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Unusual staining pattern: Basolateral staining in micropapillary carcinoma

Dr. Jaffer, MD, details the interpretation of biomarker testing in invasive micropapillary carcinomas.

Basolateral Staining in Micropapillary Carcinoma Banner Image

Shabnam Jaffer

MD

Shabnam Jaffer, MD, is Chair of the Department of Pathology and Laboratory Medicine at Lenox Hill Hospital, Northwell Health and Professor of Pathology at Hofstra Northwell School of Medicine. In this article, Dr. Jaffer details the interpretation of biomarker testing in invasive micropapillary carcinomas. She discusses the alternative staining pattern observed in these cases and how to use the ASCO-CAP guidelines to more reliably establish the biomarker profile of patients.

What is invasive micropapillary carcinoma? How often do you encounter this staining pattern?

Invasive micropapillary carcinoma is a variant of ductal carcinoma characterized by an inside out morular growth pattern (Figure 1).^1-3 The tumor cells consist of cell clusters that appear to float in a hollow space with associated retraction artifacts devoid of endothelial lining cells.² The reversed polarity in these tumors can be demonstrated by an epithelial membrane antigen (EMA) stain, which shows positive cell membrane staining towards the stroma.¹ The pseudopapillary clusters lack fibrovascular cores and comprise of cells that have intermediate to high grade nuclei, with variable pleomorphism containing macronucleoli and granular eosinophilic cytoplasm.² The pure type, composed of 90% micropapillary features, accounts for 0.9-2.0% of all invasive carcinomas, whereas the mixed type, seen as a component of invasive carcinomas, amounts to 7.4%.¹Due to their association with lymphovascular tropism and lymph node metastases, these tumors exhibit aggressive behavior.¹ The tumors may also be associated with apocrine and mucinous carcinomas of the breast and in the majority of cases, are ER and PR positive, while the positivity of HER2 can vary, ranging from 12.5% to 95%.^1,4

Figure 1. Invasive micropapillary carcinoma of the breast. The tumor is composed of morula-like clusters floating in empty, clear spaces lined by delicate strands of stroma (hematoxylin-eosin, original magnification 50X).³

How do you distinguish a basolateral staining pattern from other unusual staining patterns? Are there any similarities with other subtypes?

A basolateral HER2 IHC staining pattern is seen in invasive micropapillary carcinoma of the breast, corresponding to the basolateral lining of the cell membrane.^1,2

“It is characterized by a linear C- or U-shaped phenomenon of HER2 staining that spares the luminal pole of the cell membrane (which faces the stroma due to the reversed polarity) (Figure 2).”^1,2

The HER2 staining in these cases is incomplete and is not within the standard definitions to categorize HER2 expression, which define IHC 2+ staining as weak-to-moderate complete membrane staining observed in >10% of tumor cells with recommendation to perform reflex ISH testing.⁵ However, in addition to the standard definitions, the guidelines suggest that unusual staining patterns such as basolateral staining should be reported as IHC 2+ equivocal.⁵ In micropapillary carcinomas, the staining intensity can be variable between moderate and intense, and can be associated with HER2 gene amplification by FISH.⁶ In contrast, some invasive well-differentiated ductal carcinomas may exhibit weak or weak-to-moderate HER2 IHC basolateral staining but are only rarely associated with amplification.⁶ These cases usually occur due to the use of high sensitivity rabbit monoclonal anti-HER2 antibodies and should be interpreted with caution, to not overcall as equivocal (IHC 2+).⁶

Figure 2. HER2 IHC classification guideline. a. Invasive micropapillary carcinoma (IMPC) with only basolateral membrane staining and strong intensity in more than 10% of tumor cells was classified as HER2 IHC positive (3+). b. IMPC with only basolateral membrane staining, with weak-to-moderate intensity in more than 10% of tumor cells, was classified as HER2 IHC equivocal (2+). Original magnification 200X, a and b).¹

What recommendations does the 2023 ASCO-CAP guideline update give on scoring this staining pattern by HER2 IHC? Do you have any further pieces of advice which you adopt in your own clinical practice?

The 2013 ASCO-CAP guidelines for HER2 testing stated that incomplete membranous staining that is faint or barely perceptible and in >10% of tumor cells was categorized as IHC 1+, while complete, weak-to-moderate membranous staining was categorized as IHC 2+.⁷ Invasive micropapillary carcinoma characterized by having an unusual basolateral HER2 immunohistochemical staining pattern shows incomplete moderate-to-strong staining and could not be compartmentalized into either of the 2013 IHC 1+ or IHC 2+ criteria.²

“This unusual IHC staining pattern led ASCO-CAP to modify their IHC 2+ recommendations in 2018 to weak-to-moderate complete membrane staining observed in >10% of tumor cells, and recommended follow up with reflex ISH testing.”⁵

The change was due to the fact that these carcinomas may harbor HER2 amplification.² Furthermore, the guidelines also provide additional guidance for defining unusual staining patterns, like basolateral staining, such that if encountered, these cases should be reported as IHC 2+ equivocal.⁵ Basolateral staining may also rarely be seen in conventional invasive ductal carcinomas.⁶

What are your key takeaways for the pathology community to optimize the identification and scoring of invasive micropapillary carcinoma by HER2 IHC?

