Journey of the iodide transporter NIS: from its molecular identification to its clinical role in cancer.

The Na+/I- symporter (NIS) is an intrinsic plasma membrane protein that mediates the active transport of I- in the thyroid, lactating mammary gland, stomach and salivary glands. The presence of NIS in the thyroid is exploited in diagnostic scintigraphic imaging and radioiodide therapy in thyroid cancer. The continued rapid progress in NIS research (aimed at the elucidation of the Na+-dependent I- transport mechanism, the analysis of NIS structure-function relations and the study of the tissue-specific regulation of NIS at all levels), holds potentially far-reaching medical applications beyond thyroid disease, in breast cancer and malignancies in other tissues.

Rapid communication: predominant intracellular overexpression of the Na(+)/I(-) symporter (NIS) in a large sampling of thyroid cancer cases.

Here we report the analysis of the Na(+)/I(-) symporter (NIS) protein expression in 57 thyroid cancer samples by immunohistochemistry with high-affinity anti-NIS Abs. As many as 70% of these samples exhibited increased NIS expression with respect to the normal surrounding thyroid tissue. Most significantly, NIS was located in these samples either in both the plasma membrane and intracellular compartments simultaneously, or exclusively in intracellular compartments. This suggests that NIS is clearly expressed or even overexpressed in most thyroid cancer cells, but malignant transformation in some of these cells interferes either with the proper targeting of NIS to the plasma membrane, or with the mechanisms that retain NIS in the plasma membrane after it has been targeted. The results further indicate that, in addition to indicating NIS expression in cases where it is absent (approximately 30%), improvements in (131)I radioablation therapy might result from promoting targeting of NIS to the plasma membrane in the majority (approximately 70%) of thyroid cancers.

[Aspergillosis of the sphenoid sinus: presentation as a pituitary mass]. / Hypophysistumor képében jelentkezó ritka kórkép: a sinus sphenoidalis invazív aspergillosisa.

A rare manifestation of aspergillosis in the central nervous system is its invasion through the sphenoidal wall into the sella turcica representing itself as a pituitary mass. The symptoms may be headache, visual defect caused by compression of the chiasma, hypopituitarism and diabetes insipidus. In the majority of cases only the postoperative histology leads to the correct diagnosis. A case of invasive aspergillosis was reported here with the clinical picture of a pituitary tumor and without underlying immunodeficiency.

The mammary gland iodide transporter is expressed during lactation and in breast cancer.

The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer.

Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology.

The Na(+)/I(-) symporter (NIS) is an intrinsic membrane protein that mediates the active transport of iodide into the thyroid and other tissues, such as salivary glands, gastric mucosa, and lactating mammary gland. NIS plays key roles in thyroid pathophysiology as the route by which iodide reaches the gland for thyroid hormone biosynthesis and as a means for diagnostic scintigraphic imaging and for radioiodide therapy in hyperthyroidism and thyroid cancer. The molecular characterization of NIS started with the 1996 isolation of a cDNA encoding rat NIS and has since continued at a rapid pace. Anti-NIS antibodies have been prepared and used to study NIS topology and its secondary structure. The biogenesis and posttranslational modifications of NIS have been examined, a thorough electrophysiological analysis of NIS has been conducted, the cDNA encoding human NIS (hNIS) has been isolated, the genomic organization of hNIS has been elucidated, the regulation of NIS by thyrotropin and I(-) has been analyzed, the regulation of NIS transcription has been studied, spontaneous NIS mutations have been identified as causes of congenital iodide transport defect resulting in hypothyroidism, the roles of NIS in thyroid cancer and thyroid autoimmune disease have been examined, and the expression and regulation of NIS in extrathyroidal tissues have been investigated. In gene therapy experiments, the rat NIS gene has been transduced into various types of human cells, which then exhibited active iodide transport and became susceptible to destruction with radioiodide. The continued molecular analysis of NIS clearly holds the potential of an even greater impact on a wide spectrum of fields, ranging from structure/function of transport proteins to the diagnosis and treatment of cancer, both in the thyroid and beyond.

Hypothyroidism in transgenic mice expressing IFN-gamma in the thyroid.

