Classic Variant Of Papillary Thyroid Carcinoma Research Articles

Abstract 6277: Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching

Abstract The tall cell variant of Papillary Thyroid Carcinoma (TCV-PTC) is the most common aggressive variant of PTC. The impact of TCV-PTC on patients’ prognosis still remains controversial. Moreover, the clinico-pathological and prognostic effect of TCV-PTC from Middle Eastern ethnicity remains unexplored. We aimed to study TCV-PTC in comparison to classical PTC in Middle Eastern patients and their impact on prognosis. We performed a retrospective cohort study of tall cell variant (TCV-PTC) and classic variant of papillary thyroid carcinoma (CV-PTC) after post-surgical radioactive iodine therapy. We used the propensity score matching (1:3 matching ratio) to account for differences between recipients of TCV-PTC vs CV-PTC. Univariate and multivariate analysis were performed to assess the independent factors for persistent/recurrent disease. Kaplan-Meier curve analyses were used to compare disease-free survival (DFS). In total, 174 (16.3%) patients with TCV-PTC and 891 (83.7%) patients with CV-PTC were included. After propensity score matching, 174 pairs of patients were selected (TCV-PTC, n = 174; CV-PTC, n = 522). In the matched analysis, higher proportions of TCV-PTC experienced persistent/recurrent disease compared with CV-PTC (25.7% vs 31.4%; p = 0.0119). In multivariate analyses of clinical and tumor characteristics, histological type of TCV-PTC (odds ratio, 2.09; 95% confidence interval, 1.28-3.40; p = 0.0031) was associated with increased risk of persistent/recurrent disease. The five-year DFS rates for the TCV-PTC and CV-PTC groups were 48.5% and 73.1%, respectively. The Kaplan- Meier analysis indicated that the TCV-PTC group (p < 0.0001) had shorter DFS. In conclusion, when other clinico-pathological factors were similar, this propensity score matched analysis showed that histological subtype TCV-PTC is by itself an independent predictive marker of persistent/recurrent disease in Middle Eastern patients. Therefore, individualized therapeutic approaches might be needed for this aggressive PTC subtype. Citation Format: Khawla S. Al-Kuraya, Sandeep K. Parvathareddy, Abdul K. Siraj, Saeeda O. Ahmed, Nabil Siraj, Manal Manakhan, Hassan Aldossari. Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6277.

Expression of pY397-FAK and Its miR Regulators Drive Dedifferentiation in the Thyroid Neoplasia Spectrum.

Thyroid carcinomas are growing malignancies worldwide. They encompass several diagnostic categories with varying degrees of dedifferentiation. Focal adhesion kinase is involved in cellular communication and locomotion. It is regulated on a posttranscriptional level by miR-7, miR-135a, and miR-138 and on a posttranslational level by autophosphorylation at Y397 (pY397-FAK). We related regulators of FAK with histologic dedifferentiation, clinicopathological factors, and differential diagnosis in the thyroid neoplasia spectrum. We classified 82 cases into 5 groups with increasing aggressiveness: healthy tissue, follicular and classical variants of papillary thyroid carcinoma (PTC), dedifferentiated PTC, and anaplastic carcinoma. MiRs were analyzed by RT-qPCR. Protein expression of pY397-FAK was analyzed by immunohistochemistry (separately in the membrane, cytoplasm, and nuclear compartment) and Western blot. All three miRs were upregulated in healthy tissue compared to malignant, while pY397-FAK was downregulated. MiRs and pY397-FAK were not mutually correlated. MiR-135a-5p was decreasing while membranous and cytoplasmic pY397-FAK increased with dedifferentiation. Neither miR correlated with clinicopathological factors. MiR-135a-5p, miR-138-5p, and membranous and cytoplasmic pY397-FAK discriminated the follicular from the classical variant of PTC. Disturbances of FAK regulation on different levels contribute to neoplastic dedifferentiation. pY397-FAK exerts its oncogenic role in the membrane and cytoplasm. Diagnostically, miRs-135a-5p, miR-138-5p, and membranous and cytoplasmic pY397-FAK differentiated between classical and follicular PTC.

Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma Is Related to a Poor Outcome: A Comparison Study Using Propensity Score Matching

ObjectiveThe clinical outcome of diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) remains controversial. We aimed to determine whether DSV-PTC is associated with an increased risk of persistent/recurrent disease. MethodsWe performed a retrospective cohort study of DSV-PTC and classic variant of papillary thyroid carcinoma (CV-PTC) after postoperative radioactive iodine therapy. We used propensity score matching (1:3 matching ratio) to account for differences between the recipients of DSV-PTC and CV-PTC. Univariate and multivariate analyses were performed to assess the independent factors for persistent/recurrent disease. The Kaplan-Meier curve analyses were used to compare disease-free survival (DFS). ResultsIn total, 35 (12.7%) patients with DSV-PTC and 240 (87.3%) patients with CV-PTC were included. After propensity score matching, 35 pairs of patients were selected (DSV-PTC, n = 35; CV-PTC, n = 105). In the matched analysis, a higher proportion of patients with DSV-PTC experienced persistent/recurrent disease than that of those with CV-PTC (25.7% vs 5.7%, P = .003). In the multivariate analyses of clinical and tumor characteristics, only the histologic type of DSV-PTC (odds ratio, 6.288; 95% confidence interval, 1.900-20.811; P = .003) was associated with an increased risk of persistent/recurrent disease. The 5-year DFS rates for the DSV-PTC and CV-PTC groups were 69.2% and 93.6%, respectively. The Kaplan-Meier analysis indicated that the DSV-PTC group (P= .001) had shorter DFS. ConclusionThis propensity score–matched analysis found that the histologic type of DSV-PTC may increase the risk of persistent/recurrent disease.

Nomogram for preoperative prediction of high-volume lymph node metastasis in the classical variant of papillary thyroid carcinoma.

The objective of our study was to construct a preoperative prediction nomogram for the classical variant of papillary thyroid carcinoma (CVPTC) patients with a solitary lesion based on demographic and ultrasonographic parameters that can quantify the individual probability of high-volume (>5) lymph node metastasis (HVLNM). In this study, a total of 626 patients with CVPTC from December 2017 to November 2022 were reviewed. Their demographic and ultrasonographic features at baseline were collected and analyzed using univariate and multivariate analyses. Significant factors after the multivariate analysis were incorporated into a nomogram for predicting HVLNM. A validation set from the last 6 months of the study period was conducted to evaluate the model performance. Male sex, tumor size >10 mm, extrathyroidal extension (ETE), and capsular contact >50% were independent risk factors for HVLNM, whereas middle and old age were significant protective factors. The area under the curve (AUC) was 0.842 in the training and 0.875 in the validation set. The preoperative nomogram can help tailor the management strategy to the individual patient. Additionally, more vigilant and aggressive measures may benefit patients at risk of HVLNM.

Clinical outcomes of a cohort of 271 patients with lung metastases from differentiated thyroid carcinoma.

Lung is the most common site of distant metastases from differentiated thyroid carcinoma (DTC). To investigate the outcomes of a cohort of patients with DTC and lung metastases (LM). A retrospective analysis of a cohort of 271 patients with LM was performed. The female-to-male ratio was 1:1 and the median follow-up time was 5.9 (1.1-38.4) years. Papillary thyroid carcinoma (PTC) was the most frequent type (83.4%), mainly the classic variant, followed by follicular thyroid carcinoma (FTC, 10.3%) and Hürthle cell carcinoma (HTC, 6.3%). The prevalence of PTC, FTC and HCC was different between the micronodular and macronodular LM groups [87.4%, 6.3% and 6.3% vs. 74.6%, 19.0% and 6.3%, respectively (p = .013)]. Only 5.0% of the patients had LM diagnosed after a period of remission. LM were submitted to radioactive iodine treatment (RAIT) in 84.5% (52.8% showed 131 iodine avid metastases). Complete remission was only achieved in 12.2%. Micronodular disease and age <55 years at LM diagnosis were associated with a better prognosis (p < .05). We found no difference in survival between patients with LM treated or not with RAIT. However, in patients submitted to RAIT, there was a tendency for longer survival in the group of patients with 131 I avid lesions. The classic variant of PTC was the most frequent histology found in LM of DTC. LM are rarely diagnosed in the follow-up when complete remission is achieved after surgery and 131 I. Younger age at LM diagnosis and a micronodular pattern are associated with a better prognosis.

Diagnostic utility of CK19 and galectin-3 in differentiating papillary thyroid carcinoma from nonneoplastic lesions of thyroid.

