Discussion
This case of an unusual presentation of PTC with a coincidental microMTC and challenging histopathology has a number of teaching points. Firstly, the presence of brain metastasis in DTC confers poor prognosis, with mean overall survival between 7-33 months5. Cerebral hemispheres are the most common site of intracranial metastasis, with less common sites being the cerebellum, brainstem and pituitary6. For patients with single brain metastasis and good performance status, surgical resection remains first-line therapy for optimal overall survival, followed by whole brain radiotherapy or stereotactic radiosurgery7. Stereotactic radiosurgery for brain metastasis is effective in achieving local control, with median survival of 14 months and shorter survival with higher number of metastases8. While RAI is required for treatment of the DTC, uptake by metastatic lesions is overall low, possibly due to reduced expression of the sodium iodine symporter in these lesions9. Apart from RAI, tyrosine kinase inhibitors (TKIs) are a class of drugs which directly inhibit mutant protein kinases and are efficacious in RAI-refractory DTC10–12. Our patient’s FDG-PET scan demonstrated new skeletal lesions that were avid which were not seen on the post-RAI131I scan, suggestive of RAI-refractory disease. Ten-year survival rates in metastatic DTC with loss of RAI avidity fall to only 10%13.
Genetic profiling in 20 DTC patients with brain metastases revealed the most common mutations as TERT promoter (TERTp ) (80%),BRAFV600E (55%) and concurrent mutations (50%)5. TERTp were associated with poorer survival, higher prevalence of distant metastases and RAI-refractory disease5. Synergistic effects between coexistentTERTp and BRAFV600E mutations also reduces overall survival compared to BRAFV600Emutation alone14.
Up to 10-15% of all MTCs are incidental findings after thyroidectomy for other indications including PTC15. In a large series of 2897 patients undergoing thyroidectomy for PTC, only 11 (0.37%) cases harboured both PTC and MTC, of which all MTC cases were sporadic. Mean PTC tumour size was 1.95cm compared to 1.20cm for the MTC component, and none were microMTC16. Similarly, incidental MTC prevalence in multinodular goiter specimens is 0.1-1.3%15. There has been debate on the clinical relevance of microMTC and the extent of their management. Distant metastases were found in 5.2% of microMTC cases in one study17. Ten-year survival in patients with localised disease was comparable to PTC at 95.7%, but drops with regional (86.7%) or distant metastases (50%), suggesting that microMTCs can be clinically aggressive17. While almost all patients with familial MTC harbor RET germline mutations, in a study of patients with sporadic MTC, the prevalence of somatic RETmutations ranged from only 11.3% in patients with microMTC up to 58.8% in those with MTC >3cm18. As the prevalence of RET mutations is low in microMTC, current ATA guidelines have not recommended routine testing in these patients19. While some microMTCs may be clinically significant, there is a paucity of data to fully risk stratify those that occur concurrently with other PTC.
The unusual factor in this case is the absence of PTC in the final thyroidectomy pathology specimen. Intra-operatively, the primary 30mm PTC was thought to originate from left level VI lymph nodes. Absence of PTC in the thyroidectomy specimen with evidence of metastatic lymph node disease has been rarely reported in the literature, and may represent a microcarcinoma unable to be detected by the pathologist20. However, this patient presented with sonographic findings of an intrathyroidal nodule with FNA highly consistent with PTC (Bethesda VI) as well as FDG-PET uptake separately in the left thyroid and lymph nodes. It is possible that the PTC had originated from ectopic thyroid tissue that has been overrun by tumour.