|Year : 2023 | Volume
| Issue : 1 | Page : 41-44
Atypia of undetermined significance/follicular lesion of undetermined significance (Bethesda Category - III) in thyroid cytology: Experience from a tertiary health care center from Eastern India
Prateek Das1, Rashmi Patnayak1, Rajesh Bhola1, Amitabh Jena2
1 Department of Pathology, Institute of Medical Sciences and SUM Hospital, Bhubaneswar, Odisha, India
2 Department of Surgical Oncology, Institute of Medical Sciences and SUM Hospital, Bhubaneswar, Odisha, India
|Date of Submission||01-Jan-2023|
|Date of Acceptance||16-Jan-2023|
|Date of Web Publication||15-Feb-2023|
Department of Pathology, Institute of Medical Sciences and SUM Hospital, Bhubaneswar, Odisha
Source of Support: None, Conflict of Interest: None
Introduction: Fine-needle aspiration (FNA) cytology is a reliable method to diagnose thyroid lesions. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is universally followed for thyroid cytology reporting. Out of the six categories described, Category III, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is the most heterogeneous one. Materials and Methods: In this study conducted in a tertiary health care center in Eastern India over 2 ½-year period, 868 thyroid FNAs were performed and the cytology smears were interpreted using the TBSRTC. There were 32 FNAs in Category III. Histopathology report was available in nine cases. Results: The risk of malignancy (ROM) considering noninvasive follicular thyroid carcinoma with papillary nuclear features (NIFTP) as benign was 9.3% and by considering NIFTP as malignant was 21.8%. Conclusion: The ROM for AUS/FLUS in our study was within the revised ROM criteria. In Category III, surgery is preferable in nodules which harbor suspicious features either clinically or according to ultrasound findings.
Keywords: Atypia of undetermined significance/follicular lesion of undetermined significance, Bethesda system, fine-needle aspiration cytology, thyroid
|How to cite this article:|
Das P, Patnayak R, Bhola R, Jena A. Atypia of undetermined significance/follicular lesion of undetermined significance (Bethesda Category - III) in thyroid cytology: Experience from a tertiary health care center from Eastern India. Bangladesh J Endocrinol Metab 2023;2:41-4
|How to cite this URL:|
Das P, Patnayak R, Bhola R, Jena A. Atypia of undetermined significance/follicular lesion of undetermined significance (Bethesda Category - III) in thyroid cytology: Experience from a tertiary health care center from Eastern India. Bangladesh J Endocrinol Metab [serial online] 2023 [cited 2023 Mar 29];2:41-4. Available from: https://www.bjem.org/text.asp?2023/2/1/41/369659
| Introduction|| |
Over the years, fine-needle aspiration (FNA) cytology has emerged as a fairly reliable method of diagnosing thyroid lesions. This in turn significantly influences clinical decisions regarding management. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is followed worldwide for thyroid cytology reporting. It provides universal reporting guidelines. The initial TBSRTC system (2007) was modified in 2017. It classifies thyroid FNA into categories such as (I) nondiagnostic, (II) benign, (III) atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), (IV) follicular neoplasm/suspicious for follicular neoplasm, (V) suspicious for malignancy, and (VI) malignant., Among these categories, Category (III) AUS/FLUS is the most heterogeneous one. This category is associated with a low risk of malignancy (ROM) (5%–15%) and, in the absence of other suspicious features, can be managed with a repeat FNA. This ROM has been recently revised to 10%–30% if non invasive follicular thyroid neoplasm with papillary (NIFTPs) are considered malignant and 6%–18% when NIFTP is excluded from the malignant group.
There are scarce data in Indian literature regarding this Category III. Hereby, we have analyzed our data regarding Bethesda Category III.
| Materials and Methods|| |
This study was carried out in a tertiary care center in Eastern India for 2½ years. All the patients visiting the cytology department who underwent FNA for thyroid swelling were included in the study. Details of clinical history and family history were collected along with thyroid function reports and ultrasound (US) findings. All the patients gave consent for the FNAC procedure as well as for the subsequent publication of data in the condition of anonymity. This study was approved by the Institutional Ethics Committee.
Patients underwent FNA which was performed by a cytopathologist. Few cases underwent US-guided FNA by the radiologist using a 25-or 27-gauge needle and the FNA slides were stained and interpreted. For each case, one to four passes were made. The stains used were Diff-Quik, hematoxylin and eosin, and Papanicolaou stain. An air-dried, Diff-Quik-stained slide was assessed for adequacy immediately following FNA. The remaining slides were alcohol-fixed and stained with hematoxylin and eosin and Papanicolaou stain.
