Context.—Primary cardiac tumors are rare and the great majority are benign neoplasms. Mass-forming reactive and pseudoneoplastic growths are less common, but recognizing and distinguishing these lesions from the neoplasms they resemble is critical to appropriate patient care.
Objective.—The general clinical, imaging, gross pathologic, and histologic features of 5 important pseudoneoplasms (inflammatory myofibroblastic tumor, hamartoma of mature cardiac myocytes, mesothelial/monocytic cardiac excrescences, calcified amorphous tumor, and lipomatous hypertrophy of the atrial septum) are discussed, with an emphasis on features differentiating them from other benign and malignant tumors.
Data Sources.—Pertinent citations of the literature and observations from the authors' experience are drawn upon.
Conclusions.—While lacking malignant potential, these lesions can be associated with considerable morbidity and occasional mortality. Their recognition is important in guiding patient management, providing both guidance for appropriate therapy and avoidance of inappropriately aggressive and toxic treatments.
Tumors of the heart, whether neoplastic or not, are infrequently encountered in surgical or autopsy pathology. Their scarcity and the spectrum of lesions spanning reactive conditions, and both benign and malignant neoplasms, often generate considerable diagnostic difficulty. This section focuses on 5 reactive and “pseudoneoplastic” tumors of the heart, which mimic true neoplasms either grossly (including by clinical imaging) or microscopically, and include (1) inflammatory myofibroblastic tumor (IMT), (2) hamartoma of mature cardiac myocytes (HMCM), (3) mesothelial/monocytic incidental cardiac excrescences (MICE), (4) calcified amorphous tumor (CAT), and (5) lipomatous hypertrophy of the atrial septum (LHAS).
Aspects of these lesions distinguishing them from the neoplasms they may resemble are highlighted. The general clinical, gross, imaging, and histologic features are discussed along with any pertinent genetic or immunophenotypic aspects. While these lesions do not have malignant potential, they are certainly associated with significant morbidity and mortality by affecting valvular function, cardiac conduction/electrical excitability, and by leading to obstruction of blood flow or embolization.
INFLAMMATORY MYOFIBROBLASTIC TUMOR
Fewer than 40 cases of cardiac IMT have been reported,1,2 though its possible counterpart tumor in other sites (particularly lung, bladder, and intra-abdominal organs) is far more common.3 As mass lesions in the heart composed of spindle cells in an often myxoid background, a variety of benign and malignant lesions are typically included in the differential diagnosis for these lesions.
While studies of IMT occurring in other organ sites (bladder, lung, and soft tissue) and in younger patients suggest that IMT is likely a true neoplasm (with conserved chromosomal translocations and possible evidence of viral transformation), the etiologic derivation of cardiac IMT (which shows important differences from IMT at other sites) remains unclear. In other organ sites, and particularly in pediatric tumors, rearrangements involving the anaplastic lymphoma kinase (ALK-1) gene are seen in up to 67% of tumors4 and overexpression of ALK-1 protein by immunohistochemistry is seen in 40% to 60% of tumors.5,6 It is unclear whether IMT not showing evidence of ALK-1 alteration represents a reactive process resembling neoplastic IMT or a true neoplasm driven by other transformative mechanisms. While available studies of cardiac IMT are limited to case reports7,8 and a single series,1 ALK-1 expression has been reported in only 14% of tumors.1 Cytogenetic studies for ALK-1 rearrangements have been reported in only 1 case of cardiac IMT, showing normal intact ALK-1.8 Another cardiac IMT tested for ALK-1 rearrangements by fluorescence in situ hybridization in our laboratory showed no rearrangement at this locus (D.V.M., unpublished data, 2007).
