Fine needle aspiration cytology (FNA) forms an important means of detecting thyroid pathologies with a substantial amount of reliability, influencing clinical management. To provide universal reporting guidelines to all cytopathologists, the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was formulated in 2007 (1) and later revised in 2017 (2,3). This system classifies a thyroid FNA into six diagnostic categories namely (I) non-diagnostic, (II) benign, (III) atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), (IV) follicular neoplasm/suspicious for follicular neoplasm, (V) suspicious for malignancy, and (VI) malignant; each category having an implied risk of malignancy (ROM) and recommended management protocol. The system has been widely adopted across the world for thyroid cytology reporting (4).
The AUS/FLUS category is the most heterogeneous among the six subcategories, defined by a set of nine distinct diagnostic criteria. TBSRTC has laid down guidelines for permissible frequency and ROM of the AUS/FLUS to prevent overuse and for quality control (1). Meta-analysis studies have documented a wide range in the frequency and ROM of AUS/FLUS (5-9). However, most of the data analyzed in these studies is derived from western publications. Also, differences in thyroid clinical practice have been documented between Asia and the West (10-14), but lack detailed meta-analysis work-up.
India, owing to iodine-deficiency, has a high prevalence of endemic goitre. A recent meta-analysis on the status of thyroid cytology in India reported a high ROM in the AUS/FLUS subcategory (15).
Therefore, the present systematic review and meta-analysis aimed to review the literature on AUS/FLUS across the globe, assessing the category’s prevalence, resection rate (RR) and ROM, while comparing the data from India with the rest of Asia and the West. We present the following article in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) reporting checklist (available at http://dx.doi.org/10.21037/gs-20-392).
Search strategy and study identification
We searched for relevant articles in PubMed and Google search engines from January 2009 till Dec 2019. We searched using the terms “AUS Thyroid” and “FLUS Thyroid”. All studies which were found on the internet were evaluated. Additionally, we carried out a thorough evaluation of the citations within the included publications and reviews. We followed the recommendations of the PRISMA statement (16).
Selection criteria and abstract screening
After searching electronic databases, search results were imported into Mendeley (Elsevier, Amsterdam, Netherlands). Two reviewers (PG, SAG) independently screened the titles and abstracts for potential articles. Studies fulfilling the following criteria were included: (I) use of TBSRTC 2007 for reporting thyroid cytopathology, with (II) availability of data regarding the total number of thyroid FNAs, the distribution of cases according to TBSRTC 2007 or at least mentioning the total number of AUS cases reported, the number of AUS cases undergoing resection, and number of AUS cases with a malignant diagnosis.
The exclusion criteria were: (I) use of other classification systems or TBSRTC 2017 for reporting, (II) inadequate data provided to calculate the frequency, RR or ROM of the AUS category, e.g., studies based only on cases with available surgical follow-up, (III) studies based on tru-cut biopsy, (IV) those dealing with only pediatric population, (V) those dealing solely with sub-centimetric nodules, (VI) studies using pre-operative ultrasound and molecular tests that can bias the RR and ROM, (VII) case reports, (VIII) reviews, (IX) conference-related proceedings, posters, theses, (X) use of a language other than English, and (XI) publications where only abstract was available. In case of more than one study being published from the same institute with overlapping time period, and potential of overlapping data, only the study with the higher number of cases was included. Diagnosis of repeat aspirations, in case performed, was not considered. Discrepancies, if any, were resolved by discussion and consensus.
Full-text screening and data extraction
All the potential articles were screened by the two reviewers. The studies were segregated into three groups depending upon the location of the institute where the study was carried out, as those from India, (rest of) Asia or from the West. The data as defined above was recorded in an excel sheet with pre-defined headings. The various headings used in the excel were as follows: name of the researcher, year in which the study was published, institution, country, the total number of thyroid nodules aspirated, number of cases designated AUS, number of AUS aspirates that were resected and number of malignant cases at resection. As many studies included were published prior to 2016, to maintain uniformity Non-Invasive Follicular Thyroid neoplasm with Papillary-like nuclear features (NIFTP), wherever specified, was deemed malignant. Histopathology details of malignancies were also noted.
