Clinical history

A 48-year-old male originally from Yemen, with no significant past medical history, presented with chest pain, shortness of breath, bilateral leg swelling, fever, and generalized weakness. Initial vital signs indicated sinus tachycardia, and subsequent laboratory studies revealed transaminitis, acute kidney injury (AKI), pancytopenia, markedly elevated ferritin, elevated troponin, and hypertriglyceridemia. Further analysis indicated an elevated interleukin-2 soluble receptor (CD25). Computed tomography (CT) imaging revealed splenomegaly and a solitary right middle lobe lung mass exceeding 3 cm in size, accompanied by pericardial and bilateral pulmonary effusions (Fig. 1). There was no evidence of lymphadenopathy or other mass lesions.

Fig. 1
figure 1

Chest CT with intravenous contrast. a Axial and b coronal chest CT with lung windows depicts the right middle lobe mass. Groundglass and linear densities in the lower lungs likely reflect passive atelectasis adjacent to the pleural effusions. c Axial image through the lower thoracic with soft tissue windows demonstrates the high-density moderate volume pericardial effusion. Note the absence of a left para cardiac mass. d More superiorly, the dependently layering pleural fluid is of higher density than the more inferior collection

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Initially, a lung biopsy of the right lower lobe nodule was performed followed by an echocardiogram, which confirmed the presence of a pericardial effusion, as well as a heterogeneous mass situated lateral to the left ventricle and adjacent to the apical inferolateral wall. Pericardiocentesis was performed and the fluid was sent to cytology. A bone marrow biopsy demonstrated hemophagocytosis with no evidence for lymphoma. Additionally, Epstein-Barr virus (EBV) viremia was detected, leading to a presumptive diagnosis of hemophagocytic lymphohistiocytosis (HLH) secondary to EBV viremia. Subsequent cytologic analysis of pericardial fluid revealed extranasal natural killer/T-cell lymphoma. Consequently, the final diagnosis was revised to HLH secondary to EBV-associated extranasal NK/T-cell lymphoma.

The patient’s condition rapidly deteriorated, progressing to multiorgan failure. Acute hypoxic respiratory failure necessitated mechanical ventilation, liver failure, and AKI demanded continuous renal replacement therapy. Given the patient’s poor performance status and tenuous clinical condition, a regimen directed toward the EBV infection and HLH was initiated including an interleukin-1 receptor antagonist (anakinra), dexamethasone, rituximab, and etoposide. A more intensive chemotherapy regimen to treat the underlying lymphoma was not deemed a viable option at this time. Unfortunately, the patient’s condition quickly escalated to multiorgan failure. Blood cultures revealed cryptococcus neoformans, and tragically, the patient expired.

Materials and methods

An ultrasound-guided lung biopsy of the right middle lobe nodule obtained a specimen measuring 2.7 × 1.9 × 0.1 cm, which was subsequently prepared within a formalin-fixed tissue block before being sectioned. Hematoxylin and eosin (H&E) stain was used for morphological examination. The following antibodies were used for immunohistochemistry stains: EBER ISH, Ki-67, CD56, CAM5.2, TTF-1, P40, chromogranin, and synaptophysin. Separate fresh core tissue was sent for flow cytometric study with the following antibody combinations: kappa, lambda, CD10, CD19, CD20, CD23, CD2, CD3 and CD4, CD 5, CD7, CD8, CD13, CD14, CD34, CD36, CD38, CD45, CD56, and CD64.

Pericardiocentesis was conducted, resulting in the drainage of 100 mL of serous fluid. The fluid cells were concentrated through centrifugation using a standard laboratory protocol and submitted for flow cytometric immunophenotyping, cytologic examination, and immunohistochemical stains including MOC-31, BER-EP4, B72.3, chromogranin, synaptophysin, TTF1, NapsinA, P40, CD45, CD3, and CD30. Additionally, CD20 and Ki-67 analyses were conducted.

Bone marrow aspiration was performed on the right posterior iliac crest and slides were prepared manually and stained with Wright’s stain using an automated Sysmex SP-10. Bone marrow aspirate sample for slide preparation was collected into ethylenediaminetetraacetic acid (EDTA) containing petri dish and was sent for flow cytometry with antibodies specific for precursor cells, B cells, T cells, myeloid cells, and monocytic cells. Bone marrow trephines were collected in formalin solution and sectioned at two microns thickness at two levels and stained with H&E stain. The following antibodies were used for immunohistochemical studies of the bone marrow trephines: CD2, CD3, CD4, CD5, CD7, CD56, EBER, PD-L1, CD30, CD34, CD56, CD 45, ALK, and granzyme B.

DNA was extracted from unstained sections of the cell block from the lymph node according to standard protocols. Genomic DNA was purified from the provided specimen. T-cell receptor gamma chain gene rearrangements were investigated using the Invivoscribe T Cell Receptor Gamma Gene Rearrangement Assay 2.0. PCR products were separated by capillary electrophoresis.

Result

Bone marrow biopsy revealed hypercellular marrow featuring myeloid hyperplasia associated with increased foamy-appearing histiocytes with frequent engulfed immature erythroid cells consistent with hemophagocytosis (Fig. 2). Concurrent flow cytometry and morphologic analysis of the bone marrow revealed no evidence for lymphoma or other malignancy. The pericardial fluid cytology revealed many atypical intermediate to large-sized lymphocytes with a high mitotic/apoptotic rate exhibiting moderate deep-blue cytoplasm, relatively fine chromatin, and occasional prominent nucleoli (Fig. 3). Concurrent flow cytometry on pericardial fluid (Fig. 4) demonstrated a correlate population with an aberrant immunophenotype supportive of NK/T-cell lineage, featuring surfaceCD3 ( −), cytoCD3 ( +), and CD56 ( +), with expression of CD45, CD38, CD2, and HLA-DR. Notable negative markers include CD4, CD5, CD7, CD10, CD13, CD16, CD19, CD20, CD33, CD34, CD36, CD57, CD64, CD158a/b/e, TCRαβ, TCRγδ, MPO, and TdT. The proliferation index estimated by Ki-67 staining was more than 95%. Staining on cell block material regarding EBER-ISH was positive (Fig. 3). Further immunohistochemical staining for PD-L1 and CD30 was both diffusely positive. The collective morphologic and immunophenotypic findings were consistent with an extranasal NK/T-cell lymphoma. A biopsy of the nodule within the right middle lobe lung revealed predominately blood clot and wide-spread necrosis; however, rare atypical cells demonstrated scattered positivity for EBER-ISH and CD56 and exhibited increased Ki-67 staining consistent with involvement of NK/T cell lymphoma. Our study identified 80,100 IU/ml of EBV DNA in plasma using PCR. The molecular testing is negative for T-cell receptor gamma chain gene monoclonal rearrangement.

Fig. 2
figure 2

Hemophagocytosis in bone marrow aspirates (Wright-Giemsa). Histiocyte engulfing mature red blood cells

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Fig. 3
figure 3

Microscopic appearance of lymphoma in pericardial fluid. a Hematoxylin and eosin stain shows intermediate to large-sized atypical lymphoid cells with irregular nuclear contours, numerous apoptotic cells, and brisk mitosis in the cell block. b, c Immunostains show the lymphoma cells are positive for CD56 and granzyme B (× 400). d Immunostain with ki-67 shows a high proliferative index (> 95%) in lymphoma cells (× 400). e In situ hybridization with EBV encoded RNA (EBER) is positive (× 400)

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Fig. 4
figure 4

Flow cytometric immunophenotyping of CD45, CD3, CD2, and CD56 expression for an aberrant NK/T-cell population (red) compared to reactive T-lymphocytes (blue)

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Discussion

Cardiac lymphoma is rare accounting for only 1–2% of primary cardiac neoplasms; it preferentially involves the right heart chambers, particularly the right atrium, with the myocardium most commonly implicated [1, 2]. Cardiac lymphomas are nearly exclusively diffuse large B-cell lymphoma with occasional descriptions of B-lymphoblastic leukemia and Burkitt lymphoma [3, 4]. When lymphoma involves the heart, patients may be asymptomatic or exhibit non-specific symptoms including dyspnea, chest discomfort, pre-syncope, or syncope, dependent upon the location of cardiac involvement. In general, it has been proposed that cardiac tumors may present in 1 of 3 ways [5]: (1) systemic, constitutional, or paraneoplastic symptoms including fever, arthralgias, weight loss, and fatigue; (2) mass effect in the heart altering myocardial function and blood flow leading to arrhythmias, interference with heart valve function, or a pericardial effusion with or without tamponade; (3) thromboembolic event related to the tumor.

