Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature.Medullary Thyroid Carcinoma Medullary thyroid carcinoma represents 10% of all thyroid malignancies and 25% are familial in origin. It is an interesting and unusual tumor. Medullary thyroid carcinoma is a tumor of neuroendocrine origin and is functional, producing hormone calcitonin. It tends to metastasize early, however many patients live for many years even with distant metastasis. Seventy-five percent of medullary carcinomas are sporadic in origin. The familial form comprises the remaining 25% and is itself composed of three groups: Multiple Endocrine Neoplasia types 2A and 2B, and an entity known as Familial Medullary Thyroid Carcinoma. This last group has no characteristic abnormalities aside from MTC. The Multiple Endocrine Neoplasia Syndromes, however, have several characteristic features. MEN 1, or Wermer's syndrome, is not associated with medullary carcinoma, unlike both MEN 2A and 2B. It consists of parathyroid hyperplasia, pituitary adenomas and pancreatic adenomas. MEN 2A is characterized by the constellation of medullary thyroid carcinoma, parathyroid hyperplasia, and pheochromocytoma. MEN2B consists of medullary thyroid carcinoma, pheochromocytoma, a marfanoid body habitus, and mucosal ganglioneuromatosis. This syndrome is not associated with the cardiovascular and optic problems typical of Marfan's syndrome. In an analysis of medullary thyroid carcinoma patients in the German Registry, it was found that 25% of all MTCs were identifiable as having a familial association. Sixteen percent were associated with MEN2A, 3% with MEN2B and 5% were simply familial medullary thyroid carcinoma. This high rate of heritability makes screening very important, and fortunately the gene responsible for heritable medullary carcinoma has been discovered, and testing is available. For this reason, genetic testing can rule out the heritable forms of medullary carcinoma with 95% confidence, and once the mutation of the index case is established, the accuracy of screening for family members approaches 100%. Analysis for RET proto-oncogene mutations is now commercially available and should be considered in all patients with medullary thyroid carcinoma. A positive screening test mandates screening of all first-degree relatives. There are several clinical differences in the behavior of the familial versus the sporadic forms of medullary thyroid carcinoma. The familial types are generally multicentric and bilateral, whereas sporadic tumors are unifocal. Familial tumors are more aggressive than their sporadic counterparts. They are prone to local invasion and earlier metastasis. Onset tends to be several decades earlier in life in familial cases, and they seem to appear earlier in women than in men. Neither subgroup has an overall gender predilection, however. Medullary thyroid carcinoma is a unique malignancy. It is derived from neuroendocrine cells within the thyroid called C-cells, also known as parafollicular cells. C-cells are embryologically discreet from the rest of the thyroid. They are of neural crest origin and arise from the ultimobranchial body, whereas the thyroid anlage begins as an epithelial diverticulum and migrates downward from the base of tongue. C-cells migrate into the thyroid lobes where they exist in nests around the follicles of the thyroid gland. Histologically, medullary thyroid carcinoma is a well-circumscribed but unencapsulated tumor without evidence of normal colloid-containing follicles. Note here the definite transition between essentially normal follicle-containing thyroid tissue and the cancerous area. Nests of cells show round to oval cells with oval pleiomorphic nuclei. Familial forms of medullary thyroid carcinoma are thought to derive from precursor c-cell hyperplasia. Hyperplasia is not thought to precede sporadic medullary thyroid carcinoma. Amyloid is seen in around 25% of medullary carcinomas. It is the only known amyloid-producing tumor of the thyroid. Apple-green birefringence under plane-polarized light is characteristic of amyloid stained with Congo red. C-cells produce calcitonin which is a powerful inhibitor of osteoclastic activity. It also increases renal excretion of calcium. Elevated serum calcium and elevated serum gastrin levels stimulate calcitonin secretion. Its overall effect is to compensate for hypercalcemia. Elevated calcitonin does not cause hypocalcemia, nor does its absence cause hypercalcemia. Calcitonin is produced by C-cells in both their normal and pathologic states. Hypercalcitoninemia occurs with C-cell hyperplasia AND medullary thyroid carcinoma. In fact, calcitonin levels are considered to be useful in estimating tumor load. If calcitonin levels remain high after total thyroidectomy, it is considered likely that residual or metastatic disease is present. High calcitonin levels may also be seen in a few other tumors. Small cell lung cancer is one example. Carcinoembryonic antigen may also be elevated in medullary carcinoma. Elevation of CEA is a poor prognostic factor, as it correlates with the presence of distant metastasis. Immunohistochemical staining is positive for calcitonin and carcinoembryonic antigen, but