Female Papillary Thyroid Cancer Research Articles

Female Papillary Thyroid Cancer Survivors Are at Increased Risk of Adenomyosis and Endometrial Hyperplasia.

Thyroid cancer (TC) is the most common endocrine cancer worldwide, affecting mainly women of reproductive age. However, no data exist about its association with endometrial or uterine disorders. This study aimed to assess the risk of hyperproliferative pathology of the reproductive system in female ТС survivors. This was a cross-sectional study of female patients aged 20-45 years diagnosed with papillary TC (PTC) from 1994-2018. Age-matched females with normal thyroid structures served as controls. One hundred and sixteen patients (mean age 36.7±61 years) and 90 age-matched controls were included. PTC survivors demonstrated an increased risk for adenomyosis [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.3-4.8] and endometrial hyperplasia (OR 3.9, 95% CI 1.1-14.3), compared with controls. The risk for adenomyosis was higher after the ten post-operative years (OR 5.3, 95% CI 2.29- 12.05) than during the first 5-10 years (OR 2.3, 95% CI 1.02-5.10) and increased with the number of RAI courses and the degree of TSH suppression. The risk of endometrial hyperplasia was most evident during the first five years post-thyroidectomy (OR 6.0, 95% CI 1.4-25.5), especially in patients with TSH <0.1 mU/L (OR 6.8, 95% CI 1.4-33.28) No difference in uterine leiomyomas or endometrial polyps was found between PTC survivors and controls. Female PTC survivors are at increased risk of endometrial hyperplasia and adenomyosis compared with those with normal thyroid structures.

Female papillary thyroid cancer survivors are at increased risk of hyperproliferative pathology of the reproductive system

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Exposure to Polychlorinated Biphenyls and Organochlorine Pesticides and Risk of Thyroid Cancer in Women

Background: Both polychlorinated biphenyls (PCB) and organochlorine pesticides (OCP) have been associated with thyroid hormone disruption, but their relationship to thyroid cancer is not known. Methods: We investigated the relationship between serum PCB and OCP concentrations and papillary thyroid cancer (PTC) in 250 incident female PTC cases and 250 female controls frequency-matched on age, all residing in Connecticut. Interviews and serum samples were collected from 2010-2013. Samples were analyzed for 32 different chemicals using gas chromatography with isotope dilution high resolution mass spectrometry. We calculated odds ratios (OR) and 95% confidence intervals (CI) using single pollutant logistic regression models for concentrations (per interquartile range) of individual PCB/OCP and summed groups of structurally or biologically similar PCB/OCP, adjusted for education, family history of cancer, alcohol consumption, and body mass index. Sub-analyses included stratification by tumor size (&lt;=1 cm and &gt;1 cm) and birth cohort (born before or in 1960 and born after 1960). We also applied three multi-pollutant approaches (standard multi-pollutant regression, hierarchical Bayesian modeling, principal components regression analysis) to investigate associations with exposures to multiple PCB/OCPs. Results: No PCB/OCPs were positively associated with PTC risk in primary analyses. Statistically significant associations were observed for 9 of the 32 chemicals and 3 summed groups of similar chemicals in the younger birth cohort based on single-pollutant models. Multi-pollutant analyses suggested null associations overall. Conclusions: Our results using single and multi-pollutant modeling do not generally support an association between PCB or OCP exposure and PTC risk, but some associations in the younger birth cohort suggest that additional investigation into early-life exposures and subsequent thyroid cancer risk may be warranted.

Exposure to polychlorinated biphenyls and organochlorine pesticides and thyroid cancer in connecticut women

BackgroundThyroid cancer incidence has increased substantially over the past decades, and environmental risk factors have been suggested to play a role. Polychlorinated biphenyls (PCB) and organochlorine pesticides (OCP) are established thyroid hormone disruptors, but their relationship to thyroid cancer is not known. MethodsWe investigated the relationship between serum PCB and OCP concentrations and papillary thyroid cancer (PTC) in 250 incident female PTC cases and 250 female controls frequency-matched on age, all residing in Connecticut. Interviews and serum samples were collected from 2010 to 2013. Samples were analyzed for 32 different chemicals using gas chromatography with isotope dilution high resolution mass spectrometry. We calculated odds ratios (OR) and 95% confidence intervals (CI) using single pollutant logistic regression models for concentrations (per interquartile range) of individual PCB/OCP and summed groups of structurally or biologically similar PCB/OCP, adjusted for education, family history of cancer, alcohol consumption, age, and body mass index. Sub-analyses included stratification by tumor size (≤ and >1 cm) and birth before or during peak PCB production (born in 1960 or earlier and born after 1960), as exposures during early life may be important. We also applied three multi-pollutant approaches (standard multi-pollutant regression, hierarchical Bayesian modeling, principal components regression analysis) to investigate associations with co-exposures to multiple PCB/OCPs. ResultsNo PCB/OCPs were positively associated with PTC in primary analyses. Statistically significant associations were observed for 9 of the 32 chemicals and 3 summed groups of similar chemicals in the those born during peak production based on single-pollutant models. Multi-pollutant analyses suggested null associations overall. ConclusionsOur results using single and multi-pollutant modeling do not generally support an association between PCB or OCP exposure and PTC, but some associations in those born during peak production suggest that additional investigation into early-life exposures and subsequent thyroid cancer risk may be warranted.

Exposure to Polybrominated Diphenyl Ethers and a Polybrominated Biphenyl and Risk of Thyroid Cancer in Women: Single and Multi-Pollutant Approaches.

Thyroid cancer incidence is the most rapidly increasing malignancy; rates are three times higher in women than men. Thyroid hormone-disrupting flame-retardant chemicals, including polybrominated diphenyl ethers (PBDE) and polybrominated biphenyls (PBB), may contribute to this trend. We investigated the relationship between PBDE/PBB exposure and papillary thyroid cancer (PTC) in 250 incident female papillary thyroid cancer cases and 250 female controls frequency-matched on age. Interviews and postdiagnostic serum samples were collected from 2010 to 2013. Serum samples were analyzed for 11 congeners. We calculated ORs and 95% confidence intervals (95% CI) using single-pollutant logistic regression models for continuous and categorical lipid-adjusted serum concentrations of PBDE/PBB, adjusted for age, alcohol consumption, and education. We applied three multi-pollutant approaches [standard multipollutant regression models, hierarchical Bayesian logistic regression modeling (HBLR), principal components analysis (PCA)] to investigate associations with PBDE/PBB mixtures. In single-pollutant models, a decreased risk was observed at the highest (>90th percentile) versus lowest (<median) category of BDE-209 concentrations (OR, 0.47; 95% CI, 0.23-0.98); an elevated PTC risk was observed at the highest versus lowest category of BB-153 concentrations (OR, 1.81; 95% CI, 0.96-3.39). In standard multi-pollutant models, an interquartile range increase in BDE-100 concentrations was associated with increased PTC risk (OR, 1.18; 95% CI, 1.01-1.38). HBLR and PCA yielded no statistically significant results. Our results using single- and multi-pollutant modeling do not generally support a positive association with PBDE/PBB and PTC risk. Prospective studies with more advanced statistical approaches to analyze mixtures and populations with higher exposures could reveal new insights.

Identification of β-hydroxybutyrate as a potential biomarker for female papillary thyroid cancer.

Aim: β-Hydroxybutyrate (BHB) was proved to be a differential metabolite of papillary thyroid cancer (PTC) by semiquantitative analysis, while whether BHB could be used as a potential biomarker for female PTC still needed to be validated. Materials & methods: An LC-MS/MS method with surrogate matrix was established to validate serum BHB in specified PTC patients. Conclusion: Serum BHB levels in PTCs were significantly higher than those in HCs. For both serum BHB with a cut-off value of 312.5 ng/ml and serum BHB/creatinine of 33.5 μmol/mmol, a promising prediction rate to distinguish low-grade PTCs from HCs with satisfactory sensitivity and specificity was achieved,indicating that serum BHB might be proved as a useful biomarker for low-grade female PTC.

Active and Passive Smoking, BRAFV600E Mutation Status, and the Risk of Papillary Thyroid Cancer: A Large-Scale Case-Control and Case-Only Study.

PurposeThe association between tobacco smoking and thyroid cancer remains uncertain. We evaluated the associations of active and passive smokingwith the risk of papillary thyroid cancer (PTC), the most common type of thyroid cancer, and with the BRAFV600E mutation, the most common oncogenic mutation in PTC related to poor prognosis.Materials and MethodsWe conducted this study with newly diagnosed PTC patients (n=2,142) and community controls (n=21,420) individually matched to cases for age and sex. Information on active and passive smoking and potential confounders were obtained from structured questionnaires, anthropometric measurements, and medical records. BRAFV600E mutation status was assessed in PTC patients. We evaluated the associations of active and passive smoking with PTC and BRAFV600E mutation risk using conditional and unconditional logistic regression models, respectively.ResultsWe did not find associations between exposure indices of active and passive smoking and PTC risk in both men and women, except for the association between current smoking and lower PTC risk. Cumulative smoking ≥ 20 pack-years was associated with lower BRAFV600E mutation risk in male PTC patients (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.30 to 1.00). The CI for the association was wider in female PTC patients (OR, 0.23; 95% CI, 0.02 to 2.62), possibly owing to a smaller sample size in this stratum.ConclusionWe did not find consistent associations between active and passive smoking and PTC risk. Cumulative smoking ≥ 20 pack-years was associated with lower BRAFV600E mutation risk in male PTC patients.

High iodine intake and central lymph node metastasis risk of papillary thyroid cancer

The relationship between iodine intake and clinicopathologic characteristics of papillary thyroid cancer (PTC) is unclear. We aim to investigate the relationship between iodine intake and central lymph node metastasis (CLNM) of PTC. A total of 4040 consecutive patients with PTC receiving thyroidectomy and central lymph node dissection were enrolled from 2013 to 2018. Pathological features of tumors and urinary iodine concentration (UIC) were recorded. Multivariate analysis was performed to investigate the association between iodine intake and CLNM of PTC. More than adequate (UIC: 200.0-299.9 μg/L) and excessive iodine intake (UIC ≥ 300.0 μg/L) were present in 1741 cases (43.09%). Iodine deficiency (UIC ≤ 99.9 μg/L) was inversely associated with female PTC risk only with OR (95% CI): 0.48 (0.29–0.80) relative to adequate iodine intake (UIC: 100.0–199.9 μg/L). However, more than adequate and excessive iodine intake was not associated with PTC risk among the general population and patients with thyroid nodules. In addition, high iodine intake was not associated CLNM risk of PTC. After defining CLNM as metastatic lymph nodes ≥ 2, excessive iodine intake was marginally associated with CLNM among female PTC patients with OR (95% CI): 1.25 (0.99–1.57) by multivariate analysis. Additionally, excessive iodine intake was marginally associated with larger tumor size and capsular invasion. Furthermore, we found that female PTC patients were more closely linked with iodine intake than male ones. In conclusion, high iodine intake appears not to be an initiator, but may be a weak promoter for female PTC progression, which needs further validation.

Thyroid Uptake and Effective Half-Life of Radioiodine in Thyroid Cancer Patients at Radioiodine Therapy and Follow-Up Whole-Body Scintigraphy Either in Hypothyroidism or Under rhTSH.

Adjuvant radioiodine therapy (RITh) for differentiated thyroid carcinoma is performed either with thyroid hormone withdrawal or with administration of recombinant human thyroid-stimulating hormone (rhTSH). Heterogeneous results have been obtained on the impact of the method of patient preparation on thyroid uptake and whole-body effective half-life. A higher radiation exposure using thyroid hormone withdrawal for several weeks compared with rhTSH was reported in prior studies. It was the aim to examine whether these findings are reproducible in a modern protocol with a short interval between surgery and RITh. Methods: A retrospective study was performed on patients admitted for adjuvant RITh for differentiated thyroid carcinoma at the University Hospital of Cologne over a 5-y period from 2010. Dose rate measurements were analyzed for 366 patients, and subgroup analyses were performed for papillary thyroid cancer (n = 341) and follicular thyroid cancer (n = 25) patients, sex, length of hypothyroidism, and normal versus decreased glomerular filtration rate (GFR). Results: The median interval between surgery and RITh was 18 d for thyroid hormone withdrawal and 25 d for rhTSH (P < 0.01). The mean thyroid uptake was 4.2% ± 1.8% for the 300 hypothyroid patients versus 3.8% ± 1.6% (P = 0.12) for the 66 rhTSH patients. Whole-body half-life in the hypothyroid group was significantly longer at 19.3 ± 7.7 h versus 16.4 ± 4.6 h in the rhTSH group (P < 0.01). Results were predominantly influenced by data from the largest subgroup, that is, female papillary thyroid cancer patients. Within this group, whole-body half-life was significantly shorter in the rhTSH treatment arm. Duration of hypothyroidism and a decrease in GFR less than 60 mL/min/1.73 m2 significantly influenced results, with an increased whole-body half-life occurring in the hypothyroid group. When patients returned for whole-body scintigraphy, thyroid, half-life, and whole-body half-life were significantly shorter in the rhTSH groups, resulting in a low thyroid and remaining-body dose. Conclusion: With a shortening of the time between surgery and adjuvant RITh, thyroid uptake is not significantly changed but whole-body half-life becomes longer in the hypothyroid group. Radiation exposure for most patients is not significantly different. However, patients with a hypothyroid phase of more than 4 wk, and in particular those with a decreased GFR, experience higher radiation exposure.

High Urinary Iodine, Thyroid Autoantibodies, and Thyroid-Stimulating Hormone for Papillary Thyroid Cancer Risk.

Thyroid nodules have become a common clinical problem, and the clinical importance of thyroid nodules lies in the determination of thyroid cancer. This study aims to evaluate the risk factors for papillary thyroid cancer (PTC) with regard to urinary iodine concentration (UIC), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TGAb) in comparison to thyroid nodular goiter (NG). Among the 2041 patients, 43.8% of which showed more than adequate (UIC 200-299μg/L) and excessive iodine (UIC ≥ 300.0μg/L) status. Compared with adequate iodine intake, iodine deficiency (UIC < 100μg/L) was inversely associated with multifocality (OR 0.59, P = 0.040), while more than adequate iodine intake was independently associated with an increased risk of larger tumor size (OR 1.33, P = 0.002) in female PTC patients but not in males. No significant difference in UIC was observed between patients with PTC and NG, suggesting that high iodine intake may be related with the growth of PTC, but not with its oncogenesis. Besides, positive for TPOAb and TGAb were individually associated with papillary thyroid microcarcinoma (PTMC) risk (OR 2.05 and 1.71, respectively, both P < 0.05) in female patients with tumor foci < 1cm but not in males. Furthermore, younger age (< 46years), TGAb positivity and small thyroid nodules in both sexes, higher TSH, TPOAb positivity, and multifocality in females could all predict PTC risk (all P < 0.05). These results might have clinical significance for managing patients with thyroid nodules and those with thyroidectomy.

Upregulation of the ESR1 Gene and ESR Ratio (ESR1/ESR2) is Associated with a Worse Prognosis in Papillary Thyroid Carcinoma: The Impact of the Estrogen Receptor α/β Expression on Clinical Outcomes in Papillary Thyroid Carcinoma Patients.

A gender disparity exists with respect to the incidence of papillary thyroid cancer (PTC), suggesting that sex hormones such as estrogen play a role in PTC development and progression. In this study, we compared estrogen receptor gene expression patterns in PTCs to determine the clinical significance of estrogen gene expression in PTC. We analyzed ESR1 and ESR2 messenger RNA expression counts using data from The Cancer Genome Atlas (TCGA). To validate the results of TCGA analysis, we analyzed microarray data (GSE 54958) from the Gene Expression Omnibus. ESR1 gene expression and ESR ratio (ESR1/ESR2) were significantly higher in PTC tissues than in paired normal thyroid tissues (mean 659.427 vs. 264.045 for ESR1, 92.017 vs. 19.064 for ESR ratio). Among female patients, ESR1 expression and ESR ratio were negatively correlated with increased age. ESR1 expression and ESR ratio were higher in patients with classic PTC, lymphovascular invasion, BRAF V600E mutation, and radioiodine therapy. Classification analysis demonstrated that higher ESR1 expression and a higher ESR ratio faced a worse overall survival (hazard ratio 6.348 for ESR1, 4.031 for ESR ratio). Validation microarray analysis demonstrated that ESR1 expression and ESR ratio were higher in tumor tissues, classic PTC, and BRAF V600E. Higher ESR1 expression and a higher ESR ratio were associated with aggressive prognostic factors and worse overall survival in female PTC patients. Our results suggest that ESR1 and ESR ratio can be used as prognostic markers to predict female patient survival and have potential as a therapeutic target.

Differential expression patterns and clinical significance of estrogen receptor-α and β in papillary thyroid carcinoma

BackgroundThe incidence of papillary thyroid cancer (PTC) is markedly higher in women than men during the reproductive years. In vitro studies have suggested that estrogen may play an important role in the development and progression of PTC through estrogen receptors (ERs). This study aimed to investigate the expression patterns of the two main ER subtypes, α and β1 (wild-type ERβ), in PTC tissue and their clinical significance.MethodsImmunohistochemical staining of thyroid tissue sections was performed to detect ER expression in female patients with PTC (n = 89) and nodular thyroid goiter (NTG; n = 30) using the Elivision™ plus two-step system. The relationships between ER subtype expression and clinicopathological/biological factors were further analyzed.ResultsThe positive percentage and expression levels of ERα were significantly higher in female PTC patients of reproductive age (18–45 years old; n = 50) than age-matched female NTG patients (n = 30), while ERβ1 exhibited the opposite pattern. There was no difference in ERα or ERβ1 expression between female PTC patients of reproductive age and those of advanced reproductive age (>45 years old; n = 39). In the female PTC patients of reproductive age, ERα expression level was positively correlated with that of Ki-67, while ERβ1 was negatively correlated with mutant P53. Furthermore, more patients with exclusively nuclear ERα expression had extrathyroidal extension (ETE) as compared with those with extranuclear ERα localization. VEGF expression was significantly decreased in female PTC patients of reproductive age with only nuclear ERβ1 expression when compared with those with extranuclear ERβ1 localization. In PTC patients of advanced reproductive age, neither ERα nor ERβ1 expression showed any correlation with that of Ki-67, mutant P53, VEGF, tumor size, TNM stage, ETE, or lymph node metastases.ConclusionsThe differential expression patterns of the two ER subtypes between PTC and NTG indicate that ERα may be a useful immunohistochemical marker for differential diagnosis of PTC. The associations of ER subtype expression with Ki-67, mutant P53, VEGF expression and ETE in female PTC patients of reproductive age suggest that estrogen-activated ERα may mediate stimulatory effects on PTC growth and progression whereas ERβ1 has some inhibitory actions.

Association of ATM Gene Polymorphism with PTC Metastasis in Female Patients.

