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.

A Case of Medullary Thyroid Carcinoma Combined with Papillary Microcarcinoma and Literature Review

Background: The histologic type of thyroid carcinomas includes follicular, papillary carcinomas, and medullary carcinomas. The reports about the histological, immunohistochemical, and ultrastructural characteristics of each kind of thyroid carcinomas were common, but the simultaneous occurrence of a medullary and papillary carcinoma as 2 distinct tumors has been reported extremely rarely. Objects: To explore the pathogenesis, clinicopathological characteristics, immunohistochemical phenotype, and pathological diagnosis of medullary thyroid carcinoma combined with papillary thyroid microcarcinoma. Methods: The clinicopathological characteristics and immunohistochemical phenotype of a patient with left medullary thyroid carcinoma combined with right papillary thyroid microcarcinoma were retrospectively studied. Then, relevant literature was thus reviewed. Results: General appearance: The size of the left thyroid lobe was 2.5 × 2 × 1 cm, the cut surface was gray and red, and a nodule with a diameter of 1.3 cm could be observed. The cut surface of the nodule was gray and yellow, solid, and hard. The size of the right lobe of the thyroid gland was 0.7 × 0.6 × 0.5 cm, and a gray nodule with a diameter of 0.4 cm was seen on the cut surface. The cut surface of the nodule was gray, solid, and hard. Observation under the microscope: the left nodular tumor cells were round, oval, or plasma cell-like, some areas were arranged in nests, and some areas were arranged in beams. Calcification and sheet-like eosinophilic amyloid deposits could be seen in the stroma. The nodule on the right showed a branched papillary structure, the covering cells on the surface of the nipple were ground glass-like nuclei, and nuclear grooves and pseudo-inclusion bodies in the nucleus could be observed. Immunohistochemistry: left lobe tumor cells Calcitonin, CEA, TTF-1, CD56, CgA, and Syn are all (+), CK19 and TG were both (−);right lobe tumor cells CK19 and TG are both (+), Calcitonin, CD56, CgA, and Syn are all (−). Conclusions: The origin, clinicopathological manifestations, and immunophenotypes of medullary thyroid carcinoma and papillary thyroid carcinoma are different. It is relatively rare for the two to occur at the same time. The diagnosis mainly depends on the microscopic morphology and immunophenotype characteristics.

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.

Recurrent medullary thyroid carcinoma treated with percutaneous ultrasound-guided radiofrequency ablation:A case report

BACKGROUND Treatment for neck lymph node metastases after adequate initial surgery in medullary thyroid carcinoma(MTC)has been controversial.Ultrasound(US)-guided radiofrequency ablation(RFA)has been widely used in recurrent welldifferentiated thyroid carcinoma.Here,we report for the first time the use of RFA in a patient with recurrent MTC.CASE SUMMARY We report the case of a 56-year-old woman with cervical lymph node metastases of MTC.Four years previously,she had undergone a total thyroidectomy and neck lymph node dissection.A neck US revealed many enlarged nodes during the follow-up period.Moreover,the serum calcitonin jumped to 198.17 pg/mL,which strongly indicated the recurrence of MTC.Subsequently,two metastatic lymph nodes were confirmed by US-guided fine-needle aspiration-cytology and fineneedle aspiration-calcitonin,and then the patient was treated with RFA.Four months later,the neck US and a contrast-enhanced US showed obvious shrinkage in the ablation zones,and the serum calcitonin dropped to 11.80 pg/mL.CONCLUSION This case suggests that RFA may be an effective and safe treatment for local recurrent MTC.

