Diagnosis Of Primary Effusion Lymphoma Research Articles

Isolated Monoclonal T-Cell Receptor Gene Rearrangement in a Lung Adenocarcinoma Harboring MET Exon 14 Skipping: Diagnostic Pitfall.

In the diagnostic workup of poorly differentiated tumors, T-cell receptor (TCR) clonality has long been considered as evidence of T-cell lymphoma. MET exon 14 skipping (METex14) is a mutation typically seen in lung adenocarcinoma. Herein, we present the first report of METex14 lung adenocarcinoma with isolated monoclonal TCRγ gene rearrangement. A 69-year-old woman presented to an outside hospital with pleural effusions. A pleural decortication demonstrated malignant cells positive for CD30 and CD138 but negative for BerEP4, KRT5, and EMA. An equivocal HHV8 staining was interpreted as positive, leading to the erroneous outside diagnosis of primary effusion lymphoma. Additional workup at our institution revealed a lack of HHV8 and T-cell markers but the presence of TCRγ clonality, pankeratin, and TTF1 expression. Repeat TCRγ testing on the in-house biopsy was negative for clonality. Next-generation sequencing detected METex14, confirming the diagnosis of lung adenocarcinoma. The potential diagnostic pitfall and prognostic/predictive implications are discussed.

Rare Case of Primary Effusion Lymphoma mimicking Pulmonary Tuberculosis

Primary effusion lymphoma (PEL) is a rare large B-cell non-Hodgkin lymphoma (NHL) that usually occurs in immunosuppressed individuals in advanced stages of the disease, presenting as body cavity effusions without detectable tumor mass. We report a 61-years old man presented to the emergency room complaining of effort-related dyspnoea, low-grade fever, night sweats, and a dry cough for several days. He was then put on empirical anti-tubercular treatment (ATT) suspecting Pulmonary Tuberculosis. General examination revealed a decrease oxygen saturation, tachypnea, a bulging tenderness lymph node on the neck. Chest computerized tomography (CT) scan indicated pericardial and pleural effusion with mediastinal dilatation suspected thymoma or lymphoma. A Cardiocentesis needle aspiration was performed; however, the histological pattern was not specific. The patient underwent a surgical biopsy of a left supra-clavicular lymph node. A Classical Hodgkin lymphoma nodular sclerosis type was found in the histopathology examination. Immunohistochemistry detected the tumour cellular markers (i.e., CD30). Chemotherapy treatment for 6 cycles resulted an excellent outcome. In conclusion, radiologists play a vital role in the diagnosis of PEL, detecting effusions in body cavities and excluding the existence of solitary masses or pleural nodules or masses, ultimately narrowing down the differential diagnoses.

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.

Treatment Outcomes and Prognostic Factors in 40 Patients with Primary Effusion Lymphoma

