Although primary tumors of the heart are rare, their incidence at autopsy is variably reported as between 0.0017 percent and 0.19 percent, and myxomas account for nearly half of all such primary cardiac neoplasms. Typically, these are benign solitary tumors that arise in middle-aged women at the fossa ovalis on the left atrial side of the interatrial septum.14,15 These tumors do not metastasize. Cardiac myxomas can present with a variety of constitutional symptoms, heart failure, and embolic stroke, and diagnosis of a cardiac myxoma is typically made by echocardiography. Prompt surgical resection is recommended to avoid embolic events, and surgical resection is usually curative without tumor recurrence. Several hematologic, immunologic, and rheumatologic disorders (e.g., anemia, polycythemia, fever, rheumatoid arthritis, vasculitis, lupus-like syndrome, and Raynaud phenomenon) have all been associated with the presence of myxomas. These systemic abnormalities have been reported to result from myxoma secretion of interleukin-6, and they can resolve with tumor resection.16 Histologically, cardiac myxomas are comprised of small stellate cells against a bland proteoglycan myxoid background (Fig. 47.1-1).2 The tumors are thought to arise from a subendothelial pluripotent stem cell, sometimes referred to as a “reserve” cell.17 Accordingly, a number of organized structures, including acinar elements, regions of extramedullary hematopoiesis, and blood vessels, are occasionally noted within these tumors consistent with differentiation along a variety of lineages such as epithelial, hematopoietic, endothelial, muscular, and osteogenic.
Histopathology of a cardiac myxoma. Cardiac myxomas are comprised of small stellate cells against a myxoid proteoglycan background. Shown is a cardiac myxoma from a patient with Carney complex.
Approximately 7 percent of individuals with cardiac myxomas are affected by the familial disorder Carney complex and have associated noncardiac findings.12,18 More than two-thirds of Carney complex patients have developed one or more cardiac myxomas.3,12,15,18 Although cardiac myxomas in Carney complex are histologically indistinguishable from the more common sporadic cardiac myxomas (Fig. 47.1-1), 2 their clinical presentation and course can be quite distinct (Table 47.1-1).12,15,18,19 Consistent with Carney complex's transmission as an autosomal dominant trait, cardiac myxomas in this complex exhibit no age or gender preference. Although they most often arise, like their sporadic counterparts, in the left atrium, they can occur in any of the four cardiac chambers and may present with multiple lesions in the same or different chambers. Furthermore, despite adequate resection, Carney complex cardiac myxomas can recur at sites distant from the initial surgery within even a single year or many years later. Patients have experienced multiple recurrences and have required more than three cardiac surgeries in their lifetime.12,15,18,19 Because of the high risk of tumor recurrence, patients with Carney complex, unlike patients with sporadic cardiac myxomas, should undergo annual surveillance echocardiography throughout their lifetime (Fig. 47.1-2C).
Table 47.1-1: Differences in Clinical Features Between Nonfamilial and Familial Cardiac Myxomas |Favorite Table|Download (.pdf) Table 47.1-1: Differences in Clinical Features Between Nonfamilial and Familial Cardiac Myxomas
|Clinical Feature ||Sporadic ||Familial |
|Female gender preference ||Yes ||No |
|Typical age of presentation ||Middle age ||Postpuberty |
|Left atrial predominance ||Yes ||Yes |
|Ventricular and right atrial tumors ||Rare ||Common |
|Multicentric tumors ||Rare ||Common |
|Other noncardiac tumors ||Rare ||Common |
|Spotty pigmentation of the skin ||No ||Yes |
|Endocrinopathy ||Rare ||Common |
Clinical features of Carney complex. Examples of cutaneous, endocrinologic, and cardiac manifestations in a family affected by Carney complex. A, Multiple lentigines: irregularly shaped brown-to-black macules are present on the face and vermilion border of the lips. B, Abdominal CAT scan imaging showing liver myxoma (white arrow) and adrenal hypertrophy (black arrow). C, Echocardiogram showing a large myxoma (*) arising from the wall of the right atrium (RA). Individuals in this family are affected by a DFST163 mutation in the PRKAR1α gene.6
Spotty skin pigmentation, usually lentigines, is present in almost all patients with Carney complex (≥95 percent).3–5 Lentigines are skin lesions characterized by basal cell layer hyperpigmentation associated with melanocytic hyperplasia.20 Small (pinpoint to 6 mm), round, irregularly shaped brown-to-black macules characteristically occur in the center of the face and vermilion border of the lips (Fig. 47.1-2A). Spotty pigmented lesions of the conjunctiva, eyelids, and external ears are also frequently observed.21 Other affected areas include genitalia, trunk and, less commonly, oral and perianal mucosae. In about 20 percent of Carney complex patients, spotty skin pigmentation may include the common blue nevus and/or the exceptionally rare epithelioid blue nevus, which has only been reported in Carney complex patients.22,23 Blue nevi are nonmalignant blue to black, domed, small (<1 cm) lesions, occurring on the face, head, neck, trunk, and extremities. These nonmalignant lesions do not recur at the initial site after excision.
