International Journal of Hematology-Oncology and Stem Cell Research 2018. 12(3):234-247.

Liquid Biopsy in Thyroid Cancer: New Insight
Fatemeh Khatami, Seyed Mohammad Tavangar


Thyroid cancer, one of the most widespread malignancies of the endocrine-related system that over the past three decades, has a vivid increasing rate. The diagnosis and management of it is dependent on the tumor type and stage. Thyroid cancer is divided into four main types, including PTC (papillary thyroid carcinoma), FTC (follicular thyroid carcinoma), MTC (medullarly thyroid carcinoma), and ATC (anaplastic thyroid carcinoma). The development of the noninvasive diagnostic tool for plasma genotyping, also known as “liquid biopsy”, brings a new insight for cancer diagnosis and prognosis. It is mainly containing circulating tumor DNA (ctDNA), circulating tumor cell (CTC), exosomes and extrachromosomal circular DNA (ecDNA). Liquid biopsy as a new plasma genotyping source brings a new prospective of tumor monitoring and therapy.  It beneficially reduces the need of tissue biopsy and made early recognition of relapse as well. This article summarizes its components characteristics and their benefit in diagnosis and treatment of thyroid cancer.


Biopsy, Carcinoma, Thyroid Cancer, Endocrine System Diseases, cfDNA, CTCs

Full Text:



Marrinucci D, Bethel K, Luttgen M, et al. Circulating tumor cells from well-differentiated lung adenocarcinoma retain cytomorphologic features of primary tumor type. Arch Pathol Lab Med. 2009; 1 33(9):1468-71.

Alix-Panabières C, Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov. 2016; 6(5):479-91.

Bardelli A, Pantel K. Liquid Biopsies, What We Do Not Know (Yet). Cancer Cell. 2017; 31(2):172-179.

Jr LAD, Bardelli A. Liquid Biopsies: Genotyping Circulating Tumor DNA J Clin Oncol. 2014; 32(6):579-86.

Mandel P, Metais P. [Not Available]. Comptes rendus des seances de la Societe de biologie et de ses filiales. 1948; 142(3-4):241-3.

Leon SA, Ehrlich GE, Shapiro B, et al. Free DNA in the serum of rheumatoid arthritis patients. J Rheumatol. 1977; 4(2):139-43.

Shapiro B, Chakrabarty M, Cohn EM, et al. Determination of circulating DNA levels in patients with benign or malignant gastrointestinal disease. Cancer. 1983; 51(11):2116-20.

Jahr S, Hentze H, Englisch S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001; 61(4):1659-65.

Chan KCA, Zhang J, Hui ABY, et al. Size Distributions of Maternal and Fetal DNA in Maternal Plasma. Clin Chem. 2004; 50(1):88-92.

Mouliere F, Robert B, Arnau Peyrotte E, et al. High Fragmentation Characterizes Tumour-Derived Circulating DNA. PLoS One. 2011; 6(9):e23418.

Stroun M, Lyautey J, Lederrey C, et al. About the possible origin and mechanism of circulating DNA: Apoptosis and active DNA release. Clin Chim Acta. 2001; 313(1–2):139-42.

Anker P, Stroun M, Maurice PA. Spontaneous release of DNA by human blood lymphocytes as shown in an in vitro system. Cancer Res. 1975; 35(9):2375-82.

Stroun M, Maurice P, Vasioukhin V, et al. The Origin and Mechanism of Circulating DNA. Ann N Y Acad Sci. 2000; 906:161-8.

Stroun M, Lyautey J, Lederrey C, et al. Alu Repeat Sequences Are Present in Increased Proportions Compared to a Unique Gene in Plasma/Serum DNA. Ann N Y Acad Sci. 2001; 945(1):258-64.

Stroun M, Anker P, Maurice P, et al. Neoplastic Characteristics of the DNA Found in the Plasma of Cancer Patients. Oncology. 1989; 46(5):318-22.

