A 45-year-old previously healthy man comes to the office for evaluation of a neck lump. The patient first noticed the swelling a month ago while shaving, and it has progressively enlarged. He has had no fever, neck pain, hoarseness, or difficulty breathing or swallowing. The patient does not use tobacco, alcohol, or illicit drugs. Temperature is 36.7 C (98 F), blood pressure is 110/70 mm Hg, and pulse is 78/min. On physical examination, there is a nontender, firm nodule in the upper portion of the left thyroid lobe. Laboratory studies reveal a normal serum TSH and elevated serum calcitonin levels. Neck ultrasonography shows a 2-cm hypoechoic thyroid nodule with microcalcifications. Fine-needle aspiration of the nodule reveals spindle-shaped cells in an amorphous background. Which of the following gene alterations most likely contributed to this patient's current condition?

Question

A 45-year-old previously healthy man comes to the office for evaluation of a neck lump.  The patient first noticed the swelling a month ago while shaving, and it has progressively enlarged.  He has had no fever, neck pain, hoarseness, or difficulty breathing or swallowing.  The patient does not use tobacco, alcohol, or illicit drugs.  Temperature is 36.7 C (98 F), blood pressure is 110/70 mm Hg, and pulse is 78/min.  On physical examination, there is a nontender, firm nodule in the upper portion of the left thyroid lobe.  Laboratory studies reveal a normal serum TSH and elevated serum calcitonin levels.  Neck ultrasonography shows a 2-cm hypoechoic thyroid nodule with microcalcifications.  Fine-needle aspiration of the nodule reveals spindle-shaped cells in an amorphous background.  Which of the following gene alterations most likely contributed to this patient's current condition?

Quizplus · Accepted Answer

11ec160b_39fc_4c99_9249_030986918caf_MD0001_00 This patient has medullary thyroid cancer (MTC) presenting with a palpable nodule and elevated serum calcitonin. MTC is a neuroendocrine tumor that arises from calcitonin-secreting C (parafollicular) cells. Microscopy shows nests or sheets of polygonal or spindle-shaped cells, often with extracellular amyloid deposition (consisting of full-length calcitonin). MTC is often seen in the context of multiple endocrine neoplasia type 2 (A and B), although the majority of cases are sporadic. Paraneoplastic symptoms (eg, diarrhea, flushing) can occur due to elevated calcitonin levels; however, calcium is usually normal, possibly due to the downregulation of calcitonin receptors. MTC is associated with activating mutations in the RET proto-oncogene; mutations are commonly found in sporadic MTC, and germline mutations are present in more than 95% of patients with familial MTC. The RET proto-oncogene codes for a membrane-bound tyrosine kinase receptor involved in cell cycle regulation. In patients with MTC, constitutive activation of the receptor leads to unregulated cellular proliferation. (Choice A) The anaplastic lymphoma kinase (ALK) oncogene codes for a transmembrane receptor tyrosine kinase. Mutations are common in anaplastic large cell lymphoma and non-small cell lung cancer. (Choice C) The MEN1 gene codes for a tumor suppressor protein. Mutations are associated with multiple endocrine neoplasia type 1 (pituitary adenomas, primary hyperparathyroidism, pancreatic neuroendocrine tumors) but not type 2. (Choice D) p53 is a tumor suppressor protein involved in DNA repair, apoptosis, and cell cycle control. Inactivating mutations or deletions are present in a large percentage of human tumors, including anaplastic thyroid cancer, but not typically in early-stage MTC. (Choice E) BCL2 (B-cell lymphoma 2) is an antiapoptotic gene that enhances cell survival. Its expression is upregulated in many cancer cells. BCL2 mutations are common in many follicular lymphomas. (Choice F) Mutations in JAK2 (Janus kinase 2) are seen in a variety of myeloproliferative disorders such as primary polycythemia and essential thrombocythemia. Educational objective: Medullary thyroid cancer is a neuroendocrine tumor that arises from calcitonin-secreting C (parafollicular) cells. It is often seen in the context of multiple endocrine neoplasia type 2 (A and B), although the majority of cases are sporadic. Both sporadic and familial medullary thyroid cancers are associated with mutations in the RET proto-oncogene. __________ References: Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer. (http://www.ncbi.nlm.nih.gov/pubmed/26678667)

A 45-Year-Old Previously Healthy Man Comes to the Office for Evaluation