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. 2023 Mar 30;90(5):356–364. doi: 10.1159/000530429

Primary Effusion Lymphoma in an HIV-Negative Patient with Chronic Myeloid Leukemia Treated with Dasatinib

Ivo N SahBandar a, Chandler B Sy a, Tayler van den Akker a, David Kim a, Julia T Geyer a, Amy Chadburn a, Ethel Cesarman a, Giorgio Inghirami a, John N Allan b, Momin T Siddiqui a, Madhu M Ouseph a,✉
PMCID: PMC10614567  PMID: 36996787

Abstract

Introduction

Primary effusion lymphoma (PEL) is a malignant lymphomatous effusion, which by definition is Kaposi sarcoma herpesvirus/human herpesvirus 8-positive. PEL typically occurs in HIV-infected patients but can also occur in HIV-negative individuals, including in organ transplant recipients. Tyrosine kinase inhibitors (TKIs) are currently the standard of care for patients with chronic myeloid leukemia (CML), BCR::ABL1-positive. Although TKIs are extremely effective in treating CML, they alter T-cell function by inhibiting peripheral T-cell migration and altering T-cell trafficking and have been associated with the development of pleural effusions.

Case Presentation

We report a case of PEL in a young, relatively immunocompetent patient with no history of organ transplant receiving dasatinib for CML, BCR::ABL1-positive.

Discussion

We hypothesize that the loss of T-cell function secondary to TKI therapy (dasatinib) may have resulted in the unchecked cellular proliferation of Kaposi sarcoma herpesvirus (KSHV)-infected cells, leading to the emergence of a PEL. We recommend cytologic investigation and KSHV testing in patients being treated with dasatinib for CML who present with persistent or recurrent effusions.

Keywords: Primary effusion lymphoma, Lymphoma, Chronic myeloid leukemia, Dasatinib

Established Facts

  • •

    Primary effusion lymphoma (PEL) involves body cavities and usually occurs in HIV-positive individuals.

  • •

    PEL cases occurring in HIV-negative individuals have been reported in organ transplant recipients.

  • •

    Tyrosine kinase inhibitors (TKIs), including dasatinib, alter T-cell function by inhibiting peripheral T-cell migration and altering T-cell trafficking.

  • •

    TKIs, especially dasatinib, have been associated with the development of pleural effusions and pleural effusion-associated lymphomas in patients being treated for chronic myeloid leukemia.

Novel Insights

  • •

    We report a case of PEL in a young HIV-negative patient, previously diagnosed with chronic myeloid leukemia (CML), BCR::ABL1-positive, with no history of organ transplant, following treatment with dasatinib.

  • •

    Our report is the first to describe the development of PEL following dasatinib treatment for CML in an HIV-negative patient.

  • •

    We hypothesize that altered T-cell function secondary to dasatinib treatment may result in unchecked proliferation of Kaposi sarcoma herpesvirus-infected cells, the emergence of a malignant clone, and the development of PEL.

Introduction

Primary effusion lymphoma (PEL) is a B-cell neoplasm that typically presents as an effusion within body cavities, usually, but not always, without an associated extracavitary mass [1]. This entity was initially described in 1989 as an AIDS-related lymphoma, which was subsequently linked to infection by Kaposi sarcoma herpesvirus (KSHV), also called human herpesvirus 8 (HHV8) in 1995 [2, 3]. Moreover, it is frequently associated with coinfection by the Epstein-Barr virus (EBV) [1]. PEL, which typically occurs in middle-aged HIV-infected men, accounts for approximately 4% of AIDS-related non-Hodgkin lymphomas and <1% of lymphomas in HIV-negative individuals [4]. Although less common, PEL can also occur in HIV-negative immunocompromized patients following organ transplant [5]. However, whether other iatrogenic conditions can lead to the development of PEL remains to be fully defined.

