INTRODUCTION

The pathological examination of thyroid samples is important for establishing the diagnosis of differentiated thyroid carcinoma (DTC), and it also provides useful information for the risk stratification assessment (¹). On the other side, the TNM AJCC/UICC staging system is recommended for predicting disease mortality (¹).

The 2009 version of the American Thyroid Association (ATA) thyroid cancer guidelines proposed a three-tiered risk stratification system in which specific clinical-pathologic features are used to estimate the risk of structural incomplete response (SIR) and the probability of an excellent response to treatment (²). The variables taken into account for risk stratification in the 2009 version of the ATA guidelines were: evidence of microscopic or gross extrathyroidal extension, presence of aggressive histology, completeness of tumor resection, existence of metastatic lymph node/s and/or distant metastasis, and observation of RAI-avid disease outside the thyroid bed (²).

In this first ATA risk of recurrence (RR) classification system, many important features were not taken into account. For example, any patient with lymph node metastasis was deemed to have an intermediate RR. In fact, the risk of structural disease can vary from 4% if having fewer than five metastatic lymph nodes, or 5% if all involved lymph nodes are less than 0.2 cm, to 19% if more than five lymph nodes are involved or 27%-32% if any metastasis in the lymph node is larger than 3 cm (³,⁴). Additionally, follicular thyroid carcinomas (FTCs) with vascular invasion, initially classified by the 2009 ATA system as intermediate RR, have an excellent prognosis when minor vascular invasion is present but may have a high RR (30%-55%) when more than four foci are demonstrated in the pathological examination (⁵,⁶).

Although the 2009 risk stratification system has proven to be a valuable tool for initial risk stratification in DTC (⁷–¹⁰), modifications were required to better assess the RR of DTC patients. The recently published 2015 version of the ATA guidelines included specific prognostic variables: the extent of vascular invasion, the extent of lymph node involvement (number and size of metastatic lymph nodes and presence of extranodal extension), and mutational status (BRAF and/or TERT when available) (¹). As a result, the low risk category was expanded to include patients with small-volume lymph node metastases (clinical N0 or < 5 pathologic N1 micrometastases, < 0.2 cm in the largest dimension), the intermediate RR group now considers only a subset of patients with lymph node metastases (clinical N1 or > 5 pathologic N1 with all involved lymph nodes < 3 cm in the largest dimension), and a second group, with intermediate to high risk of recurrence, now includes those cases with large-volume lymph node involvement (any metastatic lymph node > 3 cm in the largest dimension, > 3 lymph node metastasis with extranodal extension) and FTC with extensive vascular invasion (> 4 foci of vascular invasion or extracapsular vascular invasion). The 2015 guidelines defined this new version of the RR as the “modified risk stratification system from ATA 2009 guidelines” (MRSS ATA 2009) and were validated by our and other groups around the world in ablated and non-ablated patients (¹¹–¹⁴).

The vascular invasion (≥ or < 4 foci), the magnitude of extrathyroidal extension, the size of the largest metastatic focus in lymph nodes, the presence of extranodal extension, and the status of the resection margins were not uniformly informed in the historic pathologic reports that were used to assess the RR of DTC patients in our hospital and most centers in Latin America, with the exception of the number of lymph node metastases.

However, the additional benefit of adding the previously mentioned specific features for reclassifying patients has not yet been established. Therefore, our objective was to compare the historic RR and the responses to treatment to risk stratification systems estimated with historical pathology reports and contemporary re-review of the slides by two expert pathologists.

SUBJECTS AND METHODS

RESULTS

The demographics, clinical features, and MRSS ATA 2009 for each of the 63 patients included in this study are seen in Table 2.

The percentages of new specific histological features assessed after the pathological review are detailed in Table 3.

After the review of the pathologic slides, a change in the RR category was made in 25.4% (16/63) of the cases. Out of 46 patients initially classified as low RR, 2 patients were reclassified as intermediate RR because of extranodal extension in fewer than 3 lymph nodes, 4 patients were reassigned to the intermediate-high RR group because of surgical margins involved, and 1 patient finally was diagnosed as harboring an NIFTP (Table 4).

Out of 17 patients initially classified as intermediate RR, 3 were reassigned to the low RR group (1 because of a change in the histology variant and 2 due to the presence of micrometastasis in all involved lymph nodes) whereas 5 patients were reclassified to the intermediate-high category (4 because of surgical margins involved and 1 because more than 3 metastatic lymph nodes with extranodal extension were present). Three patients with positive surgical margins also had at least 1 lymph node metastasis > 3 cm in the largest dimension. One patient who initially was assigned to the intermediate RR group was diagnosed as NIFTP (Table 4).

Finally, the percentages of initial response to therapy and the final clinical outcomes were compared between the initial RR assessed before and after the pathology slide review. The percentage of SIR at initial evaluation changed from 6.7 to 2.4% (p = 0.6254) in the low risk group and from 12.5 to 20% (p = 0.6171) in the intermediate risk group (Table 5). The frequency of SIR at final follow-up changed from 2.2 to 0% (p = 1) in patients with low RR and from 6.3 to 20% (p = 0.5304) in patients with intermediate RR (Table 6).

