Article

AIDS-Associated Cardiac Lymphoma— A Review: Apropos a Case Report

Journal of the International Association of Providers of AIDS Care 1-9 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2325957414520981 jiapac.sagepub.com

Larry M. Bush, MD, FACP1,2, Jose G. Urrutia, MD3, Eduardo A. Rodriguez, MD3, and Maria T. Perez, MD, FCAP4

Abstract Despite treatment with potent and effective combination antiretroviral medications, the incidence of non-Hodgkin lymphoma (NHL) in the population living with HIV/AIDS remains significantly higher than that in noninfected individuals. The majority of the HIVinfected patients with NHL present with advanced stage extranodal disease of the B-cell phenotype. Lymphomas are the second most common tumors involving the heart in HIV-infected patients. Although the heart may serve as the primary focus of the lymphoma, in most HIV-related cases, cardiac lymphomatous involvement is part of a metastatic process that originated elsewhere. Keywords lymphoma, cardiac, AIDS

Introduction The introduction of combination antiretroviral therapy (cART; previously referred to as highly active antiretroviral therapy) in the mid-1990s heralded the dramatic reduction in mortality as well as a substantial decline in the incidence of opportunistic infections in those living with HIV/AIDS. While the profound defect in cell-mediated immunity brought about by HIV infection has also contributed to the markedly increased risk of developing certain malignancies, prior to the onset of cART, such neoplasms accounted for less than 10% of deaths in the HIVinfected population.1 Somewhat surprisingly, this number has dramatically increased, as currently nearly 30% of all deaths in HIV-infected patients are in some fashion attributable to a malignant condition.2 Although Kaposi sarcoma (KS) was the first and most frequent malignancy to be recognized as related to AIDS,3 non-Hodgkin lymphoma (NHL) also became an AIDS-defining illness in 1985. In fact, before the use of cART, NHL was reported to be the initial AIDS diagnosis in 2.5% to 5% of HIV-infected individuals.4 At this time, an estimated 5% to 20% of HIV-positive persons develop NHL, which translates into a 200-fold increased risk of developing this type of cancer compared with the risk of HIV-negative individuals. Interestingly, recent analysis of data from prospective cohort studies5 demonstrates that since the initiation of cART, nonAIDS-defining cancers (NADCs), or those other than KS, NHL, and cervical carcinoma, have been found to occur in excess in HIV/AIDS-infected individuals when compared with the general population. Risk factors for the development of NADCs remain uncertain. Moreover, the exact role of the virus-related immunosuppression in this observed increased incidence of these malignancies remains somewhat controversial.6

Non-Hodgkin lymphomas presenting in patients living with HIV/AIDS patients encompass a heterogeneous group of malignancies. Although low-grade lymphomas occur infrequently in HIV-infected individuals, according to the criteria set forth by the Centers for Disease Control and Prevention, only intermediate or high-grade lymphomas are considered AIDS defining.7 Furthermore, the World Health Organization classifies lymphomas by their occurrence in immunocompetent persons, in HIV-positive patients, or in those individuals with other forms of immunosuppression.8 The majority of the HIV-infected patients with NHL present with advanced stage extranodal disease of the B-cell phenotype. Diffuse large B-cell lymphomas, which include the centroblastic (most cases of primary central nervous system lymphoma) and immunoblastic subtypes, account for approximately 60% of all lymphomas in persons living with AIDS. Burkitt and Burkitt-like lymphoma represent the second most 1

Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA 2 University of Miami–Miller School of Medicine, JFK Medical Center, Palm Beach County, FL, USA 3 Internal Medicine, University of Miami–Miller School of Medicine, JFK Medical Center, Palm Beach County, FL, USA 4 Division of Pathology and Laboratory Medicine, Integrated Regional Laboratory Pathology Services, JFK Medical Center, Palm Beach County, FL, USA Corresponding Author: Larry M. Bush, Comprehensive Infectious Diseases, LLC, 5503 South Congress Avenue, Suite 104, Atlantis, FL 33462, USA. Email: [email protected]

