Pancreatic Pathology Online

Multiple Endocrine Neoplasia (MEN) Syndrome

Dr Sampurna Roy MD                July 2016

 

Multiple endocrine neoplasia (MEN) types 1 and 2 are hereditary cancer syndromes. They are characterized by the occurrence of many benign and malignant tumours.

This condition is rare and is characterized by adenomatosis of the pituitary, parathyroids, and pancreas (MEN type 1).

It is frequently associated with the Zollinger-Ellison syndrome, in which case gastrin-secreting islet cell tumors are usual.

The syndrome reflects the functional state of the neoplastic glands and may be quite complex.

Such adverse conditions as acromegaly, pituitary dwarfism, hypogonadism, hyperparathyroidism, and the carcinoid syndrome have been described either alone or in various combinations.

Multiple endocrine neoplasia with peptic ulceration is inherited as an autosomal dominant gene with a high level of penetrance.

Since abnormal growth of different tissues is the major common feature of this condition, the gene abnormality has been described as pleiotropic.

The syndrome has been documented in various ethnic groups, including Italian, Swiss, Mexican, and Puerto Rican families.

Multiple endocrine neoplasia type 2 (MEN2) is a rare autosomal dominant syndrome caused by mutations in the RET protooncogene and is characterized by a strong penetrance of medullary thyroid carcinoma (all subtypes) and is often accompanied by pheochromocytoma (MEN 2A/2B) and primary hyperparathyroidism (MEN 2A).

A variant of the multiple endocrine neoplasia syndrome - Sipple’s syndrome, or MEN type 2A - consists of multiple tumours of the adrenal medulla (pheochromocytomas), medullary carcinomas of the thyroid (calcitonin-secreting tumors) and parathyroid hyperplasia may be present in some cases.

In this condition the pancreas is normal and hypergastrinemia and peptic ulceration are absent.

 

MEN 2B or MEN3 is clinically similar to MEN2A.

According to recent advances it is a distinct form of syndrome.

In addition to medullary carcinoma the patients may present with pheochromocytomas. The other lesions in MEN2b are neuromas / ganglioneuromas in the skin, oral cavity, respiratory tract and gastrointestinal tract.

 

Carriers of a MEN1 or RET gene mutation can be identified before manifestation of the disease.

Family screening allows the early diagnosis and therapy of gene carriers.

Early thyroidectomy in young patients with MEN2 results in a high cure rate of medullary thyroid carcinoma.

A few years ago a novel multiple endocrine neoplasia syndrome, named multiple endocrine neoplasia type 4 (MEN4), was discovered  based on studies conducted on a MEN syndrome in the rat (named MENX). The rat and the human syndromes are both caused by germline mutations in the Cdkn1b/CDKN1B gene, respectively.

 

Zollinger-Ellison Syndrome (Gastrinoma):

Zollinger-Ellison syndrome comprises a triad of recalcitrant peptic ulcer disease, gastric hypersecretion, and an endocrine cell tumor elaborating gastrin.

Lesions:

Sixty percent of gastrinomas are malignant, with spread to lymph nodes and metastasis; 40% are benign.

Gastrinomas are most common in the pancreas, but 10 to 15% arise in the duodenum.

The histologic and ultrastructural features are similar to normal intestinal and gastric G cells.

Peptic ulcers are in the usual sites in the stomach or duodenal in 75% of cases.

Abnormally, located ulcers in the stomach or first and second portion of duodenum occur in 25%.

The stomach shows hyperplasia of parietal cells.

Clinical features:

Features include striking gastric hypersecretion  with intractable ulcers and severe diarrhea, with fluid and electrolyte imbalance and malabsorption.

Surgical removal is extraordinarily difficult, with recurrence of symptoms postsurgically common.

 

Tumours in Zollinger-Ellison Syndrome:

Before the advent of immunocytochemistry it was thought that the great majority of gastrinomas occurred in the pancreas.

The paradox remained, however, the gastrin secreting G cells are not found in the normal pancreas but are present in the gastric antral and duodenal mucosa.

Re-analysis by immunocytochemistry of older pancreatic resections done for Zollinger-Ellison syndrome (ZES) showed that some of the tumours thought to be gastrinomas contained no gastrin.

The explanation for this probably lies in the fact that approximately 40% of patients with ZES have Multiple Endocrine Neoplasia Type 1 Syndrome (MES-1).

Equally, 40% to 60% of patients with MEN-1 have ZES.

It has now been shown that the great majority of gastrinomas in patients with MEN-1 are to be found in the duodenum.

Here they are usually small, often multiple and can easily be missed at surgery unless specifically sought.

By contrast, gastrinomas in patients with ZES who do not have MEN-1  (sporadic ZES) are usually solitary and over half are to be found in the pancreas.

Forty per cent are, however, still present in the duodenum.

Majority of the duodenal tumors metastasize to regional pancreatic lymph nodes, but inspite of this, 10-year survivals of up to 85% have been reported.

Compared to duodenal gastrinomas, pancreatic gastrinomas are more frequently large and likely to cause widespread liver metastases.

Patients with metastatic gastrinoma to the liver have a 5 year survival rate of less than 20%.

Thus pancreatic gastrinomas tend to behave as neuroendocrine carcinomas producing an ectopic hormone, while duodenal gastrinomas, which do not produce an ectopic hormone, are less likely to be aggressive having a course which has been likened to that of papillary carcinoma of the thyroid.

The great majority of patients with MES-1 have pancreatic tumours which are usually multiple - in some cases hundreds of microscopic lesions are present.

A large variety of tumours can be found.

Glucagonomas are most frequent, followed by insulinoma and PPomas.

As described above gastrin immunostaining is rare.

 

Further reading

Diagnostic and therapeutic strategies in Zollinger-Ellison syndrome associated with multiple endocrine neoplasia type I (MEN-I): experience of the Zollinger-Ellison Syndrome Research Group: Bichat 1958-1999.

Diagnosis and treatment of multiple endocrine neoplasia type 1 (MEN1).

Type I multiple endocrine neoplasia--Wermer syndrome.

The pathology of insulinoma and gastrinoma. The location, size, multicentricity, association with multiple endocrine type-I neoplasms and malignancy

Diagnosis and preoperative imaging of multiple endocrine neoplasia type 2: current status and future directions.

Multiple endocrine neoplasia type 1 associated with breast cancer: A case report and review of the literature.

Nonfunctional Metastatic Parathyroid Carcinoma in the Setting of Multiple Endocrine Neoplasia Type 2A Syndrome.

Multiple endocrine neoplasia syndromes associated with mutation of p27.

Multiple endocrine neoplasia type 4

Multiple endocrine neoplasia (MEN).

 

 

Dr Sampurna Roy  MD

Consultant  Histopathologist (Kolkata - India)


 

 

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