Primary cardiac lymphoma (PCL), defined as a kind of non-Hodgkin’s lymphoma (NHL) merely involving the heart and/or pericardium (1) or NHL presenting with cardiac manifestations as well as the bulk of the tumor was located in the heart (2), is a really rare malignancy accounting for 1.3% of primary cardiac tumors and 0.5% of extra-nodal lymphomas (3).
Extra-nodal natural killer/T-cell lymphoma (ENKTL) is a distinct subtype of natural killer (NK) cell lymphoma, although uncommon in western counties, it makes up 5% to 10% of all lymphomas in Chinese people. In ENKTL, nasal cavity and other parts of the upper aerodigestive tract are primarily involved, but primary heart involvement, as far as we know, has seldom been reported.
In this report, we focus on an extremely rare case of primary cardiac NK/T-cell lymphoma arising in a 40-year-old woman, and a brief review of the literature is presented. We present the following case in accordance with the CARE-Guideline (4).
A 40-year-old Han ethnic woman without history of cardiovascular and other disorders manifesting as paroxysmal chest congestion, nausea for about 20 minutes on 15th November 2014, after five days the chest congestion reoccurred with palpitate and electrocardiogram revealed ventricular tachycardia, so amiodarone was used but failed to cardiovert. Then she was admitted to the department of cardiology of our hospital, clinical examination showed only hypotension of 97/58 mmHg, the heart rate was 112 and regular. Her hemoglobin (Hb) was 100 g/L, white blood cell (WBC) count 10.26×109/L with increased neutrophil, platelet count 337×109/L, troponin-I 2.72 ng/mL (normal range: 0–0.028). The patient was a farmer and had no history of discomforts like this. No evidence and previous history of human immunodeficiency virus, treponema pallidum and human hepatitis B virus infection. Electrocardiogram revealed T-wave inversion in V1-6, II, III, aVF leads. Coronary angiography showed only 50% stenosis of mid-left anterior descending coronary artery. CT scan and cardiac ultrasonic contrast showed an 87 mm × 78 mm mass at right atrioventricular groove and pericardial effusion. To confirm the tumor origin and find out if there were metastases, a whole-body PET/CT scan (Figure 1) was applied to this woman, and it revealed only a mass of accelerated glycolytic metabolism (SUV 7.1) at right atrioventricular groove and pericardial effusion, indicating the mass was a certain kind of malignancies. On 26th November, the patient felt sudden chest congestion, palpitate and profuse sweating, so an emergent thoracic exploring operation was performed, which showed plenty of dark red pericardial effusion, a huge mass of about 80×70×50 mm3 at right atrioventricular groove and many nodules about the size of a grain of rice on the heart surface especially on the surface of pulmonary trunk. During the emergent thoracic exploring operation, some of the nodules were collected to perform pathological examination. And eventually the histologic and immunohistochemical examination (Figure 2) demonstrated the diagnosis of NK/T-cell lymphoma, with the phenotypic features of LCA (+), Fli-1 (−), VIM (+), PCK (−), S100 (−), HMB45 (−), CD20 (−), CD79a (−), PAX-5 (−), CD2 (+), CD3 (+), CD5 (−), CD43 (+), mum-1 (−), bcl-2 (+), CD10 (−), bcl-6 (−), CD56 (+), GrB (−), CD30 (−), ALK (−), CD68 (−), TdT (−), MPO (−), TIA-1 (+), SMA (−), EMA (−), CD31 (−), CD34 (−), des (−), Ki-67 (Li 96%).
After recovery from the surgery, the patient was transferred to our department, and then we conducted some further examinations. Bone marrow cytology and biopsy inspection showed no signs of bone marrow involvement. Serum troponin-I level was 1.029 ng/mL and lactate dehydrogenase (LDH) 382 U/L (normal range: 135–214), quantification of circulating Epstein-Barr virus (EBV)-DNA was 1.98×105 copies/mL (normal range: <500 copies/mL). Thus the final diagnosis was primary cardiac NK/T cell lymphoma (Ann Arbor stage IE, IPI score 1). On 12th December the GELOX regimen was applied to the patient (Gemcitabine 1,500 mg as an intravenous drip on day 1 and day 8, oxaliplatin 150 mg as an intravenous drip on day 1, pegaspargase 3,750 IU as an intramuscular injection on day 1). After chemotherapy the patient’s fibrinogen seriously decreased so before she left hospital fresh frozen plasma was infused, in addition LDH level and EBV-DNA were reexamined as the results of 226 U/L and 9.99×103 copies/mL, respectively. The patient no longer complained with chest congestion when came back to hospital, and her LDH was 242 U/L and EBV-DNA 5.53×104 copies/mL, other standard laboratory tests disclosed no obvious abnormalities except mild anemia. Echocardiography revealed the mass at right atrioventricular groove was 20×20 mm2. Next the patient received chemotherapy as following: methotrexate (MTX) 4,800 mg as a continuous intravenous drip on day 1 (with calcium folinate to rescue), pegaspargase 3,750 IU as an intramuscular injection on day 2, dexamethasone (DEX) 40 mg as an intravenous drip from day 1 to 4. Just like the previous, fresh frozen plasma was infused, furthermore granulocyte-colony-stimulating factor (G-CSF) was utilized as a consequence of neutropenia. Similarly, before the third course some laboratory tests were conducted, LDH was 320 U/L and EBV-DNA 1.17×104 copies/mL, WBC count was 1.5×109/L with neutrophil count 0.22×109/L, Hb 66g/L and Plt count 93×109/L, coagulation function tests were normal. Echocardiography revealed the mass was 19×13 mm2. The patient received G-CSF and blood transfusion in advance of the chemotherapy as same as the second course. After chemotherapy the patient suffered from severe fibrinogen decrease and grade IV marrow suppression with neutrophil count as little as 0.01×109/L, PLT count 8×1012/L. Some days later, gastrointestinal bleeding and pulmonary infection arose, finally the patient died of multiple organ failure (MOF) despite various active treatments, and the last detection of EBV-DNA was 8.3×103 copies/mL. The timeline of interventions and outcomes was summarized as Figure 3.
