Ectopic ACTH-producing Tumors Research Articles

Size Heterogeneity ofβ-MSH in Ectopic ACTH-Producing Tumors: Presence ofβ-LPH-Like Peptide

Gel chromatographic, immunologic and biologic properties of beta-melanocyte-stimulating hormone (beta-MSH) in tumor tissues obtained from eight patients with the ectopic ACTH syndrome were studied and compared to those of pituitary beta-MSH. Size heterogeneity of immunoreactive beta-MSH was found in all the tumors studied as well as in normal human pituitaries. Both the tumors and pituitaries contained immunoreactive beta-MSH of a larger molecular size than the well-characterized beta-MSH of small molecular size. The large molecular weight beta-MSH also predominated in the plasma. It was found to be bioactive by an in vitro MSH assay, immunologically indistinguishable from human beta-MSH, and chromatographically very similar to beta-lipotropic hormone (beta-LPH). Tryptic digestion of the large molecular weight beta-MSH under controlled conditions promptly produced bioactive beta-MSH of small molecular size, followed by the appearance of immunologically active but biologically inert fragments. These results suggest that the ectopic ACTH-producing tumor as well as the pituitary elaborate beta-LPH-like peptide which might be the predominant component of immunoreactive beta-MSH in man.

Effect of salicylates on renal gluconeogenesis

important etiologic cause. In this work, 12 patients were studied under basal conditions and during tests of pituitary and adrenal function with the objective of making a differential diagnosis. The 12 patients were divided by age into two subgroups of six patients each. The prepubertal group had tumors, with the exception of one child with bilateral hyperplasia: one basophil adenoma, one adenocarcinoma, two ectopic ACTH-producing tumors (thymoma and embryoma), and one adrenal adenoma. The pubertal group consisted of five with bilateral hyperplasia and one with an adrenal adenoma. The tumors did not respond to stimulation or suppression tests, except for the adrenal adenoma which showed a hyperresponsiver}ess to the infusion of ACTH. The results of attempts at inhibition of the bilateral hyperplasia were as follows: four inhibited with a small dose of dexamethasone, one partially inhibited with a large dose, and no inhibition in one patient. The last patient also did not respond to intravenous ACTH stimulus, presenting with a very high secretion of cortisol (156 mg/day/m2). This marked adrenal hyperactivity explains its tumor-like behavior. TREATMENT. Two patients with bilateral hyperplasia received conventional 4,000 r pituitary radiotherapy with no result; five patients had bilateral adrenalectomy with no deaths. The three 9 patients with adrenalectomy who had had no previous hypophyseal radiotherapy developed a syndrome of hyperpigmentation, one with enlargement of the sella turcica and diplopia. All patients received rotating 5,000 r pituitary cobalt therapy. The results suggest that optimum therapy would be bilateral adrenalectomy plus radiotherapy.

In VitroRelease and Biosynthesis of Tumor ACTH in Ectopic ACTH Producing Tumors

Tumor tissues obtained from 4 patients with the ectopic ACTH syndrome were studied for release and synthesis of tumor ACTH, using an in vitro incubation system. The effect of various agents on release of tumor ACTH was evaluated in three cases; beta-MSH released and adenosine 3',5'-monophosphate (cyclic AMP) formed in the tissue were determined in one. Biosynthetic experiments using labeled amino acid incorporation were performed in two cases. Secretion of tumor ACTH was significantly stimulated in all cases by crude rat median eminence extract which was also effective in stimulating beta-MSH secretion associated with elevated tissue cyclic AMP levels in one. Addition of cyclic AMP and dibutyryl cyclic AMP caused a significant increase in release of both tumor ACTH and beta-MSH in one. Biogenic amines (norepinephrine and serotonin) markedly elevated tussie cyclic AMP levels without a corresponding increase of hormone release in one. Incorporation experiments revealed that 3H- or 14C-phenylalanine was incorporated into immunoreactive ACTH of a larger molecular size (big ACTH) in both cases by chromatographic procedures. However, biological activity of big ACTH was found to be undetectable by an in vivo steroidogenic assay. A mild tryptic digestion of the big forms resulted in the appearance of little ACTH to which the major radioactive peak shifted. These data suggest that the mechanism of release of tumor ACTH and beta-MSH is very similar to that of the pituitary, and that intracellular cyclic AMP may in part play some role in release of both hormones. It is also suggested that some ectopic ACTH producing tumors predominantly synthesize big ACTH, a possible precursor of ACTH, with less bioactivity.

Studies on ectopic ACTH-producing tumors.II. Clinical and biochemical features of 30 cases

This report describes the clinical and biochemical features of 30 cases of ectopic ACTH-producing tumors diagnosed by the detection of ACTH in the tumor tissues. Several uncommon tumors, such as tumors of the esophagus, stomach, and larynx, were included in this series. None of the patients with bronchogenic carcinoma showed signs of classical Cushing's syndrome, whereas 7 of the remaining 13 patients with other tumors were Cushingoid in appearance. Adrenocortical hyperfunction was present in 61 percent at the first examination and developed during the course of the disease in 18 percent more. In the remaining patients (21 percent), adrenocortical function remained within normal limits. These results indicate that there exist ectopic ACTH-producing tumors without clinical and biochemical sequelae of excess hormone. In some of the tumor extracts studied, MSH and CRF-like activities and serotonin were detected. This suggests that multiple hormone production is not uncommon in ectopic ACTH-producing tumors.