Delgado PO, Alves BC, Gehrke Fde S, et al. Characterization of cell-free circulating DNA in plasma in patients with prostate cancer. Tumour Biol. 2013; 34(2):983-6.

Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985-90.

Kohler C, Barekati Z, Radpour R, et al. Cell-free DNA in the circulation as a potential cancer biomarker. Anticancer Res. 2011; 31(8):2623-8.

Schwarzenbach H, Hoon DSB, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011; 11(6):426-37.

Stroun M, Anker P. Nucleic acids spontaneously released by living frog auricles. Biochem J. 1972; 128(3):100p-101p.

Stroun M, Lyautey J, Lederrey C, et al. About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta. 2001; 313(1-2):139-42.

Kajbafzadeh A-M, Payabvash S, Salmasi AH, et al. Smooth muscle cell apoptosis and defective neural development in congenital ureteropelvic junction obstruction. J Urol. 2006; 176(2):718-23.

Xia L, Li Z, Zhou B, et al. Baseline mutation profiling of 1134 samples of circulating cell-free DNA and blood cells from healthy individuals. BioRxiv. 2016:089813.

Roninson IB, Broude EV, Chang BD. If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist Updat. 2001; 4(5):303-13.

Wang BG, Huang HY, Chen YC, et al. Increased plasma DNA integrity in cancer patients. Cancer Res. 2003; 63(14):3966-8.

Trejo-Becerril C, Perez-Cardenas E, Taja-Chayeb L, et al. Cancer progression mediated by horizontal gene transfer in an in vivo model. PLoS One. 2012; 7(12):e52754.

Ansari J, Yun JW, Kompelli AR, et al. The liquid biopsy in lung cancer. Genes Cancer. 2016; 7(11-12):355.

Qin Z, Ljubimov VA, Zhou C, et al. Cell-free circulating tumor DNA in cancer. Chin J Cancer. 2016; 35:36.

Marzese DM, Hirose H, Hoon DS. Diagnostic and prognostic value of circulating tumor-related DNA in cancer patients. Expert Rev Mol Diagn. 2013; 13(8):827-44.

Saffar H, Sanii S, Heshmat R, et al. Expression of galectin-3, nm-23, and cyclooxygenase-2 could potentially discriminate between benign and malignant pheochromocytoma. Am J Clin Pathol. 2011; 135(3):454-60.

Leary RJ, Sausen M, Kinde I, et al. Detection of Chromosomal Alterations in the Circulation of Cancer Patients with Whole-Genome Sequencing. Sci Transl Med. 2012; 4(162):162ra154.

Chan KCA, Jiang P, Zheng YWL, et al. Cancer Genome Scanning in Plasma: Detection of Tumor-Associated Copy Number Aberrations, Single-Nucleotide Variants, and Tumoral Heterogeneity by Massively Parallel Sequencing. Clin Chem. 2013; 59(1):211-24.

Nawroz H, Koch W, Anker P, et al. Microsatellite alterations in serum DNA of head and neck cancer patients. Nat Med. 1996; 2(9):1035-7.

Khatami F, Noorinayer B, Ghiasi S, et al. Lack of effects of single nucleotide polymorphisms of the DNA methyltransferase 1 gene on gastric cancer in Iranian patients: a case control study. Asian Pac J Cancer Prev. 2009; 10(6):1177-82.

Khatami F, Larijani B, Heshmat R, et al. Meta-analysis of promoter methylation in eight tumor-suppressor genes and its association with the risk of thyroid cancer. PloS one. 2017; 12(9):e0184892.

Khatami F, Mohebi SR, Ghiasi S, et al. Effects of amino acid substitution polymorphisms of two DNA methyltransferases on susceptibility to sporadic colorectal cancer. Asian Pac J Cancer Prev. 2009; 10(6):1183-8.

Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet. 2012; 13(10):679-92.

