Continuing Education Activity

Plasmablastic lymphoma (PBL) is an uncommon but aggressive subtype of diffuse, large B-cell lymphoma classically seen in association with HIV infection. Despite significant advances in the field of lymphomas since this subtype was first described in a case series by Delecluse et al in 1997, PBL continues to pose challenges with diagnosis and management. The primary organs involved are the gastrointestinal system, lymph nodes, oral mucosa, and sometimes the skin. Patients usually present with extranodal masses involving the oral cavity or the gastrointestinal tract. Nodal disease without extranodal involvement is rare.

PBL is diagnosed primarily through histologic evaluation with or without genetics and immunophenotyping. However, diagnosing PBL is difficult due to overlapping features with plasmablastic myeloma and other high-grade lymphomas with plasmablastic morphology. Chemotherapy remains the cornerstone of the management of PBL and requires a multidisciplinary approach incorporating medical oncology and infectious disease experts. At the same time, PBL has an aggressive and relapsing course, which results in poor outcomes despite the institution of multi-drug intensive chemotherapy regimens and autologous stem cell transplantation. Optimal treatment strategies remain unclear partly because of the relative rarity of this disease. This activity for healthcare professionals is designed to enhance the learner's competence when managing plasmablastic lymphoma, equipping them with updated knowledge, skills, and strategies for timely identification, effective interventions, and improved care coordination, leading to better patient outcomes and reduced morbidity.

Objectives:

• Assess the pathophysiology of plasmablastic lymphoma.

• Identify the histopathologic findings of plasmablastic lymphoma.

• Select the appropriate evaluation methods to diagnose a patient with plasmablastic lymphoma.

• Implement modalities to improve care coordination among interprofessional team members to improve outcomes for patients affected by plasmablastic lymphoma.

Introduction

Plasmablastic lymphoma (PBL) is an uncommon but aggressive subtype of diffuse, large B-cell lymphoma. Despite significant advances in the field of lymphomas since this subtype was first described in a case series by Delecluse et al in 1997, PBL continues to pose challenges with diagnosis and management.[1] Patients usually present with extranodal masses involving the oral cavity or the gastrointestinal tract. Nodal disease without extranodal involvement is rare.[2] 

PBL is diagnosed primarily through histologic evaluation with or without genetics and immunophenotyping. However, diagnosing PBL is difficult due to overlapping features with plasmablastic myeloma and other high-grade lymphomas with plasmablastic morphology. Chemotherapy remains the cornerstone of the management of PBL and requires a multidisciplinary approach incorporating medical oncology and infectious disease experts. At the same time, PBL has an aggressive and relapsing course, which results in poor outcomes despite the institution of multi-drug intensive chemotherapy regimens and autologous stem cell transplantation.[3] These challenges are compounded by the rarity of this condition and the lack of large prospective trials to determine optimal management. 

Etiology

While the exact etiology of this disease remains unknown, there is abundant clinical data linking PBL with certain chronic viral infections. For instance, there is a strong association between PBL and HIV infection. In the seminal case series by Delecluse, 15 of the 16 patients described were HIV positive.[1] This association has been reinforced by subsequent studies, which estimate that nearly two-thirds of cases were HIV positive.[4] Furthermore, PBL has been described in other immunosuppressed but HIV-negative individuals, including those who have undergone solid organ or bone marrow transplantation or with underlying autoimmune disorders.[5] PBL is also strongly associated with Epstein-Barr virus (EBV) coinfection.[3] Several case series support an association between PBL and HHV-8 infection.[6][7]

Epidemiology

The actual incidence of HIV-positive and HIV-negative PBL remains unknown.[3] However, studies have estimated that PBL comprises about 2% of all HIV-related lymphoma cases.[8] Conversely, a large US-based case series found that 69% of patients with PBL were HIV positive, confirming the bidirectional association between these conditions.[4] Interestingly, there appears to be a male predominance in the HIV-positive population, while the HIV-negative population has a female predominance.[3][2] Male predominance is also seen in posttransplant PBL and pediatric PBL.[3] It should be noted that pediatric PBL is rare and predominantly seen in the setting of HIV infection.[2][9][10] The median age of diagnosis is 42 years in HIV-positive individuals and 55 years in the HIV-negative population. The poor prognosis of this lymphoma is reflected in the median survival of 6 to 11 months.[11]

