Table 1.

Timeline, characteristics, and summary of the findings of the included studies

Year	Title	Main method(s)	Summary of findings	Ref.
2005	Primary thyroid malignancies in Tehran, Iran	Descriptive epidemiology study	Slightly increase in the incidence of TC in Tehran. The survival rate of patients was high. Survival time of men and women with TC in Tehran were similar.	[5]
2006	Endocrine cancer in Iran: based on cancer registry system	Descriptive epidemiology study	Improving the intake of iodine in previously deficient populations was associated with an increase in the incidence of PTC.	[6]
			The frequency of histological forms of thyroid carcinoma was similar to what can be found in iodine-rich areas.
2006	Immunohistochemical analysis of survivin expression in thyroid follicular adenoma and carcinoma	IHC	Survivin is a potential candidate in the distinction between FTA and FTC.	[7]
2007	Vitamin D receptor gene polymorphisms in patients with thyroid cancer	RFLP	There are no correlation between the polymorphisms located at 3′ end of vitamin D receptor gene and risk of TC.	[8]
2009	Associations between HLA-C alleles and papillary thyroid carcinoma	HLA typing	HLA-C alleles are predisposing factors in PTC in Iranian population.	[9]
2009	Expression of EGFRvIII in thyroid carcinoma: immunohistochemical study by camel antibodies	Antibody production	Diagnostic value of smaller heavy chain camel antibodies against EGFRvIII in thyroid neoplasms.	[10]
		Western-blot
		IHC
2009	Immunohistochemical analysis of nm23 protein expression in thyroid papillary carcinoma and follicular neoplasm	IHC	There is no relationship between the expression of nm23 protein and patientsʼ sex and age.	[11]
			nm23 is not a beneficial biomarker for assessing the invasion of DTC or the distinction between FTC and FTA.
2009	Prevalence of BRAFV600E mutation in Iranian patients with papillary thyroid carcinoma: A single-center study	RFLP	The BRAFV600E mutation is detected in 72% of classical variant of PTC and 100% of tall cell variant of PTC.	[12]
			There is no significance association between BRAFV600E mutation prevalence and sex, age, lymph node metastasis, and extrathyroid extension.
2010	HLA-DR association in papillary thyroid carcinoma	HLA typing	HLA-DRB1*04 is predisposing factor in PTC in Iranian population.	[13]
2011	Molecular analysis of the RET proto-oncogene key exons in patients with medullary thyroid carcinoma: A comprehensive study of the iranian population	Sequencing	17.6% of sporadic cases of medullary thyroid carcinoma (MTC) carried a germ-line mutation in RET gene.	[14]
			Most mutations detected in the families occurred in cysteine codons.
			Germ-line mutation carriers have an earlier age onset of MTC versus the sporadic ones.
2011	Evaluating clinical practice guidelines developed for the management of thyroid nodules and thyroid cancers and assessing the reliability and validity of the AGREE instrument	Mixed methods (Systematic search, Secondary data analysis…)	‘Scope and purpose’ and ‘clarity and presentation’ clinical guidelines have the highest domain scores based on the AGREE instrument.	[15]
			‘Rigor of development’ and ‘clarity and presentation’ acquired the highest correlations with overall evaluation scores.
2011	Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma	Combined bisulfite restriction analysis	Promoter hypermethylation of P16, TSHR and RASSF1A genes play important role in PTC pathogenesis.	[16]
2011	Incidence of second primary malignancies during a long-term surveillance of patients with differentiated thyroid carcinoma in relation to radioiodine treatment	Retrospective cohort study	The overall rate of second primary malignancies was not increased following a minimum interval of 3 years from the first I131 therapy. The probability of this occurrence may be profoundly increased in cases who had received a cumulative dose of I131 more than 40 GBq (1.08 Ci).	[17]
2012	Multifaceted suppression of aggressive behavior of thyroid carcinoma by all-trans retinoic acid induced re-differentiation	Cell culture	All-trans retinoic acid treatment could inhibit the aggressive manners of TC and/or potentiate the effect of arsenic trioxide chemotherapy medicine.	[18]
		Proliferation assay
		C ratio and morphological analysis
		Colony formation assay
		qRT-PCR
		Radioimmunoassay
2012	Survivin gene polymorphism association with papillary thyroid carcinoma	Genotyping	Survivin gene polymorphism correlated with the risk of PTC in Iranian population.	[19]
2012	Expression of matrix metalloproteinase-2, but not caspase-3, facilitates distinction between benign and malignant thyroid follicular neoplasms	IHC	The potential value of measuring MMP2 expression in discrimination between FTA and FTC.	[20]
2013	Evaluation of MMP2 and Caspase-3 expression in 107 cases of papillary thyroid carcinoma and its association with prognostic factors	IHC	Evaluating the expression of MMP2 in PTC patients may be a useful marker in predicting of tumor aggressiveness.	[21]
			There is no significant correlation between Caspase-3 expression and vascular invasion in patients with PTC.