negative for thyroglobulin, which is NOT produced by C-cells. Quantification of calcitonin levels begins with a serum calcitonin. However, baseline serum calcitonin levels will be normal in 30% of medullary carcinomas. Pentagastrin stimulation gives increased sensitivity and specificity. Injection of 0.5 micrograms per kilogram pentagastrin will cause a hypernormal release of calcitonin in patients with medullary thyroid carcinoma. The test is performed by injecting pentagastrin intravenously at time zero. Then serum calcitonin levels are drawn at zero, two, five, ten and fifteen minutes. There is a characteristic elevation of calcitonin associated with a high load of c-cells. Other tumors, such as small cell carcinoma of the lung, may have elevated baseline calcitonin, but non-C-cell tumors will not stimulate with pentagastrin. No definitive imaging study has been established for medullary carcinoma, however several modalities have been suggested for use in detection of residual disease and metastases. Symptoms associated with medullary carcinoma are secondary to high serum calcitonin. Some patients complain of diarrhea and flushing. Hoarseness may be indicative of involvement of the recurrent laryngeal nerve. The presence of any of these symptoms is considered to be a poor prognostic factor. Diarrhea and flushing occur with high calcitonin levels, which correlates with high tumor load, and invasion of the recurrent laryngeal nerve indicates locally aggressive behavior. A study of 78 medullary carcinomas in Italy found that only 44% of patients were dead at 10- to 22-years follow-up. Of the surviving patients, half appeared to be free of disease and the other half were alive with residual disease. The median follow-up time for the patients with residual disease was 12.2 years. The familial forms tend to be on the more aggressive side, with MEN2B being the most aggressive. Patients with the sporadic form of the disease are more likely to live for many years, even with distant metastases. Treatment of medullary carcinoma is surgical. Recommended surgical treatment is total thyroidectomy with central compartment node dissection. The central compartment extends from the hyoid bone to the innominate vein and from carotid sheath to carotid sheath. In tumors suspicious for metastasis the dissection is extended to include nodal levels 2 through 5. Some authors recommend extension inferiorly to include the superior mediastinum because 50% of metastatic medullary tumors will involve nodes in this region. Preoperative work up should be designed not only around staging of disease, but should take into account the high rate of associated pathology. Recall that 25 % of medullary carcinomas are familial, and the majority of these are associated with multiple endocrine neoplasia. Pheochromocytoma is found in 50% of MEN 2A and 2B patients. This translates to a potential 10% of medullary carcinoma patients having a pheochromocytoma. It is very important to exclude this preoperatively, in order to avoid intraoperative hypertensive crisis. Twenty-four-hour urine catecholamines and metanephrines are an effective screening device. Penetrance of hyperparathyroidism in Multiple Endocrine Neoplasia type 2A is 20%. A serum calcium should be obtained preoperatively in all patients with medullary thyroid carcinoma. If calcium is elevated or if there is suspicion of MEN 2A, a parathyroid hormone level should be obtained. Remember that an elevated calcitonin does not cause hypocalcemia. Postoperatively, persistenthypercalcitoninemia indicates residual disease. In the face of an exaggerated response to pentagastrin stimulation, further dissection of the central compartment and the lateral neck has been attempted. Subsequent normalization of calcitonin has been reported in 10% to 20% of these cases. No role for chemotherapy has been established in the treatment of medullary thyroid carcinoma. Radiation is used for palliation or in cases with large amounts of residual tumor after operation. An apparently sporadic case of medullary thyroid carcinoma may be the index case of a familial kindred. Bilateral tumors or concomitant C-cell hyperplasia suggest a familial form of medullary carcinoma. All medullary thyroid carcinoma patients should undergo genetic testing for the known RET proto-oncogene mutations associated with the disease. A positive screen should prompt testing of all first-degree family members. Penetrance of medullary carcinoma is one hundred percent in all the familial forms. Therefore a prophylacticthyroidectomy is indicated in all persons testing positive. The timing of prophylactic thyroidectomy is a subject for some debate. It is clear that in adults thyroidectomy should be performed as soon as possible due to the high rate of metastasis. In children the situation is more complicated. The risks of performing thyroidectomy in a small child must be weighed against the risk of metastasis. It is considered surgically advantageous to wait until the child is in the age range of 6 - 10 years, however, foci of medullary carcinoma have been found in the thyroids of children as young as 7 months of age and metastasis has been reported in children as young