Esteller M, Sanchez-Cespedes M, Rosell R, et al. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res. 1999; 59(1):67-70.

NASSERI‐MOGHADDAM S, Malekzadeh R, Sotoudeh M, et al. Lower esophagus in dyspeptic Iranian patients: a prospective study. J Gastroenterol Hepatol. 2003;18(3):315-21.

Silva J, Dominguez G, Villanueva M, et al. Aberrant DNA methylation of the p16INK4a gene in plasma DNA of breast cancer patients. Br J Cancer.1999; 80(8):1262-4.

Wong IH, Lo YD, Zhang J, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res. 1999; 59(1):71-3.

Kawakami K, Brabender J, Lord RV, et al. Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. J Natl Cancer Inst. 2000; 92(22):1805-11.

Lecomte T, Berger A, Zinzindohoué F, et al. Detection of free‐circulating tumor‐associated DNA in plasma of colorectal cancer patients and its association with prognosis. Int J Cancer. 2002; 100(5):542-8.

Warton K, Samimi G. Methylation of cell-free circulating DNA in the diagnosis of cancer. Front Mol Biosci.2015; 2:13.

Zhai R, Zhao Y, Su L, et al. Genome-wide DNA methylation profiling of cell-free serum DNA in esophageal adenocarcinoma and Barrett esophagus. Neoplasia. 2012; 14(1):29-33.

Schwarzenbach H, Nishida N, Calin GA, et al. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 2014; 11(3):145-56.

Best Myron G, Sol N, Kooi I, et al. RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics. Cancer Cell. 28(5):666-76.

Joosse Simon A, Pantel K. Tumor-Educated Platelets as Liquid Biopsy in Cancer Patients. Cancer Cell. 28(5):552-4.

Khatami F, Larijani B, Tavangar SM. The presence of tumor extrachomosomal circular DNA (ecDNA) as a component of liquid biopsy in blood. Medical Hypotheses. Med Hypotheses. 2018; 114: 5-7.

Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011; 331(6024):1559-64.

Riquet M, Rivera C, Gibault L, et al. [Lymphatic spread of lung cancer: anatomical lymph node chains unchained in zones]. Rev Pneumol Clin. 2014; 70(1-2):16-25.

Plaks V, Koopman CD, Werb Z. Cancer. Circulating Tumor Cells. Science. 2013; 341(6151):1186-8.

Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006; 127(4):679-95.

Ashworth T. A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust Med J. 1869; 14(3):146-9.

Fehm T, Sagalowsky A, Clifford E, et al. Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res. 2002; 8(7):2073-84.

Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer. 2003; 3(6):453-8.

Yu M, Ting DT, Stott SL, et al. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature. 2012; 487(7408):510-3.

Sleijfer S, Gratama JW, Sieuwerts AM, et al. Circulating tumour cell detection on its way to routine diagnostic implementation? Eur J Cancer. 2007; 43(18):2645-50

Hayes DF, Smerage J. Is there a role for circulating tumor cells in the management of breast cancer? Clin Cancer Res. 2008; 14(12):3646-50.

Pantel K, Riethdorf S. Pathology: are circulating tumor cells predictive of overall survival? Nat Rev Clin Oncol. 2009;6(4):190-1.

Panteleakou Z, Lembessis P, Sourla A, et al. Detection of circulating tumor cells in prostate cancer patients: methodological pitfalls and clinical relevance. Mol Med. 2009; 15(3-4): 101–114.

Esmaeilsabzali H, Beischlag TV, Cox ME, et al. Detection and isolation of circulating tumor cells: principles and methods. Biotechnol Adv. 2013; 31(7):1063-84.

Nieva J, Wendel M, Luttgen MS, et al. High-definition imaging of circulating tumor cells and associated cellular events in non-small cell lung cancer patients: a longitudinal analysis. Phys Biol. 2012; 9(1):016004

Hou JM, Krebs M, Ward T, et al. Circulating tumor cells as a window on metastasis biology in lung cancer. Am J Pathol. 2011; 178(3):989-96.

