Plasmablastic Lymphoma (PBL) is an uncommon but aggressive subtype of diffuse, large, B-cell lymphoma. The diagnosis of PBL is difficult because its features overlap with myeloma and lymphoma. The primary organs involved are usually the gastrointestinal system, lymph nodes, oral mucosa and sometimes the skin. It has a very aggressive disease course comprising relapses and refractoriness to chemotherapy. PBL is a very rare diagnosis, and hence there is no established standard to treat PBL.[rx]
Plasmablastic lymphoma (PBL) is an aggressive B-cell malignancy that highly correlated with human immunodeficiency virus (HIV).[rx] Recently, PBL is also identified as a subtype of non-Hodgkin lymphoma (NHL), and it is the estimated incidence of PBL accounts for approximately 5% of all HIV-positive NHL cases.[rx] Despite the strong relationship with HIV infection, PBL could also influence HIV-negative patients.[rx] Previously, a case report has recorded the characteristics of the first PBL case in an HIV-negative individual.[rx] It is speculated the HIV-negative PBL cases might derive from previous lymphoproliferative or autoimmune disorders.[rx] However, incidence of HIV-negative PBL is still unclear.
Lymphomas originate as somatic mutations in lymphocyte progenitor cells (B-cells, T–cells, or both). They are commonly classified as Hodgkin’s and non-Hodgkin’s lymphomas (NHL). Plasmablastic lymphoma (PBL) is classified under the category of ‘Mature B-cell neoplasms’, according to the 2016 revised classification of lymphoid neoplasms by the WHO.[rx] The NHL classification given by the WHO in 2001 has divided the lymphomas: (1) according to the cells of origin B-cell origin and T-cell/NK cell origin and (2) according to the Type-Indolent lymphomas and aggressive lymphomas.[rx]
The NHL are characterized by diffuse or nodular sheets of lymphocytes or lymphoblasts without the presence of Reed–Sternberg cells,[rx] whereas the Hodgkin’s lymphomas are B–cell-derived neoplasms in which the Reed–Sternberg cells form its pathognomonic feature.
Causes of Plasmablastic Lymphoma
It is more prevalent in patients with human immunodeficiency virus (HIV) and Ebstein-Barr virus (EBV) infections and patients with a suppressed immune system (such as patients on immunosuppressive medications). In the literature, there are rare cases of PBL described in patients who harbor none of these infections.[rx]
Symptoms of Plasmablastic Lymphoma
Plasmablastic lymphoma is strongly associated with HIV infection and other causes of immunodeficiency including organ transplantation and advanced age. Although the majority of cases occur in immunodeficient patients, approximately 35% of cases in a recent meta-analysis occurred in immunocompetent individuals. There is a pronounced male predominance, with approximately 70% to 80% of cases occurring in men. Although rare cases have been reported in the pediatric population, the majority occur in adults, with a median age at diagnosis of approximately 50 years. However, patients with HIV infection tend to have an earlier onset, with a median age at presentation of 38 years. In a small minority of cases, PBL is the initial presentation of HIV infection. The most common site of involvement in HIV-positive and HIV-negative patients is the oral cavity/jaw, followed by the gastrointestinal tract, lymph nodes, and skin. The distribution of disease occurring in the post-transplant setting differs in that lymph nodes and skin are the most common sites, with less frequent involvement of the oral cavity/jaw and gastrointestinal tract. Most cases of PBL present with advanced-stage disease (Ann Arbor stage III or IV).
Diagnosis of Plasmablastic Lymphoma
Histopathology
It is a high-grade neoplasm combining features of B-cell and plasma-cell neoplasms under the microscope. It appears as large cells with an immunoblastic appearance, with moderately abundant cytoplasm, central oval nuclei with prominent nucleoli. The immunophenotype for plasmablastic lymphoma is similar to that in plasma cell neoplasms, positive for CD79a, IRF-4/MUM-1, BLIMP-1, CD38, and CD138. The neoplastic cells are negative for B-cell markers CD19, CD20, and PAX-5; however, may be weakly positive for CD45. Few cases express T-cell markers CD2 or CD4. MYC is also expressed in half of the cases of PBL. Ki-67 proliferation index is usually high in most cases. EBV can be detected by EBV coded RNA expression, which is the most sensitive means to detect an EBV infection.
History and Physical
Patients usually present with B symptoms: fevers, weight loss, and night sweats. Since the oral cavity and the gastrointestinal (GI) tract are the most common sites of disease, weight loss is the most common presenting symptom. Lymphadenopathy is not commonly seen in these patients.
Evaluation
An evaluation includes a complete blood count (CBC), complete metabolic panel (CMP), lactate dehydrogenase (LDH), uric acid, hepatitis panel, HIV testing, EBV RNA testing, and a bone marrow biopsy to evaluate the bone marrow involvement.
Treatment of Plasmablastic Lymphoma
There is no standard chemotherapy protocol for the treatment of PBL. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine (CODOX-M/IVAC), or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) are possible options. Recently, a few studies have reported the potential value of the proteasome inhibitor bortezomib and thalidomide in PBL patients. The introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs) and CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials. The aim of this paper is to review the recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and outcome in patients with PBL.
Since PBL is very uncommon, it has been very difficult to establish a chemotherapy regimen which would be the standard of care. CHOP (Cyclophosphamide, Vincristine, Doxorubicin, and Prednisone) is considered inadequate due to the highly aggressive nature of the lymphoma. Other regimens such as dose-adjusted EPOCH or cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ alternating with ifosfamide, etoposide and high-dose cytarabine (IVAC) or hypofractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyper-CVAD) can be considered as treatment options for this highly aggressive lymphoma. Chemotherapy usually involves 6 to 8 cycles of these regimens. Most experts believe that EPOCH should be regarded as first in the treatment of PBL. A meta-analysis confirmed the benefit of EPOCH over CHOP in HIV-positive PBL. Intrathecal chemotherapy is not well-studied in these cases and can be offered on a case to case basis. In the literature, intrathecal methotrexate and high-dose cytarabine have been used in patients in the past. In the refractory setting other chemotherapeutic options such as bortezomib in combination with doxorubicin or lenalidomide can be considered although they are not well studied in this setting. They work well for myeloma, and since PBL has some of those immunophenotypic markers, these agents can be used as a last resort. Patients whose disease is chemosensitive should also be considered for an autologous stem cell transplant in first remission. Patients with HIV should begin or continue their anti-retroviral therapy under direction from an infectious disease specialist.
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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. 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 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 survival 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.[rx]
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