Our findings support our hypothesis, based on the 8th edition of the AJCC classification, that in classical PTC, patients aged ≥55 years have comparatively higher risk of locally advanced disease than those <55 years. We reveal that the incidence of aggressive pathological features was higher and the incidence of histopathological characteristics associated with an aggressive course much higher in PTC patients in the older group than in those in the younger group. These findings might explain why this age cut off is effective. This may explain our observation that among patients with the same pTNM stage, prognoses were much worse in patients aged ≥55 years than in those aged <55 years. In our study, we also found that the incidence of pathological features characteristic of aggressive cases of PTC increased with patient age, with individuals with aggressive characteristics of PTC being slightly older than those without such characteristics. To extend the life spans of older patients with PTC, it is crucial to assess all risk factors for aggressive entities of PTC and as well as postsurgical prognosis; while some demographic factors, including sex, are not correlated with aggressive features of PTC, we found that older age is correlated with a more aggressive course.
We observed a higher rate of LNM and distant metastasis in older patients versus younger patient. A significantly higher risk of presence of LNM (N1) was observed in ≥45 years old group, however more expressive results were found for the patients ≥55 years old group, where the risk of locally advanced disease and LNM were higher. None of the patients below 55 years old showed distant metastasis, but 19 patients above 55 years old showed M1. A potential partial explanation for this observation lies in the histopathological characteristics of PTC in these groups of patients. Compared to younger PTC patients, in older PTC patients, we observed a higher number of aggressive features, indicating the potential for more aggressive tumor spread (to distant regions and not only to regional lymph nodes). Consistent with these results, we additionally found that the prevalence of LNM was higher in older than in younger PTC patients.
Our survival analysis further suggested that prognoses are worse in older patients than their younger counterparts, potentially because the incidence of aggressive PTC features is higher in the older group. We noted that forms of PTC without capsular infiltration were much more frequently observed in younger than in older patients, while infiltrative subtypes were more common in older than in younger patients; these findings might explain the better prognoses observed in the younger patients. Similarly, some authors have reported that patients with encapsulated PTC have an excellent prognosis, while those with infiltrative tumors have a comparatively worse prognosis (17,18). Importantly, some genetic differences between encapsulated and infiltrative neoplasms have been identified (18). Nikiforov et al. (17) determined that most patients with encapsulated PTC underwent only lobectomy, and patients treated in this way had a very low risk of adverse outcomes over long-term follow-up. Based on these and similar findings, in 2016, cases of encapsulated PTC were formally classified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (17,19). Conversely, some authors found that there was no difference in postsurgical outcomes between PTC patients treated with lobectomy vs. thyroidectomy, but also that RAI therapy provided no survival benefit (4,20-22). The survival analysis performed in our study suggests that clinicians should consider both patient age and the results of histopathological examinations when treating PTC patients. This approach may save some patients, especially younger individuals with comorbidities, from undergoing unnecessary aggressive therapies. Even the 2015 ATA Management Guidelines for Patients with Differentiated Thyroid Cancer recommends hemithyroidectomy without RAI therapy in low-risk patients (16), and some authors have, based on these guidelines, begun to identify which groups of patients may be at risk of overtreatment with RAI ablation after surgery for low-risk PTC (23).
The situation is completely different in PTMC patients. Ito et al. (24), for example, revealed that there are significant age-specific differences in cancer biology among indolent, clinically silent PTMC and advanced PTC – in particular, the incidences of larger tumors, LNM and disease progression were estimated to be lower in older patients and higher in younger patients. Similar observations were presented by Kim et al. (6), who showed that extrathyroidal extension and LNM were significantly less frequent in older patients with PTMC than in patients with larger PTC. They suggested, based on this finding, that older patients with clinically silent PTMC should be considered for active observation rather than surgical treatment (6). In our study, we identified some clinical and histopathological characteristics of PTC that, when absent, may permit clinicians to avoid aggressive therapy in older patients. Additionally, we confirmed that among PTC patients one ultrasound feature i.e. microcalcifications and some histopathological features like extrathyroidal extension, capsular and vascular invasion, LNM and distant metastasis are more common in older than in younger patients, and are risk factors for a poor prognosis. We observed these features mainly in patients ≥55 years old. According to some authors, the use of LNM in risk stratification remains controversial (25), while many other studies have presented LNM as a significant risk factor for poor outcomes in PTC (13,26). In contrast, other authors have reported inconsistent conclusions concerning the impact of LNM on PTC (25). Analyses have also shown that in FTC but not PTC, an older age at diagnosis is a significant risk factor for disease-specific mortality (27). Zhang et al. (28) compared younger, middle-aged and older patients with PTC and found that bilateral LNM was more likely to occur in the older patients (45-65 years old) than in the younger groups. They additionally concluded that the tumors in the older group were more likely than those in the middle and younger groups to show capsular and extrathyroidal invasion. Kim et al. (6) proposed that tumor size and LNM are independent predictors of recurrence in older patients with PTC. De Castro et al. (29) added that tumor size, local extent (T stage) and nodal status (N stage) are also important prognostic factors in patients ≥45 years old. In our study, we observed that some risk factors, such as LNM, capsular invasion and distant metastasis, were more common in older patients than in younger patients. We estimated that age cut off of 55 appears more relevant than 45 to discriminate patients according to N+ and M+. We found that an age of 55 years is a clearly useful cut off threshold for stratifying PTC patients, with patients younger and older than this age having better and poorer prognoses, respectively, consistent with a recent study (14). Those authors used Cox proportional hazards analysis to assess the association between specific risk factors and the prognosis of WDTC and showed, consistent with our findings, that an age of 55 years is an effective cut-off threshold for risk stratification in PTC patients. This age threshold effectively stratifies patients with aggressive tumors, and our data indicate there is no need to increase this threshold. We confirmed the results reported by Gillanders et al. (30), which supported increasing the age threshold from 45 to 55 years. Because the evidence supporting the use of an age of 45 years as a cut-off for stratification had become controversial, we performed our study and show that an age of 55 years seems very reasonable, contrary to some authors who proposed that no age cut-off is appropriate for significant risk stratification (31,32). Our data indicate that an age cutoff of 55 years could help clinicians perform risk stratification. For example, patients aged ≥55 years are more likely than their younger counterparts to present PTC with clinicopathological features pathognomonic for aggressive entities, while <55 years old very often have indolent, clinically silent PTC. The aggressive clinicopathological features observed in older PTC are likely responsible for their comparatively poorer survival and prognosis. Access to these data may help clinicians deciding whether to perform more radical treatment. Equally important is that clinicians may be able to prevent unnecessary surgery and aggressive postsurgical RAI therapy in older patients with PTC without invasive features on histopathological examination.
Our study has some limitations. First, it is limited by its retrospective design, which prevented adjustment for some confounding factors. Second, this was a single-center analysis; to better understand this issue, multicenter analysis will be necessary. Third, due to the indolence of PTC and PTMC, our study was conducted over a relatively short follow-up period; a longer follow-up period is needed to completely assess the impact of PTC characteristics on prognosis and mortality. All individuals after operation were routinely sent to the oncology center for consultation and potential adjuvant radioiodine treatment (RAI). Due to lack of absolutely all data regarding RAI therapy we did not present these details.