Pathology Lab V - Tumors of the Heart

PATHOLOGY LAB V-TUMORS OF THE HEART.

Arben Santo.

CASE OUTLINE.

Case Presentation: Anthony D. Cardiac tumors

Atrial myxoma

Carney complex

Lipoma

Papillary fibroelastoma Rhabdomyoma

OBJECTIVES .

After completing this unit the student will be able to:

1. Discuss the epidemiology of cardiac myxomas and heart tumors in general. 2. Describe the location and the gross and microscopic pathology of myxoma

3. Describe the clinical manifestations of cardiac myxoma

4. Describe the diagnostic methods of cardiac myxoma

5. Describe the complications and principles of treatment of cardiac myxoma

6. Describe Carney complex 7. Describe lipoma, rhabdomyoma and papillary fibroelastoma

REFERENCES .

1. Gyanendra Sharma, L Michael Prisant: Atrial Myxoma, eMedicine, 2004,

http://www.emedicine.com/med/topic186.htm/ 2. Mary C Mancini: Cardiac Neoplasms, Primary, eMedicine, 2002,

http://www.emedicine.com/med/topic280.htm

3. Edwin Rodríguez, Rosa M Cintron-Maldonaldo: Cardiac Tumors, eMedicine, 2003,

http://www.emedicine.com/ped/topic2635.htm

4. Robbins and Cotran Pathologic Basis of Disease, 8th edition, 2010, Chapter 12, pages 583-584.

CASE PRESENTATION: ANTHONY D.

This 50-year-old contraction worker with no significant past medical history presented to his primary care physician with a three

month history of fatigue and dyspnea on exertion that worsened after a day’s work. The patient’s job consisted of physical labor, i.e., building homes; however, he had never had similar symptoms in the past. He denied having dizziness, light -headedness,

nausea, chest pain or palpitations. His past medical history was significant only for remote alcohol abuse. Family history was

significant for coronary artery disease and colon cancer.

On physical examination, he appeared in no distress; vital signs were normal. Cardiac examination revealed a II/VI holosystolic

murmur. Laboratory studies were normal. Chest radiograph showed pulmonary venous hypertension with left atrial enlargement. An ECG showed sinus bradycardia at 48 beats per minutes with a borderline prolonged, notched P wave in the inferior leads,

however not fulfilling criteria for a typical “P mitrale” pattern.

In view of his dyspnea on exertion, the patient was referred to a cardiologist for an echocardiogram, which showed a normal left

ventricle with an ejection fraction of > 60%, left atrium dilation (51.5 mm) with a normal mitral valve. A left atrial mass,

consistent with a myxoma, was noted attached to the interatrial septum. A CT scan of the thorax showed a large, 4 x 6 x 4 cm left

atrial mass, which was adherent to the inter-atrial septum. The mass prolapsed through the mitral valve during diastole and resulted in a significant narrowing of the mitral valve outflow into the left ventricle.

The patient underwent thoracotomy with successful excision of the tumor and its pedicle. Histology of the excised mass was

consistent with atrial myxoma. Following surgery, the patient returned to his regular life. Follow-up echocardiography at 6

months showed no evidence of recurrence of the atrial mass.

1. Definition. Cardiac tumors may be primary (benign or malignant) or metastatic (malignant). Myxoma, a benign primary tumor, is the most

common type. Cardiac tumors may occur in any cardiac tissue: endocardium, myocardium, pericardium, valvular tissue, and

cardiac connective tissue.

2. Epidemiology.

(A) Primary cardiac tumors. Primary cardiac tumors are found in < 1/2000 people at autopsy. About 75% of primary tumors are

benign, but they are of clinical importance since they can be difficult to diagnose clinically and, due to their position, can be life threatening. Almost any cardiac tumor can cause arrhythmia, sudden death or cardiac failure.

About half of benign tumors are atrial myxomas. Other benign tumors of the heart include rhabdomyoma, lipoma, fibroma, and

papillary fibroelastoma. Rhabdomyomas are the second most common benign cardiac tumor and account for approximately 10 %

of all benign cardiac neoplasms.

