What Is the Best Criterion for Repetition of Fine-Needle Aspiration in Thyroid Nodules with Initially Benign Cytology?

Abstract

Background:

Traditionally, repetition of fine-needle aspiration (FNA) is indicated for thyroid nodules with initially benign cytology if they exhibit growth. The importance of a repetition has also been demonstrated in the case of suspicious ultrasonography (US) findings. Some authors even consider routine repetition of FNA. The objective of this study was to evaluate the best criterion for FNA repetition in thyroid nodules with initially benign cytology.

Methods:

This was a prospective study. Patients with solid nodules that initially showed a benign cytology were selected. The first group was formed by nodules exhibiting suspicious features on initial US (group A, n = 55). The other group consisted of growing nodules without suspicious US features (group B, n = 82). Nongrowing nodules without suspicious features on initial US were divided into two groups: nodules that became suspicious on US (group C.1, n = 18) and those that continued to be unsuspicious (group C.2, n = 398).

Results:

In group A, the second FNA resulted in the diagnosis of malignancy in 10 cases (18.2%). In group B, malignancy was confirmed in two cases (2.4%). In group C.1, two nodules were confirmed to be malignant (11.1%). No case of carcinoma was observed in group C.2. Considering the sensitivity and number of FNA biopsies necessary for the detection of each false-negative case of the first FNA, the best criterion to repeat FNA was a suspicious initial or subsequent US. The growth of nodules with unsuspicious US findings was of poorly specificity and required a larger number of FNA biopsies to detect one case of malignancy.

Conclusions:

Ultrasonographic features of the nodule are the best parameter for the indication of FNA repetition in nodules with initially benign cytology, while the growth of nodules with unsuspicious US findings has a poor positive predictive value for malignancy.

Introduction

Nodular thyroid disease is frequent in clinical practice and benign cytology is the most common result of fine-needle aspiration (FNA). Although the negative predictive value of benign cytology is high, follow-up, including eventual FNA repetition, is recommended in view of the nonnegligible percentage of false-negative cases. This repetition is recommended by many guidelines when the nodule exhibits significant growth (1 –6), although some studies show that this parameter alone has a low positive predictive value (PPV) (7 –11) and low sensitivity (10,12 –14) for malignancy. The importance of FNA repetition has also been highlighted when initial ultrasonography (US) is suggestive of malignancy despite benign cytology and the absence of nodule growth (8,9). However, few guidelines recommend a second FNA of these nodules. A third possible indication for FNA repetition in cases in which the initial cytology was benign is the occurrence of suspicious US findings. This indication is mentioned in some guidelines (2,4,6), while others do not consider it (1,3,5). Finally, some authors consider routine FNA repetition for nodules with benign cytology (i.e., irrespective of growth and ultrasonographic features) (5).

In view of this controversy, the objective of this prospective study was to evaluate which of the previous criteria (i.e., growth, initial US suggestive of malignancy, occurrence of suspicious ultrasonographic findings, or routine repetition) is most adequate to establish an indication of FNA repetition in nodules with initially benign cytology, considering the sensitivity and number of FNA biopsies necessary for the detection of each false-negative case of the first FNA.

Patients and Methods

Study design

This was a prospective study. The selection criteria, follow-up protocol of the patients, indications for FNA repetition, and ultrasonographic definitions were predefined and rigorously followed.

Selection of patients

All patients with nodular thyroid disease consecutively seen by the authors from 2009 to 2014 were studied. Patients with nodules submitted to FNA (Table 1) whose first cytology was benign were selected. Patients with hypercalcitoninemia (calcitonin >100 pg/mL), compressive symptoms, or voluminous nodules, and patients with nodules detected during preoperative assessment of primary hyperparathyroidism were excluded since they were referred for surgery despite benign cytology. In view of the need for individual management, subjects with familial thyroid carcinoma and those exposed to ionizing radiation or neck radiotherapy in childhood or adolescence, and oncologic patients with nodules detected incidentally by [¹⁸F]fluorodeoxyglucose positron emission tomography were not included. Only solid or predominantly solid nodules [≤25% of the cystic component (1,2,7,15)] were included because these nodules exhibit a higher risk of malignancy and growth (7), and because alteration in size in predominantly cystic lesions is possible due to changes in the cystic component (15).

Table 1.

