Diagnosis of ectopic ACTH production syndrome

The presence of ectopic ACTH production syndrome can be suspected by a rapid increase in muscle weakness and peculiar hyperpigmentation in patients. The syndrome most often develops between 50 and 60 years of age with equal frequency in men and women, while Itsenko-Cushing's disease begins between 20 and 40 years, and in women 3 times more often than in men. In most cases, women get sick after childbirth. Ectopic ACTH production syndrome caused by osseous cell carcinoma, on the contrary, is more common in young male smokers. Ectopic ACTH syndrome is rarely observed in children and the elderly.

A rare case of ectopic adrenocorticotropic hormone production syndrome caused by nephroblastoma was described in a 5-year-old Japanese girl. Within 2 months, the child developed Cushingoid obesity, facial roundness, darkening of the skin, and age-appropriate sexual development. Blood pressure rose to 190/130 mm Hg, plasma potassium content was 3.9 mmol/l. A significant increase in 17-OCS and 17-CS was detected in daily urine. Intravenous pyelography showed an abnormal configuration of the left kidney, and selective renal arteriography revealed impaired blood circulation in its lower part. The tumor, nephroblastoma, was removed during surgery, and 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 hypercorticism regressed and adrenal function returned to normal.

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

The clinical features of hypercorticism, typical for an ectopic tumor, are the absence of obesity, pronounced muscle weakness, hyperpigmentation of the skin, swelling of the face, limbs, symptoms of cancer intoxication. In cases of the development of ectopic ACTH production syndrome with typical manifestations of hypercorticism, the disease develops over several months and is severe. In some patients, the disease can develop slowly, as in the case of pituitary origin. These variants of the clinical course of ectopic ACTH secretion syndrome are associated with the type of secretion of neoplasms, since ectopic tumors can secrete forms of ACTH with greater and lesser activity than ACTH.

Adrenal function in ectopic adrenocorticotropic hormone secretion syndrome is characterized by a significant increase in the urinary content of 17-OCS and 17-KS, very high plasma cortisol levels, and increased rates of cortisol and corticosterone secretion compared to other forms of hypercorticism. If in Itsenko-Cushing's disease the rate of cortisol secretion fluctuates around 100 mg/day, then in ectopic tumors it is 200-300 mg/day.

The content of ACTH in plasma is an important indicator for the diagnosis of ectopic syndrome. Its level usually increases from 100 to 1000 pg/ml and higher. Almost 1/3 of patients with ectopic ACTH secretion syndrome may have the same increase in the level of this hormone as in Itsenko-Cushing disease.

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

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

Ectopic ACTH syndrome caused by a tumor of the adrenal medulla 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 MSH. The ACTH level in the vein flowing from the right adrenal gland was higher than from the left one. A diagnosis was made: tumor of the right adrenal gland. Histological examination revealed a paraganglioma originating from the adrenal medulla and hyperplasia of the adrenal cortex. Localization of the ectopic ACTH secretion syndrome in the mediastinum, thyroid gland, pancreas and other organs is possible by determining ACTH in the blood obtained by draining the pulmonary and splenic venous system. In ectopic tumors accompanied by hypercorticism, there is usually no reaction of the pituitary-adrenal system to the introduction of dexamethasone, metopirone, and lysine vasopressin. This is due to the fact that the tumor autonomously secretes ACTH, which in turn stimulates the secretion of hormones by the adrenal cortex and causes its hyperplasia. Hypercortisolemia suppresses the secretion of pituitary ACTH. Therefore, after the introduction of exogenous corticosteroids (dexamethasone) and ACTH stimulators (metopirone and lysine vasopressin), the secretion of adrenocorticotropic hormone in most patients with the syndrome of ectopic ACTH production is not activated or inhibited. However, a number of cases have been reported when in patients with an ectopic tumor it was possible to reduce the level of ACTH in the blood and 17-OCS in the urine with intravenous and oral administration of large doses of dexamethasone. Some patients respond to the introduction of metopirone. A positive reaction to dexamethasone and metopirone is noted when the ectopic tumor secretes corticoliberin. This is explained by two reasons: the preservation of the hypothalamic-pituitary relationship and the ability of the primary tumor cells to respond to metopirone, i.e., to a decrease in the level of cortisol in the plasma.

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

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

Topical diagnostics of ectopic tumors is complicated. In addition to selective determination of ACTH, various X-ray examination methods and computed tomography are used for this purpose. The search should begin with examination of the chest as the area of the most frequent localization of ectopic tumors. Tomographic examination of the lungs is used to determine the main group of tumors of the chest (lungs and bronchi). Often, foci of oat cell carcinoma of this organ are very small, poorly and late diagnosed, often after removal of the adrenal glands, 3-4 years after the onset of the syndrome. Mediastinal tumors (thymomas, chemodectomas) are usually visible on lateral radiographs or detected by computed tomography. Thyroid tumors are detected by scanning with ¹³¹ 1 or technetium as "cold" areas. In half of the cases of tumors localized in the chest, oat cell lung cancer is detected, the second most common are tumors of the thymus, then bronchial carcinoid.

