Muc-1 Expression May Help Characterize Thyroid Nodules but Does Not Predict Patients’ Outcome

Our purpose was to evaluate MUC1 clinical utility in the diagnosis and prognosis of thyroid cancer patients. We studied the protein expression of MUC1 in 289 thyroid carcinomas and 121 noncancerous thyroid nodules. There were 41 follicular carcinomas (FC) and 248 papillary thyroid carcinomas (PTC) including 149 classic (CPTC), 20 tall cell (TCPTC) and 79 follicular variants (FVPTC). In addition, we used a quantitative real-time PCR (q-PCR) method to measure MUC1 mRNA expression levels in 108 carcinomas, 23 hyperplasias, and 19 FA. According to their serum Tg levels and other evidences of recurrence/metastasis, the patients were classified as free-of-disease (185 cases) or bad outcome (56 cases, 10 deaths). MUC1 protein was identified in 80.2% PTC; 48.8% FC; 68.3% FVPTC; 70% TCPTC; 21.8% FA; 30% hyperplasias and 6% normal thyroid tissues. MUC1 distinguished benign from malignant thyroid tissues (sensitivity?=?89%; specificity?=?53%). MUC1 also differentiated FC from FA (p?=?0.0083). q-PCR mRNA expression of MUC1 also distinguished malignant from benign nodules (Mann–Whitney test, p?MUC1 expression was associated with any clinical or pathological feature of aggressiveness or outcome. We suggest that MUC1 expression may help differentiate follicular patterned thyroid lesions.     

Classical and Follicular Variant Papillary Thyroid Carcinoma: Comparison of Clinical,Ultrasonographical, Cytological,and Histopathological Features in 444 Patients

Follicular variant papillary thyroid carcinoma (FVPTC) is the most common variant of papillary thyroid carcinoma (PTC) after classical PTC (CPTC). In this study, we aimed to compare functional status, ultrasonographical features, cytological results, and histopathological characteristics of patients with CPTC and FVPTC. Preoperative thyroid functions, thyroid autoantibodies, ultrasonographical features, cytology, and histopathology results of 354 (79.9%) CPTC and 90 (20.3%) FVPTC patients were reviewed retrospectively. Sex distribution, mean age, thyroid autoantibody positivity, and thyroid dysfunctions were similar in two groups. Among 320 patients with preoperative ultrasonography (US) findings, a hypoechoic halo was observed more frequently (p = 0.003), and marginal irregularity was observed less commonly (p = 0.024) in FVPTC lesions. In CPTC, rate of malignant cytology (p = 0.001), and in FVPTC, rate of suspicious cytology (p < 0.001) were significantly higher. Histopathologically, mean tumor diameter was markedly higher in FVPTC compared to CPTC (16.89 ± 13.86 vs 10.64 ± 9.70 mm, p < 0.001), while capsular invasion and extrathyroidal spread were significantly lower in patients with FVPTC (p = 0.018 and p = 0.039, respectively). FVPTC tend to have more benign features in US and less malignant results in cytology. Higher tumor size in FVPTC might be explained by the recognition of clinical importance of these lesions after reaching particular sizes due to benign US features.     

Thyroid Cancers with Benign-Looking Sonographic Features Have Different Lymph Node Metastatic Risk and Histologic Subtypes According to Nodule Size

A decision to perform fine needle aspiration (FNA) on thyroid nodules mainly depends on sonographic features. We investigated if lymph node metastasis (LNM) risk differed by tumor size of thyroid cancers without suspicious sonographic features. Three hundred sixty patients with thyroid cancers with benign looking sonographic features were grouped by nodule size on ultrasonography (US) (≤ or >1 cm). The clinicopathologic parameters were compared between the groups. A multivariate analysis was performed to discover the independent factors predicting the presence of LNM. The nodules greater than 10 mm on US (n?=?157) demonstrated a larger tumor size on histology (17.9?±?14.5 vs. 5.6?±?2.4 mm, P?P?P?P?=?0.007). A multivariate analysis revealed that classical PTC, extrathyroidal extension, and the US nodule size >10 mm were independent predictive factors of LNM after adjusting for age, sex, TSH level, and multifocality. Thyroid cancers larger than 10 mm with benign US features are more likely to be nonclassical PTC than those with smaller diameters. The larger ones also have an increased risk of LNM in classical PTC. These cases require a more aggressive approach to FNA.     

