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/PPARγ 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).

The Impact of Noninvasive Follicular Variant of Papillary Thyroid Carcinoma on Rates of Malignancy for Fine-Needle Aspiration Diagnostic Categories

“…The BRAF V600E mutation is the most common mutation in classical PTC with RET/PTC rearrangements seen at a lower frequency; in contrast, RAS mutations and PAX8/PPARc rearrangements are the most frequent alterations associated with FTC (14)(15)(16)(17). While FVPTCs have frequent RAS mutations and can harbor PAX8/ PPARc rearrangements, some have the BRAF V600E mutation or a RET/PTC rearrangement, albeit at a much lower frequency than classical type PTC (6,14,(18)(19)(20)(21)(22). In the past decade it has become clear that not all FVPTCs are biologically alike.…”

“…Additionally, about a quarter of infiltrative FVPTCs harbor the BRAF V600E mutation and a small percentage have a RET/ PTC rearrangement (6). In contrast, encapsulated or partiallyencapsulated/well-circumscribed FVPTCs with no associated capsular penetration or lymphovascular invasion (i.e., NFVPTCs) have virtually no metastatic potential or risk of recurrence, and most groups have shown that they are associated with RAS mutations and PAX8/PPARc rearrangements, but lack the BRAF V600E mutation (2,3,5,6). Thus, it is likely that infiltrative FVPTCs are contributing to the classical PTClike clinical and molecular features of FVPTC; whereas the NFVPTCs are more akin to follicular adenomas and FTCs, with invasion determining the clinical course.…”

“…FVPTCs that demonstrate infiltrative growth have a significant rate of lymph node metastases, a potential to recur, and have a BRAF V600E mutation frequency of roughly 25% (2)(3)(4). In contrast, encapsulated, partially-encapsulated, or well-circumscribed FVPTCs without capsular penetration or lymphovascular invasion (i.e., noninvasive tumors) have very little, if any, metastatic potential or recurrence risk (3,5,6). Additionally, most groups have shown that the noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) harbors RAS and PAX8/ PPARc mutations but lacks the BRAF V600E mutation that is often associated with high-risk histopathologic features (7,8).…”

The atypical thyroid fine‐needle aspiration: Past, present, and future

“…16,55 However, a negative molecular result using the panel above is much less useful, in large part because many tumors, particularly PTC-FV , are negative for all of them or positive only for RAS mutations, which have much lower specificity and are noted in benign and malignant thyroid neoplasms. 56,57 A major obstacle to the application of a limited panel of molecular markers to thyroid FNA is the finding that currently available markers tend to work well with lesions that are readily diagnosed by cytomorphology; they are not as useful for the difficult thyroid FNA lesions diagnosed as AUS/FLUS, SFN, or suspicious for malignancy (PTC-FV). More recently, microarray data from > 200 genes have been used to produce a ''benign thyroid fingerprint'' that has the potential for use in guiding the management of patients with an AUS/FLUS interpretation.…”

Identification of a novel HRAS variant and its association with papillary thyroid carcinoma

“…HRAS is one of the most commonly mutated genes in PTC, particularly in variants identified in follicular (14)(15)(16)(17) and Hurthle cells (18), reflecting its key regulatory functions. The contribution made by HRAS to PTC progression is poorly understood.…”