Abstract
Graphical abstract
Abstract
Objective
The objective of this study was to analyze the evolution in the diagnosis and management of indeterminate thyroid nodules over three time periods.
Methods
In total, 3020 patients with thyroid nodules underwent cytological evaluation during three periods (2006–2008, 2012–2014, 2017–2019). The distribution of diagnostic cytology, risk of malignancy, diagnostic performance indices of fine needle aspiration (FNA), and cytologic–histologic correlation in indeterminate cytology were analyzed.
Results
Only 2.2% of cytology tests were insufficient for a diagnosis. About 86.9% cytology was benign, 1.7% malignant, and 11.4% indeterminate. Indeterminate cytology rates were 15.9% (2006–2008), 10.1% (2012–2014), and 10% (2017–2019). Surgery was performed in 13% of benign cytology, resulting in malignant histology in 2.7%. All malignant and suspicious cytology underwent surgery, with malignancy confirmed in 98% and 77% of cases, respectively.
All ‘indeterminate with atypia’ cytology (2006–2008) and Bethesda IV (2012–2014; 2017–2019) underwent surgery, with malignancy confirmed in 19.6%, 43.8%, and 25.7%, respectively. In the ‘indeterminate without atypia’ category (2006–2008) and Bethesda III (2012–2014; 2017–2019), diagnostic surgery was performed in 57.7%, 78.6%, and 59.4%, respectively, with malignancy confirmed in 3.3%, 20.5%, and 31.6%. The FNA sensitivity was 91.6%, with a negative predictive value greater than 96% in all periods. The specificity exceeded 75% in the last two periods.
Conclusion
The Bethesda system reduces indeterminate cytology and improves the accuracy of FNA diagnosis. We reported a higher proportion of malignancy than expected in Bethesda III, underscoring the importance of having institution-specific data to guide decision-making. However, there is a need for risk stratification tools that allow for conservative management in low-risk cases.
Introduction
Clinical management of the thyroid nodules is based on a combination of clinical risk factors, functional status, ultrasound patterns, and cytologic findings when fine needle aspiration (FNA) is indicated (1, 2, 3, 4, 5, 6, 7, 8, 9). A cytological diagnosis carries a certain risk of malignancy (ROM), which has implications for clinical recommendations. While FNA is an efficient and cost-effective diagnostic procedure, it is important to note that histological study remains the ‘gold standard’ for accurate diagnosis of nodular lesions (10). One of the main limitations of this diagnostic test is the occurrence of indeterminate results, which are observed in approximately 20–30% of samples (11, 12). False positives can lead to ‘unnecessary’ diagnostic surgeries and are often associated with indeterminate cytology. False negatives are usually caused by inappropriate selection of the puncture site or errors in sample collection, although the use of ultrasound guidance has significantly reduced them (13).
In January 2006, the Endocrinology and Nutrition Unit at the Virgen de la Victoria Hospital in Malaga (Spain) started a high-resolution multidisciplinary unit. The management of this pathology has been influenced by guidelines published by international scientific societies, including those from 2006 (14, 15, 16), 2009/2010 (17, 18), and 2015/2016 (3, 4). The year 2009 was a turning point due to the standardization of ultrasound risk stratification systems (19) and the publication of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) (20), which led to changes in the categorization of cytological diagnoses, each of them with an implicit ROM and subsequent implications for clinical approaches. In 2016, the 2009-TBSRTC classification underwent revision (21) based on new data and contributions in the field of nodular pathology, the introduction of molecular testing as an adjunct to cytopathology, and, in particular, the reclassification of a subgroup of non-invasive follicular variant papillary carcinoma as non-invasive follicular neoplasia with papillary-like nuclear findings (NIFTP), thus excluding it from the list of thyroid malignancies (22). NIFTPs accounted for a significant proportion of ‘malignancies’ in the indeterminate categories, with implications for ROM. In fact, the 2017-TBSRTC (11) classification introduced a change in the diagnostic criteria for ‘follicular neoplasm’; cases with a follicular pattern and mild nuclear changes not diagnostic of papillary carcinoma (PTC) could be included in this category. The third edition of TBSRTC (2023) (12) has recently been published and provides updated ROM estimates based on data reported after 2017-TBSRTC (23).
Currently, the approach to Bethesda III diagnosis is determined by clinical and ultrasound risk factors (24, 25, 26, 27, 28, 29, 30, 31). It is generally reasonable to adopt a conservative approach with ultrasound surveillance and repeat FNA (3, 8, 16, 32). If available, the study of molecular markers may be a useful tool (3, 33, 34, 35), although the high cost prevents widespread use. Surgery is usually recommended for nodules with Bethesda IV cytological diagnosis; however, molecular testing should be considered prior to surgery (3, 8, 16). According to 2016-AACE/ACE/AME (16) and 2023-ETA (8) guidelines, close clinical follow-up should be considered in cases with favorable clinical and ultrasound features, especially for nodules smaller than 15 mm. Recent publications suggested risk stratification based primarily on ultrasound data and cytological findings to allow conservative management in low-risk cases and thus avoid unnecessary diagnostic surgeries, especially in the absence of molecular testing (28, 36, 37, 38, 39). Finally, there are large differences between Western and Asian countries with lower resection rates and higher ROM in Asian series (37, 40).
Thus, local casuistry should guide decision-making in the indeterminate diagnostic categories to ensure consistency with the reality of each institution (23). The aim of this study is to analyze the distribution of diagnostic cytology, their ROM, the diagnostic performance rates of FNA, and the cytologic–histologic correlation at different time intervals for indeterminate cytology.
Materials and methods
Patients and design
This retrospective observational study included patients who were referred to the monographic unit of the Hospital Virgen de la Victoria of Malaga (Spain) with nodular pathology of the thyroid gland. Patients were consecutively included in a database (previous informed consent). Clinical, functional, and ultrasound assessments were performed in all cases. For the indication of FNA, the criteria of the guidelines in force at that time were applied. We selected three time intervals: before the publication of the 2009-TBSRTC (2006–2008); after this publication (2012–2014); and, finally, from the publication of the 2017-TBSRTC (2017–2019). All patients who underwent FNA in each of these intervals were included in the analysis. In our institution, we do not have access to molecular studies.
