Thyroid gland
Papillary carcinoma
Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

Authors: Rachel Jug, M.D., David Poller, M.D., Xiaoyin "Sara" Jiang, M.D. (see Authors page)
Editorial Board Member Review: Andrey Bychkov, M.D., Ph.D.

Revised: 10 May 2018, last major update April 2018

Copyright: (c) 2016-2017, PathologyOutlines.com, Inc.

PubMed Search: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features
Cite this page: Jug, R., Poller, D., Jiang, X. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/thyroidglandNIFTP.html. Accessed October 22nd, 2018.
Definition / general
  • Formerly known as "noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC)"
  • Suggested to rename lesion to NIFTP based on international, multicenter consensus study showing evidence for indolent biological behavior (lack of metastasis or recurrence) (Mod Pathol 2016;29:698)
  • Discrepancies commonly affecting nuclear feature evaluation were simplified and criteria were established (see Microscopic (histologic) description below) to provide reproducible standards for separating NIFTP from benign hyperplastic nodules and follicular adenoma morphologically with an overall classification accuracy of 94.3% (JAMA Oncol 2016;2:1023)
Essential features
  • Encapsulated / circumscribed neoplasm with follicular growth pattern and nuclear features of papillary thyroid carcinoma
  • Diagnosis of NIFTP requires surgical excision specimen with complete evaluation of tumor to normal interface to exclude capsular invasion
  • Most commonly associated molecular alterations are RAS mutations
  • Indolent disease course with excellent long term survival (following surgical excision; lobectomy / partial thyroidectomy sufficient)
Epidemiology
Pathophysiology
  • NIFTP is considered a borderline RAS lineage tumor between follicular adenoma and follicular carcinoma or invasive EFVPTC
Diagrams / tables

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Contributed by David Poller, M.D.:

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Mutations in various types of thyroid tumors

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Putative molecular pathogenesis of thyroid tumors

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Indeterminate cytological diagnosis



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NIFTP incidence

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Nuclear score

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Diagnostic algorithm

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History of NIFTP

Diagnosis
Pathologic diagnostic criteria:
  • Inclusion criteria
    • Major features:
      • Encapsulation or clear demarcation
      • Follicular growth pattern with less than 1% papillae (see comment below)
      • If solid, trabecular or insular patterns seen; these in total should be less than 30% of the total tumor volume
      • No psammoma bodies
      • Nuclear features of papillary thyroid carcinoma (enlargement, crowding / overlapping, elongation, irregular contours, grooves, pseudoinclusions, chromatin clearing), nuclear score should be 2 or 3
    • Minor features:
      • Dark colloid
      • Irregularly shaped follicle
      • "Sprinkling sign"
      • Follicles cleft from stroma
      • Multinucleated giant cells within follicles
  • Exclusion criteria:
    • Any capsular or vascular invasion but if the whole capsule has not been examined thoroughly then the default diagnosis is still noninvasive encapsulated FVPTC (EFVPTC) and it is NOT a NIFTP
    • True papillary structures in more than 1% of tumor volume, psammoma bodies, infiltrative border
    • Tumor necrosis (not associated with FNA), increased mitoses (defined as at least 3 per 10 HPF)
    • Cell / morphological characteristics of any other papillary thyroid carcinoma variant (e.g., tall cell, columnar cell, cribriform morular, diffuse sclerosing, etc.) or oncocytic lesion (JAMA Oncol 2016;2:1023)
  • Additional exclusion criteria (2017, Hum Pathol 2018 Jan 12 [Epub ahead of print], Pathol Int 2018 Apr 19 [Epub ahead of print])
    • No papillae
    • No BRAFV600E and TERT promoter mutations
    • No distant metastasis
  • Diagnosis of NIFTP is possible only on surgical samples because it requires careful capsule evaluation
  • No reliable preoperative modalities (sonography, fine needle aspiration cytology (FNAC), molecular testing) are available at this time
Radiology description
  • Wider than tall shape, smooth borders, occurrence in multinodular glands and no calcifications (Diagn Cytopathol 2018;46:139)
  • Perinodular and intranodular Doppler flow patterns, minimal Doppler flow grade
  • Similar to follicular adenoma and minimally invasive follicular carcinoma (Diagn Cytopathol 2017;45:533)
Radiology images

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Ultrasonography

Prognostic factors
  • Excellent, based on an international, multidisciplinary, retrospective study in which all 109 participants with noninvasive follicular variant of papillary thyroid carcinoma (EFVPTC) were alive with no evidence of disease at a median followup time of 13 years (JAMA Oncol 2016;2:1023, Mod Pathol 2016;29:698)
Case reports
Treatment
Gross description
Gross images

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Gross and histology of EFVPTC
Reference

Microscopic (histologic) description
  • Nuclear features of papillary thyroid carcinoma present
    • Each category is assigned a score of 0 or 1, resulting in an overall score between 0 - 3, where a total of 0 - 1 is not diagnostic of NIFTP and 2 - 3 is diagnostic of NIFTP
    • Size and shape: nuclear enlargement, overlapping, crowding, elongation
    • Nuclear membrane irregularities: irregular contours, grooves, pseudoinclusions
    • Chromatin characteristics: clearing with margination, glassy nuclei
  • Fibrous capsule may be thick, thin, partial or the lesion may be well circumscribed / clearly demarcated from adjacent thyroid tissue
  • Follicular growth pattern may be microfollicular, normofollicular or macrofollicular with abundant colloid (JAMA Oncol 2016;2:1023)
Microscopic (histologic) images
Scroll to see all images.

Images hosted on PathOut server:

Contributed by Andrey Bychkov, M.D., Ph.D.:

Circumscribed follicular patterned nodule

Tumor interface with a thin capsule

Microfollicular pattern

Major and minor diagnostic features

Dark colloid with scalloping and clefting

Free floating tumor fragment in vessel


Small piece of tumor floats in vascular lumen

Processing artifact with distorted nuclei

Distorted nuclei due to artifact

Vesicular-like
nuclei due to
tissue degeneration



Contributed by Rachel Jug, M.D.:

Low power (2×) H&E images demonstrating clear circumscription of the encapsulated lesion with a predominantly follicular growth pattern


High power (40×) H&E images demonstrating nuclear features of PTC



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Noninvasive follicular thyroid neoplasm

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Low power

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Medium power

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5.6 cm NIFTP


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High power

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NIFTP vs HCC


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NIFTP vs PDTC

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NIFTP vs FTC

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NIFTP vs FVPTC

Encapsulated follicular patterned lesion


Nuclear features

Virtual slides

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Various NIFTP virtual
slides, contributed by
the NIFTP consortium

Cytology description
  • FNAC samples are usually hypercellular with neoplastic cells possibly with focal nuclear features of papillary thyroid carcinoma arranged in microfollicles
  • Nuclear features are subtler than those of conventional papillary thyroid carcinoma; nuclear inclusions are very infrequent or absent as compared with classical type papillary carcinoma and papillae are absent
  • Colloid may be present
  • Cannot distinguish invasive encapsulated follicular variant of papillary thyroid carcinoma from NIFTP on cytology because the capsule cannot be evaluated by FNA; however NIFTP has few intranuclear inclusions and does not normally show papillae on FNA
  • Most NIFTP cases are clustered within the categories follicular neoplasm (FN) / suspicious for follicular (SFN), atypia of unknown significance (AUS) / follicular lesion of unknown significance (FLUS) and suspicious for malignancy
  • In case of cytologic features suggestive of FVPTC / NIFTP, optional notes in cytologic diagnosis may be used to acknowledge NIFTP: "Although the architectural features suggest a follicular neoplasm (or another Dx category), some nuclear features raise the possibility of an invasive FVPTC or its recently described indolent counterpart, NIFTP; definitive distinction among these entities is not possible on cytologic material" (Thyroid 2017;27:1341)
  • References: Cancer Cytopathol 2016;124:181, Hum Pathol 2016;54:134, Am J Clin Pathol 2015;144:850, Cancer 2016;124:699
Cytology images

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Microfollicular pattern, nuclear enlargement

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Microfolliclar pattern

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Microfollicles, nuclear grooves

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Enlarged nuclei

Molecular / cytogenetics description
Videos

Nomenclature change for thyroid tumors: NIFTP (2017) by Prof. Yuri Nikiforov, University of Pittsburg

Board review question #1
    Which of the following mutations is most commonly associated with NIFTP?

  1. BRAF V600E
  2. PAX8 / PPAR gamma rearrangement
  3. PIK3CA
  4. RAS family
  5. TERT promoter
Board review answer #1
D. RAS family

NIFTP shares molecular alterations similar to those seen in follicular lesions (follicular adenoma and follicular carcinoma).
Board review question #2
    Which of the following features differentiates a PTC from a NIFTP?

  1. Follicular growth pattern
  2. Nuclear elongation
  3. Nuclear grooves
  4. Thick colloid
  5. True papillae
Board review answer #2
E. True papillae

The presence of any true papillae is an exclusion criteria for making a diagnosis of NIFTP. Other exclusion criteria include capsular invasion, increased mitotic rate and tumor necrosis.