Emerging Biomarkers in Thyroid Practice and Research

Thyroid cancer is the most common endocrine malignancy. Recent developments in molecular biological techniques have led to a better understanding of the pathogenesis and clinical behavior of thyroid neoplasms. This has culminated in the updating of thyroid tumor classification, including the re-categorization of existing and introduction of new entities. In this review, we discuss various molecular biomarkers possessing diagnostic, prognostic, predictive and therapeutic roles in thyroid cancer. A comprehensive account of epigenetic dysregulation, including DNA methylation, the function of various microRNAs and long non-coding RNAs, germline mutations determining familial occurrence of medullary and non-medullary thyroid carcinoma, and single nucleotide polymorphisms predisposed to thyroid tumorigenesis has been provided. In addition to novel immunohistochemical markers, including those for neuroendocrine differentiation, and next-generation immunohistochemistry (BRAF V600E, RAS, TRK, and ALK), the relevance of well-established markers, such as Ki-67, in current clinical practice has also been discussed. A tumor microenvironment (PD-L1, CD markers) and its influence in predicting responses to immunotherapy in thyroid cancer and the expanding arena of techniques, including liquid biopsy based on circulating nucleic acids and plasma-derived exosomes as a non-invasive technique for patient management, are also summarized.

Chinese Interest in Thyroid Related Diseases: Evidence from Baidu Index

Background: Common thyroid diseases are hyperthyroidism, hypothyroidism, thyroiditis, thyroid tumor and so on. Baidu is currently the most widely used online search tool in China, has developed an internet search trends collection and analysis tool called the Baidu Index. The aim of the present study was to understand the trend and characteristics of public’s online attention to thyroid diseases, and to explore the value of Baidu Index in monitoring online retrieval behavior of thyroid related information.Methods: Taking the period from January 1, 2011 to December 31, 2019 as the time range into consideration, we used the big data analysis tool of Baidu Index and took “thyroid nodules”, “thyroid cancer”, “thyroiditis” “hyperthyroidism” and “hypothyroidism” as the keywords, the data of “search index” and “media index” were recorded on a weekly basis, and all information were aggregated into quarterly and annual to generate the final data which was carried out for secondary analysis. Pearson correlation analysis was used to analyze the correlation between the search index of keywords and the year. One-way Analysis of Variance was used to analyze the differences between search index and media index.Results: Among the five keywords, thyroid nodule search index had the highest growth rate (640%), followed by thyroid cancer (298%). The media’s attention to thyroid diseases had been declining year by year. Unlike the public’s attention, the media index of hyperthyroidism was significantly higher than other keywords.Conclusion: Over the past nine years, the public's attention to thyroid related diseases has been increasing gradually. Baidu Index is an effective tool to track the health information query behavior of Chinese internet users, which can provide a cost-effective supplement to traditional monitoring system.

The modified transmanubrial approach in thyroid malignant tumors: an optimal and less invasive surgical option.

- We retrospectively evaluated a large series of patients (n: 15) underwent a modified transmanubrial approach for wide mediastinal resection in case of malignance thyroid mass - In fourteen cases, also with thyroid tumor involving the middle line. A bilateral mTMA was necessary to perform a cava vein resection. - No major postoperative and cutaneous/sternum complications were detected. - mTMA allows an optimal exposure of the upper thoracic inlet achieving a complete radical oncological resection of the tumor/lymph-node and a safety vascular/tracheal control. - As a limitation, the modified mTMA is anatomically more demanding and not familiar for most surgeons in comparison to sternotomy

Case Report and Systematic Review: Sarcomatoid Parathyroid Carcinoma—A Rare, Highly Malignant Subtype

BackgroundParathyroid carcinoma (PC) is a rare malignancy, the incidence of which is less than 1/1 million per year. Sarcomatoid parathyroid carcinoma (SaPC) is an extremely peculiar subtype; only three cases have been reported internationally. It consists of both malignant epithelial components and sarcomatoid components (mesenchymal origin) simultaneously. This “confusing” cancer exhibits higher invasiveness, and traditional surgery does not appear to achieve the expectation, which differs significantly from that of general PC.ObjectiveTo characterize the clinicopathologic features of SaPC and explore similarities and differences between SaPC and general PC.Materials and MethodsWe collected clinical data of SaPC cases from our center and literature. The SaPC case in our center was presented. To better understand the characteristics of SaPC, we also reviewed clinical information in general PC cases from our center and literature within the last 5 years, and a systematic review was performed for further comparison.ResultsA 60-year-old woman was admitted for a neck mass and hoarseness. After the surgery, she was confirmed as SaPC and ultimately developed local recurrence at 3 months. Together with the reported cases from literature, four cases of SaPC (three cases from literature) and 203 cases of general PC (200 cases from literature) were reviewed. Both tumors showed obvious abnormalities in parathormone (PTH) level and gland size. Compared to general PC, SaPC has a later age of onset (60.50 ± 7.42 vs. 51.50 ± 8.29), relatively low levels of PTH (110.28 ± 59.32 vs. 1,156.07 ± 858.18), and a larger tumor size (6.00 ± 1.63 vs. 3.14 ± 0.70). For SaPC, all four cases were initially misdiagnosed as thyroid tumors (4/4). Spindle cell areas or transitional zones were common pathological features in SaPC cases (3/4).ConclusionSaPC is a very rare pathologic subtype of PC and appears to be much more easily misdiagnosed as a thyroid tumor. Spindle cell areas or transitional zones are highly possible to be pathological features in its sarcomatoid components. Despite many similarities, there are some differences between SaPC and general PC—SaPC does not show the obvious endocrine feature but stronger aggressiveness. Surgical treatment of SaPC does relieve life-threatening symptoms and improve quality of life even with recurrence in the short term.

