• Encoded by gene ERBB2 (erythroblastic oncogene B2)
• Also known as CD340 proto-oncogene Neu

• Rate of positivity in colon cancer is about 3 - 5%
• HER2 overexpression can be detected by immunohistochemical staining (IHC) for HER2 protein, fluorescence in situ hybridization (FISH) for ERBB2 gene amplification on paraffin embedded tissue or reverse transcription polymerase chain reaction (RT-PCR) for overexpression of ERBB2
• HER2 IHC assesses the level of expression of the membrane receptor; score range from 0 - 3+ (see table)
• Specimens with equivocal IHC results should then be validated using FISH
  • FISH can be used to measure the number of copies of the gene which are present and is thought to be more reliable than IHC
  • Results of FISH are reported as negative (not amplified) or positive (amplified)
• HER2 positive colorectal tumors have shown potential benefit from combination therapy with HER2 targeted therapy (trastuzumab plus lapatinib), which represents a standard treatment after failure of conventional therapy (Mod Pathol 2015;28:1481)

• Consensus panel recommendations on HER2 IHC scoring for colorectal cancer (HERACLES diagnostic criteria) (Mod Pathol 2015;28:1481)
• Refer to gastric scoring criteria described here for fam-trastuzumab deruxtecan-nxki eligibilty (see HER2 stomach/GE junction)

Immunohistochemistry staining	Immunohistochemistry expected pattern	Immunohistochemistry classification	FISH test
No staining (0)	---	Negative	No
Faint staining (1+) any cellularity	Segmental or granular	Negative	No
Moderate (2+) in < 50% cells	Any	Negative	No
Moderate (2+) in ≥ 50% of cells	Circumferential, basolateral or lateral	Equivocal	Yes
Intense (3+) in ≤ 10% cells	Circumferential, basolateral or lateral	Negative	No
Intense (3+) in > 10%	Circumferential, basolateral or lateral	Positive	No

• HER2 overexpression has been controversially linked to prognosis
• Some studies showed no significant difference in disease free survival between patients whose cancers were HER2 positive and HER2 negative and is thought to be not a predictor of outcome; however, 5 year cancer specific survival was improved in patients whose cancers were HER2 positive versus negative (Am J Surg Pathol 2013;37:522)
• Other studies showed HER2 overexpression in colorectal cancer was associated with poorer 3 year and 5 year survival and correlated with advanced stage and high mitotic activity (Int J Colorectal Dis 2007;22:491, Histol Histopathol 1995;10:661)

Contributed by Roula Katerji, M.D. and Aaron R. Huber, D.O.

While reviewing the HER2 immunohistochemical stains of a biopsy specimen of colon adenocarcinoma, the pathologist observes that ≥ 50% of cells have moderate lateral staining. Repeated immunohistochemical stains showed the same pattern. The correct interpretation and next step of this finding according to the HERACLES trial is

1. Equivocal because there is moderate lateral or basolateral staining in ≥ 50% of tumor cells; FISH is the next step
2. Negative because a positive result is strong circumferential membrane staining in > 70% of tumor cells, FISH is not required
3. Negative because only moderate complete basolateral (and not lateral) membrane reactivity is a considered equivocal result, FISH is not required as a next step
4. Positive because a positive result is moderate lateral or basolateral reactivity in at least 10% of neoplastic cells
5. Positive because there is intense lateral membrane positivity in ≥ 50% of cells

A. An equivocal result of HER2 staining in colorectal adenocarcinoma is moderate (2+) in ≥ 50% of cells in circumferential, basolateral or lateral. First retest with IHC is mandatory to make sure you have > 50% cellularity; if confirmed the next step is to do FISH. If amplified, the results are interpreted as positive. The remaining answer choices are incorrect because they deviate from this criterion. Choice B is incorrect because you need moderate (2+) in ≥ 50% of cells to have equivocal results and the next step is FISH. Choice C is incorrect because moderate circumferential lateral or basolateral staining in more than 50% is considered equivocal. Choice D is incorrect because positive result is when you have intense staining (3+) and not moderate. Choice E is incorrect because the image doesn’t show intense staining in ≥ 50% of cells; this choice describes the positive results of HER2 IHC test and FISH is not mandatory as a next step.

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Reference: HER2 colon