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Thyroid Gland Abnormalities in Patients with the Syndrome of Spotty Skin Pigmentation, Myxomas, Endocrine Overactivity, and Schwannomas (Carney Complex)

Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development (C.A.S.); the Warren Magnuson Clinical Center, Diagnostic Radiology Department (N.A.C., J.L.D., T.S.); and the Cytopathology Section, National Cancer Institute (A.A., A.F.), National Institutes of Health, Bethesda, Maryland 20892; the Department of Pediatrics, Georgetown University Children’s Medical Center (C.A.S.), Washington, D.C. 20007; and the Emeritus Staff, Department of Laboratory Medicine and Pathology, Mayo Clinic (J.A.C.), Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Dr. Constantine A. Stratakis, Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 10N 262, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Carney complex is a multiple neoplasia and lentiginosis syndrome that affects endocrine glands, including the pituitary, adrenals, and testes; thyroid gland involvement has not been unequivocally demonstrated. In the present study, the medical records of 12 families with Carney complex (53 affected patients) were reviewed for evidence of thyroid abnormality; 2 patients with thyroid carcinoma (1 papillary and 1 follicular; 3.8%) and 1 with follicular adenoma were identified in 3 unrelated kindreds. Six affected members of these kindreds were then screened for the presence of thyroid disease (familial cases). We also studied 5 patients with the complex who had no affected relatives (sporadic cases). These 11 patients consisted of 5 adults [mean age, 33.2 ± 9.2 (±SD) yr] and 6 children and adolescents (mean age, 13.8 ± 2.5 yr). All had normal results of physical and biochemical examination of the thyroid gland (total and free T₄, T₃, and TSH levels). Thyroid ultrasonography showed hypoechoic, cystic, solid, or mixed lesions in 3 of the 5 adults (60%) and 4 of the 6 children (67%). Two patients underwent fine needle aspiration biopsy, which identified follicular lesions. Thyroid gland abnormalities were documented in 5 siblings and 1 parent-child pair. We conclude that thyroid gland pathology is 1) common in patients with Carney complex; 2) includes a spectrum of abnormalities ranging from follicular hyperplasia and/or cystic changes to carcinoma; and 3) is inherited in an autosomal dominant manner, like the other manifestations of the syndrome; it is therefore, a candidate component of the syndrome. Ultrasonography is useful in the detection and clinical follow-up of these lesions.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
CARNEY COMPLEX is a multiple neoplasia and lentiginosis syndrome inherited in an autosomal dominant manner in approximately half of the reported patients and occurring sporadically in the remaining cases (1, 2, 3). Affected individuals present with numerous pinpoint, brown to black macules on the skin and mucosae (lentigines); cafe-au-lait spots, blue nevi, and other pigmented lesions; and a variety of nonendocrine and endocrine tumors (1, 3). These include myxomas of the heart, skin, breast, and other sites; primary pigmented nodular adrenocortical disease, a pituitary-independent, bilateral, primary adrenal disorder causing Cushing’s syndrome; GH-producing pituitary adenoma; and testicular Sertoli and Leydig cell tumors (4, 5, 6). Since the first description of the syndrome, more than 200 patients have been reported in the world literature, and new components of the syndrome have been identified (7, 8, 9).

Carney complex shares components of its endocrine and skin pathology with the familial multiple endocrine neoplasias, lentiginoses (Peutz-Jeghers syndrome and others), and the McCune-Albright syndrome (MAS) (10, 11). The genetic defect responsible for Carney complex remains elusive, but its locus in the human genome was recently identified (11, 12). Studies of tumors excised from affected patients have indicated that the molecular abnormality may be a gain of function mutation, analogous to those occurring in the ret protooncogene and the stimulatory -subunit of the guanine nucleotide-binding protein (G_s) gene in multiple endocrine neoplasia types IIA and IIB, and MAS, respectively (13).

The thyroid gland is affected in almost all conditions with which Carney complex has similarities (14); its involvement in the complex was probable from the results of a review of 51 patients with this disease; five (10%) had thyroid lesion(s), including a carcinoma (11). It was also recently suggested that "patients with Carney complex may have a greater expression of differentiated thyroid carcinoma than would be expected by chance, although this has not been specifically quantified" (15).

