Approach

Diagnosis of multiple endocrine neoplasia (MEN) syndromes involves careful screening of patients with endocrine tumors. Diagnostic suspicion is raised if numerous symptoms are present. Diagnosis of MEN1 is based on patients having 2 or more MEN1-associated tumors, or 1 associated tumor and a first-degree relative with the condition, or on the basis of genetics alone with a diagnosed pathogenic mutation of MEN1.[3]

Historical factors

  • Hyperparathyroid symptoms are present in at least 90% of patients with MEN1 and are the first manifestation of the syndrome in the majority of cases.[8] The mean age at diagnosis of hyperparathyroidism is earlier than in sporadic cases (<40 years) and includes symptoms of hypercalcemia: kidney stones (from nephrolithiasis), abdominal pain, constipation, and, in severe cases, confusion and dehydration; and reduced bone mineralization (osteopenia, osteoporosis).[8]

  • Symptoms from hypersecretion of pituitary adenoma hormones include amenorrhea, erectile dysfunction, and infertility (from hyperprolactinemia); progressive enlargement of hands, feet, and face (from acromegaly); moon facies, weight gain, easy bruising, and slow wound healing (from hypercortisolism); and/or anxiety, heat intolerance, tremor, and weight loss (from mild- to moderate- hyperthyroidism).[8]

  • Adrenal lesions are usually bilateral, nonfunctional, and indolent. However, adrenocortical carcinoma (with symptoms of hypertension, altered menses, weight gain, and/or impotence) may be present.[38] Pheochromocytomas may be asymptomatic if catecholamines are converted to inactive metabolites within the tumor. However, if catecholamine hypersecretion is episodic, symptoms usually include the classic triad of sweating, palpitations, and headache. Catecholamine secretion can also be chronic.

  • Pancreatic lesions (present in 30% to 75% of patients) can range from asymptomatic microadenomas to invasive carcinomas. Pancreatic and intestinal neuroendocrine tumor symptoms may include symptoms of Zollinger-Ellison syndrome such as epigastric pain, vomiting, diarrhea, hematemesis, and melena. Up to 50% of gastrinomas are metastatic at presentation.[30]

  • MEN2A patients may present with symptoms of Hirschsprung disease (abdominal pain and/or altered bowel habit) or cutaneous lichen amyloidosis (itchy or nonitchy rash).[16][17]

  • MEN2B patients may present with marfanoid body habitus (tall and thin with long fingers and high arched palate) and mucosal neuromas on the lips, tongue, and eyelids. Patients with MEN2B medullary thyroid cancer and pheochromocytoma are at higher risk of early metastasis, and this should be assessed for when histories are taken.[39][40]

  • Patients with medullary thyroid cancer are usually relatively asymptomatic; however, symptoms in patients with hormonally active metastatic disease include flushing and diarrhea.[7] In later stages, symptoms of Cushing syndrome may develop (including weight gain, easy bruising, slow wound healing, and low-trauma fractures).[7]

Family history

Patients with familial cases are classed as those with at least one first-degree relative with symptoms.[37] Patients with family histories of relevant endocrine tumors, hypersecretion-related symptoms, or sudden death (may occur with pheochromocytoma) require further screening.

Physical exam

  • Fibrous, erythematous facial papules (indicative of facial angiofibromas or collagenomas) may be present in patients with MEN1. It is reported in the literature that between 40% and 80% of patients with MEN1 have multiple (>5) facial lesions;[41] however, this is not commonly seen in clinical practice.

  • Hypertension may be a feature of patients with hyperparathyroidism and/or pheochromocytomas (with chronic catecholamine hypersecretion). Other pheochromocytoma findings include pallor, tachycardia, tremor, and a postural drop in blood pressure. Other hyperparathyroid findings include evidence of previous fractures due to osteoporosis, hematuria from nephrolithiasis, corneal calcification, and, in severe cases, confusion and dehydration.

  • Moon facies, obesity, and osteoporosis (from Cushing syndrome); oversized hands, feet, and face (from acromegaly); tachycardia, lid lag, tremor, and warm skin (from thyrotoxicosis); and infertility may be present in patients with hypersecretion of pituitary adenoma hormones.