About 25% of all primary cardiac tumors are malignant, sarcomatous in nature. Malignant tumors of the heart include

angiosarcoma, leiomyosarcoma, osteosarcoma, fibrosarcoma and malignant fibrous histiocytoma. Angiosarcomas are the most

common of primary cardiac malignant tumors. Leiomyosarcomas are the second most common primary cardiac malignant tumor.

(B) Metastatic cardiac tumors. Metastatic tumors are 30 to 40 times more common. The most common sources of metastatic tumors include (in approximate order of frequency): lung cancer, breast cancer, lymphoma, leukemia, esophageal carcinoma and

malignant melanoma. The figure shown is a cardiac metastasis from a malignant melanoma. Note the heavy pigmentation and the

infiltration of the tumor along the intercellular spaces. Metastatic disease results from contiguous extension (examples are the

lung cancer or esophageal cancer), or hematogenous spread (melanoma). Finally, tumor may reach the heart by retrograde flow

through mediastinal and tracheobronchial lymphatic channels. 3. Clinical manifestations.

The clinical symptoms caused by cardiac tumors are generally secondary to their mass effect, local invasion, embolization, or

constitutional symptoms. An intracardiac tumor mass may obstruct blood flow, compromise valve function, or induce

neurological catastrophe secondary to tumor embolization. The location of the tumor determines the type of symptoms produced,

which can include syncope, angina, dyspnea, edema, ascites, depression of pump function, cardiomyopathy, and pulmonary hypertension. Some tumors produce no symptoms and are found incidentally as a consequence of secondary symptoms such as

stroke or evidence of peripheral embolization.

DEFINITION.

Atrial myxoma is a benign tumor found in the heart. It originates from the atrial septum and grows in the left atrial or right atrial chamber. This tumor is derived from multipotential mesenchymal cells of the subendocardium.

EPIDEMIOLOGY.

Atrial myxoma is the most common primary cardiac tumor; it accounts for about 40-50% of all primary heart tumors. Cardiac myxoma is a tumor of adults: the mean age of patients is 56 years.

Incidence in women is 4 times that in men.

LOCATION.

Myxomas can arise in any of the four chambers of the heart: about 75% of them occur in the left atrial cavity. Up to 25% of cases

are found in the right atrium. The most common site of attachment is at the border of fossa ovalis in the left atrium, although

myxomas can originate from the posterior or anterior atrial wall. The mobility of the tumor depends upon the extent of

attachment to the interatrial septum and the length of the stalk.

MORPHOLOGY.

1. Gross appearance.

Myxomas range from small (less than 1 cm) to large (up to 10 cm), and they are sessile or pedunculated masses. Macroscopically

the tumors have a broad-based attachment to the endocardium and protrude into the cardiac chamber either as a rounded, smooth surfaced mass or as a mass of polypoid fronds. They have a soft, friable and gelatinous appearance often associated with areas of

hemorrhage. The tumor can be large enough to extend into the mitral valve orifice.

2. Microscopic appearance .

Microscopically, myxoma is composed of round, spindled, polygonal, or stellate cells embedded in an abundant loose myxoid

stroma, rich in acid mucopolysaccharides. Sometime cells arrange to form solid cords.

The normal cell of origin of myxomas is still unknown, despite careful study by electron microscopy and immunohistochemistry.

The multipotential mesenchymal cell of the subendocardium has been suggested as the cell from which these tumors originate.

The microscopic structure of the tumor with abundant ground substance and stellate-shaped cells is considered to mimic the structure of undifferentiated mesenchyme of the embryonic stage.

CLINICAL PRESENTATION.

There are three modes of clinical presentation:

1. Obstruction of blood flow. The most common symptoms and signs relate to obstruction to the blood flow. The large and pedunculated myxomas are

sufficiently mobile to move into or through the atrioventricular valves during the diastole or systole. The prolapse of the t umor

into the atrioventricular orifice mimics mitral or tricuspidal stenosis. For example, myxoma of the left atrium manifests itself with

dyspnea on exertion that may progress to orthopnea, paroxysmal nocturnal dyspnea and pulmonary edema. Myxoma of the right

atrium manifests itself with fatigue, peripheral edema, hepatomegaly and ascites. 2. Auscultatory signs.