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common histological types, accounting for 25% to 30% of NHL. The remaining percentage predominantly includes cases of plasmablastic lymphoma (including the multicentric variant of Castleman disease). A distinct and significantly more rare form of NHL, originally described in HIV-infected persons in 1989, consists of a primary lymphomatous effusion contained within a serosal body cavity.9 This entity, hence termed primary effusion lymphoma (PEL), may involve pleural, pericardial, and peritoneal spaces; characteristically, there is absent or minimal involvement of neighboring solid tissue and no evidence of lymphadenopathy.10 Multiple risk factors have been identified in the development of NHL in HIV-infected persons. The immune dysfunction brought about by HIV is thought to be the primary mechanism, with patients having CD4 counts of less than 100 cells/mL, along with high HIV RNA viral loads, to be at particular risk.11 What is more, there exists a significant relationship between the lymphoma subtype that develops in HIV-positive patients and their level of immunosuppression.8 Although those with advanced AIDS more often have immunoblastic NHL and PEL, Burkitt NHL tends to be seen in patients with more preserved immunity.12 Deregulation of the immune system function is thought to lead to loss of control of oncogenic viruses, such as Epstein-Barr virus (EBV) and human herpes virus 8, resulting in malignant transformation. Epstein-Barr virus is assumed to cause malignant transformation of lymphoid cells through the expression of viral genes in various latency programs.13 Accordingly, sequences of EBV DNA are found in 40% to 50% of systemic AIDS-related NHLs in contrast to only 10% to 20% of cases of NHL in the HIVnegative population.14 HIV in and of itself has not been considered an oncogenic virus.15 Nevertheless, a direct oncogenetic role of HIV has been postulated stemming from the observation of a clonally integrated HIV genome in tumor-associated macrophages.16 The activation and proliferation of these macrophages are believed to result in cytokine overexpression via progressive impairment of dendritic cell function, leading to a polyclonal expansion of B lymphocytes, with eventual evolution to a monoclonal process.17,18 The usual presentation with advanced systemic disease, together with the strong tendency for the lymphoma to involve extranodal sites (ie, the central nervous system, liver, gastrointestinal tract, and bone marrow), is the hallmark of NHL in HIV-infected patients. Direct cardiac involvement by any one of the various malignancies associated with HIV infection is rare, with KS invasion of the epicardium and pericardium being the most common.19 Lymphomas, the majority of which consist of high-grade B-cell tumors such as large cell immunoblastic or Burkitt lymphomas, are the second most common tumors involving the heart in HIV-infected patients.20 In the general population, lymphoma is usually recognized as the third most frequent metastatic malignancy involving the heart when considering absolute numbers (following lung and breast carcinomas) and the second most frequent when considering the relative incidence of metastasis (following melanoma).21 However, the incidence of cardiac lymphomas has considerably increased, albeit

mainly in HIV-infected individuals.21 Herein is presented a case of cardiac lymphoma in an untreated patient living with AIDS, which led to his rapid demise. Apropos this case, we review the literature on AIDS-associated cardiac lymphomas.

Case Report A 45-year-old man with untreated AIDS presented to our hospital, complaining of a several-month history of intermittent fever, night sweats, and a 30 lb weight loss. He was void of any localizing signs or symptoms suggestive of a specific etiology. His most recent CD4 count was 12 cells/mL. Initial laboratory studies were significant for a moderate degree of pancytopenia. Relevant imaging studies included a computerized tomographic (CT) scan of his chest and abdomen, whereupon several pulmonary nodules ranging in size from 4 mm to 1.5 cm, along with a 5.6 cm low-density mass in the left ventricular apex (Figure 1A) were noted. No lymphadenopathy was identified. A separate CT scan of the abdomen and pelvis demonstrated 2 masses (3.8 and 1.7 cm) situated on the dome of the liver (Figure 1B), and a mass (6  8.9 cm) involving the posterior wall of the urinary bladder at the region of the left ureterovesicular junction, producing moderate left hydroureteronephrosis (Figure 1C). Circumferential wall thickening of the ascending colon was also identified and was believed to represent a neoplastic process. A 2-dimensional transthoracic echocardiogram confirmed the presence of a lobulated mass in the left ventricular apex (Figure 2). The patient underwent a CT scan guided core biopsy of the liver, providing a histologic diagnosis of a high-grade B-cell lymphoma (Figure 3A). Unfortunately, the material provided was insufficient for further studies pertinent for subclassification purposes. However, the touch preparations displayed fairly numerous histiocytes-containing apoptotic bodies, conferring a ‘‘starry-sky’’-like pattern reminiscent of Burkitt or Burkittlike lymphoma (Figure 3B). Flow cytometry analysis of the liver mass confirmed the involvement of a B-cell lymphoproliferative process coexpressing CD10. The neoplastic B cells accounted for 4% of the total cellularity; expressed CD19, CD20, CD22, CD38, CD10; and showed monoclonal lambda immunoglobulin light chain restriction. A bone marrow aspirate and biopsy were found to be normocellular for the patient’s age and negative for involvement by the high grade B-cell lymphoma. His hospital stay was complicated by a decline in his renal function, obstructive uropathy requiring the placement of a left-sided percutaneous nephrostomy tube, and respiratory difficulties deemed secondary to pulmonary emboli, prompting anticoagulation with intravenous heparin. Chemotherapy was initiated using rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH). Sadly, he had cardiopulmonary arrest the following day and was not able to be successfully resuscitated. An autopsy was not obtained.

