Cardiovascular and Pulmonary Pathology in Systemic Disease
Case 6 -
Cardiac Myxoma Occurring in the Setting of the Carney (Myxoma) Syndrome.
Henry D. Tazelaar and Marie-Christine Aubry
PDF File (3.1 MB)
A 19-year-old woman presented three months following a stroke at which time she was found to
have an antiphospholipid antibody (APA). At the time of evaluation for the APA, she was noted to have
numerous freckles on her face and lips and a periumbilical soft-tissue mass. Further work-up included an
echocardiogram, at which time multiple mobile intracardiac masses were identified involving the left
atrium and ventricle, and right ventricle. She underwent surgical excision of both the cardiac and
soft-tissue mass. Your section is from the right ventricular mass.
Slides illustrating Case 6 are in the accompanying PDF of the Powerpoint presentation.
Cardiac myxoma occurring in the setting of the Carney (myxoma) syndrome. The other cardiac
tumors and the periumbilical tumor were also myxomas.
Microscopic sections in this case show a fairly typical cardiac myxoma. The histologic appearance of
cardiac myxomas is distinctive and differs from that of soft-tissue myxomas. There is an abundant myxoid
matrix of mucopolysaccharide and relatively few "myxoma cells". The myxoma cells are generally stellate
in shape. The nuclei are usually oval and measure up to two times the diameter of histiocyte nuclei.
They usually lack prominent nucleoli. Some cells may be multinucleated forming syncytia that assume a
variety of shapes. Structures formed by these multinucleated cells include cords, rings with multiple
cell layers, and the flattened lining of the tumor surface. The multinucleated cells may also form
ball-like clusters floating within the matrix. These cells appear to differentiate along endothelial
lines and blood filled capillaries may be present within the rings and cores of cells. The important
point about this case is not only recognizing the diagnosis per se, but that it is one of several myxomas
identified at the time of evaluation and that this one occurred in the right ventricle. These findings
make it highly likely that this patient has the Carney (myxoma) syndrome which is of course confirmed by
the physical examination which showed multiple lentigines, and a soft tissue myxoma as well.
The majority of myxomas (greater than 75%) are pedunculated left atrial masses attached to the
endocardium of the fossa ovalis. Right atrial myxomas, which represent most of the remainder, are less
likely to be attached to the fossa ovalis, but this is still the most common location even in the right
atrium. About 5% of myxomas grow on both sides of the fossa as bi-atrial dumb-bell-shaped tumors.
Secondary changes which can be present in myxomas include calcification (16%), hemorrhage (79%),
ossification (8%), Gamna Gandy bodies (17%), extra-medullary hematopoiesis (7%), thymic rests (1%), and
glandular inclusions (1 – 3%). Embolization may come from pieces of the myxoma breaking off, or from
thrombi which may form on the surface.
The immunohistochemical profile of myxomas is somewhat controversial. The cells variably express
endothelial antigens, including ulex europaeus, factor VIII - related antigen and CD34. S-100 protein
may also be expressed in myxoma cells. Factor XIIIa may also be expressed in some cells, but the
significance of this finding is unknown.
The differential diagnosis for cardiac myxoma is relatively short and includes mainly malignant, cardiac
tumors. Myxomas range from being paucicellular as seen in the current case to moderately cellular. The
more cellular ones can occasionally cause diagnostic difficulty with myxoid malignant fibrous
histiocytomas and the so-called cardiac myxosarcoma. This latter term is currently not used
in standard classifications for soft-tissue tumors. It does appear to be a somewhat distinctive tumor
which may very well represent the malignant end of the cardiac myxoma neoplasia spectrum. (However,
there is no good evidence of a sequential transformation of a cardiac myxoma to a myxosarcoma). Most
cardiac myxosarcomas may well represent myxoid malignant fibrous histiocytomas. The most important
histologic criteria to differentiate myxosarcomas from myxoma is the absence of the typical cords, rings,
and capillary structures formed by myxoma cells. In contrast, myxosarcomas tend to have arborizing
vascular structures and can become quite cellular. In addition, the presence of significant mitotic
activity (greater than 1 mitotic figure per 10 high-powered field) should alert one to the possibility of
a cardiac malignancy, either a myxosarcoma or another of the more common sarcomas arising within the
cardiac chambers (leiomyosarcoma, malignant fibrous histiocytoma). Finally, the presence of the tumor
cell necrosis is extraordinarily rare in myxomas and should suggest the possibility of malignancy. The
presence of glandular inclusions within a cardiac myxoma usually raises the differential of metastatic
adenocarcinoma. Recognition of this entity, however, should allow one to arrive at the correct
diagnosis. This differential is summarized in Table 1.
Carney syndrome encompasses previously described cardiac myxoma syndromes such as LAMB (Lentigines,
Atrial myxoma, Mucocutaneous myxoma and Blue nevi) syndrome and NAME syndrome (representing Nevi, Atrial
myxoma, Myxoid neurofibromata, Ephelides; or "Nevi, Atrial myxoma, Mucinosis of the skin, and Endocrine
overactivity). Carney's syndrome is an autosomal dominate condition comprising cardiac and cutaneous
myxomas, cutaneous hyperpigmentation, and endocrine overactivity. Cardiac myxomas occurring in the
Carney complex account for approximately 7% of all cardiac
Table 1 - Differential Diagnosis of Cardiac Myxomas
| ||Cellularity ||Mitotic Activity ||Arborizing Vessels ||Myxoma cell rings and cords ||Necrosis|
|Myxoma ||+-++ ||- ||+ ||+++ ||-|
|Myxoid MFH ||+-+++ ||++-+++ ||- ||- ||++|
|Myxo-sarcoma ||+-++ ||+ ||+ ||- ||++|
myxomas. The differences between patients with familial and nonfamilial cardiac myxomas are shown below
in Table 2.
