Causes and pathogenesis of ectopic ACTH production syndrome

Causes of the syndrome of ectopic ACTH production. The syndrome of hypercorticism caused by ectopic ACTH production is detected in tumors of both non-endocrine organs and endocrine glands. Most often, this syndrome develops in tumors of the chest (lung cancer, carcinoid and bronchial cancer, malignant thymomas, primary thymus carcinoids and other mediastinal tumors). Less often, the syndrome accompanies tumors of various organs: parotid, salivary glands, urinary and gall bladder, esophagus, stomach, colon. The development of the syndrome in melanoma and lymphosarcoma has been described. Ectopic ACTH production has also been detected in tumors of the endocrine glands. ACTH secretion is often detected in cancer of the islets of Langerhans. Medullary thyroid cancer and pheochromocytoma, neuroblastoma occur with the same frequency. Much less frequently, ectopic ACTH production is detected in cancer of the cervix, ovaries, testicles and prostate gland. It was also found that in many malignant tumors that produce ACTH, clinical manifestations of hypercorticism are not observed. At present, the causes of ACTH production in cell tumors have not yet been found. According to Pearse's assumption in 1966, based on the concept of the APUD system, groups of cells formed from nervous tissue are present not only in the central nervous system, but also in many other organs: the lungs, thyroid and pancreas, the urogenital area, etc. The cells of tumors of these organs, under conditions of uncontrolled growth, begin to synthesize various hormonal substances. These include releasing hormones, which are produced in a healthy person in the hypothalamus; tropic hormones similar to pituitary hormones: ACTH, STH, TSH, prolactin, gonadotropins, ADH. In addition, secretion of parathyroid hormone, calcitonin, prostaglandins, kinins, erythropoietin, placental lactogen, enteroglucagon, etc. has been detected in tumors.

Clinical syndromes that develop as a result of the production of hormonal substances are still poorly studied and represent one of the most interesting problems of neuroendocrinology and oncology.

Pathogenesis of the syndrome of ectopic ACTH production. A characteristic feature of the syndrome of ectopic hormone production is the direct connection of the endocrine syndrome with the appearance of a tumor of some organ and a high level of the hormone or hormones in the blood. Regression of clinical manifestations and a decrease in hormone levels after tumor removal confirm these provisions. Detection of the corresponding hormones in tumor cells is a fairly reliable proof of their ectopic production.

The chemical nature of ACTH in the plasma of patients with the syndrome of ectopic ACTH production in tumors is unusual. Various forms of immunoreactive ACTH have been found, the so-called large, medium and small. Predominance of "large" ACTH with a relative molecular weight of about 30,000 was found in tumors. It is assumed that its form is passive and only its conversion to ACTH makes the substance active in stimulating the biosynthesis of hormones in the adrenal cortex. It was later shown that ACTH with a higher relative molecular weight is a common precursor not only for ACTH, but also for endorphins and lipotropins. In addition to these forms of ACTH, the presence of several terminal fragments - C- and its N-molecules - was found in tumors with ectopic production of adrenocorticotropic hormone. In ectopic tumors DN Orth et al. The presence of opioid substances was demonstrated for the first time in 1978. Along with corticotropins, alpha- and beta-endorphins and lipotropins were isolated from pancreatic cancer cells. Thus, the tumor secreted many substances from a common precursor. Further studies confirmed that an ectopic tumor (oat cell lung cancer ) is capable of synthesizing all forms of corticotropins, endorphins and lipotropins and that, in terms of their ability to produce them simultaneously, these tumor cell hormones are almost identical to normal human pituitary corticotrophs. There are some differences in the enzymatic processes.

With the development of the study of tumors capable of synthesizing ACTH, it was discovered that other hormones are also formed in them. In addition, tumors synthesize hypothalamic hormones - corticotropin-releasing hormone, prolactin-releasing hormone.

G. V. Upton was the first to show that pancreatic and lung tumors were capable of synthesizing CRF-like activity. Later, this substance was found in medullary thyroid carcinoma, intestinal cancer, and nephroblastoma. A patient with thyroid cancer, in addition to clinical manifestations of hypercorticism, had lactorrhea. The tumor secreted, along with corticotropin-stimulating activity, a prolactin-stimulating factor, which, in turn, caused the synthesis of prolactin in the pituitary gland. This was proven by studying the pituitary cell culture. After removal of the thyroid tumor, the patient's manifestations of hypercorticism and lactorrhea disappeared. In addition to two hormones similar to hypothalamic ones, the tumor contained a large amount of calcitonin.

In ACTH-ectopic syndrome, synthesis of serotonin and gastrin, luteinizing and follicle-stimulating, is also observed in tumors.

Pathological anatomy. In ACTT-ectopic syndrome, the adrenal glands are significantly enlarged due to hyperplasia and hypertrophy, mainly of the zona fasciculata cells. Electron microscopic examination revealed a large number of mitochondria of various sizes, including giant ones, and a well-developed lamellar complex.

Tumors that secrete CRH-ACTH are always malignant and are found in the lungs - oat cell carcinoma, in the thyroid gland - medullary carcinoma, in the adrenal medulla - solid chromaffinoma, in the mediastinum - chemodectoma, in the pancreas - one of the varieties of carcinoid.

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