The Flip Side of NIFTP: an Increase in Rates of Unfavorable Histologic Parameters in the Remainder of Papillary Thyroid Carcinomas

The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed to replace noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) both to promote more conservative management of these tumors and spare patients the psychological burden of a cancer diagnosis. This reclassification will lower the incidence of papillary thyroid carcinoma (PTC). In addition, it could result in an increase in the rates of unfavorable histologic prognosticators for PTC overall because NIFTPs had previously accounted for many of the PTCs without these features. Our aim was to evaluate the potential impact of the reclassification of NIFTP on the rates of extrathyroidal extension, lymphovascular invasion, and lymph node metastases in PTC. We identified all PTCs clinically over 1 cm diagnosed on surgical resection between August 2010 and August 2012. The histopathologic characteristics, including PTC subtype, tumor size, presence of extrathyroidal extension and lymphovascular invasion, and surgical margin and lymph node status were all recorded. Based on these parameters, cases were classified according to the American Thyroid Association (ATA) risk stratification system for structural disease recurrence. Tumor slides for cases initially diagnosed as FVPTC were reviewed to identify tumors that would now be classified as NIFTPs. Our cohort included 348 cases of PTC, of which 94 (27%) would now be classified as NIFTPs. After excluding NIFTPs from the PTC category, there were increased rates of extrathyroidal extension (26% up from 19%, p = 0.046), lymphovascular invasion (37% up from 27%, p = 0.0099), and lymph node metastases (26% up from 19%, p = 0.045) among the remaining PTCs. Based on these changes in histologic features, 10% fewer cases were defined as ATA low risk (62% down from 72%, p = 0.0081). Our results indicate that the downgrading of some carcinomas to NIFTP will increase the rates of higher risk histologic parameters in the remaining PTCs by statistically significant margins. Although the overall survival for PTC is very high and would likely not be changed significantly by the introduction of NIFTP, additional studies evaluating the impact of the NIFTP shift are warranted.     

Total Surface Area Is Useful for Differentiating between Aggressive and Favorable Multifocal Papillary Thyroid Carcinomas

PurposeThe purpose of the present study was to identify more useful parameters for predicting behaviors of multifocal papillary thyroid carcinoma (PTC).ResultsIn 588 PTCs, tumor multifocality was found in 179 PTCs (30.4%). Multifocal tumors were significantly associated with extrathyroidal extension, lymph node metastasis, and higher tumor stage grouping (p<0.001, p<0.001, and p<0.001, respectively). The rates of nodal metastasis increased with greater TSA and TTD in PTCs. Multifocal papillary thyroid microcarcinomas (mPMCs) with TSA >3.14 cm² had higher rates of nodal metastasis than mPMCs with TSA ≤3.14 cm² (p=0.038); however, there was no significant difference between mPMCs with TTD >1.0 cm and with TTD ≤1.0 cm (p=0.325). In addition, nodal metastasis was more frequent in mPMCs with TSA >3.14 cm² than in unifocal papillary thyroid microcarcinomas (uPMCs) (TD ≤1.0 cm) (p=0.002), but not overt unifocal PTCs (TD >1.0 cm) (p=0.244).ConclusionOur results suggest that mPMCs with TSA >3.14 cm² show more aggressive behavior than uPMCs and mPMCs with TSA ≤3.14 cm². TSA could be useful in distinguishing aggressive mPMCs from favorable cases.     

The Cytoplasmic Expression of MUC1 in Papillary Thyroid Carcinoma of Different Histological Variants and its Correlation with Cyclin D1 Overexpression

This study addressed the immunohistochemical expression of MUC1 in papillary thyroid carcinoma (PTC) of different histotypes, sizes, and morphological features of aggressiveness, and its correlation with the overexpression of cyclin D1, a target molecule of the Wnt pathway. MUC1 expression was examined in a total of 209 PTCs. Cytoplasmic MUC1 expression was elevated in the tall, columnar cell and oncocytic variants (100%), Warthin-like (78%), and conventional PTCs (61%), and in papillary microcarcinoma (PMC) with the conventional growth pattern (52%). On the contrary, it was low in the follicular variant (27%) of PTC and PMCs with follicular architecture (13%). Cytoplasmic MUC1 accumulation did not associate with any clinicopathological features except peritumoral lymphoid infiltration in PTCs and in PMCs with the conventional growth pattern. MUC1 staining correlated with cyclin D1 overexpression in conventional PTCs and PMCs and PMCs with follicular architecture. The results demonstrate that MUC1 expression varies broadly in different histological variants of PTC, being the lowest in tumors with follicular structure. In general, it does not prove to be a prognosticator of PTC aggressiveness. A high correlation between MUC1 and cyclin D1 implies MUC1 involvement in the Wnt cascade functioning in a large subset of human PTCs and PMCs.     