Left atrial myxomas may cause auscultatory signs of mitral stenosis (e.g. the typical murmur, an opening snap, an accentuated

first heart sound). Murmurs of mitral insufficiency may also result from chronic damage to the valve leaflets or interference with

valve closure. Clinical differentiation between a left atrial tumor and primary mitral valve disease may be suggested by the

influence of body position on the intensity of murmurs and the opening snap. 3. Embolization.

Another group of symptoms is related to embolization. Myxomas are frequently friable and consequently embolic phenomena are

the next most common mode of presentation. Embolism occurs in about 30-40% of patients. Since these tumors are most often

located in the left atrium, their embolism is generally systemic. Embolization of the central nervous system may result in

transient ischemic attacks, stroke or seizure. Involvement of the retinal arteries may result in vision loss. Systemic embolization of myxoma fragments can cause occlusion of any artery, including the coronary, renal or mesenteric. On occasion, the diagnosis

of cardiac myxoma is made following histopathological examination of surgically excised embolic material.

On the right side, embolization results in pulmonary embolism and infarction. Multiple recurrent small emboli may result in

pulmonary hypertension and development of cor pulmonale.

4. General, constitutional (inflammatory) symptoms. These include fever, weight loss, arthralgias and Raynaud phenomenon. They also include leukocytosis, elevated erythrocyte

sedimentation rate, elevated C-reactive protein and serum gamma globulin levels, anemia, etc. Constitutional symptoms are

likely due to the elaboration by some myxomas of the cytokine interleukin-6, a major mediator of the acute phase response.

IMAGING STUDIES .

Chest radiography reveals an abnormal cardiac silhouette, mimicking mitral stenosis, i.e., mild cardiomegaly and pulmonary

venous congestion.

The two-dimensional transthoracic echocardiographic visualization is usually diagnostic: tumor location, size, attachment and

mobility can be assessed with this technique. Notice that an atrial myxoma must be differentiated from a left atrial thrombus .

Transesophageal echocardiography is more sensitive than transthoracic echocardiography and is the test of choice.

CT scanning and MRI are very helpful in detecting cardiac tumors as well.

Before the era of two-dimensional echocardiography, atrial myxomas were usually diagnosed by cardiac catheterization and

angiocardiography. With this technique myxoma appears as an intracardiac filling defect.

COMPLICATIONS

Cardiac arrhythmias, sudden death and congestive heart failure are all complications of clinically unrecognized cardiac

myxomas.

PRINCIPLES OF TREATMENT.

There is no known medical treatment for atrial myxoma. Operative resection of the tumor is the treatment of choice and surgery

is usually curative. The recurrence rate is 10.5%. Recurrences are usually attributed to incomplete excision of the tumor.

1. Definition.

While a myxoma is usually sporadic, in about 7% of cases, this tumor presents as a component of a complex heritable disorder. Carney complex combines cardiac myxomas with several other pathological conditions that include:

(A) Lentiginosis. Spotty pigmentation of the skin in the form of lentiginosis. It so characteristic that can make the diagnosis. It

appears as small (0.2 -1.0 cm) brown-to-black macules typically located around the upper and lower lips, on the eyelids, ears and

the genital area. Cutaneous myxomas (B) Endocrine tumors. Endocrine conditions such as adrenal cortical adenoma (with cortisol hypersecretion manifesting clinically

with Cushing syndrome) or thyroid follicular adenomas.

2. Genetics.

Carney complex is inherited as an autosomal dominant trait. Mutations in the PRKAR1A gene encoding the R1 alpha regulatory

subunit of protein kinase A have been shown to cause Carney complex. PRKAR1A may act as a tumor suppressor gene by regulating PKA activity, which in turn can suppress or stimulate the cell growth and differentiation.

3. Epidemiology.

Carney complex is a rare disease. About 500 patients have been registered by the NIH-Mayo Clinic and the Cochin Center

(France).

1. Definition.

Lipomas are localized, well-circumscribed, benign tumors composed of mature fat cells that may occur in the subendocardium,

subepicardium, myocardium or heart valves.

2. Locations. Lipomas are most often located in the left ventricle, right atrium, or atrial septum. Lipoma of atrioventricular valve involves both

mitral and tricuspid valve. It causes valvular insufficiency. Lipomatous hypertrophy of the atrial septum is associated with

cardiac arrhythmias. Lipomatous hypertrophy of the atrial septum is a non-neoplastic lesion caused by hyperplastic fat cells

(adypocytes). Subendocardial lipoma may form large polypoid masses with intracavitary extension and cause valve stenosis or

insufficiency. 3. Clinical presentation.

