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  • 1. 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 thelocation and the gross and microscopic pathology of myxoma 3. Describe theclinical manifestations of cardiac myxoma 4. Describe thediagnostic methods of cardiac myxoma 5. Describe thecomplications 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, 2. Mary C Mancini: Cardiac Neoplasms, Primary, eMedicine, 2002, 3. Edwin Rodríguez, Rosa M Cintron-Maldonaldo: Cardiac Tumors, eMedicine, 2003, 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 dyspneaon exertion that worsened after a day’s work. The patient’s job consisted of physicallabor, i.e., building homes; however, he had never had similar symptoms in thepast. Hedenied 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 physicalexamination, 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.
  • 2. In view of his dyspneaon 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 thethorax showed a large, 4 x 6 x 4 cm left atrial mass, which was adherent to the inter-atrial septum. Themass prolapsed through the mitral valve during diastole and resulted in a significant narrowing of themitral 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.
  • 3. 2. Epidemiology. (A) Primary cardiac tumors. Primary cardiac tumors are found in < 1/2000 peopleat 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 theheart include angiosarcoma, leiomyosarcoma, osteosarcoma, fibrosarcoma and malignant fibrous histiocytoma. Angiosarcomas are the most common of primary cardiac malignant tumors. Leiomyosarcomas are thesecond most common primary cardiac malignant tumor. (B) Metastaticcardiac tumors. Metastatictumors 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. Notethe heavy pigmentation and the infiltration of the tumor along the intercellular spaces. Metastaticdisease 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 lymphaticchannels. 3. Clinical manifestations. The clinical symptoms caused by cardiac tumors are generally secondary to their mass effect, local invasion, embolization, or constitutionalsymptoms. An intracardiac tumor mass may obstruct blood flow, compromise valve function, or induce neurological catastrophesecondary to tumor embolization. The location of the tumor determines the typeof symptoms produced, which can include syncope, angina, dyspnea, edema, ascites, depression of pump function, cardiomyopathy, and pulmonary hypertension. Some tumors produceno symptoms and are found incidentally as a consequence of secondary symptoms such as strokeor evidence of peripheral embolization. DEFINITION. Atrial myxoma is a benign tumor found in the heart. It originates from theatrial septumand grows in theleft atrial or right atrial chamber. This tumor is derived from multipotentialmesenchymal 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 theheart: about 75% of them occur in the left atrial cavity. Up to 25% of cases are found in the right atrium. Themost common siteof attachment is at theborder of fossaovalis in the left atrium, although
  • 4. myxomas can originate from the posterior or anterior atrial wall. The mobility of thetumor depends upon the extent of attachment to the interatrial septumand 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 theendocardium and protrudeinto thecardiac 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.
  • 5. The normal cell of origin of myxomas is still unknown, despitecareful study by electron microscopy and immunohistochemistry. The multipotentialmesenchymal cell of the subendocardium has been suggested as the cell from which these tumors originate. The microscopic structureof the tumor with abundant ground substance and stellate-shaped cells is considered to mimic the structureof 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 theblood flow. Thelarge and pedunculated myxomas are sufficiently mobile to move into or through the atrioventricular valves during thediastole or systole. Theprolapseof the tumor into theatrioventricular orifice mimics mitral or tricuspidalstenosis. For example, myxoma of theleft atrium manifests itself with dyspneaon exertion that may progress to orthopnea, paroxysmal nocturnal dyspneaand pulmonary edema. Myxomaof 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 typicalmurmur, 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 thesetumors are most often located in the left atrium, their embolism is generally systemic. Embolization of thecentral nervous systemmay 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 theright side, embolization results in pulmonary embolism and infarction. Multiplerecurrent 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. Constitutionalsymptoms are likely due to the elaboration by some myxomas of thecytokine interleukin-6, a major mediator of theacute phaseresponse. IMAGING STUDIES. Chest radiography reveals an abnormal cardiac silhouette, mimicking mitral stenosis, i.e., mild cardiomegaly and pulmonary venous congestion.
  • 6. 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 theera 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 OFTREATMENT. There is no known medical treatment for atrial myxoma. Operativeresection of the tumor is thetreatment of choice and surgery is usually curative. The recurrence rate is 10.5%. Recurrences are usually attributed to incomplete excision of the tumor.
