Multiple Endocrine Neoplasia

Overview

Definition

Multiple endocrine neoplasia (MEN) syndromes are genetic disorders characterized by the presence of ≥ 2 endocrine tumors.

Types

• MEN1: 
  • Characterized by either clinical setting:
    • Predilection for hyperplasia/tumors commonly involving the parathyroid glands, anterior pituitary gland, and pancreatic islet cells
    • Presence of a tumor associated with MEN1 in a family with clinically confirmed MEN1
• MEN2:
  • Characterized by a predisposition to develop medullary thyroid carcinoma (MTC), parathyroid tumors, and pheochromocytoma
  • General subtypes:
    • MEN2A: MTC, pheochromocytoma, primary hyperparathyroidism/parathyroid adenoma
    • MEN2B or MEN3: MTC, pheochromocytoma, neuromas
• MEN4:
  • Fairly new entity
  • Similar to MEN1
  • Tumors of parathyroid glands, anterior pituitary gland, and pancreatic islet cells, in association with gonadal, adrenal, renal, or thyroid tumors

General descriptions

MEN1

MEN1 syndrome

• Formerly known as Wermer syndrome
• Commonly involves the 3 P’s: Parathyroid glands, anterior Pituitary gland, and Pancreatic islet cells

Etiology and epidemiology

• Genetics:
  • Autosomal dominant inheritance
  • Mutation of MEN1 gene (protein product is menin)
  • Gene is located on the long arm of chromosome 11 (11q13).
• Prevalence: 2 per 100,000 individuals
• In 90% of cases, the condition MEN1 syndrome is inherited from an affected parent.
• Pancreatic neuroendocrine tumors (NETs) occur at an earlier age when associated with MEN1.

Pathophysiology

• Menin (coded by MEN1) regulates genome stability, proliferation, and apoptosis.
• Mutation of the gene increases the risk of the development of neoplasia.
• In approximately 10% of individuals, de novo mutations of MEN1 occur, which are associated with nonfamilial/sporadic MEN1 syndrome.

Clinical presentation

• Endocrine:
  • Primary hyperparathyroidism (95% of cases):
    • ↑ Parathyroid hormone (PTH), ↑ calcium
    • “Stones (nephrolithiasis), bones (osteopenia), abdominal groans (obstipation), and psychic moans (neuropsychiatric symptoms)”
  • Entero-pancreatic NETs (50%–80%):
    • Gastrinoma (most common entero-pancreatic tumor): Zollinger-Ellison syndrome (ZES) characterized by peptic ulcers, reflux, diarrhea
    • Insulinoma: hypoglycemia
    • Glucagonoma: diabetes, necrolytic migratory erythema (NME), anemia, deep vein thrombosis, and neuropsychiatric symptoms
    • VIPoma: chronic watery diarrhea, wheezing, flushing
    • Somatostatinoma: diabetes mellitus, steatorrhea, and cholelithiasis
  • Pituitary adenomas (30%–40%):
    • Prolactinoma (20%): hyperprolactinemia
    • Growth hormone-secreting: acromegaly, gigantism
    • Adrenocorticotropic hormone-secreting: Cushing’s disease
  • Carcinoid tumors:
    • Thymic
    • Bronchial
    • Gastric enterochromaffin-like tumor
  • Adrenal cortical tumor (40%): nonfunctioning
• Non-endocrine origin:
  • Lipoma
  • Angiofibroma
  • Collagenoma

Diagnosis

• Clinical findings may be either:
  • Occurrence of ≥ 2 MEN1 primary tumors
  • Family history of clinical diagnosis of MEN1 + 1 primary MEN1-associated tumor
• DNA testing:
  • Benefit of routine testing in MEN1 is unclear in relation to management.
  • Diagnosis made on a case-by-case basis:
    • The index patient with MEN1
    • 1st-degree relatives of known carriers of MEN1 mutation
    • Atypical or suspicious MEN1
• Screening other family members:
  • Primary hyperparathyroidism is the most common feature of MEN1 syndrome.
  • Asymptomatic family members can undergo these less-expensive optional tests: 
    • Serum calcium
    • PTH
    • Vitamin D levels

