Medical expert of the article
New publications
Multiple endocrine tumor syndrome
Last reviewed: 04.07.2025
All iLive content is medically reviewed or fact checked to ensure as much factual accuracy as possible.
We have strict sourcing guidelines and only link to reputable media sites, academic research institutions and, whenever possible, medically peer reviewed studies. Note that the numbers in parentheses ([1], [2], etc.) are clickable links to these studies.
If you feel that any of our content is inaccurate, out-of-date, or otherwise questionable, please select it and press Ctrl + Enter.
The term “multiple endocrine tumor syndrome” (MES) includes diseases in which tumors of neuroectodermal origin (adenomas or cancers) and/or hyperplasia (diffuse, nodular) are detected in more than two endocrine organs.
Causes of multiple endocrine tumor syndrome.
Most cases of multiple endocrine tumor syndromes occur in families with autosomal dominant expression of certain genes, so they are also called familial multiple endocrine tumor syndromes (FMETS).
The first suggestion about the involvement of many endocrine organs in the syndrome was made by H. Erdheim in 1904. He described a patient with a pituitary adenoma and hyperplasia of the parathyroid glands. Later, various combinations of endocrine gland tumors were described.
[ Symptoms of multiple endocrine tumor syndrome.
At present, there are 3 main types of SSMEO: I, IIa and IIb, III.
The main clinical symptoms of multiple endocrine tumor syndrome
I (Wermer syndrome) |
II |
III |
|
IIa (Sipple syndrome) |
IIb |
||
Tumors of the parathyroid glands (solitary, rarely multiple) or hyperplasia of all glands Islet tumors (insulinoma, glucagonoma, gastrinoma, VIPoma, etc.) Tumors (somatotropinoma, prolactinoma, corticotropinoma, etc.) |
Medullary thyroid cancer Pheochromocytoma Hyperparathyroidism (50% of cases) |
Medullary thyroid cancer Pheochromocytoma Hyperparathyroidism (rare) Neuromas of the mucous membranes Muscular and skeletal pathology Neuropathy |
Hyperparathyroidism Pheochromocytoma Carcinoid of the duodenum |
Multiple endocrine tumor syndrome type I
This group of diseases includes patients primarily with the familial form of hyperparathyroidism. This syndrome is characterized by hyperplasia of all parathyroid glands in combination with a tumor of the pancreas and/or pituitary gland, which can secrete gastrin, insulin, glucagon, VIP, PRL, STH, ACTH in excess, causing the development of the corresponding clinical manifestations. Multiple lipomas and carcinomas can be combined with the syndrome of multiple endocrine tumors type I. Hyperparathyroidism is the most expressed endocrinopathy in the syndrome of multiple endocrine tumors type I, and it is observed in more than 95% of patients. Less common are gastrinomas (37%) and prolactinomas (23%). Even less common, in 5% of cases, is insulinoma, somatotropinoma, ACTH-producing pituitary tumor, VIPomas, carcinoids, etc.
A characteristic feature of hyperparathyroidism in multiple endocrine tumor syndrome type I is its rapid relapse after initial resection of the parathyroid glands. Hyperparathyroidism is most often the first manifestation of the syndrome. Detection of hyperplasia of the parathyroid glands in patients is a reason for screening in order to identify other neuroendocrine disorders (detection of pathology of the endocrine pancreas and pituitary gland). In this syndrome, hyperparathyroidism alone rarely manifests itself before the age of 15 years. Hyperplasia of the parathyroid glands is of humoral origin, since in recent years it has been shown that the plasma of these patients contains a factor stimulating the growth of parathyroid cells in vitro. It has also been found that its mitogenic activity is, on average, 2500% higher than that of the plasma of healthy people, and many times higher than that of patients with sporadic cases of hyperparathyroidism alone. This factor has been found to be related to the main causes of fibroblast growth, and it is apparently also involved in the hyperplasia of epithelial cells of the parathyroid glands and, possibly, in the formation of tumors in the pancreas and pituitary gland.
Pancreatic pathology in multiple endocrine tumor syndrome type I consists of multifocal proliferation of neuroendocrine cells of the islets of Langerhans and their ductal precursors. In approximately % of cases, beta cells with hyperproduction of insulin and development of hypoglycemia are mainly involved in the pathological process. Insulomas can be multiple and secrete not only insulin, but also glucagon, somatostatin, pancreatic polypeptide (II), etc. When other neuroendocrine cells of the islets of Langerhans are involved in the pathological process, clinical manifestations are varied and depend on the type of eutopic or ectopic hormone produced by neoplastic cells. When excess gastrin is formed, peptic ulcers of the stomach develop (Zollinger-Ellison syndrome), when there is an excess of VIP - watery diarrhea (Werner-Morrison syndrome), and when there is an excess of glucagon - glucagonoma syndrome. There are known cases of ectopic formation of STH-RH by these tumors, leading to the development of the clinical picture of acromegaly. In such patients, the STH-RH test is negative: the administered STH-RH or its analogue does not affect the level of STH in the blood, which is a reliable differential diagnostic criterion that allows differentiating ectopic formation of STH-RH.
