MicroRNAs in thyroid cancer with focus on medullary thyroid carcinoma:potential therapeutic targets and diagnostic/prognostic markers and web based tools

This review aimed to describe the inculpation of microRNAs(miRNAs)in thyroid cancer(TC)and its subtypes,mainly medullary thyroid carcinoma(MTC),and to outline web-based tools and databases for bioinformatics analysis of miRNAs in TC.Additionally,the capacity of miRNAs to serve as therapeutic targets and biomarkers in TC management will be discussed.This review is based on a literature search of relevant articles on the role of miRNAs in TC and its subtypes,mainly MTC.Additionally,web-based tools and databases for bioinformatics analysis of miRNAs in TC were identified and described.MiRNAs can perform as oncomiRs or antioncoges,relying on the target mRNAs they regulate.MiRNA replacement therapy using miRNA mimics or antimiRs that aim to suppress the function of certain miRNAs can be applied to correct miRNAs aberrantly expressed in diseases,particularly in cancer.MiRNAs are involved in the modulation of fundamental pathways related to cancer,resembling cell cycle checkpoints and DNA repair pathways.MiRNAs are also rather stable and can reliably be detected in different types of biological materials,rendering them favorable diagnosis and prognosis biomarkers as well.MiRNAs have emerged as promising tools for evaluating medical outcomes in TC and as possible therapeutic targets.The contribution of miRNAs in thyroid cancer,particularly MTC,is an active area of research,and the utility of web applications and databases for the biological data analysis of miRNAs in TC is becoming increasingly important.

An overview of the contemporary diagnosis and management approaches for anaplastic thyroid carcinoma

Thyroid carcinoma is a complex disease with several types,the most common being well-differentiated and undifferentiated.The latter,“undifferentiated carcinoma”,also known as anaplastic thyroid carcinoma(ATC),is a highly aggr-essive malignant tumor accounting for less than 0.2%of all thyroid carcinomas and carries a poor prognosis with a median survival of 5 months.BRAF gene mutations are the most common molecular factor associated with this type of thyroid carcinoma.Recent advances in targeted biological agents,immuno-therapy,stem cell therapy,nanotechnology,the dabrafenib/trametinib com-bination therapy,immune checkpoint inhibitors(ICI)and artificial intelligence offer novel treatment options.The combination therapy of dabrafenib and tra-metinib is the current standard treatment for patients with BRAF-V600E gene mutations.Besides,the dabrafenib/trametinib combination therapy,ICI,used alone or in combination with targeted therapies have raised some hopes for improving the prognosis of this deadly disease.Younger age,earlier tumor stage and radiotherapy are all prognostic factors for improved outcomes.Ultimately,therapeutic regimens should be tailored to the individual patient based on surveillance and epidemiological data,and a multidisciplinary approach is ess-ential.

Current status of anaplastic thyroid carcinoma

In this editorial we comment on the article by Pavlidis et al,published in the recent issue of the World Journal of Oncology.We focus on the recent contributions in the management of anaplastic thyroid carcinoma,highlighting the importance of surgery and radiotherapy as first line therapies in its management and the introduction of new systemic therapies beyond chemotherapy,focused on molecular alterations,an essential step in the diagnosis and included in clinical guidelines for the selection of the ideal treatment.In contrast to other neoplasms,immunotherapy,is still beginning in studies of this pathology with encouraging results.Therefore,multimodal management of the pathology together with new drugs seems to be the logical step to increase the survival of this neoplasm.