Management

•  Treatment:
  • Removal of tumors:
    • Parathyroidectomy
    • Excision of pancreatic and gastric/enteric tumors
    • Transsphenoidal surgery for pituitary tumors
  • Proton pump inhibitors given for patients with ZES
• Additional surveillance for asymptomatic family members with confirmed MEN1 mutation (MEN1 carriers):
  • Observe for signs and symptoms of MEN1-associated tumors
  • Annual monitoring of serum calcium, PTH, and prolactin levels
  • Baseline imaging (entero-pancreatic neoplasia and pituitary tumors) + follow-up
• Prognosis:
  • Approximately 30% of patients succumb to causes associated with MEN1.
  • Pancreatic endocrine tumors and carcinoids have malignant potential and contribute to a higher risk of mortality in affected patients.

Mnemonic

To recall the locations of tumor development in MEN1, remember the 3 Ps:

• Pituitary
• Parathyroid
• Pancreas 

MEN2

MEN2 syndrome

• MEN2A: 
  • Formerly known as Sipple’s syndrome
  • Variants:
    • Classical MEN2A (most common): MTC, pheochromocytoma, primary hyperparathyroidism
    • MEN2A with cutaneous lichen amyloidosis (CLA)
    • MEN2A with Hirschsprung’s disease (HD)
    • Familial MTC only
• MEN2B: 
  • MTC, pheochromocytoma
  • Associated with Marfanoid habitus, mucosal neuromas (lip, tongue), and intestinal ganglioneuromas

Etiology and epidemiology

• Genetics:
  • Autosomal dominant inheritance pattern
  • Mutation of RET (REarranged during Transfection) proto-oncogene (coding for a transmembrane tyrosine kinase)
  • Gene is located in chromosome 10 (10q11.2).
• Prevalence of 1 in 30,000 individuals
• MEN2B is less common, comprising only 5%–6% of MEN2 cases.

Pathophysiology

• Activation of RET leads to stimulation of multiple downstream pathways (involving kinases) → cell growth and proliferation
• MEN2 is associated with gain-of-function mutation of the RET gene.
• Risk of MTC is dependent on the codon involved in germline mutation:
  • Most MEN2A: RET codon Cys634Arg
  • Most MEN2B: RET codon Met918Thr (highest risk of early metastasis and aggressive MTC)

Clinical presentation

• MEN2A (classical):
  • MTC (95%–100%): 
    • Neck mass or lymph node
    • Peak incidence by 3rd decade of life
  • Pheochromocytoma (50%): 
    • Hypertension, tachycardia, headache, and sweating
    • Average age on presentation: 25–32 years
    • Can be bilateral
  • Primary hyperparathyroidism (25%)
• MEN2 with CLA: 
  • Interscapular or extensor lesions described as papular, scaly, and pruritic
  • Pathology: contains amyloid deposits
• MEN2 with HD: aganglionic megacolon (absent autonomic ganglion cells in the colon)
• MEN2B:
  • MTC (95%–100%): presents at a slightly earlier age than MEN2A
  • Pheochromocytoma (50%): similar to MEN2A
  • Mucosal neuromas
  • Intestinal ganglioneuromas
  • Marfanoid habitus

Diagnosis

• Suspect MEN2 in patients presenting with MTC, pheochromocytoma, or related tumors:
  • < 35 years of age
  • Multicentric and/or bilateral lesions
  • In addition to family history
• Tests for specific tumors:
  • Pheochromocytoma: plasma-fractionated metanephrines, then CT of the adrenal gland
  • Hyperparathyroidism: serum calcium, PTH
  • MTC: obtain serum calcitonin, neck ultrasound, and thyroid biopsy if a mass is present
• DNA testing (RET mutation analysis):
  • Compared to MEN1, genetic testing offers a clear benefit for diagnosing family members (especially individuals at risk for aggressive MTC).
  • Indications:
    • Clinically confirmed MEN2
    • Presence of MTC or pheochromocytoma + a family member with either condition
    • Presence of MTC or pheochromocytoma or related tumors with suspicious features (young age, multicentric lesions, 2 different organs affected)
    • Sporadic MTC
    • 1st and 2nd-degree relatives of patients with MEN2
• If there is no RET mutation or no autosomal dominant pattern:
  • ≥ 2 classic clinical features of MEN2A required for diagnosis
  • Majority of classic clinical features of MEN2B required for diagnosis

