EGFR Expression and V600E BRAF Mutations Influence Disease Progression in Thyroid Carcinoma
Kevin E Fisher, Charles E Hill, Cora Foulks, Collin J Weber, Jyotirmay Sharma, Cynthia Cohen. Emory University, Atlanta, GA
Background: The worldwide incidence of thyroid carcinoma is steadily rising with a concomitant increase in disease-associated mortality. Activating mutations in BRAF are associated with aggressive disease in papillary thyroid carcinoma (PTC). Epidermal growth factor receptor (EGFR) is an upstream receptor in the BRAF signaling pathway and is overexpressed in anaplastic carcinoma (APC). We investigated how oncogenic mutations in BRAF and EGFR and EGFR protein expression influenced disease outcomes in the four major thyroid carcinoma subtypes: PTC, follicular (FC), medullary (MC), and APC.
Design: Two pathologists scored 79 cases of thyroid carcinoma from a TMA for EGFR intensity (0–3+) and percent positivity (0–100%). High EGFR expression (EGFR-H) was defined as 3+ staining or 2+ staining of ≥ 50% of cells. DNA was successfully extracted from single paraffin blocks of 59 cases for mutational analysis (MA). Activating BRAF V600E (T→A 1799) or EGFR exon 21 L858R (T→G 2573) mutations, or EGFR exon 19 deletions (del 2235-2249/2236-2250; del E746-A750) were determined using pyrosequencing. The subtypes tested (IHC/MA) included PTC (23/18), FC (35/33), MC (9/2), APC (12/6), and unclassifiable (1/1). Statistical significance was determined using Fisher's exact test.
Results: In PTC, EGFR-H correlated with lymph node (LN) metastases (p< 0.01) but not with survival or recurrence. EGFR expression increased the risk of recurrence in Hurthle cell variant of FC (p= 0.054). EGFR-H was seen in all APCs (12/12). No EGFR expression was seen in MC (0/9). None (0/59) of the carcinomas demonstrated EGFR exon 19 deletions or exon 21 activating mutations. 10% (6/59) of the carcinomas harbored V600E BRAF mutations (2 APCs and 4 metastatic PTCs) and all 6 expressed high levels of EGFR by IHC. V600E BRAF mutations correlated with LN metastases (p< 0.01) and 50% (3/6) of patients with BRAF mutations survived <6 months.
Conclusions: EGFR expression increased the risk of recurrence in Hurthle cell variant of FC, and EGFR-H correlated with LN metastases in PTC. V600E BRAF mutations were associated with LN metastases and decreased survival. No E746-A750 deletions or L858R EGFR mutations were identified by pyrosequencing suggesting that alternate mechanisms for EGFR overexpression are involved in thyroid carcinogenesis. The finding that all cases of V600E BRAF mutations coexpressed EGFR-H suggests that in thyroid carcinomas unlike in lung adenocarcinomas, EGFR expression and downstream BRAF activating mutations may not be mutually exclusive.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 97, Monday Morning