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The 2015 WHO Classification of Tumors of the Heart and Pericardium

Open ArchivePublished:December 24, 2015DOI:https://doi.org/10.1016/j.jtho.2015.11.009

      Abstract

      This article reviews the nomenclature of benign and malignant neoplasm of the heart and pericardium in the 4th edition of the World Health Organization's Classification, with emphasis on differences since the 3rd edition of 2004. The tumours are divided into benign, malignant, and intermediate tumors of uncertain behavior, with separate sections on germ cell tumours and tumors of the pericardium. There are important updates in the sarcoma classification, with emphasis on the most common site, the left atrium. The importance of the new genetic finding in cardiac myxomas, namely somatic mutations in the PRKAR1A gene underscores the importance of this alteration in the pathogenesis of these tumors. Challenges on the classification of each entity are discussed.

      Keywords

      Introduction

      The fourth edition of the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart
      presents a classification of cardiac tumors that is outlined in Table 1. Tumors are separated into benign tumors, tumors of uncertain biologic behavior, germ cell tumors, and malignant tumors. The overall characteristics of heart tumors are presented in Table 2.
      Table 1Tumors of the Heart
      Adapted with permission from Travis et al.
      Benign Tumors and Tumor-Like ConditionsICD-O Codes
       Rhabdomyoma8900/0
       Histiocytoid cardiomyopathy
       Hamartoma of mature cardiac myocytes
       Adult cellular rhabdomyoma8904/0
       Cardiac myxoma8840/0
       Papillary fibroelastoma
       Hemangioma, NOS9120/0
      Capillary hemangioma9131/0
      Cavernous hemangioma9121/0
      Arteriovenous malformation9123/0
      Intramuscular hemangioma9132/0
       Cardiac Fibroma8810/0
       Lipoma8850/0
       Cystic tumor of the atrioventricular node8454/0
       Granular cell tumor9580/0
       Schwannoma9560/0
      Tumors of uncertain biologic behavior
       Inflammatory myofibroblastic tumor8825/1
       Paraganglioma8680/1
      Germ cell tumors
       Teratoma, mature9080/0
       Teratoma, immature9080/3
       Yolk sac tumor9071/3
      Malignant tumors
       Angiosarcoma9120/3
       Undifferentiated pleomorphic sarcoma8830/3
       Osteosarcoma9180/3
       Myxofibrosarcoma8811/3
       Leiomyosarcoma8890/3
       Rhabdomyosarcoma8900/3
       Synovial sarcoma9040/3
       Miscellaneous sarcomas
       Cardiac lymphomas
       Metastatic tumors
      Tumors of the pericardium
       Solitary fibrous tumor8815/1
      Malignant8815/3
       Angiosarcoma9120/3
       Synovial sarcoma9040/3
       Malignant mesothelioma9050/3
       Germ cell tumors
      Teratoma, mature9080/0
      Teratoma, immature9080/3
      Yolk sac tumor9071/3
      ICD-O, International Classification of Diseases for Oncology; NOS, not otherwise specified.
      Table 2Clinicopathologic Features of Primary Heart Tumors
      Adapted with permission from Travis et al.
      Histologic TypeAgeSite in HeartMultiplicitySyndromic Association
      Fetuses, IinfantsChildrenAdultsLayerLocation
      Benign congenital tumors
      Rhabdomyoma+++Myocardium
      Boldface indicates an exclusive site.
      VentriclesUsualTuberous sclerosis
      Fibroma++++MyocardiumVentricle, ventricular septumRareGorlin syndrome
      Histiocytoid cardiomyopathy+++/1Endocardium, myocardiumVentricles, atrial, AV SA nodesAlways
      Benign acquired tumors
      Myxoma+/-++EndocardiumLA, atrial septumRareCarney complex
      RA, atrial septum
      Papillary fibroelastoma++EndocardiumValves > atria > ventriclesOccasional
      Hemangioma
      Hemangioma is considered alternatively as a congenital tumor, especially in children.
      +++Myocardium Endocardium
      Especially the capillary type.
      Atria > ventriclesUnusual
      Lipomatous hypertrophy++Myocardium of atrial septum
      Lipoma++Myocardium, epicardium, endocardiumAll sitesRare
      Inflammatory myofibroblastic tumor
      Inflammatory myofibroblastic tumors are sometimes considered low-grade malignancies, although none in the heart has metastasized.
      ++++/-EndocardiumValves > atriaOccasional
      Germ cell tumors
      Teratoma++++/-Pericardial cavityNo
      Ventricular septum (rare)
      Yolk sac tumor+++Pericardial cavityNo
      Ventricular septum (rare)
      Malignant tumors
      Angiosarcoma+/-++All layersRight atrium, pericardiumOccasional
      UPS/myxofibrosarcoma+/-+/-++EndocardiumLeft atriumRare
      Other sites
      Rhabdomyosarcoma+/-+++MyocardiumVentriclesNo
      Leiomyosarcoma+/-++EndocardiumLeft atriumNo
      Lymphoma+/-++MyocardiumRight atrium, othersOccasional
      WHO, World Health Organization; AV, atrioventricular; SA, sinoatrial; LA, left atrium; RA, right atrium; UPS, undifferentiated pleomorphic sarcoma.
      a Boldface indicates an exclusive site.
      b Hemangioma is considered alternatively as a congenital tumor, especially in children.
      c Especially the capillary type.
      d Inflammatory myofibroblastic tumors are sometimes considered low-grade malignancies, although none in the heart has metastasized.

