Abstract
Introduction
Although thymic epithelial tumors (TET) commonly infiltrate mediastinal structures, cardiac involvement is uncommon and has not been systematically studied. The purpose of this study was to describe our single-institution experience of the clinical presentation, treatment and follow up of cardiac involvement in patients with TETs.
Methods
A single institution retrospective review of cardiac involvement among patients with TETs from 2008 to 2012.
Results
The frequency of cardiac involvement was 4%. All five patients with confirmed cardiac disease had left heart involvement. Only one patient was symptomatic. Myocardial invasion was the most common mode of involvement followed by trans-venous spread. Surgical resection of the involved area was attempted in three patients: in one, surgery was aborted due to extensive myocardial involvement; in the other two patients, resection was incomplete. Surgery averted a potentially catastrophic hemodynamic complication in one patient. However, cardiac tumor recurred in both patients who underwent incomplete resection. One patient underwent radiation therapy resulting in complete regression of an aortic root mass.
Conclusions
This study represents the most comprehensive review of cardiac involvement in patients with TETs. In contrast to previous single-case reports, we found a preponderance of asymptomatic presentation, left heart involvement and myocardial invasion. Dynamic cardiovascular magnetic resonance imaging should be considered in cases when cardiac involvement is suspected. While immediate surgical resection is indicated for impending hemodynamic compromise, long-term palliation with surgery for myocardial involvement appears poor, especially when complete resection cannot be performed. Radiation therapy should be considered in selected patients.
Keywords: thymic epithelial tumors, cardiac tumors, cardiovascular magnetic resonance imaging
Thymic epithelial tumors (TET) are the most common anterior mediastinal tumors in adults.1 TETs tend to spread along the serosal surfaces, i.e., along the pleura and pericardium. Although they commonly infiltrate mediastinal structures, cardiac extension is often limited to the pericardium and intracardiac extension is rare.2 There are several single-case reports of intracardiac extension of TETs, but these reports lack details of treatment, follow up, outcomes and moreover details of cardiac involvement due to use of computed tomography (CT) or echocardiogram as primary imaging modalities. To our knowledge, there are no systematic reports of clinical presentation, patterns of involvement, treatment and outcome of cardiac involvement in TETs.
MATERIALS AND METHODS
A retrospective review was performed of patients with TETs who were evaluated in the Thoracic Oncology Clinic, National Cancer Institute to study the clinical presentation, patterns of cardiac involvement, treatment and outcome. All patients had histologically confirmed thymoma or thymic carcinoma. Dynamic cardiovascular magnetic resonance imaging (cardiac MRI) was performed (1.5 Tesla, gadolinium enhancement) when cardiac involvement was suspected on CT/echocardiogram or prior to surgery after neoadjuvant chemotherapy. Demographic information, treatment history, details of cardiac involvement, tumor characteristics, treatment, and follow up were obtained from medical records. All patients were enrolled on investigational protocols and signed consents approved by the Institutional Review Board.
RESULTS AND DISCUSSION
One hundred and twenty two patients with TETs were evaluated between January 2008 and June 2012. There was a comparable number of patients with thymoma, 59 (48%) and thymic carcinoma, 63 (52%). Nearly all patients (98%) presented with advanced stages (Masaoka Stage III and IV) of disease. Cardiac involvement was diagnosed in five (males 3; females 2; age range, 31–60 years). Demographic information, details of cardiac involvement, treatment, outcome and follow up of patients are summarized in Table 1. Only five patients (4%) had confirmed cardiac involvement (Figure 1). All five patients had left heart involvement, a finding which has been rarely described in TETs. Left ventricle (LV) was involved in three patients (cases 1, 4, 5) while left atrium (LA) was involved in two (cases 2, 3). We are aware of only one prior report of LV involvement with TETs.3
Table 1.
Patient Demographic Information, Details of Cardiac Involvement, Treatment, Outcome and Follow Up
| Pt. No Age Sex | Stage/ Histology at diagnosis¶ | Time from initial diagnosis to detection of cardiac involvement (years) | Areas of cardiac involvement | Mode of cardiac involvement | Histology of cardiac mass | Treatment | Outcome* | Follow up* |
|---|---|---|---|---|---|---|---|---|
| 1 31M | IVA AB | 3 | LV RA,SVC | IV via myocardium | B3/TC | S (R2) | Cardiac and extra-cardiac recurrence at 6 w | Continuing systemic therapy at 10 m |
| 2 44M | IVB AB | 8 | LA | IA via PV | TC | S (R2) | Cardiac recurrence at 2 weeks and extra-cardiac recurrence at 3 m | Died at 5 m |
| 3 60F | IV B3 | 4 | LA, AoR RA | IA via myocardium | NA | IMRT | Shrinkage of cardiac and extra-cardiac tumors | No evidence of disease at 8 m |
| 4 60M | IVA B3 | 7 | LV | Myocardium | NA | Observation | Stable cardiac involvement at 2 y | Continues systemic therapy at 2.7 y |
| 5 40F | IVA B1 | 0.6 | LV | Myocardium | B2 | S (R2) | Extra-cardiac PD at 2 m | Died at 7 m |
LA, left atrium; SVC, superior vena cava; RA, right atrium; PV, pulmonary vein; LV, left ventricle; AoR, Aortic root; IA, intra-atrial; IV, intra-ventricular; TC, thymic carcinoma NA, not applicable; PD, progressive disease; S, surgical resection; R2, residual gross disease remains unresected; IMRT, intensity modulated radiation therapy; w, weeks; m, months; y, years
Masaoka stage and WHO histological grade
Outcome and follow up are recorded as time elapsed from surgery, radiation (patients 1,2, 3, 5) or from detection of cardiac involvement (patient 4)
Figure 1.