Tyrosine kinase inhibitors (TKIs), which bind to the BCR::ABL1 kinase domain and disrupt the signal transduction pathways of protein kinases, have become the standard of care for patients with BCR::ABL1-positive chronic myeloid leukemia (CML) [1, 6]. Imatinib was the first tyrosine kinase inhibitor approved for the treatment of CML, BCR::ABL1-positive. Since then, newer and more effective TKIs have been developed. Dasatinib, a second generation TKI, has shown superior efficacy in terms of rates of complete cytogenic and major molecular responses compared to its predecessor imatinib. However, although the majority of adverse events occurred less often with dasatinib compared with imatinib, pleural effusions are more frequently seen in association with dasatinib therapy [7].

Here, we discuss a novel case of a young patient with a history of CML, BCR::ABL1-positive, well-controlled with dasatinib and with no history of HIV/AIDS or organ transplant who developed recurrent pleural effusions and was ultimately diagnosed with PEL. While previous reports have described patients treated with dasatinib who went on to develop KSHV-negative B-cell lymphomas, to the best of our knowledge, our report is the first to describe the development of PEL following dasatinib treatment for CML in a relatively immunocompetent patient.

Case Presentation

The patient is a 43-year-old male from the Caribbean with a history of CML, BCR::ABL1-positive, diagnosed in 2015, who subsequently developed recurrent pleural effusions. The patient was initially treated with imatinib but was switched to dasatinib 3 years later due to suboptimal clinical and molecular responses. After 3 years of dasatinib treatment, the patient developed pleuritic right-sided chest pain and shortness of breath that worsened with exertion. A chest X-ray showed new bilateral pleural effusions associated with presumed passive atelectasis. A PET CT revealed a moderate volume, partially loculated, right pleural effusion without focal FDG nodularity or FDG avid lymphadenopathy above or below the diaphragm. A thoracentesis, with removal of 1,500 mL of serosanguinous pleural fluid, was performed, which based on cytologic examination, did not contain neoplastic cells (Fig. 1a–c). Immunohistochemistry performed on the cell block for KSHV (latency-associated nuclear antigen [LANA]/HHV8) was negative (Fig. 1d) as was in situ hybridization for EBV (EBER) (Fig. 1e). Immunostaining for CD45 (Fig. 1f) and calretinin highlighted the hematopoietic and mesothelial cells, respectively. Concurrent pleural fluid flow cytometric analysis showed no immunophenotypic evidence of a hematolymphoid neoplasm. Based on these findings, the patient’s pleural effusions were thought to be secondary to dasatinib. The patient’s dasatinib treatment was discontinued for 2 weeks and subsequently restarted at a lower dose.

Fig. 1.

Fig. 1.

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Pleural fluid sample from the initial thoracentesis. The cells within this sample were obtained 6 months before the PEL diagnosis, as seen in the cell block (hematoxylin/eosin stain, ×20 original magnification with ×40 inset (a)), thin prep (Papanicolaou smear, ×20 original magnification with ×40 inset (b)), and cytospin (Giemsa stain, ×20 original magnification with ×40 inset (c)), and consisted of lymphocytes, histiocytes, and mesothelial cells. The cells were negative for KSHV (LANA/HHV8) (immunoperoxidase, ×20 original magnification (d)) and negative for EBV (EBER) (in situ hybridization, ×20 original magnification (e)). CD45 highlighted the hematopoietic cells (immunoperoxidase, ×20 original magnification (f)).

Six months after his first pleural effusion and 5.5 months after reinitiating dasatinib, the patient complained of recurrent right-sided chest pressure and symptoms similar to what he experienced with his previous pleural effusion. Chest X-ray showed a moderate right pleural effusion with atelectasis. The left lung was clear without a significant pleural effusion. An ultrasound-guided right-sided thoracentesis drained 1,550 mL of slightly cloudy amber fluid. Pleural fluid cytology showed medium to large-sized atypical cells with amphophilic cytoplasm containing vacuoles and irregular nuclei with prominent nucleoli (Fig. 2a–c). Immunohistochemistry performed on the cell block of this specimen showed that the aberrant cells were positive for CD45, MUM-1, CD38, CD138, CD30, and LANA/HHV8 (Fig. 2) and negative for CD20, PAX5, CD3, CD34, CD117, CD163, and EMA. In situ hybridization showed that the cells were negative for kappa and lambda light chain expression but were weakly positive for EBV (EBER) (Fig. 2e). In addition, the atypical cells were negative for the mesothelial markers calretinin (Fig. 2k) and WT-1 and the epithelial markers CK5/6, Ber-EP4, B72.3, and claudin-4.

