RET/PTC3 Rearrangement in Papillary Thyroid Carcinoma: Possible Marker of Tumor Progression

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To the Editor:
There seems to be a disagreement in the article.1 On the one hand, it is stated: “Rearranged during transfection/papillary thyroid carcinoma (RET/PTC)-positive TCs were more often associated with stage III/IV disease (40% vs 15%; P < 0.001) and recurrence (10% vs 0.7%; P < 0.001; mean follow-up 33 ± 21 months). Distant metastasis was highest in patients with RET/PTC-positive TC.”1 On the other hand, a tendency of a decrease in the frequencies of different mutations along with the tumor advancement from the TNM stage T1 to T4 is recognizable from the table “Histologic Characteristics of Thyroid Cancer by Mutation.”1 In particular, the following percentages are given for RET/PTC: T1, 57%; T2, 8%; T3, 22%; T4, 14%.1 This seems to disagree with the citation in the beginning of this letter. The tumor progression is generally accompanied by accumulation of mutations. It is theoretically possible that RET/PTC-positive tumor cell clones disappear in the course of the tumor progression. This supposition, however, needs experimental evidence. Furthermore, the above-cited numerical data on RET/PTC might be in agreement with the concept that RET/PTC-positive thyroid cancers (TCs) rarely evolve to less differentiated forms, that is, prevalence of RET/PTC rearrangements is low in poorly differentiated and undifferentiated TCs.2 A plausible explanation is the fact that only a fraction of poorly and undifferentiated TC derives from papillary carcinoma with RET/PTC rearrangements, whereas the rest develops along other carcinogenetic pathways.3 However, some evidence exists that tumors carrying RET/PTC3 rearrangement may be prone to dedifferentiation.4
It was reported that RET/PTC3 rearrangement is associated with more aggressive phenotype and larger tumor size.2–5 A considerable part of TC detected during the first decade after the Chernobyl accident was papillary carcinomas of the relatively high-grade solid subtype with a high prevalence of RET/PTC3 rearrangements.6,7 On the contrary, among the cases diagnosed 10 years after the accident and later prevailed RET/PTC1. The percentage of the RET/PTC-positive TC in general was higher during first decade after the accident than later on.6
Thyroid cancer was rarely diagnosed in Belarus and Ukraine before the Chernobyl accident compared with more developed nations; more details and references are shown in reference.8 Accordingly, there must have been a pool of undiagnosed TC in the population before the accident. In the Russian Federation, TC was started to be registered separately only in 1989 when the screening began, and the TC incidence in children and adolescents started to increase rapidly. Besides, some patients from noncontaminated territories were probably registered as Chernobyl victims. According to the previously discussed hypothesis, some advanced TC cases, accumulated in the population and brought from noncontaminated areas, were misinterpreted as aggressive radiogenic cancers developing after a short latency.8 It is therefore not surprising that the first-wave TC after the accident were on average larger in size and less differentiated than those detected later,7 when the pool of neglected TC had been exhausted by the screening. Considering the high prevalence of RET/PTC3 rearrangements in TCs detected during the first decade after the accident, this is another argument in favor of the association of this marker with a later stage of the tumor progression.
It was noticed that the cohort of early TCs after the Chernobyl accident with the preponderance of RET/PTC3 has been globally unique.4 In sporadic TC, RET/PTC1 is usually the most prevalent RET rearrangement.4 It should be commented that Chernobyl cohorts have been unique not worldwide, but in more developed countries, where a majority of studies have been performed. In India, similarly to Chernobyl, RET/PTC3 were the most prevalent RET rearrangements,9 which has probably been caused by later diagnostics.

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