as 6 years. To summarize, medullary carcinoma of the thyroid is a productive tumor, producing calcitonin. Twenty-five percent of all medullary carcinomas are familial, and genetic testing for RET proto-oncogene mutations is available and appropriate for all cases of this tumor. In family members found to have the responsible RET gene utation, prophylactic thyroidectomy is the appropriate treatment. Case Presentation: JK is a 75 year-old man who presented to the VA Otolaryngology Clinic with a slowly-enlarging left neck mass. The mass had been present for several months, but was otherwise asymptomatic. He denied other medical problems or family history of malignancy. Fine needle aspirate was suspicious for medullary thyroid carcinoma, and the patient was taken to the Operating Room for a total thyroidectomy and left modified radical neck dissection. Final pathology was significant for 7 cm by 3 cm mass in the thyroid, metastases to three paratracheal nodes, and invasion of the surrounding musculature. The patient received post-operative radiation therapy. It is now 4 years later. JK has a solitary hepatic nodule, which is medullary thyroid carcinoma by CT-guided needle biopsy. He has no jaundice, abdominal pain or other symptoms, and the size of the nodule has been stable for over a year. An octreatide scan was performed in January of 1999, which was negative for evidence of medullary carcinoma in the neck or in the abdomen. At that time JK's serum calcitonin was 7,820 picograms per milliliter, the normal range being from 3 to 26. Several months later, his calcitonin was redrawn and was 9,200. JK is currently asymptomatic and functioning normally. Barbet J, Peltier P, Bardet S, Vuillez JP, Bachelot I, Denet S, Olivier P, Leccia F, Corcuff B, Huglo D, Proye C, Rouvier R, Meyer P, Chatal JF. Radioimmunodetectio of MTC using Indium 111 Bivalent Hapten and Anti-CEA x anti-DPTA-Inidium Bispecific antibody. J Nucl Med 1998;39:1172-1178. Cote CG, Wohlik N, Evans D, Goepfert H, Gagel RF. RET proto-oncogene mutations in multiple endocrine neoplasia Type 2 and medullary thyroid carcinoma. J Clin Endocrinol Metab 1995; 9: 609-630. Donis-Keller H, Dhensen D, Chi D, Carlson KM, Toshima K, Lairmore TC. Mutations in the RET proto-oncogene are associated with MEN2A and FMTC. Hum Mol Genet 1993; 2:851-856. Ellenhorn JDI, Shah JP, Brennan MF. Impact of therapeutic regional lymph node dissection for MTC. Surgery 1993;114:1078-1082. Frilling A, Dralle H, Eng C, Raue F, Broelsch CE. Presymptomatic DNA screening in families with MEN 2 and FMTC. Surgery 1995;118:1099-1104. Gagel RF. Multiple endocrine neoplasia. William's Textbook of Endocrinology. New York: WB Saunders, 1992, pp.1573-1653. Gagel RF, Tashjian Jr AH, Cummings T. The clinical outcome of screening for MEN 2A: An 18-year experience. New Engl J Med 1988;318:478-484. Goodfellow PJ, Wells Jr SA. RET proto-oncogene and its implications for cancer. J Natl Cancer Inst 1995;87:1515-1523. Kolby L, Wangberg B, Ahlman H, Tisell LE, Falling M, Forssell-Aronsson E, Nilsson O. Somatostatin receptor sybtypes, octreaotide scintigraphy and clinical response to ocreotide treatment in patients with neuroendocrine tumors. World J Surg 1998;22:679-683. Komminoth P, Kunz EK, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, Roth J, Heitz PU. Analysis of RET proto-oncogene point mutations distinguishes heritable from nonheritable MTC. Cancer 1995;76:479-489. Levine MA. Laboratory evaluation of calciotropic hormones and minerals. Diagnostic Endocrinology Mosby, 1996. Marzano LA, Porcelli A, Biondi B, Lupoli G, Delrio P, Lombardi G, Zarilli L. Surgical management and follow-up of medullary thyroid carcinoma. J Surg Oncol 1995;59:162-168. Moley JF. Medullary thyroid cancer. Surgical Clin North Am: Endocrine Surg, 1995, pp. 405-420. Myers EN, Suen JY. Cancer of the Head and Neck. New York: WB Saunders Company, 1996. Pacini F, Romei C, Miccoli P, Elisei R, Molinaro R, Mancusi F, Iacconi P, Basolo F, Martino E, Pinchera A. Early treatment of hereditary MTC after attribution of MEN 2 gene carrier status by screening for RET gene mutations. Surgery 1995;118:1031-1035. Rockall TA, Watkinson JC, Clark SEM, Douek EE. Scintigraphic evaluation of glomus tumors. J Laryngol Otol 1990;104:33-36. Sadley TW. Langman's Medical Embryology. Baltimore: Williams and Wilkins, 1995. Shaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin North Am 1998; 31: 823-831. Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961;31:163-166. Tissell L, Hansson G, Jansson S. Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery 1986;99:60-66. Wohllk N, Cote GJ, Evans DB, Goepfert H, Ordonez NG, Gagel RF. Application of genetic screening information to the management of medullary thyroid carcinoma and multiple endocrine neoplasia Type 2. Endocrinol Metab Clin North Am 1996;25:1-25. Wohllk N, Cote GJ, Bugalho MM, Ordonez N, Evans D, Goepfert H, Khorana S, Schultz P, Richards CD, Gagel RF. Relevance of RET proto-oncogene mutations in sporadic MTC. Click here to view slides from this presentation (pdf file). Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2005 Baylor College of Medicine
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