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BENIGN TUMORS OF THE AORTIC VALVE
Papillary Fibroelastoma
Clinical Features
Papillary fibroelastoma (PFE) is the second most common primary cardiac tumor after
myxoma and the most common valvular tumor, mainly affecting the aortic valve (in 52%
cases) and accounting for three-quarters of cardiac valvular tumors [8–13]. Its estimated
prevalence ranges between 0.02% and 0.45% in post-mortem and open heart surgery
procedures, respectively [14]. With the increasing use of echocardiography, the diagnoses of
PFE have been raising in asymptomatic patients, their actual prevalence being very likely
underestimated [11, 13, 15]. PFE can be detected at all ages, but it is more common between
the 4th and 8th decade (mean age 60 years) with a slight male preponderance (55%) [9]. It is
nowadays recognized as a true neoplasia as supported by cytogenetic analyses, but in the past
it has been considered a hamartoma, a giant form of Lambl’s excrescence originating from a
thrombus or an unusual response to infection or to hemodynamic injury [8, 12, 16].
In most patients, PFE is asymptomatic and incidentally diagnosed, but it carries a high
risk of embolization and in up to 35% patients it can be clinically manifest [10, 14, 17, 18].
Because of the embolic risk, a few authors suggest that even incidentally diagnosed and
asymptomatic PFEs should be surgically treated [13]. Surgical tumor resection is curative and
usually allows valve sparing with an excellent outcome and almost no recurrence (maximum
1.6% of surgical cases) [13].
Another possible – although rare – mechanism of cardiac events is a transitory or
permanent direct coronary ostium occlusion from a coronary cusp PFE [16, 17, 19].
Although PFE is usually a single tumor, in a few patients it may be multifocal, affecting
the same or different sites of the heart [10]. It may be found on the aortic [9, 20–22] or the
ventricular [18] side of a leaflet, the left coronary cusp being the least affected one.
Imaging
Historically, PFE mostly represented an incidental (post-mortem or surgical) finding, but
it is now increasingly diagnosed by echocardiography, the best tool to study this lesion [12,
13, 23]. Trans-esophageal echocardiography (TEE) is more sensitive, but less accessible and
more invasive than trans-thoracic echocardiography (TTE). TEE is also used during surgery,
to guide tumor resection and to check the results [13, 21]. At echocardiography, PFE usually
appears as a small (typically less than 2 cm), often mobile, pedunculated or sessile mass, with
speckled appearance and a strippled pattern near the edges [23, 24]. The core (pedicle) is
usually very echodense, thus enabling clinicians to differentiate it from vegetations and
thrombi [25].
By CT, PFE shows as a hypodense mass with irregular borders, whereas by CMR it can
be detected as a small, round, homogeneous mass with an intermediate signal intensity on T1and a hyperintense one on T2-weighted images. It can be differentiated from a lipoma by fatsaturation sequences [24, 26].
Coronary angiography is used when PFE presents with angina symptoms or when a
concomitant coronary artery disease is suspected. It can disclose occlusions or dilatations of
coronary arteries due to embolism; moreover, a filling defect can be seen in cardiac chambers
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or in the first tract of ascending aorta because of the mass’s presence. However, angiography
is not recommended for PFE evaluation, because it is less sensitive than echocardiography
and it carries a high risk of embolization due to catheter traumatism on the tumor surface
[16].
Macroscopic Features
PFE diameter may be up to 70 mm, but it usually does not exceed 20 mm [9, 16]. It is a
small, soft, sessile or – more often – pedunculated mass, this latter form being quite mobile
and at higher risk of embolization [27]. The typical appearance of a surgical specimen of PFE
(after immersion into water or saline solution) is commonly described as “sea anemone-like”
because it is made of a central stalk with multiple papillary fronds [9, 28] (Figure 1A).
Sometimes, organized thrombi attached to the tumor’s surface can hide its typical papillary
structure.