野生型RET和RET/PTC融合基因在成人散发性甲状腺乳头状癌中的表达及其意义

目的探讨野生型BET（WT-RET）及RET／PTC1、3融合基因在成人散发性甲状腺乳头状癌（PTC）中的表达及其与临床病理学指标的关系和意义。方法用逆转录-聚合酶链反应（RT-PCR）检测102例石蜡与新鲜（43例）甲状腺病变组织（PTC66例,对照组各种良恶性肿瘤及良性病变共36例）中WT-RET和RET／PTC1、3融合基因的表达并结合临床资料进行分析。结果（1）62％（41／66）PTC患者≥40岁。38％（25／66）PTC伴淋巴细胞性甲状腺炎,59％（39／66）伴淋巴结转移,5例（7.6％）有远处转移。（2）RET原癌基因的酪氨酸激酶区（BET-TK）检出率为68．1％（45／66）。BET原癌基因断裂点（BP）与TK的同时检出率在PTC中28．8％（19／66）,腺瘤中12．5％（1／8）,表明存在WT-BET转录物。（3）RET／PTC检出率21．2％（14／66）,其中5例BET／PTC1阳性（7．6％）,9例RET／PTC3阳性（13．6％）。6例（9％）PTC同时表达BET／PTC和WT-BET。36例对照组病例中未检测到RET／PTC融合基因。（4）统计学分析,PTC病例中WT-BET与RET／PTC1融合基因的表达与性别、年龄、肿瘤大小、多灶性、伴淋巴细胞浸润及淋巴结转移等临床病理学指标无关（P〉0．05）。结论RET／PTC融合基因在散发性成人PTC中表达率低,其诊断和判断预后的价值不大。WT-BET在甲状腺肿瘤的滤泡形成过程中起一定作用。     

Apoptosis and proliferation related molecules (Bcl-2, Bax, p53, PCNA) in papillary microcarcinoma versus papillary carcinoma of the thyroid

AIM: To gain a better insight into the differences in biological behaviour between papillary microcarcinoma (PMC) and clinically evident papillary thyroid carcinoma (PTC). METHODS: Immunohistochemical analysis of apoptosis related molecules (Bcl-2, Bax, p53) and proliferation related marker (PCNA) in 39 archival cases of PMC and 46 cases of PTC. RESULTS: Bcl-2 and Bax were expressed in most PMCs and PTCs. The average Bcl-2 staining score did not differ significantly between PMCs and PTCs (p > 0.05), but the average Bax score was significantly lower in PMCs (p < 0.05). The Bcl-2/Bax ratio was significantly higher in PMCs than in PTCs (p < 0.05). The expression of p53 was similar in PMCs and PTCs, without a correlation with clinical data, but was associated with high Bax expression (p < 0.05) in these cases in both groups. Non-malignant tissue expressed only Bcl-2, but not p53 or Bax. PCNA expression was significantly lower (p < 0.05) in PMC than in PTC and positively correlated with tumour size (p < 0.05). CONCLUSIONS: The higher Bcl-2/Bax ratio and lower proliferative activity in PMC suggest differences from PTC in the balance between apoptosis and proliferation. However, the presence of p53 and Bax in PMC indicates malignant potential, and thus PMC should be treated with caution.     

Features of Papillary Thyroid Microcarcinoma in the Presence and Absence of Lymphocytic Thyroiditis