Single neonatal irradiation induces long-term gene expression changes in the thyroid gland, which may be involved in the tumorigenesis

Exposure to ionizing radiation in childhood has been recognized as a risk factor for thyroid cancer. We previously demonstrated that neonatal X-irradiation induced specific deformation of the thyroid follicles. Here, we further analyzed this model to understand the possible relationship with thyroid carcinogenesis. Wistar rats were subjected to cervical X-irradiation at different ages of 1–8 weeks old and at different doses of 1.5–12 Gy. For tumor promotion, rats were fed with an iodine-deficient diet (IDD). In cervically X-irradiated neonatal rats, the size of thyroid follicles decreased, accompanied by an increase in the number of TUNEL-positive cells. Fas and Lgals3 mRNA levels increased, while Mct8 and Lat4 expressions decreased. The co-administration of IDD induced the proliferation and the upregulation in Lgals3 expression, resulting in thyroid adenoma development at 28 weeks post-exposure. Our data demonstrated that single neonatal X-irradiation induced continuous apoptotic activity in the thyroid with the long-term alternation in Fas, Mct8, Lat4, and Lgals3 mRNA expressions. Some of these changes were similar to those induced by IDD, suggesting that neonatal X-irradiation may partially act as a thyroid tumor promoter. These radiation-induced thyroidal changes may be enhanced by the combined treatment with IDD, resulting in the early development of thyroid adenoma.

Towards Optimized Bioavailability of 99mTc-Labeled Barbiturates for Non-invasive Imaging of Matrix Metalloproteinase Activity

Introduction Dysregulated activity of matrix metalloproteinases (MMPs) drives a variety of pathophysiological conditions. Non-invasive imaging of MMP activity in vivo promises diagnostic and prognostic value. However, current targeting strategies by small molecules are typically limited with respect to the bioavailability of the labeled MMP binders in vivo. To this end, we here introduce and compare three chemical modifications of a recently developed barbiturate-based radiotracer with respect to bioavailability and potential to image MMP activity in vivo. Methods Barbiturate-based MMP inhibitors with an identical targeting unit but varying hydrophilicity were synthesized, labeled with technetium-99m, and evaluated in vitro and in vivo. Biodistribution and radiotracer elimination were determined in C57/BL6 mice by serial SPECT imaging. MMP activity was imaged in a MMP-positive subcutaneous xenograft model of human K1 papillary thyroid tumors. In vivo data were validated by scintillation counting, autoradiography, and MMP immunohistochemistry. Results We prepared three new 99mTc‐labeled MMP inhibitors, bearing either a glycine ([99mTc]MEA39), lysine ([99mTc]MEA61), or the ligand HYNIC with the ionic co-ligand TPPTS ([99mTc]MEA223) yielding gradually increasing hydrophilicity. [99mTc]MEA39 and [99mTc]MEA61 were rapidly eliminated via hepatobiliary pathways. In contrast, [99mTc]MEA223 showed delayed in vivo clearance and primary renal elimination. In a thyroid tumor xenograft model, only [99mTc]MEA223 exhibited a high tumor-to-blood ratio that could easily be delineated in SPECT images. Conclusion Introduction of HYNIC/TPPTS into the barbiturate lead structure ([99mTc]MEA223) results in delayed renal elimination and allows non-invasive MMP imaging with high signal-to-noise ratios in a papillary thyroid tumor xenograft model.

