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STUDER, DERWAHL
Mechanisms of nonneoplastic endocrine hyperplasia--a changing concept: a review focused on the thyroid gland.Studer H, Derwahl M. Endocr Rev. 1995 Aug;16(4):411-26. Review.
"An important part of clinical endocrinology deals with diseases caused by benign and malignant nodules growing within originally homogeneous endocrine glands. In the search for the pathogenesis of these nodules, two concepts have been advanced: either the hyperplastic tissue is considered to result from chronic intense stimulation by a trophic hormone, eventually causing the growth of polyclonal nodules (a concept known as NNEH) or else, the nodules are thought to represent true clonal tumors. It has been realized rather recently that NNEH accounts only for a small minority of rare endocrine diseases, with the exception of highly prevalent iodine deficiency goiters and, in a broader sense, for Graves' disease. Indeed, secondary hyperplasia of endocrine glands resulting from long-lasting chronic hormonal overstimulation cannot explain a large number of essential features of the diseased glands. As best documented for the thyroid gland, outstanding among the characteristics of hyperplastic glands that do not fit into the simple concept of NNEH are the inevitable nodular transformation, the frequent autonomy and irreversibility of nodular growth, the loss of function in many cells and nodules, and the tremendous regional heterogeneity of growth and function including loss of coordination between these two main features of any living cell. Hyperplasia resulting from long-lasting stimulation by a trophic hormone is not a fully reversible process, as is often thought, but definitely increases the total cell mass and leaves behind, after cessation of the stimulus, a population of newly generated cells. This process is common to NNEH and true neoplastic growth. A review of common and disparate traits between endocrine hyperplasia and neoplasia must be based on the following generally accepted facts (excluding in-depth consideration of malignancy).
"1. Many endocrine tumors are clonal while others are polyclonal. For example, pituitary and sporadic parathyroid adenomas are nearly always clonal while in the thyroid, multiple clonal nodules of different origin may coexist with polyclonal nodules.
"2. Clonal growth does not necessarily indicate that the autonomous expansion of a tumor is driven by presently known genetic gain-of-function or loss-of-inhibition mutations or by cytogenetic aberrations.
"3. Genetic mutations and chromosomal aberration in endocrine tumors are not necessarily primary events in the tumorigenesis but may as well be a late secondary phenomenon in growing tissue.
"4. Clonal nodules may overgrow from primarily polyclonal ones. The best evidence to date comes from the rare clonal parathyroid adenomas with allelic loss of chromosome 11 evolving in tertiary hyperparathyroidism. (ABSTRACT TRUNCATED AT 400 WORDS)"
Nodular goiter and goiter nodules: Where iodine deficiency falls short of explaining the facts.Derwahl M, Studer H. Exp Clin Endocrinol Diabetes. 2001;109(5):250-60. Review. [abstract only]
"While the concept of iodine deficiency (ID) still dominates most discussions about the pathogenesis of multinodular goiter (MNG), the present review focuses on those mechanisms that may cause MNG in the absence of ID. Among the many facets of MNG that cannot simply be explained by ID, are the frequent occurrence of the disease in patients not exposed to ID, the autonomous growth of goiters - often accompanied by subclinical or even overt thyrotoxicosis -, the inverse relationship between goiter size and serum TSH, the multifocal, heterogeneous and nodular growth pattern, the heterogeneity of function with the familiar patchy iodine metabolism on scintiscans, the growth of clonal and polyclonal nodules, the prominent genetic predisposition. Even the notoriously low intrathyroidal iodine concentration - common to endemic as well as to sporadic goiter - is a secondary, rather than a primary event. Thus, the fundamental process of goitrogenesis, is independent from ID but operates through mechanisms innate to the hereditary and acquired heterogeneity among the thyrocytes themselves. In this view, goiter nodules and nodular goiters are true benign neoplasias arising by mechanisms common to all benign endocrine and nonendocrine neoplasms. However, superimposed iodine shortage greatly enhances the incidence of MNG and shifts its clinical appearance toward younger ages by adding one more growth factor - presumably enhanced TSH secretion - to an intrinsically activated growth regulating network."
Multinodular goitre: 'much more to it than simply iodine deficiency'.Derwahl M, Studer H. Baillieres Best Pract Res Clin Endocrinol Metab. 2000 Dec;14(4):577-600. Review. [abstract only]
"While the concept of iodine deficiency (ID) still dominates most discussions about the pathogenesis of multinodular goiter (MNG), the present review focuses on those mechanisms that may cause MNG in the absence of ID. Among the many facets of MNG that cannot simply be explained by ID, are the frequent occurrence of the disease in patients not exposed to ID, the autonomous growth of goiters - often accompanied by subclinical or even overt thyrotoxicosis -, the inverse relationship between goiter size and serum TSH, the multifocal, heterogeneous and nodular growth pattern, the heterogeneity of function with the familiar patchy iodine metabolism on scintiscans, the growth of clonal and polyclonal nodules, the prominent genetic predisposition. Even the notoriously low intrathyroidal iodine concentration - common to endemic as well as to sporadic goiter - is a secondary, rather than a primary event. Thus, the fundamental process of goitrogenesis, is independent from ID but operates through mechanisms innate to the hereditary and acquired heterogeneity among the thyrocytes themselves. In this view, goiter nodules and nodular goiters are true benign neoplasias arising by mechanisms common to all benign endocrine and nonendocrine neoplasms. However, superimposed iodine shortage greatly enhances the incidence of MNG and shifts its clinical appearance toward younger ages by adding one more growth factor - presumably enhanced TSH secretion - to an intrinsically activated growth regulating network."
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