Incidental Papillary Thyroid Carcinoma: Diagnostic Findings in a Series of 287 Carcinomas

The recent increase in the detection of papillary thyroid carcinoma (PTC) has been influenced by the finding of incidental tumours. To this group, carcinomas measuring less than 1 cm (the so-called microcarcinomas) as well as those above 1 cm belong. Analyzing a case series from our own experience, this paper focuses on the current pre-operative diagnostic challenges that can lead to PTC incidental discovery. For this retrospective study, 287 patients with a PTC diagnosis were selected. For each, the following variables were analysed: sex, age, ultrasound (US) appearance, number of thyroid nodules, PTC size, PTC variants and presence of other associated pathology. Pre-operative fine needle aspiration (FNA) results were classified according to the five-tiered SIAPEC system. For 281 patients, the US-guided FNA results were available. Cytohistological correlation was evaluated in terms of FNA sensitivity and false negative rate. An incidental PTC was found in 45.2 % of patients. The majority of these were due to unsuccessful US detection of malignant nodules (103 cases); incorrect cytological diagnosis was responsible for the other 24 cases. The most powerful clinical confounding factors were: multinodular background versus single nodule presentations (p?p?2 cm) due to tumour heterogeneity. Although with limitations related to the tumour’s intrinsic features and the thyroid background, US-guided FNA, especially if performed by a dedicated multidisciplinary team, is a powerful diagnostic tool for detecting malignant thyroid nodules. To the state of the art, we propose a practical clinical-pathological cut-off for this procedure, setting it at 5 mm.     

The preeminence of growth pattern and invasiveness and the limited influence of <Emphasis Type="Italic">BRAF</Emphasis> and <Emphasis Type="Italic">RAS</Emphasis> mutations in the occurrence of papillary thyroid carcinoma lymph node metastases

Prognostic factors indicative of papillary thyroid carcinoma (PTC) aggressive behaviour remain incompletely established partially due to the different composition of the series on record regarding the relative proportion of classic PTC (CPTC) and follicular variant PTC (FVPTC) subtypes. Several clinico-morphological features of PTC, together with the occurrence of BRAF mutations, are still not fully accepted as markers of aggressiveness. In the present clinico-pathological study of a series of 75 CPTC and FVPTC cases, we evaluated the relative contribution of the morphological features of the tumours and their BRAF and N-RAS status for the occurrence of nodal metastases. The morphological features most closely related to the occurrence of nodal metastases were extra-thyroid extension and poorly circumscribed growth pattern, in both CPTC and FVPTC. Additional features significantly associated to nodal metastases were multicentricity in the CPTC and vascular invasion in the FVPTC group. BRAF V600E mutation was detected in 29% of tumours, 41% of CPTC and 16% of FVPTC; N-RAS Q61R mutation was detected in 6% of tumours, 3% of CPTC and 10% of FVPTC. BRAF mutation was significantly more frequent in the CPTC group and in females, and it was detected only in patients older than 20 years, suggesting a late tumourigenic effect in the development of PTC. BRAF mutation was not significantly associated to any of the other studied features related to aggressiveness or nodal metastases. These results highlight the importance of infiltrative growth pattern and invasiveness over the presence of BRAF mutation in classic and follicular variant PTC for the development of nodal metastases.     