2013	MicroRNAs networks in thyroid cancers: focus on miRNAs related to the fascin	Narrative reviews	Increased miRNAs expression in 32% of TCs.	[22]
			Decreased miRNAs expression in 38% of TCs.
2013	Essential genes in thyroid cancers: focus on fascin	Narrative reviews	The importance of P53, RAS, RET, BRAF, PPARγ and Fascin genes in TC.	[23]
2014	Characterization of wild-type and mutated RET proto- oncogene associated with familial medullary thyroid cancer	Sequencing	Mutation-based stability shift findings in RET showed that C.G2901A (P.C634Y) and C.G2901T (P.C634F) mutations were destabilizing, hence the stabilizing factor was C.G2251A (P.G691S) mutations.	[24]
		Modeling
		Molecular docking
		Simulation
			The importance of the simultaneous analysis of the mutations in improved chemotherapy resistance and designing new anticancer drugs.
2014	The beneficial effects of valproic acid in thyroid cancer are mediated through promoting redifferentiation and reducing stemness level: an in vitro study	Cell culture assay	Redifferentiation of ATC cell line and reduction of stemness properties of PTC cell line using Valproic acid.	[25]
		Cytotoxic assay
		C ratio and morphological analysis
		Colony formation assay
		qRT-PCR
		Hoechst 33342 staining
2016	Antisense-miR-21 enhances differentiation/ apoptosis and reduces cancer stemness state on anaplastic thyroid cancer	Cell culture	miR-21 has a role in stemness properties, growth, differentiation, and apoptosis.	[26]
		Virus packaging and transduction
		Apoptosis assay
		Cell cycle assay
		qRT-PCR
		IRMA
2016	Cancer stem-like cell behavior in anaplastic thyroid cancer: A challenging dilemma	Cell culture	This study reconfirmed the concept of CSC as origin of ATC.	[27]
		MACS
		qRT-PCR
2017	Meta-analysis of promoter methylation in eight tumor-suppressor genes and its association with the risk of thyroid cancer	Meta-analysis	Among RASSF1, TSHR, PTEN, SLC5A, DAPK, P16, RARβ2, and CDH1 tumor suppressor genes, promoter methylation of SLC5A8 and CDH1 is associated with the risk of TC development.	[28]
2017	Precision medicine approach to anaplastic thyroid cancer: advances in targeted drug therapy based on specific signaling pathways	Narrative reviews	To appoint the best strategy for ATC therapy, personalized medicine can use different data such as a patient’s genetics and clinical background.	[29]
2018	Decreased apolipoprotein A4 and increased complement component 3 as potential markers for papillary thyroid carcinoma: A proteomic study	Proteomics study	Proteomic study showed that the apolipoprotein A4 decreased and complement component 3 increased in serum of patients with PTC.	[30]
2018	Serum-based metabolic alterations in patients with papillary thyroid carcinoma unveiled by non-targeted 1H-NMR metabolomics approach	1H-NMR	Serum metabolites are different between malignant and benign thyroid nodules.	[31]
2019	Promoter methylation of four tumor suppressor genes in human papillary thyroid carcinoma	MS-HRM assay	Among SLC5A8, RASSF1, MGMT, and DNMT1 tumor suppressor genes, promoter methylation of SLC5A8, RASSF1, and MGMT is different between PTC and goiter tissue samples.	[32]
2019	Circulating ctDNA methylation quantification of two DNA methyl transferases in papillary thyroid carcinoma	Bisulfite treatment	A number of ctDNA promoter regions of MGMT and DNMT1 genes are hypermethylated in plasma and tissue samples of PTC patients.	[33]
		MS-HRM assay
			The methylation status of ctDNA promoter regions of MGMT and DNMT1 genes and tissue DNA are related to each other.
2019	Transcript-level regulation of MALAT1-mediated cell cycle and apoptosis genes using dual MEK/Aurora kinase inhibitor “BI-847325” on anaplastic thyroid carcinoma	3D cell culture	Targeting the regulatory network of lncRNA MALAT1 may be a more effective therapeutic approach for ATC.	[34]
		qRT-PCR
2019	The role of ATP-binding cassette transporters in the chemoresistance of anaplastic thyroid cancer: a systematic review	Systematic review	ABC transporters are the major determinants of chemotherapy resistance in ATC.	[35]
2019	Determination of ATP-competitive inhibitor drug toxicity in anaplastic thyroid cancer based on cell characteristics and three-dimensional cell culture	3D cell culture	The 3D cell culture systems are useful for obtaining the most appropriate anticancer drug with the most effective dose in ATC cell lines.	[36]
		Cytotoxic assay
		CFSE staining
2020	Investigation of promoter methylation of FSCN1 gene and FSCN1 protein expression in differentiated thyroid carcinomas	Bisulfite treatment	FSCN1 promoter is hypomethylated in patients with PTC while the methylation status is not altered in FTC.	[37]
		IHC
			Hypomethylation of FSCN1 promoter in PTC does not promote to overexpression of FSCN1.