The slides were screened by minimum of two cytopathologists. Bethesda System for Reporting Thyroid Cytopathology was followed to categorize the FNAs.,
| Results|| |
In this 2½-year study period, a total of 868 thyroid FNA were performed (unpublished data). Out of these 32 cases belonged to Bethesda Category III. Majority of AUS/FLUS cases belonged to the age group of 21–30 years. Histopathology report was available for nine cases. Seven of these cases had undergone hemithyroidectomy and total thyroidectomy was done for two cases.
According to histopathology, three cases were malignant. Two were papillary carcinoma of thyroid and one was follicular carcinoma. There were four cases of follicular adenoma with features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The two benign cases include one adenomatous goiter and one follicular adenoma [Figure 1].
|Figure 1: (a) Sheets of thyroid follicular cells (Diff-Quik × 200). (b) Cytology of AUS/FLUS-thyroid follicular cells exhibiting anisonucleosis (Diff-Quik ×400). (c) Cytology of AUS/FLUS (Diff-Quik ×400). (d) Cytology of AUS/FLUS showing vague nuclear inclusions (Diff-Quik ×400). AUS/FLUS: Atypia of undetermined significance/follicular lesion of undetermined significance|
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The two cases of papillary carcinoma which were reported under Category III were small in size and had undergone cystic degeneration. Moreover, the case reported as follicular carcinoma had scant cellularity and was hemorrhagic in nature. These patients were advised to repeat US-guided FNA. However, they underwent surgery according to patients' preferences.
To estimate the rate of malignancy, the formula used was the one used by Ho et al.
The lower bound estimate was calculated by dividing the number of confirmed malignancies by the total number of AUS/FLUS nodules. The assumption was that all observed (nonoperated) AUS/FLUS nodules were benign. This assumption is subjected to verification bias, and therefore underestimates the prevalence of malignancy. The upper bound estimate was calculated by dividing the number of confirmed malignancies by the number of AUS/FLUS nodules selected for surgery. These nodules were selected for surgery depending on other clinical or ultrasonographic suspicious features. Therefore, in these cases selection bias exists, overestimating the prevalence of malignancy. The true prevalence is likely to lie between the lower and upper bound estimates. In this study, the lower bound estimate was 9.3%. This is subjected to verification bias. The upper bound of the estimate is 21.8%. This is subjected to selection bias. Hence, most likely, the true prevalence is between these two values.
| Discussion|| |
Thyroid cancer forms around 3% of all malignancies. It is the most common endocrine malignancy. The incidence is variable across the globe and even within a country. In Indian subcontinent, the incidence is highest in the Southern and North-Eastern regions. In one of the previous studies conducted in a tertiary health care center in South India, the authors had reported high incidence of malignancy in solitary thyroid nodules. In a study from Singapore, the authors have stated that there is significant heterogeneity in the outcomes of the AUS/FLUS categories between and within regions.
According to the Global Cancer Statistics 2018, there is an over ten-fold difference in incidence across different parts of the world in both females and males, the highest incidence area being in North America (23.1/100,000 in females and 6.9/100,000 in males) and the lowest incidence area in Western Africa (1.5/100,000 in females and 0.5/100,000 in males).,
In thyroid swellings, FNAC is the primary screening modality. FNAC helps in triaging them as benign or malignant. TBSRTC was introduced to maintain uniformity in reporting across the world and to facilitate easy interpretation by clinicians. The six cytology categories of the TBSRTC group thyroid lesions ranging from benign to malignant. Category III (AUS/FLUS) is the most heterogeneous one. It is a well-defined group of thyroid lesions, which can be most accurately diagnosed and managed with cytomorphology, molecular, and ancillary studies.
The use of Category III has to be limited to < 10% of the thyroid aspirates at any given center. In the present study, the cases in the category accounted for 3.6% of cases.
In Category III, an AUS/FLUS nodule following resection may reveal features of either benign or malignant lesions. According to TBSRTC 2007 recommendation, AUS/FLUS aspirates are managed by repeat FNA. Resection in AUS/FLUS nodules is recommended for nodules which are clinically or radiologically suspicious. The implied ROM of AUS/FLUS as per the recent edition of TBSRTC has been revised to 10%–30% if NIFTP is considered malignant and 6%–18%, on excluding NIFTP from the malignant group. In the present study group, if we consider NIFTP as malignant. The ROM is 21.8% and if we include NIFTP in the benign group, then ROM is 9.3%. This value falls within the revised ROM for AUS/FLUS as per the recent edition of TBSRTC.