Various presentations of cardiac involvement of thymic malignancies using cardiac magnetic resonance (CMR) imaging (top frame) and corresponding computed tomography (CT) images (lower frame) are depicted. (A) Left atrioventricular groove mass (arrows) with direct intraventricular extension (upper left corner) from case 1. (B) Left atrial mass (arrows) is depicted extending from contiguous lung mass invasion via pulmonary vein (upper right corner) in case 2.* (C) Direct intra-atrial invasion (arrows) of extracardiac mass found in case 3. (D) Left anterior wall mass (arrows) with direct myocardial invasion as seen in case 5. (E) Direct myocardial extension into the lateral wall of the left ventricle seen in case 4.* Cardiac structures are labeled. Abbreviations: RA = right atrium; LA = left atrium; RV = right ventricle; LV = left ventricle; AoV = aortic valve; AO = Aorta; PA = Pulmonary Artery
*CT images were not ECG-gated during acquisition.
**CT image for case 3, courtesy of Dr. Christopher Sibley, MD
Tumor involvement of the heart can manifest in different ways: lung or mediastinal mass with direct invasion of adjacent heart; central mass extending into the LA and right atrium (RA) via the pulmonary vein (PV) and vena cava, respectively; pericardial effusion; or myocardial infiltration.4 In this series, one patient (case 2) had transvenous intracardiac extension via the PV while others had myocardial invasion (cases 1, 3, 4 and 5) from adjacent lung, mediastinal or epicardial mass. In two patients, the myocardial involvement extended as intracardiac masses (cases 1 and 3). In previous reports, extension of tumor thrombus into RA via the SVC, presumably due to invasion of thymic vein which drains into the brachiocephalic vein, was the most common mode of cardiac invasion, followed less commonly by direct invasion from adjacent tumor.3, 5, 6 The majority of patients in previous reports came to medical attention with symptoms related to SVC obstruction, reflecting the greater frequency of RA/SVC involvement. In this series, cardiac involvement was diagnosed while patients were still asymptomatic, with only one exception (case 2).
Autopsy reports suggest that myocardial involvement with cancer overall is rare.7 Four patients (cases 1, 3, 4 and 5) had areas of atypical gadolinium enhancement on cardiac MRI, suggestive of myocardial involvement. In two of them (cases 1 and 5), myocardial involvement was confirmed intra-operatively wherein dense myocardial invasion precluded complete surgical resection. Despite LV myocardial involvement, LV systolic and diastolic function was preserved in two of the four patients (cases 1 and 5). In one patient, an observed decrease in LV ejection fraction (45%; case 4) was likely due to concurrent coronary artery disease. In previous reports, only six cases of myocardial involvement of TETs have been described.3, 5, 8–10
In three patients (cases 1, 2 and 5), the histological appearance of intracardiac tumors were different from that at initial diagnosis. In case 1, histological features of the intracardiac mass resembled thymic carcinoma, but organotypic features were maintained, favoring a diagnosis of B3 thymoma (Figure 2). In case 2, pathology of the intracardiac mass showed poorly differentiated carcinoma with extensive necrosis. In both cases, the initial histology was AB thymoma. In case 5, the initial histology was B1, whereas the intrapericardial tumor was B2. The histological evolution could possibly be a reflection of tumor heterogeneity and the extent of sampling.11 However, the histological changes, specifically in cases 1 and 2, could represent transformation of a pre-existing thymoma to a more malignant phenotype and may have contributed to increased invasiveness. Previous reports have documented the association of increased tumor growth and invasiveness with the emergence of carcinoma from thymoma and support the existence of a continuum of differentiation between thymoma and thymic carcinoma.12
Figure 2.
Histological appearance of the anterior mediastinal tumor of patient 1 at diagnosis (A) showing features of AB thymoma. Cardiac tumor (B) of the same patient approximately three years after diagnosis, shows histological features resembling thymic carcinoma with areas of necrosis (bold arrow) and mitotic figures (thin arrow). Since organotypic features were maintained, a diagnosis of B3 thymoma was favored [hematoxylin-eosin, original X 40].
Although MRI is not used routinely in TETs, it provides improved resolution, soft-tissue contrast and tissue characterization. Malignant tumors in general have low signal intensity on T1-weighted images, high signal intensity on T2-weighted images, and varying degrees of enhancement after contrast material administration. MRI is also useful in distinguishing thymomas from thymic carcinoma and can better delineate the extent of involvement to guide surgical and/or radiation therapy (RT) planning.13, 14 Dynamic cardiac MRI should be strongly considered in TETs when cardiac involvement is suspected.
