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CARNEY'S COMPLEX Chapter 21 - Jason A. Berner, M.D. and Dimitris A. Papanicolaou, M.D. October 23, 2003 |
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CARNEY'S COMPLEX Chapter 21 - Jason A. Berner, M.D. and Dimitris A. Papanicolaou, M.D. October 23, 2003 |
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Carney's complex is a syndrome characterized mainly by "myxomas, spotty pigmentation, and endocrine overactivity", predominantly involving hypercortisolism and/or growth hormone overproduction in addition to other clinical features. The history of the disease dates back as far as 1932 when Harvey Cushing reported a 24-year-old male with hypercortisolism, a pituitary macroadenoma, "numerous pigmented nevi on the chest", and a skin lump. The term "Carney's Complex" however, was not coined until 1985 when Dr. J.A. Carney at the Mayo Clinic, MN first described the manifestations of the syndrome (Carney et al., 1985).
Carney's complex has been reported in 384 patients; 43% were males and 57% were females. The patients with Carney's complex constitute a diverse ethnic population including European-Americans, African-Americans, and Asians from all continents. Seventy percent of cases with Carney's complex were familial (total of 67 affected families), whereas 88 cases were sporadic; 12 cases were genetically indeterminate (Stratakis et al., 2001).
Carney's Complex appears to be transmitted in an autosomal dominant pattern, although the inheritance pattern of the disease has not always followed the rules of Mendelian genetics. Forty-three cases of transmission occurred through a female, as compared to only 9 cases from a male affected parent. However, this disparity in transmission does not necessarily imply non-Mendelian genetic patterns of transmission; many patients with Carney's complex harbor large-cell calcifying Sertoli-cell tumors (LCCTST), which can impact on male fertility, affecting male transmission of the disease.
Although the exact genetic inheritance of Carney's complex is not fully understood, some progress of the genetics of Carney's complex has been made, providing more insight into the mechanism of the disease. Casey et al. demonstrated that mutation in the protein kinase R1alpha subunit is linked to familial cardiac myxomas and Carney's complex (Casey et al, 2000). Through linkage analysis, Casey and his colleagues mapped the genetic defect to the 17q24 gene locus (Casey et al., 1998). This gene locus corresponds to the PRKAR1alpha gene encoding the R1alpha regulatory subunit of cAMP-dependent protein kinase A (PKA). The PRKAR1alpha gene is thought to function as a tumor suppressor gene. PRKA R1alpha was found to be mutated in approximately half of the known Carney's complex kindreds (Stratakis et al., 2001).
Furthermore, through sequence analysis, frameshift mutations were shown in three unrelated families with the Carney's complex. These mutations resulted in truncation of the R1alpha transcript and a subsequent haploinsufficiency of the R1alpha subunit. The myxoma cells were shown to retain both the wild-type and mutant PRKA R1alpha alleles and wild-type R1alpha protein was stably expressed. A truncated R1alpha protein was not detected, indicating that there is only a deficiency of R1alpha at this time. Because of the haploinsufficiency of the R1alpha protein, the R1alpha to R2beta regulatory subunit protein ratio is reversed which could theoretically lead to tumorigenesis.
In 2002, Groussin et al. further demonstrated that mutations of the PRKA R1alpha gene appear to cause tumorigenesis. In this study, the PRKA R1alpha gene was sequenced in patients with Cushing's syndrome secondary to sporadic Primary Pigmented Nodular Adrenal Disease (PPNAD) without other features of Carney's complex. Three cases revealed de novo germ-line mutations. However, one of the patients had a macronodule and upon PRKA R1alpha gene sequencing of the nodule DNA, a somatic mutation was discovered, further supporting the role of the PRKA R1alpha gene as a tumor suppressor gene (Groussin et al, 2002).
Besides the PRKA R1alpha gene involvement with Carney's, another gene locus at chromosome 2p16 appears to be linked to Carney's complex (Stratakis et al., 1996). Most of the remaining kindreds with Carney's complex who did not have PRKA R1alpha mutations mapped to this locus displaying the genetic heterogeneity of the syndrome.
