Deciphering Cardiac Sarcomas: Etiology, Diagnosis, and Therapeutic Frontiers

Abstract

Cardiac sarcomas, characterized by their rarity and aggressive nature, pose substantial diagnosis and treatment challenges. This Commentary emphasizes a multidisciplinary approach integrating clinical insights, advanced imaging techniques, histopathological analysis, and molecular diagnostics to achieve effective personalized patient management. It discusses the critical role of surgical resection in managing localized disease, complemented by adjuvant therapies such as chemotherapy and radiotherapy, to improve patient outcomes. This Commentary highlights emerging treatments including targeted therapies and immunotherapy, and calls for sustained research efforts to better understand the molecular underpinnings of these tumors and develop more effective treatments.

Main article text

Introduction

Cardiac sarcomas, although rare, pose major clinical challenges, because of their aggressive behavior and limited treatment options. Herein, we examine the multifaceted aspects of cardiac sarcomas, including their etiology, pathogenesis, diagnostic modalities, therapeutic interventions, and prognostic considerations (Figure 1). By elucidating the intricate landscape of these malignancies, we hope to provide clinicians and researchers with a deeper understanding to guide clinical practice and advance therapeutic strategies.

Figure 1

Understanding Cardiac Sarcomas: Etiology, Classifications, Diagnosis, and Treatments.

Figure 1 illustrates the general traits of cardiac sarcoma, a rare and heterogeneous tumor arising from the heart and potentially associated with certain genetic mutations. It categorizes cardiac sarcoma based on histological subtypes and delineates diagnostic approaches, encompassing imaging techniques and histopathological examination, which are indispensable for precise diagnosis. The description of the treatment plan encompasses surgical excision, chemotherapy and radiation therapy, customized to tumor characteristics and patient-specific factors.

Etiology and Pathogenesis of Cardiac Sarcomas

Cardiac sarcomas, rare malignancies originating from the heart’s mesenchymal tissue, exhibit complex etiological and pathogenic mechanisms. Although the specific triggers remain elusive, emerging evidence highlights the involvement of genetic variations influencing critical signaling pathways. Dysregulation of angiogenic factors, such as VEGFR2, promotes neovascularization within the tumor microenvironment, and facilitates tumor growth and metastasis [1]. In addition, malfunctioning oncogenic signaling pathways, such as KRAS and TP53 mutations, contribute to sarcoma development. Molecular aberrations, including fusion genes such as ETV6-NTRK3 in fibrosarcoma and genetic variations affecting striated muscle development in rhabdomyosarcoma, underscore the heterogeneity of cardiac sarcomas [2, 3]. Metastatic spread to the heart, often from hepatic origins, further complicates diagnosis and differentiation between primary and secondary sarcomas.

Addressing these challenges requires molecular genetic techniques, such as identification of fusion genes and chromosomal abnormalities, for precise diagnosis and treatment stratification. Overall, understanding the intricate interplay among genetic susceptibility, dysregulated signaling pathways, and environmental factors is crucial for advancing therapeutic strategies and improving outcomes for patients with cardiac sarcomas.

Diagnostic Modalities

The diagnosis of cardiac sarcomas poses a considerable challenge, because of their nonspecific clinical presentation and rarity. A systematic diagnostic approach, incorporating clinical evaluation, advanced imaging techniques, histopathological analysis, and molecular testing, is essential for accurate and timely diagnosis. Clinical manifestations vary widely, ranging from asymptomatic incidental findings to symptoms such as dyspnea, chest pain, and palpitations, which may mimic other cardiac conditions. Echocardiography, the initial imaging modality of choice, enables detection of cardiac masses and assessment of their anatomical characteristics. Cardiac magnetic resonance imaging and computed tomography scans provide complementary information regarding tumor location, size, and tissue characteristics, thereby aiding in treatment planning and prognostication [4]. Histopathological examination of tissue specimens obtained via biopsy or surgical resection remains indispensable for confirming the diagnosis and subclassifying cardiac sarcomas according to their histological features and immunohistochemical profiles. Molecular testing, including next-generation sequencing and fluorescence in situ hybridization, may offer insights into underlying genetic alterations, and may guide therapeutic decision-making and prognostic assessment.

