The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4565-4568
Copyright © 2003 by The Endocrine Society
Cushing’s Syndrome Due to Medullary Thyroid Carcinoma: Diagnosis by Proopiomelanocortin Messenger Ribonucleic Acid in Situ Hybridization
R. C. Smallridge,
K. Bourne,
B. W. Pearson,
J. A. van Heerden,
P. C. Carpenter and
W. F. Young
Division of Endocrinology (R.C.S.), and Department of Otorhinolaryngology (B.W.P.), Mayo Clinic, Jacksonville, Florida 32224; Orlando Diabetes and Endocrine Specialists (K.B.), Orlando, Florida 32835; and Department of General Surgery (J.A.v.H.) and Divisions of Endocrinology, Metabolism, and Nutrition (P.C.C., W.F.Y.), Mayo Clinic, Rochester, Minnesota 55905
Address correspondence to: R. C. Smallridge, M.D., Division of Endocrinology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224. E-mail: smallridge.robert{at}mayo.edu.
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Abstract
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Medullary thyroid carcinoma (MTC) rarely causes ectopic ACTH syndrome. We describe a 38-yr-old man with renal stones who had a 5-cm MTC removed in 1992. He was RET-protooncogene positive (codon 618). Serum calcitonin was 1597 pg/ml postoperatively. In 1996 he had rib fractures, bruising, weakness, and three to four stools per day. Laboratory studies revealed an elevated 24-h urine-free cortisol (780 µg/d), epinephrine (66 µg/d), and calcium (558 mg/d). Baseline serum cortisol was 23.9 µg/dl and decreased to 12.9 and 4.5 µg/dl after 2 mg and 8 mg dexamethasone suppression, respectively. Plasma ACTH was 170 pg/ml and decreased to 75 and 24 pg/ml after dexamethasone. Bone density t-score was -4.3 (trochanter). Computed tomography scans showed multiple cervical nodes and 2-cm right adrenal nodule. Magnetic resonance imaging (MRI) scan showed a prominent, homogeneous pituitary; the adrenal MRI scan was not typical for a pheochromocytoma. Serum CRH was less than 6.6 pg/ml. Bilateral adrenalectomy revealed two adjacent right adrenal pheochromocytomas and corrected the elevated urine cortisol (30 µg/d), epinephrine (0 µg/d), and calcium (281 mg/d) but not plasma ACTH (125 pg/ml). Neck dissection reduced calcitonin by 96% (5300 to 120 pg/ml) and ACTH by 91% (125 to 11 pg/ml). Carcinoembryonic antigen was reduced from 32.0 to 2.3 ng/ml. Immunohistochemical stain was negative for ACTH in the MTC-positive lymph nodes and the pheochromocytoma. Proopiomelanocortin mRNA by in situ hybridization was positive in the MTC but not in the pheochromocytoma. A repeat pituitary MRI scan was normal. The differential diagnosis of ACTH-dependent Cushing’s syndrome in this case included pituitary disease or ectopic ACTH, either from medullary thyroid carcinoma or pheochromocytoma. ACTH stains were unrevealing, but proopiomelanocortin mRNA in situ hybridization in MTC tissue and plasma ACTH response to neck dissection confirmed MTC as the source of ectopic ACTH.
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Introduction
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CUSHING’S SYNDROME (CS) IS classified as ACTH dependent or ACTH independent. The former includes pituitary-dependent Cushing’s disease and ectopic ACTH secretion. Bronchial carcinoid tumors and primary lung cancer most commonly cause ectopic ACTH secretion, but a number of other neoplasms also produce ACTH, including medullary thyroid carcinoma (MTC) and pheochromocytoma. Elevated plasma levels of ACTH distinguish ACTH-dependent causes of CS from adrenal cortical neoplasms. However, ectopic sources of ACTH may preferentially secrete an ACTH precursor (1, 2, 3).
We report the case of a 38-yr-old man who presented to the Mayo Clinic in March 1996 with a history of metastatic MTC, residual locoregional metastases, and the recent onset of moderately severe ACTH-dependent CS. Preoperative imaging studies included a pituitary magnetic resonance imaging (MRI) scan showing mild homogeneous pituitary enlargement and abdominal computerized tomography (CT) and MRI scans demonstrating a right adrenal nodule. The etiology of his CS was aided by in situ hybridization (ISH) studies, which identified proopiomelanocortin (POMC) mRNA but not ACTH, by immunostain in the MTC.