The FNAs were performed by cytopathologists with experience in thyroid cytology, under ultrasound guidance, with prior informed consent. Between 2006 and 2008, indeterminate cytological diagnoses were classified into two categories: ‘follicular proliferation’ (FP), which included diagnoses of FP or FP associated with thyroiditis (ROM, 6.3%); and ‘FP with atypia’ (FPwA), which included diagnoses of FP of the microfollicular adenoma type, FP with oncocytic cells, or FP with atypia (ROM, 25%) (41). Cytologic diagnoses from 2012 to 2014 and 2017 to 2019 were categorized according to 2009-TBSRTC (20) and 2017-TBSRTC (11), respectively. The definition of indeterminate categories included atypia of undetermined significance (AUS) Bethesda III, follicular neoplasm (FN) Bethesda IV, and suspicious for malignancy (SFM) Bethesda V in both periods.
This retrospective study was carried out after obtaining a favorable opinion from the Research Ethics Committee of the Province of Málaga (CEIC), in accordance with current legislation in Spain (Organic Law 15/1999 on the Protection of Personal Data, and Law 14/1986 on General Health, and any other applicable legislation).
Statistical analysis
Statistical analysis of the data was performed using SPSS (version 22.0, for Windows). Absolute and relative frequency distributions were used for categorical variables. The histological result was considered the gold standard for estimating ROM. To calculate the diagnostic performance indices, FPwA and malignant cases (2006–2008) and Bethesda IV–VI cases (2012–2014 and 2017–2019) were considered positive tests, as surgery was recommended in 100% of these cases. Benign cases were considered negative tests, as the cytological result did not lead to a surgical indication.
Results
Frequency and distribution of cytological categories by period
In total, 3020 patients with thyroid nodules underwent cytological evaluation. The distribution of cytologic diagnoses in each time interval is presented in Table 1. In the overall series, only 2.2% of cytology tests were insufficient for diagnosis. In the period 2006–2009, 82.4% of the cytological results were benign, 1.7% malignant, and 15.9% indeterminate (7.3% FP and 8.6% FP with atypia). The distribution of diagnostic cytology between 2012 and 2014 was 87.5% Bethesda II, 6.7% Bethesda III, 1.9% Bethesda IV, 1.5% Bethesda V, and 2.4% Bethesda VI. In the interval between 2017 and 2019, it was 88.8 % Bethesda II, 2.3% Bethesda III, 5.9% Bethesda IV, 1.8% Bethesda V, and 1.2% Bethesda VI. Indeterminate cytologic findings were obtained in 15.9% between 2006 and 2008, in 10.1% between 2012 and 2014, and in 10% between 2017 and 2019.
Classification of the FNA results, surgeries indicated and performed, and histology of the surgical specimen according to the cytologic category in the period 2006–2008; to TBSRTC 2009 in the period 2012–2014; and to the TBSRTC 2017 in the period 2017–2019. Data are presented as n (%).
| Total FNA | Total FNA with surgery indicated | Total FNA with surgery performed | Benign histology | Malignant histology | NIFTP | |
|---|---|---|---|---|---|---|
| Cytologic category (2006–2008) | NA | |||||
| Benign | 587 (82.4) | 97 (16.5) | 84 (14.3) | 82 (97.6) | 2 (2.4) | |
| FP | 52 (7.3) | 33 (63.5) | 30 (57.7) | 29 (96.7) | 1 (3.3) | |
| FP atypia | 61 (8.6) | 61 (100) | 56 (91.8) | 45 (80.4) | 11 (19.6) | |
| Malignant | 12 (1.7) | 12 (100) | 12 (100) | 1 (8.3) | 11 (91.6) | |
| Total | 712 (100) | 203 (28.5) | 182 (25.6) | 157 (86.3) | 25 (13.7) | |
| TBSRTC 2009 (2012–2014) | NA | |||||
| II | 735 (87.5) | 100 (13.6) | 79 (10.7) | 76 (96.2) | 3 (3.8) | |
| III | 56 (6.7) | 48 (85.7) | 44 (78.6) | 35 (79.5) | 9 (20.5) | |
| IV | 16 (1.9) | 16 (100) | 16 (100) | 9 (56.2) | 7 (43.8) | |
| V | 13 (1.5) | 13 (100) | 13 (100) | 3 (23) | 10 (77) | |
| VI | 20 (2.4) | 20 (100) | 20 (100) | 0 (0) | 20 (100) | |
| Total | 840 (100) | 197 (23.5) | 172 (20.5) | 123 (71.5) | 49 (28.5) | |
| TBSRTC 2017 (2017–2019) | ||||||
| II | 1246 (88.8) | 189 (15.2) | 171 (13.7) | 167 (97.7) | 4 (2.3) | 0 (0) |
| III | 32 (2.3) | 19 (59.4) | 19 (59.4) | 11 (57.9) | 6 (31.6) | 2 (10.5) |
| IV | 83 (5.9) | 74 (89.2) | 74 (89.2) | 50 (67.5) | 19 (25.7) | 5 (6.8) |
| V | 25 (1.8) | 25 (100) | 24 (96) | 5 (20.8) | 18 (75) | 1 (4.2) |
| VI | 17 (1.2) | 17 (100) | 17 (100) | 0 (0) | 17 (100) | 0 (0) |
| Total | 1403 (100) | 324 (23.1) | 305 (21.7) | 233 (76.4) | 64 (21) | 8 (2.6) |
FNA, fine needle aspiration; FP, follicular proliferation; NA: non-applicable; NIFTP, non-invasive follicular thyroid neoplasm with papillary-like nuclear features; TBSRCT, The Bethesda System for Reporting Thyroid Cytopathology.
Risk of malignancy and cytohistological correlation
Period 2006–2008
Table 1 summarizes the surgical outcomes for cases that underwent surgery. During this period, 25.6% of nodules with diagnostic cytology were surgically treated, with 13.7% of them showing histologically malignant results. Furthermore, 14.3% of patients with cytologically benign nodules underwent surgery, and in 97.6% of cases, the surgical biopsy confirmed benignity. All patients with malignant nodules underwent surgery, with malignancy confirmed in 91.6% of cases.
