Primary central nervous system plasmablastic lymphoma in an HIV-positive patient

Abstract

Plasmablastic lymphoma (PBL) is a rare subtype of diffuse large B-cell lymphoma, highly associated with HIV and Epstein-Barr virus (EBV) infections. It commonly presents in extranodal sites, often an oral mass, but reports of primary central nervous system PBL (PCNSPBL) are exceedingly rare. Here, we report on a 33-year-old man with newly diagnosed HIV infection who presented with acute-onset unilateral visual disturbance and was found to have biopsy-proven PCNSPBL. The neoplastic cells displayed a plasmacytoid appearance, with the expression of CD38 and CD138, and were positive for EBV by in situ hybridisation for EBV-encoded RNA. Systemic workup revealed the presence of Kaposi sarcoma, but no evidence of lymphoma. He is currently being treated with high-dose methotrexate, as well as antiretroviral therapy for his HIV infection, and has achieved a complete response.

Background

First identified by Delecluse in 1997,¹ plasmablastic lymphoma (PBL) is a rare and aggressive subtype of diffuse large B-cell lymphoma (DLBCL), with B-cell immunoblasts and a plasma cell phenotype. PBL most commonly presents in HIV-infected patients, accounting for about 2% of HIV-associated lymphomas, with rare reports of incidence in other immunosuppressed patients or those with lymphoproliferative or autoimmune disorders.² It has a predilection for extranodal sites, especially the oral cavity.¹ PBL may involve the central nervous system (CNS), but primary CNSPBL (PCNSPBL) is exceedingly rare.

Case presentation

A 33-year-old man with a recent diagnosis of co-infection with HIV and syphilis presented with right eye blurriness and floaters. At the time of his HIV diagnosis 3 months earlier, he had presented with similar symptoms in the left eye and was diagnosed with retinal necrosis; however, he did not follow-up with either a retina or infectious disease specialist, and at the time of presentation, he was not being treated for HIV or syphilis.

Investigations

His CD4 count was 4/μL, and PCR for HIV detected 343 730 copies/mL. Rapid plasma reagin and syphilis-specific antibody tests were positive. PCR for human herpesvirus 8 (HHV-8) showed 27 100 copies/mL. A lumbar puncture performed on admission showed 4 WBCs, zero RBCs, protein of 50 mg/dL, glucose of 52 mg/dL, and negative cytology. Cerebrospinal fluid (CSF) flow cytometry demonstrated a small number of CD8-positive lymphocytes but no evidence of lymphoma. CSF Venereal Disease Research Laboratory (VDRL) titre was elevated at 1:32 and cytomegalovirus (CMV) immunoglobulin (Ig)G antibody was positive. He was treated simultaneously for neurosyphilis and CMV infection. A brain MRI then revealed enhancing lesions within the right frontal, temporal and occipital lobes, as well as right thalamus, caudate head and the splenium of the corpus callosum (figure 1). An image-guided biopsy of the temporal lesion revealed a dense proliferation of plasmacytoid and plasmablastic cells, CD20-negative, lambda light chain restricted and strongly positive for Epstein-Barr virus (EBV)-encoded RNA (EBER) (figure 2). Immunohistochemistry for anaplastic lymphoma kinase (ALK) was negative. Flow cytometry of the tissue demonstrated a population of monoclonal cells with a plasma cell phenotype, positive for CD19, CD38, CD45 (moderate) and CD138, and negative for CD20, CD22, CD56, CD117, and surface kappa and lambda Ig light chains. A bone marrow biopsy showed normocellular marrow (60% cellularity) with maturing trilineage haematopoiesis and no evidence of lymphoma. CT scan of the chest, abdomen and pelvis demonstrated scattered bilateral lung nodules and opacities, concerning for infectious or inflammatory aetiology, but no pathological lymphadenopathy. Lactate dehydrogenase was elevated to 387 IU/L (normal range 125–240 IU/L). He was diagnosed with PCNSPBL.

Figure 1.

MRI images at the time of presentation. Axial T1-weighted images showing enhancing lesions in the (A) corpus callosum and (B) right temporal and occipital regions. Diffusion-weighted images (C) show diffusion restriction of the corpus callosum lesion, confirmed on the apparent diffusion coefficient map (D).

Figure 2.

(A) H&E staining of the tumour showing abnormal plasmacytoid cells with eccentric nuclei and abundant cytoplasm. (B) Positive staining for EBER. In situ hybridisation for immunoglobulin kappa (C) and lambda (D) light chains show monoclonal lambda expression in the lymphoma cells. EBER, Epstein-Barr virus-encoded RNA.