Thyroid neoplasm is one of the most common endocrine neoplasms. The diagnosis and the distinction between malignant and benign neoplasms can be difficult, but it has clinical, therapeutic, and prognostic significance. Hence, it is necessary to make precise diagnosis by using biomarkers. This is a laboratory observational study considering histologically diagnosed cases of papillary thyroid carcinoma (PTC) and nonneoplastic thyroid lesions. Immunohistochemistry (IHC) staining was done on tissue sections of all cases for CK19 and galectin-3 using appropriate positive and negative controls. The expression of immunomarkers was evaluated by a semi-quantitative method as negative, weak positive, moderate positive, and strong positive. The data were entered in Microsoft Excel sheet and were analyzed using SPSS 22 version software. A total of 52 cases were considered for the study, of which 26 cases each were PTC and nonneoplastic lesions of thyroid. Among the 26 PTC cases, 6 were classical variant of PTC (CVPTC) and 20 were follicular variant of papillary thyroid carcinoma (FVPTC). Among 26 nonneoplastic cases, 13 each were nodular hyperplasia cases and lymphocytic thyroiditis. There was a statistically significant (P < 0.01) association of CK19 and galectin-3 expression between CVPTC and FVPTC. There was no statistically significant association (P = 0.271) of CK19 expression between PTC and nonneoplastic cases. There was a statistically significant association (P = 0.003) of galectin-3 expression between PTC and nonneoplastic cases. Galectin-3 expression can be used to differentiate PTC from nonneoplastic lesions of thyroid in ambiguous cases. Galectin-3 and CK19 expression can be used to classify PTC into CVPTC and FVPTC.

Whole Tumor Capsule Is Prognostic of Very Good Outcome in the Classical Variant of Papillary Thyroid Cancer.

Tumor capsule integrity is becoming a relevant issue to predict the biological behavior of human tumors, including thyroid cancer. This work aims to verify whether a whole tumor capsule in the classical variant of papillary thyroid carcinoma (CVPTC) could have as a predictive role of a good outcome as for follicular variant (FVPTC). FVPTC (n = 600) and CVPTC (n = 554) cases were analyzed. We distinguished between encapsulated-FVPTC (E-FVPTC) and encapsulated-CVPTC (E-CVPTC) and, thereafter, invasive (Ei-FVPTC and Ei-CVPTC) and noninvasive (En-FVPTC and En-CVPTC) tumors, according to the invasion or integrity of the tumor capsule, respectively. Cases without a tumor capsule were indicated as invasive-FVPTC (I-FVPTC) and invasive-CVPTC (I-CVPTC). The subgroup of each variant was evaluated for BRAF mutations. E-FVPTC was more frequent than E-CVPTC (P < .001). No differences were found between En-FVPTC and En-CVPTC or between Ei-FVPTC and Ei-CVPTC. After 18 years of follow-up, a greater number of not-cured cases were observed in Ei-CVPTC with respect to Ei-FVPTC, but not in En-CVPTC to En-FVPTC. Multivariate clustering analysis showed that En-FVPTC, En-CVPTC, and Ei-FVPTC have similar features but different from I-FVPTC and I-CVPTC and, to a lesser extent, from Ei-CVPTC. A total of 177 of 614 (28.8%) cases were BRAFV600E mutated, and 10 of 614 (1.6%) carried BRAF-rare alterations. A significantly higher rate of En-CVPTC (22/49, 44.9%) than En-FVPTC (15/195, 7.7%) (P < .0001) were BRAFV600E mutated. En-CVPTC is less prevalent than En-FVPTC. However, it has good clinical/ pathological behavior comparable to En-FVPTC. This finding confirms the good prognostic role of a whole tumor capsule in CVPTC as well. New nomenclature for En-CVPTC, similar to that introduced for En-FVPTC (ie, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NIFTP) could be envisaged.