It is known that the prevalence of lymphocytic thyroiditis (LT) is higher in patients with papillary thyroid carcinoma (PTC), that gender influences this association, and that certain features of PTC occur more frequently in patients who also have LT. These relationships have not been studied in patients with papillary thyroid microcarcinomas (PTMC), however. Therefore, we performed a study to compare the clinical and pathological features of patients with PTMC who did and did not have LT. We collected the 323 consecutive patients following excision of PTMC diagnosed as papillary carcinoma on preoperative needle aspiration cytology. We analyzed the demographic, serologic, and pathologic data of those cases with categorization into four groups based on presence of LT and neck lymph node metastasis. In all PTMC, the presence of LT did not influence the frequency of lymph node metastasis (27 of 105 [25.7%] vs. 48 of 218 [22.0%]). Among the patients with metastatic PTMC, LT was noted significantly more often in female than male patients (95.2% vs. 79.8%). In metastatic PTMC, multifocality and bilaterality was more frequent in with LT than without LT (44.4% vs. 29.2%; 29.6% vs. 14.6%). Both the presence of serum thyroglobulin antibody (TgAb; p = 0.016) and serum microsomal antibody (p = 0.013) were highly correlated with the presence of LT. Twenty-seven of 105 patients (25.7%) with PTMC with LT had nodal metastasis. Co-existing LT was noted predominantly in women, influenced more often multifocality and bilaterality of tumors, and higher frequency of metastasis to lateral compartment lymph nodes.     

Aberrant BRAF splicing as an alternative mechanism for oncogenic B‐Raf activation in thyroid carcinoma

Activating BRAF mutations have recently been reported in 28–83% of papillary thyroid carcinomas (PTCs). However, it is not known whether aberrant BRAF splicing occurs in thyroid carcinoma. To investigate aberrant BRAF splicing and its association with BRAF mutation in thyroid tumours, we studied aberrant BRAF splicing and BRAF mutation from 68 thyroid tumours. BRAF^V600E mutation was detected in 20 of 43 PTCs and all three anaplastic thyroid carcinomas (ATCs). There is a higher frequency of BRAF mutation in PTC patients with stage III and IV tumours compared with stage I and II. Novel BRAF splicing variants were detected in 12 PTCs, three follicular variants of PTC (FVPTCs), and one ATC, as well as in two thyroid carcinoma cell lines, ARO and NPA. These variants did not have the N‐terminal auto‐inhibitory domain of wild‐type B‐Raf, resulting in an in‐frame truncated protein that contained only the C‐terminal kinase domain and caused constitutive activation of B‐Raf. These variants were significantly associated with advanced disease stage and BRAF^V600E mutation (p < 0.001, Fisher exact test). Furthermore, expression of these variants in NIH3T3 and CHO cells could activate the MAP kinase signalling pathway, transform them in vitro, and induce tumours in nude mice. These data suggest that BRAF splicing variants may function as an alternative mechanism for oncogenic B‐Raf activation. Combination of the BRAF^V600E mutation and its splicing variants may contribute towards disease progression to poorly differentiated thyroid carcinoma. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Minichromosome maintenance protein 3 is a candidate proliferation marker in papillary thyroid carcinoma

The proliferative capacity of tumor cells is a characteristic feature in the whole growing tumors. Many pathologists and clinicians have used the estimation of cell proliferation for prognostic information. Minichromosome maintenance protein 3 (MCM3) is known to have a role on the initiation and regulation of DNA replication during cell cycle. The aim of this study was to evaluate the potential applicability of one of the MCM proteins, MCM3, as a proliferation marker in papillary thyroid carcinoma (PTC) with correlation to clinicopathological parameters. We performed the immunohistochemical analysis for MCM3 and Ki-67 in 60 cases of PTC and Western blot analysis for MCM3 expression in 6 PTCs and normal thyroid tissues. The comparison of MCM3 labeling index (LI) to tumor size (P = 0.031) and extrathyroidal extension (P = 0.037) was statistically significant while that of Ki-67 LI to them was not. Moreover, a significant association was not observed between MCM3 and Ki-67, but the MCM3 LI was considerably higher. Western blot analyses revealed that the MCM3 protein expression levels were overexpressed in all PTCs. On the contrary, the levels of MCM3 were very low or absent in all normal thyroid tissues. Our results indicate that MCM3 may be a more reliable proliferation marker than Ki-67 in accessing the growth of tumor and evaluating tumor aggressiveness of PTC.     

Cytokeratin 19 immunoreactivity in the diagnosis of papillary thyroid carcinoma: a note of caution.

