Rhabdomyoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

Synonyms and keywords: Rhabdomyomatous neoplasm; Adult rhabdomyoma; Genital rhabdomyoma; Fetal rhabdomyoma; Rhabdomyomatous mesenchymal hamartomas

Overview

Rhabdomyoma is a benign tumor of striated muscle. Rhabdomyomas are rare and can be classified into cardiac type and extracardiac type. The most common primary benign pediatric tumor of the heart is cardiac rhabdomyoma which can be seen mainly in fetal life and children, second most common primary benign cardiac tumor in children is fibroma. Most tumors regress spontaneously, prognosis depends on the location of tumor and size. Cardiac rhabdomyoma is strongly associated with tuberous sclerosis. Cardiac rhabdomyoma is seen almost always in the pediatric age group and is associated with tuberous sclerosis, neurofibromatosis, and sebaceous adenomas. Extracardiac rhabdomyoma can be divided into three groups (adult, fetal, and genital types) with distinct clinical and morphological differences. The adult type is a slowly growing mass which typically involves the head and neck. Fetal type is seen in the head and neck region. The genital type is almost always found in the vulvovaginal region of older women. Treatment of adult type rhabdomyoma of head and neck depends upon the severity of clinical symptoms.

Classification

Rhabdomyoma may be classified into the following subtypes:

Neoplastic

Neoplastic rhabdomyomas may be further classified into the following types:

• Adult
• Fetal
• Genital

Hamartomataous

Hamartamatous rhabdomyomas may be further classified into the following types:

• Cardiac rhabdomyoma
• Rhabdomyomatous mesenchymal hamartomas of the skin(RMH) which is a rare congenital malformation involving the dermis and subcutaneous tissue, it can present as skin tag or even trigeminal neuralgia case reported.

Staging

There have not been sufficient studies for the staging of rhabdomyoma. There is staging based on site, tumor size and metastases for rhabdomyosarcoma, which is a malignant tumor of striated muscle.

Pathophysiology

Pathogenesis

Cardiac Rhabdomyoma

• Cardiac rhabdomyoma is typically seen in cases of tuberous sclerosis and the pathogenesis involves mutations in the TSC1 and TSC2 genes.
• Mutations in the TSC1 and TSC2 genes affect downstream molecular signalling pathways, primarily the mTOR pathway that leads to disrupted cellular growth, proliferation and motility.
• Activation of mTOR pathway leads to increased translation and protein production by ribosomal protein S6 kinase beta-1 (p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), contributing to the abnormal cell growth and proliferation
• Cardiac rhabdomyoma is usually diagnosed during the second or third trimester on ultrasound, rhabdomyoma appears as round, homogeneous, hyperechogenic masses in the ventricles, and they sometimes appear as multiple foci in the ventricles and septal wall. Differential diagnosis between rhabdomyoma, fibroma or myxoma using ultrasonography for a single cardiac mass remains difficult.
• Cells usually lose their ability to divide and undergo apoptosis via a ubiquitin-mediated pathway and regression of the hamartoma ensues.
• Result can be complete or partial regression of hamartoma tumor.

Extracardiac Rhabdomyoma

• The pathogenesis of extracardiac rhabdomyoma is largely unknown, however, constitutive activation of the Hedgehog signalling (SHH pathway activation) and association with Gorlin’s syndrome have been implicated as the two key mechanisms leading to development of these soft tissue tumors.

Location

• Approximately 90% of adult rhabdomyoma are found in head and neck.
• Adult rhabdomyoma is localized to the oropharynx, the larynx, and the muscles of the neck.
• Fetal rhabdomyoma occurs most often in the subcutaneous tissues of the head and neck in children.
• Genital rhabdomyoma most often involves the vagina or vulva.
• Location of cardiac rhabdomyoma determines the clinical presentation, it usually is multi foci and involves the myocardium of both ventricles and/or the interventricular septum, but can be found in the atrium as well as endocardium.