Raman-based cytopathology: an approach to improve diagnostic accuracy in medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a rare form of thyroid malignancy that can be diagnostically challenging on fine needle aspiration (FNA) cytology. Ancillary tests such as elevated serum or immunohistochemical positive calcitonin have been helpful, yet they can occasionally provide false positive results. In search for an alternative method to improve diagnostic accuracy (DA), we applied hyperspectral Raman spectroscopy to characterize the biochemical composition of single cells from MTC and compared their spectral information to cells from other types of thyroid nodules. Hyperspectral Raman images of 117 MTC single cells from digested tissue were obtained with a line-scan hyperspectral Raman microscope and compared to 127 benign and 121 classic variant of papillary thyroid carcinoma (CVPTC) cells. When principal component analysis and linear discriminant analysis were used to classify the spectral data, MTC cells were differentiated from benign and CVPTC cells with 97% and 99% DA, respectively. In addition, MTC cells exhibited a prominent Raman peak at 1003 cm-1, whose intensity is 84% and 226% greater on average than that observed in benign and CVPTC cells, respectively. When specifically utilizing only this peak as a spectral marker, MTC cells were separated from benign and CVPTC cells with 87% and 95% DA, respectively. As this peak is linked to phenylalanine, which is known to be associated with calcitonin release in thyroid parafollicular cells, the increased intensity further suggests that this Raman peak could potentially be a new diagnostic marker for MTC. Furthermore, preliminary data from MTC cells (n=21) isolated from a simulated FNA procedure provided similar Raman signatures when compared to single cells from digestion. These results suggest that "Raman-based cytopathology" can be used as an adjunct technique to improve the diagnostic accuracy of FNA cytopathology at a single cell level.

Ablation therapy using a low dose of radioiodine may be sufficient in low- to intermediate-risk patients with follicular variant papillary thyroid carcinoma.

ObjectivesFollicular variant papillary thyroid carcinoma (FVPTC) is treated similarly to classical variant papillary thyroid carcinoma (cPTC). However, FVPTC has unique tumour features and behaviours. We investigated whether a low dose of radioiodine was as effective as a high dose for remnant ablation in patients with FVPTC and evaluated the recurrence of low-intermediate risk FVPTC.MethodsData from cPTC and FVPTC patients treated with I-131 from 2004 to 2014 were reviewed. Demographics, tumour behaviour, lymph node metastasis, and local recurrence data were compared between FVPTC and cPTC patients. Then, low-intermediate risk FVPTC patients were divided into low, intermediate, and high I-131 dose groups, and postoperative I-131 activities were analysed to evaluate the effectiveness of I-131 therapy for thyroid remnant ablation.ResultsIn total, 799 cases of FVPTC (n = 168) and cPTC (n = 631) treated with I-131 were identified. Patients with FVPTC had a larger primary nodule size than cPTC, but lymph node metastases and local recurrence were more prevalent in cPTC than in FVPTC. For the low-, intermediate-, and high-dose groups, success rates of ablation did not differ (82.0%, 80%, and 81.3%, respectively).ConclusionFVPTC differs from cPTC in behaviour. Low-dose ablation may be sufficient in FVPTC patients with low-intermediate disease risk.

Familiar tumor with multiple faces- A 5 yr study of papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is the most common malignant tumour of thyroid. Papillary thyroid carcinoma, follicular, columnar, microcarcinoma, diffuse sclerosing. Several variants have been described considering size, architecture, cellular properties, additional tumour components, stromal features and combination of the above mentioned characteristics. Our aim is to study the histopathological variants of PTC. Age group of the patients ranged from 20-50yrs with female predominance. Of the total 44 cases of PTC, classical variant of PTC was the most common accounting for 48% (21) cases followed by 34% (15) of follicular variant. It is important to know all the possible morphological demonstrations of PTC to recognize this common tumour of the thyroid. Although some variants are just morphological challenges for the pathologists, some others may behave worse than conventional PTC and need a more aggressive clinical management. Keywords: Papillary thyroid carcinoma, Follicular, Columnar, Microcarcinoma, Diffuse sclerosing.

Correlation of papillary thyroid carcinoma different subtypes BRAF mutation and ultrasonic characteristics