To evaluate the expression of cytokeratin (CK) 19, we stained sections obtained from formalin-fixed, paraffin tissue blocks of 35 thyroid tumors (follicular adenoma [FA], 20; papillary thyroid carcinoma [PTC], 10 follicular variant [FV] and 5 usual type) and scored the extent of staining as follows: 1+ (<5% positively stained cells), 2+ (5%-25% positively stained cells), 3+ (25%-75% positively stained cells), and 4+ (>75% positively stained cells). All 15 PTCs (including 10 FV-PTCs) were CK19 positive: 14 were 4+ and 1 (FV-PTC) was 2+. All 20 FAs also were CK19 positive: 15 were 1+, 1 was 2+, 4 were 3+, and none was 4+. In the FAs that were scored 1+, reactivity usually was confined to follicular cells lining cystically dilated atrophic follicles that lacked the typical nuclear features of PTC. The remaining FAs showed more diffuse reactivity, which was, however, less intense than that observed in the PTCs. Thus, immunoreactivity for CK19 is not specific for PTC, although we acknowledge that the extent and intensity of staining are considerably greater in this tumor than in FA. There were no significant differences in staining for CK19 between nonneoplastic follicles adjacent to PTCs and those adjacent to FAs.     

Comparison of metabolic ratios of urinary estrogens between benign and malignant thyroid tumors in postmenopausal women

Background

Estrogen metabolism may be associated with the pathophysiological development of papillary thyroid carcinoma (PTC).

Methods

To evaluate the differential estrogen metabolism between benign and malignant PTCs, estrogen profiling by gas chromatography–mass spectrometry was applied to urine samples from postmenopausal patients with 9 benign tumors and 18 malignant stage I and III/IV PTCs.

Results

The urinary concentration of 2-methoxyestradiol was significantly lower in the stage I malignant patients (3.5-fold; P?<?0.025) than in the benign group. The metabolic ratios of 16α-OH-estrone/estrone and estriol/estradiol, which are responsible for 16α-hydroxylase activity, were increased more than 2.5-fold in the advanced-stage malignant PTC (P?<?0.02 each). The more than 6.2-fold decrease in the urinary 2-/16α-hydroxylase ratio in stage III/IV malignant PTC was consistent with the ratio in postmenopausal patients with endocrine gland cancers. In addition, reductive 17β-hydroxysteroid dehydrogenase (17β-HSD; estradiol/estrone or estriol/16α-OH-estrone) was present at significantly higher levels in subjects with stage III/IV malignant PTCs than in benign subjects (>3.5-fold difference; P?<?0.002). In particular, the estriol/16α-OH-estrone ratio differentiated between the benign and early-stage malignant patients (P?<?0.01).

Conclusions

Increased 16α-hydroxylation and/or a decreased 2-/16α-ratio, as well increased reductive 17β-HSD, with regard to estrogen metabolism could provide potential biomarkers. The devised profiles could be useful for differentiating malignant thyroid carcinomas from benign adenomas in postmenopausal women.

     

Genome-wide expression analysis of Middle Eastern papillary thyroid cancer reveals c-MET as a novel target for cancer therapy

In an attempt to find genes that may be of importance in malignant progression of papillary thyroid carcinoma (PTC) in the Middle East, which therefore can be targeted in cancer therapy, we screened and validated the global gene expression in PTC using cDNA expression arrays and immunohistochemistry (IHC) on tumour tissue microarrays. Twenty-nine PTC tissue specimens were compared with seven non-cancerous thyroid specimens by use of cDNA microarray. Results for selected genes were confirmed by quantitative real-time PCR. Protein expression of selected genes was further studied using a tissue microarray consisting of 536 PTCs and compared with histologically non-cancerous tissue samples. One hundred and ninety-six genes were overexpressed in PTC tissues relative to non-cancerous thyroid tissues. The genes that were up-regulated in PTC were involved in cell cycle regulation, cell signaling, and oncogenesis. Among these genes, c-MET was identified by immunohistochemical methods as a protein that is overexpressed in 37% of PTCs and was significantly associated with more aggressive behaviour, eg higher stage, nodal involvement, and tall cell variant (p value = 0.01, 0.01 and 0.04, respectively). In this study, 55% of the PTC cases expressed activated AKT (P-AKT), which suggests that activated AKT may play an important role in PTC tumourigenesis. The fact that most of the PTC cases that had activated AKT showed overexpression of c-MET (p = 0.027) leads us to hypothesize that c-MET may be an alternative mechanism of AKT activation in Middle Eastern PTCs. Finally, our data suggest that c-MET dysregulation is associated with aggressive behaviour and may serve as a molecular biomarker and potential therapeutic target in this disease.     

Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing,less aggressive thyroid neoplasms?

