Comparative accuracy of fine-needle aspiration cytology between larger and smaller size thyroid nodules

INTRODUCTION

In clinical practice, thyroid nodules are common, with a higher prevalence in women. These nodules are found in approximately 50% of healthy individuals and, in most cases, do not result in substantial symptoms. Approximately 80–90% of thyroid nodules are estimated to be benign. Patients at risk for developing thyroid cancer are those with a history of head-and-neck radiation exposure and a family history of thyroid cancer.^[1]

The primary goal of managing these nodules is to exclude malignancy; this is often achieved through neck ultrasonography (US) and thyroid fine-needle aspiration cytology (FNAC). The US is a valuable, non-invasive tool for identifying nodules harboring possible malignancy. Radiological findings such as microcalcifications, taller-than-wide nodule dimensions, solid irregular nodule borders, and hypoechogenicity can raise suspicion of thyroid cancer.^[2]

Thyroid cytology is a simple diagnostic tool for thyroid nodules, thereby decreasing unnecessary surgeries in most benign cases, with a reported mean sensitivity and specificity of 83% and 92%, respectively.^[3] However, there are conflicting data about the accuracy of FNAC in larger thyroid nodules, particularly those larger than 4 cm. Several researchers have shown similar FNAC performance between larger and smaller nodules,^[4] while other studies have found higher rates of false-negative FNAC in larger thyroid nodules, and some have even recommended immediate surgery for nodules larger than 4 cm regardless of the FNAC results.^[5]

Based on these inconsistent findings, we aim in this study to evaluate the accuracy of thyroid FNAC in detecting malignancy in smaller nodules compared to larger nodules and to determine whether the probability of indeterminate or non-diagnostic thyroid FNAC is higher when the size of the nodule is larger.

MATERIAL AND METHODS

RESULTS

Baseline characteristics of the study sample

We had 345 patients who fulfilled the inclusion criteria; the majority were female (86.7%) and older than 40 years of age (53.9%). Approximately half of the patients had benign post-operative histology, and the other half were found to have thyroid cancer. The median nodule size was higher for benign nodules (3.1 cm), whereas for malignant nodules, the median size was 2.7 cm. Most benign nodules had low suspicion US features (49.6%), and most of the malignant sample had high-risk US features (48.1%). The majority of the cohort had indeterminate (FLUS/AUS, FN, SUSP) thyroid cytology results, accounting collectively for 49.3% of the cohort, followed by benign cytology in 29.3%, malignant cytology in 12.8%, and finally non-diagnostic cytology in 8.7%. Table 1 illustrates the baseline characteristics of the study sample. Figures 1, 2a, and b illustrate examples of thyroid nodules of different sizes and characteristics with the corresponding cytology.

Table 1: Baseline characteristics of the study sample.

