A Nod to the Nodes: An Overview of the Role of Central Neck Dissection in the Management of Papillary Thyroid Carcinoma.

Lymph node metastasis in thyroid cancer is common and associated with an increased risk of locoregional recurrence (LRR). Although therapeutic central neck dissection is well established, prophylactic central node dissection (pCND) for microscopic occult nodal involvement is controversial and recommendations are based on low-level evidence. The potential benefits of pCND such as reducing LRR and re-operation, refining staging, and improving surveillance are enthusiastically debated and the decision to perform pCND must be weighed up against the increased risks of complications.

Salvage Cryoablation for Local Recurrences of Thyroid Cancer Inseparable from the Trachea and Neurovascular Structures.

PURPOSE: To demonstrate safety, feasibility, and effectiveness of cryoablation of recurrent papillary thyroid cancer ineligible for reoperation because of scarring, eligible for focal ablation as defined within 2015 American Thyroid Association guideline sections C16 and C17. MATERIALS AND METHODS: With multidisciplinary consensus, cryoablation was performed with curative intent for 15 tumors in 10 patients between January 2019 and July 2021. Demographics, procedural details, and serial postprocedural imaging findings were analyzed. RESULTS: The mean age was 72.5 years (range, 57-88 years), and 80% of the patients were women. The tumors (mean size, 16 mm ± 6; range, 9-29 mm) received 1 session of cryoablation with 100% technical success. The mean and median postcryoablation tumor volumetric involution rates were 88% and 99%, respectively, with 9 (60%) of 15 tumors involuting completely or down to the scar and 6 (40%) involuting partially at the end of the study period. Tumor size did not increase after cryoablation (0% local progression rate). All tumors abutted the trachea, skin, and/or vascular structures, and hydrodissection failed in all cases because of scarring. The major adverse event rate was 20% (3/15), with 2 cases of voice change and 1 case of Horner syndrome; all resolved at 6 months with no permanent sequelae. No vascular, tracheal, dermal, or infectious adverse events occurred during a mean follow-up of 242 days (range, 114-627 days). One patient died at 386 days after cryoablation because of unrelated cholangiocarcinoma. CONCLUSIONS: Cryoablation of local recurrences of papillary thyroid cancer abutting the trachea and/or neurovascular structures in the setting of hydrodissection failure because of scarring yielded a mean volumetric involution of 88%, primary efficacy of 60%, and objective response rate of 100% with no local recurrences or permanent complications during a mean follow-up of 242 days. The secondary efficacy and longer-term outcomes remain forthcoming.

Intraoperative Radiofrequency Ablation for Contralateral Benign Nodules in Unilateral Thyroid Cancer Patients to Relieve Anxiety.

INTRODUCTION: For unilateral papillary thyroid carcinoma (PTC) with contralateral benign nodules, optimal extent of surgery remains controversial. This retrospective cohort study was performed to evaluate the life quality of patients who underwent lobectomy alone and lobectomy with radiofrequency ablation (RFA). METHODS: From October 2014 to October 2018, unilateral PTC patients with contralateral benign nodules reported by fine-needle aspiration cytology who encountered anxiety about contralateral nodule progression underwent lobectomy for PTC and intraoperative RFA for contralateral nodules. The patients who underwent thyroid lobectomy were matched for sex, age at time of surgery, number, size, and location of primary tumors and contralateral nodules to the patients who underwent lobectomy with intraoperative RFA. Three questionnaires were used to evaluate life quality in the two groups. The complications and rate of patients who were not required to receive thyroid-stimulating hormone suppression therapy were recorded. RESULTS: One hundred forty-eight patients with 194 contralateral nodules underwent RFA in the lobectomy plus RFA group, and age- and sex-matched patients underwent thyroid lobectomy alone. The mean volume reduction ratio was 67.7% at 12 mo and 95.2% at 24 mo. After a median follow-up of 4.2 y, nine patients (6.1%) in the lobectomy plus RFA group and 17 (11.5%) in the thyroid lobectomy-alone group underwent completion thyroidectomy (P = 0.100). Patients who underwent lobectomy plus RFA had a better quality of life in terms of anxiety, physiological health, social and family aspects, and psychological and sensory features that were measured cross-sectionally at 6 mo using three instruments. CONCLUSIONS: Intraoperative RFA is effective in terms of volume reduction of contralateral nodules and improved quality of life for unilateral PTC patients with anxiety about disease progression.

