Adrenocortical carcinoma is a rare tumor, and only limited information is available about its natural history and the effects of therapy. We studied 105 patients (75 female and 30 male; mean age, 46 years) with adrenocortical carcinoma who were referred to us between 1963 and 1987. The average duration of symptoms before diagnosis was 8.7 months. At the time of diagnosis, 68 percent of the patients had endocrine symptoms, and 30 percent had distant metastases. Hormonal studies showed that 79 percent of the tumors were functional. Eighty patients underwent surgery, and 59 also received the adrenal cytotoxic agent mitotane. The median disease-free interval after surgery was 12.1 months (range, 1 to 175). Tumor dissemination occurred in 82 percent of the patients, most commonly to the lung, liver, and adjacent organs. The median survival time was 14.5 months (range, less than 1 to 175), and the five-year survival was 22 percent. Age over 40 years and the presence of metastases at the time of diagnosis were the only factors recognized as indicating a poor prognosis. Mitotane controlled hormonal secretion in 75 percent of the patients. Eight mitotane-treated patients had partial tumor regression, but the drug did not have a significant effect on survival. We conclude that adrenocortical carcinoma carries a poor prognosis. Mitotane therapy may offer transient benefits, particularly in controlling endocrine symptoms.

The salivary cortisol concentration is an excellent indicator of the plasma free cortisol concentration. To establish its normal and pathological ranges, salivary cortisol concentrations were measured in 101 normal adults, 18 patients with Cushing's syndrome, and 21 patients with adrenal insufficiency. The normal subjects had a mean (+/- SEM) salivary cortisol concentration of 15.5 +/- 0.8 nmol/L (range, 10.2-27.3) at 0800 h and 3.9 +/- 0.2 nmol/L (range, 2.2-4.1) at 2000 h (n = 20). The mean value 60 min after ACTH administration in 58 normal subjects was 52.2 +/- 2.2 nmol/L (range, 23.5-99.4), and it was 1.4 +/- 1.1 nmol/L (range, 1.6-3) at 0800 h in 23 normal subjects given 1 mg dexamethasone 8 h earlier. In patients with primary or secondary adrenal insufficiency (n = 21) the mean salivary cortisol level was 7.5 +/- 0.4 nmol/L (range, 1.9-21.8) 60 min after ACTH. In patients with Cushing's syndrome (n = 7), the mean value after the 1-mg dexamethasone suppression test was 16.1 +/- 7.8 nmol/L (range, 5.8-66.8). No overlap was found between the values in the normal subjects and those in the patients during the dynamic tests. Discrepancies between salivary and total plasma cortisol were found in 8 patients with adrenal insufficiency, which may be explained by the effects of drugs such as thyroid hormones, Op'-dichlorodiphenyldichloroethane, and psychotropic agents. We conclude that salivary cortisol measurements are an excellent index of plasma free cortisol concentrations. They circumvent the physiological, pathological, and pharmacological changes due to corticosteroid-binding globulin alterations and offer a practical approach to assess pituitary-adrenal function.

Transsphenoidal pituitary surgery was performed in 64 patients with Cushing's disease in search of a corticotroph adenoma. In 4 patients, profuse local bleeding prevented completion of the exploration. Of the 60 patients who had an adequate exploration, 4 could not be followed after surgery. Short term assessment of the surgical outcome (3-6 months postoperatively) was performed on 60 patients, including the 4 who had incomplete pituitary exploration. Forty-two patients (70%) were judged as immediate successes [urinary cortisol excretion, less than 90 micrograms (less than 248 nmol)/day]; the mean urinary cortisol excretion and plasma ACTH level fell from 463 +/- 70 (+/- SE) to 26.7 +/- 3.6 micrograms/day (1277 +/- 193 to 74 +/- 10 nmol/day; n = 33) and from 111 +/- 33 to 36 +/- 14 pg/mL (24 +/- 7 to 8 +/- 3 pmol/L; n = 23) in patients who had both measurements pre- and postoperatively. Eighteen patients (30%) were judged as immediate failures; neither urinary cortisol excretion nor plasma ACTH levels changed significantly in patients who had both measurements pre- and postoperatively. The preoperative epidemiological, clinical, hormonal, and radiological characteristics of the 2 groups were similar. Histological examination of pituitary fragments removed in 58 of the 60 patients evaluated postoperatively revealed the presence of tumoral tissue in a higher percentage of patients in the immediate success group (72%) than in the immediate failure group (24%; P less than 0.01). The 42 patients in the immediate success group were followed from 6 months to 7 yr (median, 2 yr); 6 patients had recurrences from 2-3 yr after operation. Actuarial analysis indicates that the probability of a patient remaining well 6 yr after surgery is 72 +/- 20% (95% confidence limit). Most of the patients in the immediate success group had transient ACTH deficiency preceding a progressive return to normal pituitary-adrenal function.