Patrícia Sabino de Matos

Prevalence of papillary microcarcinoma of the thyroid in Brazilian autopsy and surgical series.

In order to search for parameters to differentiate patients at low and high risk for development of thyroid cancer, we studied thyroids from 166 consecutive autopsies and 261 thyroids that were surgically resected for thyroid diseases in general. We found 32 papillary microcarcinomas, corresponding to 7.8% of autopsies and 7.2% of surgical material, with a higher incidence between 30 and 49 yr of age. Both genders were similarly affected: 9.3% of the men and 8.8% of the women in autopsy series, and 6.2% of the men and 7.3% of the women in surgical series, suggesting that hormonal factors may favor the subsequent development of clinical lesions in women. Although associated nodular goiter has been observed in 54% of autopsies and 26% of surgical specimens, while Hashimotos thyroiditis only in surgical material (15% of the cases), we were not able to correlate risk of malignancy with any concomitant lesion. The smallest papillary microcarcinomas presented most frequently as nonencapsulated nonsclerosing tumors without inflammatory infiltrate or fibrosis, suggesting that they may represent the early stages of development. Our data show a relatively high and similar frequency of papillary microcarcinomas in surgical and autopsy series, but do not demonstrate risk factors for clinical evolution.

Role of ultrasound, clinical and scintigraphyc parameters to predict malignancy in thyroid nodule

BackgroundThis study aimed to evaluate clinical, laboratory, ultrasound (US) and scintigraphyc parameters in thyroid nodule and to develop an auxiliary model for clinical application in the diagnosis of malignancy.MethodsWe assessed 143 patients who were surgically treated at a single center, 65% (93) benign vs. 35% (50) malignant lesions at final histology (1998-2008). The clinical, laboratory, scintigraphyc and US features were compared and a prediction model was designed after the multivariate analysis.ResultsThere were no differences in gender, serum TSH and FT4 levels, thyroid auto-antibodies (TAb), thyroid dysfunction and scintigraphyc results (P = 0.33) between benign and malignant nodule groups. The sonographic study showed differences when the presence of suspected characteristics was found in the nodules of the malignant lesions group, such as: microcalcifications, central flow, border irregularity and hypoechogenicity. After the multivariate analysis the model obtained showed age (>39 years), border irregularity, microcalcifications and nodule size over 2 cm as predictive factors of malignancy, featuring 81.7% of accuracy.ConclusionsThis study confirmed a significant increase of risk for malignancy in patients of over 39 years and with suspicious features at US.

Identifying a Risk Profile for Thyroid Cancer

The large use of simple and effective diagnostic tools has significantly contributed to the increase in diagnosis of thyroid cancer over the past years. However, there is compelling evidence that most micropapillary carcinomas have an indolent behavior and may never evolve into clinical cancers. Therefore, there is an urgent need for new tools able to predict which thyroid cancers will remain silent, and which thyroid cancers will present an aggressive behavior. There are a number of well-established clinical predictors of malignancy and recent studies have suggested that some of the patients laboratory data and image methods may be useful. Molecular markers have also been increasingly tested and some of them appear to be very promising, such as BRAF, a few GST genes and p53 polymorphisms. In addition, modern tools, such as immunocytochemical markers, and the measure of the fractal nature of chromatin organization may increase the specificity of the pathological diagnosis of malignancy and help ascertain the prognosis. Guidelines designed to select nodules for further evaluation, as well as new methods aimed at distinguishing carcinomas of higher aggressiveness among the usually indolent thyroid tumors are an utmost necessity.

Application of the Minkowski–Bouligand fractal dimension for the differential diagnosis of thyroid follicular neoplasias

