|Year : 2020 | Volume
| Issue : 2 | Page : 214-220
|HER-2/neu over expression in gall bladder adenocarcinoma: A quest for potential therapeutic target
Pragya Jain1, Surbhi Goyal1, Geeta Chauhan1, Kaushik Majumdar1, Shahajad Ali1, Puja Sakhuja1, Anil K Agarwal2
1 Department of Pathology, GIPMER, Jawaharlal Nehru Marg, 64 Khamba, New Delhi, India
2 Department of Gastro-Surgery, GIPMER, Jawaharlal Nehru Marg, 64 Khamba, New Delhi, India
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|Date of Web Publication||18-Apr-2020|
| Abstract|| |
Background: Gall bladder carcinoma (GBC) is an aggressive malignancy with high mortality and aggressive course, with palliation as the only available option. Objectives: To evaluate frequency of HER-2/neu overexpression in GBC and to seek its correlation, if any with conventional clinicopathological parameters and survival. Methods: Immunohistochemistry (IHC) was performed on 200 cases of GBC, 32 cases of dysplasia, and 100 cases of chronic cholecystitis. Fluorescent in situ hybridization (FISH) was performed on 30 randomly selected cases of GBC to validate IHC. HER-2/neu overexpression (IHC 3+/FISH amplification ≥2.2) was correlated with clinicopathological parameters by Chi-square test.P < 0.05 was considered significant. Survival analysis was done by log-rank test and Kaplan-Meier analysis. Results: HER-2/neu overexpression was seen in 14% (28/200) GBC cases but was not found in dysplasia and chronic cholecystitis. Majority of these cases were ≤grade 2 and in advanced stage, however this was not statistically significant. A lower mean survival in HER-2/neu positive group as compared to HER-2/neu negative group (17.1 ± 2.3 month versus 67.6 ± 8.5 month, respectively) was observed. Concordance between IHC and FISH was seen in 18/19 cases. Conclusion: This study delineates a subset of GBC patients with HER-2/neu overexpression, in whom targeted therapy can offer a survival benefit.
Keywords: Fluorescent in situ hybridization, gall bladder adenocarcinoma, HER-2/neu, immunohistochemistry
|How to cite this article:|
Jain P, Goyal S, Chauhan G, Majumdar K, Ali S, Sakhuja P, Agarwal AK. HER-2/neu over expression in gall bladder adenocarcinoma: A quest for potential therapeutic target. Indian J Pathol Microbiol 2020;63:214-20
|How to cite this URL:|
Jain P, Goyal S, Chauhan G, Majumdar K, Ali S, Sakhuja P, Agarwal AK. HER-2/neu over expression in gall bladder adenocarcinoma: A quest for potential therapeutic target. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 May 31];63:214-20. Available from: http://www.ijpmonline.org/text.asp?2020/63/2/214/282708
| Introduction|| |
Gall bladder carcinoma (GBC) is an aggressive malignancy accounting for 1.2% of all new cancer related cases and 1.7% of all cancer related deaths worldwide. The distribution is geographically heterogeneous due to variability in risk factors. According to GLOBOCAN observatory 2018, Bolivia has highest number of reported cases of GBC followed by Chile.
The disease burden is on rising trend in northern India due to increase in lifestyle-related modifiable risk factors. It is 14th most common malignancy in India with annual incidence of 2.5% and mortality rate of 2.75%.
In early stages GBC is usually asymptomatic, therefore not detected. Majority of patients present in advanced stage when palliation remains the only possible therapeutic option. Due to limited intervention, the prognosis remains dismal. Better insight into the molecular pathogenesis is needed to develop an effective targeted therapy which can offer a hope of better survival in these patients.
After successful implementation of HER-2/neu directed therapy in breast and gastric adenocarcinoma, interest on similar lines is generated in GBC as well. In 2013, phase II trial (NCT00478140) was conducted to evaluate efficacy of HER-2/neu directed therapy in biliary tract malignancy including GBC, however it was terminated due to limited participation. Javle et al. studied response of transtuzumab in 9 patients of GBC and found good response (complete/stable/partial) in 89% cases. In view of encouraging results, studies are needed to support the importance of targeted therapy in GBC.
