Indian Journal of Pathology and Microbiology
Home About us Instructions Submission Subscribe Advertise Contact e-Alerts Ahead Of Print Login 
Users Online: 365
Print this page  Email this page Bookmark this page Small font sizeDefault font sizeIncrease font size


 
  Table of Contents    
ORIGINAL ARTICLE  
Year : 2022  |  Volume : 65  |  Issue : 2  |  Page : 321-327
Concordance of HER2 status tested by IHC and FISH in biopsy and surgical resection specimens and comparison with clinicopathological features in gastric carcinoma


1 Department of Pathology, Health Sciences University, Antalya Training and Research Hospital, Antalya, Turkey
2 Department of Gastroenterological Surgery, Health Sciences University, Antalya Training and Research Hospital, Antalya, Turkey
3 Department of Medical Oncology, Health Sciences University, Antalya Training and Research Hospital, Antalya, Turkey

Click here for correspondence address and email

Date of Submission11-May-2020
Date of Decision07-Jul-2020
Date of Acceptance14-Feb-2021
Date of Web Publication14-Apr-2022
 

   Abstract 


Context: HER2-targeted therapy has been shown to benefit HER2-positive gastric cancer. It is very important to determine the HER2 expression level correctly to select the appropriate test and sampling method. Aim: In this study, we investigated the frequency of overexpression of HER2 and intratumoral heterogeneity of HER2-positive cases, comparison of HER2 used immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) performance in biopsy and resection specimens, the correlation of HER2 status between biopsy and resection specimens, and its relationship with clinicopathological findings. Materials and Methods: Formalin-fixed, paraffin-embedded specimens of a total of 40 surgically resected and biopsy specimens of gastric cancer were analyzed. HER2 status was examined using both IHC and FISH techniques, and the findings and their association with different clinicopathological parameters were evaluated. Results: The concordance rate between the results of IHC and FISH in biopsy and resection specimens was 96.6% and 86.6%, respectively. In paired 20 cases, the overall concordance rate of HER2-IHC and HER2-FISH status between biopsy and resection specimens was 90% and 100%, respectively. HER2-IHC analysis revealed that 5/40 cases were IHC 2+ and only 1 of 5 IHC 2+ cases demonstrated HER2-FISH amplification. Conclusion: Our results showed that HER2-IHC was well concordant with FISH in cases with a score of 0/1+ or 3+ and demonstrates strong concordance between biopsy and resection specimens. FISH should be performed when the IHC result is equivocal. In our study, no statistically significant correlation was observed between HER2 positivity and clinicopathological parameters. Overall, both biopsy and resection specimens are appropriate for HER2 testing.

Keywords: Biopsy, floresan in situ hybridization, gastric cancer, HER2, immunohistochemistry, intratumoral heterogeneity, resection

How to cite this article:
Nergiz D, Alikanoğlu AS, Süren D, Gömceli &, Öztürk B. Concordance of HER2 status tested by IHC and FISH in biopsy and surgical resection specimens and comparison with clinicopathological features in gastric carcinoma. Indian J Pathol Microbiol 2022;65:321-7

How to cite this URL:
Nergiz D, Alikanoğlu AS, Süren D, Gömceli &, Öztürk B. Concordance of HER2 status tested by IHC and FISH in biopsy and surgical resection specimens and comparison with clinicopathological features in gastric carcinoma. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Dec 6];65:321-7. Available from: https://www.ijpmonline.org/text.asp?2022/65/2/321/343202





   Introduction Top


Gastric cancer is one of the most important causes of morbidity and cancer-related mortality worldwide.[1] Gastric carcinogenesis was first described as Correa cascade. Gastric cancers have environmental and genetic multifactorial etiologies.[2]

The human protooncogene Human Epidermal Growth Factor 2 (HER2) encodes a phosphoprotein located on the chromosome 17 related to the epidermal growth factor receptor. It has tyrosine kinase activity and encodes the Erb-B2 gene. This protein is responsible for cell growth, survival, adhesion, migration, and differentiation. HER2 expression has been associated with malignant cell transformation and poor prognosis in several tumors.[3] HER2 gene expression is variable in stomach cancers.[4],[5],[6] Cancer cells with HER2 expression can be targeted in several ways.[1],[7] In the randomized phase III Trastuzumab for Gastric Cancer (ToGA) trial, trastuzumab-based treatment has been shown to increase overall survival in advanced gastric cancers with HER2 expression.[8]

In this study, we investigated the frequency of overexpression of HER2 in biopsy and surgical resection materials by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) methods, and the diagnostic value of IHC in predicting HER2 status and the compatibility between biopsy and resection materials. We further evaluated intratumoral heterogeneity of HER2-positive cases. We aimed to compare the sampling method, demographic and clinicopathological features in HER2 negative and positive gastric carcinomas.


