Data on the optimal management of RM from DTC, their influence on morbidity and overall survival remains scarce (Zunino et al. 2019). Being aware of the unusual or rare locations of thyroid metastases helps in early diagnosis and proper patients' management (Madani et al. 2015). The use of SPECT/CT imaging in the follow-up of DTC patients provides precise anatomical localization and characterization of RM that may be missed or misinterpreted in planar WBI scan (Palaniswamy and Subramanyam 2018b).
PTC represents 53.3% in our study population. Zunino et al., and Madani et al., reported nearly similar results which were explained by higher incidence of papillary carcinoma in their population (Zunino et al. 2019; Madani et al. 2015). In contrast to See et al. (See et al. 2017) who found that FTC was more common than PTC and most frequently associated with distant metastasis than papillary carcinoma due to hematogenous spread.
The mean age of our patients at the time of diagnosis was 55.8 years and only two patients were younger than 40. Similar findings were reported in the literature (Dhanani et al. 2021; Lee and Soh 2010).
Female gender represents 60% of our series; this may be explained by higher incidence of DTC in females. Previous meta-analysis showed that male population had higher risk to develop distant metastasis and therefore a poor prognosis compared to females (Vuong et al. 2018).
Most of RM lesions from DTC were found to develop metachronously in previous studies (Yoon et al. 2020; Zunino et al. 2019; Madani et al. 2015). Conversely, in our series 60% of the detected RM lesions were synchronous. This may be explained by recent improvement in lesion detection after use of hybrid imaging. Similar results were observed by Albano who reported 62% synchronous metastases in their study population (Albano et al. 2018, 2019).
In our study, all RM lesions were iodine avid and continued concentrating I-131 throughout the follow-up period and so treated with multiple doses of radioactive iodine as a first choice. In contrast to these results, Albano et al. reported loss of RAI avidity during follow-up, more frequently (50%) of metachronous metastases and 15% of synchronous metastases (Albano et al. 2019). Most of our study population (66.67%) showed favorable response to RAIT, even in cases with multi-organ distant metastases. This indicates that RM does not always represent a poor prognostic factor for disease outcome. Patients who showed bad prognosis with disease progression had lesions in vital organs, e.g., brain, or were resistant to RAIT. These patients were candidate for tyrosine kinase inhibitor therapy which is not available in our region.
From our study, it was noted that the mean of cumulative radio-iodine activities administered in patients with metachronous metastatic lesions was significantly higher than synchronous lesions. Similar results were reported by a previous study by Albano et al., they also observed that total RAI activities administrated, and the total number of doses was significantly higher in metachronous than synchronous metastases (Albano et al. 2019). In addition to RAIT, other systemic and local therapies may be considered including, metastatectomy, external beam RTH and radiofrequency ablation (Djenic et al. 2015; Paspala et al. 2019). This was considered in our patients where surgery was applied to solitary isolated RM in two cases in addition to RAIT and both cases showed disease regression. Complementary treatment with palliative surgery or external beam RTH was added according to each case especially for patients with multi-organ metastases. More future studies recommended by Djenic et al., to establish therapeutic algorithm with accurate and definitive care of such cases with RM (Djenic et al. 2015).
Adding SPECT/CT with RM identification has a significant impact on patients' management. In the present study management changed in 66.67% of patients by adding local therapy (RTH and metastatectomy) or avoiding inappropriate treatment/ horrible surgery such as eye enucleation in case of eye metastasis misdiagnosed as eye melanoma or monitoring therapy without change in management with favorable response to RAIT if discovered early like in pancreatic and kidney metastases.
Although death from thyroid carcinoma is rare, it occurs mainly in metastatic patients with 5-year survival rate of about 15.3% in multi-organ metastasis (Wang et al. 2014). Three patients (20%) in our study died due to disease progression. Two of them had multi-organ metastases in addition to the rare metastatic site. Similar results were published by Yoon et al., who reported 31.6% death rate in their study due to progressive disease (Yoon et al. 2020).
Regarding sites of metastatic disease, metastatic invasion of the skull bone is rare and develops in only 2.5%-5.8% of the cases and mostly affects the sella turcica, pituitary gland, cavernous sinus and sphenoid sinus (Osorio et al. 2017; Sheikh et al. 2018). Herrin we presented a case of sella turcica metastasis, she was treated by RAIT and RTH and still has evidence of residual disease like in our case Fig. 1. The reported incidence of renal metastases is about 3% for the papillary subtype and 6–20% for the follicular subtype (Falzarano et al. 2013; Patel et al. 2011). We reported 2 cases of renal metastases, one of them had papillary and the other had follicular carcinoma.
Few reported cases of pancreatic metastases from thyroid carcinoma. Most of them derived from papillary thyroid carcinoma. Distant metastases to other organs were encountered in half of these cases (Murakami et al. 2018). Herein we have a case of female patient, FTC who also had bone and lung metastases in addition to renal and pancreatic metastases. She had good response to RAIT Fig. 2.
For DTC, the brain is an unusual site for distant metastases, occurring in about 1% of cases (Kim et al. 2009). By their nature they represent an immediate threat to patients. The uptake of RAI by brain metastatic lesions is low (0–25% of cases) (Lee et al. 2015). In our study we have one case from three cases with solitary brain metastatic lesion that was treated by surgical excision. In accordance with previous studies (Choi et al. 2016; Henriques de Figueiredo et al. 2014), we observed that DTC patients usually presented with other extracranial metastases at time of diagnosis in addition to brain metastases Fig. 3.
Regarding bone metastases from DTC, the rate is higher for FTC (7–28%) than PTC (1–7%). This explained by the tendency of FTC to spread hematogenously. A single bone metastasis in DTC patients is very rare. Palaniswamy et al. reported 3 cases of solitary bone metastases to sacrum, humerus and scapula (12). We reported a case of solitary bone metastasis to iliac bone.
Only 58 cases of muscular metastasis from DTC have been reported, from 1907 to 2017. The most frequent muscles involved are the gluteus muscles. The majority of muscular metastases are correlated with worse survival (Tunio et al. 2013). In our series we have only one case of skeletal muscle metastases to temporalis and pterygoid muscles, the patient is female with FTC and she also had lung metastases, she received RAIT with progressive disease till now.18F FDG-PET /CT was done for confirmation Fig. 4.
Based on the literature, only 112 cases of metastases from DTC to parapharyngeal spaces reported in the last two decades (Giordano et al. 2015). Perfect surgical excision favors response to RAIT with even complete resolution as in our cases.
The existence of eye metastases secondary to primary thyroid neoplasm is an unusual event, with only 22 reported cases from 1979 to 2012, most of them occurred late in the disease course (Avram et al. 2004). In our case choroidal metastasis had occurred 20 years after diagnosis.
Some limitations need to be addressed
One limitation is small sample size due to the rarity of such cases. Exclusion of rare cases with insufficient data (absence of SPECT/CT images or confirmatory imaging) underestimates the exact number of cases with RM. Unavailability of tyrosine kinase inhibitor drugs in our region rendering assessment of its response on patients with progressive course.
Recommendation
Furthermore, studies are needed to establish therapeutic algorism in such rare cases and to assess the response to tyrosine kinase inhibitor drugs especially in resistant cases to RAIT.