Grossly, IMT is typically soft and somewhat translucent, showing textural variation that often includes fleshy and fibrous portions (Figure 1). This variation is reflected in the histopathologic appearance of IMT, with myofibroblasts present in areas of loose myxoid matrix (Figure 2, A), densely collagenized stroma (Figure 2, B), and occasional areas of compact cellularity.4 Cytologic atypia is at most low grade (as in Figure 2, A) and mitotic activity is infrequent (<2 per 10 high-power fields).1 The myofibroblastic cells show spindled, stellate, and rare epithelioid forms. The nuclei are elongated and show vesicular chromatin with occasional prominent nucleoli. Inflammation is invariably present throughout the lesion, though the intensity varies, and is comprised of plasma cells and lymphocytes with lesser numbers of granulocytes (Figure 2, C), including eosinophils (which can be a helpful diagnostic clue). Patchy necrosis, likely due to torsion and mechanical trauma, has been described in some cases.1
IMT is distinguished from myxofibrosarcoma and low-grade fibromyxosarcoma by the presence of diffuse inflammation and absence of typical delicate “curvilinear” vessels characteristic of these sarcomas.9,10 Unlike cardiac myxoma, IMT lacks perivascular rings and trabecular cords of “myxoma” cells suspended in a loose matrix.11
IMTs show no apparent predilection for a particular cardiac chamber. They tend to arise from endocardial surfaces (including the valves) and form pedunculated polypoid masses. They are readily imaged by echocardiography and appear bright on ultrasound. Cardiac magnetic resonance imaging demonstrates these tumors to be isodense to the surrounding myocardium on T1-weighted imaging, but bright on T2-weighted imaging. They often show delayed enhancement with gadolinium.12 They are unique among cardiac tumors in having an associated inflammatory syndrome of fever, malaise, weight loss, and thrombocytosis in many cases.13 These effects are thought to stem from IMT-mediated cytokine expression (IL-6), a phenomenon first described in tumors arising in other organ sites.13 They are most common in the first 2 decades of life,1,2 though they have been seen in patients as old as 76 years.13 They typically come to clinical attention because of obstruction of blood flow at some level within the heart.
The treatment for these tumors is surgical, and while cardiac IMT has been reported to recur locally, there have been no documented cases with metastases, though in at least one patient, peripheral embolization of IMT has occurred.1
An early report of patients with IMT found human herpesvirus 8 genome in the tumor nuclei,14 though others have not substantiated this in larger series.15,16 In our experience, immunohistochemical staining for this virus in cardiac IMT (3 cases) also fails to confirm this observation (D.V.M., unpublished data, 2007).
HAMARTOMA OF MATURE CARDIAC MYOCYTES
This unusual tumor was first described in 1988 in a case report from Japan17 and in subsequent reports detailing larger series (15 cases total) a decade later.18,19 As bulky intramural ventricular masses, hamartomas typically raise clinical suspicion for cardiac fibroma or rhabdomyoma, as well as invasive malignancy. Histologically, they show only the cellular pleomorphism associated with mature (adult) myocyte hypertrophy. In specimens submitted for frozen section interpretation, the benign appearance imparted by its low cellularity and lack of cytologic atypia, as well as its resemblance to normal myocardium, can be a source of diagnostic discordance (if not disbelief) between pathologist and surgeon.
Grossly, HMCMs appear paler than the surrounding myocardium and often have a fibrous texture and sheen (Figure 3). They can resemble old infarction, though with increased wall thickness and distortion of the neighboring ventricular wall. They are generally circumscribed, but with poorly defined borders. Hamartoma of mature cardiac myocytes occurs in the ventricle more than 90% of the time (usually the left ventricle), and the reported atrial occurrences have been exclusively right sided. Microscopically, they show features almost identical to those of hypertrophic cardiomyopathy20 (myocyte hypertrophy, myocyte disorganization or disarray, and interstitial fibrosis or adiposity) (Figure 4). In addition, focal myocyte vacuolization, thick-walled arteries, and dilated venules have been noted.19
Once the tissue is recognized as representing a mass lesion (as mentioned previously), the main histologic mimic is rhabdomyoma, a tumor composed of vacuolated immature “spider cell” myocytes as opposed to mature hypertrophied muscle cells. Additionally, rhabdomyoma, particularly when multiple, occurs in the setting of tuberous sclerosis. There is no such association for HMCM.
