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Stains

BRAF

Reviewer: Nat Pernick, M.D. (see Reviewers page)
Revised: 5 January 2012, last major update January 2012
Copyright: (c) 2002-2012, PathologyOutlines.com, Inc.

General
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● Serine / threonine specific protein kinase, part of the RAS/MAPK pathway regulating the growth, maturation, proliferation, survival and apoptosis of cells
● Abbreviation for v-raf murine sarcoma viral oncogene homolog B1
● Gene commonly mutated in papillary thyroid carcinoma and melanoma
● V600E mutation (valine at residue 600 replaced by glutamic acid) renders BRAF constitutively active and increases its kinase activity (Nature 2002;417:949)

Diagrams
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MAPK signaling pathway

Clinical features
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● The drug Vemurafenib / Zelboraf®, used to treat melanoma, interrupts the BRAF/MEK/ERK pathway, only when BRAF has the V600E mutation (valine replaced by glutamic acid)

Uses by pathologists
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● Colorectal carcinoma: differentiate Lynch syndrome (BRAF negative) from sporadic MSI tumors (BRAF mutation in 40-50%); mutation analysis for anti-EGFR treatment (Arch Pathol Lab Med 2011;135:578), prognostic value (Arch Pathol Lab Med 2010;134:1225)
● Melanoma: mutation analysis for treatment (Vemurafenib, N Engl J Med 2011;364:2507, J Skin Cancer 2011;2011:423239); may provide prognostic information (Arch Pathol Lab Med 2011;135:860)
● Thyroid: mutation analysis for thyroid FNA to detect papillary carcinoma (Endocr J 2007;54:399, Hum Pathol 2012;43:89), prognostic value (Arch Pathol Lab Med 2011;135:569)

Micro images
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Prevalence of BRAF mutations in different histologic variants of thyroid papillary carcinoma

Negative stains
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● Ewing sarcoma (Hum Pathol 2011 Dec 21 [Epub ahead of print])

Molecular-BRAF mutations
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● Anus: anorectal melanoma (5%, Hum Pathol 2011 Dec 8 [Epub ahead of print])
● CNS: pilocytic astrocytomas (most, Arch Pathol Lab Med 2011;135:558), pleomorphic xanthoastrocytoma (60%, PLoS One 2011;6:e17948)
● Colon: serrated adenoma (Cancer Res 2003;63:4878), serrated fibroblastic polyps/intramucosal perineuriomas (63%, Am J Surg Pathol 2010;34:1663), colorectal carcinoma (V600E mutation occurs in 40%-50% of sporadic MSI colorectal cancers, Arch Pathol Lab Med 2011;135:1269)
● Esophagus: 1 of 10 melanomas (Mod Pathol 2011;24:495)
● GIST (13% of wild type, Am J Clin Pathol 2010;133:141)
● Leukemia/lymphoma: hairy cell leukemia (60-100%, Haematologica 2011 Dec 1 [Epub ahead of print], N Engl J Med 2011;364:2305) versus none/rare in other B cell leukemia/lymphomas
● Lung: micropapillary adenocarcinoma (20%, Am J Clin Pathol 2009;131:694)
● Lymph nodes: benign nevi (Am J Surg Pathol 2009;33:568)
● Ovary: malignant struma ovarii (Am J Surg Pathol 2007;31:1337)
● Skin: congenital pattern nevi (71%, J Invest Dermatol 2007;127:179), nevi (81%, Am J Dermatopathol 2007;29:534); Langerhans cell histiocytosis (57%, Blood 2010;116:1919), melanoma (50% have V600E mutation; these tumors are usually not associated with sun damage)
● Thyroid: Spitz nevi (some, Mod Pathol 2006;19:1324), anaplastic carcinoma (50%); papillary thyroid carcinoma (36-69%, Arch Pathol Lab Med 2011;135:569); less common in follicular variant than classic (31% versus 58%, Hum Pathol 2011;42:500), rare in diffuse sclerosing variant (Mod Pathol 2007;20:779); not found in Hashimoto's thyroiditis (Am J Clin Pathol 2009;132:906)

Molecular/other images
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BRAF melting curves

   
Chromatograms in Spitz nevus (left) and diffuse sclerosing papillary thyroid carcinoma (right)


Hairy cell leukemia and other leukemias/lymphomas


Mass spectrometry traces for BRAF mutation

End of Stains > BRAF

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