Background: Primary effusion lymphoma (PEL) is a rare, B cell non-Hodgkin lymphoma (NHL) caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8, that is strongly associated with HIV infection. PEL often presents as malignant body cavity effusions but can also present as extracavitary masses. Patients may also have concurrent Kaposi sarcoma (KS) or multicentric Castleman disease (MCD). 80% of PEL is also positive for EBV, and in a cohort of 20 patients we previously showed EBV + PEL had improved overall survival (OS) (Lurain et al. Blood 2019). PEL prognosis is poor compared to other HIV-associated NHL with median survival of 6-10 months. While patients are often treated with chemotherapy regimens used in other NHL, the optimal front-line and subsequent-line treatments are unknown. In this largest cohort of patients with PEL in the United States, we evaluated survival, prognostic markers, and second-line treatments in relapsed/refractory disease.Methods: We analyzed clinical records of all patients with PEL treated in the HIV and AIDS Malignancy Branch at the National Cancer Institute from 2000-2021. We collected demographics, disease characteristics, concurrent KS and MCD, EBV status of tumor by EBER staining, and laboratory data at diagnosis as well as at progression and subsequent lines of therapy. We calculated overall survival (OS) of all patients and progression-free survival (PFS) in those who received front-line EPOCH by Kaplan-Meier method. The survival of extracavitary vs. cavitary PEL was compared using an exact log-rank test. A univariate Cox proportional hazard model was performed to determine prognostic variables associated with OS.Results: We identified 40 patients with PEL: 38 cisgender men, 2 cisgender women; 18 non-Hispanic Black, 6 Hispanic, 16 non-Hispanic White; median age 41 years. At diagnosis of PEL, 29 patients had concurrent KS, and 7 had concurrent MCD. Eight patients had only extracavitary disease, and 5 had leptomeningeal disease. All but 1 had HIV, and all with HIV received antiretroviral therapy. At diagnosis, median HIV viral load (VL) was 50 (IQR: 27-8323) copies/mL, median CD4 + cell count was 100 (IQR:44-395) cells/µL, and median KSHV VL was 4147 copies/10 6 cells (IQR:178-68,526). One patient died prior to receiving treatment. Of the 39 patients who received front-line treatment, 38 received combination chemotherapy (EPOCH [36], CHOP [1], ICE [1]) with rituximab added in 34 patients to treat concurrent MCD or deplete the KSHV-infected B cell reservoir. One patient received pembrolizumab as up-front therapy due to concurrent progressive multifocal leukoencephalopathy. Twenty-three (57%) had complete remission (CR) by Lugano criteria. Median PFS after front-line EPOCH was 16.4 months (Figure 1a), and median OS in all patients was 35.6 months (Figure 1b), with 5-year OS of 44%. Median OS for patients with extracavitary disease was significantly higher than in patients with cavitary disease (p=0.023, Figure 1c). EBER-positive tumors (HR=0.21, p=0.005) were associated with improved survival, while concurrent KS, MCD, leptomeningeal disease, and baseline CD4 and KSHV VL were not associated with OS outcomes.Eleven patients with relapsed/refractory disease received second-line therapy, including combination chemotherapy (3); brentuximab (3); pembrolizumab (1); pembrolizumab and pomalidomide (1); interferon-alpha, ganciclovir, and bevacizumab (1); bortezomib, ganciclovir, and zidovudine (1); and radiation to pelvic lymph nodes (1). Five of these patients received subsequent treatment after disease progression, including 2 patients with leptomeningeal PEL, 1 who received daratumumab and 1 who received pomalidomide and pembrolizumab with ongoing CRs at 12 months and 33 months, respectively.Conclusion: Patients with PEL had a median OS of 35.6 months, which is improved from previous reports. Patients with extracavitary PEL appear to have improved OS, and we confirmed our prior study noting EBER-positive PEL is a positive prognostic marker. Promising chemotherapy-sparing treatment regimens in relapsed/refractory PEL, include pembrolizumab, pomalidomide, and daratumumab. [Display omitted] DisclosuresUldrick: Regeneron: Current Employment; Roche: Research Funding; Merck: Other: Receives study drug; Celgene: Research Funding. Yarchoan: Celgene: Research Funding; Merck: Other: Clinical Trial Support; EMD-Serano: Other: Clinical Trial Support; Eli Lilly: Other: Clinical Trial Support; CTI BioPharma: Other: Clinical Trial Support; Janssen Pharmaceuticals: Other: Clinical Trial Support; U.S. Dept of Health and Human Services: Patents & Royalties. Lurain: EMD-Serrono: Research Funding; BMS-Celgene: Research Funding; CTI Biopharma: Research Funding; Merck: Research Funding; Janssen: Research Funding.

Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)–associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

Without a silhouette.

Primary effusion lymphoma (PEL) is a kind of malignant lymphoma that develops without a tumor mass. A fluid smear is of no use for the diagnosis of miscellaneous condition. Repeated cell‐block smear with immunostaining is useful for the diagnosis of PEL.

WHERE ARE THE EFFUSIONS?

SESSION TITLE: Fellows Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Primary effusion lymphoma (PEL) is a rare and aggressive subset of B-cell lymphoma that is commonly associated with immune deficiencies such as HIV/AIDS and organ transplant. It commonly manifests as a serous effusion in either pleural, pericardial or peritoneal spaces, and is associated with human herpesvirus-8 (HHV-8) or Epstein-Barr virus (EBV). One study showed that about one third of patients with the diagnosis of PEL did not have effusions; but were diagnosed by pathology of solid tumors. CASE PRESENTATION: A 58-year-old man with a multi-decade history of HIV infection was referred to the Emergency Department for anemia and low CD4 T cell count with elevated HIV viral load. He had a long history of HIV infection. Other medical problems include Kaposi sarcoma, hypertension, and spinal osteoarthritis. His physical exam was notable for pre-auricular and inguinal lymphadenopathy. Initial laboratory evaluation included anemia, leukocytosis with left shift, thrombocytopenia, elevated serum protein, low bicarbonate and elevated lactate. He was given fluid resuscitation, broad-spectrum antibiotics, and vasopressor support. Cerebrospinal fluid studies showed high total protein at 72, 88% lymphocytes. Continued evaluation of his lymphadenopathy, anemia and thrombocytopenia included detection of EBV and HHV-8. Excisional biopsy of left cervical lymph node showed clusters and sheets of large atypical cells with plasmablastic morphology admixed with small mature lymphocytes and plasma cells. The suspected diagnosis was primary effusion lymphoma without lymphomatous effusions. His course was complicated by respiratory insufficiency requiring non invasive ventilation in the setting of new bilateral ground glass opacities. He was treated for pneumonia with clinical improvement. He became altered on the medical floor, and a guardian was appointed for his medical decision making. In light of HIV-associated lymphoma with unclear benefit to aggressive chemotherapy, his guardian opted for comfort care and he was discharged to home hospice. DISCUSSION: We present a case of PEL presenting in a patient with long-standing HIV infection and history of Kaposi sarcoma. Despite the name, not all cases have lymphomatous effusions on presentation. PEL is uncommon, and available information is based on case series. The treatment of PEL involves multi-drug chemotherapy, including use of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and methotrexate. One case series of 28 patients treated for PEL with CHOP had median overall survival of 6.2 months . Another case series of 51 patients treated for PEL using CHOP-like regimen and the addition of methotrexate showed median overall survival 10.2 months . CONCLUSIONS: The prevalence of PEL is low; but should be considered in in patients with long standing HIV infection and Kaposi sarcoma. Reference #1: Guillet, S., Gérard, L., Meignin, V., Agbalika, F., Cuccini, W., Denis, B., Katlama, C., Galicier, L. and Oksenhendler, E. (2016), Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution. Am. J. Hematol., 91: 233-237. doi:10.1002/ajh.24251 Reference #2: Kazuyuki Shimada, Fumihiko Hayakawa, Hitoshi Kiyoi; Biology and management of primary effusion lymphoma. Blood 2018; 132 (18): 1879–1888. doi: https://doi.org/10.1182/blood-2018-03-791426 Reference #3: Emmanuelle Boulanger, Laurence Gérard, Jean Gabarre, Jean-Michel Molina, Christophe Rapp, Jean-François Abino, Jacques Cadranel, Sylvie Chevret, and Eric Oksenhendler Prognostic Factors and Outcome of Human Herpesvirus 8–Associated Primary Effusion Lymphoma in Patients With AIDS (2005) Journal of Clinical Oncology 23:19, 4372-4380 DISCLOSURES: No relevant relationships by Saud Alrawaf, source=Web Response No relevant relationships by Benjamin DelPrete, source=Web Response No relevant relationships by Lisa Glass, source=Web Response No relevant relationships by Marwa Oudah, source=Web Response