Of the indeterminate nodules, 76.1% underwent surgery, resulting in a histopathologically malignant outcome in 14% of cases. In the indeterminate FP subcategories ‘without’ and ‘with’ atypia, diagnostic surgery was indicated in 63.5% and 100%, respectively. It is worth noting that 96.7% of cases with FP were benign upon biopsy. In the FP subcategory with atypia, 80.4% of the cases operated on were benign. The indeterminate cytology showed a high percentage of adenomas (65.6% in the FP category and 51.1% in the FP with atypia category). Notably, the proportion of oncocytic adenomas was significantly higher in the FP with atypia category compared to the FP category (17.8% vs 3.4%) (Table 2).
Cytologic–histologic distribution in the intervals 2006–2009, 2012–2014, and 2017–2019. Data are presented as n or as n (%).
| 2006–2009 | 2012–2014 | 2017–2019 | ||||||
|---|---|---|---|---|---|---|---|---|
| FP | FP atypia | III | IV | V | III | IV | V | |
| Malignant histology, n | 1 | 11 | 9 | 7 | 10 | 6 | 19 | 18 |
| PTC | 1 (100) | 8 (72.7) | 8 (88.9) | 0 | 18 (90) | 5 (83.3) | 13 (68.4) | 16 (88.8) |
| FTC | 0 | 2 (18.2) | 1 (11.1) | 5 (71.4) | 0 | 1 (16.7) | 3 (15.8) | 1 (5.6) |
| Oncocytic carcinoma | 0 | 1 (9.1) | 0 | 2 (28.6) | 0 | 0 | 2 (10.5) | 1 (5.6) |
| MTC | 0 | 0 | 0 | 0 | 2 (10) | 0 | 1 (5.3) | 0 |
| Benign histology, n | 29 | 45 | 35 | 9 | 3 | 11 | 50 | 5 |
| Hyperplastic nodule | 7 (24.1) | 16 (35.6) | 16 (45.7) | 4 (44.4) | 4 (33.3) | 7 (63.6) | 25 (50) | 1 (20) |
| Follicular adenoma | 18 (62.2) | 15 (33.3) | 15 (42.9) | 4 (44.4) | 4 (33.3) | 3 (27.3) | 17 (34) | 3 (60) |
| Oncocytic adenoma | 1 (3.4) | 8 (17.8) | 0 | 1 (11.2) | 1 (33.4) | 0 | 5 (10) | 0 |
| Hashimoto’s thyroiditis | 3 (10.3) | 6 (13.3) | 4 (11.4) | 0 | 0 | 1 (9.1) | 3 (6) | 1 (20) |
FP, follicular proliferation; FTC, follicular thyroid carcinoma; MTC, medullary thyroid carcinoma; PTC, papillary thyroid carcinoma.
Regarding malignant histopathologic findings, only one case of PTC was identified in the FP category. In the FP category with atypia, histological malignancy was confirmed in 19.6% of cases. Of these cases, 72.7% were PTC (62.5% follicular variants), 18.2% were follicular carcinomas (FTCs), and 9.1% were oncocytic carcinomas. It is worth noting that 72.7% of the malignant biopsies in this category displayed some follicular architectural component. Importantly, none of the indeterminate categories were confirmed to be medullary carcinoma upon biopsy (Table 2).
The sensitivity and specificity of cytology, considering biopsy as the gold standard, were 91.6% and 64.1%, respectively. The negative predictive value (NPV) for benign cytology was 97.6%.
Period 2012–2014
During this period, 20.5% of nodules with diagnostic cytology underwent surgery, and 28.5% of them were histologically malignant. Furthermore, 10.7% of patients with cytologically benign nodules underwent surgery, and in 96.2% of cases, the surgical biopsy confirmed benignity. All cytological malignant cases were confirmed histologically. About 85.9% of the indeterminate nodules were ultimately operated on, resulting in a histopathologically malignant outcome in 35.6% of the cases (Table 1).
Surgery was indicated in 85.7% of the AUS Bethesda III cytology (Table 1). The malignancy rate was 20.5%, with 88.9% of PTC and 11.1% of FTC. About 79.5% of the cases were benign, with nodular goiter accounting for 45.7% of cases, 42.9% being adenomas, and 11.4% being Hashimoto’s thyroiditis. In the Bethesda IV category, all cases underwent surgery, with a malignancy rate was 43.8%, of which 71.4% were FTC and 28.6% were oncocytic carcinoma. Among benign cases, 55.6% were adenomas and 44.4% nodular goiters. In the Bethesda V category, 77% of cases were malignant, with 90% of those being PTC (Table 2).
The cytology’s sensitivity and specificity were 92.5% and 86.4%, respectively. The NPV for AUS Bethesda III was 96.2%. A positive test was not considered ‘a priori’ for the calculation of the indicators, given that clinical management in the AUS Bethesda III category does not necessarily imply diagnostic surgery. However, an additional analysis was performed since approximately 79% of the cases underwent surgery. This analysis included this category in the true positives, resulting in a sensitivity and specificity of cytology of 93.9% and 61.8%, respectively.
Period 2017–2019
During this period, 21.7% of nodules with diagnostic cytology underwent surgery, resulting in a histologically malignant outcome in 21% of them (23.6% if NIFTP was included). Furthermore, 13.7% of patients with cytologically benign nodules underwent surgery, and surgical biopsy confirmed benignity in 97.7% of cases. All cytologically malignant cases were confirmed histologically (refer to Table 1). Of the indeterminate nodules (Bethesda III–V), 83.6% underwent surgery, with 36.8% of the total resulting in a histopathologically malignant outcome. If the results of NIFTP were considered malignant, this percentage would rise to 43.6% (Table 1).
In our series, the percentage of malignancy in the Bethesda III category was 31.6%, with PTC accounting for 83.3%. For the Bethesda IV category, the percentage of malignancy was 25.7%, with PTC accounting for 68.4% (follicular variant in 92% of them), FTC for 15.8%, oncocytic for 10.5%, and medullary carcinoma for 5.3%. In the Bethesda V category, 77% of cases were malignant, with 88.8% of them being PTC (Table 2). Repeating FNA was indicated in 31.3% of Bethesda III, obtaining a benign result in 50%, and Bethesda IV in the other 50%, which required diagnostic surgery.