There is variation in ROM in various studies. According to a study conducted by Deniwar et al., the Bethesda risk stratification system underestimated malignancy rates in benign, indeterminate, and nondiagnostic cytopathologic categories.
Whereas Ho et al. have reported an estimated prevalence of 26.6%–37.8% ROM in AUS/FLUS thyroid nodules. In their study, the incidence of malignancy after an index AUS/FLUS diagnosis was also similar to the rate after consecutive AUS/FLUS diagnoses. They concluded that repeat FNA may not have clear utility in clinical decision-making. Huhtamella and Kholová found 14.7% ROM for AUS/FLUS.
In another study by Turkyilmaz et al., the malignancy rate for nodules diagnosed as AUS/FLUS that underwent repeated FNA after AUS/FLUS was as follows, the lower and upper thresholds for the malignancy rate were 19.3% and 66.3%, respectively, higher than the expected malignancy rates of the National Cancer Institute.
Li et al. have opined that the cytologic interpretations for the majority of NIFTP cases were AUS/FLUS in their study. There was a relative decrease in ROM in AUS/FLUS when NIFTP was not considered malignant.
Here, in our study, the patients who underwent surgery were all advised to repeat USG-guided aspiration. The decision of surgery was according to patients' preferences.
Limitations of this study apart from the bias stated include the lack of extended follow-up period. A multi-institutional study with better follow-up is essential to further subgroup the lesions included in this category.
In Italian consensus for the classification and reporting of thyroid cytology, indeterminate lesions are classified as at low and high ROM. We have not used this system of classification.
| Conclusion|| |
In our study, the ROM was 9.3% to 28.1%. The upper limit was within the revised ROM in TBSRTC. In future, the molecular study will definitely play an important role in categorizing benign and malignant lesions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Guleria P, Mani K, Agarwal S. Indian experience of AUS/FLUS diagnosis: Is it different from rest of Asia and the West? A systematic review and meta-analysis. Gland Surg 2020;9:1797-812.
Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Thyroid 2009;19:1159-65.
Cibas ES, Ali SZ. The 2017 Bethesda system for reporting thyroid cytopathology. J Am Soc Cytopathol 2017;6:217-22.
Ho AS, Sarti EE, Jain KS, Wang H, Nixon IJ, Shaha AR, et al.
Malignancy rate in thyroid nodules classified as Bethesda category III (AUS/FLUS). Thyroid 2014;24:832-9.
Jena A, Patnayak R, Prakash J, Sachan A, Suresh V, Lakshmi AY. Malignancy in solitary thyroid nodule: A clinicoradiopathological evaluation. Indian J Endocrinol Metab 2015;19:498-503.
Ooi LY, Nga ME. Atypia of undetermined significance/follicular lesion of undetermined significance: Asian versus non-Asian practice, and the Singapore experience. Gland Surg 2020;9:1764-87.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Li R, Wang Y, Du L. A rapidly increasing trend of thyroid cancer incidence in selected East Asian countries: Joinpoint regression and age-period-cohort analyses. Gland Surg 2020;9:968-84.
Geramizadeh B, Bos-Hagh S, Maleki Z. Cytomorphologic, imaging, molecular findings, and outcome in thyroid follicular lesion of undetermined significance/atypical cell of undetermined significance (AUS/FLUS): A mini-review. Acta Cytol 2019;63:1-9.
Deniwar A, Hambleton C, Thethi T, Moroz K, Kandil E. Examining the Bethesda criteria risk stratification of thyroid nodules. Pathol Res Pract 2015;211:345-8.
Huhtamella R, Kholová I. Thyroid Bethesda category AUS/FLUS in our microscopes: Three-year-experience and cyto-histological correlation. Cancers (Basel) 2019;11:1670.
Turkyilmaz S, Ulusahin M, Celebi B, Cekic AB, Mungan S, Kucuktulu U, et al.
Thyroid nodules classified as atypia or follicular lesions of undetermined significance deserve further research: Analysis of 305 surgically confirmed nodules. Cytopathology 2017;28:391-9.
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. Diagn Cytopathol 2018;46:148-53.
Valabrega S, Santolamazza G, Romanelli F, Scapicchio G, D'Angelo F, Bellotti C, et al.
Cancer rate of the indeterminate lesions at low or high risk according to Italian system for reporting of thyroid FNA. Front Endocrinol (Lausanne) 2018;9:371.