Cardiac Fibroma

Etiology

Cardiac fibroma is a medical condition associated with Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome. However, most patients with cardiac fibroma do not exhibit the complete expression of this genetic disorder. Gorlin-Goltz syndrome is an autosomal dominant, multisystem disorder caused by mutations in the PTCH1 or SUFU tumor suppressor genes located at chromosome 9q22.3. These genes produce a protein that suppresses tumor growth by inhibiting the Hedgehog signaling pathway. Gorlin-Goltz syndrome is estimated to have a prevalence of 1 in 57,000 to 1 in 164,000, with a man-to-woman ratio of 1:1 and an incidence rate of 1 in 19,000 live births.[9][10] As an autosomal dominant disease, this condition is typically inherited from an affected parent but can also occur de novo in 20% to 30% of cases.[11]

Epidemiology

According to the World Health Organization (WHO) 2021 classification, cardiac fibroma primarily affects children, accounting for approximately 90% of cases.[12] Most cases are detected either in infants or in utero. While cardiac fibromas typically present in infancy before the first year of life, in individuals with nevoid basal cell carcinoma syndrome, they have been reported to develop up to age 60.[13][14] Cardiac fibromas are the second most common benign cardiac tumor in children, following rhabdomyoma. They are also frequently detected as the second most common tumor in fetuses, often due to prenatal diagnosis.[15] Early detection and monitoring are crucial for managing cardiac fibromas in both pediatric and prenatal care settings.

Pathophysiology

Cardiac fibromas predominantly affect the ventricles, with atrial fibromas being extremely rare. According to the latest WHO classification, nearly all cardiac fibromas originate in the interventricular septum, while the remaining cases occur in either the left or right ventricle. Fibromas in the left ventricle are 5 times as common as in the right ventricle.[12] One hypothesis suggests that tumor size increases with physiological cardiac growth and ceases to grow when the heart reaches maturity, typically in individuals between the ages of 17 and 20. Consequently, as the heart undergoes somatic growth, the fibroma's relative size decreases compared to the cardiac mass, although, unlike rhabdomyoma, fibromas never completely resolve.[16]

Septal involvement and diagnosis before the age of 17 are associated with a poor prognosis. This can be attributed to younger patients having smaller hearts and a higher tumor-to-heart ratio compared to older individuals, resulting in low cardiac output and adverse outcomes.[15] Fibromas affecting the interventricular septum often lead to conduction defects and arrhythmias. Unlike cardiac rhabdomyoma, cardiac fibromas rarely regress spontaneously and often present with arrhythmias (32%), primarily ventricular tachycardia (with a risk exceeding 50%), ventricular fibrillation, murmurs (20%), and abnormal chest x-ray (20%).[4] Although coronary arteries are typically unaffected, there have been reports of large fibromas causing coronary compression.

Histopathology

Cardiac fibromas appear as isolated, white, whorled tumors on gross examination. Histologically, they lack a capsule but are well-circumscribed. Composed of monomorphic fibroblasts exhibiting minimal to no atypia, these lesions may present with infiltrative margins into the cardiac muscle despite their macroscopic demarcation.[17] To establish continuity, distinguishing rare cases of multiple fibromas from peripheral outgrowths requires careful sectioning. The cellularity typically diminishes with patient age, accompanied by increased collagen deposition. Mitotic activity is chiefly observed in infantile cases. Perivascular aggregates of lymphocytes and histiocytes, or sparse chronic inflammation at the tumor-myocardium junction, may occasionally occur. Calcification is a prevalent finding across all age groups affected by these fibromas.[18][19] Immunohistochemistry reveals myofibroblastic differentiation in the tumor cells, with positive staining for vimentin and smooth muscle actin. However, CD34, S100, and HMB45 exhibit negative staining, aiding the differential diagnosis.[18][20]

History and Physical

Cardiac fibromas may be asymptomatic. Typical presentations of cardiac fibromas, determined by the tumor location, include:

• Heart murmurs
• Arrhythmias
• Congestive heart failure
• Sudden death [21]

Nevoid basal cell carcinoma syndrome may present with lamellar or early calcification of the falx, odontogenic (jaw) keratocysts, palmar pits, plantar pits, and a predisposition for basal cell carcinomas. Characteristic facial features include macrocephaly, frontal bossing, and hypertelorism. Skeletal anomalies, early childhood medulloblastoma, cleft lip/palate, and occasional occurrences of ovarian fibromas in girls have also been reported in association with nevoid basal cell carcinoma syndrome.[22] 

Evaluation

Fibromas are noncontractile solid masses that can appear in the ventricular wall and are detectable on echocardiography. Computed tomography (CT) scans typically depict them as homogeneous masses with soft-tissue attenuation, often revealing calcifications. On T1-weighted magnetic resonance images (MRI), fibromas appear as well-circumscribed isointense or hyperintense regions within the myocardium, while they appear hypointense on T2-weighted MRI. Fibromas typically do not enhance following intravenous contrast administration.