Do medullary thyroid carcinoma patients with high calcitonin require bilateral neck lymph node clearance?A case report

BACKGROUND In clinical work,85%-90%of malignant thyroid diseases are papillary thyroid cancer(PTC);thus,clinicians neglect other types of thyroid cancer,such as medullary thyroid carcinoma(MTC).CASE SUMMARY We report a 53-year-old female patient with a preoperative calcitonin level of 345 pg/mL.There was no definitive diagnosis of MTC by preoperative fine-needle aspiration cytology or intraoperative frozen pathology,but the presence of PTC and MTC was confirmed by postoperative paraffin pathology.The patient underwent total thyroidectomy and bilateral central lymph node dissection.Close follow-up at 1.5 years after surgery revealed no signs of recurrence or metastasis.CONCLUSION The issue in clinical work-up regarding types of thyroid cancer provides a novel and challenging idea for the surgical treatment of MTC.In the absence of central lymph node metastasis,it is worth addressing whether patients with high calcitonin can undergo total thyroidectomy and bilateral central lymph node dissection without bilateral lateral neck lymph node dissection.

Incidental diagnosis of medullary thyroid carcinoma due to persistently elevated procalcitonin in a patient with COVID-19 pneumonia:A case report

BACKGROUND Procalcitonin(Pct)is a common biomarker in clinical practice,especially in the era of coronavirus disease 2019(COVID-19)infection.Although it is frequently used for the diagnosis and prognostication of bacterial infections or sepsis,it is also elevated in a few other conditions,including medullary thyroid carcinoma(MTC).CASE SUMMARY A 43-year-old female presented with moderately severe COVID-19 pneumonia in April 2021.She gradually recovered clinically;however,despite normalization of other inflammatory markers,Pct levels remained persistently elevated.Further workup identified the cause as left lobe MTC with locoregional metastasis.Calcitonin levels were high,and carcinoembryonic antigen levels were normal.The patient underwent total thyroidectomy and neck dissection,which was followed by another radical neck dissection due to residual disease.Currently,she is doing well,nearly having completed her course of external beam radiotherapy with no recurrence.Pct is well documented as a screening tool for MTC,especially because of its stable nature compared to calcitonin in the community settings.It is important to keep in mind the differential diagnosis of MTC in patients with persistently elevated Pct levels despite normal levels of other acute phase reactants.To the best of our knowledge,this is the first report from Asia of such an incidental diagnosis of MTC due to persistently elevated Pct levels in a patient with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.CONCLUSION Persistently elevated Pct levels can occur in any pro-inflammatory state including infections,sepsis,or acute respiratory distress syndrome.In the current setting,SARS-CoV-2 infection is one such clinical scenario,and in rare situations of persistent elevation,MTC may need to be ruled out.

Effects of rearranged during transfection mutation on calcitonin and procalcitonin expression in sporadic medullary thyroid carcinoma

Objective The aim of this study was to investigate the effects of rearranged during transfection(RET)mutation on the expressions of calcitonin(CTn)and procalcitonin(PCT)in sporadic medullary thyroid carcinoma(SMTC).Methods RET mutation was detected by polymerase chain reaction direct sequencing in 64 cases of SMTC,and the expression levels of CTn and PCT in SMTC tissues were detected using the immunohistochemical streptavidin-perosidase(SP)method.The effect of RET mutations on the expression of CTn and PCT along with its relationship with clinicopathological parameters were analyzed.Results The expression rates of CTn and PCT in SMTC tissues were 90.6%(58/64)and 67.2%(43/64),respectively.CTn and PCT expression were found to be associated with tumor size and lymph node metastasis(P<0.05)but not with gender,age,or tumor capsule invasion(P>0.05).There was a significant correlation between CTn and PCT expression(r=0.269,P=0.041),and the intensity of positive CTn expression was positively correlated with RET mutation(r=0.507,P=0.000).However,PCT expression was not associated with RET mutation(r=0.188,P=0.136).Conclusion High expression of CTn and PCT was associated with the progression of medullary carcinoma,and the intensity of CTn expression was associated with RET mutation.PCT may provide valuable information for the diagnosis and prognosis of SMTC.

