Addressing diagnostic gaps in thyroid pathology: a multiplex protein panel as an adjunctive tool for risk stratification and differentiation of thyroid neoplasms

Kitsilovskaya, N. A.; Butenko, I. O.; Vakaryuk, A. V.; Kovalenko, A. V.; Gremyacheva, V. D.; Kozhemyakin, G. L.; Lazareva, A. A.; Lebedeva, A. A.; Baraboshkin, N. M.; Fedorov, O. V.; BONDARENKO, E. E.; IOUTSI, V. A.; AKSENOVA, T. N.; MOKRYSHEVA, N. G.; Govorun, V. M.

doi:10.64898/2026.01.15.699717

bioRxiv · 10.64898/2026.01.15.699717

Addressing diagnostic gaps in thyroid pathology: a multiplex protein panel as an adjunctive tool for risk stratification and differentiation of thyroid neoplasms

Kitsilovskaya, N. A.·Butenko, I. O.·Vakaryuk, A. V.·Kovalenko, A. V.·Gremyacheva, V. D.·Kozhemyakin, G. L.·Lazareva, A. A.·Lebedeva, A. A.·Baraboshkin, N. M.·Fedorov, O. V.·BONDARENKO, E. E.·IOUTSI, V. A.·AKSENOVA, T. N.·MOKRYSHEVA, N. G.·Govorun, V. M.

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Abstract

Fine-needle aspiration biopsy of thyroid nodules frequently yields indeterminate results, leading to unnecessary diagnostic surgeries. We evaluated a targeted plasma proteomics approach to differentiate benign follicular thyroid adenoma (FTA) from malignant papillary thyroid carcinoma (PTC). Using LC-MRM mass spectrometry with stable isotope-labeled standards (SIS), we quantified a multiplex protein panel in plasma samples from 267 patients. The analytical workflow incorporated an MS-based assessment of preanalytical hemolysis to prevent bias associated with thyroid-related blood composition changes and multiple rounds of randomization allowed assessment of batch effects. While previously proposed low-abundance thyroid cancer markers were rarely detected in the cohort, a signature of high-abundance plasma proteins successfully stratified the patients. The malignant PTC phenotype was characterized by a significant increase in apolipoprotein A1 and myosin-9, along with elevated CD14 and kininogen-1. Benign FTA was associated with higher levels of acute-phase proteins, including ceruloplasmin and complement C1q subunit C. Simple PCRE model with 20 parameters based on 4 major plasma proteins allowed to build a classifier with specificity that can be adjusted with regard to epidemiology and medical resource. This study establishes a foundational mass spectrometry-based framework that utilizes systemic proteomic profiles to differentiate underlying pathologies and improve clinical decision-making regarding patient management. By enabling additional stratification of patients with Bethesda IV cytology, who are otherwise frequently subjected to unwarranted diagnostic operations, this multiplex MS approach provides a potential non-invasive triage tool to reduce unnecessary surgical interventions for indeterminate thyroid nodules.

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Kitsilovskaya, N. A., Butenko, I. O., Vakaryuk, A. V., Kovalenko, A. V., Gremyacheva, V. D., Kozhemyakin, G. L., Lazareva, A. A., Lebedeva, A. A., Baraboshkin, N. M., Fedorov, O. V., BONDARENKO, E. E., IOUTSI, V. A., AKSENOVA, T. N., MOKRYSHEVA, N. G., Govorun, V. M.. 2026-01-16. Addressing diagnostic gaps in thyroid pathology: a multiplex protein panel as an adjunctive tool for risk stratification and differentiation of thyroid neoplasms. https://doi.org/10.64898/2026.01.15.699717

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