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The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central lymph node dissection (CLND), remains controversial. This meta-analysis was conducted to investigate the clinicopathologic factors predictive of central compartment lymph node metastasis (CLNM) in patients diagnosed with PTMC.PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library were searched from their inception to September 2013. Published studies that explored the association between clinicopathologic factors and CLNM in PTMC patients were included. From the identified studies, we extracted the number of individuals with or without each risk factor to calculate the CLNM-positive proportions and used fixed/random-effects models for the meta-analyses of overall relative risk (RR). The pooling analysis on the association between CLNM or the different CLNDs and prognosis was also conducted.A total of 19 eligible studies that included 8345 patients were identified. Three studies did therapeutic CLND, while the other 16 studies performed prophylactic CLND in PTMC patients. Meta-analyses revealed that CLNM was associated with male gender (RR = 1.36; 95 % CI 1.22-1.52, p = 0.001), younger age (45 years; RR = 1.15; 95 % CI 1.04-1.27, p = 0.006), larger tumor size (5 mm; RR = 1.51 95 % CI 1.32-1.65, p = 0.001), multifocality (RR = 1.40; 95 % CI 1.27-1.54, p = 0.001), and extrathyroidal extension (RR = 1.81; 95 % CI 1.34-2.43, p = 0.001). Meta-regression analysis indicated that a disparity in the proportion of PTMC patients with CLNM in each study was the main factor resulting in heterogeneity among the 19 studies. In addition, the pooling analyses suggested that CLNM did not significantly predict neck recurrences [hazard ratio (HR) = 0.95, 95 % CI 0.67-1.22, p = 0.054], and the prophylactic CLND group did not improve local control significantly compared to the therapeutic group (RR = 0.96, 95 % CI 0.46-2.01, p = 0.544).Prophylactic CLND may be performed in PTMC patients with clinically uninvolved central lymph nodes but with high risk factors; multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for central nodes in PTMC.

Four single nucleotide polymorphisms (SNPs) have been reported to be associated with thyroid cancer risk in two genome-wide association studies (GWASs) and were validated in a Chinese population. Because of a lack of further clinical and functional evidence, the clinical significances of these SNPs remain unknown. Four GWAS-identified SNPs of papillary thyroid cancer (PTC), rs965513, rs944289, rs966423 and rs2439302, were genotyped in a case-control study of 838 patients with PTC and 501 patients with benign thyroid tumor (BTT) from the Chinese Han population. The associations between these SNPs, clinicopathologic features, and the outcome of the PTC patients were examined. The CT and CT + TT genotypes of rs966423 were more common in PTC patients with extrathyroidal extension and more advanced T stage. The TC and TC + CC genotypes and the C allele of rs944289 were significantly less frequent in patients with multifocal disease. No correlation was observed between GWAS-identified SNPs and disease persistence of PTC after a short-term follow-up. Significantly different allele distributions between the PTC and BTT groups were observed for all four selected SNPs. Individuals with more than five risk alleles were 8.84-fold (95% CI 3.23-24.17) more likely to suffer from PTC compared with those with zero or 1 risk allele. GWAS-identified SNPs affect the individual predisposition to PTC without interacting with existing Hashimoto thyroiditis and BTT lesions. GWAS-identified SNPs were associated with certain clinicopathologic features of PTC, and may contribute to identifying PTC patients with different clinical patterns. Large prospective studies are required to further evaluate the diagnostic and prognostic power of these genetic markers.

