A piece of the puzzle: what does BRAF status mean in the management of patients with papillary thyroid carcinoma?

Since the identification of the BRAFV600E (BRAF) mutation in thyroid cancer nearly 10 yr ago, it has become the focus of numerous studies (1, 2). BRAF has been detected in about 45% (range, 26–83%) of all papillary cancers and less frequently in poorly differentiated and anaplastic thyroid cancers (1, 2). Because papillary thyroid cancer (PTC) accounts for 85% of all thyroid cancers, it is the most common mutation found in thyroid cancer. The detection of BRAF in cytological specimens is highly specific for thyroidcancer, even in lesionswith indeterminate cytology (3).BRAFhasbeen reported tobeamarkerofmore aggressive and invasive cancer (1, 2). It has been associated with an increased risk for extrathyroidal extension, lymph node and distant metastases, higher TNM/AJCC stage, and an increased risk for recurrence (1, 2). These observations have led to suggestions that assessment of BRAF status should be added to other traditional risk factors to better predict outcome. It has also been suggested that ascertainment of BRAF status might be useful in directing the extent of initial surgery(includingprophylacticneckdissection), the use or dose of I131, the intensity of follow-up and TSH suppression, and the choice of drugs for patients with progressive disease unresponsive to I131 (1, 2). Not all studies, however, have supported the view that BRAF status is an independent predictor of the extent of disease or outcome (4). Some studies find it not to be predictive at all (5, 6); some find it only significant in univariate but not multivariate analysis (4), whereas others find it to be useful in addition to other specific clinical and histological features (7). It is in this context, that Sancisi et al. (8) conducted their study of BRAF status in metastatic PTC reported in this issue of the JCEM. They identified 47 patients with well-differentiated PTC and distant metastases and assessed for the presence of BRAF in all the primary tumors and from the metastatic disease in five of the patients with BRAF primary tumors. As a control, they evaluated the primary tumor in 75 PTC patients who never had distant metastases and remained free of disease for at least 7 yr. In the control group, 44%ofthetumorswereBRAFpositive,whereas inthegroup with metastatic disease only 29.8% were BRAF positive. Amongthefatalcases,30.1%wereBRAF .Amongpatients with distant metastases, the tall cell variant (TCPTC) accounted for 71.5% of the BRAF tumors, whereas among the disease-free patients, it accounted for only 30.3% of the BRAF tumor patients. Of those that could be assessed, all but four of the patients with metastatic disease also had extrathyroidal extension of the primary tumor, regardless of BRAF status, whereas among the disease-free patients it was absent in 50% of the BRAF and 63.6% of the BRAF patients (8). In addition, two patients with BRAF primary lesions did not have the mutation detected in the metastatic focus. They conclude that BRAF positivity alone is not a predictor of distant metastases or fatal outcome and may not predict aggressive behavior. When the BRAF mutation is expressed in the thyroid in animal models, they develop aggressive thyroid cancers (1). Most BRAF tumors do not carry mutations in RAS or the RET/PTC rearrangement (1). Activation of the MAPK pathway through BRAF has been shown to induce a number of cellular events that could promote refractoriness to iodine uptake and a stimulus for growth and invasion (1, 2). This does not prove, however, that in humans the presence of BRAF is a primary abnormality leading to the development of PTC or that BRAF tumors are inherently more aggressive. Several lines of evidence from