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) Clinical History 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. Diagnosis: Cardiac myxoma occurring in the setting of the Carney (myxoma) syndrome. The other cardiac tumors and the periumbilical tumor were also myxomas. Discussion 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 Age (yrs.) 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 % Patients Myxomas Heart Skin 61 37 Lentiginosis, blue nevi Face, lips, conjunctiva 67 Endocrine tumors Adrenal Testis Pituitary 33 30 11 Schwannomas Upper gastrointestinal tract, sympathetic chain 11 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. 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