      Problems in Classification and Changes since the Third Edition

      Cardiac sarcomas represent the tumor type with the greatest need for clarification in terms of classification. The revised World Health Organization (WHO) classification (see Table 2) has simplified the classification of sarcomas with a predilection for the left atrium (the most common site in the heart), but problems persist.
      Most left atrial sarcomas show no differentiation other than along fibroblastic or myofibroblastic lines and have a variegated histologic appearance (Fig. 1). These sarcomas, when they occur in the heart, often have myxoid areas and less frequently have bone matrix formation. This group of sarcomas, when they occur in soft tissue, has included low-grade lesions (fibrosarcoma, myxofibrosarcoma, myxosarcoma, fibromyxosarcoma), and intermediate- to high-grade lesions (myxoid malignant fibrous histiocytoma, malignant fibrous histiocytoma). In the soft tissue, the relative frequency of malignant fibrous histiocytoma, a name that has been changed to undifferentiated pleomorphic sarcoma, is debated and ranges from less than 10% to 70% of tumors.
      • Miettinen M.
      Fibroblastic and myofibroblastic neoplasms with malignant potential.
      • Weiss S.W.
      • Goldblum J.R.
      • Folpe A.L.
      Undifferentiated pleomorphic sarcoma
      Enzinger and Weiss's Soft Tissue Tumors.
      The lack of diagnostic agreement among experts in soft-tissue pathology makes classification of similar tumors in the heart, where they are much rarer, difficult. However, there is general consensus that high-grade sarcomas previously called malignant fibrous histiocytoma are now classified as undifferentiated pleomorphic sarcoma to conform with the WHO classification of soft-tissue tumors.
      • Fletcher C.D.M.
      • Chibon F.
      • Mertens F.
      Undifferentiated/unclassified sarcomas.
      Figure thumbnail gr1
      Figure 1Variations on left atrial sarcomas. (A) An entirely benign appearing area from a surgically excised left atrial mass. (B) Another area from the same tumor with myxoid mildly pleomorphic tumor cells, classified as myxofibrosarcoma by current World Health Organization guidelines. (C) A metastatic deposit in the iliac bone that occurred 1.5 years later; note similar appearance to the tumor (from the same patient) in B. The coarse capillary pattern is somewhat reminiscent of myxofibrosarcoma of soft tissue. (D) A different left atrial sarcoma, open biopsy. There is significant atypia, but no myxoid change in this area. The tumor by imaging was invading through the atrial wall (not shown). Amplification of the MDM2 proto-oncogene, E3 ubiquitin protein ligase gene (MDM2) was not present. Despite the relative lack of pleomorphism, the best classification by current World Health Organization criteria is undifferentiated pleomorphic sarcoma.
      Regarding the lower-grade sarcomas, the older designations in the third edition of the WHO book have now been combined into the one term myxofibrosarcoma. Although this simplifies the classification, it is problematic because some tumors have little if any myxoid areas, and the term fibrosarcoma, which is applied to a shrinking group of soft-tissue sarcomas, is no longer in the classification of heart tumors. The remaining designation for low-grade left atrial sarcomas is myxofibrosarcoma, which was previously applied to malignant fibrous histiocytomas with at least 25% myxoid areas and is accurate descriptively for most low-grade left atrial sarcomas. When they occur in the heart, however, they tend not to show features typical of soft-tissue myxofibrosarcoma (namely, well-developed, prominent capillaries forming curvilinear profiles); therefore, the applicability of this term to left atrial sarcomas may be questionable.
      • Miettinen M.
      Fibroblastic and myofibroblastic neoplasms with malignant potential.
      As more data accumulate regarding molecular and cytogenetic characterization of cardiac myxofibrosarcoma and undifferentiated pleomorphic sarcoma, modifications to the current classification will continue to evolve. A unifying concept, designating left atrial sarcomas with amplification of the MDM2 proto-oncogene, E3 ubiquitin protein ligase gene (MDM2) as intimal sarcoma, has been proposed.
      • Neuville A.
      • Collin F.
      • Bruneval P.
      • et al.
      Intimal sarcoma is the most frequent primary cardiac sarcoma: clinicopathologic and molecular retrospective analysis of 100 primary cardiac sarcomas.
      Intimal sarcoma is used to designate sarcomas of the pulmonary artery
      • Burke A.P.
      • Yi E.S.
      Pulmonary artery intimal sarcoma.
      and aorta,
      • Bode-Lesniewska B.
      • Debiec-Rychter M.
      Intimal sarcoma.
      which are primarily intraluminal and present with embolic phenomena. The rationale behind using this term for cardiac sarcomas is that the MDM2 amplification, which had previously been limited to liposarcomas and a small number of other sarcomas, was recently found in most pulmonary artery “intimal” sarcomas and undifferentiated cardiac sarcomas.
      • Bode-Lesniewska B.
      • Debiec-Rychter M.
      Intimal sarcoma.
      In the third edition of the WHO classification, intimal sarcoma is mentioned as a synonym or alternative designation and was not adopted as a histologic subtype of left atrial sarcomas because there is currently no evidence that intimal sarcomas at other sites (for example, the aorta) have MDM2 amplification, and because only a subset of left atrial sarcomas are MDM2 amplified.
      • Maleszewski J.J.
      • Tavora F.
      • Burke A.P.
      Do “intimal” sarcomas of the heart exist?.
      In any event, the term intima is inappropriate for the left atrium, although it is true that undifferentiated left atrial sarcomas are often histologically identical to sarcomas of great arteries, especially those in the aorta.
      Another somewhat problematic area in classification of cardiac sarcomas is that of tumors with bone matrix formation. In the third edition, sarcomas with osteosarcoma or chondrosarcoma were classified as a subtype of undifferentiated pleomorphic sarcoma.
      • Burke A.P.
      • Tazelaar H.
      • Butany J.W.
      • et al.
      Cardiac sarcomas.
      Partly to conform to the WHO classification of soft-tissue tumors,
      • Rosenberg A.E.
      Extraskeletal osteosarcoma.
      the current edition places these tumors in a separate category analogous to extraskeletal osteosarcomas of the soft tissue. Importantly, these tumors often have areas of chondrosarcoma, as well as areas resembling myxofibrosarcoma or undifferentiated pleomorphic sarcoma (Fig. 2). In addition, the osseous component may appear very bland, as in the case of extraskeletal osteosarcomas of soft tissue.
      • Rosenberg A.E.
      Extraskeletal osteosarcoma.
      Molecular studies including MDM2 amplification have not been reported for cardiac osteosarcomas, so the ultimate relationship between these and related tumors is not yet known.
      Figure thumbnail gr2
      Figure 2Osteosarcoma, left atrium. (A) Autopsy specimen (cut open, four-chamber view) shows an infiltrative, pale and gritty mass (asterisk) centered in the left atrium with contiguous mitral valve invasion (arrow). (B) Some areas were myxoid and relatively bland, similar to myxofibrosarcoma. (C) The bone formation in this invasive area of tumor (into the pulmonary vein) showed well-differentiated osteoid. (D) In some areas, there is chondrosarcoma. (E) Other areas show poorly differentiated osteosarcoma.
      Since the publication of the third edition, a major advance in the genetics of cardiac myxoma, the most common heart tumor, has been reported. Nearly 10% of all sporadic myxomas and 30% of those with immunohistochemical loss of PRKAR1A protein (cAMP-dependent protein kinase type I-alpha regulatory subunit) expression show somatic mutations in the protein kinase, cAMP-dependent, regulatory subunit type I alpha gene (PRKAR1A). These findings document a role of PRKAR1A in genesis of sporadic myxomas, unlike previously believed.
      • Maleszewski J.J.
      • Tavora F.
      • Burke A.P.
      Do “intimal” sarcomas of the heart exist?.