Label	Total n=345	Histopathology		Test statistic value	P-value
		Benign n=172 (49.9)	Malignant n=173 (50.1)
Age, years, Mean±SD	42.97±13.83	43.52±13.30	42.43±14.36	t=0.73	0.4653
Pre-operative TSHa, Median (Q1, Q3)	1.6 (0.8, 2.7)	1.3 (0.7, 2.3)	1.8 (1.1, 3.0)	Z=3.81	0.0001
Size of the nodule, cm, Median (Q1, Q3)	3.0 (1.9, 4.2)	3.1 (2.0, 4.5)	2.7 (1.7, 4.0)	Z=2.22	0.0266
Age categories, n (%)				χ2=0.85	0.3564
≤40 years	159 (46.1)	75 (43.6)	84 (48.6)
>40 years	186 (53.9)	97 (56.4)	89 (51.4)
Sex, n (%)				χ2=1.55	0.2128
Female	299 (86.7)	153 (89.0)	146 (84.4)
Male	46 (13.3)	19 (11.0)	27 (15.6)
Type of surgery, n (%)				χ2=25.09	<0.0001
Hemithyroidectomy	82 (24.0)	59 (34.3)	23 (13.5)
Hemithyroidectomy followed by total thyroidectomy	17 (5.0)	3 (1.7)	14 (8.2)
Total thyroidectomy	243 (71.1)	110 (64.0)	133 (78.2)
Size of nodule, n (%)				χ2=4.97	0.0833
<2 cm	88 (25.5)	35 (20.3)	53 (30.7)
2–4 cm	168 (48.7)	88 (51.2)	80 (46.2)
>4 cm	89 (25.8)	49 (28.5)	40 (23.1)
USb features, n (%)				χ2=31.54	<0.0001
Benign	11 (4.0)	10 (7.1)	1 (0.8)
Very low suspicion	9 (3.3)	5 (3.5)	4 (3.0)
Low suspicion	112 (40.9)	70 (49.6)	42 (31.6)
Intermediate suspicion	52 (19.0)	30 (21.3)	22 (16.5)
High suspicion	90 (32.8)	26 (18.4)	64 (48.1)
Bethesda, n (%)				χ2=88.87	<0.0001
Non-diagnostic or unsatisfactory	30 (8.7)	15 (8.7)	15 (8.7)
Benign	101 (29.3)	77 (44.8)	24 (13.9)
AUSc	82 (23.8)	49 (28.5)	33 (19.1)
FNd or suspicious of FN	49 (14.2)	24 (14.0)	25 (14.5)
Suspicious of Malignancy	39 (11.3)	5 (2.9)	34 (19.7)
Malignant	44 (12.8)	2 (1.2)	42 (24.3)

aTSH: Thyroid-stimulating hormone, ^bUS: Ultrasound, ^cAUS: Atypia of undetermined significance, ^dFN: Follicular neoplasm. SD: Standard deviation

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Figure 1:

Thyroid ultrasound image displays a low-risk nodule, occupying the left lobe. Cytology analysis was Bethesda 3. Postoperative histopathology was benign.

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Figure 2:

(a) Thyroid ultrasound image displays a high-risk 1.3 cm nodule at the left lobe. (b) Thyroid cytology:Intranuclear inclusions and nuclear grooves classic feature of papillary thyroid carcinoma are apparent in this image (×60, Papanicolaou stain, Scale bar=50 μm).

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DISCUSSION

Thyroid cytology is a simple diagnostic tool for thyroid nodules, with an overall reported sensitivity and specificity 72% and 99%.^[12] Thereby, it decreases unnecessary surgeries in most benign cases. In this study, our results indicated that nodule size does not affect the probability of obtaining an indeterminate or non-diagnostic FNAC. In addition, our results indicated no difference in the accuracy of the FNAC between smaller and larger thyroid nodules.

Similarly, multiple other studies concluded that greater nodule diameter is not linked to the diagnostic utility of US-guided FNAC.^[13,14] Moreover, many other more recent studies have had similar results, with no relation found between different nodule sizes and the false-negative rate (FNR) of FNAC. In one study, the FNR for FNAC was low at (4.1%).^[15] Furthermore, another study compared the FNR between nodules ≥4 cm and smaller nodules <4 cm. FNAC FNR was 6.6% in nodules ≥4 cm compared to 4.2% in nodules <4 cm. The FNR was mainly driven by the follicular and Hurthle cell carcinomas in nodules ≥4 cm in size.^[16]

At the same time, several other studies have suggested that the diagnostic accuracy of FNAC in nodules larger than 3–4 cm is significantly lower compared to smaller nodules. In a study comprised of 323 nodules with benign pre-operative FNAC, nodules ≥3 cm in size had an FNR of 11.7%, and the FNR was 4.8% for nodules <3 cm.^[17] The former-mentioned study and also another similar study by Kim et al. suggested direct surgery for any thyroid nodule above 3 and 4 cm in size, respectively.^[5]

A study by Koo et al. on 690 thyroid nodules concluded that the diagnostic accuracy for FNAC drops as the size of the nodule increases. In their study, nodules between 1 and 4 cm had a diagnostic accuracy ranging between 94.4% and 99%, while in nodules above 4 cm, the diagnostic accuracy dropped to 87.5%.^[18] A systematic review that included studies up to July 2013 concluded that larger nodule sizes reduce cytological accuracy.^[19] In contrast, a similar –however – more recent systematic review that collected studies up to December 2017, concluded the opposite, where nodule size did not influence the FNAC accuracy.^[20]