  • Palpable thyroid nodules, flushing, and late Cushing syndrome signs may indicate medullary thyroid cancer.

  • Gastrointestinal bleeding (from elevated gastrin levels) may be detected in patients with Zollinger-Ellison syndrome.

  • Marfanoid body habitus (tall, thin, dolichostenomelia, arachnodactyly) and mucosal neuromas contribute to the very distinct phenotypes of MEN2B patients.

  • Hepatomegaly and/or regional lymphadenopathy may be evident if metastatic disease is present.

Genetic testing

Affected families require genetic counseling regarding screening of family members and future generations. Family members should be directly tested if familial mutations are known; haplotype analysis may be used to identify affected individuals when no mutations have been identified. Screening is recommended for patients with ≥2 characteristic tumors, or young age of onset.[3][10]

The prevalence of MEN1 in apparently sporadically occurring tumors is generally low, meaning that the indications for genetic testing are ambiguous. However, genetic screening for MEN1 mutations is warranted in patients with: early age at onset, such as hyperparathyroidism before 40 years of age; multiple tumors in the same gland or organ regardless of age; and some endocrine tumors, such as gastrinomas and thymic NETs.[8] Negative test results do not rule out MEN1 in patients meeting the appropriate clinical criteria, as between 5% to 25% of patients with MEN1 may not have mutations of the MEN1 gene.[3] If no mutation in the coding region is found by standard sequencing techniques, the use of different methods to detect large gene deletions, intronic abnormalities, other genetic abnormalities such as rearrangements, or abnormalities in the "non-coding" exon 1 is indicated.[3][8]​​ If there are existing genetic test results, do not order a duplicate test unless there is uncertainty about the existing result, for example the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[42]​ A negative test result may also be due to a phenocopy, that is, the presence of disease manifestations usually associated with mutations of a particular gene but instead are due to another etiology, for example, a sporadic hyperparathyroidism and a pituitary adenoma due to germline mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene.[3][8]

Syndromal variants due to other genetic defects (as yet unidentified) may also exist.

Patients with positive MEN2 family histories who are unaware of their carrier status require genetic testing for RET proto-oncogene mutations. Patients with sporadic medullary thyroid cancer also require screening for RET proto-oncogene mutations. Screening is positive in up to 20% of these patients. Most RET proto-oncogene mutations are known, meaning the false-negative rate of RET proto-oncogene screening tests is relatively low (between 2% and 5%).[37] Twenty-four percent of patients with apparently sporadically occurring pheochromocytoma have been found to have germline mutations in succinyl dehydrogenase B, C, or D, or in the genes underlying other familial syndromes including MEN2 (RET proto-oncogene), von Hippel-Lindau disease (VHL gene, chromosome 3), neurofibromatosis type 1 (NF1 gene, chromosome 17), and tuberous sclerosis (TSC1 gene, chromosome 9; TSC2 gene, chromosome 16).[43] These mutations are frequently associated with younger age, multifocal tumors, and extra-adrenal tumors. The incidence of succinyl dehydrogenase D mutations varies from 2% to 11%, and the incidence of succinyl dehydrogenase B mutations has been reported to be as high as 9.5%, when screening large groups of apparently sporadic pheochromocytomas.[11]

Biochemical screening

All genetic carriers, and those with high clinical suspicion despite negative gene tests, require biochemical screening (usually annually) relevant to their syndrome. Patients with symptoms suggesting specific hormonal excesses require additional testing.

  • MEN1 and MEN2A patients require monitoring of calcium levels to assess for primary hyperparathyroidism.

  • Pituitary adenoma patients require monitoring of serum prolactin, insulin-like growth factor-1 levels, and the other anterior pituitary hormones. Serum prolactin levels can be elevated due to a prolactinoma, stalk effect from a nonfunctioning macroadenoma, and in 15% to 20% of growth hormone-secreting adenomas. Cushing syndrome can develop in these patients and should be sought clinically.

  • Patients with MEN1 may benefit from annual measurements of serum chromogranin A, proinsulin, pancreatic polypeptide, vasointestinal peptide, gastrin, and glucagon (fasting gut peptides). Elevated levels of these hormones may indicate the presence of neuroendocrine tumors, and annual screening can assist early detection, although positive results require confirmation with other tests.

