Cardiac Rhabdomyoma Pathology

Cardiac rhabdomyoma is the most common primary pediatric tumor of the heart and is considered to be a hamartoma of developing cardiac myocytes. ^{[1, 2, 3, 4]} This tumor may demonstrate mild atypical histologic features, but it lacks the capacity for metastasis or invasion. Although the behavior of a cardiac rhabdomyoma is benign, the positioning within critical areas in the heart can lead to lethal arrhythmias and chamber obstruction. The natural history of cardiac rhabdomyomas is one of spontaneous regression. ^[4]

Cardiac rhabdomyomas most frequently arise in the ventricular myocardium; however, they may also be located in the atria, the epicardial surface, or the cavoatrial junction.

This tumor is mitotically inactive and lacks the capacity to spread. No staging system exists.

Cardiac rhabdomyomas are the most common cardiac tumor detected during fetal life and childhood ^{[4, 5, 6]} ; they are usually detected before birth or during the first year of life. They account for over 60% of all primary cardiac tumors. ^[7] Studies have demonstrated that the incidence of cardiac rhabdomyoma is 0.002-0.25% at autopsy, 0.02-0.08% in live-born infants, and 0.12% in prenatal reviews. ^[8] Because of the use of ultrasonography as part of routine prenatal screening, it is increasingly common for cardiac rhabdomyomas to be clinically recognized in utero. ^{[9, 10]}

Cardiac rhabdomyomas frequently occur in association with tuberous sclerosis, ^{[6, 11]} an autosomal dominant–inherited or sporadically occurring disorder characterized by widespread hamartomas that variably involve the brain, kidneys, heart, skin, and other organs. About 50% of patients with tuberous sclerosis develop a cardiac rhabdomyoma. Similarly, approximately 51-86% of children diagnosed with cardiac rhabdomyomas demonstrate clinical or radiologic evidence of tuberous sclerosis or have a positive family history. ^{[4, 12]}

Cardiac rhabdomyomas can occur sporadically, in association with congenital heart malformations, or in the setting of certain genetic disorders.

Sporadic mutations are responsible for more than 50% of rhabdomyomas. ^[13] In rare cases, tetralogy of Fallot, Ebstein abnormality, and hypoplastic left heart syndrome can be associated with cardiac rhabdomyoma; this association complicates both management and prognosis.

The genetic disorder most commonly associated with cardiac rhabdomyoma is tuberous sclerosis. Other genetic disorders associated with cardiac rhabdomyomas include Down syndrome in the setting of tuberous sclerosis and basal cell nevus syndrome. ^{[8, 14, 15]}

The clinical features of cardiac rhabdomyomas vary widely, depending on the location, size, and number of tumors in the heart. Although cardiac rhabdomyomas can be associated with intrauterine fetal demise, many are detected incidentally during routine antenatal sonographic screening.

Symptoms of cardiac rhabdomyomas arise because of chamber or valve obstruction, arrhythmias, or failure resulting from extensive myocardial involvement. Tumors obstructing the right-side inflow or the outflow of the ventricles can lead to decreased cardiac output, atrial and caval hypertension, hydrops fetalis, and death. Arrhythmias, both ventricular and atrial, are not uncommon.

Wolff-Parkinson-White syndrome has been found to be more common in patients with tuberous sclerosis than in the general population. This increased frequency may be secondary to rhabdomyomas located at the atrioventricular junction. The tumor cells may act to create an accessory pathway. Regression of the tumor is associated with resolution of the arrhythmia and loss of the delta wave on electrocardiography (ECG).

Congestive heart failure and a low cardiac output can occur when the tumor extensively involves the myocardium or the ventricular papillary muscles. Cyanosis and decreased peripheral pulses can result. Death occurs because of obstruction of ventricular blood flow, arrhythmias, valve stenosis, or loss of functional myocardium secondary to extensive tumor involvement.

The presence of cardiac rhabdomyomas (especially multiple rhabdomyomas) is strongly suggestive of tuberous sclerosis. Consequently, a detailed family history should be obtained and genetic counseling should be offered even in the absence of other signs of the disease. Patients should be examined for associated clinical and pathologic features of tuberous sclerosis. ^[16]

The classic clinical triad of tuberous sclerosis includes mental retardation, epilepsy, and facial angiofibromas. The presence of multiple cardiac rhabdomyomas often precedes the manifestation of the cutaneous and neurologic features of the disease.

Consequently, the physical examination of the newborn may yield unremarkable results. However, hypopigmented "mountain ash" macules, angiofibromas, and retinal astrocytic tumors are early features that can occasionally be seen at birth. Other late-occurring cutaneous manifestations of tuberous sclerosis include subcutaneous nodules, subungual fibromas, linear epidermal nevi, and café-au-lait pigmentation.