Single-port transaxillary robotic thyroidectomy (START): 200-cases with two-step retraction method

Background This study aims to report the results of a pioneering clinical study using the single-port transaxillary robotic thyroidectomy (START) for 200 patients with thyroid tumor and to introduce our novel two-step retraction method. Methods START was performed on consecutive 200 patients using the da Vinci Single-Port (SP) robot system from January 2019 to September 2020 at the Yonsei University Health System, Seoul, Korea. The novel two-step retraction technique, in which a 3.5 cm long incision is made along the natural skin crease, was used for the latter 164 patients. The surgical outcome and invasiveness of the SP two-step retraction method were analyzed. Results Among the 200 cases who underwent START, 198 were female and 2 were male, with a mean age of 34.7 (range: 13–58 years). Thyroid lobectomy was performed for 177 patients and total thyroidectomy was performed for 23 patients. Ten patients had benign thyroid nodules, whereas the other 190 had thyroid malignancy. The mean body mass index (BMI) was 22.2 ± 3.7 kg/m2 (range: 15.9–37.0 kg/m2). All of the operations were performed successfully without any open conversions, and patients were discharged on postoperative day 3 or 4 without significant complication. The mean operative time for thyroid lobectomy with the two-step retraction method was 116.69 ± 23.23 min, which was similar to that in the conventional robotic skin flap method (115.33 ± 17.29 min). We could minimize the extent of the robotic skin flap dissection with the two-step retraction method. Conclusions START is a practical surgical method. By employing the new two-step retraction method, we can maximize the cosmetic and functional benefits for patients and reduce the workload fatigue of surgeons by increasing robotic dependency.

Environmental Paraben Exposure and Risk of Thyroid Cancer and Benign Nodules: A Pilot Study

Parabens are widely used as preservatives, which have been found to affect thyroid function in toxicological studies. However, population studies on whether they are associated with thyroid tumor remain unclear. This study aims to investigate the relationship between environmental paraben exposure and thyroid cancer and benign nodules. The detectable percentages of methyl paraben, ethyl paraben, and propyl paraben in the urinary samples of 425 study subjects were 99.06%, 95.29% and 92.00%, respectively. In the single pollutant model, we found statistically significant difference between certain parabens and thyroid cancer/ benign nodules. Further, we found the mixture effect of parabens on increased risk of thyroid cancer (OR = 0.24, 95% CI: 0.18, 0.31) and benign nodule (OR =1.33, 95% CI: 0.86, 1.80). The significant gender-associated effects were found in associations with certain parabens and thyroid cancer and benign nodules (Both P for interactions < 0.05). Overall, our results showed that individual exposure of paraben mixtures may be associated with the risk of thyroid cancer and benign nodules, and there were gender differences.

Explore the Diagnostic Efficiency of Chinese Thyroid Imaging Reporting and Data Systems by Comparing With the Other Four Systems (ACR TI-RADS, Kwak-TIRADS, KSThR-TIRADS, and EU-TIRADS): A Single-Center Study

PurposeTo explore the characteristics of C-TIRADS by comparing it with ACR-TIRADS, Kwak-TIRADS, KSThR-TIRADS and EU-TIRADS.MethodsA total of 1096 nodules were collected from 884 patients undergoing thyroidectomy in our center between May 2018 and December 2020. Divided the nodules into two groups: “&gt;10mm” and “≤10mm”. Ultrasound characteristics of each nodule were observed and recorded by 2 doctors, then classified based on ACR-TIRADS, Kwak-TIRADS, KSThR-TIRADS, EU-TIRADS, and C-TIRADS.ResultsA total of 682 benign nodules cases (62.23%) and 414 malignant nodules cases (37.77%) were identified. The ICC value of each guideline was:0.937(ACR-TIRADS), 0.858(EU-IRADS), 0.811(Kwak-TIRADS), 0.835(KTA/KSThR-TIRADS) and 0.854(C-TIRADS). The nodule malignancy rates in the groups(Kwak-TIRADS 4B, C-TIRADS 4B、4C) of two sizes were significantly different (all p&lt;0.05). There was no statistical difference in the other grades of two sizes (all p&gt;0.05). Unnecessary biopsy rates were the lowest in C-TIRADS (49.02% p&lt;0.001). Furthermore, Kwak-TIRADS had the highest sensitivity and NPV (89.9%, 91.0%, all p&lt;0.05), while C-TIRADS had the highest specificity and PPV (82.3%, 69.2%, all p&lt;0.05). C-TIRADS and Kwak-TIRADS had the highest accuracy (76.0%, 72.5%, P=0.071). The AUCs of the 5 guidelines were C-TIRADS(0.816, P&lt;0.05), Kwak-TIRADS(0.789, P&lt;0.05) KTA/KSThR-TIRADS and ACR-TIRADS(0.773, 0.763, P=0.305), EU-TIRADS(0.734, P&lt;0.05). The AUCs of the five guidelines were not statistically different between “nodules&gt;10mm” and “nodules ≤ 10mm” (all P&gt;0.05).ConclusionsAll five guides showed excellent interobserver agreement. C-TIRADS was slightly efficient than Kwak-IRADS, KTA/KSThR-TIRADS and ACR-TIRADS, and had greater advantages than EU-TIRADS. The diagnostic abilities of the five guidelines for “nodules ≤ 10mm” were not inferior to that of “nodules&gt; 10mm”. C-TIRADS is simple and easy to implement and can provide effective thyroid tumor risk stratification for thyroid nodule diagnosis, especially in China.