   Materials and Methods Top


Patient selection

Formalin-fixed, paraffin-embedded specimens of a total of 40 surgically resected (subtotal or total resection) and biopsy specimens (20 patients with both endoscopic biopsy and resection materials, 10 patients with only biopsy, and 10 patients with only resection materials) of gastric cancer patients diagnosed between 2016 and 2017 were analyzed. HER2 status was examined using both IHC and FISH techniques, and the findings and their association with different clinicopathological parameters were evaluated. Hematoxylin Eosin and immunohistochemistry stained slides were removed from the archive, and all cases were reviewed, the diagnoses were confirmed, and immunohistochemistry stained slides were re-evaluated. Normal human mammary gland tissue as negative control and known cases of HER2 positive breast cancer as positive control were used for HER2 staining controls.

IHC protocol and scoring

Immunohistochemical analyses were performed using Her2/Neu primary monoclonal antibody (at 1:300 dilution, Her2/Neu rabbit monoclonal antibody, SP3 clone, Cell Marque). Sections of 3–4 μm thick were mounted on poly-L-lysine coated slides. Immunohistochemical analysis was performed using Ventana Benchmark XT automated staining system, according to the manufacturer's protocol. The Ruschoff/Hofmann method proposed in the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines was used for HER2-IHC scoring [Table 1].[9] The cases included in the 3+ category were considered positive for HER2 protein overexpression, whereas 0 and 1+ cases were regarded as negative [Figure 1]a and [Figure 1]c.
Table 1: Immunohistochemistry scoring for HER2 gastric carcinoma as per Ruschoff/Hofmann method[9]

Click here to view
Figure 1: (a) Strong basolateral membranous reactivity; IHC 3+/Positive (×100) (b) HER2 (red)/CEP17 (green) ratios ≥2.2; FISH Positive (×1000) (c) No membranous reactivity in any tumor cell; IHC 0/Negative (×100) (d) HER2 (red)/CEP17 (green) ratios <1.8; FISH Negative (×1000)

Click here to view


FISH protocol and scoring

The PathVysion HER2 DNA Probe kit (LSI HER2/neu Spectrum Orange/chromosome 7 centromere probe CEP17 Spectrum Green) was used for FISH analysis, according to the manufacturer's protocol. Sections of 3–4 μm thick were mounted on poly-L-lysine coated slides. The HER2 / CEP17 ratio was determined by counting the HER2 signals and CEP17 signals in at least 20–60 invasive tumor cell nuclei in three different areas for each tissue section. In equivocal or indeterminate cases, signal counts were performed in an additional number of tumor cells. Bio view Duet FISH imaging system was used to facilitate evaluation. The method recommended in the ASCO/CAP guidelines was used for HER2-FISH assessment.[9] Amplification of the HER2 gene was defined as positive for HER2 / CEP17 ratio ≥2.2 and an average number of HER2 copies >6; negative for HER2 amplification was defined as a HER2 / CEP17 ratio <1.8 and an average number of HER2 copies <4 and equivocal for HER2 amplification was defined as a HER2/CEP17 ratio >1.8 <2.2 and an average number of HER2 copies ≥4 and <6 [Figure 1]b and [Figure 1]d.

Heterogeneity analysis

One tissue block which contained the largest amount of differentiated tumor was selected for the evaluation of the intratumoral HER2 heterogeneity in HER2 positive patients. Each tissue block was examined in two sections.

The HER2 heterogeneity was scored by criteria adapted from Ahn et al.'s study.[10] The cutoff value between HER2 homogeneity and heterogeneity was determined to be 90% in biopsy and surgical resection specimens with FISH positive, IHC score of 3+ or IHC score of 2+ with FISH positive status. HER2 heterogeneity was not evaluated in cases with <10% staining in resection specimens and <5 neoplastic cell staining in biopsy specimens. Intratumoral heterogeneity of HER2 was defined when a case showed HER2 amplification in <90% of tumor cells.

Ethical approval

This study was reviewed and approved by the ethics committee of Health Sciences University, Antalya Training and Research Hospital (Approval number: 3/5, 2019-011).

Statistical analysis

For the analyses of data, SPSS version 22 (SPSS Inc., Chicago, IL, USA) was used. The data are presented with descriptive statistics, n (%) and mean ± standard deviation (SD), and median (min-max) values. Pearson Chi-square test and Fisher's Exact test were used to analyze the relationships between categorical variables. Mann-Whitney U test and Student's t test were used to analyze the difference between the measurement values of the two groups. Concordance rate and k values were calculated by Cohen's kappa (k). A value of P < 0.05 was considered statistically significant in all tests.


   Results Top


Comparison of HER2-IHC and FISH results in biopsy and surgical resection specimens

The results for HER2-IHC and FISH in the 30 biopsies and surgical resection specimens are shown in [Table 2]. In the FISH analysis of the biopsy specimens, HER2 amplification was observed in 6 cases (20%; all with an IHC score of 3+) and HER2 amplification was not found in cases having an IHC score of 0/1+ or 2+. In the biopsy specimens, the overall concordance rate between IHC and FISH methods was 96.6% (k: 0.94). In the FISH analysis of the surgical resection specimens, HER2 amplification was observed in 7 cases (23.3%; six with an IHC score of 3+ and one with an IHC score of 2+), and HER2 amplification was not found in cases having an IHC score of 0/1+. In surgical resection specimens, the overall concordance rate between IHC and FISH methods was 86.6% (k: 0.82). In biopsy and surgical resection specimens, FISH and IHC results were consistent, there was a significant correlation between IHC and FISH (P < 0.001, P < 0.001).
Table 2: Comparison of HER2-IHC and FISH results in biopsy and surgical resection specimens (n=30)

Click here to view


Comparison of HER2-IHC and FISH results between matched biopsy and surgical resection specimens

The comparison of HER2-IHC and FISH status between 20 biopsies and matched surgical resection specimens is shown in [Table 3] and [Table 4]. HER2-IHC amplification was observed in 4 cases. HER2 amplification was not found in cases having an IHC score of 0/1+ or 2+. Of the 20 cases, 2 cases showed HER2-IHC scores of 2+ in biopsies, but 0/1+ in resection specimens. The concordance rate of HER2-IHC was 90% (k: 0.75) between biopsies and matched surgical resection specimens. HER2-FISH amplification was observed in 4 cases. HER2 amplification was not found in cases having an IHC score of 0/1+ or 2+. The concordance rate of HER2-FISH was 100% (k: 1) between biopsies and matched surgical resection specimens. Positive four cases showed concordance in both biopsy and surgical resection specimens, and there was a significant correlation of HER2-IHC and FISH status between biopsy and matched surgical resection specimens (P < 0.001, P < 0.001).
Table 3: Comparison of HER2-IHC status between matched biopsy and surgical resection specimens (n=20)

Click here to view
Table 4: Comparison of HER2-FISH status between matched biopsy and surgical resection specimens (n=20)

Click here to view


HER2 status and clinicopathological factors

The correlation between HER2 status and patient clinicopathological features is shown in [Table 5] and [Table 6]. In this study, there were 33 male and 7 female patients, and the mean age of the patients at diagnosis was 61 years. The mean tumor diameter was determined as 5.6 cm (± 2.6) in resection specimens and 0.4 cm (± 0.2) in biopsy specimens. In HER2 positive cases, the mean number of biopsy fragments was 5.0 (± 1.26), and the mean number of tumor fragments was 3.83 (± 1.47). The number of lymph nodes removed ranged from 6 to 53 with a mean of 22, and the number of metastatic lymph nodes removed ranged from 1 to 28 with a mean of 8. HER2 amplification was not associated with age, gender, tumor location, tumor size, biopsy fragment number and tumor-containing fragment number, histological grade, intestinal metaplasia, neuroendocrine differentiation, pT, pN or metastasis status, pathologic TNM stage, vascular invasion, perineural invasion, the median number of lymph nodes and metastatic lymph nodes, Lauren's classification, WHO classification and inflammatory response in the microenvironment (P > 0.05).
Table 5: Comparison of the clinic and pathologic parameters in HER2 positive/negative patients

Click here to view
Table 6: Comparison of TNM status and pathologic TNM stage in HER2 positive/negative surgical resection specimens

Click here to view


HER2 amplification and intratumoral heterogeneity

HER2 heterogeneity was found in 5 cases (55.6%) of 9 HER2-positive cases in 40 patients. All 5 cases showed a heterogeneous pattern in both IHC and FISH methods.