O'Flaherty JD, Gray S, Richard D, et al. Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer. Lung Cancer. 2012; 76(1):19-25.

Gallo M, De Luca A, Maiello MR, et al. Clinical utility of circulating tumor cells in patients with non-small-cell lung cancer. Transl Lung Cancer Res. 2017; 6(4):486-498.

Fidler IJ, Poste G. The "seed and soil" hypothesis revisited. Lancet Oncol. 2008; 9(8):808.

Krebs MG, Hou J-M, Ward TH, et al. Circulating tumour cells: their utility in cancer management and predicting outcomes. Ther Adv Med Oncol. 2010; 2(6): 351–365.

Coman DR, de LR, Mcc UM. Studies on the mechanisms of metastasis; the distribution of tumors in various organs in relation to the distribution of arterial emboli. Cancer Res. 1951; 11(8):648-51.

Theodoropoulos PA, Polioudaki H, Agelaki S, et al. Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer. Cancer Lett. 2010; 288(1):99-106.

Aktas B, Tewes M, Fehm T, et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009; 11(4):R46.

Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006; 7(2):131-42.

Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003; 15(6):740-6.

Yang J, Mani SA, Weinberg RA. Exploring a new twist on tumor metastasis. Cancer Res. 2006; 66(9):4549-52.

Aceto N, Bardia A, Miyamoto DT, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158(5):1110-1122.

Khatami F, Aghayan HR, Sanaei M, et al. The Potential of Circulating Tumor Cells in Personalized Management of Breast Cancer: A Systematic Review. Acta Med Iran. 2017; 55(3):175-93.

Rack B, Schindlbeck C, Jückstock J, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014; 106(5): dju066.

Tavangar SM, Shojaee A, Tabriz HM, et al. Immunohistochemical expression of Ki67, c-erbB-2, and c-kit antigens in benign and malignant pheochromocytoma. Pathol Res Pract. 2010; 206(5):305-9.

Omidfar K, Moinfar Z, Sohi AN, et al. Expression of EGFRvIII in thyroid carcinoma: immunohistochemical study by camel antibodies. Immunol Invest. 2009; 38(2):165-80.

de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008; 14(19):6302-9.

de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 364(21):1995-2005.

Yap TA, Olmos D, Brunetto AT, et al. Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol. 2011; 29(10):1271-9.

Bianchini D, Omlin A, Pezaro C, et al. First-in-human Phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide to exon 4 of the androgen receptor mRNA in patients with castration-resistant prostate cancer. Br J Cancer. 2013; 109(10):2579-86.

van der Pol E, Boing AN, Harrison P, et al. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012; 64(3):676-705.

Keller S, Sanderson MP, Stoeck A, et al. Exosomes: from biogenesis and secretion to biological function. Immunol Lett. 2006; 107(2):102-8.

Edgar JR. Q&A: What are exosomes, exactly? BMC Biol. 2016; 14: 46.

Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol. 1983; 97(2):329-39.

Zhang W, Xia W, Lv Z, et al. Liquid Biopsy for Cancer: Circulating Tumor Cells, Circulating Free DNA or Exosomes? Cell Physiol Biochem. 2017; 41(2):755-768.

Raposo G, Nijman HW, Stoorvogel W, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996; 183(3):1161-72.

Sheridan C. Exosome cancer diagnostic reaches market. Nat Biotechnol. 2016; 34(4):359-60

Mouritzen P, Fredsøe JC, Blondal T, et al. Abstract B40: A two-microRNA signature in urinary exosomes for diagnosis of prostate cancer. AACR; 2016.

Webb S. The cancer bloodhounds. Nat Biotechnol. 2016; 34(11):1090-1094.

