Rare Extraoral Plasmablastic Lymphoma in the Context of HIV and Toxoplasmosis: A Detailed Case Analysis With Therapeutic Insights.

Summary Bortezomib‐enhanced EPOCH therapy effectively achieves a complete metabolic response in the rare, aggressive CD138‐negative extraoral Plasmablastic lymphoma in an HIV‐positive patient with resolved cerebral toxoplasmosis and low Epstein–Barr virus involvement, underscoring the value of intensive treatment for this diagnostically challenging malignancy.

Introduction

HIV infection substantially augments susceptibility to opportunistic infections and malignancies due to progressive immunodeficiency. Cerebral toxoplasmosis, caused by Toxoplasma gondii , is one of the most prevalent AIDS‐defining opportunistic infections, entangling more than 13 million HIV‐infected people, typically manifesting when CD4 counts fall below 100 cells/μL [ 1 ]. Although prophylaxis with cotrimoxazole combined with effective antiretroviral therapy is the main treatment protocol, still some patients remain at risk for secondary neoplastic conditions.

Plasmablastic lymphoma (PBL) is a scarce and aggressive form of B‐cell lymphoma, accounting for less than 1% of non‐Hodgkin lymphoma [ 2 ]. First it was reported as a subtype of diffuse large B‐cell lymphoma (DLBCL) in 1997 restricted to the oral cavity in HIV patients [ 3 ]. Its predominantly known for its oral site involvement in immunocompetent notably HIV patients notwithstanding extraoral sites which are being proclaimed in recent years [ 4 , 5 ]. Its high mortality and relapse rate are due to an aggressive clinical course, as well as the diagnostic challenge imposed by contiguous morphologic appearance to some other DLBCL subtypes and Plasmablastic cell myeloma (PCM) [ 6 ].

Here we present an extremely rare case of a 48‐year‐old woman with a history of HIV and cerebral toxoplasmosis which developed sinonasal PBL.

Case Examination

A 48‐year‐old female with a documented history of HIV, diagnosed 2 years earlier and managed with antiretroviral therapy (ART; emtricitabine/tenofovir 200/300 mg daily, dolutegravir 50 mg daily), was previously found to have cerebral toxoplasmosis. Initial diagnostic evaluation included a brain CT scan, which identified multiple ring‐enhancing lesions in the left frontal and right parietal lobes, measuring 9 mm and 16 mm, respectively, consistent with cerebral toxoplasmosis. The patient was treated with cotrimoxazole (960 mg daily) alongside ART. Two months following this diagnosis, she presented to Imam Khomeini Hospital with a 2‐week history of progressively worsening facial pain, right‐sided facial swelling, sore throat, postnasal drip, and dysphagia. On physical examination, right‐sided facial swelling, mild right orbital proptosis, and bilateral cervical lymphadenopathy (level II, firm, nontender, approximately 1–2 cm) were noted. Neurological examination revealed no focal deficits. Oropharyngeal examination demonstrated mucosal erythema and tonsillar enlargement, with no evidence of oral cavity masses.

Brain MRI with and without contrast revealed a sinonasal mass, most prominent on the right side, with nasopharyngeal involvement and bilateral neck lymphadenopathy present. The mass showed uniform mild enhancement and restriction, all in favor of lymphoma. Right orbital proptosis without canal involvement was seen Notably, no residual lesions indicative of cerebral toxoplasmosis were detected on the MRI (Figures 1 and 2 ).

Laboratory results showed hemoglobin of 10.5 g/dL, white blood cell count of 4.2 × 10 9 /L, platelet count of 180 × 10 9 /L, and normal liver and renal function. The patient's most recent CD4 count was 120 cells/μL, and HIV viral load was 500 copies/mL, indicating suboptimal viral suppression, likely due to incomplete adherence or possible ART resistance, though resistance testing was not performed.

Immunohistochemical results with positive MUM1/IRF4 and negative CD20 and weakly positive CD138 were in favor of terminally differentiated large B‐cell lymphoma, with the most probable diagnosis of plasmablastic lymphoma (Table 1 ) (Figures 3 , 4 , 5 ).

