Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is rare, benign lesion using modified stringent diagnostic criteria: Reclassification and outcome study

Journal Pre-proof Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is rare, benign lesion using modified stringent diagnostic criteria: Reclassification and outcome study

David Cubero Rego, Hwajeong Lee, Anne Boguniewicz, Timothy A. Jennings PII:

S1092-9134(19)30368-5

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https://doi.org/10.1016/j.anndiagpath.2019.151439

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YADPA 151439

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Please cite this article as: D.C. Rego, H. Lee, A. Boguniewicz, et al., Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is rare, benign lesion using modified stringent diagnostic criteria: Reclassification and outcome study, (2019), https://doi.org/10.1016/j.anndiagpath.2019.151439

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Journal Pre-proof Title: Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) is rare, benign lesion using modified stringent diagnostic criteria: reclassification and outcome study

Authors: David Cubero Regoa, Hwajeong Leea, Anne Boguniewicza, Timothy A. Jenningsa Anatomic Pathology, Albany Medical College, Albany, NY 12208, USA.

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Electronic address: [email protected]

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Corresponding author: David Cubero Rego

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Declaration of competing interest: None to declare.

Journal Pre-proof Abstract Background: Rigid diagnostic criteria for NIFTP have been recently proposed. The frequency of NIFTP using the new criteria is unknown, and whether abortive papillae are associated with BRAFV600E mutation has not been studied. The aim of this study is to identify NIFTP by a retrospective review of Follicular Variant of Papillary Thyroid Carcinoma (FVPTC), and to study its incidence as well as the association between immunohistochemical BRAFV600E expression and abortive papillae in NIFTP.

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Design: Thyroid tumors diagnosed as FVPTC or NIFTP over a period of 18 years (2000 – 2017) were identified using the laboratory information system. The final pathology reports

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were reviewed and potential NIFTP were retrieved. The archived slides for these cases were

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independently reviewed by 2 pathologists. BRAFV600E (clone: VE1) immunostain was

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performed on representative tumor blocks. Clinical information including follow-up data was obtained from the electronic medical records. Results: Among the 1918 cases with the

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diagnosis of papillary thyroid carcinoma (PTC), 589 (30.7%) of FVPTC and 136 cases of

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potential NIFTP were identified. After the review of the archived pathology slides, 29 lesions were morphologically reclassified as NIFTP. Four (13.7 %) of these were positive for

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BRAFV600E; no association was found between the presence of abortive papillae and BRAFV600Eexpression (p=0.3). Exclusion of the 4 cases with BRAFV600Eexpression resulted in 25 lesions of final NIFTP, representing 4.2 % of the FVPTC and 1.3 % of the PTC. The mean age of the NIFTP patients was 50 years, 87.5 % were females. The mean size of the lesions was 1.4 cm (0.1-4.0 cm). Intranuclear pseudoinclusions were not identified, and abortive papillae were identified in 60% of NIFTP. The average follow-up was 70 (28-166) months. There were no adverse events (recurrence or metastasis) in the NIFTP group. Conclusion: When strictly defined, NIFTP comprises 1.3% of cases perviously classified as PTC. In morphological NIFTP, no correlation is found between the presence of abortive papillae and the BRAFV600E expression. Intranuclear pseudo-inclusions are not observed in NIFTP. Modification of current morphological criteria to include BRAFV600E immunohistochemistry test may stratify NIFTP with benign outcome.

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Keywords: NIFTP, BRAFV600E, Papillary thyroid carcinoma.

Journal Pre-proof Introduction It is estimated that 52,070 new cases of thyroid cancer will be diagnosed in the US in 2019 (1). Thyroid cancer is one of the most rapidly increasing cancers in the US, largely due to increased detection rate and probable overdiagnoses (2). In large part, the increase is attributed to a rise in the incidental diagnosis of papillary thyroid microcarcinoma (mPTC) and the follicular variant of papillary thyroid carcinoma (FVPTC), diagnoses made with some degree of subjectivity (3).

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FVPTC was first proposed by Lindsay et al (4) and further defined by Chen and Rosai in

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1977 in a series including only invasive tumors (5). Over time, with the widespread use of

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cytology, the diagnosis of FVPTC evolved to depend solely on the presence of characteristic nuclear features such as enlarged elongated shape, chromatin clearing, and nuclear

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membrane irregularity. This led to progressive lowering of the nuclear alteration threshold

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required for the diagnosis (6). Other architectural features such as the presence of invasion were not required, resulting in tumors with varying outcomes collectively being designated as

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FVPTC.