  • 7. 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 theskin in theform of lentiginosis. It so characteristic that can make thediagnosis. It appears as small (0.2 -1.0 cm) brown-to-black macules typically located around theupper and lower lips, on theeyelids, 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 thecell growth and differentiation. 3. Epidemiology. Carney complex is a rare disease. About 500 patients have been registered by theNIH-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.
  • 8. 2. Locations. Lipomas are most often located in theleft ventricle, right atrium, or atrial septum. Lipoma of atrioventricular valve involves both mitral and tricuspid valve. It causes valvular insufficiency. Lipomatous hypertrophy of theatrial septum is associated with cardiac arrhythmias. Lipomatous hypertrophy of theatrial septumis a non-neoplastic lesion caused by hyperplasticfat 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 producevalvular 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 themost 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.
  • 9. 5. Clinical presentation. Most papillary fibroelastomas are asymptomatic. But papillary fibroelastomas has been well documented as a possiblecause of systemicand 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 theuse of echocardiography. Echodensity of thetumor's central connective tissuecore strongly supports thediagnosis and allows differentiation from other intracardiac tumors, vegetations, or mural thrombi. RHABDOMYOMA. 1. Definition. Cardiac rhabdomyoma is themost 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 theuse of ultrasonography as part of routine prenatalscreening. 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-systemgenetic disease that causes benign tumors to grow in the brain and on other vital organs such as thekidneys, 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. Thefunction 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. Peoplewith 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 myocyteovergrowth. Because they often regress spontaneously, rhabdomyomas are considered by some to be hamartomas rather than true neoplasms.
  • 10. 5. Morphology. (A) Gross appearance. Themost common locations for these tumors are theleft 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 themyocardium or they can extend into the ventricular cavity. (B) Microscopicappearance. 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 thecell 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 theheart. 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 ofleftatrial myxoma except:
  • 11. Aortic dissection Dyspnea on exertion that may progress to orthopnea,paroxysmal nocturnal dyspnea and pulmonaryedema. Murmurs of mitral stenosis ofregurgitation Systemic emboli Fever, weightloss,arthralgias 2. A 35-year-old man presents to the emergencydepartmentwith sudden onsetofpallor,coldness and absentpulse in the lower left extremity. The patientundergoes a successful thrombectomyand pathologic studies ofthe specimen reveal nests ofpolygonal, stellate,and spindled cells on an abundantextracellular matrix.Which of the following is the mostlikelydiagnosis? Cardiac myxoma Cholesterol embolism Buerger disease Takayasu disease Atrial fibrillation 3. In which chamber of the heartare atrial myxomas mostcommonlyobserved? Rightventricle Rightatrium 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 ofmelanoma Papillaryfibroelastoma 5. A 54-year-old man presented with daily fevers, fatigue, and drenching nightsweats for 4 months and unintentional weightloss of20 pounds over 6 weeks.Pastmedical historyincluded hypertension,and hyperlipidemia.There was no historyof travel outside the United States,and no known contact with tuberculosis.Outpatientwork-up for fever of
  • 12. unknown origin was negative.A contrast-enhanced CTscan ofthe chest, abdomen,and pelvis identified a left atrial cardiac myxoma. The patientwas admitted to the hospital for excision of the tumor.On admission,he had a temperature of38.6 C (101.48 F), pulse 100/min,blood pressure 120/80 mm Hg,and respiratoryrate of 16/min. Physical and cardiorespiratoryexamination was essentiallynormal.Laboratoryvalues on admission were as follows: WBC count 5,700/mm3 (reference range,4000-10,000),hematocrit26.9% (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 preoperativelyto delineate the atrial myxoma revealed a highly mobile, pedunculated mass (4 x 2 cm) attached to the posterior wall ofthe left atrium via a stalk measuring 1.5 cm.Because of the moderate size the mass did notprolapse into the left ventricle. Mitral valve leaflets were normal.Successful excision of the tumor was performed on day 8 of admission.Histopathologyconfirmed the diagnosis ofmyxoma. The postoperative course was uneventful.His fever resolved and he recovered well after the procedure.This patient’s cardiac myxoma was characterized by which of the following modes ofclinical presentation? Murmurs of mitral insufficiency Constitutional symptoms Pulmonarythromboembolism Systemic embolization of myxoma fragments Obstruction to the blood flow 6. Which of the following is the mostcommon benign cardiac tumor? Papillaryfibroelastoma Myxoma Lipoma Rhabdomyoma Fibroma 0 6 0 65 mdavis 905516262 admin2 Pathology OMS II 0 0 999999 0