• Cell surface receptor that functions in normal cell growth, encoded by ERBB2
• Gene amplification and protein overexpression lead to tumorigenesis
• HER2 testing identifies tumors that may respond to HER2 targeted therapy with trastuzumab

• A cytoplasmic marker, overexpression of which bodes poor prognosis in untreated gastric and gastroesophageal junction (GEJ) adenocarcinomas
• Receptor overexpression or gene amplification identifies tumors that might respond to HER2 targeted therapy with trastuzumab
• Immunohistochemistry for HER2 is scored on a 4 tiered scale that ranges from 0 to 3+
• Strong lateral or complete basolateral membrane staining is adequate for positivity in gastric and GEJ adenocarcinomas, unlike in breast cancers, where circumferential membrane reactivity is required for positivity
• HER2 is assessed differently in resection and biopsy specimens, with the major difference being that only a cluster of 5 positive cells is required in a biopsy

• Gene is ERBB2 (erythroblastosis oncogene B2)
• Protein has variably been termed CD340, HER-2, HER2 and HER2 / neu

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• In gastric adenocarcinomas, only lateral or basolateral membranous staining (not circumferential staining) by IHC is necessary for positivity
• Positive FISH is HER2:CEP17 ratio ≥ 2.0 (dual probe assays) or HER2 copy number > 6.0 (single probe assays) (Mod Pathol 2012;25:637)
• In the U.S., a positive HER2 testing result is IHC 3+ or positive ISH (Gastric Cancer 2014;17:1)
• In Europe, a positive result is IHC 3+ or IHC 2+ with positive ISH (Gastric Cancer 2014;17:1)

Table 1: HER2 testing for gastric and GEJ adenocarcinomas (Histopathology 2008;52:797, Arch Pathol Lab Med 2016;140:1345)

Pattern of HER2 membrane reactivity by IHC in surgical specimen	Pattern of HER2 membrane reactivity by IHC in biopsy specimen	HER2 score by IHC	HER2 status by IHC	Recommendations for ISH testing and treatment
No reactivity or membrane reactivity in < 10% of tumor cells	No membrane reactivity in cancer cells	0	Negative	No ISH testing HER2 targeted treatment not recommended
No more than faint partial membrane reactivity in 10% or more of tumor cells	A cluster of at least 5 cancer cells with no more than faint membrane reactivity regardless of the percentage of positive cancer cells	1+	Negative	No ISH testing HER2 targeted treatment not recommended
10% or more of the tumor cells show weak to moderate lateral or complete basolateral membrane reactivity	A cluster of at least 5 cancer cells with weak to moderate lateral or complete basolateral membrane reactivity regardless of the percentage of positive cancer cells	2+	Equivocal	Reflex to ISH Administer HER2 targeted treatment only if ISH positive
10% or more of the tumor cells show strong lateral or complete basolateral membrane reactivity	A cluster of at least 5 cancer cells with strong lateral or complete basolateral membrane reactivity regardless of the percentage of positive cancer cells	3+	Positive	No ISH testing Eligible for HER2 targeted treatment

Contributed by Aaron R. Huber, D.O.

Contributed by Aaron R. Huber, D.O.


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• Gastroesophageal junction, mass, biopsy:
  • Adenocarcinoma
• Immunohistochemistry HER2 analysis:
  • Results: Positive
  • Interpretation: 3+
• Methodology:
  • Antibody and assay methodology: Rabbit anti-human HER2, HerceptestTM (FDA-approved test kit), (Dako, Carpenteria, CA).
  • Control slides examined: External kit slides provided by manufacturer (cell lines with high, low and negative HER2 protein expression) and in-house known HER2 amplified control tissue were evaluated along with the test tissue and showed appropriate staining.
  • Interpretation: Interpretation based on recommendations put forth by Hofmann et al. in assessment of a HER2 scoring system for gastric cancer: results from a validation study in Histopathology 2008;52:797.

Interpretation criteria

3+ Positive	Surgical specimen with moderate to strong complete or basolateral membranous reactivity in more than 10% of cancer cells Biopsy sample with cohesive cluster with moderate to strong complete or basolateral membranous reactivity
2+ Equivocal	Surgical specimen with weak to moderate complete or basolateral reactivity in more than 10% of cancer cells Biopsy sample with cohesive cluster with weak to moderate complete, basolateral or lateral membranous reactivity
1+ Negative	Surgical specimen with faint barely perceptible membranous reactivity in more than 10% of cells Biopsy sample with cohesive cluster with faint or barely perceptible membranous reactivity
0 Negative	Surgical specimen with no reactivity or reactivity in less than 10% of cells Biopsy sample with no membranous reactivity in any cancer cell

• See also the HER2 biomarker reporting template of the College of American Pathologists at: CAP: Template for Reporting Results of HER2 (ERBB2) Biomarker Testing of Specimens from Patients with Adenocarcinoma of the Stomach or Gastroesophageal Junction [Accessed 5 August 2020]

While reviewing the HER2 immunohistochemical stains of a biopsy specimen of gastroesophageal junction adenocarcinoma, the pathologist observes that multiple groups of more than 5 tumor cells that constitute 5% of the neoplasm show strong complete lateral and basolateral membranous reactivity. The correct interpretation of this finding is

1. Equivocal because only strong complete basolateral (and not lateral) membrane reactivity is a positive result
2. Negative because a positive result is strong circumferential membrane staining in > 10% of tumor cells
3. Negative because a positive result is strong lateral or complete basolateral membrane reactivity in ≥ 10% of the cancer cells
4. Positive because a positive result is moderate lateral or basolateral reactivity in at least 10% of neoplastic cells
5. Positive because there is strong lateral or complete basolateral membrane positivity in a cluster of more than 5 cancer cells

E. A positive HER2 result on immunohistochemistry (a 3+ score) in a gastric biopsy specimen is strong lateral or complete basolateral staining in a cluster of at least 5 cancer cells, regardless of the percentage of the tumor that the cluster comprises. The remaining answer choices are incorrect because they deviate from this criterion. It is noteworthy that HER2 is interpreted differently in surgical specimens than in biopsies as at least 10% of the neoplastic cells in surgical specimens must show strong complete lateral or basolateral staining to count as a positive result (answer choice C). Choice B is the definition of a positive result (3+ score) in breast cancers. HER2 is also scored using different criteria in gastric and breast cancers.

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Reference: HER2 stomach/GE junction