      Congenital and Childhood Tumors

      Histiocytoid Cardiomyopathy

      Histiocytoid cardiomyopathy has in the past been designated oncocytic cardiomyopathy, Purkinje cell hamartoma, or more simply cardiac hamartoma. It is a multifocal hamartomatous collection of cells that resemble modified myocytes of the conduction system.
      • Malhotra V.
      • Ferrans V.J.
      • Virmani R.
      Infantile histiocytoid cardiomyopathy: three cases and literature review.
      Histiocytoid cardiomyopathy is rare, with fewer than 150 reported instances. Most affected patients are infants in the first year of life who have ventricular tachyarrhythmias or die suddenly. More than one-third of children have additional anomalies, both cardiac and extracardiac. Recently, a novel mutation in the NADH:ubiquinone oxidoreductase subunit B11gene (NDUFB11) has been identified in a few probands by direct sequencing, suggesting a role in the pathogenesis of the disease.
      • Shehata B.M.
      • Cundiff C.A.
      • Lee K.
      • et al.
      Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo NDUFB11 mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy.
      Grossly, the tumors are present as endocardial or myocardial nodules and may involve the sinoatrial and atrioventricular nodes. Histologically, the cells are finely vacuolated, rounded myocytes that ultrastructurally demonstrate numerous mitochondria and disordered myofibrils. There have been sporadic reports of mutations in mitochondrial genes; only a few cases (5%) are familial.
      • Vallance H.D.
      • Jeven G.
      • Wallace D.C.
      • et al.
      A case of sporadic infantile histiocytoid cardiomyopathy caused by the A8344G (MERRF) mitochondrial DNA mutation.