Histology is not always required for diagnosis in the presence of clinical phenotype and MRI findings. Electrocardiograms (ECG) of most patients with fibroma reveal T-wave abnormalities, with VT morphologies largely consistent with an origin near the tumor site. In adults, fibromas may present as fixed defects on myocardial perfusion imaging.[14]

Treatment / Management

Given the rarity of cardiac fibromas, which occur in 1 in 280,000 births, the optimal clinical management remains unclear, presenting a challenge for pediatric cardiologists. The literature suggests various management strategies, including surgical resection, single ventricle palliation, cardiac transplant, and even conservative treatment with antiarrhythmic medications.

Implanting a defibrillator to prevent malignant arrhythmias in infants carries a substantial risk of complications. A defibrillator should be considered only after ruling out other options and discussing the risks and benefits with the parents. One common approach involves placing an endocardial defibrillator lead around the heart’s posterior in the epicardial space, coupled with epicardial pace/sense leads. Alternatively, another option is to utilize epicardial pace/sense leads and tunnel an endocardial defibrillator lead along the intercostal space. However, with an epicardial defibrillator, the risk of lead fracture is significant, with a reported 5-year failure rate of 50%.[23](B2)

Medical management with amiodarone and beta-blockers has shown efficacy, particularly in small and apically located fibromas. These fibromas often respond well to antiarrhythmic medications, potentially eliminating the need for defibrillators. Surgical resection has demonstrated curative potential, eliminating the necessity for defibrillators and long-term antiarrhythmic medications. This approach is also viable for large fibromas with favorable outcomes. However, a notable challenge is the scarcity of cardiac centers with expertise in fibroma removal.

Surgery is typically recommended in individuals between the ages of 1 and 3, considering factors such as arrhythmia severity, medication tolerance, defibrillation lead integrity, and symptomatic presentation. Although the location and size of the tumor can complicate surgical intervention, morbidity and mortality rates remain low. Due to the limited number of patients, comparative effectiveness studies on these treatments are challenging.[23](B2)

In patients with tumors not amendable to resection due to their size and extensive involvement of cardiac structures, several documented cases of single ventricle palliation have emerged. For instance, in a case involving a large right ventricle fibroma, single ventricle palliation was achieved through balloon atrial septostomy and the placement of a systemic-to-pulmonary shunt. This approach facilitates unobstructed venous return to the left atrium and left ventricle, supporting systemic and pulmonary circulation. Such ventricular palliation techniques, among others, have served as a bridge to heart transplantation for patients with inoperable cardiac fibromas.[24](B3)

Differential Diagnosis

Differential diagnoses for cardiac fibromas include the following:

• Cardiac rhabdomyoma: The presence of calcification aids in distinguishing cardiac fibroma from rhabdomyoma.
• Myxomas: Unlike myxomas, cardiac fibromas are intramural, predominantly ventricular, and lack a stalk, while myxomas are selectively atrial.
• Teratomas
• Lipomas: In contrast to fibromas, which are intramural and solitary, lipomas are typically epicardial, multiple, and encapsulated primary cardiac tumors.
• Hemangiomas: These typically exhibit a rich vascular stroma, a feature absent in fibromas. 

Surgical Oncology

Stereotactic radiosurgery has been described as a management step for ventricular arrhythmias in unresectable cardiac fibromas. However, it is not universally recognized as a treatment.[25]

Prognosis

In infancy, cardiac fibromas that are not surgically resectable due to their size and extensive myocardial infiltration often carry a poor prognosis, potentially necessitating defibrillator implantation or cardiac transplantation.[26] Conversely, resectable tumors, even if incompletely removed, have a favorable prognosis. In one study, the median survival of patients with cardiac fibromas following successful surgery was reported to be 27 years.[27]

Complications

Untreated cardiac fibromas elevate the risk of fatality, primarily due to the potential development of lethal ventricular arrhythmias. Early detection and appropriate medical intervention are crucial in managing the condition and reducing the associated risks.