Association between microRNA polymorphisms and papillary thyroid cancer susceptibility

Objectives: Papillary thyroid cancer (PTC) is the most common subtype of thyroid cancer, which accounts for 80-90% of all thyroid cancer cases. Though the pathological mechanism hasn’t been fully understood, it is reported that both environmental and genetic factor may contribute to the PTC susceptibility. MicroRNAs (miRNAs) are small non-coding RNA molecules which function as the suppressors to participate in a variety of biological processes. Accumulating evidence suggests that polymorphisms of miRNAs were associated with the tumorigenesis of various cancers, including PTC. In this article, we focus on the association between four common microRNA polymorphisms (miR-146a, miR-608, miR-933, and miR-149) and PTC risk in a Han Chinese population. Methods: In this case-control study, we recruited 1,398 participants in total, including 369 PTC patients, 278 patients with thyroid benign nodules (BN) and 751 normal controls. The miRNAs polymorphisms were genotyped and analyzed by using MALDI-TOF mass spectrometry. The odd ratios and their 95% confidence interval (95% CI) were calculated to evaluate the association between miRNAs polymorphisms and PTC risk. Furthermore, a meta-analysis based on previous studies was conducted to comprehensively assess the diagnostic performance of miR-146a in the PTC diagnosis. Results: The miR-146a polymorphisms were shown to be significantly correlated with elevated risk of PTC under the heterozygous, homozygous, dominant and allelic models by comparing the genotype distribution between PTC cases and healthy controls, as well as between PTC cases and BN cases. However, the result of meta-analysis showed no significant association between miR-146a polymorphisms and PTC risk. Conclusions: Our study indicated that the miR-146a polymorphism was significantly associated with PTC risk. In contrast, meta-analysis revealed no evidence of association between miR-146a variants and PTC risk. Further studies are required to elucidate the role of miR-146a in the etiology of PTC.     

Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma.

The tall-cell variant (TCV) of papillary thyroid carcinoma (PTC), characterized by tall cells bearing an oxyphilic cytoplasm, is more clinically aggressive than conventional PTC. RET tyrosine kinase rearrangements, which represent the most frequent genetic alteration in PTC, lead to the recombination of RET with heterologous genes to generate chimeric RET/PTC oncogenes. RET/PTC1 and RET/PTC3 are the most prevalent variants. We have found RET rearrangements in 35.8% of TCV (14 of 39 cases). Whereas the prevalences of RET/PTC1 and RET/PTC3 were almost equal in classic and follicular PTC, all of the TCV-positive cases expressed the RET/PTC3 rearrangement. These findings prompted us to compare RET/PTC3 and RET/PTC1 in an in vitro thyroid model system. We have expressed the two oncogenes in PC Cl 3 rat thyroid epithelial cells and found that RET/PTC3 is endowed with a strikingly more potent mitogenic effect than RET/PTC1. Mechanistically, this difference correlated with an increased signaling activity of RET/PTC3. In conclusion, we postulate that the correlation between the RET/PTC rearrangement type and the aggressiveness of human PTC is related to the efficiency with which the oncogene subtype delivers mitogenic signals to thyroid cells.     

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.     

Controversies in papillary microcarcinoma of the thyroid

Papillary thyroid carcinomas that are smaller than 1 cm are classified as papillary microcarcinomas (PMC). These lesions are frequently detected as incidental findings on autopsy or in surgical specimens. They are often multifocal. The relationship between PMC and clinical papillary thyroid carcinoma (PTC) is not clear. In patients with clinical thyroid cancer, PMC may represent intrathyroidal metastases; they may be the earliest form of future large lesions. These uncertainties raise questions about appropriate clinical management of patients with these lesions. Review of the literature substantiates the argument that clinically evident PTC may be distinctly different from solitary or multifocal PMC in terms of etiology and biologic behavior, supporting a conservative approach to management.     