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Case Report
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A 34-yr-old man underwent thyroidectomy in 1992 for a painful 5 x 3 x 3-cm right thyroid nodule. He had a history 8 yr earlier of bilateral renal stones. At the time of thyroid surgery, serum calcium was 10.3 mg/dl. Pathology revealed MTC and two hyperplastic parathyroid glands. Postoperatively, calcitonin levels ranged from 2500–4700 pg/ml and carcinoembryonic antigen of 37.6 ng/ml. Genetic testing detected a mutation in exon 10, codon 618 (TGC 
CGG) in the RET protooncogene. His mother, sister, and a nephew also had MTC.
In March 1996, the patient was referred to Mayo Clinic, Jacksonville, Florida, with symptoms of muscle weakness, easy bruising, skin rash, hyperdefecation, and multiple rib fractures. His blood pressure was 134/100 mm Hg; he had a Cushingoid appearance with an erythematous scaly dermatitis of his buttocks, chest, abdomen, and arms, and palpable cervical lymph nodes. His muscle strength was mildly decreased.
The patient’s laboratory studies before and after two surgical procedures are depicted in Table 1
. He had elevated urine cortisol, epinephrine, and calcium levels. Plasma cortisol and ACTH were elevated, with partial suppression after low-dose dexamethasone (2 mg/d x 2 d) and normal suppression after a high dose (8 mg/d x 2 d). He had severe osteoporosis, with a t score of -4.3 in his left trochanter.
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TABLE 1. Laboratory studies before and after neck and adrenal gland surgeries in a man with multiple endocrine neoplasia IIA and Cushing’s syndrome
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A CT scan of the patient’s neck showed multiple enlarged cervical nodes (Fig. 1, left). Adrenal imaging showed a 2-cm right adrenal nodule on CT scan (Fig. 1, middle). This nodule showed some increased intensity on MRI but was not classic for a pheochromocytoma (Fig. 1, right). A pituitary MRI scan showed a prominent homogeneous pituitary gland.
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FIG. 1. Left, CT scan of the neck demonstrates residual medullary thyroid carcinoma in multiple lymph nodes (arrows) in a 38-yr-old man with CS. Middle, An adrenal CT scan illustrates (arrow) a 2-cm right pheochromocytoma. Right, An adrenal MRI scan shows some increased intensity in the right adrenal but not a classic image of pheochromocytoma
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The differential diagnosis of this patient’s ACTH-dependent CS most likely was due to ectopic ACTH secretion from his pheochromocytoma or MTC or possibly from a pituitary microadenoma. Inferior petrosal sinus sampling was not performed because a gradient would not have distinguished pituitary ACTH secretion from ectopic CRH production. Because of the severity of his CS and the multiple potential causes, laparoscopic bilateral adrenalectomy (J.A.v.H.) was performed. Histopathology demonstrated two adjacent pheochromocytomas in the right adrenal gland. Postoperatively, the patient’s urinary cortisol, epinephrine, and calcium were no longer elevated (Table 1
), but plasma ACTH remained high.
The patient subsequently underwent a neck dissection (B.W.P.) at Mayo Clinic (Jacksonville, FL) with removal of multiple lymph nodes containing MTC (Fig. 2A). Postoperatively, calcitonin and ACTH levels decreased by 96% and 91%, respectively. A follow-up pituitary MRI scan showed a less prominent gland.
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FIG. 2. Histologic findings in a 38-yr-old man with medullary thyroid carcinoma and CS. A, Hematoxylin and eosin stain of a cervical lymph node showing pinkish material consistent with amyloid. B, POMC mRNA appears as cytoplasmic blue material by ISH in lymph node containing MTC. C, POMC mRNA by ISH is not detectable in the adrenal pheochromocytoma
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Special stains were performed to aid in localizing the source of ACTH production. ACTH immunohistochemistry was done as previously reported (4). The ACTH antibody, used at a 1:500 dilution, was from DAKO (Carpinteria, CA). Immunostaining was done with the avidin biotin complex peroxidase method. Normal pituitary tissue was used as the positive control. Substitution of normal rabbit serum for the primary antibody was used as the negative control. ISH for POMC was done with oligonucleotide probes (5). Digoxigenin-labeled probes were used with a recently reported method (6). Formalin-fixed, paraffin-embedded tissues were used for ISH. Normal pituitary was used as a positive control. A digoxigenin-labeled calcitonin oligonucleotide probe was used as a negative control.
Although the serologic response strongly suggested that MTC tissue was responsible, immunohistochemical stains for ACTH were negative in both the adrenal and thyroid tumors (data not shown). In contrast, POMC mRNA was detected by ISH in the MTC tissue (Fig. 2B) but not in the pheochromocytoma (Fig. 2C).
