PREDICTIVE VALUE OF SERUM TSH AND FREE T4 LEVELS IN DIFFERENTIATING MALIGNANT FROM BENIGN THYROID NODULES: A SYSTEMATIC REVIEW
Keywords:
thyroid nodule, thyrotropin, thyroid stimulating hormone, free thyroxine, thyroid neoplasms, diagnosis, systematic reviewAbstract
Background. Thyroid nodules are detected in most adults but few are malignant. Serum thyroid-stimulating hormone (TSH) is measured in almost every nodule work-up, yet guidance uses it to select patients for scintigraphy rather than to grade cancer risk. Whether TSH, or free thyroxine (FT4), adds usable diagnostic information for the individual nodule is unsettled.
Objective. To determine whether pre-diagnostic serum TSH or FT4 discriminates malignant from benign thyroid nodules verified by cytology or histopathology in adults.
Methods. Systematic review reported to PRISMA 2020. PubMed/MEDLINE and the Consensus index were searched to 17 July 2026; strings for Scopus, Embase, Web of Science and CENTRAL are supplied for execution. Eligible studies were observational nodule cohorts reporting TSH or FT4 against a cytological or histological reference standard. Risk of bias was assessed with QUADAS-2, certainty with GRADE. Effect measures were not convertible, so synthesis was narrative by outcome.
Results. Twelve studies comprising 10,497 adults, recruited 1984-2021 across seven countries, met the criteria. Nine reported higher TSH in malignant than benign nodules; three found no association. Adjusted odds ratios ranged from 1.49 to 11.18, the largest confined to the highest TSH strata of one cohort. Reported thresholds spanned 0.9 to 2.26 mU/L, each derived within the cohort that evaluated it, none externally validated. FT4 was measured in four studies but analysed in two, which disagreed. Nine of twelve studies were at high risk of bias, most often from patient selection restricted to operated patients. Certainty was very low throughout.
Conclusion. Higher serum TSH is associated with malignancy in most but not all nodule cohorts. The association is not reproducible at any threshold, so TSH cannot serve as a stand-alone triage test, and the FT4 evidence is too sparse to judge. TSH is best used as one weak contributor within a multivariable assessment, not as an independent diagnostic criterion.
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Copyright (c) 2026 Ni Luh Gede Taman Kristanti, I Gusti Ngurah Bayu Paramartha, Ni Komang Okyantri Dana Pertiwi (Author)
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