Comparison of Different Mandibular Jawlines Classifications on Transoral Endoscopic Thyroidectomy for Papillary Thyroid Carcinoma: Experiences of 690 Cases.

BACKGROUND: The influences of patients' different mandibular jawlines on transoral endoscopic thyroidectomy via vestibular approach (TOETVA) have not been described before. The objective of this study was to introduce a new classification to assess different mandibular jawlines, and to evaluate the effects on TOETVA in terms of safety, feasibility, and postoperative feelings in the treatment of papillary thyroid carcinoma (PTC). METHODS: The crossing angle of esthetic plane and mandibular plane was defined as Wang Angle, used to assess patients' different mandibular jawlines. Mandibular classifications of A (angle: 80° ~ 110°), B (angle > 110°), and C (angle < 80°) types were compared to evaluate the surgical outcomes of TOETVA by a retrospective study. 690 patients of PTC who received TOETVA were included in this study, which were divided into three groups according to mandibular classifications. RESULTS: Clinicopathological characteristics of the patients including age, gender, body mass index, tumor size, Hashimoto thyroiditis were similar in the three groups. Patients' length of jay in group C was significantly longer than group A and group B (P < 0.01). The ratios of using suspension system in group C were significantly higher than group A and group B (P < 0.01). The scores of postoperative visual analogue scale (VAS) and ratios of mandibular swell in group C were significantly higher than group A and group B (P < 0.01). There was no significant difference in the three groups regarding surgical outcomes, including postoperative vocal cord paralysis, hypocalcemia, serum white blood cells and C-reactive protein levels. CONCLUSIONS: The Wang angle and mandibular jawline classifications were firstly introduced in TOETVA. All the patients of class A, B, and C mandibular jawline can achieve safe and effective surgical outcomes in the treatment of PTC with TOETVA. Patients of class C need more assistance of suspension system, would experience higher scores of VAS, and higher ratios of mandibular swell compared with class A and B.

Ambient particulate matter air pollution is associated with increased risk of papillary thyroid cancer.

BACKGROUND: The association between exposure to air pollution and papillary thyroid carcinoma is unknown. We sought to estimate the relationship between long-term exposure to the fine (diameter ≤ 2.5 µm) particulate matter component of air pollution and the risk of papillary thyroid cancer. METHODS: Adult (age ≥18) patients with newly diagnosed papillary thyroid carcinoma between January 1, 2013 and December 31, 2016 across a single health system were identified using electronic medical records. Data from 1,990 patients with papillary thyroid carcinoma were compared with 3,980 age- and sex-matched control subjects without any evidence of thyroid disease. Cumulative fine (diameter <2.5 µm) particulate matter exposure was estimated by incorporating patients' residential zip codes into a deep learning neural networks model, which uses both meteorological and satellite-based measurements. Conditional logistic regression was performed to assess for association between papillary thyroid carcinoma and increasing fine (diameter ≤2.5 µm) particulate matter concentrations over 1, 2, and 3 years of cumulative exposure preceding papillary thyroid carcinoma diagnosis. RESULTS: Increased odds of developing papillary thyroid carcinoma was associated with a 5 µg/m3 increase of fine (diameter ≤2.5 µm) particulate matter concentrations over 2 years (adjusted odds ratio = 1.18, 95% confidence interval: 1.00-1.40) and 3 years (adjusted odds ratio = 1.23, 95% confidence interval: 1.05-1.44) of exposure. This risk differed by smoking status (pinteraction = 0.04). Among current smokers (n = 623), the risk of developing papillary thyroid carcinoma was highest (adjusted odds ratio = 1.35, 95% confidence interval: 1.12-1.63). CONCLUSION: Increasing concentration of fine (diameter ≤2.5 µm) particulate matter in air pollution is significantly associated with the incidence of papillary thyroid carcinoma with 2 and 3 years of exposure. Our novel findings provide additional insight into the potential associations between risk factors and papillary thyroid carcinoma and warrant further investigation, specifically in areas with high levels of air pollution both nationally and internationally.

DIO3OS as a potential biomarker of papillary thyroid cancer.

