Carney Complex 

Updated: May 05, 2016
Author: Craig T Basson, MD, PhD; Chief Editor: Richard A Lange, MD, MBA 

Overview

Practice Essentials

Carney complex is an autosomal dominant syndrome associated with spotty pigmentation of the skin, endocrinopathy, and endocrine and nonendocrine tumors, including the following:

  • Myxomas of the skin, heart, breast, and other sites

  • Primary pigmented nodular adrenocortical disease

  • Psammomatous melanotic schwannomas

  • Growth hormone–producing pituitary adenomas

  • Testicular Sertoli-cell tumors

  • Possibly, other benign and malignant neoplasms and conditions, including tumors of the thyroid gland and ductal adenomas of the breast, as well as acromegaly due to somatomammotroph hyperplasia and adenomas not dependent on growth hormone–releasing hormone

Signs and symptoms

Skin:

  • Pigmentation, including blue nevi of the face, lips, sclera, trunk, or genital mucosa

  • Cutaneous myxomas

  • Generalized hyperpigmentation, obesity, striae, or cushingoid appearance

Masses:

  • Cutaneous

  • Thyroid

  • Breast

  • Testis mass/enlargement (secondary to myxoma)

Neurologic:

Patients may exhibit neurologic deficits secondary to tumor emboli.

Cardiac:

Upon physical examination, an accentuated first heart sound can be appreciated in patients with cardiac myxomas. Other symptoms include the following:

  • Diastolic apical rumbling murmur (mimicking mitral stenosis)

  • Holosystolic murmur best heard at apex and radiating to axilla (mitral regurgitation)

  • Tumor "plop"

Systemic:

  • Fever

  • Clinical signs of anemia

  • Weight loss

  • Arthralgia

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies used in the diagnosis of Carney complex include the following:

  • Complete blood count (CBC)

  • Glucose/electrolytes

  • Erythrocyte sedimentation rate

  • Thyroxine/thyroid-stimulating hormone

  • Adrenocorticotropic hormone

  • Growth hormone

  • Twenty-four–hour urinary cortisol excretion test and dexamethasone stimulation test: To evaluate for primary pigmented nodular adrenocortical disease (PPNAD) as part of Carney complex[1]

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 1 cavity is found.[2]

Transthoracic echocardiogram of a left atrial myxo 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.

Mass lesions in Carney complex usually require biopsy/resection to provide a histopathologic diagnosis.

See Workup for more detail.

Management

In Carney complex, medical care is restricted to the treatment of endocrine overactivity, which is commonly present. No specific drug is useful in the management of myxomas.

Surgery is necessary to resect intracardiac myxomas and to prevent embolic stroke or valvular obstruction.[3]

Extracardiac myxomas and nonmyxomatous benign lesions should be resected if they produce symptoms via local extension. Large or symptomatic skin myxomas or other benign lesions also can be excised.

Rare malignant tumors require resection, as well as, possibly, adjunctive therapy and referral to an oncologist.

See Treatment for more detail.

Background

Carney complex is an autosomal dominant syndrome associated with spotty pigmentation of the skin, endocrinopathy, and endocrine and nonendocrine tumors. (See Pathophysiology, Etiology, and Clinical Presentation.)

These tumors include myxomas of the skin, heart, breast, and other sites; primary pigmented nodular adrenocortical disease, psammomatous melanotic schwannomas; growth hormone–producing pituitary adenomas; testicular Sertoli-cell tumors; and, possibly, other benign and malignant neoplasms and conditions, including tumors of the thyroid gland and ductal adenomas of the breast, as well as acromegaly due to somatomammotroph hyperplasia and adenomas not dependent on growth hormone–releasing hormone (see the image below). (See Clinical Presentation and Workup.)

Transthoracic echocardiogram of a left atrial myxo 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.

Carney complex accounts for 7% of all cardiac myxomas. Although primary tumors of the heart are rare in all age groups, they are still important to consider in differential diagnoses of valvular disease, congestive heart failure, and arrhythmia. Although myxomas are the most common cardiac tumors in adults, they are relatively rare in infants and children. (See Epidemiology and DDx.)

While myxomas are usually sporadic, several familial, autosomal dominant conditions that combine lentiginosis and cardiac myxomas have been described. Previously termed syndromes, such as LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi) syndrome and NAME (nevi, atrial myxoma, myxoid neurofibroma, and ephelides) syndrome, now are grouped under the broader category of Carney complex. (See Workup.)