Cardiac Angiosarcoma

Cardiac angiosarcoma, arising from endothelial cells lining the blood vessels within the heart, are among the most aggressive subtypes of cardiac sarcomas. These tumors exhibit infiltrative growth patterns and have a tendency toward early metastasis, thereby leading to poor prognosis. Surgical resection, when feasible, remains the primary treatment modality for localized disease, with the goal of achieving complete tumor excision and negative margins. Adjuvant chemotherapy, typically using anthracycline-based regimens, has been applied to decrease the risk of recurrence and improve survival outcomes [5]. Radiation therapy may be used as an adjuvant therapy or definitive treatment for unresectable disease, with an aim to enhance local control and palliate symptoms. Emerging targeted therapies, including anti-angiogenic agents and tyrosine kinase inhibitors, hold promise in select patients, and offer novel treatment options to improve outcomes [6]. Immunotherapy, leveraging immune checkpoint inhibitors, is a promising avenue for further investigation; this therapy harnesses the body’s immune response to target tumor cells and improve survival rates [7]. Ongoing clinical trials evaluating the efficacy of immunotherapeutic agents in cardiac angiosarcoma have the potential to reshape the treatment landscape and improve patient outcomes.

Cardiac Leiomyosarcoma

Cardiac leiomyosarcoma, although rare, poses diagnostic and therapeutic complexities necessitating a comprehensive approach. Although its etiology remains enigmatic, ongoing research is providing insights into effective management strategies. Diagnosing cardiac leiomyosarcoma entails meticulous evaluation of clinical manifestations alongside use of advanced imaging techniques. Echocardiography and computed tomography scans are critical in identifying characteristic masses within the cardiac chambers. However, definitive diagnosis relies on histopathological analysis using specific markers, such as desmin and caldesmon, to aid in differentiation from other cardiac tumors [8].

Therapeutic interventions for cardiac leiomyosarcoma involve a multidisciplinary approach. Although no established treatment protocols exist, emerging research highlights potential avenues for targeted therapy [9]. Investigations of irisin’s role in cardiac remodeling have shown promise in mitigating disease progression by decreasing oxidative stress and modulating signaling pathways. In addition, studies on prognostic biomarkers including HMGA1 have yielded insights into predicting chemotherapy sensitivity and may guide personalized treatment strategies [10].

In conclusion, advancements in diagnostic modalities and therapeutic approaches have provided cause for optimism in improving outcomes in patients with cardiac leiomyosarcoma. Continued research endeavors will be crucial to unravel the complexities of this rare malignancy and optimize management strategies to meet the unmet needs of affected individuals.

Cardiac Rhabdomyosarcoma

Cardiac rhabdomyosarcoma presents substantial challenges in clinical oncology, because of its rarity and complex pathogenesis. The precise etiology remains poorly understood, and genetic variations affecting striated muscle development have been hypothesized to be contributing factors. Unlike its pediatric counterpart, rhabdomyoma, cardiac rhabdomyosarcoma occurs across sexes and shows no racial predilections [11]. Therapeutic strategies have been predominantly multimodal and individualized. Previous studies have investigated alternating chemotherapy regimens such as vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide for managing intermediate-risk rhabdomyosarcoma and undifferentiated sarcoma [12]. Surgical interventions, including total orthotopic heart transplantation, have shown promise in cases in which complete tumor resection is not feasible. The lack of standardized treatment guidelines underscores the need for comprehensive studies to delineate optimal therapeutic strategies, particularly for primary cardiac tumors. Molecular karyotyping has identified actionable genetic targets implicated in disease progression, thereby offering opportunities for targeted therapies tailored to individual tumor profiles.

Emerging evidence, including the successful treatment with novel agents such as eribulin, underscores the importance of exploring alternative treatment modalities [13]. In the future, research efforts aimed at elucidating the molecular underpinnings of cardiac rhabdomyosarcoma and conducting robust clinical trials will be essential to advance understanding and management of this rare malignancy.

Cardiac Fibrosarcoma

Cardiac fibrosarcoma is a challenging malignancy known for its aggressive behavior and tendency toward local recurrence and distant metastasis. Histopathological examination remains crucial for confirming the diagnosis of cardiac fibrosarcoma, which is characterized by spindle-shaped cells forming interlacing fascicles, mitotic activity, and necrotic areas. Immunohistochemical staining, particularly for markers such as smooth muscle actin and vimentin, may assist in differentiating fibrosarcoma from other cardiac tumors [14].

Treatment of cardiac fibrosarcoma is complicated by its aggressive nature and high rates of recurrence and metastasis. Surgical resection, the primary approach, is challenged by tumors’ infiltrative nature. Sun et al. have reported median and average survival times after tumor removal, thus highlighting the need for improved post-treatment strategies to mitigate recurrence and metastasis. Prognostic factors such as age, sex, tumor size, and histologic grading influence survival outcomes in cardiac fibrosarcoma [15]. Higher-grade tumors exhibit a greater propensity for metastasis, thus emphasizing the importance of early diagnosis and intervention. In addition, the association of cardiac fibrosarcoma with nevoid basal cell carcinoma syndrome underscores the importance of recognizing syndromic presentations and their implications in patient management.