Table 2 - Findings in Nonfamilial and Familial Cardiac Myxoma
| ||Nonfamilial (Mayo Clinic) ||Familial (Reported) ||p|
|Patients (no.) ||51 ||24 || |
|Females (%) ||76.5 ||33.3 ||<0.001|
| Mean ||51.3|| 23.9 || |
| SD ||14.1|| 11.6 ||<0.001|
| Range ||17-75|| 4-48 || |
|Left atrium affected (%) ||86.3|| 62.5 ||0.014|
|Multicentric tumor (%) ||5.9|| 33.3 ||0.003|
|Other conditions (%) ||3.9|| 20.8 ||0.031|
From Carney JA, Am J S Pathol; 1985;9:53-55.
In addition, tumors occurring in patients with the Carney complex have a tendency to recur, even if
completely excised. Therefore, the excision of a myxoma from an unusual location in a young patient,
particularly male, should alert the pathologist to question the possibility of the myxoma complex being
present. Although one study failed to find any histologic differences between myxomas occurring in the
familial as opposed to nonfamilial setting, in the AFIP experience, myxomas occurring in the myxoma
complex have a tendency to be more myxoid and more often have degenerative changes. Table 3 shows the
essential components of the Carney complex.
Table 3 - The Distribution of the Essential Components
Of the Carney Complex
|Myxomas ||Heart |
|Lentiginosis, blue nevi ||Face, lips, conjunctiva ||67|
|Endocrine tumors ||Adrenal |
|Schwannomas ||Upper gastrointestinal tract,|
Carney JA. Seminars in Dermatology, 1995;14:90-98.
The lentigines tend to occur (in decreasing order) on the face (especially the periocular and
perioral zones), eyelids (including lid margins) and ears, vermilion borders of the lips, trunk, neck,
conjunctive or sclera, vulva, (especially the labia minora), limbs, and backs of the hand.
Microscopically, these lesions show a spectrum of changes but most frequently appear as a benign lentigo
(hyper pigmentation of the basal epidermal layer and hyperplasia of melanocytes with or without
elongation of rete-pegs) and blue nevi. A particular variant of the blue nevus, the epithelioid blue
nevus which features primarily globular and polyhedral, rather than spindle cells, seems to be
particularly associated with the Carney complex as well. Other pigmented lesions include
ephelides, junctional nevi, compound nevi, atypical blue nevi, and
combinations of these.
The cutaneous myxomas, as seen in this case, are usually asymptomatic soft papules or subcutaneous
nodules. The majority are small (1cm or less). Multiple such lesions have occurred in about 75% of
patients. The more frequent anatomic locations include the head and neck region, the trunk and flank,
and the perineum, genitalia, and buttocks. Less frequently, do they involve the extremities.
Microscopically, the tumors contain mesenchymal cells set at a mucinous matrix containing capillaries,
collagen, a few reticulin fibers, as well as mast and inflammatory cells. Although they may be sharply
circumscribed, most tumors do not appear to have a distinct capsule. The myxoma cells somewhat resemble
a fibroblast and have elongate multi-polar or bipolar cell processes. These cells have a modest amount
of cytoplasm that is indistinctly delimited and usually does not contain vacuoles. Approximately 25% of
these myxomas can contain associated keratinous cysts with an epidermoid mode of keratinization,
keratinous cysts with proliferating cells suggesting poorly formed trichofolliculomas, and a pattern a
anastomosing epithelial cells present in thin strands.
About one fifth of patients have an unusual adrenal lesion known as Primary Pigmented Nodular Adrenal
Disease (PPNAD). This is often associated with Cushing's syndrome. Pathologically, such adrenals
show studding of the external cut surfaces by small (less than 4 mm) black, brown, dark green, red, or
yellow nodules. Microscopically, these are composed of enlarged globular cortical cells with granular
eosinophilic cytoplasm containing lipofuscin.
The myxoid breast lesions (myxoid fibroadenomas) have a more myxoid stroma than the usual
fibroadenoma. Such lesions are often bilateral and or multiple.
The large-cell calcifying Sertoli cell tumor affects about 30% of the male patients and may be
bilateral (40%) and multicentric within each affected testes. The lesions are usually discovered in
teenagers during investigations for sexual precocity, on routine physical exam, or on specific
examination because of the presence of other features of the Carney complex. These tumors are well
demarcated, yellow-tan, and are composed of nests and cords of cells with abundant eosinophilic cytoplasm
in a myxoid to collagenous stroma. The stroma is calcified or ossifies in 50% of cases.
Approximately 10% of patients have pituitary adenomas. There appear to be no distinctive features
of the adenomas occurring in the myxoma complex.
A more distinctive lesion strongly associated with the complex is the psammomatous melanotic
schwannoma. Common sites are the upper alimentary tract and peri-vertebral sympathetic chains.
These tumors are usually black, brown, or blue and encapsulated. They are composed of large and small
polygonal epithelioid and spindle cells often arranged in an organoid pattern. They contain cytoplasmic
melanin, laminated calcifications, fat, and areas suggestive of schwannian or nevus cell differentiation.
The tumors show positive immunoreactivity for S-100 protein. The majority of these lesions are benign,
although approximately 10% have proven to be malignant.
Recently, a genetic locus on chromosome 17 q2 which appears to be associated with the complex has been
identified. It is possible that more than one genetic locus is involved since other investigators have
identified an abnormality on the short arm of chromosome 2. Given the wide phenotypic expression
characteristic of this disease, this is not particularly surprising. Such chromosome abnormalities,
however, are currently being utilized to confirm the presence of the complex in particular families.
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