Primary Cardiac Myxofibrosarcoma of the Left Atrium with Heterologous Elements Mimicking a Cardiac Myxoma

Introduction

Primary cardiac tumors are extremely rare, accounting for a small fraction of all cardiac masses, with an estimated frequency ranging from 0.0017% to 0.33% [1,2], mostly reported by autopsy series. Most primary cardiac tumors are benign (75%) [1,3], and about half of cases are cardiac myxomas. Cardiac malignancies are mostly secondary tumors, either by direct infiltration or metastatic spread, while primary cardiac malignancies represent only 20% [2] to 25% [4,5] of all cardiac tumors, with an incidence ranging from 0.0017% to 0.07% on autopsy series [6,7].

Primary cardiac sarcomas are even rarer, with an incidence of 0.0001% on autopsy series [5], representing 75% to 95% of all primary cardiac malignancies [1], and 1% of all soft tissue sarcomas [8]. The most common sarcoma encountered in the heart is the undifferentiated pleomorphic sarcoma, accounting for at least 50% of cases [1], while angiosarcoma is the most common differentiated malignancy, representing about 25% to 45% of cases. Cardiac myxofibrosarcomas account for only 10% of all primary cardiac malignancies. A variety of other exceptionally rare histologic subtypes of sarcomas can be encountered in the heart, including osteosarcomas (10%), rhabdomyosarcomas (5%), leiomyosarcomas (10%), and synovial sarcomas (5%) [1,7].

About 90% of patients present with unspecific symptoms at the time of diagnosis, including fatigue, thromboembolism, arrhythmias, dyspnea, chest pain, and congestive heart failure, affecting relatively young patients, with a median age of 41.87 years at diagnosis [9]. The most common site of origin is the left atrium in around 58.1% of cases, followed by the left atrium involving the pulmonary vein in 16.1%, the right atrium or ventricle in 16.1%, and the left ventricle in 9.7% of cases [5,9]. The median size at diagnosis is 4.3 cm, ranging from 1.2 to 8 cm, with previous series reporting a longer median survival (91.20 months) in tumors measuring less than 4.0 cm [9].

Case Report

A 65-year-old man presented to the Emergency Department with abrupt and intense chest pain, which radiated to both arms. Prior history of asthma and long-term, non-treated, arterial hypertension was known. Upon admission, his blood pressure was 130/80 mmHg, and his heart rate was 180 beats per min. An electrocardiogram showed atrial fibrillation. Echocardiography revealed an echogenic well-defined polypoid tumor located on the left atrium, obliterating the mitral valve and prolapsing into the left ventricle during diastolic phase. Mild blood regurgitation during systolic phase was also recorded. Further, a contrast-enhanced thoracoabdominal computed tomography scan was performed, showing the union of this tumor to the atrioventricular septum, and magnetic resonance imaging revealed partial protrusion of the tumor through the mitral valve, obstructing blood flow (Figure 1). No additional masses were found in either study. The radiologists’ report suggested cardiac myxoma, and malignancy was not suspected. The tumor was completely removed surgically and sent for histopathological evaluation.

Gross examination displayed a rounded smooth-surfaced mass with a wide-based stalk, measuring 4.5 cm in its greater diameter; the cut surface was heterogeneous, solid, tan to yellow, with focal myxoid areas and extensive hemorrhagic degeneration (Figure 2). Some foci of calcification were identified.

Histopathological evaluation revealed a multinodular architectural pattern, with alternating hypocellular and hypercellular areas. Hypocellular areas were formed by noncohesive spindle to stellate cells, with mild to moderate pleomorphism, immersed into loose myxoid stroma with interlaced collagen fibers. Hypercellular areas show cellular fascicles and lobules of spindled to pleomorphic cells, with moderate pleomorphism, hyperchromatic nuclei, and occasional prominent nucleoli (Figure 3). Some areas of osseous and chondroid differentiation were identified, with hyaline cartilage displaying foci of atypia. Immunohistochemical evaluation of the tumor revealed membranous immunoreactivity for CD34, negativity for calretinin (Figure 3) and MDM2, and a Ki67 proliferative index of 70%. Several foci of necrosis and hemorrhagic degeneration were identified (Figure 4), representing less than 50% of the tumor. The tumor was graded according to the French National Federation of Comprehensive Cancer Centres (FNCLCC) guidelines by scoring tumor differentiation, mitotic count, and proportion of necrosis. The proportion of hypocellular-to-hypercellular areas determined the differentiation score as 2, mitotic count (11 mitoses in 10 high-power fields) determined the mitotic score as 2, and the proportion of necrosis (<50%) determined the tumor necrosis score as 1. According to the final score (5 points), the tumor was diagnosed as intermediate-grade myxofibrosarcoma with mature osseous and atypical chondroid components.

