Diagnostics of the syndrome of ectopic production of ACTH

The presence of the syndrome of ectopic production of ACTH can be suspected with the rapid growth in patients of muscle weakness and peculiar hyperpigmentation. The syndrome often develops between 50 and 60 years of life with equal frequency in men and women, while Itenko-Cushing's disease begins between 20 and 40 years, and in women is 3 times more likely than in men. She is in most cases sick of women after childbirth. The syndrome of ectopic AKTG production, caused by ovine cell carcinoma, on the contrary, is more common in young smokers. It is not often that the syndrome of ectopic production of ACTH is observed in children and people of advanced age.

A rare case of the syndrome of ectopic production of adrenocorticotropic hormone, caused by nephroblastoma, was described in a Japanese girl of 5 years. Within 2 months the child developed cushingoid obesity, roundness of the face, darkening of the skin, sexual development was consistent with age. Arterial blood pressure rose to 190/130 mm Hg. The potassium content in the plasma was 3.9 mmol / l. A significant increase in 17-ACS and 17-CS in daily urine was found. Intravenous pyelography showed a violation of the configuration of the left kidney, and in selective renal arteriography, a violation of the blood circulation of its lower part was detected. The operation removed the tumor - nefroblastoma, metastases were not detected. The tumor synthesized "large" ACTH, beta-lipotropin, beta-endorphin and corticotropin-releasing-like activity. After removal of the kidney tumor, the symptoms of hypercorticosis regressed, and the function of the adrenal glands normalized.

The diagnosis of the syndrome of ectopic AKTH production consists of clinical manifestations of the disease, the determination of the function of the hypothalamic-adrenal system and the topical diagnosis of the ectopic tumor.

Features of the clinical picture of hypercorticism, characteristic for ectopic tumor, are the absence of obesity, pronounced muscle weakness, hyperpigmentation of the skin, swelling of the face, extremities, symptoms of cancer intoxication. In cases of development of the syndrome of ectopic production of ACTH with typical manifestations of hypercorticism, the disease develops within several months and is of a severe nature. In some patients, the disease can develop slowly, as in pituitary origin. These variants of the clinical course of the syndrome of ectopic secretion of ACTH are associated with the type of secretion of tumors, since ectopic tumors can secrete forms of ACTH with greater and less activity than ACTH.

Adrenal function in the syndrome of ectopic secretion of adrenocorticotropic hormone is characterized by a significant increase in urinary 17-OC and 17-CS, a very high level of cortisol in the plasma and increased rates of secretion of cortisol and corticosterone compared with other forms of hypercorticoidism. If the rate of secretion of cortisol fluctuates around 100 mg / day in the course of the Itenko-Cushing disease, then it is 200-300 mg / day for ectopic tumors.

ACTH plasma content is an important indicator for the diagnosis of ectopic syndrome. Its level usually rises from 100 to 1000 pg / ml and above. Almost one third of patients with the syndrome of ectopic secretion of ACTH can have the same increase in the level of this hormone as in the case of the Itenko-Cushing disease.

In the diagnostic plan, the increase in corticotropin content above 200 pg / ml and the results of selective determination of adrenocorticotropic hormone content in various veins are important in the syndrome of ectopic ACTH production. An important role in the diagnosis of the syndrome of ectopic production of ACTH is the ratio of the concentration of ACTH obtained by catheterization of the lower temporal sinus to the simultaneously determined level of the hormone in the peripheral vein. This indicator for ectopic tumors is 1.5 and lower, while in the case of Itenko-Cushing's disease it varies from 2.2 to 16.7. The authors believe that the use of the ACTH index obtained in the inferior temporal sinus is more reliable than in the jugular vein.

For a topical diagnosis of an ectopic tumor, retrograde catheterization of the inferior and superior vena cava is used, and blood taken from the right and left adrenal glands is withdrawn separately. Studies of the content of ACTH in these samples make it possible to detect an ectopic tumor.

