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The ATA Guidelines on Management of Thyroid Nodules and Differentiated

Thyroid Cancer Task Force Review and Recommendation on the Proposed
Renaming of eFVPTC without Invasion to NI...

Article  in  Thyroid · January 2017

DOI: 10.1089/thy.2016.0628

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es on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion to NIFTP (doi: 10.10
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© Mary Ann Liebert, Inc.
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The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion

The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid

Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC
This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

without Invasion to NIFTP

Bryan R. Haugen, M.D.1 (Chair), Anna M. Sawka, M.D., Ph.D.2, Erik K. Alexander,
M.D.3, Keith C. Bible, M.D., Ph.D.4, Patrizio Caturegli, M.D.5, M.P.H., Gerard M. Doherty,
M.D.6, Susan J. Mandel, M.D., M.P.H.7, John C. Morris, M.D.4, Aziza Nassar, M.D.8, Furio
Pacini, M.D.9, Martin Schlumberger, M.D.10, Kathryn Schuff, M.D.11, Steven I. Sherman,
M.D.12, Hilary Somerset, M.D.1, Julie Ann Sosa, M.D.13, David L. Steward, M.D.,14 Leonard
Wartofsky, M.D.15, and Michelle D. Williams, M.D.12

1
University of Colorado School of Medicine, Aurora, Colorado.

2
University Health Network, University of Toronto, Toronto, Canada.
to NIFTP (doi: 10.1089/thy.2016.0628)

3
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting

4
The Mayo Clinic, Rochester, Minnesota.
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5
Johns Hopkins University School of Medicine, Baltimore, Maryland.

6
Boston Medical Center, Boston, Massachusetts.

7
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

8
The Mayo Clinic, Jacksonville, Florida

9
The University of Siena, Siena, Italy.

10
Institute Gustave Roussy and University Paris Sud, Villejuif, France.

11
Oregon Health and Science University, Portland, Oregon.

12
University of Texas M.D. Anderson Cancer Center, Houston, Texas.

13
Duke University School of Medicine, Durham, North Carolina.

14
University of Cincinnati Medical Center, Cincinnati, Ohio.

15
MedStar Washington Hospital Center, Washington, DC.

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 Thyroid
es on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion to NIFTP (doi: 10.10
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This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion
to NIFTP (doi: 10.1089/thy.2016.0628)
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Running title: ATA Recommendation on NIFTP

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The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion

Abstract
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American Thyroid Association (ATA) leadership asked the ATA Thyroid Nodules and

Differentiated Thyroid Cancer Guidelines Task Force to review, comment on and make

recommendations related to the suggested new classification of Encapsulated Follicular Variant

Papillary Thyroid Carcinoma (eFVPTC) without capsular or vascular invasion to noninvasive

follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The task force consists

of members from the 2015 guidelines task force with the recusal of three members who were

authors on the paper under review. Four pathologists and one endocrinologist were added for

this specific review. We assessed the manuscript proposing the new classification and related
to NIFTP (doi: 10.1089/thy.2016.0628)

literature. We recommend that the histopathologic nomenclature for Encapsulated Follicular

Variant Papillary Thyroid Carcinoma (eFVPTC) without invasion may be re-classified as a

This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting
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NIFTP given the excellent prognosis of this neoplastic variant. This is a weak recommendation
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based on moderate-quality evidence. We also note that retrospective studies are needed to

validate the observed patient outcomes (and test performance in predicting thyroid cancer

outcomes), as well as implications on patients’ psychosocial health and economics.

