Carney, J. Aidan

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.

AbstractIn the absence of distant disease, the pathologic diagnosis of malignancy in pheochromocytoma or paraganglioma is impossible. In an effort to establish the true incidence of recurrence in this disease, we have analyzed long‐term follow‐up (average, 15.8 years) of 98 patients who underwent complete resection of localized, noninvasive, histologically‐benign pheochromocytomas and paragangliomas at our institution between 1960 and 1976.Eighty‐eight patients had nonfamilial, sporadic pheochromoctyoma/ paraganglioma. Nine had multiple endocrine neoplasia (MEN) type 2 (2A: 7, 2B: 2), and 1 had familial pheochromocytoma. Seventy‐nine patients had single pheochromocytomas; 10 had single extraadrenal tumors (paragangliomas); and 9 had multicentric or bilateral adrenal tumors.Six patients (6.5%) developed recurrent pheochromocytoma after documentation of normal postoperative urinary catecholamine levels. One of these patients had MEN 2A. The recurrences developed at intervals from 5 to 13 years following initial resection. These were distant in 3 patients, local in 2, and both local and distant in a single patient. None of the recurrences occurred in the 13 patients who, on pathologic rereview, had either local or vascular invasion. No paraganglioma recurred.Life‐long follow‐up of all patients who have had pheochromocytomas or paragangliomas resected is mandatory.

AbstractThe etiology, prognosis, and optimal management of primary gastric carcinoids remain controversial. Records of 36 consecutive patients with gastric carcinoid (15 men) were reviewed retrospectively between 1975 and 1990. Follow‐up was complete in 97% of cases. Mean age at diagnosis was 58.4 years (range 24–82 years). The clinical presentations included anemia (72%), pain (69%), and carcinoid syndrome (11%). Associated autoimmune and endocrine abnormalities were common and included atrophic gastritis (67%), pernicious anemia (58%), hypothyroidism (39%), diabetes (19%), Addison's disease (6%), and hyperparathyroidism (6%). Lesions were nonantral in 78%, involving only the corpus in 42%, the fundus in 28%, and only the antrum in 8%; 42% were multiple. Urinary 5‐hydroxyindoleacetic acid (5‐HIAA) and serum gastrin levels were elevated in 17% and 50% of those tested, respectively. Histologic examination revealed that 28% of lesions were ≥2 cm, and 33% had liver metastases on presentation or developed them during follow‐up. Eight patients (22%) died of tumor with a median survival of 39 months. The presence of metastases, atypical histology, serosal involvement, and size > 2 cm were adverse prognostic factors. In patients without hypergastrinemia (n=6), 66% developed metastases, 60% had elevated 5‐HIAA, and 50% died of carcinoid tumor. In sharp contrast, those patients with hypergastrinemia and “typical” gastric carcinoids (n=15), metastases and death did not occur (p<0.003 and p < 0.005, respectively, compared with eugastrinemic patients). In the latter group (hypergastrinemia and typical histology), pernicious anemia was common (73%); solitary lesions and serosal penetration were seen comparatively less often (33% versus 100%, p<0.005 and 0% versus 33%, p<0.05, respectively); and no lesion measured > 2.0 cm compared to 66% in the group without elevated gastrin (p<0.002). No patient with hypergastrinaemia had elevated levels of 5‐HIAA. Overall survival at 5 and 10 years was 58% and 28%, respectively. Survival was 80% at 5 and 10 years in the hypergastrinemic group. Gastric carcinoid tumors that are histologically atypical, large (>2 cm), or present without elevated gastrin are potentially lethal and require aggressive therapy. In contrast, gastric carcinoids with typical histology and hypergastrinemia are rarely lethal, and conservative management with local excision and close observation is appropriate.

The morphology of the canine cardiac myosin molecule has been investigated in the electron microscope with Hall's mica-replica technique. The molecule is an elongated rod (shaft) of nonuniform diameter with a globular expansion (head) on one end. Statistical analysis of the lengths of 1908 molecules showed that the mean length was 1610 ± 250 A; the mean length of the head was 210 ± 20 A; and the diameter of the head and that of the shaft were 35 to 40 and 15 to 20 A, respectively. About one-third of the molecules had single or multiple, fairly sharp, angulations along their shafts. Rarely, some details of the substructure of the molecule have been observed. Large, spindle-shaped aggregates, measuring 0.5 to 1 µ in length and 50 to 100 A in diameter, were produced by dilution of the myosin solutions. These aggregates were readily visualized in the electron microscope by means of Huxley's negative-staining technique. Projections often were visible along the length of the aggregates except at a central zone where they were frequently absent. The aggregates resembled the thick myofilaments of the myocardium and appeared similar to those produced by Huxley from skeletal myosin solutions.

AbstractFunctioning extraadrenal paragangliomas represent more than 10% of all pheochromocytomas, occur at diverse anatomic locations, and are said to have a higher malignancy rate than intraadrenal pheochromocytomas. Sixty‐six patients had surgery for catecholamine‐producing paragangliomas between 1952 and 1992. Median follow‐up was 8.8 years. Median age was 40 years (11–67 years); the male/female ratio was 29:37. Familial disease occurred in 9 patients (13.6%), and 10 patients (15.2%) also developed adrenal pheochromocytoma. Solitary paragangliomas occurred in 52 patients: 46 abdominal, 4 thoracic, and 2 head and neck. Fifty‐three tumors developed in 14 patients with multiple paragangliomas: 38 abdominal and 15 thoracic. Of 28 patients with solitary tumors undergoing localization studies over the past 10 years accurate localization was achieved in 27. There was one operative death; 15 patients had persistent disease; and 50 were cured postoperatively. Of those cured, nine developed recurrence, disease‐free survival being 86%, 80%, and 80% at 5, 10, and 20 years. Metastatic disease was found in 14 patients (21%), 7 of whom have died. An additional 10 patients (15%) had locally invasive disease, of whom 4 have died. Cause‐specific survivals at 5, 10, and 20 years were 90%, 83%, and 72%. Risk factors for death from pheochromocytoma were tumor size > 5 cm (p= 0.0002), metastatic disease (p= 0.001), and tumor invasion (p= 0.0023). Cause‐specific survival for patients with tumors > 5 cm was 59% at 15 years compared to 100% among patients with tumors ≤ 5 cm (p= 0.0003). Functional paragangliomas are frequently malignant and are associated with a high incidence of persistent or recurrent disease. Tumor size > 5 cm and the occurrence of invasive or metastatic disease are strong predictors of outcome. Most tumors are abdominal, and imaging is highly successful for localization.