Epigenetic abnormalities as well as genetic abnormalities may play a vital role in the tumorigenesis of papillary thyroid cancer (PTC). The present study aimed to analyze the function and methylation status of the HOXD10 gene in PTC and aimed to identify relationships between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics of PTC. A total of 152 PTC patients were enrolled in the present study. The methylation status of the HOXD10 promoter was analyzed by quantitative methylation-specific polymerase chain reaction (Q-MSP). BRAFV600E mutation status was analyzed by polymerase chain reaction (PCR) followed by DNA sequencing. HOXD10 mRNA expression level was analyzed by real-time polymerase chain reaction (RT-PCR). 5-Aza-2-deoxycytidine (5-Aza) treatment was performed in 4 PTC cell lines to observe the change in HOXD10 expression. Transwell, cell cycle and apoptosis assays were then performed in an HOXD10-overexpressing PTC cell line. Furthermore, we analyzed the associations between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics in PTC. Overexpression of HOXD10 suppressed the migration of PTC cells, and promoted cell apoptosis. Q-MSP showed that methylation levels of the HOXD10 promoter were significantly higher in PTC tissues than levels in the adjacent normal thyroid tissues (P=0.02). In addition, expression of HOXD10 was decreased in the PTC cell lines and PTC tissues compared with that noted in the adjacent normal thyroid tissues (P=0.008). However, BRAFV600E mutation was detected in 42.1% of PTC patients enrolled. In addition, the BRAF mutation status was associated with the methylation and expression level of HOXD10 in PTC. We then observed that 5-Aza treatment could revert the expression of HOXD10 in PTC cell lines. Moreover, the hypermethylation of HOXD10 was associated with invasion of the primary tumor and age >45. In conclusion, the HOXD10 gene may act as a tumor suppressor in PTC. The aberrant hypermethylation and decreased expression of the HOXD10 gene were shown in PTC patients, particularly in those with BRAFV600E mutation. The epigenetic suppression of the HOXD10 gene may play a role in the tumorigenesis of PTC, and it is a prospective biomarker for the diagnosis and prognosis of PTC.

(1) Background: The genetic predisposition to papillary thyroid cancer (PTC) is far from clearly elucidated. Rs2292832 is a genetic polymorphism that located in the precursor of mir-149 and has been studied in diverse cancers. Thus far, the role of rs2292832 in PTC tumorigenesis and progression was unclear, (2) Method: Rs2292832 was genotyped in 838 PTCs, 495 patients with thyroid benign tumors (BNs) and 1006 controls in a Chinese Han population. Clinicopathological data was collected and compared. The expression level of mature mir-149 was examined in 55 normal thyroid tissue samples, (3) Results: The CC genotype of rs2292832 was significantly associated with an increased risk of PTC compared with TT homozygote (OR = 1.60, 95% CI: 1.72–2.20, p = 0.003) and TT/TC combined genotype (OR = 1.54, 95% CI: 1.14–2.09, p = 0.005). Rs2292832 is an independent risk factor correlated with tumor invasion (p = 0.006) and higher T stage in PTC patients (p = 0.007), but uncorrelated with short-term disease persistence of PTC. PTC subjects carrying CC genotype have lower mir-149-5p expression than those with TC genotype (p = 0.002). Twelve predicted target genes have been identified by collaboratively using computational tools, (4) Conclusion: Rs2292832 was possibly involved in the susceptibility and local progression of PTC in Chinese patients, by altering the expression level of mir-149-5p and its target genes.

Because interaction existed between PTEN and RET-RAS-RAF-MAPK pathway, H4-PTEN (a newly identified gene rearrangement), RET/PTC and BRAF mutation were scanned in 125 Chinese patients with papillary thyroid carcinoma (PTC). H4-PTEN were detected in 9.6% of PTC and the frequency of the occurrence of BRAF mutation and/or RET/PTC in H4-PTEN positive tumors was extremely high (75%). On the other hand, age has an important effect on the aberration formation and young age renders more prone to multi-genetic events. A combinational scanning of these involved changes will improve the predictive value of molecular aberrations in the treatment of PTC.

Background There are few reviews on the clinical features and prognosis of young patients with papillary thyroid cancer and bilateral cervical metastases. We have investigated the long-term impact of initial surgical and medical therapy on such patients. Methods A retrospective study was performed on 24 young patients (11 females and 13 males) with papillary thyroid cancer and bilateral cervical lymph node metastases, ranging in age from 11 to 20 years (mean age, 16.6 years), who were treated in our institution from 1 January 1970 to 31 December 1985. Results All the patients in this group were followed up for 20 years. The survival of the patients at 20 years was 91.7%. The recurrence of local tumor and distant metastases was 20.8% and 12.5%, respectively. Based on analysis of the clinical data, we determined that the completeness of the surgical excision had a significant correlation with tumor recurrence. Conclusion These young patients with papillary thyroid cancer and cervical metastases have a good prognosis after suitable treatment. Chin Med J 2008;121(1):63-66

Background: Papillary thyroid cancer (PTC) often presents as multifocal. However, the association of multifocality with poor prognosis remains controversial. The aim of this retrospective study was to identify the characteristics of PTC with multiple foci and to evaluate the association between multifocality and prognosis. Methods: We reviewed the medical records of 496 patients who underwent total thyroidectomy for PTC. Patients were classified as G1 (1 tumor focus), G2 (2 foci), and G3 (3 or more foci). We analyzed the clinicopathological features and clinical outcomes in each classification. A Cox regression model was used to assess the relationship between multifocality and recurrence or cancer mortality. Results: The G1, G2 and G3 groups included 287, 141 and 68 patients, respectively. The mean age was 47.1 ± 16.1 yr in G1, 41.1 ± 18.4 yr in G2, and 35.5 ± 15.9 yr in G3 and differed significantly among the 3 groups (p= 0.001). The proportion of extrathyroidal extension, central lymph node metastasis (CLNM), and lateral lymph node metastasis (LLNM) in the G1 to G3 groups increased with increasing number of tumor foci. The Kaplan–Meier curves revealed that G3 had the shortest recurrence-free survival, and differences were significant among the 3 groups (p = 0.001, Log Rank test). Furthermore, cancer-specific survival rates decreased significantly with increasing number of tumor foci (p= 0.041). Independent predictors of recurrence by multivariate Cox analysis included >3 tumor foci [HR 2.60, 95% confidence interval (CI) 1.53-4.39, p= 0.001] and extrathyroidal extension (HR 1.95, CI 1.12-3.38, p= 0.018). Conclusion: An increase in the number of tumors is associated with a tendency toward more aggressive features and predicts poor prognosis in PTC.

The impact of coexistent Hashimoto's thyroiditis (HT) on lymph node metastasis (LNM) and prognosis in papillary thyroid microcarcinoma (PTMC) remains controversial. We evaluated the association of coexistent HT with clinicopathologic parameters, LNM, and prognosis by retrospectively reviewing a series of consecutive patients treated for PTMC at Fudan University Cancer Center from January 2005 to December 2010. Of all 1,250 patients with complete data for analysis, 364 (29.1 %) had coexistent HT (HT group) and 886 patients (70.9 %) had no evidence of HT (control group). The HT group had higher proportion of female (87.9 vs 70.1 %) patients, higher mean level of thyroid-stimulating hormone (TSH) (2.39 vs 2.00 mIU/L), and lower incidence of extrathyroidal extension (7.4 vs 11.7 %) than those in the control group. However, the incidence of LNM and recurrence was similar between the two groups, and HT was not associated with LNM and recurrence. A series of clinicopathologic factors identified for predicting LNM and recurrence in the control group did not show any prediction in the HT group. In summary, this study suggested that coexistent HT had insignificant protective effect on LNM and prognosis in PTMC, which was inconsistent with prior studies. Further studies aiming to determine novel predictors are recommended in PTMC patients with coexistent HT.

MicroRNAs (miRNAs) are small non-coding RNA molecules that are involved in a variety of cellular functions. Single nucleotide polymorphisms (SNPs) have been identified in mature miRNAs (mmSNPs), some of which have been linked to cancer risk; however, it is unclear which mmSNPs contribute to the susceptibility to thyroid tumors. In the present study, we examined the influence of selected mmSNPs on the risk of thyroid tumor. After systematic in silico screening, seventeen mmSNPs were identified and genotyped in a Chinese population including 828 patients with papillary thyroid cancer (PTC), 488 patients with benign thyroid tumor (BN), and 1038 cancer-free controls. Multivariate logistic regression analyses were conducted to evaluate the association of SNP genotypes and alleles with the risk of developing PTC and BN. Three SNPs (rs67106263 in mir-3144, GA versus GG, OR = 1.35, 1.09–1.68; rs4919510 in mir-608, CC versus GG/GC, OR = 0.76, 0.60–0.97; and rs79402775 in mir-933, AA versus GG/GA, OR = 1.76, 1.00–3.12) were associated with PTC risk. A combined effect of unfavorable genotypes was observed to give increased PTC risk in a dose-dependent manner. In addition, three SNPs (rs10061133 in mir-449b, rs79402775 in mir-933 and rs4919510 in mir-608) showed at least borderline correlations with the risk of BN. False-positive report probability was assessed for significant findings. The rs67106263 SNP was associated with the expression level of mir-3144 in thyroid tissue. These results indicate that mmSNPs may contribute to genetic susceptibility to thyroid tumors. Large validation and functional studies are required to further explore the role of mmSNPs in carcinogenesis.

