Multiple Endocrine Neoplasia (MEN Syndrome)
Multiple Endocrine Neoplasia [MEN] Type 1
Multiple Endocrine Neoplasia [MEN] Type 2A
Multiple Endocrine Neoplasia [MEN] Type 2B
Genetic susceptibility to Multiple Endocrine Neoplasia [MEN]
Family history of Multiple Endocrine Neoplasia [MEN]
Are You Confident of the Diagnosis?
What you should be alert for in the history
Characteristic findings on physical examination
Expected results of diagnostic studies [histopathology, serologic tests, genetic tests, imaging studies]
Diagnosis confirmation [Describe those conditions in the differential diagnosis that may reasonably mimic the diagnosis and explain their distinction]
Multiple endocrine neoplasias (MENs) are autosomal dominant inherited disorders that can result in significant morbidity and mortality. MEN syndromes are classified into MEN type 1 and MEN types 2A and 2B.
MEN1, formerly known as Wermer’s syndrome, has a genetic predisposition to develop multiglandular parathyroid disease, benign and malignant neuroendocrine tumors of the pancreas and duodenum, and adenomas of the anterior pituitary. Two of the three major lesions must be present for the clinical diagnosis. In family members of patients with known MEN1, the presence of one major lesion is diagnostic. Clinical diagnosis is confirmed by genetic testing.
Characteristic findings on physical examination
Primary hyperparathyroidism (PHPT) caused by multiple parathyroid adenomas is the most common clinical expression of MEN1, and is the first manifestation in approximately 90% of patients. Patients present with signs and symptoms consistent with sporadic PHPT, and include nephrolithiasis, abdominal pain, lethargy, psychiatric disturbances, fragility fractures and osteoporosis.
The second most frequent manifestations of MEN1 are pancreaticoduodenal tumors. The two most common functional tumors are gastrinomas and insulinomas. Patients with gastrinomas present with classic signs and symptoms of Zollinger-Ellison syndrome: abdominal pain, reflux, secretory diarrhea, and weight loss. Patients with insulinomas present clinically with neuroglycopenia (confusion, anxiety, tremor, and diaphoresis), fasting hypoglycemia, and reversal of symptoms after administration of glucose.
Nonfunctional pancreaticoduodenal tumors become symptomatic only as a result of their location or growth and mass effect on surrounding structures. Clinical presentation of pituitary tumors includes visual field defects, blurred vision, and headaches. The most common pituitary tumor, a prolactinoma, may cause galactorrhea, amenorrhea, infertility in women, and hypogonadism in men.
Less common physical examination findings may include cutaneous or mucosal abnormalities encompassing multiple subcutaneous lipomas, multiple facial angiofibromas, hypomelanotic macules, gingival papules, and collagenomas.
MEN2A and MEN2B, also known as Sipple’s syndrome, are characterized by the presence of medullary thyroid carcinoma (MTC) presenting clinically as a thyroid mass or nodule, and pheochromocytomas. Pheochromocytomas may either be asymptomatic or present with symptoms of episodic diaphoresis, headaches, anxiety, palpitations, and hypertension referable to the catcholamines produced by these tumors.
Parathyroid disease, a common finding in MEN2A, is not a feature of MEN2B. Manifestations of parathyroid disease are described above. MEN2B, however, is distinguished by multiple mucosal neuromas and distinctive marfanoid body habitus. Neuromas can cause enlarged and nodular lips as well as thickened eyelids (see
Mucosal neuromas of the tongue.
Skeletal abnormalities may occur and include genu valgum, pes cavus, and kyphoscoliosis. These characteristics are often recognized at infancy, affording the physician the opportunity to diagnosis MEN2 before the thyroid and adrenal components clinically manifest. Ophthalmic abnormalities with slit lamp examination may reveal thickened corneal nerves. Further, gastrointestinal endoscopic surveillance may reveal multiple gastrointestinal ganglioneuromas. Patients with MEN2 either present as an index case or as a member of a known MEN2 kindred. Index cases are most likely to present with MTC, and the age of onset depends on the underlying genetic mutation.
