The incidence of well-differentiated thyroid cancer (WDTC) has steadily increased over the past few decades, due largely to improvements in diagnostic modalities. This increase in both tumor incidence and improved detection has also led to significant increases in the incidence of thyroid cancer recurrence [1]. These improvements have led to earlier diagnosis and treatment, particularly in patients with recurrent disease, resulting in improved survival, even for those with distant metastases at presentation [2]. Although overall prognosis in WDTC remains excellent in comparison with that in other malignancies [3], recent improvements in WDTC diagnostics have had little effect on mortality, with the disease-specific death rate remaining stable at -1.3% [4].

Recurrence of thyroid cancer is often associated with increased morbidity, although it is also thought to have an impact on mortality. Patients who developed a recurrent disease after curative treatment have shorter survival compared with disease-free counterparts, with 50% to 60% eventually dying of the disease [4]. In response, current management guidelines recommend aggressive detection and control of recurrent disease while minimizing morbidity to the patient [5]. Recent studies estimate recurrence rates of WDTC at -30%, with the majority of recurrences occurring within the first 10 years after primary surgical treatment [6]. Age, male gender, increased tumor size, extra-thyroidal extension, nodal metastases at presentation, and aggressive histological type are just some of the factors known to increase the likelihood of cancer recurrence [7].

Recent studies conducted in Hawaii [89] and Los Angeles, California [10] have identified Filipinos as the ethnic group with the highest incidence of thyroid cancer. Among this population, thyroid cancers were also found to be more aggressive and recurrent in nature [11], with a significantly higher risk of malignancy in Filipinos with thyroid nodules compared with in other racial ethnicities [12]. However, despite this greater risk, no study has directly examined the recurrence rates, risk factors, and long-term outcomes of Filipinos with WDTC. Here, we examined recurrence rates and investigated risk factors associated with recurrence in Filipino patients diagnosed with WDTC.

A total of 649 patients with papillary thyroid cancer (PTC) and 79 patients with follicular thyroid cancer (FTC) were included in this study, with a mean follow-up duration of 53±12 and 83±23 months, respectively. Only five patients were lost to follow-up and therefore excluded from analysis. Of this group, 214 patients (32.9%) with PTC and 23 patients (29.1%) with FTC developed a recurrence, with mean intervals of 13±6 and 26±15 months from thyroidectomy, respectively. Patients with FTC were older at presentation and had less lymph node involvement at presentation. Tumor sizes for recurrent PTC and FTC were nearly similar (3.30±2.0 cm vs. 3.27±2.0 cm, P=0.36). More than 50% of patients with a recurrence underwent repeated radioactive iodine ablation therapy, averaging two sessions of -200 to 300 mCi total received dose. Nearly 25% of patients underwent repeated surgical resection to remove tumor remnants or lymph node metastases. Compared with patients with recurrent PTC, more patients with recurrent FTC underwent additional external beam radiotherapy. Chemotherapy was not a common treatment modality used in this population. Recurrent FTC had a higher mortality rate, relative to PTC (8.7% vs. 0.9%, respectively) (Table 1).

Male sex, age >45 years, history of smoking, alcohol intake, tumor size >4 cm, multifocality of cancer, bilateral lobe involvement, tall cell variant histology, lymph node metastases at presentation, distant metastases at presentation, and high MACIS scores (>7) were identified as significant risk factors for the recurrence of PTC in Filipinos. In contrast, follicular variant histology and postsurgical radioactive iodine ablation therapy were identified as significant protective factors against PTC recurrence (Table 2). A multivariate logistic regression analysis of all significant factors revealed that age >45 years, lymph node metastases at presentation, distant metastases at presentation, and multifocality of cancer were independent risk factors, whereas follicular variant histology and postsurgical radioactive iodine ablation therapy were protective against PTC recurrence regardless of stage at presentation (Table 3). The relationship of the significant variables involved in PTC recurrence, regardless of effect, are clearly visible using a Kaplan-Meier curve (Fig. 1).

