University of TurinItaly

NON INVASIVE FOLLICULAR TUMORS WITH PAPILLARY-LIKE NUCLEI (NIFT-P)

Veenendaal, April 13, 2018

Mauro PapottiM. Volante F. MalettaJ. Metovic

PTC-likeFT+NI+

WHO CLASSIFICATION OF ENDOCRINE TUMORS

June 2017

WHO 2017

Hobnail var.

Follicularpatterned

tumors

WD THYROID TUMORSCURRENT STATUS

FA FTC

PA PTC

WD THYROID TUMORS….DETAILED TYPING….

FA

PA

WI FTCMI FTC

PTCCl., FV,..

EFVPTC non inv

IFVPTCmicroCa cl.V

Lloyd RV et al: Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. AJSP 28:1336-1340, 2004.

Split diagnosis occurred up to 40%!

Using 87 cases of FVPTC from Mayo Clinic

modified from Kakudo 2015

ENCAPSULATED FOLLICULAR TUMORS

Conclusion on 83 tumors

ENCAPSULATED FOLLICULAR TUMORS WITH PTC NUCLEI (towards “NIFT-P”)

Background

Diagnostic PTC type nuclear features in encapsulated tumors?

1. Nuclear enlargement (oval shape & elongation) 2. Overlapping nuclei. 3. Irregularity of nuclear contours (grooves) 4. Cytoplasmic nuclear inclusion (DD vacuoles:

>50% nuclear area with distinct border and cytoplasmic staining color)

5. Ground glass nuclei, clear or powdery nuclei

The WHO textbook stated that in tumors without complex papillary structures, the diagnosis of PTC relies on these nuclear features, which should be present in a significant proportion of the neoplasm If they are minor/focal, it should be classifed as uncertain category (WDT-UB).

Liu Z Cancer Sci 2011; Kakudo K Endocr J 2011 – modified from Kakudo 2015

FTC

no

FA

PTC-N

yes equivocal no

EnFV-PTC WDT-UB

Encapsulated Follicular Cell Tumours

Diffuse/

Predominate

Minor/

Focalyes

Both are called PTC

in most Western countries

Capsular invasion

equivocal

FT-UMP

modified from Kakudo 2015Liu Z et al. Cancer Sci, 2011

Kakudo K et al. Endocr J, 2011

“NIFT-P” Background & study design

PTC includes follicular var. (no papillae), -which includes encapsulated forms, -which include 100% non invasive forms,-which follow an indolent course.

Are these “cancers” (ie malignant)?Are these papillary adenomas (but no papillae)?Are these follicular adenomas (but PTC nuclei)?Are these something else?

-24 pathologists from 3 continents-250 cases individually reviewed & scored -10 TC to discuss diagnostic criteria -decision on the name for this new entity

Score 0 1 432

Nuclear Features Score for “EFVPTC”

Nik

iforov

20

15

(p

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nal

com

mu

nic

ati

on

)

Score 5 6 987

Nuclear features:

1. Size and Shape

Enlargement

Elongation

Overlapping

2. Membrane Irregularities

Irregular contours

Grooves

Pseudoinclusions

3. Chromatin Characteristics

Chromatin clearing

Margination of chroma-

tin to membrane

Glassy nuclei

Nuclear score: Sum of three nuclear features (each 0 or 1)So total score will vary between 0 and 3

Absent/insufficiently expressed (0) Present/Sufficient (1)

(May 18,

2015)

Slight changes not sufficient to call “yes” !

modified from Nikiforov 2015

New nuclear feature score for “EFVPTC”

My understanding after>200 case review, several exercises, 8 TC, 2 day meeting

Example of NIFTP

WD THYROID TUMORS

FA

PA

WI FTCMI FTC

PTCCl, FV, ..microCa cl.V

IFVPTC

EFVPTC non inv

Non invasive/encapsulatedfollicular tumors including PTC

WD THYROID TUMORSWHERE DOES NI EFVPTC STAND?

FA

PA

WI FTCMI FTC

PTCCl, FV, ..microCa cl.V

IFVPTC

EFVPTC non inv

EFVPTC non inv

EFVPTC non inv

EFVPTC non inv

?

?

??

WD THYROID TUMORSREVISION OF EFVPTC non invasive

FA

PA

WI FTCMI FTC

PTCCl, FV, ..microCa cl.V

IFVPTC

NO papillae

WHY THE NAME NIFTP?

Highly criticized terminology !!

But you should first be aware of the proposed alternatives…..!!!

JAMA ONCOLOGY Apr 14 2016

MOLECULAR PROFILE OF NIFTP

RAS gene mutations are more common than BRAF in follicular variant PTC

FVPTC MOLECULAR PROFILE

BRAFRAS

InfiltrativeEncapsulated

FVPTC MOLECULAR PROFILE

NIFTP MOLECULAR PROFILE

Seethala AJSP 2017,41,446

TERT promoter mutations usually do notoccur in NIFTP. One true case is reported, with no high grade features. Unexplained

Jiang XS. Cancer 2016, 124,893

ETV-NTRK3 rearrangements usually do notoccur in NIFTP. Reported cases exist, butthe capsule was not entirely examined, and rare papillae or infiltrative growth may beidentified

RAS mutations in EFVPTC / NIFTP vs BRAF or RET/PTC in infiltrative FVPTC

Kim TH. Histopathology 2018, 72,648

PTC nuclei & papillae vs follicles

NIFTP VALIDATION PAPERS

Additional features: -multifocal tumors-bilateral tumors-microcarcinomas-large NIFTP

Large NIFTPs appear to have an extremely lowrisk of recurrence (zero in this cohort), even afterconservative tx, without RAI. Surgical treatment alone (lobectomy) appears to be adequate.

NIFTP PAPERS

2017

2017

NIFTP: ATA GUIDELINES(...) It is recommended that the histopathologic nomenclature for EFVPTC without invasion be reclassified as a NIFTP, given the excellent prognosis of thisneoplastic variant. (...)

It is also noted that prospective studies are needed to validate the observed patient outcomes(and test performance in predicting thyroid canceroutcomes), as well as implications on patients' psychosocial health and economics.

2017;27:481-483. American Thyroid Association Guidelines on the Management of ThyroidNodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of Encapsulated Follicular Variant Papillary Thyroid Carcinoma WithoutInvasion to Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features.

NIFTP: summary of diagnostic cluesas of 2018

-PTC like nuclear features (score 0-3)-Only scores 2-3 indicate NIFTP (vs FA)-Extensive capsular sampling (possibly all)-NO papillae (originally <1%)-NO psammoma bodies (linked to papillae)-NO infiltrative growth into the capsule-NO upper limit of NIFTP size (ok even >4)-Lower cutoff at 1 cm; sub-cm cases exist

-NO BRAF mutations-Reported NIFTP with mets are not NIFTP!

Hung & Barletta. A user’s guide to NIFTP. Histopathology 2018

Seethala et al. NIFTP: a review for pathologists. Mod Pathol 2018

NIFTP: summary of diagnostic cluesas of 2018

Nuclear features:

1. Size and Shape

Enlargement

Elongation

Overlapping

2. Membrane Irregularities

Irregular contours

Grooves

Pseudoinclusions

3. Chromatin Characteristics

Chromatin clearing

Margination of chroma-

tin to membrane

Glassy nuclei

Nuclear score: Sum of three nuclear features (each 0 or 1)So total score will vary between 0 and 3

Absent/insufficiently expressed (0) Present/Sufficient (1)

Slight changes not sufficient to call “yes” !

modified from Nikiforov 2015

NIFTP & FNA CYTOLOGY

PAPILLARY ARCHITECTURE

+/-

PTC

FTC

NUCLEAR IRREGULARITIES

VASCULAR INVASION

and / or

CAPSULAR PENETRATION

FNA YES

FNA NO

FNA NO

FNA YES

PTC type Nuclear Features

FNA DIAGNOSIS OF NIFTP?

-96 cases from 6 University hospitals (Torino, Bologna, Pisa)-Revision of anonymized surgical casesoriginally diagnosed as EFVPTC, WDT-UMP or FA with occasional clear nuclei, and having the corresponding FNA materialavailable-Criteria for NIFTP

-Exclusion criteria: no encapsulation, VI, capsular penetration, papillae in >1%, multifocality, Hurthle cellchanges (ie oncocytic variant PTC)

FNA DIAGNOSIS OF NIFTP?

Correspondinghistologicalfeatures

96 FNA+surgery from 6 Univ. hospitals

FNA DIAGNOSIS OF NIFTP?

SAME CRITERIA:1. Size and Shape

• Enlargement

• Elongation

• Overlapping

2. Membrane Irregularities

• Irregular contours

• Grooves

• Pseudoinclusions

3. Chromatin Characteristics

• Chromatin clearing

• Margination to membrane

• Glassy nuclei

Cell blocks

*Mostly Bethesda category IV or V (Tir 3b or 4)*In a well demarcated nodule (at US) with follicular growth & more or less evident PTC nuclei, consider NIFTP & at least avoid the category «malignant» (Bethesda VI or Tir 5)

NIFTP IN FNAB CYTOLOGY

+ Aug 2, 2015

Giemsa HE PAP

NIFTP IN FNAB CYTOLOGY2017

III 20%, IV 42%, V 25%, VI 4%

Strickland KC, Vivero M, …, Barletta J, Krane JF. Pre-operative CytologicDiagnosis of Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): A Prospective Analysis. Thyroid 2016 Jul 25.

Excluding 7 indeterminate cases, 89% (8/9) of nodules classified as NIFTP/FVPTC on FNA demonstrated follicular-patterned lesions on histology (5 NIFTP, 1 invasive FVPTC, 2 follicular adenomas). Cytopathologistsprospectively identified cPTC in 95% (38/40) of cases.

NIFTP IN FNAB CYTOLOGY

Ibrahim AA, Wu HH. FNA Cytology of Noninvasive Follicular Variant of Papillary Thyroid Carcinoma Is Cytomorphologically Distinct From the Invasive Counterpart. Am J Clin Pathol 2016 Sep;146:373-7.

Matched FNA & surgical samples: 23 noninvasive FVPTC and 27 cases infiltrative FVPTC (n = 16) or encapsulated FVPTC with invasion (n = 11).

FNA diagnoses: NIFTP: 4 benign lesions, 14 FLUS, 4 FN, 1 suspicious, no PTC.

Invasive FVPTC group: no benign, 4 FLUS, 3 FNs, 12 suspicious, 8 PTC.

CONCLUSIONS: There is a distinction in the cytologic diagnosis between noninvasive and invasive FVPTC. The invasive subtype was diagnosed by FNA as suspicious for PTC or PTC in nearly 75% of cases, while only one (4%) case for the noninvasive subtype was diagnosed as suspicious for PTC (P < .05).

NIFTP IN FNAB CYTOLOGYHahn SY et al. Preoperative differentiation between noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and non-NIFTP. Clin Endocrinol(Oxf) 2016 Oct 19. 208 resected FVPTC: 34 NIFTP (16·3%) and 174 non-NIFTP (83·7%).

Clinical factors, the biopsy techniques and ultrasonography (US) imaging characteristics were compared between NIFTP and non-NIFTP groups.

The most common biopsy diagnosis of NIFTP was Bethesda category V

(28·6%) in the US-FNA group and category IV (45·5%) in the US-CNB group.

By US, NIFTP had lower suspicion of malignancy than non-NIFTP (p:0.024).

NIFTP lacks malignant US features and is better triaged using US-CNB than

using US-FNA to facilitate the surgical management.

Jeon MJ et al. Impact of Reclassification on Thyroid Nodules with Architectural Atypia: From Non-Invasive Encapsulated FVPTC to NIFTP. PLoS One 2016;11:e0167756

-Impact of reclassification from EFVPTC to NIFTP [Resected 384/1301 nodules, 30%].

-Reviewed 1301 thyroid nodules with architectural atypia in core needle biopsy (CNB)

-Classified into atypia of undetermined significance with architectural atypia (AUS-A, 984, 76%) or follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN, 317, 24%).

-The malignancy rate was estimated: 7-35% in AUS-A nodules and 28-49% in FN/SFN nodules. After reclassification, the malignancy rate was 5-24% & 23-39% respectively.

CONCLUSIONS: After reclassification of non-invasive EFVPTCs to NIFTPs, the

malignancy rate of thyroid nodules with architectural atypia in CNB specimens was

decreased. However, there were no preoperative factors differentiating other

malignancies from NIFTPs.

NIFTP IN FNAB CYTOLOGYH

C

J

C

NIFTP IN FNAB CYTOLOGY: score 0-1

NIFTP IN FNAB CYTOLOGY: score 2

score 2.5 ?

NIFTP IN FNAB CYTOLOGY: score 3

I) Nondiagnostic //

II) Benign <1%

III) Follicular lesion / 5-10%

atypia of undetermined significance

IV) Follicular neoplasm / 20-30%

suspicious for follicular neoplasm

V) Suspicious for malignancy 50-75%

VI) Malignant 100%

Risk of malignancyBethesda 2007 and 2010

Evaluation of risk of malignancychanges in the Bethesda classification

Risk of malignancy changes in the Bethesda classification

-1,886 thyroid FNAs with surgical follow-up -EFVPTC were 27% (94/343) of the malignant cases.-Malignancy ratios in nondiagnostic, benign, atypia/FLUS, FN, suspicious for malignancy, and malignant categories were 13, 7, 45, 30, 72, 98%, respectively. -If EFVPTC was not regarded as malignant, malignancy ratios would decrease to 6.5, 6, 30, 10, 48, 87% for each category.-The most significant decrease occurred in follicular neoplasm category (66% relative decrease)

Canberk et al. New concept of the encapsulated FVPTC and its impact on the Bethesda system for reporting thyroid cytopathology: a single-institute experience. Acta Cytol 2016;60:198-204.

-Tested by Nanostring 798 miRNA expression profiles to distinguish between NIFTPs (#19) vs FA (#18) and infiltrative FVPTC (#18).

-miR-146-5p, miR-221-5p, miR-222-3p, miR-30e-3p, and miR-152-3p could significantly discriminate between benign and malignant lesions (P<0.001). Infiltrative FVPTC have high levels of miR-146-5p, miR-199a-5p, miR-199b-5p, miR-1285-5p, miR-1915-3p, miR-4516, and low miR-148b-3p.

-miR-152-3p, miR-185-5p and miR-574-3p were significantly downregulated in NIFTPs compared with FA, whereas miR-10a-5p and miR-320e can discriminate between NIFTPs and infiltrative FVPTC.

-A panel of these markers could have high diagnostic potential & could be applied to presurgicalindeterminate lesions by FNA.

MOLECULAR DATA OF NIFTP IN FNA

Borrelli N,…, Basolo F. miRNA expression profiling of NIFTP compared with FA and infiltrative FVPTC. Mod Pathol 2017;30:39-51

MOLECULAR TESTS for FNA CYTOLOGY

Encapsulated non invasive FT

AFIP 2014

WHO 2017

0.5-8%

0.6-7.6%

NIFT-P “FORMULA”

Mauro Papotti, Univ Turin

++NI PTC-likeFT = NIFT-P

Growth +Architecture+Cytology=

no papillae

no invasion

Thank you!!

Mauriziano hospital, dr Gianni DeRosa

University of Turin

Medical School

San Luigi hospital

Molinette hospital