In the present study, two Carney complex patients with thyroid carcinoma and one with a benign follicular adenoma were reviewed retrospectively. Screening of affected members of their families and of patients with sporadic disease provided evidence that thyroid gland pathology was common in patients with Carney complex despite clinical and biochemical euthyroidism. Importantly, thyroid carcinoma developed in these patients in a background of a variety of follicular lesions, indicating the need for careful and frequent evaluations of the thyroid gland of affected patients.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients

The institutional review boards of NICHHD, NIH, and the Mayo Clinic approved the contact of families with Carney complex and the participation of patients and their relatives in the present study, after giving informed consent (protocol 95-CH-0059). All patients were seen by two of the authors (C.A.S. and J.A.C.). A complete description of the 51 affected individuals from 11 kindreds has been published (11). Kindred CAR.110 was reported previously (16). The medical records, thyroid ultrasonographic and other radiological studies, and tissue specimens of two patients with thyroid carcinoma and one with a large follicular adenoma from three unrelated kindreds (CAR.01, CAR.110, and CAR.102, respectively) were reviewed retrospectively (one had been treated at the NIH, and the remaining two at other institutions). The relatives of the three probands were screened for the presence of Carney complex manifestations according to the criteria set by Stratakis et al. (11). Tissue slides from thyroidectomies and/or lobectomies and biopsies were reviewed by one of the authors (J.A.C.) for confirmation of the diagnosis. Three patients from family CAR.01, one from family CAR.110, two from family CAR.102, and five other patients without any family history of Carney complex (sporadic cases), were enrolled in the prospective study (Table 1). When available, relatives of patients with sporadic disease underwent physical examination by one of the authors (C.A.S.); none had stigmata of the complex. There was no history of exposure to head or neck irradiation in any of the patients.

Each patient underwent physical examination and ultrasonography (US) of the thyroid gland at least annually. If a lesion was present, biannual evaluation was undertaken. Serum total and free T₄, T₃, and TSH levels were determined during each of the follow-up visits. The follow-up time of the 11 patients studied prospectively was 1.7 \ 0.13 yr (Table 1).

US was performed with a linear 5.0- or 7.5-MHz transducer. The patients were positioned supine with the neck hyperextended on a neck roll and were scanned in both the longitudinal and transverse planes. Images were recorded on film. The lesion echogenicity was compared with that of the normal thyroid parenchyma and characterized as isoechoic, hypoechoic, hyperechoic, or mixed. The images were read independently by three radiologists (N.A.C., J.L.D., and T.S.).

A fine needle aspiration (FNA) biopsy was performed in the three index cases with thyroid carcinoma (n = 2) and follicular adenoma (n = 1) and in two of the screened patients who were euthyroid but had thyroid lesions identified by US that grew during the follow-up period. The procedure was performed under US guidance using a 21-gauge needle and under local or general (in the case of a child) anesthesia as previously described (17). Other studies (thyroid autoantibodies and uptake studies) were obtained when clinically indicated according to standard protocols.

Thyroid function assays

Serum T₄ was measured by a fluorescence polarization immunoassay (TDxFLx, Abbott Laboratories, North Chicago, IL). Free T₄ was determined by a direct (nondialysis) RIA (Incstar Co., Stillwater, MN) and/or a nonisotopic chemiluminescent immunoradiometric (IRMA) assay (Sanofi-Pasteur Diagnostics, Chaska, MN). TSH was measured by an IRMA (MAI clone, Serono Diagnostics, Milan, Italy). The sensitivity of the assay was 0.01 IU/mL. T₃ and T₄-binding globulin were measured by RIA [Quanticoat (Kallestad Diagnostics, Chaska, MN) and Immophase (Corning, Medfield, CA), respectively]. The titers of antithyroid gland antibodies (antimicrosomal, antithyroglobulin, antiperoxidase, and thyroid-stimulating Igs) and thyroglobulin levels were determined by commercially available kits [Thymune, Murex Diagnostics (Norcross, GA) and Smith-Kline (London, UK), respectively].

Histopathology

Tissue fixed in formalin-acetic acid-alcohol was paraffin embedded, sectioned, and stained with hematoxylin and eosin, according to standard protocols. The lesions identified pathologically were classified according to the current WHO classification system (17, 18).

Statistical analysis

All data are expressed as the mean \ SE. Statistical comparisons were made by Student’s t test, ² test, and/or Fisher’s analysis; P < 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Review of Carney complex kindreds

In our review of 53 patients with Carney complex from 12 unrelated kindreds, 6 individuals with thyroid pathology were identified (11.3%; 5 reported in Ref. 11; patient 2 of this report is an additional case). Three of these patients were available for further investigation; their sonographic and pathological findings were reviewed. Among their relatives, 6 were affected with Carney complex and had thyroid gland investigation. In addition, 5 patients with the sporadic form of the disorder were screened for thyroid disease (Table 1).

Case reviews (patients 1–3)

Patient 1 had a single thyroid nodule involving the lower right lobe and the isthmus of the gland at age 30 yr. Sonography identified a hypoechoic nodule (10 x 6 x 8 mm) at the isthmus, and two smaller hypoechoic lesions were seen at the upper pole of the left lobe (6 x 7 x 6 mm) and at the lower pole of the right lobe (5 x 5 x 6 mm), respectively. FNA biopsy of the largest lesion revealed findings suggestive of follicular variant papillary thyroid carcinoma (PTC). The patient underwent thyroidectomy; there were multiple foci of PTC throughout both lobes and invading the adjacent lymph nodes. The patient received radioiodine treatment; she has been disease-free for 8 yr postoperatively.