In 4 of 5 cases, heterogeneity was observed in both paired biopsy and surgical resection specimens, and these cases were positive with both IHC and FISH methods. In the remaining one case, heterogeneity was observed only in the resection specimen. In this case, HER2-FISH was evaluated positively although HER2-IHC was evaluated equivocal (2+).

HER2 heterogeneity was demonstrated in 4 of 6 (66.6%) HER2 positive cases in 30 biopsy specimens and 5 of 7 (71.4%) HER2 positive cases in 30 surgical resection specimens.

The mean age of the patients at diagnosis was 58.4 years in the heterogeneous group and 58.2 in the homogeneous group. Both heterogeneous and homogeneous cases were observed more frequently in males and intestinal-type tumors.

In the heterogeneous group, the mean number of biopsy fragments was 5.4 (± 1.94) and the mean number of tumor fragments was 3.8 (± 1.64). In the homogenous group, the mean number of biopsy fragments was 4.7 (± 0.95), and the mean number of tumor fragments was 3.7 (± 1.25).

Age, gender, tumor location, tumor size, biopsy fragment number and tumor-containing fragment number, histological grade, intestinal metaplasia, neuroendocrine differentiation, pT, pN and metastasis status, pathologic TNM stage, vascular invasion, perineural invasion, the median number of lymph nodes and metastatic lymph nodes, Lauren's classification, WHO classification and inflammatory response in the microenvironment in the heterogeneous group was similar results to that in the homogeneous group, and no statistically significant relationship was found between them (P: 0.4, P: 0.37, P: 0.34, P: 0.23, P: 0.45, P: 0.35, P: 0.11, P: 0.59, P: 0.86, P: 0.19, P: 0.38, P: 0.31, P: 0, 17, P: 0.86, P: 0.86, P: 0.3, P: 0.45, P: 0.4, P: 0.59, P: 0.25, respectively).


   Discussion Top


Her2/neu (cerb-B2) gene is considered as one of the genetic factors in the pathogenesis of gastric cancers and is associated with poor prognosis. The ToGA trial found a significant correlation between HER2 expression and response to trastuzumab therapy and has been shown to increase overall survival in advanced gastric cancers with HER2 expression.[8] In order to provide the correct treatment in gastric cancers, it is very important to determine the HER2 expression level correctly and to select the appropriate test in routine practice. There are a limited number of studies in the literature that analyzed whether small biopsy materials are sufficient for accurate evaluation and accurate results and if re-evaluation is required in resection materials of patients whose HER2 expression is evaluated in biopsy materials due to frequent heterogeneity in gastric cancers; therefore, new studies are needed. In our study, we investigated the frequency of overexpression of HER2 in biopsy and resection materials by IHC and FISH methods, and the diagnostic value of IHC in predicting HER2 status and the compatibility between biopsy and resection materials. We further evaluated intratumoral heterogeneity of HER2-positive cases. We aimed to compare the sampling method, demographic, and clinicopathological features in HER2 negative and positive gastric carcinomas.

Sakai et al.[11] described HER2 overexpression in gastric carcinoma for the first time in 1986. HER2 gene expression is variable in gastric cancers but is often between 5% -30%.[5],[6] The reason for the variable frequency of HER2 expression is considered to be regional or racial differences.[12] The HER2 overexpression rate encountered in our cases accounts for 22.5% (9/40) of all gastric adenocarcinomas, similar to that reported elsewhere in the literature. In the ToGA trial, the concordance rate between IHC and FISH was 87%.[8],[13] In our study, the concordance rate between IHC and FISH was found 87.5% (k: 0.83). Additionally, many subsequent studies reported that the concordance between IHC and FISH is very high. Especially, very high concordance rates were found between IHC 0/1+ and FISH negative cases and between IHC 3+ and FISH positive cases.[13],[14],[15] Hofmann et al.[14] demonstrated that the concordance rate of IHC 3+ and FISH positive cases was 100% and IHC 0/1+ and FISH negative cases was 95.5%. HER2 amplification was found in 36% of IHC 2+ cases. In our study, the concordance rate between IHC 3+ and FISH positive cases was found as 100%, and the concordance rate between IHC 0/1+ and FISH negative cases was found as 95.8% in biopsy materials. Only one IHC 2+ case was detected, and HER2 was not found amplified in this case. In resection materials, the concordance rate between IHC 3+ and FISH positive cases and the concordance rate between IHC 0/1+ and FISH negative cases was found as 85.7% and 87%, respectively. Twenty five percent of IHC 2+ cases were found to be FISH positive. The concordance rate between the results of IHC and FISH in biopsy and resection specimens was found as 96.6% (k: 0.94) and 86.6% (k: 0.82), respectively. A statistically significant relationship was detected between HER2-IHC and HER2-FISH methods in both biopsy and surgical resection materials.

