Multiple endocrine neoplasia syndrome is a group of hereditary diseases characterized by multiple tumor or hyperplastic lesions of the endocrine glands. Clinical manifestations of multiple endocrine neoplasias are caused by the type of syndrome: in MEN type 1, the parathyroid glands, adenohypophysis, pancreas are involved in the pathological process; in MEN type 2A, the thyroid gland and adrenal glands; in MEN type 2B, the thyroid gland, parathyroid glands, adrenal glands and mucous membranes. Diagnosis of multiple endocrine neoplasias includes genetic studies, laboratory tests, imaging instrumental studies. Therapeutic tactics for multiple endocrine neoplasias include surgical removal of glandular tumors.
Meaning
The term “multiple endocrine neoplasia” (MEN) in endocrinology combines hereditary autosomal dominant syndromes occurring with hyperplasia or tumors of several endocrine glands. Most often, the thyroid and parathyroid glands, pituitary gland, adrenal glands, pancreas, gastrointestinal tract, nervous system are involved in the syndrome of multiple endocrine neoplasia. Neoplasia can be manifested by adenomatosis, hyperplasia or carcinomatosis of the endocrine glands.
Taking into account the characteristic localization of neoplasia and the main clinical symptom complexes, MEN type 1 (Vermeer syndrome), MEN type 2A (Sipple syndrome), MEN type 2B (Gorlin syndrome) are distinguished.
Multiple endocrine neoplasia type 1
Characteristic
The components of multiple endocrine neoplasias of type 1 are lesions of the parathyroid glands, pituitary gland, pancreas, less often — thyroid gland, adrenal glands and gonads.
Multiple endocrine neoplasias of type 1 were first described in 1954 and according to the author were called Vermeer syndrome. With type 1 MEN, primary hyperparathyroidism develops in 90% of cases; pancreatic tumors develop in 80% of patients; pituitary adenomas develop in 65% of cases. Damage to the adrenal glands can be represented by hyperplasia or adenomas; thyroid gland – adenomas, thyroid cancer, colloidal goiter, thyrotoxicosis or chronic lymphocytic thyroiditis. Among the more rare concomitant disorders there are lipomas, stomach polyps, lung cancer, schwannomas, testicular tumors, etc.
Causes
There are sporadic and hereditary forms of multiple endocrine neoplasia type 1.
In most cases, type 1 MEN is a genetically determined pathology with an autosomal dominant type of inheritance. It is believed that multiple endocrine neoplasias of type 1 are associated with inheritance of the llql3 locus on the XI chromosome. In hereditary forms, mutations occur in both germinative and somatic cells; in sporadic forms, only in somatic cells. Considering the possibility of developing neoplasia of neuroectodermal cells, it is assumed that the pathogenetic relationship of MEN syndromes with related ectopic hormonal syndromes.
With multiple endocrine neoplasia of type 1, not all signs of the disease can manifest equally. All three components of type 1 MEN are detected only in a third of cases.
Symptoms
An early manifestation of multiple endocrine neoplasia type 1 in most cases is hyperparathyroidism, which usually develops at the age of 25-30 years. In the initial period, patients are concerned about decreased appetite, nausea, weight loss, constipation, and sometimes renal colic caused by the discharge of salts and small concretions. The stage of advanced symptoms occurs with muscle weakness in the proximal extremities, bone pain, memory loss, depressive states, polydipsia and polyuria. In rare cases, hyperparathyroidism with multiple endocrine neoplasia of type 1 is accompanied by the development of seizures and a comatose state.
In general, hyperparathyroidism in MEN type 1 has a milder course in comparison with primary hyperparathyroidism: cases of chondrocalcinosis, rim keratitis, calcification of the auricles, etc. are extremely rare. At the same time, diffuse osteoporosis and compression fractures of the vertebrae are typical for multiple endocrine neoplasias of type 1.
Pituitary adenomas with multiple endocrine neoplasms of type 1 can be represented by prolactinomas, somatotropinomas, corticotropinomas. The presence of prolactinoma leads to the development of hyperprolactinemic hypogonadism: dysmenorrhea, galactorrhea, infertility (in women); sexual disorders, gynecomastia – in men. Somatotropinomas are accompanied by acromegaly, persistent headache, myasthenia gravis, memory loss, etc.; corticotropinomas cause the development of Itsenko—Cushing’s disease, less often hypopituitarism. With multiple endocrine neoplasia of type 1, as a rule, pancreatic tumors are detected: insulinomas, gastrinomas, vipomas, extremely rarely – glucagonoma, somatostatinomas, etc.
Insulinomas are often multiple; in 3-6% of cases – malignant. Clinical manifestations of insulinoma are caused by the development of hypoglycemic syndrome. The second most common tumor of the pancreas in multiple endocrine neoplasia type 1 is gastrinoma, accompanied by the development of Zollinger—Ellison syndrome. Vipoma is a hormone-active tumor of the APUD system, secreting excessive amounts of vasoactive intestinal polypeptide; causes permanent or intermittent diarrhea, steatorrhea, hypotension, skin rashes, dehydration.
Diagnostics
Reliable diagnosis of multiple endocrine neoplasia type 1 is based on the identification of at least 2 components of this syndrome. Laboratory changes may include an increase in the level of ionized calcium, hypophosphatemia, an increase in the level of parathyroid hormone, insulin, prolactin, STH, gastrin, etc. For the purpose of topical diagnosis of tumors of the endocrine glands, ultrasound and NMR tomography of the parathyroid glands, scintigraphy, selective arteriography; radiography of the Turkish saddle, CT or MRI of the brain; ultrasound and ultrasonography of the pancreas are performed.