Nuclear characteristics are important for the differential diagnosis between benign or malignant neoplasias. Subjective interpretation by an observer, however, may cause diagnostic insecurity [5]. Quantitative morphologic analyses can be helpful in this situation [19]. There are several ways to perform karyometry, which may be done by basic morphometry [8,10,14, 16,17,21–24,28], or by sophisticated texture analysis based on digitalized images [2–7,11–13,20,25–27,29– 31]. Due to the fractal nature of chromatin organization in interphase nuclei [15], the scale-invariant self similiarity is an important texture feature, which can be estimated by the fractal dimension (FD) [1,3,9,13,31]. For the analysis of nuclear chromatin in routinely stained slides it has been suggested that besides the FD, the goodness-offit (GOF) of the regression line in the loglog plots, which are essential for the FD estimation, could be important [3]. In this investigation we tried to find out whether this new parameter GOF could also be useful for differential diagnosis in surgical pathology. We compared the FD and GOF of nuclear chromatin in routinely HE stained paraffin sections of follicular adenomas and minimally invasive follicular carcinomas of the thyroid. Our study consisted of 18 follicular adenomas and 24 microinvasive follicular carcinomas from our files. Tumors with a diameter up to 6 cm had been completely embedded in paraffin. For larger tumors the number of paraffin blocks taken had been d + 4 (d representing the largest diameter in cm). Diagnosis was based on criteria of the World Health Organization Histological Classification [18]. From each tumor 100 nuclei were randomly taken from routinely stained 5 μm HE stained paraffin sections using the Kontron Zeiss KS300 system (0.1 μm/pixel spatial resolution; 1.25 numerical aperture; 100× oil immersion objective) by one examiner blinded to the diagnosis. The images were converted to grayscale format with levels of luminance ranging between 0 (absence of light) and 255 (very bright). Then a pseudo-three-dimensional “landscape-like” representation was created using the gray level (luminance) of each pixel (picture element) as the height of a z-axis. The fractal dimension (FD) was determined according to Minkowski–Bouligand extended to three dimensions, as described earlier [3]. The linear regression was estimated in a log-log plot composed of 30 points. The goodness-of-fit (GOF) was determined by the R2 value of the regression between the real and the estimated values. For each nucleus the distribution of the residuals was compared with the normal distribution by the Kolmogorov–Smirnov test. Then for each patient the percentage (P ) of cells with normally distributed residuals was calculated [3]. Group comparison was done by the Mann–Whitney test (WinStat software). Patients of both groups were of similar age with a mean for adenomas of 40.3 years (range 17–72 years) and a mean for minimally invasive carcinomas of 49.5 years (range 19 to 88 years; p > 0.05). The same was true for the tumor size (mean for adenomas: 3.6 cm, range 1.0–7.0 cm; mean for minimally invasive carcinomas: 3.4 cm, range 1.3 to 8.5 cm; p > 0.05). There was no statistically significant difference (p > 0.05) of the FD values between both groups: adenoma mean value 2.424 (range 2.347 to 2.505); minimally invasive carcinomas: 2.432 (range 2.339 to 2.499). The R2 values, however, were significantly different (p < 0.05), ranging between 0.922 and 0.953 (mean 0.939) in adenomas and between 0.929 and 0.952 (mean 0.943) in minimally invasive carcinomas. The percentage of cells with a Gaussian distribution of the residuals ranged from 58 to 97% (mean 79%) for adenomas and between 48 and 94% (mean 75%) for minimally invasive carcinomas. The fractal dimension is derived from the slope of the curve in a log–log-diagram, assuming that this

Thyroid imaging reporting and data system score combined with Bethesda system for malignancy risk stratification in thyroid nodules with indeterminate results on cytology

The thyroid imaging reporting and data system (TI‐RADS) was designed to better select patients who had undergone fine‐needle aspiration biopsies (FNABs) with high sensitivity and accuracy. However, the combination of TI‐RADS scores and Bethesda system categories in indeterminate thyroid nodules has not been examined extensively.

Chromatin Texture is Size Dependent in Follicular Adenomas But Not in Hyperplastic Nodules of the Thyroid

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

Long-term follow-up of an 8-year-old boy with insulinoma as the first manifestation of a familial form of multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary cancer syndrome characterized mostly by parathyroid, enteropancreatic, and anterior pituitary tumors. We present a case of an 8-year-old boy referred because of hypoglycemic attacks. His diagnosis was pancreatic insulinoma. Paternal grandmother died due to repeated gastroduodenal ulcerations and a paternal aunt presented similar manifestations. At a first evaluation, the father presented only gastric ulceration but subsequently developed hyperparathyroidism and lung carcinoid tumor. During almost 15 years of follow-up, three brothers and the index case presented hyperparathyroidism and hyperprolactinemia. Molecular study showed a G to A substitution in intron 4, at nine nucleotides upstream of the splicing acceptor site, causing a splicing mutation. All affected members of the family have the same mutation. Paternal grandmother and aunt were not studied and the mother does not carry any mutation. MEN1 is a rare condition that requires permanent medical assistance. Early clinical and genetic identification of affected individuals is essential for their own surveillance and also for genetic counseling.