HER-2/neu is proto-oncogene encoding tyrosine kinase receptor located on 17q12-q21. Amplification and protein overexpression leads to continual and uncontrolled cell proliferation. Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are two commonly used modalities for HER-2/neu overexpression with high concordance rates (88.2%). Heterogeneity exists in the literature regarding frequency of HER-2/neu overexpression in GBC. Prognostic role of HER-2/neu in GBC is also not clear. Some authors have found significant correlation of HER-2/neu overexpression with tumor grade and patient survival while few failed to establish any significant correlation.,
Despite increasing trends of GBC, very few studies that too with small sample size have been reported in literature.,, We undertook this study to evaluate frequency of HER-2/neu overexpression using IHC in GBC and its correlation with conventional clinicopathological parameters and patient survival rate.
| Methods|| |
The present study was conducted in the department of pathology and gastrointestinal surgery. We included 200 consecutive cases of cholecystectomy specimens from August 2009 to May 2018 that were operated with radiological suspicion of carcinoma or had prior cytology proving carcinoma. Other histological subtypes including the adenosquamous and mixed adeno-neuroendocrine tumor were excluded. The histopathological parameters namely tumor grade, perineural/lymphovascular invasion, dysplasia of the adjoining mucosa, depth of invasion, nodal status, pathological stage as per AJCC, and overall survival (in months) of all the GBC cases were evaluated and tabulated on a prestructured performa. Minimum 1 year of follow-up was taken for cases (telephonic conversations/OPD visits) wherever possible. IHC was done on formalin-fixed paraffin embedded (FFPE) sections in all cases. FISH was performed to validate the IHC results on randomly selected 30 GBC cases. HER-2/neu immunoexpression was also assessed in 100 cases of chronic cholecystitis which served as control group and 32 cases of incidentally diagnosed dysplasia of the gall bladder mucosa. Institutional ethics committee clearance was taken prior to commencement of the study.
Protocol for immunohistochemistry using HER-2/neu antibody
Immunoexpression of HER-2/neu was assessed on 4 um FFPE sections using clone SP3, rabbit monoclonal antibody (1:150) by Thermofischer as per standard operating procedure and subsequently standardized in the department. Conventional two-day procedure using microwave method of antigen retrieval using tris/EDTA buffer (pH 9). Confirmed breast carcinoma cases with HER-2/neu overexpression were taken as positive control. Positive control slides were put with each batch.
HER-2/neu staining was evaluated using guidelines by Ruschoff et al. for gastric adenocarcinoma as shown in [Table 1]. The membranous staining is considered significant and is given a score. Cytoplasmic staining was not considered for interpretation.
Protocol for FISH using dual colored ZytoLight SPEC HER-2/CEN 17 probe kit
The Probes used included a locus specific identifier (LSI) HER-2/neu labelled in Spectrum Green and a chromosome enumerator probe (CEP) 17 labelled in Spectrum Orange. FISH was performed on 1.5 μm thick paraffin embedded sections. On day one pretreatment using warmed acetic acid solution for 15 min and protein denaturation using pepsin solution was done for 10 min. Final hybridization using 10 μL ZytoLight FISH probe was done. On day 2, washing using WASH buffer A followed by incubation with 3 μL DAPI/antifade solution was done for 15 min in dark. Necessary washing after each step was done. Slides were evaluated under fluorescent microscope.
Evaluation of HER-2/neu amplification by FISH
Signal enumeration was conducted at 1000 × magnification with the appropriate filter. At least 20 cells (nonoverlapped tumor nuclei) were evaluated for HER-2/CEN and the average value was taken. In equivocal cases additional 20 were counted. HER-2/neu gene amplification is defined in terms of HER-2/CEN 17. Ratio of ≥2.2 was taken as positive/amplified. A range of 1.8–2.2 was considered equivocal and <1.8 was considered negative.