The patient was transferred to the Intensive Care Unit and subsequently to the Internal Medicine Ward, where he experienced a surgery-related cardiorespiratory arrest due to ventricular fibrillation, and died 1 month after the surgical event.

Discussion

Due to the rarity of cardiac primary neoplasms, evidence for optimal diagnostic and therapeutic management is limited without an established standardized approach, decided according to the guidelines of soft tissue sarcomas in other sites. Sarcomas of the heart are very aggressive tumors with a poor prognosis, with a reported incidence of relapse and distant metastases ranging from 42.9% to 45.5% and 19% to 72.2% [1,5,9], respectively, with overall survival of 11 to 45.7 months, in various retrospective case series [1,9,10], with varying results depending on the size of the tumor and the status of the resection margins. In a retrospective study by Habertheuer et al, patients in whom complete tumor resection was possible had a median survival of 45.7 months, compared with only 9.3 months in those in whom complete resection was not possible [10]. In the present case, our patient was older than the reported median age at presentation and had a previous history of asthma and hypertension, which worsened his postoperative prognosis.

Myxofibrosarcomas are thought to originate from the fibroblasts of the cardiac connective tissue, more commonly on the left atrium in around 58.1% of cases. Soltani et al compiled all the cardiac myxofibrosarcomas reported in the English literature from 2018 to 2024, identifying 31 reported cases, with 93.5% located on the left atrium, with a median size of 4.31 cm [11], similar to our case. In the heart, they can be asymptomatic until the tumor is large enough to obstruct blood flow, causing symptoms such as dyspnea, chest pain, and congestive heart failure [4].

A multidisciplinary approach is essential for diagnosing cardiac tumors, requiring a combination of advanced imaging techniques. Transthoracic and transesophageal echocardiography provide the first line of visualization and an assessment of the blood flow, location of the tumor, and potentially involved chambers and valves. Three-dimensional echocardiography improves accuracy in assessing tumor volume and location, while magnetic resonance imaging offers superior resolution and detailed tumor characterization. Computed tomography scans are useful for detecting metastases, while positron emission tomography scans can aid in differentiating between benign and malignant masses [6,12]. Imaging findings suggestive of malignancy include tumor size greater than 5 cm, involvement of more than one cardiac chamber, hemorrhagic pericardial effusion, exophytic masses with a broad attachment base, and tumoral extension into the mediastinum [1].

Microscopically, myxofibrosarcomas are lobulated neoplasms, characterized by a multinodular growth pattern, with alternate hypocellular myxoid areas and hypercellular areas displaying spindled cells with varying grades of pleomorphism. Myxofibrosarcomas can be graded following the 3-tier system used for soft tissues sarcomas, stated by the FNCLCC. This system scores, from 1 to 3 points, the histopathological findings observed in 3 categories: tumor differentiation, mitotic count, and percentage of necrosis. A score of 2 to 3 points qualifies the tumor as low grade, a score of 4 to 5 points as intermediate grade, and a score of 6 to 8 points as high grade. Additional notes may be considered for specific tumors. In the case of myxofibrosarcomas, tumor differentiation is qualified according to the proportion of hypocellular-to-hypercellular areas. The presence of heterologous elements has not been described to affect grading evaluation and is not mentioned in the FNCLCC criteria. Even though grading cardiac myxofibrosarcomas by the FNCLCC guidelines is still controversial, high-grade tumors have been described to have significantly lower overall survival and worse prognosis [13]. Low-grade tumors display non-cohesive spindle to stellate cells embedded into an abundant myxoid stroma; while higher-grade tumors present a predominance of sheets and fascicles of spindled to pleomorphic cells condensed around blood vessels, with brisk mitoses, atypia, hemorrhage, and necrosis. The case of our patient presented a heterologous atypical chondroid matrix, as well as metaplastic mature bone formation; these findings are exceptional, with only one case displaying osteoid formation reported in the literature [5].

