in 6 of 45 patients. In 56 of 64 HHV8-negative patients, systemic therapy was initiated within 3 months after diagnosis. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens with or without rituximab (n = 48) were the most common primary treatments. The overall response and complete response rates were 95% and 73%, respectively. Three patients did not progress without systemic treatment for a median of 24 months. With a median 25-month follow-up, the 2-year overall survival and progression-free survival rates were 84.7% and 73.8%. Sixteen patients died; 12 were lymphoma-related deaths. Thus, most EBL cases in Japan are HHV8-negative and affect elderly patients. The non-GCB subtype is predominant. Overall, primary HHV8-negative EBL exhibits a favorable prognosis after anthracycline-based chemotherapy.

Lymphoid Neoplasms With Plasmablastic Differentiation: A Comprehensive Review and Diagnostic Approaches.

Plasmablastic neoplasms encompass several entities including plasmablastic lymphoma, plasmablastic plasmacytoma/multiple myeloma, primary effusion lymphoma and its extracavitary variant, anaplastic lymphoma kinase-positive large B-cell lymphoma, and Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specified. Morphologically, the tumor cells are large with eccentrically located nuclei, prominent nucleoli, and basophilic/amphophilic cytoplasm. Immunophenotypically, the tumor cells express plasma cell-related antigens including CD38, CD138, interferon regulatory factor-4 (IRF4)/MUM1, PR domain zinc finger protein-1 (PRDM1), and/or X-box binding protein-1 (XBP1), with frequent loss of CD20. These tumors are diagnostically challenging for general pathologists due to their overlapping morphology and immunophenotype, and due to their rarity, and particularly so when clinical and radiologic information is insufficient. We also discuss HHV8-negative effusion-based lymphoma due to its overlapping features with primary effusion lymphoma. In this review, we focus on the useful diagnostic markers and pertinent molecular findings in these distinct entities and propose a practical diagnostic algorithm using anaplastic lymphoma kinase, HHV8, in situ hybridization for Epstein-Barr virus-encoded small RNA, immunoglobulin M, light chain stains, and clinicoradiologic criteria to avoid misdiagnosis. At the molecular level, MYC protein overexpression with or without MYC rearrangement and PRDM1-inactivating mutations or deletions are noted in a subset of such tumors, especially in plasmablastic lymphoma. Prognosis in these entities is dismal with conventional CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Therefore, novel target therapies, such as anti-CD30 agents, and/or immune blockade therapy, are potential treatment options in the future.

CLINICALLY INDOLENT PRIMARY HHV8‐NEGATIVE EFFUSION‐BASED LYMPHOMA IS CHARACTERIZED BY COMPLEX GENOMIC ALTERATIONS WITH AGGRESSIVE FEATURES

Human herpesvirus 8-negative effusion-based lymphoma (HHV8-negative EBL) is a distinct lymphoma entity related to fluid overload states caused by underlying medical conditions such as cardiac failure or renal insuffciency. Due to a phenotypical resemblance with secondary effusion of diffuse large B-cell lymphoma (DLBCL), HHV8-negative EBL is easily misdiagnosed. However, in contrast to DLBCL, HHV8-negative EBL follows a mild clinical course that is largely determined by comorbidity and high age at diagnosis, underpinning the importance to differentiate between the two entities. From the files of the Dept of Pathology, AmsterdamUMC/VUMC, we retrospecively identified 11 cases of HHV8-negative EBL. All patients presented with isolated pleural (n=10) or pericardial effusion (n=1). Age at presentation ranged from 60-92 years (median 85 years). All cases, except one, showed a mature B-cell immunophenotype (CD20, CD79a positive), one case showed plasmacytic differentiation (CD138 positive). All were EBER negative, 9/10 showed a non-GCB phenotype and 1/10 a GCB-phenotype (Hans/Tally alogorithms). We performed extensive genomic profiling using a custom-made all-in-one assay (NimbleGen EZ SeqCap) to determine genome wide copy number alterations, mutations (369 genes) and translocations (12 target regions) on 8 HHV8-negative EBL cases. A mean number of 33.6 copy number gains and losses per case were found, with recurrent focal deletions of chromosome 3p14.2 and 6q21 in 6/8 cases, encompassing tumor supressor genes FHIT and PRDM1, respectively. We observed a high rate of mutations across genes frequently involved in DLBCL, including patterns of somatic hypermutation (PIM1, KLHL1, BCL2). The most abundant hotspot mutation was found in MYD88L265P (3/8 cases). In addition, 5/8 cases had one or more translocations, involving MYC (n=2), BCL2 (n=1), BCL6 (n=2), TP63 (n=1), EXOC2 (n=1) and KMT2D (n=1), with Ig and non-Ig partners, of which one MYC/BCL6 double hit context. We conclude that HHV8-negative EBL is characterized by heterogeneous genomic features with frequent mutations, copy number aberrations and translocations, similar to aggressive B-cell lymphomas, but despite this follows an indolent clinical course. Keywords: diffuse large B-cell lymphoma (DLBCL); elderly; molecular genetics.

Human Herpesvirus 8-Negative and Epstein-Barr Virus-Positive Effusion-Based Lymphoma in a Patient with Human Immunodeficiency Virus.

A 39-year-old man infected with human immunodeficiency virus (HIV) was admitted to our hospital because of sudden onset of chest pain. Chest radiography revealed pneumothorax of the right lung. Computed tomographic scans disclosed a 5.8-cm-sized emphysematous bulla in the right middle lobe of the lung. Histologically, the wedge-resected lung showed medium to large atypical cells within the bullous cavity of the Pneumocystis jirovecii pneumonia, without solid mass formation. These atypical cells were confirmed to be large B-cell lymphoma, Epstein-Barr virus–positive and human herpesvirus 8–negative. Therefore, this case was not diagnosed as primary effusion lymphoma, but effusion-based lymphoma arising in an emphysematous cavity of an HIV-infected patient. This type of effusion-based lymphoma has never been reported, and, although rare, it should be noted in order to clinically diagnose this lymphoma.

HHV8-negative effusion based lymphoma: a series of 17 cases at a single institution

Human herpesvirus 8-positive (HHV8+) primary effusion lymphoma is a well-recognized clinicopathologic entity. In contrast, HHV8-negative (HHV8-) effusion-based lymphoma (EBL) is incompletely characterized and under-recognized. We describe 17 cases of HHV8- EBL at our institution. Cytology and available immunohistochemistry and cytogenetics were reviewed. Patient demographics, history, and outcome were obtained from medical records. The effusions were pleural (n = 9; 53%), peritoneal (n = 4; 24%), pericardial (n = 3; 18%), and pleural and pericardial (n = 1; 6%). Fifteen cases (88%) were CD20+ and 15 had sufficient information for classification by Hans algorithm (CD10, BCL6, MUM1): 11 (73%) nongerminal center and 4 (27%) germinal center phenotype. Epstein-Barr virus in situ hybridization was negative in 16 cases (94%). Three of 14 cases were MYC+ by immunohistochemistry. Fluorescence in situ hybridization, performed on 5 of the 17 cases, showed a MYC rearrangement in 1 case and a BCL6 rearrangement in 2 cases. Most patients were elderly (median age 86 years) and female (82%). Human immunodeficiency virus testing results, available in 4 patients, were negative. Seven (41%), including 1 of 2 heart transplant recipients, had congestive heart failure. Follow-up (5 days to 12 years) was available for 16 patients including 4 who survived ≥8 years. Only 1 of the 8 known deaths was clinically attributed to lymphoma. HHV8- lymphomas that occur in body cavity effusions without detectable lymphomatous masses are usually composed of large CD20+ lymphoid or lymphoplasmacytoid cells. In contrast to HHV8+ primary effusion lymphoma, patients with HHV8- EBL are usually elderly, lack a documented human immunodeficiency virus-positive history, and have a longer disease specific survival.

Kaposi sarcoma herpesvirus/human herpesvirus‐8–negative effusion‐based lymphoma: Report of 3 cases and review of the literature

Primary effusion lymphoma (PEL) is a rare subtype of large B-cell lymphoma that arises in body cavities without detectable tumor masses. PEL is universally associated with Kaposi sarcoma herpesvirus (KSHV)/human herpesvirus-8 (HHV8). Despite overlapping features, KSHV/HHV8-negative effusion-based lymphoma is a distinct entity from PEL. To date, 52 cases have been reported. The authors report 3 additional cases received in their laboratory from 2007 to 2012. Clinical data, cytomorphologic features, and immunophenotypic features of the 3 cases were described and compared with those reported in the literature. The cells in HHV8-negative effusion lymphoma commonly revealed large cell, immunoblastic morphology and B-cell immunophenotype. The 3 cases demonstrated cytomorphologic and immunophenotypic variability. Cytomorphologically, 1 case contained large, highly atypical cells with a moderate amount of cytoplasm, round nucleus, coarsely granular chromatin, and a single macronucleolus. The other 2 cases had medium to large atypical cells with high nuclear-to-cytoplasmic ratios, slightly irregular to cleaved nuclei, and multiple conspicuous nucleoli. One case had a null phenotype with aberrant cytokeratin expression. B-cell phenotype was established by clonal immunoglobulin heavy-chain rearrangement using polymerase chain reaction, whereas the other 2 cases demonstrated a B-cell phenotype by flow cytometry and immunohistochemical staining. All 3 cases were negative for both HHV8 and Epstein-Barr virus. HHV8-negative effusion lymphoma exhibits clinical, cytomorphologic, and immunophenotypic variability. Cases with a null-phenotype can be particularly challenging. When effusion lymphoma is suspected, ancillary tests are helpful. Moreover, HHV8 detection is critical in differentiating PEL and HHV8-negative effusion lymphoma, because they have overlapping features yet different prognoses.

