INTRODUCTION
Although anaplastic thyroid cancer (ATC) is a rare malignancy, representing only 2% of thyroid cancers, it is notorious for its aggressive behavior and dismal prognosis, with a median overall survival time of 3–5 months.1,2 ATC often manifests suddenly and progresses rapidly; approximately 50% of patients present with distant metastasis at diagnosis,2 highlighting the critical need for timely diagnosis and immediate treatment initiation. Moreover, ATC frequently metastasizes to the brain, with reported incidence rates ranging from 3% to 11%.2,3 Brain metastasis (BM) often leads to neurological deficits, significantly diminishing the quality of life. In addition, thyroid cancer BMs exhibit a bleeding tendency, leading to serious neurologic deterioration.4 Therefore, identifying associated factors for BM in patients with ATC is essential for early detection, which could substantially improve both the quality of life and overall prognosis.
The 2021 American Thyroid Association guidelines recommend brain magnetic resonance imaging (MRI) at the time of initial staging in patients being considered for therapy.5 Although this recommendation is classified as strong, the guideline rates the quality of supporting evidence as low.5 Brain MRI is also advised when clinically indicated, typically in the presence of symptoms suggestive of brain metastases, such as neurologic deficits or headache.5 However, guidance remains limited regarding the use of brain MRI in clinical scenarios beyond initial staging and the presence of neurological symptoms.
The associated factors for BM in patients with ATC remain undetermined due to the rarity of this disease. Therefore, the purpose of our study was twofold: first, to identify the factors associated with the occurrence of BM, and second, to assess the diagnostic yield of brain MRI conducted either during the initial evaluation of ATC or in patients with associated factors, as identified in our study.
SUBJECTS AND METHODS
1. Participants
This retrospective, observational, single-institution study was approved by the Institutional Review Board of our institution, which waived the requirement for informed consent. We conducted a retrospective search of electronic medical records from May 2008 to July 2024 and identified 187 patients with pathologically confirmed ATC via surgical resection or biopsy. Of these, 101 patients were excluded because they had not undergone brain MRI for the evaluation of BM, and an additional nine were excluded because of concurrent primary malignancies other than thyroid cancer. Finally, 77 patients were included in this study (Fig. 1). A total of 152 BMs were observed in 77 patients. A total of 104 brain MRI scans were obtained for the following reasons: initial staging, apparent neurological symptoms, and progression of distant metastasis.
2. Baseline characteristics
Initial stages were determined according to the Eighth Edition of the American Joint Committee on Cancer guidelines. The presence or absence of extracranial metastases and neurological symptoms, including headache, dizziness, nausea, focal neurological deficits, seizures, cognitive impairment, syncope, and altered mental status, was evaluated at the time of brain MRI surveillance. Data on sex and age were retrieved from electronic medical records. Primary tumor size was measured based on the largest diameter observed on neck computed tomography or ultrasound scans. In addition, BRAF, TERT promoter, RAS, and PIK3CA mutations, as well as the Ki-67 labeling index, were assessed whenever feasible. Peptide nucleic acid-mediated clamping polymerase chain reaction was utilized to detect BRAF mutations.6 TERT promoter mutations were identified through pyrosequencing,7 and RAS and PIK3CA mutations were investigated using next-generation sequencing.8
3. Diagnostic yield of brain MRI with different BM associated factors
The diagnostic yield of brain MRI, defined as the proportion of patients with true-positive BMs among those with certain BM-associated factors, served as the secondary outcome of this study. Specifically, the yield was calculated by dividing the number of true-positive results by the total number of patients presenting with each BM-associated factor. We calculated the diagnostic yield of brain MRI performed during initial staging and assessed the yield of brain MRI specifically in patients with extracranial metastasis, neurological symptoms, or extracranial progression. Extracranial progression was defined as tumor progression outside the brain based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria (i.e., progressive disease), which led to a change in the treatment regimen.
