Abstract
This review of medical literature examines the criteria for diagnosis of noninvasive follicular thyroid neoplasm with papillarylike nuclear features.
A study from the international multidisciplinary group, published in April 2016, proposed reclassification of a type of low-risk thyroid cancer as noninvasive follicular thyroid neoplasm with papillarylike nuclear features (NIFTP), eliminating the term cancer from the tumor name.1 Since then, the new term has been recommended for use by many professional societies and included as a new thyroid tumor entity in WHO Classification of Tumours of Endocrine Organs from the World Health Organization published in 2017. Over the course of 18 months, more than 80 peer-reviewed publications have reported institutional experience with NIFTP.
Methods
We reviewed English-language publications through PubMed (January 24, 2018), using a keyword search for NIFTP. We focused on large patient cohorts with tumors meeting the diagnostic criteria for NIFTP.
Results
Five studies, all retrospective, reported large series of patients (>70) with NIFTP (Table).2,3,4,5,6 The first 3 studies included 285 patients; they reported no tumor-related adverse events after a mean follow-up ranging from 5.8 to 11.2 years.2,3,4 These series included patients with multifocal and bilateral tumors and those with large tumors (>4 cm), supporting the initial finding of indolent clinical behavior of NIFTP.
Table. Characteristics of Reported Series With More Than 70 NIFTP Cases.
| Source | No. of NIFTP Cases | Tumor Size, cm | Length of Follow-up, y | Adverse Outcomes | Additional Features of the Cohort |
|---|---|---|---|---|---|
| Thompson,2 2016 | 77 | Mean (range), 3.3 (0.7-9.5) | Mean (range), 11.2 (1.2-12.3) | 0 | 51% Multifocal, 14 bilateral |
| Rosario et al,3 2016 | 129 | Median (range), 3.5 (1.1-7.0) | Median (range), 6.0 (1.0-12.2) | 0a | None |
| Xu et al,4 2017 | 79 Selected based on size ≥4 cm | Median (range), 4.5 (4.0-8.0) | Median (range), 5.8 (0.3-26.0) | 0 | Including 25 patients with no RAI treatment and at least 4 y of follow-up |
| Parente et al,5 2018 | 102 | Mean (range), 3.1 (1.1-10.0) | Mean (range), 5.7 | 6 (6%); 5 nodal, 1 distant metastasis b |
None |
| Cho et al,6 2017 | 105 With <1% papillae criterion | Mean (range), 1.3 (0.3-5.0) | Median (range), 3.0 (1.4-8.0) | 4 (4%); 3 nodal,c 1 distant metastasis |
BRAF V600E found in 10 (10%) cases; synchronous papillary microcarcinoma in 19 (18%) cases |
| 95 With 0% papillae criterion | Mean (range), 1.3 (0.3-5.0) | Median (range), 3.0 (1.4-8.0) | 2 (2%); 2 nodal metastasis c |
No BRAF V600E; synchronous papillary microcarcinoma in 18 (19%) cases |
Abbreviations: NIFTP, noninvasive follicular thyroid neoplasm with papillarylike nuclear features; RAI, radioactive iodine.
One case of NIFTP with coexisting papillary microcarcinoma had lymph node metastasis.
Single central-compartment lymph node metastasis in each case; size of metastatic foci and timing of detection (at presentation or on follow-up) not stated.
All micrometastases (<2 mm) in central compartment lymph nodes found at the time of surgery.
However, 2 other studies reported that 4% to 6% of patients with nodules meeting the diagnostic criteria for NIFTP were found to have metastasis.5,6 Many of these tumors had at least some papillary structures identified, revealed BRAF V600E mutation, and showed metastasis to regional lymph nodes and not distant sites. All of these features are characteristics of classic papillary thyroid carcinoma (PTC) and are rarely seen in an invasive encapsulated follicular variant of PTC, which is an invasive counterpart of NIFTP. The initial report that established NIFTP as a preinvasive form of encapsulated follicular variant PTC demonstrated that both tumor types typically harbor RAS or other RAS-like mutations and not BRAF V600E, and if invasion develops, the tumors metastasized to distant sites and not the regional lymph nodes.1 This finding raises a concern that incorrect application of diagnostic criteria for NIFTP can lead to misdiagnosis of classic PTC with prominent follicular pattern as NIFTP.