The meta-analysis was performed using the DerSimonian-Laird method and their 95% confidence intervals (CI) were calculated using the random effects model. The frequency, RR and ROM of AUS were determined by calculating the proportion of AUS cases to the total number of aspirates, nodules resected to the total number of AUS aspirates and malignant nodules on resection to the total number of resected nodules (ROM-resection), respectively and then multiplied by 100. The overall ROM (ROM-overall) was calculated taking the total number of AUS aspirates as the denominator. Forest plots were generated displaying prevalence with corresponding 95% CI. The variation in the magnitude of the effect was examined and heterogeneity was quantified using I-squared statistic. Funnel plots were used to detect potential reporting bias and small/large study effects and the Egger’s regression method was used to assess asymmetry. Sensitivity analysis was carried out to investigate the effect of studies that had very large prevalence. One-way ANOVA test was used to compare frequencies, RR, and ROM among Indian, Asian and Western practices. A P value of <0.05 was considered statistically significant.
We found a total of 15,000 studies on the internet when we used the selected phrases for search in PubMed and Google search engines for the defined period. Of these, 60 studies [18 from India (13,17-33), 12 from Asia (13,34-44), and 30 from the West (8,45-73)] (Table 1) fulfilled all the inclusion and exclusion criteria. The study by Bychkov et al. (13), is an Asian multi-institutional study, from which the data from India was extracted, and analyzed with the rest of the studies from India. The studies by Faquin (53) and Zhou (73) were multi-institutional and both had data from the University of Pennsylvania. Hence, due to the possibility of there being an overlap, the patient data of the University of Pennsylvania was excluded from the paper by Zhou et al. (73).
There were a total of 201,657 thyroid FNAs out of which 14,279 were from Indian studies, 62,448 from the other Asian studies, and 124,930 were from the studies of the Western region.
Considering all studies from all three zones, pooled estimate of frequency was 7.3% (6.3–8.3%), of RR was 41.9% (37.4–46.6%), of ROM-resection was 33.3% (26.8–39.9%) and of ROM-overall was 11.1% (9.3–12.9%).
Considering the three areas separately (Figures 1-3), the pooled frequency of AUS ranged from 5.8% (India) to 8.7% (Asia) (Table 2, Figures 1A,2A,3A) and did not vary significantly across the three regions (Table 3). The pooled RR was highest in India (52.9%) and lowest in the rest of Asia (26.5%) (Figures 1B,2B,3B); pooled prevalence for ROM-resection was highest in Asia (45.9%) but lowest in the West (26.3%) (Table 2; Figures 1C,2C,3C) and was significantly different between the two regions (P<0.01) (Table 3). ROM-overall was similar across the three regions, ranging from 10.1% to 14.4% (Figures 1D,2D,3D).
Even after sensitivity analysis, heterogeneity across the studies persisted. The pooled estimate of RR in India decreased from 52.95% (38.56–67.35%) to 46.69% (32.87–60.51%) and the pooled estimate of ROM-resection in Asia decreased from 45.86 (32.15–59.56%) to 35.00% (22.05–47.96%).
Funnel plots demonstrated presence of publication bias mostly in Indian and Western studies (Figure 4).
Considering results of only those studies in which histopathological outcome of all malignancies was specified, papillary thyroid carcinoma (PTC) was the most common surgical diagnosis (87.9%; 1,082/1,231), but PTC subtypes were not detailed in all reports. Of the studies with details available, borderline tumors and low-grade cancers (NIFTP, follicular variant of PTC and tumors of uncertain malignant potential) constituted 41.7% (40/96) of the available diagnoses from India, 24.4% (82/336) from Asia and 51.8% (246/475) from the West. The rest of the malignant diagnoses included other PTC variants (including papillary microcarcinoma), follicular carcinoma, Hurthle cell carcinoma, poorly differentiated thyroid carcinoma, anaplastic thyroid carcinoma, medullary thyroid carcinoma, lymphoma and metastasis. There was no case of hyalinizing trabecular adenoma.
Thyroid cancer forms around 3% of all malignancies and is the most common endocrine malignancy (74). The incidence varies across the globe and even across different regions of a country. In India, the incidence is highest in the southern and north-eastern regions (75,76).
FNAC is the primary screening test performed for all thyroid swellings, aiding in segregating benign from malignant. To maintain uniformity in reporting across the World and facilitate easy interpretation by the clinicians, TBSRTC was formulated in 2007 (1). Of the six cytology categories described under TBSRTC, category III (AUS/FLUS) is the most heterogeneous. Its use has to be limited to less than 7% (revised to 10%) of the thyroid aspirates at any given center (1-3).
