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A disparity in gender incidence has been reported in both papillary thyroid carcinoma (PTC) and chronic lymphocytic thyroiditis (CLT) diseases frequently associated and whose incidence has been increasing in parallel. We aimed to analyze differences in morphometric variables between male and female PTC patients and their relationship with the presence of concurrent CLT. The nuclear texture features of 100 hematoxylin-eosin stained nuclei from 100 consecutive classic PTC patients enrolled in our service were compared with their clinical and pathological features, including the presence of CLT. All patients were submitted to a standard management protocol and followed-up for 13-248 months (Mo = 117 months). Chromatin in women tended to present a denser and more homogeneous structure, in a less mottled pattern, with higher values of energy (p = 0.008) and diagonal moment (p = 0.032) than men. Concurrent CLT was more prevalent in women (41.42%) than in men (13.33%, p = 0.04) and was associated with higher cluster prominence values (p = 0.027), a parameter that indicates a predominance of high nuclear contrasted heterochromatin. A multivariate logistic regression analysis showed that higher cluster prominence was independently correlated with chromatin in patients who presented CLT but did not demonstrate any association between concurrent CLT and gender. We were unable to demonstrate any association between gender and any characteristic of tumor aggressiveness or patients outcome. Our results suggest that chromatin texture of hematoxylin-eosin stained nuclei in paraffin sections of PTC cells is related to both gender and concurrent CLT.

Purpose: Zona thinning (ZT) is a technique used to improve pregnancy rates among patients ≥38 years old and/or patients presenting previous implantation failure. The objective of the study was to determine whether ZT has a beneficial effect on patients younger than 37 years who are undergoing the first ICSI attempt.

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

New insights in prognostic predictions are urgently needed for papillary thyroid carcinoma (PTC). The present study aimed to investigate whether computerized analysis of chromatin texture allows the identification of PTC patients with a poor prognosis.We randomnly selected paraffin-embedded blocks from surgical specimens of 103 classic cases of PTC. During follow-up, 68 of the patients were classified as free of disease, whereas 35 presented with recurrences. Characteristics of chromatin were obtained from digitized images of at least 100 randomly selected tumor nuclei per patient. An independent series of 30 goiters was used to validate our observations.Stage, age and distant metastases were found to serve as independent prognostic factors for survival. In addition, multivariate Cox regression confirmed variable cluster prominence as an independent prognostic factor. By comparing malignant and benign nodules, we found that the PTC lesions presented with higher nuclear perimeters, nuclear areas, Minkowski fractal dimensions, optical densities and nuclear longest chords.From our results we conclude that, in conjunction with clinical and histopathological data, morphometric data may provide relevant prognostic information in PTC patients.

Cooccurrences of chronic lymphocytic thyroiditis (CLT) and thyroid cancer (DTC) have been repeatedly reported. Both CLT and DTC, mainly papillary thyroid carcinoma (PTC), share some epidemiological and molecular features. In fact, thyroid lymphocytic inflammatory reaction has been observed in association with PTC at variable frequency, although the precise relationship between the two diseases is still debated. It also remains a matter of debate whether the association with a CLT or even an autoimmune disorder could influence the prognosis of PTC. A better understanding about clinical implications of autoimmunity in concurrent thyroid cancer could raise new insights of thyroid cancer immunotherapy. In addition, elucidating the molecular mechanisms involved in autoimmune disease and concurrent cancer allowed us to identify new therapeutic strategies against thyroid cancer. The objective of this article was to review recent literature on the association of these disorders and its potential significance.

OBJETIVO E MÉTODOS: Com o propósito de investigar a contribuição do exame da cromatina nuclear no diagnóstico diferencial das lesões foliculares da glândula tireoide, foram estudadas 76 amostras previamente submetidas à análise de expressão proteica de HBME-1, CK-19 e galectina-3. RESULTADOS: HBME-1 confirmou-se como o mais sensível marcador imunoistoquímico de malignidade. Uma série de variáveis morfométricas, densitométricas e de textura foram úteis na distinção entre os diferentes tipos de lesão folicular. Entre essas variáveis, o r², parâmetro relacionado à granularidade do núcleo, apresentou a melhor acurácia, sensibilidade, especificidade, valor preditivo positivo e negativo, diferenciando lesões benignas de malignas. CONCLUSÃO: A morfometria analítica de imagem da cromatina nuclear pode acrescentar acurácia ao diagnóstico diferencial das lesões de padrão folicular.