Epidemiology/ Clinical Presentation
Pituitary involvement with Carney's syndrome was found in 11% of patients. The pituitary involvement in these patients manifested as growth hormone-producing pituitary adenomas resulting in acromegaly or gigantism. The earliest and latest onset of symptoms secondary to growth hormone-secreting pituitary tumors were at ages 11 and 27 year, respectively (Carney et al., 1985)
For screening purposes, we recommend annual measurement of serum IGF-I for post-pubertal pediatric patients and for adult patients. For those patients without overt clinical manifestations of pituitary disease or in patients that are suspected of having early pituitary disease, further testing with oral glucose tolerance test should be performed. Removal of the tumor by transsphenoidal surgery is the treatment of choice.
B. Primary Pigmented Nodular Adrenal Disease (Ppnad)
PPNAD is an adrenocorticotropic hormone (ACTH)-independent process resulting in hypercortisolism (i.e. Cushing's syndrome). Hypercortisolism is caused by multiple autonomously functioning pigmented adrenocortical nodules ranging in size from submicroscopic to 10 mm in diameter; the adrenal gland is usually of normal weight. The adrenal glands feature multiple black and brown cortical nodules that contain large cells with pigment-laden, eosinophilic cytoplasm in the presence of internodular cortical atrophy. Furthermore, PPNAD is characterized by undetectable or low levels of ACTH that do not suppress to high dose dexamethasone and may even paradoxically increase after dexamethasone administration (Stratakis et al., 1999).
In a study involving 88 cases of the PPNAD, half were not familial and were not associated with other conditions of Carney's complex. Seventy-four of the 88 patients with PPNAD had clinical Cushing's syndrome, 5 had only biochemical evidence of adrenocortical hyperfunction or autonomy without clinical findings, and 9 had no investigation of adrenal function (Carney et al., 1992).
The reported weight of the individual adrenal glands ranged from 0.9 to 13.4 g and total adrenal weight ranged from 4.3 to 17 g with a mean of 9.6 g. Of the 74 individual glands available, 38 weighed less than 4g and 36 weighed greater than 4 g. This demonstrates that the glands in Carney's complex are usually normal in size. The glands externally may appear lumpy secondary to black, brown, or dark-red nodules- usually less than 4mm in diameter- disrupting the normal contour of the gland. The nodules were separated by yellow, atrophic cortex, 0.6 mm or less in some adrenals, while in others there is little or no cortex separating the nodules. The cortex between the nodules was usually markedly atrophic and contained cells that were greatly reduced in size. The cortex was normal in a few cases; it was rarely hyperplastic. The nodules within the adrenal glands in PPNAD corresponded to unencapsulated, circumscribed, round, oval, or sausage-shaped aggregates of cortical cells. Although unencapsulated, the nodules were sharply demarcated from the remainder of the cortex and most appeared to originate deep in the cortex almost at the level of the medulla. The cells of the nodules were large and globular. Cytoplasmic staining ranged from eosinophilic to clear. The brown pigment, lipofuscin, was contained in many of the cells. The nuclei were vesicular, of moderate size, and generally regular, although sometimes they could be pycnotic, enlarged, and hyperchromatic, usually without mitotic figures.
Clinically, 72 of the 88 patients in the above study presented with symptoms and signs of hypercortisolism. The most common presenting signs or symptoms of Cushing's syndrome with PPNAD were approximately the same as those associated with Cushing's syndrome and included central obesity, weight gain, hirsutism, and hypertension in addition to other manifestations. One of the most remarkable clinical signs is the prominence of osteoporosis in Cushing's syndrome with PPNAD.
The biochemical diagnosis of autonomous glucocorticoid secretion was documented in most of the above cases of PPNAD. Hypercortisolism was established by increases in urinary free cortisol (UFC) and 17-hydroxycorticosteroids above the upper limit of normal. The values were 5.8 +/- 9.7 and 2.1 +/- 1.0 fold above normal for the UFC and 17-hydroxysteroid levels respectively in patients that were tested. Lack of suppression by low-dose dexamethasone administration was found in all patients tested. In almost all cases, high-dose dexamethasone administration failed to suppress endogenous glucocorticoid production by greater than 50%. ACTH administration failed to stimulate glucocorticoid secretion in 17 of 21 cases and metyrapone failed to stimulate glucocorticoid secretion as well. Furthermore, no increase in ACTH was observed after ovine corticotropin-releasing hormone administration.
