Introduction

The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently introduced to recognize the indolent behavior of thyroid neoplasms previously classified as noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) [1]. These tumors are encapsulated or well circumscribed, have a follicular architecture, and have “papillary-like” nuclear features, including nuclear enlargement, contour irregularities, grooves, and clearing [1–4]. By definition, NIFTPs lack capsular penetration, lymphovascular invasion, extrathyroidal extension, and lymph node metastases. Molecularly, they predominantly harbor RAS mutations, though a smaller subset has been found to have the BRAF K601E mutation and PPARG and THADA fusions [1, 5, 6]. In the last several decades, FVPTC has accounted for an increasing percentage of papillary thyroid carcinoma (PTC). Jung and colleagues reported that FVPTCs accounted for 10% of all PTCs diagnosed at the University of Pittsburgh between 1974 and 1985 (with classical PTC accounting for 52%), but for 25% of PTCs diagnosed in 2009 (with classical PTCs accounting for 19%, and the bulk of the remaining tumors classified as microcarcinomas) [7]. This study was conducted prior to the characterization of NIFTP; however, it is likely that a significant subset of the tumors would represent NIFTPs. In the few studies that have evaluated the impact of NIFTP on thyroid carcinoma diagnoses, tumors previously diagnosed as noninvasive FVPTC (now NIFTP) accounted for between 9 and 25% of thyroid carcinomas [3, 8–10]. Although the introduction of the NIFTP nomenclature was aimed to reduce the overtreatment of an indolent thyroid tumor and spare patients the psychological burden of a cancer diagnosis [1, 11], the introduction of NIFTP will have additional consequences. Our group and others have previously reported the impact that the introduction of NIFTP could have on fine needle aspiration diagnoses, with NIFTP decreasing the risk of malignancy for all Bethesda diagnostic categories [8, 10, 12]. Additionally, the emergence of NIFTP will also affect the interpretation of molecular testing of thyroid nodules [13–15]. The introduction of NIFTP could potentially also result in an increase in the rates of unfavorable histologic prognosticators for the remaining PTCs because NIFTPs had previously accounted for a significant subset of PTCs without these features. Our aim was to evaluate the potential impact of the reclassification of NIFTP on rates of extrathyroidal extension, lymphovascular invasion, margin status, and lymph node metastases in PTC. Additionally, we assessed how the changes in histologic parameters would affect risk stratification for structural disease recurrence according to the American Thyroid Association (ATA) guidelines.

Materials and Methods

Study Population and Data Acquisition

Approval from the Brigham and Women’s Hospital investigation review board was obtained. From a database of thyroid resection specimens received between August 2010 and August 2012, we retrospectively identified 348 cases which were diagnosed as PTC. For each case, demographic and clinical information (including age, gender, and type of surgery) and histopathologic characteristics (including tumor size and location, extrathyroidal extension, lymphovascular invasion, surgical margin status, and lymph node status) were obtained from the pathology reports.

Tumor slides for cases diagnosed as FVPTC on resection were reviewed to identify tumors that would now be categorized as NIFTP. Tumors diagnosed as FVPTC had an entirely or nearly entirely follicular architecture (<1% papillae) and “papillary-like” nuclear features (including nuclear enlargement, elongation, contour irregularities, grooves, and clearing). NIFTPs included encapsulated tumors with a complete fibrous capsule separating the tumor from the surrounding benign parenchyma and partially-encapsulated/well-circumscribed tumors that had a partial capsule or entirely lacked a capsule but had a sharp interface between the tumor and benign parenchyma. FVPTCs that had infiltrative growth, capsular penetration, or lymphovascular invasion were classified as infiltrative/invasive FVPTC. An example of a tumor that would now be characterized as NIFTP is shown in Fig. 1.

Fig. 1
figure 1

Example of a noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). a The tumor is very well circumscribed and has an entirely follicular architecture. b There is a sharp interface between the tumor and benign parenchyma. c “Papillary-like” nuclear features are present (including nuclear enlargement, contour irregularities, grooves, and clearing)

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ATA Risk Stratification

Tumors were classified according to the ATA risk stratification system for structural disease recurrence [16]. Low-risk tumors were intrathyroidal tumors with ≤5 lymph node micrometastases (<0.2 cm in size). Intermediate risk tumors were those with aggressive histology (such as tall cell variant), microscopic extrathyroidal extension, >5 lymph node metastases, lymph node metastases ≥0.2 cm but <3 cm in size, or lymph node metastases with extranodal extension. High-risk tumors were those with gross extrathyroidal extension, incomplete tumor resection, or with any metastatic lymph node ≥3 cm in size. Determination of gross extrathyroidal extension and incomplete tumor resection was based on the surgical operative note in the patient medical record.

Statistical Analysis

Correlations were determined using Fisher’s exact test or unpaired t test, as appropriate. p Values less than 0.05 were determined to be statistically significant. Statistical analysis was performed using Prism (GraphPad Software, Inc., La Jolla, CA).

Results

A total of 348 cases which had been diagnosed as PTC on surgical resection were identified. Of these patients, 82 (24%) were men and 266 (76%) were women, with a mean age of 48 years at the time of resection (range 18–83 years). Seventy-five (22%) patients underwent partial or hemithyroidectomy, while 273 (78%) had a total or near total thyroidectomy. Lymph nodes were sampled in 222 (64%) cases. Of the 348 cases, FVPTC accounted for 132 (38%) cases, classical type 163 (47%) cases, tall cell variant 27 (8%) cases, and other variants 26 (7%) cases. Of the 132 cases diagnosed as FVPTC, 94 (71%) would now be classified as NIFTP.