Studies on surgical methods for sporadic micromedullary thyroid carcinoma

Background:To observe the changes in serum calcitonin levels after application of different surgical methods for primary medullary thyroid microcarcinoma(MTMC)and explore a more reasonable surgical method.Methods:A retrospective analysis of 36 patients with MTMC,16 in group A and 20 in group B,was performed.In group A,tumors were single and confined to the thyroid lobe,and thyroid lobectomy with isthmusectomy was performed.In group B,tumors were in the isthmus or invaded the thyroid gland,or there were multiple foci in bilateral lobes,and patients with primary foci underwent total thyroidectomy.The median follow-up time was 3.6 years.Clinical and pathological characteristics and changes in serum calcitonin(CTn)and carcinoembryonic antigen levels after the surgery were compared between the 2 groups.Results:The difference in the biochemical cure rate after surgery was statistically significant between patients with preoperative serum calcitonin levels<150 pg/mL and≥150 pg/mL(P<0.01).No significant differences in the biochemical cure rates and serum calcitonin levels were noted at different time points after surgery between group A and group B(P>0.05).One recurrence and metastasis were observed in each group after surgery.Conclusions:After performing different surgical methods for the primary foci of MTMC,the changes in serum calcitonin and carcinoembryonic antigen levels are similar.Especially for patients with single foci confined to the thyroid lobe without lateral cervical lymph node metastasis and with serum calcitonin levels<150 pg/mL,the unilateral thyroid lobectomy with isthmectomy can achieve the same therapeutic effect and biochemical cure rate as total thyroidectomy.

Childhood Papillary Thyroid Carcinoma: A Case Report

Background: Thyroid cancer is a rare disease yet the most common endocrine malignancy in pediatrics. Unlike adult patients, children with thyroid nodules typically don’t complain of pain, soreness, or difficulty swallowing. Additionally, using the recommended therapy for adults to treat paediatrics is not appropriate. There is an unmet need for updated unique guidelines for the management of papillary thyroid carcinoma (PTC) in paediatrics and adolescents. Case Report: A 12-year-old girl had an atypical presentation of metastatic PTC in lymph nodes. She was treated initially with hemi-thyroidectomy, followed by total thyroidectomy. A multidisciplinary team followed her up till successful results were found. Conclusion: Due to the difference in pathophysiology between thyroid tumors in children and adults, a unique approach to PTC management is to be implemented. Further trials are required for a better understanding of risk factors, the likelihood of recurrence, and the long-term side effects of the chosen management plan.

Investigation of Calcitonin and Calcitonin Gene-related Peptide in 88 Cases of Medullary Thyroid Carcinoma

Objective： To investigate the changes of calcitonin （CT） and calcitonin gene-related peptide （CGRP） in patients with medullary thyroid carcinoma （MTC）. Methods： Fifty-eight cases of MTC were selected and the relationship between the CT levels and metastasis was investigated. The immunohistochemical method was used to detect the expression of CT and CGRP in the 58 samples of MTC tissues. The CT and CGRP in 30 newly diagnosed MTC inpatients were measured before operation and in the first few days after operation using a radioimmunoassy. Results： （1） The rate of residual tumor had a significant difference between the normal serum CT group one month after operation and the elevated group at the same period （P〈0.01）. （2） Immunohistochemical study revealed the positive rate of CT was about 98%, and that of the CGRP was 87.8%. （3） Part of the patients had an elevated CGRP levels while CT levels was normal. （4） The serum CT levels were decreased to a stable range one week after operation. Conclusion： CT is a useful index to evaluate the efficacy of surgical treatment. The measurement of serum CGRP is helpful in the diagnosis of MTC, especially for those whose preoperative CT levels are normal.

Clinical and Sonographic Assessment of Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma

The purpose of this study was to assess the differences in clinical and sonographic features of papillary thyroid carcinoma（PTC） between cervical lymph node metastatic（CLNM） and nonmetastatic groups.Clinical data of PTC patients（414 patients with 624 malignant nodules） who underwent a preoperative ultrasonography and surgery between June 2010 and March 2015 at Renmin Hospital of Wuhan University were retrospectively analyzed.Clinical factors,preoperative ultrasound features and the final pathological findings were obtained.The differences in the sonographic features of PTC between the CLNM group and the non-CLNM group were analyzed.There were 187 CLNM and 227 non-CLNM patients.The median age at the diagnosis of this cohort was 45.4 years old（ranging from 18 to 77 years）.Ultrasonographic parameters that were significantly associated with CLNM [OR=2.569（1.502,4.393）,P〈0.001）] were as follows：the mulifocality of the nodules,size over 2 cm,the presence of microcalcifications,the distance ratio（DR） pattern showing the contact of the nodules with the thyroid capsule,and the extracapsular spread of the nodules.No significant differences in age,gender,thyroid stimulating hormone（TSH） levels and other ultrasonography parameters were found between the CLNM and the non-CLNM groups.Therefore,our results suggest that a larger size,microcalcifications,mulifocality,and the DR pattern showing the contact of the nodules with the thyroid capsule and extracapsular spread are significantly more indicative of CLNM in PTC.

