Evaluation of thyroid nodules classified as Bethesda category III on cytology and their malignancy rate: An institutional experience

INTRODUCTION

Thyroid gland nodules are common, occurring in around 50% of population above 60 years of age.[1] In the last few years, detecting thyroid nodules increased dramatically, due to the wide range availability of imaging modalities. Hence, the number of thyroid fine needle aspiration (FNA) sampling increased.[234567] Reporting thyroid FNAs was an area of challenge for most of the pathologists and physicians; in terms of terminology and diagnoses clinical implications, so a standardized system was established for the first time by the National Cancer Institute State of the Science Conference[8910] in 2007, which resulted in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Since establishing the (TBSRTC), a uniform, six-tiered reporting system was initiated to be used by the pathologists internationally. It helps them to communicate thyroid FNAs interpretations with the physicians in terms of briefing and clinical applicability.[11] The implantation of the system has given a step forward in terms of quality of reporting thyroid FNAs, giving more reliable transparent reports and reducing the number of unnecessary surgeries and their complications.[12] While most of the thyroid gland nodules are benign, around 5% of them harbor malignant changes.[13]

FNA is an essential test for triaging thyroid gland nodules and determining the risk of malignancy and assessing whether the patient should be followed up or assigned for a surgical excision of the thyroid gland. However, many controversies have been raised up regarding some of the categories, in which AUS/FLUS (Bethesda category III) is one of the main controversial categories. The cytological findings of AUS/FLUS (Bethesda category III) are not sufficient to categorize the lesion as benign, suspicious for malignancy or malignant. It is used by many cytopathologists as the last resort, with only 7% of the FNAs receiving this diagnosis.[1415] For both cytopathologists and physicians, it was a gray zone between benignity and malignancy. The risk of malignancy in this category was 10%–30%,[16] but it was found to differ widely depending on the type of atypia noted in the aspirate. It is found to be higher in cytological atypia and lower in follicular architectural atypia.[9161718192021] Moreover, the accurate incidence is found to vary among different institutions. In contrast to the Bethesda recommendations, the American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA) recommend to combine AUS/FLUS (Bethesda category III) with Follicular neoplasm/Suspicious of Follicular Neoplasm (Bethesda category IV),[2223] as this group recommends surgical excision in most cases.

As per the (TBSRTC), the diagnosis of AUS/FLUS (Bethesda category III) is usually given in certain circumstances,[16] such as the presence of prominent population of microfollicles that does not fulfill the criteria of “Follicular neoplasm/Suspicious for follicular neoplasm” (scenario 1), the predominance of Hürthle cells in a sparsely cellular aspirate with scant colloid (scenario 2), follicular cell atypia caused by drying or clotting artifacts (scenario 3), a moderately or markedly cellular sample which is composed exclusively of Hürthle cells (scenario 4), the presence of focal features suggestive of papillary carcinoma [Scenario 5 – Figure 1], the presence of cyst-lining cells which appear atypical (scenario 6), the presence of minor population of follicular cells with nuclear enlargement and prominent nucleoli (scenario 7), the presence of atypical lymphoid infiltrates (scenario 8), and atypia not otherwise specified (scenario 9). In this study, we introduced those nine scenarios to elaborate more on the causes of categorizing the thyroid nodules FNAs as AUS/FLUS (Bethesda category III) by cytopathologists.

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Figure 1

(a) Cellular smears with benign follicular cells (arrow) and few clusters with enlarged nuclei, nuclear grooves and vague inclusions (asterisk). (b) Few cells with enlarged nuclei and prominent nucleoli

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METHODS

We retrospectively studied and reviewed all the cases diagnosed as AUS/FLUS (Bethesda category III) between the periods (January 2013–December 2017) at Salmaniya Medical Complex. A total number of 889 FNAs were reviewed, and all the data were collected through the institutional laboratory information system (i-Seha). We only received a few readymade slides, and they were diagnosed by our cytopathologists as AUS/FLUS (Bethesda category III). A few were done blindly at the FNA clinic by pathologists using 23–25 Gauge needles, while most of the other cases were done by consultant radiologists using 23 Gauge needle under ultrasound guidance. Usually, three to four passes were obtained along with a bedside (DiffQuik stain) to check the adequacy of the sample. Half of the smears were air dried and stained with (Giemsa stain), and the other half were fixed and stained with (Papanicolaou stain). Cellblock preparations were only done when there is sufficient material.

All the cases were reported using the (TBSRTC).[11] The surgery was done based on whether there were pressure symptoms on the vital structures in the neck, concerning radiological findings or any clinical suspicion for malignancy. The estimation of the rate of malignancy was subjected to biases because not all the thyroid FNAs categorized as AUS/FLUS (Bethesda category III) were exposed to surgery. Therefore, we determined the conceivable range of malignancy rate by dividing the number of malignant cases; confirmed by surgical excision, by the total number of FNAs – categorized as AUS/FLUS – done during the study. Moreover, we assumed that all cases which were not operated on were benign. The cases that were designated as AUS/FLUS (Bethesda category III) were obtained using the nine different scenarios. A correlation between the first FNA cytology report, the second FNA cytology report – if done – and the histology reports were obtained. Some of the cases were designated with more than one scenario, therefore, we added all the scenarios for designating the thyroid cytology as AUS/FLUS (Bethesda category III).