IFN-gamma has been implicated with contradictory results in the pathogenetic process of autoimmune (Hashimoto's) thyroiditis, the most common cause of hypothyroidism in adults. To test whether the local production of IFN-gamma can lead to thyroid dysfunction, we have generated transgenic mice that express constitutively IFN-gamma in the thyroid follicular cells. This expression resulted in severe hypothyroidism, with growth retardation and disruption of the thyroid architecture. The hypothyroidism derived from a profound inhibition of the expression of the sodium iodide symporter gene. Taken together, these results indicate a direct role of IFN-gamma in the thyroid dysfunction that occurs in autoimmune thyroiditis.

Molecular study of the sodium-iodide symporter (NIS): a new field in thyroidology.

The active transport of iodide into the thyroid is mediated by the Na(+)-I- symporter (NIS), an intrinsic membrane protein. NIS plays key roles in thyroid pathophysiology as the route by which I- reaches the gland for thyroid hormone biosynthesis, and as a means for diagnostic scintigraphic imaging and for radioiodide therapy in thyroid cancer. The molecular characterization of NIS started with the isolation in 1996 of a cDNA encoding rat NIS, and has subsequently led to a virtually new field in thyroidology. The research reviewed in this article clearly has far-reaching implications in the areas of structure/function of transport proteins, thyroid pathophysiology, hormone action mechanisms, cell differentiation and cancer.

The blood spot thyrotropin method is not adequate to screen for hypothyroidism in the elderly living in abundant-iodine intake areas: comparison to sensitive thyrotropin measurements.

We investigated whether the blood spot thyrotropin (TSH) method was adequate for screening elderly subjects with abundant iodine intake (median excretion 330 microg/g creatinine) for hypothyroidism. In 97 healthy adults (group A), 210 nursing home residents (group B) and 265 elderly subjects living at home (group C) serum (sensitivity < 0.02 mU/L, cost 1.2 U.S. dollars [USD]) and blood spot TSH (sensitivity < 1.0 mU/L, cost 0.4 USD) were measured, and the sensitivity and specificity of different blood spot TSH cutoff points to detect cases with elevated serum TSH were calculated. Elevated (> 3.5 mU/L) serum TSH levels (group A, 6.2%; group B, 16.2%; group C, 22.3%; B > A, p = 0.025; C > A, p < 0.001) were detected with the required sensitivity of greater than 0.9 only if the cutoff point of the blood spot TSH was set as low as 2.5 mU/L, but this led to a considerable loss of specificity. At cutoff point 2.5 mU/L, the rate of positivity was 39.3% and the cost of blood spot screening/person increased to 0.88 USD, considering that positive cases have to be rechecked by serum TSH to exclude false positivity. Cases with significantly elevated (> 10.0 mU/L) serum TSH (group A, 1.03%; group B, 2.85%; group C, 2.20%) were detected at blood spot cutoff points 10.0-4.0 mU/L with a sensitivity of 1.0 and without considerable loss of specificity. We conclude that while screening for hypothyroidism in the elderly population with abundant iodine intake is justified by the high prevalence of elevated ultrasensitive serum TSH values, the sensitivity of the blood spot method is insufficient to detect the subclinical hypothyroidism accurately and would, therefore, fail to detect most affected subjects.

[Ganglioneuroma of the adrenal gland]. / Mellékvese ganglioneuromák.

149 patients with adrenal incidentalomas were examined. Sixty-eight cases were histologically confirmed, five of them had ganglioneuromas. On the basis of these patients history current knowledge of this benign tumour was summarized. Histological and pathological characteristics of one tumour suggest that ganglioneuromas may develop by maturing of malignant neuroblastic tumours. The clinical symptoms (abdominal pain, meteorism) were local. In 2 of 5 cases mildly elevated levels of urinary vanillylmandelic acid and catecholamine could be measured. One patient had persisting hypertension after surgery. In an other patient previous diarrhoea stopped after the removal of tumour. On the basis of ultrasound and computertomographic features, the size and origin of a tumour and its relation to the surrounding organs can be well characterized. One patient was inoperable because of an infiltratively spreading tumour, but during five years of follow-up no tumour progression could be observed with computertomography. After surgery we could follow only 2 of 4 patients. Until now no recurrence of tumour were detected.