Predictive factors for central lymph node metastases in papillary thyroid microcarcinoma

Papillary thyroid microcarcinoma(PTMC)measures 1 cm or less in its longest dimension.The incidence of PTMC is increasing worldwide.Surgery is the primary treatment;however,prophylactic central lymph node dissection is controversial,and discrepancies between different guidelines have been noted.Routine prophylactic central lymph node dissection may result in hypoparathyroidism and recurrent laryngeal nerve injury in some patients without lymph node metastasis,while simple thyroidectomy may leave metastatic lymph nodes in high-risk patients.To selectively perform prophylactic lymph node dissections in high-risk patients,it is important to identify predictive factors for lymph node metastases in patients with PTMC.Several studies have reported on this,but their conclusions are not entirely consistent.Several clinicopathologic characteristics have been identified as risk factors for central lymph node metastases,and the most commonly reported factors include age,gender,tumor size and location,multifocality,bilaterality,extrathyroidal extension,and abnormal lymph node found using ultrasound.Here,we provide an overview of previous studies along with a favorable opinion on or against these factors,with the aim of increasing the understanding of this topic among the medical community.In addition,current opinions about prophylactic central lymph node dissection are reviewed and discussed.

The active surveillance management approach for patients with low risk papillary thyroid microcarcinomas: is China ready?

Due to exponential increases in incidences,low risk papillary thyroid microcarcinoma(PTMC)has become a clinical and social issue in recent years.An active surveillance(AS)management approach is an alternative to immediate surgery for patients with low risk PTMC.With decreased doubts about the safety and validity due to evidence from a large number of studies,the AS approach has become increasingly popular worldwide.However,Chinese thyroid surgeons still lag behind other countries in their knowledge of clinical practices and research related to AS.To promote the implementation of AS in China,thyroid surgeons should understand the implications,advantages,and disadvantages of management approaches for AS,and should also consider the willingness of Chinese patients,the impact on the medical billing system,and the enthusiasm of doctors.Thus,a management approach for AS based on the Chinese population should be developed to reduce the risk of disease progression and enhance patient adherence.Herein,we summarize the recent research achievements and deficiencies in AS approaches,and describe the initial experiences regarding AS in the Chinese population,in order to assist Chinese thyroid surgeons in preparing for AS management in the era of PTMC precision medicine.

Skull metastasis in papillary carcinoma of thyroid:A case report

Papillary thyroid carcinoma with metastasis to the skull is extremely rare.We report a case of unsuspected papillary thyroid carcinoma with skull metastasis.A 48-year-old female patient presenting with painless,pulsatile,progressively increasing swelling in the occipitoparietal region of the scalp approached for an X-ray of the skull.Ultrasound of palpable swelling in the neck revealed a heteroechoic lesion with increased vascularity.Foci of calcification were seen involving both lobes of the thyroid.Ultrasound of scalp showed a destructive mass in the skull with increased vascularity.Biopsy of thyroid lesions revealed branching papillae having a dense fibrovascular core covered by cuboidal epithelial cells with nuclei having a clear ground glass appearance.This case illustrates how isolated extensive skull metastasis can be found in papillary carcinoma patients without causing significant morbidity.Therefore,in the clinical course of thyroid papillary carcinoma,skull metastasis should be considered,and the patients should be meticulously investigated and followed up.

