Bethesda thyroid categories associated with tumor aggression in single-center study

The 2023 Bethesda System for Reporting Thyroid Cytopathology was associated with thyroid cancer aggressiveness, histologic subtype and molecular alterations in a retrospective study of 8,595 patients who underwent ultrasound-guided fine-needle aspiration at Sun Yat-sen Memorial Hospital, Sun Yat-sen University. The results indicate that the six-category classification conveyed information beyond the probability that a sampled thyroid nodule was malignant, although the retrospective design and surgically selected analysis cohort limit how broadly the associations can be interpreted. Researchers analyzed patients who underwent ultrasound-guided thyroid fine-needle aspiration between January 2016 and February 2025.

The available records included ultrasonographic features, cytologic diagnoses, clinicopathologic characteristics, molecular-testing results and final histologic outcomes. Each aspiration was assigned to one of the six 2023 Bethesda categories: nondiagnostic, benign, atypia of undetermined significance, follicular neoplasm, suspicious for malignancy or malignant. Of the 8,595 specimens, 3.5% were nondiagnostic, 60.2% were benign, 8.3% indicated atypia of undetermined significance, 3.7% represented follicular neoplasm, 1.9% were suspicious for malignancy and 22.4% were classified as malignant.

The malignancy rate increased stepwise through the higher Bethesda categories. Among the 2,960 patients who underwent thyroidectomy and entered the histopathologic analysis, malignancy rates were 39.7% for atypia of undetermined significance, 47.6% for follicular neoplasm, 78.0% for suspicious for malignancy and 99.2% for malignant cytology. Higher categories were also significantly associated with extrathyroidal extension, multifocality, lymphovascular invasion and lymph-node metastasis, with the reported comparisons yielding p-values below 0.05.

These were statistical associations in a retrospective surgical cohort; the analysis did not demonstrate that a Bethesda category caused any pathological feature. Cancer histology also differed across the cytologic categories. Classic variant papillary thyroid carcinoma accounted for 70.9% of cancers in the malignant Bethesda group, compared with 25.0% in atypia of undetermined significance, 14.4% in follicular neoplasm and 10.9% in suspicious for malignancy; the difference was significant at p<0.0001.

The analysis linked the preoperative cytologic category not only with the likelihood of cancer but also with the subtype identified in surgical specimens. Molecular results followed a related distribution: the frequency of the BRAF V600E mutation was 43.4% among Bethesda III cancers and 56.9% among Bethesda V cancers, while the high-risk alterations TERT, TP53 and PIK3CA were observed predominantly in the suspicious-for-malignancy category. Together, the observations support using the 2023 Bethesda System as a preoperative stratification tool that may help characterize a thyroid cancer’s likely subtype, molecular profile and aggressive pathological features.

The evidence remains bounded by the study design: it was conducted at a single center, was based on records collected over nine years, and its detailed histopathologic comparisons included only patients who underwent thyroidectomy. The full aspiration cohort also contained many benign results that did not lead to surgery, whereas operative outcomes were available for 2,960 patients. Within that surgically selected cohort, however, the study provides a measured association between increasingly severe Bethesda classifications and several indicators of tumor aggressiveness, offering a finer view of thyroid cancer than a simple benign-versus-malignant distinction.

Subject of Research: Associations between 2023 Bethesda cytology categories, thyroid cancer subtype, molecular alterations and pathological aggressiveness

Article Title: The 2023 Bethesda system is associated with aggressive features and histologic subtype in thyroid cancer

Article References: Xie, J., Liu, Y., Ding, W., & Luo, D. (2026). The 2023 Bethesda system is associated with aggressive features and histologic subtype in thyroid cancer. BMC Cancer. https://doi.org/10.1186/s12885-026-16903-5

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16903-5

Keywords: Bethesda System, thyroid cancer, fine-needle aspiration, cytopathology, tumor aggressiveness, papillary thyroid carcinoma, BRAF V600E, lymphovascular invasion, lymph-node metastasis, thyroidectomy, Bethesda, system