The Impact of the Bethesda System for Reporting Thyroid Cytopathology

“Nevertheless, even with this new classification system proposed to improve the management of thyroid nodules, its implementation has not always necessarily led to the desired outcomes.”

Introduced to the USA in the early 1980s, fine needle aspiration (FNA) has become essential in the evaluation of thyroid nodules that have become ubiquitous in the clinical setting. In reporting FNA results, 15–30% would be classified as ‘indeterminate’, a category that encompassed a wide spectrum of thyroid nodular biology. This reporting system, however, was criticized owing to its ambiguity and represented a clinical challenge [1]. Accurate FNA diagnosis of thyroid nodules remained problematic owing to individual pathologist and institutional variability in FNA cytology interpretation and low inter-rater concordance. Furthermore, subsequent treatment for thyroid nodules in the ‘indeterminate’ category was not standardized among thyroid surgeons. To address these inadequacies in the management of indeterminate FNA cytology, a consensus panel sponsored by the National Cancer Institute created an updated classification system known as the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) in 2007. The goal of creating a uniform reporting system for thyroid FNA cytology was to facilitate more reliable interpretation of thyroid cytopathology and communication among multidisciplinary providers [1]. Each cytopathologic category for thyroid FNA was stratified with a malignancy risk and a corresponding management recommendation [1,2]. The previously utilized ‘indeterminate’ category was redefined and subdivided into Bethesda III and Bethesda IV categories in an attempt to give clarity to clinical practitioners. Many studies have since confirmed that the BSRTC appropriately risk-stratifies patients with thyroid nodules preoperatively [2]. Nevertheless, even with this new classification system proposed to improve the management of thyroid nodules, its implementation has not always necessarily led to the desired outcomes.

In particular, Bethesda category III, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), has brought confusion about proper management of such designated thyroid nodules. The BSRTC recommendation for Bethesda III category nodules is to repeat FNA for definitive diagnosis after 3–6 months [1]. The implementation of the BSRTC at many institutions has been reported with variable results including the frequency of patients with Bethesda III nodules, propensity to follow guidelines, incidence of malignancy and number of surgeries performed. From one large academic center experience, BSRTC implementation was associated with lower rates of malignancy within Bethesda III specimens and thyroidectomy rates were not altered [3].

Another large academic center looked at patients with Bethesda III cytology who either followed BSRTC for repeat FNA, or underwent immediate surgical intervention [4]. No difference in thyroidectomy rates between each group was appreciated. However, a higher malignancy rate in final pathology was observed in the patients who underwent immediate surgical intervention than predicted by the BSRTC. The patient population in this surgical series was highly selected compared with the general population. In addition, many of these patients had other risk factors that gave them a higher likelihood to undergo surgical resection for underlying thyroid malignancy. In the authors’ practice, FNA results are not only taken into consideration, but also risk factors for malignancy, suspicious ultrasound findings, as well as patient preference.

Another study from a major cancer center examined the implications of a Bethesda III diagnosis and found that the current BSRTC guidelines were not being followed, as most patients had not undergone repeat FNA, but rather, elected to undergo surgical resection for definitive diagnosis [5]. In the authors’ surgical practice, many patients given the option of repeat FNA instead often chose to directly undergo thyroidectomy. This study also showed that the malignancy rate from their group was higher than estimated by current Bethesda guidelines.

One clinical scenario that the BSRTC fails to address is if a subsequent benign FNA biopsy negates a previously atypical FNA biopsy (Bethesda III category) allowing the patient to forego surgical resection for definitive diagnosis. Although studies have identified patients with an AUS/FLUS diagnosis on first FNA, and a benign diagnosis on subsequent FNA, no long-term outcome data are reported for this subset of patients who did not undergo surgical resection who may harbor occult cancer [4]. Since no recommendations for this specific group of patients exists, individual practitioners are left to manage these patients, which may result in more variability in the management of thyroid nodules. In this situation, if patients elect nonsurgical management, interval ultrasound and/or FNA are recommended.

Such studies show that clinicians primarily rely on their judgment and experience to treat their patients that sometimes preclude recommendations set forth by the BSRTC guidelines. These studies all put the BSRTC recommendations into question of whether or not these new recommendations provide the best management options for patients with Bethesda III thyroid nodules, since everyday clinical practice still shows flaws in these guidelines. Many factors must be considered in the management of patients with AUS/FLUS thyroid nodules including subjective information, such as pathologists’ interpretation of FNA cytology, risk factors, imaging studies and patient preference, which can make following even the best of guidelines varied and unpredictable. Although the BSRTC was created in an attempt to bring better management to patients with Bethesda III thyroid nodules, the results are still mixed in regards to whether or not it succeeded. The BSRTC guidelines remain recommendations with multiple other factors playing a part in final management decisions that cannot be accepted universally in each individual patient.

Recent tests have been devised to limit the subjectivity of cytologic diagnosis in patients with indeterminate thyroid nodules. The Afirma (Veracyte, CA, USA) test was designed to provide more accurate diagnosis from FNA of simple thyroid cytology, resulting in the avoidance of unnecessary surgery in those patients with benign disease [6]. This diagnostic test is a gene expression classifier (GEC), looking at molecular markers from 142 genes and testing their expressivity in each aspirated thyroid cytology sample. The GEC can accurately exclude thyroid cancer and, therefore, can be used in different aspects in the management process, determining which patients require surgical resection for definitive diagnosis and to what extent of procedure the patient needs. With a negative predictive value over 94% and an estimated 90% reduction in surgical intervention, this is one of the most accurate, objective tests to be used for the evaluation of thyroid nodules, despite its low positive predictive value of 38% [7]. The GEC is recommended and most useful for AUS/FLUS thyroid nodules to rule out malignancy, which is most challenging category to clinicians in determining their proper management. Analytic validity has been established for most of the markers, yet its clinical validity remains unclear. Since its release for clinical use in 2010, there have been preliminary studies confirming the test’s long-term validity. In a large, multicenter prospective trial, follow-up clinical assessment confirmed a low false-negative rate of the Afirma test, and those clinical recommendations for surgical resection dropped by 93%. Conversely, a single academic institution found that using the Afirma test resulted in only a 4.2% reduction in thyroidectomy volume [8]. Despite a small reduction in surgical intervention, this study suggested that a highly selected population of patients referred to surgeons are more likely to undergo surgical resection due to multiple factors, not just based on one diagnostic test, such as Afirma. Nevertheless, the future implication of this diagnostic modality remains to be seen.

Although objective tests and the BSRTC guidelines were created in an attempt to standardize care, clinical judgment and experience remains paramount in the care of patients with thyroid nodules. While certain sections of the BSRTC are straightforward and can be universally followed, other BSRTC recommendations remain unclear. Furthermore, additional factors need to be considered other than FNA results when managing patients. With recent molecular tests used to provide more accurate diagnosis of thyroid nodules in addition to standard cytology, the current management of thyroid nodules continues to evolve. Nevertheless, the BSRTC is an important foundation in which to base clinical practice, but it should not be the only criterion to consider.

Financial & competing interest disclosures

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.