Microscopic Features
The definitive diagnosis of PFE relies on histology, which shows multiple papillary
fronds radiating from a central stalk (Figure 1B). In each frond, three main layers can be
observed: an inner central core of dense avascular matrix, with collagen, elastic fibers, and
rare spindle cells; a loose myxoid tissue rich in acid mucopolysaccharides; and an external
single layer of flat endothelial cells [28, 29]. Longitudinally oriented elastic fibers are a
histological hallmark for the diagnosis [16].
These histological features allow the differential diagnosis from other valvular tumors,
endocarditic vegetations, thrombi and Lambl’s excrescences to be made [9, 21, 28, 30].
A B
Figure 1. A multifocal papillary fibroelastoma with fine papillary fronds that are displayed by water
immersion (A). Histology shows that the papillary fronds are lined by an endothelial layer and have a
connective tissue core with elastic fibers (B; Hematoxylin and Eosin staining, original
magnification 2x).
Myxoma
Clinical Features
So far, less than twenty aortic valve myxomas have been reported [31–33]. Clinical
presentation largely depends upon size, shape, mobility and mass surface characteristics. The
most common symptoms are dyspnea and/or angina [32, 34–37]; signs of subaortic stenosis
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have also been reported in a case [31], but patients may also be asymptomatic [38, 39]. The
right coronary and the non-coronary leaflets are more frequently involved, with the tumor
located on the edge of the leaflet [32] or in fewer cases on the ventricular aspect [31, 33, 34,
36]. The mass may be polypoid and sessile or papillary, the first type often causing
obstructive or heart failure symptoms and the latter one embolic phenomena [40–42] with
distal ischemia, such as transient ischemic attacks or strokes [41, 43–45], lower limb ischemia
[46, 47] and acute myocardial infarction [34].
Imaging
In most cases, the first diagnosis of the mass is done by TTE [32]. Aortic myxomas may
show a heterogeneous core with necrosis, hemorrhages and calcifications which appear as
cystic spaces and echo-lucent spots, respectively [21, 42], and the papillary forms may
present multiple stretched villi [42]. Their brightness increases after administering contrast
agents because of the tumor vascularity [47]. CT or CMR can give additional information
about size, location and shape, tissue composition and anatomical characteristics for surgical
planning [21, 25]. On non-contrast-enhanced CT images, a myxoma appears as a hypodense
mass [48] and, after administration of contrast, as a filling defect, i.e., a hypodense region
with non-homogeneous enhancement indicating areas of necrosis or hemorrhage [47, 48].
Using CMR, T1-weighted images show myxomas as isointense to the myocardium and T2weighted images as hyperintense, since they have a great amount of extracellular water. As in
CT, they can show non-homogeneous contrast enhancement [48]. Cine images are
particularly useful as myxomas are often highly mobile, especially when pedunculated [48].
Macroscopic Features
Only single myxomas have been reported, the diameter ranging from 0,6 to 4 cm (most
cases <1,5 cm) [32]. They appeared as myxoid (gelatinous) [36, 37, 44], sessile or more
commonly pedunculated masses, with papillary and villous [43] or solid and smooth surfaces
[35, 37–39, 41, 43, 47, 49]. Sometimes, they can present hemorrhagic areas [36, 44].
Microscopic Features
A B
Figure 2. A myxoma with the myxoid stroma and the lepidic cells in evidence (A; Hematoxylin
and Eosin staining, original magnification 4x) that are immunoreactive for calretinin
(B; Immunoperoxidase staining with Hematoxylin counterstaining, original magnification 10x).
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Myxomas show an abundant myxoid, mucopolysaccharide-rich matrix embedding a
variable number of stellate, oval, polygonal, or spindle (lepidic) cells without mitotic activity,
immunoreactive for calretinin and S100, forming solid nests or perivascular cuffs as seen in
the other cardiac myxomas (Figure 2A,B) [35, 36, 39, 44, 45, 47, 49–52].
The definitive diagnosis of aortic valve myxoma relies on histology, since its
macroscopic features mimic PFE (Kim et al. 2012), LEs, endocarditic vegetations or thrombi
[21, 45, 49, 53], but also hemangiomas and angiosarcomas [49].