Although the existence of the complex as an unrecognized inherited syndrome was first suggested in 1985, combinations of several components of the syndrome and their familial occurrence were reported earlier.[4] The Carney complex gene 1 was later identified as the regulatory subunit 1A of protein kinase A (PRKAR1A) located at 17q22-24.[5, 6] An inactivating heterozygous germ-line mutation of PRKAR1A has been documented in about two thirds of individuals with Carney complex. (See Pathophysiology and Etiology.)

Endocrine overactivity is one of the characteristics of this syndrome.[7] In fact, corticotropin hormone–independent Cushing syndrome due to primary pigmented nodular adrenocortical disease is an important characteristic of Carney complex. (See Workup and Treatment.)

Patient education

The family should be aware that this is an autosomal dominant disorder with a 50% chance that the offspring of an affected individual will have the disorder.

Pathophysiology

Carney complex is inherited as an autosomal dominant trait with variable penetrance. Cardiac myxomas are thought to arise from primitive subendocardial mesenchymal multipotent precursor cells. However, these cells have not been specifically identified yet. The systemic symptoms (eg, fever, arthralgia, elevated sedimentation rate, lupuslike rashes) that accompany some myxomas may be due to the production of the proinflammatory cytokine interleukin-6 by the myxoma.

Mutations in the PRKAR1A gene encoding the R1α regulatory subunit of protein kinase A have been shown to cause Carney complex.[8, 5, 6, 9] In an analysis of 51 unrelated patients with Carney complex, 65% were shown to have mutations in the PRKAR1A gene. PRKAR1A may act as a tumor suppressor gene by regulating protein kinase A activity, which in turn can suppress or stimulate cell growth and differentiation.[10]

Carney complex genes are associated with genomic instability; cell lines established from Carney complex tumors accumulate chromosomal changes, including telomeric associations and dicentric chromosomes.

A variant form of Carney complex associated with distal arthrogryposis has been identified. Analysis of a large family with cardiac myxomas and other typical findings of Carney complex, as well as trismus-pseudocamptodactyly, revealed a missense mutation in the MYH8 gene that encodes perinatal myosin heavy chain.[11] Further studies of families with similar phenotypes revealed that this missense mutation was a common founder mutation. These findings suggest a role for protein kinase A and perinatal myosin heavy chain in cardiac tumorigenesis.

Cardiac involvement

Cardiac myxomas in the Carney complex often are multiple, can occur in any cardiac chamber, and have a predilection to recur at distant intracardiac and extracardiac sites after initial surgical resection. These tumors may grow in diameter by as much as 1.8 cm/y. Initial genetic analyses suggested that a gene defect may map to arm 2p.[12, 13] Subsequent linkage analysis in several families affected by the Carney complex, including some of the families initially proposed to be linked to chromosome 2, mapped a disease locus to band 17q2.[14]

Although they usually are benign, cardiac myxomas are associated with significant cardiac morbidity due to stroke from tumor embolization and heart failure from intracardiac valvular obstruction.

Extracardiac involvement

In addition to cardiac myxomas, individuals with Carney complex exhibit spotty pigmentation of the skin, particularly on the face, trunk, lips, and sclera. Pigmentation also may affect the mucosal surfaces of the oral or genital regions.

Extracardiac myxomas may also occur in the breast, testis, thyroid, brain, and adrenal gland. (See the image below.) Nonmyxomatous tumors, such as pituitary adenomas, psammomatous melanotic schwannomas, and Sertoli cell tumors of the testis, also may be observed. Impaired fertility has been observed in males with Carney complex.

A pedunculated, flesh-colored cutaneous myxoma tha A pedunculated, flesh-colored cutaneous myxoma that is 1.5 cm in diameter on trunk. Courtesy of Dermatology, NYU, and Ann Stoecker, medical photographer.