Is new American Thyroid Association risk classification for hereditary medullary thyroid carcinoma applicable to Chinese patients? A single-center study

Objective: The American Thyroid Association (ATA) proposed a new risk classification for hereditary medullary thyroid carcinoma (MTC) in 2015. This study aimed to assess whether the new guidelines are suitable for the Chinese population, and reported our experience on prophylactic thyroidectomy. Methods: A total of 73 patients from 22 families were screened as rearranged during transfection (RET) mutation carriers from 2010 to 2016 in Cancer Hospital, Chinese Academy of Medical Science; the medical history for each patient was collected. Based on the initial treatment, we identified the risk factors for poor prognosis by univariate and multivariate logistic regression. Then, 4 RET mutation carriers were enrolled for prophylactic thyroidectomy, and their pathological data and follow-up outcomes were recorded. Results: In univariate and multivariate logistic regression analyses, age at initial surgery and risk classification were significant risk factors for stage III/IV hereditary MTC at initial diagnosis. The likelihood was increased by 11.6% per year of age at initial surgery [95% confidence interval (95% CI), 1.040-1.198; P=0.002). It was 7.888 times more likely to have III/IV stage disease for ATA highest risk patients, compared to ATA moderate risk individuals (95% CI, 1.607-38.717; P=0.003). Postoperative pathological results showed all 4 multiple endocrine neoplasia type 2A (MEN2A) patients had C-cell hyperplasia (CCH); multifocal malignancies were detected in 3 of them. All 4 patients were cured biochemically, and none developed permanent hypoparathyroidism. Conclusions: In Chinese individuals, hereditary MTC aggressiveness is in line with the new ATA risk classification. Germline RET gene mutation carriers should undergo prophylactic thyroidectomy according to basal serum calcitonin levels.

Active surveillance in low risk papillary thyroid carcinoma

In recent decades,while the incidence of thyroid cancer has increased exponentially around the world,mortality has remained stable.The vast majority of this increase is attributable to the identification of intrathyroidal papillary microcarcinomas,which exhibit slow growth rates with indolent courses.A diagnosis of thyroid cancer based upon the presence of these small tumors could be considered as an overdiagnosis,as the majority of these tumors would not likely result in death if left untreated.Although surgical resection was the classical standard therapy for papillary microcarcinomas,active surveillance(AS)has emerged over the last three decades as an alternative approach that is aimed to recognize a minority group of patients who will clinically progress and would likely benefit from rescue surgery.Despite the encouraging results of AS,its implementation in clinical practice is strongly influenced by psychosocial factors.The aim of this review is to describe the epidemiology,clinical evolution,prognostic factors,and mortality of papillary thyroid microcarcinomas.We also summarize the AS strategy according to published evidence,characterize the criteria for selecting patients for AS according to risk factors and environmental characteristics,as well as analyze the current limitations for AS implementation.

Active surveillance as a management strategy for papillary thyroid microcarcinoma

Active surveillance(AS)can be considered as a treatment strategy for low risk papillary thyroid microcarcinoma(PTMC),with the absence of clinically apparent lymph nodes,extrathyroidal extensions,and distant metastasis.After reviewing the reports on AS of low risk PTMCs worldwide,we introduced AS,and discussed the selection criteria for active surveillance candidates based on different guidelines and the follow-up schedules.Moreover,the requirement of cytological diagnosis,progression evaluation methods,necessity of thyrotropin suppression,and medical costs were issues that both clinicians and patients considered.The usefulness of AS for low risk PTMC patients depended on accurate and confidential evaluation of patient risk.Clinicians may adopt measures like dynamic monitoring,risk stratification,and making personal follow-up schedules to minimize these potential risks.By appropriately selecting PTMC patients,AS can be an effective alternative treatment to immediate surgery.

Concomitant paraganglioma and thyroid carcinoma:A case report

BACKGROUND Paraganglioma/pheochromocytoma and medullary thyroid carcinoma can coexist and are often found in multiple endocrine neoplasia(MEN). However,very few cases highlight papillary thyroid carcinoma. We present herein a rare case of head and neck paraganglioma associated with papillary thyroid carcinoma.CASE SUMMARY A 51-year-old man presented to our department with right-sided neck swelling and hypertension. Physical examination showed neck masses with obvious pulsation. Concentrations of serum calcium, phosphorus, parathormone, thyroid stimulating hormone, free thyroxine, and calcitonin were within normal limits.Enhanced computed tomography revealed an irregular solid nodule, located in the carotid artery bifurcation. A low-density nodule of the thyroid isthmus with a spot-like dense shadow was also detected. The diagnosis of carotid body tumor was raised and an ultrasound-guided fine needle aspiration biopsy of the thyroid nodule revealed papillary thyroid carcinoma. The patient underwent surgery for lesion excision, total thyroidectomy, and neck dissection, and the pathology was reported as paraganglioma and papillary carcinoma. Genetic studies showed negative results for germline mutation of succinate dehydrogenase subunit D on 11q23. He was treated with ^(131)I after surgery and remained disease-free so far.CONCLUSION The presence of concomitant paraganglioma and thyroid papillary carcinoma could be either coincidental or a result of an unknown mutation.

