Description
Multiple Endocrine Neoplasia Type 2 (MEN2) is a rare inherited disorder characterised by a propensity to develop neoplasms in multiple endocrine organs. These tumours most commonly involve the adrenal glands, parathyroid glands, and the thyroid.
Pathogenesis
MEN2 is caused by mutations in the RET (REarranged during Transfection) proto-oncogene on chromosome 10. This gene produces a protein involved in cell signalling related to cell growth and differentiation. When mutated, it can lead to continuous cell division and tumour formation. The syndrome follows an autosomal dominant inheritance pattern.
Epidemiology, Risk Factors & Associations
- MEN2 is a rare disorder, affecting approximately 1 in 30,000 individuals.
- Autosomal dominant pattern of inheritance
- No known environmental risk factors or lifestyle habits have been associated with the development of MEN2.
Subtypes
- MEN2A (70-80% of cases): Medullary thyroid cancer (MTC), pheochromocytoma, and primary hyperparathyroidism (PHP).
- MEN2B (5% of cases): MTC, pheochromocytoma, mucosal neuromas, marfanoid habitus, and gastrointestinal symptoms.
- Familial Medullary Thyroid Cancer (FMTC) (<20% of cases): MTC only.
Clinical Features
- Medullary Thyroid Carcinoma (MTC): It’s the most common tumour in all forms of MEN2. It is usually the earliest manifestation of MEN2A and MEN2B. Symptoms include palpable thyroid nodule(s), hoarseness due to laryngeal nerve invasion, dysphagia due to oesophageal compression, and symptoms related to high calcitonin levels like diarrhoea. Also, the elevation of serum calcitonin is an early biochemical marker of MTC.
- Pheochromocytoma: These tumours of the adrenal medulla are common in MEN2A and MEN2B but less common in FMTC. They secrete catecholamines, causing symptoms such as episodic hypertension, palpitations, headache, sweating, and pallor (classic pheochromocytoma spell). Also, persistent hypertension may be present.
- Parathyroid adenoma or hyperplasia: This is common in MEN2A and can lead to hypercalcemia. Symptoms include fatigue, muscle weakness, depression, bone pain, nausea, and increased thirst and urination.
- Mucosal Neuromas: These are characteristic of MEN2B and typically involve the lips and tongue. They can cause a characteristic appearance with enlarged, bumpy lips, and can lead to speech difficulties.
- Marfanoid habitus: This is a characteristic feature of MEN2B and includes features such as tall stature, long limbs and fingers, pectus excavatum or pectus carinatum, and scoliosis.
- Other Features in MEN2B: These include eye abnormalities such as thickened corneal nerves, gastrointestinal complications such as constipation and megacolon due to ganglioneuromatosis of the gut.
Pathological Features
Histopathology
- MTC: Characterised by nests or trabeculae of cells producing calcitonin.
- Pheochromocytoma: Characterised by nests (“Zellballen”) of neuroendocrine cells.
Genetics
Mutations in the RET proto-oncogene are seen in all subtypes of MEN2, with different mutations associated with different subtypes and varying clinical severity.
Radiological Features
MRI
- MTC: Typically show hypointense on T1-weighted images and variable intensity on T2-weighted images.
- Pheochromocytoma: Characteristically hyperintense on T2-weighted images.
CT
- MTC: Usually well-defined, hypoattenuating compared to the thyroid gland, and enhance after contrast administration.
- Pheochromocytoma: Typically shows a large adrenal mass with heterogeneous enhancement post-contrast.
PET
- Can be used to identify metastases in MTC and localise pheochromocytoma.
US
- MTC: Typically presents as a solid, hypoechoic nodule in the thyroid.
Differential Diagnosis
- Sporadic MTC, pheochromocytoma, or parathyroid adenoma: Considered in patients with isolated findings that may be part of MEN2, but without the typical pattern of associated features.
- MEN1: May also present with tumours in endocrine glands, but typically involves different organs (parathyroid, pituitary, pancreas).
- Von Hippel-Lindau disease: Can also cause pheochromocytomas, but has additional features like haemangioblastomas and renal cell carcinomas (specifically clear cell carcinoma).
Management
- Genetic testing: Recommended for individuals with a family history of MEN2 and for those diagnosed with MTC.
- Prophylactic thyroidectomy: Recommended for patients with known RET mutations, often during infancy.
- Management of individual tumours as per standard guidelines.
- Regular surveillance for disease features.