Fibroma
Cardiac fibromas are the second most frequent cardiac tumors in the pediatric age after
rhabdomyomas [5, 54, 55]. Cardiac fibromas are considered congenital tumors that may
become clinically manifest later in life and are also known as cardiac fibromatosis. They have
also been found in association with Gorlin syndrome [5].
Clinical Features
Cardiac fibromas are often associated with arrhythmias; moreover, they can cause
hemodynamic compromise and congestive heart failure. They may also be found incidentally
in asymptomatic patients. They usually arise in the left ventricular free wall, inter-ventricular
septum or right ventricular free wall, but they can also infiltrate the myocardial wall. An
exceptionally rare form of isolated fibroma has been described in the aortic valve of an elder
woman [54]. Cardiac fibromas are benign lesions; nonetheless, most of them require surgery
and even cardiac transplantation (when they are unresectable and diffusely infiltrating the
myocardium) [5, 54, 55]. Sometimes, they obliterate the ventricular cavity. Aortic fibromas
can cause outflow obstruction, thus requiring surgical excision.
Imaging
At echocardiography, a fibroma typically appears as a well-circumscribed, solitary mass.
By CT, the mass shows low attenuation and it can also present calcifications, a helpful feature
for diagnosis. By CMR, because of the fibrous nature of the tumor, the signal intensity is
often reduced, compared to the adjacent uninvolved myocardium; contrast-enhanced imaging
usually demonstrates a hypoperfused tumor core. In the single case report of aortic valve
fibroma, TTE and TEE revealed a 9 x 7 mm, medium-echogenic mass on the right coronary
cusp of the aortic valve, passively moving with the leaflet. CT showed no enhancement [54].
Macroscopic Features
Fibromas are well-defined, solitary lesions with smooth margins; their dimensions are
usually great, ranging from 1 to 20 cm in diameter (average 3 cm). The typical appearance is
of an elongated, lobulated or disc-shaped firm mass of a homogenous pearly-gray color.
Calcifications are quite common, whereas cystic changes, hemorrhages, and necrosis are
usually absent.
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Microscopic Features
Cardiac fibromas are constituted by a fibroblastic (Figure 3) or a myofibroblastic
proliferation interspersed among large amounts of collagen [5, 55]. Dystrophic calcifications
are seen in approximately 25% of cases. The histological examination shows relatively bland
stellate and spindle-shaped fibroblasts separated by a collagenous or collagenous-myxoid
matrix. Mitotic activity is either absent or minimal. Some cells can have a myofibroblastic
immuno-phenotype, with focal reactivity for muscle-specific and alpha-smooth muscle actin
and/or cytokeratin in few cases. Desmin, S100 protein, and CD34 are usually not expressed
[56].
Figure 3. A fibroma, constituted by a fibrous stroma with scattered fibroblastic cells (Hematoxylin and
Eosin staining, original magnification 4x).
Hemangioma
Cardiac hemangiomas or angiomas are benign vascular tumors or malformations,
accounting for <5% of benign cardiac tumors, occurring at all ages (mean age 55 years) [5,
57]. Although most cardiac hemangiomas are found incidentally, patients may present with
dyspnea, arrhythmias, signs of heart failure and pericardial effusion; they may be associated
to vascular syndromes e.g., Kasabach-Merritt [57]. They have been rarely reported on the
aortic valve [58–61], the most frequent locations being represented by the lateral wall of the
left ventricle (21%), the anterior wall of the right ventricle (21%), the inter-ventricular septum
(17%) and the right ventricular outflow tract [55, 57].
Imaging
By echocardiography, hemangiomas are usually hyperechoic, circumscribed, and often
intra-cavitary masses [58]. With CT they are usually circumscribed and heterogeneous and
are characterized by low attenuation and bright enhancement with contrast administration.
With CMR, they may show intermediate to high intensity signal on T1 weighted images, very
intense signal on T2 weighted images, and enhance brightly with contrast administration [57].
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Macroscopic Features
These tumors are often large, and their gross appearance depends on the size of the
vascular spaces within. They may be poorly circumscribed, slightly raised or infiltrating the
surrounding tissue [62].
Microscopic Features
They are microscopically constituted by multiple dilated thin-walled vessels (cavernous
type), smaller vessels resembling capillaries (capillary type) (Figure 4A), dysplastic
malformed arteries and veins (arterio-venous hemangioma, cirsoid aneurysm), or often have
combined features of cavernous, capillary and arteriovenous hemangiomas, and many contain
fibrous tissue and fat [62]. Capillary hemangiomas present thin walled capillaries with scant,
sometimes myxoid stroma whereas cavernous hemangiomas are usually non capsulated
masses with infiltrative borders, constituted by large cavernous spaces separated by
connective stroma and can show thrombosis and calcifications [62]. Immunostaining for
endothelial cells such as CD31 (Figure 4B) and CD34 is strongly positive [61]. Those
reported on the aortic valve are mainly constituted by capillary vessels and can be covered by
normal endothelium [58], or by a thrombus [59].
A B
Figure 4. A capillary hemangioma with a fibrous stroma (A; Hematoxylin and Eosin staining, original
magnification 4x); the endothelial cells are immunoreactive for the CD31 endothelial antigen (B;
Immunoperoxidase staining with Hematoxylin counterstaining, original magnification 10x).
Inflammatory Myofibroblastic Tumor
Initially described as an inflammatory pseudotumor, inflammatory myofibroblastic tumor
(IMT) is nowadays considered a true tumor [5]. IMT is a ubiquitous neoplasia, but it is more
frequently found in soft tissues and viscera of children and young adults (mean age 10 years).
Cardiac IMTs are rare, clinical symptoms being related to their location within the heart:
patients can be asymptomatic, present a constitutional syndrome (fever, weight loss, malaise)
or cardiac symptoms such as chest pain, heart failure, arrhythmia, murmur, syncope and also
sudden death, mainly due to coronary embolization [63, 64]. Lesions size ranges from 1 cm to
8.6 cm and they appear like a yellowish-white to gray mass, solid, glistening, nodular or
polypoid, with or without a pedicle. Pathognomonic histologic features are spindled
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myofibroblastic cells with no cytologic atypia or nuclear pleomorphism and a chronic
inflammatory infiltrate composed of lymphocytes, plasma cells and histiocytes.
Immunohistochemistry show positivity for vimentin, smooth muscle actin, desmin (76% of
cases), CD34, CD68, whereas ALK-1 is usually negative in cardiac IMTs [63, 65].
PRIMARY MALIGNANT TUMORS OF THE AORTIC VALVE
Primary malignant cardiac tumors are rare, cardiac metastases being the first malignancy
of the heart [1, 3]. They are mainly represented by sarcomas, especially angiosarcomas and
rhabdomyosarcomas, but also leiomyosarcomas, synovial and intimal sarcomas have been
reported [5]. Primary or secondary lymphomas (almost exclusively non-Hodgkin lymphomas)
have also been described in the heart [5]. Malignant tumors do not show any gender
predominance nor age predilection, although some histotypes are prevalent at different ages
(i.e., rhabdomyosarcoma in children and young adults); they grow progressively and most of
them show poor prognosis [1, 3, 5]. Distant metastases may occur to sites such as liver, bone,
and brain [3].
The diagnosis of the mass is usually done by TTE, but CT and CMR are useful for a
better definition of tumor characteristics, the definitive diagnosis requiring histology and
ancillary techniques such as immunohistochemistry and molecular techniques (fluorescence
in situ hybridization (FISH) and/or PCR/RT-PCR). In the last decades, endomyocardial
biopsy has been increasingly proved to be a valuable diagnostic tool for pre-operative
diagnosis [66, 67].