Skull metastasis revealing a papillary thyroid carcinoma

Although thyroid carcinoma is a relatively common form of malignancy,metastatic spread to the skull is rare.Here,we report a case of papillary thyroid carcinoma with frontal and parietal metastasis.A 61-year-old Chinese woman presented with a one year history of a growing mass on the center of the frontal and parietal bone,initially thought to be meningioma.Biopsy of the skull base mass after intracalvarium excision,indicated a tumor of thyroid origin.One month later the patient underwent a total thyroidectomy.Pathological examination confirmed a diagnosis of papillary thyroid carcinoma with frontal and parietal bone metastasis.Based on this experience,the key to successful management of the skull metastasis of thyroid carcinoma is prompt diagnosis and appropriate treatment.Skull metastasis should be considered at the outset of the clinical course of papillary thyroid cancer.To facilitate this,patients should be meticulously investigated by a multidisciplinary team to improve quality of life.

Didactic surgical experience of thyroid metastasis from renal cell carcinoma: A case report

BACKGROUND The optimal therapeutic strategy in treating thyroid metastasis from renal cell carcinoma(RCC) has not been clearly established. Here we describe a case of didactic surgical experience of the disease which caused massive intraoperative bleeding.CASE SUMMARY A 59-year-old male patient presented with a thyroid left lobe soft mass detected by chest computed tomography scans prior to the surgical treatment of RCC of the left kidney. The thyroid mass was initially considered to be benign, then he underwent left radical nephrectomy. One year after the nephrectomy, stereotactic radiosurgery was performed for brain metastasis. During follow-up, the thyroid nodule gradually grew, and the patient manifested swallowing discomfort. Under a clinical diagnosis of thyroid follicular neoplasm, left hemithyroidectomy was performed. Although hemithyroidectomy is usually a safe and straightforward procedure, massive bleeding from markedly developed tumor vessels made the operation very difficult. The thyroid tumor was finally diagnosed as metastasis from clear cell RCC. CONCLUSION For proper timing of the surgery, a clinician should take into consideration the possibility of thyroid metastasis of RCC when a thyroid lesion is found in patients with RCC or in patients with a previous history of RCC. We recommend that thyroid metastasis of RCC should be resected as early as possible even if a patient has other metastatic sites.

Acute coronary syndrome: a rare case of multiple endocrine neoplasia syndromes with pheochromocytoma and medullary thyroid carcinoma

Pheochromocytoma is a tumor arising from neuroectodermal chromaffin tissues in the adrenal gland or extra-adrenal paraganglia(paragangliomas). The prevalence of the tumor is 0.1%-0.6% in the hypertensive population, of which 10%-20% are malignant. Pheochromocytoma produces, stores, and secretes catecholamines, as well as leads to hypertensive crisis, arrhythmia, angina, and acute myocardial infarction without coronary artery diseases. We report a case of acute coronary syndrome(ACS) with a final diagnosis of multiple endocrine neoplasia with pheochromocytoma and medullary thyroid carcinoma(MTC).

Hypomethylation of Thyroid Peroxidase as a Biomarker for Hepatocellular Carcinoma with Tumor Thrombosis