Studies on Ectopic ACTH-Producing Tumors: I. Measurement of ACTH in Tumor Tissue

Studies on Ectopic ACTH-Producing Tumors: I. Measurement of ACTH in Tumor Tissue

Activities in Detection of Ectopic ACTH Producing Tumors

A study group on ectopic hormone-producing tumor was organized in Japan in 1967. During the first three years, this group conducted endocrine screening tests on 438 cases of malignant tumor consisting mainly of carcinoma of the lung, and detected ectopic ACTH-producing tumor in four cases of carcinoma of the lung and one case of carcinoma of the colon. It was noted that typical clinical signs of Cushing's syndrome were lacking in all five cases, suggesting the importance of screening tests. In all these cases, urinary excretion of 17-OHCS and the level of plasma cortisol, which dexamethasone failed to suppress, were high. Clinical picture revealed edema, pigmentation and hypertension. Laboratory findings included hypokalemia and a high degree of impairment of glucose tolerance. Concentration of ACTH in tumor tissue measured by radioimmunoassay was considerably higher than that measured by bioassay.

Acinic cell adenocarcinoma of the parotid with ectopic production of adrenocorticotropic hormone

A documented case of acinic cell adenocarcinoma of the parotid glands with metastases to the nodes, liver and lung, with ectopic ACTH production, is presented. Our patient had manifestations typical of excessive ectopic ACTH production, characterized by hypokalemic alkalosis and weakness but no hypertension, striae or the typical fat distribution of Cushing's syndrome. The pathologic specimens assured the origin of the tumor to be acinic cell. Assays of blood and of both primary and metastatic tumors demonstrated excessive ACTH. Urinary steroid excretion studies using the double isotope dilution method revealed elevated cortisol and corticosterone levels but normal aldosterone and desoxycorticosterone levels. These results suggest that hypertension occurring with ectopic ACTH-producing tumors may not necessarily be related to the concomitant hypokalemic alkalosis. The findings in this patient suggest that hypokalemia is not necessarily a sequel of increased mineralocorticoid but may be the result of excess production of cortisol and/or corticosterone. A documented case of acinic cell adenocarcinoma of the parotid glands with metastases to the nodes, liver and lung, with ectopic ACTH production, is presented. Our patient had manifestations typical of excessive ectopic ACTH production, characterized by hypokalemic alkalosis and weakness but no hypertension, striae or the typical fat distribution of Cushing's syndrome. The pathologic specimens assured the origin of the tumor to be acinic cell. Assays of blood and of both primary and metastatic tumors demonstrated excessive ACTH. Urinary steroid excretion studies using the double isotope dilution method revealed elevated cortisol and corticosterone levels but normal aldosterone and desoxycorticosterone levels. These results suggest that hypertension occurring with ectopic ACTH-producing tumors may not necessarily be related to the concomitant hypokalemic alkalosis. The findings in this patient suggest that hypokalemia is not necessarily a sequel of increased mineralocorticoid but may be the result of excess production of cortisol and/or corticosterone.

Vasopressin in the evaluation of pituitary-adrenal function.

The plasma cortisol response to an intramuscular injection of 10 units of lysine vasopressin was evaluated in 19 normal subjects and in 35 patients with various disturbances of endocrine function and was compared with the response to standard adrenocorticotrophic hormone (ACTH) and metyrapone tests. A rise in plasma cortisol of 6 µg/100 ml or greater occurred in all 19 normal subjects and in 22 of the 35 patients studied. In general, the results of metyrapone and vasopressin testing were in agreement, but discordant results were obtained in 9 of the 35 patients. Two of these nine patients had a normal vasopressin but subnormal metyrapone response, and, conversely, seven patients had a subnormal vasopressin and normal metyrapone response. These data suggest that vasopressin may yield evidence of impaired ACTH release not otherwise shown by metyrapone. Furthermore, these data—particularly the diminished vasopressin responses in two patients with hypothalamic disease—raise serious doubt concerning the theory that hypothalamic and pituitary disease may be distinguished on the basis of vasopressin and metyrapone testing. Six of seven patients with Cushing's syndrome with adrenocortical hyperplasia, including one with a pituitary tumor, responded normally to vasopressin, whereas one patient with adrenocortical carcinoma failed to respond, thus supporting the contention that vasopressin may be useful in distinguishing Cushing's syndrome on a pituitary basis from that secondary to other causes. However, further studies are indicated in such patients, particularly in those with functioning adrenocortical adenoma and ectopic ACTH-producing tumor.