Damage to the pituitary gland (hyperplastic changes or adenomas) develops in 1/3 of patients with multiple endocrine tumor syndrome type I. In this case, clinical signs of pituitary insufficiency or syndromes caused by excess of various pituitary hormones may also occur.
To identify families with multiple endocrine tumor syndrome type I, annual screening of its members is performed, which includes determination of serum calcium and parathyroid hormone levels in the blood for the early detection of parathyroid gland damage. Radioimmunoassay of gastrin and other pancreatic hormones in the blood should be performed for the early diagnosis of pancreatic islet apparatus damage. For the early detection of adenohypophysis damage, it is advisable to determine the levels of PRL and other pituitary hormones, as well as to conduct an X-ray examination of the sella turcica.
Multiple endocrine tumor syndrome type IIa
It is characterized by the presence of medullary thyroid cancer, pheochromocytoma, and hyperplasia or tumors of the parathyroid glands in patients. The combination of medullary thyroid cancer with pheochromocytoma was first described in detail by Sipple (1961), so this variant of multiple endocrine tumor syndrome is called Sipple syndrome. It is also inherited in an autosomal dominant manner with high penetrance, but with varying expression. The mutation in most cases of multiple endocrine tumor syndrome types IIa and IIb is reduced to a deletion of the short arm of 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 glands is sometimes detected even in the absence of clinical signs of dysfunction, during surgery for medullary thyroid cancer. Severe hypercalcemia in such patients is rare and, as in multiple endocrine tumor syndrome type I, is accompanied by the formation of kidney stones.
Medullary thyroid cancer of C-cell origin, often accompanied or preceded by C-cell hyperplasia. This tumor produces amyloid and various polypeptides. Less often, these tumors secrete serotonin, which causes the development of carcinoid syndrome, ACTH with the development of Itsenko-Cushing syndrome. Diarrhea caused by the secretion of VIP by the tumor occurs in 32% of patients with medullary thyroid cancer. Medullary thyroid cancers are malignant, mostly bilateral tumors (unlike sporadic cases), often metastasize to the cervical and mediastinal lymph nodes, lungs and liver. Typical tumor markers are calcitonin and histaminase. High levels of calcitonin, carcinoembryonic antigen (CEA), histaminase, etc. are determined in the blood of patients.
To diagnose medullary thyroid cancer, the calcium level in the blood is determined under basal conditions and under conditions of tests with pentagastrin and intravenous calcium administration. These compounds stimulate the release of calcitonin and allow the diagnosis of C-cell hyperplasia and MTC. The most informative test is with pentagastrin (at the rate of 0.5 mcg/kg in 5-10 ml of physiological solution), administered intravenously for 60 seconds. Blood for the study is taken before the test at the 2nd, 5th, 10th, 15th, 20th and 30th minute after the start of the injection.
Calcium loading: calcium chloride in 50 ml of normal saline to a final concentration of 3 mg/kg body weight by slow intravenous injection over 10 min. Blood is drawn before, at the end of the injection, and after 5, 10, and 20 min to determine calcitonin levels. Medullary thyroid cancer usually appears on a scan as a cold nodule or lesion. Like pheochromocytomas, medullary thyroid cancers can sometimes take up 131 1-methyliodobenzylguanidine, which, on the one hand, indicates their ability to produce catecholamines, and on the other hand, indicates that this drug can be used for diagnostic and therapeutic purposes in such variants of medullary thyroid cancer. Treatment of patients with medullary thyroid cancers is surgical. Total thyroidectomy with removal of regional lymph nodes is indicated.