Management

•  General principles:
  • Surgical treatment based on tumor(s) that are present: 
    • Thyroidectomy
    • Adrenalectomy
    • Parathyroidectomy
  • In MTC:
    • Pheochromocytoma must be ruled out before any surgery is performed.
    • If pheochromocytoma is present, adrenalectomy is performed before thyroidectomy to avoid fatal complications.
  • In pheochromocytoma:
    • Prior to adrenalectomy, preoperative alpha blockade is recommended to prevent a hypertensive crisis.
    • If bilateral adrenalectomy is needed, glucocorticoids are administered to avoid adrenal insufficiency.
  • In hyperparathyroidism, monitoring after surgery is necessary:
    • For hypoparathyroidism
    • For recurrent or superior laryngeal nerve injury
• Further recommendations for carriers of RET mutation:
  • Risk of MTC depends on the codon mutation.
  • Prophylactic thyroidectomy depends on the risk: 
    • High-risk mutation (codon Met918Thr): surgery within the 1st year of life
    • Annual screening for other patients; age-dependent timing of surgery
  • Annual determination of fractionated metanephrines (proceed with imaging if positive)
  • Serum calcium (proceed with PTH if elevated)

Mnemonic

To recall the location of tumor development in MEN2, remember the 3 Ps:

• MEN2A: 2 Ps
  • Parathyroid
  • Pheochromocytoma
• MEN2B: 1 P
  • Pheochromocytoma

MEN4

MEN4 syndrome

• Limited data given; findings emerged over the past decade
• Initially named MENX in rats
• Characterized by:
  • MEN1-associated tumors (parathyroid adenomas, pituitary adenomas, and pancreatic NETs)
  • With gonadal, renal, thyroid, and adrenal tumors

Etiology and epidemiology

• Genetics:
  • Autosomal dominant inheritance pattern
  • Mutation of the cyclin-dependent kinase inhibitor (CDKN) gene CDKN1B
  • Found in chromosome 12p13
• Patients exhibiting MEN1 tumors:
  • Approximately 10% do not have the MEN1 gene mutation.
  • In about 3% of cases, the gene involved is CDKN1B.

Pathophysiology

• Loss-of-function CDKN1B mutations identified in patients with MEN1-like tumors.
• Results in reduced cell-cycle checkpoint protein, p27 (regulates transcription, inhibiting cell-cycle progression)
• Decreased function of p27 → genomic instability, unchecked cell growth and proliferation

Clinical presentation

• Parathyroid adenoma (in approximately 80% of patients)
• Pituitary adenoma (in approximately 37% of patients) can vary from:
  • Nonfunctional
  • Somatotropinoma
  • Prolactinoma
  • Corticotropinoma
• Pancreatic NETs: less penetrance than MEN1
• Renal tumors
• Some reports indicate reproductive and adrenal tumors.

Diagnosis

• Definitive guidelines are lacking, given the rarity of the condition and the few reported cases.
• Offer genetic testing for patients with CDKN1B mutations who exhibit features of MEN1 tumors but are MEN1 mutation-negative
• Genetic testing can be offered to 1st-degree relatives too.

Management

• Primary hyperparathyroidism (adenoma): parathyroidectomy
• Pituitary adenoma: transsphenoidal surgery per indications
• Excision of pancreatic NETs
• Surveillance for other tumors

