Multiple Endocrine Neoplasia Type 1 (MEN I, Wermer Syndrome)

Article Author:
Gurdeep Singh
Article Editor:
Ishwarlal Jialal
Updated:
4/3/2019 3:22:18 PM
PubMed Link:
Multiple Endocrine Neoplasia Type 1 (MEN I, Wermer Syndrome)

Introduction

Multiple endocrine neoplasia type 1 (MEN1) is a rare endocrine tumor syndrome with high penetrance. It primarily causes neoplasia of parathyroid glands, anterior pituitary gland, and the neuroendocrine tissue of gastro-entero-pancreatic tissue.

Hyperparathyroidism is most common and occurs in 90% of cases; pancreatic neuroendocrine tumor occurs in 60% and pituitary adenoma in 40% cases.

It is also known as Wermer syndrome.[1]

The MEN1 patient may also develop other endocrine and non-endocrine tumors like carcinoid tumors of the thymus, bronchus, or stomach, adrenocortical tumor, cutaneous tumors, central nervous system (CNS)  tumors, leiomyoma, lipoma, collagenoma, and angiofibroma.

MEN1 gene testing in an index case can confirm the diagnosis and allow early detection of asymptomatic mutation carriers, years before an MEN1-associated tumor can be detected. However, around 20% of MEN1 kindred have no mutation in the MEN1 gene.[2]

Unfortunately, there is no genotypic-phenotypic correlation in MEN1, leading to different manifestations, even among family members, but nonsense and splicing mutations are associated with more aggressive neuroendocrine tumors.

Etiology

Germline inactivating mutations of the MEN1 gene on chromosome 11 cause MEN1 syndrome. MEN1 syndrome is an autosomal dominant syndrome that occurs in around 90% of cases usually inherited from the affected parent or because of a de novo mutation in about 10% of cases.

 Marini et al. published an analysis of germline MEN1 mutations in 410 patients and found 99 different mutations, 41 frameshift, 26 missense, 13 nonsense, 11 splicing site mutations, 4 in-frame small deletions, and 4 large intragenic deletions spanning over 1 exon. They also found that gastro-entero-pancreatic tumors were more common in patients with nonsense mutations and thoracic neuroendocrine tumors were more common in individuals bearing a splice mutation.[3]

About 20% of MEN1 kindreds lack any detectable mutation in the MEN1 gene; thus, clinical diagnostic criteria remain essential in the diagnosis of this syndrome.

Germline mutation of CDKN1B has been found to cause pituitary adenomas, parathyroid adenomas, and pancreatic neuroendocrine tumors. Therefore, it is possible that mutations in this gene could account for MEN1 syndromes without MEN1 gene mutation.

Epidemiology

Diagnosis of MEN1 is established if the  index case has at least 2 of the primary manifestations of MEN1 (tumor of parathyroid glands, anterior pituitary gland and neuroendocrine tissue of gastro-entero-pancreatic tissue) or at least one MEN1-related tumor and a first-degree relative with confirmed MEN1 (positive MEN1 gene mutation) or the index case has the pathologic mutation in the MEN1 gene.

MEN1 syndrome is rare with an incidence of 0.25% and estimated prevalence between 0.02 to 0.2 per thousand. The disorder affects all age groups and has been reported in children as young as 5 years.

Clinical and biochemical manifestations develop in over 94% of the patients by the fifth decade.

MEN1 has been shown to affect men and women equally,  in the study by Gaudet et al  of 734 MEN1 patients there was a slight female preponderance (57.8%). The prevalence of pancreatic tumors was higher in men because of gastrinomas. The prevalence of pituitary tumors was slightly higher in women, and thymic tumors were exclusively found in men.[4]

Cushing disease may be the first presentation in children with MEN1 as reported by Makri et al. in their retrospective chart review of 238 patients admitted at National Institute of Health (NIH) for evaluation of hypercortisolemia. Out of these, 6 patients had MEN1; 5 cases were familial; one case was sporadic.[5]

History and Physical

A comprehensive history should be obtained during an initial visit as MEN1 can affect multiple organs. Complete family history can lead to early diagnosis as MEN1 may affect members of the same family. Patients in the same family may have different manifestations due to heterogeneous phenotypic expression.

A complete physical examination during initial and follow-up visits should be done to detect any visual field changes or a mass in the neck or abdomen area. Physicians identify MEN1 in many patients after incidental, abnormal lab or imaging studies. Symptoms may differ depending upon which organs are affected. The physical examination may be normal in many of these patients as the tumor size may be small.

