Atypia of undetermined significance/follicular lesion of undetermined significance: Asian vs. non-Asian practice, and the Singapore experience

Abstract

The Bethesda System for Reporting Thyroid Cytopathology has paved the way for comparisons of the practice of thyroid cytology in many different regions. However, there have been comparatively few studies documenting differences between Asian and non-Asian practice. Here, we aim to compare a few key parameters between the two regions, focusing on the indeterminate category of atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS). We compared its incidence, resection rates (RRs), risk of malignancy (ROM), rate of repeat fine needle aspiration (rFNA), ROMs of cytomorphologic subcategories of nuclear atypia (AUS-N) vs. architectural atypia (AUS-A), and, finally, the incidence of papillary thyroid carcinoma (PTC) vs. follicular neoplasms (FNs) in resected AUS/FLUS cases in Asian and non-Asian regions. Where possible, these metrics were compared with the Singapore experience from a tertiary referral institution. While the incidence of AUS/FLUS was similar in both regions, we found geographical differences in the RRs and ROMs, which may reflect a higher collective threshold for surgery in Asian countries. However, both cohorts showed higher ROMs in the AUS-N subcategory as compared to the AUS-A subcategory, supporting the subclassification of the AUS/FLUS based on the presence of nuclear atypia. We also observed a higher incidence of AUS-N coupled with a higher incidence of PTC in resected AUS/FLUS nodules in Asian cohorts, while AUS-A and follicular-patterned neoplasms featured more prominently in the non-Asian cohorts. These incidences may account for the starkly different molecular approaches that we noted-in Asian (chiefly Korean and Chinese) centers, BRAF mutational analysis was favored, while gene panels and gene expression classifiers were more frequently applied in non-Asian centers (chiefly in the United States of America). Overall, the data from Singapore appears more closely aligned to non-Asian trends, despite its geographical location in Southeast Asia and its predominantly Asian population. We conclude that there is significant heterogeneity in the outcomes of the AUS/FLUS categories between and within regions, which is only partially explained by regional variations, and may also reflect different regional diagnostic and management practices. This highlights the importance of understanding the local context in the interpretation of indeterminate Bethesda categories, rather than adopting a "one-size fits all" approach.

Keywords: Bethesda classification; atypia of undetermined significance (AUS); fine needle aspiration cytology; follicular lesion of undetermined significance (FLUS); thyroid.

Figure 1

Forest plots of meta-analysis on the resection rates of AUS/FLUS nodules. (A) Asian series; (B) non-Asian series. AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance.

Figure 2

Forest plots of meta-analysis on the risk of malignancy of AUS/FLUS nodules. (A) Asian series; (B) non-Asian series. AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance.

Figure 3

Forest plots of meta-analysis on risk of malignancy of AUS-A vs. AUS-N. (A) Asian countries; (B) non-Asian countries. AUS-A, AUS/FLUS with architectural atypia; AUS-N, AUS/FLUS with nuclear atypia; AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance.

Figure 4

Forest plots of meta-analysis on incidences of AUS subgroups between Asian and non-Asian series. (A) AUS-N incidence; (B) AUS-A incidence. AUS-A, AUS/FLUS with architectural atypia; AUS-N, AUS/FLUS with nuclear atypia; AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance.

Figure 5

Histologic outcomes in Asian vs. non-Asian series. (A) Incidence of PTC; (B) proportion of FVPTC (among PTCs); (C) incidence of FNs. PTC, papillary thyroid carcinoma; FVPTC, follicular variant papillary thyroid carcinoma; FNs, follicular neoplasms.

Figure 6

Example of AUS case with histologic resection. (A,B) This case was categorized as atypical (AUS) primarily because of nuclear features such as focal nuclear enlargement, occasional oval nuclei and variably pale chromatin (A: Diff-Quick stain, original magnification ×600; B: Papanicolaou stain, original magnification ×600). (C,D) Histology follow-up revealed a follicular adenoma (H&E stain, original magnification ×40, ×200). AUS, atypia of undetermined significance.

Figure S1

Funnel plots of sample estimates from studies included in pooled analysis of the following: (A) incidence of AUS/FLUS; (B) RR of AUS/FLUS; (C) OROM of AUS/FLUS; (D) incidence of AUS-A; (E) incidence of FN. AUS/FLUS, atypia of undetermined significance/follicular lesion of undetermined significance; RR, resection rate; OROM, overall risk of malignancy; AUS-A, AUS/FLUS with architectural atypia; FN, follicular neoplasm.

Figure S2

Funnel plot of sample estimates from studies that compared ROMs between the cytomorphological subgroups (AUS-A vs. AUS-N). AUS-A, AUS/FLUS with architectural atypia; AUS-N, AUS/FLUS with nuclear atypia; ROM, risk of malignancy.