4. MRI acquisition
Routine MRIs to evaluate BMs were performed using a Siemens 3T Vida scanner (Siemens Healthineers; Erlangen, Germany) or a GE 3T Discovery MR750 scanner (GE Healthcare; Milwaukee, WI, USA). The BM MRI protocol included T1-weighted imaging (T1WI), T2-weighted imaging, fluid-attenuated inversion recovery, SWI, and contrast-enhanced T1WI. Contrast-enhanced images were acquired after administration of gadobutrol (0.2 mmol/kg, Gadovist; Bayer Schering Pharma, Berlin, Germany). The detailed parameters are provided in Supplementary Table 1.
5. Statistical analysis
The baseline characteristics were compared between patients with and without BM. Continuous variables were compared using Student’s t-test, whereas categorical variables were compared using the χ² or Fisher’s exact test. To identify the associated factors for the occurrence of BM in ATC, multivariable logistic regression analysis was performed using independent factors, including age at initial cancer diagnosis, sex, primary tumor size, presence or absence of extracranial metastasis, and neurological symptoms. Statistical analyses were performed using R software (version 4.3.2). Statistical significance was set at p<0.05.
RESULTS
1. Patient characteristics
The study included 77 patients, with a nearly equal distribution of males (37, 48.05%) and females (40, 51.95%), and a mean age of 61.52±13.19 years. Among the patients, 19 exhibited BMs, whereas 58 did not. A comparison of the initial tumor stages between the two groups revealed a significant difference (p=0.006). In addition, extracranial metastases at the time of brain MRI surveillance were more frequently observed in patients with BMs than in those without BMs (94.74% vs. 58.62%, p=0.004). Specifically, lung metastasis was more common in patients with BMs (84.21% vs. 53.45%, p=0.017). In addition, neurological symptoms were more prevalent in patients with BMs than in those without BMs (73.68% vs. 31.03%, p=0.001). No significant differences were noted in sex, age at ATC diagnosis, thyroid tumor size, or BRAF/TERT promoter/RAS/PIK3CA gene mutations between the two groups (Table 1).
2. Associated factors for BM occurrence
The multivariable logistic regression analysis revealed that the occurrence of BM was independently associated with the presence of extracranial metastasis (odds ratio [OR]=16.09, 95% confidence interval [CI]: 2.39–360.7, p=0.019) and neurologic symptoms (OR=5.95, 95% CI: 1.73–24.08, p=0.007) at the time of surveillance brain MRI. The other analyzed factors were not statistically significant (Table 2).
3. Diagnostic yield of brain MRI with different BM associated factors
The diagnostic yields of brain MRI for different BM associated factors are summarized in Table 3. Of the 49 brain MRI scans conducted for initial staging, three revealed BMs, resulting in a diagnostic yield of 6.12% (3/49). Among the 68 brain MRI scans of patients with extracranial metastases, 18 were reported to show BMs, yielding a diagnostic rate of 26.47% (18/68). Of the 36 brain MRI scans from patients presenting with neurological symptoms, 14 confirmed the presence of BM, with a diagnostic yield of 38.89% (14/36). We evaluated the diagnostic yield of BM in patients who underwent brain MRI due to extracranial progression. Of the 29 brain MRI scans, 13 revealed BMs, with a diagnostic rate of 44.83% (13/29).
DISCUSSION
This retrospective study aimed to identify the associated factors for the occurrence of BMs in patients with ATC. Our findings indicate that BM occurrence is significantly associated with the presence of extracranial metastasis at the time of brain surveillance, and the presence of neurological symptoms. Multiple logistic regression analysis confirmed that extracranial metastasis and neurological symptoms were independent predictors of BMs in patients with ATC. Furthermore, the diagnostic yield of surveillance brain MRI was 26.47% in patients with extracranial metastasis and 38.89% in those with neurological symptoms. These findings suggest that brain MRI may be clinically useful in ATC patients with extracranial metastasis or neurological symptoms.