ACTH-ectopic syndrome caused by a tumor of the medulla of the adrenal gland was detected by determining the ACTH content in venous blood obtained by retrograde catheterization of the inferior vena cava. It was shown that the tumor secretes ACTH and MCG. In the vein flowing from the right adrenal gland, the level of ACTH was higher than from the left one. A diagnosis was made: a tumor of the right adrenal gland. Histological examination revealed paraganglioma, originating from the adrenal medulla, and hyperplasia of the cortical layer of the adrenal glands. Localization of the syndrome of ectopic secretion of ACTH in the mediastinum, thyroid gland, pancreas and other organs is possible in the determination of ACTH in the blood obtained by draining the pulmonary and splenic venous system. With ectopic tumors accompanied by hypercorticism, there is usually no reaction of the pituitary-adrenal system to the administration of dexamethasone, metapyron, and lysine-vasopressin. This is due to the fact that the tumor autonomously secrets ACTH, which in turn stimulates the secretion of hormones by the adrenal cortex and causes its hyperplasia. Hypercortisolemia inhibits the secretion of pituitary ACTH. Therefore, after the administration of exogenous corticosteroids (dexamethasone) and ACTH stimulants (metopyrone and lysine-vasopressin), the secretion of adrenocorticotropic hormone in most patients with the syndrome of ectopic production of ACTH is not activated or inhibited. However, there have been reports of a number of cases in which patients with ectopic tumors were able to reduce ACTH in the blood and 17-ACS in the urine with intravenous and oral high doses of dexamethasone. Some patients respond to the administration of methopyrone. A positive reaction to dexamethasone and methopyrone is noted when the ectopic tumor secretes corticoliberin. This is due to two reasons: the preservation of hypothalamic-pituitary relationships and the possibility of primary tumor cells to respond to metopirone, ie, to a decrease in the level of cortisol in the plasma.

In the patient with colon cancer, production of corticoliberin was detected, which in turn stimulated corticotrophs of the pituitary gland, and this led to the preservation of the ability of the pituitary to respond to a decrease in the level of cortisol caused by the appointment of methopyrone. The authors also suggest a second explanation of the patients' positive response to this drug. The corticotropin-lowering factor, produced by the ectopic tumor, stimulates the secretion of ACTH in it, which causes adrenal hyperplasia. Hypercortisolemia completely suppresses the hypothalamic-pituitary function. Therefore, the increase in ACTH in response to metopirone does not occur at the level of the pituitary gland, but in the tumor (in this case, for colon cancer). A hypothetical scheme of possible physiological relationships in ectopic tumors between the hypothalamic-pituitary-adrenal system and the tumor that produces KRG-ACTH is given. Under these conditions, tumor hormones simultaneously stimulate the function of the pituitary and adrenal glands in the patient's body. Thus, their function is influenced by double stimulation - ACTH pituitary and tumor. The principle of the "feedback" is not excluded between the tumor and the adrenal glands. The complexity of the diagnosis of the syndrome of ectopic production of ACTH is also that in some tumors there is a periodic secretion of corticotropin and corticosteroids. The mechanism of this phenomenon has not yet been fully studied, but it is associated with uneven development of the tumor or with hemorrhage occurring in ectopic tumors. There were several cases of periodic hormone secretion by carcinoid cells of the lungs, thymus and pheochromocytoma.

It is possible that the cyclicity of secretion observed in tumors with ectopic ACTH production affects the results of the tests with dexamethasone and methopyron. Therefore, the interpretation of the obtained data is sometimes difficult, for example, with a paradoxical increase in corticosteroids in the appointment of dexamethasone.

Topical diagnosis of ectopic tumors is complex. In addition to the selective determination of ACTH, various X-ray methods of investigation and computed tomography are used for this purpose. Searches should begin with a study of the chest as the region of the most frequent localization of ectopic tumors. To determine the main group of tumors of the chest (lungs and bronchi), a tomographic examination of the lungs is used. Often foci of ovarian cancer of this organ are very small, poorly and late diagnosed, often after removal of the adrenal gland, 3-4 years after the onset of the syndrome. Mediastinal tumors (thymomas, chemodectomes) are usually seen on the lateral radiographs or are detected by means of computed tomography. Thyroid tumors are detected when scanning with ¹³¹ 1 or technetium as "cold" areas. In half of cases of tumors localized in the chest, oat cell lung cancer is detected, second place in the frequency of tumors of the thymus, then bronchial carcinoid.

Diagnosis and treatment of patients in whom ectopic ACTH syndrome is caused by a pancreatic tumor is complex. Often a tumor is an accidental finding. Symptoms of the disease has a number of characteristics. Thus, in a patient with Isenko-Cushing syndrome and pancreatic carcinoid with multiple metastases, marked symptoms of hypercorticoidism developed over a period of several months, one of the manifestations of which was hypokalemic alkalosis, hyperpigmentation of the skin, and progressive muscular weakness. A sharp decrease in potassium in the blood serum can be explained by the high rate of cortisol secretion (10 times more than in healthy ones) and corticosterone (4 times higher than normal).

Differential diagnosis of the syndrome of ectopic production of ACTH. Clinical manifestations of hypercorticism are similar for different etiology of the disease - Izenko-Cushing's disease, adrenal gland tumor - glucosteroma and ectopic AKTG syndrome. After 45 years you can suspect another source of hypercorticism, and not a disease Itenko-Cushing. Intensive pigmentation and pronounced hypokalemia almost always correspond to the syndrome of ectopic production of ACTH, although in 10% of patients hyperpigmentation occurs in the case of Itenko-Cushing's disease. In patients with a tumor of the adrenal cortex, it never occurs. Expressed hypokalemia can occur both in the case of Izenko-Cushing's disease, and with glucosteromas in severe patients.

