Analysis of BRAFV600E Mutational Status and the Biology of Papillary Thyroid Microcarcinoma.
Yusheng Han, Wendy Sacks, Angela Treml, Xuemo Fan, Shikha Bose, Jean Lopategui, Glenn Braunstein, David Frishberg. Cedars Sinai Medical Center, Los Angeles, CA
Background: Papillary thyroid microcarcinomas (PTMCs) usually have an excellent clinical outcome, but recent studies have demonstrated that a significant number of PTMCs may show more aggressive behavior, with extrathyroidal extension and cervical lymph node metastasis. During the past few years, it has become evident that aberrant signaling through the RAS–RAF–MEK cascade is crucial for the development of thyroid cancer. BRAF mutation has been reported to be correlated with high aggressiveness, such as advanced disease stage and cervical lymph node metastasis in thyroid papillary carcinoma. However, the importance of BRAF mutation in prognostication of PTMCs is still unclear, and has not been studied in North American patients. BRAFV600E mutation is the most common BRAF mutation that accounts for over 90% of all BRAF mutations. In this study, we analyzed the occurrence of BRAFV600E mutations in PTMCs to elucidate the relationship between the occurrence of BRAF mutations and biologic behavior.
Design: This retrospective study was performed in 40 cases of PTMCs between the years 1999 to 2007. BRAFV600E mutation was detected by real-time PCR for all cases on formalin fixed, paraffin embedded sections. Statistical significance was determined by Fisher's exact test and Student t-test.
Results: Among the 40 cases, 18 cases demonstrated lymph node metastases and 9 cases with extrathyroidal extension at time of surgery. Overall, 55.3 % of PTMCs harbored a BRAFV600E mutation. BRAFV600E was present in 87.5 % of cases with lymph node metastases, and 31.8% of cases without lymph node metastases (P<0.01). The prevalence of BRAFV600E mutation was higher in stage T3/T4 PTMCs than in stage T1 (P<0.05). Among BRAFV600E-positive cases 66.7% showed lymph node metastasis as compared with only 11.8% of wild-type BRAF PTMCs (P<0.01). Among all other clinicopathologic features that we analyzed, BRAFV600E mutation was found to be uncorrelated with age, focality, vascular invasion, multinodular goiter, or lymphocytic thyroiditis. In 4 to 10 years of follow-up only 2 cases of PTMC showed evidence of clinical recurrence; both were BRAFV600E-mutated.
Conclusions: BRAF mutated PTMCs exhibit signs of higher aggressiveness than PTMCs without this mutation. BRAF mutation could be a marker useful in identifying PTMCs that require a more intensive primary treatment, such as node exploration. The role of BRAF in long-term behavior of this usually indolent tumor is less clear, and studies with longer term follow up are needed.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 82, Monday Morning