Immunohistochemistry

• Immunohistological cell markers include:
  • Muscle specific actin, phosphotungstic acid hematoxylin (PTAH), desmin, and myoglobin.
  • Dystrophin is shown to be expressed in the cell membranes.

Associated Conditions

• Cardiac rhabdomyoma is associated with a variety of abnormalities such as :
  • Tuberous sclerosis (most common associated genetical abnormality)
  • Brain lesions
  • Down syndrome
  • Wolff-Parkinson-White syndrome (WPW)
  • Ebstein anomaly
  • Tetralogy of Fallot
  • Hypoplastic left heart syndrome

Gross Pathology

• On gross pathology, round or polypoid mass in the region of the neck are characteristic findings of adult rhabdomyoma.
  • Round or lobulated, well-circumscribed masses which can be up to 10 cm in diameter.
  • Isolated or multiple.
  • Solid tan-white homogeneous consistency, often watery and glistening on their cut surface.
  • Infrequently, calcification and hemorrhage.

Cardiac rhabdomyoma Gross. Source: http://peir2.path.uab.edu/pdl/dbra.cgi?uid=default&view_search=1

Microscopic Pathology

• On microscopic histopathological analysis, characteristic findings of adult rhabdomyoma include:
  • Polygonal cells with eosinophilic granular cytoplasm that is mixed with intracellular vacuolated cells.
  • Rhabdomyomas are very well differentiated similarly to striated muscle cells which present markers such as actin, desmin, and myoglobin; dystrophin on their cell membranes.
• Histopathologic findings of fetal rhabdomyoma include spindle-shaped cells with vacuolated clear cytoplasm due to loss of glycogen or granulated ones.
• On microscopic histopathological analysis, characteristic findings of genital rhabdomyoma include:
  • Fibroblast cells among them mature striated cells.
  • A matrix containing varying amounts of collagen and mucoid material
• On microscopic histopathological analysis, characteristic findings of cardiac rhabdomyoma include of classic "spider cells" muscle cells similar to embryonic myofibrils.
• On microscopic histopathological findings of Rhabdomyomatous mesenchymal hamartoma (RMH) which is a rare congenital lesion of the dermis and soft tissues consisting of a disordered and varied collection of mature adipose tissue, skeletal muscle, adnexal elements, and nerve bundles. Rhabdomyomatous mesenchymal hamartoma has different names including striated muscle hamartoma, congenital midline hamartoma, and hamartoma of cutaneous adnexa and mesenchyme. Several published cases report the occurrence of RMH within the setting of other uncommon congenital abnormalities.

fetal rhabdomyoma H&E stain [https:https://en.wikipedia.org/wiki/Rhabdomyoma#/media/File:Fetal_intermediate_cellular_type_rhabdomyoma.JPG source:Jerad M Gardner, MD]

Causes

• Adult rhabdomyomas are matured neoplasms of clonal origin.
• Cardiac rhabdomyoma may be caused by either sporadic mutation or in the setting of certain genetic disorders.
• The genetic disorder commonly associated with cardiac rhabdomyoma is tuberous sclerosis. Other genetic disorders associated with cardiac rhabdomyomas include basal cell nevus syndrome and Down syndrome in the setting of tuberous sclerosis.
• The familial form of tuberous sclerosis are hamartomas that can involve the kidneys, heart, skin, brain, and other organs.
• Cardiac rhabdomyoma can be the only presenting sign of tuberous sclerosis and there are strongly related, in fact, tuberous sclerosis in a fetus can be detected as cardiac rhabdomyoma on ultrasound.
• Molecular evidence of this association has been identified as the TSC2 gene missense mutation.
• Cardiac rhabdomyoma is caused by a mutation in the TSC1 on chromosome 9q34 that encodes for protein hamartin, and TSC2 on 16p13 that encodes for tuberin. These genes are both tumor suppressor genes that assist in the regulation of growth and differentiation of developing cardiomyocytes

Differentiating Rhabdomyoma from Other Diseases

• Rhabdomyomas must be differentiated from other diseases, such as:

• Fibroma
• Rhabdomyosarcoma
• Hibernoma
• Reticulohistiocytoma
• Tuberous sclerosis
• Granular cell tumors

Differential Diagnosis of Cardiac Rhabdomyoma

Cardiac rhabdomyoma should be differentiated from other cardiac tumors that present as a cardiac mass. The following are the differentials:

Site of Tumor	Malignant Potential	Type of Tumor	Tissue of Origin	Age of Presentation	Location	Morphology	Signs and Symptoms			MRI Findings
							Systemic Manifestations	Cardiac Manifestations	Embolic Manifestations
Primary Cardiac Tumor	Primary Benign	Myxoma	Mesenchymal	Between third to sixth decade of life	Left atrium (75%) Right atrium (15-20%) Arise from border of fossa ovalis	1-15 cm in diameter Pedunculated Polypoid Smooth and lobulated Villous and pappillary appearance associated with embolization	Constitutional symptoms Carney complex: Spotty skin pigmentation Endocrinal tumors such as sertoli testicular tumors, pituitary adenomas, thyroid tumors Schwanomma NAME syndrome: Nevi Atrial myxoma Myxoid neurofibroma Ephelides LAMB syndrome: Lentigo (small brown patches on the skin) Atrial myxoma Blue nevi	Dyspnea Mitral regurgitation (LA) Right heart failure (RA) Cardiomegaly	Pulmonary hypertension and pulmonary emboli (RA)	Oval mobile left atrial lesion Heterogenous enhancement Attachment to fossa ovalis
		Rhabdomyoma	Striated Muscle	Majority (80%) in infants (<12 months) Most common cardiac mass in childhood 50-70% of all pediatric tumors	Ventricles Interventricular septum	1-3 cm in size Yellow-gray color Firm Circumscribed lobulated Majority multiple if associated with tuberous sclerosis (of those with no association, 50% are single)	Associated with tuberous sclerosis: Developmental delay Renal tumors (angiomyolipomas) Phakomas (white retinal spots) Hypomelanic macules (ash leaf spots) Ungal fibromas Facial angiofibromas Headache Blurred vision Arrhythmias Benign brain tumors (cortical tubers, subependymal nodules)	Outflow obstruction (both right and left ventricles) Arrhythmias (ventricular pre-excitation, Wolff-Parkinson White syndrome) Spontaneous regression in young cases (< 4 years); seldom regress in adult cases		Multiple masses isointense to muscle tissue on T1 images Hyperintense on T2 images
		Fibroma	Fibrous	Children (1/3rd in infants)	Ventricles Ventricular septum >Left ventricular free wall > Right ventricle > Atria Central calcification	Solitary	Cyanosis	Atypical chest pain Heart failure Cardiomegaly Biventricular hypertrophy Atrioventricular nodal block		Solitary mass Low intensity on T2 weighted image
		Fibroelastoma	Valvular endocardium		Valvular endocardium (Adults-Aortic, children-Tricuspid) Ventrucular surface of aortic and pulmonary valves and atrial surface of atriventricular valves	< 1 cm in diameter Solitary Papillary Flower-like appearance with multiple attachments to valve Short pedicle	Asymptomatic Association with hypertrophic obstructive cardiomyopathy (HOCM)	Subacute bacterial endocarditis	Pulmonary embolism	T1 and T2 weighted images show uniform intermediate signal intensity similar to myocardium Homogeneous late gadolinium contrast enhancement
		Hemangioma	Vascular	< 1 year to 70 years < 2 % of primary cardiac tumors	Right Ventricle Left ventricle Right atrium Small percentage in interatrial septum and left atrium	Polypoid Encapsulated	Cyanosis Kasabach-Merritt syndrome (giant hemangiomas): Thrombosis Thrombocytopenia Coagulopathy	Pericardial effusions CHF Arrhythmias	Pulmonary embolism Ischemic stroke	Intermediate density on T1 images Hypointense on T2 images Multicystic enhancing lesion Involvement of epicardium or pericardium
		Lipoma	Adipose	Between fourth to sixth decade of life	Left ventricle (most commonly subendocardium) Right atrium	Sessile and small (specially subendocardial that protrude into cardiac chambers) Broad pedicle Growth into pericardial space	Asymptomatic	Dyspnea Local compression (subepicardial) Arrhythmia	Ischemic stroke	Epicardial on intramural lesion High intensity on T1 weighted image Drop out on fat saturation images
