Background: PAX8/PPARγ rearrangement is a common genetic alteration in follicular thyroid carcinoma (FTC) and has been reported with variable frequency in papillary thyroid carcinoma (PTC). The diagnostic and phenotypic features of thyroid nodules positive for PAX8/PPARγ on preoperative examination are not well understood.
Methods: The prevalence of PAX8/PPARγ rearrangement was analyzed in a series of 2015 consecutive thyroid nodules that underwent molecular analysis on cytology specimens and in 446 surgically removed PTCs. For all PAX8/PPARγ positive cases, cytology and surgical pathology slides were examined and the available clinical records were reviewed.
Results: Twenty-two PAX8/PPARγ rearrangements were identified, including 16 detected preoperatively and 6 postoperatively. The incidence of PAX8/PPARγ in PTC was 1.1%. Cytologically, most of these nodules were diagnosed as a follicular neoplasm (73%), followed by the diagnosis of atypia of undetermined significance (19%), and none of the cases was diagnosed as cytologically malignant. All nodules with PAX8/PPARγ detected preoperatively and surgical follow-up available were found to be malignant, among which the most common diagnosis was the encapsulated follicular variant of PTC. Overall, among 20 PAX8/PPARγ-positive tumors that were surgically excised, 17 (85%) were PTC and 3 (15%) were FTC. On follow-up available for 17 patients (mean, 22.4 months), 16 PAX8/PPARγ-positive cancers showed no evidence of biochemical or structural recurrence, whereas 1 patient with FTC developed bone metastasis.
Conclusions: In this series, PAX8/PPARγ rearrangement found in thyroid nodules had a 100% predictive value for differentiated thyroid cancer, and was more predictive of PTC than FTC. However, almost all PTC carrying PAX8/PPARγ were encapsulated follicular-pattern tumors, distinguished from FTC only by nuclear features. Although most tumors carrying this mutation appear to be clinically indolent, at least on short-term follow-up, distant metastasis can develop from FTC positive for PAX8/PPARγ.