Syndrome of multiple endocrine tumors

The term "syndrome of multiple endocrine tumors" (SMEO) combines diseases in which tumors of neuro-ectodermal origin (adenomas or cancers) and / or hyperplasia (diffuse, nodular) are detected in more than two endocrine organs. 

Causes of the syndrome of multiple endocrine tumors

Most cases of syndromes of multiple endocrine tumors occur in families with autosomal dominant expression of certain genes, therefore they are also called family endocrine tumors syndromes (SSMEO).

The first assumption on the involvement of many endocrine organs in the syndrome was expressed by N. Erdheim in 1904. He described the patient with an adenoma of the pituitary gland and hyperplasia of the parathyroid glands. Further, various combinations of endocrine gland tumors have been described. 

[1], [2], [3], [4]

Symptoms of the syndrome of multiple endocrine tumors

To date, there are 3 main types of SSSEO: I, IIa and IIb, III.

The main clinical symptoms of the syndrome of multiple endocrine tumors

I (Vermeer syndrome)	II		III
	IIa (Sipple's syndrome)	IIb
Tumors of parathyroid glands (solitary, rarely multiple) or hyperplasia of all glands Ostrovye tumors (insulinoma, gluconoma, gastrinoma, VIPoma, etc.) Tumors (somatotropinoma, prolactinoma, corticotropinoma, etc.)	Medullary thyroid cancer Pheochromocytoma Hyperparathyroidism (50% of cases)	Medullary thyroid cancer Pheochromocytoma Hyperparathyroidism (rarely) Neurons of the mucous membranes Pathology of muscles and skeleton Neuropathy	Hyperparathyroidism Pheochromocytoma Carcinoid of the duodenum

Syndrome of multiple endocrine tumors of type I

This group of diseases includes patients primarily with the family form of hyperparathyroidism. In this syndrome, hyperplasia of all parathyroid glands in combination with a pancreatic and / or pituitary tumor that can secrete in excess gastrin, insulin, glucagon, VIP, PRL, STH, ACTH, causing the development of appropriate clinical manifestations is detected. Multiple lipomas and carcinomas can be combined with the syndrome of multiple endocrine tumors of type I. Hyperparathyroidism is the most expressed endocrinopathy in the syndrome of multiple endocrine tumors of type I, and it is observed in more than 95% of patients. Less common are gastrinomas (37%) and prolactinomas (23%). Even more rarely, in 5% of cases, insulinoma, somatotropinoma, ACTH-producing pituitary tumor, WIPO, carcinoids, etc. Develop.

A feature of hyperparathyroidism in the syndrome of multiple endocrine tumors of type I is its rapid recurrence after the initial resection of the parathyroid glands. Hyperparathyroidism is often the first manifestation of the syndrome. Detection of parathyroid gland hyperplasia in patients with parathyroid gland hyperplasia is the reason for screening to identify other neuroendocrinal disorders (pathology of the endocrine pancreas and pituitary gland). In this syndrome, one hyperparathyroidism is rarely seen at the age of 15 years. Hyperplasia of parathyroid glands of humoral origin, as in recent years it has been shown that the plasma of these patients contains a factor that stimulates the growth of parathyroid cells in vitro. It was also found that its mitogenic activity is 2500% higher on average than the plasma of healthy people, and is many times higher than in patients with sporadic cases of one hyperparathyroidism. It was found that this factor is related to the main causes of fibroblast growth, and it is obviously involved in hyperplasia of epithelial cells of the parathyroid glands. And, possibly, to the formation of tumors in the pancreas and pituitary gland.

The pathology of the pancreas in the syndrome of multiple endocrine tumors of type I lies in the multifocal proliferation of neuroendocrine cells of the islets of Langerhans and their ductal progenitors. Approximately in% of cases, mainly beta cells with hyperproduction of insulin and development of hypoglycemia are involved in the pathological process. Insulinomas can be multiple and secrete not only insulin, but also glucagon, somatostatin, pancreatic polypeptide (II), etc. When other non-neuroendocrine cells of the Langerhans islands are involved in the pathological process, the clinical manifestations are diverse and depend on the type of eutopic or ectopic hormone that produces neoplastic cells . When excessive amounts of gastrin are formed, peptic ulcers of the stomach develop (Zollinger-Ellison syndrome), with an excess of VIP, watery diarrhea (Werner-Morrison syndrome), and with glucagon excess, glucagonome syndrome. There are cases of ectopic formation of these STG-RH tumors, leading to the development of a clinical picture of acromegaly. In such patients, the test with STG-RG is negative: the introduced STG-RG or its analog does not affect the level of STH in the blood, which is a reliable differential diagnostic criterion that allows to differentiate the ectopic formation of STG-RH.