Hamartomas of mature cardiac myocytes may be detected at any age, but the majority are detected before age 20. There is a distinct male predominance (4 males: 1 female). They typically come to clinical attention because of palpitations, exertional light-headedness, dyspnea, chest discomfort, or even sudden death.19 They have also been found incidentally at autopsy in presumably asymptomatic individuals.18 Hamartomas of mature cardiac myocytes show high echogenicity by ultrasound and appear hypointense on T1 magnetic resonance imaging with only modest gadolinium enhancement.21 The differing appearance in comparison to the adjacent myocardium, mirroring the gross pathology, often leads to high suspicion for a malignant neoplasm.
The risk of clinically significant recurrence of HMCM is very low and the tumor does not metastasize. It must be distinguished from hypertrophic cardiomyopathy, which can show localized or asymmetric involvement of the ventricles (particularly the septum). Hypertrophic cardiomyopathy does not lead to discrete mass formation, however, and grossly, the involved areas are congruous in color and texture to the adjacent myocardium. Hypertrophic cardiomyopathy is highly associated with germline sarcomere protein mutations. Given the disparate gross phenotype of HMCM, it seems unlikely that an association with sporadic mutations in these same genes would be observed, but such studies have not been performed.
CALCIFIED AMORPHOUS TUMOR
While the pathogenesis of this entity is not well understood, CAT is a clinically important pseudoneoplasm because it often raises high suspicion for malignancy. As bulky intracavitary masses with calcification evident on imaging studies, these are often mistaken for osteosarcoma or calcified myxoma. The histopathologic appearance, fortunately, is straightforward and entirely benign, characterized by degenerating fibrin debris and dystrophic calcification without significant cellularity or atypia.
Grossly, CATs consist of conglomerated red-brown, dry, clot-like material with a tendency to crumble when cut (Figure 5, a). Chalky and focally mineralized calcification is typically present in the center of the tumors and decalcification may be necessary before processing for histology (Figure 5, b). Microscopically, they are remarkably similar from case to case. They are predominantly composed of what appears to be degenerating fibrin with variable, usually central, nodular calcium deposits (Figure 6). Osseous metaplasia has been described in one case.22 There is also mild to moderate chronic inflammation, especially near the base of the lesion, and occasionally, capillaries may also be present. Organization (proliferating fibroblasts, capillaries, and loose myxoid extracellular matrix) is conspicuously absent. Hemosiderin deposition and cholesterol clefts are rarely seen. Most cases (60%) show fresh fibrin on the surface—a potential source of emboli.22
Calcified amorphous tumors can arise in any cardiac chamber and have occurred on the mitral valve as well. They can reach a size of up to 9 cm in greatest dimension (a right atrial CAT with extension along a central line in a patient receiving total parenteral nutrition). The largest series in the literature describes an age range from 16 to 75 years (mean, 52 years) for 7 women and 4 men. The patients presented with a wide variety of symptoms including embolic phenomenon (50%), shortness of breath, or orthopnea (30%), though some were asymptomatic (10%).22 Their condition is, of course, benign though 1 patient had a recurrence develop at the site of resection 29 months later23 and 2 patients had residual calcium at the site of the original mass, but no symptoms.22 By cardiac magnetic resonance imaging, they show hypointense signal characteristics without gadolinium enhancement.24
Surgical resection of CATs is prompted by clinical suspicion of malignancy or due to obstructive or embolic complications. They are distinct from ordinary mural thrombi in that they lack significant fibroblastic proliferation and organization. In a sense, they resemble noninfectious thrombotic endocarditis were it not for their size and typically nonvalvular location. The initiating factors leading to fibrin aggregation, as well as the reason for this tendency for thrombotic material to “mummify” and undergo dystrophic calcification rather than the usual process of involution through organization, are not clear.