Intratumoural lymph vessel density is related to presence of lymph node metastases and separates encapsulated from infiltrative papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) gives frequently rise to nodal metastases via lymphatic vessels while follicular thyroid carcinoma (FTC) metastasises mainly via blood vessels to lung and bones. The follicular variant of PTC (FVPTC) encompasses the infiltrative subtype (I-FVPTC), which shares most of the features of classic PTC (CPTC), and the encapsulated subtype (E-FVPTC), which appears to be related to minimally invasive FTC. In an attempt to contribute to the understanding of the aforementioned differences, we evaluated intratumoural and peritumoural lymph vessels density (LVD), using the immunomarker D2-40 in a series of E-FVPTC, I-FVPTC, and CPTC with known BRAF and RAS status. None of the E-FVPTC cases presented extra-thyroid extension, lymph vessel invasion or nodal metastases, at variance with I-FVPTC and CPTC cases. The BRAF V600E mutation was detected in 8.3% of E-FVPTC, 25.0% of I-FVPTC and in 40.7% of CPTC, while N-RAS Q61R mutation was detected only in 10.3% of FVPTC cases. Only one case of E-FVPTC (8.3%) had intratumoural D2-40-stained vessels in contrast to their presence in 76.5% of the cases of I-FVPTC. Intratumoural LVD determined by D2-40 expression correlated with the occurrence of extra-thyroid extension, lymph vessel invasion and lymph node metastases in PTC cases. At variance with intratumoural LVD, peritumoural LVD was not associated with any clinic-pathological or molecular feature, being similar in E-FVPTC, I-FVPTC and CPTC. Our study highlights the role of intratumoural lymph vessels in PTC nodal metastisation and reinforces the importance of distinguishing E-FVPTC from I-FVPTC regarding invasiveness, metastatic pattern and molecular profile.     

Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant

Although the follicular variant of papillary thyroid carcinoma (FVPTC) has been classified as a papillary cancer based on nuclear features, its follicular growth pattern and potential for hematogenous spread are more characteristic of follicular carcinoma. To gain insight into the biologic nature of FVPTC, we compared genetic alterations characteristic of papillary and follicular thyroid carcinomas in 24 FVPTCs and 26 classic PTC (CPTCs). In FVPTCs, we observed ras mutation in 6 of 24 cases (25%), BRAF mutation in 1 of 13 cases (7.6%), and ret rearrangement in 5 of 12 cases (41.7%). In CPTCs, we found ras mutation in no case, BRAF mutation in 3 of 10 cases (30%), and ret rearrangement in 5 of 11 cases (45%). One FVPTC exhibited simultaneous ras mutation and ret/PTC1 rearrangement, and one CPTC harbored simultaneous BRAF mutation and ret/PTC3 rearrangement. Based on these findings, we concluded that ras mutation correlates with follicular differentiation of thyroid tumors whereas ret activation is associated with papillary nuclei but not with papillary architecture. ret activation is not exclusive of ras or BRAF mutation, whereas ras and BRAF mutations are mutually exclusive. The implications of these results for follicular and papillary carcinogenesis are discussed.     

Septin 7 immunoexpression in papillary thyroid carcinoma: A preliminary study

Papillary thyroid carcinoma (PTC) is the most common type among thyroid cancers. The diagnosis of PTC may be challenging when follicular variant (FVPTC) of this disease is present due to the resemblance of nuclear properties of the classical type (CVPTC). However, making use of ancillary molecular markers in the diagnosis of PTC may help. In our study, we aimed to evaluate the SEPT7 protein expression in PTC. A total of 55 paraffin block tissue samples comprising encapsulated FVPTC (FVPTC(e), n = 25), and CVPTC (n = 15), and benign hyperfunctioning thyroid nodules (HypN, n = 15) were used in this study. Nuclear, cytoplasmic, and overall (total) SEPT7 protein expression levels were determined by using immunohistochemistry. Nuclear, cytoplasmic, and overall SEPT7 expressions (p = 0.02, p = 0.001, p = 0.002, respectively) were significantly lower in FVPTC(e) tissues when compared to HypN. In CVPTC group, nuclear expression was significantly lower (p = 0.004) while overall and cytoplasmic expressions were not changed (p > 0.05). In HypN group, highest nuclear (mean = 2.73), cytoplasmic (mean = 2.86), and overall (mean = 2.86) expression scores were detected. Significantly lower SEPT7 expression in all expressional categories in FVPTC(e) group may be a sign of different molecular signature in this type of tissue.     