To assess the degree of secondary lesions of internal organs in multiple endocrine neoplasias of type 1, extended blood biochemistry (glucose, alkaline phosphatase, electrolytes, creatinine, urea, residual nitrogen, etc.) is studied; urine samples are carried out according to Zimnitsky and Sulkovich; kidney ultrasound, excretory urography; ECG, fibrogastroduodenoscopy; densitometry, finger radiography, long tubular bones , etc .
Treatment
With multiple endocrine neoplasia of type 1, treatment usually begins with the removal of the parathyroid glands (parathyroidectomy); then pancreatic tumors are removed (enucleation, resection of the pancreatic head, distal resection, pancreatoduodenal resection, etc.). With the malignant nature of tumors, postoperative chemotherapy is indicated.
With respect to pituitary adenomas included in the syndrome of multiple endocrine neoplasia type 1, an adenomectomy may be undertaken, drug or remote radiation therapy may be performed.
Multiple endocrine neoplasia types 2A and 2B
Characteristic
Multiple endocrine neoplasia type 2A syndrome includes medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. The disease was described in 1959 by J. Sipple, in connection with which it is also referred to in the literature as Sipple syndrome.
With multiple endocrine neoplasia type 2B (Gorlin syndrome), in addition to the above components, there are mucosal neurinomas, neuropathies and pathology of the musculoskeletal system.
Causes
The etiology of type 2 MEN syndromes is associated with autosomal dominant inheritance of a mutation of the RET proto-oncogene on the X chromosome, in the 10p11 region.2. In patients with type 2A MEN, mutations affect codons 609, 618, 620 and 634 in exon 10 and codons 768 and 804 in exon 11; in type 2B MEN, 918 is the codon of exon 11. Mutations of the RET proto-oncogene cause its activation, which causes uncontrolled cell growth and neoplastic transformation.
Multiple endocrine neoplasias of type 2 occur with a frequency of 1-10 cases per 100 thousand population.
Symptoms
Early manifestations of multiple endocrine neoplasia type 2A include medullary thyroid cancer originating from parafollicular cells and secreting calcitonin. Symptoms are poor; in a third of cases, diarrhea and carcinoid syndrome associated with the production of vasoactive peptides (histamine, serotonin, prostaglandins) by the tumor may occur. Even less often, thyroid carcinoma secretes ACTH, causing the development of Itsenko-Cushing syndrome. In most cases, medullary thyroid cancer is detected when examining patients for nodular goiter.
Pheochromocytoma in multiple endocrine neoplasia type 2A is found in half of patients, usually after a tumor lesion of the thyroid gland. Pheochromocytoma, as a rule, is accompanied by moderate transient or permanent arterial hypertension, general weakness, hyperhidrosis, hypersalivation, polyuria. With a crisis course of pheochromocytoma, there is a high probability of ventricular fibrillation, acute heart failure, pulmonary edema, hemorrhagic stroke.
Signs of hyperparathyroidism in the syndrome of multiple endocrine neoplasia type 2A may be a decrease in appetite, nausea, epigastric pain, renal colic. Type 2A MEN can occur in combination with primary amyloidosis of the skin or Hirschsprung’s disease.
With the syndrome of multiple endocrine neoplasia type 2B, the development of pathology of the musculoskeletal system and multiple neurinomas of the mucous membranes is added to medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism.
Patients with multiple endocrine neoplasia type 2B have a marfan-like appearance; they often have curvature of the spine, funnel-shaped deformation of the chest, horse foot, arachnodactyly, dislocations of the femurs. Neurinomas are more often localized on the tongue, mucous lips, cheeks, gastrointestinal tract. They are painless white-pink nodules 1-3 mm in size. On the part of the digestive system, diarrhea, constipation, megacolon may be noted.
Diagnostics
The identification of individual components of multiple endocrine neoplasias of type 2 is based on the principles of diagnosis of the corresponding diseases.
During the examination, ultrasound and scintigraphy of the adrenal glands and thyroid gland are performed, the level of blood calcium and hormones (thyroglobulin, calcitonin, ACTH, catecholamines, parathyroid hormone) is determined. Genetic screening makes it possible to detect a mutation of the RET proto-oncogene.
Treatment
In the syndrome of multiple endocrine neoplasia type 2, treatment provides for the primary removal of pheochromocytoma – unilateral or bilateral adrenalectomy. With bilateral removal of the adrenal glands, permanent replacement glucocorticoid and mineralocorticoid therapy is required for the prevention of chronic adrenal insufficiency.
The next stage is thyroidectomy with lymphodissection. In the postoperative period, thyroxine preparations are prescribed to correct postoperative hypothyroidism. In the case of inoperable thyroid carcinoma, chemotherapy is performed.
Surgical tactics for hyperparathyroidism in multiple endocrine neoplasia type 2 may involve subtotal parathyroidectomy, in some cases – total removal of the parathyroid glands with autotransplantation of parathyroid tissue into the forearm muscle.
Forecast
Genetic screening and dynamic observation of patients with multiple endocrine neoplasias of type 1 make it possible to identify and control the course of the syndrome, which significantly improves the prognosis for this pathology. With multiple malignant tumors of the pancreas, the prognosis is much worse.
In the syndrome of multiple endocrine neoplasia type 2, the prognosis is also unfavorable, largely determined by the operability and metastasis of thyroid cancer and pheochromocytoma.