Molecular mutations as a possible factor for determining extent of thyroid surgery

Abstract

Background Molecular testing of thyroid nodules is a diagnostic tool used to better understand the nature of thyroid nodules. The aim of this study is to better comprehend the relationship between specific mutations and aggressive behavior of the tumour as demonstrated on postoperative pathological analysis. Methods A retrospective chart review of 103 cases was performed. Included were patients who had undergone molecular testing using a panel that tests for 9 mutations (ThyGenX®) and were found to have malignant tumours. The following gene alterations were found pre-operatively in the nodules: BRAF V600E (n = 32), BRAF K601E (n = 4), NRAS (n = 11), HRAS (n = 4), KRAS (n = 3), RET/PTC1 rearrangement (n = 1), TERT promoter (n = 2), PAX8-PPARγ rearrangement (n = 1), and 45 cases where no mutation was detected. Aggressive behavior was defined by extra-thyroidal extension (ETE), lymph node metastasis (LN+), and the following variants of papillary thyroid carcinoma: tall cell, solid, diffuse sclerosing, columnar cell and hobnail. Chi-squared testing was performed to compare groups. Results The group with BRAF V600E, RET/PTC1 rearrangement, and TERT promoter mutations was associated with ETE 37.1%, and LN+ 45.7% of the time compared to 4.3 and 13.0% in the group with other mutations, and 4.4 and 4.4% in the group with no mutations (p-value 0.02, p-value < 0.001, p-value 0.006). In addition, the BRAF V600E, RET/PTC1 rearrangement, and TERT mutations group demonstrated tall cell variants (17.1%), columnar cell variants (5.7%), and hobnail variants (3%). The other mutations group demonstrated columnar cell variants (4.3%), and the no mutations group demonstrated solid variants (2.2%). Conclusions In this study, BRAF V600E, RET/PTC1 rearrangement, and TERT mutations were associated with aggressive behaving thyroid malignancies as defined above. Molecular testing may be a useful method to anticipate aggressive tumour types and therefore assist in planning the extent and timing of surgery.

GADD45B Transcript Is a Prognostic Marker in Papillary Thyroid Carcinoma Patients Treated With Total Thyroidectomy and Radioiodine Therapy

“…These frequencies are comparable to the ones available in the TCGA database (BRAF: 59.7%, RAS: 13% RET: 6.3% TERT: 9.4%) (6). Although reports in the literature show that BRAF and TERT mutations are related to aggressive thyroid tumors (8,9,35,36), no association was found with the recurrence risk in our set of cases. This result may be explained by the inclusion of patients treated exclusively by total thyroidectomy and radioiodine therapy.…”

“…The most common genetic driver alterations found in PTC are BRAF (60%) and RAS (13%) point mutations, TERT promoter mutation (9%), and RET/PTC fusion (6%) (6). BRAF and TERT mutations have been frequently associated with more aggressive thyroid carcinomas (7)(8)(9)(10). Although the coexistence of both alterations has a synergic effect (11), their role in the prognosis of PTC is still controversial (12,13).…”

Do we need PD‐L1 as a biomarker for thyroid cytologic and histologic specimens?

“…4,5,17 Also, interpretations of results (ie, membranous and/or cytoplasmic staining of tumor cells) varies in different reports. In addition to these inherent preanalytical, analytical, and postanalytical issues, PD-L1 is a protein that is expressed with biologic continuity, akin to a microRNA, and often shows significant intratumoral heterogeneity (both spatial and temporal), 5,14,15 unlike a genetic alteration such as a BRAF V600E mutation, which is a binary system, [9][10][11] or p16 immunohistochemistry for human papillomavirus-related squamous cell carcinoma ("block positivity"). Thus, it is even more crucial for PD-L1 immuno histochemistry to choose optimal cutoff levels to define positive and negative results in order for the test to have any predictive value.…”

“…Different molecular tests (ie, Afirma [Veracyte Inc], ThyroSeqV3 [University of Pittsburgh Medical Center/CBLPath‐Sonic], ThyGenX/ThyraMIR [Interpace Diagnostics, LLC], and RosettaGX Reveal [Rosetta Genomics, Ltd]) can be used successfully to overcome this inherent limitation of FNAC and to refine preoperative diagnosis and risk stratification, with increasingly diagnostic performances . Large multigene panels like ThyroSeqV3 can also identify a small subset of aggressive thyroid cancers, especially those with BRAF V600E, TP53 , and/or TERT promoter mutations, which is very helpful to determine the extent and timing of surgery . This novel approach is promising, although these tests are still expensive, not widely available, and still need extensive validation in large series and integration with clinical and histologic data.…”

“…[9][10][11] Large multigene panels like ThyroSeqV3 can also identify a small subset of aggressive thyroid cancers, especially those with BRAF V600E, TP53, and/or TERT promoter mutations, which is very helpful to determine the extent and timing of surgery. 11 This novel approach is promising, although these tests are still expensive, not widely available, and still need extensive validation in large series and integration with clinical and histologic data.…”