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Artifacts with low HER2 expression: Cytoplasmic blush

Case contributed by Hannah Wen, MD, PhD

The importance of reporting discrete HER2 IHC scores

Hannah Wen

MD, PhD

Case details

Age
56
Gender
Female

Tumor grade
3
Primary/metastatic breast cancer
Metastatic
Type of breast cancer
Invasive breast carcinoma of no special
type (NST)
Hormone receptor status
ER: Negative (<1% nuclear staining)
PR: Negative (0% nuclear staining)
HER2 by IHC
0 without membrane staining
Pre-analytic variables and technical issues
None
Ki-67
Not performed
Treatment received
Endocrine therapy and CDK4/6 inhibitor
Disease progression
Yes
Specimen type in metastatic setting
Core biopsy

In this case, the patient with a history of HR-negative/HER2-negative invasive ductal carcinoma of the left breast presented with metastatic carcinoma in the right axilla. HER2 IHC testing was performed on the core biopsy of the right axillary mass that classified the tumor as HER2-negative. This case highlights the challenge of interpreting HER2 IHC with cytoplasmic staining.¹

Case summary

A 56-year-old female was initially diagnosed with HR-positive, HER2-negative invasive ductal carcinoma in the left breast. The patient underwent bilateral mastectomy and received endocrine therapy. She subsequently developed metastatic disease to the bone, treated with endocrine therapy and CDK4/6 inhibitor. The disease progressed with metastasis to the right axilla. Ultrasound guided core biopsy of the right axillary mass revealed metastatic carcinoma, poorly differentiated. HER2 IHC testing was repeated on the axillary mass sample.¹

How were pre-analytic and analytic variables controlled for the case?

A sample obtained from an ultrasound guided biopsy was placed in 10% neutral buffered formalin at the time of the procedure. The sample was fixed for 21 hours. HER2 IHC testing was performed with Ventana PATHWAY anti-HER2/neu 4B5 assay, according to the manufacturer’s protocol.¹

What does the HER2 IHC staining indicate?

The HER2 IHC slide at 40X power of magnification shows tumor cells with abundant cytoplasmic granular staining. Cytoplasmic only staining, regardless of its percentage and intensity, should not be considered for HER2 IHC scoring.^2,3

The presence of cytoplasmic staining makes it difficult to assess true faint to weak incomplete membrane staining, especially if the faint to weak incomplete membrane staining is present in a small percentage of cells (1-10%).¹

Figure 1. HER2 IHC with cytoplasmic staining (40X).¹

How were the results reported?*

Invasive carcinoma (block: 2)

Estrogen Receptor (6F11; Ventana):

Negative (<1% nuclear staining)

Progesterone Receptor (Clone 16; Ventana):

Negative (0% nuclear staining)

HER2 (4B5, Ventana):

Negative (0), no membrane staining

“The presence of cytoplasmic staining makes it difficult to assess true faint to weak incomplete membrane staining, especially if the faint to weak incomplete membrane staining is present in a small percentage of cells.”

Discussion

The assessment of HER2 IHC requires careful attention to pre-analytic, analytic, and post-analytic factors, especially when distinguishing⁴:

HER2 IHC 0 from IHC 1+
IHC 0 with focal (1-10%) faint, incomplete staining from IHC 0 without membrane staining

For the macroscopic examination of cases at the low end of the HER2 IHC spectrum, follow the following best practice recommendations^2-4:

Examine HER2 IHC staining at high power (40X)
Assess the staining pattern, intensity, and percentage of tumor cells
Recognize unusual staining patterns and artifacts
Exclude cytoplasmic staining from the HER2 IHC scoring

Considerations

Pay careful attention to pre-analytic factors when assessing IHC 0 with focal faint, incomplete staining and IHC 0 without membrane staining⁴
Cytoplasmic only staining, regardless of its percentage and intensity, should not be considered when assessing HER2 IHC scores^3,4

You can find more information on how to approach assessment of HER2 IHC 0 with faint, incomplete staining and IHC 0 without membrane staining cases in Microscopy Series - Assessment of HER2 IHC in breast cancer: The lower end of HER2 expression, by clicking here.

*These practice considerations represent the opinions of the Breast Pathology Faculty. Members of the Breast Pathology Faculty have been contracted as paid advisors through Daiichi Sankyo and AstraZeneca and have received compensation for their time.

CDK4/6, cyclin-dependent kinase 4/6; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; NST, no special type; PR, progesterone receptor.

1. Data on file. Daiichi Sankyo, Inc. Basking Ridge, NJ. 2. Wolff AC, et al. J Clin Oncol. 2007;25(1):118-145. 3. Grassini D, et al. Pathobiology. 2022;89:278-296. 4. Wolff AC, et al. Arch Pathol Lab Med. 2023;147(9):993-1000.

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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.

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Assessing HER2 IHC with cytoplasmic staining

In this case, the HER2 IHC on a segmental mastectomy specimen from a primary invasive ductal carcinoma showed an unusual cytoplasmic staining pattern.

by Savitri Krishnamurthy, MD

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

Artifacts with low HER2 expression: Cytoplasmic blush

Hannah Wen

MD, PhD

Case details

Age

Gender

Tumor grade

Primary/metastatic breast cancer

Type of breast cancer

Hormone receptor status

HER2 by IHC

Pre-analytic variables and technical issues

Ki-67

Treatment received

Disease progression

Specimen type in metastatic setting

Case summary

How were pre-analytic and analytic variables controlled for the case?

What does the HER2 IHC staining indicate?

Figure 1. HER2 IHC with cytoplasmic staining (40X).¹

How were the results reported?*

Invasive carcinoma (block: 2)

Discussion

Considerations

Explore more Clinical Case Reviews

Assessing HER2 IHC with cytoplasmic staining

In this case, the HER2 IHC on a segmental mastectomy specimen from a primary invasive ductal carcinoma showed an unusual cytoplasmic staining pattern.

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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Artifacts with low HER2 expression: Cytoplasmic blush

Hannah Wen

MD, PhD

Case details

Patient information

Age

Gender

Case information

Tumor grade

Primary/metastatic breast cancer

Type of breast cancer

Hormone receptor status

HER2 by IHC

Pre-analytic variables and technical issues

Ki-67

Treatment received

Disease progression

Specimen type in metastatic setting

Case summary

How were pre-analytic and analytic variables controlled for the case?

What does the HER2 IHC staining indicate?

Figure 1. HER2 IHC with cytoplasmic staining (40X).1

How were the results reported?*

Invasive carcinoma (block: 2)

Discussion

Considerations

Explore more Clinical Case Reviews

Assessing HER2 IHC with cytoplasmic staining

In this case, the HER2 IHC on a segmental mastectomy specimen from a primary invasive ductal carcinoma showed an unusual cytoplasmic staining pattern.

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?

Figure 1. HER2 IHC with cytoplasmic staining (40X).¹