Discussion Primary cardiac lymphoma was first defined as a distinct cardiac neoplasm in 1978.22 When strictly defined as an

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Figure 2. Two-dimensional transthoracic echocardiogram confirming the presence of a lobulated mass in the left ventricular apex (between block arrows).

Figure 1. A, Computed tomography scan of the chest with contrast, demonstrating a filling defect in the apex of the left ventricle due to the presence of a mass (block arrow). B, Computed tomography scan of the abdomen with contrast, showing 2 distinct nodular masses in the right lobe of the liver (block arrows). C, Computed tomography scan of the pelvis with contrast, revealing a mass involving the posterior wall of the urinary bladder (block arrows).

extranodal malignant lymphoma of any cell type involving only the heart and pericardium without dissemination, they comprise less than one-half of 1% of all extranodal lymphomas. Nevertheless, cardiac involvement by malignant lymphoma is more common than generally assumed, with autopsy series documenting invasion of the heart in nearly 9% to 24% of all disseminated NHL disease.23-26 The reported incidence of extranodal NHL has significantly increased since the 1990s. In large part, this may be attributed to improved diagnostic techniques, along with a growing portion of the population that is immunosuppressed for a variety of reasons with a

longer life expectancy, particularly those infected with HIV. The vast majority of cardiac lymphomas are derived from B-cell lineage, mostly diffuse large B-cell lymphoma type, although Burkitt, immunoblastic, plasmablastic, as well as T-cell lymphomas have also been described.27 Generally occurring in elderly adults (mean age 62.1) with a male predominance, they often remain asymptomatic until which time they produce a mass effect, local invasion, or embolization. The clinical presentation of lymphoma of the heart, regardless of whether present as a primary malignancy or as an extranodal site of metastasis, may include constitutional symptoms, pericardial effusion with or without tamponade, tumor embolization, outflow or valve obstruction, as well as invasion of the conduction system resulting in arrhythmias. Superior vena cava syndrome alone may also be the initial presenting manifestation. Factors such as tumor location, size, and growth rate of the mass, as well as friability, all play a role in the signs and symptoms of these lymphoproliferative tumors of the heart. Anatomically, approximately two-thirds of primary cardiac lymphomas occur as a single nodular or polypoid tumoral mass and are most often localized in the right atrium. The pericardium, right ventricle, left atrium, left ventricle, and atrial septum, respectively, are the next most frequently involved cardiac sites.28 Some have postulated that the right side of the heart is involved more frequently because of thoracic duct drainage of lymph into the superior vena cava, thereby exposing the right heart more readily to preexisting nodal lymphoma.29 Several cases of cardiac lymphoma in HIV-positive patients have previously been reported (Table 1), the preponderance of which was diagnosed in those individuals having advanced disease and with cardiac involvement as part of disseminated lymphoma. In one large series that included both HIV-positive and HIV-negative patients, only 26% of HIV-infected individuals were free of extracardiac lymphoma (ie, met the definition of primary cardiac lymphoma), whereas 76% of HIV-negative patients and 74% of those with unknown HIV status had disease limited to the heart and/or pericardium at the time of initial diagnosis.29 In keeping with the majority of HIV-associated lymphomas, those involving the heart typically are aggressive