Expression of hypoxia-inducible factor 1 alpha in papillary thyroid carcinoma is associated with desmoplastic stromal reaction and lymph node metastasis

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer, and it early metastasizes into regional lymph nodes. We evaluated immunohistochemically the expression of the hypoxia marker hypoxia-inducible factor 1α (HIF-1α) as well as extracellular matrix protein tenascin C as a marker of stroma remodelling in a cohort of 160 PTCs. Expression of HIF-1α was seen focally accentuated in 100 of the 160 tumours (62.5 %) including 16 cases with equivocal staining (faint staining or only single-cell staining) and 84 cases with unequivocal staining. HIF-1α expression correlated with the degree of desmoplastic stromal reaction as well as with the expression of tenascin C (p?<?0.001, Kruskal–Wallis test, respectively). Moreover, expression of HIF-1α was significantly associated with the presence of lymph node metastases (p?<?0.001, Mann–Whitney test) as well as signs of invasion, namely, peritumoural and extrathyroidal invasion as well as angioinvasion (p?=?0.024, p?<?0.001, p?=?0.017, Mann–Whitney test, respectively). Additionally, PTC with unequivocal HIF-1α nuclear staining was a larger tumour than PTC with negative (?) or equivocal HIF-1α expression (p?<?0.001, Kruskal–Wallis test). Interestingly, the expression of HIF-1α was not significantly associated with BRAF V600E status (p?>?0.05, Mann–Whitney test). Our data show that the expression of HIF-1α is associated with stroma remodelling processes within the tumour and, thus, may play an important role in an invasive behaviour of these tumours independent of BRAF mutation status.     

Predictive Factors of Malignancy in Thyroid Nodules with a Cytological Diagnosis of Follicular Neoplasm

In cases of follicular neoplasm identified by thyroid fine-needle aspiration (FNA), surgery is required to achieve a precise diagnosis. We investigated potential clinical factors for the preoperative prediction of malignancy in thyroid nodules with a cytological diagnosis of follicular neoplasm. We retrospectively reviewed the data of 97 patients who were diagnosed with follicular neoplasm by FNA and had undergone surgery at the Korea Cancer Center Hospital between April 2010 and April 2012. Age, sex, laboratory data (such as thyroid-stimulating hormone, free T4, thyroglobulin (Tg), and Tg antibody), and ultrasonographic findings were reviewed from the electronic medical records. Of 97 patients, 50 (51.5 %) were diagnosed with benign nodules, 16 (16.5 %) with follicular thyroid carcinoma (FTC), and 31 (32.0 %) with papillary thyroid carcinoma (PTC). In comparison with the features of benign nodules, FTC presented with a large nodule size, high serum Tg level, isoechogenicity, calcifications, and peripheral halo, whereas PTC exhibited traits similar to those of benign nodules, except for high serum Tg level and the presence of calcifications on ultrasonography. Therefore, a high serum Tg level (≥75 ng/mL) and calcification were the only significant predictive factors for malignancy in case of follicular neoplasm (p?<?0.01). Serum Tg levels and the presence of calcification on ultrasonography are important clinical features to predict malignancy in thyroid nodules with cytological diagnosis of follicular neoplasm.     

The Role of Epithelial Mesenchymal Transition Markers in Thyroid Carcinoma Progression

Understanding the molecular mechanisms involved in thyroid cancer progression may provide targets for more effective treatment of aggressive thyroid cancers. Epithelial mesenchymal transition (EMT) is a major pathologic mechanism in tumor progression and is linked to the acquisition of stem-like properties of cancer cells. We examined expression of ZEB1 which activates EMT by binding to the E-box elements in the E-cadherin promoter, and expression of E-cadherin in normal and neoplastic thyroid tissues in a tissue microarray which included 127 neoplasms and 10 normal thyroid specimens. Thyroid follicular adenomas (n?=?32), follicular thyroid carcinomas (n?=?28), and papillary thyroid carcinomas (n?=?57) all expressed E-cadherin and were mostly negative for ZEB1 while most anaplastic thyroid carcinomas (ATC, n?=?10) were negative for E-cadherin, but positive for ZEB1. A validation set of 10 whole sections of ATCs showed 90 % of cases positive for ZEB1 and all cases were negative for E-cadherin. Analysis of three cell lines (normal thyroid, NTHY-OR13-1; PTC, TPC-1, and ATC, THJ-21T) showed that the ATC cell line expressed the highest levels of ZEB1 while the normal thyroid cell line expressed the highest levels of E-Cadherin. Quantitative RT-PCR analyses showed that Smad7 mRNA was significantly higher in ATC than in any other group (p?<?0.05). These results indicate that ATCs show evidence of EMT including decreased expression of E-cadherin and increased expression of ZEB1 compared to well-differentiated thyroid carcinomas and that increased expression of Smad7 may be associated with thyroid tumor progression.     

