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 Table of Contents  
Year : 2021  |  Volume : 9  |  Issue : 2  |  Page : 94-99

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features and updates in bethesda system for thyroid fine-needle aspiration cytology: An overview

Pathology and Laboratory Medicine, Karkinos Healthcare, Kerala, India

Date of Submission26-Oct-2021
Date of Acceptance05-Nov-2021
Date of Web Publication17-Dec-2021

Correspondence Address:
Dr. Ajit Nambiar
Director, Pathology and Laboratory Medicine, 3rd Floor, JLN Stadium Metrostation, Kaloor, Kochi 682017, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jhnps.jhnps_66_21

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Thyroid cancer incidence rising in the community has been a matter of concern. The possibility of a certain category of papillary carcinoma, namely the encapsulated follicular variant contributing to this rise needed a thorough look in. Scientific evidence has led to this category to be taken out from the malignant categorization even though the entity has the presence of the typical papillary nuclei. A new well-defined indolent category of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has been defined with both inclusion and exclusion criteria. This has led to some disruption in the risk of malignancy assessments in the Bethesda system of thyroid fine-needle aspiration cytology. Importantly, cytology is limited in distinguishing the invasive from encapsulated follicular variants of papillary thyroid carcinomas. The new Bethesda system provides for a descriptive footnote in the category 4–6 on the need to consider the indolent counterpart NIFTP. Furthermore, category 3, atypia of undetermined significance (AUS)/follicular lesion of undetermined significance is well defined with an explanation for the reason behind using this terminology as this is a heterogeneous category. The NIFTP group is associated with RAS mutations unlike the BRAF mutations in the classical papillary carcinomas.

Keywords: Follicular thyroid neoplasms, neoplasm with papillary-like nuclear features, pathology, thyroid cancer, thyroidectomy

How to cite this article:
Nambiar A. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features and updates in bethesda system for thyroid fine-needle aspiration cytology: An overview. J Head Neck Physicians Surg 2021;9:94-9

How to cite this URL:
Nambiar A. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features and updates in bethesda system for thyroid fine-needle aspiration cytology: An overview. J Head Neck Physicians Surg [serial online] 2021 [cited 2023 May 29];9:94-9. Available from: https://www.jhnps.org/text.asp?2021/9/2/94/332729

  Introduction Top

Papillary carcinomas of the thyroid are the most common cancers of the thyroid. The incidence of this tumor has increased, and one possible reason is enhanced surveillance.[1],[2] The intensified approach to thyroid nodules and the use of ultrasound have resulted in the increased incidence of early cancers with indolent behavior. Another important reason for over-diagnosing thyroid cancers is the phenomenon of increase in the diagnosis of the follicular variant of papillary thyroid cancer (FVPTC).[3]

Papillary cancers have traditionally been diagnosed based on their typical nuclear features. The FVPTC variant is a derivative of the pattern of arrangement and the nuclear features. It is now clear that the FVPTC variant, especially the encapsulated subcategory (EFVPTC) has an indolent behavior.[4],[5] More so molecularly, this entity is distinct from the infiltrative subcategory.[6] Despite these backgrounds, the EFVPTC were being treated like conventional PTC. This needed concerted consensus work to arrange data to redefine the entity and replace the word “cancer.”

The change will have far-reaching implications in the practice of thyroid cytology, including discussions in a multidisciplinary team meeting regarding management and cytology histology accuracy along with the estimation of risk of malignancy (ROM).[7],[8] The inability of cytology to estimate invasion may result in over-calling these lesions as category 5 or 6 on the Bethesda system for thyroid fine-needle aspiration (FNA).

  Advent of the Term Niftp Top

It is ironical that follicular neoplasms of the thyroid had benign and malignant categories but not the papillary neoplasms of the thyroid. Truly speaking the earlier classifications of thyroid did mention about papillary cystadenomas in the 1950s, but slowly that terminology lost its importance.[9] A paper published on the follicular variant of papillary carcinoma in 1977 by Chem and Rosai changed everything.[10] Juan Rosai later did mention that “the repercussions of that little article, dealing with a mere six cases, went beyond their wildest expectation, and led some people to erroneously believe that they were the originators of that concept.” However, the fact is that within a few years the follicular variant of papillary carcinoma became one of the most common diagnoses in thyroid carcinoma diagnosis.

The nuclear features played the mischief. We defined papillary carcinomas based on the nuclear features, but in the case of follicular variants, this became a spoiler. What we witnessed was a lowering of the threshold for the follicular variant of PTC and this trend was, unfortunately, more so with the experts than with practicing pathologists.

Hence, we were dealing with three different scenarios. The Bologna retrospective series for the three entities provided percentages over the entire papillary carcinoma [Table 1].[11]
Table 1: Bologna series retrospective review 2000–2015 – percentage of the follicular variant in all of the papillary carcinomas

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The Memorial group studied the behavior of the FVPTC according to its encapsulated and infiltrative forms.[12] The infiltrative FVPTC spread to lymph nodes like classical PTC, while encapsulated FVPTC behaved like the follicular adenoma/carcinoma group of tumors.

Importantly, none of 43 patients with noninvasive, encapsulated FVPTC developed recurrences, including 31 patients who underwent lobectomy alone, with a median follow-up of 11.1 years.

What followed was another interesting development that came from a group of pathologists in charge of reviewing all the cases of thyroid carcinoma developing in the population exposed to the Chernobyl radioactive fallout proposed placing these neoplasms in the category of “well-differentiated tumors of uncertain malignant potential” followed by a note emphasizing the extremely high probability of a permanent cure following a conservative operation (usually a lobectomy) and the lack of indication for additional surgery.[13] Hence, a movement developed considering the encapsulated follicular-patterned tumors behave favorably (i.e., they are cured by a lobectomy) in the overwhelming majority of the cases.

The stigma of cancer, the morbidity of unnecessary overtreatment and the money factor involved in treatments lead to the need for a process of clarity in world practice. Twenty-four pathologists from 13 sites across 5 countries looked at 109 encapsulated FVPTC with a follow-up 10–26 years and at 101 invasive FVPTC with a follow-up 1–18 years.[14] Initial periods of teleconferencing followed by a face-to-face meeting at Mass General, Boston. The key question of this entire exercise was to do clinical outcomes in noninvasive encapsulated FVPTC warrant a reclassification of this tumor as nonmalignant. The outcome of this group of very low-risk-adverse outcomes was the new term“Noninvasive follicular thyroid neoplasms with papillary-like nuclei features” (NIFTP).

  Diagnostic Criteria of Niftp Top

“The Endocrine Pathology Society Conference for Re-examination of the Encapsulated FVPTC” based on extensive evaluation of noninvasive cases, outcome data, and the development of a set of inclusion criteria, has issued the term.[14] This term was internationally accepted as this avoid the term “cancer” for a low-risk tumor. The inclusion criteria are listed in [Table 2].
Table 2: Inclusion criteria for noninvasive follicular thyroid neoplasm with papillary-like nuclear features

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The important inclusion criteria included:

Encapsulated or partially encapsulated/circumscribed

Circumscribed tumors need not be strictly completely encapsulated (even partial encapsulation) are included in the inclusion criteria. Invasion is an exclusion criterion. Although the minimum size criterion is not mentioned, it would be appropriate to even include <1 cm tumors and not call them “incidental” or “microscopic.” The tumor should be adequately sampled to include the capsule or advancing front to categorically exclude the invasion pattern.

Follicular growth pattern

The tumor shows the predominant follicular pattern. Follicles are usually monotonous but may be variable. Papillae should be <1%, with the presence of psammoma bodies an exclusion criterion.

Nuclear features

The characteristic nuclear features that define the papillary nuclei must be seen. It is usually noted that in practice they are seen focally and patchy in distribution. No minimum percentage of the tumor showing the apt nuclear features has been stated or quantified. The nuclear feature scoring guide [Table 3] is a good referral and shows excellent reproducibility.
Table 3: Scoring criteria for nuclear features of papillary thyroid carcinoma

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Exclusion criteria


No capsular invasion or invasion into adjacent parenchyma (in nonencapsulated tumors), extrathyroidal extension, perineural or lymphovascular emboli are accepted in the definition of NIFTP. Adequate sampling of the capsular parenchymal interface is recommended.

Pattern of growth

The presence of patterns other than follicular like the solid, insular, and trabecular are accepted as long as they do not exceed 30% mark within the tumor. Furthermore, the presence of other variant cell types such as tall cell, hobnail, cribriform-morular, or columnar cell excludes the use of NIFTP. Cells with oncocytic cytoplasm are also excluded from the definition of NIFTP.


The presence of comedonecrosis or confluent geographic areas of necrosis, not associated with FNA excludes the diagnosis of NIFTP.[15]


The presence of >3 mitoses per 10 high power fields (using a ×400) also is an exclusion criterion and is more in keeping with poorly differentiated carcinomas.[16]

  Molecular Features Top

The classical PTC shows predominantly the BRAF V600E mutation without exhibiting the RAS or PAX8/PPARg mutations. The latter mutations in contrast are associated with follicular patterned tumors of the thyroid. Very interestingly, it has been noted that there is a mix when we deal with follicular patterns with papillary nuclear features. The FVPTC is shown to be 2 tumors. The encapsulated or circumscribed noninvasive one showing genotype and behavioral profile that is in keeping with the follicular neoplasms and the invasive ones are similar to classical PTC with predominantly the BRAF mutations.[17],[18] The NIFTP group, therefore, are associated with RAS mutations and shows an indolent clinical course.

The diagnostic algorithm for the follicular lesions of the thyroid is given in [Figure 1].
Figure 1: Diagnostic Algorithm for follicular lesions

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  Changes in Bethesda Classification Top

The Bethesda system for reporting thyroid cytopathology was first formalized by experts in thyroid at the NIH, Maryland in 2007. The first edition of the subsequent book came out in 2010 and the second edition in 2018.[7],[19] The main changes between the two are listed in [Table 4]. The classification systems need to be a dynamic document which will incorporate changes as information are updated. The different entities under the category I to VI in Bethesda system are enumerated in [Table 5].[7],[19]
Table 4: Comparison of the first and second edition of “The Bethesda system for reporting thyroid cytopathology”

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Table 5: Diagnostic categories in Bethesda system of reporting thyroid cytopathology

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The major changes include changes in ROM percentages over the two editions for AUS/follicular lesion of undetermined significance (FLUS), FN/suspicious of follicular neoplasm (SFN), and SFM. The major reason for this change is the renaming of the noninvasive follicular variant of papillary thyroid carcinoma to NIFTP. The second major change is the advent of reflex molecular testing and recommendations in management and explanatory notes. Furthermore, there is an increase in the upper limit of use of AUS/FLUS in practice from 7% to 10%.

The ROM is derived from retrospective review of literature of all thyroid cytology follow-up cases.[7],[8],[20] There is a bias of overestimation as it is based only on cases undergoing surgical excision. Added to this, there is a lack of correlation in most cases between thyroid nodules seen on radiology and those excised and lack of agreement on final histopathology diagnosis.

There is a stark difference in the molecular profile of follicular lesions between encapsulated and invasive follicular neoplasms with papillary-like nuclei and add to that lack of agreement on the presence or absence of papillary nuclear features. Molecular tests with at least a BRAF testing will help and therefore are provided in the guidelines for atypia of unknown significance (AUS)/FLUS category as well as SFN.[21],[22]

The management of AUS/FLUS shows the advent of molecular testing as well as lobectomy. The molecular test includes testing for BRAF V 600E mutation analysis alone, although the sensitivity is low. The expanded molecular panel with the Afirma gene expression classifier shows higher sensitivity.[23] The decision for surgery over continued observation is based on the clinical risk factors, cytological, molecular, radiological information as well as patient preference.[15]

  Impact of Niftp on Thyroid Cytology Practice Top

The practice of cytology is largely limited by the lack of information on the advancing front of the lesion. An invasive front seen on surgical pathology changes the perspective on a nodule. With this in mind, the important derivative is that an NIFTP diagnosis is a grey zone diagnosis on cytology. The presence of the nuclear feature of papillary-like nuclei is common to AUS/FLUS, FN/SFN, and SFM. It is important to note that NIFTP cannot be reliably distinguished from other follicular patterned lesions by use of cytology alone.[24]

The presence of nuclear enlargement, chromatin clearing, and nuclear contour irregularities help distinguish NIFTP from benign nodules (Bethesda category 2) on cytology. Similarly, the presence of papillae, nuclear pseudo inclusions, and the presence of psammoma bodies help distinguish NIFTP from classical papillary thyroid carcinoma diagnosis (Bethesda category 6) on cytology.

The use of descriptive notes is another highlight of the second edition of TBSRTC. The descriptive notes help promote conservative surgical management. Although this may sound defensive, it will help limit overtreatment and overdiagnosis of carcinomas in thyroid pathology.[25]

The descriptive notes for NIFTP included in the second edition for categories include:[7]

  • FN/SFN: The histopathologic follow-up of cases diagnosed as such includes follicular adenoma, follicular carcinoma, and follicular variant of papillary thyroid carcinoma, including its recently described indolent counterpart NIFTP
  • SFM: The cytomorphologic features are suspicious for a follicular variant of papillary thyroid carcinoma or its indolent counterpart NIFTP
  • Malignancy: A small proportion of cases (3-4%) diagnosed with malignant and compatible with papillary thyroid carcinoma may prove to be NIFTP on histopathologic examination.

  Criteria for Handling Atypia in Thyroid Cytology Top

The use of the term atypia in AUS/FLUS needs an explanation for the reason behind using this terminology as this is a heterogeneous category.[7],[26] The following are reasons for the use of this category:

Cytological atypia

(a) Focal cytological atypia-Most of the cells look benign but few cells do show nuclear enlargement, pale chromatin, and irregular nuclear contours. Nuclear pseudo inclusion is however not acceptable. (b) Extensive but mild cytological atypia in the nuclear features. (c) Atypical cyst lining show cells with abundant cytoplasm, nuclear enlargement with elongation, prominent nucleoli, and presence of nuclear grooves. Moreover, (d) presence of histiocytoid cells.

Architectural atypia

Rare cluster of predominantly microfollicular pattern or presence of three-dimensional clusters is a low-risk criterion, especially in a low cellularity lesion.

Both cytological and architectural atypia

Hurthle cells either (a) exclusively in a sparsely cellular aspirate or (b) moderate to markedly cellular aspirate but a background clinical setting suggesting lymphocytic thyroiditis or multinodular goiter.

Atypia, not otherwise specified

(a) presence of psammomatous calcification in absence of nuclear features of papillary carcinoma and (b) presence of minor population of follicular cells with nuclear enlargement, often accompanied by prominent nucleoli. These findings are considered benign in the appropriate setting of the history of radioactive iodine, carbimazole, or other pharmaceutical agents. The category of AUS/FLUS is however applicable if the cytological findings are however prominent or in the uncertainty of the clinical history from the patient.

Atypical lymphoid cells, rule out lymphoma: It is ideal to repeat the aspirate for flow cytometry, but the term is preferred if the degree of atypia is insufficient to label “suspicious for malignancy.”

  Conclusions Top

NIFTP is indeed a challenging diagnosis on cytology. However, every effort should be made to identify potential ones with the focus to encourage conservative surgical management. The updated Bethesda system has been incremental with the refinements to help understand the criteria for grouping better and accommodate the new entity of NIFTP. The defining clarity provided to NIFTP will help serve a better understanding of the lesions in the thyroid. This will help address the overdiagnosis in papillary carcinoma. Furthermore, importantly the entity clearly demonstrates that no aggressive management is recommended but patients should have continued to follow-up.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


This material has never been published and is not currently under evaluation in any other peer reviewed publication.

Ethical approval

No applicable as this is a review article.

Informed consent

Not applicable as this is a review article.

  References Top

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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