E.S. Kozorezova1, S.E. Titov2, U.V. Veryaskina3, I.V. Sleptsov4, S.L. Vorobyev5, R.A. Chernikov6, A.A. Uspenskaya7, A.V. Zolotoukho8, V.P. Govorushkina9, E.I. Karamysheva10, Kushlinskii V.D. Nazarov11, N.E. Kushlinskii12

1, 12 N.N. Blokhin National Medical Research Center of Oncology Ministry of Health of the Russian Federation (Moscow, Russia)

2 Institute of Molecular and Cellular Biology of the Siberian Department of the Russian Academy of Sciences (Novosibirsk, Russia)

2, 3 AO Vector-Best (Novosibirsk, Russia)

4, 6–9 Pirogov Clinic of High Medical Technologies of St. Petersburg State University (Saint-Petersburg, Russia)

5 National Center for Clinical Morphological Diagnostic (Saint-Petersburg, Russia)

1, 10, 12 Russian University of Medicine, Ministry of Health of Russia (Moscow, Russia)

11 I.P. Pavlov First Saint Petersburg State Medical University (Saint-Petersburg, Russia)

1 kozorezovaes@yandex.ru, 2 titovse78@gmail.com, 3 microrna@inbox.ru, 4 newsurgery@yandex.ru, 5 slvorob@mail.ru, 6 yaddd@yandex.ru, 7 Uspenskaya_anna@mail.ru, 8 a.zolotoukho@gmail.com, 9 GovorLera@mail.ru, 10 prof.karamysheva@gmail.com, 11 Nazarov19932@mail.ru, 12 kne3108@gmail.com

Oncocytic carcinomas (OC) are radioiodine-resistant forms of thyroid cancer (TC) with an unfavorable prognosis, prone to distant metastasis and dedifferentiation into more malignant forms of TC. Differentiating OC from oncocytic adenomas (OA) of the thyroid gland at the preoperative stage is associated with significant difficulties, as neither imaging diagnostic methods nor cytological evaluation of aspirates obtained during fine-needle biopsy of thyroid lesions can distinguish malignant from benign processes. The search for effective preoperative molecular markers is a highly relevant task aimed at the early detection of OC and their differentiation from the predominant OA.

The purpose aim of this work is to identify molecular genetic markers that can increase the predictive capabilities of diagnosing OC and OA at the preoperative stage.

This retrospective study included 104 conventional cytological samples of oncocytic tumors obtained from 104 patients during fine-needle aspiration biopsy of thyroid lesions. The results of preoperative methods (ultrasound, cytological examination) were compared with the results of postoperative histological examination. Based on the results of the latter, patients were divided into two groups: 73 patients with OA and 31 patients with OC. The study examined 23 molecular genetic markers (mRNA of 10 genes: FN1, Geminin, CDKN2A, TIMP1, CITED1, TPO, SLC26A7, HMGA2, CPQ, RXRG; 12 microRNA: miR-125b-5p, miR-146b-5p, miR-148b-3p, miR-199b-5p, miR-21-5p, miR-221-3p, miR-223-3p, miR-31-5p, miR-375, miR-451a, miR-551b-3p, miR-885-5p; the ratio of mitochondrial and nuclear DNA). The resulting diagnostic characteristics for determining OС (including the 95% confidence interval): sensitivity 93.5% (78.6-99.2%), specificity 100.0% (95.1-100.0%), accuracy 98.0% (93.2-99.8%), PPV-100.0% (88.1-100.0%), NPV - 97.3% (90.5-99.3%). The final diagnostic panel, which included miR-221, the CITED1 gene, and the ratio of mitochondrial and nuclear DNA as markers, turned out to be highly specific (100%) and quite sensitive (93.5%).

The obtained results allow us to conclude that the use of additional molecular diagnostic methods can help more effectively stratify patients with oncocytic thyroid tumors according to the degree of risk of malignancy at the preoperative stage. However, validation in a larger sample, including other types of thyroid lesions associated with oncocytic transformation of the thyroid epithelium, is necessary.

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