C634Y mutation in RET-induced multiple endocrine neoplasia type 2A:A case report

BACKGROUND Multiple endocrine neoplasia type 2(MEN2)is a rare,autosomal dominant endocrine disease.Currently,the RET proto-oncogene is the only gene implicated in MEN2A pathogenesis.Once an RET carrier is detected,family members should be screened to enable early detection of medullary thyroid carcinoma,pheochromocytoma,and hyperparatitity.Among these,medullary thyroid carcinoma is the main factor responsible for patient mortality.Accordingly,delineating strategies to inform clinical follow-up and treatment plans based on genes is paramount for clinical practitioners.CASE SUMMARY Herein,we present RET proto-oncogene mutations,clinical characteristics,and treatment strategies in a family with MEN2A.A family study was conducted on patients diagnosed with MEN2A.DNA was extracted from the peripheral blood of family members,and first-generation exon sequencing of the RET protooncogene was conducted.The C634Y mutation was identified in three family members spanning three generations.Two patients were sequentially diagnosed with pheochromocytomas and bilateral medullary thyroid carcinomas.A 9-yearold child harboring the gene mutation was diagnosed with medullary thyroid carcinoma.Surgical resection of the tumors was performed.All family members were advised to undergo complete genetic testing related to the C634Y mutation,and the corresponding treatments administered based on test results and associated clinical guidelines.CONCLUSION Advancements in MEN2A research are important for familial management,assessment of medullary thyroid cancer invasive risk,and deciding surgical timing.

Ultrasonographic features of medullary thyroid carcinoma and their diagnostic values

Background Medullary thyroid carcinoma （MTC） is a rare malignant tumour and usually difficult to diagnose with ultrasound. The aim of the study is to summarize the sonographic features of MTC and evaluate their diagnostic values.Methods We analyzed the sonographic features of 35 MTCs and 50 benign nodules with respect to nodular size,echogenecity, internal content, shape, height/width, border, peripheral halo, calcifications and colour flow pattern. The ratio of long to short axis, echogenecity, internal content and calcifications were also assessed in cervical lymph nodes.The differences in sonographic features between MTCs and benign nodules were analyzed with Chi square test. The diagnostic efficiency of each sonographic feature was determined.Results The main sonographic features of MTC were hypoechogenicity （including marked hypoechogenicity） （n=34,97%）, internal solid content （n=29, 83%）, taller than wide （n=34, 97%）, well defined border （n=24, 69%）,microcalcifications or macrocalcifications （n=23, 66%）. The echogenicity, internal content, shape, peripheral halo and calcifications were significantly different between these two groups, while the tall/wide, border, and pednodular and intranodular vascularisation were not significantly different. Among all the individual sonographic features, irregular shape had the highest diagnostic efficiency with a sensitivity of 51% and specificity of 92%. The combination of marked hypoechogenicity, microcalcifications, and irregular shape yielded a sensitivity of 77% and specificity of 86%.Conclusions The typical sonographic features of MTC are hypoechogenicity, predominantly solid, irregularly shaped with intranodular micro- or macro-calcifications. The combination of multiple sonographic features is helpful, but not definitive, for the diagnosis of MTC.

Integrated DNA-based/biochemical screening for early diagnosis of multiple endocrine neoplasia type 2A (MEN2A)

Multiple endocrine neoplasia type 2A （MEN2A）, a subtype of MEN2, is characterized by medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism. A Han Chinese pedigree with MEN2A was investigated following confirmation of the proband＇s diagnosis by pathological findings and DNA/biochemical screening. DNA samples from 4 other family members were collected and exon 5, 8, 10, 11, 13, 16 and 18 of the RET proto-oncogene were sequenced and then analyzed. A missense mutation of TGG （Trp） to TGC （Cys） at codon 634 （the classic MEN2A mutation） in exon 11 of the RET gene was detected in 3 family members, including the proband. Sequencing data were compared with the human gene mutation database. Elevated serum calcitonin level was detected initially; medullary thyroid carcinoma was revealed in the 3 cases and adrenal pheochromocytoma was also found in the proband. Elective operations were successfully performed on the adrenal and thyroid glands because of pheochromocytoma and medullary thyroid carcinoma. Our case study confirms that integrated DNA-based/biochemical screening is crucial for early diagnosis of MEN2A and is helpful in the screening of their relatives. In addition, DNA-based screening may occasionally uncover a previously unknown RET sequence.