Cardiac lipomas may be asymptomatic, or produce valvular dysfunctions or arrhythmias.

1. Definition.

Papillary fibroelastomas are curious, usually incidental, sea-anemone-like lesions, most often identified at autopsy. Clonal cytogenetic abnormalities have been reported, suggesting that fibroelastomas are unusual benign neoplasms. They resemble the

much smaller, usually trivial, Lambl excrescences that are frequently found on the aortic valves of older individuals.

2. Epidemiology.

The incidence of papillary fibroelastoma is less than 10% of all cardiac tumors. Cardiac papillary fibroelastomas are the third-

most-common benign tumors of the heart, after myxomas and lipomas, and they are the most common valvular neoplasm. Papillary fibroelastoma occurs equally often in males and females. They are most commonly seen in the 5th decade of life.

3. Location.

Papillary fibroelastomas originate from the valves or the endothelial surface of the heart. In a recent review of 410 reported

cardiac papillary fibroelastomas, 84% arose from cardiac valves. Another study reported cardiac papillary fibroelastomas to arise

from aortic, mitral, tricuspid, and pulmonic valves in 35%, 25%, 17%, and 13% of cases, respectively 4. Morphology.

These tumors are small, avascular masses. They are mobile with a thin stalk (43%) and have a mean diameter of 0.3 × 1.0 cm.

They have multiple papillary fronds that cause them to resemble sea anemones. Histologically, papillary fibroelastomas consist of

a central core of myxoid connective tissue containing abundant mucopolysaccharide matrix covered by a surface endothelium.

5. Clinical presentation.

Most papillary fibroelastomas are asymptomatic. But papillary fibroelastomas has been well documented as a possible cause of

systemic and pulmonary embolism with life-threatening complications. Consequences of embolism include stroke, myocardial

infarction, pulmonary embolism, and, less commonly, transient cerebral ischemic attack, angina, congestive heart failure, syncope, and sudden death.

6. Diagnosis.

Detection of papillary fibroelastomas has increased with the use of echocardiography. Echodensity of the tumor's central

connective tissue core strongly supports the diagnosis and allows differentiation from other intracardiac tumors, vegetations, or

mural thrombi.

RHABDOMYOMA.

1. Definition.

Cardiac rhabdomyoma is the most common benign congenital cardiac tumor. Cardiac rhabdomyomas are usually detected

prenatally or during the first year of life; they are increasingly clinically recognized in utero because of the use of ultrasonography as part of routine prenatal screening.

2. Epidemiology.

Congenital cardiac tumors are rare. Rhabdomyomas account for 60% of them.

3. Etiology.

Rhabdomyomas are strongly associated with tuberous sclerosis, a rare, multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. Tuberous sclerosis is inherited in an

autosomal dominant manner.

4. Genetics.

Tuberous sclerosis is caused by mutations in either TSC1 (‘tuberous sclerosis 1’) or TSC2 (tuberous sclerosis 2’) tumor

suppressor genes. TSC1, located on chromosome 9, encodes for the protein hamartin; TSC2, located on chromosome 16, encodes for the protein tuberin. The function and interaction of these proteins are not yet fully understood, although they are tumor

suppressors. TSC1 and TSC2 function according to Knudson’s ‘two-hit’ hypothesis. People with tuberous sclerosis are born with

one mutated copy of the TSC1 or TSC2 gene in each cell. However, enough hamartin or tuberin is usually produced from the

other, normal copy of the gene to regulate cell growth effectively. In individuals with tuberous sclerosis, a second TSC1 or TSC2

mutation typically occurs in multiple cells over an affected person's lifetime. The loss of hamartin or tuberin in different types of cells leads to the growth of tumors in many different organs and tissues. TSC1 or TSC2 expression is completely lost in cardiac

rhabdomyomas that occur in the setting of tuberous sclerosis, providing a mechanism for the myocyte overgrowth. Because they

often regress spontaneously, rhabdomyomas are considered by some to be hamartomas rather than true neoplasms.

