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Walid Zeyghami Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Marie-Louise Uhre Hansen Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Kathrine Kronberg Jakobsen Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Christian Groenhøj Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Endocrinology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Clinical Sciences, University of Copenhagen, Copenhagen, Denmark

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Christian von Buchwald Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Clinical Sciences, University of Copenhagen, Copenhagen, Denmark

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Christoffer Holst Hahn Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Thyroid cancer (TC) represents the most common endocrine malignant tumor. Liquid biopsy has been suggested as a new and accurate biomarker in cancer. This systematic review analyzes the existing literature on circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free DNA integrity index (cfDI), and their potential as biomarkers for TC, including the subtypes: differentiated (papillary and follicular), medullary, and anaplastic. A systematic search was performed in PubMed, Embase, and Cochrane databases for published articles in English between 1 January 1970 and 6 September 2022 (PROSPERO: CRD42022358592). The literature search generated a total of 635 articles. In total, 36 articles were included (patients = 2566). Four studies reported that higher levels of CTCs were associated with metastases and worse prognosis. Nineteen studies found the presence of mutated ctDNA in TC patients. The diagnostic accuracy in detecting BRAFV600E as ctDNA was determined in 11 studies regarding papillary TC. The pooled sensitivity, specificity, and diagnostic odds ratio were estimated at 56% (95% CI 36–74), 91% (95% CI 84–95) and 12 (95% CI 4.09–33.11), respectively. Four studies concluded that the cfDI was higher in patients with TC compared to benign thyroid lesions and healthy controls. The detection of CTCs, ctDNA, and cfDI may have a potential prognostic value in TC in relation to diagnosis, disease progression, and treatment efficacy. Despite the promising potential of CTCs, ctDNA, and cfDI in TC management, limitations hinder direct comparison and generalization of findings. Standardized methodologies, larger patient cohorts, and a consensus on relevant markers are needed to validate their clinical applicability and enhance TC management.

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Jes Sloth Mathiesen Department of ORL Head & Neck Surgery, Odense University Hospital, Odense, Denmark
Institute of Clinical Research, University of Southern Denmark, Odense, Denmark

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Jens Peter Kroustrup Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Peter Vestergaard Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Mette Madsen Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark

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Kirstine Stochholm Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark

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Per Løgstrup Poulsen Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark

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Åse Krogh Rasmussen Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark

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Sten Schytte Department of ORL Head & Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Henrik Baymler Pedersen Department of ORL Head & Neck Surgery, Aalborg University Hospital, Aalborg, Denmark

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Christoffer Holst Hahn Department of ORL Head & Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark

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Jens Bentzen Department of Oncology, Herlev Hospital, Herlev, Denmark

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Mette Gaustadnes Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

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Torben Falck Ørntoft Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

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Thomas van Overeem Hansen Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark

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Finn Cilius Nielsen Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark

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Kim Brixen Institute of Clinical Research, University of Southern Denmark, Odense, Denmark

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Anja Lisbeth Frederiksen Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark

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Christian Godballe Department of ORL Head & Neck Surgery, Odense University Hospital, Odense, Denmark

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