In an attempt to reduce overdiagnoses and overtreatment of indolent thyroid tumors, an

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international, multidisciplinary, retrospective study group proposed a term “noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)” for a group of encapsulated or well-circumscribed thyroid tumors with follicular architecture and nuclear features of PTC (3). In this original study, no adverse events were found in 109 cases of NIFTP, thus NIFTP was considered a lesion with very low risk of adverse outcome (less than 1%). Although two subsequent studies have shown a risk of lymph node metastases and lung metastases in about 5% and 1% of the NIFTP patients, respectively (7,8), these findings were not confirmed in the majority of cohorts reported (9-15). Also, the diagnosis of NIFTP has lowered the risk of malignancy (ROM) of the “indeterminate” Bethesda system categories (16) wherein the vast majority of NIFTP cases are clustered (Categories III, IV

Journal Pre-proof and V), and category VI (17).The NIFTP was recognized in the latest edition of the WHO classification of thyroid tumors (18). The reported incidence of NIFTP is highly variable between less than 1% to 28% of all PTC (19), reflecting the subjectivity intrinsic to the application of the established criteria. A recent population-based study reported the incidence of 0.75% in Denmark (20). NIFTP diagnosis has also been rendered on lesions that were not included in the original cohort, including multiple lesions in the same gland (9), lesions smaller than 1 cm (12), larger than 4 cm (10)

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and in pediatric patients (15). Recently, additional criteria have been proposed for the diagnosis of NIFTP (21), to include

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negative result for BRAFV600E, absence of true papillae, and the need for a complete

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assessment of the capsule. In the original set of criteria, up to 1% of true papillae were

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accepted (3). In the newly proposed criteria, this minimal true papillae criterion has changed to “abortive papillae”. Abortive papillae are arbitrarily defined as a protruding conglomerate

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core (22).

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of follicular cells of less than 3 cells on each side and without a well-developed fibrovascular

The goal of the present study is firstly, to reclassify FVPTC cases diagnosed in a single

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center over 18 year-period and investigate the incidence of NIFTP using the newly proposed stringent criteria, and secondly, to assess the association between the presence of abortive papillae and the occurrence of BRAFV600E mutation.

Journal Pre-proof Materials and Methods The study was approved by the Institutional Review Board (IRB) at Albany Medical Center, Albany, NY. Pathology reports of thyroid nodules classified as FVPTC or NIFTP at our institution between January 2000 and December 2017 were retrieved. The cases were searched using the natural language search function of the laboratory information system (LIS), using the following terms in the final diagnosis field: NIFTP, thyroid, follicular, papillary, and carcinoma. Retrieved pathology reports were reviewed and cases of potential NIFTP

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were further identified. Archived glass slides of the potential NIFTP cases were retrieved and reviewed independently by two pathologists, and “morphologic” NIFTP were identified.

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Cases excluded from the NIFTP were classified according to their histologic features using

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current World Health Organization terminology (18).

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The modified current criteria for NIFTP were used to classify a tumor as NIFTP (21) [Table 1]. An abortive papilla was defined as a protruding conglomerate of follicular cells of 3 cells

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each side without a well-developed fibrovascular core (22). True intranuclear cytoplasmic

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pseudoinclusions were considered present if they met the following criteria: one per nucleus; present in scattered cells and not the majority of cells; had a crisp border

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resembling nuclear membrane; contained material with tinctorial and textural similarity to the peripheral cytoplasm (usually eosinophilic and dense) (23). The presence or absence of nuclear pseudo-inclusions was documented. Cases with discordant interpretation were rereviewed at a multihead microscope and a consensus was obtained. Immunohistochemistry (IHC) staining for BRAFV600E was performed on representative blocks in the “morphologic” NIFTP cases with an anti-BRAFV600E monoclonal antibody (clone: VE1, Ventana/Roche antibody), using Optiview detection kit on the Ventana/Roche Ultra benchmark machine according to the manufacturer’s recommendations. A tumor was considered as BRAFV600E positive when diffuse granular cytoplasmic stain was identified. Morphologic NIFTPs with negative BRAFV600E staining were finally considered NIFTP. Clinical information including age, gender and follow-up data of NIFTP patients was obtained from the electronic medical records and the Hospital Cancer Registry. Adverse events were

Journal Pre-proof defined as the occurrence of locoregional recurrence or metastasis during the follow-up period. Pre-operative fine needle aspiration results of NIFTPs were reviewed, when available. For statistical analysis, SPSS 17.0 (SPSS, Chicago, IL) was used. Fisher's exact test was used to assess the association between the presence of abortive papillae and the immunohistochemical expression of BRAFV600E. A P-value ≤ 0.05 was considered statistically

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significant.

