Endocrine Abstracts

Introduction: active surveillance (AS) is feasible and safe for low-risk papillary thyroid carcinoma with diameter ≤ 1.3 cm (mPTC), as this type of cancer shows a low percentage of progression. At the present time, there are no prognostic factors which could help to identify mPTCs at higher risk of progression. The aim of this prospective study is to find a specific molecular signature of cases that showed disease progression during AS and which would allow their early identification.

Methods: NGS sequencing of fine needle aspiration cytology (FNAC) specimens from 95 patients enrolled in the AS program was performed to analyze key somatic driver alterations or gene fusions implicated in PTC tumorigenesis. TERT promoter analysis was performed using Sanger sequencing or droplet digital PCR (ddPCR). Disease progression was defined as the growth of the mPTC (at least 3 mm in all the three diameters) or the appearance of a metastatic lymph node.

Results: BRAF p.V600E mutation was found in 66.3% (63/95) of mPTC cases and it was the most common somatic alteration, followed by RAS oncogene mutations, detected in 3.2% of cases (3/95: 2 NRAS and 1 KRAS), and gene fusions, detected in 3.2% of cases (3/95: 1 RET-PTC1, 1 TGF-NTRK1, 1 ALK imbalance). No TERT promoter mutations (C228T and C250T) were found in the analyzed mPTC cases (84/95). After a median follow-up of 24 months, 8/95 patients (8.4%) showed a disease progression: 2/8 (25%) showed an increase in nodule dimensions, while 6/8 (75%) showed the appearance of small lymph node metastasis. All these 8 patients were submitted to surgery, and they all had a PTC at the final histological diagnosis. Five (5/8) patients had a BRAF p.V600E mutation, 1/8 patient had a RAS mutation, while 2/8 showed no mutations. It was observed that all the BRAF p.V600E positive cases showed lymph node metastases, while the only case with a RAS mutation had progression due to nodule enlargement. The comparison between the molecular profile and the clinical outcome of the mPTC cases (stable versus progressing disease) showed no correlation (P-value=0.06) and could not identify a molecular signature for mPTC cases indicating a higher risk of disease progression.

Conclusions: the identification of the most common driver mutations, such as BRAF, RAS, or gene fusions, is not helpful for the early identification of mPTC cases that will show disease progression during follow-up in the AS program.