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To the Editor: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, and an excellent long-term prognosis is attained in most patients.1 However, aggressive variants of PTC, including tall cells, columnar cells, insular cells, solid cells, and diffuse sclerosing subtypes, are associated with higher recurrence and reduced survival rates.2 The role of radioactive iodine (RAI) therapy in managing these aggressive variants remains controversial, particularly regarding its impact on cancer-specific survival (CSS).3 The 2015 American Thyroid Association (ATA) guidelines classify aggressive PTC variants as intermediate risk factors for recurrence but do not provide clear recommendations for RAI therapy.4 While some studies suggest that RAI therapy improves overall survival (OS) in certain subgroups, others report no CSS benefit, even in patients with distant metastases.5 To address this uncertainty, we analyzed a large cohort of patients with aggressive PTC variants from the Surveillance, Epidemiology, and End Results (SEER) database (https://seer.cancer.gov/), using propensity score matching (PSM) to control for confounding factors. In addition, the administration of RAI therapy after total thyroidectomy for malignancy may be multifactorial. Hence, other risk factors that potentially drive the decision to administer RAI for aggressive PTC variants were also discovered in our study. This retrospective study included patients diagnosed with aggressive PTC variants (tall cells, diffuse sclerosing, insular cells, and solid cells) between 2001 and 2020, as identified from the SEER database. Patients aged 0.05) Supplementary Table 1, https://links.lww.com/CM9/C609. In the original cohort, the median follow-up period was 79 months, with a 5-year CSS rate of 95.55%. No significant CSS benefit was observed with RAI therapy in either the original or PSM cohorts (P = 0.241 and P = 0.288, respectively) Supplementary Figure 2 and Supplementary Table 2, https://links.lww.com/CM9/C609. To explore the impact of RAI therapy on CSS in patients with aggressive variants of PTC, a Cox proportional hazards regression analysis was conducted in the PSM cohort Supplementary Table 3, https://links.lww.com/CM9/C609. The results revealed that age ≥55 years, tumor size (20–40 mm), lymph node metastasis, and distant metastasis were unfavorable prognostic factors for aggressive PTC (all P values 5 positive lymph nodes or distant metastases (M1 stage) had significantly improved CSS after RAI therapy (HR = 0.40, P = 0.035; HR = 0.40, P = 0.025, respectively) Supplementary Table 4, https://links.lww.com/CM9/C609. This advantage was further verified via Kaplan–Meier survival curves in patients with >5 positive lymph nodes or M1 stage disease, as shown in Figure 1 (P = 0.038; P = 0.012).Figure 1: K–M survival curves for cancer-specific survival between the radioactive iodine therapy group and the nonradioactive iodine therapy group. (A) Patients with aggressive PTC variants and >5 positive lymph nodes. (B) Patients with aggressive PTC variants and M1 stage disease. K–M: Kaplan–Meier; PTC: Papillary thyroid cancer; RAI: Radioactive iodine.According to the 2015 ATA guidelines, aggressive variants of PTC are well-known independent factors for considering RAI therapy after total thyroidectomy.1 However, the T stage of aggressive PTC variants that can benefit from RAI therapy is still unclear.1 Based on our current study, an in-depth examination of the T stage provides evidence that RAI treatment may not be appropriate for patients with aggressive PTC with any T stage, because their CSS is similar to that of patients who did not receive RAI therapy Supplementary Table 4, https://links.lww.com/CM9/C609. This result seems somewhat unexpected because extensive ETE (T3) or vascular invasion (T4) is a high-risk factor for recurrence, and the benefits of RAI treatment have been widely recognized.6 A possible reason for this phenomenon may be that the cohort of patients with T3 stage disease in this study included some patients with minimal ETE, which is no longer used as the classification standard for T3 stage disease because of its limited effect on PTC prognosis.7 In studies related to adjuvant therapy, recurrence-free survival is a commonly used endpoint, which may explain the unexpected results observed when OS and CSS are used as endpoints. There is a lack of data on the effect of RAI therapy on recurrence, which makes it impossible to fully determine whether RAI treatment is beneficial for patients with aggressive T3/T4 stage PTC. In terms of the number of metastatic lymph nodes, several studies4,5 have shown that the risk of recurrence positively relates to a greater number of positive lymph nodes at initial presentation. Sugitani et al4 reported that the risk of recurrence was significantly higher in patients with >5 lymph node metastases (19%) than in those with 5 metastatic lymph nodes was associated with a significantly worse disease-free survival than the presence of 5 positive lymph nodes. This report shows that patients with aggressive PTC variant and >5 positive lymph nodes may gain a CSS advantage from RAI therapy. In addition to the number of positive lymph nodes, the relationship of the largest dimension of metastatic lymph nodes with a recurrence has also been reported, and pathologic N1 with any metastatic lymph node ≥3 cm in the largest dimension was stratified as a high-risk factor for recurrence.1 In addition, extranodal extension (ENE) in positive lymph nodes is an important risk factor for recurrence.8 However, whether these metastatic lymph node characteristics help distinguish aggressive variants in patients with PTC who could gain a CSS advantage from those receiving RAI therapy remains unknown due to the lack of these data in the SEER database. Hence, based on our CSS findings, we propose and highlight the potential intended use of RAI therapy for patients with aggressive PTC variants and >5 positive lymph nodes or M1 stage disease, but not for all patients with aggressive PTC variants. Notably, although individuals without these characteristics do not potentially benefit from RAI therapy for CSS, whether RAI therapy should be performed remains to be determined. On the one hand, patients who had been exposed to external beam radiation were excluded from the study because they may be considered incurable. On the other hand, patients with incurable disease may receive a combination of various therapies, including palliative surgery, RAI therapy, external radiotherapy, and targeted drug therapy. Therefore, it is difficult to evaluate the benefits of RAI therapy alone accurately. However, as mentioned earlier, recurrence-free survival is the classical endpoint of adjuvant RAI therapy, which was not evaluated in the present study for these aggressive PTC variants because of the lack of recurrence data in the SEER database. This study has several limitations, including its retrospective design and lack of data on RAI dosage, recurrence, and molecular markers such as BRAF mutations. Prospective studies with longer follow-up periods and more detailed treatment data are needed to validate these findings. Availability of data and materials The data used during the current study are available from the SEER database. Conflicts of interest None.
Ye et al. (Mon,) studied this question.