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Figure 3. A, Liver core biopsy demonstrating effacement of the normal architecture due to the replacement of hepatocytes by lymphoid cells (medium magnification 200, hematoxylin–eosin stain). B, Touch imprint of the same liver core biopsy showing numerous monotonous lymphoid cells displaying high cellular turnover features: numerous mitosis (gray block arrows) and ‘‘starry-sky’’ appearance (scattered macrophages with phagocytized intracytoplasmic cellular debris, white block arrows).

B-cell NHLs of the Burkitt type. Because of the extremely poor prognosis, once this neoplasm has invaded the heart, cardiac involvement as the initial manifestation of HIV-related lymphoma is quite uncommon.46 Some feel that a large solitary right atrial mass in conjunction with a pericardial effusion in HIV-positive patients should be considered lymphoma until proven otherwise.19 Overall, early diagnosis of cardiac lymphoma is difficult, owing to its nonspecific clinical manifestations of congestive heart failure, chest pain, pericardial effusions, and/or arrhythmias. Quite often, the patient is void of any specific clinical manifestations that would be attributed to cardiac disease.36 In one reported series of cardiac lymphomas, right-sided heart failure, dyspnea, cardiac tamponade, and rhythm disturbances were reported as the most frequent clinical manifestations.56 The bone marrow, gastrointestinal organs, central nervous system, and liver are found to be the other more prevalent extranodal sites of disseminated lymphomatous disease. In our patient, the prominent presenting features including fever, night sweats, and weight loss were often referred to as ‘‘B’’ symptoms of lymphoma, with few, if any, clinical manifestations that would implicate a cardiac process. Given his presentation with an advanced lymphoproliferative process, we were unable to determine whether or not the heart was the primary or one of the secondary sites of his lymphoma. In the correct clinical setting, consideration of cardiac lymphoma often begins following the detection of cardiomegaly, signs of congestive heart failure, and pericardial or pleural effusions on plain chest radiographs. Two-dimensional imaging using transthoracic and transesophageal echocardiographies (TTE and TEE) are cardiac imaging modalities that allow for accurate evaluation and quantification of masses and ventricular wall thickening.21 Furthermore, contrast echocardiography can be helpful in delineating the endocardial border for evaluation of the global and segmental left ventricular function.57

Computed tomography and magnetic resonance imaging (MRI) scans are quite sensitive, not only allowing the diagnosis of these often ill-defined, infiltrating masses but may also provide information as to the degree of tumor vascularization and necrosis.58 Ultimately, in order to make a definitive diagnosis, cytology of pericardial fluid or histologic examination of the tissue mass obtained via either a transvenous biopsy or exploratory thoracotomy is required. Cardiac lymphoma, especially in an HIV-positive patient, should be considered a systemic disease, thus early systemic chemotherapy is the preferred initial treatment modality. Radiation therapy alone, or as is more often the case with chemotherapy, is undertaken less frequently. Surgical intervention intended for curative purposes is discouraged and is generally reserved for palliative reasons such as relieving obstruction. Controlled, randomized studies aimed at determining the best chemotherapeutic regimen for treating cardiac lymphoma have not been carried out. In general, combination chemotherapy with EPOCH or cyclophosphamide, doxorubicin, vincristine, and prednisolone is currently the recommended initial treatment. Rituximab is often added to the regimen if the lymphoma has been determined to be CD20 positive. Because of a high likelihood of concurrent central nervous system disease, cytologic and flow cytometry analysis of the cerebrospinal fluid is indicated in all HIV-positive patients. The administration of prophylactic intrathecal methotrexate is frequently added, particularly in those patients with 2 or more extranodal sites of lymphoma.54 Response and survival data for cardiac lymphoma are derived mainly from case reports beginning with what may be the first described case occurring in 1939 and a few series of various sizes since that first report.29,59,60 Because published reviews to date have either included few HIV-positive patients or reported without regard to immune status, the reported data may not apply to lymphoma and the heart in the population

