Reviews in Endocrine & Metabolic Disorders 2000;1:183±196 # 2000 Kluwer Academic Publishers. Manufactured in The Netherlands. Expression Patterns of Cellular Growth-Controlling Genes in Non-Medullary Thyroid Cancer: Basic Aspects Nicholas J. Sarlis, M.D., Ph.D. Clinical Investigator, Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch (CEB), National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD Key Words. thyroid cancer, gene mutations, oncogenes, tumor suppressor genes, cell cycle control, apoptosis, growth factors, differentiation Introduction Thyroid cancer represents the most common type of endocrine malignancy and accounts for most of the deaths due to endocrine cancers [1]. There are 13,900 newly diagnosed cases of thyroid cancer each year in the US (90% of the total number of cases of newly diagnosed endocrine cancers) and 1,120 deaths each year due to this disease [2]. In humans, thyroid carcinomas are histogen- etically derived from either the follicular cell epithelium or the embryologically separate parafollicular (or C-) cells, which are of ectodermal origin. The latter are the source of calcitonin and other neuropeptides, and their neoplastic transformation gives rise to medullary thyroid cancer (MTC), a histologically uniform tumor which represents approx 3%±5% of thyroid malignancies [3]. MTC may occur either as a hereditary or a nonhereditary entity. Hereditary MTC can occur either alone (familial MTC) or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes. Recent molecular genetic studies have shown that germline mutations in the RET proto-oncogene underlie the pathogenesis of hereditary MTC, while somatic mutations in this gene may be found in approx 50% of sporadic MTCs (reviewed in [4]). These data suggest that most MTC cases can be viewed as phenotypic manifestations of a monogenic disorder at the molecular level. In contrast to MTC, carcinomas arising from the follicular thyrocytes (non-medullary thyroid carcinomas) present with an astonishing lack of uniformity in their histologic features and are classi®ed in various subtypes. The major categories of these tumors are: papillary (PTCs), follicular (FTCs) and anaplastic thyroid carci- nomas (ATCs) [5]. The biological behavior of these subtypes of cancer is highly divergent, re¯ected in differences in their prognosis (by indices of morbidity and mortality), patterns of metastasis, and ``clinical aggressiveness'', which, in turn, are dictating widely dissimilar modes of treatment and patterns of serial clinical follow-up. In this review, we will concentrate on non-medullary thyroid carcinomas, henceforth desig- nated as ``thyroid cancers''. The differences in clinical manifestations and patterns of growth along the spectrum of thyroid carcinomas have led to the hypothesis that the molecular basis of their pathogenesis is equally diverse. Indeed, before the era of molecular genetics, it was evident that the degree of histologic differentiation of thyroid carcinomas was often predictive of their biological behavior, the most extreme example being the correlation of the undiffer- entiated state of ATC with its highly malignant potential [6]. However, the relationship between the grade of histologic differentiation and the biological behavior among the subtypes of thyroid cancer other than ATC has been more tenuous. Approx 90% of thyroid cancers present with well-differentiated cellular features. The predominant subtype of well-differentiated thyroid carcinomas (WDTCs) is PTC (80±85% of cases), followed by FTC (15±20% of cases) [7]. Epidemiologic and clinical observations resulted in the recognition that certain rare variants of thyroid carcinomas, i.e. tall cell and diffuse sclerosing histologic variants of PTC, as well as poorly-differentiated, Hurthle cell (oxyphilic) and insular variants of FTC, portended a poor prognosis and had aggressive biological behavior [8]. In re¯ection of the features of the above aggressive subtypes of thyroid carcinomas, as well as undifferentiated ATCs, the Address correspondence to: Nicholas J. Sarlis, M.D., Ph.D. Clinical Investigator, Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch (CEB), National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bldg 10, Rm 8D12C, 10 Center Drive, Bethesda, Maryland 20892-1758, USA, E-mail: njsarlis@helix.nih.gov 183