Plasmablastic lymphoma

Plasmablastic lymphoma lesions are most commonly rapidly growing, soft tissue masses that may be ulcerating, bleeding, and/or painful. This is particularly the case for individuals with HIV/AIDS-negative disease. Individuals who develop PBL following organ transplantation are EBV/AIDS-positive in >85% of cases. Most post-transplant and HIV/AIDS-positive patients have an extremely aggressive disease. However, patients whose major contributing factor to PBL-development is EBV-positivity often present with, and continue to have, a significantly less aggressive disease than other patients with PBL. It is similarly clear that, on average, individuals who are elderly (>68 years) or have HIV/AIDS-negative disease likewise present with, and continue to have, a significantly less aggressive cancer. == Pathophysiology ==

In addition to the immunodeficiency-causing viral disease, HIV/AIDS (which is an AIDS-defining clinical condition); and immunosenescence due to age (e.g. >60 years). Rare cases of PDL have also occurred as a transformation of a low grade B-cell malignancy such as chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Studies also find that 60-75% of individuals diagnosed with PBL have Epstein–Barr virus-infected plasmablasts. The virus in infected plasmablastic cells appears to be in its latency I phase; consequently, these infected cells express EBV products such as EBER nuclear RNAs and BART microRNAs. These RNAs promote infected cells to proliferate, avoid attack by the host's immune system's cytotoxic T-cells, and, possibly, block the infected cells' apoptosis (i.e. programmed cell death) response to injury.) 3) frequent duplications in certain areas of chromosomes 1, 7, 11, and 22 (these duplications are similar to those often seen in diffuse large cell lymphoma); 4) reduced expression of at least 13 genes that are involved in B-cell responses to signaling agents. 5) increased expression of genes which promote the maturation of B-cells toward plasma cells (e.g. CD38, CD138, IR4/MUM1, XBP1, IL21R, and, as just indicated, PRDM1); and 6) reduced expression of genes characteristic of B-cells (e.g. CD20 and PAX5). == Diagnosis ==

Microscopic examination of involved PBD masses and infiltrates generally reveals diffuse proliferations of immunoblast-like cells with prominent features of plasma cells, i.e. plasmablastic cells. as indicated in the following descriptions. Anaplastic lymphoma kinase-positive large B-cell lymphoma Unlike PBL, the plasmablastic cells in anaplastic lymphoma kinase-positive large B-cell lymphoma strongly express the product of the ACVRL1 gene, i.e. activin receptor-like kinase 1 (ALK1) and are not infected with EBV and therefore do not express this virus's EBER or BART RNAs. Human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified Unlike PBL, the plasmablastic cells in human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified express products of herpesvirus 8 (also termed Kaposi sarcoma virus) such as LANA-1 protein. Also unlike PBL, these plasmablastic cells do not express CD30, CD138, CD79a, or a clonal IgM antibody and usually are not EBV-infected and therefore usually do not express this virus's EBER or BART RNAs. Primary effusion lymphoma In contrast to PBL, the plasmablastic cells in primary effusion lymphomas, whether HHV8-positive or HHV8-negative, usually strongly express CD45 and in HHV8 cases express HHV8 proteins such as the LANA-1 protein. Primary effusion lymphoma, HH8-negative also differs from PBL in that its plasmablastic cells frequently express certain B-cell marker proteins such as CD20 and CD79a. Plasmablastic plasma cell lymphoma Various factors distinguish plasmablastic plasma cell lymphoma from PBL. Prior diagnosis of plasma cell lymphoma (i.e. multiple myeloma or plasmacytoma), the presence of lytic bone lesions, increased levels of serum calcium, renal insufficiency, and anemia, and the presence of a myeloma protein in the serum and/or urine favor the diagnosis of plasmablastic plasma cell lymphoma rather than plasmablastic lymphoma. Ultimately, however, the marker proteins expressed by the plasmablastic cells in the two diseases are almost identical and a diagnosis of "plasmablastic neoplasm, consistent with PBL or multiple myeloma" may be acceptable in some cases according to the current World Health Organization classification. Other B-cell lymphomas The plasmablastic cells in B-cell lymphomas, including diffuse B-cell lymphomas, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma generally express CD20 and often express CD45 marker proteins. While PBL plasmablastic cells weakly express CD20 in 10% of cases, the strong expression of CD20 and the expression of CD45 virtually rules out PBL. == Treatment ==

The treatments for PBL have ranged from radiotherapy for localized disease to various chemotherapy regimens for extensive disease. The chemotherapy regimens have included CHOP (i.e. cyclophosphamide, hydroxydoxorubicin (or doxorubicin), vincristine, and either prednisone or prednisolone); CHOP-like regimens (e.g. CHOP plus etoposide); hyper-CVAD-MA (i.e. cyclophosphamide, vincristine, doxorubicin, dexamethasone and high dose methotrexate and cytarabine); CODOX-M/IVAC (i.e. cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate and ifosfamide, etoposide, and high-dose cytarabine); COMB (i.e. cyclophosphamide, oncovin, methyl-CCNU, and bleomycin); and infusional EPOCH (i.e. etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). While the experience treating PBL with radiation alone has been limited, patients with localized disease have been treated with doxorubicin-based chemotherapy regimens plus radiotherapy. Daratumumab is a prepared monoclonal antibody that binds to CD38 and thereby directly or indirectly kills cells, including the plasmablasts in PBL, that express this marker protein on their surfaces. ==Prognosis==

Overall, patients receiving one of the cited chemotherapy regimens have achieved disease-free survival and overall survival rates of 22 and 32 months, respectively. The National Comprehensive Cancer Network recommends the more intensive regimens (e.g. hyper-CVAD-MA or infusional EPOCH) to treat the disease. These regimens have attained 5 year overall and disease-free survivals of 38% and 40%, respectively. Too few patients have been treated with autologous hematopoietic stem cell transplant in addition to chemotherapy for conclusions to be made. A few patients with HIV/AIDS-related PBL disease who were treated with highly active antiretroviral therapy (HAART) directed against the human immunodeficiency virus (i.e. HIV) have had remissions in their PDL lesions. == History ==

A study by Green and Eversole published in 1989 reported on 9 individuals afflicted with HIV/AIDS who presented with lymphomatous masses in the oral cavity; these lymphomas were populated by apparently malignant Epstein–Barr virus-infected plasmablasts that did not express T-cell lymphocyte marker proteins. Eight years later, Delecluse and colleagues described a lymphoma, which they termed plasmablastic lymphoma, that had some features of a diffuse large B-cell lymphoma but unlike this lymphoma developed exclusively in the oral cavity, consisted of plasmablasts that lacked B-cell as well as T cell marker proteins and, in 15 of 16 cases, were infected with EBV. In 2008, the World Health Organization recognized this lymphoma as a variant of the diffuse large cell lymphomas. Subsequent to this recognition, numerous studies found this lymphoma to occur in a wide range of tissues besides the oral cavity and in individuals with various other predisposing immunodeficiency conditions. In 2017, this Organization classified PBL as the most common member of a rare subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation. == See also ==