Approach Considerations
Lab studies
Laboratory studies used in the diagnosis of Carney complex include the following:
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Complete blood count (CBC)
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Glucose/electrolytes
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Erythrocyte sedimentation rate
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Thyroxine/thyroid-stimulating hormone
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Adrenocorticotropic hormone
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Growth hormone
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24-hour urinary cortisol excretion test and dexamethasone stimulation test: To evaluate for primary pigmented nodular adrenocortical disease (PPNAD) as part of Carney complex [2]
Imaging studies
Echocardiography is the investigation of choice to define cardiac involvement in Carney complex. [3]
Electrocardiography
Although electrocardiography reveals no features that are specific to Carney complex, it may reflect the presence of left atrial enlargement or pulmonary hypertension.
Cardiac catheterization
This may be indicated on an individual basis prior to surgical resection if coexisting coronary artery disease is a possibility.
Imaging Studies
Echocardiography
Echocardiography is the investigation of choice to define cardiac involvement in the Carney complex (see the image below). Occasionally, evidence of myxomas in more than one cavity is found. [3]
Transthoracic echocardiogram of a left atrial myxoma in an individual with Carney complex. A 42-year-old woman with a history of spotty pigmentation on the face and cutaneous myxomas presented for annual surveillance echocardiography. Findings from previous echocardiograms were normal. Echocardiography now revealed a 1.0 X 1.3-cm mass (arrow) in the left atrium (LA) arising from the interatrial septum above the mitral valve. No prolapse was seen into the left ventricle (LV). Histopathology upon surgical excision demonstrated that the lesion was a myxoma.
Echocardiography also defines the presence of associated valvular involvement. Left atrial myxomas may prolapse through the mitral valve orifice, creating functional mitral stenosis, or may produce progressive valve leaflet damage, leading to mitral insufficiency.
In addition, echocardiography is useful for follow-up of patients after surgical removal of the tumor to detect recurrence of myxomas.
Transesophageal echocardiography reaches a sensitivity of 100%. It is useful to define the precise anatomical relationships of small tumors and to detect the presence of multiple cardiac myxomas.
Other imaging studies
Body computed tomography (CT) scanning or magnetic resonance imaging (MRI) may be appropriate to exclude extracardiac thoracic, abdominal, or paraspinal tumors, as well as to evaluate intracardiac tumors.
Testicular ultrasonography may be used to exclude testicular tumors and to assess large-cell, calcifying Sertoli-cell tumors of the testes.
Salient imaging signs of primary pigmented nodular adrenocortical disease are contour abnormality and hypodense spots within the gland. [29]
Genetic Evaluation
Patients thought to have Carney complex should be evaluated by a cardiologist/geneticist with experience in the management of inherited cardiovascular disease. [33]
Referral to an endocrinologist may be appropriate if endocrinologic problems are suggested by symptoms or laboratory studies
The initial step in the workup of patients with Carney complex is the ascertainment of a detailed family history to establish if the patient's disease represents a new mutation or is part of a familial syndrome. [5] Studies have shown that linkage analysis of extended families can provide diagnostic information for individuals with equivocal findings; however, these techniques remain research tools that generally are not available clinically.
Mutational analysis of the PRKAR1A gene may be a useful adjunctive diagnostic test. In the presence of a family history of arthrogryposis, testing for a mutation of MYH8 may be appropriate as well. However, such DNA-based testing currently remains the province of research laboratories (see GeneReviews).
Histologic Findings
Mass lesions in Carney complex usually require biopsy/resection to provide a histopathologic diagnosis. (See the image below.)
Polypoid neoplasm of fibrillary collagen and uniform stellate cells within abundant connective tissue mucin. Note telangiectasia and ramification of tumor as strands through a myxoid dermis (hematoxylin-eosin). Courtesy of Dermatology, NYU School of Medicine; photography by Anca Croitoru, MD, and Scott Sanders, MD.
Myxomas
In general, myxomas are globular, hard, and mottled lesions with hemorrhage. Histologically, they are composed of stellate or globular myxoma cells, endothelial cells, macrophages, mature or immature smooth muscle cells, and a variety of intermediate forms embedded in an abundant acid mucopolysaccharide ground substance. (See the image below.)
A pedunculated, flesh-colored cutaneous myxoma that is 1.5 cm in diameter on trunk. Courtesy of Dermatology, NYU, and Ann Stoecker, medical photographer.
Freckles (ephelides)
Freckles are small (1- to 10-mm), tan-red or light brown macules that first appear in early childhood after sun exposure. Once present, they fade and reappear in a cyclic fashion with winter and summer. The observed hyperpigmentation of the freckle is the result of increased amounts of melanin pigment in the basal keratinocytes. The melanocytes are relatively normal in number, although they may be slightly enlarged.