Conclusion

In conclusion, cardiac sarcomas pose major diagnostic and therapeutic challenges, because of their rarity and aggressive behavior. A multidisciplinary approach integrating clinical expertise, advanced imaging techniques, histopathological analysis, and molecular testing, is essential for accurate diagnosis and personalized treatment planning. Surgical resection remains the cornerstone of therapy for localized disease, and adjuvant therapies have crucial roles in optimizing outcomes. Emerging targeted therapies and immunotherapeutic agents have shown promise in select patients, thus underscoring the need for ongoing research to advance treatment options and increase long-term survival rates. Enhancing understanding of the molecular mechanisms driving tumorigenesis and metastasis may pave the way to more effective targeted therapies and personalized treatment approaches, thus ultimately improving outcomes for patients with cardiac sarcomas.

Acknowledgments

The first author, XZW, is deeply grateful to his parents, Wang Ning and Ma Zhifeng, for their support and many enlightening discussions.

Conflict of Interests

The authors declare no conflicts of interest.

Citation Information

Download Citation.

References

1. R Liu, D Chen, F Dong, H Wang, JF Shang, F Teng. Primary cardiac angiosarcoma: a clinicopathological and molecular genetic analysis of thirteen cases. Zhonghua Bing Li Xue Za Zhi 2023;52(6):599–605.

2. C Leduc, SM Jenkins, WR Sukov, JG Rustin, JJ Maleszewski. Cardiac angiosarcoma: histopathologic, immunohistochemical, and cytogenetic analysis of 10 cases. Hum Pathol 2017;60:199–207.

3. I Machado, R Claramunt-Alonso, J Lavernia, I Romero, M Barrios, MJ Safont, et al. ETV6::NTRK3 fusion-positive wild-type gastrointestinal stromal tumor (GIST) with abundant lymphoid infiltration (TILs and tertiary lymphoid structures): a report on a new case with therapeutic implications and a literature review. Int J Mol Sci 2024;25(7):3707.

4. PA Araoz, HE Eklund, TJ Welch, JF Breen. CT and MR imaging of primary cardiac malignancies. Radiographics 1999;19(6):1421–34.

5. A Narezkina, HK Narayan, AE Zemljic-Harpf. Molecular mechanisms of anthracycline cardiovascular toxicity. Clin Sci (Lond) 2021;135(10):1311–32.

6. N Kumari, S Bhandari, A Ishfaq, SRR Butt, C Ekhator, A Karski, et al. Primary cardiac angiosarcoma: a review. Cureus 2023;15(7):e41947.

7. Z Zeng, Z Mei, M Chen, H Cao, Q Xiang, H Cai, et al. Cadonilimab plus anlotinib effectively relieve rare cardiac angiosarcoma with multiple metastases: a case report and literature review. Clin Res Cardiol 2024;113(2):358–65.

8. S Sankarasubramanian, P Prabhakar, MK Narasimhan. Genetic insights into cardiac tumors: a comprehensive review. Med Oncol 2022;39(11):164.

9. R Cruz Palomera, JD Valencia Gonzalez, J Guzmán Olea, RE Gutiérrez Castañeda, JF Rodríguez Alvarado, J Camacho Huembes, et al. A monster into the heart: an unusual presentation of cardiac leiomyosarcoma. Egypt Heart J 2023;75(1):101.

10. DS Moura, JL Mondaza-Hernandez, P Sanchez-Bustos, M Peña-Chilet, JA Cordero-Varela, M Lopez-Alvarez, et al. HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study. Cell Mol Life Sci 2024;81(1):219.

11. V Cantarín-Extremera, B Bernardino-Cuesta, C Martín-Villaescusa, J Melero-Llorente, A Hernández-Martín, C Aparicio-López, et al. Tuberous sclerosis complex: analysis of areas of involvement, treatment progress and translation to routine clinical practice in a cohort of paediatric patients. Rev Neurol 2021;73(5):141–50.

12. CA Arndt, AG Nascimento, G Schroeder, PJ Schomberg, JP Neglia, SF Sencer, et al. Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide. Eur J Cancer 1998;34(8):1224–9.

13. S Ota, T Shimonaga, S Yuki, K Kuraoka, T Ogawa, T Hirata. Primary cardiac rhabdomyosarcoma successfully treated with eribulin: a case report. Anticancer Drugs 2020;31(3):304–9.

14. MG Asakawa, MK Ames, Y Kim. Primary cardiac spindle cell tumor in a dog. Can Vet J 2013;54(7):672–4.

15. D Sun, Y Wu, Y Liu, J Yang. Primary cardiac myxofibrosarcoma: case report, literature review and pooled analysis. BMC Cancer 2018;18(1):512.