Thyroid FNA terminology: The case for a single unified international system for thyroid FNA reporting

The use of reporting terminologies for thyroid FNA cytology enables standardisation and international alignment of the reporting of thyroid cytology results, which is essential. There are currently three major internationally recognised systems: Bethesda (TBS), UK RCPath (Thy), and Italian (TIR). A fourth terminology system used in Japan has identical categories to TBS but with different nomenclature. The aim of this review is to discuss the strengths and weaknesses of the TBS, UK RCPath, and TIR systems, and to make the case for international terminology harmonisation and standardisation.


| INTRODUC TI ON
There have been long-standing efforts to standardise thyroid FNA reporting terminology. In 2008 The Bethesda System for Reporting Thyroid Cytopathology (TBS) was launched. 1 In 2021 worldwide, the majority of thyroid FNA cytology aspirates are reported using TBS, 2,3 or a Japanese adaptation of TBS although the UK RCPath 4 and Italian 5 terminology systems are also used (see Tables 1 and 2). With TBS there is some variation between Western and Asian countries in the reported pooled risks of malignancy (ROM) in the various categories. 6

| D IAG NOS TI C PERFORMAN CE OF THE VARIOUS TERMINOLOG IE S
The UK RCPath terminology shows similar diagnostic performance to TBS as measured by ROM in the various categories, 7 although with differences; eg some but not all publications from the UK show comparatively higher rates for non-diagnostic FNA (Thy1) 8 and UK RCPath also classifies cysts in a slightly different way to the Bethesda system. 4 The results obtained using the three major terminology systems, TBS, 2 UK RCPath, 4 and Italian, 5 are all now validated by meta-analyses of ROM 7,[9][10][11][12][13][14][15] and all three terminologies show relatively moderate to good interobserver agreement in the different cytological categories, [16][17][18][19][20][21] although there is still a need for international thyroid FNA terminology standardisation.

| PROB LEMS IN ACHIE VING INTERNATIONAL S TANDARDISATION
Historically, efforts to achieve standardisation in international thyroid cytology terminology have been held back by the fact that the final histopathological diagnosis in a significant number of cases in thyroid disease can be subjective and is subject to significant interobserver variation. There are well known problems of interobserver variation in the assessment of capsular 22,23 and vascular invasion 24 in suspected thyroid cancer, two of the major diagnostic criteria for malignancy. In 2017 the WHO Classification of Tumours of the Endocrine Organs introduced revised terminology for encapsulated follicular thyroid neoplasms. 25 Prior to 2016, in some centres with higher diagnostic rates for papillary thyroid cancer over 20% of newly diagnosed thyroid cancers were diagnosed as encapsulated follicular variant of papillary thyroid carcinoma.
In most cases after 2017 these tumours would now be re-designated NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features), a very low risk of malignancy lesion and not a cancer. 26 This in turn has consequences for the diagnosis of thyroid cancer on FNA cytology 27,28 with inevitable reductions in the risk of malignancy in the various TBS, 2 UK RCPath, 29 or Italian 14 terminology cytological categories, although the size of the reduction in the risk of malignancy depends on the cytological category and the overall prevalence of NIFTP. Published rates of NIFTP range from 0%-2% to over 20% [30][31][32][33][34][35] depending on the institutional diagnostic threshold for NIFTP, which in turn rests principally on the criteria for papillary carcinoma-type nuclei used in histopathological assessment in the relevant centre.

| S TRENG TH S AND WE AK NE SS E S OF THE VARI OUS TERMINOLOGY SYS TEMS
It would be useful to highlight some of the strengths and weaknesses of the various terminology systems. Worldwide, TBS is the single most utilised terminology for thyroid FNA reporting and most peerreviewed publications use TBS. As also highlighted above, there are quite wide variations in the reported outcomes of TBS when comparing published results of Western practice with Asian practice. 6 TBS also emphasises specific management for each diagnostic category. 2 The UK RCPath system takes a less prescriptive attitude, stating that the patient management decisions should be made by multidisciplinary teams and that all patients with higher-risk, eg Thy 4 and Thy 5 FNA (equivalent to TBS category V/Italian TIR 4, and TBS category VI/Italian TIR 5), should be discussed within the multidisciplinary setting, whereas the need for multidisciplinary discussion of lower risk fine needle aspirates is at the discretion multidisciplinary teams. 4 All three terminologies, TBS, 2 UK RCPath 4 and Italian, 5 have indeterminate categories; in TBS these are categories III and IV, 2 in UK RCPath they are Thy 3a and 3F, 4 and in the Italian system they are TIR 3A and TIR 3B. 5 Meta-analyses of the three systems show that the one system which demonstrates the most progressive incremental risk of malignancy in the indeterminate categories is the Italian system, 14

| THE FUTURE
TBS terminology 2  can be attributed to multidisciplinary treatment differences and diagnostic threshold differences, at least some of which are based on differing care pathways for the management of nodules. In Japan and some other parts of Asia there is increased use of non-operative policies, ie surveillance for smaller thyroid nodules reported as cytologically malignant. 38 The inherent subjectivity of many of the diagnostic cytology subcategory thresholds, as shown by interobserver reproducibility studies which indicate only moderate levels of interobserver concordance and comparatively poor interobserver concordance for some indeterminate categories, eg Thy3a, is also another likely explanation. 16

| CON CLUS ION
In conclusion, while thyroid reporting cytology terminology should by definition align with histopathology terminology, like any other computer algorithm or expert system it is only as good as its validation benchmarks. Where there are known international geographic and inter-institutional differences in diagnostic thresholds for thyroid lesions and cancer, particularly for histopathologically subjective diagnoses such as NIFTP (published rates ranging from 0%-2% to over 20% [30][31][32][33][34][35], these issues create a problem for comparative studies of thyroid FNA cytology in different countries. Molecular pathology holds promise in terms of refining diagnostic thresholds in borderline diagnostic cases. It is now widely accepted that the presence of specific gene mutations in histopathology or cytopathology specimens from the thyroid, eg BRAF V600E mutations in a primary thyroid lesion, are almost always associated with thyroid carcinoma, similarly less common gene mutations such as TP 53 and TERT promoter mutations, and some other less common translocations are almost invariably associated with thyroid carcinoma.

CO N FLI C T O F I NTE R E S T
The authors have no conflicts of interest to declare.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable-no new data generated.