KSHV/HHV8-negative Effusion-based Lymphoma, a Distinct Entity Associated With Fluid Overload States

Human herpesvirus-8 (HHV8)-positive effusion-based lymphomas have been termed primary effusion lymphoma (PEL) in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Kaposi sarcoma herpesvirus (KSHV)/HHV8-negative effusion-based lymphomas (KSHV/HHV8-negative EBLs) resembling PELs have been reported in the literature and in many cases have been (mis)classified as PEL-like lymphomas. Herein, we present a series of cases and a review of KSHV/HHV8-negative EBLs. This lymphoma, although cytomorphologically resembling PEL, is a distinct entity with characteristic clinical and pathologic features. Patients are older, generally human immunodeficiency virus negative and not immunosuppressed, frequently hepatitis C positive compared with the population baseline, and often have an underlying medical condition leading to fluid overload. The lymphoma cells express pan-B-cell antigens in 86.7%, and CD20 is expressed in 71.1% of the cases. The lymphoma is often of germinal center B or mixed germinal center B/activated B-cell signature with the Hans classifier, and Epstein-Barr virus is positive in nearly 30% of cases. Rare T-cell lymphomas were also reported. Clinical outcomes and response to therapy, including isolated aspiration, are relatively favorable compared with cases of PEL. We suggest that HHV8-negative effusion-based lymphoma is a distinct entity associated with fluid overload states.

Clinical importance of human herpes virus-8 and human immunodeficiency virus infection in primary effusion lymphoma

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma that usually develops in immunosuppressed patients infected with human herpes virus-8 (HHV-8) in conjunction with human immunodeficiency virus (HIV) infection. However, there are several reports of HHV-8-related HIV-negative cases and HHV-8-unrelated HIV-negative cases, mainly in immunodeficient and elderly patients. Here, we report one case of HHV-8-related HIV-negative PEL with gastric cancer (case 1) and one case of HHV-8-unrelated HIV-negative effusion-based lymphoma (case 2), both in elderly men. A 73-year-old man and a 79-year-old man were admitted because of lymphomatous effusions, and no mass was detectable in both cases. They were diagnosed as having malignant effusion lymphoma on the basis of cytological findings indicating atypical lymphoid cells and the expression of CD20 and CD79a. To detect evidence of HHV-8 infection in neoplastic cells, immunocytochemical staining for ORF73/ latent nuclear antigen-1 (LNA-1) was performed. The results revealed that case 1 was ORF73-positive, and case 2 was ORF73-negative. Rituximab-based chemotherapy (R-THPCOP: rituximab, pirarubicin, cyclophosphamide, vincristine, prednisolone) was administered to both patients and complete remission was achieved in both. Compared to most HIV-positive PEL cases, these two cases showed a good response to chemotherapy. In cases of PEL, we should focus on HHV-8 infection and HIV status for determining prognosis.

Primary Effusion Lymphoma in Women: Report of Two Cases of Kaposi's Sarcoma Herpes Virus-Associated Effusion-Based Lymphoma in Human Immunodeficiency Virus-Negative Women

Recent molecular evidence suggests an association with a new herpes virus, Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8), and primary effusion lymphomas (PEL). PELs have a characteristic morphology, phenotype, and clinical presentation with malignant effusions in the absence of a contiguous solid tumor mass. Most cases of PEL have occurred in human immunodeficiency virus (HIV)-positive male patients who are coinfected with Epstein-Barr virus (EBV). This report describes two cases of PEL in HIV- and EBV-negative women. In one patient, a pleural cavity PEL was preceded by classic Kaposi's Sarcoma (KS) of the lower extremities. In the second patient, PEL developed in an artificial cavity related to the capsule of a breast implant. Both cases had the characteristic morphologic appearance of high-grade anaplastic/B-cell immunoblastic lymphomas, with loss of B-cell differentiation antigens, clonal immunoglobulin heavy chain gene rearrangements, and expression of activation antigen CD30. Both cases were negative for EBV, herpes virus simplex, and cytomegalovirus (CMV). DNA extracted from both lymphomas and skin KS specimen showed KSHV sequences by molecular analysis. This report expands the spectrum of KSHV-associated disease to include PEL in HIV-negative women.