Differential diagnostic criteria for hypercortisy

Indicators	Disease of Itenko-Cushing	Corticosteroma	Syndrome of ectopic production of ACTH
Clinical manifestations of hypercortisy	Expressed	Expressed	Can be expressed not completely
Age of patients	20-40 years old	20-50 years old	40-70 years old
Melasma	Slightly expressed, rare	Absent	Intensive
Potassium in plasma	Normal or reduced	Normal or reduced	Significantly reduced
ACTH in plasma	Up to 200 pg / ml	Not determined	100-1000 pg / ml
Cortisol in plasma	Increased by 2-3 times	Increased by 2-3 times	Increased 3-5 times
17-OC in the urine	Increased by 2-3 times	Increased by 2-3 times	Increased 3-5 times
Response to dexamethasone	Positive or negative	Negative	Positive or negative
Reaction to metopyrone	Positive or negative	Negative	Positive or negative

A more accurate diagnostic criterion is the determination of ACTH in plasma. With Isenko-Cushing's disease, the hormone level is often elevated in the afternoon and at night and, as a rule, does not increase above 200 pg / ml. In patients with tumors of the adrenal cortex, ACTH is either not detected, or remains within normal limits. With the syndrome of ectopic production, ACTH-indices of adrenocorticotropic hormone content in most patients are above 200 pg / ml. In the case of Itenko-Cushing's disease, a significant increase in the ACTH content is found in the jugular vein and temporal sinus, while in ectopic tumors the detection of a high concentration of ACTH in the vein depends on the location of the tumor.

The content of cortisol in plasma and urine and 17-ACS in urine is equally elevated in the case of Itenko-Cushing's disease and glucosteromas and is significantly increased in patients with the syndrome of ectopic AKTH production. Of great importance for the differential diagnosis are tests with dexamethasone and methopyron.

In the majority of patients with Isenko-Cushing's disease, 2 mg dexamethasone is administered 4 times a day for 2 days and the level of 17-ACS in urine is decreased by more than 50%, but 10% of patients do not. With glucosteromes, a decrease in the content of 17-ACS after the administration of dexamethasone does not occur. In patients with the syndrome of ectopic production, the ACTH reaction to dexamethasone, as in adrenocortical tumors, is negative, but in some, it may be positive. The reaction to metopyron in most patients with Isenko-Cushing's disease is positive, but in 13% of patients it is possible to have a negative reaction. With glucosteromas - always negative, with ectopic tumors, usually negative, but in some patients there is also a positive.

Not in all cases of hypercorticism is it easy to find the cause that causes it. For example, it is very difficult to put a differential diagnosis between carcinoma of the pituitary gland and the syndrome of ectopic production of ACTH. JD Fachinie et al. Observed a patient with a malignant tumor of the pituitary gland, but with clinical and laboratory data, as in the syndrome of ectopic ACTH production. In a middle-aged man against a background of weight loss, increased blood pressure, generalized melasma, hypokalemic alkalosis, hyperglycemia, a significant increase in free cortisol in urine and ACTH in the plasma. The level of cortisol in plasma and 17-ACS in urine paradoxically increased with the administration of dexamethasone and changed normally with the appointment of methopyrone. The ACTH content in the jugular and peripheral vein was the same. On pneumoencephalography and carotid angiography, a tumor of the Turkish saddle with suprasellar growth was detected. At histological examination of the removed tumor, a degranulated basophilic adenoma of the pituitary with a cytological picture of the carcinoma was found. Thus, in this case, the Itenko-Cushing's disease was caused by a malignant tumor of the pituitary gland.

Symptoms were the same as in the syndrome of ectopic AKTH production. Data of pneumoencephalography allowed to correctly diagnose.

It is equally difficult to differentiate glucosteroma from the syndrome of ectopic AKTH production. DE Schteingart et al. Described the patient at the age of 41 with the clinic of Isenko-Cushing syndrome. The cause of hypercortisolemia was a tumor of the adrenal medulla that secretes ACTH. The detection of hyperplastic adrenal glands and the determination of ACTH in veins flowing from the adrenals made it possible to determine the tumor of the adrenal medulla.

The differential diagnosis between Ithenko -Cushing's disease, glucosteroma and ectopic tumor is sometimes extremely difficult. In some patients it can be delivered years after adrenalectomy. For all forms of hypercorticism, an earliest diagnosis is necessary, since hypercortisolemia is a big threat to the body. Ectopic tumor is characterized by malignant course and metastasis. Late diagnosis of the syndrome of ectopic products ACTH limits the conduct of therapeutic measures.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]