Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns

Abstract

The follicular variant of papillary thyroid carcinoma usually presents as an encapsulated tumor and less commonly as a partially/non-encapsulated infiltrative neoplasm. The encapsulated form rarely metastasizes to lymph node, whereas infiltrative tumor often harbors nodal metastases. The molecular profile of the follicular variant was shown to be close to the follicular adenoma/carcinoma group of tumors with a high RAS and very low BRAF mutation rates. A comprehensive survey of oncogenic mutations in the follicular variant of papillary thyroid carcinoma according to its encapsulated and infiltrative forms has not been performed. Paraffin tissue from 28 patients with encapsulated and 19 with infiltrative follicular variant were subjected to mass spectrometry genotyping encompassing the most significant oncogenes in thyroid carcinomas: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1 and other related genes. There was no difference in age, gender, tumor size and angioinvasion between encapsulated or infiltrative tumors. Infiltrative carcinomas had a much higher frequency of extrathyroid extension, positive margins and nodal metastases than encapsulated tumors (P<0.05). The BRAF 1799T>A mutation was found in 5 of 19 (26%) of the infiltrative tumor and in none of the encapsulated carcinomas (P=0.007). In contrast, RAS mutations were observed in 10 of 28 (36%) of the encapsulated group (5 NRAS_Q61R, 3 HRAS_Q61, 1 HRAS_G13C and 1 KRAS_Q61R) and in only 2 of 19 (10%) of infiltrative tumors (P=0.09). One encapsulated carcinoma showed a PAX8/PPARgamma rearrangement, whereas two infiltrative tumors harbored RET/PTC fusions. Encapsulated follicular variant of papillary thyroid carcinomas have a molecular profile very close to follicular adenomas/carcinomas (high rate of RAS and absence of BRAF mutations). Infiltrative follicular variant has an opposite molecular profile closer to classical papillary thyroid carcinoma than to follicular adenoma/carcinoma (BRAF>RAS mutations). The molecular profile of encapsulated and infiltrative follicular variant parallels their biological behavior (ie, metastatic nodal and invasive patterns).

Figure 1

Infiltrative follicular variant of papillary thyroid carcinoma. (a) Low-power view showing tumor (T) growing in a follicular pattern with marked fibrosis and an infiltrating advancing front (arrow). (b) Medium power showing tongues of tumor-infiltrating nonneoplastic thyroid without interposition of a capsule (arrow). (c) High-power view of the nuclear features of papillary thyroid carcinoma: hypochromatic, irregular and overlapping nuclei with grooves (the latter indicated by an arrow). (d) Mass spectrometry traces for BRAF mutation from the tumor. Note the mutant BRAF_T1799A (indicated by M) and wild-type (W) peaks.

Figure 2

Encapsulated follicular variant of papillary thyroid carcinoma. (a) Low-power view showing tumor (T) surrounded by its capsule (cap) with no invasion. (b) Medium-power view revealing follicular growth with densely eosinophilic colloid characteristic of the follicular variant of papillary thyroid carcinoma. (c) High-power view of the nuclear features of papillary thyroid carcinoma: hypochromatic, irregular and overlapping nuclei with grooves (the latter indicated by an arrow). (d) Mass spectrometry traces for NRAS codon 61 mutation from the tumor. Note the mutant NRAS 182G (indicated by M) and wild-type (W) peaks.

Figure 3

Infiltrative follicular variant of papillary thyroid carcinoma metastatic to lung at presentation. (a, b) A 35-year-old male with BRAF_T1799A mutation. Medium power of primary tumor (a) shows tumor growing in a follicular pattern with marked fibrosis. High power (b) reveals clear, irregular and overlapping nuclei. (c, d) A 53-year-old male with no mutations detected. Medium power of primary tumor (c) shows tongues of infiltrating tumor with marked fibrosis. High power of follicle lined by clear, irregular and overlapping nuclei with grooves (arrow).

Figure 4

A 36-year-old male with encapsulated follicular variant of papillary thyroid carcinoma harboring a PAX8/PPARγ rearrangement. (a) Medium power showing follicles with densely eosinophilic colloid characteristic of the follicular variant of papillary thyroid carcinoma. (b) High power showing clear, irregular and overlapping nuclei with grooves (arrow).

Figure 5

BRAF and RAS mutational patterns of follicular variant of papillary thyroid carcinoma according to its encapsulated and infiltrative subtypes. The mutational pattern of encapsulated follicular variant of papillary thyroid carcinoma is similar to follicular adenoma/carcinoma, whereas infiltrative follicular variant of papillary thyroid carcinoma has a BRAF and RAS genotype in between follicular adenoma/carcinoma and classical papillary carcinoma, although closer to the latter. The mutational patterns of encapsulated and infiltrative follicular variant of papillary thyroid carcinomas parallel their lymph node metastatic rate.