The Gray Zone in Thyroid Nodules: Atypia of Undetermined Significance/Follicular Lesion with Unknown Significance

Major purpose of the management of thyroid nodules is to distinguish between malignant nodules and the benign ones. Nodules with the cytology result Atypia of Undetermined Signifi cance or Follicular Lesion of Undetermined Signifi cance are still a diagnostic challenge. Initial presentation of the Bethesda System was based on 7% diagnosing rate and around 5-15% malignancy rate for these nodules; however, clinical practice presents with higher rates for both variables. Recent studies showed that when these nodules are grouped by cytological features; compared with the architectural atypia group, the cytological atypia group has a signifi cantly higher risk of malignancy. Cytological sub-classifi cation, ultrasonographic evaluation and genetic tests in selected cases should be used in the management of these nodules. Mini Review The Gray Zone in Thyroid Nodules: Atypia of Undetermined Signifi cance/ Follicular Lesion with Unknown Signifi cance Selami Ilgaz Kayılıoğlu*, Ufuk Utku Göktuğ and Tolga Dinç Ankara Numune Eğitim ve Araştırma Hastanesi, Hacettepe Mah Talatpaşa Bul No. 4, Altindag, Turkey Dates: Received: 01 June, 2017; Accepted: 12 June, 2017; Published: 13 June, 2017 *Corresponding author: Selami Ilgaz Kayılıoğlu, Department of General Surgery, Ankara Numune Research and Training Hospital, Turkey, Tel: 00-90 533 203 6595; Fax: 00-90 312 311 4340; E-mail:


Introduction
Management of thyroid nodules is still one of the main topics in endocrine surgery. Nodules can be detected in the thyroid glands of around 60% of the population according to the American Thyroid Association [1]. Major purpose of the management of these nodules is to distinguish between malignant nodules and the benign ones. At this point, fi ne needle aspiration biopsy is the most valuable tool we currently have. Although it is massively used around the world for a signifi cant time, there are still gray zones that put us in a diffi cult decision making when evaluating the results. The Bethesda System for Reporting Thyroid Cytopathology is the main source for this decision making process. According to this classifi cation there are 6 main diagnostic categories, 4 of which have relatively less controversy going on around. These diagnostic categories are non-diagnostic, benign, suspicious for malignancy and malignant. "Do"s and "Don't"s are quite clear with these categories. However, it is not the same way with the "Atypia of Undetermined Signifi cance or Follicular Lesion of Undetermined Signifi cance (AUS/FLUS)" and the "Follicular Neoplasm or Suspicious for a Follicular Neoplasm" category. Here, we are discussing the AUS/FLUS category.
When evaluating a fi ne needle aspiration biopsy patient, category 3 -AUS/FLUS may be the most unwanted result for many clinicians. According to Bethesda statement in 2009, only around 7% of fi ne needle aspirations are expected to be interpreted as AUS/FLUS by cytopathologists. However, there are multiple studies that state higher rates. A fi ve-year multi-institutional analysis with 6,872 cases evaluated by 28 cytopathologists showed that use of FLUS category varied among pathologists from 2.5 to 28.8% and among institutions from 3.3 to 14.9% [2]. Another study from a respected center with almost 4000 patients reported the overall rate of AUS as 9.8% [3]. Another signifi cant and also important fact that the further studies on Bethesda System point out is that the malignancy rates are higher than it was expected. It was stated on 2009 that the risk of malignancy is probably close to 5% to 15% in all AUS patients [1]. However, this rate is reported as 28.3% for FLUS and 32% for AUS patients in the above mentioned studies [3]. In a similar study of ours, we found that 35% of patients who undergone surgical resection due to AUS/ FLUS were diagnosed malignant [4]. Initial presentation of the Bethesda System was based on 7% diagnosing rate and around 5-15% malignancy rate; however, clinical practice does not seem to tone with these expectations.
Standart approach to patients with AUS/FLUS is repeat fi ne needle biopsy [5]. Due to uncertainty of the diagnosis and heterogeneity among AUS/FLUS patients cytopathologists and clinicians focused on this issue recently to clarify the diagnoses and classify this group of patients to increase homogeneity. Sub-classifi cation of AUS/FLUS nodules is being made based on detailed cytopathological features. A recent study grouped these patients into two groups as cytological atypia and architectural atypia, and showed that compared to the architectural atypia group, the cytological atypia group had a 2.64-fold increase in the risk of malignancy [6]. Similarly, a prospective study with 98 patients showed that 41.5% of AUS/FLUS nodules with nuclear atypia were malignant, whereas only 15.5% of AUS/FLUS nodules with architectural atypia were so [7]. This relatively new and striking information makes one think that routine use of further sub-classifi cation may be inevitable in the near future.
As one of the most valuable tools of thyroid imaging, ultrasound is highly relied on by clinicians. Lately, there has been increasingly more evidence on the valuable assistance of Thyroid Image Reporting and Data System (called TIRADS) in management of thyroid nodules with AUS [8]. A meta-analysis of fourteen studies showed that ultrasound has signifi cant sensitivity and specifi city rates in AUS/FLUS patients: 75% and 48%, respectively [9]. It is clear that ultrasound should support the diagnosis process.  [10,11].
In conclusion, management of thyroid nodules is mostly based on fi ne needle aspiration cytology fi ndings. Bethesda category 3 -AUS/FLUS nodules are the most dreadful ones, due to their potential of malignancy that one cannot underestimate.
Today, ultrasound is accepted as an important diagnostic tool to help prediction of malignancy, alongside cytopathology.
Consequently, working in a team with trained and experienced cytologists and radiologists seems essential to provide decent prediction rates in AUS/FLUS nodules.