		Paraganglioma	Nervous (chromaffin cells of the sympathetic ganglia)	Average age of presentation is 11-13 years	Left atrium (under the aorta and the pulmonary artery) Interatrial septum Left ventricle Right ventricular outflow tract	3-8 cm Well-defined Broad base Encapsulated Heterogeneous Hypervascular	Majority asymptomatic May present with symptoms of catecholamine excess: Tachycardia Hypertension Palipitations Fever Diaphoresis Positive for chromogranin and synaptophysin Association with succinate dehydrogenase (SDH) mutation	Dyspnea Valvular obstruction (murmurs) Acute coronary syndrome (anginal pain)	Enascement of coronary arteries by tumor	Well defined lesion arising from atrial walls or septum Bright on T2 weighted imaging
		Atrioventricular Node Tumor	Endodermal	Average age of diagnosis is 38 years Female to male ratio 3:1	Triangle of Koch in the AV nodal region of the atrial septum	2 mm to 2 cm Multiple Cystic Thickening of the atrial septum	Most common cardiac tumor leading to sudden death Emery-Dreifuss muscular dystrophy Midline developmental defects along the central vertical body axis: Thyroglossal duct cysts Cysts in the ovaries, breasts Ventricular septal defect Encephalocele Positive for: Cytokeratin CAM5.2 Cytokeratin AE1/AE3 Cytokeratin 34βE12 Cytokeratin 5/6 (CK5/6) Cytokeratin 7 (CK7) Epithelial membrane antigen (EMA) Carcinoembryonic antigen (CEA) Carbohydrate antigen (CA)19.9, p63, bcl2, galectin 3	Palpitations Dyspnea Chest pain Diziness Syncope Complete heart block Partial AV block Paroxysmal atrial arrhythmia Spontaneous intermittent pre-excitation	Myocardial infarction Ischemic stroke	Hypointense cardiac mass on standard imaging Hyperintensity on late gadolinium enhancement (LGE) images with heterogeneous contrast enhancement
		Lipomatous hypertrophy of the interatrial septum	Adipose	> 60 years	Limbus of the fossa ovalis (sparing fossa ovalis membrane)	> 2 cm Interatrial septum maybe upto 7 cm in thickness	Mostly asymotmatic May present with obstructive symptoms such as syncope in rare cases of extension into superior vena cava Associated with: Increased age Obesity Arrhythmias	Palpitations Dyspnea Fatigue	-	Diffuse or nodular thickening of atrial walls Hyperintense to normal myocardium Hypointense to pericardial and posterior mediastinal fat
	Primary Malignant	Fibrosarcoma	Fibrous		Left sided (atrial mostly)	Sessile or pedunculated protruding masses in ventricular cavities Soft Lobulated Gelatinous	Fever Fatigue Malaise Weight loss Cytoplasmatic positivity for a-SMA	CHF Pericardial infiltration (effusions)	Pulmonary embolism Ischemic stroke Metastasis	Heterogenous or isointense to myocardium on T1 weighted images
		Angiosarcoma	Vascular	Third to fifth decade of life	Right atrium	Broad-based Internal hemmorrhage	Fever Fatigue Weight loss Congestion Superior vena cava syndrome Embolic stroke Endothelial marker D2-40	Dyspnea CHF Pericardial effusions Cardiac tamponade	Pulmonary embolism Ischemic stroke Metastasis	Arterial phase enhancement
		Rhabdomyosarcoma	Mesenchymal	Most common primary sarcoma of children Average age of presentation is 20 years	Left sided (atrial mostly)	Multiple Three types: Embryonic Pleomorphic Alveolar	Fever Fatigue Weight loss Metastasize to lung and lymph nodes	CHF Arrhythmias	Pulmonary embolism Ischemic stroke Metastasis	Intermediate-to-hypointensity compared with muscle on T1 images Hyperintense on T2-weighted imaging with heterogeneous contrast enhancement
		Lymphoma	Lymphoid	First to ninth decade of life Males > females	Right sided mostly	Majority solitary (1/3rd multiple)	Associations: Chronic immunosupression Epstein Barr virus HIV Diffuse large B cell lymphoma	May involve epicardium and pericardium	Pulmonary embolism Ischemic stroke Metastasis
Secondary CardiacTumor	Metastastatic Malignant	Metastasis	Skin (Melanoma) Lung carcinoma Lymph (leukemia and lymphoma) Breast carcinoma Smooth muscle (Esophageal carcinoma)	Any age	Tumors metastasizing via hematogenous route present as multiple intramyocardial masses: Melanoma Leukemia Sarcoma Tumors metastasizing via venous system as right sided mass: Renal cell carcinoma Hepatocellular carcinoma Lung tumor metastasizes to left atrium	Multiple	Fever Fatigue Weight loss Dysphagia Lymphadenopathy Night sweats	Pericardial effusions Dyspnea Arrhytmia Outflow obstruction	Pulmonary embolism Ischemic stroke Metastasis

