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Improved Molecular Classification of Serrated Lesions of the Colon by BRAF V600E

Posted on May 07 2014

Pathology Top Pick

Since tumors of the proximal colon have been shown to develop in a short period of time, many recent studies have targeted the precursor lesions of colorectal cancer. While the classical pathway of colorectal cancer development is via the APC and KRAS mutations, tumors can also develop from serrated precursor lesions through BRAF mutations, and these serrated lesions are considered to be the precursor lesion in over one-third of colorectal cancers.

Serrated lesions are known to include sessile serrated adenomas as well as traditional serrated adenomas. While hyperplastic polyps were once considered to have no malignant potential, recent publications have described mutated subtypes with neoplastic potential. The BRAF V600E mutation has been identified in a subset of hyperplastic polyps morphologically classified as microvesicular hyperplastic polyps. Since BRAF mutation status may assist in classification of precursor lesions, and BRAF sequencing of all polyps is not suitable for everyday pathology practice, the advent of an immunohistochemical stain specific for the BRAF V600E mutation has proven useful in classifying these lesions.

A new study by Mesteri et. al. Modern Pathology (2014) 27,135-44 investigated the BRAF V600E mutation status by immunohistochemisty (BRAF V600E mutation-specific antibody VE1, Spring Bioscience) of 194 serrated lesions of the colon (42 sessile serrated adenomas, 16 traditional serrated adenomas, 119 microvesicular hyperplastic polyps, and 17 goblet-cell rich hyperplastic polyps) and 20 conventional adenomas. They found that 100% (42/42) of sessile serrated adenomas and 94% (15/16) of traditional serrated adenomas were positive for the BRAF stain. While 62% of all hyperplastic polyps were positive for the BRAF stain, 71% of those hyperplastic polyps classified as microvesicular hyperplastic polyp stained positively. None of the goblet-cell rich hyperplastic polyps or conventional adenomas was positive for the BRAF immunostain.

The findings support the theory that sessile lesions almost always progress through a BRAF-mutated pathway, while conventional adenomas do not generally progress through this pathway. Additionally, the malignant potential of microvesicular hyperplastic polyps has been recently debated, and this study confirms that a subset of these lesions may have malignant potential. Since microvesicular hyperplastic polyps and sessile serrated adenomas can be difficult to differentiate on a small biopsy, the need for a marker to identify those microvesicular hyperplastic polyps with malignant potential is necessary. While the study found that that the BRAF mutation correlates with nuclear atypia and stratification, nuclear atypia was also found in 43% of those lesions that did not harbor the mutation.   Therefore, morphologic evaluation is insufficient in predicting BRAF mutation status. The authors suggest that microvesicular hyperplastic polyps be classified with regard to BRAF V600E mutation status as possible precursors of the serrated neoplasm pathway. However, further data are necessary in order to accurately classify these lesions, since “non-malignant” lesions like melanocytic nevi have also been shown to harbor BRAF mutations.

Mesteri I et. al. 2014 Improved molecular classification of serrated lesions of the colon by immunohistochemical detection of BRAF V600E. Modern Pathology 27:135-144

Editorial by Johnathan Klein MD