      Rhabdomyoma

      Rhabdomyoma is the most common heart tumor diagnosed in fetuses and infants, and like histiocytoid cardiomyopathy, it is considered a congenital hamartoma. The diagnosis is made from before birth to the age of 6 years, with a mean of age of diagnosis of 2 weeks; there is no sex predilection. Cardiac rhabdomyoma is strongly associated with tuberous sclerosis. These tumors may be incidental findings or may cause symptoms by obstruction of blood flow or incitement of arrhythmias. The most frequent site is the ventricular myocardium, with occasional protrusion into the cavity. Rhabdomyomas are typically multiple and do not calcify, in contrast to cardiac fibroma. On imaging, they are characterized by homogeneous echogenicity. Histologically, cardiac rhabdomyomas form nodules of rounded myocytes with large vacuoles and intervening strands of myocyte cytoplasm. The vacuoles are secondary to intracytoplasmic accumulation of glycogen. Because the natural course of cardiac rhabdomyoma is spontaneous regression, surgical removal is considered only with significant outflow obstruction or refractory arrhythmias.

      Rare Hamartomas

      Several relatively common tumors in the heart are considered hamartomas, including rhabdomyoma, histiocytoid cardiomyopathy, fibroma, and sometimes papillary fibroelastoma. One of the least common is the “hamartoma of mature cardiac myocytes,” which is composed entirely of heart muscle cells. Its distinction from rhabdomyoma is that the cells appear mature without the vacuolization seen in rhabdomyoma.
      Unlike rhabdomyoma, hamartomas of mature cardiac myocytes occur in adults.
      • Raffa G.M.
      • Malvindi P.G.
      • Settepani F.
      • et al.
      Hamartoma of mature cardiac myocytes in adults and young: case report and literature review.
      Histologically, they resemble areas of myofiber disarray as seen in hypertrophic cardiomyopathy but are circumscribed masses.
      • Burke A.P.
      • Ribe J.K.
      • Bajaj A.K.
      • et al.
      Hamartoma of mature cardiac myocytes.
      Other rare hamartomatous tumors in the heart contain areas of mature fat as a component of the lesion. These include hamartoma of cardiac valves,
      • Bhat S.P.
      • SI G.G.
      • Chikkatur R.
      • et al.
      Lipomatous hamartoma of mitral valve.
      which have a mixture of fat and fibrous tissue, and rare intramuscular cardiac tumors with fat, vessels, heart muscle cells, and nerves.
      • Bradshaw S.H.
      • Hendry P.
      • Boodhwani M.
      • et al.
      Left ventricular mesenchymal hamartoma, a new hamartoma of the heart.
      Because this so-called mesenchymal hamartoma has been reported only once and overlaps significantly with intramuscular hemangiomas (except for the nerve tissue), it is not considered a separate entity in the WHO classification of heart tumors.

      Cardiac Fibroma

      Cardiac fibroma, like histiocytoid cardiomyopathy and cardiac rhabdomyoma, is a hamartomatous lesion that is present from birth; however, the onset of symptoms typically occurs later, with the mean age of onset being 11 years and time of onset ranging from birth to adulthood. There is a slight predominance among males. Signs and symptoms include ventricular arrhythmias, cyanosis, dyspnea, and sudden death. The left ventricle is the most frequent site of involvement. Grossly, the tumors resemble fibroids and are circumscribed (Fig. 3). Microscopically, the edges of the tumors infiltrate the myocardium. The tumor cells resemble fibroblasts, and there is variable collagen and elastic tissue. Calcifications are common. Tumors that are symptomatic are treated by resection, which results in complete excision in nearly 75% of tumors. Some patients may require an orthotopic heart transplant.
      • Nathan M.
      • Fabozzo A.
      • Geva T.
      • et al.
      Successful surgical management of ventricular fibromas in children.
      • Kobayashi D.
      • L'Ecuyer T.J.
      • Aggarwal S.
      Orthotopic heart transplant: a therapeutic option for unresectable cardiac fibroma in infants.
      Figure thumbnail gr3
      Figure 3Left ventricular fibroma in an asymptomatic middle-aged male. (A) Contrast-enhanced electrocardiography-gated cardiac computed tomography image demonstrates an oblong, homogeneous soft-tissue mass (arrows) in the lateral left ventricle that is partly surrounded by epicardial fat. (B) Axial magnetic resonance image (double inversion recovery) confirms an oblong, hypointense mass (arrows) associated with the left ventricular wall that is partly outlined by epicardial fat (middle). (C) Gross photo of a ventricular fibroma (cut section) reveals firm, whorled white tissue (right). (D) Histologic section shows a bland spindle cell tumor with background fibrous tissue.