Many recent studies reported 74%–96% concordance rates between biopsy and surgical resection methods using IHC and in situ hybridization techniques.[13],[16],[17],[18] There are not many studies investigating the concordance between biopsy and resection specimens after correlating all of the IHC results of the materials with the FISH method. Kanayama et al.[13] reported a concordance rate of 91.4% between IHC and Dual-color in situ hybridization (DISH) or FISH methods in their study. Qiu et al.[18] demonstrated HER2 concordance rate of 91.4% between biopsy and surgical specimen by FISH examination in IHC 2+ cases. Our study showed a high concordance rate of 90% (k: 0.75) in the HER2-IHC test and 100% (k: 1) in the HER2-FISH test between biopsy and surgical resection specimens.

The frequency of HER2 heterogeneity is between 4% and 79%.[13],[19] The ToGA trial reported the frequency of HER2 heterogeneity was 30% in HER2 positive cases.[20] The frequency of HER2 heterogeneity in HER2 positive cases was found 69.4% in the Motoshima et al.'s[19] study and 64.6% in the Ahn et al.'s[10] study. Our study showed the frequency of HER2 heterogeneity as 55.6% in HER2 positive cases. The factors such as the absence of exact agreement in intratumoral heterogeneity scoring criteria, the subjectivity of assay interpretation, and different geographic regions might explain the discordance in intratumoral heterogeneity rates in HER2 positive patients in the literature.

The effect of HER2 heterogeneity on the prognosis of gastric cancer patients is unclear.[19] Motoshima et al.[19] found that the HER2 homogeneity group had a significantly worse prognosis compared with the HER2 heterogeneity group. In their study, heterogeneous tumors were more frequently observed in pathologic TNM stage 3, although homogeneous tumors were more frequently observed in pathologic TNM stage 4. Kurokawa et al.[21] found no significant difference in prognosis between the two groups. They demonstrated that the pathologic TNM stage of the heterogeneous and homogeneous group was similar. Motoshima et al.[19] and Kurokawa et al.[21] found no statistically significant relationship between pathologic TNM stage and intratumoral heterogeneity. In our study, the number of HER2 heterogeneity cases according to pathologic TNM stage was 1 case (20%) in stage II and 4 cases (80%) in stage III. The number of HER2 homogeneity cases according to pathologic TNM stage was 1 case (25%) in stage IV and 3 cases (75%) in stage III. The pathologic TNM stage in the heterogeneous group was similar in the homogeneous group, and no statistically significant relationship was found between them (P: 0.17).

Motoshima et al.[19] found that age, gender, Lauren's classification, perineural and lymphovascular invasion were not significantly different between the heterogeneous group and the homogeneous group. Our findings are similar to this report. On the other hand, Kurokawa et al.[21] observed a statistically significant relationship between HER2 heterogeneity and Lauren's classification.

In many studies, as in our study, no relationship was observed between HER2 positivity and age, tumor size, perineural, and lymphovascular invasion.[8],[22],[23],[24],[25] However, sufficient data have not been obtained to evaluate the relationship between HER2 status and the WHO classification, intestinal metaplasia, and neuroendocrine differentiation. Giuffrè et al.[5] reported that HER2 positivity rate was higher in tubular type carcinomas, and there was a significant relationship between WHO subtype and HER2 status. We found a higher HER2 positivity rate in tubular carcinomas, but no statistically significant relationship was found between them.

