Cytopathology In Focus: The significance of NIFTP for thyroid cytology

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• Nuclear size and shape (enlargement, overlapping, elongation).
• Nuclear membrane irregularities (irregular contours, grooves, pseudoinclusions).
• Chromatin characteristics (clearing with margination/glassy nuclei).

Each nuclear feature is scored as present (1) or absent (0), so if two or three are present, the tumor has nuclear features of NIFTP; if zero or one, it is a follicular neoplasm.

Can I make the diagnosis on cytology?

Cytologists will quickly recognize that several of the preceding diagnostic criteria can be assessed only on surgical specimens. It is therefore not possible to make a definitive diagnosis of NIFTP cytologically. Already, several studies have evaluated the cytologic interpretations that precede a surgical diagnosis of NIFTP, and they have shown that NIFTP can be found in every category of the Bethesda System for Reporting Thyroid Cytopathology. The vast majority, however, are classified in the indeterminate categories: atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), and suspicious for malignancy (SFM).^4,5

This fits with the limited available literature on cytologic features of NIFTP, which typically finds overlapping follicular groups of cells rather than features associated with papillary architecture (for example, true papillae, branching groups, caps, or psammoma bodies) and nuclei that have some but not all of the nuclear features of PTC. In particular, intranuclear pseudoinclusions are absent or rare in the vast majority of cases of NIFTP. So while a diagnosis of NIFTP cannot be made cytologically, there does appear to be a constellation of cytologic features that raise its consideration.^6-9

There is no consensus at present as to what Bethesda category to assign to a lesion in which NIFTP is suspected. Depending on the degree of nuclear and architectural changes, AUS/FLUS, FN/SFN, or SFM may be appropriate, perhaps with a comment noting the pathologist’s consideration of the NIFTP diagnosis. As total thyroidectomy is considered unnecessary for NIFTP, an attempt should be made to avoid using the malignant category for cases with these features. A commentary by Krane, et al., published last year provides a more in-depth discussion of the cytologic interpretation of a possible NIFTP.¹⁰

Can I still make a diagnosis of papillary carcinoma on cytology?

Yes. Retrospective studies have suggested that even with no changes to diagnostic criteria for PTC, the risk of malignancy for the PTC category would shift only slightly, from 99 percent to 96 percent in the largest such study.⁴ With only minor common-sense adjustments to one’s diagnostic thresholds (such as requiring evidence of papillary architecture, or more than rare pseudoinclusions, before making a definitive diagnosis of PTC), the changes in performance characteristics of the malignant category and frequency of its use should be minimal.

What happens to the Bethesda System?

While revisions to the Bethesda System for Reporting Thyroid Cytopathology are underway, they are unlikely to incorporate major categorical changes in response to NIFTP, based on the limited literature to date. However, the risk of malignancy associated with the various categories is likely to shift significantly. The impact will be greatest for the indeterminate categories. In the largest study of this effect, among cases that underwent surgery, the risk of malignancy for AUS/FLUS decreased from 31 percent to 18 percent, FN/SFN decreased from 33 percent to 18 percent, and SFM decreased from 83 percent to 59 percent.4 The change had a much smaller effect on the other Bethesda categories: The risk of malignancy for non-diagnostic decreased from 25 percent to 24 percent, that for benign decreased from nine percent to six percent, and that for malignant decreased from 99 percent to 96 percent.

The appropriate management for some categories may need to be re-evaluated in light of these shifts. In particular, the practice among some surgeons of conducting total thyroidectomy for the SFM category may be excessively aggressive for a category with only a 59 percent risk of malignancy. Because of this it may be worth notifying pertinent clinical teams of the reduced risk of malignancy for the SFM category given the new diagnostic landscape with NIFTP.

What happens with molecular testing?

Many clinicians have begun to request molecular testing in an attempt to better define appropriate management of indefinite thyroid FNAs. The change in terminology will affect the reported performance characteristics of most commercially available tests. The risk of malignancy associated with the BRAF V600E mutation should be unaffected, as this mutation appears to be specific to classic and tall cell variants of PTC and is absent in NIFTP. The commercially available gene expression classifier (GEC) type tests included NIFTP in their training sets as malignant and so would be expected to yield an abnormal result for NIFTP. The reclassification of NIFTP can therefore be expected to reduce the specificity and positive predictive value of the test for malignancy, without affecting sensitivity or negative predictive value. The overall effect on the mutation-based panels will be similar; however, the effect on performance of the individual genes reported will be more complicated, with significant reduction in the risk of malignancy associated with some genes, such as RAS, but no change in others, such as BRAF V600E. Since the current recommendation for NIFTP is hemithyroidectomy, the usefulness of molecular testing for indicating who requires surgery versus clinical follow-up may not be affected substantially.

Should I go back and reclassify all my old thyroid surgical pathology diagnoses?

Probably not. As most patients will have already received definitive treatment of their NIFTP, reclassification is unlikely to have an impact on their management going forward. For patients very recently diagnosed as noninvasive follicular variant PTC, discussion with the treating physicians about reclassification and management options for the patient may be appropriate. Our opinion is that patients were accurately diagnosed within the constructs of the time and that applying new or novel principles to prior diagnoses is not a worthwhile endeavor.

My clinicians have questions. What should I discuss with them?

Many aspects of the reclassification are important to clinicians, and they are likely to be receiving guidance from their professional societies and publications. Some of the most important points to share with your clinicians include the following:

• Most noninvasive FVPTCs have been reclassified as NIFTP. Recommended management for NIFTP is hemithyroidectomy alone.
• NIFTP cannot be diagnosed on cytology but can be suggested in some cases. The lesion will usually be classified as AUS/FLUS, FN/SFN, or SFM.
• The risk of malignancy for a malignant category diagnosis remains very high. The risk of malignancy for indefinite diagnoses will be substantially lower. Thought should be given to management alterations for these categories.
• The performance characteristics of molecular testing will also be altered substantially.

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.
2. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA. 2006;295(18):2164–2167.
3. Ahn HS, Kim HJ, Welch HG. Korea’s thyroid-cancer “epidemic”—screening and overdiagnosis. N Engl J Med. 2014;371(19):1765–1767.
4. Faquin WC, Wong LQ, Afrogheh AH, et al. Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thyroid Cytopathology. Cancer Cytopathol. 2016;124(3):181–187.
5. Strickland KC, Howitt BE, Marqusee E, et al. The impact of noninvasive follicular variant of papillary thyroid carcinoma on rates of malignancy for fine-needle aspiration diagnostic categories. Thyroid. 2015;25(9):987–992.
6. Maletta F, Massa F, Torregrossa L, et al. Cytological features of “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” and their correlation with tumor histology. Hum Pathol. 2016;54:134–142.
7. Howitt BE, Chang S, Eszlinger M, et al. Fine-needle aspiration diagnoses of noninvasive follicular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2015;144(6):850–857.
8. Strickland KC, Vivero M, Jo VY, et al. Preoperative cytologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a prospective analysis. Thyroid. 2016;26(10):1466–1471.
9. Bizzarro T, Martini M, Capodimonti S, et al. Young investigator challenge: the morphologic analysis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on liquid-based cytology: some insights into their identification. Cancer. 2016;124(10):699–710.
10. Krane JF, Alexander EK, Cibas ES, Barletta JA. Coming to terms with NIFTP: a provisional approach for cytologists. Cancer. 2016;124(11):767–772.

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Dr. Staats, an associate professor and director of the cytopathology service, University of Maryland School of Medicine, Baltimore, is a member of the CAP Cytopathology Committee. Dr. Witt, vice chair of the committee, is medical director of cytopathology, ARUP Laboratories, and an assistant professor, University of Utah Health Sciences Center, Salt Lake City.