Fig. 2.

Fig. 2.

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Pleural fluid sample from the thoracentesis at the time of PEL diagnosis, as seen in the cell block (hematoxylin/eosin stain, ×20 original magnification with ×40 inset (a)), thin prep (Papanicolaou smear, ×20 original magnification with ×40 inset (b)), and cytospin (Giemsa stain, ×20 original magnification with ×40 inset (c)), and consisted of atypical cells with pleomorphic nuclei and abundant cytoplasm. The atypical cells were positive for KSHV (LANA/HHV8) (immunoperoxidase, ×20 original magnification with ×40 inset (d)) and weakly positive for EBV (EBER) (in situ hybridization, ×20 original magnification with ×40 inset (e)). Malignant cells stained positive for CD38 (f), CD138 (g), CD30 (h), and MUM-1 (i). CD45 highlighted the hematopoietic cells (j), and calretinin highlighted the few associated mesothelial cells (k) (immunoperoxidase, ×20 original magnification (f–k)).

Flow cytometric analysis performed on the pleural fluid showed a discrete population of cells with high forward scatter characteristics which co-expressed CD45 (dim), CD38, and CD30 (dim) and lacked expression of immunoglobulin light chains. Background T cells and B cells were highlighted by expression of CD3 and CD20, respectively. PCR-based molecular genetic studies demonstrated clonal rearrangements in the immunoglobulin heavy chain and immunoglobulin light chain kappa genes. These findings were diagnostic of PEL. A concurrent bone marrow biopsy demonstrated features diagnostic of CML, BCR::ABL1-positive, in the chronic phase without PEL involvement. PET/CT scans demonstrated a partially loculated right pleural effusion without FDG-avid nodularity or masses. Molecular genetic studies performed on the peripheral blood demonstrated the presence of BCR::ABL1 p210 transcripts at 0.611% on the International Scale (IS). Serologic studies for HTLV-1/2, HIV-1/2 antibodies, and HIV-1 p24 antigen as well as quantitative RT-PCR for EBV performed on peripheral blood were negative. Following his diagnosis, combination chemotherapy was initiated.

Four months following his initial diagnosis, after completion of six cycles of combination chemotherapy, the patient was admitted with sepsis, neutropenic fever, and right pulmonary effusion. A thoracentesis was performed, and 1,500 mL of turbid yellow fluid was removed. The pleural fluid was composed of mostly segmented neutrophils (82%). Flow cytometric analysis of the pleural fluid showed a minute population of atypical cells which co-expressed CD38 and CD138, suspicious for involvement by the patient’s previously diagnosed PEL. However, there were some immunophenotypic differences, including co-expression of CD56 and lack of definite CD30 expression. Pleural fluid cytology showed few scattered medium-to-large-sized atypical cells that were positive for CD38, CD138, MUM-1, and LANA and negative for CD30 and EBER, consistent with a low-level involvement by the patient’s known history of PEL. Taken together, these results indicated that the patient’s worsening pleural effusion may have been the result of an underlying pulmonary infection secondary to his neutropenic state in the background of residual PEL. The patient’s symptoms improved following drainage of his pleural effusion, antibiotic therapy, and pleurodesis. He is currently being monitored as an outpatient.

Discussion

Here, we have described a HIV-negative patient with a history of BCR::ABL1-positive CML who developed recurrent pleural effusions following treatment with dasatinib. Thoracentesis of the pleural fluid revealed KSHV-positive, weakly EBV-positive large aberrant cells with an immunophenotype and genetic composition consistent with PEL. Although PEL occurs most commonly in HIV-infected individuals, it can also present in immunocompromized HIV-negative individuals, including in organ transplant recipients [8–10]. While most cases are associated with EBV infection, this is not required for pathogenesis [11].