MESOTHELIAL/MONOCYTIC INCIDENTAL CARDIAC EXCRESCENCES
In 1990, Luthringer et al25 reported an unusual cardiac lesion resembling histiocytoid (epithelioid) hemangioma, but demonstrating apparent mesothelial differentiation as well. Two additional reports confirmed the presence of mesothelial cells in these lesions; both groups regarded the lesions as pseudotumors, with one suggesting an artifactual (iatrogenic) genesis.26 The term MICE was proposed27 and the theory put forward that they formed through aggregation of histiocytes, mesothelial cells, and fibrin, similar to the means employed in preparing cell blocks from cytologic fluid specimens. In the body, this process may be initiated by suction catheter tips and other surgical and endoluminal instruments, but perhaps this also occurs spontaneously when a mesothelium-lined space is entered or opened, accounting for cases that have been identified in endomyocardial biopsy specimens (when there is perforation of the right ventricular free wall). Cases originally diagnosed as “chemoreceptor tissue” and “metastatic adenocarcinoma” have since been shown to be MICE and, thus, it is clear that these lesions have caused at least some confusion for experienced pathologists.28 They continue to be the subject of case reports.29
Grossly, MICE vary from gray-white to dark red to brown and are frequently associated with obvious thrombus, but are usually discrete and distinct from other tissue submitted (eg, valves, myocardial biopsies, portions of the aorta). The lesions range in size from microscopic to 3 cm in diameter. Histologically, they are composed of 2 predominant cell types (Figures 7 and 8): a histiocytoid cell (round to oval with pink cytoplasm, well-defined nuclei with prominent nuclear grooves, and occasional nucleoli) and a taller columnar or cuboidal cell. The histiocytoid cells are positive for CD68 and lysozyme and, ultrastructurally, have features typical of histiocytes with convoluted nuclei, prominent nucleoli, and cytoplasm rich in reticulin and surface pseudopodia. The cuboidal cells are usually present in small groups, strips, or tubular arrangements, have smaller amounts of eosinophilic cytoplasm, and have small, round, noncleaved nuclei with inconspicuous nucleoli. These cells react with antibodies to keratin, calretinin, cytokeratin (CK) 5/6, but are negative for carcinoembryonic antigen, CD15, Factor VIII–related antigen, CD31, CD68, and lysozyme.
Mesothelial cell features are seen by electron microscopy and include haphazardly arranged intermediate filaments and surface microvilli with well-developed desmosomes. Inflammatory cells (neutrophils, occasional lymphocytes, and eosinophils), adipocyte-like vacuoles, and foreign material can also be seen within MICE. The lesions lack blood vessels or capillaries and have no supporting stroma. This is an important feature distinguishing them from localized mesothelial hyperplasia, which can also form incidentally detected excrescences and contain sheets of mesothelial cells, macrophages, and fibrin (Figure 9, A and B). Papillary architecture is commonly seen in reactive mesothelial hyperplasia, but even when well-formed papillae are not seen, the presence of vessels and stroma (either in fibrovascular cores or less organized arrangements) is a universal finding distinguishing mesothelial hyperplasia from MICE.
Mesothelial/monocytic incidental cardiac excrescences have been identified in cardiac chambers, on cardiac valves, in the pericardial sac, as well as in the ascending aorta, mediastinum, and pleural space. They have also been reported in microscopic sections of endomyocardial and transbronchial biopsies and have been identified incidentally in specimens submitted as lymph nodes during sampling for lung cancer staging.30–33 Mesothelial/monocytic incidental cardiac excrescences are usually identified incidentally (rather than being the reason for a procedure) and are often described by the surgeon as being “free floating.”
