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HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation
Soomin Ahn, Ji Won Woo, Kyoungyul Lee, So Yeon Park
J Pathol Transl Med. 2020;54(1):34-44.   Published online November 6, 2019
DOI: https://doi.org/10.4132/jptm.2019.11.03
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AbstractAbstract PDF
Human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification is found in about 20% of invasive breast cancers. It is a sole predictive marker for treatment benefits from HER2 targeted therapy and thus, HER2 testing is a routine practice for newly diagnosed breast cancer in pathology. Currently, HER2 immunohistochemistry (IHC) is used for a screening test, and in situ hybridization is used as a confirmation test for HER2 IHC equivocal cases. Since the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines on HER2 testing was first released in 2007, it has been updated to provide clear instructions for HER2 testing and accurate determination of HER2 status in breast cancer. During HER2 interpretation, some pitfalls such as intratumoral HER2 heterogeneity and increase in chromosome enumeration probe 17 signals may lead to inaccurate assessment of HER2 status. Moreover, HER2 status can be altered after neoadjuvant chemotherapy or during metastatic progression, due to biologic or methodologic issues. This review addresses recent updates of ASCO/CAP guidelines and factors complicating in the interpretation of HER2 status in breast cancers.

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Original Articles
Serous Adenocarcinoma of Fallopian Tubes: Histological and Immunohistochemical Aspects
Natalia Hyriavenko, Mykola Lyndin, Kateryna Sikora, Artem Piddubnyi, Ludmila Karpenko, Olha Kravtsova, Dmytrii Hyriavenko, Olena Diachenko, Vladyslav Sikora, Anatolii Romaniuk
J Pathol Transl Med. 2019;53(4):236-243.   Published online April 11, 2019
DOI: https://doi.org/10.4132/jptm.2019.03.21
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AbstractAbstract PDF
Background
Although primary cancer of the fallopian tubes is a relatively rare type of tumor in female reproductive organs, its mortality is quite high. It is important to identify molecular and biological markers of this malignancy that determine its specific phenotype.
Methods
The study was carried out on samples received from 71 female patients with primary cancer of the fallopian tubes. The main molecular and biological properties, including hormone status (estrogen receptor [ER], progesterone receptor [PR]), human epidermal growth factor receptor (HER2)/neu expression, proliferative potential (Ki-67), apoptosis (p53, Bcl-2), and pro-angiogenic (vascular endothelial growth factor) quality of serous tumors were studied in comparison with clinical and morphological characteristics.
Results
ER and PR expression is accompanied by low grade neoplasia, early clinical disease stage, and absence of lymphogenic metastasis (p < .001). HER2/neu expression is not typical for primary cancer of the fallopian tubes. Ki-67 expression is characterized by an inverse correlation with ER and PR (p < .05) and is associated with lymphogenic metastasis (p < .01). p53+ status correlates with high grade malignancy, tumor progression, metastasis, negative ER/PR (p < .001), and negative Bcl-2 status (p < .05). Positive Bcl-2 status is positively correlated with ER and PR expression and low grade malignancy.
Conclusions
Complex morphologic (histological and immunohistochemical) study of postoperative material allows estimation of the degree of malignancy and tumor spread to enable appropriate treatment for each case.