2020	Hypermethylated RASSF1 and SLC5A8 promoters alongside BRAFV600E mutation as biomarkers for papillary thyroid carcinoma	qRT-PCR	Plasma cfDNAs originate from tumor tissue because the pattern of methylation and mutation of BRAFV600E in plasma and tissue DNA is the same.	[38]
		Bisulfite treatment
		MS-HRM assay
			The BRAFV600E cfDNA mutation is the best predictive biomarker for PTC.
			Hypermethylation in the proximal promoter regions to the RASSF1 and SLC5A8 genes has sensitivity and specificity for discriminating between PTC and benign thyroid nodules.
2020	Gut microbiome and radioiodine-refractory papillary thyroid carcinoma pathophysiology	Mini review	GM might be related to RAIR-PTC through different molecular mechanisms associated with the NIS regulation as the main factor in I− uptake.	[39]
2020	Molecular mechanisms of long non-coding RNAs in anaplastic thyroid cancer: A systematic review	Systematic review	LncRNAs such as GAS5, CASC2, and MIR22HG may serve as prognosis markers.	[40]
			LncRNAs Klhl14-AS, PCA3, and HOTAIRM1 may act as molecular therapeutic targets.
2020	Bioinformatic study on effect of Xanthohumol as bioactive compound of hop in the inhibition of the MAPK/ERK pathway in thyroid cancer	Evaluation of physicochemical, phamacokinetic, and pharmacodynamic characteristics	Xanthohumol acts as an inhibitor of MAPK/ERK pathway in TC cells.	[41]
			Xanthohumol, as a natural small molecule, does not have the potential to develop resistance in TC cells.
		Molecular docking

Abbreviations: 1H-NMR, hydrogen-1 nuclear magnetic resonance; 3D, three-dimensional; ABC, ATP binding cassette; AGREE, Appraisal of Guidelines Research and Evaluation; ATC, anaplastic thyroid carcinoma; BRAF, v-Raf murine sarcoma viral oncogene homolog B; CASC2, cancer susceptibility candidate 2; CDH1, cadherin 1; cfDNA, circulating cell-free DNA; CFSE, 5,6-carboxyfluorescein N-hydroxysuccinimidyl ester; CSC, cancer stem cell; ctDNA, circulating tumor DNA; Ci, cuire; DAPK, death associated protein kinase; DNMT1, DNA methyltransferase 1; DTC, differentiated thyroid cancer; EGFRvIII, epithelial growth factor receptor variant III; FSCN1, fascin actin-bundling protein 1; FTA, follicular thyroid adenoma; FTC, follicular thyroid carcinoma; GAS5, growth arrest special 5; GBq, gigabecquerel; GM, gut microbiome; HLA-C, major histocompatibility complex class I C; HLA-DR, major histocompatibility complex class II DR; HLA-DRB1, major histocompatibility complex class II DR beta1; HOTAIRM1, HOX antisense intergenic RNA myeloid 1;IHC, immunohistochemical; I⁻, iodine; LncRNA, long non-coding RNA; IRMA, immunoradiometric assay; Klhl14, kelch like family member 14; MACS, magnetic-activated cell sorting; MALAT1, metastasis associated lung adenocarcionoma transcript 1; MEK, mitogen-activated protein kinase kinase 1; MEN 2A, multiple endocrine neoplasia type 2A; MGMT, O-6-methylguanine-DNA methyltransferase; MIR22HG, MIR22 host gene; miRNA, micro RNA; MMP2, matrix metallopeptidase 2; MRI, magnetic resonance imaging; MS-HRM, methylation-sensitive high resolution melting; MTC, medullary thyroid carcinoma; NIS, sodium/iodide symporter; P16, cyclin dependent kinase inhibitor 2A; P53, tumor protein P53; PPARγ, peroxisome proliferator activated receptor gamma; PCA3, prostate cancer antigen 3; PTC, papillary thyroid carcinoma; PTEN, phosphatase and tensin homolog; RAIR, radioiodine-refractory; RARβ2, retinoic acid receptor beta; RASSF1A, Ras association domain family member 1; RFLP, restriction fragment length polymorphism; qRT-PCR, quantitative real-time polymerase chain reaction; RAS association domain family member 1; RET, ret. proto-oncogene; SLC5A8, solute carrier family 5 member 8; TC, thyroid cancer; TSHR, thyroid stimulating hormone receptor