Continuing Education Activity

Cardiac fibromas, the second most common primary cardiac tumor in children after rhabdomyoma, are characterized by their composition of connective tissue and fibroblasts. Despite their benign nature, they can present symptomatic challenges such as intracavitary obstruction, coronary artery compromise, and conduction defects, which may lead to sudden death. Pediatric cardiac tumors often coincide with genetic conditions, exemplified by the association of rhabdomyoma with tuberous sclerosis and the presence of cardiac fibromas in 3% to 5% of patients with nevoid basal cell carcinoma syndrome, also known as Gorlin or Gorlin-Goltz syndrome.

This continuing education activity provides an in-depth review of the diagnostic workup for cardiac fibromas. Clinicians enhance their understanding of this condition and optimize patient care by exploring the various imaging modalities and treatment options available. Further, this activity emphasizes the importance of a collaborative approach among healthcare professionals in managing cardiac fibroma cases. Through interdisciplinary coordination, including dermatologists, pediatricians, geneticists, and cardiologists, healthcare teams can provide comprehensive care tailored to each patient's unique needs, ultimately improving outcomes for individuals affected by cardiac fibromas.

Objectives:

• Differentiate cardiac fibromas from other cardiac tumors and nonneoplastic conditions based on clinical presentation and diagnostic findings.

• Screen high-risk populations, such as individuals with genetic syndromes associated with cardiac fibromas, for early detection and intervention.

• Implement evidence-based management strategies tailored to patients' needs and clinical presentation, including surgical resection and medical therapy.

• Collaborate with healthcare teams to develop coordinated care plans and ensure continuity of care throughout the patient's treatment journey.

Introduction

Primary cardiac tumors are rare, having a reported incidence of 0.03% to 0.32%; 75% of these tumors are benign.[1][2][3][4] Among children, cardiac fibromas rank as the second most common primary cardiac tumor after rhabdomyoma. Cardiac rhabdomyomas and fibromas are classified within the subset of nonneoplastic hamartomas. Composed primarily of connective tissue and fibroblasts, cardiac fibromas, although benign, can manifest symptoms due to intracavitary obstruction, inflow and outflow tract obstruction, coronary artery compromise, thromboembolic events, conduction defects, and can even lead to sudden death.[4][5][6] Pediatric cardiac tumors often coincide with genetic conditions. For instance, rhabdomyoma is associated with tuberous sclerosis, while approximately 3% to 5% of patients with nevoid basal cell carcinoma syndrome, also known as Gorlin or Gorlin-Goltz syndrome, present with cardiac fibromas.[7][8]

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]

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]

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]

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.

Consultations

Individuals newly diagnosed with nevoid basal cell carcinoma syndrome should be promptly referred to dermatologists, pediatricians, and geneticists for comprehensive evaluation. According to guidelines, obstetrics-gynecology, and psychology evaluations are recommended to facilitate cancer surveillance and to ensure early identification of potential complications.[8]

Deterrence and Patient Education

Patients diagnosed with nevoid basal cell carcinoma syndrome, which occurs in a notable percentage of individuals with cardiac fibromas, should be educated regarding the associated risks. Due to their predisposition to basal cell carcinoma, these patients are strongly advised to apply sunscreen, limit sun exposure, and avoid ionizing radiation.

Pearls and Other Issues

Key facts to keep in mind about cardiac fibroma are as follows:

• Cardiac fibromas are rare primary cardiac tumors, accounting for a small percentage of cardiac neoplasms.
• They often present in infancy or childhood and can be asymptomatic or present with symptoms related to intracardiac obstruction, arrhythmias, or thromboembolic events.
• Cardiac fibromas are typically intramural and most commonly involve the interventricular septum, although they can occur in other cardiac structures.
• Diagnosis is typically made through imaging modalities such as echocardiography, CT scans, or MRI. Histological examination may be necessary for confirmation.
• Treatment options include surgical resection, medical management with antiarrhythmic medications, and, in some cases, cardiac transplantation. The choice of management depends on factors such as tumor size, location, and the patient's clinical condition.
• Cardiac fibromas are intramural and typically do not embolize or regress. While they may cease growth, as the heart matures, the tumor-to-heart size ratio may improve, potentially obviating the need for surgery. Thus, a conservative watch-and-wait approach may be suitable for symptomatic pediatric patients with stable conditions and no risk of sudden cardiac death.
• The prognosis varies depending on factors such as tumor size, location, and response to treatment. Resectable tumors generally have a more favorable prognosis compared to unresectable ones.

Enhancing Healthcare Team Outcomes

Given its wide phenotypic variations, nevoid basal cell carcinoma syndrome poses a diagnostic challenge, necessitating a high index of suspicion for timely recognition. In sporadic cases, diagnosing nevoid basal cell carcinoma syndrome in proband should prompt genetic testing of other family members. Management involves appropriate cancer screening and preventive measures. This includes regular screening for basal cell carcinoma, with recommendations for sunscreen application, sun exposure reduction, and avoidance of ionizing radiation. Additionally, early childhood medulloblastoma warrants attention, with annual brain MRI with contrast recommended for children younger than 8 years.

The diagnosis of cardiac fibroma, although rare as an initial presentation, should prompt an evaluation of nevoid basal cell carcinoma syndrome and a thorough assessment of the patient’s medical and family history. As previously noted, individuals diagnosed with nevoid basal cell carcinoma syndrome face an increased risk of both benign and malignant neoplasms at an early stage. Therefore, experts advocate for coordinated multispecialty care to ensure comprehensive surveillance of these patients.[28]