Damage to the pituitary gland (hyperplastic changes or adenomas) develops in 1/3 of patients with the syndrome of multiple endocrine tumors of type I. In this case, there may be clinical signs of pituitary insufficiency or syndromes caused by an excess of various pituitary hormones.

To identify families with the syndrome of multiple endocrine tumors type I, an annual screening of its members is carried out, which includes the determination of serum calcium levels and parathyroid hormone in the blood for early detection of damage to the parathyroid glands. It is necessary to conduct a radioimmunological determination of the concentration of gastrin and other pancreatic hormones in the blood for the purpose of early diagnosis of the lesions of the islet apparatus of the pancreas. For early detection of lesions of the adenohypophysis, it is advisable to determine the levels of PRL and other pituitary hormones, as well as to conduct an x-ray study of the region of the Turkish saddle.

Syndrome of multiple endocrine tumors of type IIa

It is characterized by the presence in patients with medullary thyroid cancer, pheochromocytoma and hyperplasia or tumors of parathyroid glands. The combination of medullary thyroid cancer with pheochromocytoma was first described in detail by Sippl (1961), therefore this variant of the syndrome of multiple endocrine tumors is called Sipple syndrome. It is also inherited in autosomal dominant type with high penetrance, but with different expression. The mutation in most cases of the syndrome of multiple endocrine tumors of type IIa and IIb is reduced to the deletion of the short arm of the chromosome 20.

Hyperparathyroidism occurs in a significant proportion of patients (approximately 50% of cases) and is often the first clinical symptom of the disease. Hyperplasia of the parathyroid gland is sometimes seen even in the absence of clinical signs of impairment of their function, during surgery for medullary thyroid cancer. Severe  hypercalcemia  in these patients is rare and, as in the syndrome of multiple endocrine tumors of type I, is accompanied by the formation of stones in the kidneys.

Medullary thyroid cancer of C-cell origin, it is often accompanied or preceded by C-cell hyperplasia. This tumor produces amyloid and various polypeptides. More rarely, these tumors secrete serotonin, which causes the development of carcinoid syndrome, ACTH with the development of the Itenko-Cushing syndrome. 32% of patients with medullary thyroid cancer have diarrhea due to secretion of the tumor by VIP. Medullary thyroid cancers are malignant, mostly bilateral tumors (in contrast to sporadic cases), often metastasize into the cervical and mediastinal lymph nodes, the lungs and the liver. Typical tumor markers are calcitonin and histamine. In the blood of patients, high levels of calcitonin, carcinoembryonic antigen (KEA), histamine, etc. Are determined.

For the diagnosis of medullary thyroid cancer, the determination of the level of calcium in the blood under basal conditions and under the conditions of conducting samples with pentagastrin and with intravenous administration of calcium is used. These compounds stimulate the release of calcitonin and allow the diagnosis of C-cell hyperplasia and MTC. The most informative test with pentagastrin (at the rate of 0.5 μg / kg in 5-10 ml of physiological solution), administered intravenously for 60 seconds. Blood for examination is taken before the test at the 2-, 5-, 10-, 15-, 20- and 30th minutes after the injection.

Load with calcium: Calcium chloride in 50 ml of physiological saline at a final concentration of 3 mg / kg body weight as a slow intravenous injection for 10 min. Blood to determine the level of calcitonin is taken before, at the end of the injection and after 5, 10 and 20 minutes. On a scan, medullary thyroid cancer usually appears as a cold node or focus. Like pheochromocytomas, medullary thyroid cancers can sometimes absorb  ¹³¹ 1-methyliodobenzylguanidine, which on the one hand indicates their ability to produce catecholamines, on the other, that this drug can be used for diagnostic and therapeutic purposes in such cases of medullary cancer thyroid gland. Treatment of patients with medullary thyroid cancers is surgical. Total thyroidectomy with removal of regional lymph nodes is shown.

Pheochromocytomas in the syndrome of multiple endocrine tumors of type IIa are often (in 70% of patients) multiple, bilateral. Even in the case of unilateral tumors in the opposite adrenal gland, hyperplasia of the cells of the medulla layer, which in turn is the source of the tumor or tumors, often occurs. Pheochromocytomas are found in families with the syndrome of multiple endocrine tumors of type II in approximately 50% of cases and in 40% of families in which medullary thyroid cancer has been detected. Pheochromocytomas are mostly secreted adrenaline, in contrast to sporadic cases in which the main hormone produced by the tumor is norepinephrine. Two-sided pheochromocytomas of adrenal localization can be combined with the paracangliomy of the Zukkerkandl organ. Much of the pheochromocytoma in the syndrome of multiple endocrine tumors of type IIa is benign. Their clinical manifestations vary greatly and in most cases do not allow them to be diagnosed quickly. The bulk of patients lack classic paroxysms in combination with hypertensive crises. Many complain of rapid fatigue, bouts of tachycardia and sweating. For diagnostic purposes, conventional methods for determining the level of catecholamines in blood and urine with an adrenaline / noradrenaline ratio measurement, as well as provocative tests with inhibition (clonidine) and stimulation (histamine and pentolamine) of catecholamine release are used for diagnostic purposes. However, in order to avoid serious complications, the latter are not widely used. Moreover, clonidine has limited use for the detection of pheochromocytomas in the syndrome of multiple endocrine tumors of type II because these tumors, unlike sporadic cases, produce mainly adrenaline, and not norepinephrine, whose secretion is primarily inhibited by clonidine. A simple non-invasive provocative test with physical exertion is also used, which can be used in patients of any age and physical condition. It is produced using submaximal physical exercise on an electric bicycle ergometer, which gradually increases until the patient begins to experience discomfort and easy fatigue. At this time, measure the heart rate, blood pressure, ECG. Blood for examination is taken before starting the sample after a light breakfast through a venous catheter, after 30 minutes of rest and immediately after stopping work in a prone position. In patients with pheochromocytoma, an increase in the level of adrenaline is statistically significantly higher than in persons without pheochromocytoma. The same is characteristic for the relationship of adrenaline -  dopamine. Computed tomography makes it possible to identify a pheochromocytoma with a diameter of more than 1 cm, while  ¹³¹ 1-methyl iodine-benzylguanidine allows the determination of pheochromocytoma metastases. Surgical treatment, as a rule, bilateral adrenalectomy.

Screening for the syndrome of multiple endocrine tumors of type II includes three components: anamnesis (a detailed history of life for 2-3 generations), examination of the patient, including the detection of signs of the presence of tumors of the thyroid gland, chromaffin tissue, etc .; manifestations of the syndrome in its various variants; laboratory examination of the patient and his immediate family.

Syndrome of multiple endocrine tumors IIb type

On clinical symptoms, the syndrome is similar to the syndrome of multiple endocrine tumors of type IIa, but it differs genetically from it. It appears in people of younger age, parathyroid glands are rarely affected. Patients usually have normocalcemia and a normal level of immunoreactive parathyroid hormone (PTH). At the same time, the level of PTH does not decrease with intravenous administration of calcium, which is not observed in patients with the syndrome of multiple endocrine tumors of type II.

The main difference of the syndrome of multiple endocrine tumors of IIb type is the presence of multiple neur mucous membranes of the oral cavity, lips, eyelids, which are often detected already in childhood. They are especially distinctly visible on the tip and lateral surface of the tongue in the form of multiple nodules up to 1 cm in diameter. Neurons are formed almost throughout the entire LCG, up to the anus. Many patients with this syndrome have a marfan-like appearance and other skeletal and muscular manifestations: a horse's foot, slipping of the femoral head, kyphosis, scoliosis, deformation of the anterior thoracic cage. All these phenotypic changes give patients a distinctive appearance. The prognosis with this syndrome is worse than in the syndrome of multiple endocrine tumors of type IIa, because of the aggressive nature of tumor growth. In patients with the syndrome of multiple endocrine tumors of the IIb type, clinical manifestations associated with the presence of medullary thyroid cancer often come to the fore. The latter in these cases is the most common cause of death of patients.

It is argued that there is a type III syndrome of multiple endocrine tumors that combines a number of diseases: pheochromocytoma, Recklinghausen's disease, duodenal carcinoid. There are also data on mixed syndromes of multiple endocrine tumors. With these syndromes, a specific specific component of one of the clear types of the syndrome of multiple endocrine tumors is combined with the elements of the other. So, there are families in which an islet pancreatic tumor is combined with a pheochromocytoma emanating from the adrenal medulla, and in these cases the disease is inherited by an autosomal dominant type. Adenomas of the pituitary gland can be combined with paragangliomas. In some of these patients, parathyroid glands are involved in the pathological process. In these cases, hypercalcemia is detected. Pituitary adenomas can also be combined with other variants of syndromes of multiple endocrine tumors of type IIa and IIb.

Combined different syndromes of multiple endocrine tumors confirm the theory of the existence of a single progenitor cell for all cells of the APUD system, although it is possible that with malignant growth, cell dedifferentiation occurs, during which tumor cells begin to produce different polypeptides.

Forecast

Timely detection of individuals with multiple endocrine tumors in its various manifestations and adequate surgical treatment improves the prognosis of the disease and prolongs the life of patients.

[5], [6], [7], [8], [9], [10]