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The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion

This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

American Thyroid Association (ATA) leadership asked the ATA Thyroid Nodules and

Differentiated Thyroid Cancer Guidelines Task Force to review, comment on and make

recommendations related to the suggested new classification of Encapsulated Follicular Variant

Papillary Thyroid Carcinoma (eFVPTC) without capsular or vascular invasion to noninvasive

follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) [1]. The task force

consists of members from the 2015 guidelines task force with the recusal of three members who

were authors on the paper under review. Four pathologists and one endocrinologist were added

for this specific review.

to NIFTP (doi: 10.1089/thy.2016.0628)

ATA Task Force Recommendation statement: The histopathologic nomenclature for

This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting
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Encapsulated Follicular Variant Papillary Thyroid Carcinoma (eFVPTC) without invasion may
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be re-classified as a NIFTP given the excellent prognosis of this neoplastic variant. Prospective

studies are needed to validate the observed patient outcomes (and test performance in predicting

thyroid cancer outcomes), as well as implications on patients’ psychosocial health and

economics. (Weak Recommendation, Moderate-quality evidence).

It is important to highlight that the proposed change is in our view primarily semantic in nature,

and intended to change nomenclature for this low-risk neoplasm that is more accessible,

reassuring and understandable to non-experts and patients. The proposed reclassification should

not be interpreted as indicative of a changed risk profile of an inherently low-risk neoplasm, nor

supporting a non-surgical approach to these neoplasms, as accurate preoperative identification of

NIFTP has not yet been demonstrated. Furthermore, the proposed change to NIFTP does not, in

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The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion

our opinion, affect recommendations in the 2015 ATA Management Guidelines for Adult
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Patients with Thyroid Nodules and Differentiated Thyroid Cancer [2] as discussed below.

Scientific study

As a primary scientific study, the authors retrospectively collected pathology slides from 268

patients at 13 institutions with eFVTPC [1]. The patients were divided into eFVPTC without

tumor capsule or vascular invasion (n=138) or with invasion (n=130). Ultimately, there was

consensus by >50% of pathologists for 109 surgical pathology specimens without invasion and
to NIFTP (doi: 10.1089/thy.2016.0628)

101 with invasion. Those without invasion needed to have clinical follow-up for at least 10
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years (median 13 years, range 10-26 years). Another criterion for inclusion was that none of the
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patients without tumor capsule invasion could have received therapeutic radioiodine. This was a
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retrospective 2-arm comparative study (analogous to case-control study) design to compare

noninvasive eFVPTC not treated with RAI (61% had lobectomy only) with invasive eFVPTC

(86% thyroidectomy, 80% radioiodine). The patients were selected on retrospective review of

pathology records from 13 different institutions, but it is not clear that all consecutive or random

patients meeting eligibility criteria were selected, which raises concern for selection bias.

The authors found that all of the patients with noninvasive eFVPTC were alive without evidence

of disease or a recurrence after the median 13 year follow-up, although the specific follow-up

criteria to determine disease-free status was not fully defined. Conversely, of the 101 patients

with invasive eFVPTC, 12 had noted ‘adverse events’ (7 with persistent/recurrent disease, 5 with

biochemical evidence of disease), 5 had distant metastases, and there were 2 deaths attributed to

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The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion

thyroid cancer despite a shorter median (3.5 years) follow-up. There was no formal statistical
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comparison of adverse events in the invasive vs. noninvasive eFVPTC groups, which is a minor

methodologic concern.

The authors further noted in the discussion: “In the English language literature, only 2 (0.6%) of

352 well-documented noninvasive encapsulated/well-circumscribed FVPTCs recurred.” A

recent retrospective surgical review of 77 patients with NIFTP in a large community-based

health system showed no structural or biochemical recurrences after a median FU of 11.8 years

(range 1.2-1.2 years), despite most patients having only thyroidectomy or lobectomy [3]. Some
to NIFTP (doi: 10.1089/thy.2016.0628)

of the patients in this study were also in the current study under review [1]. This overall
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summary of multiple non-randomized studies together with the data presented in the article
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under review is felt to be moderate-quality evidence that noninvasive eFVPTC is a very low risk
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neoplasm, and the name change to NIFTP is reasonable. There are, however, some limitations

causing minor to moderate concern about internal validity of the results, leading to a weak

recommendation for the name change.