The efficacy of long term thyrostatic treatment in elderly patients with toxic nodular goitre compared to radioiodine therapy with different doses.

The objective of the study was to investigate the efficacy of long term thyrostatic versus radioiodine treatment of hyperthyroidism in old age. Our study is a retrospective analysis of the therapeutical outcome in 66 patients over 60 years of age with toxic nodular goitre. The patients were divided in two groups: Group A: 28 patients on methimazole treatment: starting dose 5-30, median (M) 10 mg, maintenance dose 2.5-15 (M = 5) mg, follow up 6 to 240 months (M = 23.5 months). Group B: 38 patients treated by either 100-300 MBq (N = 14, subgroup B1) or 325-1000 MBq (N = 24, subgroup B2) 131I, follow up: 18 to 156 months (M = 48 months). The efficacy of the different therapeutical approaches were compared by calculating the occurrence rate of persisting and relapsing thyroid dysfunctions and associated side effects. The 28 patients on methimazole treatment became euthyroid after 1-16 (M = 5) months but numerous relapses occurred in the follow up: hyperthyroidism, clinical: 5, subclinical 13, (relapse duration: M = 8 months; associated symptoms: hypertension in 4, cardiac arrhythmia in 3, cerebral embolism in 1, angina pectoris in 2, weight loss in 2 cases). Poor patient's compliance (9/28) or dose reduction by the physician (5/28) were the main causes of the relapses. Transient clinical (3 cases) or subclinical (6 cases) hypothyroidism also occurred (duration: 1-3 M = 2 months, no clinical symptoms). In 7 out of 14 (50%) patients receiving 100-300 MBq 131I (Group B1) hyperthyroidism persisted (versus 4/24 -16.7%- in Group B2 following 325-1000 MBq 131I; chi2(1) = 4.78 P = 0.028), methimazole treatment had to be continued in 9/14 patients (64.3%) (versus 5/24 -20.8%)- in Group B2., chi2(1) = 7.18 P = 0.0074) and in 5/14 (35.7%) the radiotherapy had to be repeated (versus 5/24 -020.8%- in Group B2, not sign.). Our conclusions are: 1) long term thyrostatic treatment is not safe in elderly patients with toxic nodular hyperthyroidism, mainly because of poor compliance or dose reduction by the physician; 2) radioiodine treatment as the first choice should be recommended for these patients and higher doses should be preferred.

In old age the majority of thyroid peroxidase autoantibodies are directed to a single TPO domain irrespective of thyroid function and iodine intake.

OBJECTIVE: We have examined (1) which epitopes on thyroid peroxidase (TPO) are recognized by TPO autoantibodies (TPO-Aab) in old age and to what extent? (2) Does the TPO-Aab pattern differ in euthyroid and hypothyroid elderly subjects or does it depend on their iodine intake? DESIGN: TPO-Aab positive sera obtained from a screening study of nursing-home residents living in areas of varying iodine intake were tested by competition studies with monoclonal antibodies (mAbs) recognizing different epitopes on TPO. SUBJECTS: The nursing-home residents with TPO-Aab positivity were from (A) an iodine abundant area (Eastern Hungary, median iodine excretion -MIE-: 0.462 mumol/mmol creatinine, N = 13); (B) an area of obligatory iodinated salt prophylaxis since the 1950s (Slovakia, MIE: 0.090 mumol/mmol creatinine, N = 11); (C) a moderately iodine-deficient area (Northern Hungary, MIE: 0.065 mumol/mmol creatinine, N = 13). MEASUREMENTS: Thirteen murine TPO antibodies generated against several epitopes of the four (A, B, C, D) antigenic domains on the TPO were co-incubated with the TPO-Aab positive sera on TPO coated microtitre plates. The amount of mAb bound was estimated after further incubation with goat anti-mouse antibodies, conjugated with horseradish peroxidase and tetramethylbenzidine as chromogen. The TPO-Aab positive sera were characterized by the pattern of percentage of inhibition of mAb binding caused by the TPO-Aabs. RESULTS: TPO-Aabs inhibited only the binding of mAbs raised against the antigenic domains A (mAb9, mAb2, mAb60) and B (mAb64, mAb59, mAb18, mAb15). The extent of inhibition depended upon the TPO-Aab titre but in all cases the binding of mAb9 was inhibited to the highest degree. The percentage inhibition of mAb9 was (a) 34 +/- 17% (M +/- SD) caused by sera (N = 8) with TPO-Aab titre 1/100-1/200 (higher than that of all mAbs recognizing domain B, P < 0.01-P < 0.001), (b) 76 +/- 18% caused by sera (N = 14) with TPO-Aab titre 1/1000 (higher than that of all other mAbs -P < 0.01-P < 0.001, except mAb64), (c) 99 +/- 4% caused by sera (N = 15) with TPO-Aab titre 1/4000-1/16,000 (higher than that of all other mAbs, P < 0.01-P < 0.001). Thus, only mAb9 was inhibited completely by high titres of TPO-Aabs. The qualitative and quantitative distribution pattern of mAb inhibition was similar in the subgroups of elderly hypothyroid and euthyroid subjects with comparable TPO-Aab levels, as well as in the subgroups with varying iodine intake. CONCLUSIONS: (1) In old age, there is a polyclonal TPO autoantibody response but the majority of the autoantibodies are directed to the TPO region mapped by or close to mAb9 (domain A); (2) the autoantibody response does not differ in elderly subjects with or without the clinical manifestations of autoimmune thyroid disease and does not depend on the iodine supply of the elderly subjects.

