RAF Mutation Varies in Thyroid Cancer
Published: Aug 26, 2013
Whether BRAF mutations can be used to determine the likelihood of lymph node metastases of papillary thyroid cancer remains unclear because of the mutation's strong association with aggressive subtypes of the cancer, researchers reported.
In a multivariate analysis of almost 400 patients with any thyroid cancer subtype who underwent total thyroidectomy and central lymph node dissection, independent associations with lymph node metastases were found for BRAF mutations (OR 2.37, 95% CI 1.41-3.98, P=0.001), tumor size greater than 2 cm (OR 1.62, 95% CI 1.01-2.61, P=0.045), and extra-thyroid extension (OR 2.77, 95% CI 1.58-4.86, P<0 .001="" a="" according="" href="http://www.hopkinsmedicine.org/profiles/results/directory/profile/0007252/martha-zeiger" style="color: #003f85; outline-style: none; text-decoration: none;" target="_blank" to="">Martha A. Zeiger, MD
, of Johns Hopkins School of Medicine, and colleagues.However, when the analysis was limited to the most common classical variant, papillary thyroid cancer, and the highly aggressive subtypes that are closely associated with BRAFmutations such as the follicular variant were excluded, there was no significant association between the mutation and lymph node metastases (P=0.244), the researchers reported in theJournal of Clinical Endocrinology & Metabolism.
"Regarding [papillary thyroid cancer] as a homogeneous entity could lead to miscalculations and/or misunderstandings of relationships between independent predictors, such as BRAFstatus, and dependent outcomes, including [lymph node metastases]," Zeiger and colleagues wrote.
While papillary thyroid cancer usually carries a good prognosis, patients with lymph node involvement at the time of diagnosis are at increased risk for recurrence.
Whether or not all patients should undergo bilateral prophylactic lymph node dissection following thyroidectomy has been a subject of controversy, with advocates arguing that some studies have found occult nodal metastases in as many as 80% of patients, and opponents suggesting that most occult micrometastases aren't clinically important.
"Because of the controversy surrounding the appropriate surgical management of [papillary thyroid cancer], more accurate risk stratification is needed to guide treatment," the researchers stated.
They noted that "molecular tumor profiling" has become increasingly popular as a diagnostic and prognostic aid, with the BRAF V600E mutation that activates the MAPK pathway being a focus of considerable attention.
This mutation also has been linked with other types of cancer, such as leukemia, melanoma, and lung cancer.
But the evidence for BRAF mutations as being predictive in thyroid cancer has been conflicting, and studies have had limitations such as selection bias.
Therefore, to clarify the prognostic utility of BRAF mutations for lymph node metastases in thyroid cancer, Zeiger and colleagues conducted a retrospective study of all 388 patients who underwent thyroidectomy followed by central lymph node dissection in four tertiary care centers between January 2009 and December 2011.
A total of 315 of the patients had classical variant papillary thyroid cancer, 41 had the follicular variant, 31 had the tall cell variant, and one had a poorly differentiated tumor.
Among the classical variant group, more than three-quarters were women, and mean age was 46. The mean tumor size was 1.89 cm, and 80% had the BRAF V600E mutation.
The multivariate analysis limited to this group found significant positive associations for lymph node metastases with tumor size greater than 2 cm (OR 2.04, 95% CI 1.20-3.48,P=0.009) and extra-thyroid extension (OR 2.20, 95% CI 1.18-4.09, P=0.013), but not with theBRAF mutation.
Age of 45 and older had a significant negative association with lymph node metastases (OR 0.41, 95% CI 0.25-0.67, P<0 .001="" p="">
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In the subgroup with the follicular variant subtype, strong independent associations with lymph node metastases were found for the BRAF mutation (OR 9.69, 95% CI 1.05-89.33,P=0.45) and extra-thyroid extension (OR 34.04, 95% CI 1.4-827.51, P=0.030).
In the other subgroup, which included the aggressive forms such as the tall cell variant, 71% of patients with the BRAF mutation had metastases to the lymph nodes, and none of the patients without the mutation had metastatic disease.
Bivariate analysis in this subgroup found that the BRAF mutation was the only independent predictor of lymph node metastases (P=0.006).
These findings suggest that "BRAF mutation may be differentially associated with the risk of [lymph node metastases] across [papillary thyroid cancer] subtypes," the researchers stated.
"Further research is warranted before factors such as BRAF mutation are included in treatment algorithms that do not take into account tumor histology," they cautioned.
This additional research should include prospective studies involving multiple centers, they added.
Limitations of the study included small numbers of patients with the aggressive subtypes and its retrospective design.
The study was supported by the Johns Hopkins University School of Medicine.
The authors reported no financial disclosures.
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