Cases Of Primary Effusion Lymphoma Research Articles

Primary Effusion Lymphoma (PEL) and Primary Effusion-like Lymphoma (PEL-LL): A Comparative Study of Clinicopathologic Features and Outcomes

Background: While PEL is a well-established distinct WHO entity, PEL-LL is poorly defined and has been characterized differently by different researchers. Over the years, it encompassed PEL that expressed mature B-cell markers, extra-cavitary solid PEL, and recently the HHV8-unrelated PEL-like lymphomas. For this study, we defined PEL-LL as PEL-like lymphomas expressing mature B-cell phenotype. We conducted this study to compare the clinicopathological characteristics of PEL and PEL-LL and their impact on clinical outcomes. Methods: To study the clinicopathologic characteristics, therapeutic interventions, overall survival (OS), disease-free survival (DFS), and prognostic factors, we compiled a pooled database of 381 cases of PEL and PEL-LL. Chi-square and t-test were used to test the statistical significance of differences in parameters. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on OS and DFS. Results: A total of 381 (268 PEL, 113 PEL-LL) patients were identified. PEL and PEL-LL median ages were 51 and 74 (p < 0.0001), respectively. There was a male preponderance with M:F of 7 with PEL versus 2 with PEL-LL (p < 0.0001). The median OS was 6 months for PEL and 16 months for PEL-LL (p = 0.006). Compared to the thoracic cavity, involvement of the peritoneal cavity was associated with worse OS in both PEL and PEL-LL. Still, PEL-LL maintained better outcomes for each risk group (24 and 7 vs. 11 and 4 months, p < 0.0001). In the absence of HIV infection, PEL-LL has a superior OS to PEL (19 vs. 6 months, p = 0.002). However, HIV infection erases this survival advantage (6 vs. 6.5 months). In both entities, active treatment was associated with better OS (19 vs. 10 and 9 vs. 2 months, p < 0.0001). However, the untreated PEL-LL arm did as well as the treated PEL arm. Achieving CR as the best response to therapy in both PEL-LL and PEL was associated with superior OS (108 vs. 7 and 70 vs. 2 months, p < 0.0001). While dose-intense chemotherapy regimens did not impact OS in PEL-LL, they were associated with better OS in PEL (22 vs. 18 and 15 vs. 8 months, p = 0.03). Conclusions: This is the first study to compare PEL and PEL-LL expressing mature B-cell phenotype. It identifies key factors that impact OS that vary between the two entities. It also supports that PEL and PEL-LL represent two different disease entities regardless of their similar presentation.

Abstract 6750: Primary effusion lymphoma descriptors and clinicopathologic determinants of survival: Analysis of a pooled database

Abstract Background Primary effusion lymphoma (PEL) is a rare and aggressive type of B-cell non-Hodgkin lymphoma presenting primarily as lymphomatous effusions in body cavities and less often as solid extracavitary masses. It is typically associated with human herpesvirus 8 (HHV8) infection and occasionally with Epstein-Barr virus (EBV) co-infection. It is commonly seen in immunocompromised states, such as human immunodeficiency virus (HIV) infection, organ transplantation, immunosuppressive therapy, or advanced age. Due to our limited understanding of this disease, we conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in this rare and unique lymphoma subtype. Methods To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 303 cases of PEL. All cases with an unequivocal expression of CD19 and CD20 expression were excluded. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Result A total of 304 patients with confirmed PEL were identified. The median age was 49, with a peak incidence between 42 and 56 years. There was a male preponderance with M:F of 10. The majority (71%) was associated with HIV infection, with a median CD4 count of 108. Sixty-eight percent were cavitary with the pleural, pericardial, and peritoneal cavities involved in 56%, 20%, and 30%. The median duration of symptoms before diagnosis was 1.5 months. Patients presented with constitutional symptoms, hepatosplenomegaly, lymphadenopathy, and bone marrow involvement in 31%, 10%, 20%, and 16%. The median OS of the whole group was 6.5 months. Presentation with constitutional symptoms (p=0.026), extracavitary/solid tumors (p=0.03), and normal platelet counts (p=0.04) were associated with better median OS. Cavitary disease with effusions restricted to the thoracic cavity had also better median OS (p<0.0001). PEL occurrence in the context of immunosuppression due to transplantation had poor median OS (p=0.004). While having Kaposi sarcoma tended to impact OS negatively (p=0.08), Castleman’s disease did not. Compared to no treatment, combination chemotherapy alone, chemotherapy with anti-retroviral therapy, and stem cell transplant were statistically superior with a median OS of 1.5, 8, 30, and 16 months, respectively (p<0.0001). Conclusion This study presents updated clinicopathologic data from a pooled cohort of patients with PEL. It identifies the type of clinical setting contributing to immunodeficiency, disease presentation, the primary location of cavitary disease, and treatment approach as key determinants of OS. Citation Format: Supriya Gupta, Christopher Graham, Philip A. Haddad. Primary effusion lymphoma descriptors and clinicopathologic determinants of survival: Analysis of a pooled database. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6750.