Evaluation

Evaluation of hyperparathyroidism involves measurement of serum calcium and PTH. The PTH level may be minimally elevated or in a high-normal range which can lead to a delay in making the diagnosis. 

Imaging modalities like parathyroid USG and sestamibi scan are of limited value due to diffuse hyperplasia involving many glands in MEN1 patients.

Evaluation of gastro-entero-pancreatic tumors involves measurement of gastrin, glucagon, insulin, proinsulin, C-peptide, chromogranin A, pancreatic polypeptide, and vasoactive intestinal peptide (VIP).

Different modalities like transabdominal ultrasound, CT, MRI, octreoscan, and 68Ga-DOTATOC PET imaging are used for evaluation of gastro-entero-pancreatic tumors.

Endoscopic ultrasound has been found to be the most sensitive single modality to detect pancreatico-duodenal tumors. Multiple studies have reported significant superiority of EUS as compare to CT scan and somatostatin-receptor scintigraphy.[6]

Evaluation of pituitary gland tumors includes measurement of pituitary hormones including prolactin, growth hormone, IGF-1, follicle-stimulating hormone (FSH), luteinizing hormone, adrenocorticotropic hormone (ACTH), TSH, T4, and cortisol.[7] These tumors most commonly secrete the hormone prolactin, followed by growth hormone. Serial basal PRL levels greater than 200 ng/ml confirm a prolactinoma and elevated IFG-1 levels with the failure of GH to suppress during an oral GTT confirm a GH secreting adenoma. Non-secreting pituitary tumors can cause hypopituitarism by compression of the pituitary gland. MRI of the pituitary gland with contrast is the best diagnostic imaging. Thin cuts through pituitary gland should be done to avoid missing small tumors. Pituitary MRI is also used to evaluate the effectiveness of treatment during follow up of pituitary tumors.

Treatment / Management

Parathyroid

Primary hyperparathyroidism (PHPT) is the most common and the  first clinical manifestation of MEN1. It affects around 90% of MEN1 patients and is commonly diagnosed during the second decade of life.

Multi-gland, nodular hyperplasia is typical in MEN1 hyperparathyroidism, and it presents as hypercalcemia or its complications.

MEN1-related PHPT is associated with more severe bone disease despite a milder biochemical presentation (PTH value in the normal range) when compared with sporadic PHPT.[8]

Parathyroid cancer is sporadic in MEN1.  Di Meo et al. reported 17 cases of parathyroid cancer of which 59% were seen in men, and the median age of diagnosis was 50.[9]

Treatment of PHPT in MEN1 with subtotal parathyroidectomy versus total parathyroidectomy is controversial. Total parathyroidectomy with forearm transplantation has been shown to be associated with the lesser chance of persistent hyperparathyroidism, but there is a significant risk of hypoparathyroidism with total parathyroidectomy (22% to 36%) compared to 10% with subtotal parathyroidectomy.[2]

Gastro-Entero-Pancreatic Tumors

The neuroendocrine tumor (NET) of gastro-entero-pancreatic tissue occurs in around 30% to 75% of cases, but post-mortem studies have shown a prevalence of up to 80% to 100%.[10] A nonfunctioning NET is more common than a functioning tumor.

Pancreaticoduodenal NET in MEN1 presents early in life,  is almost always multiple, and have uncertain behavior with a risk of malignancy. 

Functioning NET secreting gastrin can cause peptic ulcer disease because of increased gastric acid secretion, known as Zollinger-Ellison Syndrome. Functioning NET can also cause hypoglycemia by secreting an excessive amount of insulin, but tumors secreting pancreatic polypeptide may not cause any clinical manifestations.[11]

Gastrinoma

The most frequent islet cell neoplasm is gastrinoma. Gastrinomas in MEN1 can be pancreatic or duodenal and are mostly diagnosed in the third or fourth decade of life. Detailed history and physical examination and biochemical evaluation should be done in patients with gastrinoma because around one-third of patients with gastrinoma have MEN1. These patients have hypergastrinemia and increased gastric acid output.

Duodenal gastrinomas in MEN1 syndrome are usually small (smaller than 1 cm), multifocal, and occur mainly in the proximal duodenum.  Lymph node metastasis occurs in 45% to 95% of both pancreatic and duodenal gastrinoma, but liver metastasis is less common in duodenal NET.[10]

Insulinoma

Insulinoma is the second most common functional pancreatic NET; they represent around 10% to 30% patients of pancreatic NET in MEN1. These tumors secrete a significant amount of insulin which can cause the clinical manifestation of hypoglycemia including neuroglycopenic symptoms and sometimes severe hypoglycemia causing seizure or loss of consciousness. Patients with insulinoma due to MEN1 are mostly young (younger than 40 years old) when compared with insulinoma patients without MEN1 (older than 40 years old).[11]

Fasting hypoglycemia with a glucose level of less than 45 mg/dl with concomitant hyperinsulinemia with an insulin level greater than 6 uU/mL is diagnostic of insulinoma.[12] An elevated level of proinsulin and C-peptide can confirm the diagnosis of insulinoma.