Despite the large amount of information accumulated on the role played by ret activation in the oncogenesis of papillary thyroid carcinoma (PTC), the biological and clinical significance of such activation ‘in vivo’ remains controversial. The aim of this study was to address some of the existing controversies by comparing two groups of unselected PTCs, one with and the other without ret rearrangement, with regard to several clinicopathological and biological features. Thirty-three PTCs were selected at random. ret rearrangement was found in eight cases (24·2 per cent) using Southern blot analysis. The mean age of the patients with tumours displaying ret rearrangement (28±3·1 years) was significantly lower than that of the patients harbouring cases that did not present rearrangement (45±2·9 years). The large majority of the tumours with ret rearrangement displayed a papillary or mixed follicular–papillary pattern and very low proliferative activity. ret rearrangement correlated significantly with decreased cytoplasmic expression of E-cadherin. No significant differences were found regarding the gender of the patients, tumour size, multicentricity, extrathyroidal growth, vascular invasion, lymphocytic infiltration, lymph node involvement or the expression of E-cadherin (membrane), c-erb-B2, c-met, Bcl-2, and vimentin. It is proposed that sporadic PTCs harbouring a ret rearrangement occur frequently as slow growing, papillary, or predominantly papillary tumours that do not usually progress towards less differentiated neoplasms representing what might be described as a Bonsai phenotype. © 1998 John Wiley & Sons, Ltd.     

Papillary carcinoma of thyroid: A 30-yr clinicopathological review of the histological variants

Many histological variants of PTC have been described and some are known to have prognostic significance. However, their relative frequencies and associated clinicopathological features in a large cohort of patients with PTC treated at a single institution have seldom been documented. We reclassified 1035 malignant thyroid tumors treated in a 30-yr study period, into variants of PTC according to current histological criteria and analyzed their features. Six hundred and fifty two patients (153 men; 499 women) with PTC were identified. PTC accounted for 72.8% of primary thyroid cancers. Conventional papillary carcinoma (n=300) accounted for 46% of PTC and papillary microcarcinoma 27.8% (n=181). The frequencies of the common histological variants were follicular (17.6%, n=115), tall cell (4%, n=26), and diffuse sclerosing (1.8%, n=12). Uncommon histological variants including solid (n=5), diffuse follicular (n=5), papillary carcinoma with focal insular component (n=3), columnar cell (n=2), papillary carcinoma with fasciitis-like stroma (n=2), and oncocytic (n=1) were also noted. Histological variants of PTC had different age presentation, tumor size, frequencies of lymph node metastases, calcification, metaplastic bone, and psammoma bodies, when compared with conventional PTC. We conclude that a high prevalence of different variants of PTC with distinct clinico-pathological features can be documented. Recognition of these histological variants may be important for better management of patients with PTC.     

<Emphasis Type="Italic">BRAF</Emphasis><Superscript>V600E</Superscript> Mutation in Papillary Thyroid Carcinoma: Significant Association with Node Metastases and Extra Thyroidal Invasion

B-Raf (BRAF) is the strongest activator in the downstream of MAP kinase signaling. The somatic point mutation of BRAF gene (V600E) is the most common and specific event in papillary thyroid carcinoma (PTC). However, its prevalence is variable among different studies and its association with clinico-pathological features is controversial. This study tests the prevalence of BRAF ^V600E mutation in thyroid cancer patients in Indian subcontinental population. We analyzed 140 thyroid tumor specimens for BRAF gene mutation at codon 600 using mutant-allele-specific amplification, single-strand conformation polymorphism, Mutector assay, and DNA sequencing of the PCR-amplified exon 15. BRAF mutation at codon 600 was detected in 46 of 86 PTC patients (53.4%) from Indian subcontinental cohort. Frequency of mutation varied across the subtypes of PTCs. BRAF ^V600E mutation was more common in the conventional PTC (38 out of 62; 61%) than in the follicular variant of PTC (2 out of 17; 11.7%). None of the 8 follicular thyroid adenomas, 14 follicular thyroid carcinomas, 16 medullary thyroid carcinomas, and 16 benign hyperplasia patients showed any exon 15 mutation. We found significant correlation between BRAF mutation status and extra-thyroidal invasion, lymph node metastasis, and tumor stage. However no correlation was observed with gender, age, and tumor size of the patients. Thus our findings suggest that BRAF ^V600E is a prevalent genetic alteration in adult sporadic PTCs in Indian cohort and it may be responsible for the progression of classic variant of PTC to metastatic and poorly differentiated subtype and likely to have significant impact on its diagnostic and prognostic management.     