RARE CASE OF OVERLAPPING PRIMARY EFFUSION LYMPHOMA AND KAPOSI SARCOMA INFLAMMATORY CYTOKINE SYNDROME IN IMMUNOSUPRESSED PATIENT

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Kaposi’s sarcoma-associated herpes virus (KSHV) is a potent oncogenic and immunomodulatory virus. We present a patient with high KSHV viral load with primary effusion lymphoma (PEL) and the rarely reported Kaposi’s sarcoma inflammatory cytokine syndrome (KSICS). CASE PRESENTATION: 31-year-old male with AIDS (CD4 of 45 cell/µL, viral load 170,000) and Kaposi Sarcoma treated with liposomal doxorubicin, admitted for shortness of breath (SOB), lower extremity (LE) and scrotal edema. Physical examination: tachycardia, bibasilar crackles, 3+ pitting edema of LE extending to the sacrum, and violaceous, erythematous KS lesions on the torso. Initial studies notable for anemia (Hgb 9.0 g/dl), otherwise unremarkable including brain natriuretic peptide and microbiology studies. A chest x-ray demonstrated bilateral pleural effusions with loculation on the left, which was later confirmed on a chest computed tomography scan, that also revealed enlarged mediastinal lymph nodes. Echocardiography showed preserved ejection fraction. A doppler ultrasound of LE was negative for deep vein thrombosis. During hospital course, patient became progressively anemic, hemodynamically unstable and profoundly SOB, ultimately requiring transfer to the intensive care unit where he was intubated and started on vasopressors. A thoracentesis with cytology positive for large pleomorphic lymphocytes, CD45+/HHV8+/EBER+ by immunohistochemistry. Flow cytometry showed monotypic B-cell population positive for HLA-DR, CD38, CD45 (dim), and kappa light chain (dim) restricted, consistent with a diagnosis of PEL. Serum studies demonstrated markedly elevated levels of IL6 and IL10 and the clinical presentation suggested a rare condition associated with KSHV, KSICS. The patient unfortunately died despite resuscitative efforts. DISCUSSION: PEL is the least common of all HIV related lymphomas and presents as lymphomatous growth in a liquid phase in a body cavity without extracavitary lesions. The pathogenic mechanism of KSHV is uncertain but almost all cases are associated with this virus. Malignant cells are monoclonal B cells that express CD38 and contain KSHV viral inclusions and the majority demonstrate EBV coinfection . Another disease diagnosed in patient is KSICS, a rarely reported systemic inflammatory syndrome associated with high KSHV viral load and elevated IL6 and IL10, secreted by infected cells. Presentation is similar to sepsis but without obvious source of infection. CONCLUSIONS: This case illustrates varying and overlapping presentations of KSHV infection in immunocompromised patient. Therapy does not exist and KS could not be treated due to the poor condition of patients. Patients have a high mortality rate and often misdiagnosed. Our patient received antibiotics for the presumptive sepsis before a diagnosis was made. It will be important to recognize this syndrome early to support attempts to develop effective therapies. Reference #1: Narkhede M, Arora S, Ujjani C. Primary effusion lymphoma: current perspectives. Onco Targets Ther. 2018;11:3747–3754. Published 2018 Jun 28. doi:10.2147/OTT.S167392 Reference #2: Polizzotto MN, Uldrick TS, Hu D, Yarchoan R. Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome [published correction appears in Front Microbiol. 2017 Aug 21;8:1572]. Front Microbiol. 2012;3:73. Published 2012 Mar 2. doi:10.3389/fmicb.2012.00073 DISCLOSURES: No relevant relationships by Arsenije Kojadinovic, source=Web Response No relevant relationships by Prabhjot Mundi, source=Web Response No relevant relationships by Pahnwat Taweesedt, source=Web Response