The oncogenic activity of RET point mutants for follicular thyroid cells may account for the occurrence of papillary thyroid carcinoma in patients affected by familial medullary thyroid carcinoma

Activating germ-line point mutations in the RET receptor are responsible for multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma (MTC), whereas somatic RET rearrangements are prevalent in papillary thyroid carcinomas (PTCs). Some rare kindreds, carrying point mutations in RET, are affected by both cancer types, suggesting that, under specific circumstances, point mutations in RET can drive the generation of PTC. Here we describe a family whose siblings, affected by both PTC and MTC, carried a germ-line point mutation in the RET extracellular domain, converting cysteine 634 into serine. We tested on thyroid follicular cells the transforming activity of RET(C634S), RET(K603Q), another mutant identified in a kindred with both PTC and MTC, RET(C634R) a commonly isolated allele in MEN2A, RET(M918T) responsible for MEN2B and also identified in kindreds with both PTC and MTC, and RET/PTC1 the rearranged oncogene that characterizes bona fide PTC in patients without MTC. We show that the various RET point mutants, but not wild-type RET, scored constitutive kinase activity and exerted mitogenic effects for thyroid PC Cl 3 cells, albeit at significantly lower levels compared to RET/PTC1. The low mitogenic activity of RET point mutants paralleled their reduced kinase activity compared to RET/PTC. Furthermore, RET point mutants maintained a protein domain, the intracellular juxtamembrane domain, that exerted negative effects on the mitogenic activity. In conclusion, RET point mutants can behave as dominant oncogenes for thyroid follicular cells. Their transforming activity, however, is rather modest, providing a possible explanation for the rare association of MTC with PTC.     

Thyroid microcarcinoma: fine-needle aspiration diagnosis and histologic follow-up

The increased sensitivity of many imaging modalities (ultrasound, computed tomography scan, magnetic resonance imaging) has resulted in the identification of thyroid nodules, measuring 1 cm or less. Usually these small lesions are regarded as incidental and are not sampled by fine-needle aspiration (FNA). However, some of these lesions undergo FNA because of suspicious radiology findings (multifocality, calcification, etc) or in patients with a history of radiation to the head and neck region. We present FNA findings and histologic follow-up of 39 thyroid nodules that measured 1.0 cm or less. All FNAs were performed under ultrasound guidance. The lesions ranged in size from 0.2 to 1.0 cm. Twenty-two lesions were diagnosed as papillary carcinoma (PTC), 4 as medullary carcinoma (MC), and 13 as suspicious for PTC on FNA. Histologic follow-up showed PTC in 35 and MC in 4 cases; 11 PTC were multifocal (31%) and lymph node metastases were present in 8 (16%) cases. Ultrasound-guided FNA is effective in the sampling of thyroid cancers that are 1.0 cm or less. The present study shows that some of these lesions can be clinically significant.     

Cystic papillary thyroid carcinoma in fine needle aspiration may represent a subset of the encapsulated variant in WHO classification

This study audits the reliability of ultrasound‐guided fine needle aspiration (FNA) in excluding papillary thyroid carcinoma (PTC) in thyroid cysts containing mural nodules, and investigates the histological counterpart of cystic PTC diagnosed on FNA. Using a 10–5 MHz ultrasound probe and a 27‐gauge needle, solid portions of thyroid nodules were sampled and assessed immediately using both Diff‐Quik and Ultrafast Papanicolaou stains. Unlike usual PTCs that demonstrate hypercellularity, the aspirates of cystic PTC showed low cellularity and consisted of papillae with atypical nuclei scattered in abundant thin colloid. Over a period of 13 years, histological follow‐up was obtained from 11 women and 6 men in whom cystic PTC was reported on FNA. This represented 4.4% of 383 cases of PTC reported and 0.25% of all thyroid FNAs performed. In all 17 cases, histopathology showed encapsulated PTC in various stages of cystic degeneration. Sonography correlated well with histopathology, where findings ranged from cysts with small mural nodules to solid nodules with pockets of thin colloid. In 87 patients with thyroid cysts containing mural nodules, FNA findings were benign, as was clinical follow‐up that ranged from 1 to 12 years. In conclusion, ultrasound‐guided FNA, if performed in the manner described, can reliably distinguish cystic PTC from a benign cyst with a mural nodule. Cystic PTC on FNA in this series correlates to a subset of the encapsulated variant of PTC, an entity described in the 1988 WHO Histological Typing of Thyroid Tumours in the good prognostic category. Diagn. Cytopathol. 2010;38:721–726. © 2009 Wiley‐Liss, Inc.     

