Thyroid follicular oncogenesis in iodine-deficient and iodine-sufficient areas: Search for alterations of the ras, met and bFGF oncogenes and of the Rb anti-oncogene

To gain insights into the role of iodine deficiency in favoring thyroid tum origenesis (particularly of the follicular histotype), 22 Sicilian patients with thyroid tumors were selected for having lived permanently in either o ne of two areas of different iodine availability. Eleven patients (age 46.1 +/-14.6 years, mean+/-SD; 10 females and 1 male) were from the iodine-defic ient (ID) areas of the provinces of Messina and Catania (mean urinary excre tion of iodine=48.1 mu g/24 hours). Thyroid tumors were follicular or Hurth le cell adenomas (no.=3), follicular carcinomas (FC, no.=4), papillary carc inomas (PC, no.=2) and anaplastic carcinomas (no.=2). Eleven patients (age 47.1+/-15.2 years; 10 females and 1 male) were from the metropolitan area o f Messina, an area of relative iodine-sufficiency (IS) (urinary excretion o f iodine=95.2 mu g/24 hours). These 11 patients had serum levels of TSH tha t were significantly lower than the corresponding values of the 11 patients from the ID area (0.76+/-0.33 vs 1.80+/-1.22 mU/l, p=0.01) The tumors of t he 11 patients from the IS area were: follicular or Hurthle cell adenomas ( no.=6), Hurthle cell carcinoma (no.=1), FC (no.=2), PC (no.=2). Molecular b iology studies revealed that both the normal as well as the tumor tissue of all 22 patients did not harbor any of the three classical activating mutat ions (codons 12, 13 and 61) in any of the three ras oncogenes. Similar nega tive results were obtained as far as loss of heterozygosity of the retinobl astoma (Rb) anti-oncogene is concerned. Immunohistochemistry studies were p erformed to investigate expression of c-met and basic fibroblast growth fac tor (bFGF) proto-oncogenes. Only one Hurthle cell carcinoma and the two PC from the IS group, and one FC and the two PC from the ID group stained for the c-met oncogene. Expression of c-met was greater (3+) in the four PC (co ncerning 70-80% of the tumor cells) than in the other two cancers (1+; <5% of the tumor cells). In the IS group, positivity for bFGF was detected in 3 /6 adenomas, 1/2 FC, the Hurthle cell carcinoma and the two PC. In the ID g roup, positivity for bFGF was observed in 2/3 adenomas, 2/4 FC, the two PC and the two anaplastic carcinomas. The 8 positive cases from the ID group h ad a greater level of bFGF expression than the 7 positive cases from the IS group (intensity of staining = 2.0+ vs 1.57+). Interestingly, the greatest expression of bFGF was seen in the cases with peri-tumoral lymphocytic inf iltration from either group. In the ID group correlations between (i.) pre- intervention serum TSH and intensity of tumoral staining for bFGF, (ii.) se rum TSH and per cent of tumoral cells reactive with anti-bFGF and (iii.) be tween intensity of staining for bFGF and per cent of tumoral cells bFGF +ve were higher than in the IS group. We conclude that activating mutations of ras, loss of DNA from the Rb locus and over-expression of both c-met and b FGF are of no pathogenetic relevance in driving thyroid tumorigenesis of io dine-deficient areas. (J. Endocrinol. Invest. 21: 680-687, 1998) (C)1998, E ditrice Kurtis.