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Hyperthyroidism caused by nodular goiters is a common disease of aging cats. Growth and iodine metabolism were studied by autoradiography in normal and hyperfunctioning thyroid tissue obtained from cats injected with 125I before surgery, and in xenografts, grown in nude mice, after double-labeling with 131I and [Hjthymidine.Hyperthyroid cat goiters contain single or multiple hyperplastic nodules, consisting of highly cellular tissue with an iodine metabolism exceeding that of the surrounding normal tissue.

IntroductionThe clonality of human tumors can be studied by X inactivation/methylation analysis in female patients heterozygous for X-linked DNA polymorphisms. We present a detailed study on

Functional and morphologic heterogeneity of human multinodular goiters was investigated in 300 samples from "cold" and "hot" regions of 20 goiters transplanted onto nude mice. Transplants were labeled with [Hjthymidine and radioiodine, while the host's thyroid-stimulating hormone (TSH) secretion was either stimulated or suppressed. Proliferation and function of follicular cells were assessed in whole follicles reconstructed from autoradiographs of serial sections.

Epidermal growth factor (EGF) has widespread growth effects, and in some tissues proliferation is associated with the nuclear localization of EGF and epidermal growth factor receptor (EGFR). In the thyroid, EGF promotes growth but differs from thyrotropin (TSH) in inhibiting rather than stimulating functional parameters. We have therefore studied the occurrence and cellular distribution of EGF and EGFR in normal thyroid, in Graves' disease, where growth is mediated through the thyrotropin receptor (TSHR), and in a variety of human thyroid tumors. In the normal gland the staining was variable, but largely cytoplasmic, for both EGF and EGFR. In Graves' disease there was strong cytoplasmic staining for both EGF and EGFR, with frequent positive nuclei. Nuclear positivity for EGF and particularly for EGFR was also a feature of both follicular adenomas and follicular carcinomas. Interestingly, nuclear staining was almost absent in papillary carcinomas. These findings document for the first time the presence of nuclear EGF and EGFR in thyroid. Their predominant occurrence in tissues with increased growth (Graves' disease, follicular adenoma, and carcinoma) may indicate that nuclear EGF and EGFR play a role in growth regulation in these conditions. The absence of nuclear EGF and EGFR in papillary carcinomas would suggest that the role played by EGF in growth control differs between papillary carcinoma and follicular adenomas/carcinomas of the thyroid.

The prominent characteristics of euthyroid and hyperthyroid human nodular goiters are the regional variability of iodine metabolism and the appearance of "hot" autonomous follicles. No explanation for the pathogenesis of the interfollicular heterogeneity of iodine turnover has yet been offered. We have investigated whether the recently demonstrated polyclonality of normal follicular epithelia could possibly be related to goiter heterogeneity. The present work demonstrates, by means of autoradiographic and histological techniques, that single cells or tiny cell families with widely differing metabolic properties are normally present within single mouse, rat, and human thyroid follicles. In animals, intercellular heterogeneity is demonstrated in respect to 1) iodinating capacity, 2) peroxidase content, 3) endocytotic response to TSH, and 4) proneness to replicate. Moreover, [3H] thymidine labeling of stimulated mice thyroids reveals that mitotic cells are not randomly distributed; some follicles contain large colonies of rapidly replicating cells, and these clonogenic cells give rise to new follicles. Since simple goiter formation invariably implies replication of normal thyroid follicles, we conclude that the large differences in iodine turnover among the follicles of simple goiters are a consequence of the generation of new, metabolically heterogeneous follicles from genetically distinct cell clusters existing with the epithelia of all normal mother follicles.

Spontaneous feline hyperthyroidism is a unique experimental model of toxic nodular goiter. To determine whether feline toxic goiter is caused by extrathyroidal stimulating factors or by the intrinsic autonomy of follicular cells, primary cultures of enzymatically dissociated follicles from 15 hyperthyroid cat goiters and from 3 normal cat thyroid glands were embedded in collagen gels. Growth and function in chemically defined media were assessed by autoradiography after double labeling with 3H-thymidine and 131I-Na. Iodine organification in follicles from normal glands was TSH dependent, but intense radioiodine organification occurred in follicles from hyperfunctioning goiters even in the absence of TSH. Similarly, twice as many follicular cells of hyperfunctioning thyroid tissue, maintained without TSH in the medium, were labeled after exposure to 3H-thymidine than in follicles from normal glands. The results strongly suggest that intrinsic alterations of cell function lead to autonomy of follicular growth and function and subsequently to the development of hyperplastic nodules, causing thyrotoxicosis. The reason for the focal nature of the disease remains an unresolved challenge. Further investigation using this model may further understanding of the growth of autonomous endocrine tumors.