Indications for Fine-Needle Aspiration Adopted in This Study for Nonautonomous Thyroid Nodules

Nodule suspicious on US (see definition in Methods) ≥5 mm

Solid or predominantly solid hypoechoic nodule ≥10 mm

Solid or predominantly solid iso- or hyperechoic nodule ≥15 mm

Complex or spongiform nodule ≥20 mm

US, ultrasonography.

Follow-up protocol and indication for FNA repetition

The patients included in the study were submitted to a repeat US after 6 and 12 months and then annually. None of the patients received laser or radiofrequency ablation, radioiodine therapy, percutaneous ethanol injection, or thyrotropin (TSH) suppression. The nodules were divided into four groups. The first group was formed by nodules whose initial US was suggestive of malignancy (group A, n = 55) and these nodules were routinely submitted to FNA repetition after 6 months. The second group consisted of nodules whose initial US did not suggest malignancy (n = 505) and that exhibited significant growth during follow-up (group B, n = 82). Nodules with initial US findings not suggestive of malignancy and without significant growth (n = 416) were divided into two groups: nodules that became suspicious on US (group C.1, n = 18) and nodules that remained unsuspicious (group C.2, n = 398). FNA was repeated in group C.1 when the nodules became suspicious. As a control, nodules of group C.2 matched, if possible, for volume to nodules of group C.1 at a proportion of 3:1 were selected at the end of the study and also submitted to a second FNA. In groups B, C.1 and C.2, the minimum follow-up was 12 months (up to 60 months, median 42 months).

The study was approved by the local Research Ethics Committee.

Ultrasonography

US was performed with a linear multifrequency 12–14 MHz transducer for morphological analysis (B-mode) and for power Doppler evaluation. The images were analyzed by experienced professionals before FNA.

Definitions

Solid or predominantly solid nodules with the following features were defined as suspicious: (i) marked hypoechogenicity (a relatively hypoechoic pattern when compared to the adjacent strap muscle), (ii) microcalcifications, or (iii) two or more findings including hypoechogenicity, microlobulation or irregular margins, incomplete peripheral or sparse central calcification, a taller-than-wide shape (being greater in the anteroposterior dimension than in the transverse dimension), and predominant or exclusive central vascularization (16). This definition has been used at our institution (8,17 –21), and its value was demonstrated for nodules with cytology findings in the categories benign (8), follicular lesions or atypia of undetermined significance (20), follicular neoplasm (18), suspicious for malignancy (19), and nondiagnostic (21). Additionally, this definition is consistent with recommendations in all current guidelines (1 –6).

Significant growth was defined as an increase >50% in the initial volume of the nodule (22), calculated as length × width × depth × 0.52 (22) (www.thyroid.org/thyroid-physicians-professionals/calculators/thyroid-with-nodules).

Fine-needle aspiration

FNA was guided by US. The smears were analyzed by pathologists experienced in thyroid pathology. The cytological diagnosis was classified as nondiagnostic, benign, indeterminate (follicular lesion or atypia of undetermined significance [FLUS or AUS], suspicious for or follicular neoplasm), suspicious for malignancy, or malignant. The pathologist analyzing the second cytology was unaware of the first cytology result and the US findings.

Statistical analysis

Means were compared between groups by the Student t-test or the nonparametric Mann–Whitney U test. Fisher's exact test or the χ² test was used to detect differences in the proportion of cases. A p-value of < 0.05 was considered significant.

Results

The groups were similar in terms of sex, age, and TSH concentrations at the beginning of the study (Table 2). Although the median size of the nodules on initial US was similar in the four groups, nodules <10 mm were only observed in group A since in the remaining groups (initial US not suggestive of malignancy) FNA was only performed in the case of nodules ≥10 mm.

Table 2.

Characteristics of the Patients and Nodules at the Beginning of the Study

	Group A	Group B	Group C.1	Group C.2
No. of patients	55	79	18	54
Female/male	47/8	64/15	15/3	49/6
Age, range (median), years	16–82 (45)	18–76 (43)	21–80 (46)	20–73 (46)
TSH, range (median), mIU/L^a	0.5–8 (2.1)	0.4–6.4 (2)	0.8–8.7 (2.2)	0.5–5.4 (1.98)
No. of nodules^a	55	82	18	54
Nodule size (largest diameter), range (median), mm^a	6–39 (23)	10–40 (24)	10–38 (26)	10–39 (25)
Nodules ≥10 mm (largest diameter)^a	45	82	18	54

Data obtained at the time of initial US before the first fine-needle aspiration (FNA) which revealed benign cytology.

