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CASE REPORT Table of Contents  
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Rare diagnosis of an Epstein-Barr virus-positive extracavitary/solid variant of primary effusion lymphoma by duodenal endoscopic biopsy in a human immunodeficiency virus-seronegative and immunocompetent patient: A case report

1 Department of Pathology, Bezmialem Vakif University, Istanbul, Turkey
2 Department of Hematology, Bezmialem Vakif University, Istanbul, Turkey

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Date of Submission29-Nov-2022
Date of Decision29-Jan-2023
Date of Acceptance10-Feb-2023
Date of Web Publication31-Mar-2023


Primary effusion lymphoma and its tissue-based subtype extracavitary/solid variant was first described in human immunodeficiency virus (HIV)-seropositive patients. We report the case of a 50-year-old HIV-seronegative male patient who presented with icterus and cholestasis. Computed tomography revealed a 80 × 56 mm abdominal mass. Fine-needle aspiration biopsy was performed from the celiac lymph nodes and pancreatic head, under endoscopic ultrasonography guidance. A duodenal endoscopic biopsy was taken from the infiltration area, and a core biopsy was performed for the portal hilar mass. All biopsies showed similar cytohistopathological features. LCA-positive lymphoid neoplasia had a plasmacytoid/anaplastic morphology and null cell phenotype. HHV-8 and Epstein-Barr virus-encoded small RNAs (EBER) were diffuse positive. The patient, who did not have an effusion, was diagnosed with an extracavitary/solid variant of primary effusion lymphoma. Virus-associated lymphoproliferative disorders should be considered in the differential diagnosis of patients without a history of immunosuppression or HIV infection.

Keywords: EBV, endoscopic biopsy, HHV8, HIV, primary effusion lymphoma

How to cite this URL:
Guler B, Cetin G. Rare diagnosis of an Epstein-Barr virus-positive extracavitary/solid variant of primary effusion lymphoma by duodenal endoscopic biopsy in a human immunodeficiency virus-seronegative and immunocompetent patient: A case report. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Jun 1]. Available from:

   Introduction Top

Primary effusion lymphoma (PEL) is a rare B-cell lymphoma that was first identified in individuals with AIDS (acquired immunodeficiency syndrome).[1] The tissue-based subtype that develops with a solid mass formation without effusion is defined as the extracavitary/solid variant of PEL. Activation of lymphotropic human herpesvirus 8 (HHV-8) replication constitutes the most important step in the pathogenesis of PEL.[2] Although PEL is not usually considered as a differential diagnosis in immunocompetent individuals, rare cases have been reported in the literature.[3],[4],[5],[6]

In this article, a male patient with extracavitary PEL presented with findings of icterus and cholestasis diagnosed using duodenal endoscopic biopsy. He had no history of immunosuppression or immunodeficiency. Serous effusion was nonexistent. For this case, we think that endoscopic ultrasonography (EUS)-guided fine-needle aspiration (FNA) slides and liver core biopsy sections are useful for obtaining different cytopathological and histopathological views of the neoplasm.

   Case Report Top

A 50-year-old human immunodeficiency virus (HIV) seronegative male patient presented with complaints of vomiting and icterus in June 2019, with the following laboratory values: alanine aminotransferase, 760 U/L; aspartate aminotransferase, 410 U/L; alkaline phosphatase, 838 U/L; gamma-glutamyl transpeptidase, 1055 U/L; total bilirubin, 5.6 mg/dL; and direct bilirubin, 3.7 mg/dL. He had no history of malignancy, drug use, hepatitis B or C infection, and other causes of immunosuppression. A hypodense 80 × 56 mm mass lesion with a lobulated contour was observed predominantly in the periportal region on abdominal computed tomography (CT). The maximum standardized uptake value was 18.3 on positron emission tomography (PET)/CT. No serous effusion was detected. EUS-guided FNA using a 22-gauge needle was performed from the pancreatic head and celiac lymph node. After an endoscopic biopsy, sample was taken from the duodenum infiltration site, the main bile duct was selectively cannulated, sphincterotomy was performed, and a metal stent was placed. A CT-guided core needle biopsy was performed for the portal hilar mass.