Riahi R, Gogoi P, Sepehri S, et al. A novel microchannel-based device to capture and analyze circulating tumor cells (CTCs) of breast cancer. Int J Oncol. 2014; 44(6):1870-8.

Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013; 497(7447):108-12.

Ignatiadis M, Lee M, Jeffrey SS. Circulating Tumor Cells and Circulating Tumor DNA: Challenges and Opportunities on the Path to Clinical Utility. Clin Cancer Res. 2015; 21(21):4786-800.

Li M, Diehl F, Dressman D, et al. BEAMing up for detection and quantification of rare sequence variants. Nat Methods. 2006; 3(2):95-7.

Baker M. Digital PCR hits its stride. Nat Methods. 2012; 9(6):541.

Leary RJ, Sausen M, Kinde I, et al. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med. 2012; 4(162):162ra54.

Chan KC, Jiang P, Zheng YW, et al. Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem. 2013; 59(1):211-24.

Yeo ZX, Chan M, Yap YS, et al. Improving indel detection specificity of the Ion Torrent PGM benchtop sequencer. PLoS One. 2012; 7(9):e45798.

Sabetkish S, Kajbafzadeh AM, Sabetkish N, et al. Whole‐organ tissue engineering: Decellularization and recellularization of three‐dimensional matrix liver scaffolds. Annu Rev Biomed Eng. 2011; 13:27-53.

Loman NJ, Misra RV, Dallman TJ, et al. Performance comparison of benchtop high-throughput sequencing platforms. Nat Biotechnol. 2012; 30(5):434-9.

Takai E, Totoki Y, Nakamura H, et al. Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer. Adv Exp Med Biol. 2016; 924:13-17.

Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014; 20(5):548-54.

Leary RJ, Kinde I, Diehl F, et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med. 2010; 2(20):20ra14.

Riethdorf S, Fritsche H, Muller V, et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin Cancer Res. 2007; 13(3):920-8.

Thege FI, Lannin TB, Saha TN, et al. Microfluidic immunocapture of circulating pancreatic cells using parallel EpCAM and MUC1 capture: characterization, optimization and downstream analysis. Lab Chip. 2014; 14(10):1775-84.

Saucedo-Zeni N, Mewes S, Niestroj R, et al. A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire. Int J Oncol. 2012; 41(4):1241-50.

Ozkumur E, Shah AM, Ciciliano JC, et al. Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci Transl Med. 2013; 5(179):179ra47.

Vona G, Sabile A, Louha M, et al. Isolation by size of epithelial tumor cells: a new method for the immunomorphological and molecular characterization of circulatingtumor cells. Am J Pathol. 2000; 156(1):57-63.

Wu S, Liu Z, Liu S, et al. Enrichment and enumeration of circulating tumor cells by efficient depletion of leukocyte fractions. Clin Chem Lab Med. 2014; 52(2):243-51.

Joosse SA, Gorges TM, Pantel K. Biology, detection, and clinical implications of circulating tumor cells. EMBO Mol Med. 2015; 7(1): 1–11.

Dragovic RA, Gardiner C, Brooks AS, et al. Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis. Nanomedicine. 2011; 7(6):780-8.

Lim J, Yeap SP, Che HX, et al. Characterization of magnetic nanoparticle by dynamic light scattering. Nanoscale Res Lett. 2013; 8(1): 381.

Graham MD. The Coulter principle: Imaginary origins. Cytometry A. 2013; 83(12): 1057–1061.

Sharma S, Gillespie BM, Palanisamy V, et al. Quantitative nanostructural and single-molecule force spectroscopy biomolecular analysis of human-saliva-derived exosomes. Langmuir. 2011; 27(23):14394-400.

Aras O, Shet A, Bach RR, et al. Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia. Blood. 2004; 103(12):4545-53.

Petersen KE, Manangon E, Hood JL, et al. A review of exosome separation techniques and characterization of B16-F10 mouse melanoma exosomes with AF4-UV-MALS-DLS-TEM. Anal Bioanal Chem. 2014; 406(30):7855-66.