The initially proposed diagnostic criteria for NIFTP allowed for less than 1% papillae.1 However, the intention of the authors was to accept single rudimentary, hyperplastic-type papillae and not true papillae with well-developed nuclear features seen in classic PTC. In light of the recent publications, it is likely that a broader use of the “less than 1% papillae” criterion can lead to diagnosing tumors with biological and clinical characteristics of classic PTC as NIFTP.
Discussion
Although several studies published since the initial NIFTP report attest to low malignant potential of this tumor, cases of several patients with micrometastasis in regional lymph nodes and tumors apparently meeting the proposed diagnostic criteria for NIFTP have been reported. To avoid misdiagnosing these tumors as NIFTP, we propose to substitute the criterion of “less than 1% papillae” with the criterion of “no well-formed papillae” (Box). Furthermore, we suggest that in addition to a strict requirement for examination of the entire tumor capsule in tumors with pronounced nuclear features of PTC (nuclear score 3),1 examination of the entire tumor should be performed to exclude the presence of papillary structures. This proposal is based on the fact that NIFTP more frequently shows moderately expressed nuclear features of PTC (nuclear score 2) and their overt presence should raise a suspicion for classic PTC. If molecular or immunohistochemical testing demonstrates mutations typical of classic PTC, such as BRAF V600E or other BRAF V600E-like mutations (eg, RET/PTC fusions) or high-risk mutations, such as TERT, this should trigger an exhaustive search for invasive features and papillary formations. A similar approach should be used if BRAF V600E mutation is detected by immunohistochemistry.
Box. Revised Diagnostic Criteria for NIFTP.
Primary
Encapsulation or clear demarcationa
-
Follicular growth pattern with:
No well-formed papillae
No psammoma bodies
<30% solid/trabecular/insular growth pattern
Nuclear score 2-3b
No vascular or capsular invasionc
No tumor necrosis or high mitotic activityd
Secondarye
Lack of BRAF V600E mutation detected by molecular assays or immunohistochemistry
Lack of BRAF V600E-like mutations or other high-risk mutations (TERT, TP53)
Footnotes
Abbreviation: NIFTP, noninvasive follicular thyroid neoplasm with papillarylike nuclear features.
Thick, thin, or partial capsule or well circumscribed with a clear demarcation from adjacent thyroid parenchyma.
Typically nuclear score 2 (moderately expressed nuclear features of papillary thyroid carcinoma). In tumors with florid nuclear features of papillary thyroid carcinoma (nuclear score 3), the entire tumor should be examined to exclude the presence of papillae. Molecular testing for BRAF V600E and other mutations or immunohistochemistry for BRAF V600E is advisable but not required for tumors with nuclear score 3.
Requires microscopic examination of the entire tumor capsule interface.
High mitotic activity, defined as 3 or more mitoses per 10 high-power fields (×400).
Secondary criteria are helpful but not required for NIFTP diagnosis.
References
- 1.Nikiforov YE, Seethala RR, Tallini G, et al. . Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2(8):1023-1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Thompson LD. Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma: a name change to noninvasive follicular thyroid neoplasm with papillary-like nuclear features would help prevent overtreatment. Mod Pathol. 2016;29(7):698-707. [DOI] [PubMed] [Google Scholar]
- 3.Rosario PW, Mourão GF, Nunes MB, Nunes MS, Calsolari MR. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Endocr Relat Cancer. 2016;23(12):893-897. [DOI] [PubMed] [Google Scholar]
- 4.Xu B, Tallini G, Scognamiglio T, Roman BR, Tuttle RM, Ghossein RA. Outcome of large noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Thyroid. 2017;27(4):512-517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Parente DN, Kluijfhout WP, Bongers PJ, et al. . Clinical safety of renaming encapsulated follicular variant of papillary thyroid carcinoma: is NIFTP truly benign? World J Surg. 2018;42(2):321-326. [DOI] [PubMed] [Google Scholar]
- 6.Cho U, Mete O, Kim MH, Bae JS, Jung CK. Molecular correlates and rate of lymph node metastasis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features and invasive follicular variant papillary thyroid carcinoma: the impact of rigid criteria to distinguish non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Mod Pathol. 2017;30(6):810-825. [DOI] [PubMed] [Google Scholar]