Differential diagnosis

The differential diagnosis for PBL includes other BCLs and plasma cell disorders, including plasmablastic (anaplastic) myeloma (table 1). An underlying history of renal disease, hypercalcaemia, monoclonal paraproteinaemia or bone marrow involvement favours myeloma. HIV or EBV positivity favours PBL. Primary effusion lymphoma (PEL) is another BCL associated with HIV³ and immunosuppression⁴ that can present as an extracavity mass with a similar immunophenotype with plasma cell markers and loss of pan-B-cell antigens and may be positive for EBV. However, PEL is invariably associated with human herpesvirus 8 (HHV-8),³ unlike PBL. In a review of 590 PBL cases, none were HHV-8-positive.² Similarly, multicentric Castleman’s disease can be distinguished from PBL on the basis of HHV-8 positivity. Our patient did have HHV-8 viraemia, but his pathology was consistent with PBL. The HHV-8 was likely implicated in his Kaposi sarcoma. ALK-positive LBCL (ALK+LBCL) displays an immunoblastic or plasmablastic phenotype similar to PBL, lacking pan-B-cell antigens and showing variable CD45 expression.⁵ The key to differentiating it from PBL is immunohistochemistry for ALK, which will be positive in ALK+LBCL and always negative in PBL.^{2 5} ALK+LBCL is rarely associated with HIV and never positive for EBV.⁵ Other BCLs on the differential diagnosis include EBV-positive DLBCL, not otherwise specified (EBV +DLBCL, NOS), and, in the case of patients like ours with CNS involvement, primary CNS lymphoma (PCNSL). Both EBV +DLBCL, NOS and PCNSL can be distinguished easily from PBL on the basis that the former two express pan-B-cell antigens.^{6 7} Poorly differentiated carcinoma metastatic to the CNS may also appear similar to PCNSPBL, though would not be expected to express plasma cell markers or be positive for EBV

Table 1.

Differential diagnosis of PBL

Entity	Differentiating features
Plasmablastic (anaplastic) myeloma	Hypercalcaemia, renal disease, monoclonal paraproteinaemia, bone marrow involvement favour plasmablastic myeloma Rarely HIV-positive or EBV-positive
PEL	Invariably associated with HHV-8 Most commonly involves serosal surfaces (pleura, pericardium, peritoneum)
Multicentric Castleman’s disease	HHV-8-positive
ALK-positive LBCL	Positive immunohistochemistry for ALK Rarely associated with HIV, and never EBV-positive
EBV-positive DLBCL-NOS	Expresses pan-B-cell antigens
PCNSL	Expresses pan-B-cell antigens
Metastatic poorly differentiated carcinoma	Rarely expresses plasma cell markers Not EBV-positive

ALK, anaplastic lymphoma kinase; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; HHV-8, human herpesvirus 8; LBCL, large B-cell lymphoma; NOS, not otherwise specified; PBL, plasmablastic lymphoma; PCNSL, primary CNS lymphoma; PEL, primary effusion lymphoma.

Treatment

Antiretroviral therapy (ART) was started, and we initiated chemotherapy with high-dose intravenous methotrexate, at 3.5 g/m².

Outcome and follow-up

The patient is alive at this time, >9 months following diagnosis and is still undergoing therapy with high-dose methotrexate. His brain MRI following nine cycles of high-dose methotrexate showed a complete response in the right thalamic lesion and a very good response in the frontal and parietal–occipital lesions. A repeat MRI weeks after starting chemotherapy showed new mesenteric and retroperitoneal lymphadenopathy, and subsequent biopsy revealed changes consistent with early Kaposi sarcoma, but no morphological evidence of lymphoma. The most recent PCR for HIV showed <20 copies/mL.

Discussion

PBL, first described in 1997¹ and currently a defined subtype of lymphoma by the WHO since 2001, is an aggressive lymphoma of mature B cells with an immunophenotype resembling plasma cells.⁸ It is highly associated with HIV, with approximately 50%–70% of reported PBL cases related to HIV infection.^9–11 Within the category of HIV-associated lymphomas, it is rare, accounting for only about 2% of the total,¹² though it is considered an AIDS-defining malignancy. Among HIV-negative patients, solid organ or haematopoietic stem cell transplantation is the major risk factor, as these are associated with approximately 6%–12% of PBL cases.^{2 9} PBL is strongly linked with EBV infection. In the largest reviews of cases, 66% of PBL cases demonstrated EBV positivity on the basis of EBER in situ hybridisation or immunohistochemical staining of EBV-encoded latency membrane protein 1 (LMP1).^{2 9} The incidence was even greater in HIV-positive patients, in whom 74%–75% of PBL cases were EBV-positive.^{2 9 13} PBL has a strong male predominance, 70%–80% of cases occur in men, and is a disease primarily of adults, with a median age at onset of 46 years.⁹

PBL has a strong predilection for the oral cavity, though other extranodal sites and nodal sites are reported. The CNS can be involved; however, it more commonly occurs as a secondary phenomenon.^{14 15} Our patient represents one of only seven cases of PCNSPBL reported in the literature; the characteristics of previously reported cases can be seen in table 2. The majority (4/6) of these cases have occurred in HIV-positive patients. In situ hybridisation for EBV was positive in two of five cases for which it was reported. Our patient was HIV-positive, and the tumour was positive for EBER.

Table 2.

