Breast malignant, males, children
Breast cancer
HER2 (c-erbB2)

Author: Monika Roychowdhury, M.D. (see Authors page)

Revised: 20 October 2016, last major update February 2012

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: HER2 [title] breast

Cite this page: HER2 (c-erbB2). PathologyOutlines.com website. http://pathologyoutlines.com/topic/breastmalignanther2.html. Accessed December 3rd, 2016.
Definition / General
  • HER2 gene encodes transmembrane growth factor receptor (p185)
  • Cytoplasmic tyrosine kinase is constitutively active when overexpressed due to homo/heterodimerization (diagram)
  • “3+” protein staining is associated with HER2 gene amplification at 17q21
  • The biologic impact of HER2 gene amplification is not due to (a) mere chromosome 17 polysomy without HER2 gene amplification (Am J Surg Pathol 2005;29:1221) or (b) chromosome 17 aneusomy [aneusomy means other than 2 copies of chromosome] (Mod Pathol 2002;15:137)

HER2 gene amplification
Detection of HER2 gene amplification
ASCO / CAP recommendations
  • Click here for 2013 update
    • Determine HER2 by IHC for all invasive breast cancer cases
    • Specific procedures are recommended to reduce assay variation
    • Define HER2 amplification as either 3+ IHC staining (uniform, intense stain of > 30% of tumor cells), FISH of > 6 HER2 gene copies / nucleus or FISH ration > 2.2
    • Define negative tests as 0 or 1+ IHC, FISH < 4.0 or FISH ratio < 1.8
    • Classify other results as equivocal, and perform additional testing
    • Labs should show 95% concordance with another validated test (Arch Pathol Lab Med 2007;131:18, Mod Pathol 2008;21 Suppl 2:S8); similar recommendations in UK (J Clin Pathol 2008;61:818)
  • FDA and ASCO / CAP schemes for HER2 evaluation select patients differently, with major discordances for low-grade, borderline HER2 amplification (Am J Clin Pathol 2008;129:907); high concordance between FISH and ISH requires modification of FDA scoring system (Mod Pathol 2008;21:1271)
  • Standardized formalin fixation (minimum of 6 hours for core biopsies) is also important for IHC / FISH concordance (Arch Pathol Lab Med 2009;133:775), as is not delaying formalin fixation by more than one hour (Mod Pathol 2009;22:1457)
  • Guidelines for evaluating genetic heterogeneity in HER2 testing have been produced (Arch Pathol Lab Med 2009;133:611)
Terminology
  • Also called Human Epidermal growth factor Receptor 2, c-erbB2, neu, ERBB2, CD340
Diagrams / Tables

Images hosted on Nature servers:

HER2 / neu testing algorithm

Case Reports
Micro Images

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3+: IHC



Images hosted on Nature servers:

3+: IHC

3+: IHC, CISH and FISH



Heterogeneous staining

FISH amplification



2+: IHC

1+: IHC

Strong versus weak staining



FISH: amplified and not amplified

Not amplified - CISH and FISH

CISH amplification: clusters and single signals



CISH and IHC

Various images

DCIS with ER and HER2 double immunostaining

Ductal hyperplasia, ADH, DCIS, and invasive carcinoma

CISH - not amplified, amplified, borderline amplification, equivocal signals



Images hosted on other servers:

IHC and FISH

Immunohistochemistry
  • 0 (negative) - no staining or membrane staining in < 30% of tumor cells
  • 1+ (negative) - faint membrane staining in > 30% of tumor cells; only part of membrane is stained
  • 2+ (weak positive) - weak / moderate complete membrane staining in > 30% of tumor cells
  • 3+ (strong positive) - strong complete membrane staining in > 30% of tumor cells

  • Note: 30% threshold is from ASCO / CAP scheme in 2008, prior threshold was 10%

  • IHC stain scores of 0 / 1+ (negative / weak) or 3+ (strong) are predictive of FISH results (negative and positive amplification respectively)
  • 2+ is not predictive and has significant interobserver variability (Mod Pathol 2001;14:1079)
  • Suggested to perform FISH or PCR for 2+ tests (Am J Clin Pathol 2005;123:766)
  • For equivocal HER2 results by FISH or PCR on breast core biopsies, recommended to evaluate on larger tumor sample (Am J Clin Pathol 2008;129:383)
  • Normalization of IHC markedly improves concordance between IHC and FISH (Mod Pathol 2008;21:1271)
  • Serum HER2 levels may predict histopathologic response to chemotherapy (Am J Clin Pathol 2007;128:630), and presence of HER2 mRNA-positive circulating tumor cells is independent prognostic factor in women with early breast cancer (Breast Cancer Res Treat 2009;117:525)
  • HER2 gene status remains highly conserved as breast cancers metastasize; the discrepancies present are often due to interpretational difficulties and heterogeneity of HER2 amplification (Breast Cancer Res 2007;9:R31)
Additional References