Citations

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  • Rare non-serous fallopian tube cancers: institutional experience and literature review
    Dmitrii Sumtsov, Georgyi Sumtsov, Nataliia Hyriavenko, Mykola Lyndin, Kateryna Sikora, Nataliia Kalashnik, Svitlana Smiian, Igor Gladchuk
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    M. Lytvynenko
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    Mandy Womble, Megan E. Schreeg, Allison Hoch, Enoch B. de Souza Meira, Derek Foster, Christopher Premanandan, Tatiane T. Negrão Watanabe
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  • Problems of primary fallopian tube cancer diagnostics during and after surgery
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    REPRODUCTIVE ENDOCRINOLOGY.2021; (59): 66.     CrossRef
Potential Role for a Panel of Immunohistochemical Markers in the Management of Endometrial Carcinoma
Amany Salama, Mohammad Arafa, Eman ElZahaf, Abdelhadi Mohamed Shebl, Azmy Abd El-Hameed Awad, Sylvia A. Ashamallah, Reda Hemida, Anas Gamal, Abd AlRahman Foda, Khaled Zalata, El-Said M. Abdel-Hady
J Pathol Transl Med. 2019;53(3):164-172.   Published online February 28, 2019
DOI: https://doi.org/10.4132/jptm.2019.02.12
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AbstractAbstract PDF
Background
In order to improve the efficacy of endometrial carcinoma (EC) treatment, identifying prognostic factors for high risk patients is a high research priority. This study aimed to assess the relationships among the expression of estrogen receptors (ER), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), Ki-67, and the different histopathological prognostic parameters in EC and to assess the value of these in the management of EC.
Methods
We examined 109 cases of EC. Immunohistochemistry for ER, PR, HER2, and Ki-67 were evaluated in relation to age, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and grade, depth of infiltration, cervical and ovarian involvement, lymphovascular space invasion (LVSI), and lymph node (LN) metastasis.
Results
The mean age of patients in this study was 59.8 ± 8.2 years. Low ER and PR expression scores and high Ki-67 expression showed highly significant associations with non-endometrioid histology (p = .007, p < .001, and p < .001, respectively) and poor differentiation (p = .007, p < .001, and p <. 001, respectively). Low PR score showed a significant association with advanced stage (p = .009). Low ER score was highly associated with LVSI (p = .006), and low PR scores were associated significantly with LN metastasis (p = .026). HER2 expression was significantly related to advanced stages (p = .04), increased depth of infiltration (p = .02), LVSI (p = .017), ovarian involvement (p = .038), and LN metastasis (p = .038). There was a close relationship between HER2 expression and uterine cervical involvement (p = .009). Higher Ki-67 values were associated with LN involvement (p = .012).
Conclusions
The over-expression of HER2 and Ki-67 and low expression of ER and PR indicate a more malignant EC behavior. An immunohistochemical panel for the identification of high risk tumors can contribute significantly to prognostic assessments.

Citations

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HER2 Status and Its Heterogeneity in Gastric Carcinoma of Vietnamese Patient
Dang Anh Thu Phan, Vu Thien Nguyen, Thi Ngoc Ha Hua, Quoc Dat Ngo, Thi Phuong Thao Doan, Sao Trung Nguyen, Anh Tu Thai, Van Thanh Nguyen
J Pathol Transl Med. 2017;51(4):396-402.   Published online June 19, 2017
DOI: https://doi.org/10.4132/jptm.2017.04.24
  • 8,439 View
  • 148 Download
  • 8 Web of Science
  • 7 Crossref
AbstractAbstract PDF
Background
Human epidermal growth factor receptor 2 (HER2) is related to the pathogenesis and poor outcome of numerous types of carcinomas, including gastric carcinoma. Gastric cancer patients with HER2 positivity have become potential candidates for targeted therapy with trastuzumab.
Methods
We investigated 208 gastric cancer specimens using immunohistochemistry (IHC), fluorescence in situ hybridization and dual in situ hybridization (ISH). We also investigated the concordance between IHC and ISH. The correlation between HER2 status and various clinicopathological findings was also investigated.
Results
In total, 15.9% (33/208) and 24.5% (51/208) of gastric cancers showed HER2 gene amplification and protein overexpression, respectively. A high level of concordance between ISH and IHC analyses (91.3%, κ = 0.76) was found. A significant correlation between HER2 status and intestinal-type (p < .05) and differentiated carcinomas (p < .05) was also noted. The HER2 heterogeneity was high in gastric cancers; we found 68.8% phenotypic heterogeneity and 57.6% genotypic heterogeneity. Heterogeneity in HER2 protein expression and gene amplification showed a close association with diffuse histologic type and IHC 2+.
Conclusions
HER2 protein overexpression and gene amplification were detected in 24.5% and 15.9% of gastric cancer specimens, respectively. Intestinal-type showed a higher level of HER2 protein overexpression and gene amplification than diffuse type. HER2 status also showed a significant relationship with well- and moderately-differentiated carcinomas. The ratio of phenotypic and genotypic heterogeneity of HER2 was high in gastric carcinomas and was associated with HER2 IHC 2+ and diffuse histologic type.