Variants in the ATM‐CHEK2‐BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma

The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6‐fold in first‐degree relatives of PTC patients. The familial risk could be explained by high‐penetrance mutations in yet unidentified genes, or polygenic action of low‐penetrance alleles. Since the DNA‐damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low‐penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e‐10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM‐ CHEK2‐ BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations. © 2014 Wiley Periodicals, Inc.     

Papillary thyroid carcinoma presenting as a solitary soft tissue arm metastasis in an elderly hyperthyroid patient. Case report and review of the literature

A case of papillary thyroid carcinoma (PTC) presenting as a solitary metastasis in the right arm muscle is described in an elderly hyperthyroid male patient. A 2-cm nodule in the right bycipites muscle was found to be a papillary carcinoma of thyroid origin and a primary, 3.5-cm tumor was subsequently found in the left lobe of a hyperfunctioning gland due to toxic goiter. Both tumors were well differentiated PTC, follicular variant. No high grade features, nor extrathyroidal spread, nor regional lymph node metastases were found, but histology evidenced intrathyroidal vascular invasion. After radical surgery and radioiodine therapy, the patient is currently disease-free 4 years after diagnosis. This is the third reported case of PTC manifesting as a single soft tissue metastasis and the first associated with hyperthyroidism. Hematogenous spread of differentiated PTC is rare, although less unusual in PTC follicular variant. Histological vascular invasion, hypervascularity and increased blood flow in the hyperfunctioning thyroid gland might have facilitated the dissemination of malignant tumor cells through the bloodstream. Literature data indicate that PTC in elderly patients is increasing and is often clinically aggressive. Radical surgical and radiometabolic treatments are required also in this age group to improve clinical outcome.This work was partially supported by grants from the Italian Ministry of Education and University (ex 60% to MP).     

Papillary thyroid carcinoma with lymph node metastases

Papillary thyroid cancer (PTC) is the most frequently occurring human thyroid cancer with good prognosis following appropriate treatment. Lymph node (LN) metastases are the main way through which PTC spread cancer cells. The mechanisms underlying PTC with local invasion, LN metastases and distant metastases are not well investigated. Tumor secrete cytokines, such as vascular endothelial growth factor (VEGF)-C and -D bind to VEGF receptors on lymphatic endothelial cells and induce proliferation (budding) from nearby lymphatic capillaries and growth of new lymphatic capillaries. About one-third of patients can be diagnosed at the time of surgical findings. Different image studies, such as ultrasonography with fine needle aspiration cytology, scintigraphic localization and positron emission tomography were reported to detect LN metastases. Important factors in predicting LN metastases are vascular invasion, male gender, absence of tumor capsule, and perithyroid involvement. Tumor recurrence in LN after primary treatment of PTC had an independent and highly significant negative effect on survival in patients over 45 year-old. Recombinant adeno-associated virus-mediated gene transfer of sVEGFR3-Fc is a feasible therapeutic scheme for blocking lymphogenous metastasis. In conclusion, aggressive surgical procedures performed by experienced surgeons or postoperative radioactive iodine therapy to minimize local recurrence of LN for PTC patients with high risk.     

