HER2 IHC 3+ with Pending FISH: Likelihood of Negative Result
When HER2 immunohistochemistry is 3+, the likelihood of a negative FISH result is very low, approximately 5-15%, with the vast majority (>90%) of IHC 3+ cases showing HER2 gene amplification by FISH 1, 2.
Evidence from Large-Scale Data
The most robust data comes from the 2018 ASCO/CAP guideline analysis, which examined multiple large laboratory datasets 2:
- Mayo Clinic data (3,089 cases): Among IHC 3+ cases, 91.7% showed FISH amplification 3
- Multiple reference laboratories consistently demonstrated that IHC 3+ cases have amplification rates ranging from 83.3% to 91.7% 2, 3
- The discordance rate (IHC 3+ but FISH negative) ranges from 7-17% across different studies 4, 5
Clinical Implications
Why This Matters
The 2023 ASCO/CAP guidelines explicitly address this scenario 1:
- If IHC is 3+, the diagnosis is HER2 POSITIVE regardless of certain FISH patterns
- This reflects the recognition that strong, uniform protein overexpression (IHC 3+) is clinically meaningful even in rare cases where gene amplification is not detected
Common Causes of Discordance
When IHC 3+ cases are FISH-negative (the minority), potential explanations include:
- Chromosome 17 polysomy - increased CEP17 signals can mask true amplification ratios 6
- Technical issues - fixation artifacts, tissue processing problems, or counting errors
- Biological heterogeneity - sampling different tumor areas between tests
- True polysomy without amplification - rare cases with increased HER2 copies but no true gene amplification 6
Practical Guidance
What to Expect
- Most likely outcome (>85%): FISH will be positive, confirming HER2-positive status
- Less likely outcome (5-15%): FISH will be negative or equivocal
If FISH Returns Negative
According to current guidelines 1:
- Review both IHC and FISH slides together to ensure concordant areas were assessed
- Consider technical issues with either test
- In cases with average HER2 signals ≥6.0 but ratio <2.0 (Group 3), if IHC is 3+, the diagnosis remains HER2 POSITIVE 1
- Consider chromosome 17 polysomy as a confounding factor
Key Caveat
The 2023 guidelines prioritize IHC 3+ results in specific scenarios, meaning that even with certain FISH patterns previously considered negative, the case may still be classified as HER2-positive if IHC shows strong, uniform 3+ staining 1. This represents a shift toward recognizing that protein overexpression itself has clinical significance for treatment decisions.
Bottom Line
With IHC 3+, you should anticipate FISH confirmation in approximately 85-92% of cases. The small percentage of discordant results requires careful technical review and may still result in a HER2-positive diagnosis depending on the specific FISH pattern and guideline algorithms 1, 2.
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