Sarcoma
Sarcomas are the most frequent primary malignant tumors of the heart, but they
exceptionally involve the left cardiac valves [1-5]. Their symptoms depend upon size and
localization and the diagnosis of the mass is usually done by echocardiography, TEE first. An
undifferentiated sarcoma of the aortic and mitral valves has been described in a 72-year-old
woman [68]. Preoperative TEE highlighted the presence of masses on both left valves, the
aortic valve showing a partially cystic tumor. After excisional surgery with dual valve
replacement, histology showed an undifferentiated sarcoma. In the last decade, most
undifferentiated cardiac sarcomas have been shown to be constituted by intimal sarcomas that
have been described in the aorta [69] and major pulmonary vessels [70], as well as in cardiac
chambers [69]. It is a highly pleomorphic neoplasia with high mitotic activity, showing no
immunophenotypic cell differentiation and MDM2 overexpression (Figure 5).
A synovial sarcoma involving the right coronary aortic valve leaflet and the adjacent
inter-ventricular septum has also been described [71]. Diagnosis is based on histological
examination, which shows a monomorphic (spindle cells) or heterogeneous (spindle and
epithelioid cytokeratin/epithelial membrane antigen (EMA)-immunoreactive cells) lesion.
Additionally, exclusion criteria for other diseases must be met and the gene translocation
t(X;18) (p11.2;q11.2) (present on approximately 90% of synovial sarcomas) can often be seen
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via FISH on histologic sections [5, 71–73]. Although chemotherapy can give short-term
benefits in these patients, overall prognosis for cardiac sarcomas is poor [1, 3, 4, 72–74].
A B
Figure 5. An intimal sarcoma of the aorta involving the aortic valve annulus and characterized by
pleomorphic and undifferentiated cells (A; Hematoxylin and Eosin staining, original magnification
10x), a few of them expressing MDM2 (B; Immunoperoxidase staining with Hematoxylin
counterstaining, original magnification 10x).
Non-Hodgkin Lymphoma
Cardiac involvement is not uncommon in lymphomas, but valvular involvement has only
been exceptionally reported. In autopsy series, 18% of patients with systemic lymphomas had
metastases to the heart, but only one had valvular involvement [75, 76]; and indeed there are
isolated case reports of valve involvement in lymphoma cases [77], with only one describing
a primary lymphoma affecting native valves [78] and the few others describing a primary
lymphoma affecting prosthetic valves [79, 80]. Primary cardiac lymphomas (PCLs) represent
less than 0.01% of all cardiac tumors, usually affect patients after the fifth decade of life and
are almost exclusively represented by non-Hodgkin lymphomas [81, 82]. PCLs present in
immunocompromised, immunosuppressed and HIV-positive patients, but it has also been
described in immunocompetent patients [2, 83]. Symptoms are often sub-acute and
nonspecific with few cases presenting with acute symptoms, including heart failure and even
sudden death, diagnosis being very challenging [67]. Echocardiography may show an
intracavitary mass or pericardial effusion, CT a heterogeneous contrast enhancement and
CMR a variable signal intensity and contrast enhancement, but the differential diagnosis
requires histology and immunophenotyping [66, 81]. The most frequent cardiac lymphoma is
represented by the diffuse large B-cell non-Hodgkin lymphoma that is constituted by large
CD20 immunoreactive cells, diffusely infiltrating the cardiac structures and showing a high
proliferating (MIB1) index with or without EBV positivity [81,83].
The prognosis is usually poor because of the nonspecific symptoms and of the late
diagnosis, but in patients with earlier diagnosis and appropriate treatment (chemotherapy) it is
apparently improving in recent years [67, 84].
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CARDIAC METASTASES
Cardiac metastases are more common than primary cardiac tumors, at least in adults.
They usually have a poor prognosis, with survival after diagnosis ranging from 6 weeks to 15
months; moreover, they often are unrecognized without autopsy. They have been detected in
autopsy studies of cancer patients in up to 15% of cases [85–87]. Valve metastases are very
rare, probably because of the continuous cusps motion and absence of vessels on the cusps
themselves. They can present with a neoplastic thrombotic endocarditis.
