Subclassification of AUS/FLUS Category for Thyroid Nodules: Trials and Evidence-Based Clinical Management

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Background

The worldwide growing incidence of thyroid nodules and papillary thyroid cancer is already a common malignancy of the endocrine system ranging from 10 – 70 % of adult population. The 2007 National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference and the subsequent Bethesda System for Reporting Thyroid Cytopathology (BSRTC) recommend that each thyroid FNA report begin with six distinct diagnostic categories. Each risk category needs evidence-based clinical management.

The “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS) category in the BSRTC is a heterogeneous category of cases that are not clearly benign or malignant. The category of AUS/FLUS has been heavily debated and also includes cases with non-specific patterns affected by compromising factors such as air-drying artifact, low cellularity, or obscuring elements.
The risk of malignancy (ROM) associated with different subgroups remains unresolved; ROM for AUS/FLUS varies greatly among medical centers. The category of AUS/FLUS was originally proposed for a group of lesions that contained cells with too great a degree of architectural and/or nuclear atypia to be definitively diagnosed as benign but insufficient atypical features to be classified as suspicious for a follicular neoplasm, suspicious for a malignancy, or malignant.
The frequency of AUS/FLUS interpretation should be in the range of approximately 7% of all thyroid FNA interpretations. It also includes specimens with borderline cellularity/compromised quality. Therefore, there have been differences in its utilization, with significant variability in rates of AUS/FLUS among institutions. Moreover, rates of malignancy among this category have varied widely, ranging from 6% to 48% among selected subsets of the patients undergoing surgery
Subclassification of AUS/FLUS might be helpful in identifying nodules with a high ROM in this category and improving the management of such nodules. The AUS subcategory indicates a higher risk of malignancy than the FLUS subcategory. To resolve some of these problems, recent studies of the malignancy risk in AUS/FLUS suggest a two-tier subclassification of the AUS/FLUS category:
1-Low cellularity with predominant microfollicular architecture and absence of colloid; and
2-Nuclear features not characteristic of benign lesions (nuclear atypia) attributable to strict criteria for the evaluation of cancer probability.

This Research Topic aims to include original research articles, (mini)reviews, systematic reviews, meta-analyses, on themes related to:
- Insights regarding the Bethesda System for Reporting Thyroid Cytopathology (BSRTC)
- BRAF molecular testing for the stratification of ROM into high-risk and low-risk AUS cases;
- morphological subcategorization, based on atypia qualifiers and molecular testing, potential improvement of malignancy risk stratification of AUS/FLUS patients;
- Different qualifiers of AUS/FLUS thyroid FNA e.g. BRAF, RAS, RET/PTC, and PAX8/PPARg alterations
- hybrid molecular and morphological subcategorization systems in improving the malignancy risk stratification of thyroid FNA samples diagnosed as AUS/FLUS.

Keywords: Thyroid nodules, Fine-needle aspiration (FNA) cytology, Bethesda System for Reporting Thyroid Cytopathology (BSRTC), The risk of malignancy (ROM), Cytologic atypia [CyA], Architectural atypia (AA), Hürthle cell changes (HC), Regressive changes (RC), Preparation artifacts (AR), Atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)

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