The histological diagnosis of NIFTP was obtained in 10.5%, 6.8%, and 4.2% of Bethesda III, IV, and V cases, respectively. NIFTPs accounted for 25%, 26.3%, and 5% of the ‘non-benign’ biopsies of Bethesda categories III, IV, and V, respectively.
The cytology sensitivity and specificity (excluding NIFTP) were 93.1% and 75.2%, respectively, with an NPV of 97.7% for Bethesda II. Since approximately 59.4% of the Bethesda III cases underwent surgery, an additional analysis was performed, including this category in the true positives, resulting in a sensitivity and specificity of cytology of 93.7% and 71.7%, respectively.
Discussion
Understanding the reality of our clinical practice is the first step toward critical reflection that improves our daily medical practice. Objective knowledge is essential to evaluate our approach to thyroid disease, compare it with prevailing trends, and draw relevant conclusions to improve diagnostic and therapeutic performance. In the overall series, only 2.2% of cytology tests were insufficient for diagnosis, which supports the experience of the professionals performing the technique and was an intrinsic quality criterion of our cohort.
The distribution of diagnostic cytology from 2006 to 2008 was comparable to our group’s previously published data (41), with 82.4% benign, 15.9% indeterminate, and 1.7% malignant. The frequency of the indeterminate/suspicious category is at the lower limit of the range reported in the literature, between 15% and 30% (14, 15, 16). Bukhari et al. highlighted the disparity in the distribution of indeterminate diagnoses among published series (3–45%), emphasizing the need to reflect on the diagnostic criteria for this category and the estimation of its ROM (42).
After a careful review of cytologic terminology, the publication of TBSRTC brought an agreed classification of thyroid cytology (20). Our study found that between 2012–2014 and 2017–2019, 10% of the cytologies were indeterminate, representing Bethesda III category less than 7% of the total diagnoses, which met the recommended quality criteria. The literature reports a wide range of Bethesda IV diagnoses, ranging from 2% to 25% (11, 20). In our series, it represented less than 6% of the diagnostic results. The same was true for the Bethesda V category, which accounted for less than 2% of the cytologic diagnoses, at the lower end of the published references. Finally, malignant cytologic diagnosis accounted for less than 3% of the results in all time intervals analyzed, consistent with the literature (40). In our study, we found that the proportion of indeterminate cytologic results was lower than the reported references of 20–30% (11, 20, 43). We also observed a decrease in the frequency of these diagnoses over time, with a decrease from 15.9% before 2009 to 10% from 2009 onward. This suggests an improvement in diagnostic categorization with the use of the Bethesda system.
Surgical treatment was indicated in all cytological findings suspicious for malignancy (Bethesda V) and in the indeterminate ‘follicular proliferation with atypia’ (before 2009) and FN Bethesda IV (from 2009). The reason for the surgical recommendation was the cytological diagnosis itself, regardless of other clinical or ultrasound features. This was in line with current guideline recommendations before 2009 (14, 15, 16), between 2009 and 2014 (17, 18), and as of 2015/2016 (3, 4). According to the 2023 European Thyroid Association Clinical Practice Guidelines, surgery is recommended for all nodules with cytological diagnosis of Bethesda IV, regardless of ultrasound features. However, if available, molecular testing should be considered prior to operation, and for those smaller than 15 mm with favorable ultrasound features, close clinical follow-up should be considered (8). Unfortunately, in our institution, we do not have access to those molecular studies. Recent publications suggested risk stratification based primarily on ultrasound data and cytological findings to enable conservative management in low-risk cases and thus avoid unnecessary diagnostic surgeries (28, 36, 37, 44).
In our study, surgery was recommended in 63.5% of nodules with indeterminate cytology described as ‘follicular proliferation without atypia’ (2006–2008) and in 85.7% of Bethesda III diagnoses (2012–2014). In both periods, diagnostic surgery was the recommendation for indeterminate cytology (14, 15, 17, 18). Prior to the publication of the TBSRTC (20), we adopted a non-surgical attitude in 36.5% of cytology ‘follicular proliferation’, in accordance with the initial findings of our first 2 years experience, which revealed only 6.3% of histological malignancy in cases that were operated on in this category (41). This may justify that the conservative decision was more common than expected according to guideline recommendations (14, 15).
In 2016, the clinical management and follow-up of thyroid disease underwent substantial changes with the publication of the ATA Guidelines and the AACE/ACE/AME 2016 Guidelines (3, 4), mainly in cases of indeterminate cytology. Currently, the approach to indeterminate Bethesda III diagnosis is determined by clinical and ultrasound risk factors (24, 25, 26, 27, 28, 29, 30, 31). It is generally reasonable to adopt a conservative approach with ultrasound surveillance and/or repeat FNA, although the usefulness of the latter option has been subject to controversy (24, 45, 46). If available, the study of molecular markers may be a useful tool (3, 33, 34, 35), although its high cost prevents widespread use. A recent meta-analysis on the usefulness of repeating the FNA concluded that the second FNA reclassified approximately two-thirds of the cases, with benign results obtained in 50% of the second cytology, with a high NPV (96%) (32). In our population, diagnostic surgery was proposed in the first instance in 59.4% of the Bethesda III cases between 2017 and 2019, not by the cytological diagnosis itself, but rather due to size criteria (42%) and suspected ultrasound pattern (37%) and, in 21% of cases due to patient preference. Repeating FNA was indicated in 31.3%, obtaining a benign result in 50% and Bethesda IV in the other 50%, which required diagnostic surgery. In the three time intervals analyzed, the number of false negatives was less than 4%, aligning with the results of the studies in the literature (11, 12, 20).
For cases that underwent surgery due to indeterminate cytology before 2009, 86% of histological findings were benign and 14% were malignant. However, the ROM differed depending on whether the follicular lesion smear contained architectural atypia, cellular atypia, oncocytic cells, and microfollicles, or not (19.6% vs 3.3%, respectively). These data are consistent with our previously published diagnostic performance indices from the years before the implementation of TBSRTC (41), in which we disaggregated these two subgroups with different ROMs. In fact, several publications at that time (47) proposed subclassifying indeterminate lesions into those suspicious for PTC, those suspicious for FNs predictive of malignancy (high cellularity, predominantly microfollicular architecture, and little dense colloid), and those suspicious for follicular neoplasia not predictive of malignancy (moderate cellularity, little colloid, and only focal microfollicular architecture).
