Prognostic significance of the Bethesda cytological classification in recurrent thyroid carcinoma

Introduction. The Bethesda System for Reporting Thyroid Cytopathology allows to standardize interpretation of fine needle aspiration biopsy of thyroid nodules with assessment of suspected malignancy risk. Analysis of prognostic significance of cytological data, using the Bethesda System as an example, is necessary for determination of tumor process aggressiveness and possibility of development of recurrences.
Aim. To study prognostic significance of the Bethesda System for Reporting Thyroid Cytopathology in recurrent thyroid carcinoma.
Materials and methods. Results of examinations and surgical interventions performed at the Altai Regional Oncological Dispensary (Barnaul) during a 3-year period in 503 patients (423 women (84.1 %) and 80 (15.9 %) men) with thyroid carcinoma are analyzed. In 440 patients, thyroid carcinoma in surgical material was found for the first time (R0 – primary patients); in 63 patients, disease recurrence was diagnosed (R1 – presence of recurrence). At the time of surgery, median patient age was 51 years (interquartile range 40–62 years). The inclusion criterion for the study was morphologically confirmed diagnosis of thyroid carcinoma; the exclusion criterion was the absence of cytological examination per the Bethesda System in patients with recurrent carcinoma. Data from medical records, disease histories and cancer registry were evaluated taking into account clinical and anamnestic characteristics of a special classifier for determination of risk factors of disease recurrence. Data processing was performed using Microsoft Excel software. At the preoperative stage, in primary patients, results of ultrasound and cytological examination of the fine needle aspiration biopsy of thyroid nodules were analyzed. Results of cytological examination per the Bethesda System were considered as an independent risk factor of recurrence. Orange Data Mining (version 3.3.37.0) and RStudio (version 4.3.1) software were used for data analysis. Distributions of quantitative variables were evaluated using the Kolmogorov–Smirnov and Shapiro–Wilk tests. Normal distribution hypothesis was rejected at p <0.20 for Kolmogorov–Smirnov test and at p <0.05 for Shapiro–Wilk test.
Results. According to the data, median time to recurrence was 2 years (Q₁–Q₃ – 1–6 years), minimal time to its development was 1 year, maximal – 20 years. 1-year recurrence-free survival was 100 %, 3-year was 91 %, 5-year was 86 %, 10-year was 59 %, 15-year was 25 %. Mean time to recurrence in 50 % of patients was 9.8 ± 0.9 years. Risk of recurrence of thyroid carcinoma of category IV per the Bethesda System was 3.623 times (72.4 %) lower compared to category III (hazard ratio 0.276; 95 % confidence interval 0.110–0.691; p = 0.006). Recurrence-free survival in patients with thyroid carcinoma of category VI per the Bethesda System was significantly higher (р = 0003 and p < 0.001) than in patients with category III and IV cytopathology.
Conclusion. Cytological conclusion of category III per the Bethesda System is 2.755 times more common in recurrence group than of category VI. Category VI cytopathology, 88.7 % of which are papillary thyroid carcinoma with conclusive cell signs, is characterized by relatively low risk of recurrence. Cytologic conclusion of categories III and IV per the Bethesda System is an unfavorable prognostic factor in preoperative diagnostics due to undetermined interpretation of the pathology. These categories are commonly observed in patients with more aggressive disease progression.

1. Malignant neoplasms in Russia in 2021 (morbidity and mortality). Ed. by A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2022. 252 p. (In Russ.).

2. Ali S.Z., Baloch Z.W., Cochand-Priollet B. et al. The 2023 Bethesda system for reporting thyroid cytopathology. J Am Soc Cytopathol 2023;12(5):319–25. DOI: 10.1016/j.jasc.2023.05.005

3. Ali S.Z., Baloch Z.W., Cochand-Priollet B., Schmitt F.C., Vielh P., VanderLaan P. A. The 2023 Bethesda system for reporting thyroid cytopathology. Thyroid 2023;33(9):1039–44. DOI: 10.1089/thy.2023.0141

4. Crescenzi A., Palermo A., Trimboli P. Cancer prevalence in the subcategories of the indeterminate class III (AUS/FLUS) of the Bethesda system for thyroid cytology: a meta-analysis. J Endocrinol Invest 2021;44(7):1343–51. DOI: 10.1007/s40618-021-01526-3

5. Bagıs M., Can N., Sut N. et al. A Comprehensive approach to the thyroid Bethesda category III (AUS) in the transition zone between 2nd edition and 3rd edition of the bethesda system for reporting thyroid cytopathology: subcategorization, nuclear scoring, and more. Endocr Pathol 2024;35(1):51–76. DOI: 10.1007/s12022-024-09797-1

6. Maletta F., Massa F., Torregrossa L. et al. Cytological features of “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” and their correlation with tumor histology. Hum Pathol 2016:54:134–42. DOI: 10.1016/j.humpath.2016.03.014

7. Coca-Pelaz A., Rodrigo J. P., Agaimy A. et al. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): what do we need to know? Virchows Arch 2024;485(6):977–87. DOI: 10.1007/s00428-024-03953-y

8. Titov S.E., Demenkov P.S., Lukyanov S.A. et al. Preoperative detection of malignancy in fine-needle aspiration cytology (FNAC) smears with indeterminate cytology (Bethesda III, IV) by a combined molecular classifier. J Clin Pathol 2020;73 (11):722–7. DOI: 10.1136/jcli\npath-2020-206445

9. Siraj A.K., Parvathareddy S.K., Annaiyappanaidu P. et al. Male sex is an independent predictor of recurrence-free survival in middle eastern papillary thyroid carcinoma. Front Endocrinol (Lausanne) 2022;13:777345. DOI: 10.3389/fendo.2022.777345

10. Wu S.S., Lamarre E.D., Yalamanchali A. еt al. Association of treatment strategies and tumor characteristics with overall survival among patients with anaplastic thyroid cancer: a single-institution 21-year experience. JAMA Otolaryngol Head Neck Surg 2023;149(4):300–9. DOI: 10.1001/jamaoto.2022.5045

11. Proietti A., Signorini F., Giannini R. et al. Outcomes of the tall-cell variant of papillary thyroid carcinoma in patients with different ages: a 17-year mono-institutional experience. Cancers (Basel) 2023;15(7):2152. DOI: 10.3390/cancers15072152

12. Ruiz E., Kandil E., Alhassan S. at al. An integrative multi-omics analysis of the molecular links between aging and aggressiveness in thyroid cancers. Aging Dis 2023;14(3):992–1012. DOI: 10.14336/AD.2022.1021