Utility of Routine Frozen Section of Thyroid Nodules Classified as Follicular Neoplasm

Meta-Analysis of Diagnostic Tests

Jhorman Grisales, MD; Alvaro Sanabria, PhD


Am J Clin Pathol. 2020;153(2):210-220. 

In This Article

Abstract and Introduction


Objectives: To evaluate the diagnostic performance of frozen section in thyroid nodules classified as follicular neoplasm.

Methods: A diagnostic test meta-analysis was designed. Studies that assessed frozen section in patients with thyroid nodules and a fine-needle aspiration biopsy result of Bethesda IV were selected. The outcomes measured were the number of false- and true-positive and -negative results. We used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) instrument for methodological quality assessment and a bivariate mixed-effects regression framework and a likelihood-based estimation of the exact binomial approach.

Results: Forty-six studies from 1991 to 2018 were included. Most studies had moderate methodological quality. The overall sensitivity and specificity were 43% (95% confidence internal [CI], 0.34–0.53) and 100% (95% CI, 0.99–1.00), respectively. The hierarchic summary receiver operating characteristic curve showed an area under the curve of 0.91 (95% CI, 0.80–0.97).

Conclusions: Frozen section demonstrates moderate diagnostic performance in patients with follicular neoplasm, and its utility for making intraoperative decisions is limited. Its routine use should be discouraged.


Thyroid nodules are the most common condition treated by head and neck surgeons. Ultrasonography and fine-needle aspiration biopsy (FNAB) are the tried and true techniques for determining malignancy and deciding on the specific treatment. Traditionally, FNAB results are classified as low, moderate, or high risk of malignancy. Since 2009, when the Bethesda classification was adopted,[1] FNAB results have been divided into six categories that help to guide surgical conduct. At one extreme, the Bethesda V and VI nodules, with a high incidence of malignancy, are treated mainly by surgery. At the other extreme, Bethesda I and II nodules undergo more studies or are followed given their low incidence of malignancy. In the midrange are nodules categorized as Bethesda III and IV, also known as atypia, undetermined results, and follicular pattern or follicular neoplasia. In these cases, the probability of malignancy is moderate, and classification is difficult for pathologists.[2] For surgeons, nodules in this category are challenging because the surgical decision depends on many factors, including a family history of disease, the ultrasonographic characteristics of the nodule, and the operative findings. Currently, the American Thyroid Society (ATA) guidelines recommend repeating the FNAB for Bethesda III nodules and performing a partial or total thyroidectomy for Bethesda IV nodules depending on the nodule size, given a risk of malignancy of 15% to 25%.[3] However, this approach implies the performance of a high number of unnecessary thyroidectomies with the consequent operative risk and the necessity for external thyroid hormone support.[4]

To avoid this high rate of diagnostic surgery, intraoperative frozen section (iFS) has been recommended for decades as a tool to determine the benign or malignant lineage of the nodule and to avoid unnecessary total thyroidectomies and the risk of damage to laryngeal nerves and parathyroid glands.[5] This approach is defended by some authors, whereas others disregard its use. A great quantity of information exists about the performance of iFS in the management of thyroid nodules; however, research on the specific category of undetermined nodules is scarce, with high heterogeneity in the methods used and the patients studied.

The aim of this study was to evaluate the diagnostic performance (sensitivity, specificity, predictive values, and likelihood ratios [LRs]) of iFS in nodules classified as Bethesda IV, follicular pattern, or follicular neoplasm, using a systematic review and meta-analysis methodology.