Expected results of diagnostic studies
Diagnosis of MEN syndrome is based on genetic testing, biochemical evaluation, and imaging. In MEN1 no correlation has been found between specific mutations in the MEN1 gene and the phenotype of affected patients. Therefore, using genetic testing to predict malignant potential and prognosis is not possible. However, when an initial case of MEN1 is diagnosed clinically, DNA evaluation of the patient and their presymptomatic first-degree relatives should be completed.
Mutation screening should be considered in young patients less than 45 years of age with PHPT, particularly in those with multigland disease or recurrent hyperparathyroidism, in the absence of renal disease. In contrast to MEN1, phenotype-genotype correlations are seen in MEN2. Therefore, the results of a genetic test may dramatically alter treatment in these patients, especially the presymptomatic ones. Guidelines for MEN2 genetic testing for the RET germline mutation include index case patients with a clinically confirmed diagnosis. In addition, asymptomatic at-risk relatives, all first-degree relatives, and second-degree relatives if testing of the first-degree link is not possible should undergo genetic testing. Given the clinical importance of identifying the RET mutation, all individuals with seemingly sporadic MTC or pheochromocytoma should be tested for the mutation.
Biochemical diagnosis for MEN1 includes a work-up surrounding the three associated major tumors. Parathyroid tumors would result in an elevated serum calcium level in the presence of either an elevated level of parathyroid hormone (PTH) or an inappropriately non-suppressed PTH. Evidence of gastrinoma consists of an increased fasting serum gastrin level (>100 pg/ml) and gastric acid hypersecretion (>15 mEq/hr with no previous gastric surgery). The diagnosis of an insulinoma is associated with inappropriate hyperinsulinemia concomitant with profound hypoglycemia (blood glucose <40mg/dL). In addition C-peptide, sulfonylurease, and anti-insulin antibodies should be measured to eliminate the possibility of factitious hypoglycemia.
Nonfunctional pancreatic neuroendocrine tumors may be detected by measurement of serum chromogranin A and pancreatic polypeptide. Elevated prolactin, somatotrophin, or corticotrophin may be measured to identify pituitary adenomas. Biochemical workup for MEN2 includes basal serum calcitonin and carcinoembryonic antigen (CEA) levels, both of which would be elevated in MTC. Elevated plasma-free metanephrines/normetanephrines or 24 hour urinary catecholamines, VMA and metanephrines/normetanephrines are indicative of pheochromocytomas. Additionally testing for primary hyperparathyroidism as described above should be performed.
Imaging of the parathyroids, thyroid, adrenals, pituitary, and pancreas should be performed as indicated by biochemical findings or as part of disease surveillance, approximately once a year.
Who is at Risk for Developing this Disease?
The estimated frequency of MEN1 is 1 in 30,000 people. However, the actual prevalence may be underestimated, as the syndrome is not often completely recognized. The clinical expression of MEN1 typically begins in the third decade for women and the fourth decade for men, with the onset of disease being rare before age 10 years. The MEN1 syndrome has no predilection for race, ethnicity, or geographic location. The diagnosis of MEN1 should be considered in patients presenting with early-onset hyperparathyroidism, multiple gland parathyroid disease, or rare neuroendocrine tumors. Given the hereditary nature of the disease, all children of a parent with MEN1 have a 50% chance of developing the syndrome.
MEN2 has been identified in 500-1,000 kindreds, with MEN2A accounting for 75% of all MEN2 cases. Both MEN2A and MEN2B have a high penetrance for MTC and approximately 90% of MEN2 carriers have evidence of MTC. Other rare variants of MEN2 include MEN2A with cutaneous lichen amyloidosis, MEN2A with Hirschsprung’s disease, or familial MTC (FMTC). Several criteria must be met to be classified as having FMTC, which includes more than 10 carriers displaying MTC in a kindred, multiple affected members older than 50 years, and an adequate workup to exclude pheochromocytomas or PHPT. Approximately 25% of MTC cases are recognized as hereditary.
What is the Cause of the Disease?