Human herpesvirus‐8–positive primary effusion lymphoma in HIV‐negative patients: Single institution case series with a multidisciplinary characterization

Primary effusion lymphoma (PEL) is a very rare non-Hodgkin lymphoma caused by human herpesvirus-8 (HHV8) that grows in liquid phase within body cavities. The diagnosis of PEL is based on cytology but requires confirmatory ancillary tests. PEL occurs mainly in association with HIV infection. This study describes 9 cases of PEL in HIV-negative patients and compares their characteristics with 10 HIV-associated cases of PEL diagnosed at a single institution in Italy between 1995 and 2019. Clinical records were reviewed for demographic data, comorbidities, laboratory abnormalities, and outcome. PEL samples were evaluated for cytomorphology, immunophenotype, immunoglobulin (IG)/T cell receptor (TR) rearrangements, and HHV8 and Epstein-Barr virus (EBV) viral loads in effusion supernatants. HIV-unrelated PEL occurred in 8 elderly patients (7 men, 1 woman) and 1 young adult with primary antibody deficiency. Cytology revealed HHV8-positive lymphoma cells lacking B/T cell antigens and exhibiting 2 cell patterns (polymorphous or monotonous). IG was clonally rearranged in all cases; aberrant TRG occurred in 2 cases. Effusion supernatants had more than 106 HHV8 DNA copies per mL and variable loads of EBV DNA. Compared with HIV-associated PEL, the HIV-negative cohort was characterized by older age, less frequent association with Kaposi sarcoma and/or multicentric Castleman disease, comparable but less abnormal laboratory parameters, and a nonsignificant survival benefit. PEL cases with low apoptosis were associated with better prognosis. To the best of our knowledge, our case series of HIV-unrelated PEL is the largest thus far, expands the spectrum of cytological findings, and supports the need for a multidisciplinary approach in the diagnostic workup.

Human Herpes-8 virus copy to cell ratio: A diagnostic tool in primary effusion lymphoma

Primary effusion lymphoma (PEL) is a serious sequel to Human Herpes Virus 8 (HHV8) infection in the immunosuppressed host. Usually requiring a cytological diagnosis, body cavity effusions are often referred for investigation for possible PEL. Although absence of HHV8 effectively refutes this, the presence of HHV8 DNA, though indicative is not diagnostic. Referred effusion and plasma samples from 10 patients with HHV8-related pleural and pericardial effusions were submitted for quantitative investigations. HHV8 DNA and human DNA from unseparated effusion extracts have been quantified allowing estimation of virus-to-cell ratios in effusion fluid. These ratios varied widely between 0.003 and 700. Five fluids had in excess of 106 HHV-8 DNA genome equivalents per ML (GEq/ML), ranging between 18 and 300 million GEq/ML. Four of these five effusions were from patients with cytologically proven PEL and had virus to cell (V:C) ratios between 100 and 700 to 1. The remaining high load effusion exhibited a ratio of 1.6 to 1 and came from a patient with extensive thoracic Kaposi’s sarcoma. Five effusion fluids with low viral loads exhibited virus to cell ratios between 0.003 and 0.5. High effusion HHV8 load, though supportive of a diagnosis of PEL is less accurate than using virus to cell ratios.

IL-13 Expression Characterizes Effusions Associated with Primary Effusion Lymphoma but Not Other Disorders Caused By Kaposi Sarcoma Herpesvirus (KSHV)