      Cystic Tumor of the Atrioventricular Node

      Cystic tumors of the atrioventricular node are rare choristomatous lesions composed of ectopic glands that occur in the area of the atrioventricular node and the atrial septum. Ten percent of patients have other midline defects. Because of these tumors' location, congenital heart block is a typical manifestation. Histologically, the cysts are benign and lined by flattened cuboidal or squamous epithelium. Sudden death is the most common initial manifestation of disease. Most patients are female (in a ratio of 3:1), with the diagnosis being made in the fourth decade of life. Most atrioventricular nodal tumors are diagnosed incidentally at autopsy, with a history of heart problems or as the cause of sudden death. There are a few case reports of successfully resected atrioventricular nodal tumors.

      Germ Cell Tumors (Teratoma and Yolk Sac Tumor)

      The vast majority of germ cell tumors within the pericardium occur in the pericardial space, do not involve the heart muscle or endocardium, and are classified as pericardial germ cell tumors (see later). Myocardial germ cell tumors are rare, with scattered reports of teratomas and yolk sac tumors occurring in the ventricular or atrial septum.
      • Patel A.
      • Rigsby C.
      • Young L.
      Cardiac teratoma of the interventricular septum with congenital aortic stenosis in a newborn.

      Nonneoplastic Tumors of Adults

      Papillary Fibroelastoma

      Papillary fibroelastoma is a benign endocardial papillary growth that histologically resembles Lambl excrescences (reactive excrescences found in along the lines of closure and typically affecting the aortic valve in older adults) (Fig. 4). Papillary fibroelastomas are larger than nodules of Arantius and can be found anywhere along the endocardial surface. The most common locations are the aortic valve, followed by the mitral valve, left ventricular endocardium, and tricuspid valves.
      • Burke A.
      • Jeudy Jr., J.
      • Virmani R.
      Cardiac tumours: an update: Cardiac tumours.
      Because papillary fibroelastomas are easily seen by echocardiography, they are readily diagnosed and resected. Symptoms result from embolism, usually in the form of syncope or transient ischemic attacks, or from prolapse into the coronary ostia that causes chest pain. Although there is still debate about the neoplastic nature of the lesion, papillary fibroelastoma is currently the most commonly excised heart mass, recently surpassing myxoma. Grossly, the tumors are soft, rounded nodules that expand upon placement in fluid. Surgical approach generally involves resection only, with sparing of underlying valve tissue.
      Figure thumbnail gr4
      Figure 4Papillary fibroelastoma. (A) An elderly with recent cognitive decline and multiple lacunar infarcts on the magnetic resonance image. Contrast-enhanced electrocardiography-gated cardiac computed tomography image, sagittal plane reconstruction shows a 1.3 cm papillary lesion (arrow) connected to the left aortic valve by a narrow stalk. (B) Contrast-enhanced electrocardiography-gated cardiac computed tomography image reconstructed through the aortic valve plane shows proximity of the lesion (arrow) to the left main coronary ostium (arrowhead). Gross resected specimen (C) and histologic section (D) reveal multiple papillary fronds arising from a central stalk.

      Lipomatous Hypertrophy of the Atrial Septum

      Lipomatous hypertrophy is not considered as a separate entity in the fourth edition of the WHO classification of heart tumors, as in the prior edition; it is mentioned only in the differential diagnosis of lipoma and considered a benign neoplasm. However, lipomatous hypertrophy may be a mass detected by imaging and resected for diagnosis or because of obstructive symptoms.
      • Burke A.
      • Jeudy Jr., J.
      • Virmani R.
      Cardiac tumours: an update: Cardiac tumours.
      • Burke A.
      Primary malignant cardiac tumors.
      Histologically, in distinction to lipoma, lipomatous hypertrophy is composed of brown fat and cardiac myocytes and is therefore a form of hamartoma or hyperplasia. Lipomatous hypertrophy is often an incidental finding on imaging, but it may cause obstruction to blood flow in the superior vena cava and cardiac arrhythmias. A recent study found a cytogenetic abnormality in one of 47 cases of the series, suggesting that at least a subset of these lesions may be true neoplasms.
      • Bois M.C.
      • Bois J.P.
      • Anavekar N.S.
      • et al.
      Benign lipomatous masses of the heart: a comprehensive series of 47 cases with cytogenetic evaluation.