Clinical Relevance

• Hyperparathyroidism: a condition associated with elevated blood PTH levels. Hyperparathyroidism can be classified as primary, secondary, or tertiary, based on the pathogenesis. Primary hyperparathyroidism is a disease of the parathyroid gland associated with abnormal PTH secretion. Secondary hyperparathyroidism results from abnormal calcium metabolism, which, when untreated, can progress to the tertiary type, which is associated with parathyroid gland hypertrophy and PTH oversecretion. Diagnosis is based on serum PTH, calcium, phosphate, and urinary calcium levels. Surgical parathyroidectomy is performed in patients with primary and tertiary hyperparathyroidism. Secondary hyperparathyroidism requires treatment of the underlying disease.
• Gastrinoma: tumors that secrete gastrin and are responsible for ZES. Gastrinomas are associated with MEN1. The tumor, which is often malignant, can arise from the pancreas, stomach, small bowel, and/or lymph nodes. Zollinger-Ellison syndrome is associated with elevated gastrin levels and gastric acid production, and manifests with peptic ulcers, gastroesophageal reflux, and diarrhea. Diagnosis is based on fasting serum gastrin levels. Management involves the surgical resection of gastrinomas and/or symptomatic management for unresectable disease.
• Insulinoma: a NET that manifests with hypoglycemia caused by inappropriately high secretion of insulin. Insulinomas more commonly present as a solitary benign tumor, but can sometimes be associated with MEN1. Symptoms of hypoglycemia and adrenergic stimulation include palpitations, weakness, diaphoresis, abnormal behavior, tremors, and blurring of vision. Diagnosis is based on biochemical testing. Surgical resection is the treatment of choice.
• Glucagonoma: a glucagon-secreting tumor, originating from the α cells of the pancreatic islets. Most glucagonomas are malignant, and many are part of MEN1. Elevated glucagon levels lead to increased gluconeogenesis and glycogenolysis. Patients present with diabetes, NME, weight loss, anemia, deep vein thrombosis, and neuropsychiatric symptoms. Diagnosis is based on lab tests showing elevated glucagon levels and a pancreatic mass on imaging studies. Management is usually supportive and involves octreotide therapy (a somatostatin analog). Surgical resection is attempted in localized disease. Chemotherapy and targeted molecular agents are used in advanced cases.
• VIPoma: a rare tumor characterized by the hypersecretion of vasoactive intestinal polypeptide (VIP). The tumor arises from the pancreas and manifests with chronic watery diarrhea with concomitant hypokalemia and dehydration, as well as wheezing and flushing (known as Verner-Morrison or WDHA syndrome). Most tumors arise sporadically, but some are associated with MEN1. Diagnosis is based on determining serum VIP levels. Treatment consists of the medical management of symptoms and complete surgical removal of the tumor.
• Pituitary adenoma: a tumor that develops within the anterior lobe of the pituitary gland. Pituitary adenomas are classified based on size as either micro- or macroadenomas and their ability to secrete hormones. Non-functioning or non-secretory adenomas do not secrete hormones but compress the surrounding pituitary tissue and lead to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type they evolved from and can lead to hyperpituitarism.
• Carcinoid tumor: a small, well-differentiated, slow-growing NET commonly found in the GI and bronchopulmonary tracts. Carcinoid syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by the tumors. Vasoactive substances produced by the GI NET do not cause carcinoid syndrome until the tumors metastasize to the liver. Symptoms of carcinoid syndrome include flushing, diarrhea, and wheezing. Treatment primarily involves surgical tumor resection and the use of somatostatin analogs.
• Thyroid cancer: a malignancy arising from the cells of the thyroid gland and calcitonin-producing C cells (medullary carcinomas). Driver mutations involving the receptor tyrosine kinase pathway, family history of cancer or related syndromes, and ionizing radiations increase the risk. Thyroid cancer may present as a thyroid nodule or enlarged cervical lymph nodes. Diagnosis is by determining thyroid stimulating hormone levels, as well as ultrasound and biopsy. Treatment is via thyroidectomy, with radioactive iodine therapy and systemic therapy depending on the type and extent of the thyroid malignancy.
• Pheochromocytoma: a catecholamine-secreting tumor derived from chromaffin cells, with the majority originating in the adrenal medulla. Pheochromocytomas can also arise from the sympathetic ganglia (paragangliomas). Excessive catecholamine production can cause hypertension, tachycardia, headache, and sweating. Diagnosis is based on plasma-fractionated metanephrines. Surgical resection is the only curative treatment.