Previously reported cases of primary CNSPBL

	Year	No of cases	HIV	EBV	CNS location	CSF	Treatment	Outcome (time to follow-up)
Shuangshoti et al 28	2008	1	+	−	Basal ganglia	+ (Cytology)	MTX (IT); planned WBRT	Unknown: lost to follow-up
Ustun et al 14	2009	1	+	−	Frontal lobe	Not reported	WBRT, steroids	Deceased (3 days)
Urrego et al 15	2011	1	+	+	Frontal lobe	+ (Cytology, flow cytometry)	None	Unknown:entered hospice care
Mathews et al 29	2011	1	+	Unknown	Leptomeningeal	+ (Cytology, flow cytometry)	Thiotepa (IT)	Unknown: not reported
Zhang et al 30	2012	1	−	+	Frontal–parietal lobe	Not reported	R-CHOP	Alive (11 months)
Romero et al 18	2016	1	−	−	Frontal lobe	+ (Flow cytometry)	HD MTX (IV), cytarabine, MTX (IT), WBRT	Alive (11 months)
Current		1	+	+	Temporal lobe, occipital lobe, thalamus, caudate head	–	HD MTX (IV)	Alive (9 months)

CNS, central nervous system; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; HD, high dose; IT, intrathecal; IV intravenous; MTX, methotrexate; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; WBRT, whole brain radiation therapy.

Pathologically, PBL has a characteristic appearance and immunophenotype that distinguishes it from DLBCL, plasma cell dyscrasias or—in the case of our patient—PCNSL. Most PBLs display sheets of immunoblastic cells with abundant cytoplasm and prominent nucleoli.¹⁶ Nodal and non-oral extranodal PBLs may have more of a plasmacytoid appearance, with eccentric nuclei and small nucleoli.¹⁶ PBLs of all types tend to have frequent mitotic figures, apoptotic bodies and tingible body macrophages, lending it a ‘starry sky’ appearance.¹⁷ Immunophenotypically, PBL typically expresses plasma cell markers such as CD38, CD138 and MUM1. The B-cell markers CD20 and PAX-5 are usually absent.¹⁷ Our patient’s flow cytometry results matched this pattern. CD79a is often positive, and though leucocyte common antigen/CD45 is often negative, it may be weakly expressed, as was the case in our patient.

The prognosis of PBL is poor, with a median overall survival of 10–15 months in HIV-positive patients,^{9 11 13} and 9–11 months in HIV-negative patients.^{9 11} In the few reported cases of PCNSPBL, survival is even more dismal, ranging from 3 days to 11 months.^{14 18} An intermediate-to-high International Prognostic Index (IPI) score has been associated with worse outcomes in HIV-positive patients with PBL.^{19 20} EBV positivity has not consistently been shown to impact the survival in patients with PBL;10 11 13 19 however, in one large meta-analysis, it was found to be associated with improved survival.⁹ Other factors that portend a worse outcome include ECOG performance status of ≥2,^{19 20}age >60,^{11 19} bone marrow involvement, high Ki-67^{10 11} and MYC rearrangement.²⁰ The major factor that predicts longer survival is the achievement of a complete response (CR) or partial response (PR) to therapy.¹⁰ Use of ART was also associated with improved outcomes in HIV-positive patients.^{10 21}

The management of patients with PBL is challenging, as there is no consensus first-line therapy for the disease. Although cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)/CHOP-like regimens have been used, the National Comprehensive Cancer Network (NCCN) guidelines recommend against CHOP²² because of poor outcomes with this regimen. Rather the NCCN guidelines recommend more aggressive regimens such as dose-adjusted EPOCH, CODOX-M/IVAC or hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine. However, in the few reviews including patients treated with these aggressive regimens, no clear survival advantage was observed.^{10 19 20} Consensus opinion is that intrathecal therapy should be given as CNS prophylaxis, considering the high proliferation rate and frequent extranodal involvement.² Autologous stem cell transplantation (SCT) for PBL has been reported in case series as a consolidation strategy after high-dose chemotherapy, both for HIV-positive²³ and HIV-negative patients,²⁴ with promising results. A large European review of 24 patients with PBL who received autologous SCT demonstrated a 2-year overall survival of 53%, with significantly improved survival and relapse risk among patients who underwent SCT while in CR.²⁵ Because of the rarity of CNS involvement by PBL, no consensus exists on the management of PCNSPBL. In the six earlier reported cases, three received intrathecal chemotherapy either as monotherapy or part of a chemotherapy/radiotherapy regimen. One patient received R-CHOP alone. Based on data showing favourable responses to high-dose methotrexate (3.5–8 g/m²) in PCNSL,^{26 27} our patient was treated with high-dose methotrexate (3.5 g/m²).

Learning points.

• Plasmablastic lymphoma (PBL) is a rare subtype of diffuse large B-cell lymphoma highly associated with HIV and Epstein-Barr virus infections.

• Primary central nervous system PBL (CNSPBL) is exceedingly rare. No standard treatment exists for primary CNSPBL, and the prognosis is very poor.

• High-dose chemotherapy as used in primary CNS lymphoma may offer a chance for complete response.