Analysis of risk factors and prognosis in differentiated thyroid cancer with focus on minimal extrathyroidal extension

In this study we were able to show that - even when accounting for other established risk factors - patients with M-ETE were not more likely to show metastases at initial diagnosis. Additionally, the rate of recurrence or development of metastases in the course did not differ significantly when compared to patients with a TCT.

However, post-primary treatment differed significantly among both cohorts, as M-ETE patients underwent RAIT with higher cumulative activities and EBRT at higher frequencies.

It is therefore still unanswered whether the lack of statistically significant differences regarding the recurrence rate is attributable to the differing treatment of both cohorts or the negligible impact of M-ETE on patient prognosis.

If the former is true, the diagnosis of M-ETE warrants a more extensive post-primary treatment. If the latter is true, M-ETE patients in this cohort were likely subject to overtreatment.

The answer to this question -and in a broader sense the role of adjuvant RAIT in general- is a matter of debate and currently hindered by a lack of evidence. It has to be answered conclusively by future randomized controlled trials focusing on patient-relevant outcome measures, as advised by the authors’ of the Martinique statements [21].

Similar to the present study, Furlan et al. did not observe statistically significant outcome differences between patients with M-ETE vs. TCT. Interestingly, patients diagnosed with FTC with TCT were more likely to show metastases at initial diagnosis [22] compared to their counterparts with FTC with M-ETE. A study by Shin et al. yielded comparable results, with no higher recurrence rate in patients with M-ETE vs. those without [23].

While the role of M-ETE has yet to be elucidated conclusively, the role of macroscopic extrathyroidal extension (ETE) appears to be clearer:

In 1991 a study by Akslen and Myking demonstrated that extrathyroidal extension (ETE) was a negative prognostic marker in a patient collective that is comparable to ours with regards to the distribution of age, sex, and histopathological subtype [24]. They separately assessed the prognostic impact of thyroid capsular invasion and major extrathyroidal growth, which they defined as any infiltration of skeletal muscle, large nerves or lipomatous tissue in accordance to the 1987 UICC classification. Both features were associated with a reduced survival time. In contrast to our study, a significant association between tumor capsular invasion and the presence of lymph node metastases was found. Interestingly, no statistically significant differences in survival times were found when comparing patients with thyroid capsular invasion vs. major extrathyroidal growth, which led the authors to the conclusion that tumor capsular infiltration should be viewed as a marker for early extrathyroidal extension.

This was confirmed by Yasumoto et al. in 1996, who analyzed different risk factors within a study cohort of 357 patients and showed that ETE defined any infiltration of the trachea, nerves or lymphoid tissue lead to an increase disease specific mortality rate [25]. Similar to our study, initial N1-disease was associated with a higher recurrence rate. Mean patient age and the fraction of FTCs were slightly higher than in our collective, whereas the sex distribution was comparable.

Studies examining the prognostic role of ETE have shown that patients with an infiltration into the soft-tissue posterior to the thyroid gland show a worse outcome than patients, in whom the soft-tissue anterior to the thyroid capsule is infiltrated. Still in both cases outcome is influenced negatively [26]. Yet in this analysis the extension of ETE is not taken into account, which leads to the question, whether any ETE is a bad prognostic marker or just macroscopic ETE.

To our knowledge this is the first study using the concept of matching partners comparing patients with similar tumor size and histopathology, with the only difference being the absence or presence of M-ETE.

Interestingly, age > 55 years was not significantly associated with a higher risk for disease. This is in contrast to a prior study by Trimboli et al. [27], who showed that high-risk patients (as stratified by ATA criteria [28]) older than 55 years had the highest risk for relapse and significantly shorter disease-free survival. A possible explanation is the assumably small number of high-risk patients, as patients with tumors showing macroscopic ETE were not included, and the generally smaller sample size. Additionally, age as an independent risk factor for tumor recurrence was tested on the entire study cohort, not separately for risk groups.

Limitations include that in our collective M-ETE patients were treated more aggressively, receiving EBRT at higher rates and receiving RAIT with higher activities of ¹³¹Iodine. This constitutes a potential confounder: Prior studies by Farahati et al. [29] as well as Tsang et al. [30] have shown lower recurrence rates in PTC with either residual disease or perithyroidal tumor infiltration, age > 40 years and nodal involvement undergoing additional EBRT. However, other studies have not replicated these results so that the benefit of adjuvant EBRT is questionable and thus the impact on our study results likely minor [8].

All patients with R1 resection (14.4 %) underwent RAIT. Conversely, all patients, in whom RAIT was omitted, had had an R0 resection.

A limitation entails that histopathological reports were obtained from different institutes. As the interobserver variation in the assessment of minimal extrathyroidal extension is high, it is not out of question that some patients were misclassified, thus negatively impacting our study results [31]. Nonetheless, medical diagnostics and treatment do not always occur under hypothetical idealized conditions. Thus, our study results are, to a large extent, close to real-world clinical scenarios, in which DTC patients are referred with histopathological reports from different institutes and not exclusively from a reference pathologist for thyroid tumors.

Additionally, due to the follow-up time of 5 years, late recurrences could have been missed. However, the literature suggests that the majority of tumor recurrences in differentiated thyroid carcinoma occur within 5 years of initial diagnosis [32].