Objective Thyroid hormones(THs)regulate multiple physiological activities in the liver,including cellular metabolism,differentiation,and cell growth,and play important roles in the pathogenesis of hepatocellular carcinoma(HCC).Thyroid peroxidase(TPO)is a key molecule involved in the THs synthesis and signaling pathway.As an epigenetic modification,DNA methylation has a critical role in tumorigenesis with diagnostic potential.However,the connection between THs and DNA methylation has been rarely investigated.Methods The methylation of key TH-related genes was analyzed by in-house epigenome-wide scanning,and we further analyzed the methylation levels of the TPO promotor in 164 sample pairs of HCC and adjacent non-cancerous tissues by Sequenom EpiTYPER assays,and evaluated their clinical implications.Results We identified that the methylation of the TPO promoter was downregulated in the HCC tissues(P<0.0001)with a mean difference ranging from 18.5%to 22.3%.This methylation pattern correlated with several clinical factors,including a multi-satellite tumor,fibrous capsule,and the presence of tumor thrombus.The receiver operator characteristic(ROC)curve analysis further confirmed that the percent methylated reference(PMR)values for TPO were predictive of the tumor[the area under the curve(AUC)ranged from 0.755 to 0.818]and the thrombosis in the HCC patients(the AUC ranged from 0.706 to 0.777).Conclusion These findings demonstrated that epigenetic alterations of TPO,as indicated by the PMR values,were a potential biomarker for HCC patients with tumor thrombosis.

Photoacoustic detection of follicular thyroid carcinoma using targeted Nano-Au-Tripods

Follicular thyroid carcinoma(FTC)is the second most common form of thyroid malignancy,and it is associated with more aggressive growth and worse long-term survival outcomes relative to papillary thyroid carcinoma(PTC).Reliable approaches to preoperative FTC detection,however,remain to be established.Herein,a targeted Affibody-Au-Tripod nanoprobe was developed and successfully utilized to facilitate the targeted photoacoustic imaging(PAI)of epidermal growth factor receptor(EGFR)-positive cells and tumors.These Affibody-Au-Tripods were found to be highly sensitive and specific for cells expressing EGFR when used as a PA contrast agent in vitro,and studies conducted in an FTC-133 subcutaneous tumor model system in mice further revealed that these Affibody-Au-Tripods were able to specifically target these EGFR-expressing tumors while providing a strong photoacoustic signal in vivo.Importantly,these nanoprobes exhibited negligible cytotoxicity and robust chemical and physical stability,making Affibody-Au-Tripods promising candidates for targeted PAI-based FTC diagnosis.In addition,these nanoprobes have the potential to facilitate the individualized treatment of patients harboring EGFRpositive tumors.

Characteristics of clear cell renal cell carcinoma metastases to the thyroid gland: A systematic review

BACKGROUND Thyroid gland is an uncommon site for metastases from clear cell renal cell carcinoma(CCRCC)and literature is scarce.Due to the variable and often long lag time before development of metastases in patients with CCRCC,thyroid nodules may be misdiagnosed initially as benign.This systematic review aims at a better understanding of the nature of these metastases.METHODS A bibliographic search was performed using PubMed(1990-2019),key words being“renal cell carcinoma,thyroid,kidney cancer,clear cell.”147 cases were analyzed.The patient’s characteristics assessed were:age,sex,stage,size of metastases,lag time,diagnostic modality,initial symptoms,treatment and outcome in last documented follow up.Binary logistic regression,Spearman’s rho and ANOVA were used to identify differences between the existing variables.RESULTS The mean age(±SD)was 64±(10)years in males and 64(±11)in females.The mean lag time to diagnosis of thyroid metastases was 8.7(±6.3)years.Gender distribution of the patients was 46.3%male,52.4%female.There was a weak correlation between lag time and size of metastases,not statistically significant.Size of metastases was significantly higher in symptomatic patients(6.06±3.51 cm)compared to those with painless mass(4.6±0.29 cm)and asymptomatic ones(3.93±1.99 cm)(P=0.03).Fine Needle Aspiration was diagnostic in 29.4%of cases,47.1%were non diagnostic.Most patients(80.3%)underwent thyroid surgery.At 1 year follow up,55.6%of patients operated were alive versus 35.3%who did not have surgery,though this was not statistically significant(P=0.1).CONCLUSION A larger size of thyroid metastasis was more likely to present with symptomatology.A high index of suspicion is warranted when evaluating thyroid nodules in CCRCC patients.There was no significant difference in outcome between patients who underwent surgery and those who did not.With the wider use of immune check-point inhibitors and tyrosine kinase inhibitors in metastatic CCRCC,surgery may eventually be reserved only for palliative purposes.