Abstract
BackgroundPrognosis among patients with differentiated thyroid cancer is widely variable. Better understanding of biologic subtypes is necessary to stratify patients and improve outcomes.MethodsIn patients diagnosed with classic histology papillary thyroid cancer treated from 1973 to 2009, BRAF V600E mutation status was determined on surgical tumor specimens by restriction fragment length polymorphism analysis. A tissue microarray (TMA) was constructed from tumor specimens in triplicate and stained by immunohistochemistry for RET, phospho‐MEK, MAPK(dpERK), PPARγ, and phospho‐AKT(pAKT). Stained slides were scored independently and blindly by two investigators and compared to tumor and patient characteristics and outcomes.ResultsA total of 231 patients had archived formalin‐fixed, paraffin‐embedded tumor tissue available and were included on the TMA. Mean age at diagnosis was 44 years (range 6‐82 years); proportion of patients with female sex was (72%); 2015 American Thyroid Association (ATA) risk stratification was low (26%), intermediate (32%), and high (42%). BRAF V600E mutation was found in 74% of specimens, and IHC was scored as positive for RET (61%), MAPK (dpERK) (14%), PPARγ (27%), and pAKT (39%). Positive RET staining was associated with a lower risk of recurrence (HR = 0.46, 95% CI 0.22‐0.96). No other molecular biomarkers were independent predictors of recurrence on univariable analysis. On RPA, patients with RET‐negative and either MAPK(dpERK)‐positive or pAKT‐positive tumors were identified to have a high risk of recurrence (HR = 5.4, 95%CI 2.5‐11.7). This profile remained associated with recurrence in a multivariable model including ATA risk stratification (HR = 2.8, 95% CI 1.3‐6.0).ConclusionCharacterization of molecular pathways involved in cPTC tumorigenesis may add further risk stratification for recurrence beyond the 2015 ATA risk categories alone.
Highlights
Thyroid cancer represents the most common endocrine malignancy, accounting for an estimated 53 990 new diagnoses in the United States in 2018.1 Papillary thyroid cancers (PTC) account for 65%‐88% of all thyroid cancers.[2]
Post‐thyroidectomy pathological findings play an important role in prognosis, and along with patient age and total body iodine uptake scan, comprise the three‐tiered risk stratification system endorsed in the American Thyroid Association (ATA) 2015 guidelines to predict risk of recurrent disease.[3]
BRAF V600E mutation was significantly enriched in the ATA intermediate‐ (73%) and high‐risk (82%) groups compared to low‐risk (61%) patients (P = 0.01; Table 2)
Summary
Thyroid cancer represents the most common endocrine malignancy, accounting for an estimated 53 990 new diagnoses in the United States in 2018.1 Papillary thyroid cancers (PTC) account for 65%‐88% of all thyroid cancers.[2]. The proto‐oncogene BRAF V600E mutation has been extensively studied and characterized in the PTC literature, though with conflicting associations with recurrence in multiple studies. A pooled meta‐analysis of 14 studies including 2470 PTC patients found BRAF mutation was associated with twice the risk of recurrence (24.9% vs 12.6%, P < 0.00001).[4] It is unclear whether BRAF mutation independently confers additional risk as it is often linked to aggressive histological findings.[5] Though BRAF mutation is quite prevalent (30%‐80%),[6] even in the intermediate‐ and high‐risk groups, BRAF mutation alone is not consistently prognostic. BRAF V600E mutation was prevalent (67%), but was not associated with recurrence or disease‐specific survival.[7] This suggests that additional molecular drivers may be responsible for aggressive cPTC. We sought to characterize the molecular expression at the protein level of five factors along the BRAF and RAS pathways in a large single institution cohort of PTC patients with long clinical follow‐up. We sought to identify molecular signatures that may be associated with clinical outcomes
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