Stage, age, and EBV status impact outcomes of plasmablastic lymphoma patients: a clinicopathologic analysis of 61 patients

Plasmablastic lymphoma is an uncommon type of non-Hodgkin lymphoma with overlapping features of lymphoma and plasma cell neoplasms [7‐9]. Although earlier studies described neoplasms that, in retrospect, were likely examples of PBL [10], it was not until 1997 that PBL was recognized as a distinct entity. At that time, Delecluse et al. described 16 patients who had aggressive B cell lymphoma with plasmacytic differentiation characterized clinically by a predilection for the oral cavity and a high association with both HIV and EBV infection [11]. Many case reports and small case series have since been published, and the concept of PBL has been expanded to include similar tumors in non-oral sites arising in patients with other forms of immunodeficiency (HIV-negative) as well as immunocompetent patients [12, 13].

The high association of PBL with immunosuppression, oral cavity involvement, male gender, EBV infection, and aggressive clinical behavior [14] has been traditionally stressed in the literature. Several of these features were identified in our study group. The prevalence of oral/nasal involvement in the HIV-positive patients in our group was comparatively high (45 %), similar to findings reported by others [5, 13, 15]. In addition, EBV infection was also common (70 %) in our study group, with the highest relative incidence being in the PBL-HIV group as noted previously [5, 13]. However, our study group differed from other cohorts [13] in terms of having a comparatively low (20/50; 40 %) prevalence of HIV-positive patients.

There is no consensus yet regarding the optimal therapeutic approach for patients with PBL. Combination chemotherapy is commonly used, in addition to cART for HIV-positive patients. The current National Comprehensive Cancer Network guidelines recommend using intensive chemotherapy regimens such as CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate alternating with ifosfamide, etoposide, and high-dose cytarabine), dose-adjusted EPOCH, or hyper-CVAD [16]. This is based primarily on data derived from case reports and small case series. In addition, regimens similar to those used to treat plasma cell myeloma that incorporate bortezomib and consolidation with high-dose chemotherapy followed by autologous stem cell transplant have been suggested [17]. Castillo et al. recommended recently frontline EPOCH (+/− bortezomib) with intrathecal prophylaxis during each cycle of EPOCH followed by consolidative high-dose chemotherapy and autologous SCT in first remission, if possible [13]. In our study, intensive chemotherapy showed similar or even worse results due to treatment-related complications compared with CHOP, in line with results identified in other studies [15, 18]. In addition, there was no apparent benefit of hyper-CVAD-based therapy over other regimens on EFS and OS (p = 0.186, p = 0.404). On the other hand, the number of PBL patients in our study group who received autologous SCT is too small to draw any conclusions.

The outcome of PBL patients in this study was similar to that reported by others, with a median OS of 6.5 months [5, 19]. Favorable prognostic factors documented in the literature include low stage, achieving clinical remission with chemotherapy, age <60 years, oral location, and absence of MYC/IGH gene rearrangement [12]. Our univariate analysis showed that age <60 years and low stage were associated with better OS. Although the use of cART in HIV-positive patients has been reported to improve outcomes among PBL patients [15], our findings and those of others have not been able to confirm the prognostic value of cART [20]. Additionally, in contrast to previous reports, we were unable to confirm the detrimental effect of MYC gene rearrangements in our patient cohort [5, 13, 20].

Immunophenotyping plays an important role in establishing a diagnosis of PBL. The neoplastic cells are commonly positive for CD138, MUM1, and CD38, and they are negative for CD45, CD20, and PAX5. Cytoplasmic immunoglobulins are expressed commonly [1]. However, the immunophenotypic profile of PBL is variable. Four cases in our series were negative for CD138. In these cases, the diagnosis of PBL was supported by additional markers such as MUM1, monotypic cytoplasmic immunoglobulin light chain expression, and EBER positivity combined with negativity for CD20 and PAX5. Additional markers including PRDM1/BLIPM1 and XBP1s have also been shown to be helpful in identifying a plasmablastic immunophenotype [21]. As described by others [14], CD10 expression (typically absent in normal plasma cells) was detected in a sizeable subset of cases (13/32; 41 %) in our study group.

It is essential to exclude other neoplasms whose clinical, morphologic, or immunophenotypic features might overlap with PBL. Such differential diagnostic considerations include anaplastic (or pleomorphic) plasma cell myeloma, extramedullary plasmacytoma (anaplastic, plasmablastic, and plasmacytic), DLBCL with plasmacytoid differentiation, anaplastic lymphoma kinase (ALK)-positive large B cell lymphoma, extracavitary or solid variant of primary effusion lymphoma (PEL), DLBCL associated with HHV8-positive multicentric Castleman disease, and EBV-positive plasmacytoma in immunocompetent patients (EPIC). Patients with plasma cell myeloma usually have elevated serum and urine paraprotein, lytic bone lesions, and other evidence of end-organ damage, and their neoplastic cells are rarely positive for EBV. Eight PBL patients in this series had bone marrow involvement in addition to systemic disease. All those tested were negative for serum paraprotein. It is noteworthy that there is no consensus in the literature regarding the utility of serum or urine paraprotein in distinguishing PBL from plasma cell myeloma, and some reported patients with PBL had an M-protein [14]. Another important entity in the differential diagnosis of PBL is DLBCL with plasmacytoid differentiation wherein the absence of immunosuppression and lack of EBV infection are much more common than in PBL. ALK expression defines a form of DLBCL that often can exhibit plasmablastic features. The presence of ALK expression by immunohistochemistry and the identification of ALK gene rearrangement typically establish the diagnosis of ALK-positive large B cell lymphoma. Extracavitary/solid variant of PEL can closely resemble PBL, but these tumors by definition are positive for the HHV8 virus [22‐26]. DLBCL arising in HHV8-associated multicentric Castleman disease is similarly positive for HHV8 by definition [27]. The distinction between plasmablastic and anaplastic plasmacytoma and PBL is challenging. Similar to PBL, extramedullary plasmacytoma in general also frequently involves the head-and-neck region but, unlike PBL, only rare cases have been reported to be EBV-positive. The latter, recently termed EPIC, arise in the head-and-neck region or the gastrointestinal tract in immunocompetent patients [28]. EPIC lesions are composed of mature-appearing plasma cells. Unlike PBL, they lack a “starry-sky” pattern or cytologic atypia and often have a brisk CD8-positive cytotoxic T cell infiltrate in the background.

In summary, PBL is a rare neoplasm with variable clinical presentation and pathologic characteristics. Our study shows a higher frequency of primary extranodal involvement, HIV-negative status, and response to CHOP chemotherapy than has been commonly underscored in the literature. Our findings suggest that younger patients with low-stage disease treated with chemotherapy may have a favorable prognosis.