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Assessing HER2 IHC with cytoplasmic staining

Case contributed by Savitri Krishnamurthy, MD

The importance of reporting discrete HER2 IHC scores

Savitri Krishnamurthy

MD

Case details

Age
45
Gender
Female

Tumor grade
1
Primary/metastatic breast cancer
Primary
Type of breast cancer
Invasive ductal carcinoma
Hormone receptor status
ER: Positive (80%, moderate intensity)
PR: Positive (80%, moderate intensity)
HER2 by IHC
0
HER2 by FISH:
Negative (not amplified)
Pre-analytic variables and technical issues
None
Ki-67:
10%
Specimen type in primary setting
Segmental mastectomy
Additional features:
No evidence of lymphovascular invasion, tumor infiltrating lymphocytes mild

In this case, the HER2 IHC on a segmental mastectomy specimen from a primary invasive ductal carcinoma showed an unusual cytoplasmic staining pattern. HER2 was scored IHC 0. FISH was performed at an outside institution and was reported as negative ahead of the patient seeing a clinician. Without any pre-analytical or technical issues, the cause of the staining pattern is unclear, but it may include: HER2 internalization, cytoplasmic dimerization, phosphorylation, intensive HER2 transcription and presence of a cytoplasmic truncated HER2.^1,2

Figure 1. HER2 IHC staining (IHC 0, 20X).

View whole slide image

What does the HER2 IHC staining indicate?

As seen in Figure 1, the HER2 IHC shows diffuse cytoplasmic staining of mild intensity with no evidence of membranous staining. Based on these observations, the tumor would be categorized as IHC 0, as cytoplasmic HER2 staining should not be included in interpretation. FISH analysis of the tumor was negative for HER2 gene amplification (HER2/CEP17 ratio = 1.13, HER2 copy = 1.70).

Discussion

The case demonstrates an unusual cytoplasmic HER2 staining pattern, which can make interpretation of this case challenging, as the presence of extensive cytoplasmic staining may hinder visualization and assessment of membrane staining of tumor cells.

The 2023 ASCO-CAP guideline update provides strict criteria for HER2 IHC categorization.³ A tumor can be scored as HER2 IHC 0 if there is no evidence of staining or incomplete, faint/barely perceptible membranous staining in <10% of tumor cells.³ Cytoplasmic staining is considered non-specific and should not be included in final HER2 IHC interpretation.⁴

Occasionally, diffuse cytoplasmic HER2 IHC staining can be encountered despite a lack of any pre-analytic issues. The cause of this artifactual staining may be unknown.¹ In cases with cytoplasmic HER2 staining, subsequent ISH testing may be helpful.⁴

Some specific instances have been suggested to lead to the formation of this unusual cytoplasmic staining pattern. These include: HER2 internalization, cytoplasmic dimerization, phosphorylation, intensive HER2 transcription and presence of a cytoplasmic truncated HER2.^1,2 In these instances, there is usually no evidence of HER2 gene amplification or increased levels of HER2 mRNA.^1,2

Considerations:

Unusual cytoplasmic HER2 staining can make interpretation of HER2 IHC challenging⁴

Cytoplasmic HER2 IHC staining is considered as non-specific and should not be included in the evaluation⁴

Subsequent ISH testing may be helpful in these cases⁴

Pathologists may find it helpful to familiarize themselves with cases that can be challenging to interpret. To explore more cases with challenging staining patterns, see pages 31 to 39 of HER2 expression in breast cancer: A comprehensive reference, found in the Breast Tumors Resources.

ASCO, American Society of Clinical Oncology; CAP, College of American Pathologists; CEP17, chromosome enumeration probe 17; ER, estrogen receptor; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; Ki-67, proliferation marker; PR, progesterone receptor.

1. Blok EJ, et al. Clinical Medicine Insights: Oncology 2013;7:41-51. 2. Horiguchi S, et al. J Med Dent Sci 2010;57:155-163. 3. Wolff AC, et al. Arch Pathol Lab Med 2023;147(9):993-1000. 4. Wolff AC, et al. J Clin Oncol 2007;25(1):118-145.

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In this series of articles, the Pathology Faculty share their experience with complex clinical cases and highlight practices that help to aid consistency in HER2 IHC scoring.

The importance of reporting discrete HER2 IHC scores

In this case, the patient presented with primary breast cancer classified as HER2-negative.

by Marilyn Bui, MD, PhD

Assessing HER2 IHC with edge artifacts

In this case, the HER2 IHC of a core needle biopsy specimen from an invasive breast carcinoma showed signs of edge artifact.

by Gary Tozbikian, MD

Interpreting HER2 IHC with an extensive in situ component

In this case, there was an extensive in situ component present along with the invasive carcinoma, and HER2 IHC scores were discordant between the two.

by Hannah Wen, MD, PhD

Assessing HER2 IHC with cytoplasmic staining

Savitri Krishnamurthy

MD

Case details

Age

Gender

Tumor grade

Primary/metastatic breast cancer

Type of breast cancer

Hormone receptor status

HER2 by IHC

HER2 by FISH:

Pre-analytic variables and technical issues

Ki-67:

Specimen type in primary setting

Additional features:

Figure 1. HER2 IHC staining (IHC 0, 20X).

What does the HER2 IHC staining indicate?

Discussion

Considerations:

Explore more Clinical Case Reviews

The importance of reporting discrete HER2 IHC scores

In this case, the patient presented with primary breast cancer classified as HER2-negative.

Assessing HER2 IHC with edge artifacts

In this case, the HER2 IHC of a core needle biopsy specimen from an invasive breast carcinoma showed signs of edge artifact.

Interpreting HER2 IHC with an extensive in situ component

In this case, there was an extensive in situ component present along with the invasive carcinoma, and HER2 IHC scores were discordant between the two.

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Assessing HER2 IHC with cytoplasmic staining

Savitri Krishnamurthy

MD

Case details

Patient information

Age

Gender

Case information

Tumor grade

Primary/metastatic breast cancer

Type of breast cancer

Hormone receptor status

HER2 by IHC

HER2 by FISH:

Pre-analytic variables and technical issues

Ki-67:

Specimen type in primary setting

Additional features:

Figure 1. HER2 IHC staining (IHC 0, 20X).

What does the HER2 IHC staining indicate?

Discussion

Considerations:

Explore more Clinical Case Reviews

The importance of reporting discrete HER2 IHC scores

In this case, the patient presented with primary breast cancer classified as HER2-negative.

Assessing HER2 IHC with edge artifacts

In this case, the HER2 IHC of a core needle biopsy specimen from an invasive breast carcinoma showed signs of edge artifact.

Interpreting HER2 IHC with an extensive in situ component

In this case, there was an extensive in situ component present along with the invasive carcinoma, and HER2 IHC scores were discordant between the two.

Quick Links

Breast Cancer Links

Gastric Cancer Links

About Us

Legal

What is a Daiichi Sankyo Company or AstraZeneca authorized person?