Thyroid Nodules with Indeterminate FNAC According to the Italian Classification System: Prevalence, Rate of Operation, and Impact on Risk of Malignancy. An Updated Systematic Review and Meta-analysis

Abstract

A thyroid nodule classified as indeterminate on fine-needle aspiration cytology (FNAC), hereafter referred to as an indeterminate thyroid nodule (ITN), represents a clinical dilemma. The Italian Consensus for the Classification and Reporting of Thyroid Cytology (ICCRTC) divides ITNs into low- and high-risk categories (i.e., TIR3A and TIR3B, respectively) to better manage patients. This study aimed to achieve high-evidence estimates of the prevalence, rate of operation, and risk of malignancy of ITNs, including TIR3A and TIR3B ITNs. This systematic review was conducted according to MOOSE to retrieve all original studies citing ICCRTC. The last search was performed in February 2022. The risk of bias of the included studies was assessed. Separate proportion meta-analyses were performed with a random-effect model using OpenMeta[Analyst]. The online search processed 271 studies, and 33 were finally considered. First, the cancer prevalence among ITNs was 32.4%. Second, the cancer prevalence among TIR3As was 12.4%, with heterogeneity (I₂ 90%) explained by a linear correlation between sample size and cancer rate (p = 0.009). Third, the cancer prevalence among TIR3Bs was 44.4%, with heterogeneity (I₂ 75%) explained by the inverse correlation between sample size and cancer rate (p = 0.031). Fourth, the prevalence of ITNs, TIR3A, and TIR3B among FNACs was 29.6%, 12.6%, and 12.9%, respectively, with sample size and TIR3B prevalence being inversely correlated (p = 0.04). Fifth, the operation rates of ITNs, TIR3A, and TIR3B were 54.3%, 48.3%, and 75.2%, respectively, and the sample size and TIR3A operation rate were inversely correlated (p = 0.010). These data strongly support the division of ITNs into low- and high-risk subcategories. Importantly for clinical practice, the cancer rate among ITNs is significantly influenced by the study sample size.

Keywords: Carcinoma; Fine-needle aspiration (FNAC); Indeterminate nodules; Italian Consensus for the Classification and Reporting of Thyroid Cytology; Risk of malignancy; Thyroid.

Fig. 1

Flow of records found

Fig. 2

Meta-regression analysis to explore the cancer rate of TIR3A according to study sample size. Any circle identifies one study, and its size differs according to the study weight

Fig. 3

Meta-regression analysis to explore the cancer rate of TIR3B according to study sample size. Any circle identifies one study, and its size differs according to the study weight

Fig. 4

Meta-regression analysis to explore the prevalence of TIR3B among FNACs according to study sample size. Any circle identifies one study, and its size differs according to the study weight

Fig. 5

Meta-regression analysis to explore the operation rate among TIR3A cases according to study sample size. Any circle identifies one study, and its size differs according to the study weight

Fig. 6

Two cases of thyroid nodules cytologically classified as indeterminate. The upper figures illustrate a nodule classified as TIR3A. Left: Several microfollicular clusters may be observed in a blood-stained background. The cell groups show a certain degree of monotony with slightly enlarged nuclei and finely irregular chromatin. No clear-cut nuclear grooves or intranuclear cytoplasmic inclusions (INCI) are noticed. Right: the postsurgical histological sample showed a follicular variant papillary carcinoma with follicular-patterned lesion where thyrocytes show enlarged nuclei with chromatin clearing and occasional nuclear grooves and INCI. Nuclei also show a tendency to overlap. The follicular lumens contain dense colloid. The lower figures illustrate a TIR3B case. Left: the cytological picture shows abundant cellularity organized into microfollicular structures or trabeculae. Thyrocytes show nucleocytoplasmic atypia with enlarged and pleomorphic nuclei with granular chromatin. The cytoplasm is moderately or well represented, sometimes showing a granular appearance. Colloid is scant. Right: the postsurgical histology showed a classical papillary thyroid carcinoma, made up of papillary clusters of thyrocytes with enlarged nuclei, overlapping and chromatic clearing. Moreover, INCI, nuclear grooves and small nucleoli can be seen