Diagnosis and treatment of patients with ectopic ACTH syndrome caused by a pancreatic tumor are difficult. The tumor is often an accidental finding. The symptoms of the disease have a number of features. Thus, a patient with Itsenko-Cushing syndrome and pancreatic carcinoid with multiple metastases developed pronounced symptoms of hypercorticism over several months, one of the manifestations of which was hypokalemic alkalosis, hyperpigmentation of the skin, and progressive muscle weakness. A sharp decrease in the potassium content in the blood serum can be explained by the high rate of secretion of cortisol (10 times more than in healthy people) and corticosterone (4 times higher than normal).

Differential diagnostics of ectopic ACTH production syndrome. Clinical manifestations of hypercorticism are similar in different etiologies of the disease - Itsenko-Cushing's disease, adrenal tumor - glucosteroma and ectopic ACTH production syndrome. After 45 years, another source of hypercorticism can be suspected, and not Itsenko-Cushing's disease. Intense pigmentation and pronounced hypokalemia almost always correspond to the syndrome of ectopic ACTH production, although in 10% of patients hyperpigmentation is also found in Itsenko-Cushing's disease. In patients with adrenal cortex tumor, it never occurs. Severe hypokalemia can be found both in Itsenko-Cushing's disease and in glucosteromas in severe patients.

Differential diagnostic criteria for hypercorticism

Indicators	Itsenko-Cushing's disease	Corticosteroma	Ectopic ACTH production syndrome
Clinical manifestations of hypercorticism	Expressed	Expressed	May not be fully expressed
Age of patients	20-40 years	20-50 years	40-70 years
Melasma	Weakly expressed, rare	Absent	Intensive
Plasma potassium	Normal or low	Normal or low	Significantly reduced
ACTH in plasma	Up to 200 pg/ml	Not defined	100-1000 pg/ml
Plasma cortisol	Increased by 2-3 times	Increased by 2-3 times	Increased by 3-5 times
17-OCS in urine	Increased by 2-3 times	Increased by 2-3 times	Increased by 3-5 times
Reaction 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. In Itsenko-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 adrenal cortex tumors, ACTH is either not detected or remains within normal limits. In the syndrome of ectopic ACTH production, the adrenocorticotropic hormone levels in most patients are above 200 pg/ml. In Itsenko-Cushing's disease, a significant increase in ACTH is detected 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-OCS in urine is equally elevated in Itsenko-Cushing disease and glucosteromas and significantly increases in patients with ectopic ACTH production syndrome. Tests with dexamethasone and metopirone are of great importance for differential diagnosis.

In most patients with Itsenko-Cushing's disease, when 2 mg of dexamethasone is prescribed 4 times a day for 2 days, the level of 17-OCS in daily urine decreases by more than 50%, but such a response is not observed in 10% of patients. In glucosteromas, there is no decrease in the content of 17-OCS after the introduction of dexamethasone. In patients with the syndrome of ectopic ACTH production, the reaction to dexamethasone, as in tumors of the adrenal cortex, is negative, but in some it can be positive. The reaction to metopirone in most patients with Itsenko-Cushing's disease is positive, but in 13% of patients it can be negative. In glucosteromas - always negative, in ectopic tumors, as a rule, negative, but in some patients it can be positive.

The cause of hypercorticism is not easy to find in all cases. For example, it is very difficult to differentiate between pituitary carcinoma and ectopic ACTH syndrome. JD Fachinie et al. observed a patient with a malignant pituitary tumor, but with clinical and laboratory data as in ectopic ACTH syndrome. In a middle-aged man, against the background of weight loss, increased blood pressure, generalized melasma, hypokalemic alkalosis, hyperglycemia, a significant increase in free cortisol in the urine and ACTH in the plasma were found. The level of cortisol in the plasma and 17-OCS in the urine paradoxically increased with the introduction of dexamethasone and changed normally with the prescription of metopirone. The ACTH content in the jugular and peripheral vein was the same. Pneumoencephalography and carotid angiography revealed a tumor of the sella turcica with suprasellar growth. Histological examination of the removed tumor revealed a degranulated basophilic adenoma of the pituitary gland with a cytological picture of carcinoma. Thus, in this case, Itsenko-Cushing's disease was caused by a malignant tumor of the pituitary gland.

The symptoms were the same as in the syndrome of ectopic ACTH production. The pneumoencephalography data allowed the correct diagnosis to be made.

It is no less difficult to differentiate glucosteroma from the syndrome of ectopic ACTH production. DE Schteingart et al. described a 41-year-old patient with clinical features of Itsenko-Cushing syndrome. The cause of hypercortisolemia was a tumor of the adrenal medulla secreting ACTH. Detection of hyperplastic adrenal glands and determination of the ACTH content in the veins flowing from the adrenal glands made it possible to determine the tumor of the adrenal medulla.

Differential diagnosis between Itsenko-Cushing's disease, glucosteroma and ectopic tumor is sometimes extremely difficult. In some patients, it can be made years after adrenalectomy. For all forms of hypercorticism, the earliest possible diagnosis is necessary, since hypercortisolemia poses a great threat to the body. An ectopic tumor is characterized by a malignant course and metastasis. Late diagnosis of ectopic ACTH syndrome limits treatment.

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