In the present study, extracranial metastasis was a significant predictor of BM in patients with ATC. This finding aligns with the well-established notion that BMs frequently arise in settings of extensive metastasis.9,10 Previous research has demonstrated that 58.8% of patients with BMs also concurrently presented with extracranial metastases. 9 In addition, several studies utilizing genome-wide molecular techniques have proposed two modes of disease progression: one suggests a monoclonal origin, where metastases descend from a common “metastatic precursor”; and the other posits that multiple metastatic lesions are seeded by different clones present within the primary tumor.11 Furthermore, evidence indicates that metastasis-to-metastasis seeding occurs more frequently than metastases originating directly from the primary tumor.12-14 Another noteworthy finding from our study is that patients with lung metastases were more likely to develop BMs compared with those without lung metastases (Fig. 2). Previous studies also reported the co-existence of other organ metastases and BMs in patients with thyroid cancer.3,15 The most frequent coexisting metastatic sites were the lungs (85%).15 Although the specific mechanisms underlying this phenomenon are unknown, one plausible explanation involves the route of metastasis. As the central nervous system lacks a lymphatic system, cancer cells can only reach the brain through the bloodstream. Lung cancer frequently metastasizes to the brain via this pathway.16 Similarly, lung metastases may have a predisposition to spread to the brain. Nonetheless, further research is required to draw definitive conclusions.
Current guidelines recommend brain MRI at the time of initial staging in ATC patients being considered for therapy, although the quality of evidence supporting this recommendation is rated as low.5 Notably, the diagnostic yield of brain MRI in patients with stage II non-small cell lung cancer (NSCLC)—for whom routine screening is recommended by National Comprehensive Cancer Network (NCCN) guidelines—has been reported as 4.68%.17,18 In our study, the yield during the initial staging was 6.12%, indicating a potentially higher prevalence of brain metastases in ATC compared to stage II NSCLC. These findings provide further support for routine screening brain MRI in ATC patients, consistent with current recommendations.
Recent studies have explored the ATC mutational landscape and enhanced our understanding of the molecular pathogenesis of thyroid cancer. The BRAF-V600E mutation, occurring in 10-50% of ATCs, activates the mitogen-activated protein kinase pathway leading to uncontrolled cell proliferation, is correlated with poor prognosis in ATC patients and is strongly related to extra-thyroidal invasion and cervical lymph node metastasis in papillary thyroid cancer.19,20 A study on a mouse model revealed that BRAF-V600E mutation coexisting with a mutation of PIK3CA, which is one of the catalytic subunits of the phosphatidylinositol-3 kinase enzyme complex, can lead to the development of ATC.21 Telomerase reverse transcriptase (TERT) promoter mutation, which is associated with cellular immortality and tumorigenesis by maintaining telomere length at the ends of chromosomes, is linked to aggressive, metastatic, and thyroid stem cell phenotypes.22 Furthermore, concomitant BRAF/PIK3CA and TERT promoter mutations are linked to poor prognosis in patients with ATC.23,24 In our study, neither BRAF-V600E mutation nor concomitant BRAF/PIK3CA and TERT promoter mutation were associated with the development of BM. These findings suggest that the process of BM is influenced by a complex interplay of different biological factors beyond the inherent aggressiveness of the primary tumor.
This study has certain limitations. First, as this was a single-institution retrospective analysis, our findings may not be generalizable. For example, not all patients with extracranial progression underwent brain MRI, our calculated diagnostic yield in this population may differ from that of real-world data. Second, ATC is very rare; although the number of patients was the largest compared with that of previous studies, it was not large enough to draw a robust conclusion. Therefore, multicenter studies with larger sample sizes are required to validate our findings and explore the underlying biological mechanisms. Lastly, genetic analyses were not available for some patients, which may have influenced the results.
In conclusion, our results provide support to the current recommendations to perform brain MRI at initial staging and in the presence of neurological symptoms in ATC pa-tients. Beyond these established indications, we identified extracranial metastasis as an independent and significant factor associated with BM. These findings suggest that brain imaging should also be considered in asymptomatic patients with extracranial metastasis, which may help guide more comprehensive surveillance strategies in ATC management.
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