To investigate the utility of nuclear chromatin texture assessment in the differential diagnosis of follicular patterned lesions, by means of examining 76 samples previously submitted to the immunohistochemical protein analysis of HBME-1, CK-19 and galectina-3.HBME-1 confirmed to be the most sensitive marker of malignancy. A series of morphometric, densitometric and texture variables were useful in the discrimination of the different types of follicular lesions. Among these variables, r(2), a parameter related to the granularity of the nucleus presented the best accuracy, sensitivity, specificity and positive and negative predictive values, distinguishing benign from malignant lesions.The morphometric analysis of nuclear chromatin images may add accuracy to the differential diagnosis of follicular patterned lesions.

In their interesting contribution, Wang et al. (1) described an automated system for the diagnosis of follicular thyroid lesions, which was based on the analysis of nuclear texture features in histologic slides. According to the authors, the method was able to classify with 100% accuracy between normal thyroid tissue, follicular adenomas, and follicular carcinomas. However, the system had been trained with digitalized images of only few neoplasias, five follicular adenomas (mean lesion size of 4.8 cm), and five follicular carcinomas (a mean lesion size of 2.8 cm) as well as with images of nontumoral tissue. Recently, it had been demonstrated that in follicular adenomas the chromatin texture was size dependent, when analyzing digitalized, gray-value transformed images of nuclei in routinely hematoxylin-eosin (HE)-stained paraffin sections. In nuclei of larger adenomas, the entropy values, the fractal dimension, and the diagonal moment were significantly increased, whereas the values of the second angular moment and local homogeneity were decreased, when compared with the nuclei of smaller adenomas (2). Therefore, we would like to ask whether the considerable size differences between follicular adenomas and carcinomas in the study of Wang et al. (1) might have contributed to the extraordinary classification success claimed by the authors. To test our hypothesis, we made the following simulation study based on adenomas and carcinomas from previous studies on thyroid neoplasias in our laboratory (2,3,4). From each tumor, digitalized images of 100 randomly selected nuclei had been captured in bitmap format from routinely HE-stained 5-μm thick histologic sections (2,3). The nuclei were interactively segmented and then converted to an eight-bit gray scale by calculating the luminance. The material comprised 18 follicular adenomas and 24 microinvasive follicular carcinomas. The final diagnosis had always been done by a meticulous examination of serial step sections. From this collection, we choose a combination of eight folicular carcinomas, so that their mean diameter of 2.78 cm had approximated well with that of the carcinomas from the study of Wang and coworkers (2.8 cm) (1). Then we selected with the help of random numbers, 100 sets of eight follicular adenomas each. The mean lesion size of these random sets varied between 1.98 and 5.21 cm. If our previously mentioned hypothesis was correct, then the ability to discriminate between nuclei of adenomas and carcinomas should vary with changing diameters of the adenoma cases. We calculated nuclear texture features using variables of the gray-level co-occurrence matrix (second angular moment, entropy, energy, peak prominence, standard deviation, cluster shade, and cluster prominence) as well as Shannon's entropy of the gray level histogram and the fractal dimension according to Sarkar. All these variables had shown to be useful for texture analysis in previous studies (1,4–10). In a further step, we created 100 pairs composed of (a) always the aforementioned group of eight carcinomas with a mean diameter of 2.78 cm and (b) one of the 100 randomly choosen adenoma sets with, of course, varying mean lesion size (see Supporting Information). For each pair, we compared the nine texture features with the help of the t-test (P < 0.05 for significant differences) and recorded, for each comparison, the percentage of statistically significant texture features by plotting these data versus the mean diameter of the adenoma set in a diagram (Fig. 1). Figure 1 Box and Whiskers diagram showing relationship between mean lesion diameter of the adenoma group and the number of nuclear texture features separating significantly adenomas and carcinomas. Nine texture variables had been tested in each case. The number ... As we can easily notice, in very large adenomas nearly all nuclear texture features were significantly different from those of the carcinoma group. But these differences were rapidly vanishing, when we compared the carcinomas with smaller adenomas. With a mean adenoma lesion size of 4.8 cm, as in the study under discussion (1), approximately 80% of the texture parameters showed significant differences. However, when the mean diameters of adenomas and carcinomas were very similar (∼2.8 cm), this number had dropped below 20%. There was a highly significant direct correlation (Spearman's correlation coefficient r = 0.72; P < 0.0001) between the mean lesion size of the adenoma cases and the percentage of significant different texture features between adenomas and carcinomas. We believe that the extraordinary good discrimination results reported in the study of Wang et al. (1) might largely be based on this effect and would have been worse, if smaller adenomas had been included in the investigation. Therefore, the data presented in the study of Wang et al. (1) are not able to test the quality of the program. To get a realistic view of the diagnostic power of the proposed automated system, the authors should repeat the evaluation with a considerably larger data set, after increasing the number of adenomas and carcinomas, both comprising a large spectrum of tumor diameters.

Sir,In his interesting review article in Pathology, Tadrous1 comments on the use of the term ‘objective’ and addresses several technical and conceptual problems in image analysis. We totally agree ...