Patients can also exhibit a spectrum of endocrine overactivity, including Cushing syndrome secondary to primary pigmented nodular adrenocortical hyperplasia. Thyroid and pituitary dysfunction may be observed as well.[15, 16]

Etiology

Because family members with the same mutation can show distinct phenotypes, Carney complex may be viewed as a multifactorial disorder arising from various genetic and environmental factors.[17]

In a study of families with Carney complex, Casey et al identified mutations in the PRKAR1A gene.[10] In addition, Kirschner and colleagues detected a loss of heterozygosity in the vicinity of the PRKAR1A gene.[18] This gene encodes the protein kinase A regulatory subunit 1-alpha (R1α), on chromosome 17q. The investigators subsequently identified 3 unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analyses of PRKAR1A activity have inconsistently demonstrated altered PKA activity in Carney complex tumors compared with non–Carney complex tumors.

Kirschner et al[19] also screened the mutations present in 54 Carney complex kindreds. In 14 of the mutations that were mapped to the PRKAR1A locus, they found a premature stop codon; one altered the initiator ATG codon. The messenger ribonucleic acids (mRNAs) resulting from this mutation were unstable, and they rapidly decayed. In addition, the PRKAR1A products were absent in the affected cells. Casey et al and Veugelers et al demonstrated that in fact loss of heterozygosity and nonsense-mediated decay occurred during the pathogenesis of some Carney complex cases but not all.[10, 11]

The role of PDE11A as a possible gene modifier of the phenotype was evaluated in a series of 150 patients with Carney complex, with the high frequency of PDE11A variants identified. It remains unknown if this gene is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation.[20]

Epidemiology

Occurrence in the United States

Cardiac myxomas are the most common primary cardiac tumor in the general population, occurring with a frequency of 7 cases per 10,000 individuals. Myxomas occurring as part of Carney complex account for 7% of all cardiac myxomas.

International occurrence

More than 150 patients have been identified as having Carney complex since its recognition in 1985. Cases in persons with only limited involvement may not be reported. The syndrome is distributed worldwide.

Race-, sex-, and age-related demographics

Most patients who are affected with Carney complex are white, although the disease has been described in blacks and other racial groups.

The mean patient age at diagnosis of Carney complex is 10-20 years, although the condition may arise in persons of any age and either sex. Sporadic myxomas generally affect middle-aged adults, particularly females.

Prognosis

Complications associated with Carney complex include the following:

  • Recurrent myxoma growth: Myxomas recur in approximately 12-22% of familial cases and in about 1-2% of sporadic cases; individuals with recurrent cardiac myxomas may require additional cardiac surgery to resect these tumors; the prognosis in Carney complex, which is generally good, depends on the proclivity of cardiac myxomas to recur

  • Congestive heart failure

  • Stroke: Cerebellar ischemic stroke can result from emboli from an atrial myxoma; ischemic stroke has been described as a presentation of recurrent cardiac myxoma in Carney complex[21]

  • Peripheral embolization, including in the coronary, retinal, renal, celiac, femoral, and pulmonary arteries

  • Pulmonary hypertension

Intracardiac myxomas may create ball-valve obstructions that cause unexpected syncopal attacks, cardiac insufficiency, and sudden death in apparently healthy young children and adults.

Women with Carney complex may be at a high risk for recurrent atrial myxomas that lead to multiple strokes.[22] Early identification of a female patient with Carney complex may facilitate stroke prevention.

Extracardiac tumors may produce morbidity by local extension. Endocrine dysfunction also often is symptomatic, but it may be subclinical.

The psammomatous melanotic schwannomas are typically benign; they metastasize, however, in as many as 10% of cases.

Mortality

Cardiac myxomas account for a mortality rate of 25% in patients with this syndrome. Cardiac myxomas are a silent killer, causing major disability with its embolic capacity and even sudden death.

Although the mortality rate is less than 2% during excisions of primary cardiac tumors, the risks associated with open-heart surgery increase with each successive operation.

 

Presentation

History

Patients may present with symptoms of congestive heart failure, transient ischemic attack, or stroke.

Manifestations of Carney complex can also include Cushing syndrome (symptoms of which may develop in young patients) and skin changes associated with pigmentation, with spotty cutaneous pigmentation being a major clue to the diagnosis of Carney complex.[23] The presence of subtle buccal and perioral lentigines may also be an important clue.[24] Other symptoms include the following:

  • The skin is fragile and thin

  • Patients bruise easily and heal poorly

  • The bones are weakened, and routine activities such as bending, lifting, or rising from a chair may lead to backaches and rib and spinal column fractures

  • Severe fatigue, muscle weakness, high blood pressure, and high blood sugar levels may be present

