Rate of Malignancy in Thyroid Nodules Having Atypia of Undetermined Significance on FNAC

Rate of Malignancy in Thyroid Nodules Having Atypia of Undetermined Significance Abstract Introduction & Background: The global incidence of thyroid cancer is rapidly increasing largely due to incidental thyroid nodules being found on ultrasonography. Fine Needle Aspiration Cytology (FNAC)is not only a reliable screening test, but also a reliable and cost-effective method for the differential diagnosis of a thyroid nodule. Atypia of Undetermined Significance (AUS) or Follicular Lesion of Undetermined Significance (FLUS) is


Introduction
The incidence of thyroid cancer is increasing globally mainly because of finding incidental thyroid nodules on ultrasonography. These Nodules are seen in 50% of patients aged 50 years. However, the risk of malignancy in these nodules is 5% to 7%. Most commonly used preoperative diagnostic tool is Fine-Needle Aspiration Cytology (FNAC) for cancer risk stratification in thyroid nodules weather palpable or image detected [1,2]. In the year 2007, the National Cancer Institute (NCI), Bethesda, Maryland, United States, organized the NCI Thyroid Fine Needle Aspiration State-of-the-Science Conference, and an initiative was undertaken to publish an atlas and guidelines using a standardized nomenclature for the interpretation of thyroid fine needle aspirates (FNAs), known as the Bethesda system for reporting thyroid cytopathology [3]. The atlas describes six diagnostic categories of lesions: Non-diagnostic/unsatisfactory, benign, atypical follicular lesion of undetermined significance (AFLUS), "Suspicious" for Follicular Neoplasm (SFN), Suspicious for Malignancy (SM), and malignant [4]. The six diagnostic categories of the Bethesda system have individual implied risks of malignancy that influence management paradigms.
Out of all these 6 categories ,it is type 3ie atypical nodules (AUS/FLUS) that pose management challenges. Bethesda system recommends a repeat follow-up FNA biopsy for cases of thyroid nodules with AUS/FLUS. Reports indicate that about 30% of such cases were still diagnosed as being cytologically indeterminate thyroid nodules despite a repeat FNA biopsy [5]. It makes treatment decisions difficult for clinicians concerned with the optimal management of thyroid nodules. To overcome this problem, several modalities other than repeat FNA have been proposed, such as Core Needle Biopsy (CNB) [6], gene expression classifier test [7], and multi-gene next-generation sequencing assay [8]. Diagnostic accuracy of these modalities is questionable and moreover they are either not available or are very expensive . Since its advent, FNAC became a routine practice for thyroid nodule assessment, and the role of intraoperative frozen section biopsy has been debated. Few authors advocate the use of frozen section because of the very low false positive rates and the high specificity, of up to 90% [9,10]. However, several recent series report very low sensitivities, ranging from 22% to 51% [11,12].
Actually Not all of these patients with atypia of thyroid nodules on FNAC under go surgery because of many patient and clinician related factors so it is difficult to actually calculate the risk of malignancy in these nodules .
The risk of malignancy in Bethesda-III category ranges from 12% to 69% in the resected specimens [13][14][15][16]. This wide variation could be partly explained due to interobserver variability both at the time of obtaining the specimen and during the cytological interpretation. Moreover, the prevalence of malignancy in the population could influence the percentages of malignancy in the resected specimens. However, eliminating the AUS/FLUS category decreases the FNAC sensitivity and increases the rates of false negative and false positive results [17]. Therefore, it has been suggested that institution-specific and local data should guide the subsequent management of indeterminate nodules. This study was conducted to calculate the risk of malignancy in atypical thyroid nodules in our institute to have institute specific data to help us in making guide lines for management of indetermined nodules. Future studies can be conducted with multiple institutes to get local data for entire community.

Objective
To determine the rate of malignancy in thyroid nodules having atypia of undetermined significance by comparing pre operative FNAC with post thyroidectomy histopathology.

