Recent advances in the treatment of thyroid carcinoma
Authors: S. A. Wells
Journal: CA A Cancer Journal for Clinicians (1996)

Diseases of the thyroid gland are common, and most are of a metabolic or immunologic nature. Malignancies of the thyroid are uncommon, and there is probably no organ where there is a greater range of biologic behavior of the malignant phenotypes. Papillary thyroid carcinoma, the most common thyroid malignancy, is one of the least aggressive cancers in humans. However, the giant cell variety of undifferentiated thyroid carcinoma, the least common thyroid carcinoma, is highly lethal, and few patients with this cancer survive three years from the time of diagnosis. Overall, few patients with thyroid malignancy die from their disease. Given the relatively well-defined histologic types of malignancy of the thyroid gland and the sound understanding of the natural history of the specific histologic types of tumors, one would think that the management of patients afflicted with these malignancies would be relatively straightforward. However, this is not the case. The main reason for the controversy is that there has never been a prospective, randomized, controlled trial evaluating the operative management of patients with any type of thyroid cancer. Considering the small number of patients who develop the disease and the relatively slow growth patterns characteristic of the more common types of thyroid malignancy (i.e., papillary carcinoma and follicular carcinoma), such trials may never be done. Nevertheless, we can learn a great deal from retrospective evaluation of data about these patients, and such is provided in the excellent review written by Drs. Robert Gagel, Helmuth Goepfert, and David Callender in this issue of CA-A Cancer Journal for Clinicians.1 In discussing thyroid carcinomas, it is best to divide them into the differentiated and undifferentiated types. Differentiated thyroid carcinomas account for 80 percent of all thyroid malignancies and are of either a papillary or follicular type. Medullary thyroid carcinoma, while in the thyroid gland, is not of the thyroid gland. The progenitor “C-cells” derive from the neural crest. In birds and fishes, the C-cells are located in a separate site called the ultimobranchial body. Undif-ferentiated thyroid carcinomas are either of the small cell (B-cell lymphomas) or the giant cell type. With differentiated and medullary thyroid carcinomas, early diagnosis and treatment are important. Improved prognosis is directly related to the following: young age at the time of diagnosis, small tumor size, absence of local tissue invasion, absence of regional lymph node or distant metastasis, and favorable histologic type. Therefore, it is important to diagnose thyroid malignancy at an early stage when operative therapy is associated with a good prognosis. In considering patients who present with a thyroid nodule, it is important to determine if there is any history of exposure to external-beam radiotherapy, especially in childhood. It is known that at least one third of patients with such exposure will develop thyroid nodules, and about one third of these patients will develop a thyroid malignancy, almost always of the papillary or follicular type.2 There is thought to be little, if any, increased risk of thyroid carcinoma in patients treated with radioactive iodine for generalized toxic goiter. However, a very high incidence of a virulent form of papillary thyroid carcinoma occurred in children in the Ukraine and Belarus who were under the umbrella of the fallout from the Chernobyl nuclear accident.3 An increased risk of thyroid carcinoma in survivors of the nuclear explosions in Japan at the close of World War II has also been documented.4 It is also important to ask a patient with a thyroid nodule if there is any family history of thyroid malignancy. Medullary thyroid carcinoma often occurs in a hereditary pattern as either multiple endocrine neoplasia type 2A (MEN 2A),5 multiple endocrine neoplasia type 2B (MEN 2B),6 or familial medullary thyroid carcinoma (FMTC).7 The large majority of papillary, fol-licular, or medullary types of thyroid carcinomas grow slowly and metastasize to regional lymph nodes and distant sites after the primary tumor has been present for several years. Some patients with papillary carcinoma present with local invasion of the trachea, but at the time of en bloc resection of the thyroid carcinoma and the trachea, there is minimal regional or distant spread of disease. Some of these patients are cured by this aggressive resection. It is difficult to tell which patients with differentiated thyroid carcinoma need a total thyroidectomy and which will benefit from a lesser resection.8, 9 Therefore, because a total thyroidectomy can be performed relatively easily and with minimal morbidity, this procedure is most often performed for all patients with papillary, follicular, or medullary thyroid carcinoma. Over the last five years, we have learned a great deal about the molecular biology of thyroid carcinoma. The most clearly defined molecular events involve the RET proto-oncogene and its relationship to papillary carcinoma and medullary carcinoma. At least 40 percent of papillary thyroid carcinomas are associated with a pericentromeric inversion on chromosome 10.10 A portion of the chromosome containing the RET protooncogene is inverted, and the RET proto-oncogene is cleaved at the site of the breakpoint and repositioned close to a promotor that leads to its expression. The etiologic significance of this event is unknown at present. Another important molecular event occurs in patients with MEN 2A,11, 12 MEN 2B,13-15 and FMTC. It has been shown that these diseases result from specific and inheritable mutations in RET. In MEN 2A and FMTC, several mutations have been described, all of which occur either in the external ligand binding segment of the proto-oncogene or just inside its transmembrane portion. In all cases of MEN 2B, a single mutation occurs at codon 918 in the internal catalytic core. At present, little is known about the function of RET. However, the identification of these discrete mutations has provided the opportunity for prophylactic therapy of patients with the type 2 MEN syndromes. The mutations can be demonstrated by direct DNA testing of the white blood cells of kindred members with MEN 2A, MEN 2B, or FMTC. Because the mutations are present at the time of conception and can be demonstrated either in utero or soon after birth, a therapeutic strategy can be designed that would prevent the onset of the disease. This amounts to prophylactic removal of the thyroid gland in youngsters before they manifest biochemical or clinical evidence of medullary thyroid carcinoma, the most common cause of death in patients with these syndromes.16 This strategy, which is highly effective in patients with these familial thyroid diseases, will doubtless be employed for patients with other forms of hereditary solid organ malignancies and in some patients with sporadic cancers as well. We are certain to learn much more about the etiology and biologic behavior of thyroid malignancies as molecular and genetic medicine continue to unlock the secrets of cell biology. As the metabolic pathways and the mechanisms of cell growth are elucidated, it is likely that we will treat patients with thyroid malignancies by yet to be designed pharmacologic therapies rather than the operative techniques that we employ today.