Objective To investigate the correlation of BRAF mutation frequency with cervical lymph node metastasis, and to compare the ultrasonic characteristics in patients with BRAF mutation in papillary thyroid carcinoma (PTC) different subtypes. Methods The tumor samples were collected from 139 PTC patients who underwent thyroidectomy. And they were classified by histological subtype into 3 groups: classic variant of papillary thyroid carcinoma (CVPTC) group(34 cases), follicular variant of papillary thyroid carcinoma (FVPTC) group(36 cases), tall cell variant (TCV) group(69 cases). The BRAF mutation frequency and the correlation with cervical lymph node metastasis among 3 groups were analyzed, then the ultrasonic characteristics with BRAF mutation in PTC different subtypes were compared. Results ①The frequency of BRAF mutation was statistically significant different in different subtypes(χ2=6.390, P=0.041), and the frequency in TCV was 86.9%. There was also a statistical difference between BRAF mutation frequency and cervical lymph node metastasis among three subtypes (χ2=13.106, P=0.041). ②There was no statistically significant difference among the three groups in nodule number, echo level, internal structure, boundary, crossbar, morphology and acoustic halo of patients with BRAF mutation (P>0.05). ③A single factor analysis was performed for the ultrasonographic characteristics of patients with BRAF mutation, and there were significant statistical differences among the 3 groups in calcification type (χ2=21.7, P=0.001) and close to the envelope (χ2=7.726, P=0.021). ④Multivariate logistic regression showed that BRAF mutation was an independent influence factor affecting the calcification type of different histological subtypes in PTC patients. Conclusions ①BRAF mutation is correlated with cervical lymph node metastasis in different PTC subtypes. ②BRAF mutation is an independent influence factor affecting the morphology type of different calcification subtypes in PTC. The CVPTC group is mainly microcalcification, and the TCV group is mainly macrocalcification. Key words: Ultrasonography; Papillary thyroid carcinoma; Subtypes; BRAF gene

Impact of Gender and Age on the Prognosis of Differentiated Thyroid Carcinoma: a Retrospective Analysis Based on SEER.

The incidence of thyroid cancer in females is significantly higher than that in males; however, females are more likely to have more favorable outcomes. We aimed to determine the characteristics of differentiated thyroid carcinoma (DTC) subtypes in males and females, and to compare their clinical behavior and survival. A total of 68,337 cases were recruited from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. The disease-specific survival (DSS) of follicular variant papillary thyroid carcinoma (FVPTC) and follicular thyroid carcinoma (FTC) were similar to that of classical variant papillary thyroid carcinoma (CPTC) in male patients (FVPTC vs. CPTC, adjusted hazard ratio (aHR) = 0.947, P = 0.776; FTC vs. CPTC, aHR = 1.512, P = 0.104). In premenopausal female (< 55years old), FVPTC had better DSS than CPTC (aHR = 0.321, P = 0.038) while FTC had worse DSS than CPTC (aHR = 3.272, P = 0.013); in postmenopausal female, FTC had poorer prognosis than CPTC (aHR = 2.145, P = 0.002), no statistical difference was found between CPTC and FVPTC (aHR = 0.724, P = 0.087). For patients younger than 55years, women had significantly better DSS compared with men with CPTC (aHR = 0.376, P < 0.001) and FVPTC (aHR = 0.102, P < 0.001). However, no difference was observed in patients older than 55years. Interestingly, outcomes of FTC were not affected by gender in patients of all ages. These results suggested that different clinical behaviors and outcomes of DTC subtypes should be considered in patients with different genders.

Abstract 180: OPNa variant expression is associated with matrix mineralization in thyroid cancer cell lines

Abstract Osteopontin (OPN) and its three spliced variants (OPN-SV: OPNa, OPNb and OPNc) are overexpressed in several tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common variety of thyroid cancer (TC), being the histologic type which often presents desmoplasia (collagen deposition) and dystrophic calcification, including a fairly typical feature, the psammoma bodies (PB). This study aims to investigate the OPN-SV expression in classical variant of PTC (cPTC) and the role of OPN in calcification and collagen deposition into the extracellular matrix of thyroid cancer cell lines. Total OPN and OPN-SV expression was analyzed by immunohistochemistry and real time PCR in a series of 48 cPTC cases and three diffuse sclerosing PTCs. The association of OPN expression and the presence of PB as well as between PB in cPTC and the clinicopathological features of the tumors were evaluated. TPC-1 and c643 TC cell lines overexpressing OPN-SV were tested for the ability to promote calcification and to synthesize collagen in vitro. We also evaluated the expression of calcification markers, including osteocalcin and collagen I. Overexpression of OPNa transcripts was significantly associated with the presence of PB in cPTC samples. The presence of PB in cPTC was associated with younger patients and lymph node metastasis. Moreover, OPNa overexpression displayed a strong capacity to promote calcification and substantial collagen deposition in thyroid cancer cell lines. Upon OPN knockdown, the mRNA expression levels of calcification markers (osteocalcin and collagen I) were downregulated, further evidencing the involvement of OPN on activating these processes. Our data suggest that OPNa plays a role in the extracellular matrix calcification associated with cPTC. Basic research on the interactions between OPNa overexpression by tumor cells and the surrounding microenvironment can give clues for a better understanding of cPTC biology and phenotype. Citation Format: Luciana B. Ferreira, Raquel T. Lima, Ana Clara Santos da Fonseca Bastos, Andreia Machado Silva, Catarina Tavares, Ana Pestana, Elisabete Rios, Catarina Eloy, Manuel Sobrinho-Simões, Etel Rodrigues Pereira Gimba, Paula Soares. OPNa variant expression is associated with matrix mineralization in thyroid cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 180.

