Plasmablastic Lymphoma: A Review of Clinicopathologic Features and Differential Diagnosis

Plasmablastic lymphoma is strongly associated with HIV infection and other causes of immunodeficiency including organ transplantation and advanced age.⁶  Although the majority of cases occur in immunodeficient patients, approximately 35% of cases in a recent meta-analysis occurred in immunocompetent individuals.^2,7  There is a pronounced male predominance, with approximately 70% to 80% of cases occurring in men.²  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.¹  However, patients with HIV infection tend to have an earlier onset, with a median age at presentation of 38 years.⁸  In a small minority of cases, PBL is the initial presentation of HIV infection.⁶  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.⁶  The distribution of disease occurring in the posttransplant 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.^2,6  Most cases of PBL present with advanced-stage disease (Ann Arbor stage III or IV).² 

The morphologic features of PBL vary slightly depending on the site of disease. Most cases of PBL arising in the oral cavity/jaw in the setting of HIV infection display diffuse sheets of large immunoblastic cells with abundant cytoplasm, vesicular chromatin, and prominent, often centrally placed nucleoli (Figure 1, A and B).^1,9  In contrast, cases of PBL arising in lymph nodes and extranodal sites other than the oral cavity/jaw in HIV-negative patients tend to display a greater degree of apparent plasmacytic differentiation including eccentric nuclei, smaller nucleoli, and frequent paranuclear hofs.⁹  Frequent mitotic figures, apoptotic bodies, and intermixed tingible body macrophages (a “starry-sky” appearance) are also characteristic of PBL, regardless of site. Confluent areas of necrosis are also occasionally present.¹⁰ 

The characteristic immunophenotype seen in PBL includes expression of markers of plasmacytic differentiation including CD138, CD38, and IRF4/MUM1 (Figure 1, C).^1,10  In contrast, expression of pan–B-cell markers including CD20 and PAX-5 is usually absent.¹⁰  However, CD79a expression is often seen in PBL, whereas CD45 (LCA) is usually weakly expressed or absent. Expression of CD4, CD10, CD30, and/or CD56 has also been reported in a subset of cases.^6,10,11  The Ki-67 proliferation index usually exceeds 90%.¹²  In situ hybridization for Epstein-Barr virus (EBV)–encoded RNA is positive in the majority of cases (Figure 1, D). However, the proportion of cases that are positive for EBV-encoded RNA varies according to the patient's immune status. Approximately 75% of cases occurring in the setting of AIDS are positive for EBV.²  About two-thirds of cases arising in transplant recipients are positive for EBV, whereas only about half of cases occurring in immunocompetent individuals are EBV-positive.² 

The most common cytogenetic abnormality seen in PBL is rearrangement of the MYC gene at 8q24, with the immunoglobulin genes acting as the most frequent translocation partners.^2,13  Approximately half of PBL cases contain a MYC rearrangement, but this proportion is somewhat higher in EBV-positive tumors than in those that are negative for EBV.¹³  In addition to MYC rearrangements, gains of MYC are also occasionally seen in PBL.¹³  Not surprisingly, many cases of PBL are also positive for MYC by immunohistochemistry.⁶ 

The most challenging consideration in the differential diagnosis of PBL is distinction from plasmablastic (anaplastic) plasma cell myeloma, as the morphologic and immunophenotypic features of these 2 entities are virtually identical.¹⁰  The distinction usually rests on correlation with clinical, laboratory, and radiographic findings. Features such as renal dysfunction, a significant paraprotein, osteolytic lesions, hypercalcemia, and diffuse bone marrow involvement favor a diagnosis of plasmablastic plasma cell myeloma.¹⁴  In contrast, EBV positivity in the neoplastic cells, association with HIV infection, and a high Ki-67 proliferation index support a diagnosis of PBL.

Although primary effusion lymphoma (PEL) usually presents as a serous effusion, rare cases of PEL present as a solid tumor mass.^15,16  Such cases are referred to as extracavitary PEL, and must be considered in the differential diagnosis of PBL. Like PBL, extracavitary PEL is strongly associated with HIV infection and displays immunoblastic and/or plasmablastic morphology. Primary effusion lymphoma also displays an immunophenotype that closely resembles that of PBL, with expression of plasma cell–related markers, absence of pan–B cell antigens, and frequent positivity for EBV.^17,18  However, extracavitary PEL can be readily distinguished from PBL by its universal association with human herpesvirus 8, a feature not seen in PEL.

ALK-positive large B-cell lymphoma is a rare type of B-cell lymphoma that, similar to PBL, is composed of large immunoblastic cells that express plasma cell-related antigens, lack expression of pan B-cell markers, and typically show weak or absent CD45 expression (Figure 2, A through C).¹⁹  As the name implies, the neoplastic cells in ALK-positive large B-cell lymphoma are positive for ALK in a granular, cytoplasmic staining pattern when assessed by immunohistochemistry, a feature that allows for easy distinction from PBL (Figure 2, D). In contrast to ALK-positive anaplastic large cell lymphoma, ALK-positive large B-cell lymphoma is typically negative for CD30. The most common translocation present in ALK-positive large B-cell lymphoma is the t(2;17)(p23;q23) rather than the t(2;5)(p23;q35) that is most often seen in ALK-positive anaplastic large cell lymphoma.^20–22 

Because of the immunoblastic appearance that is frequently seen in PBL, immunoblastic diffuse large B-cell lymphoma is also a differential diagnostic consideration (Figure 3, A through C). However, the expression of pan–B-cell antigens (ie, CD20, CD19, and PAX-5) in immunoblastic diffuse large B-cell lymphoma makes this distinction reasonably straightforward, as PBL is usually negative for these markers (Figure 3, D).

The prognosis of PBL is poor, with an overall median survival of 8 months.²  Although HIV-negative patients are reported to have a worse prognosis in some series, other studies, including a recent large meta-analysis of 277 PBL patients, report no significant difference in the overall survival of HIV-positive and HIV-negative patients.^2,12,23,24  CD45 expression is reported to be associated with a better prognosis, whereas the presence of a MYC aberration predicts a worse prognosis.^2,25  The effect of EBV status on prognosis is unclear, as EBV positivity is reported in some studies to be associated with a better prognosis, whereas other studies claim that EBV status is not predictive of outcome.^2,26  As would be expected, advanced stage and poor performance status are associated with worse outcomes.²⁵ 

In contrast to treatment for most cases of DLBCL, chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone is generally considered to be inadequate therapy for PBL.¹²  Instead, more intensive regimens such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine are typically used.¹²  Because PBL displays a degree of plasmacytic differentiation, agents that are used in the treatment of plasma cell myeloma (eg, bortezomib and lenalidomide) have also been used to treat PBL with some success.^27–30  In the uncommon circumstance that PBL expresses CD20, rituximab has been added to the chemotherapy regimen.²⁸  Small studies have reported a possible benefit to using autologous stem cell transplantation in the setting of relapsed and refractory disease, but prospective randomized trials are lacking.³¹ 

Plasmablastic lymphoma is a rare, aggressive neoplasm that most commonly occurs in the setting of HIV infection and is associated with a dismal outcome in most cases. Awareness of this entity is essential in the diagnosis of a suspected lymphoma that lacks expression of CD45 and markers of B-cell or T-cell lineage. Appropriate use of immunohistochemistry and correlation with clinical, laboratory, and radiographic findings are crucial in establishing the correct diagnosis.