According to Petrich et al. (5) who analyzed the characteristics of 197 patients diagnosed of PCL and reported in the literature, PCL is more common in elderly people with the median age of 63-year-old (9 to 90-year-old), and has a male predominance with the male-to-female ratio of 1.94. Symptoms at onset are non-specific, dyspnea was most common, and other common symptoms were arrhythmia, chest pain, constitutional complaints including fever, chills, sweats and weight loss, while few patients presented with superior vena cava syndrome. In 179 of 197 cases who had described chamber involvement, 92% affected the right chambers, and the right atrium was most frequently compromised followed by right ventricle, left atrium and left ventricle.
As to the female patient we reported, she was in her forties and right ventricle was involved, with no specific symptoms at onset. But PCL related ventricular tachycardia (VT) was not so common in literatures. Since the mass presenting in our case invaded right ventricle myocardium, we supposed that the likely mechanism accounting for PCL related VT is just similar with some cardiomyopathies, such as hypertrophic cardiomyopathy that has been tightly associated with the development of VT (6). Moreover, the real specificity of this case consists in the histological type—NK/T cell lymphoma. As is reported, the overwhelming majority of PCL is B-cell origin, among which the subtype of diffuse large B-cell lymphoma (DLBCL) is the most common (5,7). Primary cardiac T-cell lymphomas are extremely rare and only have been reported as single-case reports both in adults and children, especially in immunocompetent individuals (8-12), and interestingly, in 4 of 9 cases the pathological type was T cell lymphoblastic lymphoma (T-LBL), which requires to accumulate more cases to explore whether the T-LBL is the most common type of T-cell PCL. And of note, to the best of our knowledge, this is the second reported primary cardiac NK/T-cell lymphoma (12), but not like the case we reported, CT scan of other parts or PET/CT scan were not performed in literature (12) so that the diagnosis of PCL was not absolutely precise.
The diagnosis of PCL is usually delayed for reasons of its rarity and insufficient recognition. Chest CT scan, echocardiography including transthoracic of transesophageal, magnetic resonance imaging are all useful diagnostic techniques, but the final diagnosis should to be confirmed by pathological examination through needle biopsy even thoracic surgery, as well as cytology of pericardial diffusion that was reported to be diagnostic in 60% of cases (13).
As for its rarity, the best therapeutic approach to PCL was not established, but similarly to other NHLs, chemotherapy and/or radiotherapy were mostly taken, with surgery not improving the therapeutic effect (14). And as to ENKTL, a highly aggressive disease with grim prognosis, whose optimal treatment strategies have not been fully defined, often showed limited response to conventional chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), at least partly because of frequent multidrug resistance gene expression by tumor cells (15). So different with Lepeak et al. reported (12), at beginning we chose the GELOX regimen, which was proved superior to CHOP regimen in early stage ENKTL patients (16). Furthermore, ENKTL shows a tight association with Epstein-Barr virus (EBV), and the plasma EBV-DNA load at presentation is associated with clinical disease stage and treatment response, the rapid drop of EBV-DNA during therapy is a good maker of outcome (17,18). Thus, when the load of EBV-DNA was higher than that at the end of the first course, the more intensive regimen consisting of L-asparaginase, methotrexate and dexamethasone, which has been evaluated to be effective in patients with refractory or relapsing ENKTL (19), was applied to the patients in the second course with the consideration of not only improving the efficacy but also preventing central nervous system invasion. However, the more intensive therapy brought about more severe side effects, to some extent leading to the fatal complications. Radiation therapy (RT) alone, as an important treatment modality for localized disease, could produce complete response rates of up to 70% (20), but disappointingly, the efficacy of sequential RT to NK/T cell PCL was finally not able to be estimated in our case.
After all, PCL are exceedingly rare events, with its standard treatment strategies and prognosis not been fully determined, and when dealing with PCL, both the particular original site and the pathological type should be taken into account. As we emphasized in this case of NK/T cell PCL, who achieved a partial remission with at least 50% tumor mass reduction, novel effective regimen and the role of EBV-DNA testing are of great importance.
Conflicts of Interest: The authors have declared that no conflicts of interest exist.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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