A Challenging Case of Pediatric Cardiac Leiomyosarcoma: Surgery,Recurrence,and Remission With Tyrosine Kinase Inhibitor

Introduction

Leiomyosarcoma, a malignant tumor of smooth muscle, accounts for less than 8% of cardiac sarcomas and rarely involve the pulmonary valve. ¹ We describe a four-year-old girl whose pulmonary valve tumor, initially presumed benign, was diagnosed as a leiomyosarcoma on histopathology after surgical resection, recurred, and then regressed completely after pazopanib therapy, thereby avoiding a high-risk reoperation.

Case Description

A previously healthy four-year-old girl presented with multiple episodes of syncope. She was hemodynamically stable but had elevated jugular venous pressure with prominent c-v waves, a grade 3/6 ejection systolic murmur at the left upper sternal border, and a grade 4/6 harsh holosystolic murmur at the lower parasternal region, along with hepatomegaly.

Chest radiograph showed cardiomegaly with a cardiothoracic ratio of 0.7. Electrocardiogram demonstrated sinus tachycardia, right-axis deviation, and T-wave inversions in V1 to V5. Transthoracic echocardiography revealed a 19 × 12 mm isoechoic mass in the right ventricular outflow tract (RVOT), closely abutting the pulmonary valve and producing a peak gradient of 88 mm Hg (Figure 1). This was accompanied by moderate tricuspid regurgitation, mild pulmonary regurgitation, and severe right ventricular dysfunction. Based on intracardiac location and imaging features, differential diagnosis included benign tumors (eg, myxoma, rhabdomyoma), thrombus, and infective endocarditis. However, the absence of systemic signs, negative cultures, and no thrombotic risk factors made thrombus and endocarditis unlikely.

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Figure 1.

Transthoracic echocardiography in parasternal short-axis view (A) shows a 19 × 12 mm well-circumscribed, isoechoic mass in the right ventricular outflow tract (RVOT) abutting the pulmonary valve. The mass led to right ventricular outflow tract obstruction (B) with a peak gradient of 88 mm Hg (C).

Contrast-enhanced cardiac magnetic resonance imaging (CMR) was performed, which revealed a well-defined mass in the RVOT showing limited to-and-fro motion across the pulmonary annulus (Figure 2A). Pulmonary valve leaflets were not separately visualized. The mass was isointense on T1-weighted images (Figure 2B), mildly hyperintense on T2 fat-saturated images (Figure 2C). No abnormal cystic area or hemorrhagic residue was seen within the mass. On dynamic perfusion imaging, no first-pass perfusion was seen in the mass. On delayed enhancement sequences, linear hyperintense late gadolinium enhancement (LGE) was seen along with the pulmonary valve leaflets and pulmonary valve annulus. No LGE was seen within the mass (Figure 2D). Imaging characteristics on CMR were consistent with a benign mass arising from the pulmonary valve. ²

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Figure 2.

Cardiac MRI steady-state free precession (SSFP) (A) in short-axis at the level of right ventricular outflow tract shows a well-defined mass lying close to the pulmonary annulus (asterisk). The mass was isointense on T1WI (B) and hyperintense on T2WI (C). Late gadolinium enhancement (LGE) (D) shows no enhancement within the mass (asterisk), although enhancement was present along with the pulmonary annulus (white arrow). Abbreviations: MRI, magnetic resonance imaging; RV, right ventricle

Because of recurrent syncope, heart failure due to severe RVOT obstruction, and RV dysfunction, surgical resection of the tumor was performed. A bilobed mass measuring 20 × 15 mm attached to the anterior cusp and the commissure between the anterior and the left cusps of the pulmonary valve was resected (Figure 3). Assuming it to be a benign tumor based on preoperative multimodality imaging, including CMR, complete resection was avoided to preserve pulmonary valve function. A full excision would have required pulmonary valve removal and RV to pulmonary artery (PA) conduit placement, which, in a young child, carries substantial risks of early degeneration, thrombosis, and the need for multiple future reinterventions.

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Figure 3.

Intraoperative photograph during (A) and after surgical resection (B) shows a well-defined 15 × 20 mm bilobed mass (black arrow) originating from the commissure between the anterior and left cusps of the pulmonary valve.

During histopathology assessment, microscopy demonstrated a spindle cell neoplasm characterized by blunt-ended nuclei, significant necrosis exceeding 50% of the tumor volume, and a mitotic rate of 4 to 5 per 10 HPF. Proliferative activity was high, with a Ki-67 labeling index of 30% to 35%. The tumor exhibited diffuse immunoreactivity for Desmin and SMA, confirming smooth muscle lineage. Absence of staining for S100, SOX10, β-catenin, MDM2, ALK, and ERG excluded alternative diagnoses, including neural, fibromatosis-related, lipogenic, inflammatory, and vascular neoplasms. These findings were consistent with grade 2 leiomyosarcoma. ³

Serial echocardiograms on follow-up demonstrated progressive regrowth of the residual lesion from 2 mm to 8 mm within two months. PET-CT revealed focal FDG uptake at the pulmonary annulus without evidence of metastatic spread. Given the local recurrence, the patient was initiated on doxorubicin and ifosfamide, a first-line adjuvant chemotherapeutic regimen for unresectable or locally recurrent leiomyosarcoma. However, the tumor continued to grow, reaching 15 mm in size with a peak RVOT gradient of 58 mm Hg (Figure 4A-C). Considering the aggressive tumor and poor response to chemotherapy, surgical resection of the tumor was strongly considered. Surgical reintervention, however, was high-risk, especially since it would warrant resection of the main pulmonary artery and placement of an RV-PA conduit. Given these considerations, the child was started on pazopanib, an oral multitargeted tyrosine kinase inhibitor and a second-line agent approved for advanced or recurrent soft tissue sarcomas at a dose of 100 mg once daily. ⁴ Complete regression of the cardiac lesion was observed on echocardiography following six months of pazopanib therapy (Figure 4D-F). At 12 months on pazopanib therapy, there has been no recurrence. The child tolerated pazopanib well without any adverse effects. There is currently no consensus regarding the optimal duration of pazopanib therapy following a complete response. In our patient, we plan to continue pazopanib for a total of 24 months, with a structured surveillance protocol comprising clinical review every three months for the first two years, every six months for the next three years, and annually thereafter with an echocardiogram at each visit; and hematologic/biochemical monitoring during therapy.

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Figure 4.

Echocardiogram images (A-C) 6 months after surgical resection shows regrowth of the tumor and right ventricular outflow tract (RVOT) obstruction, with a peak gradient of 58 mm Hg. Six months of pazopanib therapy led to complete regression of the tumor and RVOT obstruction (D-F).

Discussion

Cardiac tumors are rare, occurring in less than 0.03% of pediatric autopsies. Primary cardiac tumors are less common than metastases. Among primary tumors, 75% are benign, with myxomas being most common in adults and rhabdomyomas in children. ¹ Malignant primary cardiac tumors consist mostly of sarcomas, including angiosarcomas, rhabdomyosarcomas, mesotheliomas, and fibrosarcomas. Leiomyosarcomas, originating from cardiac vasculature or atrial endothelium, represent less than 1% of cases and are usually found in the left atrium. ¹ Their clinical presentation ranges from asymptomatic to symptoms such as congestive heart failure and arrhythmias. These tumors grow rapidly, often metastasize to the lungs, and frequently recur after resection. ⁵

Although advanced imaging techniques, including cardiac MRI, indicated a nonperfused, well-defined pulmonary valve mass that appeared benign, histopathology and immunohistochemistry confirmed it to be leiomyosarcoma. This diagnostic challenge highlights the limitations of imaging in distinguishing between benign and malignant cardiac masses, underscoring the necessity of histopathology and immunohistochemistry for a definitive diagnosis. ⁴

Complete surgical excision offers the best chance for local control but is often limited by anatomical constraints and the need to preserve the function of adjacent cardiac structures, such as the pulmonary valve in our case. Even with radical resection, cardiac leiomyosarcomas have a high recurrence rate, usually within months, with a median postsurgical survival of 12 to 24 months. ⁶ Considering the diagnosis and incomplete resection, the child was started on chemotherapy. However, despite the chemotherapy, the residual tumor rapidly grew to 15 mm. The recurrence of RVOT obstruction and RV dysfunction necessitated treatment. High risk of reoperation and long-term problems of the RV-PA conduit prompted the adoption of pazopanib. This decision was aligned with our goal to control local and potential micrometastatic disease while deferring a high-risk reoperation. Published experience supports the use of pazopanib in sarcomas unresponsive to first-line chemotherapy, particularly when surgical morbidity is anticipated to be high.

Pazopanib is an oral, multitargeted tyrosine kinase inhibitor approved for advanced soft tissue sarcomas with failed chemotherapy. ⁷ It works by inhibiting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), and c-KIT, thereby disrupting tumor angiogenesis and cell proliferation. ⁷ It provides a median progression-free survival of three months and overall survival of 6.2 months in patients with sarcoma. Although the response is modest, it has been found useful in pediatric sarcomas unresponsive to conventional chemotherapy.^8,9 In this case, pazopanib led to the complete disappearance of the tumor, eliminating the need for high-risk reoperation.

Remarkably, six months of pazopanib treatment in our patient resulted in complete radiologic remission of the residual valve lesion. Follow-up imaging showed no evidence of recurrent disease or metastasis, indicating that targeted therapy can be a crucial adjunct or alternative when surgical options are limited or carry high risks. ¹⁰

Although pazopanib is generally well-tolerated in pediatric patients, it is essential to monitor for potential adverse effects closely. Common side effects include gastrointestinal symptoms such as nausea, vomiting, and diarrhea; dermatologic reactions, including skin rash and hair hypopigmentation; hypertension; fatigue; and hematologic abnormalities, such as anemia, neutropenia, and thrombocytopenia. ¹¹ Regular clinical monitoring and supportive management are crucial to ensure patient safety during therapy. In our patient, no significant adverse effects were noted, underscoring pazopanib's favorable risk–benefit profile in carefully selected pediatric cases.

Conclusion

Pulmonary valve leiomyosarcoma in children is extremely uncommon and can resemble benign masses on imaging. Accurate diagnosis depends on histopathology and immunohistochemistry, and its aggressive nature often results in rapid recurrence. In situations where surgical resection carries a high risk, pazopanib helps induce complete remission of residual disease, providing a viable noninvasive treatment option.