5. Morphology.

(A) Gross appearance. The most common locations for these tumors are the left ventricle and ventricular septum. Rhabdomyomas are firm, white, well-circumscribed, myocardial nodules of 0.1 cm to several centimeters that can be multiple or

singular. They can be located within the myocardium or they can extend into the ventricular cavity.

(B) Microscopic appearance. The tumor is composed of vacuolated cells with a variable number of myofibers.

Often, pathognomonic spider cells are present that have a centrally located nucleus with radial extensions to the cell periphery.

Cells stain strongly with periodic acid-Schiff stains due to their high glycogen content.

6. Clinical presentation.

The clinical features of cardiac rhabdomyomas are extremely variable and are dependent upon the location, size, and number of tumors in the heart. Symptoms arise because of chamber or valve obstruction, arrhythmias, or failure from extensive myocardial

involvement. Tumors obstructing the right-sided inflow or the outflow of the ventricles can lead to decreased cardiac output,

atrial and caval hypertension, hydrops fetalis, and fetal demise. Arrhythmias, both ventricular and atrial, are not uncommon.

7. Principles of treatment.

Because most cardiac rhabdomyomas regress spontaneously, surgery is not routinely required. However, patients with life-threatening symptoms might require surgical excision of the tumor.

1.

All of the following can be clinical manifestations of left atrial myxoma except:

Aortic dissection

Dyspnea on exertion that may progress to orthopnea, paroxysmal nocturnal dyspnea and pulmonary edema.

Murmurs of mitral stenosis of regurgitation

Systemic emboli

Fever, weight loss, arthralgias

2.

A 35-year-old man presents to the emergency department with sudden onset of pallor, coldness and absent pulse in the lower left extremity. The patient undergoes a successful thrombectomy and pathologic studies of the specimen reveal nests of polygonal, stellate, and spindled cells on an abundant extracellular matrix. Which of the following is the most likely diagnosis?

Cardiac myxoma

Cholesterol embolism

Buerger disease

Takayasu disease

Atrial fibrillation

3.

In which chamber of the heart are atrial myxomas most commonly observed?

Right ventricle

Right atrium

Left ventricle

Equally common in all four chambers

Left atrium

4.

“Spider” cells are a histological hallmark of which of the following cardiac tumors?

Rhabdomyoma

Lipoma

Myxoma

Heart metastases of melanoma

Papillary fibroelastoma

5.

A 54-year-old man presented with daily fevers, fatigue, and drenching night sweats for 4 months and unintentional weight loss of 20 pounds over 6 weeks. Past medical history included hypertension, and hyperlipidemia. There was no history of travel outside the United States, and no known contact with tuberculosis. Outpatient work-up for fever of

unknown origin was negative. A contrast-enhanced CT scan of the chest, abdomen, and pelvis identified a left atrial cardiac myxoma. The patient was admitted to the hospital for excision of the tumor. On admission, he had a temperature of 38.6 C (101.48 F), pulse 100/min, blood pressure 120/80 mm Hg, and respiratory rate of 16/min. Physical and cardiorespiratory examination was essentially normal. Laboratory values on admission were as follows: WBC count 5,700/mm3 (reference range, 4000-10,000), hematocrit 26.9% (reference range, 42-52), and platelets 177,000/mm3 (reference range 150,000-400,000). Blood cultures done on admission were negative. A transesophageal echocardiogram done preoperatively to delineate the atrial myxoma revealed a highly mobile, pedunculated mass (4 x 2 cm) attached to the posterior wall of the left atrium via a stalk measuring 1.5 cm. Because of the moderate size the mass did not prolapse into the left ventricle. Mitral valve leaflets were normal. Successful excision of the tumor was performed on day 8 of admission. Histopathology confirmed the diagnosis of myxoma. The postoperative course was uneventful. His fever resolved and he recovered well a fter the procedure. This patient’s cardiac myxoma was characterized by which of the following modes of clinical presentation?

Murmurs of mitral insufficiency

Constitutional symptoms

Pulmonary thromboembolism

Systemic embolization of myxoma fragments

Obstruction to the blood flow

6.

Which of the following is the most common benign cardiac tumor?

Papillary fibroelastoma

Myxoma

Lipoma

Rhabdomyoma

Fibroma

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