The effect of surgical treatment on secondary hyperaldosteronism and relative hyperinsulinemia in primary hyperparathyroidism.

OBJECTIVE: To evaluate the renin-aldosterone system and insulin secretion in hyperparathyroidism and their effects on blood pressure regulation. DESIGN: Studies were carried out on patients with primary hyperparathyroidism (PHPT) prior to and following removal of the parathyroid tumor. METHODS: Sixteen normotensive and euglycemic patients with PHPT were studied. The following parameters were measured: basal and stimulated plasma renin activity (PRA) and aldosterone (ALD) secretion: parathormone (PTH) and serum electrolytes. Insulin and glucose levels were measured during an oral glucose tolerance test. RESULTS: Systolic but not diastolic blood pressure showed a decrease following surgery, from 123.3+/-13.0/80+/-8.6 to 116.7+/-13.5/77.3+/-8.8 mmHg. The decrease in the systolic pressure was not clinically significant. After surgery, both the basal and stimulated PRA and ALD values decreased, and the preoperative pathological values returned to normal: PRA basal: 1.79 --> 0.70 ng/ml/h, P=0.0049; PRA stimulated: 7.76 --> 1.90 ng/ml/h, P=0.0031; ALD basal: 111.5 --> 73.0 pg/ml, P=0.0258; ALD stimulated: 392.5 --> 236.0 pg/ml, P=0.0157. The postoperative decrease in the PRA correlated with the changes in PTH levels (r=0.5442, P < 0.05, n=16) but did not correlate with the changes in serum calcium concentrations. Both the fasting and stimulated insulin levels decreased after surgery but remained within the normal range: insulin fasting: 10.2 --> 5.0 mIU/l, P=0.0218; insulin area under the curve: 5555 --> 3296 mIU/l*min, P=0.0218. There was no correlation between the changes in insulin levels and PTH or ion levels. Sodium, potassium and blood glucose levels remained unaffected by parathyroid surgery. CONCLUSIONS: In a population of normotensive hyperparathyroid patients an increased activity of the renin-aldosterone system related to PTH was found and surgery resulted in a small and insignificant decrease in blood pressure. This change was accompanied by a significant decrease in the activity of the renin-aldosterone system indicating the role of the renin-aldosterone system in the regulation of blood pressure in PHPT. Both fasting and stimulated insulin values decreased following removal of the parathyroid tumor, but with no individual correlation with PTH and calcium levels.

[Multiple endocrine adenomatosis IIB]. / Multiplex endokrin adenomatosis IIB.

The first Hungarian MEN IIB (multiplex endocrine neoplasia) syndrome is reported with the short summary of the literature about the pathogenesis and diagnosis of medullary thyroid carcinoma, presenting 80% in sporadic, 20% in hereditary form. The appearance of the patients alone (marfanoid stature, bulky lips, and ganglioneuromatosis of the tongue) may be almost enough for the presumption for the diagnosis of MEN IIB: For screening and preventing the clinical manifestation of the very aggressive medullary carcinoma in the relatives of the patient, the genetic screening is indispensable. The costs of the genetic screening and early treatment of the patients are much lower than the expenses of the traditional annual biochemical screening and the--delayed, often only supportive--treatment of the clinically manifested illness.