In the diagnostic evaluation of this rare extraoral Plasmablastic lymphoma (PBL), CD138 was selected over CD38 due to their high immunophenotypic similarity, ensuring greater specificity in identifying plasma cell differentiation. Similarly, PAX5 was avoided in favor of alternative B‐cell markers, such as CD79a, because PAX5 lacks sufficient discriminatory power to reliably distinguish PBL from other large B‐cell lymphomas or Plasmablastic myeloma. Given the uncommon nature of the disease and the aggressive behavior of the sinonasal mass, a second pathologist reviewed the pathology slides, reporting CD138 as weakly positive for membranous staining, and subsequent morphological assessment confirmed a diagnosis consistent with Plasmablastic lymphoma.

Chromogenic in situ hybridization (CISH) for EBV‐encoded RNA (EBER) was negative, indicating the absence of Epstein–Barr virus (EBV) association in this. This finding is notable, as EBV positivity is reported in up to 75% of PBL cases. The EBV‐negative status, combined with the weakly positive CD138 immunophenotype and extraoral sinonasal presentation, underscores the diagnostic complexity of this case.

CSF cytology was negative for malignant involvement, and bone marrow biopsy showed no lymphomatous involvement Figures 6 , 7 .

Differential Diagnosis

The differential diagnosis with this history and presentation includes diffuse large B‐cell lymphoma (DLBCL) subtypes, Plasmablastic myeloma, multiple myeloma, and other large B‐cell lymphomas (LBCL) due to immunophenotypic features and overlapping morphology. With a historical link to PBL, DLBCL shares large atypical lymphoid cells and high Ki‐67 proliferation but typically expresses CD20, unlike this case's CD20‐negative, weakly CD79a‐positive, and CD138/EBER‐negative profile. Plasmablastic myeloma and multiple myeloma mimic PBL's plasmacytoid morphology and starry sky background, yet are distinguished by systemic features like lytic bone lesions or paraproteinemia (absent here) and usual CD138 positivity. Other LBCLs, such as Burkitt lymphoma (with MYC translocations and CD10/BCL6 positivity) or HHV‐8‐associated primary effusion lymphoma (cavity‐based), differ from PBL's sinonasal presentation.

Additionally, infectious etiologies like oropharyngeal syphilis should be considered, as it can present with ulcerous lesions, tissue hypertrophy, mucosal patches, or cancer‐like masses in the oropharynx and sinonasal region, particularly in HIV‐positive individuals where it is known as the “great imitator” due to its variable manifestations resembling malignancies. However, syphilis was clinically ruled out based on the absence of characteristic syphilitic symptoms and the presence of positive malignancy findings, including immunohistochemistry results consistent with PBL.

Conclusion and Results

Despite the constraints of previous studies, such as limited sample sizes and significant treatment‐related toxicities, and the National Comprehensive Cancer Network (NCCN) recommendation for EPOCH chemotherapy alone, the bortezomib‐augmented EPOCH chemotherapy protocol was initiated for this patient. This decision was driven by the need for an intensive approach to manage the aggressive nature of this disease. The absence of grade 3–4 adverse events related to bortezomib supported the multidisciplinary team's decision to continue this treatment regimen, balancing its efficacy against potential risks.

Six courses of chemotherapy, including EPOCH (etoposide 50 mg/m 2 on days 1–4, prednisone 60 mg/m 2 , vincristine0.4 mg/m 2 , cyclophosphamide750 mg/m 2 , doxorubicin 10 mg/m 2 on days 1–4) and VELCADE (bortezomib, 1.3 mg/m 2 on days 1, 8, 15, of each cycle), were started for the patient with an interval of 21 days, and intrathecal prophylactic MTX (15 mg) and cytarabine (50 mg) were initiated with every cycle. The patient demonstrated overall tolerance to chemotherapy; however, intercycle periods were complicated by recurrent febrile episodes and neutropenia, necessitating repeated hospital admissions.

The patient developed grade 4 neutropenia (absolute neutrophil count ≤ 500/μL) after the initial chemotherapy cycle. To prevent further neutropenia, granulocyte colony‐stimulating factor (G‐CSF) prophylaxis was initiated, but the patient experienced anaphylactic shock following the first dose, preventing subsequent G‐CSF administration. This led to multiple episodes of febrile neutropenia, including a severe instance of septic shock triggered by a catheter‐related infection, necessitating catheter replacement and appropriate antibiotic treatment.