For analysis all the cases were divided into two groups. Group 1 included HER-2/neu positive cases including 3+ cases by IHC and/or ≥2.2 by FISH. Group 2 includes HER-2/neu negative cases (negative on IHC and FISH). The association between HER-2/neu positivity and clinicopathological parameters was done using Chi-square test. P less than 0.05 was considered statistically significant. Survival time estimates was represented using Kaplan-Meier survival graphs and comparison between the groups was done using log rank test (Mantel Cox).
| Results|| |
Mean age of presentation of GBC cases was 51.35 ± 11.43 years with a female predominance (M: F =1:4.7). The clinicopathological details of 200 GBC cases are included in [Table 2]. For chronic cholecystitis, mean age of presentation was 50.2 ± 0.5 years (M:F = 1:2.3). Thirty two cases, comprising of low grade dysplasia (27) and high grade dysplasia (5) were seen. ICPN was seen in 4 cases. Associated intestinal metaplasia and antral metaplasia was found in 10 and 15 cases respectively.
Assessment of HER-2/neu scoring by IHC
None of the cases of chronic cholecystitis, dysplasia (low grade/high grade), ICPN, intestinal metaplasia, and antral metaplasia revealed any HER-2/neu immunoexpression. Of the 200 GBC cases on which IHC was applied, 127 were negative (0 and 1+) [Image 1]a and [Image 1]b. Equivocal (2+) and positive (3+) immunoexpression was seen in 48 and 25 cases, respectively [Image 1]c and [Image 1]d. FISH analysis was performed on randomly selected 30 cases which comprised of 11 (1+), 11 (2+), and 8 (3+) cases by IHC. Of the 11 equivocal cases by IHC, three cases showed HER-2/neu amplification on FISH. Thus HER-2/neu positivity (group 1) was seen in 25 + 3 = 28 (14%) cases. Her 2 neu negative group included 135 cases which were negative on IHC (0 and1+) and negative on FISH (HER-2/CEN 7 ratio ≤1.8). There were 37 cases which were equivocal on IHC (2+), and in which FISH could not be done; these cases were excluded from the statistical analysis.
FISH was done randomly on 30 cases. Correlation of HER-2/neu overexpression by IHC and FISH is depicted in [Table 3]. All the 11 cases having 1+ score on IHC were negative on FISH. Of the eight cases that were positive on IHC (3+), 7 cases showed amplification (mean HER-2/CEN 17 = 2.6±0.67) [Image 2]a and [Image 2]b. Three out of 11 equivocal (2+) cases on IHC were found to harbor HER-2/neu amplification by FISH. Validation of IHC result by FISH was done in 30/200 (15%) cases. Concordance between FISH and IHC was calculated among positive (3+) and negative (0/1+) cases. Equivocal cases were removed during calculation of concordance. Concordance between FISH and IHC was seen in 18/19 (94.7%) cases as depicted in [Table 3].
|Table 3: Distribution of FISH results and HER-2/neu scoring (IHC) in 30 cases|
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Correlation of HER-2/neu with clinicopathological factors
The relationship of HER-2/neu status with clinicopathological parameters is depicted in [Table 4]. The mean age of presentation was not significantly different between the two groups (P = 0.885). HER-2/neu positivity was seen more in women (89%), however difference between the two groups was not statistically significant (P = 0.282). Almost two-thirds (21/28) of HER-2/neu positive cases were well-to-moderately differentiated (G ≤ 2). Sixty-one percent of HER-2/neu positive cases invaded liver or beyond as compared to 46% in HER-2/neu negative group (P =0.154). Advanced stage at the time of presentation (pTNM ≥ 3) was seen in 71% of HER-2/neu positive cases. Dysplasia in the adjoining mucosa was seen in 75% of the HER-2/neu positive cases as compared to 28% in HER-2/neu negative group (P = 0.000).
|Table 4: Correlation of HER-2/neu status with clinicopathological parameters|
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Follow-up was available in total 90 cases which comprised of 22 cases from group 1 and 68 from group 2 [Table 5]. Median survival of HER-2/neu positive patients was 24 months. Since the number of censored cases in the HER-2/neu negative group was above 50% (59.6%), isolated median survival could not be calculated for this group. The mean survival of HER-2/neu positive group was 17.1 ± 2.3 month (CI: 12.5) and HER-2/neu negative group was 67.6 ± 8.5 (CI = 50.9). The log-rank test (Mantel-Cox P =0.419) and the Kaplan-Meier survival curve [Figure 1] however did not reveal significant difference in cumulative survival between the two groups. In the HER-2/neu positive group 91% (10/11) patients died within 9 months of diagnosis in comparison to 73% (19/26) in the HER-2/neu negative group of patients.