Surgical treatment with negative margins is considered the ideal therapeutic approach; unfortunately, the extent of neoplastic infiltration can impede complete resection. Additionally, most cardiac tumors hold a limited response to chemotherapy and radiotherapy, making surgical treatment the best option in resectable tumors [4]. Some studies, however, recommend adjuvant chemotherapy or radiotherapy following surgical resection, with a combination of anthracyclines and ifosfamide [14] as the most used regimen, as it may increase these patients’ survival [10].

Consideration must be given to the inherent limitations of the location in treating primary cardiac sarcomas. Although complete surgical resection offers the best chance for survival, its practical feasibility is often hindered by the aggressive nature of these tumors, as most of these patients present with a marginally resectable or unresectable mass at the time of diagnosis [7]. Additionally, radiotherapy, effective for peripheral sarcomas, has limited applicability to cardiac sarcomas due to the heart’s sensitivity to radiation, leading to a substantial risk of cardiomyopathy and chronic pericarditis [1].

Because cardiac myxofibrosarcomas are extremely rare, little is known about their outcome patterns and molecular landscapes. Molecular characterization of cardiac myxofibrosarcomas is overly complex and heterogeneous, not showing recurrent or specific genetic alterations, with frequent gross amplifications and deletions [1].

Several key mutations have been found to contribute to myxofibrosarcoma development and progression. Alterations in TP53 are one of the most commonly associated mutations, linked to recurrence and poor prognosis. Frequent mutations are also found in ATRX and H3F3A, affecting genome stability and chromatin remodeling, respectively. Additionally, mutations in the RB1 and PIKC3A genes activate the PI3K/Akt/mTOR pathway, contributing to these tumors’ cell survival and proliferation [14]. The frequency of point mutations in these tumors is low, and the mutations recorded are highly heterogeneous, highlighting the molecular complexity of these neoplasms.

Conclusions

Due to their rarity and unspecific symptoms, primary cardiac myxofibrosarcomas tend to go unnoticed. Our patient presented with rapid-onset, unspecific cardiac symptoms. Imaging studies are essential in characterizing these neoplasms; however, their polypoid appearance can divert the attention toward benign, more frequent myxomas. In this case, computed tomography allowed us to locate the tumor in the atrioventricular septum of the left atrium, and magnetic resonance imaging showed us its protrusion through the mitral valve, while echocardiography allowed us to evaluate the tumor’s hemodynamic, functional, and organic consequences in the heart. Even after all these studies, due to its polypoid appearance, the mass was characterized pre-surgically as myxoma by radiologists and cardiologists. Extensive histological sampling and immunohistochemical evaluation are key to determine the nature of these neoplasms, especially in well-differentiated and moderately differentiated tumors. The histological presence of a myxoid tumor with hypercellular areas should warn us about the possibility of being faced with a malignant neoplasm. Negativity for calretinin excluded the myxoma diagnosis, since calretinin should be intensely immunoreactive in these tumors. In addition, the positivity for CD34, with the described histological findings, supported the diagnosis of myxofibrosarcoma.

Surgical treatment with negative margins is considered the ideal therapeutic approach; unfortunately, most patients will need further adjuvant chemotherapy. The outcomes are dismal in bigger, deeper infiltrating tumors, with patients presenting masses greater than 4 cm having a lower chance of survival [9], as was the case of our patient; additionally, pre-existing arterial hypertension contributed to his accelerated and fatal outcome. The structural changes of long-term hypertension in our patient, driven by inflammation, hypoxia, and fluid loss from postoperative stress, led to the development of ventricular fibrillation and further cardiac arrest.