MEN1 and MEN2 are hereditary cancer syndromes. Germline mutations in the MEN1 tumor suppressor gene located on chromosome 11q13 cause the MEN1 syndrome. MEN1 encodes for the protein menin. The function of menin is not well understood; however, it does participate in transcription regulation, cell proliferation, genomic stability, and regulation of apoptosis. Since MEN1 is a tumor suppressor gene, development of the syndrome requires two genetic “hits” involving both copies of the gene to result in loss of function. The first mutation is inherited in the germline and the second mutation occurs in a somatic cell of a target tissue resulting in tumor formation.
There are numerous unique germline mutations with over 300 specific mutations described in families with MEN1 thus far. Genetic testing can identify MEN1 gene mutations in 75-90% of people with clinical symptoms. A positive test result can confirm a diagnosis in an affected individual, or identify family members at risk of developing MEN1. However, a negative test cannot definitively rule out the syndrome when a mutation has not been previously identified in another family member.
Mutations in the RET proto-oncogene located on chromosome 10 cause MEN2 and affect the tyrosine kinase receptor protein. These receptors play a significant role in the regulation of cell growth and differentiation. Therefore mutations in the RET gene cause affected cells to divide uncontrollably, resulting in tumor formation. Genetic testing identifies RET mutations in 95% of people with clinical symptoms of MEN2A and MEN2B, and in approximately 88% of families with FMTC. Depending on the specific RET mutation, predicting the severity and progression of the disease is possible to some degree. This is helpful in determining screening recommendations, and timing of risk-reducing surgical intervention.
Systemic Implications and Complications
The disorders that comprise the MEN syndromes are by definition systemic. There are however, additional rare findings associated with MEN1 that include thyroid neoplasia, adrenal neoplasia and hyperplasia, and carcinoid tumors. Approximately 40% of MEN1 patients have adrenocortical lesions, which are hyperplastic, bilateral, and nonfunctioning. Hypercortisolism in MEN1 can result from an adrenocorticotropic hormone (ACTH) secreting pituitary process, a cortisol secreting adenoma, or an ACTH or corticotropin releasing factor-producing islet cell tumor or thymic carcinoid. In addition, adrenocortical carcinomas have also been described in MEN1 patients in association with insulin producing islet cell tumors raising the possibility of a shared underlying genetic cause.
Carcinoid tumors are also overrepresented in MEN1 patients and are the second most common cause of tumor-related deaths in these patients after pancreatic neuroendocrine tumors. Thymic carcinoids are the most aggressive and transcervical thymectomy performed during the operation for PHPT does not guarantee against future development of these carcinoids. Gastroduodenal carcinoid tumors can be associated with gastrin or serotonin production or nonfunctioning. Treatment involves excision and lymphadenectomy. Bronchial carcinoid tumors occur in less than 8% of patients with MEN1 and 75% are benign.
Additionally, radical surgery for MEN1 pituitary tumors may render patients panhypopituitary resulting in the need for thyroid, steroid, and possibly growth hormone replacement. Likewise, surgery for PHPT may lead to hypoparathyroidism requiring calcium and vitamin D supplementation. Finally, patients needing repeated pancreatic surgery can develop “brittle diabetes” necessitating pancreatic enzyme replacement and insulin.
Like MEN1, surgery for tumors related to MEN2 results in iatrogenic injury including hypothyroidism and adrenal insufficiency if bilateral adrenalectomy is needed. Management would include thyroid replacement therapy and gluco- and mineralocorticoid replacement, respectively.