      Neoplastic Benign Tumors of Adults

      Cardiac Myxoma

      Cardiac myxoma is the only relatively common primary heart neoplasm, occurring in one Irish estimate at a rate of 0.5 cases per million population per year.
      • MacGowan S.W.
      • Sidhu P.
      • Aherne T.
      • et al.
      Atrial myxoma: national incidence, diagnosis and surgical management.
      Although cardiac myxoma is currently considered a neoplasm, the cell of origin is debated. Tumor cells are believed to share characteristics with endocardial-mesenchymal transformation of the endocardial cushion. The presence of true glands in 2% of cardiac myxomas indicates that they are not reactive lesions. Inactivating mutations in the PRKAR1A gene are found in both sporadic and nonsporadic tumors, suggesting that immunohistochemical staining for PRKAR1A protein be performed routinely.
      • Maleszewski J.J.
      • Tavora F.
      • Burke A.P.
      Do “intimal” sarcomas of the heart exist?.
      There is a predominance in females, with the incidence ranging from 1.5 to 2 times that in men. The mean age at presentation is 53 years. Patients may be asymptomatic or show a range of symptoms, including dyspnea and constitutional symptoms; 22% of cardiac myxomas embolize and result in symptoms of stroke or peripheral ischemia. All myxomas are endocardial based and project into the heart chamber cavity. Most (85%) arise from the left atrial septum, 11% from the right atrial septum, and the remainder from a variety of sites; 1% are multiple. Grossly, they are of two types: most myxomas are smooth-surfaced, firm masses that may calcify or even ossify, and a small proportion are soft, gelatinous tumors with irregular fronds that often embolize (Fig. 5).
      • Burke A.
      • Jeudy Jr., J.
      • Virmani R.
      Cardiac tumours: an update: Cardiac tumours.
      • Burke A.
      Primary malignant cardiac tumors.
      Histologically, there are invariably diagnostic areas of myxoma cells that form rings and cords, express calretinin and CD34 antigen, and show variable endothelial differentiation. A large part of the tumor may be an organizing thrombus, which may make the distinction from thrombus difficult; however, thrombi typically do not arise from the atrial septa and do not express calretinin. After resection, there is a 1% recurrence rate. In 5% of patients, myxomas are a manifestation of Carney complex; these patients are more likely to be younger, with embolic tumors that are more often multiple and unusually located than sporadic ones are.
      Figure thumbnail gr5
      Figure 5Left atrial myxoma presenting as cerebral infarct in a 44-year-old male. (A) Contrast-enhanced electrocardiography-gated cardiac computed tomography image reconstructed at 78% of the R-R interval shows a faintly enhancing intracavitary mass (asterisk) with frond-like contour and unusual adherence to the left atrial posterior wall. (B) Specimen photograph of a myxoma demonstrates similar frond like morphology, predisposing to systemic embolization. (C) Histologic low magnification shows irregular tumor outline.

      Cardiac Paraganglioma

      Cardiac paragangliomas arise from paraganglial tissue that occurs at the base of the heart and atrium and are most common between the pulmonary trunk and ascending aorta. They are neoplasms that may invade adjacent structures and therefore require excision or rarely even transplantation.
      • Huo J.L.
      • Choi J.C.
      • DeLuna A.
      • et al.
      Cardiac paraganglioma: diagnostic and surgical challenges.
      Although one-third of paragangliomas are malignant in other sites, cardiac paragangliomas that have metastasized have been only rarely documented histologically. Their histologic appearance is similar to that of extracardiac paraganglioma. Most cardiac paragangliomas secrete catecholamines and present with systemic hypertension.

      Cardiac Lipoma

      True lipomas of the heart are rare, comprising less than 0.5% of excised tumor. These tumors may occur anywhere in the heart, with a predilection for the epicardium or endocardium. Most are clinically silent and found incidentally on imaging or at autopsy. Grossly, lipomas are usually small, single, and encapsulated. The histologic findings are classic and similar to those for lipomas elsewhere in the body. Prognosis is usually good, with rare cases being associated with arrhythmias or sudden death.

      Cardiac Sarcomas

      Rhabdomyosarcoma

      Although one would consider it likely that malignant heart tumors would arise from the predominant normal cardiac tissue, sarcomas derived from striated muscle are distinctly rare, accounting for 0% to 5% of primary cardiac sarcomas.
      • Burke A.
      Primary malignant cardiac tumors.
      Most cases appear in children, at a mean age of approximately 14 years. Rhabdomyosarcoma has a predilection for the ventricle, unlike angiosarcoma and undifferentiated sarcomas. The histologic features are usually of the embryonal subtype. Survival of rhabdomyosarcoma is poor.
      • Burke A.
      • Jeudy Jr., J.
      • Virmani R.
      Cardiac tumours: an update: Cardiac tumours.
      • Burke A.
      Primary malignant cardiac tumors.