The TBSRTC’s introduction resulted in a change in the risks associated with each indeterminate category. In the AUS Bethesda III category, the overall ROM was considered low (5–15%) in the 2009 TBSRTC (20), rising to 10–30% in the 2017 TBSRTC and 2023 TBSRTC (11, 12). However, if the risk is recalculated by excluding NIFTP from histological diagnoses of malignancy, it drops to 6–18% with an average of 16% (11, 12). These data imply that NIFTPs constituted a significant proportion of ‘malignancies’ in this category (48). The ROM differs according to the nature of atypia (49, 50). Thus, TBSRTC 2023 recommends AUS subclassification into two groups: ‘nuclear’ and ‘other’, the latter including cases with architectural atypia, oncocytic atypia, and lymphocytic atypia, among others (12). The malignancy rate in our series was 20.5% from 2012 to 2014 and 42.1% from 2017 to 2019. However, if NIFTPs were excluded from malignant diagnoses, the risk decreased to 31.6% during the latter period. The proportion of malignancy in our population was higher than that reported in the literature for both intervals, particularly in the period 2017–2019. This phenomenon may be mainly due to a selection bias, as Bethesda III cases referred to surgery are usually nodules with higher ultrasound suspicion, with some risk factor or larger size. It is also possible that some specific factor in our sample that we have not yet analyzed may be affecting the ROM of this category. Consequently, it is vital to conduct case studies at each institution to enhance decision-making (23). It is important to note that the ROM is generally overestimated if only operated cases are considered. This is because the main intervention is in those nodules with ultrasound findings, clinical risk factors, and/or anomalous molecular studies, implying a selection bias. On the other hand, when the ROM is calculated using the total of AUS Bethesda III cytological diagnoses in the denominator (if those not operated on are considered benign), the risk is underestimated. The estimated risk is extrapolated from the values of these two calculation methods, although it is possibly overestimated since publications of discrepant results are more frequent than those of expected results (51). In our series, the influence of this circumstance was reduced, as in 78.6% (period 2012–2014) and 59.4% (period 2017–2019) of cases with AUS Bethesda III cytology, surgery was performed. Malignant diagnoses in the AUS Bethesda III category corresponded to PTC in more than 80% of cases.
In the FN Bethesda IV category, our malignancy rate was 43.8% from 2012 to 2014 and 25.7% from 2017 to 2019. However, if NIFTP findings were included as malignant in the latter, it would rise to 32.5%. The current literature reports the ROM to be 25–40%. Yet, when recalculated excluding NIFTPs from total malignancies, the risk drops to 10–40% (11), with an average of 23% in 2023 TBSRTC review (12). The results of our study estimated a risk for this category at the upper limit of the interval, especially in the 2012–2014 period. In the period 2012–2014, all malignant cases in the FN Bethesda IV category were follicular lineage neoplasms. However, in the period 2017–2019, 68.4% of PTCs were observed in the total malignancies. The literature data on the predictive value of FN Bethesda IV are robust because most cases undergo surgery. It is worth noting that most cases (27–68%) correspond to PTC rather than FTC. There are several proposed explanations for this discrepancy. Some tumors, particularly follicular variant of PTC (FVPTC) and NIFTP may have PTC cellular findings that are not fully developed throughout the entire nodule and therefore may not be objectively detectable in the FNA sample. Additionally, in TBSRTC 2017 includes samples with atypical or slight nuclear changes, not conclusive of PTC, in the FN/SFN category. In these cases, an additional informative note to diagnosis is admitted as guidance for clinical management. The high proportion of PCT observed may be due to this circumstance (11). Several studies have reported that between 50% and 74% of malignant histology in this cytological category corresponds to PTC, with most of them FVPTC, although classic PTC may be present in a non-negligible percentage of cases (3–18%) (52, 53, 54). Finally, the reproducibility of the histological diagnosis of follicular adenoma, FCT, and FVPTC is imperfect, as shown in some studies of intraobserver and interobserver agreement in the diagnosis of follicular lesions with borderline nuclear changes (55). Regarding the PTC variants in our study, 92% of the cases corresponded to FVPTC, and 8% to classic forms.
The confirmation of malignancy in the Bethesda V category was 75–77% in the intervened cases, which is at the upper end of the published ranges (11, 12, 20), with 90% of cases being confirmed as PTC. Since the implementation of TBSRTC, the proportion of surgeries in our series has slightly decreased. However, we observed an increase in malignant biopsies compared to the period prior to 2009. This finding could be explained by a better selection of nodules for puncture, greater diagnostic precision of indeterminate cytology, or a combination of both factors.
Finally, in our study, in the period 2017–2019, NIFTPs represented 25%, 26.3%, and 5% of the ‘non-benign’ biopsies of Bethesda categories III, IV, and V, respectively. Therefore, it is of great interest to adopt risk stratifications with other clinical tests, such as ultrasound imaging (39), growing rate, tumor size, and cytological risk stratification, to optimize surgical judgment, especially in the absence of molecular testing.
Conclusion
Due to the high variability in the management and the diagnostic performance of FNA in nodular thyroid disease, knowing the local case study may guide more efficient decision-making. When interpreting the results of our study, it is important to consider its strengths and limitations.
Our study is limited by its observational and retrospective design, which only allows us to infer associations rather than causality. On the other hand, the population was selected sequentially, and all patients evaluated were included, minimizing selection bias. Therefore, we consider the series to be representative of the population of southern Spain. Also, the minimal percentage of insufficient and indeterminate cytology tests constitutes an inherent quality criterion within our series. A high percentage of indeterminate cytologists underwent surgery, so we have good local casuistry of the ROM in these categories. However, this data should be interpreted with caution before being applied to the general population.