Association between the HLA-G molecule and lymph node metastasis in papillary thyroid cancer

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and can present as lymph node metastasis in 30 to 65% of cases when initially diagnosed. High frequency recurrence, distant metastasis and treatment resistance can be found in cases of PTC so early diagnosis and treatment are critical for improved prognosis and better survival rates. The characterization of new biomarkers has proved useful for the diagnosis and follow-up of these patients. HLA-G is a non-classical HLA class I molecule whose expression in cancer cells has been associated with tumor evasion of immune response. Therefore, the aim of this study was to investigate the HLA-G expression and its clinical significance in PTC. Paraffin-embedded thyroid biopsies of 70 PTC patients (40 of whom had presented with metastasis) were evaluated. HLA-G-staining was observed in tumor cells in PTC, and the HLA-G expression was significantly associated with an increased occurrence of lymph node metastasis (p = 0.0006) and capsular invasion (p = 0.02). This preliminary data shows the HLA-G expression in thyroid carcinoma specimens for the first time and suggests that this expression could impair efficient anti-tumor immunity in PTC. This would indicate that HLA-G could have an independent prognostic value in PTC, principally for tumor recurrence.     

Stomatin‐like protein 2 overexpression in papillary thyroid carcinoma is significantly associated with high‐risk clinicopathological parameters and BRAFV600E mutation

Stomatin‐like protein 2 (SLP‐2), a member of the stomatin protein family, has emerged as a potential molecular hallmark of tumor progression in several human malignancies. The aim of this study was to analyze SLP‐2 expression pattern in benign and malignant thyroid tumors (n = 210) and to examine its relationship with clinicopathological parameters and BRAFV600E mutation in thyroid cancer. SLP‐2 immunohistochemical expression was not detected in benign adenomas and was absent/weak in follicular and anaplastic carcinomas. High expression levels of SLP‐2, found only in papillary thyroid carcinoma (PTC), particularly in the classical variant, were significantly associated with adverse clinicopathological parameters: lymph node metastasis (p = 0.002), extrathyroid invasion (p < 0.001), pT status (p < 0.001), and advanced tumor stage (p = 0.001). Additional genotyping of PTC cases for the BRAFV600E mutation revealed for the first time a close relation between SLP‐2 overexpression and the presence of BRAF mutation (p = 0.02) with high positive rates of lymph node metastasis (70%) and extrathyroid invasion (80%) in these cases. The significant association of SLP‐2 overexpression with unfavorable clinicopathological characteristics and BRAFV600E mutation indicates that SLP‐2 may have a role in aggressiveness of BRAF‐mutated PTC and that SLP‐2 evaluation could be clinically useful in identification of high‐risk PTC patients.     

甲状腺乳头状癌合并桥本氏甲状腺炎右侧喉返神经深层淋巴结转移情况分析

目的：探讨甲状腺乳头状癌（PTC）合并桥本氏甲状腺炎（HT）患者右侧喉返神经深层淋巴结（LN-prRLN） 的转移情况。方法： 选取本院2015 年7 月至2019 年12 月收治的123 例PTC合并HT及150 例单纯PTC病例为研究 对象,分为观察组、对照组。所有患者均行中央区淋巴结完整清扫,比较2 组颈部中央区淋巴结转移情况,分析 观察组不同临床病理特征患者LN-prRLN 转移率,采用多因素logistic 回归分析探讨观察组发生LN-prRLN 转移的 独立影响因素。结果：术后病理结果提示观察组、对照组中央区淋巴结转移率、LN-prRLN 转移总转移率、单纯 转移率,分别为43.1%、48.0%,26.8%、30.0%,4.9%、9.3%,2 组比较差异均无统计学意义。单因素分析表明 观察组癌灶最大径>2.0 cm、癌灶数量≥ 2 个、癌灶位于甲状腺下极、肿瘤侵犯包膜、甲状腺周围组织、中央区 淋巴结清扫总数≥ 5 枚、合并其他中央区淋巴结转移、颈侧区淋巴结转移患者LN-prRLN 转移发生率显著升高, 差异均有统计学意义。多因素logistic 回归分析结果表明,癌灶数量≥ 2 个与肿瘤侵犯包膜是观察组LN-prRLN 转 移发生的独立危险因素（OR=1.986、3.338）。结论：1/4 的PTC合并HT患者会出现LN-prRLN 转移,在清扫右侧 中央区淋巴结时应常规探查LN-prRLN,当癌灶数量≥ 2 个与肿瘤侵犯包膜时推荐尽量完整清扫LN-prRLN。     

Correlation between calcification and bone sialoprotein and osteopontin in papillary thyroid carcinoma

The correlation between calcification and papillary thyroid carcinoma has received increasing attention. We investigated the ability of bone sialoprotein (BSP) and osteopontin (OPN) protein levels to diagnose papillary thyroid carcinoma (PTC), and explored the correlation between BSP and OPN protein levels and calcification in PTC. Archival PTC specimens from patients with PTC with calcification and lateral cervical lymph node metastasis (LNM) were included in this retrospective immunohistochemical study. The protein levels of BSP and OPN were analysed immunohistochemically using routinely prepared tissue sections. PTC specimens from 66 patients with PTC were reviewed retrospectively (25 patients with histological calcification seen in paraffin sections, 41 patients without calcification; 35 patients with lateral cervical LNM, 31 patients without LNM). The percentage of samples that had cells that demonstrated positive protein staining differed significantly between PTC specimens, benign thyroid nodules, and adjacent normal follicular epithelium (BSP: 87.88%, 55.00%, and 42.50%, respectively; OPN: 83.33%, 70.00% and 50.00%, respectively). There was a significant difference in the immunohistochemical score (IHS) for BSP and OPN protein staining between PTC specimens with and without calcification (P < 0.05). The level of BSP protein staining was found to be significantly correlated with the level of OPN protein staining in PTC specimens. We conclude that the strong correlation between BSP and OPN and PTC suggests a role for BSP and OPN in calcification and tumor progression of PTC. BSP and OPN might be useful tumour markers for the diagnosis of PTC with limited value, because both of them had low specificity.     

The utility of aspiration cytology for the distinction of aggressive and non-aggressive papillary carcinoma of the thyroid

Preoperative identification of the aggressive variants of papillary thyroid carcinoma (PTC) by fine needle aspiration (FNAC) has been suggested and different systems for distinguishing them from classical variant of PTC have been employed, including a point-based cytology grading system as suggested by Damiani et al., that we currently use in our Institution. The aim of this paper is to verify if distinction of PTC in aggressive or nonaggressive variants impacts on surgical treatment. In 7 years, from 1998 to 2005, 13586 cases of FNAC of thyroid have been performed; among them 156 PTC. The cytological material of thirty complete thyroidectomies with histology proven papillary thyroid carcinoma were reviewed. 11/30 cases were correctly stratified into the appropriate low or high-grade category. The cytological grading system was discordant with the final histopathological diagnosis in 9/30 cases while in 10 cases the grade was not assessed. Eight cases were downgraded and therefore the low grade papillary carcinoma diagnosed at cytological level turned to be high grade at histology. When those cases were reviewed, the histology of seven cases diagnosed as tall cell variant of PTC failed to show a percentage of tumour cells higher than 50% and therefore it would be better to diagnose them as classical variant of PTC. One case was under-graded at FNAC. The case that was cytologically upgraded was a follicular variant of PTC in Hashimoto thyroiditis with a focus of tall cells. All patients underwent thyroidectomy or thyroidectomy plus lymphadenectomy and from our results the pre-operative diagnosis did not effect the surgical treatment. No patient died of the disease.     

Overexpression of cytokeratin 17 is associated with the development of papillary thyroid carcinoma and the presence of lymph node metastasis

Cytokeratin 17 (CK17), a basal/myoepithelial cell keratin, appears to play an important role in the progression of several human malignancies. Increased CK17 expression has previously described in cases of papillary thyroid carcinoma (PTC). However, no studies to date have investigated the clinical significance of CK17 expression in patients with PTC. The aim of this study was to compare the expression of CK17 in patients with PTC with that observed in normal thyroid tissue and benign thyroid lesions, and to examine the relationship between CK17 expression and clinicopathologic characteristics of patients with PTC. CK17 protein expression was evaluated by immunohistochemistry on tissue microarrays containing thyroid tissue samples from 108 PTCs, 16 nodular goiters, and 81 healthy controls. Sixty-five of the 108 (60.2%) PTC tissue samples exhibited positive CK17 expression, whereas all nodular goiters and normal thyroid tissue samples showed a complete absence of CK17 immunoreactivity. The difference in frequency of CK17 positivity between PTC (65/108, 60.2%), normal thyroid tissue (0/81, 0.0%), and benign thyroid lesions (0/16, 0.0%) was statistically significant (P<0.001). Positive CK17 expression in PTC was significantly associated with the presence of lymph node metastasis (P=0.024) and higher pN stage (P=0.028). Expression of CK17 is significantly increased in cases of PTC compared to normal tissue and benign thyroid lesions, and CK17 overexpression is associated with the presence of lymph node metastasis in patients with PTC. These findings suggest that CK17 is involved in the development and metastasis of PTC.     

Papillary thyroid carcinoma with bone formation

Bone formation is a rarely encountered finding during histological examination of papillary thyroid carcinoma (PTC). This study aimed to analyze clinicopathological parameters in patients with PTC showing bone formation, to document histological features of bone formation in PTC, and to investigate osteogenic proteins. Bone morphogenic protein (BMP)-9 is known as the most potent osteoinductive protein of the BMP subtypes. Recent research suggests that the activin receptor-like kinase (ALK) 1 is an essential cellular receptor that mediates BMP-9-induced osteogenic signaling. A retrospective review of tumor sections from 567 patients with a diagnosis of PTC was performed. Using immunohistochemistry and quantitative real-time polymerase chain reaction, we investigated the expression of ALK1 and BMP-9 in normal thyroid tissue and PTC samples with and without bone formation. Bone formation was found in 13% of patients with PTC. A significant association was seen between bone formation and old age. BMP-9 expression in tumors was increased compared to that in normal thyroid tissues. BMP-9 expression in tumors with bone formation was not significantly different from that in tumors without bone formation. ALK1 expression in tumors with bone formation was increased compared to that in normal thyroid tissue and tumors without bone formation. Our study suggests that upregulation of ALK1 might be an underlying molecular mechanism that explains osteogenesis in PTC.     

Pathology of Thyroglossal Duct: an Institutional Experience

Thyroglossal duct (TGD) is a developmental anomaly in which a remnant of the thyroid anlage is left in the neck during its descent from the foramen cecum of tongue to final pretracheal position. A persistent duct can lead to thyroglossal duct cyst (TGDC). Histologically, TGDC contains an epithelial lining of squamous or pseudostratified ciliated columnar epithelium and ectopic thyroid gland tissue in the duct wall. TGD-associated malignancy is rare, and the majority is papillary thyroid carcinoma (PTC). A total of 242 patients with a diagnosis of TGD-associated lesions were identified in our institute. Two hundred and seventeen cases were diagnosed as TGDC. Sixty-eight of 217 (31.3 %) cases of TGDC had ectopic thyroid tissue in the cystic wall. Thirty-nine cases had preoperative fine needle aspiration (FNA). Of these cases, 37 of 39 (94.9 %) demonstrated macrophages and 19 (48.7 %) also showed cells of squamous and/or columnar epithelial lining. Only two cases showed rare thyroid follicular cells. Thyroid carcinoma was identified in 18 of 242 (7.4 %) cases. All cases were diagnosed as PTC including 12 cases of classic PTC (66.7 %), 3 cases of follicular variant (16.7 %), 2 cases of tall cell variant (11.1 %), and 1 case of classic PTC with focal tall cell features (5.6 %). Nine cases had TGD component (either epithelial lining cysts or ectopic thyroid tissue). Ten patients also underwent total thyroidectomy (67 %). Of these patients, four had no tumor and one had an incidental medullary carcinoma. Five of 10 (50 %) cases had incidental PTC with a size range of 0.1–0.3 cm. Five patients had follow-up by imaging studies; no suspicious or nodular lesions were found in the thyroid. In conclusion, we report an institutional case cohort of 242 patients with TGD-associated lesions, including 217 TGDC and 18 cases of PTC. Only seven cases fulfilled the diagnostic criteria of TGD-associated PTC, i.e., the presence of components of TGD and a normal thyroid. In the remaining 11 cases, we could not differentiate with certainty between pyramidal primary thyroid PTC/Delphian node metastasis or TGD-associated PTC.     

Well-Differentiated Thyroid Carcinoma with Concomitant Hashimoto’s Thyroiditis Present with Less Aggressive Clinical Stage and Low Recurrence

Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are the most common differentiated thyroid cancers. Previous studies report that Hashimoto’s thyroiditis (HT) concomitant with PTC is unusual and improves prognosis compared to classical PTC. Few previous studies address FTC concomitant with HT. In this study, we retrospectively analyzed data from one institution and compared clinical presentations and results of treatment of PTC and FTC with and without HT. In addition, studies comparing presentation and long term follow-up prognosis in classical PTC and FTC were conducted. A total of 1,788 PTC patients and 209 FTC patients underwent thyroidectomy with or without lymph node dissection and follow-up at Chang Gung Medical Center in Linkou, Taiwan. All thyroid carcinomas were pathologically classified according to World Health Organization criteria. Histological patterns of PTC were categorized as classical PTC, or PTC with HT. Follicular thyroid carcinoma patients were categorized as FTC or FTC with HT. The dataset contained a total of 1,703 PTC cases categorized as classical PTC, 85 cases of PTC with HT, 201 cases of FTC and eight cases of FTC with HT. Analysis of Classification of Malignant Tumors (TNM) stage revealed a higher percentage of classical PTC in stage IV than HT group (12.03% vs. 4.70%). Mean tumor size of classical PTC was larger than HT group. Although 42.3% of FTC cases presented with distant metastases, no cases of FTC with HT presented with distant metastasis. Cancer-specific mortality was higher in classical PTC group than in PTC with HT. There was 53.2% of FTC without HT assigned recurrent status, and six of them died of thyroid cancer. No cancer mortality or recurrence in HT with FTC. PTC and FTC with HT presented with better clinical stage and better prognosis after same therapeutic modality. In conclusions, both PTC and FTC with HT have less aggressive clinical presentation and better prognosis.     

Association analysis between the interaction of RAS family genes mutations and papillary thyroid carcinoma in the Han Chinese population

Papillary thyroid carcinoma (PTC) is the major subtype of thyroid cancer, accounting for 75%-85% of all thyroid malignancies. This study aimed to identify the association between the interactions of single nucleotide polymorphisms (SNPs) in RAS family genes and PTC in the Han Chinese population, to provide clues to the pathogenesis and potential therapeutic targets for PTC. Hap Map and NCBI-db SNP databases were used to retrieve SNPs. Haploview 4.2 software was used to filter SNPs based on specific parameters, six SNPs of RAS gene (KRAS-rs12427141, KRAS-rs712, KRAS-rs7315339, HRAS-rs12628, NRAS-rs14804 and NRAS-rs2273267) were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) in 673 PTC patients and 657 healthy controls, the interactive effect was evaluated by crossover analysis, logistic regression and GMDR software.We found that genetic mutation in rs712 have significant associations with PTC risk after Bonferroni correction (p<0.001). The interaction between KRAS-rs12427141 and HRAS-rs12628 increased the risk of PTC (U=-2.119, p<0.05), the interaction between KRAS-rs2273267 and HRAS-rs7315339 reduced the risk of PTC (U=2.195, p<0.05). GMDR analysis showed that the two-factor model (KRAS-rs712, NRAS-rs2273267) was the best (p=0.0107). Summarily, there are PTC-related interactions between RAS family genes polymorphisms in the Han Chinese population.