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.