Finally, considering that our diagnostic performance indices of FNA were comparable to most published series, we believe that a high-resolution unit for thyroid nodules is a highly recommended option to improve the care of patients with thyroid nodules.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
MM-V was supported by Rio Hortega and now for Juan Rodes from the Spanish Ministry of Economy and Competitiveness (ISCIII) and cofounded by Fondo Europeo de Desarrollo Regional-FEDER (CM 17/00169, JR 19/00054). AMG-P was supported by a research contract from Servicio Andaluz de Salud (B-0033-2014).
Author Contributions
Conceptualization: AIA-M, IM-D, and EG; investigation: AIA-M, MM-V, and DF-G; resources: IM-D and AMG-P; writing – original draft preparation: AIA-M, IM-D, and AMG-P; writing – review and editing: AIA-M, IM-D, and AMG-P; visualization: MVO-J and IH-M; supervision: FJT. All authors read and agreed with the final version of the manuscript.
Acknowledgements
The graphic abstract was created using the Canva Pro tool; both the elements and images were purchased with a Canva Pro subscription and their use is permitted for personal and commercial use.
References
- 1↑
Perros P, Boelaert K, Colley S, Evans C, Evans RM, Gerrard Ba G, Gilbert J, Harrison B, Johnson SJ, Giles TE, et al.Guidelines for the management of thyroid cancer. Clinical Endocrinology 2014 81(Supplement 1) 1–122. (https://doi.org/10.1111/cen.12515)
- 2↑
Lee YH, Baek JH, Jung SL, Kwak JY, Kim JH, Shin JH, Korean Society of Thyroid Radiology (KSThR) & Korean Society of Radiology. Ultrasound-guided fine needle aspiration of thyroid nodules: a consensus statement by the Korean Society of Thyroid Radiology. Korean Journal of Radiology 2015 16 391–401. (https://doi.org/10.3348/kjr.2015.16.2.391)
- 3↑
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, et al.2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016 26 1–133. (https://doi.org/10.1089/thy.2015.0020)
- 4↑
Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, Paschke R, Valcavi R, Vitti P & AACE/ACE/AME Task Force on Thyroid Nodules. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules--2016 Update. Endocrine Practice 2016 22 622–639. (https://doi.org/10.4158/EP161208.GL)
- 5↑
Shin JH, Baek JH, Chung J, Ha EJ, Kim J-H, Lee YH, Lim HK, Moon W-J, Na DG, Park JS, et al.Ultrasonography diagnosis and imaging-based management of thyroid nodules: revised Korean Society of Thyroid Radiology consensus statement and recommendations. Korean Journal of Radiology 2016 17 370–395. (https://doi.org/10.3348/kjr.2016.17.3.370)
- 6↑
Tessler FN, Middleton WD, Grant EG, Hoang JK, Berland LL, Teefey SA, Cronan JJ, Beland MD, Desser TS & Frates MC et al.ACR Thyroid Imaging, Reporting and Data System (TI-RADS): white paper of the ACR TI-RADS Committee. Journal of the American College of Radiology 2017 14 587–595. (https://doi.org/10.1016/j.jacr.2017.01.046)
- 7↑
Russ G, Bonnema SJ, Erdogan MF, Durante C, Ngu R, & Leenhardt L. European Thyroid Association guidelines for ultrasound malignancy risk stratification of thyroid nodules in adults: the EU-TIRADS. European Thyroid Journal 2017 6 225–237. (https://doi.org/10.1159/000478927)
- 8↑
Durante C, Hegedus L, Czarniecka A, Paschke R, Russ G, Schmitt F, Soares P, Solymosi T, & Papini E. 2023 European Thyroid Association clinical practice guidelines for thyroid nodule management. European Thyroid Journal 2023 12 ETJ-23–ETJ-0067. (https://doi.org/10.1530/ETJ-23-0067)
- 9↑
Grani G, Sponziello M, Pecce V, Ramundo V, & Durante C. Contemporary thyroid nodule evaluation and management. Journal of Clinical Endocrinology and Metabolism 2020 105 2869–2883. (https://doi.org/10.1210/clinem/dgaa322)
- 10↑
Singh Ospina N, Iñiguez-Ariza NM, & Castro MR. Thyroid nodules: diagnostic evaluation based on thyroid cancer risk assessment. BMJ 2020 368 l6670. (https://doi.org/10.1136/bmj.l6670)
- 11↑
Cibas ES, & Ali SZ. The 2017 Bethesda System for Reporting Thyroid Cytopathology. Thyroid 2017 27 1341–1346. (https://doi.org/10.1089/thy.2017.0500)
- 12↑
Ali SZ, Baloch ZW, Cochand-Priollet B, Schmitt FC, Vielh P, & VanderLaan PA. The 2023 Bethesda System for Reporting Thyroid Cytopathology. Thyroid 2023 33 1039–1044. (https://doi.org/10.1089/thy.2023.0141)
- 13↑
Can AS, & Peker K. Comparison of palpation-versus ultrasound-guided fine-needle aspiration biopsies in the evaluation of thyroid nodules. BMC Research Notes 2008 1 12. (https://doi.org/10.1186/1756-0500-1-12)
- 14↑
Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Sherman SI, Tuttle RM, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006 16 109–142. (https://doi.org/10.1089/thy.2006.16.109)
- 15↑
Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JWA, Wiersinga W & European Thyroid Cancer Taskforce. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. European Journal of Endocrinology 2006 154 787–803. (https://doi.org/10.1530/eje.1.02158)
- 16↑
Gharib H, Papini E, Valcavi R, Baskin HJ, Crescenzi A, Dottorini ME, Duick DS, Guglielmi R, Hamilton CR, Zeiger MA, et al.American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocrine Practice 2006 12 63–102. (https://doi.org/10.4158/EP.12.1.63)
- 17↑
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009 19 1167–1214. (https://doi.org/10.1089/thy.2009.0110)
- 18↑
Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Hegedüs L, Vitti P & AACE/AME/ETA Task Force on Thyroid Nodules. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. Endocrine Practice 2010 16 468–475. (https://doi.org/10.4158/EP.16.3.468)
- 19↑
Horvath E, Majlis S, Rossi R, Franco C, Niedmann JP, Castro A, & Dominguez M. An ultrasonogram reporting system for thyroid nodules stratifying cancer risk for clinical management. Journal of Clinical Endocrinology and Metabolism 2009 94 1748–1751. (https://doi.org/10.1210/jc.2008-1724)
- 20↑
Cibas ES, Ali SZ & NCI Thyroid FNA State of the Science Conference. The Bethesda System for Reporting Thyroid Cytopathology. American Journal of Clinical Pathology 2009 132 658–665. (https://doi.org/10.1309/AJCPPHLWMI3JV4LA)
- 21↑
Pusztaszeri M, Rossi ED, Auger M, Baloch Z, Bishop J, Bongiovanni M, Chandra A, Cochand-Priollet B, Fadda G, Hirokawa M, et al. The Bethesda system for reporting thyroid cytopathology: proposed modifications and updates for the second edition from an international panel. Acta Cytologica 2016 60 399–405. (https://doi.org/10.1159/000451020)
- 22↑
Lloyd RV, Osamura RY, Klöppel G, & Rosai J. WHO Classification of Tumours of Endocrine Organs. [cited 2024 Feb 12]. (available at: https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-Endocrine-Organs-2017).