Complete surgical resection is the mainstay of therapy for thymomas and is the most important predictor of long-term survival.2 However, in select patients incapable of being rendered completely disease-free, debulking may be worthwhile for either palliation or to avoid catastrophic complications.15 One patient (case 2) underwent emergent surgical resection of intracardiac mass due to prolapse of the LA mass through the mitral annulus, causing functional mitral flow obstruction (Video 1). Although the intracardiac mass was excised, extracardiac component of the tumor could not be completely resected due to dense adhesions to myocardium from prior surgeries. Complete surgical resection could not be achieved in a second patient (case 1) due to intimate tumor involvement at the level of posterior AV groove and the nearby epicardial cardiac vessels, and thus residual infiltrative tumor remained. Surgical resection was attempted in a third patient (case 5), but had to be aborted due to extensive intrapericardial sac involvement and direct tumor extension through the pericardium into myocardium in several areas. In both cases 1 and 2, rapid tumor recurrence was noted in the areas where tumor was incompletely excised, with recurrences detected at six and two weeks after cardiac surgery, respectively. Patient 1 had rapid progression of disease despite successive treatments with systemic therapies and at 10 months after surgery was receiving a third agent. Patient 2 had a complicated post-operative course with recurrent infections, cardiac arrhythmias and respiratory failure resulting in death five months after surgery. Patient 3 was found to have rapidly progressive extra-cardiac disease two months after the attempted surgical resection and died seven months later after failing to respond to two systemic therapies. In patients with myocardial involvement, resection may often be incomplete. While immediate surgical resection is indicated if hemodynamic compromise is imminent from obstructed cardiac outflow by an intracardiac lesion (case 2), long-term palliation with surgery for myocardial involvement appears poor. Hence, surgery should be considered for cardiac involvement of TETs only if complete resection of tumor can be achieved. Alternatively, induction chemotherapy may be an option in patients with no impending compromise and limited cardiac involvement. No intervention was considered for a patient (case 4), whose cardiac involvement remained stable for over two years. He continues to receive systemic therapy for slow progression of extra-cardiac disease. Among the previously reported cases of myocardial involvement, one patient underwent incomplete surgical resection and died one month later.9 Two patients who underwent complete resection of atrial myocardial involvement had no evidence of recurrence 6 months and 29 months after surgery.8, 10 In the other three cases, neither treatment details nor outcome were reported.3, 5
RT may not be feasible in many cases due to prior radiation to the field, prior doxorubicin exposure, or risk of direct cardiac toxicity. The latter is dependent on the location and proportion of the myocardium that will be included in the treatment portals, as well as the dose of radiation to be administered. Patient 3 was not referred for surgery due to involvement of an area which was thought to be amenable to RT. She safely received a definitive dose of 63 Gray directed to the aortic root with sufficient sparing of heart resulting in complete regression of the cardiac mass on follow-up. She remains asymptomatic with no evidence of disease eight months after RT. In patients with incomplete excision, given the rapid rate of recurrence, post-operative RT may be considered.
In addition to being the largest series of patients with a systematic assessment of cardiac involvement, the strengths of this study include detailed visualization using cardiac MRI, pathologic confirmation (in operative cases) and availability of long-term follow-up. Besides the inherent biases associated with a retrospective series, over-diagnosis of asymptomatic cardiac involvement may have resulted from frequent use of imaging studies in the setting of clinical protocols.
CONCLUSION
We identified five cases of cardiac involvement from TETs in a retrospective review. The patients exhibited several uncommon features including left-sided and infiltrative myocardial involvement. Patients with TETs who present with paracardiac masses should be closely monitored radiologically for cardiac involvement, since development of symptoms may occur late. MRI is an useful tool when cardiac involvement is suspected, to delineate the extent of involvement, determine resectability and plan RT. Early recognition of intracardiac involvement might facilitate complete surgical resection. There is no benefit for incomplete surgical resection. RT in selected inoperable cases can prevent or delay cardiac complications.
Supplementary Material
Video 1: Large mass protruding into the left atrium as it extends along a pulmonary vein from a contiguous lung mass as seen on cardiovascular magnetic resonance steady-state free precession cine imaging in case 2. As depicted, the intraatrial portion of the mass has two heads, one of which is mobile and prolapses partially through the mitral annulus during diastole.
Acknowledgments
FUNDING: This research was supported by the Intramural Research Program of the National Institutes of Health
Footnotes
CONFLICTS OF INTEREST: The authors declare that no conflicts of interest exist
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Supplementary Materials
Video 1: Large mass protruding into the left atrium as it extends along a pulmonary vein from a contiguous lung mass as seen on cardiovascular magnetic resonance steady-state free precession cine imaging in case 2. As depicted, the intraatrial portion of the mass has two heads, one of which is mobile and prolapses partially through the mitral annulus during diastole.