[Glycoprotein hormone alpha-subunit secretion in non-functioning pituitary adenomas]. / Glikoprotein hormon alpha-alegység elválasztás nem funkcionáló hypophysisdaganatokban.

The aim of the present study was to investigate the prevalence of elevated free glycoprotein hormone alpha-subunit in different pituitary adenomas, to establish the diagnostic value of the basal and stimulated free alpha-subunit secretion in non-functioning adenomas. Serum basal levels of alpha-subunit were increased in 1 of 22 untreated, in 1 of 16 operated patients with non-functioning adenoma, in 6 of 28 untreated, in 1 of 7 operated patients with acromegaly, in 0 of 5 untreated prolactinomas and in 0 of 1 untreated gonadotrop adenoma. Overall free alpha-subunit levels were increased in 9 of 79 cases (11.4%). In 6 of 9 patients with untreated non-functioning adenoma thyrotrop hormone releasing hormone caused an abnormal--paradox--elevation of serum alpha-subunit. These data indicate that measurement of basal and stimulated alpha-subunit is of relatively poor value in the diagnosis of non-functioning pituitary adenomas. The transsphenoidal surgery did not resulted in a change of alpha-subunit secretion neither in patients with non-functioning adenoma nor with acromegaly. The present data confirm the view that non-functioning pituitary adenomas are not homogeneous since this subset of tumors includes adenomas that either do not secrete measurable amounts of free alpha-subunit or produce normal or supranormal amounts of subunits as consequence of still undefined biosynthetic abnormalities.

Comparative screening for thyroid disorders in old age in areas of iodine deficiency, long-term iodine prophylaxis and abundant iodine intake.

OBJECTIVE: To investigate the effect of varying amounts of iodine intake on the prevalence of thyroid dysfunction, autoimmunity and goitre in old age. DESIGN: The first screening study where elderly subjects with varying amounts of iodine supply but from the same geographical and ethnographical region (Carpathian basin) were compared, and all hormone measurements and ultrasonography were performed by the same laboratory or person. PATIENTS: Nursing home residents were screened for thyroid disorders from: (A) an iodine-deficient area, Northern Hungary (n = 119; median age 81 years; median iodine excretion (MIE) 0.065 mumol/mmol creatinine (equivalent to 72 micrograms/g creatinine); (B) an area of obligatory iodinated salt prophylaxis since the 1950s, Slovakia (n = 135; median age 81 years, MIE 0.090 mumol/mmol creatinine (equivalent to 100 micrograms/g creatinine)) and (C) an abundant iodine intake area, Eastern Hungary (n = 92; median age 78 years; MIE 0.462 mumol/mmol creatinine (equivalent to 513 micrograms/g creatinine)). MEASUREMENTS: TSH, T4, free T4, T3, thyroglobulin (Tg), antibodies to Tg (AbTg) and to thyroid peroxidase (AbTPO), iodine excretion, ultrasonography of the thyroid gland. RESULTS: In regions A, B, and C, the prevalence of unsuspected clinical hypothyroidism was 0.8%, 1.5% and 7.6% (P = 0.006), with all cases except one being antibody positive (Ab+). The occurrence of subclinical hypothyroidism was 4.2% in region A, 10.4% in region B and 23.9% in region C (P < 0.001), but only 3 of 22 cases with subclinical hypothyroidism from region C were Ab+. The overall prevalence of Ab positivity (either antiTg+ or antiTPO+) was similar in the three regions (A, 19.3%; B, 24.4%; C, 22.8%). The occurrence of hyperthyroidism (clinical plus subclinical) was 3.4% in region A, 3.0% in region B and 0% in region C (not significant). The rate of elevated Tg levels was similar in the three regions. The prevalence of goitre was 39.4%, 16.4% and 12.2% (P < 0.001), respectively in regions A, B and C. In euthyroid subjects the mean ultrasonographically determined thyroid volume was 21.9 ml in region A, 13.6 ml in region B and 15.1 ml in region C (ANOVA F = 5.76; P = 0.0038). There was no significant difference in the occurrence of cases with hypoechogenic echotexture of the thyroid gland. CONCLUSIONS: The screening for hypothyroidism in nursing home residents living in iodine-rich regions is justified by the high prevalence of unsuspected clinical hypothyroidism. The high prevalence of antibody positivity in old age is independent of the iodine supply, but iodine supply has a determining role in the development of autoimmune hypothyroidism in the aged. Most cases of subclinical hypothyroidism in iodine-rich regions are not of autoimmune origin. In old age, hypoechogenic texture of the thyroid gland is not predictive of thyroid dysfunction.