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Discussion
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CS caused by ectopic ACTH, ACTH/CRH, or CRH secretion may be difficult to distinguish from pituitary-dependent Cushing’s disease. Wajchenberg et al. (1) reviewed the clinical features in three series of ectopic ACTH syndrome as follows: classical Cushingoid features (60–100%), weight gain (44–70%), hypertension (62–92%), edema (55–60%), hyperpigmentation (32–56%), and personality changes (34–62%). They noted a spectrum of presentations in patients with ACTH/CRH production, with some cases resembling ACTH tumors and others pituitary-dependent disease (1). Laboratory features also overlapped, with 30–41% of ectopic ACTH disorders being suppressible to dexamethasone (especially bronchial carcinoids) and up to 25% of pituitary tumors not responding (1). Furthermore, patients whose tumors secrete CRH may respond to exogenous CRH in a manner similar to patients harboring pituitary tumors (1).
Not only is there similarity of clinical and laboratory findings across the various ACTH-dependent disorders, but there is also considerable similarity of tumor types among the nonpituitary ACTH-dependent syndromes (Table 2).
CS caused by ectopic ACTH and/or CRH secretion most often is due to intrathoracic lesions (bronchial or thymic carcinoids; lung carcinoma), but endocrine tumors have been responsible in a small percentage of cases (1). Wajchenberg et al. (1) reported that 2–25% of overt cases were caused by pheochromocytomas, but only 2–6% were due to medullary thyroid carcinomas. Martinez Diaz-Guerra et al. (7) reviewed the literature and identified 44 cases of CS caused by MTC. Mure et al. (8) reported four cases in patients with distant metastases. These four patients were from their total experience of 184 MTC patients, 50 of whom had distant metastases, and three or four underwent bilateral adrenalectomies to control their CS. Barbosa et al. (9) documented CS caused by MTC in only 10 of 1380 (0.07%) MTC cases. Individual cases have been reported (10, 11), as has one multiple endocrine neoplasia II-B patient with MTC and ectopic CRH secretion (12).
Our case demonstrates the difficulty that can be encountered in identifying the source of ACTH secretion in some patients. The patient had a mild homogeneous increase in pituitary size. Although we cannot definitely exclude an ectopic source of CRH causing pituitary hyperplasia, this possibility was considered unlikely because plasma CRH was less than 6 pg/ml (kindly measured by Dr. George Chrousos, National Institutes of Health), and plasma CRH is detectable or elevated in reported cases of ectopic CRH secretion (1). He also had MTC and pheochromocytoma, both of which may secrete ACTH (Table 2). The inability in this case to detect ACTH by immunostain might be due to the tendency of extrapituitary tumors to produce increased amounts of ACTH precursors (big ACTH) (1, 2, 3, 13). In one series, six of seven cases had negative immunostains for ACTH or CRH, despite inappropriately normal or elevated serum ACTH levels (9).
POMC gene expression is detected in normal tissues as well as benign and malignant tumors. The lack of clinical expression of CS may relate to the observation that most nonpituitary tissues express a truncated POMC mRNA (1). In some instances, patients with ectopic ACTH syndrome have a tumor-associated POMC RNA similar to that of normal pituitary, as reported for some bronchial carcinoids (14). POMC mRNA has been detected only rarely in MTC. Steenbergh et al. (15) were unable to identify this transcript in the primary tumor of six patients with multiple endocrine neoplasia-II, but metastatic lymph nodes from two patients with sporadic MTC expressed a POMC mRNA larger than that observed in pituitary tissue. In the current case, ISH of POMC mRNA was helpful (5). Not only was POMC identified in the MTC, but reduction in plasma ACTH correlated with removal of his MTC.
In summary, the differential diagnosis of CS in this case included pituitary-dependent Cushing’s disease or ectopic ACTH (or CRH) secretion from either the medullary thyroid carcinoma or pheochromocytoma. The undetectable CRH level did not support ectopic CRH secretion. Although ACTH stains were unrevealing, the positive POMC mRNA in the MTC tissue and the dramatic decrease in calcitonin and ACTH levels after neck dissection are consistent with MTC as the cause of this patient’s CS.
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Acknowledgments
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We thank Dr. Ricardo Lloyd for performing the immunohistochemical stains, Dr. George Chrousus for the plasma CRH measurement, and Darlene Gunsolus for typing the manuscript.
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Footnotes
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Abbreviations: CS, Cushing’s syndrome; CT, computerized tomography; ISH, in situ hybridization; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; POMC, proopiomelanocortin.
Received November 15, 2002.
Accepted June 27, 2003.
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References
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Abstract
Introduction