Schachermeyer S, Ashby J, Zhong W. Advances in field-flow fractionation for the analysis of biomolecules: instrument design and hyphenation. Anal Bioanal Chem. 2012; 404(4):1151-8.

Pospichalova V, Svoboda J, Dave Z, et al. Simplified protocol for flow cytometry analysis of fluorescently labeled exosomes and microvesicles using dedicated flow cytometer. J Extracell Vesicles. 2015; 4:25530.

Smith ZJ, Lee C, Rojalin T, et al. Single exosome study reveals subpopulations distributed among cell lines with variability related to membrane content. J Extracell Vesicles. 2015; 4: 28533.

He M, Crow J, Roth M, et al. Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology. Lab Chip. 2014; 14(19):3773-80.

Mathivanan S, Simpson RJ. ExoCarta: A compendium of exosomal proteins and RNA. Proteoics. 2009; 9(21):4997-5000.

Alimoghaddam K, Shariftabrizi A, Tavangar M, et al. Anti-leukemic and anti-angiogenesis efficacy of arsenic trioxide in new cases of acute promyelocytic leukemia. Leuk Lymphoma. 2006; 47(1):81-8.

Carrasco-Ramírez P, Greening DW, Andrés G, et al. Podoplanin is a component of extracellular vesicles that reprograms cell-derived exosomal proteins and modulates lymphatic vessel formation. Oncotarget. 2016; 7(13):16070-89.

Howitt J, Hill AF. Exosomes in the Pathology of Neurodegenerative Diseases. J Biol Chem. 2016; 291(52):26589-26597.

Valadi H, Ekstrom K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007; 9(6):654-9.

Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008; 110(1):13-21.

Rabinowits G, Gercel-Taylor C, Day JM, et al. Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer. 2009; 10(1):42-6.

Brase JC, Johannes M, Schlomm T, et al. Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer. 2011; 128(3):608-16.

Tanaka Y, Kamohara H, Kinoshita K, et al. Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer. 2013; 119(6):1159-67.

Lv LL, Cao YH, Ni HF, et al. MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis. Am J Physiol Renal Physiol. 2013; 305(8):F1220-7.

Kuwabara Y, Ono K, Horie T, et al. Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage. Circ Cardiovasc Genet. 2011; 4(4):446-54.

Dhir M, McCoy KL, Ohori NP, et al. Correct extent of thyroidectomy is poorly predicted preoperatively by the guidelines of the American Thyroid Association for low and intermediate risk thyroid cancers. Surgery. 2018; 163 (1):81-87.

Haghpanah V, Soliemanpour B, Heshmat R, et al. Endocrine cancer in Iran: based on cancer registry system. Indian J Cancer. 2006; 43(2):80-5.

National Cancer Institute. "SEER stat fact sheets: thyroid cancer." Surveillance, Epidemiology, and End Results Program website (2016).

Larijani B, Shirzad M, Mohagheghi M, et al. Epidemiologic feature of thyroid cancer based on cancer registry data system. Iranian Journal of Public Health. 2005; 34(4):1-7.

Larijani B, Shirzad M, Mohagheghi M, et al. Epidemiologic analysis of the Tehran cancer institute data system registry (TCIDSR). Asian Pac J Cancer Prev. 2004; 5(1):36-9.

Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009; 19(11):1167-214.

Nikiforov YE, Yip L, Nikiforova MN. New strategies in diagnosing cancer in thyroid nodules: impact of molecular markers. Clin Cancer Res. 2013; 19(9):2283-8. 141. Tavangar S, Monajemzadeh M, Larijani B, et al. Immunohistochemical study of oestrogen receptors in 351 human thyroid glands. Singapore Med J. 2007; 48(8):744-7.

Haddadi-Nezhad S, Larijani B, Tavangar SM, et al. Comparison of fine-needle-nonaspiration with fine-needle-aspiration technique in the cytologic studies of thyroid nodules. Endocr Pathol. 2003; 14(4):369-73.