Dynamic contrast‐enhanced MRI model selection for predicting tumor aggressiveness in papillary thyroid cancers

The purpose of this study was to identify the optimal tracer kinetic model from T₁‐weighted dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) data and evaluate whether parameters estimated from the optimal model predict tumor aggressiveness determined from histopathology in patients with papillary thyroid carcinoma (PTC) prior to surgery. In this prospective study, 18 PTC patients underwent pretreatment DCE‐MRI on a 3 T MR scanner prior to thyroidectomy. This study was approved by the institutional review board and informed consent was obtained from all patients. The two‐compartment exchange model, compartmental tissue uptake model, extended Tofts model (ETM) and standard Tofts model were compared on a voxel‐wise basis to determine the optimal model using the corrected Akaike information criterion (AICc) for PTC. The optimal model is the one with the lowest AICc. Statistical analysis included paired and unpaired t‐tests and a one‐way analysis of variance. Bonferroni correction was applied for multiple comparisons. Receiver operating characteristic (ROC) curves were generated from the optimal model parameters to differentiate PTC with and without aggressive features, and AUCs were compared. ETM performed best with the lowest AICc and the highest Akaike weight (0.44) among the four models. ETM was preferred in 44% of all 3419 voxels. The ETM estimates of K^trans in PTCs with the aggressive feature extrathyroidal extension (ETE) were significantly higher than those without ETE (0.78 ± 0.29 vs. 0.34 ± 0.18 min^?1, P = 0.005). From ROC analysis, cut‐off values of K^trans, v_e and v_p, which discriminated between PTCs with and without ETE, were determined at 0.45 min^?1, 0.28 and 0.014 respectively. The sensitivities and specificities were 86 and 82% (K^trans), 71 and 82% (v_e), and 86 and 55% (v_p), respectively. Their respective AUCs were 0.90, 0.71 and 0.71. We conclude that ETM K^trans has shown potential to classify tumors with and without aggressive ETE in patients with PTC.     

Survivin gene polymorphism association with papillary thyroid carcinoma

Survivin expression is correlated with suppression of apoptosis in human solid tumors. A polymorphism at position -31 (G/C) (rs 9904341) has been associated with cancer risk in several studies. We evaluated the correlation of this polymorphism with the risk of papillary thyroid carcinoma (PTC) in an Irananian population. The cases consisted of patients with PTC (n=123) and normal controls, composed of non-related healthy people (n=131). The frequency of GC or CC genotype in patients with PTC was significantly higher than in the controls [GC+CC vs GG, p=0.02 OR; 1.7, 95%CI (1.05-3.04)]. There was a significant difference between patients with more aggressive clinical manifestations, including lymphatic involvement compared to the controls [GC+CC vs GG, p=0.0006, OR; 3.7, 95%CI (1.6-9.2)]. The presence of C allele was significantly associated with the presence of more profound manifestations, including lymph node involvement, vascular involvement and multifocality.     

Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes

Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein. In the thyroid, the PAX8‐PPARG fusion is present in the neoplastic lesions that have a follicular architecture—follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA), while the presence of RET/PTC fusions are largely restricted to papillary thyroid carcinoma (PTC). The ability to detect fusion genes is relevant for a correct diagnosis and for therapy. We have developed a new fusion gene microarray‐based approach for simultaneous analysis of all known and predicted fusion gene variants. We did a comprehensive screen for 548 known and putative fusion genes in 27 samples of thyroid tumors and three positive controls—one thyroid cancer cell line (TPC‐1) and two PTCs with known CCDC6‐RET (alias RET/PTC1) fusion gene, using this microarray. Within the thyroid tumors tested, only well known, previously reported fusion genes in thyroid oncology were identified. Our results reinforce the pathogenic role played by RET/PTC1, RET/PTC3, and PAX8‐PPARG fusion genes in thyroid tumorigenesis. © 2012 Wiley Periodicals, Inc.     

BRAF mutations are associated with some histological types of papillary thyroid carcinoma

Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions with a particularly high prevalence in melanoma and papillary thyroid carcinoma (PTC). The hot-spot mutation BRAF(V599E) is frequently detected in PTC (36-69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC-related entities-hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAF(V599E) mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAF(V599E) was present in 75% of Warthin-like PTCs and 53% of conventional PTCs, whereas no BRAF(V599E) mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAF(V599E) was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular-papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAF(V599E) in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular-papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC.