Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features (NIFTP)

Introduction

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a recently defined entity that was accepted by the World Health Organization (WHO) in 2017. Before 2016, these tumors were diagnosed as noninvasive encapsulated follicular variants of papillary carcinoma. The nomenclature change was proposed to optimize patient care, eliminate the stigma of malignancy, and optimally de-escalate treatment and follow-up for these patients.

Definition

NIFTP is defined by WHO as a noninvasive neoplasm of thyroid follicular cells with a follicular growth pattern and nuclear features of papillary carcinoma that has a very low malignant potential. It is considered a borderline malignant or premalignant lesion rather than a benign lesion.

The diagnosis of NIFTP is based on the finding of an encapsulated or clearly demarcated nodule with a follicular growth pattern and cells revealing nuclear features of papillary thyroid cancer (PTC) and a complete lack of invasive characteristics, papillary structures, or high-grade microscopic features. A diagnosis of NIFTP can be made only after exclusion of invasion; therefore examination of the entire tumor capsule and tumor interface is required.

Epidemiology

NIFTP is a recently introduced entity, and its exact incidence is currently unknown. Based on retrospective studies estimating the prevalence of noninvasive encapsulated follicular variant papillary carcinoma, it is likely that NIFTP comprises 10% to 20% of the incidence of PTC observed before 2016 in North America and several European countries, as well as in Brazil. A significantly lower incidence of the NIFTP diagnosis may be observed in Asia, with NIFTP accounting for 1% to 5% of the papillary carcinomas. This may reflect ethnic differences or variation in histopathologic approaches to diagnosing nuclear features of papillary carcinoma by pathologists practicing in different regions. Such an altered higher diagnostic threshold would lead to diagnosing many NIFTP cases as follicular adenomas.

NIFTP is more common in females than males, with a gender ratio of 3:1 to 4:1. The tumor may occur over a wide range of ages, although most patients present during the fourth to sixth decades of life.

Etiology

The etiologic factors for NIFTP have not been established. For many years these tumors were diagnosed as a variant of papillary carcinoma, and it is likely that NIFTP and papillary thyroid carcinomas share some risk factors, such as exposure to ionizing radiation and preexisting benign thyroid nodules. Similar hormonal factors are probably involved because NIFTP has a female predominance similar to other follicular-cell derived thyroid neoplasms.

Molecular pathogenesis of NIFTP involves gene alterations common in other follicular-patterned thyroid tumors such as follicular adenoma, follicular carcinoma, and follicular variant of papillary carcinoma. NIFTPs are associated with activating mutations of one of the three RAS genes ( NRAS > HRAS >> KRAS ) found in 30% to 60% of cases. The majority of RAS point mutations involve codon 61, although codons 12 and 13 may also be occasionally involved. Other common driver mutations are PPARG (most commonly, PAX8/PPARG ) and THADA fusions and occasionally the BRAF K601E mutation. Mutations in the PTEN and DICER1 genes may also be occasionally seen. EIF1AX mutations can be found, typically co-occurring with RAS mutations. Before 2016, a large proportion of tumors with these mutations were diagnosed as encapsulated follicular variant of papillary carcinoma, and they met the current diagnostic criteria for NIFTP. Importantly, NIFTP lesions should have no BRAF V600E, RET / PTC, NTRK1 or NTRK3 fusions, or other mutations associated with classical and tall cell variant PTCs. Although few studies reported BRAF V600E in single cases or in a significant proportion of tumors considered by the authors to be NIFTP, most of those tumors are likely to have at least some well-formed papillae, and using stringent diagnostic criteria should instead be diagnosed as classic papillary carcinoma. NIFTP tumors are early, precancer lesions; therefore they are expected to have no TERT, TP53, or other mutations common in advanced and dedifferentiated thyroid cancers.

Some studies have shown that NIFTP tumors may have distinct gene expression profiles, with some having the expression profiles resembling those of follicular adenoma and others of infiltrative follicular variant papillary carcinoma. Several specific noncoding miRNAs were reported to have aberrant expression in NIFTP compared with hyperplastic nodules or invasive follicular variant papillary carcinomas.

Diagnosis