EUS-guided FNA smears showed moderate to high cellularity and a necrotic background. Discohesive atypical cells had medium- to large-sized round nuclei, coarse chromatin, and single or several small nucleoli. Some cells showed naked nuclei, and others had a moderate amount of basophilic cytoplasm and plasmacytoid morphology [Figure 1]a and [Figure 1]b. A diffuse proliferation of atypical cells that ulcerated the surface and effaced the normal architecture was observed in the duodenal endoscopic biopsy sections. In some areas, plasmacytoid morphology was predominant. Mitosis was common [Figure 1]c, [Figure 1]d, [Figure 1]e. Portal hilar mass core biopsy sections were completely infiltrated by atypical cells [Figure 1]f. Atypical cells had similar morphological features in all biopsies.
Figure 1: (a) Endoscopic ultrasonography (EUS)-guided fine-needle aspiration (FNA) slides (Papanicolaou smear, original magnification ×400) showing discohesive, scattered tumor cells with medium- to large-sized round nuclei, coarse chromatin, and single or several small nucleoli. Some cells show naked nuclei (b) EUS-guided FNA cell block (hematoxylin-eosin [H and E] staining, original magnification ×400) showing tumor cells with moderate amounts of eosinophilic cytoplasm and plasmacytoid morphology, and frequent mitotic figures (c) Duodenal endoscopic biopsy (H and E staining, original magnification × 40) showing a diffuse proliferation of tumor cells that effaced the normal architecture and ulcerated surface (d-e) Duodenal endoscopic biopsy (H and E staining, original magnification ×200 and ×400) showing tumor cells with round-to-oval or lobulated nuclei, coarse chromatin, and a moderate amount eosinophilic or clear cytoplasma. In some areas, plasmacytoid morphology is predominant. Mitosis is common (f) Portal hilar mass core needle biopsy (H and E staining, original magnification ×20, ×100, ×200) showing complete infiltration of tumor cells and similar histopathological features with other biopsies but smaller tumor cells

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Diagnostic immunohistochemical and in situ hybridization studies were performed using all three biopsies. All additional processes were performed on BenchMark Ultra (Ventana Medical Systems Inc. A Member of the Roche Group, 1910 Innovation Park Drive, Tuscon). Leukocyte common antigen (LCA) was the most important immune marker supporting the lymphoid nature in the first step [Figure 2]a. The expressions of all common B (CD20, Pax5, and CD79a) and T (CD3, CD5, CD4, CD8, CD7, CD5, and CD2) cell markers and CD30 were negative. While weak positivity was detected in the portal hilar mass sections with CD38, no reaction was observed in the duodenal sections [Figure 2]b. CD138 expression was negative. No light chain restriction was detected. MUM1 and IgM expressions were positive [Figure 2]c. Partial strong staining for the epithelial membrane antigen (EMA) was observed. Nuclear dot-like staining was detected in all tumor cells with HHV-8 latency-associated nuclear antigen 1 (LANA1, Cell Marque 13B10), which plays a key role in diagnosis [Figure 3]a. Widespread positivity in tumor cells with Epstein-Barr virus-encoded small RNAs (Epstein-Barr Virus Early RNA Probe, Ventana) was observed using an in situ hybridization method [Figure 3]b. The Ki67 proliferative index was high (80-85%). The patient was diagnosed with PEL of the extracavitary/solid variant. No lymphoma infiltration was detected in the bone marrow biopsy.
Figure 2 (a) LCA ×100 (b) CD38 ×400, Portal hilar mass core needle biopsy (c) MUM1 ×40

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Figure 3: (a) HHV8 (anti-LANA)×400 (b) In situ hybridization for Epstein-Barr virus-encoded small RNAs (EBER) ×100

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The patient's international prognostic index score was high risk (4, 59% overall survival). Treatment was started with CHOP (cyclophosphamide, adriamycin, vincristine, and methylprednisolone) therapy. After 4 treatment cycles, the tumor was nonresponsive, as evidenced by the PET-CT control scan. Partial response was achieved with 3 cycles of ICE (carboplatin, ifosfamide, mesna, and etoposide) therapy introduced in September 2019. Autologous bone marrow transplantation was performed in February 2020. Owing to the early relapse detected in April, 2 cycles of DHAP (dexamethasone, cytarabine, and cisplatin) treatment was administered in May. Preparations were started for allogeneic bone marrow transplantation due to stable disease. As sufficient regression could not be achieved, 3 cycles of BEGEV (gemcitabine, vinorelbine, bendamustine, and prednol) therapy were administered in July and August. After allogeneic transplantation, the patient died in January 2021.

   Discussion Top

The extracavitary/solid variant of PEL is extremely rare. Thus, our cytohistomorphological findings from various biopsy specimens and observations of the clinical features of our patient are worth presenting. The classic and extracavitary variants of PEL are morphologically and immunohistochemically similar. Their pleomorphic cellular morphologies can be plasmablastic, anaplastic, or immunoblastic. Morphological differential diagnosis is quite diverse in tumoral infiltrations, which lack specific defining microscopic features. The diagnosis of the extracavitary variant of PEL is challenging in patients without serous effusion, unless a defined immunosuppression or immunodeficiency is present.[2]

In addition to HIV seropositivity, solid organ transplant recipients, patients with hepatitis B or C infection, and patients with immunosuppression receiving treatment for malignancy have also been reported.[2] Another HIV-seronegative group is composed of elderly patients living in endemic areas (sub-Saharan Africa and the Mediterranean region).[7] Our immunocompetent patient was from the Mediterranean region, which is considered endemic for HHV-8 infection.