KSHV is a lymphotropic gammaherpesvirus that is preferentially present in abnormal lymphoid proliferations occurring in immune compromised individuals. Data on HHV-8 seroprevalence in the Caribbean are limited; however, the WHO reported that the combined Latin America/Caribbean region had the third highest incidence of Kaposi sarcoma in 2020 globally [12]. The mechanisms by which KSHV leads to lymphoproliferative disorders including PEL is thought to be related to the expression of transforming viral genes that can affect cellular proliferation and survival [13]. Viral transcripts including LANA, viral FLICE inhibitory protein (vFLIP), and viral cyclin (vCyclin) promote oncogenesis by multiple mechanisms including inhibition of tumor suppressor proteins by LANA, inhibition of apoptosis, and activation of NFkB by vFLIP and cell cycle dysregulation by vCyclin. Moreover, KSHV gene expression also induces production of cellular IL-6, an important growth factor for KSHV-associated neoplasms [3, 14–16]. Viral interleukin IL-6 (vIL-6), a product of KSHV that is expressed in infected cells, induces vascular endothelial growth factor (VEGF), causing increasing vascular permeability and promoting the formation of effusions [17].

PEL symptoms are associated with the accumulation of fluid in the affected body cavities. PEL-associated effusions of the pleural and peritoneal cavities can manifest as dyspnea and ascites, respectively. Cytomorphologic features of PEL are characterized by large malignant cells with round to irregular nuclei, prominent nucleoli, and deep basophilic cytoplasm that is frequently vacuolated. The cells range in appearance from immunoblastic to plasmablastic to anaplastic and exhibit a high proliferation rate with numerous mitotic figures. Often a large amount of apoptosis is seen. The malignant cells are classically positive for the lymphocyte activation markers CD30, CD38, CD71, EMA, HLA-DR and the plasma cell differentiation marker CD138. Critically, definitive diagnosis of PEL depends on detecting viral infection by KSHV in the neoplastic cells [1]. The neoplastic cells of PEL typically express CD45 but lack expression of pan-B-cell and pan-T-cell antigens, although aberrant expression of T-cell antigens may occur, especially in extracavitary PEL [18].

The pivotal role of KSHV in the pathogenesis of PEL highlights the importance of the immune system’s capability of eliminating invading viruses. Cytotoxic T lymphocytes are thought to be critical in suppressing KSHV [19]. Therefore, suppression of T-cell responses may result in failure to control KSHV infection. TKIs, including imatinib and dasatinib, are associated with alterations of T-cell function in vitro. Imatinib interferes with T-cell activation in vitro by inhibiting the proliferation of activated T cells, impairing the production of interleukin 2 and reducing the antigen-triggered expansion of cytotoxic T cells [20]. Dasatinib has been reported to inhibit peripheral T-cell migration and alter immune cell trafficking toward secondary lymphoid organs by decreasing the proportion of CCR7-positive terminal effector T lymphocytes in vitro [8]. Dasatinib has also been reported to have immunosuppressive properties due to its ability to inhibit p56Lck, which has been shown to result in the reduction of TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses [21, 22].

TKIs, especially dasatinib, have been associated with the development of benign pleural effusions in patients treated for leukemia [7]. One study suggested that dasatinib causes pleural effusions by altering pulmonary endothelial permeability in a reactive oxygen species-dependent manner [23]. Although the vast majority of dasatinib-associated pleural effusions are benign, there are several case reports describing CML patients who developed pleural effusion-associated lymphomas following treatment with dasatinib. A 2017 case report discussed a 69-year-old man with CML who developed a pleural effusion after 2 years of treatment with dasatinib. The pleural fluid cytology showed an atypical cell population with medium to large-sized pleomorphic nuclei and abundant cytoplasm that was positive for CD20, CD79a, CD99, BCL2, BCL6, and MUM-1 but was negative for EBV by in situ hybridization and KSHV by immunohistochemistry, consistent with a fluid overload-associated large B-cell lymphoma [24]. A second case report described a 56-year-old Taiwanese woman presented with pleural effusion 5 years after starting dasatinib for CML. The pleurocentesis specimen revealed a clonal B-cell population of large, atypical cells that expressed CD20, PAX5, CD79a, CD138, and BCL2 with an immunoglobulin heavy chain gene rearrangement, which was not associated with KSHV, consistent with a high-grade B-cell lymphoma [25]. More recently, another group reported on two 69-year-old men with CML and dasatinib-related pleural effusions occurring 4 and 8 years after starting treatment. The pleural fluid specimens of both patients contained KSHV-negative large B-cell effusion-based lymphomas, which were positive for CD20, PAX5, and CD79a and negative for CD138 and EMA [26]. Interestingly, the atypical cells were positive for EBV in one of the 2 cases. Thus, the differential diagnosis of a pleural effusion-associated lymphoma includes not only PEL but also fluid overload-associated large B-cell lymphoma (FO-LBCL, KSHV/HHV8-negative effusion-based lymphoma) as well as diffuse large B-cell lymphoma associated with chronic inflammation (CI-DLBCL, pyothorax-associated lymphoma), particularly among rare cases of TKI-associated pleural effusion. Table 1 compares PEL, EBL, and PAL in terms of patient characteristics, clinical presentation, etiology, and immunophenotype [1, 27, 28, 29, 30, 31].