An AUS/FLUS nodule on resection, may turn out to be non-neoplastic or neoplastic. TBSRTC 2007 recommends AUS/FLUS aspirates to be managed by repeat FNA and resection to be done only if the nodule is clinically or radiologically suspicious. The implied ROM of AUS/FLUS as per TBSRTC 2007 was 5–15% (1), which, in the recent edition of TBSRTC, has been revised to 10–30% if NIFTP is considered malignant and 6-18%, on excluding NIFTP from the malignant group (2,3). Due to the presence of data implicating geographic differences in thyroid practice (10-14), we performed this systematic meta-analysis to assess differences, if any, between the frequency, RR and ROM of AUS/FLUS across India, rest of Asia and the West.
Marked heterogeneity was found across the studies from all the zones for all the parameters assessed (I-squared ranged from 70.3% to 99.1%), as was also noted in previously published meta-analyses (6-9). This stems partly from the non-specific diagnostic criteria of AUS/FLUS. Focal/extensive but mild cytological and/or architectural atypia not enough to be classified into a higher category; atypia in follicular/lymphoid or other cells, all are grouped under AUS/FLUS (1). Hence, most of the neoplastic and non-neoplastic thyroid pathologies can show AUS/FLUS cytology, though high-grade malignancies are less represented in this category (77-80). There may also be regional and individual differences in the interpretation of the Bethesda criteria. A more robust application of TBSRTC and the practice of taking consensus before reporting, may help reduce this heterogeneity.
The overall pooled estimate of frequency of AUS/FLUS was 7.3% in our analysis. Against the recommended 7% cut-off (1), pooled estimates of frequency were marginally high in the West (7.5%) and Asia (8.7%), but low in India (5.8%).
Despite similar frequencies, the pooled estimates of RR and ROM-resection were quite different across the three geographical regions. Asia recorded the lowest RR (26.5%), suggesting that Asian clinicians took a more selective surgical approach; to avoid overtreatment, a conservative management of active follow-up is preferred for low-risk thyroid carcinomas (12), most of which show indeterminate cytology (TBSRTC categories III/IV/V). India had the highest pooled RR (53%). The reason why these patients were operated upon: whether repeat aspirate showed a higher Bethesda category, patient’s choice or due to institutional preference, is not clear. Being a developing nation, there is always a concern regarding patients being lost to follow-up, especially those from the lower socio-economic group. The western studies also showed a relatively high pooled RR (42%). Hence, patients in the West and India are more likely to be operated upon following a diagnosis of AUS than in the rest of Asia.
While the implied ROM for AUS/FLUS, as per TBSRTC 2007 is 5–15% (1), the pooled ROM-resection, considering all the included studies, was 33.3%. ROM-resection of the three zones when evaluated separately, ranged from 26–46%. Although the implied ROM has been enhanced to 10–30% in the revised TBSRTC (2,3), the values derived from Asian and Indian studies remained higher than others. A low RR is one of the causes for a high ROM-resection (46%) in the Asian population where stricter clinical and radiological criteria are followed for surgery. The opposite holds for the Western studies, and the pooled estimates of ROM of the Asian and western studies were statistically different. The pooled estimate of ROM-resection in the Indian studies was intermediate between that of Asia and West despite the highest RR. This discrepancy is difficult to explain. One of the reasons could be variability in making a decision in borderline cases with doubtful PTC-type nuclear features. A low threshold for nuclear features will lead to a cytological diagnosis of “suspicious for PTC”, decreasing the ROM of AUS/FLUS (12). This especially holds true for the follicular variant of PTC (FVPTC) and its borderline counterpart NIFTP, which show subtle nuclear features, and are more susceptible to observer variation (10,81-83). It has been documented that AUS/FLUS diagnosis recognizes low-risk PTC, mostly FVPTC and low-stage PTC in contrast to a malignant FNA diagnosis which is associated with high-risk PTC (77-80). A decrease in ROM has also been seen in the West but not so much in Asia, when cases of NIFTP are removed from malignancy (12,13), thereby suggesting that besides the lower RR of indeterminate nodules, the diagnostic threshold of PTC-type nuclear features is higher in Asia than in the West (12). Bychkov et al., in their study based on data derived from six tertiary thyroid cancer centers representing five Asian countries, documented a 6% absolute decrease in ROM of AUS/FLUS after excluding NIFTP (13), in contrast to 11% (95% CI: 4–19%) reported in a meta-analysis based on four datasets from the western population (84). In the current study, low-grade cancers were the least common (24.4%) in the Asian cohort, followed by Indian (41.7%), and Western (51.8%). This also suggests that the threshold of Indian pathologists for nuclear features is intermediate between Asian and Western pathologists. Studies comparing inter-observer variation among India, Asian and Western pathologists may help in confirming or refuting this possibility. Hirokawa in 2002 documented lack of inter-observer reproducibility between Japanese and American pathologists in interpretation of encapsulated follicular thyroid lesions on histology. The latter were more likely to diagnose them as FVPTC than the former (10). A recent study found inter and intra-observer variation in interpretation of nuclear features of NIFTP among nine Asian pathologists (82), in contrast to excellent inter-observer agreement seen in another study in which pathologists from California, Japan and UK participated (85).