- 23↑
Chen Y-H, Partyka KL, Dougherty R, Cramer HM, & Wu HH. The importance of risk of neoplasm as an outcome in cytologic-histologic correlation studies on thyroid fine needle aspiration. Diagnostic Cytopathology 2020 48 1237–1243. (https://doi.org/10.1002/dc.24557)
- 24↑
Rosario PW. Thyroid nodules with atypia or follicular lesions of undetermined significance (Bethesda category III): importance of ultrasonography and cytological subcategory. Thyroid 2014 24 1115–1120. (https://doi.org/10.1089/thy.2013.0650)
- 25↑
Yoon JH, Kwon HJ, Kim E-K, Moon HJ, & Kwak JY. Subcategorization of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS): a study applying Thyroid Imaging Reporting and Data System (TIRADS). Clinical Endocrinology 2016 85 275–282. (https://doi.org/10.1111/cen.12987)
- 26↑
Baser H, Cakir B, Topaloglu O, Alkan A, Polat SB, Dogan HT, Yazicioğlu MO, Aydin C, & Ersoy R. Diagnostic accuracy of Thyroid Imaging Reporting and Data System in the prediction of malignancy in nodules with atypia and follicular lesion of undetermined significance cytologies. Clinical Endocrinology 2017 86 584–590. (https://doi.org/10.1111/cen.13274)
- 27↑
Trimboli P, Fulciniti F, Zilioli V, Ceriani L, & Giovanella L. Accuracy of international ultrasound risk stratification systems in thyroid lesions cytologically classified as indeterminate. Diagnostic Cytopathology 2017 45 113–117. (https://doi.org/10.1002/dc.23651)
- 28↑
Grani G, Lamartina L, Ascoli V, Bosco D, Nardi F, D’Ambrosio F, Rubini A, Giacomelli L, Biffoni M, Filetti S, et al. Ultrasonography scoring systems can rule out malignancy in cytologically indeterminate thyroid nodules. Endocrine 2017 57 256–261. (https://doi.org/10.1007/s12020-016-1148-6)
- 29↑
Gao L-Y, Wang Y, Jiang Y-X, Yang X, Liu R-Y, Xi X-H, Zhu S-L, Zhao R-N, Lai X-J, Zhang X-Y, et al. Ultrasound is helpful to differentiate Bethesda class III thyroid nodules: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 2017 96 e6564. (https://doi.org/10.1097/MD.0000000000006564)
- 30↑
Barbosa TLM, Junior COM, Graf H, Cavalvanti T, Trippia MA, da Silveira Ugino RT, de Oliveira GL, Granella VH, & de Carvalho GA. ACR TI-RADS and ATA US scores are helpful for the management of thyroid nodules with indeterminate cytology. BMC Endocrine Disorders 2019 19 112. (https://doi.org/10.1186/s12902-019-0429-5)
- 31↑
Guarnotta V, La Monica R, Ingrao VR, Di Stefano C, Salzillo R, Pizzolanti G, Giannone AG, Almasio PL, Richiusa P, & Giordano C. Ultrasound parameters can accurately predict the risk of malignancy in patients with “indeterminate TIR3b” cytology nodules: a prospective study. International Journal of Molecular Sciences 2023 24 8296. (https://doi.org/10.3390/ijms24098296)
- 32↑
Bayona A, Benavent P, Muriel A, Abuchaibe C, Sharpe SC, Tarasova V, McIver B, & Valderrabano P. Outcomes of repeat fineneedle aspiration biopsy for AUS/FLUS thyroid nodules. European Journal of Endocrinology 2021 185 497–506. (https://doi.org/10.1530/EJE-21-0330)
- 33↑
Gomes-Lima CJ, Auh S, Thakur S, Zemskova M, Cochran C, Merkel R, Filie AC, Raffeld M, Patel SB, Xi L, et al.A novel risk stratification system for thyroid nodules with indeterminate cytology-A pilot cohort study. Frontiers in Endocrinology (Lausanne) 2020 11 53. (https://doi.org/10.3389/fendo.2020.00053)
- 34↑
Colombo C, Muzza M, Pogliaghi G, Palazzo S, Vannucchi G, Vicentini L, Persani L, Gazzano G, & Fugazzola L. The thyroid risk score (TRS) for nodules with indeterminate cytology. Endocrine-Related Cancer 2021 28 225–235. (https://doi.org/10.1530/ERC-20-0511)
- 35↑
Pastoricchio M, Cubisino A, Lanzaro A, Troian M, Zanconati F, Bernardi S, Fabris B, de Manzini N, & Dobrinja C. Impact of the Italian Society of Anatomic Pathology and Diagnostic Cytology classification of thyroid nodules in the treatment of indeterminate follicular lesions: five-year results at a single center. International Journal of Endocrinology 2020 2020 7325260. (https://doi.org/10.1155/2020/7325260)
- 36↑
Valderrabano P, McGettigan MJ, Lam CA, Khazai L, Thompson ZJ, Chung CH, Centeno BA, & McIver B. Thyroid nodules with indeterminate cytology: utility of the American Thyroid Association sonographic patterns for cancer risk stratification. Thyroid 2018 28 1004–1012. (https://doi.org/10.1089/thy.2018.0085)
- 37↑
Hirokawa M, Auger M, Jung CK, & Callegari FM. Thyroid FNA cytology: the Eastern versus Western perspectives. Cancer Cytopathology 2023 131 415–420. (https://doi.org/10.1002/cncy.22692)
- 38↑
Hirokawa M, Suzuki A, Kawakami M, Kudo T, & Miyauchi A. Criteria for follow-up of thyroid nodules diagnosed as follicular neoplasm without molecular testing – the experience of a high-volume thyroid centre in Japan. Diagnostic Cytopathology 2022 50 223–229. (https://doi.org/10.1002/dc.24937)