Increasing Diagnosis of Thyroid Papillary Carcinoma Follicular Variant in South-East Anatolian Region: Comparison of Characteristics of Classical Papillary and Follicular Variant Thyroid Cancers

We aimed to compare ratios of thyroid cancers diagnosed in our regional reference hospital Pathology Center in Sanliurfa city located in southeast Anatolia, and evaluate the characteristics related with follicular variant papillary thyroid carcinoma (FVPTC). We re-evaluated the specimens of last 5?years thyroidectomies by same five pathologists, by same criteria and immunohistochemical evaluation. Chi-square test was used to compare characteristics of classical pure papillary thyroid carcinomas and FVPTC groups. Stepwise multiple regression analysis was used to evaluate the factors related with presence of FVPTC. Among 400 thyroidectomies, there were 105 papillary thyroid carcinoma, 42 of them with pure PTC, and 56 with FVPC, also seven with other variants. There was increase in ratios of FVPTC/PTC between 2010 and 2011 (68.4 vs 76.7?%, p?相似文献   

Retinoid acid receptor expression is helpful to distinguish between adenoma and well-differentiated carcinoma in the thyroid

Retinoid receptors (RRs) play a key role in cell proliferation and differentiation. We characterized the expression of RA receptors and retinoid X receptors (RARs and RXRs) in a series of 111 thyroid tumors and investigated the mechanisms responsible for their deregulation: hypermethylation of the RARB2 promoter, loss of heterozygosity (LOH) in the regions of RARB and RXRA, and altered expression of CRBP1 and enzymes involved in RA biosynthesis (RDH10 and RALDH2). Expression of RALDH2 and RDH10 was conserved in 100 % of adenomas and in 90 and 98 %, respectively, of carcinomas, whereas staining for CRBP1 was decreased in 9 % of FAs and 28 % of carcinomas, mainly anaplastic carcinomas (55 %). We found an abnormal expression of RARA, RARB, RXRA, and RXRB in 67, 69, 66, and 73 %, respectively, of thyroid carcinomas (n?=?78) and in 9, 9, 9, and 33 % of follicular adenomas (n?=?33) (p?<?0.001). An abnormal staining pattern of at least two of these markers had 90 % sensitivity and 91 % specificity for a diagnosis of malignancy. Promoter hypermethylation of RARB2 was observed in some anaplastic carcinomas (14 %). LOH was found to be common at the RARB locus (3p24–3p25) and the RXRA locus (9q34), respectively, in 44 and 55 % of carcinomas and in 27 and 43 % of adenomas. In conclusion, immunohistochemical staining for RARs and RXRs may help in the differential diagnosis between well-differentiated carcinoma and follicular adenoma. Further investigation should be carried out to determine whether the characterization of RR expression might identify patients who could benefit from therapy with RA derivatives.     

Comparing Clinicopathologic and Radiographic Findings Between TT-UMP,Classical, and Non-Encapsulated Follicular Variants of Papillary Thyroid Carcinomas