The term nodular histiocytic/mesothelial hyperplasia has been proposed for these lesions.30 However, this implies a capacity to grow via a supporting stroma and blood supply, neither of which are present. While the mesothelial clusters and strips may appear hyperplasic (but are not), MICE are different from mesothelial hyperplasia. This point is emphasized because some have felt they are the same.34
Lesion of aggregated monocytes and mesothelial cells has been suggested as an alternative term for lesions occurring outside of the heart (where MICE is a misnomer)—a term which also aptly describes these lesions.
Their significance, of course, lies not so much in what they are called, but in what they are not called (eg, metastatic adenocarcinoma). It should be noted, however, that there has been 1 report of metastatic adenocarcinoma involving a cardiac MICE.35 In this particular example, a fragment of cellular debris, 0.8 cm in diameter, was found floating in the pericardial cavity and proved to contain clusters of clearly malignant cells in a patient who had a known adenocarcinoma. Therefore, not all lesions with this characteristic architecture and cell composition can be dismissed as benign.
LIPOMATOUS HYPERTROPHY OF THE ATRIAL SEPTUM
Lipomatous hypertrophy of the atrial septum, like CAT, is another lesion rarely mistaken for malignancy, histologically, but is of clinical significance owing to the frequent echocardiographic appearance of a mass protruding into the right atrium. It is also germane to the topic of pseudoneoplasms because LHAS results from a developmental aberrancy and is not an acquired neoplasm (lipoma).
Lipomatous hypertrophy of the atrial septum is a process involving the limbus of the fossa ovalis, a structure representing the embryologic septum secundum. During embryogenesis, the right and left atria are divided by progressive in-folding of the roof and upper anterior/posterior walls of the rudimentary common chamber along the midline. Mesodermal tissues are drawn into the wall of the primitive atrial septum during this process and pockets of entrapped adipose tissue remain after the heart is fully formed. In some patients, through as-of-yet undetermined processes (presumably the same ones governing this phenomenon in epicardial fat), the entrapped adipose tissue expands, resulting in bulging of the atrial septum. This is most prominent in the right atrium (since the limbus is a right atrial structure). This process seems to be age dependent and there is a weak association with obesity. The valve of the fossa ovalis and membranous atrioventricular septum are not involved by LHAS.36
When encountered in an autopsy, explant, or (rare) surgical pathology specimens, the gross appearance is the same as fatty tissue anywhere (Figure 10), though there may be more pronounced fine fibrous trabeculae. Microscopically, there is no capsule and both mature and brown fat may be seen. Entrapped atrial cardiomyocytes (Figure 11, A) may be present and often show marked hypertrophic changes. These should not be mistaken for lipoblasts or cells of liposarcoma. Typically, epicardial structures such as nerve ganglion (Figure 11, B) can also be seen in these lesions. Singly distributed hypertrophic myocytes can show significant nuclear pleomorphism and hyperchromasia (Figure 11, C) that, particularly in combination with brown fat, may be mistaken for lipoblasts or atypical adipocytic cells of lipomatous neoplasms. These cells retain sufficient sarcoplasmic elements to be recognized as myocytes.
Lipomatous hypertrophy of the atrial septum is typically detected in patients older than 50 years and is more common in women. It is most often asymptomatic, but may be implicated in supraventricular tachycardia and, in the extreme, may cause superior vena cava obstruction.
By echocardiography, though it can be mistaken for a mass, LHAS is recognized by a characteristic bilobed (dumbbell) brightly echogenic enlargement of the intra-atrial septum. Cardiac computed tomography imaging demonstrates a nonenhancing homogeneous thickening of the septum with typical fat tissue signal characteristics. By magnetic resonance imaging, the fat in the septum is hypointense on T1 imaging, without enhancement, and with the expected tissue characteristics on fat suppression sequences.37
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Dylan V. Miller, MD, Division of Anatomic Pathology— Hilton 11, Mayo Clinic, 200 First Street SW, Rochester, MN 55901 (email@example.com)