Surgical treatment is necessary for insulinoma patients. Preoperative tumor localization with different modalities including transhepatic portal venous sampling can improve the success rate of surgery. Surgical treatment can vary from enucleation of a single lesion to partial pancreatectomy. These patients can be managed medically with diazoxide or octreotide; frequent carbohydrate meals also help to lower risk of hypoglycemia.

 Tonelli et al. reported 12 MEN1 insulinoma patients who underwent surgery; distal pancreatic resection was performed in 8 patients, 4 patients had pancreatoduodenectomy and enucleation of other macroadenoma present in the remnant pancreas was done in 9 out of 12 patients. There were no clinical recurrences at a mean follow-up of 85 months, but recurrence of nonfunctioning pancreatic macroadenoma occurred in 1 out of 12 patients.[13]

Chemotherapy can be used in patients with metastatic insulinoma.

Glucagonoma

Glucagonoma occurs in less than 3% of MEN1 patients. The typical manifestations include necrolytic migratory erythema, weight loss, anemia, and stomatitis. Glucagon levels are significantly elevated in these patients, usually greater than 500 pg/ml.[14] The most common site of occurrence is the tail of the pancreas, and surgical removal is the treatment of choice. Metastatic disease is present in up to 50% to 80% patient at the time of diagnosis. Medical management includes somatostatin analogs or chemotherapy.

VIPomas are not common in MEN1. These patients present with watery diarrhea, hypokalemia, and achlorhydria, known as Verner-Morrison-syndrome. Stool volume more than 0.5 to 1 L per day during a fast is typical. Use of laxatives and diuretics should be ruled out before confirming the diagnosis of VIPoma. Similar to glucagonoma, the most common site of involvement is the tail of the pancreas. Surgical resection can be curative in the absence of metastatic disease. Medical treatment includes somatostatin analogs, metoclopramide or chemotherapy agents like 5-fluorouracil or streptozotocin.

Nonfunctioning pancreatic NET is the most common gastro-entero-pancreatic tumor.[15] These lesions cause no clinical syndrome and may secrete a small amount of pancreatic polypeptide and gastrin. These are the most frequent cause of death in MEN1 patients. There can be a delay in diagnosis of nonfunctioning pancreatic NET due to lack of any specific clinical syndrome.

Radiological screening for diagnosis of pancreatic NET in MEN1 is recommended at the age of 10 years.

Treatment of nonfunctioning pancreatic NET is challenging and controversial because of the lack of consensus on the surgical indications. Triponez et al. reported that tumor size in nonfunctioning pancreatic NET correlates with the risk of metastasis and death[15], but other studies did not confirm similar findings. Clinical practice guidelines for MEN1 recommend surgery if the size of the tumor is over 1 cm, but other studies do not recommend surgery until the size is 20 mm or more. Surgery can be considered for tumors less than 1 cm if there is rapid growth. So far tumor size has remained the deciding factor, but aggressive surgical management can cause significant complications like diabetes mellitus, steatorrhea, and early dumping syndrome. 

Pituitary Tumors

Prevalence of anterior pituitary tumors in MEN1 syndrome is around 20% to 60%, and the anterior pituitary tumor can be an initial presentation in around 25% of MEN1.

Anterior pituitary tumors in MEN1 are more common in women and are predominantly macroadenomas.[16]

Medical management includes the use of cabergoline or bromocriptine in patients with prolactinoma. Octreotide or lanreotide are used in GH producing tumors.

Studies have shown that anterior pituitary tumors in MEN1 patients are more aggressive and less likely to respond to medical management; thus requiring surgical management more often. Radiation treatment is used for patients with the residual unresectable tumor.

Surgical management is done in patients with large pituitary tumors with compression of optic nerve or tumors more than 1 cm or tumors which do not improve with medical management.

Carcinoid

Carcinoid tumors affect 3% of MEN1 patients. Common sites of involvement are the gastrointestinal (GI) tract, bronchi, pancreas, and thymus. Somatostatin analogs such as octreotide or lanreotide have been shown to cause regression of gastric carcinoid.[17] 

Bronchial carcinoids causing MEN1 are more common in  woman, but thymic carcinoids in European patients occur predominantly in men.