Seizures during the neonatal period are not infrequent. Imaging may reveal the presence of cortical or subependymal tubers. Renal angiomyolipomas usually manifest later in life. A detailed family history pertaining to the existence of relatives with features of tuberous sclerosis should also be obtained.

Rhabdomyomas are frequently diagnosed by means of fetal echocardiography during the prenatal period. Multiple lesions are often visualized in patients with tuberous sclerosis. Cardiac rhabdomyomas appear as well-circumscribed homogenous hyperechoic masses that most frequently involve the ventricles but can be found at any location in the heart. Small multiple lesions may manifest as a thickened myocardium on ultrasonography and magnetic resonance imaging (MRI).

MRI is used if the results of echocardiography are inconclusive or if aggressive surgical management is being planned. On T1-weighted MRI images, rhabdomyomas have a signal intensity similar to that of myocardium. On T2-weighted MRI images, their signal intensity is increased. MRI is also used to evaluate the presence of tuberous sclerosis involving the brain, kidneys, and liver.

Echocardiography and MRI are the main diagnostic tools. ^[17] Cardiac catheterization is seldom required. Endomyocardial biopsy and histologic assessment constitute the criterion standard for diagnosis.

Differentiation from other fetal cardiac tumors

Other primary cardiac tumors of the fetus include fibroma, myxoma, teratoma, and hemangioma. On ultrasonography, rhabdomyomas appear as round, homogeneous, hyperechoic masses located predominantly in the ventricles and the interventricular septum. They can be single or multiple.

After rhabdomyoma, cardiac fibroma is the second most common hyperechoic cardiac tumor. Cardiac fibromas are located in the myocardium (usually the ventricle) and often bulge into the chamber lumen. They are firm or rubbery and do not demonstrate hemorrhage or necrosis. Calcifications are typically present, a feature that distinguishes them from rhabdomyomas. The microscopic features of fibromas include dense fibroblasts and collagen. Elastic fibers can frequently be identified with the use of special stains.

Myxomas are endocardium-based lesions that do not infiltrate into the underlying tissue. Commonly located on the left atrial side of the interatrial septum, they can be firm and lobulated, myxoid and gelatinous, or friable and irregular. Myxoma cells possess an abundant eosinophilic cytoplasm and have indistinct cell borders. They arise in a myxoid background. Fibrosis, calcification, and thrombosis are common, and extramedullary hematopoiesis occurs in 10% of cases. They are only moderately echogenic on ultrasonography.

Using ultrasonography to distinguish between rhabdomyoma, fibroma, and myxoma when occurring as a single cardiac lesion can be extremely challenging. However, a cardiac tumor in a young patient possessing features of tuberous sclerosis or a positive family history is almost certainly a cardiac rhabdomyoma. In contrast, distinguishing rhabdomyomas from teratomas or hemangiomas is less of a diagnostic challenge.

Teratomas are extracardiac masses that are located in the pericardial cavity and are usually associated with a pericardial effusion. They are composed of both cystic and solid areas. On histology, mature derivatives of all 3 germ lines (endoderm, ectoderm, and mesoderm) are found. Skeletal muscle, cartilage, liver, pancreas, and glandular tissue have all been observed in cardiac teratomas. These tissues can be readily identified on ultrasonography.

Cardiac hemangiomas can occur in any chamber but are usually found in the right atrium. Their microscopic features are diverse. Cardiac hemangiomas can be composed of multiple thin-walled ectatic vessels (cavernous hemangioma), multiple smaller capillarylike vessels (capillary hemangioma), or thick-walled dysplastic arteries, capillaries, and veinlike vessels (arteriovenous hemangioma). On ultrasonography, hemangiomas demonstrate a complex echogenicity with cystic and solid areas mixed with calcifications.

Cardiac hemangiomas can be either intramural or endocardial. Intramural hemangiomas are poorly circumscribed lesions that are hemorrhagic and congested. They can be capillary, cavernous, or arteriovenous, and they can contain adipose or fibrous tissue. Endocardial hemangiomas are well-circumscribed lesions that are variably myxoid. They are typically capillary or mixed cavernous–capillary.

Liposarcomas may have vacuolated lipoblasts. These are invasive tumors that show features of malignancy, such as tissue destruction and necrosis. Such neoplasms would not be expected in children.

Cardiac rhabdomyomas range from 1 mm to 10 cm in their greatest dimension and can be either isolated or multiple. They most frequently arise in the ventricular myocardium but can be located in the atria, the epicardial surface, or the cavoatrial junction (see the images below). Larger lesions can cause obstruction of inflow or outflow tracts. Rhabdomyomas are round or lobulated and are grossly well circumscribed.