Computed tomography (CT) scanning of the adrenals was performed in 33 cases in the above study. The adrenals appeared normal in 45% and bilaterally enlarged in 27%. A unilateral mass was present in 15% and symmetric bilateral nodularity in 12%. The largest nodule seen on CT scan was 3 cm in diameter. Radiolabeled iodine scintigraphy ([6beta-#sup#131#/sup#I] iodomethyl-19-norcholesterol scintigraphy), performed in 18 patients, showed bilateral uptake in 16, unilateral uptake in 1, and no uptake in 1. These data show that adrenal gland imaging of Carney's complex can be indistinguishable from that of other adrenal condition characterized by adrenal nodularity, which is frequently present in other primary forms of the Cushing syndrome and in normal elderly persons.
Making the diagnosis of hypercortisolism in PPNAD can be difficult, because it usually develops slowly over several years and the clinical manifestations of Cushing's syndrome are often subtle. In addition, there is lack of specificity with radiographic imaging, as mentioned above. Furthermore, ACTH levels may not be fully suppressed, especially in mild or periodic cases of the Cushing's syndrome (Tsigos et al., 1995). Finally, even if ACTH levels are fully suppressed, there is still difficulty in differentiating hypercortisolism with PPNAD from macronodular adrenal hypercortisolism or hypercortisolism due to an adrenal adenoma. Interestingly, patients with PPNAD show a paradoxical increase in UFC and 17-OHCS in response to dexamethasone administration. A recent study applying Liddle's test (low dose dexamethasone for 2 days followed by high dose dexamethasone for 2 days) for distinction of PPNAD from macronodular adrenal disease (MAD), showed that an increase of UFC by 100% or more correctly identified patients with primary PPNAD and excluded all patients with macronodular adrenocortical disease. Therefore, Liddle's test can help differentiate PPNAD from MAD and may lead to a more timely detection of the Carney complex in asymptomatic patients (Stratakis et al., 1999).
Treatment for PPNAD involves bilateral adrenalectomy. In six patients who underwent only unilateral or subtotal adrenalectomy, recurrence or persistence of the disease was found in one hundred percent. No cases of Nelson's syndrome were reported following bilateral adrenalectomy in this group of patients (Carney et al., 1992). Finally, patients with Carney's complex should be screened annually with UFC measurements.
Cardiac myxomas are the most common primary tumor of the heart and are usually found in the left atria. In his first study delineating Carney's complex, Dr. Carney demonstrated that there are two established types of cardiac myxomas, non-familial and familial.
Non-familial Type (Not associated with Carney's Complex): This type of myxoma occurs during the fifth and sixth decades with the mean age being 51 years. This tumor is almost always a single tumor and develops usually in the left atrium. The occurrence of the tumor in the right atrium is much less common.
Familial Type: Familial atrial myxomas, in contrast to non-familial myxomas, occur earlier in life, typically presenting in the second and third decades (average age 24 years) in 29 previously described patients. The myxomas can present with cardiac, or embolic manifestations, or sudden death. The myxomas tend to be multicentric, occurring in more than one heart chamber at the same time. The myxoma was the presenting lesion in 17 out of 40 patients, followed by PPNAD in 8 patients, testicular/Sertoli cell tumors in 6 patients and skin, myxomas and spotty pigmentation in 4 patients (Carney et al., 1985).
Tumors range from a few millimeters to 8 cm in diameter in size. The surfaces are coarsely papillary or smooth, and the tumors have a gelatinous or hemorrhagic appearance. Basophilic mucoid matrix makes up most of the tumor. Mesenchymal cells, a variable number of mast cells, inflammatory cells, and arborizing capillaries are scattered within this matrix. The whole mass is covered by endothelium. The tumor cells are determined to have round, oval, or spindle small nuclei and a variable amount of acidophilic cytoplasm. Some cells are multinucleated. The cells are arranged in three ways: singly, in clusters, or in columns. Fibrosis and occasionally calcification seen in the tumors results from hemorrhage and degeneration.
