To the Editor In their interesting publication Arora et al. [1] postulate that benign thyroid nodules, such as follicular adenomas, particularly the Hurthle cell variant, but not hyperplastic nodules, might have malignant potential. Thus in the thyroid an adenoma–carcinoma sequence was postulated not only for Hurthle cell tumors [2] but also for follicular adenomas, much like that described in colon or salivary glands[3–5]. If this were the case, we would expect, in analogy to colon tumors [3], that (pre)-malignant transformations of nuclei would be more common and accentuated in larger follicular adenomas. Because epigenetic and genetic alterations related to patient prognosis may modify the chromatin texture in routine slides [3, 6–9], we tried to find out whether nuclear texture features would change with increasing size of follicular adenomas. For this purpose, we routinely reanalyzed hematoxylin & eosin-stained paraffin sections from a previous study based on the WHO Histological Classification of Tumors [10, 11]: 11 hyperplastic nodules, 18 follicular adenomas, and 24 microinvasive follicular carcinomas. Analyses were based on digitalized images of 100 randomly captured nuclei [6, 7, 9, 11–13]. We compared texture features derived from the gray value co-occurrence matrix [11–14] and the Minkowski fractal dimension [6, 11] between the three groups and then looked for correlations between texture features and the size of the nodules. Patients of all groups were of similar age with a mean of 46 years (range: 17–88 years; analysis of variance [ANOVA] p [ .0.10). The results are summarized in Table 1. Whereas the chromatin of the hyperplastic nodules is relatively homogeneous (local homogeneity) and ‘‘smooth’’ (angular second moment), its architecture in minimally invasive carcinomas is more complex (fractal dimension), with a more irregular (diagonal moment) and contrasted (entropy) chromatin arrangement. Nuclei of follicular adenomas showed intermediate texture features that were significantly correlated with the size of the nodules. In larger adenomas the entropy values (r = 0.626; p = 0.0054; Fig. 1), the fractal dimension (r = 0.482; p = 0.042; Fig. 2), and the diagonal moment (r = 0.59; p = 0.01) were increased, whereas the second angular moment (r = -0.603; p = 0.008), and local homogeneity (r = -0.627; p = 0.0053; Fig. 3) decreased. Thus the nuclear texture of smaller adenomas was more like that of hyperplastic nodules, and the chromatin of larger adenomas resembled more closely that of minimally invasive carcinomas. Nevertheless there were no significant correlations between texture and the size of hyperplastic nodules. Our results are comparable with the findings in colon tumors [3], where an increasing irregularity and loss of nuclear texture homogeneity during the adenoma–carcinoma progression was described and was supposed to be influenced by accumulated alterations in cancer-associated genes. By analogy, we believe that larger follicular adenomas might have suffered more genetic alterations than smaller ones, thus supporting the hypothesis of Arora et al. [1] positing an adenoma–carcinoma sequence for follicular K. Metze (&) R. C. Ferreira P. S. de Matos Department of Pathology, Faculty of Medicine, University of Campinas, P.O. Box 6111, 13083-887 Campinas, SP, Brazil e-mail: kmetze@fcm.unicamp.br
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