Lentigo
The term lentigo refers to a common benign hyperplasia of the melanocytes. Lentigo can occur in individuals of all ages but often occurs in infants and children. Unlike freckles, lentigines do not darken when exposed to sunlight. The essential histologic feature of the lentigo is melanocytic hyperplasia that produces a hyperpigmented basal cell layer in the epidermis in a linear fashion. Elongation and thinning of the rete ridges are also common in a lentigo.
Blue nevi
Blue nevi are characterized by highly dendritic nevus cells (as opposed to the rounded cells typical of most melanocytic nevi) that are heavily pigmented. When these cells are in the middle to deep dermis, they are blue to gray-blue at clinical examination.
Carney described an additional histopathologic variant of the blue nevus, called an epithelioid blue nevus. It is a heavily pigmented dermal lesion composed of two types of melanocytes. One type is intensely pigmented, globular, and fusiform, whereas the other type is lightly pigmented and polygonal, with large amounts of cytoplasm.
Most patients with an epithelioid blue nevus have Carney complex. However, cases of epithelioid blue nevi are also reported in children and adults with no evidence of Carney complex.
Schwannomas
Schwannomas are typically solitary, circumscribed, encapsulated tumors that are eccentrically located on the proximal nerves or spinal nerve roots. Microscopically, these tumors have regions of high and low cellularity called Antoni A and Antoni B areas, respectively. In the Antoni A tissue, foci of palisaded nuclei called Verocay bodies may be present, and the blood vessels in schwannomas often have hyaline thickening around them, indicating that pseudopalisading of the tumor nuclei may be present.
A psammomatous melanotic schwannoma is a particular schwannoma in Carney complex that is distinctive because of its heavy melanotic pigmentation and calcification. Multicentricity also frequently occurs in this tumor.
In a study of 40 melanotic schwannomas (in 18 male and 22 female patients, including 2 with Carney complex and 1 with a cutaneous myxoma that was suggestive of Carney complex), Torres-Mora et al concluded that melanotic schwannomas are distinctive malignant tumors, not benign growths that occasionally act unpredictably. The investigators suggested that melanotic schwannomas be reclassified as malignant melanotic schwannian tumors. [34]
Sertoli-cell tumors
Sertoli-cell tumors may be composed of entirely Sertoli cells or they may have a component of granulosa cells. These neoplasms may appear as firm, small nodules or, rarely, as bulky masses that cause considerable testicular enlargement. On cross sections, the surface is homogeneously gray-white to yellow.
On histologic examination, the cells in the classic form are distinctive and tall, columnar, or polyhedral, with abundant and usually vacuolated cytoplasm. The tendency for these cells to grow in cords that are highly reminiscent of spermatic tubules is distinctive.
Pituitary adenomas
In one patient with Carney complex, a pituitary microadenoma secreting growth hormone and prolactin also had admixed individual mucin-producing cells. [35]
PPNAD tumors
Primary pigmented nodular adrenocortical disease (PPNAD) tumors are characterized by lipofuscin-containing, autonomously functioning, cortisol-producing nodules surrounded by mostly atrophic adrenocortical and normal adrenomedullary tissue. The nature and origin of the tumors are unclear. [2] On gross examination, the surfaces show multiple small nodules, usually with a black to brown discoloration. In addition, the extranodular cortex is atrophic.
On histologic examination, multiple nodules are observed deep in the cortex. The cells in these nodules stain positively with periodic acid-Schiff. Outside the cortex, intense disorganization is present without normal zonation.
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Transthoracic echocardiogram of a left atrial myxoma in an individual with Carney complex. A 42-year-old woman with a history of spotty pigmentation on the face and cutaneous myxomas presented for annual surveillance echocardiography. Findings from previous echocardiograms were normal. Echocardiography now revealed a 1.0 X 1.3-cm mass (arrow) in the left atrium (LA) arising from the interatrial septum above the mitral valve. No prolapse was seen into the left ventricle (LV). Histopathology upon surgical excision demonstrated that the lesion was a myxoma.
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A pedunculated, flesh-colored cutaneous myxoma that is 1.5 cm in diameter on trunk. Courtesy of Dermatology, NYU, and Ann Stoecker, medical photographer.
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Polypoid neoplasm of fibrillary collagen and uniform stellate cells within abundant connective tissue mucin. Note telangiectasia and ramification of tumor as strands through a myxoid dermis (hematoxylin-eosin). Courtesy of Dermatology, NYU School of Medicine; photography by Anca Croitoru, MD, and Scott Sanders, MD.