In our study, as in many studies, it was reported that the HER2 status evaluated in biopsy samples is a very good indicator of HER2 status in surgical resection materials.[13],[16],[17],[18] Similar to previous studies, our results showed that HER2-IHC was well concordant with FISH in cases with a score of 0/1+ or 3+ and demonstrates strong concordance between biopsy and resection specimens for HER2 overexpression in gastric cancer. According to our study, FISH is the gold standard method to enable one to determine whether the result is true or false positive/negative. Especially, an IHC score of 2 may result in false positive and false-negative results. FISH should be performed when the IHC result is equivocal (2+). Positive (3+) or negative (0 or 1+) HER2-IHC results do not require further FISH testing. Overall, both biopsy and resection specimens are appropriate for HER2 testing, but generous sampling for biopsy specimens is necessary to ensure accurate assessment.


   Conclusion Top


We assessed the HER2 status in 40 patients (20 patients with matched endoscopic biopsy and resection materials, 10 patients with only biopsy, and 10 patients with only resection materials) of gastric cancer. This study found HER2 positivity rate as 22.5%, which is similar to the findings of previous studies. Our study showed a high concordance rate in HER2-IHC and HER2-FISH tests between matched biopsy and surgical resection specimens. Nevertheless, in our study, no statistically significant relationship was found between HER2 status and clinicopathological parameters. This result was thought to be due to the limited number of cases in our study and the number of HER2-positive tumors. We think that the data in our study will contribute to the literature, but retrospective and prospective randomized studies should be performed in larger series to correctly identify and evaluate HER2 expression and to determine the correlation between biopsy and resection samples considering tumor heterogeneity.

Acknowledgements

We thank the Health Sciences University, Antalya Training and Research Hospital for valuable support.

Financial support and sponsorship

This study was supported by the research fund of Health Sciences University, Antalya Training and Research Hospital.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Shah MA, Kelsen DP. Gastric cancer: A primer on the epidemiology and biology of the disease and an overview of the medical management of advanced disease. J Natl Compr Canc Netw 2010;8:437–47.  Back to cited text no. 1
    
2.
Correa P. Human gastric carcinogenesis: A multistep and multifactorial process first American Cancer Society Award lecture on cancer epidemiology and prevention. Cancer Res 1992;52:6735–40.  Back to cited text no. 2
    
3.
Ishikawa T, Kobayashi M, Mai M, Suzuki T, Ooi A. Amplification of the c-erbB-2 (HER-2/neu) gene in gastric cancer cells. Detection by fluorescence in situ hybridization. Am J Pathol 1997;151:761–8.  Back to cited text no. 3
    
4.
Dewan K, Madan R, Sengupta P, Bharadwaj R. Analysis of epithelial-cadherin and human epidermal growth factor receptor 2/expression in gastric carcinoma using immunohistochemistry. Indian J Pathol Microbiol 2015;58:154-7.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Giuffrè G, Ieni A, Barresi V, Caruso RA, Tuccari G. HER2 status in unusual histological variants of gastric adenocarcinomas. J Clin Pathol 2012;65:237–41.  Back to cited text no. 5
    
6.
Irkkan SÇ. HER2 assessment in gastric carcinoma. Acta Oncol Turc 2015;47:42–51.  Back to cited text no. 6
    
7.
Arteaga CL, Chinratanalab W, Carter MB. Inhibitors of HER2/neu (erbB-2) signal transduction. Semin Oncol 2001;28:30-5.  Back to cited text no. 7
    
8.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010;376:687–97.  Back to cited text no. 8
    
9.
Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB 3rd, et al. HER2 testing and clinical decision making in gastroesophagel adenocarcinoma: Guideline from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 2016;140:1345-63.  Back to cited text no. 9
    
10.
Ahn S, Ahn S, Van Vrancken M, Lee M, Ha SY, Lee H, et al. Ideal number of biopsy tumor fragments for predicting HER2 status in gastric carcinoma resection specimens. Oncotarget 2015;6:38372-80.  Back to cited text no. 10
    
11.
Sakai K, Mori S, Kawamoto T, Taniguchi S, Kobori O, Morioka Y, et al. Expression of epidermal growth factor receptors on normal human gastric epithelia and gastric carcinomas. J Natl Cancer Inst 1986;77:4–6.  Back to cited text no. 11
    
