BRAF V600E

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Stains & CD markers
BRAF V600E

Author: Andrew J. Colebatch, M.B.B.S., Ph.D.

Editorial Board Member: Christian M. Schürch, M.D., Ph.D.

Deputy Editor-in-Chief: Catherine E. Hagen, M.D.

Last author update: 3 January 2022

Last staff update: 23 June 2022

Copyright: 2003-2024, PathologyOutlines.com, Inc.

PubMed Search: BRAF V600E[TI] free full text[sb] stains

See Also: BRAF-melanoma

Table of Contents

Cite this page: Colebatch A. BRAF V600E. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsbraf.html. Accessed December 25th, 2024.

Definition / general

BRAF is a serine / threonine kinase, part of the MAPK signaling pathway
Abbreviation for v-raf murine sarcoma viral oncogene homolog B1
BRAF V600E (Val600Glu) is an activating somatic mutation

Essential features

BRAF V600E mutations can be reliably detected using immunohistochemistry
BRAF V600E status is important therapeutically in melanoma
Interpretation can be difficult due to melanin pigment

Terminology

BRAF VE1 (antibody)
BRAF V599E (older designation of mutation)

Pathophysiology

Majority due to thymine to adenine transversion at position 1799 in exon 15 of BRAF
Minority are due to an insertion deletion of 2 adenines at positions 1798 and 1799 in exon 15 of BRAF (V600E2)
Both mutations result in an identical BRAF V600E protein, which is detected by the antibody

Diagrams / tables

Images hosted on other servers:

MAPK signaling pathway

Interpretation

Cytoplasmic stain
Melanin pigment and hemosiderin can mimic brown chromogen, making interpretation of heavily pigmented lesions very difficult (if not impossible)
Variation in staining can be due to cautery, necrosis, storage time in archive and previous frozen section (Acta Neuropathol 2011;122:11)

Uses by pathologists

BRAF V600E immunohistochemistry is sensitive and specific for BRAF V600E mutations in colorectal carcinoma, papillary thyroid carcinoma and melanoma (Am J Surg Pathol 2014;38:1418, Virchows Arch 2015;467:155, Am J Surg Pathol 2013;37:61)
Melanoma: identify those melanomas sensitive to BRAF inhibitors, such as vemurafenib and dabrafenib (N Engl J Med 2011;364:2507)
Melanoma: differentiate Spitz tumors from Spitzoid melanomas (Mod Pathol 2017;30:640)
Colorectal carcinoma: differentiate Lynch syndrome (BRAF negative) from sporadic MSI tumors (BRAF mutation in 40 - 50%); prognostic (Am J Surg Pathol 2013;37:1592, Mod Pathol 2014;27:644)
Thyroid: BRAF V600E mutation associated with high risk features in papillary thyroid cancer (J Clin Endocrinol Metab 2005;90:6373)
Neuropathology: distinguishing papillary craniopharyngiomas (95% positive for BRAF V600E) from adamantinomatous craniopharyngiomas (0% positive for BRAF V600E)
Neuropathology: distinguishing glioblastoma from pleomorphic xanthoastrocytomas

Microscopic (histologic) images

Contributed by Andrew Colebatch, M.B.B.S., Ph.D. and Andrey Bychkov, M.D., Ph.D.

BRAF V600E positive nevus

BRAF V600E positive melanoma

V600E mutant protein is diffusely expressed in tumor / cancer but not normal tissue

Diffuse cytoplasmic staining

Positive staining - normal

Positive staining - disease

Melanocytic lesions
- ~50 - 80% of melanocytic nevi (Nat Genet 2003;33:19, PLoS One 2013;8:e69639)
- ~50% of lymph node capsular nevi (Hum Pathol 2017;59:48)
- ~40 - 60% of cutaneous nonacral melanomas (Nature 2002;417:949, Cell 2015;161:1681, PLoS One 2013;8:e69639)
Neuropathology
- ~60% of pleomorphic xanthoastrocytomas (PLoS One 2011;6:e17948)
- 20 - 60% of gangliogliomas (Acta Neuropathol 2011;121:397)
- 10% of pilocytic astrocytomas (Acta Neuropathol 2011;121:397)
- 95% of papillary craniopharyngioma (Nat Genet 2014;46:161)
Thyroid
- 40 - 50% of papillary thyroid carcinomas, enriched in tall cell variant (over 80%) (Virchows Arch 2015;467:155, Endocr Relat Cancer 2005;12:245)
- ~15% of poorly differentiated thyroid carcinomas (J Clin Endocrinol Metab 2013;98:E1414)
- 20 - 60% of anaplastic thyroid carcinomas (J Clin Endocrinol Metab 2013;98:E1414, Hum Mol Genet 2015;24:2318, Thyroid 2017;27:682)
Colorectal
- > 90% of sessile serrated lesions (Cancer Res 2003;63:4878, Am J Surg Pathol 2007;31:1452)
- ~10% of colorectal adenocarcinomas
~70% of borderline serous ovarian tumors and 10 - 20% of low grade serous carcinoma (Hum Pathol 2013;44:329)
Hematopathology
- Hairy cell leukemia (N Engl J Med 2011;364:2305)
- Langerhans cell histiocytosis: BRAF V600E in up to 65% of cases
- Erdheim-Chester disease: BRAF V600E in about 50% of cases
60% of ameloblastoma (J Pathol 2014;232:492)
Metanephric adenoma
Papillary craniopharyngeoma

Negative staining

Does not stain other BRAF mutations (both non-V600E and V600-non-E), including potentially actionable mutations (Am J Surg Pathol 2013;37:61)
Clear cell sarcoma (melanoma of soft parts) (N Engl J Med 2005;353:2135)
Rare in acral and mucosal melanoma (N Engl J Med 2005;353:2135)

Sample pathology report

Soft tissue, perinephric, biopsy:
- Histiocytic neoplasm with BRAF V600E mutation by immunohistochemistry, consistent with Erdheim-Chester disease in the appropriate clinical context (see comment)
- Comment: The histologic sections demonstrate adipose tissue with an infiltrate of foamy histiocytes admixed with scattered Touton giant cells. There is extensive fibrosis present. Immunoperoxidase studies were performed on paraffin embedded sections using antibodies directed against the following antigens: CD1a, CD68, CD163, factor XIIIa, IgG, IgG4, langerin, S100 and BRAF V600E. The foamy histiocytes are positive for CD68, CD163 and factor XIIIa and are negative for S100, CD1a and langerin. The lesional histiocytes are positive for BRAF V600E mutation by immunohistochemistry. There is no increase in number of IgG4 positive plasma cells or an abnormal IgG4/IgG ratio.

Board review style question #1

Which of the following statements is true regarding BRAF V600E mutations?

They do not occur in melanoma
They do not occur in papillary craniopharyngioma
They do not occur in adamantinomatous craniopharyngioma
They do not occur in papillary thyroid carcinoma

Board review style answer #1

C. Adamantinomatous craniopharyngiomas do not show BRAF V600E mutations (these tumors show WNT pathway activation with beta catenin mutations).

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Reference: BRAF V600E

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