To accommodate for the high ROM reported by various studies, TBSRTC 2017 recommended sub-classification of AUS/FLUS depending upon the nature (nuclear and/or architectural) of atypia present and the type of cells involved (follicular, Hurthle, lymphoid) along with detailed description of the case to improve pathologist-clinician communication and understanding; but the recommended management plan remains uniform across the subtypes, and includes the option of molecular testing or lobectomy besides repeat FNA (2,3). Sub-classification can help in predicting the type of likely neoplasia, which in turn can help in deciding further management (80). As we analyzed studies which had used TBSRTC 2007, the cases had not been sub-classified. Availability of molecular facilities and adequate follow-up services also impact the RR and ROM across countries as well as individual centers.
Another important factor influencing ROM is disease prevalence, which varies not only from country to country but also within different geographical areas of a country (74-76) as well as from institute to institute depending upon the level of hospital care provided. A tertiary care hospital or a cancer center is bound to have higher ROM than regional hospitals. It has also been shown that higher the ROM of all operated nodules, higher will be the ROM of each category (12). Lastly, publication bias will also affect statistics.
While the ROM-resection confers with malignancy rate among all resected nodules, the ROM-overall, which ranged from 10–14%, conveys the proportion of malignancies to total AUS aspirates. As only a proportion of the AUS/FLUS nodules get resected, the actual ROM will be somewhere between the two values. Interestingly, pooled proportions of ROM-overall were similar across the three regions (Table 2), suggesting that AUS is still a relatively homogeneous category under TBSRTC.
There are some limitations of our study. Besides the publication bias, we envisage a selection bias also as our data analysis is retrospective. Also, we had to exclude many studies where it was not possible to calculate frequency, RR or ROM of AUS/FLUS, or studies in which pre-operative radiology or molecular analyses were used which could have biased the RR and the ROM. Another limitation was the substantial heterogeneity among the included studies.
Our meta-analysis provides an updated assessment of the thyroid cytology practice in India with reference to the most heterogeneous Bethesda category of AUS/FLUS, and its comparison with the rest of Asia and the west. All the studies showed marked heterogeneity. While the pooled prevalence of AUS/FLUS was similar across the Indian, Asian and Western cohorts, and neared the recommended upper limit of 7%, the pooled RR and ROM-resection varied across the three geographical zones. The RR of AUS/FLUS in India was the highest, probably reflecting the clinician’s apprehension of patients being lost to follow-up. RR was the lowest in the rest of Asia owing to their policy of active surveillance in indeterminate aspirates with otherwise benign clinical findings. ROM of AUS/FLUS in all the three regions was higher than the recommended range; being lowest for West followed by India and highest for Asia, due to varying RRs, observer variations and cancer prevalence. All these factors lead to marked regional differences in thyroid clinical practice, much different from the prescribed international guidelines.
We thank Dr. Kennichi Kakudo for his invaluable inputs and guidance during the conduct of the study (Kennichi Kakudo, MD, PhD. Department of Pathology and Thyroid Disease Center, Izumi City General Hospital, Izumi City, Osaka 594-0073, Japan); we thank Dr. Huy Gia Vuong for guiding us in collection and analysis of data (Huy Gia Vuong, MD, PhD. Department of Pathology, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, USA); we thank Dr. Andrey Bychkov for his inputs during data collection and evaluation (Andrey Bychkov, MD, PhD. Department of Pathology, Kameda Medical Center, Kamogawa City, Chiba 296-8602, Japan).
Provenance and Peer Review: This article was commissioned by the Guest Editor (Kennichi Kakudo) for the series “Asian and Western Practice in Thyroid Pathology: Similarities and Differences” published in Gland Surgery. The article was sent for external peer review organized by the Guest Editor and the editorial office.
Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/gs-20-392
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-392). The series “Asian and Western Practice in Thyroid Pathology: Similarities and Differences” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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