The 2015 ATA Management Guidelines for Adult Patients with Thyroid Nodules and

Differentiated Thyroid Cancer devotes section B15 and Recommendation 46 (pp 37-40) to the

basic principles of histopathologic evaluation of thyroidectomy samples [2]. It is noted in

Recommendation 46B that “Histopathologic variants of thyroid carcinoma with

more…..favorable outcomes (e.g., encapsulated follicular variant of PTC without invasion…)

should be identified during histopathologic examination and reported.” The discussion further

highlights that “A completely excised noninvasive encapsulated follicular variant of papillary

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The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion

carcinoma is expected to have a very low risk of recurrence or extrathyroidal spread, even in
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patients treated by lobectomy.” Even before this proposed name change to NIFTP, the

guidelines have classified eFVPTC without invasion as a low risk neoplasm that can be treated

with lobectomy alone. Therefore, this new study does not significantly change the 2015

guidelines, other than the proposed name change.

Position paper

As a position paper, the authors were justifiably concerned that patients with eFVPTC, and in
to NIFTP (doi: 10.1089/thy.2016.0628)

particular the noninvasive subtype, were classified and at times treated similarly to patients with

classical PTC, and that these patients carried the stigma of a ‘cancer’ diagnosis. Based on their
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting
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own analysis of 109 patients, described in the paragraphs above, and their review of the
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literature, the authors propose that this neoplasm with very low potential for recurrence after

surgery alone (lobectomy or thyroidectomy), should be reclassified as a non-cancer. They

propose the name NIFTP in order to incorporate the etiology as a follicular thyroid neoplasm,

excluding the term carcinoma, and retain the morphologic description papillary-like nuclear

features, highlighting the potential overlap with classical nuclear grooves and pseudo-inclusions

which have historically been suspicious or diagnostic for PTC.

We feel that this is a reasonable suggestion of name change; however, it is important to have

additional studies to further explore the prevalence of this neoplasm subtype based on the strict

pathologic criteria, as well as studies that determine the interobserver variability of this surgical

pathology diagnosis. This proposed name change may affect how pathologists evaluate and

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The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion

report this subset of thyroid neoplasms. For example, examination of the entire capsule will now
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be required to rule out any foci of invasion (just as is the current standard of practice for

encapsulated follicular lesions). In addition, the strict diagnostic criteria will likely mandate

histologic examination of the entire lesion to ensure absence of any exclusionary criteria such as

psammoma bodies or >1% papillae. Finally, this name change presents obvious challenges for

cytology, since NIFTP is a surgical diagnosis and requires architecture for the assessment of

invasion. It follows, therefore, that there will be a small increase in false positives in the

malignant category of The Bethesda System and a modest decrease in the risk of malignancy for

the indeterminate subcategories [4-6]. The proposed name change will also affect the
to NIFTP (doi: 10.1089/thy.2016.0628)

performance of molecular tests when applied to patients with indeterminate cytology. For
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example, neoplasms harboring RAS mutations, will likely have a lower positive predictive value
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for malignancy, while nodules with no genetic mutation or a negative gene expression classifier
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will likely have a slightly higher negative predictive value. These effects will be dependent on

the prevalence of NIFTP in a given population. Since NIFTP, like follicular adenoma, requires

surgery for a definitive diagnosis, the changes in PPV and NPV of the molecular tests will not

alter the requirement of surgical intervention for these patients. Potential frameworks for

addressing cytology and molecular reporting are still evolving.

It is also unclear how these patients should be monitored. Based on the low risk for recurrence

DTC recommendations in the 2015 ATA guidelines (lobectomy sufficient – Recommendation

38A and 51B, remnant ablation not recommended – Recommendation 38B, TSH target 0.5-2

mU/L – Recommendation 59C and 59E), these general recommendations would not be different

for patients with tumors classified as NIFTP. AJCC/TNM staging would no longer be necessary.

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The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion
to NIFTP (doi: 10.1089/thy.2016.0628)
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Page 9 of 10

based upon available evidence.

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Until more long-term follow-up data are available, occasional monitoring with serum

mandatory. The length of time between follow-up evaluations in NIFTP is also not yet defined
thyroglobulin and neck ultrasound can be considered depending upon patient context, but is not
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The ATA Guidelines on Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of eFVPTC without Invasion

References
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