TSH, thyrotropin.

On the basis of the result of the second FNA, surgical excision was indicated in 37 nodules and malignancy was confirmed by histological analysis in 14 nodules (2.5% of all nodules).

Group A

In the second FNA of 55 nodules whose initial US was suggestive of malignancy, cytology was nondiagnostic in two, remained benign in 35, was indeterminate in 12 (AUS or FLUS), and was suspicious for malignancy in six. One patient with nondiagnostic cytology, 10 with indeterminate cytology, and all patients with suspicious cytology were submitted to surgery and malignancy of the nodule was confirmed in 10 cases. None of the nodules increased in volume during the interval between the first and second FNA (6 months).

Group B

FNA repetition of the 82 nodules whose initial US did not suggest malignancy, but which exhibited significant growth, revealed a nondiagnostic cytology in two, persistent benign cytology in 70, indeterminate cytology in eight (AUS/FLUS), and a suspicious cytology in one. One patient with nondiagnostic cytology and all patients with indeterminate or suspicious cytology were submitted to thyroidectomy and the malignant nature of the nodule was confirmed in two cases. At the time when a volume increase >50% was detected by US, eight nodules had become suspicious and malignancy was diagnosed in one of them; in contrast, only 1 of 74 nodules that remained unsuspicious on US was found to be malignant.

Group C.1

In the case of the 18 nodules whose initial US was not suggestive of malignancy, but became suspicious on subsequent US, although they did not exhibit significant growth, cytology continued to be benign in 12, was indeterminate in five (AUS/FLUS), and suspicious for malignancy in one. The six patients with indeterminate or suspicious cytology were submitted to surgery and two nodules were malignant.

The characteristics that rendered the 26 unsuspicious nodules on initial US suspicious on subsequent US (eight with and 18 without significant growth) are shown in Table 3.

Table 3.

Ultrasonographic Features That Rendered the Nodules (Initially Unsuspicious) Suspicious

Change in ultrasonographic feature	No. of nodules	Malignant nodules
Moderate hypoechogenicity → intense hypoechogenicity	No significant growth: 2	0
Isoechogenicity → intense hypoechogenicity	No significant growth: 1	0
Microcalcifications absent → present	No significant growth: 6	0
	Significant growth: 2	0
Margins regular → irregular	No significant growth: 7	2
	Significant growth: 3	1^a
AP/T diameter <1 → >1	No significant growth: 2	0
	Significant growth: 3	1^a

The same nodule.

AP/T, antero-posterior/transverse.

Group C.2

In the case of the 54 nodules without any of the above criteria (significant volume increase, initial or subsequent US suggestive of malignancy) that were then submitted to FNA repetition at the end of the study as a control group, cytology was nondiagnostic in one, continued to be benign in 48, and was indeterminate in five (AUS/FLUS). Four patients with indeterminate cytology were submitted to thyroidectomy, but no carcinoma was observed.

Of note, none of the 344 patients with initial US not suggestive of malignancy and nodules not exhibiting significant growth or suspicious findings during follow-up, which were not selected for FNA repetition, developed symptoms. Eighteen of these patients underwent thyroidectomy because of the patient's desire, and the nodule was not found to be malignant in any of them.

We analyzed different criteria (alone or in combination) for FNA repetition in nodules with initially benign cytology. Considering the sensitivity and the number of FNA biopsies necessary for the detection of each false-negative case of the first FNA, the best criterion was an initial or subsequent US with findings suggestive of malignancy (Table 4). The growth of nodules with unsuspicious US findings was poorly specific and required a larger number of FNA biopsies to detect one case of malignancy (Table 4).

Table 4.

Comparison of the Different Criteria for Indication of Fine-Needle Aspiration Repetition in Nodules with Initially Benign Cytology

Criterion	Nodules submitted to 2nd FNA	Malignancy of nodules submitted to 2nd FNA	Malignant nodules detected	Nodules submitted to 2nd FNA per case of malignancy
Suspicious initial US	55/560	10/55	10/14	5.5
Suspicious initial or subsequent US	81/560	13/81	13/14	6.2
Suspicious initial US or growth	137/560	12/137	12/14	11.4
Suspicious initial or subsequent US or growth	155/560	14/155	14/14	11
Growth with unsuspicious initial US	82/505	2/82	2/4	41
Growth with unsuspicious initial or subsequent US	74/479	1/74	1/1	74
All	560/560	14/560	14/14	40

See definitions of suspicious US and growth in the Methods section.

