Plasmablastic lymphoma

Plasmablastic lymphoma lesions are most commonly rapidly growing, soft tissue masses[5] that may be ulcerating, bleeding, and/or painful.[6] In a recent (2020) review of published cases, individuals presenting with PBD were typically middle-aged or elderly (range 1–88 years; median age 58 tears) males (~73% of cases).[7] Only a few cases have been reported in pediatric cases.[6] The PDL lesions occurred most commonly in lymph nodes (~23% of cases), the gastrointestinal tract (~18%), bone marrow (16%), and oral cavity (12%).[7] Less frequently involved tissues include the skin, genitourinary tract,[7] paranasal sinuses, lung, and bones.[5] While cases of PBL may present as a primary oral,[8] or, very rarely a skin[3] or lymph node[8] disease, most individuals present with a widespread stage III or IV disease which in ~40% of cases, is accompanied by systemic B-symptoms such as fever, night sweats, and recent weight loss.[2] Some 48%-63% of PBL cases occur in individuals with HIV/AIDS; ~80% of these HIV/AIDS-afflicted individuals have EBV+ disease whereas only ~50% of PBL individuals that do not have HIV/AIDS are EBV-positive.[2] Individuals who develop PBL following organ transplantation are EBV-positive in >85% of cases.[7] Most post-transplant and HIV/AIDS 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.[5] It is similarly clear that, on average, elderly patients (>68 years) likewise present with, and continue to have, a significantly less aggressive cancer.[4]

In addition to the immunodeficiency-causing viral disease, HIV/AIDS (which is an AIDS-defining clinical condition[5]), recent studies have diagnosed PBL in individuals who have one or more other causes for immunodeficiency.[7] These causes include prior organ transplantation; immunosuppressive drugs; autoimmune and chronic inflammatory diseases (e.g. hepatitis C,[3] rheumatoid arthritis, Graves' disease, Giant-cell arteritis, sarcoidosis, and severe psoriasis[9]); 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.[10] Studies also find that 60-75% of individuals diagnosed with PBL have Epstein–Barr virus-infected plasmablasts.[1] EBV infects ~95% of the world's population to cause no symptoms, minor non-specific symptoms, or infectious mononucleosis. The virus then enters a latency phase in which infected individuals become lifetime asymptomatic carriers of the virus in a set of their B-cells. Some weeks, months, years, or decades thereafter, a very small fraction of these carriers, particularly those with an immunodeficiency, develop any one of various EBV-associated benign or malignant diseases, including, in extremely rare cases, Epstein–Barr virus-positive plasmablastic lymphoma.[11] 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

The predisposing conditions described in the previous paragraph can serve to enhance the ability of the plasmablasts in PBL to: avoid the host's immune surveillance; survive for prolonged periods, grow excessively, and acquire pro-malignant gene abnormalities. Some of the gene abnormalities found in PBL include: 1) increased expression of the MYC proto-oncogene due to its rearrangement with an antibody gene by genetic recombination or, less commonly, other causes (Myc protein, the product of this gene, enhances cell proliferation, inhibits apoptosis, and promotes malignancy); 2) loss in the expression of the PRDM1 gene whose product, PRDM1/BLMP1 protein, represses the expression of Myc protein;[12]) 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);[8] 4) reduced expression of at least 13 genes that are involved in B-cell responses to signaling agents.[1] 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).[2]

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.[2] Immunostaining of these cells indicate that they lack B-cell marker proteins (e.g. CD20 and PAX5 [in ~10% of cases CD20 may be expressed at very low levels[2]]) but rather express plasma cell marker proteins (e.g. CD38, CD138, IR4/MUM1, XBP1, IL21R, and/or PRDM1). The abnormalities in gene structures and expressions reported in the Pathophysiology section, particularly rearrangement and/or over expression of the MYC proto-oncogene, may also be apparent in these cells. The presence of HIV/AIDS or other causes of immuno-incompetence (see previous section), a history of having a low-grade lymphoma, and/or the presence of EVB+ plasmablasts in the disease's lesions would support the diagnosis of PBL.[1]

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.[2]

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.[2]

A study by Green and Eversole published in 1989[15] 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[16] 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.[6] 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.[7] In 2017, this Organization classified PBL as the most common member of a rare subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation.[1]

• Lymphoma
• Epstein–Barr virus–associated lymphoproliferative diseases

Category:Lymphoid-related cutaneous conditions