PEL often has a null-cell phenotype.[2] LCA may be useful in supporting the lymphoid origin in 66-94% of patients. Variable CD30 and EMA positivity rates have been reported in PEL cases with an anaplastic morphology.[8],[9],[10] Instead of lineage-specific antibodies, CD38, CD138, and MUM1/IRF4 expressions are frequently detected in lymphoma cells.[2],[4],[8] The negative results for both lineage-specific and plasma cell markers in the duodenal biopsies made us doubt the origin of the disease. However, the detection of LCA expressions in the tumor cells in the EUS-guided FNA cell block, which was the first studied specimen, led us to insist on a lymphoid origin.

The role of Epstein-Barr virus infection, which is not essential for the pathogenesis of PEL but has been reported to be coinfection in 50-80% of patients, remains unclear. Coinfection is rarer in HIV-seronegative and immunocompetent patients. Similar to our patient, only a few cases with these features have been reported.[3],[4],[5],[6]

No standard treatment protocol has been established, as no randomized trials have conducted with large series.[2] Although various treatment options have been tried, complete remission could not be achieved in our patient, who died 19 months after the initial diagnosis. Contrary to the reports in the literature, the report of Nguyen et al.[6] that describes an HIV-seronegative female patient who was diagnosed incidentally and had an asymptomatic course without any treatment is quite interesting.

We aimed to contribute to the literature additional knowledge on extracavitary PEL through our present case. Patients may present with complaints widely different from the usual lymphoma symptoms. Diagnosis can be made using biopsy samples such as endoscopic or core biopsies that represent various tissue types. Especially for tumors with a null-cell phenotype, viral-associated lymphoproliferative neoplasms should be considered in the differential diagnosis even if the patient is immunocompetent. The addition of HHV-8 to the immunohistochemical panel for lymphoid neoplasms with an anaplastic morphology may increase the detection rate and thus the reported incidence rate of PEL.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Knowles DM, Inghirami G, Ubriaco A, Dalla-Favera R. Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of the Epstein-Barr virus. Blood 1989;73:792-9.  Back to cited text no. 1
Calabrò ML, Sarid R. Human herpesvirus 8 and lymphoproliferative disorders. Mediterr J Hematol Infect Dis 2018;10:e2018061.  Back to cited text no. 2
Tong J, Jadallah S, Rodgers WH, Jung G, Fulman M, Swaika A. A rare case of extracavitary primary effusion lymphoma in the bladder and ureter. Case Rep Hematol 2020;2020:6124325.  Back to cited text no. 3
Courville EL, Sohani AR, Hasserjian RP, Zukerberg LR, Harris NL, Ferry JA. Diverse clinicopathologic features in human herpesvirus 8–associated lymphomas lead to diagnostic problems. Am J Clin Pathol 2014;142:816-29.  Back to cited text no. 4
Ibrahim U, Saqib A, Mohammad F, Ding J, Hussein S, Atallah JP. KSHV-associated extracavitary primary effusion lymphoma in an HIV seronegative patient: A case report and review of the literature. Postgrad Med 2017;129:402-7.  Back to cited text no. 5
Nguyen Q, Bhargava P. KSHV/HHV-8 associated lymph node based lymphomas in HIV seronegative subjects. Case report and review of the literature. Human Pathology: Case Reports 2016;6:19-25.  Back to cited text no. 6
Kim Y, Leventaki V, Bhaijee F, Jackson CC, Medeiros LJ, Vega F. Extracavitary/solid variant of primary effusion lymphoma. Ann Diagn Pathol 2012;16:441-6.  Back to cited text no. 7
Guillet S, Gérard L, Meignin V, Agbalika F, Cuccini W, Denis B, et al. Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution. Am J Hematol 2016;91:233-7.  Back to cited text no. 8
Shimada K, Hayakawa F, Kiyoi H. Biology and management of primary effusion lymphoma. Blood 2018;132:1879-88.  Back to cited text no. 9
Chen BJ, Chuang SS. Lymphoid neoplasms with plasmablastic differentiation: A comprehensive review and diagnostic approaches. Adv Anat Pathol 2020;27:61-74.  Back to cited text no. 10

Correspondence Address:
Beril Guler,
Bezmialem Vakıf Üniversitesi, Tıbbi Patoloji AD. Vatan cad. Fatih-Istanbul - 34112
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_955_22


  [Figure 1], [Figure 2], [Figure 3]


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