  • Patients with MEN1 with neuroglycopenic symptoms require measurement of fasting serum glucose/insulin levels. Insulinomas are suspected if insulin levels are not suppressed in the presence of symptomatic hypoglycemia. Screening is also required for exogenous insulin (ruled out by elevated C peptide) and sulfonylurea ingestion (urine testing), both of which can cause factitious hypoglycemia.

  • Gastrinoma patients have elevated fasting gastrin levels. However, they are also elevated with Helicobacter pylori infection and chronic proton-pump inhibitor use.

  • Medullary thyroid cancer patients require measurement of calcitonin levels to monitor disease burden. In the past, calcitonin levels were also measured to diagnose MEN2 carrier status, but genetic testing is more sensitive and specific, and calcitonin level measurement is no longer recommended as a diagnostic tool.

  • Patients with MEN2 can be screened for pheochromocytoma by measuring total and fractionated metanephrines or total catecholamines in 24-hour urine collections or by measuring plasma free metanephrines. Plasma metanephrines are more sensitive but less specific in the diagnosis of pheochromocytoma, but easier for the patient to collect accurately. Do not routinely use plasma catecholamines to evaluate pheochromocytoma or paraganglioma; instead use plasma free metanephrines or urinary fractionated metanephrines.[44]​ Guidelines for the surveillance of tumor prone patients are available.[3][7]

Biopsy

Thyroid biopsy by fine needle aspiration (FNA) is recommended for thyroid nodules that have suspicious characteristics on ultrasound (including calcification, ill-defined borders, or increased vascularization). FNA samples should be stained for calcitonin. Biopsy may also be possible for suspected neuroendocrine tumors, for example those seen in the pancreas in MEN1; such biopsies may require endoscopic ultrasound guidance.[45]

Provocative testing

Abnormal responses to hormone stimulation or suppression (with various infusions or medications) can be used to predict tumor presence. This provocative testing has become less common with the development of genetic testing and sensitive biochemical detection of basal levels. For example, gastrin responses to standard meals and calcitonin responses to calcium are now only used rarely. However, insulin production during 72-hour fasting remains a common provocative test for insulinomas.

Radiographic imaging

  • MEN1 gene mutation carriers require screening every 3 years for adenomas with pituitary MRI, every year for pancreatic masses and every 3 years for adrenal masses with abdominal CT or MRI, and every 1 to 2 years for thymic or bronchopulmonary masses with chest CT or MRI.[3]

  • Octreotide or gallium-68 DOTATATE PET scans may be helpful in locating neuroendocrine tumors in the foregut and pancreas.[46]

  • 18F-fluorodihydroxyphenylalanine positron emission tomography (18F-DOPA PET)/CT appeared to be better than either PET or CT alone at diagnosing and localizing pheochromocytomas in one small study.[47] 18F-DOPA PET is more sensitive and specific than metaiodobenzylguanidine (MIBG) scanning at detecting pheochromocytoma in extra-adrenal and hereditary disease.[48]

  • Patients with primary hyperparathyroidism may have technetium 99 sestamibi scans suggestive of multiglandular disease, alerting clinicians to the possibility of MEN.

  • Patients with pheochromocytomas diagnosed by biochemical markers require adrenal medullary imaging with MIBG scintiscan. MIBG scans confirm the diagnosis and localize the neoplasia. However, MIBG scans may be useful before surgery to locate multiple foci in certain pheochromocytoma patients.

Endoscopy

Endoscopy of patients with Zollinger-Ellison syndrome can help to detect the presence of gastrinomas.

Endoscopic ultrasonography is a sensitive tool for localization of pancreatic lesions and some duodenal lesions.[49] Endoscopic evaluation of patients with evidence of neuroendocrine hormonal excess (e.g., gastrin, insulin) can be more sensitive for tumor detection than radiography.

Helicobacter pylori testing

H pylori infection is vastly more common than gastrinoma (unless patients are known to have MEN1) and should be ruled out before diagnosis is made.

Patients with ulcers and resistant gastroesophageal reflux generally have H pylori testing with urea breath tests, biopsies, or stool antigen testing as part of their initial evaluation.

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