Discussion

Considering the high prevalence of thyroid nodules and the fact that most of them have a benign cytology, studies on the management of these nodules are of major interest to clinical practice. It is known that benign cytology does not rule out the possibility of malignancy of the nodule and that these false-negative cases can be diagnosed as being malignant in subsequent FNA. However, FNA is an invasive procedure associated with complications, although rare (23). Moreover, the costs of FNA are not negligible. Also, in 10%–15% of nodules with initially benign cytology, the second cytology can be nondiagnostic or indeterminate (8,24 –26), creating a dilemma for the management of these cases: (i) follow-up with uncertainty about malignancy and the eventual negative psychological impact, or (ii) surgery that will not confirm malignancy in most of these cases. These limitations of FNA repetition in nodules with initially benign cytology contrast with the advantage of diagnosing initially false-negative cases as malignant lesions. Therefore, as discussed earlier, there is no consensus regarding FNA repetition and different positions exist (1 –6). The best strategy is to detect malignancy in the largest number of initially false-negative cases using the smallest number of repetitions of this procedure.

Although nodule growth is the still the most recommended criterion (1 –6), its PPV is very low. In the present study and in other series (7 –11), malignancy was detected in ≤2% of nodules with initially benign cytology that exhibited significant growth.

Ultrasonographic features of the nodule, which are already used for the indication of the first FNA, have also gained importance for indication of repetition of this procedure after the determination of benign cytology (8,9). However, this role of US has been suggested based on retrospective studies (9). These studies show important bias in correlating the US findings with the result of the second FNA or histology exclusively for nodules submitted to these procedures without using uniform and known criteria for this decision, in addition to the possibility of incomplete data since they were obtained retrospectively. Furthermore, it is important to compare this criterion (initial US suggestive of malignancy) with other criteria also used to indicate FNA repetition: growth (1 –6), occurrence of suspicious findings (2,4,6), and even routine repetition (4). For these reasons, the present study is important since it is a prospective study in which repetition of FNA was predefined and performed in most cases. Other characteristics of this study are also worth mentioning: (i) a significant number of nodules were analyzed; (ii) instead of evaluating a single criterion, four criteria found in the literature were compared (1 –6), including initial US suggestive of malignancy; (iii) the indications for FNA and definitions of US suggestive of malignancy and significant growth are in accordance with current guidelines; (iv) the pathologist analyzing the second cytology was unaware of the first cytology result and of the US findings, and (v) histology was obtained for all nodules with a suspicious second cytology and for 29 of 35 nodules with nondiagnostic or indeterminate FNA.

Our study shows that US is the best parameter for establishing the indication for a FNA repetition in nodules with initially benign cytology. Only one case of malignancy was detected among 136 nodules whose US was not suggestive of malignancy (groups B and C.2) and consisted of an encapsulated follicular variant of papillary thyroid carcinoma. It is known that US is less sensitive for this histological subtype (27 –29). It is also established that this subtype is less aggressive and has a better prognosis than classical papillary thyroid carcinoma (30), especially in cases in which the nodule does not exhibit suspicious US findings (31). Additionally, our results suggest that nodules that become suspicious during follow-up, exhibiting changes in margins or in anterior-posterior/transverse diameter, also deserve attention even when these changes are not accompanied by significant growth (increase >50% in the volume of the nodule). However, the number of nodules showing such changes was small.

A recent prospective study evaluated FNA repetition in 579 patients with initially benign cytology (10). Similar to the present results, nodule growth had a low PPV (<2%) and the occurrence of suspicious US findings during follow-up, although rarely observed, led to the detection of malignancy in one out of seven nodules. However, in that study (10), the authors did not report the number of nodules with an initial US suggestive of malignancy or the rate of malignancy specifically for this subgroup.

Finally, reducing the value of routine FNA repetition in nodules with initially benign cytology, no case of malignancy was found when US did not suggest malignancy and when there was no growth during follow-up.

In conclusion, this prospective study shows that ultrasonographic features of the nodule are the best parameter for the indication of FNA repetition in nodules with initially benign cytology, confirming the very low PPV of growth of nodules with US findings unsuspicious for malignancy.

Footnotes

Author Disclosure Statement

The authors declare that no competing financial interests exist.

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