Epidemiology and Demographics

• Cardiac rhabdomyomas are usually detected during the first year of life or before birth and accounts for majority of all primary cardiac tumors.
• Worldwide, rhabdomyoma is rare.
• Most of patients with tuberous sclerosis develop a cardiac rhabdomyoma. Similarly, children diagnosed with cardiac rhabdomyomas demonstrate radiologic or clinical findings of tuberous sclerosis or have a positive family history. Rhabdomyoma is extremely rare in the United States. Rhabdomyoma has a relative incidence of 5.8%.

Age

• Adult rhabdomyoma is more commonly observed among patients aged greater than 40 years old.
• Fetal rhabdomyoma is more commonly observed among patients aged between birth and 3 years.
• Cardiac rhabdomyoma is more commonly observed among patients in the pediatric age group.
• Genital rhabdomyoma is more commonly observed among patients in the young and middle-aged women.
• Rhabdomyomatous mesenchymal hamartomas of the skin is more commonly observed among newborns and infants.

Gender

• Cardiac rhabdomyoma affects men and women equally.
• Rhabdomyomatous mesenchymal hamartoma of skin is extremely rare in both genders.
• Males are more commonly affected with adult rhabdomyoma than females.
• Males are more commonly affected with fetal rhabdomyoma than females.
• Females are more commonly affected with genital rhabdomyoma than males.

Race

• There is no racial predilection for rhabdomyomas.

Risk Factors

• There are no established risk factors for rhabdomyoma.

Natural History, Complications and Prognosis

Natural History

• The majority of cases regress spontaneously(partial or complete),however there are reported cases which surgical interventions were necessary,especially if tumor causes cardiac symptoms such as arrhythmia or obstruction.
  • Early clinical features include heart failure, cardiac murmur, and arrhythmia.
  • Tumors larger in diameter are more likely to cause arrhythmias or hemodynamic instability, which are associated with an increased risk of death.
  • The majority of patients with cardiac rhabdomyoma remain asymptomatic; however, some affected patients become symptomatic in the perinatal period.

Complications

• Common complications of cardiac rhabdomyoma include development of cardiac arrhythmias, ventricular outflow tract obstruction, and congestive heart failure.

Prognosis

• prognosis is generally good; the survival rate of patients with benign rhabdomyoma is excellent, depending on location of tumor, prognosis may change.
• Rhabdomyomas on mitral or tricuspid valves can lead to regurgitation or obstruction of outflow tract thus poor prognosis.
• The long-term prognosis of cardiac rhabdomyoma is affected by the neurologic manifestations associated with tuberous sclerosis.
• The prognosis of patients with rhabdomyomas depends mainly on the size, location, number of the lesions, associated anomalies such as tuberous sclerosis.
• Metastases have not been associated with rhabdomyoma.

