PAX8/PPARγ rearrangement in thyroid nodules predicts follicular-pattern carcinomas, in particular the encapsulated follicular variant of papillary carcinoma

Abstract

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.

FIG. 1.

Cytologic and histologic appearance of the follicular variant of papillary thyroid carcinoma (PTC) positive for PAX8/PPARγ. (A) Cytologic smear shows groups of microfollicles with dense colloid; the nuclei are slightly elongated but retain smooth contours and show no nuclear grooves or pseudoinclusions, resulting in the cytologic diagnosis of “follicular neoplasm/suspicious for a follicular neoplasm” (Diff-Quik stain). (B) Cross section of the resected thyroid gland shows a well-encapsulated nodule (hematoxylin and eosin [H&E], 100×). (C) Microscopic image shows a thick capsule and predominantly microfollicular growth pattern (H&E, 100×). (D) Vascular invasion (H&E, 200×). (E) On high-power microscopic examination, the nuclei of the tumor cell are enlarged and overlapping and show chromatin clearing, significant irregularity of the nuclear contours, and occasional nuclear grooves (H&E, 400×).

FIG. 2.

Solid variant of papillary thyroid carcinoma (PTC) positive for PAX8/PPARγ. (A) Cytologic smear shows a cellular aspirate with mostly trabecular arrangement of cells and lack colloid; the cells demonstrate tridimensional clusters, are enlarged, and show some irregularity of the nuclear contours, resulting in the cytologic diagnosis of “follicular neoplasm/suspicious for a follicular neoplasm” (Papanicolaou stain). (B) Thick capsule and capsular invasion (hematoxylin and eosin [H&E], 100×). (C) Vascular invasion (H&E, 200×). (D) Trabecular and solid growth pattern of tumor cells that demonstrate elongated, enlarged and overlapping nuclei with chromatin clearing, irregularity of the nuclear contours, and scattered nuclear grooves (H&E, 400×).

FIG. 3.

Follicular thyroid carcinoma (FTC) positive for PAX8/PPARγ. (A) Cytologic smear shows well-formed microfollicles and dense colloid, resulting in the cytologic diagnosis of “follicular neoplasm/suspicious for a follicular neoplasm” (Papanicolaou stain). (B) Thick capsule with capsular invasion (hematoxylin and eosin [H&E], 100×). (C) Vascular invasion (H&E, 200×). (D) Microfollicular growth pattern demonstrates cells with round nuclei, smooth nuclear contours, and evenly distributed chromatin (H&E, 100×).