Cytological features of “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” and their correlation with tumor histology

Summary

Among thyroid papillary carcinomas (PTCs), the follicular variant is the most common and includes encapsulated forms (EFVPTCs). Noninvasive EFVPTCs have very low risk of recurrence or other adverse events and have been recently proposed to be designated as noninvasive follicular thyroid neoplasm with papillary-like nuclear features or NIFTP, thus eliminating the term carcinoma. This proposal is expected to significantly impact the risk of malignancy associated with the currently used diagnostic categories of thyroid cytology. In this study, we analyzed the fine needle aspiration biopsy (FNAB) cytology features of 96 histologically proven NIFTPs and determined how the main nuclear features of NIFTP correlate between cytological and histological samples. Blind review of FNAB cytology from NIFTP nodules yielded the diagnosis of “follicular neoplasm” (Bethesda category IV) in 56% of cases, “suspicious for malignancy” (category V) in 27%, “atypia of undetermined significance/follicular lesion of undetermined significance” (category III) in 15%, and “malignant” (category VI) in 2%. We found good correlation (κ = 0.62) of nuclear features between histological and cytological specimens. NIFTP nuclear features (size, irregularities of contours, and chromatin clearing) were significantly different from those of benign nodules but not from those of invasive EFVPTC. Our data indicate that most of the NIFTP nodules yield an indeterminate cytological diagnosis in FNAB cytology and nuclear features found in cytology samples are reproducibly identified in corresponding histology samples. Because of the overlapping nuclear features with invasive EFVPTC, NIFTP cannot be reliably diagnosed preoperatively but should be listed in differential diagnosis of all indeterminate categories of thyroid cytology.

Introduction

Cancer of the thyroid gland is the most common endocrine malignant neoplasm, and papillary thyroid carcinoma (PTC) accounts for the vast majority of cases. Generally, PTC has a favorable prognosis, with long-term survival rates in excess of 95% [1]. It is well documented that the substantial increase of the incidence of thyroid cancer is mainly due to early detection of neoplasms with indolent behavior, mainly small cancers (microcarcinomas), or the use of more relaxed histopathologic criteria for the follicular variant of PTC (FVPTC) [2], [3].

In particular, the encapsulated form of FVPTC (EFVPTC) [4] accounts for 10%-20% of all thyroid cancers currently diagnosed in Europe and North America [5], [6]. The pathological diagnosis of this variant is associated with a high degree of interobserver variability and discordance [7], [8] because it is mainly based on the detection of nuclear features of PTC, which are frequently less evident than in classical PTC. The correct recognition of this entity is thus very subjective. In addition, EFVPTC is known to have an indolent behavior [5], [9], [10]. Cases with incomplete evidence of papillary-type nuclei have been either assigned to the category of PTC, or downgraded to follicular adenoma or a category of well-differentiated tumors of uncertain malignant potential, as suggested by some European authors [11], [12], [13], [14].

A recent multi-institutional study examined a large cohort of well-annotated EFVPTC and established that none of 109 patients with noninvasive EFVPTC followed for 10-26 years developed recurrence or other disease manifestations [3]. Based on this information, the international multidisciplinary group of authors recommended to reclassify these tumors as “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP). NIFTP is defined by a set of reproducible diagnostic criteria that include nuclear features of papillary carcinoma, such as nuclear size, nuclear membrane irregularities, as well as chromatin clearing (ground glass appearance), found in a noninvasive encapsulated follicular-patterned tumor.

Fine needle aspiration biopsy (FNAB) is the most important and reliable diagnostic procedure for preoperative evaluation of a thyroid nodule. At present, most thyroid FNAB specimens are classified according to the Bethesda System for Reporting Thyroid Cytopathology which includes 6 diagnostic categories, each of them corresponding to a different risk of malignancy [15]. Other classification systems are currently in use in Europe, including those proposed by the British Thyroid Society [16] and by the Italian SIAPEC (Società Italiana di Anatomia Patologica e Citologia) [17], both of them comprising 6 diagnostic categories as well. Several previous reports pointed out the challenges in the cytological diagnosis of the FVPTC due to partially overlapping features with both benign and malignant follicular-patterned lesions [14], [18].

Although histological features of NIFTP have been well characterized [3], how reliably these features can be identified in preoperative cytology samples remains unknown. Furthermore, it remains to be determined what cytological diagnoses the NIFTP nodules will yield in thyroid FNAB and what will be the impact of reclassification of noninvasive EFVPTC on the risk of malignancy in the categories of the Bethesda System. A recent multicentric study suggested that by excluding noninvasive encapsulated FVPTCs, many of which are expected now to be diagnosed as NIFTPs, the risk of malignancy will decrease significantly in the 3 indeterminate cytology categories (Bethesda III through V) [19]. In addition, such reclassification will have a profound impact on patient management, as the lesions classified as NIFTP will not require completion thyroidectomy or postsurgical radioiodine therapy. In this study, we provide a detailed analysis of a large series of NIFTP from 3 Italian institutions to characterize their cytological features and correlate them with histological outcomes.