Diagnosis

Symptoms

• Symptoms of adult rhabdomyoma may include:

• Hoarseness
• Difficulty breathing
• Difficulty swallowing(dysphagia)
• laryngeal mass
• In a very rare occassion can present with symptoms of hyperparathyroidism if it involves parathyroid gland.

• Symptoms of genital rhabdomyoma may include the following:

• Painful sexual intercourse due to medical or psychological causes

• Symptoms of cardiac rhabdomyoma may include the following:

• Shortness of breath

• In cardiac rhabdomyoma, symptoms if present, may be caused by obstruction of blood flow through the heart or consist of rhythm disturbances, such as heart block and ventricular tachycardia.

Physical Examination

• Physical examination may be remarkable for:
• The presence of a round or polypoid mass in the region of the neck in adult rhabdomyoma
• Subcutaneous masses in the head and neck regions in fetal rhabdomyoma
• Vaginal masses in genital rhabdomyoma
• Cardiac rhabdomyoma may present with mitral or tricuspid regurgitation murmur.

Laboratory Findings

• There are no specific laboratory findings associated with rhabdomyoma.
• The following laboratory studies may be ordered to rule out additional conditions:
  • Complete blood count (CBC)
  • Hemoglobin/hematocrit
  • Platelet count
  • Urinalysis

Imaging Findings

• MRI is the imaging modality of choice for rhabdomyoma. Chest CT scan may be helpful in the diagnosis of cardiac rhabdomyoma.
• On ultrasound, rhabdomyoma is identified by single or multi foci hyper echoic mass(es) located adjacent to the myocardium.
• X-Rays of the chest and affected areas of the body may be helpful in the diagnosis of rhabdomyomas.

fetal cardiac rhabdomyoma source:Case courtesy of Dr Effendi Mansoor, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/17302">rID: 17302</a>

Other Diagnostic Studies

• Rhabdomyoma may also be diagnosed using biopsy since overlap in morphologic features between rhabdomyosarcoma (RMS) vs. rhabdomyoma makes differential diagnosis difficult.
• Any masses, including those found in the head and neck of patients with adult rhabdomyoma, should be biopsied to establish a diagnosis.

Treatment

Medical Therapy

• Treatment for rhabdomyoma is supportive care.
• patients with rhabdomyoma should be monitored with echocardiography and electrocardiography.

Adult rhabdomyoma

• Patients with laryngeal rhabdomyoma need immediate care such as nasal oxygen, intravenous fluids and if respiratory distress develops intubation before admission for surgery and surgical excision.
• Patients with adult rhabdomyoma and shortness of breath should restrain from activities which exacerbate their breathing difficulty.

Cardiac rhabdomyoma

• Pharmacological treatment available for fetal cardiac rhabdomyoma is everolimus.
• Patients with arrhythmias are treated with antiarrhythmic medications.
• Restriction on physical activities in those patients with cardiac clinical symptoms.
• Asymptomatic children with TSC and a rhabdomyoma should have echocardiography every one to three years until regression of cardiac rhabdomyoma is documented.

Genital rhabdomyoma

• In patients with genital rhabdomyoma, urinary tract obstruction may happen, therefore catheterization use may be necessary in order to avoid urinary tract infection.

• Pregnant patients need to be monitored closely, as they may require a cesarean delivery.

Surgery

Adult rhabdomyoma

• Surgical resection of the tumor can only be performed for patients with adult rhabdomyoma if airway obstruction is diagnosed, there have been reports of rare cases of laryngeal rhabdomyoma which may cause breathing difficulty for patients.

Cardiac rhabdomyoma

• In patients with cardiac rhabdomyoma who have symptoms of severe outflow tract obstruction or arrhythmias, surgical intervention can be helpful. Surgical management involves removal of the part of the tumor causing obstruction without complete excision of the entire lesion.

Prevention

• There are no primary preventive measures available for rhabdomyoma.