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 Follicular growth pattern

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 Encapsulation or clear demarcation

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Table 1. Diagnostic Criteria for NIFTP (21)

-Lack of well-developed papillae

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-No psammoma bodies

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-<30% solid/trabecular/insular growth

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pattern

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 Nuclear score 2-3 for PTC

 No vascular or capsular invasion  No tumor necrosis

 No high mitotic activity  Negative BRAFV600E

Journal Pre-proof Results Patient cohort A total of 1918 PTC cases were identified over a period of 18 years (2000-2017). Five hundred and eighty nine of 1918 (30.7%) were signed out as FVPTC. After excluding cases with invasion, focal papillary structures, large solid component, increased mitotic count or psammoma bodies on the final pathology reports, 136 cases of potential NIFTP were identified. After the review of the archived pathology slides of the 136 cases, 107 lesions

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were excluded due to the presence of true papillae (67%), invasion (30%) and presence of

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psammoma bodies (3%). Hence, 29 lesions were morphologically reclassified as NIFTP.

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Four of 29 (13.7 %) lesions were positive for BRAFV600E (Figure 1); thus 25 lesions were

Clinico-pathologic findings of NIFTP

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finally categorized as NIFTP, representing 4.2 % of FVPTC and 1.3 % of PTC in our cohort.

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The mean age of the NIFTP patients was 50 years (range 21-78 years), 87.5 % were females with a male to female ratio of 1:7. The mean size of the lesions was 1.4 cm (0.1- 4.0

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cm). Twelve nodules were located in the right lobe, 9 in the left lobe and 2 were in the

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isthmus. The nodules were bilateral in 1 case. Fine needle aspiration had been performed on 19 patients with 9 indeterminate, 2 positive for PTC and 8 negative results. Intranuclear pseudoinclusions were not identified, and abortive papillae (Figure 2) were identified in 60 % of NIFTP. No association was found between the presence of abortive papillae and BRAFV600E expression (p=0.3).

Outcome of NIFTP The median follow-up of the NIFTP patients was 70 months (range of 28-166). Among them, 13 (52%) had at least 4 years of follow-up. No adverse events (recurrence or metastasis) were reported.

Journal Pre-proof Discussion The introduction of NIFTP enabled us to further stratify thyroid nodules and predict indolent outcome. Including our 25 lesions, over 1000 cases of NIFTP have been reported in the literature. Although a great majority of reported NIFTP cases behaved in a benign manner, significant adverse events were reported in 6 patients, 5 with lymph node metastasis and one with pulmonary metastasis in Canada (7) and 3% of lymph node metastasis in South Korea (8), necessitating a need for stringent diagnostic criteria. Recently proposed additional

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diagnostic criteria for NIFTP reflect concerted efforts by experts in the field to further refine the NIFTP entity such that the histomorphology of the lesion would correlate with an indolent

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outcome (21).

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The reported rate of NIFTP diagnosis varies significantly in retrospective studies, and ranges from less than 1% up to 28% of all thyroid cancer (19). In our cohort, using the modified

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current diagnostic criteria, NIFTP represented 4.2 % of FVTC and 1.3 % of all PTC. Our

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incidence is similar to Parente et al’s report (7) wherein NIFTP represented 2.1 % of all PTCs without molecular assessment. Similarly, a multi-institutional study carried out in south

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Korea reported that NIFTP comprised 1.3% (range 0.4% to 2.6%) of 18,819 PTCs (24). On the other hand, Wong et al have found that 71 % of FVPTCs would be classified as NIFTP (25). Indeed, low reproducibility of the diagnosis of encapsulated follicular lesions of thyroid gland has been recognized; between experts, only 10%-39% of complete agreement was achieved (26-27). Likewise, Wong et al (25) have emphasized that the magnitude of the impact of NIFTP diagnosis may differ between countries and between hospitals within the same country, which needs to be publicized to clinicians and oncologists. The introduction of NIFTP category resulted in a reduction in the ROM in the Bethesda system as well. The impact is the most significant in FNA specimens classified as suspicious for malignancy, with up to 50% of reduction in ROM. There is no significant change in the ROM for FNA specimens classified as benign, and only a small decrease (3-4% on average)

Journal Pre-proof for the malignant category (28). Considering the low incidence of NIFTP in our cohort we expect minimal impact of this diagnosis on the ROM of our institution’s cytologic diagnoses. It is notable that the negative BRAFV600E expression was included in the modified criteria. The Cancer Genome Atlas (TCGA) showed that the FVPTC and conventional PTC have distinct molecular signatures. The FVPTC is associated with RAS mutations with a RAS-like molecular signature while the classical PTC has a high frequency of BRAFV600E mutations (29). Mutation of the B-type Raf kinase (BRAF) is detected in 45% to 50% of sporadic PTCs

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with higher prevalence in conventional PTC than in follicular variants. The aberrant BRAF

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protein causes constitutive activation of the BRAF serine/threonine kinase and thus leads to

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an activation of the mitogen-activated protein kinase cascade. BRAFV600E also leads to higher expression of matrix metalloproteases and increased tumor cell motility (30). Taken

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together, it appears reasonable to associate BRAFV600E expression with a potential adverse

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outcome. In order to assess the BRAFV600E expression status, we used immunohistochemistry. The clone we used (clone VE1) is a mutation-specific antibody

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(clone VE1) that allows immunohistochemical visualization of the BRAFV600E protein with high sensitivity and specificity in thyroid lesions (31). Using the immunohistochemistry, 4

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(13.8%) of 29 morphological NIFTP were excluded from the final NIFTP.