Ataxia telangiectasia mutated (ATM) gene is critical in the process of recognizing and repairing DNA lesions and is related to invasion and metastasis of malignancy. The incidence rate of papillary thyroid cancer (PTC) has increased for several decades and is higher in females than males. In this study, we want to investigate whether ATM polymorphisms are associated with gender-specific metastasis of PTC. 358 PTC patients in Northern China, including 109 males and 249 females, were included in our study. Four ATM single nucleotide polymorphisms (SNPs) were genotyped using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). Association between genotypes and the gender-specific risk of metastasis was assessed by odds ratios (OR) and 95% confidence intervals (CI) under the unconditional logistic regression analysis. Significant associations were observed between rs189037 and metastasis of PTC in females under different models of inheritance (codominant model: OR = 0.15, 95% CI 0.04–0.56, P = 0.01 for GA versus GG and OR = 0.08, 95% CI 0.01–0.74, P = 0.03 for AA versus GG, resp.; dominant model: OR = 0.49, 95% CI 0.25–0.98, P = 0.04; overdominant model: OR = 0.47, 95% CI 0.25–0.89, P = 0.02). However, no association remained significant after Bonferroni correction. Our findings suggest a possible association between ATM rs189037 polymorphisms and metastasis in female PTCs.

No association between immunohistochemical expression of p53, c- erbB-2, Ki-67, estrogen and progesterone receptors in female papillary thyroid cancer and ionizing radiation

An association has previously been reported between exposure to medical diagnostic ionizing radiation and papillary thyroid cancer in women. To further evaluate potential mechanisms in carcinogenesis, the expression of p53, c- erbB-2, as well as Ki-67, estrogen and progesterone receptors were analyzed by immunohistochemistry in 19 women exposed to X-rays and for comparison in nine women without such reported exposure. They all had papillary thyroid cancer. No difference was found between these groups. The results of this study showed that p53, c- erbB-2, Ki-67, estrogen and progesterone receptors are not involved in papillary thyroid cancer associated with exposure to medical diagnostic ionizing radiation.

Diagnostic X-ray exposure and female papillary thyroid cancer: a pooled analysis of two Swedish studies.

The aim of the present study was to evaluate the risk for female papillary thyroid cancer from occupational and medical low level radiation exposure. The analyses are based on data from two Swedish case-control studies on determinants for thyroid cancer. One hundred and eighty six thyroid cancer cases, diagnosed during 1977-89 and aged 20-70 years, were collected from cancer registers. Twice as many population controls were selected. Questionnaires were mailed in 1990-91 to living cases and controls. A high risk was found for the occupational group of dentists/dental assistants, odds ratio (OR) = 13.1, 95% confidence interval (CI) = 2.1-389. For all occupational exposure to X-rays OR = 2.1, 95% CI = 1.0-4.4 was obtained. Diagnostic X-ray exposure was associated with increased risk, with a dose-response tendency yielding OR = 2.6, 95% CI = 1.5-5.1 for the highest absorbed thyroid dose (> 1.0 mGy). If only females of 50 years or less at diagnosis were considered, higher ORs were obtained. Increased risks were also found for some site-specific examinations, some of them giving very low radiation dose to the thyroid; more than 10 dental X-rays gave OR = 3.5, 95% CI = 1.6-7.6. A potentiated risk for prior X-rays was seen among women with three or more parities, with OR = 4.7, 95% CI = 1.5-14.8. Exposure to visual display units yielded OR = 2.3, 95% CI = 0.9-5.6. As in all questionnaire-based case-control studies possible recall bias must be considered but is unlikely to cause dose-response patterns and interaction as indicated in this study.

Occupation and Female Papillary Cancer of the Thyroid

This article presents the joint results of two Swedish case-control studies regarding occupational exposure and female papillary thyroid cancer. Questionnaires inquiring about lifetime occupations and specific occupational exposures were mailed to cases and controls, aged 20 to 70 years. Some 185 female papillary or mixed cancer cases and 426 female controls were included in the analysis. Increased risks were seen for women who had worked as a dentist/dental assistant, teacher, shoemaker, or warehouse worker. In addition, occupational contacts with undefined chemicals, x-rays, or video display terminals were indicated as risk factors.