According to the 2015 American Thyroid Association (ATA) guidelines, RAI treatment is recommended for high-risk DTC, it should be considered for intermediate-risk DTC and it should not be routinely administered in low-risk patients [16]. The European Association of Nuclear Medicine disagreed with this recommendation, claiming that in low-risk patients there is a lack of solid evidence for the actual benefit of surveillance over RAI ablation [18, 20]. In particular, the issue is whether a patient who does not receive a “complete” treatment (total thyroidectomy and RAI ablation) is exposed to the risk of a late diagnosis of persistent/recurrent disease [21]. Although this is not our personal experience [22], some authors argued that 14.4% of low-risk patients with undetectable Tg and Tg antibodies had still radioiodine-avid metastatic lesions detected on post-therapeutic imaging 3–4 months after surgery and that this percentage should not be neglected [23].
We reported the case of a mi-FTC treated with the “complete” approach, according to the guidelines in force in 1994, relapsed after 24 years from the initial treatment, that today we would have likely treated just with surgery.
FTC is considered at low risk of recurrence if “minimally invasive”, namely an intrathyroidal tumor with capsular invasion and no or minimal (< 4 foci) vascular invasion. On the contrary, an FTC with extensive vascular invasion should be considered at high risk of recurrence and treated with RAI [16]. Based on the current risk stratification, our patient with a mi-FTC should not had undergone RAI treatment. Nevertheless, by using the “complete” therapeutic approach (total thyroidectomy and RAI ablation), which was in line with the recommendations of those years, the patient somehow had a benefit. Thanks to the periodic assessment of Tg levels, an early detection of the disease recurrence was possible. We might speculate that if he had been treated only with total thyroidectomy or simple lobectomy, a slight raise of Tg levels, that in our case flagged the disease recurrence, would have remained unacknowledged for some time, maybe some years. In this hypothetic scenario, we probably would have blamed the physician who made the decision on the initial treatment without RAI ablation. However, considering the early detection of the recurrence, a real benefit for this patient is debatable. From the first raise of Tg levels in 2018, the patient intensified the frequency of his medical checks and underwent two more high-dose RAI treatments, of which the second was definitively unnecessary and the first was ineffective because of the radioiodine-refractoriness. He also performed many imaging exams in search of the disease location. Over a 3-year period, he had a total of 3 CT scans and 4 PET-18FDG exams that eventually detected 3 millimetric lesions in the lung. Moreover, he was submitted to two useless 131-I treatments since it was already demonstrated that the disease was radiorefractory.
In the hypothetic scenario of an initial treatment with surgery only, the Tg increase would anyway happen and thus considered unequivocally suspicious for disease recurrence. At that point a CT scan would be performed and lung metastasis would be revealed, likely at the time to be treated.
Going back to the real case report, the “complete” treatment with surgery and RAI ablation did not spare the patient from the long-term recurrence. There are no studies available on recurrence rates specifically for FTC, treated with or without RAI. The evidences available focus on DTCs in general and, anyway, rarely consider homogenous and properly stratified populations [24]. Available data specifically on FTC concern mortality rates and found no significant differences in survival if RAI ablation is performed [25, 26]. In particular, a SEER registry secondary analysis did not find any improvement of the disease-specific survival in patients with FTC < 1 cm treated with RAI ablation in a multivariate analysis adjusted for age, histology, disease extent, type of surgery, and external beam radiation therapy [25]. However, this study focused just on small FTC (< 1 cm) and included some cases with histological aggressive features and thus not considerable as low-risk tumors. Another recent retrospective study made on 858 FTC and 476 Hürthle cell thyroid carcinoma, both < 1 cm, did not demonstrated any survival benefit in patients treated with RAI [26].
Two prospective trials, ION (NCT01398085) and ESTIMABL2 (NCT01837745) are ongoing with the purpose to compare the outcomes in low-risk DTC, including FTC, patients treated with RAI ablation. Data from ESTIMABL2 trial drawn after 3 years from the randomization showed no differences in number of tumor-related events that led to perform a subsequent RAI treatment between patients in the follow-up group (4.4%) and in the ablation group (4.1%) [15]. A long follow-up of at least 10 years will be needed in order to provide a strong and reliable evidence [20]. Otherwise, we would need to wait the long-term follow-up of low-risk FTC patients that today are not treated with RAI ablation in accordance to the 2015 ATA guidelines.
Another issue to be discussed is the dimension of the primary tumor. In this case report, the recurrence, albeit late, occurred in a patient with a 6-cm intrathyroidal tumor. It might be hypothesized that a such high dimension could enhance the risk of recurrence. Some authors suggested that, similarly to papillary thyroid cancer, in FTC there is a difference in outcome according the tumor size, although using different cut-offs [27, 28]. Sugino et al. found that in FTC the risk factors for distant metastasis during follow-up were age and a primary tumor size > 4 cm [27]. Similarly, Goffredo et al. found that a larger tumor size was correlated with a more frequent vascular invasion [30]. Nevertheless, 2015 ATA guidelines still consider FTC > 4 cm at low risk as long as it does not have a widely invasion of tumor capsule and extrathyroidal extension [16].
In conclusion, we cannot exclude that in our patient the RAI ablation might have delayed the development of the distant metastasis but certainly it was not sufficient to avoid the disease recurrence. Moreover, if it is true that the remnant ablation simplified the follow-up and allowed the early discovery of the biochemical recurrence, it did not change the outcome of the disease.
Furthermore, it has not yet been proven that RAI ablation has an effective impact on patient’s outcome and that the delayed detection and treatment of persistent/recurrent disease can reduce the chances of recovery in DTC patients who have not been RAI-ablated. From a practical point of view this case shows that the outcome of this patient was not really due to the type of treatment chosen but to the biological behavior of the tumor, likely already determined at the time of diagnosis.
