OR I G I N A L A R T I C L E

Noninvasive follicular neoplasm with papillary like nuclearfeatures: A comprehensive analysis with a diagnostic algorithm

Chanchal Rana1 | Shreyamsa Manjunath2 | Pooja Ramakant2 |

Kulranjan Singh2 | Suresh Babu1 | Anand Mishra2

1Department of Pathology, King George's

Medical University, Lucknow, India

2Department of Endocrine surgery, King

George's Medical University, Lucknow, India

Correspondence

Dr Chanchal Rana, Associate Professor,

Department of Pathology, King George's

Medical University, Lucknow.

Email: chanchal11aug@yahoo.com

Abstract

Background: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features

(NIFTP) lacks the carcinoma label, avoiding aggressive therapy, physiological, social and

financial impact of cancer diagnosis. Unfortunately, the preoperative diagnosis is still a

challenge. Varied incidence of NIFTP has been document with limited data on preopera-

tive cytological, radiological characteristics and the impact on risk of malignancy in each

category of the Bethesda system of reporting thyroid cytopathology.

Method: Retrospective analysis of 20 NIFTPs with an attempt to provide a preopera-

tive diagnostic algorithm based on the cytological and ultrasound features along with

incidence and implication on risk of malignancy in various Bethesda categories with

its impact on patient management.

Result: Incidence of NIFTP in our study was higher in comparison to that docu-

mented from other Asian countries. TIRADS 3 was the most common sonographic

diagnosis. NIFTP was commonly preceded by indeterminate or benign Bethesda cat-

egory. Major impact of excluding NIFTP form malignant category was seen on

Bethesda categories II and IV with 20% and 27% reduction in risk of malignancy,

respectively.

Conclusion: Retrospective analysis should not be confined only to follicular variant of

papillary thyroid carcinoma but cases of follicular adenoma and adenomatous colloid

nodule should always be included in review to ascertain the true incidence of NIFTP.

NIFTPs are less likely to have malignant preoperative cytology. NIFTP shares major

cytological and ultrasound features with follicular adenoma, adenomatous colloid

nodule and minimally invasive follicular papillary carcinoma. When analyzed together,

taking minor findings in consideration, can favor a diagnosis.

K E YWORD S

cytology, NIFTP, risk of malignancy, thyroid, ultrasound

1 | INTRODUCTION

The crisis in the over diagnosis and treatment of the encapsulated

papillary thyroid carcinoma, follicular variant (EFV-PTC), brought a

working group of the Endocrine Pathology Society to critically re-

examine this entity in 2016.1 As a result of this endeavor, Nikiforov

et al advocated a revision of diagnostic terminology with the funda-

mental aim of avoiding the term carcinoma, and the consequent risk

of overtreatment for noninvasive tumors that are essentially clinically

benign, with a recurrence rate < 1%.2 Hence, noninvasive follicular

thyroid neoplasm with papillary-like nuclear features (NIFTP) termi-

nology was recently introduced and incorporated in the 4th edition of

Received: 11 September 2019 Revised: 10 December 2019 Accepted: 10 December 2019

DOI: 10.1002/dc.24375

330 © 2019 Wiley Periodicals, Inc. Diagnostic Cytopathology. 2020;48:330–341.wileyonlinelibrary.com/journal/dc

the World Health Organization (WHO) Classification of Tumors of

Endocrine Organs, published in 2017, in a new chapter on borderline

tumors of follicular cell origin.3

Almost 3 years have passed since the introduction of this new

entity and experiences from different countries and institutions have

been published in an attempt to evaluate whether certain degree of

disagreement still persists or whether the new diagnostic criteria are

in complete harmony with the diagnosis and management. In spite of

Asian continent being a major contributor to worldwide prevalence of

thyroid cancer (according to GLOBOCON database; estimated 48%

new cases in 2012), the prevalence of NIFTP in Asians has not been

reported extensively as compared with the western world.4,5 There

are limited studies from Asia and even fewer form India5-10 and those

present have reported a significantly lower prevalence (0%-5%) as

compared to western data (15%-25%).2,11-14

Preoperative cytological assessment along with ultra-sonographic

evaluation of the thyroid nodule forms the basis of patient management

with thyroid nodule, hence, it becomes imperative to identify NIFTP entity

at postoperatively to prevent overtreatment and decrease morbidity in

these patients. Unfortunately, diagnostic criteria of NIFTP are primarily

based on histology and feasibility of an accurate diagnosis of NIFTP on

fine needle aspiration cytology (FNAC) and ultrasonography still remains a

controversial matter.2

Relatively questionable prognosis and nature of NIFTP has signifi-

cantly influenced The Bethesda system of reporting thyroid cytopa-

thology (TBSRTC) such that in updated 2017 guidelines, risk of

malignancy (ROM) has been calculated in two ways: when NIFTP is

not considered a malignancy, and when NIFTP is still included among

the “carcinomas.”15 The ROM decreased significantly in indeterminate

categories after removing NIFTP from tally of malignancy as early data

suggests that NIFTP constitutes a substantial proportion of the

“malignancies” hidden in these categories.16,17

Hence, this study is an attempt to comprehensively analyze

noninvasive follicular NIFPT by focusing on its prevalence in our

population, ultrasonography findings, preoperative cytological

assessment, histopathological evaluation, mutational analysis for

BRAFV600E and implication of NIFTP diagnosis on risk of malig-

nancy in various Bethesda categories along with impact on patient

management.