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Article image
Comparison of the FDA and ASCO/CAP Criteria for HER2 Immunohistochemistry in Upper Urinary Tract Urothelial Carcinoma
Gilhyang Kim, Yul Ri Chung, Bohyun Kim, Boram Song, Kyung Chul Moon
J Pathol Transl Med. 2016;50(6):436-441.   Published online October 10, 2016
DOI: https://doi.org/10.4132/jptm.2016.07.12
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AbstractAbstract PDF
Background
Human epidermal growth factor receptor 2 (HER2) is one of the known oncogenes in urothelial carcinoma. However, the association between HER2 and the prognosis of upper urinary tract urothelial carcinoma (UUTUC) has not yet been fully clarified. The aim of this study was to evaluate HER2 expression using the United States Food and Drug Administration (FDA) criteria and American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria and compare their prognostic significance in UUTUC.
Methods
HER2 expression was evaluated in 144 cases of UUTUC by immunohistochemistry (IHC) using tissue microarrays. We separately analyzed HER2 expression using the FDA and ASCO/CAP criteria. The IHC results were categorized into low (0, 1+) and high (2+, 3+) groups.
Results
Using the FDA criteria, 94 cases were negative, 38 cases were 1+, nine cases were 2+, and three cases were 3+. Using the ASCO/CAP criteria, 94 cases were negative, 34 cases were 1+, 13 cases were 2+, and three cases were 3+. Four cases showing 2+ according to the ASCO/CAP criteria were reclassified as 1+ by the FDA criteria. High HER2 expression by both the FDA criteria and ASCO/CAP criteria was significantly associated with International Society of Urological Pathology high grade (p = .001 and p < .001). The high HER2 expression group classified with the FDA criteria showed significantly shorter cancer-specific survival (p = .004), but the HER2 high and low expression groups classified with the ASCO/CAP criteria did not show significant differences (p = .161) in cancer-specific survival.
Conclusions
HER2 high expression groups were significantly associated with shorter cancer-specific survival, and our study revealed that the FDA criteria are more suitable for determining HER2 expression in UUTUC.

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    Annette Zimpfer, Said Kdimati, Melanie Mosig, Henrik Rudolf, Heike Zettl, Andreas Erbersdobler, Oliver W. Hakenberg, Matthias Maruschke, Björn Schneider
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Case Report
HER2-Positive Breast Carcinomas with Co-amplification or Gain of Chromosome 17 Centromere Locus: Report of Three Cases and an Impact on HER2 Testing.
Hyeong Chan Shin, Young Kyung Bae, Aeri Kim, Seok Ju Park
Korean J Pathol. 2011;45(6):665-669.
DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.6.665
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AbstractAbstract PDF
Recently we experienced three cases of human epidermal growth factor receptor 2 (HER2)-amplified invasive breast carcinomas associated with co-amplification or gain of chromosome 17 centromere (CEP17) in silver-enhanced in situ hybridization (SISH) analysis. These cases revealed 2+ or 3+ staining for HER2 immunohistochemistry and >6 HER2 copies per cell on SISH analyses. However, the calculated HER2/CEP17 ratios were low (<2.2) and did not fit within the HER2-positive category. We interpreted those cases as HER2-positive tumors based on the number of HER2 copies per cell. There is a potential for misinterpretation of SISH analysis in cases showing increased CEP17 copy number, based on the criterion used for HER2 positivity (HER2 copies >6 per cell vs HER2/CEP17 ratio>2.2). We recommend reporting raw SISH or fluorescence in situ hybridization data, including number of cells counted, average numbers of HER2 and CEP17 signals, and the calculated HER2/CEP17 ratio to prevent underreporting of HER2 amplification.
Original Articles
Cancer Subtypes of Breast Carcinoma with Micropapillary and Mucinous Component Based on Immunohistochemical Profile.
Sun Young Min, Eun Jung Jung, Hyesil Seol, In Ae Park
Korean J Pathol. 2011;45(2):125-131.
DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.2.125
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AbstractAbstract PDF
BACKGROUND
Micropapillary carcinoma (MPC) is known to have a worse prognosis than the other subtypes of breast cancer. Occasionally, MPC is observed in association with invasive ductal carcinoma not otherwise specified (IDC NOS), as well as mucinous carcinoma.
METHODS
We examined the immunohistochemical expression of an estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) in 127 cases of surgically resected MPC or IDC NOS with MPC. Further, we classified these cases based on their immunohistochemical profile.
RESULTS
Among the IDC NOS with MPC cases, 47 were luminal A (62.7%), 10 were luminal B (13.3%), and 9 were HER2 (12.0%). The MPC cases included 4 luminal A (50.0%), 2 luminal B (25.0%) and 1 HER2 (12.5%) subtypes. Of the mucinous carcinomas with MPC, 4 were grouped as luminal A (57.1%), 1 as luminal B (14.3%), and 2 as HER2 (28.6%) subtypes. However, among the mucinous carcinomas, 33 were categorized as luminal A (89.2%), 3 as luminal B (8.1%), and 1 as HER2 (2.7%) subtype, indicating a low incidence of HER2 subtype as compared to the other subtypes.
CONCLUSIONS
The luminal B and HER2 subtypes were prevalent in carcinomas with MPC. This result explains the poor prognosis of breast carcinomas with an MPC pattern.

Citations

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  • Investigation of Clinical Histopathologic Features and Metabolic Parameters of 18F-FDG PET/CT in Invasive Breast Carcinoma with a Micropapillary Component
    Elife Akgün, Göksel Alçın, Esra Canan Kelten Talu, Tevfik Fikret Çermik, Tuçe Söylemez Akkurt, Ebru Şen, Esra Arslan
    Molecular Imaging and Radionuclide Therapy.2023; 32(3): 221.     CrossRef
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    Georgios-Ioannis Verras, Levan Tchabashvili, Francesk Mulita, Ioanna Maria Grypari, Sofia Sourouni, Evangelia Panagodimou, Maria-Ioanna Argentou
    Breast Cancer: Targets and Therapy.2022; Volume 14: 41.     CrossRef
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    Katrina Collins, Andrew Ricci
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    Hyun-Jung Kim, Kyeongmee Park, Jung Yeon Kim, Guhyun Kang, Geumhee Gwak, Inseok Park
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HER2 Status in Gastric Adenocarcinomas Assessed by Immunohistochemistry, Automated Silver-Enhanced In Situ Hybridization and Fluorescence In Situ Hybridization.
Aeri Kim, Jung Min Bae, Se Won Kim, Mi Jin Gu, Young Kyung Bae
Korean J Pathol. 2010;44(5):493-501.
DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.5.493
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AbstractAbstract PDF
BACKGROUND
Recently, many studies have focused on human epidermal growth factor receptor 2 (HER2) status in gastric cancer due to HER2-targeted therapy using trastuzumab. We investigated HER2 overexpression and amplification and their concordance rate in Korean gastric adenocarcinomas.
METHODS
Tissue microarrays were constructed with 232 gastric adenocarcinoma samples. We performed immunohistochemistry (IHC), silver-enhanced in situ hybridization (SISH) and fluorescence in situ hybridization (FISH) for HER2.
RESULTS
IHC was negative in 94.8% (218/232), equivocal in 1.7% (4/232) and positive in 3.5% (8/232) of cases. HER2 protein expression was heterogeneous in 75% (9/12) of IHC 2+/3+ cancers. Gene amplification was observed in 6.5% (15/230) by SISH and the same 15 cases were also FISH-positive. We observed HER2 amplification in 1.4%, 27.3%, 25%, and 100% of IHC 0, 1+, 2+, and 3+ gastric adenocarcinomas, respectively. The concordance rate between IHC and SISH results was 95.7%.
CONCLUSIONS
HER2 overexpression and amplification were less frequent in gastric adenocarcinomas than breast carcinomas. Compared to breast carcinoma, (1) there may be IHC-negative but gene amplification-positive cases for HER2 and (2) frequent intratumoral heterogeneity of IHC for HER2 in gastric adenocarcinomas.