Treatment options are summarized in
Treatment options for multiple endocrine neoplasia
|Syndrome||Characteristic Features||Medical Treament||Surgical Procedures|
|MEN1||Parathyroid tumors||Treat hypercalcemia with hydration, loop diuretics, and bisphosphonates||Subtotal or total parathyroidectomy with autotransplantation and transcervical thymectomy|
|Pancreaticoduodenal tumors||Gastrinomas: PPI, H2 receptor blockersInsulinomas: palliative or temporizing glucose tabs, cornstarch, diazoxideOther functional and nonfunctional tumors: supportive care until surgery, Consider octreotide||Surgical resection for all functional tumorsNonfunctional tumors >2-3 cm, enucleation or formal resection|
|Pituitary tumors||Prolactinomas: dopamine receptor agonists (cabergoline or bromocriptine)Growth hormone secreting tumors: octreotide or pegvisomantOther tumors: no medical therapy||Prolactinomas: transsphenoidal excision for tumors unresponsive to medical therapyOther pituitary tumors: transsphenoidal excision|
|MEN2||Medullary thyroid carcinoma||None||Total thyroidectomy with central compartment node dissection+/- ipsi- or bilateral modified radical neck dissection|
|Pheochromocytoma||Alpha blockade (phenoxybenzamine) 2 weeks before operative interventionBeta blockade if patient is tachycardic||Laparoscopic adrenalectomy for tumors <8 cm (consider partial or cortical sparing procedure)Open adrenalectomy for tumors >8 cm|
|Parathyroid tumors||Treat hypercalcemia with hydration, loop diuretics, and bisphosphonates||Subtotal or total parathyroidectomy with autotransplantaion and transcervical thymectomy|
Optimal Therapeutic Approach for this Disease
The primary treatment modality of parathyroid disease associated with MEN1 is surgery. Prior to the operative procedure elevated serum calcium may be controlled with intravenous hydration with saline to correct intravascular dehydration, loop diuretics to increase renal calcium excretion and to avoid fluid overload with hydration therapy, and bisphosphonates to inhibit osteoclast-mediated bone resorption. Indications for operative intervention includes symptomatic patients (nephrolithiasis, osteoporotic fractures, or hypercalcemic crisis), total serum calcium level > 1.0 mg/dL above the assay upper limit of normal, hypercalciuria (>400 mg/24 hr), worsening bone mineral density (hip, radius, or spine), bone mineral density in the osteoporotic range (T-score < -2.5), or Zollinger-Ellison syndrome.
MEN1 is, by definition, associated with multiglandular parathyroid disease and therefore, the surgical intervention must address all four glands. A subtotal parathyroidectomy leaving half a gland in-situ versus total parathyroidectomy with autotransplantation should be performed. In addition, a transcervical thymectomy is performed to look for ectopic parathyroid tissue, as well as to detect carcinoid tumors. Further medical therapy with calcium and vitamin D replacement may be necessary secondary to possible iatrogenic hypoparathyroidism associated with the procedures.
The management of pancreaticoduodenal tumors in MEN1 patients is still controversial due to the lack of understanding regarding the natural history of the tumors. Symptomatic patients with gastrinomas may be managed medically with proton pump inhibitors and/or H2 receptor blocker therapy. However, medical management does not alter the malignant potential of the tumor and ultimately surgical resection must be undertaken. Insulinomas require surgical enucleation/resection after biochemical diagnosis has been established. Patients with biochemical evidence of MEN1 who have asymptomatic or nonfunctional tumors of the pancreas >2 cm should undergo surgical exploration. This may identify and treat disease before it is clinically apparent and reduce the risk of malignant transformation.
The most frequent pituitary tumors in MEN1 patients are prolactinomas (60%). These tumors are managed medically with dopamine receptor agonists, such as cabergoline or bromocriptine. Growth hormone secreting tumors are managed medically with the growth hormone receptor antagonist pegvisomant, or the somatostatin analog octreotide. Operative treatment is indicated for patients unresponsive to medical therapy or rapidly growing tumors. Other less common functional anterior pituitary tumors are treated by transsphenoidal excision.
Medullary Thyroid Carcinoma
In both MEN2A and MEN2B MTC is typically bilateral and multicentric and preceded by a focal or diffuse proliferation of parafollicular calcitonin-producing cells called C-cell hyperplasia. In contrast, sporadically arising MTC is typically unilateral and not preceded by premalignant proliferation. MTC associated with the MEN2B variant is particularly aggressive and has the potential for early metastases. The tumor is not responsive to chemotherapeutic or radiologic treatment regimens, and therefore, surgical therapy is the only option.