Diagnosis from thyroid aspirates. Is the cytopathologist handicapped if not fully informed about the patient?

OBJECTIVE: When fine needle aspiration cytology (FNA) of the thyroid is performed as a first-line test, the cytopathologist cannot be fully informed about the patient's data. The authors investigated whether this decreases the accuracy of FNA and results in consequences for the patient. STUDY DESIGN: FNA smears of 202 patients, 190 with benign and 12 with malignant thyroid disease, were reevaluated, supplying the cytopathologist first with only information from the case history known already at the initial admission, and subsequently with full data. RESULTS: The FNA diagnoses were corrected in 13 cases; in 8/13 they showed a more serious finding. The therapeutic modality was changed in only one case. No corrections were made in the ultimately malignant cases. CONCLUSION: In several cases the cytopathologist may be handicapped by receiving only partial information about the patient, but in our patients this had no demonstrable adverse consequences. Thus, FNA can be performed upon patient's admission.

Apoplexy of a pituitary macroadenoma as a severe complication of preoperative thyrotropin-releasing hormone (TRH) testing.

The case history of a 54-year-old male suffering from pituitary macroadenoma with suprasellar extension is reported. A TRH-test with 200 micrograms i.v. was followed by severe headache and vomiting after 60', and by development of ophthalmoplegia on the following day. Hyperdens patches on the CT scan showed haemorrhage into the tumor. A chromophobic adenoma with macroscopic and histological signs of haemorrhage was removed via the transsphenoidal route. In the postoperative period the ophthalmoplegia gradually disappeared but central hypoadrenia and hypothyroidism occurred. This is the second case in the literature showing that TRH alone and in a low dose may cause pituitary tumor apoplexy. It is concluded that TRH-testing is a risk for the patient with pituitary apoplexy. If, due to the size of the tumor the patients have to be operated on in any case, and the test is not of essential diagnostic value, the TRH-test should be done only in selected cases. Its use in the postoperative evaluation however is without risk for the patients.

Low dehydroepiandrosterone sulfate (DHEA-S) level is not a good predictor of hormonal activity in nonselected patients with incidentally detected adrenal tumors.

To assess its differential diagnostic value, dehydroepiandrosterone sulfate (DHEA-S) was measured in a nonselected cohort of 84 patients with incidentally detected adrenal tumors (incidentaloma). Of the 38 histologically confirmed cases, 6 of 12 patients with primary or metastatic malignant tumor of the adrenals and 7 of 14 patients with benign cortical adenoma had low DHEA-S levels. Thus, the sensitivity, specificity, and predictive value of a low DHEA-S level to indicate a benign adrenal tumor were 0.35, 0.50, and 0.60, and the values to indicate a cortical adenoma were 0.50, 0.67, and 0.47, respectively. Of the 14 cases of histologically confirmed benign cortical adenoma, 10 had signs of hormonal activity, but DHEA-S was suppressed in only 7 cases. Thus, the sensitivity, specificity, and predictive value of a low DHEA-S level to indicate clinically significant hormonal activity of a benign cortical adenoma were 0.60, 0.75, and 0.86, respectively. For comparison, 5 of 5 males and 2 of 5 females with metastatic carcinomatosis, but without involvement of the adrenals, also had low DHEA-S levels. The data clearly show that in nonselected cases of incidentaloma a suppressed DHEA-S level is not a good predictor of hormonal activity and that DHEA-S measurement may be valuable only after having ascertained the cortical origin and benign feature of the tumor.