BACKGROUND: Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus-8) is the causative agent of 3 disorders: primary effusion lymphoma (PEL), Kaposi sarcoma (KS), and a plasmablastic form of multicentric Castleman disease (KSHV-MCD). It also causes KSHV inflammatory cytokine syndrome (KICS), which is characterized by inflammatory symptoms and an elevated KSHV viral load. Multiple KSHV-associated diseases, which usually develop in HIV-infected patients, can present together in the same patient. Effusions can occur in each of these diseases, thereby presenting a diagnostic challenge. Identifying PEL is especially crucial as prompt treatment with multi-agent chemotherapy can be curative. We analyzed effusions from patients with KICS, PEL, and KSHV-MCD to identify distinct immunologic characteristics and virologic profiles that may aid diagnosis, inform treatment and elucidate pathogenesis.PATIENTS AND METHODS: We identified 22 HIV-infected patients with effusions [pleural effusions (20), ascites (1) and pericardial effusion (1)] with diagnoses of PEL (9 patients), KICS (8 patients), or KSHV-MCD (5 patients). All patients had a concurrent diagnosis of KS. We obtained clinical and immunologic characteristics from effusions and paired serum samples at the same timepoint for each patient. Serum and effusion cytokine levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, and IL-12p70; interferon gamma (IFN-g); tumor necrosis factor alpha (TNF-a); vascular endothelial growth factor (VEGF); and inducible protein 10 (IP-10) were evaluated using a commercial multiplex assay. Peripheral blood mononuclear cell (PBMC) and effusion- associated KSHV and Epstein Barr virus (EBV) viral DNA (KSHV-VL, EBV-VL) in PBMC and cells were quantified using PCR with primers to KSHV K6 and EBV pol. Effusion and serum immunologic and virologic characteristics were compared within each disease and separately between diseases using the Wilcoxon sign rank test and Wilcoxon rank sum test, respectively. In these exploratory analyses with few patients, no correction was made for multiple comparisons.RESULTS: In patients with PEL, the median (med) age was 42 years with med CD4+ count of 54 T-cells/μL and HIV viral load (VL) of 325 copies/mL. In those with KICS, the med age was 32 years, with a med CD4+ count of 119 T-cells/μL and HIV VL of 48 copies/mL. In patients with KSHV-MCD, the med age was 31 years, med CD4+ count of 118 T-cells/μL and HIV VL was 75 copies/mL.IL-13 was substantially higher in PEL effusions as compared to serum levels (med 16.9 vs. <0.12 ng/ml; p=0.007). In addition, patients with PEL had significantly higher levels of 6 other cytokines (IL-12p70, IL-1ß, IL-2, IL-4, IL-6 and IP-10) in effusions as compared with serum (Table 1, p<0.05). In both KSHV-MCD and KICS, IL-12p70, IL-2 and IL-4 levels were higher in the effusion as compared with serum (p<0.05).In analyses comparing serum and cytokine differences among diseases, effusions from patients with PEL had detectable levels of IL-13 (med 16.9 ng/ml; interquartile range 9.7-26.9 ng/ml) compared to patients with KSHV-MCD (med <0.114 ng/ml; p=0.0037) or KICS (med <0.114 ng/ml; p=0.0003). PEL effusions had higher IL-1ß levels as compared with KICS effusions (p=0.0028). Serum IL-10 levels were also higher in PEL as compared with KICS (med 51.6 vs. 2.5ng/mL; p=0.0015). KSHV VL levels were significantly higher in PEL effusions as compared to KICS effusions (med 31,428,571 vs. 569 copies/mL; p=0.0005) and KSHV-MCD (med 231,884 copies/mL; p=0.02).CONCLUSIONS: In HIV-infected patients, effusions can indicate a diagnosis of PEL, KSHV-MCD and/or KICS. Quantifying KSHV VL in the effusion may be useful in the diagnosis of PEL. Effusions in PEL had a distinct profile compared to the circulation or other KSHV-associated diseases, particularly with regard to elevated IL-13, which may aid in diagnosis. In contrast, the inflammatory and virologic findings in KSHV-MCD and KICS effusions roughly paralleled the levels seen in the circulation. This study suggests that KSHV upregulation of IL-13 is a unique feature of PEL, which may contribute to PEL pathogenesis through STAT6 activation and be a potential future therapeutic target. [Display omitted] DisclosuresUldrick:Celgene: Patents & Royalties: 10,001,483 B2; Celgene: Research Funding; Merck: Research Funding. Yarchoan:Celgene Corp.: Research Funding; NIH: Patents & Royalties: Patents on IL-12 for KS and cereblon-binding drugs for KSHV diseases. Spouse has patent on KSHV IL-6. Patents assigned to DHHS/NIH..

Characteristics and Outcome of HIV-Associated Primary Effusion Lymphoma (PEL) As Observed in the German HIV-Related Lymphoma Cohort Study

Introduction: Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a rare and aggressive subtype of B-cell Non-Hodgkin lymphomas (NHL). PEL usually arises in body cavities such as the peritoneum, the pleural space, and pericardium, but may also present as extracavitary lesions without effusion. Definitive diagnosis hinges on detection of viral infection by human herpes virus 8 (HHV-8) in the neoplastic cells. Optimal treatment for HIV-PEL has not been defined. The aim of the present study was to analyze clinical characteristics, treatment and outcome of pts with HIV-PEL who were included in the German HIV-related lymphoma cohort study.Methods: The German HIV-related lymphoma cohort study is a prospective multicenter study that includes adult HIV-1 infected pts with biopsy or cytologically proven HIV-related lymphoma. Patients were diagnosed at 32 participating centers in Germany and Austria since January 2005. Data on HIV-infection and lymphoma characteristics, treatments and outcomes were recorded. The present analysis focuses on pts with PEL.Results: Twelve out of 437 pts (2.7%) with HIV-NHL were diagnosed with PEL. All pts were male, and the median age at PEL diagnosis was 51.8 yrs (range, 35-64). 11 of 12 pts (92%) had stage IV disease and B-symptoms were present in 8 pts (67%). Five pts were diagnosed with a solid variant consisting of nodal and gastrointestinal (n=2), myocardial followed by gastrointestinal (n=1), pulmonary and lymph node (n=1), and lymph node followed by cutaneous involvement (n=1). The pleural space, pericardium, and peritoneum were affected in 6, 1, and 4 cases, respectively, with more than one body cavity involved in 4 pts. The median CD4-lymphocyte count at lymphoma diagnosis was 174/µl (range, 48-492), and 8 pts (67%) had an AIDS-defining illness prior to diagnosis of PEL. All but 3 pts (75%) were on combination antiretroviral treatment (cART) at time of PEL diagnosis, and HIV-RNA was below the limit of detection in 9 pts (67%). First line chemotherapy (CT) consisted of CHO(E)P-like regimens in 8 pts, liposomal doxorubicin for concurrent Kaposi sarcoma in 2 pts, and rituximab/bortezomib/liposomal doxorubcin in 1 case. One patient only received intrapleural mitoxantrone for pleural effusion. First salvage CT consisted of EPOCH (n=3) or DHAP with and without high dose chemotherapy (n=3). Further salvage treatments included the dose intensive GMALL B-ALL/B-NHL protocol, brentuximab vedotin, EPOCH, and lenalidomide, given to one patient each. After a median follow-up of 12 months for the entire study population, 2 pts (17%) were alive and in continuous complete remission. The 2-year-overall survival was 16.7%. Patients died of refractory lymphoma (n=5), neutropenic sepsis (n=1), pneumonia/non-neutropenic sepsis (n=2), hyperinflammatory syndrome (n=1), and in one case the cause of death remained unclear.Conclusions: The overall survival of patients with HIV-PEL remains poor, although long term survival may be achieved in selected cases. International collaborative studies may help to define the optimal treatment approach. DisclosuresNo relevant conflicts of interest to declare.