Classic KSHV/HHV-8-positive Primary Effusion Lymphoma (PEL): A Systematic Review and Meta-Analysis of Case Reports.

Primary effusion lymphoma (PEL) is a large B-cell lymphoma growing within body-cavities caused by the Kaposi sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 (KSHV/HHV-8). It is mainly reported in HIV-infected patients. The uncommon occurrence in the elderly supports a form paralleling classic Kaposi sarcoma (KS), i.e. classic PEL, whose characteristics are relatively underexplored. To better understand the diagnostic modalities and clinical-epidemiological features of classic PEL, articles reporting cases of PEL were identified through MEDLINE/EMBASE databases (January 1998–July 2020) and screened according to PRISMA guidelines to extract individual-level data. A comparison was also performed between classic PEL and classic KS to evaluate similarities and differences. We identified 105 subjects (median age 77 years; 86% males), mainly from Mediterranean countries (52%, first Italy) and Eastern Europe (7%). Common comorbidities were heart failure (32%), cirrhosis (16%), and malignancy (20%) including lymphoid neoplasms. Pleural cavity was the commonest site (67%). PEL diagnosis was based on cytomorphology (89%), evidence of KSHV/HHV-8 infection (94%), EBV co-infection (28%) and clonality of IGH (59%), IGK (14%), TRG (9%) alone or in multiple combinations. Compared to KS, age (P<.001), gender-ratio (P=.08) and mortality (P<.001) were significantly higher in PEL, whereas the frequency of PEL as a second primary was similar (P=.44). This is the first systematic review of classic PEL case reports highlighting heterogeneity and lack of a uniform multidisciplinary approach at diagnosis, in the absence of specific guidelines as it happens for rare cancers. It is conceivable that classic PEL is still underdiagnosed in Mediterranean countries wherein KSHV/HHV-8 is endemic.

The cytopathological spectrum of lymphomas in effusions in a tertiary center in Taiwan.

We retrospectively reviewed effusion lymphomas from our archives in a tertiary center from July 2011 to June 2019. We identified 59 specimens from 43 patients, including 7 cases with primary effusion lymphoma (PEL) and 36, secondary effusion involvement. Half of the secondary cases presented concurrently with effusion lymphoma, while the remaining half-experienced effusion lymphoma during disease progression. All patients with PELs were males with a median age of 77 and presented with massive pleural effusion. None was HIV-related. Two (29%) PEL cases were positive for human herpes virus 8 (HHV8). The only case with plasmablastic phenotype in the PEL group was positive for both HHV8 and EBV. Four patients died shortly after diagnosis; while the remaining three were alive at the last follow-up (two at 13 months and one at 99 months). Of the secondary cases, diffuse large B-cell lymphoma/high grade B-cell lymphoma was the most common (n = 16, 44%), followed by mantle cell lymphoma (n = 5, 14%). Only 8 cases (22%) were T-cell neoplasms. Prognosis for patients with secondary effusion involvement was dismal, with 1- and 2-year overall survival rates at 17% and 8%, respectively. We found a wide cytopathological spectrum of effusion lymphoma in Taiwan. Most of our PEL cases were distinct from that defined in the World Health Organization scheme by a B-cell phenotype, HHV8-negativity, and absence of immunodeficiency. As compared to PEL cases, the prognosis of those with secondary involvement was extremely poor.

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.

Clinicopathologic characteristics and survival of patients with primary effusion lymphoma

Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma confined to body cavities and universally associated with human herpesvirus type 8 infection. The prognosis of this entity remains poor, with a median survival time of 6 to 9 months. To better understand the clinicopathologic features of the disease and identify possible prognostic factors, we performed a systematic review of the literature for cases of PEL, including 2 previously unreported cases from our institution. PEL was more prevalent in men (92%), with a median age at diagnosis of 55 years. The median overall survival for the entire series was 6 months. Peritoneal involvement (HR:1.62; 95% CI:1.06–2.48) and elevated serum lactate dehydrogenase (LDH) levels (HR:2.50; 95% CI:1.21–5.19) were associated with higher risk of death, while pericardial involvement (HR:0.43; 95% CI:0.20–0.94) was associated with lower risk of death. Therefore, effusion site and serum LDH levels are potential prognostic factors in patients with PEL.

Human herpesvirus 8‐related primary effusion lymphoma in four HIV‐uninfected patients without organ transplantation

Primary effusion lymphoma (PEL) is a rare subtype of non‐Hodgkin's lymphoma. PEL is closely related in pathogenesis to human herpesvirus 8 (HHV‐8) and typically occurs in patients with significant immunodeficiency. Cases of PEL in patients without either HIV infection or transplantation have been reported from HHV‐8‐endemic areas, but very rarely from the Asia‐Pacific region. In this case series, we describe the clinical and immunohistochemical presentations of four patients in southern Taiwan who were diagnosed with HHV‐8‐related PEL. All four patients were HIV‐negative and had not received organ transplantation. To our knowledge, this is the first authentic report of HIV‐unrelated PEL from the ethnically Chinese population. Considering the non‐specific clinical manifestations, the pivotal roles of specific assays for correct diagnosis, and the dismal prognosis of PEL, it is important for clinicians to include PEL as one of the differential diagnosis when approaching HIV‐uninfected patients with unexplained exudative body cavity effusion.

Body Cavity-Based Lymphoma in a Country with Low Human Immunodeficiency Virus Prevalence: A Series of 17 Cases from the Consortium for Improving Survival of Lymphoma.

PurposePrimary effusion lymphoma (PEL) is a type of body cavity–based lymphoma (BCBL). Most patients with PEL are severely immunocompromised and seropositive for human immunodeficiency virus (HIV). We investigated the distinctive clinicopathologic characteristics of BCBL in a country with low HIV burden.Materials and MethodsWe retrospectively collected data on the clinicopathologic characteristics, treatments, and outcomes of 17 consecutive patients with BCBL at nine institutions in Korea.ResultsLatency-associated nuclear antigen 1 (LANA1) immunostaining indicated that six patients had PEL, six patients had human herpesvirus 8 (HHV8)-unrelated BCBL, and five patients had HHV8-unknown BCBL. The patients with PEL exhibited no evidence of immunodeficiency except for one who was HIV positive. One (20%) and four (80%) patients with PEL and six (100%) and zero (0%) patients with HHV8-unrelated BCBL were positive for CD20 and CD30 expression, respectively. The two patients with PEL (one HIV-positive and one HIV-negative patient) with the lowest proliferation activity as assessed by the Ki-67 labeling index survived for > 1 and > 4 years without chemotherapy, respectively, in contrast to the PEL cases in the literature, which mostly showed a high proliferation index and poor survival.ConclusionPEL mostly occurred in ostensibly immunocompetent individuals and had a favorable outcome in Korea. A watchful waiting approach may be applicable for managing HIV-seronegative patients with PEL with a low Ki-67 labeling index. A possible trend was detected among LANA1, CD20, and CD30 expression in BCBL.

Demographics and Survival in Primary Effusion Lymphoma: SEER Database Analysis

Background: Primary effusion lymphoma (PEL) is one of the least common of the AIDS-related lymphomas, accounting for less than 4% of cases. The optimal treatment for primary effusion lymphoma (PEL) remains unclear and there is a paucity of data regarding this neoplasm, which carries a uniformly poor prognosis. Antiretroviral therapy in addition to chemotherapy has shown to improve survival in a few small retrospective studies.Methods: Between 2002 and 2014, all cases of PEL were extracted from the population-based cancer registries of the Surveillance Epidemiology and End Results program (SEER). Instances of PEL were identified with the ICD-O-3 (9678) histological code. Frequency, demographics, and survival data were assessed using SPSS statistical software.Results: A total of 117 cases of PEL were identified. PEL was significantly more prevalent in men (89.7%) and in Caucasians (77.8%) with median age at diagnosis of 49 years. Median overall survival in the entire cohort was 6 months; CI, 3.7 to 8.2 months. Of all PEL cases, 62.4% received chemotherapy and 37.6% did not. Those who received chemotherapy had a median overall survival of 10 months vs less than one month when compared to subjects who did not receive chemotherapy (p = 0.002). PEL was the cause of death in 40.2% of the cases. PEL-specific median overall survival was markedly higher (29.000 months) than that of the entire cohort. Multivariable analysis demonstrated that age and race were not associated with mortality. Chemotherapy was associated with decreased mortality risk (HR, 0.45; CI, 0.28 -0.74; p = 0.002)Conclusions: In confirmation of previously published data, the highest incidence of PEL was found in Caucasian males. Subjects who received chemotherapy were found to have improved overall survival outcome. Other factors not related to PEL were associated with early mortality in this population. DisclosuresNo relevant conflicts of interest to declare.

Extracavity primary effusion lymphoma presenting in a lymph node without lymphomatous effusions

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with human herpesvirus 8 (HHV8), which usually presents as a lymphomatous body cavity effusion. Rare cases of PEL are extracavitary and manifest as a solid tumor mass. Here we report an unusual case of extracavitary PEL (EPEL) involving lymph nodes with no evidence of a body cavity effusion. The neoplasm was comprised of large pleomorphic cells with prominent nucleoli and frequent mitotic figures that expressed HHV8, EBV, CD38 and CD30, but lacked all lineage-specific markers. The patient was found to be HIV positive after the diagnosis of EPEL. Antiretroviral therapy initially reduces tumor size, but the patient expired three months later due to multiple complications. PEL and EPEL are differing manifestations of a rare disease entity as defined by the World Health Organization 2008 classification. It is unknown why a small subset of these cases forms extracavitary masses with or without malignant effusions. Comparison with mouse xenograft models may provide unique insights into the pathogenesis of this disease for possible future studies.

C-105 Lymphomas and other cancers in HIV-infected patients

Non Hodgkin lymphoma (NHL) is the most frequent cancer in patients with HIV/AIDS (PWHA) in the post-cART era. Interestingly, an increase in Hodgkin lymphoma (HL) risk with declining CD4 counts has been shown, although much less steep than NHL. The most common NHL types in PWHA are diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Some rare types of lymphomas occur nearly exclusively in PWHA patients, i.e. primary effusion lymphoma (PEL) and its solid variants, lymphoma associated with Kaposi sarcoma-associated herpesvirus (KSHV)-related multicentric Castleman disease (MCD), and plasmablastic lymphoma of the oral cavity type. Lymphomas occurring in PWHA are closely linked to other viral infection. BL, DLBCL, plasmablastic lymphoma and HL are associated with Epstein-Barr virus (EBV) infection, though not uniformly. PEL and its solid variants are consistently linked to KSHV. EBV is also expressed in 70–80% of PEL cases. Significant increases were also found for cancers of the lung, liver, anal, oropharynx, cervix and non-melanocytic skin tumors. These cancers are mostly infection-related, and exhibit pathologic features similar to those observed in HIV-negative patients. Coinfection with different viruses represents a common issue in malignancies in PWHA. MCD has become increasingly relevant in recent years given its association with HIV and KSHV infections. Although MCD, KS, PEL and HL are disease entities displaying distinct clinical and pathological features, KSHV associated MCD is usually a tangle of these different entities. A comprehensive understanding of the intricacies of the HIV, KSHV and EBV coinfection will probably lead to additional advances in therapy and managements of the affected patients.

Extracavitary primary effusion lymphoma: clinical, morphological, phenotypic and cytogenetic characterization using nuclei enrichment technique.

Primary effusion lymphoma (PEL) is a rare form of aggressive B-cell lymphoma, which typically manifests as malignant effusion in the body cavities. However, extracavitary solid variants are also described. The aim of this study was to investigate copy number aberrations in two cases of solid PEL at their first occurrences and relapse by applying a newly developed methodology of tumour nuclei enrichment. Using histological and genetic techniques, a novel protocol for tumour nuclei enrichment by flow sorting and array-comparative genomic hybridization, we characterized two cases of extracavitary PEL, one of which later relapsed as effusion. Both primary tumours were positive for HHV8 and EBV, confined to lymph nodes, and aberrantly expressed CD3, yet displaying clonal immunoglobulin gene rearrangements indicating B-cell origin. Cytogenetic characterization of primary tumours revealed modest number of aberrations, partially overlapping with previously reported affected loci. The effusional relapse in case 1 was cytogenetically related to the primary tumour but showed dramatic increase of chromosomal instability. We for the first time demonstrate a cytogenetic relationship between solid and effusional presentations of PEL. Moreover, we provide an indirect evidence of multiple malignant clones, which gave rise to clonally-related, yet karyotypically different relapsing lymphoma manifestations.

Primary Effusion Lymphoma: Secretome Analysis Reveals Novel Candidate Biomarkers with Potential Pathogenetic Significance

Primary Effusion Lymphoma: Secretome Analysis Reveals Novel Candidate Biomarkers with Potential Pathogenetic Significance

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.

Extracavitary KSHV-associated Large B-Cell Lymphoma

Primary effusion lymphoma (PEL) is a rare form of aggressive B-cell lymphoma in HIV patients, which typically presents with lymphomatous effusions in the body cavities without forming mass lesions. PEL is associated with Kaposi sarcoma-associated herpesvirus (KSHV) (also called human herpesvirus-8) with distinct clinical and pathologic features. Rare cases of KSHV-associated large B-cell lymphoma (KSHV-LBL) have been observed in the lymph nodes or extranodal sites without lymphomatous effusions during the course of disease. KSHV-LBL is generally similar to classic PEL on the basis of the clinical presentation (HIV(+) male), morphology (immunoblastic, plasmablastic, or anaplastic), immunophenotype (CD45(+), CD20(-), CD79a(-), CD30(+), CD138(+), and EMA(+)), presence of Epstein-Barr virus infection, and clonal immunoglobulin gene rearrangements. However, it is not clear whether KSHV-LBL is a distinct entity or represents part of the spectrum of classic PEL; in particular, there is no consensus diagnostic term for KSHV-LBL. In this study, we investigated the clinicopathologic features of 9 cases of KSHV-LBL from our files. An additional 43 such cases and 84 cases of classic PEL from the English literature were reviewed and compared with each other. In contrast to the classic PEL, KSHV-LBL had a very significant lower expression of CD45 (74% vs. 94%, P=0.004) but significant higher expression of CD20 (17% vs. 5%, P=0.04) and CD138 (70% vs. 38%, P=0.05). KSHV-LBL also had slightly higher positivity of CD79a (23% vs. 5%, P=0.13) and immunoglobulin light chain expression, although the difference was not statistically significant [κ chain (12% vs. 0%) and λ chain (31% vs. 21%)]. The expressions of EMA and CD30 were slightly lower in KSHV-LBL compared with those observed in PEL (57% vs. 75% and 63% vs. 76%, respectively). Interestingly, 29% (10/34) of cases of KSHV-LBL revealed aberrant CD3 expression, which may mislead to a diagnosis of T-cell lymphoma, particularly anaplastic large cell lymphoma in combination with the anaplastic morphology and expression of CD30 and EMA. Although KSHV-LBL shows different clinical presentations and some variations in immunophenotype from classic PEL, it is still uncertain, on the basis of our findings, whether it is justifiable to separate them as 2 distinct entities. Nevertheless, we feel it is necessary to have a consensus diagnostic term, and we recommend a tentative one as "KSHV-associated large B-cell lymphoma (KSHV-LBL)" to replace many different names previously used.

Extracavitary/solid variant of primary effusion lymphoma

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with human herpesvirus 8 (HHV8) infection that mostly affects patients with immunodeficiency. Primary effusion lymphoma usually presents as a malignant effusion involving the pleural, peritoneal, and/or pericardial cavities without a tumor mass. Rare cases of HHV8-positive lymphoma with features similar to PEL can present as tumor masses in the absence of cavity effusions and are considered to represent an extracavitary or solid variant of PEL. Here, we report 3 cases of extracavitary PEL arising in human immunodeficiency virus-infected men. Two patients had lymphadenopathy and underwent lymph node biopsy. One patient had a mass involving the ileum and ascending colon. In lymph nodes, the tumor was predominantly sinusoidal. The tumor involving the ileum and ascending colon presented as 2 masses, 12.5 × 10.6 × 2.6 cm in the colon and 3.6 × 2.7 × 1.9 cm in the ileum. In each case, the neoplasms were composed of large anaplastic cells, and 2 cases had "hallmark cells." Immunohistochemistry showed that all cases were positive for HHV8 and CD138. One case also expressed CD4 and CD30, and 1 case was positive for Epstein-Barr virus-encoded RNA. Evidence of B-cell differentiation was poorly developed in all tumors. These cases highlight the importance of assessing HHV8 in an anaplastic tumor that arises in a human immunodeficiency virus-positive patient and further contributes to the limited literature currently available for extracavitary PEL.

Uniform Expression of Notch1, Suppressor of B-Cell–Specific Gene Expression, in Plasmablastic Lymphoma

Although the loss of B-lineage-specific gene expression is a distinctive feature of plasmablastic lymphoma, the underlying mechanism remains poorly understood. A candidate for this mechanism is Notch1 signaling, which interferes with the activity of B-cell-specific transcription factors E2A and early B-cell factor and positively regulates the mammalian target of rapamycin (mTOR) pathway. To explore the mechanism of loss of B-cell phenotype by correlating expression of B-cell markers with that of Notch1 and downstream targets of the mTOR pathway in plasmablastic lymphoma. A combination of flow cytometric and immunohistochemical immunophenotyping techniques was used on 9 cases of plasmablastic lymphoma to correlate loss of B-cell markers with expression of Notch1 and downstream activation of the mTOR pathway. These results are compared with 5 cases of primary effusion lymphoma and 21 cases of plasma cell myeloma. Plasmablastic lymphoma cases exhibit nearly complete loss of B-cell-associated markers and uniform expression of Notch1, with a predominantly nuclear staining pattern. There is a concurrent activation of the mTOR pathway, indicated by expression of mTOR targets eukaryotic initiation factor 4E-binding protein 1 and phosphorylated ribosomal protein S6 in most cases. Similar results are seen in cases of primary effusion lymphoma and plasma cell myeloma. These findings suggest that activation of Notch1 may be involved in suppression of B-cell-specific gene expression and global loss of the B-cell phenotype in plasmablastic lymphoma, similar to primary effusion lymphoma and plasma cell myeloma. Thus, there might be a role for the Notch1 and mTOR pathways in the pathogenesis and therapy of plasmablastic lymphoma.

Notch1 in primary effusion lymphoma: a clinicopathological study

Primary effusion lymphoma is a human herpes virus 8 (HHV-8)-associated large cell lymphoma of body cavities. Detailed large-scale clinicopathological studies are rarely reported, and the underlying mechanism of lymphomagenesis remains elusive. In the present report, we studied the clinicodemographic, immunophenotypic, and cytomorphological features on a cohort of 12 cases of primary effusion lymphoma. In contrast to HHV-8, which was positive in all nine cases tested (100%), HIV was found in 75% (9/12) of cases, whereas the three HIV-negative cases were either in elderly patients (one with hepatitis C virus infection and one with asbestoses exposure) or in a heart transplantation recipient. By flow cytometry, the antigens expressed in descending order were CD38, CD71, HLA-DR, CD30, and CD45RO. B-cell markers were largely negative. Cytomorphologically, all cases showed atypical to anaplastic morphology. Notch1, a member of transmembrane signal transduction family, was found in six of seven HHV-8-positive cases (86%). In agreement with in vitro studies using human primary effusion lymphoma cell lines, we have found that Notch1 was expressed in the majority of HHV-8-positive primary effusion lymphoma cases, corroborating the notion that Notch1 may have an important role in HHV-8-mediated lymphomagenesis of primary effusion lymphoma.

Genotypic and clinicopathological characterization of Kaposi's sarcoma‐associated herpesvirus infection in Japan

Kaposi's sarcoma-associated herpesvirus (KSHV) is related causally to Kaposi's sarcoma, primary effusion lymphoma, and a subset of cases of multicentric Castleman's disease. As the numbers of acquired immunodeficiency syndrome (AIDS) patients have increased, KSHV-associated diseases have also increased in Japan. Sporadic cases of classic Kaposi's sarcoma have also been reported in Japan. In the present study, the clinicopathological characteristics of 75 samples, comprising 68 cases of Kaposi's sarcoma, 5 cases of primary effusion lymphoma, and 5 cases of multicentric Castleman's disease were investigated. All of these cases were positive for KSHV by immunohistochemistry or PCR analysis. All fifty-two of the AIDS-associated Kaposi's sarcoma cases were males, whereas 7 of the 13 non-AIDS-associated Kaposi's sarcoma cases were females. The mean age of patients with AIDS-associated Kaposi's sarcoma or primary effusion lymphoma was 46 years, whereas the mean age of patients with non-AIDS-associated Kaposi's sarcoma or primary effusion lymphoma was 71.8 and 97.5, respectively. KSHV genotypes were determined based on the sequence of variable region 1 in the K1 gene. Genotypes A and C of KSHV were detected in both AIDS- and non-AIDS-associated Kaposi's sarcoma. Genotype A was detected more frequently in AIDS-associated cases than non-AIDS-associated cases, suggesting that genotype C is broadly distributed in Japan, and genotype A spreads among AIDS patients. Genotype D was detected only in non-AIDS-associated Kaposi's sarcoma. These data confirmed the difference between AIDS- and non-AIDS-associated KSHV diseases with regard to age of onset, gender, and genotypes in Japan. J. Med. Virol. 82:400-406, 2010. (c) 2010 Wiley-Liss, Inc.