Pathophysiology

The pathophysiology of PBL is incompletely understood, but the plasmablast is believed to be the cell of origin. The plasmablast is an activated B cell that has undergone somatic hypermutation and class-switching recombination but has not yet become a mature plasma cell. Plasmablasts are a common histopathologic finding seen in reactive lymph nodes in individuals with HIV and EBV infection. These cells are normally tightly regulated by proapoptotic signals and differentiation-promoting transcription factors. EBV-derived antigens can disrupt this process by protecting B cells from Fas-mediated and B-cell receptor (BCR) mediated apoptosis.[12][13] Another important component in the pathophysiology of this disease is the MYC oncogene. Rearrangements of the MYC gene leading to amplification can be seen in up to 45% of patients with PBL.[14] MYC overexpression allows B cells to overcome negative regulators such as BCL6 and BLIMP1 and develop into plasmablasts but simultaneously blocks further differentiation into mature plasma cells by downregulating PAX5.[3] Finally, PBL is also associated with mutations and deletions of the tumor suppression gene TP53 and mutations in the regulatory JAK-STAT pathway, which likely contribute to the pathophysiology of the disease.[15][16]

Histopathology

Plasmablastic lymphoma is characterized by histopathologic features that overlap with other high-grade lymphomas and myeloma. This appearance can be challenging for the pathologist and can be misdiagnosed if a careful workup is not performed. The typical appearance of PBL is that of sheets of large cells with an immunoblastic appearance that effaces the normal tissue architecture. These cells have moderately abundant cytoplasm and central oval nuclei with prominent nucleoli. They can also exhibit a "starry sky pattern" with tingible body macrophages and mitotic figures. Extranodal PBL often demonstrates a more mature plasmacytic appearance with basophilic cytoplasm, perinuclear hof, and an eccentric nucleus that can closely mimic myeloma.[17] 

The immunophenotype for plasmablastic lymphoma is also similar to that of plasma cell neoplasms with positive immunohistochemical (IHC) staining for CD79a, IRF-4/MUM-1, CD38, and CD138. Unlike other B-cell lymphomas, PBL is usually negative for CD19, CD20, and PAX-5 but may be weakly positive for CD45. Therefore, immunophenotyping can also aid in the diagnostic evaluation of PBL.[2] PBL can also express T-cell markers CD2 or CD4 in a few cases. MYC overexpression is seen in about half of all cases. The Ki-67 proliferation index is invariably high and often exceeds 90%.[18] The cells can also be positive for CD30, which has implications for using brentuximab vedotin.[18][19][18][20] EBV can be detected by EBV-encoded RNA (EBER) expression in the majority of patients but is widespread in HIV-positive individuals.[21] BCL2 and BCL6 overexpression is not seen with PBL, which can help distinguish it from triple hit lymphoma and Burkitt lymphoma, respectively.[11]

History and Physical

Patients usually present with extranodal masses involving the oral cavity or the gastrointestinal tract. Nodal disease without extranodal involvement is rare.[2] Other extranodal sites include the genitourinary tract, the central nervous system, the lungs, the liver, bones, nasal cavities, and orbits. Most patients present with advanced disease in stage III or IV. Bone marrow involvement is common, with estimates ranging from 27% to 40% of HIV-positive individuals and 25% of HIV-negative individuals.[3][22][23]

Evaluation

PBL is diagnosed primarily through histologic evaluation with or without genetics and immunophenotyping. PBL is characterized by histopathologic features that overlap with other high-grade lymphomas and myelomas. Therefore, additional diagnostic testing may be necessary for diagnostic confirmation of PBL. Immunophenotyping can aid in diagnosing PBL as staining can help differentiate this condition from other plasma cell neoplasms.[2] Genetic analysis through fluorescence in-situ hybridization (FISH) analysis identifying a mutation of the MYC locus at 8q24 also supports a PBL diagnosis.[2] (Refer to the Histopathology section for more information on the histologic findings of Plasmablastic Lymphoma).

Evaluation should be performed as with other high-grade lymphomas. Additional laboratory tests that should be performed include a complete blood count (CBC), which often shows anemia. A complete metabolic panel (CMP), lactate dehydrogenase (LDH), and uric acid should be performed to screen for possible tumor lysis syndrome. Hepatitis viral panel, HIV testing, and EBV RNA testing should be checked. Bone marrow biopsy should be performed to evaluate for bone marrow involvement. PET CT scan can be performed to determine anatomic spread and stage.

Treatment / Management

Chemotherapy remains the cornerstone of the management of PBL and requires a multidisciplinary approach incorporating medical oncology and infectious disease experts. Surgery has no role in the treatment of PBL as with other aggressive lymphomas. Radiation therapy is restricted to consolidation in patients who are responding to systemic chemotherapy. 