DISCUSSION

A detailed pathology review of the historic histological samples of 63 DTC patients initially classified as low or intermediate RR by a validated risk stratification system (⁷–¹¹) demonstrated that, considering specific features (extent of extranodal extension, extent of vascular invasion, and surgical margin evaluation, among others), the change in percentage of SIR at initial and final evaluation did not significantly differ from the statistical point of view. However, adding these new variables to the RR classification might confer a more accurate estimation of the probability of having an SIR at final follow-up. This frequency was 6.3% in the intermediate RR group previous to the pathologic review and 20% after adding specific histological data, which is more similar to what it was reported by larger cohorts of DTC patients (21%–34%) (⁷–¹¹). Also, the excellent response at final outcome was achieved in 68.9% of low RR patients, but when patients were reclassified after the pathologic review, this percentage rose to 73.8% (without statistical difference).

Two patients from this cohort were diagnosed with the encapsulated variant of follicular thyroid carcinoma, which is currently known as NIFTP (¹⁵,¹⁶). These tumors are characterized by a follicular growth pattern without papillae formation, nuclear features of papillary thyroid carcinoma, encapsulation or clear demarcation, and no vascular or capsular invasion (¹⁵). They are associated with an indolent behavior and a very low risk of adverse outcome (¹⁵). The encapsulated forms of the follicular variant of PTC also have a distinct molecular profile, harboring predominantly RAS mutations in contrast with the more frequent BRAF mutations in the infiltrative forms (¹⁷,¹⁸). Currently, NIFTP is assumed to represent nearly two-thirds of the follicular variant PTCs (¹⁵,¹⁹,²⁰). Although the ATA 2015 task force has recently proposed that this neoplasm with very low potential for recurrence should be reclassified as a non-cancer (¹⁶), and the 2 patients with NIFTP from our cohort had an excellent response to therapy (both treated with total thyroidectomy and radioiodine ablation), isolated cases of distant metastasis have been reported (²¹–²³).

It is noteworthy that 4 patients initially classified as having a low RR were reassigned to the intermediatehigh RR group. Although it is difficult to draw a conclusion with this small cohort of patients (n = 9), this subgroup of patients showed 22% of SIR at initial evaluation, similar to what is expected in the intermediate RR group of patients (⁷–¹¹). Indeed, all of them achieved an excellent response at final follow-up. Therefore, it seems that the presence of surgical margins involved in the microscopic analysis, the presence of extranodal extension in more than 3 metastatic lymph nodes, and < 50% of tumor dedifferentiation would probably have less impact on the percentage of SIR than the macroscopic invasion of tumor into the perithyroidal soft tissues or the presence of distant metastasis (¹,⁷–¹⁰). It seems that, in the absence of extrathyroidal extension in small primary tumors, the positive margin status does not appear to be a poor prognostic indicator for local recurrence and has an excellent local recurrence-free survival, comparable to those with negative margins, at least in patients who received radioiodine remnant ablation, as it happened in our cohort (²⁴).

The presence of vascular invasion is recognized as a variable that has a negative impact on the RR (²⁵–²⁷), and it should be informed in the pathological report. It is diagnosed as a direct tumor extension into the blood vessel lumen typically attached to the wall and covered by a fibrin thrombus (²⁷). Minor vascular invasion (small number of foci confined to intracapsular vessels) appears to have a low risk of SIR (less than 5%) (²⁸–³⁰). On the contrary, more than 4 foci of vascular invasion are associated with a poor prognosis, mainly in follicular carcinomas (³⁰–³²). This situation seems to be uncommon in papillary carcinomas, even more in micro PTC, with a prevalence of less than 4% (²⁵,²⁶,²⁸,³³–³⁵). In fact, none of the 63 patients from our cohort had vascular invasion in more than 4 foci in the pathological review.

In our cohort, we considered the oncocytic variant of PTC as an aggressive histology such as columnar cell and tall cell subtypes. The oncocytic change in PTC patients was reported to have a higher recurrence rate than PTC patients without oncocytic change (30.8% vs. 11.7%) (³⁶).

One limitation of this study is the low number of patients in each RR group, which could have limited the statistical analysis. Given 2.2% and 0% SIR in the low risk groups and 6.3 and 20% SIR in the intermediate risk groups, a type I error of 5% (two-sided), and an interval confidence of 95%, a total of 966 low risk patients and 218 intermediate risk patients would have to be included to achieve a statistical power of at least 80%. It is necessary to validate these results in larger cohorts of patients. Another limitation is that every single patient in our cohort, even those classified as low risk, was treated with total thyroidectomy and RAI, a common practice in the past in most countries of Latin America (³⁷). Currently, this practice of care may not apply to many institutions where low risk patients do not receive remnant ablation, including in our hospital (¹⁴). Therefore, further analysis is necessary to validate our results in low risk patients who do not receive RAI.

In conclusion, a detailed report of specific features in the HPR of patients with DTC might give a more accurate RR classification and a better estimation of the response to treatment. If these data are not available, the RR can also be estimated, but the expected SIR might be slightly different, although not statistically significant, as we could see in our analysis.