Editorial : RET / PTC Rearrangement — A Link between Hashimoto ’ s Thyroiditis and Thyroid Cancer

RET/PTC rearrangement has been known for almost two decades as one of the most common molecular alterations in thyroid papillary carcinoma. It was discovered by Fusco et al. (1) in 1987 using a transfection assay on NIH3T3 cells, which revealed the transforming activity of DNA isolated from papillary carcinomas. The new oncogene, named RET/PTC, was subsequently found to be a fusion between the RET gene coding for transmembrane receptor tyrosine kinase and the H4 gene (2). As of today, 11 different fusion partners of RET have been identified, giving rise to specific types of RET/ PTC fusions (reviewed in Refs. 3 and 4). The two most common rearrangement types are RET/PTC1 and RET/PTC3, both of which are intrachromosomal inversions involving the long arm of chromosome 10. The rearrangement is likely to be predisposed by close positioning of the RET and its fusion partners within the nuclei of normal thyroid cells (5, 6). The fusion results in constitutive activation of the truncated tyrosine kinase portion of RET and signaling along the MAPK pathway. RET/PTC activation is believed to be oncogenic for thyroid follicular cells, because it transforms cells in vitro and results in the formation of thyroid tumors in transgenic mice (7–9). RET/PTC is found in 20–40% of adult sporadic papillary carcinomas and with higher prevalence in children and in patients exposed to radiation (3, 4). Originally, the rearrangement was considered to be specific for papillary thyroid carcinomas because it was not found in other thyroid tumors in a large series of cases studied using Southern blot analysis (10). Southern blot is a highly reliable method for the detection of chromosomal rearrangements, which, however, has limited sensitivity and requires at least approximately 10% of tumor cells within the sample for successful detection. More recently, the specificity of RET/PTC for papillary carcinomas has been challenged by several observations that reported its detection in benign thyroid follicular adenomas, benign and malignant oncocytic (Hurthle cell) tumors, and even in some nonneoplastic conditions such as Hashimoto’s thyroiditis (11–16). Most of those reports used for the analysis a highly sensitive RT-PCR technique, which is capable of the detection of a very small proportion of cells carrying a particular genetic event. Two of those studies have found both RET/PTC1 and RET/PTC3 rearrangements in virtually all thyroid glands affected by Hashimoto’s thyroiditis (12, 14). This led the authors to conclude that multiple occult papillary carcinomas exist in thyroid glands of most patients affected by this common disease, implying the necessity for their aggressive surgical treatment. However, both of these studies had substantial technical limitations because they used highly degraded RNA isolated from formalin-fixed and paraffin-embedded tissues. Furthermore, they used PCR with increased cycle numbers and more than one round of amplification, an approach that dramatically increases the sensitivity of detection but also carries a higher risk of falsepositive amplification. The results of these studies have not been reproduced in other observations using standardsensitivity PCR (17). Because of these limitations and the lack of reproducibility, the conclusions on the association between Hashimoto’s thyroiditis and the occurrence of multiple tumors in most thyroid glands were met with substantial skepticism. Nevertheless, these studies provided some evidence suggesting that RET/PTC may be present in a subpopulation of cells in the thyroid glands affected by Hashimoto’s thyroiditis. These reports added a new dimension to the long-standing controversy regarding the association between Hashimoto’s thyroiditis and follicular cell-derived thyroid tumors. This association was first proposed more than 50 yr ago by Dailey et al. (18), who found a significantly higher frequency of thyroid carcinomas and adenomas in surgically removed glands with Hashimoto’s thyroiditis than in glands unaffected by this disease. Most of the malignancies found in their series were papillary carcinomas. The subsequent studies yielded conflicting results, reporting either very high (up to 23%) or low incidence of thyroid carcinoma in the removed thyroid glands with Hashimoto’s thyroiditis (reviewed in Ref. 19). The increase in risk of thyroid cancer in patients with Hashimoto’s thyroiditis was not found in the prospective case-control studies (20, 21). The high incidence of cancer reported in several studies could still be interpreted as evidence for a relationship between the two diseases, but it did not imply whether the putative relationship is causal or merely incidental. The findings of RET/PTC rearrangement in these glands could provide a strong pathogenetic link between the two conditions. However, this would require unequivocal and reproducible detection of RET/PTC, preferably using more than one method, as well as evidence that the occurrence of the rearrangement in few cells is carcinogenic and confers the cells with the phenotypical features of papillary carcinoma. In this issue of JCEM, the paper by Rhoden et al. (22) reports a study of RET/PTC rearrangements in Hashimoto’s thyroiditis and papillary carcinomas using two detection techniques, interphase fluorescence in situ hybridization (FISH) and RT-PCR. The experiments used high-quality RNA extracted from snap-frozen thyroid tissue; microscopic examination by an experienced thyroid pathologist was undertaken to identify the papillary carcinoma foci. The authors report that in the majority of thyroid glands with Hashimoto’s thyroiditis, they were able to detect RET/PTC by FISH Abbreviation: FISH, fluorescence in situ hybridization.