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5

Male

56

39

52 31

36

47

42 34 44

44 30

36 42

41

37

NHL, large B cell

NHL, large B cell Large cell immunoblastic

NHL, large B cell

Burkitt lymphoma

Anaplastic large cell NHL Plasmablastic

NHL, large B cell NHL, large B cell

NHL, large B cell Burkitt lymphoma

Burkitt lymphoma

NHL, large B cell

Male

Female

Male Male

Male Female

Male Female Male

Male

Female

Male Male

Male

Male Male Male

Male

Male

44 30 48

30

Large B cell

Male Male Male

NHL, large B cell NHL, large B cell Large cell immunoblastic NHL

41 88 40

NHL, large B cell NHL, large B cell NHL

Male

35

34

NHL

Gender

Burkitt lymphoma

Age

Lymphoma Type

166

798

Not described 104

88 58

Not reported 400 44

110

125

20 258

98

130

Not described Not described Not described

Not described

Not described

Not described Not described Not described

80

CD4 Count

Not described Bone marrow

Bone and head

Not described

Not described Not described Not described

Not described

Liver

Not described Not described Not described

Not described

Other Organ Involvement

Lumbar spine

Not described Head

Not described Kidney and lung

Chest pain and Not described sinus tachycardia

Not described Sinus tachycardia and CHF Sinus tachycardia Syncope and bradicardia Sinus tachycardia

Liver, bowel, and lung CHF Bone marrow and lymph node Sudden death Liver CHF and chest pain Not reported Dyspnea Colon

Not described Atrial flutter, dyspnea, and SVC syndrome Not described

Atrial flutter and chest pain Not described

Dyspnea and epigastric pain CHF and angina CHF Dyspnea

Not described Not described CHF and sinus tachycardia CHF

Hepatomegaly

Cardiac Manifestation

Table 1. Summary of Reported Cases of Cardiac Lymphoma in HIV-Infected Patients.

TTE

TTE

Cardiac MRI CT chest

Cardiac MRI TTE

Autopsy TTE TTE

TTE

TEE

Cardiac MRI Cardiac MRI

CT chest

TTE

CT chest TTE TTE

TTE

MRI chest

Autopsy Autopsy TTE

TTE

Diagnostic Method

Discharged Expired 1 year after diagnosis

Expired in jail Discharged Expired 4 months after diagnosis Discharged Discharged

Expired 14 months after diagnosis Discharged

Expired 2 months after diagnosis Discharged Expired during admission

Discharged Expired during admission Expired 8 months after diagnosis Discharged

Expired during admission

Not known Not known Expired 3 months after diagnosis Expired during admission

Expired during admission

Outcome

EPOCH þ intrathecal chemo Cyclophosphamide Expired during admission

CHOP R-EPOCH

R-CHOP R-CHOP

CHOP and bleomycin EPOCH and bleomycin Not reported CHOP CHOP

CHOP CHOP and ABVD

CHOP

CHOP

CHOP Not described Not described

EPOCH þ methotrexate Vincristine

Not described Not described CHOP

Not described

Treatment

(continued)

Lather, et al50

Mendiolaza, et al49

Matsuo, et al47 Knowles, et al48

Kaplan, et al19 Iwahashi, et al46

Burke, et al43 Lizarralde, et al44 Nasta, et al45

Brinkman, et al42

Sanna, et al41

Piketty, et al39 Duong, et al40

Piketty, et al39

Pousset, et al38

Kelsey, et al35 Holladay, et al36 Horowitz, et al37

Helfand34

Goldfarb, et al33

Constantino, et al30 Guarner, et al31 Guarner, et al31 Andress, et al32

Reference

6

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46

62

41

44

NHL, large B cell

NHL, large B cell

NHL, large B cell

NHL, large B cell

Male

Male

Male

Female

Male

Gender

Not described

67

Not described

Not described

112

CD4 Count

Other Organ Involvement

CHF and sinus tachycardia

Not described

CHF, LVH, and Not described sinus tachycardia CHF, angina, and Gastric kidney and LVH ovaries CHF Adrenal glands, kidney, thyroid, psoas muscle, lungs, bowel, and brain Not described Liver

