Multiple endocrine neoplasia type 2 overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
Overview
Multiple endocrine neoplasia type 2 is part of a group of disorders that affect the endocrine system through development of neoplastic lesions in the thyroid, the parathyroid gland, and the adrenal gland. Multiple endocrine neoplasia type 2 was first described by Dr. John H. Sipple, an American physician, in 1961 by reporting a case of a patient with pheochromocytoma, medullary thyroid carcinoma and parathyroid adenoma. Development of multiple endocrine neoplasia type 2 is the result of genetic mutations. RET gene is involved in the pathogenesis of multiple endocrine neoplasia type 2. Multiple endocrine neoplasia type 2A is associated with medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Multiple endocrine neoplasia type 2B is associated with medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus, and mucosal and digestive neurofibromatosis. Surgery is the mainstay of treatment for multiple endocrine neoplasia type 2.
Historical Perspective
Multiple endocrine neoplasia type 2 was first described by Dr. John H. Sipple, an American physician, in 1961 by reporting a case of a patient with pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma.
Classification
Multiple endocrine neoplasia type 2 may be classified according to the types of tumor involved into 2 subtypes: multiple endocrine neoplasia type 2A and multiple endocrine neoplasia type 2B.
Pathophysiology
Development of multiple endocrine neoplasia type 2 is the result of genetic mutations. The RET gene is involved in the pathogenesis of multiple endocrine neoplasia. Multiple endocrine neoplasia type 2A is associated with medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Multiple endocrine neoplasia type 2B is associated with medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus, and mucosal and digestive neurofibromatosis.
Causes
Multiple endocrine neoplasia type 2 is caused by a mutation in the RET gene.
Differentiating Multiple endocrine neoplasia type 2 from Other Diseases
Multiple endocrine neoplasia type 2 must be differentiated from other hereditary tumors such as medullary thyroid carcinoma, C-cell hyperplasia pheochromocytoma, von Hippel Lindau syndrome, hereditary paraganglioma-pheochromocytoma, polycythemia and paraganglioma/pheochromocytoma syndrome, neurofibromatosis type 1, and multiple endocrine neoplasia type 1 (MEN 1).
Epidemiology and Demographics
The prevalence of multiple endocrine neoplasia type 2 is approximately 2.5 per 100,000 individuals worldwide. Multiple endocrine neoplasia type 2B manifest in early infancy while multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma manifest in adulthood.
Risk Factors
Family history is the most common risk factor in the development of multiple endocrine neoplasia type 2.
Screening
According to the American Society of Clinical Oncology, screening for multiple endocrine neoplasia type 2 by RET gene testing is recommended for children with increased risk of multiple endocrine neoplasia type 2.
Natural history, Complications and Prognosis
Multiple endocrine neoplasia type 2 has a variable natural history. Life threatening complications of multiple endocrine neoplasia type 2 include malignant hypertension, megacolon, and metastasis. Prognosis of multiple endocrine neoplasia type 2 is mainly related to the stage-dependant prognosis of medullary thyroid cancer.
Diagnosis
Diagnostic Criteria
According to the American Society of Clinical Oncology, diagnosis of multiple endocrine neoplasia type 2 requires existence of two or more specific endocrine tumors (medullary thyroid carcinoma, pheochromocytoma, or parathyroid hyperplasia). Multiple endocrine neoplasia type 2 is also diagnosed with four or more cases of medullary thyroid carcinoma without pheochromocytoma and parathyroid adenoma or if there is early onset of medullary thyroid carcinoma, mucosal neuromas of lips and tongue, disctinctive facial features with enlarged lips and marfanoid body habitus.
History and Symptoms
Symptoms of multiple endocrine neoplasia type 2 include headache, hoarseness of voice, palpitations, anxiety, pallor and weight loss.
Physical Examination
Patients with multiple endocrine neoplasia type 2 usually appear tall, thin and have disproportionately elongated extremities. Physical examination of patients with multiple endocrine neoplasia type 2 is usually remarkable for episodic hypertension, thyromegaly, and anxiety.
Laboratory Findings
Laboratory findings consistent with the diagnosis of multiple endocrine neoplasia type 2 include hypercalcemia, hypophosphatemia, elevated parathyroid hormone, and elevated norepinephrine.
Electrocardiogram
There are no specific electrocardiogram findings associated with multiple endocrine neoplasia type 2. Electrocardiogram findings in multiple endocrine neoplasia type 2 may vary depending on the underlying disease.
CT
Neck CT scan may be helpful in the diagnosis of multiple endocrine neoplasia type 2. Findings on CT scan suggestive of multiple endocrine neoplasia type 2 include irregular dense calcific foci within thyroid.
MRI
MRI scan may be helpful in the diagnosis of multiple endocrine neoplasia type 2. Findings on MRI scan suggestive of multiple endocrine neoplasia type 2 include intermediate to low signal at T1 and hyperintense signal at T2 suggesting parathyroid hyperplasia.
Echocardiography or Ultrasound
Ultrasound scan may be helpful in the diagnosis of multiple endocrine neoplasia type 2. Findings on ultrasound scan suggestive of multiple endocrine neoplasia type 2 include punctate high echogenic foci resembling calcification within the thyroid gland, solid to mixed cystic masses on adrenal gland, and homogeneously hypoechoic parathyroid gland.
Other Imaging Findings
Other imaging studies for multiple endocrine neoplasia type 2 include fluoro-di-glucose-PET, [18F]-fluorodopamine ([18F]DA) PET, and 99mTc-sestamibi scintigraphy.
Other Diagnostic Studies
Other diagnostic studies for multiple endocrine neoplasia type 2 include molecular genetic testing which include sequence analysis of select exons of mainly 10,11, 13-16 and sequence analysis of RET gene.
Treatment
Medical Therapy
The mainstay of multiple endocrine neoplasia type 2 is surgery. Medical therapies for multiple endocrine neoplasia type 2 include vandetanib, external beam radiation therapy analogues, and intensity modulated radiation therapy.
Surgery
Surgery is the mainstay of treatment for multiple endocrine neoplasia type 2.
Primary Prevention
There are no primary preventive measures for multiple endocrine neoplasia type 2.
Secondary Prevention
According to the American Society of Clinical Oncology, surveillance for multiple endocrine neoplasia type 2 by annual measurement of serum calcitonin, serum calcium, serum parathyroid hormone, and catecholamines is recommended post-surgically to monitor for recurrence and complications for multiple endocrine neoplasia type 2.
Cost-effectiveness of the Therapy
Cost-effectiveness of therapy of multiple endocrine neoplasia type 2 include targeted therapy, prophylactic thyroidectomy and restricted molecular screening.
Future or Investigational therapies
Future or investigational therapies of multiple endocrine neoplasia type 2 include treatment with axitinib, gefitinib, imatinib, motesanib, sorafenib, sunitinib, vandetanib and XL184.
Reference