BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer

J Clin Endocrinol Metab. 2021 Oct 21;106(11):3228-3238. doi: 10.1210/clinem/dgab286.


Context: How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined.

Objective: To study whether BRAF V600E affected LNM-associated mortality in PTC.

Design, setting, and participants: We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 [interquartile range (IQR) 35-58] years and median follow-up time of 58 (IQR 26-107) months.

Results: Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism.

Conclusions: LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.

Keywords: BRAF mutation; lymph node metastasis; mortality; prognostic molecular marker; risk stratification; thyroid cancer.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers, Tumor / genetics*
  • Female
  • Follow-Up Studies
  • Humans
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / mortality*
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Proto-Oncogene Proteins B-raf / genetics*
  • Retrospective Studies
  • Survival Rate
  • Thyroid Cancer, Papillary / genetics
  • Thyroid Cancer, Papillary / mortality*
  • Thyroid Cancer, Papillary / secondary
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / mortality*
  • Thyroid Neoplasms / pathology


  • Biomarkers, Tumor
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf