Plasmablastic lymphoma

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Wright stain

Plasmablastic lymphoma (PBL) is a type of

plasma cells; proliferate excessively; and accumulate in and injure various tissues and organs.[1]

The lymphomas in the lymphoid neoplasms with plasmablastic differentiation sub-group that are not PBL have sometimes been incorrectly considered to be variants of PBL. Each of the lymphomas in this subgroup of

malignancies have distinctive clinical, morphological, and abnormal gene features. However, key features of these lymphomas sometime overlap with other lymphomas including those that are in this sub-group. In consequence, correctly diagnosing these lymphomas has been challenging.[2] Nonetheless, it is particularly important to diagnose them correctly because they can have very different prognoses and treatments than the lymphomas which they resemble.[1]

Plasmablastic lymphomas are aggressive and rare malignancies that usually respond poorly to

immunocompetent, i.e. to have no apparent defect in their immune system.[2] The malignant plasmablasts in more than half the cases of PBL are infected with a potentially cancer-causing virus, Epstein–Barr virus (EBV), and rare cases of PBL appear due to the plasmablastic transformation of a preexisting low-grade B-cell lymphoma.[3] One variant of PBL, sometimes termed plasmablastic lymphoma of the elderly, has a significantly better prognosis than most other cases of PBL.[4] The development of this variant appears due, at least in part, to immunosenescence, i.e. the immunodeficiency occurring in old age.[3]

Presentation

Plasmablastic lymphoma lesions are most commonly rapidly growing, soft tissue masses

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 with PBL often present with a history of being immunosuppressed due to prior organ transplantation, immunosuppressive drug treatment, or other causes.[9] This is particularly the case for individuals with HIV/AIDS-negative disease.[7] Individuals who develop PBL following organ transplantation are EBV/AIDS-positive in >85% of cases.[7] 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.[5] It is similarly clear that, on average, individuals who are elderly (>68 years)[4] or have HIV/AIDS-negative disease[7]
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

cytotoxic T-cells, and, possibly, block the infected cells' apoptosis (i.e. programmed cell death) response to injury.[12]

The predisposing conditions described in the previous paragraph can serve to enhance the ability of the plasmablasts in PBL to: avoid the host's

IL21R, and, as just indicated, PRDM1); and 6) reduced expression of genes characteristic of B-cells (e.g. CD20 and PAX5).[2]

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.[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]

Differential diagnosis

Various lymphomas can exhibit the microscopic appearance, including plasmablastic cells, and presentation of PBL. These lymphomas can usually be differentiated from PBL by further examinations of the plasmablasts for various marker proteins and determining other factors that favor the diagnosis of these lymphomas rather than PBL,[14] 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.[8]

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

IgM antibody and usually are not EBV-infected and therefore usually do not express this virus's EBER or BART RNAs.[8]

Primary effusion lymphoma

In contrast to PBL, the plasmablastic cells in primary effusion lymphomas, whether HHV8-positive or HHV8-negative, usually strongly express

CD45[8] 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.[1]

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,[8] 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.[1]

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.[8]

Treatment

The treatments for PBL have ranged from

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]

Experimental treatments

Given the unsatisfactory results of standard chemotherapy regimens, new treatments are being explored for use in PBL.

City of Hope Medical Center is examining the feasibility and safety of gene therapy that uses recombinant RNA to target a key element in the HIV genome in patients who have HIV/AIDs and a non-Hodgkins lymphoma, including patients with plasmablastic lymphoma.[16]

Prognosis

Overall, patients receiving one of the cited chemotherapy regimens have achieved

human immunodeficiency virus (i.e. HIV) have had remissions in their PDL lesions.[2]

History

A study by Green and Eversole published in 1989[17] 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[18] 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]

See also

References

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  15. ^ "A Multicenter, Open-Label Feasibility Study of Daratumumab with Dose-Adjusted EPOCH in Newly Diagnosed Plasmablastic Lymphoma". 18 May 2021. {{cite journal}}: Cite journal requires |journal= (help)
  16. ^ "Safety and Feasibility of Gene Transfer After Frontline Chemotherapy for Non-Hodgkin Lymphoma in AIDS Patients Using Peripheral Blood Stem/Progenitor Cells Treated with a Lentivirus Vector-Encoding Multiple Anti-HIV RNAs". 15 February 2021. {{cite journal}}: Cite journal requires |journal= (help)
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