Thyroid tumors of uncertain malignant potential (TT-UMP) comprise an accepted subgroup of follicular-patterned thyroid tumors for which benignancy or malignancy cannot be precisely assessed. We aimed to evaluate the demographic characteristics, ultrasound (US) findings, and cytological results of patients with TT-UMP and compare these findings to a classical variant of papillary thyroid carcinoma (CV-PTC) and non-encapsulated follicular variant of PTC (NEFV-PTC) patients; we also evaluated the immunohistochemical characteristics of patients with TT-UMP. Twenty-four patients with TT-UMP, 672 with CV-PTC, and 132 with NEFV-PTC were included in the study. Mean longitudinal nodule size and median nodule volume were higher in the TT-UMP group than in the CV-PTC and NEFV-PTC groups (p?<?0.001 and p?<?0.001 for CV-PTC; p?<?0.001 and p?=?0.008 for NEFV-PTC). The presence of halo and peripheral vascularization was observed more frequently in the TT-UMP group than in the CV-PTC group (p?=?0.002 and p?=?0.024). Benign and follicular neoplasm/suspicious for follicular neoplasm cytological results were higher in the TT-UMP group than in the CV-PTC group (p?=?0.030 and p?=?0.001). US findings were similar between TT-UMP and NEFV-PTC groups (all, p?>?0.05). However, none of the patients with TT-UMP were called malignant; 105 patients (31.2 %) of CV-PTC and 11 patients (9.5 %) of NEFV-PTC (infiltrative FV) were classified as malignant cytologically. Tumor size was higher in the TT-UMP group than in the CV-PTC and NEFV-PTC groups (p?<?0.001 and p?=?0.006). In the TT-UMP group, positive expression of HBME-1, CK-19, and Gal-3 was found in 50, 33.3, and 25 % of patients, respectively. This study demonstrated that none of the TT-UMP patients were evaluated as malignant in preoperative cytology. However, patients with TT-UMP had higher nodule and tumor sizes than CV-PTC and NEFV-PTC patients; US features were similar between NEFV-PTC and TT-UMP patients.     

Follicular Variant of Papillary Thyroid Carcinoma: Accuracy of FNA Diagnosis and Implications for Patient Management

Follicular variant of papillary thyroid carcinoma (FVPTC) creates a continuous diagnostic dilemma among pathologists because of the paucity of nuclear changes of papillary carcinoma and overlapping features with benign and other neoplastic follicular lesions. Current guidelines for the management of thyroid nodules recommend surgery for confirmed PTC, suspicious for PTC, and follicular neoplasm cases, while further immediate diagnostic studies or treatment are not routinely required if the nodule is benign on cytology. This study is designed to determine the accuracy of cytology in the diagnosis of FVPTC, based on the Bethesda classification system, and determine the implications for patient management based on the current recommendation. Based on a retrospective review of cytologic diagnoses between January 2008 and December 2011, thyroid fine needle aspiration (FNA) cytology specimens with subsequent surgical intervention and a final diagnosis of FVPTC were selected. The cytologic diagnoses were compared with the final diagnoses, and the percentage of cases contributing to the final diagnosis of FVPTC was calculated for each diagnostic category. Triage efficiency and diagnostic accuracy were calculated. One hundred and fifty-two cases with histologic confirmation of FVPTC were identified (representing 128 patients—101 female, 27 male). All patients had undergone either lobectomy with completion thyroidectomy or total thyroidectomy. The cytologic diagnosis of “positive for malignancy” accounted for only 27 % of the final histologic diagnosis of FVPTC, while suspicious for carcinoma, follicular neoplasm, follicular lesion of undetermined significance, and benign accounted for 11, 23, 23, and 16 % of the final diagnosis of FVPTC, respectively. Only 18 % of the 55 cases tested were positive for BRAF mutation. The subtle nuclear features of FVPTC pose challenges for an accurate diagnosis. Therefore, a better approach is to triage these cases for surgical intervention and/or further evaluation of the particular nodule. Our triage efficacy for FVPTC was 84 %; however, the diagnostic accuracy of PTC was 38 %. A negative diagnosis on FNA has diagnostic and management implications for up to 16 % of cases because they may have no further immediate diagnostic studies or treatment. BRAF mutation analysis provides minimal effect on diagnostic accuracy.     