Patient 2 presented with thyroid gland enlargement at age 28 yr. Sonography revealed two small hypoechoic areas, one in each lobe. The study was repeated a year later, and multiple nodules were demonstrated. An uptake study revealed a nonfunctioning nodule on the lower pole of the right lobe; FNA biopsy results were suggestive of a follicular adenoma (Fig. 1A). Because of continued growth, the lesion was rebiopsied; findings were consistent with follicular thyroid carcinoma (FTC). The patient underwent thyroidectomy, which confirmed the diagnosis of FTC with vascular invasion (Fig. 1B). Postoperatively she received radioiodine treatment and has remained disease-free for 5 yr.

View larger version (202K): [in this window] [in a new window]   Figure 1. Thyroid lesions in a patient with Carney complex (patient 2, Table 1). A, Hematoxylin and eosin staining of an adenomatous nodule (x20). B, Follicular thyroid carcinoma (thyroglobulin-positive cells; magnification, x400).

Thyroid function and ultrasonography in familial and sporadic cases

The clinical, biochemical, and sonographic findings of the individuals studied are listed in Table 2. All patients were clinically and biochemically euthyroid. Thyroid autoantibodies were not detected. Among the 11 patients studied prospectively, only 1 (patient 7) had a single right-sided thyroid nodule on physical examination (9%).

Sonography revealed a normal sized thyroid gland in 12 of the 14 patients, including 1 of the 2 patients with cancer (patient 1). Overall, 21 lesions were detected, 8 and 13 in the right and left lobes, respectively (Fig. 2). The lesions appeared as round, well defined hypoechoic areas measuring from 1.5–6.3 mm [mean, 3.66 \ 2.04 (\SD) mm]. Eighteen of the lesions (85.7%) had internal echoes that were suggestive of a solid nodule, whereas 3 (14.3%) appeared cystic. Four patients had unilateral lesions; in the remaining patients, the lesions were bilateral. Most of the abnormalities (10 of the 21 lesions; 47.6%) were located in the lower poles of the two lobes; of the remaining lesions, 6 (28.6%) were identified in the upper poles, 4 (19%) in the middle level, and 1 in the isthmus (4.8%).

View larger version (102K): [in this window] [in a new window]   Figure 2. Ultrasonographic abnormalities of the thyroid gland in patients with Carney complex. Panels 1 and 5 represent sagittal views of the gland, whereas panels 2–4 are transverse views. Panel 1, A hypoechoic lesion (6 x 7 x 6 mm) is indicated by the arrow; it was located in the upper pole of the left lobe (patient 1). FNA biopsy was consistent with PTC, follicular variant. Lane 2, A round (10-mm) lesion in the right lobe is shown (patient 4); FNA biopsy was consistent with a follicular adenoma. 3. A 3-mm hypoechoic lesion was seen in the upper pole of the left lobe (patient 8). 4) A 5 x 7 mm lesion with mixed echogenicity in the right lobe is shown (patient 7); FNA biopsy revealed an atypical cellular pattern with follicular and Hurthle cells. 5. Two round (1.5 mm) lesions are shown in the lower pole of the left lobe (patient 10). CA, carotid artery; JV, jugular vein.

Thyroid gland histopathology

Two of the seven individuals with Carney complex that had thyroid lesions by sonographic screening underwent FNA biopsy. Patient 4 had multiple nodules; FNA findings were consistent with a benign follicular adenoma. Patient 7 had a thyroid nodule smaller than 3 mm detected at age 10 yr; a year later, the same nodule measured 5 x 7 mm (Fig. 2, panel 4) and was accompanied by two additional lesions. FNA biopsy revealed multiple Hürthle and atypical follicular cells; he underwent right hemithyroidectomy, which confirmed the presence of multiple follicular adenomatous changes with numerous Hürthle cells. With the exception of patient 5, the remaining individuals (patients 8, 11, 13, and 14) had small lesions (<3 mm; Fig. 2, panels 3 and 5) and did not undergo FNA biopsy; they are being followed biannually by clinical and sonographic examinations.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Thyroid pathology was thought to be present rarely in association with Carney complex (1, 11, 14, 15). Among 53 individuals affected with Carney complex from 12 unrelated kindreds, 6 patients with thyroid disease were identified (11%). Three of these subjects were studied in detail, 2 with thyroid carcinoma and 1 with a benign follicular adenoma. Despite clinical and biochemical euthyroidism, ultrasonography revealed abnormalities of the gland in 66% of the screened relatives affected with the complex. The same study demonstrated thyroid gland lesions in 60% of the patients with the sporadic form of the complex, who had no previous record of thyroid disease.