Notably, inpatient management was required during each of the six chemotherapy cycles to address these treatment‐related complications.

After three chemotherapy courses, FDG‐PET/CT showed only physiologic brain uptake, sinus opacification, a small calcified lung nodule, and nonmetabolic lymph nodes, consistent with complete metabolic response (Figure 8 ).

The patient was discharged and chemotherapy was continued as planned. Follow‐up imaging with a control CT scan—performed instead of FDG‐PET/CT due to financial constraints—revealed diffuse mucosal thickening involving all paranasal sinuses, with complete opacification observed in several sinuses, findings consistent with pansinusitis.

Follow‐up control CT scans, conducted twice over a 6‐month period, revealed no evidence of tumor recurrence. Laboratory findings, including erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) levels, along with physical examinations, were consistent with a complete metabolic response. Given the critical need to confirm the absence of residual disease prior to autologous stem cell transplantation, the patient was strongly advised to undergo a PET/CT scan before proceeding with the transplant.

Given the patient's achievement of complete metabolic response, they were subsequently considered a candidate for autologous stem cell transplantation. Additionally, targeted radiotherapy to the involved sinus regions was planned to consolidate disease control, addressing both the PBL and associated sinus involvement.

Discussion

HIV predisposes patients to various infections and malignancies. Representing approximately 11% of AIDS‐related lymphomas (ARLs), PBL is becoming an increasing concern for health carers, as the reports of these cases related and nonrelated to HIV are escalating in recent years [ 7 , 8 , 9 ]. Although overall prevalence of PBL is unknown, it has been found to occur more frequently in HIV positive males [ 10 ]. With EBV also seeming to have a strong association with HIV‐related PBL, with prevalence up to 74% in some studies [ 11 ]. Initially described in the oral cavity, PBL has since been reported in diverse extraoral sites such as the gastrointestinal tract, lung, CNS, mediastinum, paranasal sinuses, and testis [ 9 ]. CD138‐negative variants, often extraoral and less frequently EBV‐related, add to its heterogeneity, with the gastrointestinal tract representing the second most common extraoral site after lymph nodes, including stomach, cecum, rectum (13.3%), and anal lesions (6.7%) after lymph nodes (36.7%) in their published series of 42 cases of CD138 negative PBLs [ 12 ].

HIV‐associated PBL is usually seen with individuals whose CD4 count is around 200 cells/mm3, the mean duration of the disease is 8 years, and the average viral load is over 2,50,000 copies/ml [ 13 ]. Despite these characteristic features, PBL poses a diagnostic challenge still to date due to its overlapping immunophenotypic and morphologic features with multiple myeloma and a various spectrum of large B‐cell lymphomas (LBCL). Furthermore, infectious conditions like oropharyngeal syphilis should be considered, especially in HIV‐positive individuals, where it is recognized for its diverse presentations that can resemble malignancies, such as ulcerous lesions, tissue overgrowth, mucosal patches, or tumor‐like masses in the sinonasal area [ 14 ].

Histopathology remains the gold standard in the diagnosis of PBL, which shows monomorphic proliferation of plasmacytoid cells with eccentric nucleus, abundant cytoplasm, and a prominent central nucleolus in a starry sky background [ 6 ]. HIV‐infected patients more commonly present with monomorphic plasmablastic cell morphology, typically involving the oral cavity and sinonasal region. In contrast, PBL cases showing plasmacytic differentiation predominantly occur in extraoral sites [ 15 ]. Our patient presented with a paranasal sinus mass, specifically in the maxillary sinuses, highlighting this atypical presentation.

The neoplastic cells typically exhibit a plasma cell immunophenotype, positive for CD38, CD138, and IRF4/MUM1, with absent or weak expression of mature B‐cell markers (CD19, CD20, PAX5), and frequent CD79a expression; aberrant positivity for CD4, CD10, CD30, or CD56 may also occur [ 16 ]. Our case showed weakly positive CD79a and weakly membranous positive CD138 and positive MUM1 in lymphoid cell sheets, consistent with this profile.