Background Rs2910164, a Single nucleotide polymorphism (SNP) located in the precursor microRNA sequence of miR-146a, is the only MicroRNA sequence SNP studied in papillary thyroid cancer (PTC). Association studies had been performed in US and UK-Northern European populations, but results were inconsistence. This study evaluated the association between rs2910164 and the risk of PTC as well as benign thyroid tumor (BN), and examined the clinicopathological characteristics of PTC and BN for different genotypes. Methods This case-control study genotyped rs2910164 in 753 PTCs, 484 BNs and 760 controls in a Chinese Han population. Clinicopathological and genetic data were collected and compared. Multivariate logistic regression was performed to calculate adjusted odds ratios (ORs). Results There were no differences in rs2910164 genotype distributions between the three groups. PTC cases with three genotypes (CC, CG, GG) had similar clinicopathological characteristics except the existence of “para-cancer” BN (PTC/BN, P = 0.006). PTC/BN patients were older (P = 0.009), and had smaller cancer lesions (P

Background The goal of this study was to identify the clinicopathological factors of co-existing papillary thyroid cancer (PTC) in patients with Hashimoto’s thyroiditis (HT) and provide information to aid in the diagnosis of such patients. Methods This study included 6109 patients treated in a university-based tertiary care cancer hospital over a 3-year period. All of the patients were categorised based on their final diagnosis. Several clinicopathological factors, such as age, gender, nodular size, invasive status, central compartment lymph node metastasis (CLNM) and serum thyroid-stimulating hormone (TSH) level, were compared between the various groups of patients. Results There were 653 patients with a final diagnosis of HT. More PTC was found in those with HT (58.3%; 381 of 653) than those without HT (2416 of 5456; 44.3%; p < 0.05). The HT patients with co-occurring PTC were more likely to be younger, be female, have smaller nodules and have higher TSH levels than those without PTC. A multivariate analysis indicated that the presence of HT and higher TSH levels were risk factors for a diagnosis of PTC. In the PTC patients, the presence of HT or another benign nodule was a protective factor for CLNM, whereas no significant association was found for TSH levels. Conclusion PTC and HT have a close relationship in this region of highly prevalent HT disease. Based on the results of our study, we hypothesise that long-term HT leads to elevated serum TSH, which is the real risk factor for thyroid cancer.

To determine the predictive factors for level VI lymph node (LN) metastasis in thyroid papillary microcarcinoma (PTMC).From November 2005 to January 2007, 86 patients with PTMC with a lateral cN0 were treated by thyroidectomy and elective level VI LN dissection without comprehensive lateral neck dissection. The data from the cases were analyzed retrospectively to determine the predictive factors for level VI LN metastasis.Forty cases (46.5%) of the patients were found with level VI LN metastasis. Tumor size (or = 5 mm), thyroid capsular invasion or extracapsular invasion, enlarged level VI LN size (or = 4 mm) were found significantly related to level VI LN metastasis on univariate analysis (P0.05). Tumor size (or = 5 mm) and thyroid capsular invasion or extracapsular invasion were found to be independent predictive factors for level VI LN metastasis on multivariate analysis (P0.05).Thyroid capsular invasion or extracapsular invasion, tumor size (or = 5 mm) were significantly associated with level VI LN metastasis in patients with PTMC. Elective neck dissection in level VI should be considered particularly in patients with thyroid capsular invasion or extracapsular invasion and a tumor greater than 5 mm.