Several lines of evidence suggest that the identified thyroid gland abnormalities constitute a component of Carney complex in the patients studied. First, the frequency of thyroid lesions in these patients (66%) was significantly higher than that reported in healthy individuals. In the general population, the application of high resolution sonography has revealed unsuspected nodules in 20–44% of women and 17–19% of men, although the imaging equipment and data analysis in these studies vary considerably (19, 20, 21, 22, 23). Second, 4 of the 6 children and adolescents with the complex (67%) had thyroid nodules detected by ultrasonography, whereas similar lesions were found in only 0.05–1.8% of children in a large series (15, 20, 21, 22, 23, 24, 25). Third, our review of 59 unaffected members of the same kindreds with Carney complex did not reveal any subjects with history of thyroid disease; 2 of these individuals (the sisters of patients 1 and 7, in kindreds CAR.01 and CAR.110, respectively) were screened by the current protocol and did not have any thyroid lesions (data not shown). Fourth, thyroid pathology in our patients was often multifocal and/or bilateral and was inherited in a manner consistent with autosomal dominant transmission, both features of the complex (1, 2, 3).

The occurrence of thyroid carcinoma in patients with Carney complex is of particular interest, because this disorder is rarely associated with malignant lesions (1, 8, 11). The overall incidence of thyroid cancer in the general population is between 1–10/100,000 (15, 26, 27). Among 53 patients with the complex, 2 were identified with thyroid cancer (3.8%). Both patients presented at a relatively young age with invasive disease. Accordingly, a patient with the complex presented with extensive PTC at age 19 yr (28), and another underwent thyroidectomy at age 13 yr for a rapidly growing neoplasm (29). This is consistent with other reports of familial nonmedullary thyroid cancer (FNMTC), which appears to be present at a younger age and to have a high incidence of multifocality, invasion, and local recurrence (30, 31, 32).

Although FNMTC can occur without any other associated lesions, it is frequently present in kindreds with familial adenomatous polyposis (Gardner’s syndrome), Peutz-Jeghers syndrome, and Cowden disease, all autosomal dominant conditions that share features with Carney complex (10, 15, 30). A spectrum of lesions has been observed in FNMTC (PTC, FTC, Hürthle cell carcinoma, and anaplastic carcinoma) (30, 31, 32), although PTC appears to be more frequent (26, 27). Histologically, thyroid carcinomas in familial adenomatous polyposis, like those associated with Carney complex, differ from their sporadic counterparts and are characterized by multicentricity and unusual aggressiveness (33). Recently, genetic susceptibility for FNMTC was suggested (34), and two large kindreds with this disease were described (35).

The sonographic features of the thyroid lesions associated with Carney complex (typically small when first detected; hypoechoic, solid, cystic, or mixed lesions surrounded by tissue of normal texture) are reminiscent of those observed in the thyroid glands of patients with MAS, a condition that bears substantial similarities with the complex (10, 36). MAS patients, however, have abnormal thyroid function in as many as 42% of the cases and do not appear to have an increased incidence of thyroid cancer (36). Activating mutations of the G_s subunit are responsible for the phenotype in MAS patients (37) and have been associated with the formation of sporadic thyroid adenomas (38). However, the genetic locus of Carney complex is different from that of the G_s gene, and mutations of the latter were not found in myxomas and other tumors associated with the complex, including a thyroid carcinoma (patient 1 in this report) (11, 39).

The thyroid gland abnormalities identified in patients with Carney complex were of follicular origin, but their histopathology covered a wide spectrum of changes. Interestingly, cancer developed in two of the patients who had multifocal and/or bilateral disease (patients 1 and 2). In addition, during the short follow-up of this study, we observed the development of new lesions in five of our patients (patients 5, 7, 11, 13, and 14). Thus, thyroid disease in Carney complex may be progressive and follow the adenoma-carcinoma sequence that has been described in familial hamartoses (40, 41). This idea receives support from the high rate of genomic instability among tumors from patients with Carney complex (13). We speculate that thyroid abnormalities differ from the other components of Carney complex in their rate of malignancy, because they reflect downstream genetic effects of a gain of function mutation; as the number of additional events in the process of oncogenesis increases, the impact of the germ-line mutation diminishes (42).

In conclusion, our study documents the presence of thyroid pathology in patients with Carney complex and demonstrates the many parallels that exist between these abnormalities and other genetic diseases that affect the thyroid gland, including FNMTC. An important clinical implication of the present investigation is that patients with the complex should be frequently screened by US for the presence of thyroid lesions and the early identification of possible thyroid cancer.

Received December 12, 1996.

Revised February 20, 1997.

Accepted April 8, 1997.

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