Because of PBL's rarity, there is no consensus regarding systemic therapy; however, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) are commonly used. There is limited evidence to support a preferred chemotherapy regimen.[2] Dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) are preferred in national guidelines.[2] Chemotherapy usually involves 6 to 8 cycles combined with intrathecal chemotherapy in selected cases.[3] Patients who enter remission after induction chemotherapy should also be considered for consolidation with an autologous stem cell transplant.[24] Patients with HIV should begin or continue their anti-retroviral therapy under the direction of an infectious disease specialist.[3]

Differential Diagnosis

The following conditions, with their characteristic immunophenotypic and cytogenetic features, should be considered in the differential of PBL:

• Plasmablastic myeloma: positive plasma cell markers including CD38, CD138, and IRF4/MUM1, presence of monoclonal serum immunoglobulin, elevated serum free light chains, renal dysfunction, lytic bone lesions

• Extraosseous plasmacytoma with plasmablastic morphology: positive plasma cell markers including CD38, CD138, and IRF4/MUM1, negative for MYC rearrangement, negative EBER

• Anaplastic large cell lymphoma kinase (ALK) positive large B cell lymphoma: positive plasma cell markers including CD38, CD138, and IRF4/MUM1, positive ALK by immunohistochemistry, presence of t(2;17) or t(2;5)

• Extracavitary primary effusion lymphoma: positive pan B cell markers, including CD19, CD20, and PAX5, positive for HHV8

• HHV8 positive diffuse large B cell lymphoma: positive for IRF4/MUM1, positive for HHV8, negative EBER

• Immunoblastic diffuse large B cell lymphoma: positive pan B cell markers including CD19, CD20, and PAX5, negative for plasma cell markers, EBER may be positive, MYC rearrangements occasionally present

Surgical Oncology

There is no role for surgery in the management of PBL. Surgery is typically not recommended for any form of lymphoma.

Radiation Oncology

Radiation therapy in PBL is limited to case reports and single-institution studies.[25] Radiation therapy can be used in the refractory setting but is seldom used in the up-front treatment of PBL.[26]

Pertinent Studies and Ongoing Trials

Several ongoing trials are pertinent to PBL. These are listed below, along with the phase and current status.

• Belantamab mafodotin in plasmablastic lymphoma and ALK+ large B-cell lymphoma (NCT04676360, phase 2, recruiting)
• Pomalidomide and dose-adjusted EPOCH with and without rituximab for HIV-associated lymphomas (NCT05389423, phase 1, recruiting)
• A study of daratumumab and dose-adjusted EPOCH in plasmablastic lymphoma (NCT04139304, phase 1, recruiting)

Medical Oncology

The relative rarity of this lymphoma subtype has meant that robust prospective evidence is not available. However, retrospective studies support the use of aggressive multi-drug chemotherapy regimens similar to other high-grade lymphomas. Although widely used in other large cell lymphomas, the CHOP regimen (ie, cyclophosphamide, doxorubicin, vincristine, and prednisone) is considered inadequate in patients with PBL and therefore is not recommended.[3] Instead, current guidelines, including those published by the National Comprehensive Cancer Network (NCCN), recommend the use of dose-adjusted EPOCH (ie, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone).[2] Other regimens that have been suggested include cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, and cytarabine (CODOX-M/IVAC) and hyperfractionated cyclophosphamide, vincristine, and doxorubicin (hyper-CVAD), and dexamethasone alternating with methotrexate and cytarabine. Few studies compare these regimens, but at least one study showed superior overall survival with EPOCH compared to CHOP.[27] Another emerging regimen combining bortezomib with EPOCH has shown promising results in smaller studies but awaits confirmation from large-scale studies.[28][29]

The role of intrathecal therapy for primary prophylaxis against central nervous system involvement is uncertain in patients with PBL because of the lack of evidence. However, given the adverse features, including a high proliferation rate, frequent extranodal involvement, association with HIV infection, and presence of MYC rearrangements, considering intrathecal therapy in most patients with PBL is reasonable.

Autologous stem cell transplantation can be considered as consolidation in patients who are considered fit for such procedures as PBL tends to relapse after induction chemotherapy. However, the evidence to support this approach is limited.[30][24] The relationship between antiretroviral therapy and outcomes of PBL in HIV-positive individuals remains unclear. Two studies showed improved survival with antiretroviral therapy, but another did not.[31][32][33]

Staging

The Ann Arbor staging system is used for staging PBL, similar to other lymphomas.[34] See StatPearls' companion topic, "Lymphoma," for information on this staging system.