The patient's age, sex, biopsy site, and method of obtaining the biopsy were all registered.

By using Microsoft Excel and SPSS (20^th edition, IBM Cop. Released 2011. IBM SPSS Statistics for windows, version 20.0. Armonk, NY: IBM Corp), a calculation of the frequencies of the sex of patients, site of the biopsy, size of the nodule, the method of the first and second FNA, and the final histopathology report – if surgery was done – were collected. Correlations between age and histopathology report, age and size, gender and size of the nodule, gender and scenario, gender and histopathology report were all studied. Finally, we studied the correlation between the scenarios and histopathology report, as this will add a further step to study the risk of malignancy in each scenario.

RESULTS

A total number of 825 patients with thyroid nodules underwent 889 FNAs [Figure 2] in Salmaniya Medical Complex during (January 2013–December 2017). Among those 96 FNAs (10.7%) were designated as AUS/FLUS using the Bethesda system, in which 77 were female (80.2%) and ages between 23 and 88 years (mean of 48.8%). Forty-six nodules were on the left side (47.9%), thirty-eight on the right side (39.5%), two in the isthmus (2%), and in seven cases, the site was not mentioned in the report. It was done from bilateral nodules in 3 (3.1%) cases. 26 (27%) of patients underwent surgery without repeating the FNA, 25 (26%) patients underwent a second FNA, and 43 (44.7%) patients were followed up by ultrasound.

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Figure 2

Cytological diagnoses and the clinical management of AUS/FLUS (Bethesda category III) in SMC

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On repeating the FNA, 1 (4%) was unsatisfactory, 13 (52%) were benign, 10 (40%) were AUS/FLUS, and only 1 (4%) were categorized as malignant.

Thirty cases were surgically excised, in which four (13.3%) were diagnosed as follicular adenoma, 2 (6.6%) as Hürthle cell adenoma, 9 (30%) as multinodular goiter, 5 (16.6%) as multinodular goiter with Hashimoto thyroiditis, 1 (3.3%) as colloid nodule with Hashimoto thyroiditis, and 9 (30%) as papillary thyroid carcinoma. Among all the cases diagnosed initially as AUS/FLUS (Bethesda category III), 9 (9.3%) cases were diagnosed as papillary thyroid carcinoma.

The most common cause of designating thyroid nodule FNAs as AUS/FLUS was because there are focal features suggestive of papillary thyroid carcinoma [Table 1], including nuclear grooves, enlarged nuclei with pale chromatin, and alterations in nuclear contour and shape in an otherwise predominantly benign-appearing sample (scenario 5). The causes of designating the cases with AUS/FLUS were fourteen (14.5%) as scenario 1, 1 (1%) as scenario 2, 9 (9.3%) as scenario 3, 9 (9.3%) as scenario 4, 23 (23.9%) as scenario 5, 4 (4.1%) as scenario 6, 13 (13.5%) as scenario 7, no cases as scenario 8, and 9 (6.25%) as scenario 9. Seventeen cases were designated with more than one scenario, in which nine cases designated with scenarios (1 and 5), three cases with scenarios (4 and 5), two cases with scenarios,[56] one case with scenarios (5 and 7), and one case with scenarios (3 and 7). Only one case was designated with more than two scenarios (3, 4, and 5).

Of the 96 cases designated as AUS/FLUS (Bethesda category III), number of FNAs was obtained under ultrasound guidance was 68 (70.8%), while those done blindly at the FNA clinic were 17 (17.7%) cases. Nine cases were received as review cases from other centers. The second FNA for those which have been repeated were all repeated under ultrasound guidance, with the exception of three cases, that were done blindly at the FNA clinic.

There was a positive correlation between both the age and the final histopathology diagnosis, with a statistically significant P = 0.026 and between the gender and the final histopathology diagnosis, with a P = 0.05. There was no significant correlation between the scenario and final histopathology diagnosis.

DISCUSSION

Since the establishment the Bethesda system for reporting thyroid cytolopathology, it has been a widely used system among most of the centers to standardize the FNAs cytology reports. By using a simple language and stratifying the risk of having malignancy and making the decision of managing the patients much easier. For example, the 0%–3% risk of malignancy in the benign category (Bethesda category II), that recommends following up the patient clinically and sonographically. While the 50%–75% risk of malignancy in the suspicious for malignancy category (Bethesda category V) that obligates the surgeons to do a near total thyroidectomy or lobectomy.[11]

In addition, since the 1^st days after releasing the (TBSRTC) in 2007, AUS/FLUS (Bethesda category III) was the most controversial category for both the cytopathologists and the physicians. For the former in terms of when to designate a sample with this category, while for the latter in terms of how to manage those lesions. For cytopathologists, the AUS/FLUS (Bethesda III category), it is reserved for those cases that have a lesser degree of atypia that is not found in Categories IV and V, primarily cytological or architectural, insufficient to qualify them to higher categories.[11] Designating cases with AUS/FLUS (Bethesda III category) does not exceed 7%, and those cases have been separated because of the lower risk of having malignancy between 10% and 30%.[1415] Despite estimating the risk as 10%–30%, the actual risk remains ambiguous, with many arguments to decrease its use.[2425] However, Shi et al. found that removing this category will drop the sensitivity of the whole Bethesda system.[24]