We also intend to propose a preoperative diagnostic algorithm

based on cytological and ultra-sonographic features for NIFTP.

2 | MATERIALS AND METHODS

2.1 | Study design and sample population

This is a retrospective cohort study, which included all the patients

with thyroid swelling visiting the department of endocrine surgery,

who underwent fine-needle aspiration and/or histopathological evalu-

ation in our unit of department of pathology, between 2016 and

2018. For each patient, demographic and clinical information were

collected from hospital database.

2.2 | Cytopathological evaluation

FNAC was performed using a 23 or 24-gauge needle attached to a

10 mL syringe. Air-dried and alcohol-fixed smears were prepared and

stained with May-Grunewald-Giemsa (MGG) and hematoxylin and

eosin (HE) stain, respectively. Final cytological diagnoses were based

on the six tier diagnostic category of TBSRTC.18 These categories

include: non-diagnostic (ND), Benign, atypia of undetermined signifi-

cance/follicular neoplasm of undetermined significance (AUS/FLUS),

follicular neoplasm/suspicious of follicular neoplasm (FN/SFN), suspi-

cious for malignancy (SM) and malignant category.

2.3 | Histopathological follow-up

Histological specimens in the form of hemi-thyroidectomy (HT)/total

thyroidectomy (TT) and/or core needle biopsies (CNB) were also

included wherever present. Histological diagnoses were classified

according to the third edition of the WHO pathology and genetics of

tumors of endocrine organs as well as being staged according to the

seventh edition of the AJCC Cancer Staging Manual. CNB for histo-

pathological follow-up has been used only in cases of anaplastic thy-

roid carcinoma (ATC) they are stage IV malignancy in which

resection is not usually advised.

2.4 | Review of potential cases of NIFTP

Considering the primary requisite of NIFTP as a well-demarcated or

encapsulated nodule, all the cases previously diagnosed as EFV-PTC,

adenomatous colloid nodule or follicular adenoma (FA) were reviewed

again for the possibility of NIFTP. All the cases of PTC without any

lymph nodes metastasis were also reviewed to rule out any possibility

of missing EFV-PTC at initial diagnosis. A consensus diagnostic crite-

rion by working group of noninvasive follicular thyroid neoplasms

with NIFTP was applied for each case and diagnosis was made accord-

ingly. The diagnostic criteria include:

1. Encapsulated or clear demarcation

2. Follicular growth pattern with

a. No papillae

b. No psammoma bodies

c. <30% solid/trabecular/insular growth pattern

3. Nuclear scores 2 to 3

4. No capsular and no vascular invasion

5. No tumor necrosis

6. No high mitosis (<3 per 10 high-power fields)

Two independent pathologists evaluated these cases as well as

their corresponding FNA smears in a blinded manner. The FNA smears

were evaluated for cellularity, architecture, presence or absence of

nuclear features of PTC for which three parameters were assessed:

Nuclear size and shape (ie, enlargement, elongation and crowding/

RANA ET AL. 331

overlapping); membrane irregularity (grooves, pseudo inclusions) and

chromatin. In cases of discrepancy, a joint decision was made.

2.5 | Radiological details

The thyroid ultrasounds were reported as per The American College of

Radiology —TIRADS reporting system and scoring performed accord-

ingly. Details were gathered retrospectively and following parameters

were assessed: size, shape (oval or round), echogenicity (hypo echoic,

hyper echoic, isoechoeic, etc.), composition (solid, predominantly solid,

mixed solid-cystic), vascularity (increased or no increase), margins

(smooth, ill-defined, irregular/lobulated, extrathyroidal extension) and

calcification (present or absent).

2.6 | Malignancy follow-up rates

The results of final histopathology diagnoses were compared to FNAC

diagnoses to find out malignancy rate of each categories of TBSRTC. In

calculating the malignancy follow-up rate for the benign category, the

total number of original FNA diagnoses was used as the denominator.

For all other diagnostic categories, malignancy follow-up rates were cal-

culated by using the number of cases with follow-up histology results.

If a patient had multiple FNA samples in the same procedure yield-

ing two different diagnoses, only the diagnosis with higher malignant

potential was used for calculating malignancy follow-up rates. Papillary

microcarcinoma (<1 cm) on resection were not considered malignant

except when the prior cytological interpretation was SM or malignant,

because the subcentimeter foci may not be targeted by the needle.

The ROM was calculated in two ways, similar to 2017 BSRTC,

one by considering NIFPT as benign neoplastic lesion and secondly

including NIFTP in tally of malignancies. The difference between both

results constituted a decrease in ROM (DROM).

2.7 | Immunohistochemistry for BRAF V600Eanalysis

Immunohistochemistry (IHC) staining was performed using a commer-

cially available BRAFV600E mutation-specific antibody. In brief, after

de-paraffinization and rehydration, paraffin-embedded tissue sections

(3 μm thick) were blocked with 3% hydrogen peroxide for 4 minutes

at room temperature. Microwave-assisted heat-induced antigen

retrieval was performed using the optimized antigen retrial condition

followed by incubation with BRAF V600E-specific monoclonal mouse

antibody (clone VE1; Abcam ab228461; dilution1: 100). A case papil-

lary thyroid carcinoma with BRAFV600E mutation, proved by molecu-

lar technique, was used as a positive control.

BRAF V600E expression within the cytoplasm was subjectively

graded as: 0, no cytoplasmic staining visualized at any magnification; 1

+, weak, requiring a ×10 or greater objective to recognize flavescent

staining on the section; 2+, moderate, easy to recognize yellow

staining with a ×10 objective; and 3+, strong brown staining with a 4×

microscopic objective.

3 | RESULTS

This study-included total of 617 FNA cases reported, according to

updated TBSRTC 2017, between 2016 and 2018. The age ranged from

2 to 85 years with mean age 39.9 years and median as 40 years. There

was a female predominance with a male: female of 1:4. During the

same period, 329 histology specimens (Hemi-, total thyroidectomy and

core needle biopsies) were received and reported. However of these

617 cytology cases, histology follow-up was available in 292 patients.

Table 1 shows the distribution of various diagnostic entities

reported in different Bethesda categories. There were 28 (4.5%) non-

diagnostic smears such that the adequacy rate was 95.5%. Majority of

TABLE 1 Distribution of various diagnostic entities and Bethesdacategories in FNA samples (n = 617)

Diagnostic categoryNo ofcases (n = 617)

%Cases

Non diagnostic 28 4.5

Benign 417 67.6

Colloid nodule 306 49.6

Goiter 80 12.9

Lymphocytic thyroiditis 25 04.1

Abscess 3 0.48

Granulomatous thyroiditis 2 0.30

Subacute thyroiditis 1 0.15

AUS/FLUS 22 3.6

FN/SFN 62 10.0

Follicular neoplasm 51 08.2

Hurthle cell neoplasm 11 01.8

SM 16 2.6

Malignant

Papillary carcinoma thyroid 72 11.7

Anaplastic carcinoma thyroid 29 04.7

Metastasis 23 03.7

Medullary carcinoma thyroid 04 0.60

Non-Hodgkin's lymphoma 05 0.80

Poorly differentiated carcinoma 04 0.60

Hurthle cell carcinoma with lymph

node

02 0.30

Metastasis

Extra medullary plasmacytoma 01 0.15

Primary undifferentiated sarcoma 01 0.15

Primary squamous cell carcinoma 01 0.15

Abbreviations: AUS, atypia of undetermined significance; FLUS, follicular

neoplasm of undetermined significance; FN, follicular neoplasm; SFN,

suspicious of follicular neoplasm; SM, suspicious for malignancy.

332 RANA ET AL.

the lesions were benign (67.6) and there were only 3.6% cases

(22 cases) of AUS. There were 72 cases of FN/SFN and among these

cases and there were four cases where the possibility of FV-PTC or

NIFTP was given. All these four cases were reported between

November 2017 and December 2018 and fortunately histology follow

up was available in all four of these cases.

3.1 | Overview of NIFT cases

On the basis of the criteria used for review (as mentioned in materials

and methods), there were 54 potential cases of NIFTP among which

15 fulfilled the diagnostic criteria and hence were labeled as NIFTP.

Apart from these 15 cases, there were five more cases with primary

diagnosis of NIFTP diagnosed during November 2017 to December

2018. Therefore, a total of 20 cases of NIFTP are included in this

study. These retrospectively diagnosed 15 cases of NIFTP were ini-

tially diagnosed as adenomatous colloid nodule (two cases), follicular

adenomas (five cases) and Follicular variant-Papillary thyroid carci-

noma (eight cases).

3.1.1 | Incidence of NIFTP

We calculated the incidence of NIFTP in three ways: incidence of

NIFTP is 5.1% when all the thyroid histopathological samples were con-

sidered, 16.2% among all neoplastic lesions (benign and malignant) and

29.6% when only PTC cases were included. Majority of these patients

were female (80%) and were ≤ 35 years (75%) of age (age range

18–70 years). All these patients were biochemically normal with the

duration of nodule being 3 months to 7 years. There was no associated

lymphadenopathy, history of rapid increase or compressive symptoms.

3.1.2 | Ultrasonography details

Ultrasonography details were available in all the cases. TIRADS score

corresponded to mildly suspicious category (score 3) in 95% cases. On

gray scale, all these nodules were well circumscribed with smooth

margins and were wider than taller. They were mostly solid/predomi-

nantly solid (95%) and hyper-echoic/predominantly hyper-echoic

(85%) Comet tail sign, calcification, lobulated margin were characteris-

tically absent. Color Doppler ultrasound demonstrated an increase in

vascularity in 60% of cases, which was more common peripherally.

However, hypoechoic halo was identified in 12 cases and nodular

background was present in 16 patients. Table 2 shows ultrasonogra-

phy details of all the cases of NIFTP.

3.1.3 | Review of preoperative cytology smears

Preoperative cytology smears were available in all the cases, among

which two had nondiagnostic cytology. A majority (55.6%; 10 cases)

of the NIFTP cases had indeterminate cytology of FN/SFN. There

were seven cases (35.3%) in benign category and only one in malig-

nant. Smears in most of these cases were moderately cellular. The

most common cytological abnormality seen was significant micro fol-

licular pattern, presence of nuclear enlargement and prominent

nuclear overlapping. Nuclear grooving was also commonly seen. Fre-

quent intra-nuclear pseudo-inclusions (>3) were not identified but

occasional pseudo inclusion1,2 could be identified in two cases only.

Psammoma bodies and papillae were typically absent and there was

either no colloid or if present were in the form of thick blotches.

3.1.4 | Histopathology of NIFTP cases

On histological evaluation, 12 cases were completed encapsulated

with a thin or thick capsule and remaining cases were well demarcated

with no or partial encapsulation. There was a background of nodular

TABLE 2 Ultrasonography details of NIFTP cases (n = 20)

Type of ultrasound Features

No of cases

(%age)

Gray scale ultrasound

Circumscription Well circumscribed 20 (100%)

Invasive 00

Shape Oval 20 (100%)

Round 00

Composition Solid 10 (50%)

Predominantly solid 09 (45%)

Mixed solid cystic 01 (05%)

Cystic 00

Echogenicity Hyper echoic or

predominantly hyper

echoic

17 (85%)

Hypo echoic 03 (15%)

Isochoric 00

Calcification Present 00

Absent 20 (100%)

Other features

Comet tail sign Present 0 (0%)

Absent 20 (100%)

Hypo echogenic

halo

Present 12(60%)

Absent 08(40%)

ACR-TIRAD SCORE 2 (Not suspicious) 1 (5%)

3 (Mildly suspicious) 19 (95%)

Color Doppler ultrasound

Vascularity Increased 12 (60%)

Not increased 08 (40%)

Pattern of increased

vascularity

Central 04 (20%)

Peripheral 08 (40%)

RANA ET AL. 333

goiter in 16 cases characterized by presence of vague nodules com-

posed of variable sized colloid filled follicles.

The nuclear score was mostly 2 (80%), with common abnormali-

ties seen in nuclear shape/size (enlarged overlapping nuclei) and chro-

matin characteristics (chromatin margination or glassy nuclei). Nuclear

membrane irregularity could also be easily appreciated in many cases

however significant nuclear grooving was not as common. These

nuclear findings were mostly patchy and not uniformly present in the

entire lesion. In the remaining four cases (20%), the nuclear score was

3. Figures 1 and 2 show cytological and corresponding histological

features of NIFTP observed in some of our cases with variable nuclear

score.

3.1.5 | Risk of malignancy and impact on NIFTP onpatient management

The risk of malignancy was calculated in two ways by including as well

as excluding NIFTP from the malignancy tally. There was one core

needle biopsy specimen, which was reported as inadequate and there-

fore excluded. Hence, there were a total of 289 cases where cytology

and histology could be correlated. Table 3 shows the details of ROM

along with the percentage DROM.

The major impact of including NIFTP in malignant category was

seen in Bethesda category I (nondiagnostic) and IV (FN/SFN) where

the malignancy risk decreased from 60% to 40% and 48.6% to 21.6%,

respectively. There was also a minor decrease in risk in benign cate-

gory, however, there was no difference in suspicious and malignant

categories.

3.1.6 | BRAF V600E mutation analysis by IHC

None of these 20 cases showed any cytoplasmic positivity and hence

were reported as negative for this mutation on IHC.

3.1.7 | Surgical management

The types of initial surgeries performed included 15 hemi-

thyroidectomies and five total thyroidectomies. Fortunately, major-

ity (75%) of the patients invariably underwent a proper treatment.

However, in 25% of the cases overtreatment in the form of total

thyroidectomy could have been avoided. Among these five cases,

four were reported as FV-PTC on cytology and one was

inadequate.

F IGURE 1 Case 1 (cytology andcorresponding histology) with nuclearscore of 2. A, Cytological smeardisplaying clusters of atypical cellswith overlapping round to oval nuclei(H&E, ×400). B, Correspondinghistology with enlarged roundoverlapping nuclei with chromatinclearing and margination (H&E, ×400)[Color figure can be viewed atwileyonlinelibrary.com]

F IGURE 2 Case 2 (Cytology andcorresponding histology) with nuclearscore of 3. A, Cytological smeardisplaying clusters of atypical cellswith overlapping predominantly ovalnuclei with grooving and occasionalintranuclear inclusion (H&E, ×400). B,Corresponding histology withenlarged round to oval overlappingnuclei with chromatin clearing andmargination and irregular nuclearmembrane with prominent grooving(H&E,×400) [Color figure can beviewed at wileyonlinelibrary.com]

334 RANA ET AL.

4 | DISCUSSION

NIFTP represents a group of neoplasm, which are well demarcated,

noninvasive with follicular architecture, nuclear features similar to

papillary carcinoma thyroid and negligible risk of recurrence or metas-

tasis. At molecular level, these tumors are known to show similarity to

follicular neoplasm, demonstrating high percentage of RAS and PAX8/

PPARG rearrangement, which more commonly occur in classical PTC

and invasive follicular variant of PTC. BRAFV600E mutation has not

been documented in NIFTP, but they might have BRAF-K601E muta-

tions.19-21 Presently, after ~3 years of adopting a new terminology,

NIFTP remains the topic of interest which has significantly influenced

the practice of endocrine pathology compelling the health profes-

sionals in this field to adjust current approaches and guidelines to this

new entity.

The NIFTP working group has proposed following modification in

the diagnostic criteria documented in the original publication by

Nikiforov et al22:

1. “True papillae <1%” to be replaced by “no true papillae.”

2. Examination of entire tumor, and not just capsule, with optional,

but recommended BRAF V600E analysis using immunohistochem-

istry or molecular techniques, in cases with florid nuclear features

of PTC (nuclear score 3).

During the review process in our study, we also encountered a

case with few true papillae (<1%) present at the periphery. This case

was excluded in view of modified criteria for NIFTP. However, this

patient had been in follow up for last 3 years and has not shown any

sign of malignancy till now.

The extent of all the changes related to the NIFTP reclassification

apparently depends on the incidence of NIFTP in a certain population.

Approximately, 30 studies have been conducted in America, Europe

and Asia reporting variable incidence.2,4,5,7,9,11,16,17,23-30 Bychkov

et al, in a meta-analysis, documented an average worldwide preva-

lence rate of 9.1%, with a lower rate in Asian studies (1.6%) as com-

pared with non-Asian countries (13.3%).4 This difference could be

attributed to various perceptions of histological diagnostic thresholds,

different nature of papillary thyroid carcinoma, and different

approaches in the management of thyroid nodules. However, these

rates are based on NIFTP documented among PTC cases only. In none

of these studies, cases of adenomatous colloid nodule or follicular

adenomas were reviewed. Well demarcated/-encapsulated lesions

being the first diagnostic criterion make it important to consider these

cases as well. We had two cases of adenomatous colloid and five

cases of follicular adenomas, which were reclassified as NIFTP. In our

study, we have documented the incidence in a very elaborative way,

such that the incidence was 5.1% among all thyroid lesions while it

was 16.2% among neoplastic cases and 29.6% when only PTCs were

considered. Incidence in our setting is significantly higher as compared

to those documented in studies form Asia as well as other countries

(Table 4). All these studies so far may not truly reflect the incidence

and prevalence of this entity due to wide variation in their designs,TABLE3

Summaryofmaligna

ncyrate

aswellasFNACan

dhistologicalcorrelationin

various

Bethe

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ries

(N=230)

FNAC

Histopa

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diag

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Riskofmalignan

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Diagn

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oplastic

NIFTP

Maligna

ntROM

with

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ROM

(without

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%Dec

rease

inROM

No.o

fcases

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Hurthle

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iagn

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60.0

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22.2

22.2

0.0

FN/SFN

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96

410

8(6

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(MTC)a

nd1Hurtlecellcarcinoma)

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00

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oninvasive

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RANA ET AL. 335

TABLE4

Compa

rative

analysisofincide

ncea

anddistribu

tionofNIFTPin

various

Bethe

sdacatego

ries

Stud

y(yea

r)(Referen

ce)

Place

andye

arofstud

yNo.o

fNIFTPcases

Incide

nceNIFTP(%

)

DistributionofNIFTPin

various

Bethe

sdadiagn

ostic

catego

ries

BCI(Nondiag

nostic)

BCII(Ben

ign)

III(AUS/FLU

S)IV (FN/SFN)

V(SFM)

VI

(Malignan

t)

Strickland

17

USA

2015

85

28.0

1(1.2%)

13(15.3%)

17(20.0%)

7(8.2%)

39(45.9%)

8(9.4%)

Howittet

al31

German

y2015

72

—3(4.2%)

9(12.5%)

13(18%)

7(9.7%)

35(48.6%)

5(6.9%)

Fan

quin

etal16

USA

-Switzerlan

d2016

173

22.9

1(0.6%)

15(8.7%)

54(31.2%)

46(26.5)

42(24.3%)

15(8.7%)

Rosarioet

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Brazil2

016

126

15.0

1(0.8%)

10(8.0%)

25(20%)

53(42%)

32(25.4%)

5(4.0%)

Can

berk

etal5

Turke

y2016

94

27.6

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15(15.9%)

14(14.9%)

23(24.5%)

17(18.1%)

12(12.8%)

Sing

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al26

USA

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21

12.1%

—1(5%)

4(19%)

10(48%)

3(14%)

3(14%)

Hirokawaet

al7

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n2017

42

—2(4.9%)

2(4.9%)

5(12.2)

1(2.4%)

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27(65.9%)

Bycho

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India

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10.2%

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9(60%)

00

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111.1%)

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Korea

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3.4%

01(16.6%)

3(50%)

02(33.3%)

0

Korea

06

2.4%

00

1(16.6%)

1(16.6%)

2(33.3%)

2(33.3%)

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11

6.1%

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3(27.3%)

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3(27.3%)

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0

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Current

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oninvasive

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neo

plasm

withpap

illary-like

nuclea

rfeatures;S

FN,suspicious

offollicu

larne

oplasm.

aRefersto

incide

nceofNIFTPin

patien

tsofPap

illarythyroid

carcinoma.

336 RANA ET AL.

retrospective nature and estimation of rates based on primary search

via FNA database, which implies that the accurate rate of NIFTP

worldwide still needs to be established.

Since NIFTPs or their former equivalent (EFVPTCs) typically do

not show the full range of nuclear features seen in classic type PTCs,

particularly when the atypia is subtle or focal, they are frequently

F IGURE 3 Diagnostic algorithm based on major and minor ultrasonography and cytological features

RANA ET AL. 337

assigned an indeterminate cytological diagnosis within the TBSRTC

classification system.16,21,31-33 Contrary to these findings authors like

Hirokava et al, Stickerland et al and Howitt et al have documented

>50% NIFTP cases placed in higher Bethesda categories (SFM and

malignant).7,17,31 The reason for this discrepancy is unclear but may

be due to institutional differences in the threshold of cytological inter-

pretations. Our study also placed NIFTP in SFN/FN (52.6%) followed

by benign (31.6%) and there was only one case with malignant preop-

erative cytology. These findings again signify the fact, that a substan-

tial number of cases of NIFTPs could have been diagnosed as

adenomatous nodule/goiter; therefore for true incidence of NIFTP it

is important to review these cases as well. Prospective studies in near

future may answer these debatable territories.

The current paradigm in the treatment of patients with NIFTP is

limited surgery such as lobectomy rather than subtotal/complete thy-

roidectomy or postoperative radioiodine treatment. Therefore, com-

prehensive evaluation for the diagnosis of preoperative NIFTP is

important for clinicians to achieve better decision to manage the

patients. Preoperative diagnosis is still a challenge as ultrasonography

and FNA are two main modalities for preoperative analysis in thyroid

nodule, but unfortunately there are no diagnostic criteria for NIFTP

based on them. Chandler et al reported NIFTP cases to be more likely

to have predominant micro-follicular pattern, absent intra-nuclear

inclusions (INI) and less obvious nuclear elongation and grooves than

FVPTCs.32 Some authors have, even recommended quantification of

cytological features, example a cut-off of ≥3 being considered for

pseudo-inclusions.23,32,34 However, Ng et al found as many as 22% of

their NIFTP cases to show ≥3 INI, thus, raising doubts over reliability

of this measure.35,36

There is limited literature on ultrasonography features of NIFTP,

which could help in making a definitive diagnosis.14,37,38 NIFTP, follic-

ular adenoma, adenomatous colloid nodule and minimally invasive FV

PTC share common cytomorphological (micro-follicular pattern) and

radiologically (wider than taller circumscribed lesions) features. Minor

ultrasound findings such as comet sign (common in colloid nodule),

complete hypo genic halo (common in follicular adenoma), nodular

background (not seen in follicular adenoma), lobulated margins (FV-

PTC), etc. can be very helpful in such situation. Table 6 shows a com-

parative analysis of cytology and ultrasound features in these entities.

This is the only study from India so far which has documented the

sonography characteristic in detail. Our data suggest that NIFTP nod-

ules corresponds to TIRAD score 3 and are characterized as well cir-

cumscribed, wider than taller, mostly solid and hyper echoic lesion

with smooth outlines and peripheral increase in vascularity. Figure 3

describes a diagnostic algorithm based on major and minor ultraso-

nography and cytological features to differentiate between these enti-

ties and direct the management of these patients.

Introduction of NIFTP has also created some challenges for thy-

roid FNAC: among them, its impact on the ROM in the diagnostic cat-

egories of TBSRTC and the resulting need for modification of clinical

management guidelines may be critical.39 Clinicians should always be

aware of the malignancy rate in various Bethesda categories in their

respective hospitals to improve their management decisions. FewTABLE5

Compa

risonofim

pact

ofNIFTPonrisk

ofmaligna

ncyin

various

stud

ieswithan

dwitho

utco

nsideringNIFTPas

maligna

ncy

Stud

ies

Strick

land

etal17

Faqu

inet

al16

Laye

fieldet

al42

Can

berk

etal5

Updated

TBSR

TC15

Presentstudy

Bethe

sda

catego

ries

ROM

aROM

bDROM

ROM

aROM

bDROM

ROM

aROM

bDROM

ROM

aROM

bDROM

ROM

aROM

bDROM

ROM

aROM

bDROM

Nondiagno

stic

18.9

17.0

1.9

25.3

23.9

1.4

9.5

9.5

013

6.5

6.5

5–1

05–1

00

60.0

40.0

20

Ben

ign

13.2

5.4

7.8

9.3

5.8

3.5

10.7

7.1

3.6

7.0

6.0

1.0

0–3

0–3

02.3

1.3

1.0

AUS/FLU

S39.2

21.6

17.6

31.2

17.6

13.2

17.4

15.1

2.3

45

30

15

~10-30

6-18

4–1

222.2

22.2

0

FN/SFN

45.5

37.5

8.0

33.2

18.0

15.2

22.2

19.7

2.5

30

10

20

25-40

10-40

15

48.6

21.6

27

Suspicious

of

maligna

ncy

87.2

45.7

41.5

82.6

59.2

23.4

82.8

65.8

17.0

72

48

24

50-75

45-60

15

87.5

87.5

0

Maligna

nt98.7

93.6

5.1

99.1

95.7

3.4

100

87.2

12.8

98

87

11

97-99

94-96

3100

100

0

Abb

reviations:A

US,

atyp

iaofun

determ

ined

sign

ifican

ce;D

ROM,d

ifferenc

ein

risk

ofmaligna

ncyF

LUS,

follicu

larne

oplasm

ofun

determ

ined

sign

ifican

ce;F

N,follicu

larneo

plasm

;NIFTP,n

oninvasive

follicu

lar

thyroid

neoplasm

withpa

pillary-likenu

clea

rfeatures;R

OM,riskofmaligna

ncySF

N,suspicious

offollicu

larne

oplasm.

aRiskofmaligna

ncyby

consideringNIFTPas

maligna

ncy.

bRiskofmaligna

ncyby

notco

nsideringNIFTPas

maligna

ncy.

338 RANA ET AL.

TABLE6

Compa

rative

analysisofultrasoun

dan

dcytology

find

ings

ofNIFTPwithother

differen

tialdiagno

sis3

7,38,42

Ultraso

undfind

ings

Ade

nomatous

collo

idno

dule

NIFTP

Follicu

larad

enoma

Inva

sive

FV-PTC

Compo

sition

Mixed

(solid

andcystic)

Predo

minan

tlysolid

Predo

minan

tlycysticormixed

cystican

d

solid

lesions

Predominan

tlysolid

Ech

oge

necity

Isoecho

genicto

slightlyhy

perech

oge

nic

Predo

minan

tlyhy

perech

oge

nic

Isoecho

icorpred

ominan

tlyan

echoic

Usuallyhyp

oechoge

nic

Orien

tation

Wider

than

taller

Wider

than

taller

Wider

than

taller

Tallerthan

wider

Margin

Smooth

Smooth

Smooth

Spiculated/lobulatedmargin

Calcification

Absen

tormacro

calcification

Usually

absent

ifpresen

tthan

macro

calcification

Absen

tormacro-calcification

Micro

calcifications

Halo

Absen

tMay

bein

encapsulated

one

sCompletethin

toun

even

Inco

mplete

Comet

tailartifact

Present

Absen

tAbsen

tAbsent

Vascu

larity

Predo

minan

tlype

riph

eralflow

Predo

minan

tlype

riph

eralflow

Absen

ceofinternalflow

orpred

ominan

tly

periph

eralflow

4

Marke

dintran

odular

Nodu

larity

in

remaining

thyroid

Usuallypresen

tUsually

presen

tAbsen

tUsuallypresent

Cytology

find

ings

Architecturalfeatures

•Microfollicu

larpa

ttern

•Largeno

nbran

chingcellu

larmono

laye

red

shee

tswithco

lloid

inba

ckgroun

d

•Microfollicu

larpa

ttern

•Microfollicu

larpa

ttern

•Three

dimen

siona

lmultilaye

redshee

ts

withan

dwithtrab

ecular

pattern

•Microfollicu

larpattern

•Monolaye

rbranch

ingshee

t

Nuc

lear

enlargem

ent

Absen

tPresent

Present

Present

Nuc

lear

shap

eRoun

dun

iform

Roun

dto

ovale

nlarge

dEnlarge

droun

dto

mild

anisonu

cleo

sis

Ovaltoelongateden

larged

with

moderatean

isonucleo

sis

Nuc

lear

ove

rlap

ping

Minim

alPresent

freq

uently

Minim

alPresentSign

ifican

tly

Nuc

lear

grooving

Minim

alPresent

freq

uently

Minim

alPresentSign

ifican

tly

Intranu

clea

rpseu

do

inclusion

Usuallyab

sent

Occasiona

l1,2

Usually

absent

Frequen

t(>3)

Chromatin

Den

seGroun

dglassto

vesicu

lar

Granu

lar

Groundglassto

vesicu

lar

TruePap

illae

Absen

tAbsen

tAbsen

tMay

bepresent

Psammomabo

dies

Absen

tAbsen

tAbsen

tMay

bepresent

RANA ET AL. 339

studies have shown that NIFTP has affected malignancy risk in each

category with the greatest impact being on FN/SFN and non-

diagnostic categories.40 A recent meta-analysis by Layfield et al has

shown that NIFTP remarkably affect risk of malignancy in indetermi-

nate Bethesda categories.41 In our study, similar to those by Faquin

et al16 and Canberk et al,5 the highest reduction in risk of malignancy

was in FN/SFN Bethesda category (27%) followed by non-diagnostic

category (20%). Although lesser impact is known in benign category

but special attention should be given to this subset, which may

require closer monitoring compared to non-neoplastic benign nodules.

This notion can be backed up by the fact that NIFTP is known to be a

precursor lesion and have a propensity to progress to invasive follicu-

lar variant of PTC. The international working group for NIFTP also

postulates it as an oncogene driven clonal tumor and a precursor

tumor to invasive EFVPTC. The WHO editorial committee thus

decided to incorporate a new chapter, 2-2A: other encapsulated follic-

ular patterned thyroid tumors, in which there were two sub-chapters,

UMP and NIFTP, in the fourth edition WHO classification of tumors

of endocrine organs. They were given a behavior code of 1 (borderline

or uncertain behavior) by the WHO committee.3 NIFTP is still a newly

diagnosed enitity and long term follow up will shed more light on bio-

logical behavior in coming future. There was no impact on cases with

AUS, SFM and malignant cytology. Contrary to these findings Kim

et al documented no significant decrease in risk of malignancy after

excluding NIFT from malignant lesions.39 Comparison of our findings

with some previous studies is shown in Table 5. Our study had its

shares of limitation: firstly retrospective study with lesser number of

cases in AUS/FLUS and SFM Bethesda categories; and secondly lack

any comparison with two edges like FA in benign, and IFV-PTC in

malignant edge to proof the usefulness of the algorithm.

To conclude, ultrasonography and cytology findings when put

together can be efficiently used to suggest preoperative diagnosis of

NIFTP. NIFTPs are less likely to have malignant preoperative cytology

but can be commonly preceded by benign Bethesda category. Hence,

inclusion of cases of follicular adenoma and adenomatous colloid nod-

ule is important to determine the true incidence. Countries with

higher incidence of thyroid cancers can further work up to establish

their own malignancy risk range and parameters. Future prospective

studies are required is required to validate the proposed diagnostic

algorithm.

ACKNOWLEDGEMENT

Authors acknowledge King George's Medical University Medical

Research Unit, Department of Health Research.

CONFLICT OF INTEREST

AUTHOR CONTRIBUTION

Chanchal Rana contributed to conception and design, provision of

study materials or patients, collection and assembly of data, data analy-

sis and interpretation, final approval of manuscript and manuscript writ-

ing. Shreyamsa manjunath contributed to provision of study materials

or patients, collection and assembly of data, final approval of

manuscript and manuscript writing. Suresh Babu contributed to provi-

sion of study materials or patients and collection and assembly of data.

Pooja Ramakant contributed to conception and design, provision of

study materials or patients, final approval of manuscript and manuscript

writing. Kulranjan singh contributed to provision of study materials or

patients, final approval of manuscript and manuscript writing. Anand

Mishra contributed to provision of study materials or patients, adminis-

trative support, final approval of manuscript and manuscript writing.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on

request from the corresponding author. The data are not publicly

available due to privacy or ethical restriction.

ORCID

Chanchal Rana https://orcid.org/0000-0002-1783-7689

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How to cite this article: Rana C, Manjunath S, Ramakant P,

Singh K, Babu S, Mishra A. Noninvasive follicular neoplasm

with papillary like nuclear features: A comprehensive analysis

with a diagnostic algorithm. Diagnostic Cytopathology. 2020;

48:330–341. https://doi.org/10.1002/dc.24375

RANA ET AL. 341