Cardiac rhabdomyomas possess a solid tan-white homogeneous consistency and are often watery and glistening on their cut surface. Calcification and hemorrhage are infrequent. Intracavitary extension can occur in as many as 50% of cases.

Microscopically, cardiac rhabdomyomas are well-circumscribed nodules that lack a capsule but are distinct from the normal surrounding myocardium. The cells are round or polygonal in shape and are enlarged, with clear cytoplasm (see the image below). The clear cytoplasm is secondary to the loss of glycogen that occurs during standard slide preparation techniques. Glycogen reacts strongly with periodic acid – Schiff (PAS) stain when appropriate technique is used to prepare the slides.

The nuclei of the rhabdomyoma cells are central or eccentrically located. In some cells, eosinophilic septa stretch from the cell membrane to a centrally placed nucleus, imparting a spiderlike appearance to the cell. These "spider cells" are pathognomonic for cardiac rhabdomyomas ^[4] and are thought to represent degenerating rhabdomyocytes (see the image below). They may be found scattered in small groups throughout the myocardium or clustered together to form larger nodules.

The septa of spider cells stain strongly for ubiquitin. The ubiquitin pathway facilitates myofilament degradation, intracytoplasmic glycogen vacuolization, and the production of spider cells. Spider cells then undergo apoptosis, myxoid degeneration, and regression of the rhabdomyoma. Mitotic activity is absent and fibrosis and calcification are infrequent.

On electron microscopy, the cytoplasm of cardiac rhabdomyoma cells is filled with non – membrane-bound glycogen and small mitochondria. Poorly developed T tubules and fragmented sarcomeres are also present. Cellular junctions that resemble intercalated discs surround the cell periphery.

The myogenous origin of rhabdomyoma cells is demonstrated by the strong expression of striated muscle markers, including actin, myoglobin, vimentin, and desmin. Ubiquitin, hamartin, and tuberin are also positive. Proliferation markers such as MIB-1 are negative.

The genetic disorder most commonly associated with cardiac rhabdomyoma is tuberous sclerosis. ^[18] The familial form of tuberous sclerosis is an autosomal dominant disorder characterized by widespread hamartomas that variably involve the brain, kidneys, heart, skin, and other organs.

Genetic analysis has identified two major disease genes: TSC-1 on chromosome 9q34 encodes for the protein hamartin, and TSC-2 on 16p13 encodes for tuberin. ^[19] These are both tumor suppressor genes that appear to assist in the regulation of growth and differentiation of developing cardiomyocytes. Although TSC1 and TSC2 are the most common variants, mosaic variants also exist. ^{[20, 21, 22]}  Other genetic disorders associated with cardiac rhabdomyomas include Down syndrome in patients with tuberous sclerosis and basal cell nevus syndrome.

Cardiac rhabdomyomas tend to grow up to approximately 32 weeks' gestation, after which point the cells lose their ability to divide and undergo apoptosis. This process is probably mediated by ubiquitin, a regulatory protein that is strongly expressed in rhabdomyoma cells. Ubiquitin stimulates the degradation of myofilaments. Apoptosis ensues and leads to the eventual regression of the hamartoma. Partial or complete resolution occurs in most cases, regardless of the initial size of the tumor.

The natural history of cardiac rhabdomyomas is that of complete or partial regression with consequent resolution of symptoms. The reported survival range from 81% to 92%. ^[8]

The prognosis of patients with rhabdomyomas is chiefly determined by the number, size, and location of the lesion. ^{[4, 5]}  Most cardiac rhabdomyomas are not hemodynamically relevant and do not grow. ^[23] Tumors larger than 20 mm in diameter are more likely to cause hemodynamic disturbances or arrhythmias, which are associated with an increased risk of death. In a retrospective (1990-2016), single-center study that analyzed data from 20 infants prenatally diagnosed with cardiac rhabdomyoma, tumors larger than 30 mm in diameter were associated with postnatal arrhythmia that required treatment regardless of their number and location. ^[24]  Rhabdomyomas that obstruct the inflow or ventricular outflow tracts or that alter valve function and lead to regurgitation also carry a poor prognosis. Long-term prognosis is affected by the neurologic manifestations associated with tuberous sclerosis. ^{[4, 25, 26]}

Because the natural history of the rhabdomyoma is one of regression, most patients can be managed conservatively. Conservative management includes frequent monitoring with echocardiography and electrocardiography (ECG). Patients with arrhythmias are treated with antiarrhythmic medications. If medical treatment fails to control the arrhythmias or blood flow is severely obstructed, surgical management is recommended. Regression of the tumor is associated with resolution of the arrhythmia.

Surgical intervention is reserved for patients who have symptoms of severe hemodynamic compromise or intractable arrhythmias. Operative management involves removal of the intracavitary portion of the tumor without complete excision of the entire lesion.