|Figure 1: Kaplan-Meier survival graph depicting survival of HER-2/neu positive group and HER -2/neu negative group|
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| Discussion|| |
HER-2/neu is a proto oncogene codes for growth factor receptor with catalytic kinase activity and have four homodimers (HER 1-4). Li et al. have observed role of HER-2/neu mutated pathway in 36.8% of GBC samples and reported 37 nonsilent mutations in 15 genes involved in ERBb pathway. HER-2/neu overexpression has been reported in bladder carcinoma (12.4%), breast cancer (10.5%) and esophageal or gastroesophageal cancer (4.7%) apart from gall bladder cancer (9.8%).
HER-2/neu overexpression was found in 14% of GBC cases in our study, concordant with the reported range of 2–46.5% in the literature. This difference in frequency across the studies can be attributed to different scoring criteria, antibodies used, tissue heterogeneity, tissue processing factors, and ethnicity. We analyzed HER-2/neu overexpression as per gastric carcinoma guidelines proposed by Ruschoff et al., however majority of studies have used breast carcinoma guidelines.,,,,, Doval et al. observed a lower frequency (4%) of HER-2/neu overexpression in 50 Indian patients and labeled cases with only strong complete membranous staining as positive. Interpretation of basolateral/lateral membranous immunostaining as positive, might explain the slightly higher frequency of 14% in our study. Ata et al. followed similar scoring guidelines as ours and observed a comparable frequency of HER-2/neu immunoexpression (11.7%) in 17 Turkish GBC patients. Kumari et al. following breast carcinoma guidelines reported almost similar frequency of HER-2/neu overexpression with incomplete vs. complete membranous staining (13.4% vs 9.8% respectively) in 104 GBC patients. In the largest available series of 187 GBC patients from Chile, HER-2/neu immunoexpression was found in 12.8% cases. Since most of the previous studies had a smaller sample size and used variable scoring criteria, significant conclusions could not be drawn.
Very few studies have analyzed HER-2/neu status by FISH in GBC and a high concordance (88.2%) between IHC and FISH has been reported. A concordance between IHC and FISH was seen in 95% (18/19) cases in our study. Thus, IHC can be a convenient method in evaluation of HER-2/neu status in GBC. In our study none of the case with 1 + HER-2/neu status on IHC was amplified on FISH and 7 out of 8 cases with HER-2/neu 3+ IHC were found to harbor amplification by FISH. The discordance in one HER-2/neu 3+ cases can be explained by intratumoral heterogeneity and technical inconsistencies. Since the cutoff for the HER-2/neu positivity on IHC is in 10% analyzed cell, so concordance between these two complementary methods can depend on same proportion of adequate cell analyzed on same slide.
Review of literature yields conflicting results regarding association of HER-2/neu with clinicopathological parameters in GBC. Mean age of presentation in GBC was 51.3 years with female predominance in our study, comparable to previous Indian studies (52.34 years). On the contrary higher mean age of presentation (62.5 years) has been reported from Chile. In our study, a higher proportion of HER-2/neu positive cases were found to be well differentiated (75%), in advanced stage (71%), had higher depth of invasion (61%), and nodal metastasis (71%). However, no statistically significant correlation of HER-2/neu overexpression with tumor grade and stage could be found (P > 0.05). Kumari et al. found higher HER-2/neu expression in well differentiated GBC and stage II tumors however their results were also not statistically significant (P > 0.05). Puhalla et al. found significant correlation of HER-2/neu overexpression with advanced T stage (P < 0.02). Majority of the previous researchers have failed to establish significant correlation between HER-2/neu expression and clinicopathologic parameters in GBC.,,,
HER-2/neu expression was found in none of the cases of dysplasia, ICPN, intestinal metaplasia and pyloric metaplasia. We believe that HER-2/neu overexpression is probably a late event in the carcinogenesis cascade for GBC. This hypothesis is in agreement with the results of few available limited studies on preneoplastic lesions in gall bladder., On the contrary, Toledo et al. have found strong HER-2/neu immunoexpression in basolateral membrane in intestinal metaplasia and carcinoma in situ (91% and 90% respectively). But their cases did not reveal HER-2/neu amplification on FISH, suggesting that this event might not be relevant for precursor lesions of GBC.