Total thyroidectomy should be performed when the diagnosis of MEN2 is made based on either clinical evidence or biochemical screening. In addition, central neck compartment lymph node dissection should be undertaken to achieve local control of the disease. The role of prophylactic ipsi- or bilateral modified radical neck dissection (MRND) is controversial, but therapeutic MRND is a must. Due to the virulent nature of MTC, children with MEN2B should undergo prophylactic total thyroidectomy within the first 6 months of life. Children with MEN2A should be operated on before the age of 5 years.
The mainstay treatment of patients with pheochromocytomas is surgical resection. Patients should never undergo preoperative fine-needle aspiration biopsy (FNA) as the tumors are highly vascular. Further, FNA biopsy may precipitate a hypertensive crisis, hemorraghic event, or death. Management of pheochromocytomas involves preoperative medical managment with alpha blocking agents such as phenoxybenzamine or phentolamine for 2 weeks prior to surgery and continued to the morning of surgery. If patients develop tachycardia beta-blockade may be initiated.
The preferred method of resection is laparoscopic adrenalectomy for tumors <8cm. If the tumor size is >8cm or suspicion for malignancy exists, an open procedure should be performed. Bilateral adrenalectomy can be addressed laparoscopically. Consideration should be given to cortical sparing or partial adrenalectomy to avoid the need for cortisol dependence. If both MTC and pheochromocytoma exist concurrently, the adrenalectomy must be performed first to avoid the potential of intraoperative hypertensive crisis during thyroid resection.
Primary hyperparathyroidism associated with MEN2A is less common than PHPT in MEN1, occurring in 30% of patients. PHPT in MEN2A tends to be milder and many patients are asymptomatic. In addition, the hyperparathyroidism is caused by a single enlarged parathyroid gland and curative resection may be less aggressive than in parathyroid hyperplasia associated with MEN1. Enlarged parathyroid glands encountered during thyroidectomy for MTC should be resected. Normal appearing parathyroid glands may be left in-situ to decrease the risk of hypoparathyroidism. Consideration must be given to autotransplantation to avoid the need for reoperation in MEN2A, and the need for aggressive central neck clearance for either MEN2A or MEN2B due to the virulent nature of MTC.
In the past, surveillance and follow-up for patients with MEN1 only included testing for hyperparathyroidism, because it is the most common presenting abnormality. However, that screening method has been shown to miss the diagnosis of MEN1 in a significant number of patients.
Family members at risk for familial MEN1 should undergo genetic testing. In patients with positive genetic test results further work-up includes: (1) yearly physical examination with laboratory measurement of fasting glucose, gastrin, chromogranin A, pancreatic polypeptide, prolactin, calcium, creatinine, albumin, vitamin D, and PTH levels, and (2) imaging of the abdomen (computed tomography (CT) scan, somatostatin receptor scintigraphy, and/or endoscopic ultrasound) and the pituitary (magnetic resonance imaging) every 1-3 years. Yearly biochemical testing for hyperparathyroidism in MEN1 patients should begin at age 8 years and for functional neuroendocrine tumors of the pancreas at age 15 years.
In families with a known mutation, first-degree relatives of MEN1 patients with negative genetic testing results do not need repeated biochemical and radiographic imaging. MEN1 patients who have undergone surgery for any of the neuroendocrine tumors associated with the disease should be followed on a yearly basis with the same biochemical testing explained above. Patients with recurrent disease of the parathyroid gland or pancreas often require reoperation, while residual prolactinomas typically respond to bromocriptine therapy postoperatively. Patients with MEN1 have 50% probability of death by age 50 years, with half of the deaths due to malignancy and metastatic pancreatic neuroendocrine tumors.
Surveillance of MEN2 patients is dependent on several factors: (1) the underlying RET gene mutation, (2) level of disease involvement at the time of initial surgery, and (3) the type of operation performed. Biochemical follow-up to assess recurrent or metastatic disease includes serum calcitonin and CEA levels in patients with MTC, plasma free meta- and normetanephrines for pheochromocytoma, and serum calcium and PTH levels in patients with hyperparathyroidism.