Pheochromocytomas in type IIa multiple endocrine tumor syndrome are often (in 70% of patients) multiple and bilateral. Even in the case of unilateral tumors, the opposite adrenal gland often has hyperplasia of the medulla cells, which in turn is the source of the tumor or tumors. Pheochromocytomas are detected in families with type II multiple endocrine tumor syndrome in approximately 50% of cases and in 40% of families with medullary thyroid cancer. Pheochromocytomas secrete mainly adrenaline, unlike sporadic cases, in which the main hormone produced by the tumor is noradrenaline. Bilateral adrenal pheochromocytomas may be combined with paraganglioma of the organ of Zuckerkandl. A significant proportion of pheochromocytomas in type IIa multiple endocrine tumor syndrome are benign. Their clinical manifestations vary greatly and in most cases do not allow for their rapid diagnosis. The majority of patients do not have classic paroxysms in combination with hypertensive crises. Many complain of rapid fatigue, attacks of tachycardia and sweating. For diagnostic purposes, generally accepted methods of determining the level of catecholamines in the blood and urine with the measurement of the adrenaline/noradrenaline ratio are used, as well as provocative tests with inhibition (clonidine) and stimulation (histamine and pentolamine) of the release of catecholamines. However, to avoid serious complications, the latter are not widely used. Moreover, clonidine has limited use for detecting pheochromocytomas in multiple endocrine tumor syndrome type II due to the fact that these tumors, unlike sporadic cases, produce predominantly adrenaline, not noradrenaline, the secretion of which is primarily inhibited by clonidine. A simple noninvasive exercise challenge test is also used, which can be used in patients of any age and physical condition. It is performed using submaximal exercise on an electric bicycle ergometer, which is gradually increased until the patient begins to experience discomfort and mild fatigue. At this time, pulse rate, blood pressure, and ECG are measured. Blood for the study is taken before the start of the test after a light breakfast through a venous catheter, after 30 minutes of rest, and immediately after stopping work in a supine position. In patients with pheochromocytoma, the increase in adrenaline levels is statistically significantly higher than in individuals without pheochromocytoma. The same is true for the adrenaline- dopamine ratio. Computer tomography makes it possible to detect pheochromocytoma with a diameter of more than 1 cm, and 131 1-methyliodobenzylguanidine makes it possible to determine pheochromocytoma metastases. Treatment is surgical, usually bilateral adrenalectomy.
Screening for multiple endocrine tumor syndrome type II includes three components: anamnesis (a detailed life history over 2-3 generations), examination of the patient, including identification of signs of the presence of thyroid tumors, chromaffin tissue, etc.; manifestations of the syndrome in its various variants; laboratory examination of the patient and his immediate relatives.
Multiple endocrine tumor syndrome type IIb
In terms of clinical symptoms, the syndrome is similar to multiple endocrine tumor syndrome type IIa, but is genetically different from it. It manifests itself in younger individuals, the parathyroid glands are rarely affected. Patients usually have normocalcemia and normal levels of immunoreactive parathyroid hormone (PTH). However, the PTH level does not decrease with intravenous calcium administration, which is not observed in patients with multiple endocrine tumor syndrome type II.
The main difference between the syndrome of multiple endocrine tumors type IIb is the presence of multiple neuromas of the mucous membranes of the oral cavity, lips, eyelids, which are often detected already in childhood. They are especially clearly visible on the tip and lateral surface of the tongue in the form of multiple nodules up to 1 cm in diameter. Neuromas are formed almost along the entire length of the gastrointestinal tract, up to the anus. Many patients with this syndrome have a Marfan-like appearance and other skeletal and muscular manifestations: equine foot, slippage of the femoral head, kyphosis, scoliosis, deformation of the anterior chest. All these phenotypic changes give patients a characteristic appearance. The prognosis for this syndrome is worse than for the syndrome of multiple endocrine tumors type IIa, due to the aggressive nature of tumor growth. In patients with the syndrome of multiple endocrine tumors type IIb, 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.
There is a point of view that there is also a type III syndrome of multiple endocrine tumors, which unites a number of diseases: pheochromocytoma, Recklinghausen's disease, carcinoid of the duodenum. There are also data on mixed syndromes of multiple endocrine tumors. In these syndromes, a certain specific component of one of the clear types of syndrome of multiple endocrine tumors is combined with elements of another. Thus, there are families in which an islet tumor of the pancreas is combined with pheochromocytoma originating from the adrenal medulla, and in these cases the disease is inherited according to the autosomal dominant type. Pituitary adenomas can be combined with paragangliomas. In some of these patients, the parathyroid glands are also involved in the pathological process. In these cases, hypercalcemia is detected. Pituitary adenomas can also be combined with other variants of multiple endocrine tumor syndromes types IIa and IIb.
Combined various syndromes of multiple endocrine tumors support the theory of the existence of a single progenitor cell for all cells of the APUD system, although it is possible that during malignant growth, dedifferentiation of cells occurs, during which tumor cells begin to produce various polypeptides.
What tests are needed?
Who to contact?