      Angiosarcoma

      Angiosarcomas account for approximately 40% of cardiac sarcomas and typically present in the right atrioventricular groove, with frequent involvement of the pericardium and right atrial wall.
      • Burke A.
      Primary malignant cardiac tumors.
      On cardiac magnetic resonance imaging, angiosarcoma appears as a heterogeneous, nodular mass in the right atrium, and grossly, there are invariably areas of hemorrhage (Fig. 6). Histologically, some areas show endothelial differentiation with formation of anastomosing channels lined by atypical cells having mitotic activity. Other tumors are primarily spindled, in which case endothelial differentiation may need verification with immunohistochemical staining. Occasional tumors appear relatively low grade, in which case the differentiation from hemangioma, which also has a predilection for the right atrium, may be difficult. Time of survival of angiosarcoma is shorter than that of other histologic subtypes, with a mean of approximately 1 year, except for the unlikely tumors that can be completely excised.
      Figure thumbnail gr6
      Figure 6Angiosarcoma in a 35-year-old female. (A) Contrast-enhanced axial computed tomography scan (soft-tissue window) shows a heterogeneously enhancing mass (arrows) filling the right atrial chamber. (B) Coronal T1-weighted magnetic resonance image (black blood) demonstrates multiple areas of high signal intensity within the mass (arrows) that is consistent with hemorrhagic foci. (C) Gross specimen photograph shows the mass (arrows) in the identical orientation to the middle figure. There are several areas of purple hemorrhagic material within the tumor and within pericardial metastatic deposits (arrowheads). (D) Histologic sections shows vasoformative areas (right) and more spindled areas (left).

      Sarcomas that Occur Primarily in the Left Atrium

      Taken together, this group of tumors account for at least 50% of cardiac sarcomas, the most common being undifferentiated pleomorphic sarcoma. A small proportion of these undifferentiated sarcomas occur in other chambers, most frequently the left ventricle and right atrium. By cardiac imaging, these tumors are readily distinguished from myxomas by their infiltrative growth into the atrial wall and lack of attachment site on the atrial septum (Fig. 7). Histologically, these tumors are heterogeneous, ranging from bland collagen-rich areas that may in small samples appear benign to low-grade sarcomas with myxoid background to areas of high pleomorphism and mitotic activity (undifferentiated pleomorphic sarcoma). When there is a preponderance of spindle fibroblast-like cells with a myxoid or fibrous background, the term myxofibrosarcoma is used.
      Figure thumbnail gr7
      Figure 7Inflammatory myofibroblastic tumor. Histologically, these may resemble sarcomas or occasionally myxomas. (A) The typical low magnification shows a filiform tumor. (B) Despite the high cellularity, there are few if any mitotic figures, and there is generally a sparse inflammatory background.
      Sarcomas with specific tissue differentiation also occur in the left atrium and include leiomyosarcoma, synovial sarcoma, and extraskeletal osteosarcoma. Although the numbers of tumors in most series are small, there is some suggestion that the myxofibrosarcoma may have a better prognosis than does undifferentiated pleomorphic sarcoma or osteosarcoma, as would be expected.

      Cardiac Lymphoma

      Primary lymphomas of the heart account for 1% to 2% of all surgically resected heart tumors. The most common location is the right atrium, although all chambers may be involved. By definition, primary cardiac lymphoma must present with cardiac symptoms, with most of the tumor being intrapericardial at the time of presentation. The most common histologic type is diffuse large B-cell lymphoma, followed by follicular B-cell lymphoma, Burkitt's lymphoma, and others.
      • Jeudy J.
      • Kirsch J.
      • Tavora F.
      • et al.
      From the radiologic pathology archives: cardiac lymphoma: radiologic-pathologic correlation.

      Uncommon Cardiac Tumors with Extracardiac Counterparts

      Inflammatory Myofibroblastic Tumor

      Cardiac inflammatory myofibroblastic tumor is a rare benign neoplasm occurring in infants, children, and occasionally adults. The biologic behavior of this lesion, like that of its counterparts in other organ sites, is debated. In the WHO revision it is classified with lesions having “uncertain biologic behavior.” The confusion regarding its malignant potential arises from lack of precision in classification, as many so-called inflammatory myofibroblastic tumors of the heart include reactive inflammatory masses. When strictly applied to endocardial-based myofibroblastic tumors (typically on valves) with variable myxoid and inflammatory background, few mitotic figures (<1 in 10 high-magnification fields), and an eroded fibrinous surface, the term cardiac inflammatory myofibroblastic tumors refers to tumors that do not metastasize or invade the heart. These tumors are frequently misdiagnosed either as myxoma or sarcoma because of the possible overlap of their histologic appearance (Fig. 7). Expression of anaplastic lymphoma kinase-1 is not a reliable marker for cardiac inflammatory myofibroblastic tumor. Death due to prolapse into the coronary arteries and symptomatic embolization may occur, however.