Prognosis

Plasmablastic lymphoma carries a dismal prognosis. Untreated PBL is associated with a median survival of 3 months in HIV-positive individuals and 4 months in HIV-negative individuals.[4] Treatment with chemotherapy improves survival with median numbers of 10 months, 11 months, and 7 months in patients with HIV-positive, HIV-negative, and post-transplant PBL, respectively.[21] More recent data using dose-adjusted EPOCH showed 2-year survival rates of 47.4%, reflecting improving outcomes with aggressive chemotherapy regimens.[27] Nevertheless, these numbers reflect the poor prognosis of this disease and the urgent need for more effective therapy.

Complications

While receiving chemotherapy, these patients are at increased risk of developing complications such as immunosuppression, cytopenias, neutropenic fever, alopecia, infertility, neuropathy, and gastrointestinal toxicities such as nausea, vomiting, and diarrhea. These complications typically resolve after the completion of chemotherapy. Growth factor support with pegfilgrastim is often used to mitigate infectious complications.

Postoperative and Rehabilitation Care

Patients undergoing chemotherapy treatment might benefit from a rehabilitation program focused on physical and occupational therapy to stay active while undergoing treatment.

Consultations

Radiation oncology may be consulted to consider consolidative radiation in selected patients with PBL. Palliative care specialists should also be consulted early on during the treatment of PBL. Studies have shown that involving palliative care soon improves the quality of life in most cancer patients.[35] Infectious disease specialists must be consulted for antiretroviral therapy in HIV-positive patients with PBL, as well as for assistance with the management of infectious complications of chemotherapy.

Deterrence and Patient Education

Patients should be educated about the poor prognosis associated with this diagnosis. Before beginning treatment, they must also be counseled about the possible adverse effects of the intensive chemotherapeutic regimes. Fertility preservation must be offered to all male patients as well as women of childbearing age. Patients should also be educated about the association between this lymphoma subtype and HIV infection and encouraged to undergo testing for HIV so that they can be offered appropriate antiretroviral therapy. Patients should be encouraged to receive vaccinations for influenza and vaccinations and boosters for COVID-19 in a timely fashion because of the increased risk of severe infection with these pathogens after receiving chemotherapy. However, chemotherapy should not be delayed solely for vaccination because of the aggressive nature of this lymphoma.

Pearls and Other Issues

Plasmablastic lymphoma is a rare and aggressive subtype of lymphoma associated with a poor prognosis, especially when left untreated. Plasmablastic lymphomas are often seen in association with HIV infection and other immunosuppressed states. They are also linked with EBV infection.

Diagnosing this condition is challenging for pathologists because of its overlapping features with other plasmablastic malignancies. Making an accurate diagnosis is paramount as the treatment strategy for PBL differs from that used for other plasmablastic diseases. 

Multi-drug systemic chemotherapy is the standard of care for PBL. The relative rarity of this disease has meant that there is limited evidence to support the use of any individual regimen. Still, expert opinion and national guidelines favor the use of dose-adjusted EPOCH.

Concurrent use of intrathecal chemotherapy should be considered for prophylaxis against central nervous system involvement. Consolidation with autologous stem cell transplantation should be considered in fit patients in first remission with good response to induction chemotherapy.

Whether timely antiretroviral therapy can prevent this disease is unclear. However, studies suggest that such treatment improves outcomes in HIV-positive individuals with PBL.

Enhancing Healthcare Team Outcomes

Plasmablastic lymphoma poses many challenges in its management. These challenges begin with making the diagnosis and continue during disease management. The medical oncologist typically takes the lead in managing PBL because of the central role of systemic chemotherapy. However, a multidisciplinary approach is essential with effective communication between the medical oncologist, the pathologist, and the radiologist. The oncologist must also coordinate care with infectious disease physicians managing comorbid HIV infection as well as infectious complications of chemotherapy. Palliative care specialists and social workers must be involved in providing the patient with supportive care needs. The availability of an onco-pharmacist is essential for accurate dosing of chemotherapy, especially when using a complicated regimen like dose-adjusted EPOCH. Finally, well-trained chemotherapy nurses are needed to administer the drugs to the patient safely. To maximize effective communication between these healthcare practitioners, patients should be diagnosed with PBL and discussed at a multidisciplinary tumor board.