Systemic treatment of advanced, metastatic, medullary thyroid carcinoma

Medullary thyroid carcinoma(MTC)is a rare endocrine tumor,which arises from thyroid parafollicular C cells.Through its ability to metastasize by blood and lymphatic vessels,it can show a more aggressive clinical behavior than differentiated thyroid cancers.Mutation of RET gene is the main molecular alteration involved in MTC origin.In the case of germline RET mutation,MTC can be inherited in an autosomal dominant way and show three different phenotypes:familial medullary thyroid carcinoma and multiple endocrine neoplasia types IIA and IIB.In addition,in sporadic cases,somatic RET mutation remains the key molecular alteration in most of cases.Total thyroidectomy with prophylactic or therapeutic central compartment lymph nodes dissection is the surgical treatment of choice.Further surgical treatments and local therapies should be used in the case of single or few local or distant metastasis.However,in cases with large metastatic spread of the disease,particularly in those with significant tumor progression,additional systemic treatments are needed.In this review,we discuss the key points of systemic treatment in advanced,metastatic MTC.We provide an update on the main aspects(from biological rationale to clinical experience)of each treatment,focusing our attention on the drugs used in clinical practice in the last years.Finally,we give insights about the emerging treatments from highly selective RET inhibitors to new radionuclide therapy.

甲状腺髓样癌的分子病因学和靶向治疗进展

甲状腺髓样癌（medullary thyroid carcinoma,MTC）与转染重排基因突变、哺乳动物雷帕霉素靶蛋白细胞间信号通路活化和ras基因突变等多种基因事件密切相关.以分子病因学研究为基础的靶向治疗在转移性或局部进展、难治性MTC中显示了良好的治疗前景.随着随机临床试验的开展和新型靶向药物的应用,必将为MTC患者提供更加有效的、个体化的治疗选择.

家族性非甲状腺髓样癌病因、临床特征及干预

家族性非甲状腺髓样癌为一种相对罕见的家族性疾病,其临床表现较散发病例恶性程度高,预后差.多数学者建议采取更为激进的治疗手段,且对家系成员进行筛查.目前为止,致病基因尚未确定,可能为常染色体显性遗传病,并伴不完全外显性.明确家族性非甲状腺髓样癌的病因,以对其更好的诊治是未来的研究方向.

甲状腺髓样癌研究进展

甲状腺髓样癌（medullary thyroid carcinoma,MTC）来源于分泌降钙素和癌胚抗原的甲状腺滤泡旁细胞（又称C细胞）,且多因RET基因突变引发.它属于甲状腺癌中恶性程度较高的一类,预后相对较差.本文重点综述了近年来甲状腺髓样癌基础分子生物学研究、诊断、影像学检查及治疗方面的进展.

Neuroendocrine tumors:current therapies,notch signaling,and cancer stem cells

Neuroendocrine tumors(NETs)encompass a broad spectrum of malignancies all derived from neuroendocrine cell lineage,affecting many different organs including the gastrointestinal(GI)tract,the endocrine pancreas,the thyroid,the skin and the respiratory tract.These tumors as a group are very heterogeneous,with varying characteristics attributed to each tissue of origin and tumor subtype.The pathogenesis of the different subtypes of NETs is not fully understood,but recent studies suggest the Notch signaling pathway may be dysregulated in these tumors either by under or overexpression of Notch receptors and/or ligands,or by disruption of pathway functionality through other means.Notch receptors can function as tumor suppressors in some cellular contexts and oncogenes in others which may,in part,account for the wide range of phenotypes present in NETs.Cancer stem cells are present in these tumors and may be responsible for the high rate of chemotherapy resistance,recurrence and metastasis.The heterogeneity of NETs suggests that to fully understand the role of Notch signaling and the therapeutic implications thereof,a comprehensive and systematic analysis of Notch expression and function across all NET subtypes is required.Here we outline the current knowledge base with respect to current therapies and Notch signaling in neuroendocrine tumors of the lung,skin,thyroid,GI tract and endocrine pancreas.