In this study, we examined and correlated the histologic reports for all the cases that were designated as AUS/FLUS (Bethesda category III), in Salmaniya Medical Complex, which has been gone through a surgical excision. In our practice, cytopathologists think twice before designating any case as AUS/FLUS (Bethesda category III), for two main reasons. The first is that this diagnosis is a gray zone that does not give a definite conclusive answer regarding the nature of the nodule and this makes it difficult to take the next step in management. The second is the fear of over-designating the cases with AUS/FLUS (Bethesda category III), as this may delay managing the patients. Unlike many previous studies, our incidence of AUS/FLUS was approximately similar to the Bethesda reporting system (10.7%), and the risk of malignancy was approximately within the same risk of malignancy of the system (9.3%).

The clinical management of AUS/FLUS (Bethesda category III) is complicated and needs an effective communication between cytopathologists, radiologists, and surgeons. The 2015 American Thyroid Association task force of thyroid nodules suggests combining clinical, radiological, repetition of FNA and molecular testing. The worrisome features considered were: Size more than 4 cm, family history, and a history of radiation therapy. Ultrasound findings with increasing concern of malignancy were (hypoechogenicity, microcalcifications, irregular margins, nodules taller than wide, rim calcifications small extrusive soft-tissue component, and evidence of extrathyroidal extension).[2627] Finally, molecular testing could help in differentiating benign from malignant cases.[27] The (TBSRTC) recommendation is to repeat the FNA for such nodules within 6–12 weeks and molecular testing or lobectomy.[11] In our hospital, however, repeating FNAs was done only in 26% of the cases, while proceeding directly to surgical excision was 27%. In Salmaniya Medical Complex, we have not established any molecular testing for thyroid nodules yet.

Before proceeding further in our results, it is worth mentioning that any estimation for the risk of malignancy in AUS/FLUS (Bethesda category III) is limited by many factors. One is the limitation in doing surgical excision in some of the cases, and the other is the loss of follow-up in some.

Our criteria to designate any sample as AUS/FLUS (Bethesda category III) was followed the nine scenarios, depending on whether we have cytological or architectural atypia in our samples, but it is not fulfilling the criteria to upgrade them into further categories. About one-quarter of the cases which were designated as AUS/FLUS (Bethesda category III), was because there were a few features suggestive of papillary thyroid carcinoma, like nuclear grooves, pale chromatin along with alterations in the nuclear contour and shape in a predominantly benign appearing smears. About one-fourth of the cases were designated as AUS/FLUS (Bethesda category III), because there are focal features suggestive of papillary thyroid carcinoma, but it was not clear cut a papillary thyroid carcinoma, while one eighth of the cases were designated as AUS/FLUS (Bethesda category III), because of the presence of prominent populations of microfollicles, but not fulfilling the criteria to designate them as Follicular neoplasm/Suspicious for follicular neoplasm (Bethesda category IV).

This study faced many challenges; a critical one was the small number of cases, due to strictly using the cases designated as AUS/FLUS (Bethesda category III) in our study. Another obstacle was losing some the patients during follow-up, mainly because they were not Bahrainis, and most probably went to their home country to do the surgeries if this option was suggested by the treating surgeons.

CONCLUSION

To sum up, our results for diagnosing AUS/FLUS (Bethesda category III) meet the international estimations of designating such diagnosis (7%) and the risk of malignancy approximates the international risk (10%–30%). However, the main issue is the clinical management of such nodules. We strongly recommend standardizing the clinical management and to actively discuss these cases between the cytopathologists, radiologists and physicians in multidisciplinary team settings. Applying of consensual institutional guidelines could help in decreasing the unnecessary surgeries and their complications and give the best standard of care.

Moreover, we found a positive statistical correlation between the age and gender with the final histopathology report.

COMPETING INTERESTS STATEMENT BY ALL AUTHORS

The authors declare that they have no competing interests.

AUTHORSHIP STATEMENT BY ALL AUTHORS

All other co-authors reviewed this article before sharing it.

ETHICS STATEMENT BY ALL AUTHORS

This study was conducted with approval from the Research and Ethics committee in Salmaniya Medical Complex in the Ministry of Health in Bahrain.

LIST OF ABBREVIATIONS (In alphabetic order)

AACE/AME/ETA: The American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association.

AUS/FLUS: Atypia of undetermined significance/Follicular lesion of undetermined significance.

FNA: Fine needle aspiration.

NCI: National cancer institute.

TBSRTC: The besethesda system for reporting thyroid cytology.

EDITORIAL/PEER-REVIEW STATEMENT

To ensure the integrity and highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double-blind model (authors are blinded for reviewers and vice versa) through automatic online system.