Citations

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  • Epidemiologic Study of Human Epidermal Growth Factor Receptor 2 Expression in Advanced/Metastatic Gastric Cancer: an Assessment of Human Epidermal Growth Factor Receptor 2 Status in Tumor Tissue Samples of Gastric and Gastro-Esophageal Junction Cancer
    Kyung Won Seo, Taeyong Jeon, Sewon Kim, Sung Soo Kim, Kwanghee Kim, Byoung-Jo Suh, Sunhwi Hwang, SeongHee Choi, Seungwan Ryu, Jae Seok Min, Young-Joon Lee, Ye Seob Jee, Hyeondong Chae, Doo Hyun Yang, Sang Ho Lee
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    Jun Haeng Lee, Jae G. Kim, Hye-Kyung Jung, Jung Hoon Kim, Woo Kyoung Jeong, Tae Joo Jeon, Joon Mee Kim, Young Il Kim, Keun Won Ryu, Seong-Ho Kong, Hyoung Il Kim, Hwoon-Yong Jung, Yong Sik Kim, Dae Young Zang, Jae Yong Cho, Joon Oh Park, Do Hoon Lim, Eun S
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  • Clinical Practice Guidelines for Gastric Cancer in Korea: An Evidence-Based Approach
    Jun Haeng Lee, Jae G. Kim, Hye-Kyung Jung, Jung Hoon Kim, Woo Kyoung Jeong, Tae Joo Jeon, Joon Mee Kim, Young Il Kim, Keun Won Ryu, Seong-Ho Kong, Hyoung-Il Kim, Hwoon-Yong Jung, Yong Sik Kim, Dae Young Zang, Jae Yong Cho, Joon Oh Park, Do Hoon Lim, Eun S
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Automated Silver-enhanced In Situ Hybridization for Evaluation of HER2 Gene Status in Breast Carcinoma: Comparison with Fluorescence In Situ Hybridization and Immunohistochemistry.
Woo Jung Sung, Seok Ju Park, Mi Jin Gu, Young Kyung Bae
Korean J Pathol. 2010;44(1):28-34.
DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.1.28
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AbstractAbstract PDF
BACKGROUND
The human epidermal growth factor receptor 2 (HER2) is amplified in 20-25% of breast cancers. HER2 overexpression or amplification is associated with a worse clinical outcome and it can predict the benefit from anthracycline and anti-HER2 therapies. The HER2 status has usually been assessed by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) in clinical samples. A new silver-enhanced in situ hybridization (SISH) technique was recently introduced. Therefore we evaluated the usefulness of SISH for detecting HER2 amplification.
METHODS
Tissue microarrays (TMAs) were constructed with 144 invasive breast cancer tissue samples. We performed IHC, FISH and SISH for HER2 on the tissue sections from the TMAs and we interpreted the results according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. The concordant rates between the two different tests were calculated.
RESULTS
HER2 was overexpressed and amplified in 16.9%, 16.9%, and 18% of the cases by IHC, FISH and SISH, respectively. The concordant rates between IHC and FISH, IHC and SISH, and FISH and SISH were 95.1%, 95.7%, and 97.8%, respectively.
CONCLUSIONS
SISH can be an alternative test for evaluating HER2 amplification because the 97.8% concordance with FISH satisfies the ASCO/CAP requirement of > 95% concordance with an alternative validated method.

