Risk of Malignancy in Thyroid Nodules with Non-Diagnostic Fine-Needle Aspiration: A Retrospective Cohort Study

Abstract

Background: Fine-needle aspiration (FNA) of thyroid nodules is commonly performed, and despite the use of ultrasound (US) guidance, the rate of non-diagnostic FNAs is still significant. The risk of malignancy of thyroid nodules with a non-diagnostic FNA is not clearly defined. However, most studies exclude the majority of patients without a repeat biopsy or surgery, thus increasing the likelihood of selection bias. The aims of this study were to determine the malignancy risk in nodules with an initial non-diagnostic FNA, and to identify the factors associated with malignancy.

Methods: This was a retrospective cohort study of patients with thyroid nodules who underwent US-guided FNA between 2004 and 2010 and had a non-diagnostic result. Patients were followed until confirmatory diagnosis of the nature of the nodule was made. The outcome of malignant or benign disease was based on one of the following: (i) final surgical pathology following thyroidectomy; (ii) repeat biopsy; (iii) clinically, based on repeat ultrasound performed at least three years following biopsy; or (iv) report of thyroid status for patients without follow-up visits contacted by mail.

Results: There were 699 nodules from 665 patients included. The mean age was 59 ± 15 years, and 71.7% were women. There was complete follow-up of 495 nodules. After a median follow-up of 2.7 years, thyroid cancer was found in 15 nodules. The prevalence of malignancy was 3% (15/495). The presence of nodular calcifications was the strongest predictor of thyroid malignancy (odds ratio 5.03 [confidence interval 1.8-14.7]). Initial nodule size was inversely associated with malignancy (odds ratio 0.55 [confidence interval 0.28-0.93]). However, the 193 patients without follow-up had smaller nodules compared with those included in the analysis. None of the patients with repeatedly non-diagnostic results were diagnosed with thyroid cancer at follow-up.

Conclusion: The prevalence of thyroid cancer in nodules with non-diagnostic results is lower than the malignancy rate in thyroid nodules in general, but not negligible. They should be followed as per guidelines with heightened suspicion for nodules containing calcifications. Nodules with repeatedly non-diagnostic FNA results especially in the absence of calcifications have a low risk of malignancy and may be observed.

Keywords: FNA; diagnostic; thyroid cancer; thyroid nodule.

FIG. 1.

Follow-up of 699 non-diagnostic nodules. *Considered benign at follow-up. **If surgery or a repeat diagnostic biopsy was available, not included in the ultrasound category. ***Patients with thyroid surgery, a repeat diagnostic biopsy or ≤20% growth by ultrasound (US) ≥3 years were not contacted by mail. †Forty-one patients with a repeat biopsy that was non-diagnostic or suspicious for follicular neoplasm and 15 patients with a follow-up US <3 years or with >20% growth were contacted by mail.

FIG. 2.

Outcomes of repeated FNA of 276 initially non-diagnostic biopsies. Re-FNA, repeat fine-needle aspiration; FN, follicular neoplasm; PTC, papillary thyroid cancer; MTC, medullary thyroid cancer. *179 were FNA and 24 were core biopsies.

FIG. 3.

Ultrasound image of a cystic papillary thyroid cancer with an initial non-diagnostic fine-needle aspiration.