Differential Topographic Kinetics in the Progression of Follicular Thyroid Neoplasms

Background: The kinetic differences (proliferation and apoptosis) and their correlation with telomere length and telomerase expression by topographic compartments have not been studied in follicular thyroid proliferative lesions to date.

Design: We selected 82 follicular thyroid proliferative lesions (9 hyperplastic nodules, 22 adenomas, 14 minimally-invasive carcinomas, 24 widely-invasive carcinomas and 13 anaplastic carcinomas, classified according to WHO criteria). Representative samples were evaluated and selected for Ki-67 and telomerase immunostaining, In situ end labeling (ISEL) of DNA fragments (to detect apoptosis using Klenow fragment of DNA polymerase), and FISH-PNA of telomere in peripheral and internal tumor compartments. Appropriate controls were run in each sample. The results were statistically compared using analysis of variance and Student t-test, and considered significant if P<0.05.

Results: The Ki-67/ISEL indices revealed the predominant kinetic advantage in the internal compartments of benign follicular thyroid proliferative lesions and in the peripheral compartments of malignant follicular thyroid proliferative lesions due to statistically significant decrease of ISEL indices at internal compartment of benign follicular thyroid proliferative lesions (5.3±7.8% vs. 1.3±2.4%; P=0.0213) and at peripheral compartments in carcinomas (1.4±1.7% vs. 2.3±5.5%; P=0.0474), respectively. Telomerase expression was significantly higher in the internal compartments (p<0.001) and in malignant lesions (p<0.001), which only correlated with PNA-FISH detectable telomeres in internal compartments. PNA-FISH detectable telomeres in more than 20% of peripheral tumor cells was observed in high-grade lesions (widely-invasive and anaplastic carcinomas) only.

Conclusions: 1. Inverse and opposite proliferation/apoptosis correlations characterized follicular thyroid proliferative lesions, the kinetic advantage predominating in the internal compartment of benign lesions and in the peripheral ones of malignant lesions. 2. The direct telomere-telomerase correlation characterizes expansive internal tumor compartments, while the telomere preservation (even in the absence of detectable telomerase expression) at peripheral compartments kinetically defines high-grade lesions.