Carpenter, Paul C.

AbstractBackgroundCushing’s syndrome (CS), due to multiple etiologies, is a disorder associated with the ravages of cortisol excess. The purpose of this review article is to provide a historical synopsis of surgery for CS, review a recent 10‐year period of operative management at a tertiary care facility, and to outline a practical approach to diagnosis and management.Materials and MethodsFrom 1996 to 2005, 298 patients underwent 322 operative procedures for CS at Mayo Clinic, Rochester, Minnesota. A retrospective chart review was carried out. Data was gathered regarding demographics, preoperative assessment, procedures performed, and outcomes. Data are presented as counts and percentages. Five‐year survival rates were calculated where applicable by the Kaplan‐Meier method. Statistical analysis was carried out with SAS, version 9 (SAS Institute, Inc., Cary, NC).ResultsTwo‐hundred thirty‐one patients (78%) had ACTH‐dependent CS and 67 patients (22%) had ACTH‐independent CS. One‐hundred ninety‐six patients (66%) had pituitary‐dependent CS and 35 patients (12%) had ectopic ACTH syndrome. Fifty‐four patients (18%) had cortisol‐secreting adenomas, 10 patients (3%) had cortisol‐producing adrenocortical carcinomas, and 1% had other causes. Cure rates for first time pituitary operations (transsphenoidal, sublabial, and endonasal) were 80% and 55% for reoperations. Most benign adrenal processes could be managed laparoscopically. Five‐year survival rates (all causes) were 90%, 51%, and 23% for adrenocortical adenomas, ectopic ACTH syndrome, and adrenocortical carcinomas, respectively.ConclusionsSurgery for CS is highly successful for pituitary‐dependent CS and most ACTH‐independent adrenal causes. Bilateral total adrenalectomy can also provide effective palliation from the ravages of hypercortisolism in patients with ectopic ACTH syndrome and for those who have failed transsphenoidal surgery. Unfortunately, to date, adrenocortical carcinomas are rarely cured. Future successes with this disease will likely depend on a better understanding of tumor biology, more effective adjuvant therapies and earlier detection. Clearly, IPSS, advances in cross‐sectional imaging, along with developments in transsphenoidal and laparoscopic surgery, have had the greatest impact on today’s management of the complex patient with CS.

Abstract Background Management of patients with bilateral adrenal masses and corticotropin (ACTH)‐independent Cushing syndrome (CS) or subclinical CS is problematic. We report our experience with adrenal venous sampling (AVS) in the evaluation of 10 patients with bilateral masses who had ACTH‐independent CS or subclinical CS. Patients and Methods Ten patients (9 women, 1 man, mean age 56.4 years) with bilateral adrenal masses and ACTH‐independent CS ( n = 3) or subclinical CS ( n = 7) underwent AVS. Autonomous cortisol secretion was documented in all cases with suppressed serum ACTH concentrations and lack of cortisol suppression with dexamethasone administration. Adrenal venous sampling was performed on the second day of dexamethasone administration. Cortisol and epinephrine levels were measured from each adrenal vein (AV) and from a peripheral vein (PV). Results Mean (± SD) maximal diameter of the adrenal masses on computed tomography was 3.3 ± 1.3 cm (range: 1.2–6.0 cm). Successful catheterization was confirmed with AV:PV epinephrine gradients. A cortisol AV:PV gradient >6.5 was consistent with a cortisol‐secreting adenoma in 11 adrenal glands; 5 patients had clinically important bilateral autonomous cortisol hypersecretion, 3 had bilateral cortisol‐secreting adenomas, and 2 had ACTH‐independent macronodular adrenal hyperplasia. Adrenal venous sampling‐guided adrenalectomy was completed in all 10 patients—2 patients had total bilateral adrenalectomy and 2 others had subtotal bilateral adrenalectomy. During a mean follow‐up of 36.1 months (range: 0.7–123 months), CS or clinically important cortisol secretory autonomy did not recur. Conclusions Adrenal venous sampling contributed to the localization of autonomous hypercortisolism in the setting of ACTH‐independent CS or subclinical CS in patients with bilateral adrenal masses.

Abstract Inhaled glucocorticosteroids (ICS) are commonly prescribed for chronic obstructive pulmonary disease. No adverse effect on bone mineral density (BMD) has been proven. In a randomized double-blind, placebo-controlled trial at seven centers in North America, we recruited 412 current smokers or recent quitters with mild to moderate chronic obstructive pulmonary disease. They used inhaled triamcinolone acetonide, 600 mcg, or placebo, twice daily. We measured femoral neck and lumbar spine BMD at baseline and after 1 and 3 years, and serum osteocalcin at baseline, 3 months, 1 year, and 3 years. After 3 years, BMD at the femoral neck decreased 1.78% more with ICS than with placebo (p < 0.001). More participants in the ICS group experienced 6% or more loss of femoral neck BMD (p = 0.002). Lumbar spine BMD increased in the placebo group by 0.98% but decreased by 0.35% in the ICS group (a difference of 1.33%, p = 0.007). Changes in osteocalcin did not correlate with changes in BMD. Fractures, lost height, or osteoporosis diagnoses were not increased among ICS users compared with placebo users. In summary, the use of inhaled triamcinolone acetonide was associated with loss of BMD at the femoral neck and lumbar spine after 3 years of treatment.

Abstract OBJECTIVE To evaluate tumor control rates and complications after stereotactic radiosurgery for patients with nonfunctioning pituitary adenomas. METHODS Between 1992 and 2000, 33 patients underwent radiosurgery for treatment of nonfunctioning pituitary adenomas. Thirty-two patients (97%) had undergone one or more previous tumor resections. Twenty-two patients (67%) had enlarging tumors before radiosurgery. The median tumor margin dose was 16 Gy (range, 12–20 Gy). The median follow-up period after radiosurgery was 43 months (range, 16–106 mo). RESULTS Tumor size decreased for 16 patients, remained unchanged for 16 patients, and increased for 1 patient. The actuarial tumor growth control rates at 2 and 5 years after radiosurgery were 97%. No patient demonstrated any decline in visual function. Five of 18 patients (28%) with anterior pituitary function before radiosurgery developed new deficits, at a median of 24 months after radiosurgery. The actuarial risks of developing new anterior pituitary deficits were 18 and 41% at 2 and 5 years, respectively. No patient developed diabetes insipidus. CONCLUSION Stereotactic radiosurgery safely provides a high tumor control rate for patients with recurrent or residual nonfunctioning pituitary adenomas. However, despite encouraging early results, more long-term information is needed to determine whether radiosurgery is associated with lower risks of new endocrine deficits and radiation-induced neoplasms, compared with fractionated radiotherapy.

Abstract 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.