Racial disparities of differentiated thyroid carcinoma: clinical behavior, treatments, and long-term outcomes

BackgroundThe incidence of thyroid cancer in black Americans is significantly lower than that in white Americans, and the impact of race on the prognosis of thyroid cancer remains controversial. The purpose of this study was to determine the risk factors for survival in black and white patients and to compare the survival of differentiated thyroid carcinoma subtypes between these two races. We further investigated the association of lymph node and distant metastases with races.MethodsThis is a retrospective analysis using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. A total of 70,346 cases were included in our study. Patients’ demographics and cancer- and treatment-related characteristics were compared between the black and white Americans using chi-square and Fisher’s exact tests. For multivariate analysis, Cox proportional hazards regression were used to assess the association between potential risk factors and the survival in black and white patients.ResultBlack Americans had a worse overall survival than white Americans (HR = 1.127, P = 0.002). While disease-specific survival (DSS) was comparable, the risk factors for DSS were different between white and black Americans. Black Americans had less lymph node metastasis of classical variant papillary thyroid carcinoma (CPTC, OR = 0.476, P < 0.001) and follicular variant papillary thyroid carcinoma (FVPTC, OR = 0.522, P < 0.001), but not follicular thyroid carcinoma (FTC). However, black Americans with FVPTC, but not CPTC or FTC, had a higher potential of distant metastasis (OR = 1.715, P = 0.026). Furthermore, only white patients with tumor > 2 cm and lymph node metastasis benefited from radioactive iodine.ConclusionsThe risk factors for DSS were significantly different in white and black patients. The impact of race should be considered in treatment strategy for thyroid cancer.

Angiogenic and lymphangiogenic profiles in histological variants of papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is a well‑differentiated tumor that occurs in several histological variants whose biological behaviors remain unclear. Angiogenesis and lymphangiogenesis are critical processes that enable tumor progression. The aim of this study was to evaluate the angiogenic and lymphangiogenic phenotypes of PTC, considering the differences between histological variants. Angiogenic and lymphangiogenic profiles were analyzed by determining microvascular density (MVD) and lymphatic vessel density (LVD) in 73 cases of PTC, using immunohistochemistry. To assess the biological markers involved in blood and lymph vessel formation, the expression of vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX‑2), and p27kip1 (p27) was determined. MVD was significantly higher in patients with high‑risk PTC and in those with local extrathyroidal and vascular invasion. Positive VEGF expression was strongly associated with high MVD and age‑related tumor enlargement. The presence of lymph vessel invasion was associated with the expression of either VEGF or COX‑2. The analysis of angiogenesis and lymphangiogenesis in different histological variants of PTC revealed elevated LVD rather than MVD in the follicular variant of PTC (FV‑PTC).Lower MVD was observed in FV‑PTC relative to the classic variant of PTC (CV‑PTC). The frequency of VEGF‑positive tumors was higher in CV‑PTC than in FV‑PTC. A significant association between COX‑2 and p27 expression was observed in FV‑PTC but not in CV‑PTC. These results suggest that VEGF, COX‑2, and p27 may be important biological markers that determine the angiogenic and lymphangiogenic potentials of PTC, particularly between the follicular and classic variants.

The correlation of sodium iodide symporter and BRAF(V600E) mutation in classical variant papillary thyroid carcinoma.

