Medullary thyroid carcinoma is a C-cell, calcitonin-producing tumor that contains amyloid or an amyloid-like substance. In addition to calcitonin, it may elaborate or secrete other peptides and amines such as carcinoembryonic antigen, serotonin, neurotensin, and a high-molecular-weight adrenocorticotropic hormone-like peptide. These substances may result in a carcinoid-like syndrome with diarrhea and Cushing’s syndrome, especially when widely metastatic tumor is present. Most medullary cancer of the thyroid is sporadic (about 70% to 80%), but it can also be transmitted in a familial pattern. This tumor or its precursor, C-cell hyperplasia, occurs as a part of the multiple endocrine neoplasia type 2A (MEN2A) and type 2B (MEN2B) syndromes (45) (Table 2, Fig. 15), or, rarely, as part of the familial medullary thyroid cancer syndrome (FMTC). In FMTC, only the medullary cancer is inherited in a familiar pattern. The MEN2 syndromes are transmitted as an autosomal-dominant trait, so 50% of the offspring would be expected to have this disease. Mutations of the ret oncogene on chromosome 10 have been found to be the cause of the MEN2 syndromes (46,46a). These defects are germ-line mutations and can therefore be found in blood samples. All patients with medullary thyroid carcinoma should be screened for hyperparathyroidism and pheochromocytoma (47). If a pheochromocytoma (or its precursor, adrenal medullary hyperplasia) is present, this growth should be operated on first because it has the greatest immediate risk to the patient. Family members (including children) of a patient with medullary cancer of the thyroid should also be screened for medullary cancer of the thyroid, especially if the tumor is bilateral or if C-cell hyperplasia is present. Genetic testing for ret mutations has largely replaced screening by calcitonin in family members (46a). However, calcitonin measurement is still useful for screening patients with a thyroid mass when FNA analysis raises the possibility of medullary thyroid cancer.

Medullary cancer spreads to the lymph nodes of the neck and mediastinum, and later disseminates to the lungs, bone, liver, and elsewhere. The tumor is relatively radioresistant, does not take up radioiodine, and is not responsive to thyroid hormone suppression. Hence, an aggressive surgical approach is mandatory. The operation of choice for medullary cancer is total thyroidectomy coupled with aggressive resection of the central and mediastinal lymph nodes (46). If central lymph nodes or the lateral neck area contain tumor, careful and extensive modified radical neck dissection is required. Reoperations for metastatic tumor were rarely considered to be rewarding until the work of Tisell and Jansson (48). Their work, and that of others, demonstrated that 25% to 35% of patients with elevated circulating calcitonin levels could be rendered eucalcitoninemic after extensive, meticulous, reoperative neck dissection under magnification to remove all the tiny lymph nodes. In other patients, computed tomography (CT) and magnetic resonance imaging (MRI) have localized some sites of tumor recurrence, whereas octreotide or metaiodobenzylguanidine scanning have sometimes been helpful. Recently, technetium-labeled sestamibi scanning, and positron emission tomography combined with computerized tomography (PET-CT) have been successful in some patients.

Cure is most likely in young children who are found by genetic screening to have a mutated ret oncogene. One hopes to operate on them when C-cell hyperplasia is present and before medullary cancer has started (46a). Patients with MEN2A syndrome have a better prognosis than do those with sporadic tumor (45). Patients with MEN2B syndrome have very aggressive tumors and rarely survive to middle age. Thus, in recent years, children 5 years of age or younger who are found by genetic screening to have MEN2A have received prophylactic total thyroidectomy to prevent the development of medullary cancer. In children with MEN2B and with a mutated ret oncogene, total thyroidectomy should be considered at an earlier age, often by age 2 years, because this cancer develops at a younger age than does MEN2A (49). With these prophylactic operations, cures are expected.

Long-term studies of medullary cancer from the Mayo Clinic group have shown that in patients without initial distant metastatic involvement and with complete resection of their medullary cancer, the 20-year survival rate, free of distant metastatic lesions, was 81% (50). Overall 10- and 20-year survival rates were 63% and 44%, respectively. Thus, early diagnosis and complete initial resection of tumor are very important. Treatment of pheochromocytoma and hyperparathyroidism is discussed elsewhere.