The proliferation of benign or malignant follicular cells tends to form abortive papillae. Welldeveloped papillae have been associated with adverse outcomes, and with the presence of BRAFV600E mutations in lesions with PTC – like nuclear changes (21). The association between abortive papillae and BRAFV600E expression in the setting of NIFTP has not been studied. In our study, we did not find a significant association between the two, supporting the validity of the modified criteria. The abortive papillae were present in 60% of our NIFTP.

Interestingly, we did not find intranuclear pseudo-inclusions in the cases reclassified as NIFTP. While intranuclear pseudo-inclusion was mentioned as part of the nuclear features of

Journal Pre-proof NIFTP in the original description by Nikiforov et al (3), other authors have speculated that the existence of true pseudo-inclusions indicates well-developed nuclear features of PTC, and should raise a suspicion against the diagnosis of NIFTP. The authors advocated ubiquitin immunostain to identify real pseudo-inclusions (23). Even morphologically well characterized NIFTPs may pose a diagnostic challenge. Although Xu et al (10) reported that NIFTPs larger than 4 cm behave similar to the smaller lesions, in Parente et al’s report, the size of the NIFTP that progressed to pulmonary metastasis was

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larger than 4 cm (7). Similarly, Glomski et al (32) reported metastasis from a follicular

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adenoma without capsular or vascular invasion that was larger than 4 cm. It would be

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difficult to fully assess the capsule or border of these large lesions as more tissue remains inside the paraffin blocks and the risk of missing invasive front or true papillae would be

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higher.

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In our cohort, NIFTP behaved in a benign manner. Our findings validate the predictive power of the modified criteria in predicting indolent outcome of NIFTP. Therefore, we recommend

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the application of strict criteria including a meticulous gross examination with the submission

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of the whole lesion at 3 mm thickness to rule out the presence of true papillae or invasion, the two most frequent exclusion criteria we encountered in our study. While NIFTP largely remains a morphologic diagnosis, we recommend the use of BRAFV600E immunostain on lesions equal to or larger than 4 cm, with equivocal papillae or invasive features, and with well-developed nuclear features of PTC. Although uncommon, thyroid neoplasms originating from brachial cysts or lymph nodes with thyroid tissue (33) might be misinterpreted as metastasis and unrelated indolent lesion of the thyroid gland, such as NIFTP, may be mislabeled as a malignant lesion or as a regressed tumor (34). BRAFV600E immunostain would be a useful adjunctive in these scenarios as well. Our study has limitations implicit in retrospective studies regarding selection, misclassification and information. Also, there is a potential for ethical implication; i.e., the

Journal Pre-proof lesions previously considered malignant would be reclassified as indolent or benign by current reclassification. As previously recommended, the clinicians taking care of these patients should be alerted about the new diagnosis (35). In our institution, amendments or supplemental reports were generated for a limited number of cases only when a re-review was requested by clinicians. While we are still gathering information about NIFTP and a few adverse outcomes were reported, the American Association of Clinical Endocrinologist and American College of Endocrinology (AACE/ACEASTP) considers the lesion a low grade

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malignancy with very low risk of adverse outcome (36).

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In summary, when the strict criteria including the assessment of BRAFV600E mutation were

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applied, NIFTP was a rare lesion in our cohort. Intranuclear pseudo-inclusions were not observed. No correlation was found between the presence of abortive papillae and the

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BRAFV600E expression in morphological NIFTP. When strictly defined, NIFTP behaved as a

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benign neoplasm.

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35. Likhterov I, Osorio M, Moubayed SP, Hernandez-Prera JC, Rhodes R, Urken ML.

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Journal Pre-proof Figure 1: Positive cytoplasmic immunostaining with BRAF VE1 antibody. 40 x.

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Figure 2: Abortive papilla. H&E 400 x.

Journal Pre-proof Highlights •

NIFTP is a rare lesion with a benign behavior when strict criteria are applied.

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No correlation exists between the presence of abortive papillae and BRAFV600E

mutation.

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Intranuclear pseudo-inclusions are not observed in NIFTP.

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•