The Pathogenesis of “Hot” and “Cold” Follicles in Multinodular Goiters*

Abstract

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.

Autonomy of growth and of iodine metabolism in hyperthyroid feline goiters transplanted onto nude mice.

“…Despite suppression ofthe mouse's TSH secretion and consequent depression ofthe mouse thyroid uptake, intense organification of radioiodine was found in the hyperplastic, nodular grafts of the cat goiter, whereas it was much lower in the extranodular colloid-rich follicles (Figs. 5,6 (Fig. 7).…”

“…For autoradiography and histological examination, tissue was fixed in phosphate-buffered formalin 4%, pH 7.4, and, after dehydration in graded series of alcohols, embedded in methacrylate (JB-4 embedding mixture, Polysciences, Inc., Warrington, PA); 3-Am sections were mounted on glass slides, dipped in NTB-2 nuclear emulsion (Eastman Kodak Co., Rochester, NY), developed with Kodak D-19 developer after appropriate exposure time and counterstained with nuclear fast red (5). Additional sections were stained with periodic acid Schiff (PAS).…”

Pathogenesis of heterogeneity in human multinodular goiter. A study on growth and function of thyroid tissue transplanted onto nude mice.

“…The single most intriguing aspect of human multinodular goiter is the striking functional and morphologic heterogeneity among newly generated follicles (1)(2)(3). In previous studies on experimental goiters in animals, we have concluded that two entirely Receivedfor publication 19 June 1985. different sets of mechanisms may account for part of this heterogeneity.…”

Identifying thyroid stem/progenitor cells: advances and limitations

“…It has to be underlined that in spite of the low cell turnover that guarantees its size during a lifetime, the thyroid retains the capacity to grow by cell hypertrophy and proliferation in response to a stimulus that is controlled by the physiological negative feedback mechanism of TSH (Larsen 1982). The frequent and heterogeneous presentation in growth and function of benign and malignant nodular pathology cannot be simply explained by genetic background, environmental factors (Peter et al 1982), iodine deficiency (Studer et al 1974), mutagenic events, altered Derwahl & Studer (2002) and Krohn et al (2005)). In this complex heterogeneity in growth and function, the role of the expanded committed progenitor cell compartments of different clonal origins must be prominent rather than of stem cells.…”

“…For instance, mice and human differentiated thyrocytes divide (Ramelli et al 1982, Coclet et al 1989 and can generate new follicles (Peter et al 1982), without the need for thyroid stem cells. Transplantation experiments in nude mice have also suggested the presence within nodular goitre tissues of autonomously growing thyroid-derived cells (Peter et al 1985).…”