Epstein–Barr virus (EBV) association, detected via EBER, is present in > 50% of PBL cases, aiding diagnosis, though approximately 10% are CD138‐negative, complicating classification and necessitating integrated morphological and immunophenotypic analysis [ 17 ]. The CD138‐negative status in our case, confirmed after a second pathology review, underscores diagnostic challenges, particularly when limited IHC panels or rapid assessments are relied upon, as noted by Shweta et al. [ 18 ].

Although not supported by current evidence in terms of overall survival, the National Comprehensive Cancer Network (NCCN) recommends the use of more intensive chemotherapy regimens for PBL, including CODOX‐M/IVAC (cyclophosphamide, vincristine, doxorubicin, and high‐dose methotrexate alternated with ifosfamide, etoposide, and high‐dose cytarabine), dose‐adjusted EPOCH (etoposide, prednisone, vincristine, cyclocarbonamide, and doxorubicin), or Hyper‐CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternated with high‐dose methotrexate and cytarabine) [ 9 , 15 , 19 , 20 ].

A novel therapeutic approach demonstrated by Castillo et al. incorporated bortezomib into the EPOCH regimen (V‐EPOCH) in a retrospective case series that evaluated 16 patients. Receiving 4–6 cycles of V‐EPOCH with or without radiotherapy, using bortezomib at 1.3 mg/m 2 administered subcutaneously or intravenously weekly or twice weekly per cycle, This regimen demonstrated remarkable efficacy, with complete responses achieved in 94% of cases (15/16) and a partial response in the remaining patient. Two patients received autologous stem cell transplantation (ASCT) in first remission. Four patients (31%) experienced relapsed disease within 2 years of diagnosis, including one who achieved CR and underwent ASCT. With a median follow‐up of 48 months (range: 20–61), outcomes were particularly encouraging, showing a median overall survival of 62 months (95% CI: 17‐not reached) and a 5‐year survival rate of 63%. Notably, no mortality was observed among HIV‐positive patients in this cohort [ 21 ]. Dittus et al. [ 22 ] reported that the CR rate and 2‐year OS rate of PBL patients treated with the combination of bortezomib and the EPOCH regimen were 100% and 50%, respectively.

Despite the challenges of earlier studies, including limited patient numbers and notable treatment toxicities, the bortezomib‐enhanced EPOCH chemotherapy regimen was chosen for this patient to tackle the highly aggressive CD138‐negative extraoral Plasmablastic lymphoma. The lack of severe (grade 3–4) bortezomib‐related side effects justified the multidisciplinary team's decision to maintain this regimen, balancing its therapeutic benefits with potential risks. Our case showed a complete response with EPOCH and bortezomib treatment and is currently a candidate for autologous transplantation.

Conclusion

This report describes an unusual presentation of extraoral Plasmablastic lymphoma (PBL) in an HIV‐positive patient concurrently affected by cerebral toxoplasmosis, emphasizing the complex diagnostic and therapeutic considerations inherent to this rare and aggressive neoplasm. The attainment of a complete metabolic response with bortezomib‐enhanced EPOCH chemotherapy—despite CD138 immunoreactivity and suboptimal HIV viral suppression—highlights the potential efficacy of intensified chemotherapeutic protocols. Furthermore, it underscores the critical role of individualized treatment strategies, incorporating planned autologous hematopoietic stem cell transplantation and targeted radiotherapy, in optimizing clinical outcomes for this high‐risk patient population.

Author Contributions

Nima Alishavandi: data curation, project administration, resources, visualization. Mehrzad Kaviani: conceptualization, formal analysis, project administration, validation, visualization. Seyyed Taher Seyyed Mahmoudi: project administration, visualization, writing – original draft, writing – review and editing. Mahmoudi Masoud Mortezazadeh: project administration, resources, supervision, validation. Samira Farahmand: methodology, resources, supervision, visualization. Tahere Yousefi: methodology, project administration, resources, validation, visualization.

Ethics Statement

In this study, no additional costs were imposed on the patient. We maintained the patient's privacy, and written consent was obtained.

Consent

A written informed consent was obtained from the patient. The participant had consented to the publication of this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, [SS], upon reasonable request.

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