Shirzad M, Larijani B, Hedayat A, et al. Diagnostic value of frozen section examination in thyroid nodule-surgery at the shariati hospital (1997–2000). Endocr Pathol. 2003; 14(3):263-8.

Katoh H, Yamashita K, Enomoto T, et al. Classification and general considerations of thyroid cancer. Ann Clin Pathol. 2015; 3(1):1045.

Gild ML, Bullock M, Robinson BG, et al. Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinol. 2011 23; 7(10):617-24.

Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011; 7(10):569-80.

Saffar H, Sanii S, Emami B, et al. Evaluation of MMP2 and Caspase-3 expression in 107 cases of papillary thyroid carcinoma and its association with prognostic factors. Pathol Res Pract. 2013; 209(3):195-9.

Sanii S, Saffar H, Tabriz HM, et al. Expression of matrix metalloproteinase-2, but not caspase-3, facilitates distinction between benign and malignant thyroid follicular neoplasms. Asian Pac J Cancer Prev. 2012; 13(5):2175-8.

Mohammadi-asl J, Larijani B, Khorgami Z, et al. Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma. Med Oncol. 2011; 28(4):1123-8.

Haghpanah V, Shooshtarizadeh P, Heshmat R, et al. Immunohistochemical analysis of survivin expression in thyroid follicular adenoma and carcinoma. Appl Immunohistochem Mol Morphol. 2006; 14(4):422-5.

Tabriz HM, Adabi K, Lashkari A, et al. Immunohistochemical analysis of nm23 protein expression in thyroid papillary carcinoma and follicular neoplasm. Pathol Res Pract. 2009; 205(2):83-7.

Mohammadi-Asl J, Larijani B, Khorgami Z, et al. Prevalence of BRAFV600E mutation in Iranian patients with papillary thyroid carcinoma: a single-center study. J Appl Sci. 2009; 9(19):3593-7.

Khatami F, Larijani B, Tavangar SM. Circulating Tumor BRAF Mutation and Personalized Thyroid Cancer Treatment. Asian Pac J Cancer Prev. 2017; 18(2):293-294.

Amoli MM, Yazdani N, Amiri P, et al. HLA-DR association in papillary thyroid carcinoma. Dis Markers. 2010; 28(1):49-53.

Sarmadi S, Izadi-Mood N, Sotoudeh K, et al. Altered PTEN expression; a diagnostic marker for differentiating normal, hyperplastic and neoplastic endometrium. Diagn Pathol. 2009; 4:41.

Umetani N, Hiramatsu S, Hoon DS. Higher amount of free circulating DNA in serum than in plasma is not mainly caused by contaminated extraneous DNA during separation. Ann N Y Acad Sci. 2006; 1075:299-307.

Zane M, Agostini M, Enzo MV, et al. Circulating cell-free DNA, SLC5A8 and SLC26A4 hypermethylation, BRAFV600E: A non-invasive tool panel for early detection of thyroid cancer. Biomed Pharmacother. 2013; 67(8):723-30.

Hu S, Ewertz M, Tufano RP, et al. Detection of serum deoxyribonucleic acid methylation markers: a novel diagnostic tool for thyroid cancer. J Clin Endocrinol Metab. 2006; 91(1):98-104.

Chuang TC, Chuang AY, Poeta L, et al. Detectable BRAF mutation in serum DNA samples from patients with papillary thyroid carcinomas. Head Neck. 2010; 32(2):229-34.

Janku F, Huang HJ, Claes B, et al. BRAF mutation testing in cell-free DNA from the plasma of patients with advanced cancers using a rapid, automated molecular diagnostics system. Mol Cancer Ther. 2016; 15(6):1397-404.