To investigate the characteristics of RET/PTC and H47PTEN rearrangement and the association between gene rearrangement and clinicopathological properties of thyroid carcinoma.Rearrangement of RET/PTC-1, RET/PTC-2, RET/PTC-3, ELKS-RET and H4-PTEN (H4/PTEN and PTEN/H4) was analyzed in 139 thyroid tumor tissues by using RT-PCR and sequencing.Twelve RET/PTC-1, 6 RET/PTC-3, 6 H4/PTEN and 7 PTEN/H4 were detected in 126 papillary thyroid carcinomas. In 3 cases, both RET/PTC and H4-PTEN were identified simultaneously. However, repeated experiments did not give the same results of H4-PTEN rearrangement. The overall frequency of rearrangement was 21.4% (27/126). The patients with gene rearrangement were younger (P = 0.02) and had a higher frequency of lymph node involvement (P = 0.02). High frequency of lateral neck lymph node involvement was detected in RET/PTC positive PTC (P0.01). PTEN/H4 rearrangement could also be detected in medullary thyroid carcinoma (2/5).H4-PTEN rearrangement can occur simultaneously with RET/PTC rearrangement in PTC. High predisposition to gene rearrangement is a characteristic of PTC. The patients of PTC with gene rearrangement are younger and have a higher frequency of lymph node involvement.

To investigate the diagnosis and treatment of papillary thyroid carcinoma with endotracheal infiltration.Clinical data of 12 patients treated from January 1999 to December 2006 were retrospectively analyzed. Six patients received tracheal partial resection-sternocleidomastoid musculoperiosteal flap reconstruction (group A). Six patients received tracheal sleeve resection-end to end anastomosis (group B).Ten patients had the symptoms which indicated the tracheal invasion. Endotracheal focuses were detected in the region from 2 cm to 4 cm under glottis by endoscopy and positive rate of smear biopsy was 33%. Positive rate of CT scan was 92%. Mean diameter of carcinoma focus was 3.8 cm (from 3 cm to 7 cm), and mean number of tracheal ring resected was 4. For group A, even 7 rings were resected, and the longest longitude and latitude was 7 cm and 3 cm, respectively. For group B, the greatest number of rings resected was 4. Incidence rate of perioperative complication and mortality was 58% and 0%, respectively. Mean duration of follow-up was 49 months. One patient died of local recurrence, 1 patient died of lung metastasis. Two patients with tumor recurrence were also alive. For group A, extubation was successful in all patients.Comprehensive use of diagnostic methods, especially MRI, will give detailed information for operation. Tracheal partial resection-sternocleidomastoid musculoperiosteal flap reconstruction and tracheal sleeve resection-end to end anastomosis are safe and useful methods to reconstruct the defects caused by tracheal operation.

To discuss the evaluation of elective neck dissection (END) for the cN(0) patients with papillary thyroid carcinoma (PTC).By analyzing the recurrent and metastatic region (thyroid, group VI lymph nodes, lateral neck region, beyond neck) of 139 PTC patients treated secondly in our hospital, group VI lymph nodal metastasis is divided into recurrence of primary site and distinguished from lateral neck lymph nodes. The clinical value of END for cN(0) PTC patients is also retrospectively analyzed.Thyroidal recurrence accounts for 83% (73/88). Level VI metastasis accounts for 76% (67/88), 17 patients have received END and account for 65% (17/26). Metastasis to lateral neck lymph nodes account for 17% (17/98), among these patients, 5 patients have received END and account for 19% (5/26).For the patients with cN(0) PTC, ipsilateral thyroid lobectomy plus level VI dissection is recommended and lateral END (level II-V) is not supported. For the patients with cN(0) but UB N(+) and/or CT N(+), lateral END (level II-V) is recommended. The necessity of CT examination in the diagnosis and treatment of thyroid cancer should be emphasized.

To study the optimum type of surgical treatment for thyroid medullary carcinoma.From May 1960 to July 2000, 147 patients with thyroid medullary carcinoma were treated with surgical treatment. The results of tumorectomy, subtotal and total thyroidectomy were compared.The overall 5-, 10- and 15-year survival rates were 85.4%, 77.4% and 73.1%. The recurrence rate was lowest in the total thyroidectomy group, medium in the subtotal group and highest in tumor extirpation group (P0.05). The overall cervical lymph node metastasis rate was 72.1%. The cervical occult nodal metastasis rate in clinically N0 patients was 42.1% (occult metastasis rates in central and lateral cervical regions were 24.6% and 36.8%). Thirteen patients with persistent postoperative hypercalcitoninemia were observed from 5 months to 6 years without tumor recurrence.Total thyroidectomy is the optimal treatment for thyroid medullary carcinoma. Regardless of clinical N0 or N1, central and ipsilateral neck dissection should be considered. Patients with persistent postoperative hypercalcitoninemia should be observed closely.