The clinicopathologic characteristics of the entire cohort and of PTCs excluding NIFTPs are summarized in Table 1. For the entire cohort, the mean tumor size was 2.0 cm. Extrathyroidal extension was present in 66 (19%) cases, lymphovascular in 94 (27%) cases, and positive surgical resection margins in 39 (11%) cases. Lymph node metastases were present in 65 (19%) cases. When excluding NIFTP, there were 254 remaining PTCs, which were from 63 (25%) male and 191 (75%) female patients with a mean age of 47 years (range 18–83 years). The mean tumor size was 1.9 cm. Extrathyroidal extension was seen in 66 (26%) cases, lymphovascular invasion was present in 94 (37%) cases, and a positive resection margin was present in 39 (15%) cases. Lymph node metastases were present in 65 (26%) cases. The mean number of positive lymph nodes was 6 (range 1–38). For cases in which the size of the largest lymph node metastasis was recorded (98%), the mean size of the largest lymph node metastasis was 1.0 cm (range <0.1–5.5 cm). Eleven cases showed extranodal extension. When comparing the entire cohort and PTCs excluding NIFTPs, there were increased rates of extrathyroidal extension (26% up from 19%, p = 0.046), lymphovascular invasion (37% up from 27%, p = 0.0099), and lymph node metastases (26% up from 19%, p = 0.045). There was no difference in the rates of positive surgical resections margins detected histologically (11 to 15%, p = 0.14).

Table 1 Clinicopathologic characteristics of study patients
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The ATA risk stratification of the entire cohort and of PTCs excluding NIFTPs is summarized in Table 2. For the entire cohort, 251 (72%) cases were low risk, 84 (24%) were intermediate risk, and 13 (4%) were high risk. When excluding NIFTPs, 157 (62%) cases were low risk, 84 (33%) were intermediate risk, and 13 (5%) were high risk. When comparing the proportion of cases in each risk category between the entire cohort and PTCs excluding NIFTPs, there was a decrease in low-risk cases (62% down from 72%, p = 0.0081) and increase in intermediate-risk cases (33% up from 24%, p = 0.017). There was no difference in high-risk cases (4 to 5%, p = 0.42).

Table 2 American Thyroid Association risk stratification of study patients
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Discussion

The aim of our study was to evaluate the potential impact of the reclassification of NIFTP on rates of unfavorable histologic parameters in the remainder of PTCs. We found that the downgrading of some carcinomas to NIFTP resulted in increased rates of extrathyroidal extension, lymphovascular invasion, and lymph node metastases among the remaining PTCs by statistically significant margins. These changes in histologic parameters translated into a significant decrease in the number of cases that would be categorized as low risk according to the ATA risk stratification system for structural disease recurrence. These findings are not surprising given the lack of aggressive histopathologic features inherent to the NIFTP diagnosis, which by definition does not have lymphovascular invasion, extrathyroidal extension, or lymph node metastases. However, the potential relative increase in these features in the remainder of PTCs is important to demonstrate since it could affect the overall prognosis for patients with PTC or translate into a larger proportion of PTC patients that receive radioactive iodine (RAI) in addition to surgery. For example, the presence of lymph node metastases has been shown to affect prognosis both in older and younger patients [17, 18]. The magnitude of this impact is small, with Adam and colleagues showing that in patients younger than 45, the overall survival at 10 years was 98.2% among those without nodal metastases and 97.8% among those with nodal metastases [17]. Thus, an increase in the proportion of PTC patients with lymph node metastases due to the NIFTP shift may or may not affect prognosis. Moreover, any change in prognosis would likely only be demonstrable in large cohorts with significant follow-up time. Although the prognostic significance of extrathyroidal extension depends on the amount of extrathyroidal extension present [6, 19, 20], the presence of even minor extrathyroidal extension puts patients into the ATA’s intermediate risk of structural disease recurrence category [16]. Consequently, many, if not most, of these patients are given RAI. It is important to emphasize that the magnitude of the impact of NIFTP will differ between countries and between hospitals within the same country. Previously, it was shown that there was significant interobserver variability in the FVPTC diagnosis, largely due to differences in what was considered sufficient PTC nuclear features [21–23]. In the few studies that have retrospectively evaluated the number of thyroid carcinomas that would now be classified as NIFTP, NIFTP accounted for 9–25% of carcinomas [8–10]. More studies are needed in order to better estimate the impact of NIFTP, both at academic centers and in community practices, in different regions of the USA, and in different countries.

It is likely that the introduction of the NIFTP nomenclature will change other PTC characteristics. For example, the molecular profile of PTC will probably change. NIFTPs lack the BRAF V600E mutation and instead predominantly harbor RAS mutations, though a smaller subset has been found to have the BRAF K601E mutation and PPARG and THADA fusions [1, 5, 6, 24]. NIFTPs account for the majority of PTCs with RAS mutations [13]. Thus, the remainder of PTCs will likely have an increased rate of the BRAF V600E mutation and a lower rate of RAS mutations. The majority of studies evaluating PTCs in adults have shown that BRAF V600E mutation is associated with high-risk histopathologic features, such as increased frequency of extrathyroidal extension, lymph node metastases, and higher clinical stage [25–29]. In contrast, RAS mutations are often associated with more low-risk features [30, 31]. Our findings, at least in part, likely reflect an increase in the number of PTCs harboring a BRAF V600E mutation. Finally, the BRAF V600E mutation has been linked to RAI resistance. Thus, the introduction of NIFTP could potentially affect the efficacy rate of RAI. More studies are needed to investigate these issues.

In summary, we demonstrated that in our cohort of PTCs the NIFTP shift resulted in increased rates of extrathyroidal extension, lymphovascular invasion, and lymph node metastases. Additional multi-institutional studies are needed to confirm these findings.