Genetic heterogeneity of normal follicular cells and acquisition of new inheritable qualities by replicating epithelial cells.
It has been shown that cells of many organs, including the thyroid gland, are often polyclonal, rather than monoclonal of origin. Also from a functional aspect it appears that through developmental processes the thyroid epithelial cells forming a follicle are functionally polyclonal and possess widely differing qualities regarding the different biochemical steps leading to growth and to thyroid hormone synthesis like e.g. iodine uptake (i.e. transport), thyroglobulin production and iodination, iodotyrosine coupling, endocytosis and dehalogenation. As a consequence there is some heterogeneity of growth and function within a thyroid and even within a follicle (Fig. 17-2). Studer et al 16a demonstrated the existence of monoclonal and polyclonal nodules in the same multinodular gland. They analyzed 25 nodules from 9 multinodular goiters and found 9 to be polyclonal and 16 monoclonal. Three goiters contained only polyclonal nodules and 3 contained only monoclonal nodules. In 3 goiters poly- and monoclonal nodules coexisted in the same gland.
Figure 2. Heterogeneity of morphology and function in a human multinodular goiter. Autoradiographs of two different areas of a typical multinodular euthyroid human goiter excised after administration of radioiodine tracer to the patient. There are enormous differences of size, shape and function among the individual follicles of the same goiter. Note also that there is no correlation between the size or any other morphological hallmark of a single follicle and its iodine uptake. (with permission ref. 15).
Newly generated cells may acquire qualities not previously present in mother cells. These qualities could subsequently be passed on to further generations of cells. A possible example of this process is the acquired abnormal growth pattern that is reproduced when a tissue sample is transplanted into a nude mouse.16b Other examples are acquired variable responsiveness to TSH.13 These changes may be related to mutations in oncogenes such as ras, or others which do not produce malignancy per se, but that can alter growth and function. An example of acquisition of genetic qualities is the identification in the last few years of constitutively activating somatic mutations not only in solitary toxic adenoma, but also in hyperfunctioning nodules of toxic multinodular goiters. So far these mutations in MNG have only been found in the TSH-receptor (TSHR) gene, and not in the Gs-alpha gene. Different somatic mutations are found in exon 9 and 10 of the TSHR gene and the majority of mutations that are present in toxic adenomas are also found in toxic nodules in multinodular goiter. Sometimes different toxic nodules in the same multinodular gland harbor different mutations.16c,d An important fact is the finding of a germline mutation of codon 727 of the TSHR gene that is specifically associated with MNTG (16e). Also evidence was found for linkage of familial euthyroid goiter to the recently identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q 16f. Perhaps MNTG constitutes a heterogeneous group consisting of MNG due to multiple autonomously functioning nodules generated by somatic mutations of the TSHR (and Gs-alpha?) gene, and MNG caused by a germline mutation(s) of this gene. TSH-R mutations have also been detected in microscopically hot areas in thyroids of patients living in an iodine deficient region 17. Three dominant MNG loci have been identified in familial MNG, i.e. MNG1, 2 and 3. In MNG1 a major locus was identified on chromosome 14q by a genomic search on a single large Canadian family with 18 cases of nontoxic multinodular goiter. Although the gene for TSHR is located on this chromosome, it was excluded as a candidate gene. In the analysis of an Italian three-generation pedigree with familial MNG2, including 10 affected females and 2 affected males, a novel MNG locus was searched for. Because no male-to-male transmission was present in the study pedigree, an X-linked autosomal dominant pattern of inheritance was hypothesized and confirmed. A significant LOD score was observed in the Xp22 region A third locus, MNG3, for a dominant form of familial multinodular goiter was detected on 3q26.1-q26.3, in 2 independent Japanese families. This variant however was characterized by congenital hypothyroidism. For a review on the pathogenesis and genetics of multinodular goiter see ref (17b)
Subsequent functional and structural abnormalities in growing goiters
Follicles of second and following generations are less well formed and compartmentalization of key enzymes may become altered. Intercellular communication may become disrupted. As a consequence inter- and intrafollicular growth and function may become poorly integrated resulting in further heterogeneity.13,18