12.
Kunz PL, Mojtahed A, Fisher GA, Ford JM, Chang DT, Balise RR, et al. HER2 expression in gastric and gastroesophageal junction adenocarcinoma in a US population: Clinicopathologic analysis with proposed approach to HER2 assessment. Appl Immunohistochem Mol Morphol 2012;20:13–24.  Back to cited text no. 12
    
13.
Kanayama K, Imai H, Yoneda M, Hirokawa YS, Shiraishi T. Significant intratumoral heterogeneity of human epidermal growth factor receptor 2 status in gastric cancer: A comparative study of immunohistochemistry, FISH, and dual-color in situ hybridization. Cancer Sci 2016;107:536–42.  Back to cited text no. 13
    
14.
Hofmann M, Stoss O, Shi D, Büttner R, Van De Vijver M, Kim W, et al. Assessment of a HER2 scoring system for gastric cancer: Results from a validation study. Histopathology 2008;52:797–805.  Back to cited text no. 14
    
15.
Pyo JS, Sohn JH, Kim WH. Concordance rate between HER2 immunohistochemistry and in situ hybridization in gastric carcinoma: Systematic review and meta-analysis. Int J Biol Markers 2016;31:1–10.  Back to cited text no. 15
    
16.
Lee S, de Boer WB, Fermoyle S, Platten M, Kumarasinghe MP. Human epidermal growth factor receptor 2 testing in gastric carcinoma: Issues related to heterogeneity in biopsies and resections. Histopathology 2011;59:832-40.  Back to cited text no. 16
    
17.
Pirrelli M, Caruso ML, Di Maggio M, Armentano R, Valentini AM. Are biopsy specimens predictive of HER2 status in gastric cancer patients? Dig Dis Sci 2013;58:397–404.  Back to cited text no. 17
    
18.
Qiu MZ, Shi SM, Chen M, Wang J, Wu QN, Sheng H, et al. Comparison of HER2 and lauren classification between biopsy and surgical resection samples, primary and metastatic samples of Gastric Cancer. J Cancer 2017;8:3531-7.  Back to cited text no. 18
    
19.
Motoshima S, Yonemoto K, Kamei H, Morita M, Yamaguchi R. Prognostic implications of HER2 heterogeneity in gastric cancer. Oncotarget 2018;9:9262-72.  Back to cited text no. 19
    
20.
Grillo F, Fassan M, Sarocchi F, Fiocca R, Mastracci L. HER2 heterogeneity in gastric/gastroesophageal cancers: From benchside to practice. World J Gastroenterol 2016;22:5879-87.  Back to cited text no. 20
    
21.
Kurokawa Y, Matsuura N, Kimura Y, Adachi S, Fujita J, Imamura H, et al. Multicenter large-scale study of prognostic impact of HER2 expression in patients with resectable gastric cancer. Gastric Cancer 2015;18:691-7.  Back to cited text no. 21
    
22.
Lei YY, Huang JY, Zhao QR, Jiang N, Xu HM, Wang ZN, et al. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: A meta-analysis of literature. World J Surg Oncol 2017;15:68.  Back to cited text no. 22
    
23.
Laboissiere RS, Buzelin MA, Balabram D, De Brot M, Nunes CB, Rocha RM, et al. Association between HER2 status in gastric cancer and clinicopathological features: A retrospective study using whole-tissue sections. BMC Gastroenterol 2015;15:1–9.  Back to cited text no. 23
    
24.
Son HS, Shin YM, Park KK, Seo KW, Yoon KY, Jang HK, et al. Correlation between HER2 overexpression and clinicopathological characteristics in gastric cancer patients who have undergone curative resection. J Gastric Cancer 2014;14:180–6.  Back to cited text no. 24
    
25.
Wang H, Liao X, Zhang J. Clinicopathological factors associated with HER2-positive gastric cancer. Medicine (Baltimore) 2017;96:e8437. doi: 10.1097/MD.0000000000008437.  Back to cited text no. 25
    

Top
Correspondence Address:
Döndü Nergiz
Department of Pathology, Health Sciences University, Antalya Training and Research Hospital, Kazım Karabekir Street, Muratpaşa- 07050 Antalya
Turkey
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_535_20

Rights and Permissions


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Introduction
    Materials and Me...
   Results
   Discussion
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed802    
    Printed40    
    Emailed0    
    PDF Downloaded34    
    Comments [Add]    

Recommend this journal