Myxomas are important to identify early by echocardiogram because they are responsible for most of the deaths in patients with Carney's Complex. They can result in stroke or myocardial infarction through embolization by tissue fragments. Cases of recurrent myxomas have been reported; therefore, removal of myxomas cannot guarantee permanent cure. We recommend screening by echocardiogram in pediatric patients with Carney's Complex during the first 6 months of life and annually thereafter. For post-pubertal pediatric patients or adults, the recommendation is to screen annually with an echocardiogram as well.
Epidemiology/Clinical Presentation
Nine out of 40 patients in the first report on Carney's complex had testicular tumors that were bilateral in seven patients and multicentric in each affected testis. Six of the eight patients clinically detected were in their teens, but ages ranged from 5 to 33. The lesions in this case happened to be discovered during investigation for sexual precocity which occurred in four patients, on routine physical examination in three patients, and on specific examination of one patient (Carney et al, 1985).
Another report of 338 patients with Carney's complex revealed that 33% of male patients had a type of usually benign testicular tumor, called large-cell calcifying Sertoli cell tumor (LCCSCT). These tumors can cause precocious puberty, manifesting with gynecomastia in pre-pubertal and peri-pubertal boys, reportedly secondary to increased P-450 aromatase expression. Leydig cell tumors and adrenocortical rest tumors have also been reported (Young et al, 1995). Five cases of gynecomastia in pre-pubertal and peri-pubertal boys have been reported (Stratakis et al., JCEM 2001).
Grossly, the tumors from Carney's series were described as rock-hard and non-tender. The tumors themselves are well-demarcated and either yellow and calcified or brown and relatively soft. Under microscopic examination, these appearances corresponded to LCCSCT and a steroid-type tumor (Leydig cell tumor or adrenocortical rest tumor), respectively. Histologically, the Sertoli cell tumors were composed of large, round or polygonal cells. The copious cytoplasm was faintly to distinctly eosinophilic and very finely granular or finely vacuolated. The cells were arranged in cords or clusters as well as diffusely spread. Calcification was common. Serpiginous aggregation of the abnormal cells was found multifocally in seminiferous tubules.
The steroid cells were made of unencapsulated masses of cells with variably granular eosinophilic cytoplasm, and vesicular nuclei with large nucleoli, suggesting Leydig cell tumors. In other tumors, some at the surface of the testis or in the area of the rete testis, the size of the cells was more variable, the cytoplasm more granular, larger nucleus, and large amounts of lipofuscin and focal fatty metaplasia were present, features suggestive of adrenocortical rest tumor. Differentiating a Leydig cell tumor from an adrenocortical rest tumor is important because the treatment of choice for Leydig cell tumor is inguinal orchiectomy, but adrenal rest tumors don't have to be removed. The distinguishing pathological feature between a Leydig cell tumor and an adrenocortical rest tumor is that Leydig cell tumors contain crystalloids of Reinke. However, these crystalloids are found very infrequently in Leydig cell tumors and, without their presence, the task of distinguishing between the two is virtually impossible (Carney et al., 1985).
In Carney's first report, 2 patients were described with sexual precocity in which pituitary gonadotropins levels were determined to be low, suggesting suppression of pituitary function by an endogenous source of sex hormones, likely the testis. Ultrasound revealed testicular calcification in two of the 40 patients with the complex described by Carney.
However, while U/S is useful for initial evaluation (Premkumar et al., 1997), it is not sufficiently unique to exclude a more serious testicular malignancy such as a Leydig cell tumor. Therefore, functional activity must be used to distinguish a Leydig cell tumor from a less serious lesion such as an adrenal rest tumor. This is done via testicular vein sampling. By determining a gradient of cortisol or other adrenal products between the peripheral blood and testicular venous blood during simultaneous ACTH infusion, ACTH-dependent endocrine activity of the tumor can be proven (Shawker et al., 1992).
Five of the nine patients with testicular tumors as described by Carney underwent bilateral orchiectomy, while one patient had unilateral orchiectomy with contralateral involvement present at autopsy. However, most of the testicular tumors associated with Carney's complex are benign and the risk of malignancy is low. Therefore surgery is generally not indicated initially. Instead, we recommend that male patients have testicular ultrasonography performed at their initial evaluation. If minute calcifications are present, they should have a yearly U/S thereafter. For pediatric patients with LCCSCT, growth rate and pubertal status should be closely monitored to detect development of precocious puberty. Further testing such as bone age and further laboratory testing may be required especially if gynecomastia is present (Stratakis et al., 2001) The treatment of choice for Leydig cell tumor is inguinal orchiectomy, but adrenal rest tumors don't have to be removed (Carney et al., 1985).
Skin manifestations associated with Carney's Complex include lentigines, blue nevi, and cutaneous myxomata. Eyelid myxomas have been reported to occur in 10% of patients with the syndrome (Kennedy et al., 1987).
Clinical Presentation/Diagnosis
Characteristically, the pigmented spots are discovered on the face and vermilion borders of the lips, and on the lacrimal, caruncle, and conjunctiva. The lesions were often multiple and commonly recurred following excision. In patients with eyelid and/or eye involvement other findings besides eyelid myxomas include spotty pigmentation of the eyelids and pigmented lesions of the caruncle or conjunctival semilunar folds. It is important to note that cutaneous myxomas are detected prior to the cardiac myxoma in the majority of patients.
While cutaneous manifestations of Carney's complex are benign, they are indicative of the presence of the syndrome. In any patient with multiple cutaneous myxomas, spotty pigmentation, and/or endocrine overactivity, cardiac ultrasound should be performed (Carney et al., 1986; Grossniklaus et al., 1991).
Epidemiology/Clinical Presentation
In one study, breast myxoid fibroadenomas or other myxoid lesions were reported in 20% (19 patients) of females with Carney's complex, usually presenting as one or more discrete, asymptomatic mammary masses. Tumors were bilateral in slightly less than 10% of subjects (8 female patients). The breast lesions associated with Carney's Complex ranged in size from 2 mm to 2 cm in diameter. Mammary ductal adenoma was also found to occur in four patients.
The typical lesion from Carney's patients was grossly pink or white with a mucoid appearance. Microscopically, the tumors were discovered to be myxoid fibroadenomas. These tumors were composed of a variable number of hyperplastic mammary ducts enmeshed in a large amount of hypocellular myxoid stroma that was more myxoid and less cellular than a typical fibroadenoma. The tumors may or may not be encapsulated. In addition, ductal adenomas of the breast in Carney's patients (age 27-61) have been described as having long, straight, narrow, roughly parallel tubules composed of distinct epithelial and myoepithelial cells. Fibrous tissue separates the ducts from one another and they are surrounded by a fibrous capsule. Each of these lesions had myxoid mesenchymal lesions typical of the complex. Mammograms of these lesions may suggested (Carney et al., 1991).
No consensus guidelines have been specifically established for the monitoring of breast lesions in Carney's complex patients at this time. However, since breast carcinoma can occur in these patients, women beginning in their 20s should probably be taught to self examine for lesions and should have annual breast exams. Imaging of breast lesions using U/S, MRI, or mammogram in 9 patients with Carney's complex ages 16-61 showed that MRI revealed the most lesions. Chest and breast MRI images were false-negative in only one patient whereas mammograms and U/S scans were false-negative in three patients each. Most of the patients in the study were determined to have multiple bilateral lesions. The characteristics of all these lesions were benign suggesting that multiple biopsies should not be performed (Courcoutsakis et al., 1997). If lesions suspicious for malignancy are discovered or if patients have bloody discharge or pain, surgical consultation should be considered.
G. PSAMOMMATOUS MELANOTIC SCHWANNOMAS
Carney's complex involves tumors that affect peripheral nerves as well. In 1934 Bjorneboe first described these tumors which later became know as psammomatous melanotic schwannomas (Bjorneboe, 1934). The lesion was found to occur equally between sexes (Killeen et al., 1988). This particular tumor has malignant potential and four patients died as a result of metastasis. In a study by Carney of 31 patients with psammomatous melanotic schwannomas, 17 (55%) had the complex of myxomas, spotty pigmentation, and endocrine overactivity. Among the 17, psammomatous melanotic schwannoma occurred at an average age of 22.5 years. In one patient, the tumor was the presenting component of the complex. Nine of the 17 patients were members of 6 families with the syndrome, which was transmitted as a Mendelian autosomal dominant trait. Forty psammomatous melanotic schwannomas were found among the 31 patients. Six (19%) had multiple tumors including one patient with five tumors. Five of the six with multiple tumors had the complex. The tumors were distributed in the GI tract (11 cases), spinal nerves (11 cases), soft tissue of the trunk and extremities (9 cases), chest wall (3 cases), region of the trigeminal ganglion (2 cases) and heart, bronchus, retroperitoneum, and liver, one case each. Tumor sites included the posterior spinal nerve roots, alimentary tract, and bone.
Grossly, the tumors were black or brown, and were encapsulated. They featured large and small, polygonal, epithelium-like cells and spindle cells, cytoplasmic melanin, laminated calcifications called psammoma bodies, and immunostained positive for S 100 protein, vimentin, and HMB-45. Some tumors contained small to modest amounts of mature adipose tissue and/or osseous metaplasia. The stroma of these tumors can be sparse to abundant containing different amounts of collagen bundles, vacuolations with myxoid material, focal zones of fibrosis, and distinct fibrous nodules. Most of the blood vessels in the tumor were thin-walled sinusoids and were especially featured in spinal nerve root tumors. Hemorrhage and necrosis can occur as well. Necrosis has been reported to occur in tumors that metastasized as well as those that did not. Microscopically, metastases featured melanin but no psammoma bodies or fat (Carney, 1990).
Symptoms and/or signs included pain from spinal or other nerve involvement, mechanical dysfunction as the result of mass effect of the tumor which has been shown to involve the stomach and heart, palpable soft tissue or bony mass, symptoms of bronchial pressure, and pain resulting from destruction of bone by the tumor.
Roentgenograms and CT scans of spinal tumors revealed enlargement of the intervertebral foramina with bony erosion and sclerosis, with or without a paravertebral soft-tissue mass which is referred to as a dumbbell tumor. Myelograms displayed a partial to complete block of contrast material. Tumors on imaging were shown to cause destruction of vertebra and ribs. Luminal filling defects were observed with gastric tumors and a right atrial tumor as well. Therefore, regular X-Ray, CT, or MRI should be considered in imaging this type of tumor (Carney, 1990).
The diagnosis of a psammomatous melanotic schwannoma is made based on pathology. Usually these tumors have to be differentiated from meningiomas, regular schwannomas, malignant melanomas, pigmented neurofibromas, rhabdomyosarcomas, and clear-cell sarcomas of soft parts. The properties of melanin, fat, psammoma bodies, as well as other properties help to distinguish them from most of these other tumors. Another distinguishing feature between the psammomatous melanocytic schwannomas and regular schwannomas was that in more than half of the cases, the psammomatous melanotic schwannoma was a familial condition (Carney, 1990).
Of the 31 patients described by Carney with psammomatous melanotic schwannomas, 21 patients were alive without evidence of recurrence or metastasis 1-21 years following surgical removal. Seven patients died in all. Four of the patient's deaths were secondary to the tumor. Three of the four patients that died had Carney's Complex. Two of these patients with Carney's complex died secondary to atrial myxomas. Metastasis was discovered to occur to the following locations: lung, mediastinum, pleura, diaphragm, pericardium, endocardium, bones, liver, and spleen. Therefore, once these tumors are discovered, patient should be referred for surgical evaluation for tumor removal. Furthermore, in any patient who is determined to have a psammomatous melanotic schwannoma, testing for other components of Carney's complex, including atrial myxoma and PPNAD should be performed.
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