Thyroid & parathyroid
Low risk thyroid tumors
NIFTP
Editorial Board Member: Andrey Bychkov, M.D., Ph.D.
Last author update: 10 May 2018
Last staff update: 19 February 2024
Copyright: 2016-2024, PathologyOutlines.com, Inc.
PubMed Search: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features
Table of Contents
Definition / general | Essential features | Epidemiology | Pathophysiology | Diagrams / tables | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Molecular / cytogenetics description | Videos | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Jug R, Poller D, Jiang X. NIFTP. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/thyroidglandNIFTP.html. Accessed April 26th, 2024.
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
- Prevalence is 9.1% of all papillary thyroid cancers worldwide (although NIFTP should now be considered a noncancer) based on meta-analysis (Endocr Pathol 2018 Feb 23 [Epub ahead of print])
- Very rare in Asian population (1.6%) compared with Western series (13.3%)
- Due to various perceptions of histological diagnostic thresholds, different nature of papillary thyroid carcinoma and different approaches in the management of thyroid nodules (Endocr Pathol 2018 Feb 23 [Epub ahead of print])
- Occasionally reported in pediatric population (Cancer Cytopathol 2018;126:27, Pediatr Blood Cancer 2018;65:e26966)
Pathophysiology
- NIFTP is considered a borderline RAS lineage tumor between follicular adenoma and follicular carcinoma or invasive EFVPTC
Diagrams / tables
Contributed by David Poller, M.D.
Mutations in various types of thyroid tumors
Putative molecular pathogenesis of thyroid tumors
Indeterminate cytological diagnosis
Images hosted on other servers:
NIFTP incidence
Diagnostic algorithm
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
- Major features:
- 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
Images hosted on other servers:
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
- 37 year old woman with NIFTP showing focal spindle cell metaplasia (Int J Surg Pathol 2018;26:261)
- 76 year old woman with NIFTP and spindle cell metaplasia (Pathol Res Pract 2017;213:416)
Treatment
- It is believed that tumor excision is sufficient; no extended surgery (total / completion thyroidectomy, neck dissection), radioiodine ablation and thyroid stimulating hormone (TSH) suppression therapy needed (Endocr Pract 2017 Jul 13 [Epub ahead of print], Endocr Pract 2017;23:1150)
Gross description
- Well circumscribed, encapsulated, solid nodules (Head Neck Pathol 2011;5:51)
- Average size is 2 - 3 cm; can vary from subcentimeter (Endocrine 2018;59:143) up to 8 cm (Thyroid 2017;27:512)
Gross images
Images hosted on other servers:
Gross and histology of EFVPTC
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
Contributed by Andrey Bychkov, M.D., Ph.D. and Rachel Jug, M.B.B.Ch.
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
Clear circumscription of the encapsulated lesion with a predominantly follicular growth pattern
Clear circumscription of the encapsulated lesion with a predominantly follicular growth pattern
Nuclear features of PTC
Images hosted on other servers:
Noninvasive follicular thyroid neoplasm
Low power
Medium power
5.6 cm NIFTP
High power
NIFTP vs HCC
NIFTP vs PDTC
NIFTP vs FTC
NIFTP vs FVPTC
Encapsulated follicular patterned lesion
Nuclear features
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
Images hosted on other servers:
Microfollicular pattern, nuclear enlargement
Microfolliclar pattern
Microfollicles, nuclear grooves
Enlarged nuclei
Molecular / cytogenetics description
- Shares molecular features (RAS mutations) with follicular adenoma, follicular carcinoma and do not show BRAFV600E mutations, which is a useful diagnostic feature (Mod Pathol 2010;23:1191, Histopathology 2015;67:579)
Videos
Nomenclature change for thyroid tumors: NIFTP (2017) by Prof. Yuri Nikiforov, University of Pittsburg
NIFTP by R. Ghossein (2020)
Diagnostic dilemmas in NIFTP by N. Cipriani (2020)
Additional references
- Synopsis for pathologists: Mod Pathol 2018;31:39, Histopathology 2018;72:53
- Endocr Pathol 2015;26:191, Wikipedia: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features [Accessed 25 April 2018], Diagnostic Histopathology 2016;22:171
- Articles for pathologists: J Clin Pathol 2016;69:947, J Clin Endocrinol Metab 2016;102:15
- Articles for cytopathologists: Cancer Cytopathol 2016;124:616, Cancer 2016;124:767
- Articles for clinicians: Thyroid 2016;26:869
Board review style question #1
- Which of the following mutations is most commonly associated with NIFTP?
- BRAFV600E
- PAX8 / PPAR gamma rearrangement
- PIK3CA
- RAS family
- TERT promoter
Board review style answer #1
D. RAS family. NIFTP shares molecular alterations similar to those seen in follicular lesions (follicular adenoma and follicular carcinoma).
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Board review style question #2
- Which of the following features differentiates a PTC from a NIFTP?
- Follicular growth pattern
- Nuclear elongation
- Nuclear grooves
- Thick colloid
- True papillae
Board review style answer #2
E. True papillae. The presence of any true papillae is an exclusion criterion for making a diagnosis of NIFTP. Other exclusion criteria include capsular invasion, increased mitotic rate and tumor necrosis.
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