Context.—

This article presents a review of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), including its separation from follicular variant of papillary carcinoma of the thyroid, its evolution, and current definition and pathologic characteristics.

Objectives.—

To emphasize the understanding of the concept of NIFTP as a neoplasm based on molecular analyses, its critical histopathologic features, the microscopic findings that exclude the diagnosis, and the importance of complete sectioning of the tumor to exclude neoplasms that should be diagnosed as carcinomas. Important distinctions are discussed including difficulties with literature that shows NIFTP with metastases, inadequacy of sectioning of the tumor, and lack of descriptive histology of the surrounding thyroid and possible other lesions.

Data Sources.—

Review of articles in the English literature on NIFTP, as well as comparative papers showing differences and distinctions between this entity and papillary carcinomas.

Conclusions.—

This article concludes that with the current state of knowledge on NIFTP with studies from all over the world, this entity is a low-risk neoplasm that, when diagnosed using appropriate criteria, should not be associated with metastatic or recurrent disease, at least on intermediate length of follow-up. This review includes discussion of multifocal NIFTP, as well as the recently defined micro-NIFTP (1 cm or less), and describes features of the tumor that remain to be studied and correlated with outcome: oncocytic variants of NIFTP, percentage of allowable solid areas of growth in the lesions, and definitions of true neoplastic papillae and hyperplastic ones and how these should influence the diagnosis of NIFTP.

The entity known as thyroid follicular variant of papillary carcinoma has been a controversial one for many years. The controversy revolved around 2 features of the lesion: (1) the concept of circumscription versus infiltrative growth and (2) the degree of nuclear change and resemblance to the nuclei characteristic of classic papillary thyroid carcinoma.13 

The latter of these elicited a modestly sized body of literature reporting on the interobserver and intraobserver variability among “expert” thyroid pathologists as to how closely the nuclei should mimic the usual nuclei of papillary cancer. The variability was marked and ranged from benign (hyperplastic nodule and adenoma) to carcinoma.14  Therefore, if even experts could so infrequently agree on diagnostic criteria, where did everyone else stand on the “correct” diagnosis, most importantly the patient. This controversy, however, involved those tumors that were circumscribed or totally or partially encapsulated. (It seems the infiltrative variety of follicular variant of papillary carcinoma is quite rare but when it occurs the nuclear change is quite obvious).5 

The distinction between encapsulated (circumscribed) and infiltrative follicular variant papillary carcinoma was obvious to any pathologist and the latter entity could be diagnosed easily solely by its low-power growth pattern as well as its nuclei. However, the encapsulated subtype was problematic in 2 ways: its nuclei and the presence or absence of invasion. (To the reader: It is crucial to understand that the terms infiltrative and invasive should be segregated when discussing follicular variant carcinoma. Infiltrative refers to the growth pattern of follicular-patterned neoplasms with appropriate nuclear features that are unencapsulated and freely interdigitate with the surrounding thyroid, whereas invasive is applied to those encapsulated follicular-patterned neoplasms that show withering or capsule or vascular invasion.59 )

Arising from the subgroup of encapsulated lesions was the issue of whether invasion or noninvasion mattered with regard to prognosis. A number of studies indicated that it definitely did.810  Thus arose the concept that noninvasive follicular variant of papillary carcinoma had a very good prognosis and was a low-risk lesion in terms of metastatic potential. If this was true, questions arose as to why these were treated with radical surgery and radioactive iodine. And why were they diagnosed as “cancer” or “carcinoma”?8,11 

In 2015, an international group of physicians including pathologists, surgeons, and endocrinologists began a study under the leadership of Yuri Nikiforov, MD, of the University of Pittsburgh, Pennsylvania, to evaluate the prognostic implications of noninvasive follicular variant of papillary thyroid carcinoma. Two groups of encapsulated follicular-patterned thyroid tumors were collected from laboratories around the world: these included tumors that were encapsulated or circumscribed and without invasion, and those encapsulated follicular neoplasms that showed capsular and/or vascular invasion.12 

The follow-up in these cases indicated that the 109 cases with no invasion were not associated with any recurrences of metastases even if the patients had been treated with less than total thyroidectomy and without radioiodine. The second group however included patients with recurrences and even with distant metastases and fatal outcome. The lengths of follow-up averaged 14 years for the first group; it was shorter for the other group of patients.12 

This study confirmed the literature on encapsulated follicular tumors with abnormal nuclei—that if noninvasive, the outlook was excellent. It appeared that conservative therapy was warranted for these patients. As a conclusion, the diagnostic term noninvasive follicular tumor with papillary like nuclear features (NIFTP)” was introduced in the classification of thyroid tumors.1,6,1320 

The lay press immediately jumped to the conclusion that these lesions were benign tumors and not cancers.21  It is of interest that no one in the group of pathologists involved in the original study has ever indicated these lesions were “benign.” Indeed, many felt they were similar to preinvasive neoplasms, best compared to in situ ductal carcinoma of the breast.

As additional series from many institutions were published, cases of NIFTP with nodal metastases were reported.22  The evolution in the definition of this entity occurred with refinement of diagnostic criteria. As noted below, the criteria must exclude follicular tumors with any papillary growth, psammoma bodies, solid growth (30% or more), numerous mitoses, atypical mitoses, and true coagulative necrosis. If these histologic features are absent, a noninvasive follicular pattern tumor with abnormal nuclei can be diagnosed as NIFTP. Excluding all these features and confirming no invasion requires that the entire tumor be examined histologically.23 

Since most NIFTPs measure about 2 to 3 cm, this does not represent a large work burden for pathologists. However, some NIFTPs range up to 9 cm and can constitute a significant workload for the pathologists.10,24  Unfortunately, this is the state of the situation currently. Indeed, we have identified 3 cases of large tumors (size range, 4.4–5.8 cm) in which initial sections of the capsule failed to show invasion, but in which sectioning of the entire capsule showed several foci of transcapsular penetration; these then were carcinomas.

Although some of the pathologists in the original study were concerned about the presence of papillae in the tumors, the original description of NIFTP allowed for occasional papillae (about 1%). As more tumors of this type were evaluated, it became evident that the presence of any papillary growth indicated that the lesion was indeed capable of metastatic disease to regional nodes and was indeed a papillary carcinoma.22  (We prefer to diagnose such tumors as papillary carcinoma with predominant follicular growth pattern.) Thus the evolution of diagnostic criteria led to excluding all tumors with any papillary growth as NIFTP. A cautionary note is needed here; the papillae must be neoplastic true papillae with fibrous or fibrovascular cores lined by 1 or 2 layers of epithelium; these should be differentiated from hyperplastic or degenerative papillae, which show incomplete or absent cores and may show presence of follicles in any of the cores (subfolllicle formation). Some cases for which a vigorous preoperative biopsy was performed can show papillae in areas of infarction and hemorrhage that represent degenerative changes and not true papillae.25  Thus the presence of hyperplastic or degenerative papillae is compatible with NIFTP. It should also be noted that lymph node metastasis in some cases of NIFTP may be a separate focus of papillary thyroid microcarcinoma, classic variant in the vicinity of NIFTP or somewhere else in the thyroid (Figure 1, A through C).

Figure 1

An example of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) with an adjacent focus of papillary microcarcinoma, classic variant. A, The low-power view shows a noninvasive follicular-patterned tumor. B, The medium-power view shows a focus of papillary microcarcinoma. C, The medium-power view shows papillary microcarcinoma with well-developed papilla. It should be noted some cases of NIFTP have 1 or more foci of papillary microcarcinoma in the same thyroid gland. Some of these may represent the primary for local nodal metastasis (hematoxylin-eosin, original magnifications ×5 [A], ×10 [B], and ×40 [C]).

Figure 1

An example of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) with an adjacent focus of papillary microcarcinoma, classic variant. A, The low-power view shows a noninvasive follicular-patterned tumor. B, The medium-power view shows a focus of papillary microcarcinoma. C, The medium-power view shows papillary microcarcinoma with well-developed papilla. It should be noted some cases of NIFTP have 1 or more foci of papillary microcarcinoma in the same thyroid gland. Some of these may represent the primary for local nodal metastasis (hematoxylin-eosin, original magnifications ×5 [A], ×10 [B], and ×40 [C]).

Close modal

Since the psammoma body represents the “ghost” of a dead papilla, finding such a structure indicates papillae had been present. As noted in the prior paragraph, this excludes the lesion as a NIFTP.23 

The presence of sheetlike or solid growth (some areas may show a trabecular pattern) is problematic. The original definition of NIFTP indicated that the presence of 30% solid growth or greater should remove the lesion from the NIFTP category. In some NIFTPs (especially large lesions—greater than 3.5 cm in our experience) foci of tiny microfollicular growth will be seen. This is usually a small fraction of the entire tumor and does not exclude NIFTP.23,24 

Normal mitoses may be seen in the cells of NIFTP especially in regions of biopsy tracts. In areas removed from obvious biopsy sites, more than 3 mitoses per 10 high-power fields is considered worrisome and should make the pathologist cautious in considering the lesion as NIFTP. Any abnormal mitosis should exclude NIFTP as well.23,24 

This is a problematic area in many thyroid follicular lesions. However, helpful clues include a geographic linearity to biopsy tracts, associated hemorrhage, hemosiderin and inflammation, vascular proliferation, and metaplasia (usually bland squamous metaplasia) in biopsy tracts. The necrosis is often infarct-like rather than coagulative necrosis. Finding the latter indicates the lesion is a carcinoma and usually high grade or poorly differentiated.24,26 

It is well known that fine-needle aspiration (FNA) can effectively segregate most benign nodules from malignant nodules, as based on well-defined and validated cytomorphologic criteria. However, this clear-cut distinction between benign and malignant follicular-patterned lesions, such as follicular-patterned adenomatoid nodule, follicular adenoma, and follicular carcinoma, cannot be solely made on the basis of cytomorphologic features.2729  This lists also includes follicular variant of papillary thyroid carcinoma, as most are diagnosed as indeterminate (atypia/follicular lesion of indeterminate significance [AUS/FLUS], follicular neoplasm/suggestive of follicular neoplasm [FN/SFN]) and suggestive of papillary thyroid carcinoma (SPTC) on FNA. After the introduction of “NIFTP” in the classification of thyroid neoplasms, several studies have shown its impact on the interpretation of thyroid FNA. Since NIFTP is classified as a low-risk neoplasm and not malignant, the risk of malignancy for each diagnostic category of “The Bethesda System for Reporting Thyroid Cytology” (TBSRTC) will decrease, especially for thyroid FNA cases classified as indeterminate (AUS/FLUS or FN/SFN) or SPTC.19  Some authors30,31  have also suggested that the following cytologic features, namely, microfollicular growth pattern, absence of papillary structures, and lack of well-formed intranuclear cytoplasmic pseudoinclusions can help in the preoperative diagnosis of NIFTP (Figure 2, A through F). However, other authors have failed to confirm the reliability of these diagnostic cytomorphologic features. Interestingly, some authors32,33  have shown that ultrasound features combined with cytologic features and adjunct molecular studies may prove to be more effective in the preoperative diagnosis of NIFTP, leading to a conservative rather than a radical surgical management.

Figure 2

An example of noninvasive follicular thyroid neoplasm with papillary-like nuclear features showing radiologic-cytologic and histopathologic correlation. Ultrasonography shows a well-defined nodule (A). The cytology shows a follicular-patterned lesion demonstrating follicle formation with thick luminal colloid, and nuclei with nuclear chromatin clearing and thick nuclear membranes, features suggestive of, but not diagnostic of, papillary thyroid carcinoma (B and C). The histopathologic follow-up shows a noninvasive follicular-patterned neoplasm with nuclear features of papillary thyroid carcinoma (D through F) (Papanicolaou, original magnification ×40 [B and C]; hematoxylin-eosin, original magnifications ×5 [D], ×10 [E], and ×40 [F]).

Figure 2

An example of noninvasive follicular thyroid neoplasm with papillary-like nuclear features showing radiologic-cytologic and histopathologic correlation. Ultrasonography shows a well-defined nodule (A). The cytology shows a follicular-patterned lesion demonstrating follicle formation with thick luminal colloid, and nuclei with nuclear chromatin clearing and thick nuclear membranes, features suggestive of, but not diagnostic of, papillary thyroid carcinoma (B and C). The histopathologic follow-up shows a noninvasive follicular-patterned neoplasm with nuclear features of papillary thyroid carcinoma (D through F) (Papanicolaou, original magnification ×40 [B and C]; hematoxylin-eosin, original magnifications ×5 [D], ×10 [E], and ×40 [F]).

Close modal

Most NIFTPs that have been studied by molecular analysis are truly clonal neoplasms. Molecular alterations are seen in approximately 78% of NIFTP cases. Approximately 30% to 54% of cases harbor RAS mutation, the most common being NRAS mutation followed by HRAS and rarely, KRAS. However, NRAS mutation may also be identified in follicular carcinoma and invasive encapsulated follicular variant of papillary carcinoma, so it is not specific. A small subset of NIFTP cases harbor PPARG fusion, THADA fusions, and BRAF K601E mutations. A few studies3441  have also explored miRNA expression in NIFTP cases and have found that 2 mi-RNAs, miR-10a05p and MiR-320e, can effectively discriminate between NIFTP and infiltrative follicular variant of papillary thyroid carcinoma.

The 2nd edition of TBSRTC includes modified risk of malignancy for each diagnostic category due to NIFTP. The 2nd edition of TBSRTC also includes recommendations for explanatory notes for indeterminate categories stating that the surgical follow-up may include NIFTP.42 

It cannot be stated strongly enough as to the danger of attempting to classify a follicular thyroid tumor as NIFTP on frozen section. As noted from the discussion above, the entire lesion must be examined in order to confirm the diagnosis. This is impractical on intraoperative frozen section. In addition, if the lesion is NIFTP lobectomy is considered adequate therapy. (Also if the lesion does show invasion and is an invasive encapsulated follicular variant of papillary carcinoma, it should be a low-risk lesion and lobectomy may also be adequate therapy.)24 

In the original article defining NIFTP, all the cases involved tumors 1 cm or greater in size. None of the tumors were in the microcarcinoma size range.43  Since that article, at least 2 studies on subcentimeter lesions meeting the histologic criteria of NIFTP have appeared and both confirm that these small tumors do behave in a very low-risk manner and deserve to be diagnosed as micro-NIFTP.44,45 

The evolution of NIFTP during the past 3 years has been dramatic. Refinements in the histopathologic criteria for both the diagnosis and its exclusion have qualified the lesion and its low-risk nature. Both pathologists and treating clinicians have accepted the terminology and have recognized its prognostic importance; therapists have modified the surgical approach to these lesions with lobectomy alone as the standard therapy option.

Certain features of the lesion, however, remain to be defined and described. These include the possible existence of oncocytic NIFTP, the meaning of multifocal NIFTP, and the possible long-term prognostic implications (are the follow-up periods of 10 or even 15 years sufficient to rule out a case that may metastasize?).

From our current state of knowledge, however, we can conclude that NIFTP represents a thyroid follicular neoplasm with a very low to intermediate risk of malignant behavior. Pathologists must learn the latest criteria for its diagnosis and its therapeutic and prognostic implications. Treating clinical physicians must be educated to the latter in order to offer appropriate treatment options to affected patients and avoid costly overtreatments for this tumor.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.