      Hemangioma

      Hemangiomas and vascular malformations of the heart are heterogeneous, with a smaller group present at birth or in childhood and a larger group occurring in adulthood.
      • Burke A.
      • Johns J.P.
      • Virmani R.
      Hemangiomas of the heart. A clinicopathologic study of ten cases.
      In children the most common site is the right atrium, whereas in adults the left ventricle and cardiac valves are equally as common. A large number of hemangiomas in adults are identified incidentally, although hemangiomas in infants can cause hydrops and cardiac tamponade because of large pericardial effusions. Histologically, cardiac hemangiomas are heterogeneous, resembling cavernous or capillary hemangiomas most frequently and intramuscular hemangioma or arteriovenous malformations less frequently. Some cardiac hemangiomas that occur in adults are endocardial-based capillary or cavernous hemangiomas, often with a stalk, and they are frequently misdiagnosed as myxomas, especially when there is a myxoid background histologically (Fig. 8). Cardiac hemangiomas of the right atrium may form papillary structures, and because of their infiltrative nature, they are occasionally difficult to discern from angiosarcomas. Endocardial-based tumors are more readily excised than are intramural hemangiomas, which typically resemble intramuscular hemangiomas of soft tissue in that there is a microscopically visible admixture of fibrous tissue and fat.
      • Bradshaw S.H.
      • Hendry P.
      • Boodhwani M.
      • et al.
      Left ventricular mesenchymal hamartoma, a new hamartoma of the heart.
      Cardiac hemangiomas generally do not recur after excision and are occasionally associated with extracardiac hemangiomas, including of the gastrointestinal tract and liver.
      Figure thumbnail gr8
      Figure 8Hemangioma. (A) Low magnification demonstrating attachment along the surface of the tricuspid valve (TV). The low magnification with myxoid background suggests a myxoma, which rarely if ever occurs on valves. (B) High magnification demonstrates well-formed vessels typical of hemangioma.

      Adult Cellular Rhabdomyoma

      Fewer than five such cases have been reported. This rare tumor is included because it rounds out the spectrum of tumors derived from cardiac muscle: the three hamartomatous lesions (rhabdomyoma, histiocytoid cardiomyopathy, and hamartoma of mature cardiac myocytes), the malignant neoplasm (rhabdomyosarcoma) and the benign neoplasm (adult cellular rhabdomyoma). The latter tumor resembles those that are seen in the head and neck and are called extracardiac rhabdomyoma in distinction from the common hamartomatous lesion. Unlike rhabdomyomas, however, adult cellular rhabdomyomas are cellular tumors with a high proliferative rate, and they are neoplastic, but without metastatic potential.
      • Burke A.
      • Jeudy Jr., J.
      • Virmani R.
      Cardiac tumours: an update: Cardiac tumours.
      • Burke A.
      Primary malignant cardiac tumors.

      Tumors of the Pericardium

      Sarcoma

      Sarcomas of the pericardium are rare; the most common are synovial sarcoma (which also accounts for approximately 5% of cardiac sarcomas), angiosarcoma (which often involves both the pericardium and right atrium), and undifferentiated pleomorphic sarcoma. Classification and diagnosis is similar to that of soft-tissue counterparts.

      Mesothelioma

      Malignant mesothelioma of the pericardium is rare, accounting for fewer than 2% of all mesotheliomas. By definition, there must be a lack of pleural involvement or most of the tumor must be within the pericardial space. Only 14% of patients have a history of occupational exposure to asbestos.
      • Thomason R.
      • Schlegel W.
      • Lucca M.
      • et al.
      Primary malignant mesothelioma of the pericardium. Case report and literature review.
      Most cases are of the epithelioid type, but biphasic and desmoplastic mesotheliomas of the pericardium have been reported. Invasion of the underlying myocardium is not uncommon. Prognosis is poor because most tumors are unresectable.

      Solitary Fibrous Tumor

      Solitary fibrous tumors are low-grade spindle cell neoplasms that typically behave in a benign fashion but may recur if large and mitotically active. There are rare examples of overtly malignant solitary fibrous tumors. The most common location is the pleura, although mediastinal sites, including heart and pericardium, have been reported.

      Germ Cell Tumors

      Approximately 50 intrapericardial teratomas have been reported.
      • Burke A.
      • Virmani R.
      Pediatric heart tumors.
      Nearly half are diagnosed in utero, and most of the remainder occur in children under 15 years of age. There is a slight predominance in males. Pericardial teratomas are typically attached to the ascending aorta and project into the pericardial sac. Most are successfully resected, but deaths may occur from massive tumor or tumor recurrence. There are no reports of metastasis. The histologic findings are typically those of mature teratoma, but there may be immature elements. Unlike in the case of teratomas of the testis, there are no reports of mixed germ cell elements, other than yolk sac tumor.
      Fewer than 10 intrapericardial yolk sac tumors have been described. Most patients are infants and children, with a predominance of females. The tumors may be aggressive, with possible metastatic development.

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