Most metastatic/secondary tumors are melanomas, sarcomas, lung, and haematological
malignancies, but also breast and gastric carcinomas may secondarily involve cardiac
structures, including cardiac valves. Because of improved survival of oncological patients, an
increase in the incidence of metastatic cardiac tumors is likely to happen in the next future
[85].
The clinical presentation includes shortness of breath, cough, anterior thoracic pain,
pleuritic chest pain or peripheral edema.
Cardiac metastases can also be the first manifestation of the neoplastic disease and
require differential diagnosis that usually relies on histological investigations, including
immunohistochemistry and other ancillary techniques [88].
NON-NEOPLASTIC LESIONS (PSEUDOTUMORS)
OF THE AORTIC VALVE
The aortic valve can show non-neoplastic masses that may be difficult to differentiate
from true tumors. They are mainly represented by LEs, endocarditic vegetations, marantic
endocarditis, thrombi and pannus (especially on prostheses), but also include blood cysts,
rheumatoid nodules and calcifications [25, 89]. They can be differentiated from the site of
origin, their number and definitely by histology [9, 30].
Thrombi appear as laminated masses with irregular or lobulated borders, micro-
cavitations and no pedicle at the echocardiography. This latter element can help in
differentiating them from PFEs (Figure 6).
Figure 6. A thrombus of an aortic coronary cusp, showing fibrin and blood cells together with
cholesterol clefts (Hematoxylin and Eosin staining, original magnification 10x).
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Lambl’s excrescences are filiform lesions occurring on the line of coaptation of cardiac
valves due to wear and tear. Usually, they are smaller than PFEs and do not occur isolated
(>90% are multiple lesions) [53]. They originate as small thrombi on endocardial surface and
have the potential to embolize to distant organs, even if they usually remain asymptomatic.
Microscopically, LEs consist of a dense core of collagenous and elastic fibrils enclosed by a
single layer of endothelium; the densely hyalinized central core is lined by endocardial-type
spindle cells. LEs localize on the ventricular side of aortic valve. Their dimensions are usually
<2 mm in width and 5-10 mm in length, even if there have been case reports of giant LEs (>2
cm in diameter) that are more often associated with complications, such as ischemic stroke
due to thromboembolic events [53, 90].
The current management of LEs includes close follow-up with TEE for asymptomatic
lesions, whereas symptomatic cases undergo single or dual antiplatelet therapy or surgery,
depending on first or subsequent episodes [90].
Hamartomas of the aortic valve are extremely rare. They consist of loose connective
tissue and mature fat cells (in the lipomatous variant) or hyalinized fibrous tissue core with
dense twisted clumps of elastin and abundant mucopolysaccharide content (fibroelastic
variant) [91, 92]. A single case has also been reported of diffuse fatty infiltration in an
insufficient bicuspid valve of a young male soccer player, the fatty tissue infiltrating the
fibrous core of the leaflets [93] (Figure 7). Clinical presentation is variable, including
asymptomatic cases and patients with severe valve regurgitation, symptoms of congestive
heart failure or even fatal ischemic heart attack [91, 92].
Figure 7. A lipomatous hamartoma of a bicuspid aortic valve, showing a leaflet with diffuse
replacement of the fibrous core by adipose tissue that is S100 immunoreactive (Immunoperoxidase
staining with Hematoxylin counterstaining, original magnification 20x).
Blood cysts are small (pinpoint to pinhead), rounded, reddish brown nodules, usually
sessile but sometimes pedunculated. They are common findings in infants and seem to
disappear with age (uncommon after 6 months); they more frequently occur on the mitral and
tricuspid valves. Histologically, blood cysts consist in masses of red blood cells and few
white blood cells packed in a spherical or ovoid cyst into the connective tissue and covered
with a single layer of flat endothelium [94]. Rare cases are reported in children or adults, and
the aortic valve is an unusual localization. In a case report, a 16-year-old girl with severe
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