BACKGROUND: Papillary thyroid carcinoma (PTC) is one of the common clinical tumors, where LncRNA plays an important role in tumorigenesis and its development. The purpose of this study was to explore the role of DIO3OS in PTC. METHOD: Firstly, this study verified the expression of DIO3OS in PTC through the public database. Then, the differences in DIO3OS expression between the PTC group and paracancerous tissues were verified using the qRT-PCR. A series of in vitro experiments were conducted to verify the function of DIO3OS in PTC, while its involvement in possible pathways was analyzed by the GSEA. The ssGSEA algorithm estimated the immune status using the queue transcriptome graph derived from the TCGA database. Further, the correlation analysis was used to confirm the relationship between DIO3OS and the immune genes. RESULT: The results showed that the expression of DIO3OS was low in PTC. The same results were also confirmed by qRT-PCR analysis (P= 0.0077). In vitro, DIO3OS was localized within the cytoplasm and exosomes. Overexpression of DIO3OS hindered the proliferation, invasion, and migration of PTC cells. According to the degree of immune cell infiltration, the tumor group was divided into high immune cell infiltration group, medium immune cell infiltration group, and low immune cell infiltration group. The results showed that the DIO3OS was highly expressed in the high immune cell infiltration group (P < 0.001), which was positively correlated with the immune cell infiltration and also correlated with multiple immune genes. CONCLUSION: In summary, this study illustrated the expression pattern of DIO3OS in PTC, which may be involved in the immune-inflammatory pathway. Hence, our results may provide new diagnostic biomarkers and therapeutic targets for PTC.

Comparative pathological characteristics of papillary thyroid carcinoma with second primary non-thyroid malignancies in the region affected by the Chernobyl accident.

The aim was to study the pathological features of papillary thyroid carcinoma diagnosed with or before second primary malignancy in patients exposed to post-Chernobyl exposure. The patients selected (n = 6559) were those exposed to radiation at the age of ≤ 18 years old and developed papillary thyroid carcinoma during the years 1990-2020. Of these, 2.1% (n = 140) had second primary malignancies. To compare the histopathological characteristics of papillary thyroid carcinoma in the group under analysis, 91% (n = 128) with sufficient data were included in further analysis. The control group was formed by matching patients with age at exposure to radiation, age at surgery, gender, and place of residence. Median age at exposure was 14 years old for both groups. Besides, no difference in tumour extension and histological features of papillary thyroid carcinoma was noted between patients with synchronous or metachronous primary malignant tumours. Nevertheless, the time lag to the diagnosis of papillary thyroid carcinoma was shortened in the group with metachronous when compared to patients with synchronous second primaries (p < 0.001). Independent differences between patients with second primaries and their matched peers included tumour size {OR (95%CI) = 0.89 (0.45; 1.04)}, multiple tumours {OR (95% CI) = 1.46 (0.86; 2.42)}, lymphatic vessel invasion (OR (95%CI) 0.92 (0.61; 1.53)), blood vessel invasion (OR (95%CI) 0.41 (0.10; 1.23) and presence of numerous psammomas (OR (95%CI) 0.73 (0.39; 1.31)). The possible influence of radiative iodine treatment for development of second primaries was analysed for the group of patients with metachronous malignancies using the same approach (84 patients were compared to 252 matched patients). Independent differences also included tumour size {OR (95% CI) 0.77 (0.45; 1.30)}, lymphatic vessel invasion {OR (95%CI) 0.75(0.43; 1.28)}, blood vessel invasion {OR (95%CI) 0.17 (0.01; 0.87)}. Besides, multiple tumours were revealed more frequently in patients with metachronous primaries (OR (95%CI) 1.92 (1.0; 3.62)). To conclude, patients exposed to Chernobyl irradiation with the development of papillary thyroid carcinoma and second primary malignancy have less biological aggressive pathological characteristics of their thyroid cancers. Accordingly, these patients were less frequently treated with post-surgical radioactive iodine. Thus, 131I-irradiation may have negligible impact on the development of second primaries.

ß-Catenin Attenuation Inhibits Tumor Growth and Promotes Differentiation in a BRAFV600E-Driven Thyroid Cancer Animal Model.

BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). ß-Catenin (Ctnnb1) is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. BRAF V600E-driven tumors have been speculated to rely on Wnt/ß-catenin signaling to sustain its growth, although many details remain to be elucidated. In this study, we investigated the role of ß-catenin in BrafV600E -driven thyroid cancer in a transgenic mouse model. In Braf V600E mice with wild-type (WT) Ctnnb1 (BVE-Ctnnb1WT or BVE), overexpression of ß-catenin was observed in thyroid tumors. In Braf V600E mice with Ctnnb1 knockout (BVE-Ctnnb1null), thyroid tumor growth was slowed with significant reduction in papillary architecture. This was associated with increased expression of genes involved in thyroid hormone synthesis, elevated 124iodine uptake, and serum T4. The survival of BVE-Ctnnb1null mice was increased by more than 50% during 14-month observation. Mechanistically, downregulation of MAPK, PI3K/Akt, and TGFß pathways and loss of epithelial-mesenchymal transition (EMT) were demonstrated in the BVE-Ctnnb1null tumors. Treatment with dual ß-catenin/KDM4A inhibitor PKF118-310 dramatically improved the sensitivity of BVE-Ctnnb1WT tumor cells to BRAFV600E inhibitor PLX4720, resulting in significant growth arrest and apoptosis in vitro, and tumor regression and differentiation in vivo These findings indicate that ß-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAFV600E inhibitors. Simultaneously targeting both Wnt/ß-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAFV600E inhibitor-resistant and/or radioiodine-refractory thyroid cancer.

Prevalence of Hashimoto Thyroiditis in Adults With Papillary Thyroid Cancer and Its Association With Cancer Recurrence and Outcomes.

Importance: Hashimoto thyroiditis (HT) has been suggested to be associated with papillary thyroid cancer (PTC) development. However, its association with PTC progression remains unclear. Objective: To examine the association between HT and PTC presentation and outcomes. Design, Setting, and Participants: This retrospective cohort study included a review of patients aged 18 to 75 years who had pathologically confirmed PTC treated at a single center in China from January 1, 2001, to December 31, 2014. Data analysis was performed from November 1 to December 31, 2020. Exposures: Coexistent HT was defined according to evaluation of postoperative paraffin sections. Main Outcomes and Measures: The primary outcome was the association of HT with PTC-related mortality, assessed using Cox proportional hazards regression models. The secondary outcome was the association of HT with aggressive characteristics and structural recurrence of PTC, assessed using logistic regression and Cox proportional hazards regression with and without adjustment for related factors. Results: Of 9210 patients with PTC (mean [SD] age, 43.6 [12.0] years; 6872 [75%] women) included in the analysis, 1751 (19%) had HT. In the logistic regression model, HT was negatively associated with frequencies of primary tumor size of 4 cm or greater (adjusted odds ratio [aOR], 0.20; 95% CI, 0.12-0.33; P < .001), gross extrathyroidal extension (aOR, 0.44; 95% CI, 0.36-0.54; P < .001), extranodal extension (aOR, 0.66; 95% CI, 0.55-0.80; P < .001), and distant metastasis (aOR, 0.17; 95% CI, 0.04-0.71; P = .02). After a median follow-up of 85 months (range, 12-144 months), 131 PTC-related deaths were identified in the cohort; 2 patients who died had HT. Patients with HT had significantly superior outcomes compared with patients without HT in terms of unadjusted 10-year disease-specific survival (99.9% vs 96.6%; log-rank P < .001) and recurrence-free survival (92.0% vs 87.6%; log-rank P = .001). After adjusting for sex, age, primary tumor size, extrathyroidal extension, lymph node metastasis, distant metastasis, extent of surgery, and radioactive iodine ablation, HT was associated with decreased PTC-related mortality (hazard ratio [HR], 0.19; 95% CI, 0.05-0.76; P = .02). Stratified analysis showed that HT was associated with less frequent structural recurrence in patients with extrathyroidal extension (HR, 0.52; 95% CI, 0.38-0.71; P < .001; P = .002 for interaction) or after total thyroidectomy (HR, 0.50; 95% CI, 0.35-0.69; P < .001; P = .009 for interaction). Conclusions and Relevance: In this cohort study, patients with coexistent HT had less aggressive characteristics at presentation and better outcomes of PTC than did patients without HT. The findings suggest that autoimmune thyroiditis has a protective role in association with thyroid cancer.

OGT regulated O-GlcNAcylation promotes papillary thyroid cancer malignancy via activating YAP.

The incidence of thyroid cancer is growing rapidly during the past decades worldwide. Although most thyroid tumors are curable, some patients diagnosed with distant metastases are associated with poor prognosis. The molecular mechanisms underlying these cases are still largely unknown. Here we found that the upregulated O-Linked N-Acetylglucosamine Transferase (OGT) expression and O-GlcNAcylation (O-GlcNAc) modification in papillary thyroid cancer (PTC) were essential in tumor growth and metastasis. Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation. Our work clearly showed the critical role of OGT and YAP played in PTC tumors and made it possible for us to seek the clinical potential of manipulating OGT/YAP activity in PTC targeted therapies. These findings also confirmed OGT worked in collaboration with classical Hippo pathway kinases as an upstream regulator of YAP in PTC tumors.

Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident.

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (131I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.

BROX haploinsufficiency in familial nonmedullary thyroid cancer.

BACKGROUND: The familial nonmedullary thyroid cancer (FNMTC) is suspected to be a Mendelian condition in up to 3-8% of thyroid cancers. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. The inheritance of FNMTC appears to be autosomal dominant with incomplete penetrance and variable expressivity. The finding of the causative gene of FNMTC and the identification of patients at risk that need genetic testing were our aim. METHODS: We analyzed by whole-exome sequencing patients and non-affected relatives of five families with at least two family members affected by papillary thyroid cancer, selecting for new or extremely rare variants with predicted pathogenic value. RESULTS: A family showed, in all three affected members, a new loss-of-function variant (frameshift deletion) in BROX gene at 1q41 that was absent from all internal and external databases. In a second family with three affected relatives, we found an additional new BROX variant. The smaller families presented no variants in BROX or in the other causative genes studied. CONCLUSIONS: BROX could be a new causative gene for FNMTC. Variants in BROX may result in the haploinsufficiency of a key gene involved in the morphogenesis of MVBs, in the endosomal sorting of cargo proteins, and in EGFR. Functional studies are needed to support this result. The thorough genomic analysis by NGS in all families with three or more affected members should become a routine approach to obtain a comprehensive genetic view and find confirmative second cases.

Biologically-based modeling of radiation risk and biomarker prevalence for papillary thyroid cancer in Japanese a-bomb survivors 1958-2005.

PURPOSE: Thyroid cancer of papillary histology (PTC) is the dominant type in radio-epidemiological cohorts established after nuclear accidents or warfare. Studies on post-Chernobyl PTC and on thyroid cancer in the life span study (LSS) of Japanese a-bomb survivors consistently revealed high radiation risk after exposure during childhood and adolescence. For post-Chernobyl risk assessment overexpression of the CLIP2 gene was proposed as molecular biomarker to separate radiogenic from sporadic PTC. Based on such binary marker a biologically-based risk model of PTC carcinogenesis has been developed for observational Chernobyl data. The model featured two independent molecular pathways of disease development, of which one was associated with radiation exposure. To gain credibility the concept for a mechanistic risk model must be based on general biological features which transcend findings in a single cohort. The purpose of the present study is therefore to demonstrate portability of the model concept by application to PTC incidence data in the LSS. By exploiting the molecular two-path concept we improve the determination of the probability of radiation causing cancer (POC). MATERIALS AND METHODS: The current analysis uses thyroid cancer incidence data of the LSS with thyroid cancer diagnoses and papillary histology (n = 292) from the follow-up period between 1958 and 2005. Risk analysis was performed with both descriptive and biologically-based models. RESULTS: Judged by goodness-of-fit all applied models described the data almost equally well. They yielded similar risk estimates in cohorts post-Chernobyl and LSS. The preferred mechanistic model was selected by biological plausibility. It reflected important features of an imperfect radiation marker which are not easily addressed by descriptive models. Precise model predictions of marker prevalence in strata of epidemiological covariables can be tested by molecular measurements. Application of the radiation-related molecular pathway from our preferred model in retrospective risk assessment decreases the threshold dose for 50% POC from 0.33 (95% confidence interval (CI) 0.18; 0.64) Gy to 0.04 (95% CI 0.01; 0.19) Gy for females and from 0.43 (95% CI 0.17; 1.84) Gy to 0.19 (95% CI 0.05; 1.00) Gy for males. These improvements are still not sufficient to separate radiation-induced from sporadic PTC cases at very low doses <0.015 Gy typical for the Fukushima accident. CONCLUSIONS: Successful application of our preferred mechanistic model to LSS incidence data confirms and improves the biological two-path concept of radiation-induced PTC. Model predictions suggest further molecular validation studies to consolidate the basis of biologically-based risk estimation.

ARHGAP36 regulates proliferation and migration in papillary thyroid carcinoma cells.

The diagnosis and treatment of recurrence and metastasis in papillary thyroid carcinoma (PTC) are still clinical challenges. One of the key factors is the lack of specific diagnostic markers and therapeutic targets for recurrence and metastasis. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful approach to find specific biomarkers by dissecting expression profiling in human cancers at the resolution of individual cells. Here, we investigated cell profiles of the primary tumor and lymph node metastasis and paracancerous normal tissues in one PTC patient using scRNA-seq, and compared individual cell gene expression differences. The transcriptomes of 11,805 single cells were profiled, and malignant cells exhibited a profound transcriptional overlap between primary and metastatic lesions, but there were differences in the composition and quantity of non-malignant cells. ARHGAP36 was one of the genes that were highly expressed in almost all of the primary and metastatic malignant cells without non-malignant or normal follicular cells and was then confirmed by immunostaining in a sample cohort. Compared with the paracancerous normal tissue, the expression of ARHGAP36 in primary and metastatic carcinoma tissues was significantly higher as assayed by qRT-PCR. ARHGAP36 knockdown significantly inhibited the proliferation and migration of PTC cells in vitro and involved several proliferation and migration-associated signaling pathways by RNA seq. Our study demonstrated that ARHGAP36 is exclusively expressed in the malignant cells of primary PTC, as well as metastatic lesions, and regulates their proliferation and migration, meaning it can be used as a potential diagnostic marker and therapeutic target molecule.

Thyroid neoplasm in Makkah region, Saudi Arabia. A retrospective epidemiological study.

OBJECTIVES: To improve our local data and demographics of thyroid neoplasm in Makkah region, Kingdom of Saudi Arabia and provide some basic statistics for future studies in our local community.  Methods: A record based retrospective epidemiological study was conducted and included 314 thyroid disease patients who were presented to our centers at Makkah region, Kingdom of Saudi Arabia between December 2009 and December 2019. Results: A descriptive statistical analysis was carried out. The average age was 42.77 years, with a female-to-male ratio of 3:1, and most of the patients were Saudi (77%). Fifty-seven percent of cases were benign, while in malignant cases, 33.4% were papillary thyroid carcinoma. The mean follow-up time was 15.44 months, with excellent compliance in 39.4% of the patients.   Conclusion: Thyroid tumors have a leading incidence in head and neck tumors in Makkah, Kingdom of Saudi Arabia, mandating further studies to determine the causes and distribution in other regions of the country.

Papillary thyroid carcinoma in children with Hashimoto's thyroiditis - a review of the literature between 2000 and 2020.

OBJECTIVES: Thyroid cancer is the most common pediatric endocrine neoplasm representing 3% of all malignancies in children. Hashimoto's thyroiditis (HT) is also a common disorder in the pediatric age range. Patients with HT frequently develop enlarged thyroid with nodules. We aimed to provide a literature review on the frequency of papillary thyroid carcinoma (PTC) in patients with HT. CONTENT: A literature search of the PubMed database between 2000 and 2020 was performed, using the relevant keywords "papillary thyroid carcinoma," "Hashimoto's thyroiditis" and "children". We followed the PRISMA statement guidelines during the preparation of this review. Six studies (n=2,065 patients with HT) were retained for the final analysis. The follow-up of the patients with HT was from 2 to 10 years. PTC was diagnosed in 0.67-7.87% of the HT patients included in these studies. In patients with HT and nodules, the percentage of PTC varied between 5.13 and 35%. The overall occurrence of PTC in patients with HT was 3.07%. SUMMARY AND OUTLOOK: The number of patients developing thyroid nodules in relation to HT was increased. The development of PTC in children with HT appeared to be higher than in the normal population.

Immortalization up-regulated protein promotes tumorigenesis and inhibits apoptosis of papillary thyroid cancer.

The incidence of thyroid cancer is increasing in recent years worldwide, but the underlying mechanisms await further exploration. We utilized the bioinformatic analysis to discover that Immortalization up-regulated protein (IMUP) could be a potential oncogene in the papillary thyroid cancer (PTC). We verified this finding in several databases and locally validated cohorts. Clinicopathological features analyses showed that high expression of IMUP is positively related to malignant clinicopathological features in PTC. Braf-like PTC patients with higher IMUP expression had shorter disease-free survival. The biological function of IMUP in PTC cell lines (KTC-1 and TPC-1) was investigated using small interfering RNA. Our results showed that silencing IMUP suppresses proliferation, migration and invasion while inducing apoptosis in PTC cell lines. Changes of the expression of apoptosis-related molecules were identified by real-time quantitative polymerase chain reaction and Western blotting. We also found that YAP1 and TAZ, the critical effectors in the Hippo pathway, were down-regulated when the IMUP is silenced. Rescue experiments showed that overexpression of YAP1 reverses the tumour inhibitory effect caused by IMUP knockdown. Our study demonstrated that IMUP has an oncogenic function in PTC and might be a new target gene in the treatment of PTC.

Transcriptome network of the papillary thyroid carcinoma radiation marker CLIP2.

BACKGROUND: We present a functional gene association network of the CLIP2 gene, generated by de-novo reconstruction from transcriptomic microarray data. CLIP2 was previously identified as a potential marker for radiation induced papillary thyroid carcinoma (PTC) of young patients in the aftermath of the Chernobyl reactor accident. Considering the rising thyroid cancer incidence rates in western societies, potentially related to medical radiation exposure, the functional characterization of CLIP2 is of relevance and contributes to the knowledge about radiation-induced thyroid malignancies. METHODS: We generated a transcriptomic mRNA expression data set from a CLIP2-perturbed thyroid cancer cell line (TPC-1) with induced CLIP2 mRNA overexpression and siRNA knockdown, respectively, followed by gene-association network reconstruction using the partial correlation-based approach GeneNet. Furthermore, we investigated different approaches for prioritizing differentially expressed genes for network reconstruction and compared the resulting networks with existing functional interaction networks from the Reactome, Biogrid and STRING databases. The derived CLIP2 interaction partners were validated on transcript and protein level. RESULTS: The best reconstructed network with regard to selection parameters contained a set of 20 genes in the 1st neighborhood of CLIP2 and suggests involvement of CLIP2 in the biological processes DNA repair/maintenance, chromosomal instability, promotion of proliferation and metastasis. Peptidylprolyl Isomerase Like 3 (PPIL3), previously identified as a potential direct interaction partner of CLIP2, was confirmed in this study by co-expression at the transcript and protein level. CONCLUSION: In our study we present an optimized preselection approach for genes subjected to gene-association network reconstruction, which was applied to CLIP2 perturbation transcriptome data of a thyroid cancer cell culture model. Our data support the potential carcinogenic role of CLIP2 overexpression in radiation-induced PTC and further suggest potential interaction partners of the gene.

Papillary and Follicular Thyroid Cancer in children and adolescents: Current approach and future directions.

An increasing number of children are diagnosed with differentiated thyroid cancer. With an excellent prognosis for the majority of pediatric patients, the goal of therapy is to optimize outcome while reducing complications. Increased knowledge of the somatic, oncogenic driver mutations provides opportunities to improve the accuracy of diagnosis, to stratify surgery, and to treat patients with morbidly invasive or refractory disease. Treatment complications can be reduced by referral to regional, high-volume pediatric thyroid centers.

Thyroid cancer associated with Hashimoto thyroiditis: similarities and differences in an endemic area.

BACKGROUND: Hashimoto thyroiditis (HT) is an autoimmune lymphocytic thyroiditis and is the most common form of thyroid inflammatory diseases. The association of HT with papillary thyroid carcinoma (PTC) has been described. PTC is the most common form of malignancy associated with HT. When papillary carcinoma develops on top of Hashimoto thyroiditis, the disease tends to be less aggressive and lymph node and extra-thyroidal invasion are infrequent. RESULTS: We retrospectively examined the pathological features of our patients who were diagnosed with concomitant HT and thyroid cancer. In Egyptian patients, PTC was the main type of malignancy associated with HT (96.2%) and was often multifocal (46.2%). In contrast to the published literature, lymph node invasion and extra-thyroidal extension were as frequent in association with HT as in other cancer cohorts. We also observed the frequent occurrence of Hürthle cell metaplasia (23.1%) and the appreciable incidence of aggressive histological types of PTC (32%). CONCLUSION: Thyroid carcinoma with HT may have some aggressive features in areas with endemic goiter background.