Patients with Plasma Cell Disorders Have High EBV DNA in Peripheral Blood than the General Population.

Epstein-Barr virus (EBV) is involved in the development of a wide range of B cell lympho-proliferative disorders. Its association with plasma cell disorders (PCD) however is not clear, especially in immunocompetent patients. To explore any relationship, 39 patients of suspected PCD with positive M-band on electrophoresis and 50 healthy controls were enrolled. EBV DNA in peripheral blood was quantified using quantitative Real Time Polymerase Chain Reaction (qPCR). Of 39 patients, 15 (38.5%) had EBV DNA compared to 8/50 (16%) controls (p = 0.0008). The mean viral copy number was found to be significantly high in patients compared to controls (1.8 × 105; range = 2.6 × 103-7.6 × 105 copies/ml and 1.7 × 104; range = 7.0 × 102-6.1 × 104 copies/ml respectively; p = 0.003). This is the first study, which characterizes the frequency of EBV in circulation in patients of PCD. The significance of increased prevalence of circulating EBV and a higher viral load in our immunocompetent patients however, needs further evaluation.

Epstein - Barr virus association with plasma cell neoplasms.

AIMS: Epstein-Barr virus (EBV) expression has been reported in several hematopoietic and non-hematopoietic disorders but its expression in plasma cell neoplasms has been largely limited to immunodeficiency-related cases such as in the setting of post-organ transplantation or human immunodeficiency virus (HIV) infection. The aim of this study is to evaluate the association of EBV with plasma cell neoplasms, mainly in immunocompetent patients. METHODS AND RESULTS: We retrospectively studied 147 cases of patients with different plasma cell neoplasms (109 plasma cell myelomas, 22 plasmacytomas, and 16 monoclonal gammopathy cases). Six patients were immunocompromised. EBV was positive in 6 cases; 3 immunocompromised (2 patients with HIV infection and 1 patient was post-renal transplant) and 3 immunocompetent patients with plasmacytoma and variable plasmablastic features. CONCLUSIONS: Our data shows that EBV was negative in all plasma cell myeloma cases in immunocompetent patients and has an overall low association with the different plasma cell neoplasms in the immunocompetent setting. When expressed, it is usually associated with variable plasmablastic features.

The Kaposi's sarcoma-associated herpesvirus viral interleukin 6 gene affects metastasis and expression of B cell markers in a murine xenograft model.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a cancer-causing virus in humans, primarily affecting AIDS patients. KSHV causes a range of cancers including Kaposi's sarcoma, pleural effusion lymphoma and multicentric Castleman's disease. Current methods available for treating these cancers are relatively ineffective, and new targets for therapy are needed. The KSHV viral homolog of interleukin-6 gene (vIL-6) may play a significant role in tumor development and may serve as a new anti-cancer target, but its role in tumor formation is only partially understood. Here, a novel animal model was used to study how vIL-6 affects tumor development. Highly immune-deficient Rag2-/-γc-/- mice were transplanted with an immortalized human B cell line (BJAB) harboring either wild-type (WT) KSHV or a mutant strain lacking vIL-6 ΔvIL-6). Solid tumors developed and total tumor mass and the number of tumors were characterized. The vIL-6 gene had no significant impact on tumor mass, but significantly more tumors were detected when vIL-6 was present. Significant differences in expression of B cell markers in cells from extracted tumors were detected based upon the presence of vIL-6. B cell markers in tumor cells were also compared to the same cell type in culture, prior to xenotransplantation; B cell markers were mostly downregulated during tumor formation and these changes did not differ based upon the presence of vIL-6. The only marker that significantly increased in expression during tumor development was CD30. Tumor blood vessels were quantified to determine if more angiogenesis occurred with vIL-6-expressing virus, but there was no significant difference. These data indicate that vIL-6 plays a role in KSHV tumor formation in B cells in vivo. Further investigation into how vIL-6 manipulates CD30 expression may shed insight into KSHV oncogenesis, and may identify how vIL-6 can be targeted.

HHV8/KSHV-Positive Lymphoproliferative Disorders and the Spectrum of Plasmablastic and Plasma Cell Neoplasms: 2015 SH/EAHP Workshop Report-Part 3.

OBJECTIVES: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review immunodeficiency-related lymphoproliferative disorders with plasmablastic and plasma cell differentiation. METHODS: The workshop panel reviewed human herpes virus 8 (HHV8)/Kaposi sarcoma herpesvirus (KSHV)-associated lesions and other lesions exhibiting plasma cell differentiation, including plasmablastic proliferations with features of myeloma/plasmacytoma, plasmablastic neoplasms presenting in extranodal sites and effusion-based lymphomas, and rendered a consensus diagnosis. RESULTS: The spectrum of HHV8/KSHV-associated proliferations ranged from multicentric Castleman disease (MCD) to MCD with plasmablastic aggregates to HHV8+ diffuse large B-cell lymphoma and germinotrophic lymphoproliferative disorder. Comparisons across effusion-based lymphomas with and without HHV8/KSHV and plasmablastic lymphomas in immunodeficient and immunocompetent patients were discussed. CONCLUSIONS: The presence or absence of HHV8/KSHV is a defining feature in disorders associated with Castleman disease, although their differential diagnosis and recognition of progression may be challenging. Plasmablastic proliferations overlap with myeloma/plasmacytoma as well as extranodal and effusion-based lymphomas. The involvement of Epstein-Barr virus is typically variable.

Plasma cell neoplasms presenting with masses: a study on morphology, expression of CD56 and cyclin D1, and presence of Epstein-Barr virus in 39 Thai patients in SiriraJ Hospital.

BACKGROUND: Plasma cell neoplasms (PCNs) presenting with masses are not common. Variable morphology, expression of CD56 and cyclin D1, and Epstein-Barr virus (EBV)-encoded small RNA (EBER) status have been described with a promising diagnostic role. There is no data of these findings in Thai patients. OBJECTIVE: To study morphology, CD56 and cyclin D1 expression and EBER status in PCNs presenting with masses. MATERIAL AND METHOD: Thirty-nine mass-forming PCNs with available materials between 2006 and 2010 were identified from Siriraj Hospital pathology database. H&E slides were reviewed for morphologic grade according to Bartl grading system. Immunohistochemistryfor CD56 and cyclin D1 and EBER in situ hybridization were analyzed on tissue microarray sections of the included cases. RESULTS: Of 39 cases, it comprised 31 (79.5%) plasma cell myelomas (PCMs), five (12.8%) osseous plasmacytomas (OPs), and three (7.7%) extramedullary plasmacytomas (EMPs). Intermediate-grade morphology was common to all types of PCNs. CD56 and cyclin D1 positivity were more often in PCMs comparing with OPs and EMPs; however differences in expression of these markers among different types of PCNs were insignificant (p > 0.05). An EBER-positive EMP was identified. CONCLUSION: The majority of mass-forming plasma cell tumors in the studied population are PCM-related. Intermediate-grade morphology is common in all types of PCNs. A value of CD56 and cyclin D1 immunostains in discrimination between types of PCNs cannot be confirmed in the current study. Identification of the EBER-positive EMP suggests that EBV association in plasma cell tumor can be encountered in Thais.

Post-transplant lymphoproliferative disease of donor origin, following haematopoietic stem cell transplantation in a patient with blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare condition that originates from dendritic cells. We report on the first case of Epstein-Barr virus (EBV)-driven post-transplant lymphoproliferative disorder (PTLD) of donor origin in a BPDC patient post-allogeneic haematopoietic stem cell transplantation (HSCT). Flow cytometry study identified a cell population CD4+/CD56+/CD45RA+/CD123+/TCL1+ suggestive of BPDCN diagnosis, which was confirmed by a lymph node biopsy (cells positive for BCL11a, BDCA-2, CD2AP, CD123, TCL1 and S100). Cytogenetic analysis revealed a complex karyotype: (19 metaphase) 47,XX,t(1;6)(q21;q2?5),-13 + 2mar[11]/47, XX, +21 [3]/46,XX [5]. The patient was started on acute myeloid leukaemia (AML) induction schedule, and subsequently an allogeneic HSCT was performed. On day +36 post-HSCT, bone marrow biopsy/aspirate showed complete morphological remission, and chimerism study showed 100% donor chimera. However, on day +37, the patient was found to have enlarged cervical and supraclavicular lymphoadenopathy, splenomegaly and raised lactic dehydrogenase. EBV-DNA copies in blood were elevated, consistent with a lytic cycle. A lymph node biopsy showed EBV encoded RNA and large atypical B cells (CD45dim-, CD4+/CD56+, monoclonal for k-chain, CD19+/CD20+/CD21+/CD22+/CD38+/CD43+/CD79ß-/CD5-/CD10-), consistent with PTLD monomorphic type. Chimerism study showed that PTLD was of donor origin. This case together with the recent literature findings on BPDCN and PTLD are discussed.

Plasmablastic lymphoma of the retroperitoneum in an HIV- and HCV-positive patient: hard to diagnose and harder to treat.

Plasmablastic lymphoma (PBL) is an aggressive diffuse large B-cell lymphoma (DLBCL) with plasmablastic features that was initially described in the oral cavity of HIV-infected individuals. PBL remains a diagnostic challenge given its close morphologic resemblance and overlapping immunophenotypic patterns to other B-cell lymphoid malignancies and plasmablastic plasma cell myeloma (PCM) with extramedullary involvement. The presence of serum monoclonal protein and radiographic evidence of lytic bone lesions favors the diagnosis of plasma cell myeloma over PBL. Distinguishing PBL from PCM is important as PBL is treated with a completely different chemotherapy regimen compared to PCM. PBL carries a guarded prognostic profile among DLBCLs with high relapse rate and poor median survival. We present a case of a 44-year-old HIV-positive man who presented with a large retroperitoneal mass associated with obstructive uropathy, sacral radiculopathy, and inferior vena caval compression. The mass was initially mistaken to be a PCM on histopathology; however, subsequent investigations revealed an extra-oral PBL with plasmacytic differentiation. To our knowledge, this will be the first case of PBL of the retroperitoneum in an HIV- and HCV-positive patient and the second one at this location in the English-language literature. In this report, key differentiating points between PBL versus PCM and newer therapeutic agents such as proteasome inhibitors have been discussed along with related review of literature.

Haemangiomas, leiomyosarcoma and myeloma caused by subgroup J avian leukosis virus in a commercial layer flock.

An outbreak of simultaneously occurring haemangiomas, leiomyosarcoma and myeloma was observed in a commercial layer flock in China. The sick chickens were extremely thin and dehydrated. Scattered haemangiomas were found on the claws, breast and wings. At necropsy, haemangiomas and some other nodular tumours were also found in the internal organs. In addition, diffuse enlargement of the liver and spleen appeared in some birds. Histopathologically, haemangiomas were typically cavernous haemangiomas and haemangioendothelioma. In the diffusely swollen liver and spleen, multifocal or widespread marrow tumour cells filled with ball-like acidophilic particles in cytosol were observed, which are the characteristic pathological changes of avian myelocytomatosis. The nodular tumour cells formed by muscle bundles were of variable size, irregular shape, poorly differentiated and malaligned. Immunohistochemistry for vimentin, cytokeratin, actin (smooth muscle) and actin (sarcomeric) and Masson's staining confirmed the different cell lineage of the nodular tumour, thus leading to the diagnosis of leiomyosarcoma. The seroprevalence of avian leukosis subgroup J (ALV-J) antibodies was 13.46% (7/52), while ALV-A/B and reticuloendotheliosis virus (REV) antibodies were not detectable. The DF-1 cells inoculated by virus extracted from liver samples from 24 infected chickens were cultured and the group-specific antigen (GSA) was identified by ELISA. All samples were positive for ALV, which was further identified as ALV-J by immunofluorescence assay (IFA). PCR analysis revealed that three isolates of ALV-J proviral sequence were close to the HPRS-103 prototype strain and other Chinese field strains isolated in recent years, while one isolate (DP01) had a lower homology with them. This is the first report that ALV-J infection caused the simultaneous occurrence of haemangiomas, leiomyosarcoma and myeloma in a commercial layer flock.

Plasmablastic lymphoma: CNS involvement, coexistence of other malignancies, possible viral etiology, and dismal outcome.

The clinical and pathological findings of plasmablastic lymphoma (PBL) have been described in the literature but the etiology is not well established, and treatment options are poorly defined. We reviewed patients with PBL in our institution to characterize the clinicopathologic features in our patient population. In this retrospective analysis from a single academic institution, five patients with PBL were identified and analyzed. Human immunodeficiency virus and human herpesvirus 8 (HHV-8) were identified in 40% (two out of five) and 80% (four out of five) of these patients, respectively. Central nervous system (CNS) involvement was identified in four out of five (80%) patients. Interestingly, three out of five patients had a concurrent or preceding second primary malignancy including small lymphocytic lymphoma, endometrial cancer, and nonsmall cell lung cancer. Most of the patients had advanced disease and a poor performance status at diagnosis. Only two of the patients received systemic chemotherapy with an initial partial response. All five patients died; the median overall survival was 1 month. Our experience in patients with PBL indicates that CNS involvement is more common than reported in the literature. Coexistence of a second primary malignancy may be frequent, and prognosis remains dismal with standard lymphoma therapy. Lastly, the role of HHV-8 in the etiopathogenesis needs further trials.