Clinical utility of the imunohistochemical co-expression of p53 and MDM2 in thyroid follicular lesions

In order to investigate the possible correlation between p53 and MDM2 co-expression with clinicopathological features of differentiated thyroid cancer (DTC) and its use as diagnostic and/or prognostic markers, we used immunohistochemistry to evaluate 317 thyroid samples including 208 DTC and 94 benign nodules, in addition to 15 normal tissues. MDM2 and p53 expression were highly associated (r = 0.7161; p < 0.0001). The co-expression of p53-MDM2 was observed more frequently in malignant lesions (p < 0.0001) and helped characterize follicular patterned lesions distinguishing FVPTC from FA (p < 0.0001) and FVPTC from FTC (p < 0.0001). In addition, p53-MDM2 co-expression was associated with characteristics of less aggressiveness. It was more frequent in patients ≤45 years old (p = 0.0035), with unique tumors (p = 0.0095), tumors <2 cm (p < 0.0001), tumors without extrathyroid invasion (p = 0.0425), without metastasis at evolution (p = 0.0179), and in patients evolving free of disease after treatment (p = 0.0485). We suggest that p53-MDM2 co-expression profile analysis might help establishing diagnostic and determining prognostic of DTC patients.     

In papillary thyroid carcinoma, TIMP-1 expression correlates with BRAF V600E mutation status and together with hypoxia-related proteins predicts aggressive behavior

BRAF ^V600E causes upregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1), which promotes cell invasion in papillary thyroid carcinoma (PTC). Hypoxia-inducible factor-1α (HIF-1α) is regulated by hypoxia and also by the BRAF-mediated signaling pathway in PTC. We assessed the association of expression of TIMP-1, HIF-1α, and hypoxia-inducible carbonic anhydrase IX (CAIX) and XII (CAXII) with clinical parameters in PTC. TPC-1/BRAF ^WT wild-type and BcPAP/BRAF ^V600E -mutated PTC cell lines were selected to study the effects of the BRAF ^V600E mutation and hypoxia on expression in vitro of TIMP-1, CAIX, and CAXII proteins by immunoblotting. Higher expression of all proteins was detected in BcPAP cells exposed to hypoxia. Tissue microarray immunohistochemistry analysis was performed to study protein expression in 114 BRAF-genotyped PTC samples. Expression data on tumor tissue were compared with clinicopathological variables. TIMP-1 expression had a sensitivity of 87 % and a specificity of 83 % in identifying a BRAF mutation (P?<?0.001) and was associated with pT stage (P?=?0.001), pN stage (P?=?0.02), and multifocality (P?=?0.03). HIF-1α expression correlated with pT stage (P?=?0.05). CAIX expression was associated with pN stage (P?=?0.02), and both CAIX (P?=?0.004) and CAXII (P?=?0.05) were strongly associated with vascular invasion. We conclude that TIMP-1 protein expression is a reliable surrogate marker for BRAF-mutated status in PTC. TIMP-1 and hypoxia-regulated proteins are promising as predictors of aggressiveness in PTC and warrant further investigation as new therapeutic targets for the treatment of highly aggressive forms of PTC.     

Evaluation of Lipocalin-2 and Twist expression in thyroid cancers and its relationship with epithelial mesenchymal transition

ObjectiveTo evaluate the expressions of lipocalin-2 (LCN-2) and Twist in thyroid cancers and examine its relationship with epithelial-to-mesenchymal transition (EMT) and clinicopathological factors.Materials and methodsThe expression of LCN-2 and Twist was immunohistochemically evaluated in a total of 249 cases, including 120 patients with papillary thyroid carcinomas (PTC), 34 with follicular thyroid carcinoma (FTC), 15 with medullary thyroid carcinomas (MTC), 20 with non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), 47 with follicular adenomas (FA), and 13 with nodular hyperplasia (NH). In addition, the relationship between the expression of EMT markers E-cadherin and vimentin was investigated in malignant cases.ResultsA significant increase was observed in the LCN-2 and Twist expression from NH and FA to NIFTP, MTC, FTC, and PTC (p = 0.001). A high degree of LCN-2 expression was observed in the aggressive variants of PTC (p = 0.002). Twist^high positivity was significantly higher in cases with the EMT-positive mesenchymal phenotype (p = 0.036).ConclusionsLCN-2 and Twist can be helpful diagnostic markers in the differentiation of benign and malignant thyroid nodules. Twist^high expression supports the EMT process in thyroid cancer. LCN-2 and Twist expression may also serve as valuable predictive biomarkers in patients with thyroid cancer. In future, the determination of a LCN-2^high expression in the aggressive variants of PTC may be integrated into targeted treatment strategies.