Atypia of Undetermined Significance
Atypia of Undetermined Significance (AUS) or Follicular Lesion of Undetermined Significance (FLUS) is one of the six diagnostic categories of Bethesda system for reporting thyroid cytopathology and fits in to Bethesda category (III).
Details of Bethesda classification are given in introduction.
The prevalence of malignancy among Bethesda III category is variable, ranging from 5% to 37 % in the literature [18].

Materials and Methods
Ethical approval was taken from Dubai Scientific Research Ethics Committee (DSREC) before starting the study. Since it was a retrospective cross sectional/observation study so patients consent was not taken showing atypia of undetermined significance (AUS/FLUS) were recruited for inclusion in the study.

b.
Exclusion Criteria: Patients whose FNAC results were other than AUS/FLUS and those who did not undergo surgical intervention were excluded.
Study Design: retrospective cross sectional.
Data Collection: Data was collected retrospectively using electronic record system of hospital

Data Analysis
All analysis was done using the Statistical Package for Social Sciences (SPSS) version 28.
The variables included were age, sex, pre operative FNAC and post operative histopathology.
Records of all patients who under went thyroidectomies from jan 2018 till July 2021 were reviewed and out of these patients those who had pre operative FNAC showing atypia of undetermined significance were included in study . The pre operative FNAC of these patients was compared with post operative histopathology to see how many of these patients actually had malignancy.

Results
Over the period of 1.6 years, preoperative FNAC was performed in 120 patients who underwent thyroid surgery.
The mean age was 49.9 years.
Age distribution is shown in Figure 1           We must highlight that we have only reviewed the cases submitted to surgical intervention. This would yield a malignancy risk closer to the upper bound estimate which might be a slight overestimation of the actual risk.

Discussion
There is heterogenisity in prevalence, utilization, interpretation, and management of atypical thyroid nodules within and across different specialities [19]. There is controversy in using combination of different diagnostic tests ,biopsy practices,use of ultrasound and pathology reporting system and availability and utilization of frozen section .Although most of clinicians follow Americal thyroid association guide lines there is deviation from guidelines because management is individualized depending on availability of resources, patient's preferences as well as clinical and ultrasonic features [19]. Repeat FNAC is also not reliable as incidence of atypia on repeat cytology is 30% [5] leading to management challenge and leading back to square zero. Even if repeat FNAC comes as benign these patients need to have follow up and repeat ultrasound after 3-6 months and ultrasound finding of suspicious nodule will again require FNAC leading to wastage of resources and patient's anxiety along with management challenge for surgeons. If repeat FNAC is malignant patient anyways needs lobectomy after a delay of 3 months. Frozen section biopsy has sensitivity and specificity of 21-55 % and can easily miss carcinoma in atypical nodules so should not be done for atypical nodules [11,12].
Najah and Tresallet [20] concluded that frozen section contributed little to the diagnosis of undetermined thyroid nodules due to their low sensitivity and high false negative rates. They suggested that tumor capsular invasion, which is the hallmark to diagnose malignancy, could not be evaluated on FSs(frozen section ), and was only possible on permanent sections. In fact, frozen section jeopardize the detection of capsular invasion because of the fragmentation of the specimen during the process [14].
Our histopathology department is not recommending to go for frozen section as the definitive histopathology is often different than frozen section diagnosis so we don't use it any more for atypia and further more follicular carcinoma still can be missed on frozen section biopsy so its risky to take decision on basis of frozen section. The rate of malignancy in atypical nodules in our study is 57.14% which is very high and based on these figures we recommend to go for diagnostic lobectomy for all patients having atypia of undetermined significance on FNAC in as institute specific approach is favored based on institute specific data. This rate might not be the true representative because of small sample size but since there is no institute specific data this can be used to carry out large studies in future to make the results more generalized .

Conclusion
Based on high rate of malignancy in atypical thyroid nodules as is evident from our study (57.14%) ,all patients presenting with atypia of undetermined significance should straight away be offered diagnostic lobectomy.
Although the rate of malignancy as per our study is very high another study with larger sample size can be conducted to further analyze the results and then to implement the guidelines.