Factors including age >45 years, tumor size >4 cm, multifocality of cancer, bilateral lobe involvement, distant metastases at presentation, and incomplete thyroidectomy were all identified as significant risk factors for the recurrence of FTC in Filipinos. In contrast, postsurgical radioactive iodine ablation therapy was the only statistically significant protective factor against FTC recurrence (Table 2). A multivariate logistic regression analysis of all significant factors revealed distant metastases at presentation as the only independent risk factor, whereas postsurgical radioactive iodine ablation was further validated as a protective factor for FTC recurrence (Table 3). The relationships between variables significantly related to the recurrence of FTC, whether positively or negatively, are shown using a Kaplan-Meier curve (Fig. 2).

The incidence of WDTC continues to rise, due in part to steady progress in imaging and more sensitive monitoring methods [1]. Despite the excellent prognosis of WDTC, increasing morbidity from recurrences of this disease continues to affect long-term outcomes, leading to higher medical costs and poorer quality of life [3]. The impact of locoregional recurrence on survival continues to be controversial, as there is no established link between nodal recurrence and mortality [1314], and only distant metastases have been clearly shown to affect disease-specific survival [13]. Indeed, one study directly addressing this issue found that all the disease-related deaths in their study were due to distant recurrence, with no patients dying from uncontrolled locoregional recurrent disease [2].

Although the high recurrence rates observed in our study closely resembled those observed in the study by Kus et al. [11] among Filipinos in Canada, this association can likely be attributed to the larger baseline tumor size and delayed medical access of most of the patients in this study. Whether Filipino ethnicity represents an independent factor contributing to the aggressiveness of thyroid cancer remains difficult to discern at this time. Further genetic studies are necessary to establish the claim for more aggressive thyroid cancer behavior among Filipinos.

Disease-associated factors identified in our study were broadly comparable with those identified in other studies. Lymph node metastases at presentation appears to be the only factor consistently predictive of thyroid cancer recurrence across studies. Distant metastases at presentation has been consistently identified as an important risk factor for tumor recurrence (Table 4) [7151617]. The majority of nodal metastases start at the central nodal compartment, followed by the ipsilateral lateral nodal compartment, which is consistent with the typical lymphatic drainage pathway of the thyroid gland. Distant recurrence occurs commonly in the lung and bone but can also be seen in other sites. It has been shown that the location of recurrence has a prognostic significance for patients with recurrent WDTC, with distant metastases at presentation predictive of poor prognosis [18].

The 45-year age cutoff used by the International Union Against Cancer (UICC) TNM classification was also shown to be a significant risk factor for WDTC recurrence among Filipinos. Multifocality and bilaterality of thyroid malignancy were unique to this study as significant risk factors for WDTC recurrence. This observation may be indicative of greater aggressiveness and higher malignancy potential in thyroid nodules among Filipinos [12]. High MACIS scores in PTC (>7) were also shown to be predictive of PTC recurrence, which is consistent with its use as a potential prognostic scoring system [19].

Some variants of PTC have been associated with higher risk for disease recurrence and aggressiveness, including the tall cell variant of PTC, which is often seen as a more aggressive variant of PTC, increasing the risk for PTC recurrence [20]. On the other hand, the follicular variant of PTC was identified as a significant protective factor for PTC recurrence. This is consistent with the behavior observed in several studies on follicular variant PTC that showed lower nodal metastases at presentation with similar long-term prognoses as those of classic PTC [2122].

Among the different therapeutic modalities for WDTC, only post-surgical radioactive iodine ablative therapy was shown to significantly reduce recurrence. In our study, complete thyroidectomy was a significant protective factor according to univariate analysis, but it turned out to be insignificant when multivariate analysis was applied. This clearly proves that surgery alone is insufficient as a means of risk reduction or complete prevention of future recurrences; it must therefore be combined with post-surgical radioactive therapy [23]. Surprisingly, adequate TSH suppression therapy did not significantly lower recurrence in our study, suggesting only a minor role in our population as opposed to previous reports [24].

In conclusion, the recurrence rates for PTC and FTC in this study were 32.9% and 29.1% respectively. The most significant predictors of recurrence of PTC and FTC were nodal metastases at presentation and distant metastases at presentation, respectively. The factors contributing to the recurrence of WDTC among Filipinos that were identified in this study will be helpful in guiding treatment strategies and long-term thyroid cancer surveillance aimed to reduce future morbidity and mortality in this population.