Skin and Other Extracardiac Myxomas
Cutaneous myxomas are usually present as small (less than 1 cm), multicentric, recurring lesions, which occur in about 75 percent of Carney complex patients.3–5,21,24 The eyelid and external ear are preferentially involved, but these tumors also occur on the face, head, neck, trunk, and limbs with rare involvement of the hands and feet.25,26 There are no unusual histologic features to these cutaneous myxomas. Similar benign myxomas have also been observed in visceral organs including the liver (Fig. 47.1-2B) and spleen.4
Endocrinopathy and Primary Pigmented Nodular Adrenocortical Disease
Carney complex patients may present with several forms of adrenal, pituitary, and thyroid dysfunction (Fig. 47.1-2B). Although generally associated with endocrine overactivity, Carney complex may also involve endocrine underactivity, such as hypothyroidism.27 Endocrine dysfunction may occur in the absence of glandular neoplasms, which are also independently associated with Carney complex. Most commonly, Carney complex patients present with Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenal disorder leading to hypercortisolism.3–5 In this disorder, which occurs in about 20 percent of Carney complex patients, multiple, small, black-brown pigmented, autonomously functioning nodules are present in an atrophic adrenal cortex.28 Symptoms of Cushing syndrome are generally treated by bilateral adrenalectomy. Pharmacologic adrenalectomy is occasionally used with unusual durable results.17
Psammomatous Melanotic Schwannoma.
The psammomatous melanotic schwannoma is a very rare tumor associated with Carney complex in approximately half of occurrences.29 The presence of melanin, psammoma bodies, and fat in the tumor cells is unusual and differentiates this neoplasm from a common schwannoma. The tumor can involve the spinal nerve roots and vertebrae, and can also can affect the skin, stomach, or esophagus. Although psammomatous melanotic schwannoma is usually benign, metastasis has been documented in 10 percent of cases.29
Growth hormone-producing pituitary adenomas, resulting in gigantism and/or acromegaly, have been observed in approximately 10 percent of Carney complex patients.4,5 Prolactin-secreting adenomas have also been noted.30,31 Upon resection by transsphenoidal hypophysectomy, most Carney-complex pituitary tumors have been found to be macroadenomas.32
Thyroid tumors are infrequently observed in Carney complex. Benign thyroid nodules and cysts, Hürthle-cell adenoma, and thyroid papillary and follicular carcinoma, have all been reported.33
Mammary gland lesions occur in both females and males and have been estimated to occur in about one-fourth of Carney complex patients. They are usually asymptomatic and generally are of two histologic types: ductal adenoma with tubular features and myxoid fibroadenoma.34,35 Both neoplasms may be bilateral and tend to be multicentric within a single breast.
In a prospective study of female Carney complex patients, 60 percent had ovarian cysts. In two patients, the cysts progressed to cystadenomas and required surgery. Cystic teratoma, endometrioid carcinoma, and metastatic adenocarcinoma (but not stromal tumors) have all been observed.36
Large-cell, calcifying, Sertoli cell tumors37 are one of the rarest forms of testicular neoplasms. However, they occur in 30 percent of male Carney complex patients.3 While these tumors may be asymptomatic, they may produce estrogens and cause sexual precocity and/or gynecomastia. All identified cases showed multicentric foci within each testis and usually exhibited bilateral involvement. One Carney complex patient has died with metastasis of his testicular tumor.38 In addition to Sertoli cell tumors, other testicular lesions, including Leydig cell tumors and adrenocortical rest tumors, have been observed in Carney complex patients.5
Other neoplasms that have been reported in Carney complex patients include osteochondromyxoma; gastric carcinoma; Barrett metaplasia of the esophagus; colonic polyps/colorectal cancer; myxoid uterine leiomyoma; trichofolliculoma; pancreatic adenocarcinoma; pheochromocytoma; angiomyxoma; fibrolamellar hepatoma; lung granuloma; spermatocele; and cerebellopontine angle tumor.3,5,39,40 The significance of these lesions' association with Carney complex remains unknown.
A definitive clinical diagnosis of Carney complex is possible when at least two of the following major manifestations are present: cardiac myxomas, characteristic spotty pigmentation of the skin, or PPNAD. Any one of those major findings coupled with a family history of Carney complex is also sufficient to establish the diagnosis. The presence of a noncardiac myxoma, a psammomatous melanotic schwannoma or a Sertoli cell tumor along with any major manifestation is also highly suggestive of Carney complex. The role of other tumors or endocrinopathies in establishing a clinical diagnosis of Carney complex are less clear given the propensity of those disorders to occur in other settings as well.