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  • HER2 assessment by silverin situhybridization: where are we now?
    Francesca Sanguedolce, Pantaleo Bufo
    Expert Review of Molecular Diagnostics.2015; 15(3): 385.     CrossRef
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    Youngseok Lee, Youngjoon Ryu, Hoiseon Jeong, Hyeyoon Chang, Younghye Kim, Aeree Kim
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  • HER2 Status by Standardized Immunohistochemistry and Silver-EnhancedIn SituHybridization in Korean Breast Cancer
    Young Kyung Bae, Gyungyub Gong, Jun Kang, Ahwon Lee, Eun Yoon Cho, Ji Shin Lee, Kwang-Sun Suh, Dong Wha Lee, Woo Hee Jung
    Journal of Breast Cancer.2012; 15(4): 381.     CrossRef
  • Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting NormalHER2andTOP2AStatus
    Aeri Kim, Hyung Chan Shin, Young Kyung Bae, Min Kyoung Kim, Su Hwan Kang, Soo Jung Lee, Eun Hee Lee
    Journal of Breast Cancer.2012; 15(1): 24.     CrossRef
  • HER2-Positive Breast Carcinomas with Co-amplification or Gain of Chromosome 17 Centromere Locus: Report of Three Cases and an Impact on HER2 Testing
    Hyeong Chan Shin, Young Kyung Bae, Aeri Kim, Seok Ju Park
    The Korean Journal of Pathology.2011; 45(6): 665.     CrossRef
  • The Effectiveness of SilverIn SituHybridization in Patients with Breast Cancer: A Systematic Review
    Sunyoung Jang, Seon-Heui Lee, Soojin Kim, You-Kyoung Lee, Young-Hyuck Im, Wonshik Han, Hee-Sook Park
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    Jung Sik Jang, Eun Jeong Jang, Ji‐Young Park
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  • HER2Status in Gastric Adenocarcinomas Assessed by Immunohistochemistry, Automated Silver-EnhancedIn SituHybridization and FluorescenceIn SituHybridization
    Aeri Kim, Jung Min Bae, Se Won Kim, Mi Jin Gu, Young Kyung Bae
    The Korean Journal of Pathology.2010; 44(5): 493.     CrossRef
Protein Expression and Gene Amplification of Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer: Correlation with the Response to Gefitinib Therapy.
Jinyoung Yoo, Kyungji Lee, Ji Han Jung, Byoung Yong Shim, Sung Hwan Kim, Deog Gon Cho, Myeong Im Ahn, Chi Hong Kim, Kyu Do Cho, Hoon Kyo Kim, Seok Jin Kang
Korean J Pathol. 2008;42(1):1-8.
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AbstractAbstract PDF
BACKGROUND
Gefitinib is an EGFR tyrosine kinase inhibitor that has shown dramatic effectiveness in a subset of non-small cell lung cancer (NSCLC) patients. We evaluated the response rate to gefitinib, and the significance of the EGFR and HER2/neu status as predictive markers of the tumor response.
METHODS
The EGFR and HER2/neu protein expressions, as determined by immunohistochemistry (IHC) and gene amplification via chromogenic in situ hybridization (CISH), were analyzed in biopsy specimens from 46 patients with advanced NSCLC. After their failure with the first-line treatment, all the patients had received gefitinib treatment.
RESULTS
A partial response (PR) was achieved in 8 patients (17.4%). An EGFR overexpression was detected in 80.4% (37/46) of the tumors, and this was observed exclusively in patients with a PR (100% vs 75.3%, respectively; p=0.076). EGFR gene amplification was present in 47.8% of the tumors (22/46). HER2/neu was overexpressed in 13%(6/46) and it was amplified in 17% (7/46). The overall survival was prolonged in the female patients (p=0.007), and in patients with T1 and T2 disease (p=0.039), adenocarcinoma (p=0.010), a PR (p=0.022), an EGFR IHC+ status (p=0.033), an EGFR IHC+/CISH+ status (p=0.010), or an EGFR+/HER2/neu+ status (p=0.030). On multivariate analysis, gender, T disease and EGFR IHC/CISH remained the significant predictors of survival.
CONCLUSIONS
Gefitinib showed a modest effect for the patients with chemotherapy-refractory advanced NSCLC. A combination of EGFR IHC and CISH might be important for identifying those patients who are most likely to benefit from gefitinib therapy.

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