Cardiac Manifestation

Cardiac MRI

R-CHOP

CHOP

Not described

Autopsy

TTE

Not described

CVAP-R

Treatment

Autopsy

TTE and TEE

Diagnostic Method

Expired 4 months after diagnosis

Discharged

Expired during admission

Outcome

Vivekanandarajah, et al54 Llitjos, et al55

Armstrong, et al53

Kadhim, et al52

Gaspar, et al51

Reference

Abbreviations: NHL, non-Hodgkin lymphoma; TTE, transthoracic echocardiogram; CHF, congestive heart failure; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; MRI, magnetic resonance image; EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; CT, computerized tomography; ABVD, adriamycin (doxorubicin), bleomycin, vincristine, and dacarbazine; TEE, transesophageal echocardiogram; R, rituximab; LVH, left ventricular hypertrophy; CVAP-R, cyclophosphamide, vincristine, adriamycin (doxorubicin), prednisolone, and rituximab; chemo, chemotherapy; SVC, superior vena cava.

68

Age

NHL, large B cell

Lymphoma Type

Table 1. (continued)

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living with HIV/AIDS. Overall, the prognosis with HIVassociated cardiac lymphoma is quite poor. Adverse prognostic factors, albeit, in mixed patient populations, have been found to include a compromised immune state, extracardiac disease, left ventricular involvement, and the absence of cardiac arrhythmia.29 It is suggested that those patients with rhythm disturbances may have survived longer due to symptoms that may have led to an early presentation, diagnosis, and treatment. Although clinical improvement and significant tumor regression have been described following aggressive chemotherapy, the most common causes of death are congestive heart failure, severe infection, progression of lymphoma, pulmonary and cerebrovascular emboli, cardiac arrhythmias, and on occasion, tumor lysis syndrome.19,29,61 In reviewing the available information from previous reports of cardiac lymphoma in HIV-infected patients, we found that our patient shared the majority of the presenting clinical and diagnostic features common to most (Table 1). Specifically, >80% occurred in men with a mean age of 42 years (range, 30-88 years); presented with signs and symptoms of congestive heart failure, chest pain, or tachyarrhythmia; were discovered to have very depressed CD4 counts (only 2 had >200 cells/mL); depended upon TTE as the most frequently used diagnostic imaging modality; almost all were found to have the diffuse large B-cell lymphoma type (5 Burkitt, and 3 others) with one or more extranodal sites of disease described; and with many expiring during their presenting hospital admission regardless of receiving systemic chemotherapy.

Conclusion The availability of several highly effective antiretroviral agents has directly led to dramatic reductions in opportunistic infections and premature mortality in those living with HIV/AIDS. Nevertheless, various types of malignancies have been observed to become more prevalent in the HIV-infected population in comparison to age-matched cohorts of uninfected individuals.6 Of the 3 AIDS-defining cancers, the most frequently diagnosed is NHL, with studies examining the impact of cART on the incidence of NHL yielding somewhat contradictory results.62,63 Autopsy series suggest that cardiac involvement of disseminated lymphoma is more common than generally appreciated. Although the heart may be the primary site of the lymphoma, cardiac involvement is more often seen in the context of multifocal disease when encountered in HIV-infected and other immunocompromised patients. Diffuse large B-cell lymphoma is the most common subtype, with other histological forms, including Burkitt lymphoma, accounting for a much smaller portion of cases. The majority of HIV-infected patients with cardiac NHL are highly immunosuppressed. Patients frequently present with weight loss, fever, and night sweats and often demonstrate signs and symptoms of right-sided heart failure, arrhythmias, or embolic manifestations. The right-sided cardiac chambers and pericardium tend to be involved to a greater extent than the left ventricle or septum. Echocardiography (TTE and TEE), CT scan, and MRI are the

most sensitive diagnostic imaging modalities. Because other anatomic sites are more readily amenable to tissue sampling, biopsy of the heart (either minimally invasive or surgical) for histopathologic confirmation is uncommonly performed. Despite aggressive treatment with chemotherapy, the overall prognosis is quite poor, with early mortality related to either the malignancy itself or complications directly related to the cardiac involvement. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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