Table 1.

Comparison of primary effusion lymphoma (PEL), fluid overload-associated large B-cell lymphoma (FO-LBCL), and diffuse large B-cell lymphoma associated with chronic inflammation (CI-DLBCL)

PEL FO-LBCL CI-DLBCL
Age (median), years 40 79 65–70
Male:female ratio Mostly male 5:4 12:1
HIV status Mostly positive Negative Negative
Etiology HIV, KSHV/HHV8, EBV+/− Fluid overload EBV; artificial pneumothorax
Effusion location Pleura, pericardium, peritoneum Pleura, pericardium, peritoneum Mostly pleura
Clinical presentation Mostly effusion Effusion Solid mass
Neoplastic cell phenotype, %
 CD45 ∼75 ∼75 Positive
 CD20 <20 >95 Positive
 CD138 ∼70 <10 Negative
 KSHV Positive Negative Negative
 EBV ∼80–90 ∼10 ∼100
MYC-R Rare 20; translocations Amplification
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The previous reports described patients treated with dasatinib who went on to develop KSHV-negative B-cell lymphomas, excluding a diagnosis of PEL. Therefore, to the best of our knowledge, our report is the first to describe the development of PEL following dasatinib treatment for BCR::ABL1-positive CML in a relatively immunocompetent patient with no history of HIV infection or organ transplant. As such, we hypothesize that the loss of T-cell responses secondary to dasatinib treatment may result in unchecked cellular proliferation of KSHV-infected cells, the emergence of a malignant clone, and the development of PEL. However, regardless of the mechanism by which dasatinib may contribute to the development of PEL, we strongly recommend cytologic investigation and KSHV testing in patients being treated with dasatinib for CML who present with persistent or recurrent effusions. Given that this is the first reported case suggesting the association of dasatinib with PEL, whether dasatinib treatment should be continued in patients with CML following a diagnosis of PEL remains unclear. This decision will most likely be based on the patient’s clinical status, the effectiveness of dasatinib in treating the patient’s CML, whether there are any alternative TKIs that the patient can be treated with, and the clinician’s own judgment.

Acknowledgments

We thank the staff at the Hematopathology and Cytology laboratories at the Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, for their contribution during the data collection for this case report.

Statement of Ethics

Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. Only deidentified data were used in this manuscript, and no information revealing the patient’s identity was included. The New York Presbyterian Hospital/Weill Cornell Medicine is in compliance with the CARE guidelines for case reports. This study protocol was reviewed and approved by Weill Cornell Medicine Institutional Review Board (WCM-IRB) at Weill Cornell Medical College of Cornell University, approval number 0107004999.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding was provided for the preparation of the manuscript.

Author Contributions

I.N.S., C.B.S., T.A., D.K., and M.M.O. conceived the clinical and histologic data. J.N.A. provided clinical data. I.N.S., C.B.S., J.T.G., G.I., A.C., M.T.S., and M.M.O. analyzed the data. I.N.S., C.B.S., T.A., D.K., J.T.G., A.C., E.C., G.I., J.N.A., M.T.S., and M.M.O. wrote and edited the paper.

Funding Statement

No funding was provided for the preparation of the manuscript.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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