Gastric HER2: Biopsy and Resection That Do Not Agree
A 64-year-old has a gastric body biopsy and a subsequent subtotal gastrectomy. HER2 IHC on the biopsy shows a single tight cluster of six cells with strong complete basolateral membrane staining among roughly 400 tumor cells; everything else is 0/1+. HER2 IHC on the resection shows strong complete basolateral membrane staining in about 8% of tumor cells, weak-to-moderate complete basolateral staining in another 35%, and 1+ in the rest. Both blocks were fixed 24–30 hours in 10% NBF. The treating oncologist wants to start trastuzumab-based therapy and asks why the two specimens "say different things".
1. Score both specimens and explain why the same antibody gives apparently different answers.
Read the worked answer
Score against the criteria for the specimen type, not a single universal percentage.
- Biopsy: in gastric biopsy material, a cohesive cluster of at least five strongly stained cells is sufficient for IHC 3+, irrespective of what fraction of the tumor that represents. Six cells in a tight cluster qualifies as 3+.
- Resection: the threshold is 10% of tumor cells with strong complete, basolateral or lateral membrane staining. Here that figure is 8% - below threshold - with a further 35% weak-to-moderate, so the resection scores 2+, equivocal, reflex to ISH.
The apparent disagreement is not a staining failure. Biopsies sample a small volume, are subject to sampling error, and use a lower cellular threshold precisely because a positive result changes management. Resections estimate percentage across the whole tumor and therefore demand a defined area fraction. Both results are internally valid and both describe genuine intratumoral heterogeneity: HER2 amplification in gastric cancer is famously clonal and patchy.
The report should give intensity, percentage, membrane pattern (complete vs basolateral vs lateral), and the specimen-specific criterion applied - not just a number.
2. What is your reporting recommendation to the oncologist, and how do you handle the discordance in the record?
Read the worked answer
The clinically actionable question is whether the patient is HER2-positive, and a validated 3+ on a biopsy is a legitimate basis for therapy in gastric cancer. The correct move is neither to average the two results nor to default to the resection because it is larger.
Recommended approach:
- Do not downgrade the biopsy. Report it as 3+ with the explicit note that it was a single small cluster; quantify it so the reader can see the basis.
- Send the resection for HER2 ISH, since 2+ requires reflex testing. If ISH is amplified in the region with the 35% weak-to-moderate staining, that supports a positive call with a heterogeneous pattern and strengthens the case.
- Consider testing additional blocks from the resection to look for a 3+ focus - heterogeneity means a single section may under-sample the amplified clone.
- Put the discordance in an addendum to the surgical report, referencing the biopsy result, so that the two reports cannot be read in isolation by a different clinician.
Frame it for the oncologist as: the tumor is heterogeneous; the biopsy captured an amplified clone; the resection sampled a predominantly non-amplified area. That is biology, not error.
3. A colleague suggests simply counting all membrane-stained cells regardless of intensity to resolve the discrepancy. Why is that wrong here?
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Because it collapses a two-dimensional score into one number and discards the variable that carries the biological signal.
- Intensity distinguishes complete from incomplete and strong from weak. A cell with faint, incomplete basolateral staining is not equivalent to a cell with strong complete basolateral staining. Summing them inflates the score and can convert a 2+ into a 3+, which directly determines eligibility for a toxic and expensive therapy.
- Pattern matters in gastric cancer specifically. Basolateral and lateral membrane staining is the interpretable pattern; complete circumferential staining is the classic breast pattern. Cytoplasmic or apical-only staining must be excluded, and a total-cell count that ignores pattern will include them.
- Artifacts contaminate a naive count. Crush, cautery, edge drying and necrotic debris all take up stain and would enter the numerator.
- The 10% rule is defined on strongly stained cells, so a count that mixes intensities is measuring something the guideline does not define.
The right refinement is to score by intensity tier, state the percentage in each tier and the membrane pattern, and let the ISH result adjudicate the equivocal tier.