When assessing HER2 IHC in invasive micropapillary carcinoma, it is important to pay attention to the staining pattern and intensity.¹ These tumors predominantly demonstrate a basolateral staining pattern with an intensity that can be weak, moderate, or strong.¹ In this setting, a weak-to-moderate HER2 stain should be reflexed to FISH.⁵ Cases with strong intensity usually correlate with HER2 gene amplification by FISH. In these cases, the HER2 intensity is more significant than the completeness of the HER2 IHC stain.²

ASCO, American Society of Clinical Oncology; CAP, College of American Pathologists; ER, estrogen receptor; EMA, epithelial membrane antigen; FISH, fluorescent in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; IMPC, invasive micropapillary carcinoma; ISH, in situ hybridization; PR, progesterone receptor.

1. Perron M, et al. Arch Pathol Lab Med 2021; 145(8):979-987. 2. Zhou S, et al. Mod Pathol 2020; 33(7):1275-1286. 3. Yang YL, et al. Arch Pathol Lab Med 2016; 140(8):799-805. 4. Verras GI, et al. Breast Cancer (Dove Med Press) 2022; 14:41-61. 5. Wolff AC, et al. Arch Pathol Lab Med 2023;147(9):993-1000. 6. Bethune GC, et al. Histopathology 2017; 70(6):966-974. 7. Wolff AC, et al. J Clin Oncol 2018; 36(20):2105-2122.

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Unusual staining pattern: Basolateral staining in micropapillary carcinoma

Shabnam Jaffer

MD

What is invasive micropapillary carcinoma? How often do you encounter this staining pattern?

Figure 1. Invasive micropapillary carcinoma of the breast. The tumor is composed of morula-like clusters floating in empty, clear spaces lined by delicate strands of stroma (hematoxylin-eosin, original magnification 50X).³

How do you distinguish a basolateral staining pattern from other unusual staining patterns? Are there any similarities with other subtypes?

What recommendations does the 2023 ASCO-CAP guideline update give on scoring this staining pattern by HER2 IHC? Do you have any further pieces of advice which you adopt in your own clinical practice?

What are your key takeaways for the pathology community to optimize the identification and scoring of invasive micropapillary carcinoma by HER2 IHC?

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Decalcified bone specimen: Processing procedures

In this article, Dr. Wei, MD, PhD, discusses the use of bone specimens as samples for HER2 IHC in metastatic breast cancer.

Impact of pre-analytic variables on HER2 IHC results

In this article, Dr. Khoury, MD, reviews several different pre-analytic variables and their impact on HER2 IHC testing.

Recommendations for testing of cytology specimens

In this article, Dr. Bui, MD, PhD, discusses the advantages and disadvantages of using cytology samples for HER2 IHC testing in breast cancer.

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Unusual staining pattern: Basolateral staining in micropapillary carcinoma

Shabnam Jaffer

MD

What is invasive micropapillary carcinoma? How often do you encounter this staining pattern?

Figure 1. Invasive micropapillary carcinoma of the breast. The tumor is composed of morula-like clusters floating in empty, clear spaces lined by delicate strands of stroma (hematoxylin-eosin, original magnification 50X).3

How do you distinguish a basolateral staining pattern from other unusual staining patterns? Are there any similarities with other subtypes?

What recommendations does the 2023 ASCO-CAP guideline update give on scoring this staining pattern by HER2 IHC? Do you have any further pieces of advice which you adopt in your own clinical practice?

What are your key takeaways for the pathology community to optimize the identification and scoring of invasive micropapillary carcinoma by HER2 IHC?

Explore more Spotlight Series

Decalcified bone specimen: Processing procedures

In this article, Dr. Wei, MD, PhD, discusses the use of bone specimens as samples for HER2 IHC in metastatic breast cancer.

Impact of pre-analytic variables on HER2 IHC results

In this article, Dr. Khoury, MD, reviews several different pre-analytic variables and their impact on HER2 IHC testing.

Recommendations for testing of cytology specimens

In this article, Dr. Bui, MD, PhD, discusses the advantages and disadvantages of using cytology samples for HER2 IHC testing in breast cancer.

Quick Links

Breast Cancer Links

Gastric Cancer Links

About Us

Legal

What is a Daiichi Sankyo Company or AstraZeneca authorized person?

Figure 1. Invasive micropapillary carcinoma of the breast. The tumor is composed of morula-like clusters floating in empty, clear spaces lined by delicate strands of stroma (hematoxylin-eosin, original magnification 50X).³