The utility of multiparametric flow cytometry in the detection of primary effusion lymphoma (PEL).

Primary effusion lymphoma (PEL) is a rare B cell lymphoproliferative disorder that arises predominantly in body cavities causing malignant effusions. The incidence of PEL is very low, accounting for approximately 4% of all HIV-associated non-Hodgkin lymphomas. PEL has also been described in elderly patients and after solid-organ transplantation. It is associated in all cases with human herpes virus 8 (HHV8). We describe a case of PEL in a 88-year-old HIV-negative woman who presented with progressive dyspnea and moderate right-sided pleural effusion without significant lymphadenopathies or other effusions. The cytological study of the pleural fluid revealed a dense proliferation of large plasmablastic cells. A six-color multiparametric flow cytometry immunophenotyping study was carried out, and revealed 45% of large in size and high cellular complexity cells positive for CD45 (dim), CD38, CD138, CD30 and HLA-DR; and negative for CD19, CD20, cytoplasmatic CD79a, surface and cytoplasmic light chains Kappa and Lambda, CD3, CD4, CD5, CD7, CD8, CD28, CD56, CD81, and CD117. In situ hybridization for EBV-encoded smalI RNA was negative and immunohistochemistry for Kaposi sarcoma herpesvirus (HHV8) confirmed the diagnosis of PEL. Our results confirm that flow cytometry bring useful data in the diagnosis of large-cell lymphomas involving body cavities. © 2018 International Clinical Cytometry Society.

Extracavitary primary effusion lymphoma associated with hemophagocytic lymphohistiocytosis.

Extracavitary primary effusion lymphoma associated with hemophagocytic lymphohistiocytosis.

HHV8-Negative Body Cavity-Based Lymphoma Is Mature Large B-Cell Lymphoma That Affects Elderly and Displays Favorable Prognosis: A Multi-Center Retrospective Study of 50 Patients in Japan

[Background] Body cavity-based lymphoma (BCBL) arises in body cavity effusion without mass formation. Although there have been several case reports on HHV8-negative BCBL and the term "primary effusion lymphoma (PEL)-like lymphoma" has been coined, it is very rare and not defined in the current lymphoma classification. In those reports, HHV8-negative BCBL usually expresses B-cell markers and the prognosis seems to be better than those with HHV8-positive PEL with a few reports describing spontaneous regression of effusion. However, its clinicopathological features and prognosis remain unclear due to lack of retrospective study with sufficient number.[Method] We collected data of BCBL diagnosed between 1990 and 2014 from 42 institutions in Japan and clinicopathological features were retrospectively analyzed. We focused on clinicopathological features and prognosis of HHV8-negative BCBL, which was defined as HHV8-negative lymphoma that developed in body cavity effusion (pleural effusion, pericardial effusion, and ascites) without mass formation or extra-cavitary lesions at diagnosis. HHV8 status was assessed with immunohistochemical staining with anti-LANA-1 antibody (n=34) and/or polymerase chain reaction for HHV8 (n=31) of body-cavity effusion sample.Overall survival (OS), progression free survival (PFS), and time to progression (TTP) were calculated using Kaplan-Meier method. In patients without any systemic treatment for 3 months from diagnosis, failure of the first systemic treatment was considered as an event for PFS or TTP.[Results] Case report form of 71 patients with BCBL was collected. With central review, 4 patients did not meet the criteria of BCBL (existence of tumor mass or no objective evidence of lymphoma by morphology or immunophenotype) and 67 patients with BCBL were identified. Out of them, 50 and 6 were compatible with the diagnosis of HHV8-negative BCBL and PEL, respectively. In another 11 cases, HHV8 status could not be evaluated. In the 50 patients with HHV8-negative BCBL, male to female ratio was 1.3 : 1, and median age at the diagnosis was 76 years (57-98), HIV was negative in all of the 46 patients who were tested. Twenty-four patients (47%) had an underlying medical condition leading to fluid overload such as cirrhosis, cardiac disease, and renal dysfunction. Involved sites were pleural effusion (76%) followed by pericardial effusion (60%), and ascites (12%). Multiple sites were involved in 21 cases. The other clinical characteristics at the time of diagnosis were as follows: ECOG PS 0-1 (50%); B symptoms (14%); and elevated LDH (68%). Tumor cells expressed CD10 in 11/45 and CD20 in 48/50. Immunoglobulin light chain restriction was detected in 28/34. EBER in situ hybridization was positive in 4/32 (13%). The most common first-line systemic therapy was CHOP or CHOP-like with or without rituximab (n=38) followed by rituximab alone (n=2), rituximab with etoposide (n=2), and hyperCVAD/MA (n=1). One patient died within a month before initiating treatment, and five more patients had no systemic treatment at diagnosis for reasons such as comorbidity or frailty. Of the 43 patients treated with systemic therapy, the overall response rate was 98% with 70% achieving a complete remission. With a median follow up of 22 (0-147) months, 2-year OS, PFS, TTP of HHV8-negative BCBL was 83.6%, 76.8%, and 90.5%, respectively (Figure 1-3). Fifteen patients relapsed after achieving response: the same body-cavity effusion alone (n=7), different body-cavity effusion with or without the same site (n=2), intra- or extra-cavitary tumor mass formation (n=6). Eleven patients died and the causes of death were lymphoma (n=8) and others (n=3). Of the 5 patients without systemic treatment at diagnosis, systemic treatment was initiated in only 1 patient at 30 months due to re-emergence of effusion. The remaining 4 patients had had no systemic treatment for a median of 24 (5-147) months and 3 patients were alive without disease without any systemic therapy at last follow-up.[Conclusion] To the best of our knowledge, this is the largest retrospective study on HHV8-negative BCBL. HHV8-negative BCBL had distinct clinicopathological features from PEL. It affected HIV-negative elderly and the lymphoma cell was positive for B cell markers in most cases. Almost all of the patients responded to systemic treatment and its prognosis was favorable. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Primary effusion lymphoma with aberrant T‐cell phenotype in an iatrogenically immunosuppressed renal transplant male: Cytologic diagnosis in peritoneal fluid

Primary effusion lymphoma (PEL) is an unusual class of non-Hodgkin's lymphoma that develops in body cavities, without associated mass lesions. It has been linked to human herpes virus 8 (HHV-8), an etiological factor of Kaposi's sarcoma. Although PEL is a B-cell lymphoma, the neoplastic cells are usually of the "null" phenotype by immunocytochemistry. The relative infrequency of this entity, the absence of wide casuistic allowing a better characterization, and its unfavorable outcome, strongly support the need of a deeper knowledge. We report the clinico-biological findings of a 49-year-old male who was iatrogenically suppressed patient for 29 years because of renal transplantation. This case was diagnosed cytologically as peritoneal PEL and confirmed histologically on peritoneal biopsies. The immune status for both HHV-8 and Epstein-Barr virus (EBV) was evaluated and showed positive immunostaining only for the former. The combination of the immunocytochemistry results with the existence of a clonal rearrangement in the immunoglobulin heavy chain gene (identified by PCR) was compatible with the diagnosis of PEL. The presence of T-cell markers was consistent with the diagnosis of PEL with an aberrant T-cell phenotype.

Current concepts in primary effusion lymphoma and other effusion-based lymphomas.

Primary effusion lymphoma (PEL) is a human herpes virus 8 (HHV8)-positive large B-cell neoplasm that presents as an effusion with no detectable tumor in individuals with human immunodeficiency virus infection or other immune deficiencies. PEL is an aggressive neoplasm with a poor prognosis. PEL cells show diverse morphologies, ranging from immunoblastic or plasmablastic to anaplastic. The immunophenotype of PEL is distinct, but its lineage can be misdiagnosed if not assessed thoroughly. PEL cells usually express CD45, lack B- and T-cell-associated antigens, and characteristically express lymphocyte activation antigens and plasma cell-associated antigens. Diagnosis of PEL often requires the demonstration of a B-cell genotype. HHV8 must be detected in cells to diagnose PEL. In most cases, PEL cells also harbor the Epstein-Barr virus (EBV) genome. Similar conditions associated with HHV8 but not effusion-based are called "extracavitary PELs." PELs should be differentiated from HHV8-negative, EBV-positive, body cavity-based lymphomas in patients with long-standing chronic inflammation; the latter can occur in tuberculous pleuritis, artificial pneumothorax, chronic liver disease and various other conditions. Despite their morphological similarity, these various lymphomas require different therapeutic strategies and have different prognostic implications. Correct diagnosis is essential to manage and predict the outcome of patients with PEL and related disorders.

Soluble CD30: A Possible Serum Tumor Marker for Primary Effusion Lymphoma

The serum level of soluble CD30 (sCD30) is known to be increased with several lymphomas and to correlate with prognosis. Primary effusion lymphoma (PEL) is a highly aggressive malignant lymphoma with poor prognosis, but the existence and significance of sCD30 in PEL have not yet been investigated in detail. Since the membrane type of CD30 is frequently expressed on the surface of PEL cells, we compared the expression of the membrane type of CD30 and the production of sCD30 among PEL cell lines as well as other lymphomas. The expression of surface CD30 in various lymphoma cell lines was analyzed with flow cytometry ans sCD30 was quantified by ELISA. Both surface and sCD30 were detected on PEL cell lines as well as on Hodgkin's lymphoma and adult T-cell leukemia/lymphoma cell lines. Surface CD30 and sCD30 levels of each cell lines correlated with each other. The serum level of sCD30 appear to be a useful biological tumor marker for the diagnosis and management of CD30-positive PEL.

An unusual case of Primary Effusion Lymphoma with aberrant T-cell phenotype in a HIV-negative, HBV-positive, cirrhotic patient, and review of the literature

Primary effusion lymphoma (PEL) is an unusual, human herpes virus-8 (HHV-8)–associated type of lymphoma, presenting as lymphomatous effusion in body cavities, without a detectable tumor mass. It primarily affects human immunodeficiency virus (HIV)-infected patients, but has also been described in other immunocompromised individuals. Although PEL is a B-cell lymphoma, the neoplastic cells are usually of the ‘null’ phenotype by immunocytochemistry. This report describes a case of PEL with T-cell phenotype in a HIV-negative patient and reviews all the relevant cases published until now. Our patient suffered from cirrhosis associated with Hepatitis B virus (HBV) infection and presented with a large ascitic effusion, in the absence of peripheral lymphadenopathy or solid mass within either the abdomen or the thorax. Paracentesis disclosed large lymphoma cells with anaplastic features consisting of moderate cytoplasm and single or occasionally multiple irregular nuclei with single or multiple prominent nucleoli. Immunocytochemically, these cells were negative for both CD3 and CD20, but showed a positive reaction for T-cell markers CD43 and CD45RO (VCHL-1). Furthermore, the neoplastic cells revealed strong positivity for EMA and CD30, but they lacked expression of ALK-1, TIA-1, and Perforin. The immune status for both HHV-8 and Epstein-Barr virus (EBV) was evaluated and showed positive immunostaining only for the former. The combination of the immunohistochemistry results with the existence of a clonal rearrangement in the immunoglobulin heavy chain gene (identified by PCR), were compatible with the diagnosis of PEL. The presence of T-cell markers was consistent with the diagnosis of PEL with an aberrant T-cell phenotype.

Primary effusion lymphoma in an HIV‐negative man

A 55-year-old Caucasian male with cryptogenic cirrhosis of the liver and refractory ascites was referred for consideration of a liver transplant. There was no previous history of opportunistic infections and serological screening for human immunodeficiency virus (HIV), hepatitis B and hepatitis C was negative. Immunoglobulin levels were normal and autoantibodies and tumour markers were not detected. A computed tomography (CT) scan showed hepatomegaly with irregular hepatic architecture, established varices and marked portal enteropathy with splenomegaly and ascites but no nodal enlargement. Ascitic fluid cytology showed abundant atypical cells with hyperchromatic nuclei and many apoptotic cells (top left), macrophages and mesothelial cells. Immunophenotyping was undertaken on ascitic and pleural fluid and cells typed as mature T cells with no excess of blasts or clonally-restricted B cells. These cells expressed CD45, HLA-DR, CD38 and CD7 but no other B, T or myeloid markers. Immunohistochemistry of these cells failed because of background staining and poor preservation of cellular architecture. DNA was extracted from the ascitic fluid and gene rearrangement studies by multiplex polymerase chain reaction confirmed a monoclonal IGH@ rearrangement with a polyclonal T-cell receptor pattern. Peritoneal biopsy proved inconclusive but immunohistochemical analysis of a subsequent ascitic fluid sample showed pleomorphic lymphoid cells with plasmacytoid features, positive for CD38 (top right), CD30, epithelial membrane antigen (EMA) and MUM1/IRF4. There was strong nuclear expression of human herpesvirus 8 (HHV8) latent protein (LANA; bottom left) and Epstein–Barr virus-encoded RNA (EBER; bottom right) by in situ hybridization. A diagnosis of primary effusion lymphoma (PEL) was made. PEL is a rare large B-cell neoplasm and, in the absence of immune suppression, is particularly unusual. Confirmation of B-cell clonality by immunophenotyping may be difficult as PEL usually lacks cytoplasmic and surface immunoglobulin. CD45, HLA-DR, CD30, CD38, Vs38c, CD138 and EMA are often demonstrable. Pan-B markers may not be expressed and there may be aberrant expression of T-cell markers, making it difficult to assign lineage. Immunoglobulin genes are usually clonally rearranged, as in this case. The nuclei of the neoplastic cells are universally positive for HHV8 LANA and this is useful in establishing a diagnosis. If the cytological features are poorly preserved, histochemical staining may fail. The patient was treated with dose-attenuated cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy, but had a poor response and died within 6 months of presentation. Clinical outcomes remain poor for this disease although there are occasional reports of a response to immunomodulatory agents with chemotherapy.