BRAF(V600E) mutation was analyzed by real-time polymerase chain reaction in 96 consecutive cases with classical variant papillary thyroid cancer, and immunohistochemical staining of Na+/I- symporter (NIS) protein was evaluated. Localization (intracellular or membranous), density, and the intensity of cytoplasmic staining were characterized semiquantitatively. Extrathyroidal invasion, surgical margin positivity, and lymph node metastasis were compared with BRAF(V600E) mutation and NIS expression. Eighty-eight patients who had at least 24-month follow-up were also included in survival analysis. BRAF(V600E) mutation was determined in 78.1% (75/96) and functional NIS activity in 74% (71/96) of the cases. There were statistically significant differences in mean ages between BRAF(V600E) mutation-positive (48.6) and BRAF(V600E) mutation-negative cases (37.3; Levene test, P=.419; Student t test, P=.001). The surgical margin positivity (46.7%) and extrathyroidal extension percentage (54.7%) in the BRAF(V600E) mutation-positive group were higher than the negative (28.6% and 33.3%, respectively) group, without statistical significance (P=.138 and P=.084, respectively). Functional NIS activity was higher in BRAF(V600E) mutation-positive cases (78.1%) than mutation-negative ones (57.1%; P=.047). The possibility of moderate and intense cytoplasmic staining in BRAF(V600E) mutation-positive cases (72%) was 6.3 times higher than the possibility of weak staining (28%) in the mutation-positive cases (95% confidence interval, 2.2-18.8; P=.001). Functional NIS expression is higher in patients with classical variant papillary thyroid cancer with BRAF(V600E) mutation. However, the clinical features were not found to be associated with NIS expression. There may be different mechanisms determining the outcome of therapy.

MCM3 Protein Expression in Follicular and Classical Variants of Papillary Thyroid Carcinoma

Minichromosome maintenance (MCM) proteins are needed as licensors in the DNA replication of eukaryotic cells and transcriptional control of MCM genes has critical role in the regulation of MCM functions. Different MCM protein family members are proposed as diagnostic or prognostic markers in various cancers due to their increased proliferative potential. Among MCM family members, minichromosome maintenance protein 3 (MCM3) expressions in both mRNA and protein levels were shown to be associated with papillary thyroid carcinoma (PTC). But, the usability of MCM3 in some histological variants of PTC might be controversial due to tissue specific molecular heterogeneities. In follicular variant of papillary thyroid carcinoma (FVPTC), a number of genes including MCM3 were shown to be differentially expressed which were specific to this kind of variant. Using immunohistochemistry method, MCM3 protein expression levels were compared in FVPTC, classic variant of papillary thyroid carcinoma (CVPTC), and multi-nodular goiter (MNG) tissues in a group of 32 cases. There was meaningful differences between MNG vs. FVPTC (p = 0.016) and MNG vs. CVPTC (p = 0.019) while there was no significant difference in the comparison FVPTC vs. CVPTC (p = 0.15). Four of the 5 CVPTC cases having surrounding tissue invasion had high expression values. For FVPTC and CVPTC, MCM3 protein expression results were parallel to our previous mRNA expression study while there was downregulation in protein expression despite the increased expression of MCM3 mRNA in MNG suggesting tissue-specific post-transcriptional events in benign thyroid neoplasms of which should be focused on. Moreover, the relatively lower MCM3 protein expression in FVPTC comparing to CVPTC could be due to a different tumorigenic pathway favored in this type of tissue.

Investigation of BRAF V600E Mutation in Papillary Thyroid Carcinoma and Tumor-Surrounding Nontumoral Tissues

The aim of this study was to investigate the association between the BRAF V600E mutation incidence and histopathologic prognostic risk factors for papillary thyroid carcinoma (PTC) on the Turkish population. The contribution of BRAF V600E mutation in both tumor and tumor-surrounding nontumoral tissues of 108 patients with PTC was assessed using mutant allele-specific amplification-polymerase chain reaction. The BRAF V600E mutation was found in 52.8% of the tumor tissues, and 7.4% of the tumor-surrounding nontumoral tissues. The BRAF V600E mutation was significantly higher in the tumor tissues of the classic variant of PTC (CVPTC) cases than the follicular variant of PTC cases (p=0.001). The presence of the BRAF V600E mutation was more frequent in women, but this gender difference was not statistically significant. BRAF V600E mutation was more frequent in patients with either one of adenomatous hyperplasia or diffuse hyperplasia in tumor-surrounding nontumoral tissues (p=0.012). There was no significant difference in the BRAF V600E mutation distribution among tumor-surrounding nontumoral tissues of the two PTC variants, but it was more frequent in the CVPTC. Recent data suggest that BRAF V600E is an important marker, especially, for CVPTC. We propose that patients who had subtotal thyroid resection might have an increased risk of recurrence at the residual thyroid tissue if they have BRAF V600E mutation in their tumor-surrounding nontumoral tissues.