In our case, chest CT demonstrated a lung mass associated with pericardial and bilateral pulmonary effusions; however, cardiac infiltration was not discerned. Echocardiogram demonstrated a heterogenous mass lateral to the left ventricle and adjacent to the apical inferolateral wall with a pericardial effusion. While multimodality imaging is often necessary to identify not only the presence but often to suggest a likely etiology of a cardiac mass, it has been recommended that echocardiography should be undertaken as the initial diagnostic test to evaluate for the presence of cardiac metastatic disease [5]. However, definitive diagnosis requires histopathologic examination. The sensitivity of cytology in diagnosis of primary cardiac lymphoma in pericardial effusion samples likely varies by type of lymphoma, but a sensitivity of 20–60% has been reported [6, 7].

After reviewing the relevant literature, we found 15 cases of extranodal NK/T-cell lymphoma with cardiac involvement [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. Clinical and pathological findings are summarized in Table 1, with a median age of 45 (23–81 years) and a male predominance (11/15), aligning with World Health Organization (WHO) demographics [23]. The most frequently reported extranasal sites, as described in the International Peripheral T‐Cell Lymphoma Project, are the intestine (37%), skin (26%), testis (17%), and lung (14%) [24]. When compared to NK/T-cell lymphoma with cardiac involvement, the distribution shows the lung (8/15) is the most common involved organ system, followed by the gastrointestinal tract (6/15) and skin (4/15). Extranasal NK/T-cell Lymphoma when compared to sinonasal-type is characterized by a rapid clinical downhill course, a poor response to treatment, and a shorter survival time [25]. While a clear biological rationale for this phenomenon is lacking, it has been proposed that the distinction of “nasal-type” be dropped from the name in the 5th edition of the World Health Organization Classification of Hematolymphoid Tumors; however, the International Consensus Classification has retained this designation. [23, 26]. Furthermore, routine use of advanced imaging technology, particularly PET/CT, has demonstrated that many previously designated extranasal NK/T-cell lymphomas are associated with occult nasal primaries [27, 28]. Despite our patient undergoing thorough head CT scanning, which indicated clear paranasal sinuses and aerodigestive tract, the absence of PET imaging leaves room for uncertainty, and occult sinonasal involvement cannot be entirely ruled out.

Table 1 Summarization of reported NKTL cases involving the heart and our case
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Extranodal NK/T-cell lymphoma typically displays an immunophenotype with CD2 + , CD5 − , CD56 + , surface CD3, cCD3 − epsilon + , CD43, often positive for EBV, CD45RO, and variably expressed CD7. EBV negativity raises diagnostic skepticism. Nasal or other extranodal lymphomas that are CD3 + and CD56 − but lack EBV and cytotoxic molecules should be classified as peripheral T-cell lymphoma, NOS [23]. Studies indicate that plasma has lower sensitivity than whole blood (WB) in detecting EBV-DNA, as WB contains EBV-DNA in both peripheral blood mononuclear cells and plasma. However, in patients with ENKTL, EBV-DNA in plasma holds a better prognostic value than WB [29].

In general, primary cardiac lymphoma has an aggressive clinical course with more than 60% of patients succumbing to the disease within 2 months of diagnosis [30]. Various predictors are associated with poor outcomes including arrhythmia, impaired immune status, involvement of the left ventricle, and extracardiac disease [31], while various unfavorable prognostic factors have been described in NK/T-cell lymphomas, including advanced stage disease (stage III or IV), unfavorable International Prognostic Index (IPI) [25, 32], high circulating EBV DNA levels [33], and high Ki-67 proliferation index [25]. Cardiac involvement is associated with aggressive disease with a long-term survival rate of less than 10% and a median survival of 4.3 months, WHO citation [23]. Unfortunately, given the difficulties in establishing a definitive diagnosis, cardiac lymphoma is frequently undetected before death [34], but a prompt diagnosis with a high index of suspicion offers the best opportunity to improve overall survival.

Aggressive NK-cell leukemia shares many clinical and pathologic similarities with extranodal NK/T-cell lymphoma; to such an extent, it is unclear if it should be considered the leukemic counterpart of extranodal NK/T-cell lymphoma. Part of this justification relates to similar molecular aberrations [35,36,37] and a nearly identical immunophenotype, with only subtle differences including a more likely expression of CD16 [38]. This distinction between aggressive NK-cell leukemia from high-stage extranodal NK/T-cell lymphoma can be difficult and in some challenging cases may be considered a matter of semantics [39].