Abstract
We present the clinicopathological characteristics of primary cardiac intimal sarcoma which was widely spread throughout bi-ventricles. The patient had a wide range of clinical manifestations starting with left-sided heart failure then finally developing refractory right-sided heart failure during 44 months of follow-up.
<Learning objective: The present clinicopathological characteristics with a wide spectrum of clinical features may provide a pivotal insight into understanding primary cardiac intimal sarcoma.>
Keywords: Primary cardiac tumor, Intimal sarcoma, Valvular heart disease, Heart failure, Clinicopathology
Introduction
The development of intimal sarcomas was originally recognized as malignant mesenchymal tumors arising in large vessels of the aortic and/or pulmonary artery [1], [2], [3], while a recent immuno-histochemical study provided a possibility of the tumors as a major proportion in primary cardiac sarcomas [4]. Although the complete resection with adjuvant therapy must be the mainstay of treatment to ameliorate clinical outcomes [5], we may usually miss the optimal timing of treatment because of less knowledge as to clinical manifestations of this tumor.
Here we present the clinicopathological characteristics of primary cardiac intimal sarcoma showing a wide spectrum of clinical features during 44 months, which may provide a pivotal insight into understanding this critical disease.
Case report
A 67-year-old woman with worsening heart failure due to severe mitral stenosis and moderate aortic regurgitation was referred to our institute. The patient was living well after undergoing mitral and aortic prosthetic valve replacements. Eighteen months later, the patient developed dyspnea on light exertion. A transthoracic echocardiogram showed a new appearance of severe tricuspid regurgitation (Fig. 1A upper). Cardiac magnetic resonance imaging revealed an enlargement in the right-sided heart and also found unknown sub-endocardial opacities in the left-sided heart (Fig. 1B lower). Because of refractory tricuspid regurgitation, we decided to replace the tricuspid valve using prosthetic mechanical valve 32 months after the first surgery. We also sampled the tissue from unknown opacities in the left atrium, and identified a bundle of spindle-shaped tumor cells with an expression of mouse/human double minute 2 protein (MDM2) and cyclin-dependent kinase 4 (CDK4) in an immunohistochemical profile as well as a molecular analysis using fluorescence in situ hybridization, namely achieving a diagnosis of cardiac intimal sarcoma [4]. During 12 months after the second surgery, the right-sided heart failure progressively developed with growing opacities in bi-ventricles (Fig. 1B–D). The patient died 44 months after the first surgery. The autopsy revealed a wide spread of intimal sarcoma in bi-ventricles with a connection via a membranous ventricular septum (Fig. 2). All of the excised three valves, but not the pulmonary arteries and veins, were also retrospectively found to contain intimal sarcoma (Fig. 3). Further, the tumor was not found in the pulmonary valve and coronary artery, but one metastatic tumor was found in the liver.
Fig. 1.
(A) Severe tricuspid regurgitation in a transthoracic echocardiogram (upper panel) and the enlarged right-sided heart with sub-endocardial opacities (black arrow head) in the left atrium and ventricle in a cardiac magnetic resonance imaging (lower panel). (B–D) A series of chest X-rays (upper panels) and transthoracic echocardiograms (lower panels) during a rapid progression in right-sided heart failure after the second surgery. White arrow heads show abnormal mass.
TR, tricuspid regurgitation; RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle; TVR, tricuspid valve replacement.
Fig. 2.
Upper panels: Macroscopic findings of the whole heart (A) and a magnification of left atrium (a) and a membranous ventricular septum (b). Intimal sarcoma widely spread through LA (cross), LV (single asterisk), and RV (white arrow) with a connection via a membranous ventricular septum (double asterisk). RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.
Lower panels: Microscopic findings of the tumor. A cluster of spindle-shaped cells (A) stained with both MDM2 (C) and CDK4 (D) (arrow heads).
HE, hematoxylin and eosin stain; MDM2, mouse/human double minute 2 protein; CDK4, cyclin-dependent kinase 4.
Fig. 3.
(A–C) Macroscopic (upper panels) and microscopic (lower panels) findings of excised aortic valve (A), mitral valve (B), and tricuspid valve (C). A cluster of spindle-shaped cells was found in thickened tissues of three valves (white arrow), but not found in the tissue of pulmonary artery (D, upper panel) and pulmonary vein (D, lower panel).
RCC, right coronary cusp; LCC, left coronary cusp; NCC, non-coronary cusp; AML, anterior mitral leaflet; PML, posterior mitral leaflet; ATL, anterior tricuspid leaflet; STL, septal tricuspid leaflet; PTL, posterior tricuspid leaflet; HE, hematoxylin and eosin stain; EVG, Elastica van Gieson stain.
Discussion
We present an autopsy case showing a wide spectrum of clinical features of primary cardiac intimal sarcoma. Our clinicopathological analysis directed us to the precise diagnosis that the development of primary cardiac intimal sarcoma manifested as multi-valvular diseases and finally produced refractory heart failure due to a widespread invasion of the tumors.
The latest classification histologically categorized cardiac intimal sarcoma as undifferentiated sarcoma [3]. However, a recent study successfully figured out the characteristics of cardiac intimal sarcoma as a cluster of spindle and pleomorphic cells expressing both MDM2 and CDK4 [4], which coincided with the present case. Primary cardiac intimal sarcoma was recently reported to come up from sub-endothelial intimal mesenchymal cells and featured predominant intraluminal progressive growth with a tendency of obstruction and/or embolic tumor dissemination without treatment [4]. When considering left-sided valvular heart failure as an initial finding of the present case, we supposed a basal portion of the left ventricle as the origin of the tumor, and a rapid progression of tumors in the right-sided heart as the possible cause for development of refractory heart failure.
A complete resection of the tumors may provide a better prognosis in patients with cardiac intimal sarcoma, while a high incidence of unresectable locations in the heart may limit those advantages and the majority of patients were dead within a couple of months to a year [5], [6]. As one of the suggested strategies, the use of cardiac autotransplantation procedure, which is composed of removing the heart once for a complete surgical excision of the tumors completely ex vivo and implanting again, may provide a better survival [7]. Recent cell biology which demonstrated co-activated platelet-derived growth factor receptor alpha and epidermal growth factor receptor with overexpression of MDM2 in intimal sarcoma may provide novel insights into the effective treatments for the tumors [8]. Further investigations are required to ameliorate poor clinical outcomes in patients with this rare but so critical disease.
Conflict of interest
None of us have anything to disclose for this study.
Acknowledgments
We are deeply indebted to Dr Harukaze Yamamoto of Breast Medical Oncology, National Cancer Center Hospital for his advice regarding the final diagnosis, Ms Yuko Nagata and Ms Reina Watanabe for their contributions in preparing this article.
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