BRAF Mutational Status in Papillary Microcarcinoma: Diagnostic and Prognostic Potential

Published: Monday, Sep 24, 2012

Dr. Yuri E. Nikiforov

Yuri E. Nikiforov, MD, PhD

BRAF mutational status in papillary microcarcinoma is not enough on its own to predict aggressive tumor behavior, researchers reported during the 82nd annual meeting of the American Thyroid Association.

However, when BRAF mutational status is considered along with 3 other “modifiers” or histopathologic features of the microcarcinoma, the ability to predict how aggressive the tumor will be—and subsequently how aggressive treatment must be to prevent its spread—improves substantially. Together these 4 modifiers (BRAF mutation, location, multifocality, and fibrosis) effectively risk-stratify the 5% of papillary nodules that have the potential to metastasize from the other 95% which will have a predictably indolent course.

“The BRAFV600E mutation is present in 50% of papillary microcarcinomas and is typically discovered incidentally,” Yuri E. Nikiforov, MD, PhD, professor of pathology at the University of Pittsburgh School of Medicine, explained in an interview. Nevertheless, if the mutation is present in a nodule, “there is a 99% chance that it is a cancer, and the nodule needs to be removed to cure the disease,” he said. Thus, the presence of the BRAFV600E mutation is highly specific for the diagnosis of papillary microcarcinoma.  Marina Nikiforova, MD, associate professor of pathology at the University of Pittsburgh School of Medicine, stressed that detection of BRAF mutations must be performed at a CAP/CLIA-certified molecular diagnostics laboratory to ensure the information provided is clinically relevant.

The BRAFV600E mutation is not only an important marker for diagnosing the disease, as noted by both speakers, but for detecting which microcarcinomas may be more aggressive in their behavior. In a recent study, Niemeier et al evaluated a combination of BRAF mutations with specific histopathologic features to better risk-stratify papillary microcarcinomas (Cancer. 2012;118:2069-2077). Investigators, including principal investigator Nikiforov, tested a group of aggressive papillary microcarcinomas and nonaggressive tumors using a molecular-pathologic score.

BRAF mutations were detected in 77% of aggressive papillary microcarcinomas as well as in 32% of the nonaggressive tumors (P = .001). However, several histopathologic features differed significantly between the aggressive and nonaggressive tumor groups. By using multivariate regression analysis, a molecular-pathologic score was developed by the team that included BRAF status and 3 additional histopathologic features: superficial tumor location, multifocality, and tumor fibrosis. “By adding these 3 histologic criteria to BRAF status, sensitivity increased from 77% to 96% and specificity increased from 68% to 80%,” investigators reported. 

Analyses of an independent validation cohort also demonstrated that the same molecular-pathologic score stratified tumors into low-, moderate-, and high-risk groups with the probability of lymph node metastases or tumor recurrence in 0%, 20%, and 60% of patients, respectively.

“If a tumor has all of these 4 features—BRAF mutation, location, multifocality, and fibrosis—it has a very high aggressive potential,” Nikiforov reaffirmed. “So these are the 5% of microcarcinomas that need to be better treated to prevent complications, while the other 95% can be cured by simple surgery.”

This new molecular scoring system has been introduced at the University of Pittsburgh Medical Center, where it is currently being used to risk-stratify patients with papillary microcarcinoma.
Niemeier LA, Kuffner Akatsu H, Song C, et al. A combined molecular-pathologic score improves risk stratification of thyroid papillary microcarcinoma. Cancer. 2012;118(8):2069-2077.

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