- 39↑
Kim H, Shin JH, Kim KE, Kim MK, Oh J, & Hahn SY. Subcategorization of intermediate suspicion thyroid nodules based on suspicious ultrasonographic findings. Ultrasonography 2023 42 307–313. (https://doi.org/10.14366/usg.22096)
- 40↑
Vuong HG, Ngo HTT, Bychkov A, Jung CK, Vu TH, Lu KB, Kakudo K, & Kondo T. Differences in surgical resection rate and risk of malignancy in thyroid cytopathology practice between Western and Asian countries: a systematic review and meta-analysis. Cancer Cytopathology 2020 128 238–249. (https://doi.org/10.1002/cncy.22228)
- 41↑
Sebastián-Ochoa N, Fernández-García JC, Mancha Doblas I, Sebastián-Ochoa A, Fernández García D, Ortega Jiménez MV, Gallego Domínguez E, & Tinahones Madueño F. Clinical experience in a high-resolution thyroid nodule clinic. Endocrinologia y Nutricion: Organo de la Sociedad Espanola de Endocrinologia y Nutricion 2011 58 409–415. (https://doi.org/10.1016/j.endonu.2011.06.007)
- 42↑
Bukhari MH, Niazi S, Hanif G, Qureshi SS, Munir M, Hasan M, & Naeem S. An updated audit of fine needle aspiration cytology procedure of solitary thyroid nodule. Diagnostic Cytopathology 2008 36 104–112. (https://doi.org/10.1002/dc.20731)
- 43↑
Sebo TJ. What are the keys to successful thyroid FNA interpretation? Clinical Endocrinology 2012 77 13–17. (https://doi.org/10.1111/j.1365-2265.2012.04404.x)
- 44↑
Kakudo K, Kameyama K, Miyauchi A, & Nakamura H. Introducing the reporting system for thyroid fine-needle aspiration cytology according to the new guidelines of the Japan Thyroid Association. Endocrine Journal 2014 61 539–552. (https://doi.org/10.1507/endocrj.ej13-0494)
- 45↑
Baloch Z, LiVolsi VA, Jain P, Jain R, Aljada I, Mandel S, Langer JE, & Gupta PK. Role of repeat fine-needle aspiration biopsy (FNAB) in the management of thyroid nodules. Diagnostic Cytopathology 2003 29 203–206. (https://doi.org/10.1002/dc.10361)
- 46↑
VanderLaan PA, Marqusee E, & Krane JF. Usefulness of diagnostic qualifiers for thyroid fine-needle aspirations with atypia of undetermined significance. American Journal of Clinical Pathology 2011 136 572–577. (https://doi.org/10.1309/AJCPO0BQ2YSKPXXP)
- 47↑
Alexander EK. Approach to the patient with a cytologically indeterminate thyroid nodule. Journal of Clinical Endocrinology and Metabolism 2008 93 4175–4182. (https://doi.org/10.1210/jc.2008-1328)
- 48↑
Li W, Sciallis A, Lew M, Pang J, & Jing X. Implementing noninvasive follicular thyroid neoplasm with papillary-like nuclear features may potentially impact the risk of malignancy for thyroid nodules categorized as AUS/FLUS and FN/SFN. Diagnostic Cytopathology 2018 46 148–153. (https://doi.org/10.1002/dc.23866)
- 49↑
Sengul D, & Sengul I. Subdivision of intermediate suspicion, the 2021 K-TIRADS, and category III, indeterminate cytology, the 2017 TBSRTC, 2nd edition, in thyroidology: Let bygones be bygones? Ultrasonography 2023 42 600–601. (https://doi.org/10.14366/usg.23113)
- 50↑
Glass RE, Levy JJ, Motanagh SA, Vaickus LJ, & Liu X. Atypia of undetermined significance in thyroid cytology: nuclear atypia and architectural atypia are associated with different molecular alterations and risks of malignancy. Cancer Cytopathology 2021 129 966–972. (https://doi.org/10.1002/cncy.22495)
- 51↑
Iskandar ME, Bonomo G, Avadhani V, Persky M, Lucido D, Wang B, & Marti JL. Evidence for overestimation of the prevalence of malignancy in indeterminate thyroid nodules classified as Bethesda category III. Surgery 2015 157 510–517. (https://doi.org/10.1016/j.surg.2014.10.004)
- 52↑
Yang J, Schnadig V, Logrono R, & Wasserman PG. Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer 2007 111 306–315. (https://doi.org/10.1002/cncr.22955)
- 53↑
Deveci MS, Deveci G, LiVolsi VA, & Baloch ZW. Fine-needle aspiration of follicular lesions of the thyroid. Diagnosis and follow-up. CytoJournal 2006 3 9. (https://doi.org/10.1186/1742-6413-3-9)
- 54↑
Conzo G, Avenia N, Ansaldo GL, Calò P, De Palma M, Dobrinja C, Docimo G, Gambardella C, Grasso M, Lombardi CP, et al. Surgical treatment of thyroid follicular neoplasms: results of a retrospective analysis of a large clinical series. Endocrine 2017 55 530–538. (https://doi.org/10.1007/s12020-016-0953-2)
- 55↑
Elsheikh TM, Asa SL, Chan JKC, DeLellis RA, Heffess CS, LiVolsi VA, & Wenig BM. Interobserver and intraobserver variation among experts in the diagnosis of thyroid follicular lesions with borderline nuclear features of papillary carcinoma. American Journal of Clinical Pathology 2008 130 736–744. (https://doi.org/10.1309/AJCPKP2QUVN4RCCP)