Morbidity and mortality associated with MEN2 has improved mainly due to prophylactic thyroidectomy before the development of MTC. As mentioned previously, the course of MEN2B is more severe than MEN2A. Therefore, early recognition of genetic carrier status is crucial. It is important that children with MEN2B undergo prophylactic total thyroidectomy before age 6 months and children with MEN2A before the age of 5 years.
Patients should be told that MEN is not curable and requires lifelong surveillance. Multidisciplinary care with endocrinologists, endocrine surgeons, and geneticists is necessary in the management of this chronic disease.
Unusual Clinical Scenarios to Consider in Patient Management
Primary hyperparathyroidism, especially four gland disease, in young patients should raise the suspicion for MEN syndromes, as PHPT occurs in approximately 90% of MEN1 affected patients. The physician should keep genetic testing and counseling in mind when encountering this type of patient. Other unusual syndromes associated with the MEN2A variant include cutaneous lichen amyloidosis and Hirschsprung’s disease. These patients have pruritic cutaneous lesions located over the upper back and colonic aganglionosis due to mutations in the RET proto-oncogene.
Management of pregnant females with MEN syndromes is particularly challenging. Operations should never be performed unnecessarily during pregnancy, and especially for MEN1 given the frequent difficulty of getting pregnant in the setting of a prolactinoma. Pregnant patients with hyperaparathyroidism should maintain adequate hydration and take antiemetics to avoid a hypercalcemic crisis. In addition, patients with insulinomas should carry glucose tabs and liquid corn starch to avoid hypoglycemia. Third-trimester insulin resistance often eases the hypoglycemia associated with the insulinoma. A high-risk obstetrics team should be involved in the patient’s care, as they will need to monitor the baby after birth for hypocalcemia and hypoglycemia.
What is the Evidence?
White, M, Doherty, G. "Multiple endocrine neoplasia". Surg Oncol Clin N Am. vol. 17. 2008. pp. 439-59.(Understanding the molecular pathogenesis of MEN type 1 and type 2 has led to the development of specific DNA screening. The article highlights the importance of knowing the genetic status of patients in order to make decisions regarding surveillance and interventions.)
Skinner, M, Moley, J, Dilley, W, Owzar, K, DeBenedetti, M, Wells, S. "Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A". N Engl J Med. vol. 353. 2005. pp. 1105-13.(A study of 50 patients identified as carriers of a RET mutation characteristic of MEN2A revealed that MTC can be prevented or cured by preemptive removal of the thyroid.)
Lairmore, T, Piersall, L, DeBenedetti, M, Dilley, W, Mutch, M, Whelan, A. "Clinical genetic testing and early surgical intervention in patients with multiple endocrine neoplasia type 1 (MEN1)". Ann Surg. vol. 239. 2004. pp. 637-47.(An excellent article illustrating the need for both genetic testing and biochemical surveillance in patients harboring a MEN1 mutation to improve morbidity and mortality.)
Brandi, M, Gagel, R, Angeli, A, Bilezikian, J, Beck-Peccoz, P, Bordi, C. "Guidelines for diagnosis and therapy of MEN type 1 and type 2". J Clin Endocrinol Metab. vol. 86. 2001. pp. 5658-71.(A concensus statement from an international group primarily composed of clinical endocrinologists on the classification and mortality, indications for genetic testing, and protocols for screening MEN1 and MEN2.)
Waldmann, J, Fendrich, V, Habbe, N, Bartsch, D, Slater, E, Kann, P. "Screening of patients with multiple endocrine neoplasia type 1 (MEN-1): A critical analysis of its value". World J Surg. vol. 33. 2009. pp. 1208-18.(A prospective study evaluating the duration of screening methods including clinical examinations, imaging procedures, and extensive biochemical evaluations.)
Doherty, G. "Multiple endocrine neoplasia type 1". J of Surg Oncol. vol. 89. 2005. pp. 143-50.(Comprehensive review of the clinical presentation, biochemical, imaging, and genetic work-up of MEN1. The article also includes a literature review of the operative management of the three major tumors associated with MEN1.)
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