Thymic carcinoids are aggressive in MEN1 patients. Goudet et al. reported a survival rate of only 9.5 years after diagnosis of a thymic tumor with 70% mortality linked directly to the tumor.[4]

Screening for these patients is done with radiologic imaging like CT scan and MRI every 1 to 2 years. Biochemical evaluation is not done routinely due to lack of any specific biochemical abnormality or hormone production.

Surgical removal is the treatment of choice. Thymic carcinoid has been seen even in patients who underwent prophylactic thymectomy; therefore, surveillance with imaging is required. Radiotherapy and chemotherapy can be used in patients with an unresectable tumor or metastatic disease.

Adrenal Tumors

Asymptomatic adrenal tumors occur in around 20% to 73% of MEN1 patients. Compared to adrenal incidentalomas, there is more likelihood of hyperaldosteronism and adrenocortical cancer but less likelihood of pheochromocytoma in MEN1 patients.[18]

The incidence of adrenocortical cancer is around 1% in MEN1 patients, but this can increase up to 13% with an adrenal tumor larger than 1 cm.

Biochemical evaluation of adrenal tumors includes the evaluation of plasma free metanephrines, 1-mg overnight dexamethasone suppression test, urine-free cortisol, evening salivary cortisol,  plasma renin, and aldosterone concentration with increased aldosterone: renin ratio greater than 20 and an increase in urinary aldosterone secretion.

There is no consensus about management of nonfunctioning adrenal tumors in MEN1 patients, but because of an increased risk of adrenocortical cancer, surgery is recommended if the tumor size is larger than 4 cm or tumor size 1 to 4 cm if there is a significant measurable growth over 6 months with suspicious radiological features.

LeBodic et al. reported an immunohistochemical study of 100 pancreatic tumors in 28 MEN1 patients and found that out of 100 tumors, 83 produced a predominant hormone, 10 were pluri-hormonal, and multiple tumors had a different predominant hormonal secretion in the same patient in 23 out of 28 patients.[19]

Breast

Breast cancer is more common in female MEN1 patients and occurs at an early age. Rachel et al. found that median age of breast cancer in women with MEN1 was 45 compared to 57.5 years in female relatives without MEN1 and 61.2 in the Dutch reference population.[20]

The importance of breast cancer screening cannot be overstated in these patients.

Differential Diagnosis

Differential diagnoses of MEN1 include von Hippel-Lindau syndrome, neurofibromatosis type 1, tuberous sclerosis complex, and multiple endocrine neoplasia type 4.

Prognosis

The prognosis of the MEN1 patient is variable. Tumors associated with MEN1 are more aggressive and challenging to treat. Neuroendocrine tumors can metastasize quickly and can cause premature death. Studies have shown an increased risk of premature death and decreased average life expectancy in MEN1 patients.[21] These patients can also develop significant morbidity because of surgical complications.

Complications

The complications in MEN1 can occur because of the disease itself or due to surgery.

Pituitary tumors can cause complications like pituitary insufficiency and visual field defects.

Parathyroid tumors can cause metabolic bone disease and kidney stones. Tumors of gastro-entero-pancreatic tissue can cause complication by excessive secretion of gastrin, insulin, glucagon, or vasoactive intestinal peptide or by metastatic disease.

Deterrence and Patient Education

Patient education is vital. Once the physician diagnoses MEN1, the patient's family should see a genetic counselor to learn about the disease how it may impact the patient and patient's family. A genetic counselor should also encourage the rest of the family to get genetic testing done. Complete knowledge of the disease can help the patient to make an appropriate and informed decision.

Pearls and Other Issues

Because of the rarity of the MEN1 syndrome and the complexity of the disease, it is difficult to manage these patients.

Majority of recommendation regarding management of MEN1 patients lack a high level of evidence suggesting the need for more research in this field.  Al-Salameh et al. reported that only 11 out of the 47 recommendations for MEN1 are considered having a high level of evidence.[1]

Average life expectancy is shorter in patients with non-functioning pancreatic NET compared to MEN1 patients without pancreatic NET tumors.

Enhancing Healthcare Team Outcomes

MEN1 is a complex syndrome that increases morbidity and mortality by causing multiple aggressive tumors. These patients should be managed in a tertiary care center by an interprofessional team including an endocrinologist, endocrine surgeon, gastroenterologist, neurosurgeon, genetic counselor, nurse, pharmacist, and patient navigator or advocate for a better outcome.[22]


References

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