Sandulache VC, Williams MD, Lai SY, et al. Real-time genomic characterization utilizing circulating cell-free DNA in patients with anaplastic thyroid carcinoma. Thyroid. 2017; 27(1):81-87.

Evers C, Duose DY, Mehrotra M, et al. Liquid Biopsy: Comparison of Mutation Detection Methods for Measurement of RET M918T Circulating Cell-Free DNA in Medullary Thyroid Cancer Patients. Cancer Genetics. 2016; 209(6):287.

Khatami F, Tavangar SM. Genetic and Epigenetic of Medullary Thyroid Cancer. Iran Biomed J. 2017.

Brose MS, Cabanillas ME, Cohen EE, et al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016; 17(9):1272-82.

Lubitz CC, Parangi S, Holm TM, et al. Detection of Circulating BRAF V600E in Patients with Papillary Thyroid Carcinoma. J Mol Diagn. 2016; 18(1):100-8.

Qiu Z-L, Shen C-T, Sun Z, et al. Circulating Long Non-Coding RNAs Act as Biomarkers for Predicting 131I Uptake and Mortality in Papillary Thyroid Cancer Patients with Lung Metastases. Cell Physiol Biochem. 2016; 40(6):1377-1390.

Hsieh C-H, Lin H-C, Huang S-B, et al. Circulating epithelial cell enumeration facilitates the identification and follow-up of a patient with early stage papillary thyroid microcarcinoma: A case report. Clin Chim Acta. 2016; 454:107-11.

Tseng C-P, Lin J-D, Lin H-C, et al. Combined analysis of circulating epithelial cell count and serum thyroglobulin for differentiating disease status of the patients with papillary thyroid carcinoma. Oncotarget. 2016 29; 7(13): 17242–17253.

Dent BM, Ogle LF, O'Donnell RL, et al. High‐resolution imaging for the detection and characterisation of circulating tumour cells from patients with oesophageal, hepatocellular, thyroid and ovarian cancers. Int J Cancer. 2016; 138(1):206-16.

Xu JY, Handy B, Michaelis CL, et al. Detection and prognostic significance of circulating tumor cells in patients with metastatic thyroid cancer. J Clin Endocrinol Metab. 2016; 101(11):4461-4467.

Xu JY, Zaidi T, Cote GJ, et al. Circulating Tumor Cells (CTCs) in Metastatic Papillary Thyroid Cancer: Report of a Case-Control Pilot Study. Thyroid Neoplasia: Endocrine Society; 2016. p. PP22-3-PP-3.

Lakkaraju A, Rodriguez-Boulan E. Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol. 2008; 18(5):199-209.

Van Niel G, Porto-Carreiro I, Simoes S, et al. Exosomes: a common pathway for a specialized function. J Biochem. 2006; 140(1):13-21.

Lin J, Li J, Huang B, et al. Exosomes: Novel Biomarkers for Clinical Diagnosis. The Scientific World Journal. 2015; 2015:1-8.

Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008 29; 105(30):10513-8.

Hunter MP, Ismail N, Zhang X, et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One. 2008; 3(11): e3694.

Rabinowits G, Gerçel-Taylor C, Day JM, et al. Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer. 2009; 10(1):42-6

Tanaka Y, Kamohara H, Kinoshita K, et al. Clinical impact of serum exosomal microRNA‐21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer. 2013; 119(6):1159-67.

Takeshita N, Hoshino I, Mori M, et al. Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma. Br J Cancer. 2013; 108(3):644-52.

Samsonov R, Burdakov V, Shtam T, et al. Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer. Tumour Biol. 2016; 37(9):12011-12021.

Lee JC, Zhao JT, Clifton‐Bligh RJ, et al. MicroRNA‐222 and MicroRNA‐146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer. Cancer. 2013; 119(24):4358-65.

Lee JC, Zhao JT, Gundara J, et al. Papillary thyroid cancer-derived exosomes contain miRNA-146b and miRNA-222. J Surg Res. 2015; 196(1):39-48.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.