Only a few studies have assessed the prognostic role of HER-2/neu overexpression in GBC in terms of survival.,, A lower mean survival in HER-2/neu positive group in comparison to HER-2/neu negative (17.1 ± 2.3 month vs. 67.6 ± 8.5 month, respectively) was observed in our study. Similar to our study a worse overall survival at 5 years in HER-2/neu over expressed vs. negative cases (34% vs 41%) has been reported. Significant difference in overall survival between HER-2/neu positive and negative groups has been reported by Kim et al. (26 month vs 52 months P =0.02). On the contrary, only one study has reported better overall survival in HER-2/neu overexpressed GBC cases in comparison to negative cases (30 months vs 12 months) but this result was not statistically significant (P = 0.15). Based on all these observations, the authors believe that HER-2/neu overexpression infers a worse prognosis and poor overall survival in GBC similar to gastric carcinoma.
Various authors have studied the role of HER-2/neu-based therapies in gastric and breast carcinoma. Recently, TOGA trial (transtuzumab for gastric carcinoma) has shown to elevate median overall survival with the use of transtuzumab along with chemotherapy (13.8 months vs 11.1 months). As a result, HER-2/neu testing has been recommended in routine clinical practice in breast and gastric carcinoma.
Studies analyzing therapeutic avenues of HER-2/neu-based therapies in the biliary tract carcinoma including GBC are only a few.,, Nam et al. included GBC under blanket of biliary tract malignancy to study therapeutic implications of HER-2/neu-based therapyin vivo(xenograft models) andin vitro(cell lines). They found significant antiapoptotic and antiproliferative effects in transfected mice from GBC cell lines (SNU2773, SNU 2670). NCT00478140 clinical trial attempted to evaluate the efficacy of HER-2/neu therapy and was terminated prematurely. Key factors responsible for the same were low prevalence of GBC leading to limited participation of patients and lack of guidelines defining cut offs for HER-2/neu overexpression.
The conflicting results are mainly due to lack of standardized algorithms defining HER-2/neu overexpression in GBC and very limited number of cases studied. It is still uncertain whether same guidelines that are used for gastric and breast carcinoma can be applied to GBC. Being a biologically distinct entity, defining a cutoff value might make a significant difference in anti-HER-2/neu therapeutic outcome. Larger clinical trials and studies are needed to explore the potential of HER-2/neu-based therapy in GBC.
The limited follow-up (some patients were lost to follow-up) and limited number cases on which FISH could be done (due to financial constraints) are the main limitations of our study. Due to a significant number of censored cases (58.9%), statistically significant difference in the survival between HER-2/neu positive and negative groups could not be achieved. Despite limitations, our study holds importance as to the best of our knowledge, it is the largest study till date evaluating HER-2/neu expression in more than 200 cases of gall bladder neoplastic lesions.
| Conclusion|| |
To conclude, HER-2/neu overexpression was seen in 14% of GBC cases but not in dysplasia and metaplasia, suggesting that HER-2/neu aberrations are late events in gall bladder carcinogenesis pathway. Nevertheless, HER-2/neu overexpression did not show significant correlation with conventional clinicopathologic parameters. Although no significant difference was found in the overall survival between the HER-2/neu positive and negative groups, HER-2/neu overexpression was associated with a poor overall survival. It is worth evaluating this limited subset of GBC patients for targeted therapy that might provide a survival benefit.
This work was approved by institutional ethical committee. W.r.t to letter no: F.1/IEC/MAMC (14)/2/2012/no: 145.
The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by university grant commission (UGC.IF no- 42-59/2013).
Financial support and sponsorship
The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by university grants commission
(UGC.IF no- 42-59/2013).
Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, GIPMER, New Delhi
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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