  • Irritability, anxiety, and depression are common

  • Women may have menstrual periods that become irregular or stop

  • Men have decreased fertility, with a diminished or absent desire for sex

Associated prolactin-secreting tumors, acromegaly, and hyperparathyroidism can produce the following symptoms:

  • Prolactin-secreting tumor: Hypogonadism (eg, amenorrhea, impotence) associated with symptoms of increased prolactin levels (eg, galactorrhea) in female patients

  • Acromegaly: Headaches and visual abnormalities

  • Hyperparathyroidism: Fatigue, anemia, muscle weakness, joint pain, constipation with nausea, frequent urination (sometimes bloody), mood change with confusion, abdominal pain due to ulcers, flank or back pain due to stones, bone pain due to bone erosions or fractures, and hypertension

Cardiac myxomas may create ball-valve obstructions that cause unexpected syncopal attacks, cardiac insufficiency, and sudden death in apparently healthy young children and adults.

Right-sided myxomas with extramedullary hematopoiesis and ossification in Carney complex have been described in a patient who also had a tiny eyelid cutaneous myxoma, multiple hypoechoic thyroid follicular adenomas, and multiple small testicular tumors.[25]

Family history in patients with Carney complex may include cardiac myxomas and/or spotty pigmentation.

Physical Examination

Cutaneous

Cutaneous findings in Carney complex can include the following:

  • Pigmentation, including blue nevi of face, lips, sclera, trunk, or genital mucosa

  • Cutaneous myxomas

  • Generalized hyperpigmentation, obesity, striae, or cushingoid appearance

Masses

The following types of growths may be found:

  • Cutaneous

  • Thyroid

  • Breast

  • Testis mass/enlargement (secondary to myxoma)

Neurologic

Patients may exhibit neurologic deficits secondary to tumor emboli.

Cardiac

Cardiologic findings can include the following:

  • Accentuated first heart sound and opening snap

  • Diastolic apical rumbling murmur (mimicking mitral stenosis)

  • Holosystolic murmur best heard at apex and radiating to axilla (mitral regurgitation)

  • Tumor "plop"

Systemic

Systemic findings can include the following:

  • Fever

  • Clinical signs of anemia

  • Weight loss

  • Arthralgia

Atrial and ventricular myxomas

Upon physical examination, an accentuated first heart sound can be appreciated in patients with cardiac myxomas.

In adults, myxomas are the most common primary tumor of the heart. They arise in any of the 4 chambers or on the heart valves; however, about 90% are located in the atria. Myxomas in the atria have a left-to-right ratio of approximately 4:1.

Myxomas are mostly single and rarely multiple in several chambers. The tumors may be 1-10 cm or larger in diameter and can be pedunculated or sessile. Pedunculated atrial myxomas are often sufficiently mobile to move into or sometimes through the atrioventricular valves during diastole. Sometimes, such mobility exerts a wrecking-ball effect on the valve leaflets.

Multiple nevi, diffuse facial lentigines, and mucosal labial pigmentation

The classic presentation of Carney complex is a spotty pigmentation on the face, chest, and shoulders and on the vermilion border of the lips and conjunctiva. The pigmentation can be tan or dark brown to black.

The lesions can be irregularly shaped or sharply delineated, and they can be small or several millimeters in diameter.

Subcutaneous myxoid neurofibromas and mammary myxoid fibroadenomas

Cutaneous myxomas have a predilection for the eyelids and external ear canals, although they may affect any part of the skin.

The mammary myxoid fibroadenomas in the complex are often multiple and bilateral. These fibroadenomas are an unusual finding in an otherwise normal breast.

Signs of acromegaly

These can include the following:

  • Macroglossia

  • Prominent jaw and frontal bossing

  • Large, spadelike hands.

  • Skin tags

  • Hyperhidrosis

Signs of Cushing syndrome

Cushing syndrome can manifest with the following:

  • Thin, fragile skin

  • Easy bruising and poor healing

  • Purplish pink stretch marks on the abdomen, thighs, buttocks, arms, and breasts

  • Upper-body obesity, a rounded face, increased fat around the neck, and thin arms and legs

  • Tendency toward obesity, with slowed growth rates, in children

  • Usually, excessive hair growth in women on the face, neck, chest, abdomen, and thighs

Endocrine involvement

Endocrine involvement in Carney complex includes the following types of testicular tumors:

  • Large-cell calcifying Sertoli-cell tumor (one of the rarest testicular neoplasms)

  • Adrenocortical rests

  • Leydig-cell tumor

These tumors appear with testicular masses; about one third of affected male patients have them.