Clinical and Pathologic Features of “Sporadic” Papillary Thyroid Carcinoma Registered in the Years 2005 to 2008 in Children and Adolescents of Belarus

A systematic analysis of the clinical and pathologic patterns of childhood "sporadic" thyroid carcinoma in Belarus, in the absence of the "Chernobyl radioactive iodine factor," has never been performed. The aim of this study was to establish the essential features of "sporadic" papillary thyroid carcinoma (PTC) in Belarusian children and adolescents, and the relationship of tumor pathology to extrathyroidal extension (ETE) and lymph node metastases. This was a retrospective population-based study with assessment of histological samples of 119 cases of thyroid cancer in Belarusian children and adolescents of 0-18 years old registered during 2005-2008 years. Sporadic PTC was noted in 94 children who were not exposed to the Chernobyl radiation release. None of the 119 cases of thyroid were follicular thyroid cancer. The incidence rate of PTC was 1.13 per 100,000 persons. The median age at diagnosis was 15.1 years with fourfold predominance of diagnosis in female patients. Relapse was detected in 2% of cases with median follow-up of 4.2 years. Median tumor size was 12 mm. Three percent of the cases of PTC had multifocal growth. The classical variant of PTC was registered in 46% of the patients with thyroid cancer, the follicular variant of PTC was noted in 20% of the cases. The percent of rare types of PTC (tall cell and diffuse sclerosing) were equal to that for solid PTCs (13%, 12%, and 10%, respectively). Adolescents had a pure papillary carcinoma more often compared to children who represented tumors with mixed papillary/follicular patterns more frequently (p<0.05). Two-thirds of the patients with PTC had regional lymph node metastases. ETE was established in 39 of 74 patients in whom ETE could be assessed by morphology. Multivariate analysis showed that lymphatic invasion was the strongest independent factor associated with both ETE (p<0.0001) and lymph node metastases (p<0.0001). In 2005-2008, sporadic thyroid cancer in children of Belarus was represented by high prevalence of PTC and absence of follicular thyroid cancer. Sporadic cases of PTC in Belarus were characterized by smaller tumor size, a small number of cases with multifocal growth, an equal number of rare types and solid PTCs, a relatively high prevalence of pure papillary variant of PTC in adolescents, and a low frequency of early relapses. A high frequency of ETE and lymph node metastases was detected. The strongest morphologic factor associated with both of them was lymphatic invasion.

BRAF analysis by fine needle aspiration biopsy of thyroid nodules improves preoperative identification of papillary thyroid carcinoma and represents a prognostic factor. A mono-institutional experience

The current preoperative diagnosis of a thyroid mass relies on microscopic evaluation of thyroid cells obtained by fine needle aspiration biopsy (FNAB). More recently, FNAB has been combined with molecular analysis to increase the accuracy of the cytological evaluation. In this mono-institutional prospective study, we evaluated whether the routine introduction of BRAF testing in thyroid FNAB could help ameliorate the preoperative recognition of papillary thyroid carcinoma (PTC) in "suspended" or malignant cytological categories. Moreover, we investigated the prognostic role of the BRAFV600E mutation in PTC. BRAFV600E analysis was performed in thyroid FNAB from 270 patients classified into one of five cytological categories THY1, THY2, THY3, THY4, THY5. All subsequently underwent thyroidectomy±node dissection, from October 2008 to September 2009 in our Department. For each cytological category, we considered the definitive histological diagnosis of PTC and the presence of the BRAFV600E mutation. In 141 patients with a final tissue diagnosis of PTC, we correlated the presence of BRAFV600E with gender, age, histotype, TNM, size of the lesion, extracapsular extension, node metastases and multifocality. The prevalence of the BRAFV600E mutation, among PTCs at final tissue diagnosis, was 69%. It improved the FNAB diagnostic accuracy from 88% to 91%. The BRAFV600E mutation was correlated with older age, classical variant of PTC, advanced stages in patients > 45 years. BRAFV600E testing could play a role in improving the diagnostic accuracy of FNAB for PTC, representing a useful adjuvant tool in presurgical characterization of thyroid nodes in particular cases. There is an association between the BRAFV600E mutation and some clinico-pathological characteristics of PTC.