Papillary carcinoma in a thyroglossal duct: case report

CONTEXT Thyroglossal duct cysts are the most common congenital cervical abnormality in childhood. Malignant lesions are rare in thyroglossal duct cysts (about 1%). OBJECTIVE To report a case of papillary carcinoma in thyroglossal duct cysts. DESIGN Case report. CASE REPORT The patient was a 21-year-old female with a four-month history of an anterior midline neck mass but without other symptoms. The physical examination revealed a 4.0 cm diameter, smooth, painless, cystic nodule at the level of the hyoid bone. The thyroid gland was normal by palpation and no neck lymph nodes were found. Indirect laryngoscopy, fine-needle biopsy aspiration and cervical ultrasound were normal and compatible with the physical findings of a thyroglossal duct cyst. The patient underwent surgery with this diagnosis, under general anesthesia, and the mass was resected by the usual Sistrunk procedure. There were no local signs of invasion of the tissue surrounding the cyst or duct at surgery. The patient was discharged within 24 hours. Histopathological examination of the specimen showed a 3.5 x 3.0 x 3.0 cm thyroglossal cyst, partially filled by a solid 1.0 x 0.5 cm brownish tissue. Histological sections showed a papillary carcinoma in the thyroid tissue of a thyroglossal cyst, with normal thyroid tissue at the boundary of the carcinoma. There was no capsule invasion and the margins were negative. The follow-up of the patient consisted of head and neck examinations, ultrasonography of the surgical region and thyroid, and total body scintigraphy. The patient has been followed up for two years with no further evidence of disease.

Value of Ultrasound and Cytological Classification System to Predict the Malignancy of Thyroid Nodules with Indeterminate Cytology

Although fine-needle aspiration cytology is considered the gold standard for evaluating thyroid nodules, in about 10–30% of the cases, cytology is indeterminate. This study aimed to determine the value of cytological classification system and ultrasound (US) to predict malignancy in indeterminate thyroid nodule. This retrospective analysis enrolled 80 patients surgically treated at a single center, 75% (60) with benign vs. 25% (20) with malignant lesions at final histology. The clinical, scintigraphic, sonographic, and cytological classification (Bethesda) variables were analyzed in these selected cases of indeterminate cytology, and a prediction model was designed after the multivariate analysis. There was a 25% prevalence of malignancy (20/80). There were no differences in gender, serum thyroid-stimulating hormone and FT4 levels, thyroid auto-antibodies, thyroid dysfunction, and scintigraphic results between benign and malignant nodule groups. The border irregularity in sonographic study was at increased risk for malignancy. The cytological analysis based on Bethesda System (category IV) was an independent predictor for malignancy in indeterminate thyroid nodules. After the multivariate analysis, the model obtained showed border irregularity and Bethesda System category IV as predictive factors of malignancy in indeterminate thyroid nodules, featuring 76.9% of accuracy. This study confirmed a significant increase of risk for malignancy in thyroid nodules with indeterminate cytology showing Bethesda System category IV and suspicious features at US. These findings enhance our current limited predictive armamentarium and can be used to guide surgical decision making.

Primary thyroid tuberculosis: a rare etiology of hypothyroidism and anterior cervical mass mimicking carcinoma

OBJECTIVE The involvement of the thyroid by tuberculosis (TB) is rare. Hypothyroidism caused by tissue destruction is an extremely rare report. Our aim was to report a patient with primary thyroid TB emphasizing the importance of diagnosis, despite the rarity of the occurrence. CASE REPORT Women, 62 years old, showing extensive cervical mass since four months, referring lack of appetite, weight loss, dysphagia and dysphonia. Laboratorial investigation revealed primary hypothyroidism. Cervical ultrasound: expansive lesion in left thyroid lobe, involving adjacent muscle. Computed tomography scan: 13 cm diameter cervical mass with central necrosis. Fine needle biopsy: hemorrhagic material. SURGERY total thyroidectomy, left radical neck dissection and protective tracheotomy. The pathological examination showed chronic granulomatous inflammatory process with areas of caseous necrosis and lymph node involvement. The thyroid baciloscopy was positive. Pulmonary disease was absent. The patient was treated with antituberculosis drugs. CONCLUSIONS Thyroid TB is not frequent, and should be considered as differential diagnosis of hypothyroidism and anterior cervical mass.