Large-cell calcifying Sertoli-cell tumors may also appear as bilateral masses, but in this setting when not associated with other Carney complex findings, may reflect isolated disease unrelated to Carney complex.[26] They can also secrete estrogens, resulting in precocious puberty, gynecomastia, or both.

As many as 75% of patients with Carney complex may have multiple thyroid nodules. The nodules can appear as a goiter or thyroid mass when palpated on physical examination. Patients can also present with symptoms of hyperthyroidism or hypothyroidism.

Psammomatous melanotic schwannomas most frequently occur in the gastrointestinal tract (esophagus and stomach) and paraspinal sympathetic chain. Masses can be palpated on abdominal or paraspinal examination.

 

DDx

Diagnostic Considerations

Cardiac myxomas are rare benign neoplasms with symptoms that may mimic those of other disorders. Most occur sporadically; a relatively small proportion is part of Carney complex syndrome.[3]

Differentials in Carney complex include the following:

  • Intracardiac thrombus

  • Metastatic neoplasm to the heart

  • Breast adenoma/carcinoma

  • Testicular adenoma/carcinoma

Differential Diagnoses

 

Workup

Approach Considerations

Lab studies

Laboratory studies used in the diagnosis of Carney complex include the following:

  • Complete blood count (CBC)

  • Glucose/electrolytes

  • Erythrocyte sedimentation rate

  • Thyroxine/thyroid-stimulating hormone

  • Adrenocorticotropic hormone

  • Growth hormone

  • 24-hour urinary cortisol excretion test and dexamethasone stimulation test: To evaluate for primary pigmented nodular adrenocortical disease (PPNAD) as part of Carney complex[1]

Imaging studies

Echocardiography is the investigation of choice to define cardiac involvement in Carney complex.[2]

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 1 cavity is found.[2]

Transthoracic echocardiogram of a left atrial myxo 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 or 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.[23]

Genetic Evaluation

Patients thought to have Carney complex should be evaluated by a cardiologist/geneticist with experience in the management of inherited cardiovascular disease.[27]

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. 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 GeneTests).

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 unifo 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 tha 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

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 2 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.[28]

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.[29]

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.[1] 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.

 

Treatment

Approach Considerations

No specific drug is useful in the management of myxomas in Carney complex, with resection being the treatment of choice for cardiac myxomas. Anticoagulation also is not indicated in patients with myxomas and does not reduce the risk of emboli (which, in cardiac myxomas, are actually fragments of the tumor that have broken off).[3]

Medical care in Carney complex is restricted to the treatment of endocrine overactivity, which is commonly present. Antibiotic prophylaxis is required if valvular insufficiency exists.

Activity

In the absence of heart failure or persistent cardiac sequelae, no activity limitation is required in Carney complex.

Consultations

Consultations with the following specialists may be indicated in Carney complex:

  • Cardiologist

  • Geneticist

  • Cardiothoracic surgeon

  • Endocrinologist

  • Oncologist

Monitoring

Patients who have had Carney complex should be monitored annually with echocardiography to detect the occurrence of new cardiac myxomas. The relapse rate for these myxomas after removal is high.[30]

Annual history and physical examination also are required, to detect the development of extracardiac myxomas and other tumors, as well as the signs and symptoms of endocrine dysfunction.

Tumor Resection

As previously stated, mass lesions in Carney complex usually require biopsy/resection to provide a histopathologic diagnosis.

Surgery is necessary to resect cardiac myxomas and to prevent embolic stroke or valvular obstruction.[3] Recognize that even in the presence of resections with adequate surgical margins, cardiac myxomas may recur at locations distant from the initial operative site. These recurrences do not reflect a failure of the initial surgical treatment but instead reveal a genetic predisposition to recurrent tumor formation.

Although recurrence of cardiac myxomas (and, similarly, extracardiac myxomas) is a feature of Carney complex, it is not a feature of typical nonsyndromic sporadic atrial myxomas.

Extracardiac myxomas and nonmyxomatous benign lesions should be resected if they produce symptoms via local extension. Large or symptomatic skin myxomas also can be excised.

Rare malignant tumors require resection, as well as, possibly, adjunctive therapy and referral to an oncologist.