We believe that studies proposing lower FNAC accuracy in larger nodules are limited by many factors. First, some were conducted among different populations with different epidemiology of thyroid cancer and different surgical practices.^[21] Second, some of these studies, especially the older ones, included FNAC performed by palpation, not ultrasound-guided. Based on a systematic review and meta-analysis comparing the diagnostic accuracy of US-guided versus palpation-guided thyroid FNAC, the accuracy of US-guided FNA was found to be significantly superior. The diagnostic sensitivity and specificity by palpation were 76% and 77%, respectively, while the sensitivity and specificity using US guidance were 90% and 80%, respectively.^[22]

Third, a lot of these studies were before the era of standardized US risk stratification systems, such as the 2015 ATA nodule guidelines and TIRADS-ACR guidelines. These clinical guidelines and stratification systems have assisted immensely in better diagnostic decision-making and fine-tuning management planning. Similarly, the Bethesda system for thyroid cytology reporting has evolved remarkably over the past decade. In fact, an analysis conducted to compare the FNAC performance before and after the implementation of the Bethesda cytology system found that it decreased the frequency of non-diagnostic, FN, and SUSP. It also increased the diagnoses of benign cytology.^[23]

Fourth, some studies have concluded that lower sensitivity of FNAC in larger nodules might be related to sampling error or an incidental thyroid microcarcinoma.^[24] Indeed, when Zhu et al. retrospectively reexamined their discordant FNAC, that is, the false-negative and the false-positive cases, they found that the chief etiology of false-negative diagnoses was sampling error in 86.7% of the cases, whereas interpretation error led to most of the false-positive diagnoses.^[25] To avoid such error, it was suggested by some experts that multiple passes (2–5) should be executed from all parts of large nodules to diminish the risk of false-negative results. Alternatively, a core-needle biopsy can be utilized for thyroid nodules >2 cm with intermediate to high-risk US risk stratification as it was found to be diagnostically superior to FNAC in these circumstances and also with lower non-diagnostic rates.^[26-28]

Finally, with the introduction of NIFTP nomenclature in 2016^[29] the malignancy rates of benign and malignant FNAC specimens decreased significantly. This reduction was particularly pronounced in three indeterminate Bethesda categories.^[30,31] Furthermore, the implementation of gene expression classifiers (GEC) on indeterminate cytology, namely, AUS/FLUS and FN categories, resulted in 61% less diagnostic surgeries, regardless of the nodule size.^[32,33] Due to the high negative predictive value of these tests, such as Afirma GEC and Thyroseq V3 (96% and 97%, respectively), the management of thyroid nodules has evolved dramatically over the past few years.^[34]

Our study is strengthened by being a more contemporary view of thyroid nodules that implements the standardized US and cytology reporting systems within the same population. In this study, we utilized the gold standard of diagnosis, which is post-surgical histopathology. To the best of our knowledge, no previous study has investigated the correlation between nodule size and the probability of indeterminate or non-diagnostic cytology. Conversely, the limitations of our study are that it is retrospective and that not all thyroid cytology was read by an independent cytologist; hence, inter-observer variability is possible.

SUMMARY

We found no correlation between thyroid nodule size and the probability of indeterminate or unsatisfactory FNAC. The diagnostic accuracy of FNAC is comparable among different nodule sizes. FNAC can reliably guide the decision for surgery for larger and smaller thyroid nodules along with the diagnostic and clinical data.

AVAILABILITY OF DATA AND MATERIALS

The datasets used in this study are available on request.

ABBREVIATIONS

ATA: American Thyroid Association

FLUS/AUS: Follicular lesion of undetermined significance/atypia of undetermined significance

FN: Follicular neoplasm

FNAC: Fine needle aspiration cytology

FNR: False-negative rate

GEC: Gene expression classifiers

SAS: Statistical Analysis Software

SD: Standard deviation

SUSP: Suspicious for malignancy

TSH: Thyroid-stimulating hormone

US: Ultrasonography