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ORIGINAL ARTICLE  
Year : 2021  |  Volume : 64  |  Issue : 1  |  Page : 47-51
A study of Human Epidermal Growth factor receptor-2 [HER-2] in Carcinoma Oesophagus [Single Institutional Tertiary cancer centre study from North-East part of India]


Department of Surgical Oncology, Dr. B. Borooah Cancer Institute, Unit of Tata Memorial Centre Mumbai, A.K. Azad Road, Gopinath Nagar, Guwahati, Assam, India

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Date of Submission18-Apr-2020
Date of Decision19-Jun-2020
Date of Acceptance26-Jun-2020
Date of Web Publication8-Jan-2021
 

   Abstract 


Background: Oesophageal cancer both squamous cell [SCC] and adenocarcinoma have poor outcomes with high morbidity and mortality. Our hospital-based registry for year 2017–2018 showed that oesophageal cancer constituted 22.7% of annual case load. The main objective of this study was to determine the presence of HER-2 receptors in patients with oesophageal carcinoma in our region. Methodology: From September 2018 to September 2019, data regarding expression of HER-2 receptors was analysed in 133 patients of oesophageal carcinoma. Data were statistically described as frequencies (number of cases) and percentages where appropriate. Chi-square and Fischer's exact test was used to find out the association between categorical variables. A P value less than 0.05 was considered as statistical significant at 95% confidence interval. The statistical analysis was performed using SSPS [statistical package for the social sciences] software version 17.0. Results: A total of 133 patients were taken into study. Majority of patients were males (96) with mean age of 52 years. Squamous cell carcinoma was predominant histology. HER-2 receptor positivity was seen in 6.01% of patients. Patients with HER-2 receptor positivity presented in advanced stage with poor functional status and poor grades of differentiation. Statistically significant correlation of Her-2 expression was seen with stage (p = 0.001) and pathology of tumour (p = 0.0001). Conclusion: Squamous cell carcinoma of oesophagus still predominates in North-eastern part of India. For studying the role of effective targeted therapies knowledge of frequency of HER-2 receptor positivity is of utmost importance in our population, and our study aims to answer this question. The present study shows low prevalence of HER-2 neu overexpression in our community, probably due to disproportionately high incidence of SCC compared to adenocarcinoma. Patients with HER-2 receptor positivity presented in advanced stage with poor functional status and poor grades of differentiation.

Keywords: Adenocarcinoma, carcinoma oesophagus, HER-2 receptors, squamous cell carcinoma

How to cite this article:
Kalita D, Bannoth S, Purkayastha J, Talukdar A, Das G. A study of Human Epidermal Growth factor receptor-2 [HER-2] in Carcinoma Oesophagus [Single Institutional Tertiary cancer centre study from North-East part of India]. Indian J Pathol Microbiol 2021;64:47-51

How to cite this URL:
Kalita D, Bannoth S, Purkayastha J, Talukdar A, Das G. A study of Human Epidermal Growth factor receptor-2 [HER-2] in Carcinoma Oesophagus [Single Institutional Tertiary cancer centre study from North-East part of India]. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Apr 15];64:47-51. Available from: https://www.ijpmonline.org/text.asp?2021/64/1/47/306515





   Introduction Top


Global cancer statistics 2018 ranks oesophageal cancer as the seventh most common cancer in terms of percentage incidence of new cases according to site. Over 572,034[3.2%] new cases were reported, and registered number of deaths was 508,585[5.3%] of all sites.[1] It is expected that by 2025 incidence of oesophageal cancer is expected to rise by 140%.[2]

Though there are advances in various fields of oncology and multidisciplinary approach, most of the patients with oesophageal carcinoma present in advanced stage and outcomes still remain poor.[3]

HER-2 positivity has been seen in around 20–30% of breast cancer patients and also in gastric carcinoma.[4],[5] Positivity of HER-2 receptors is associated with aggressive biological behaviour in tumours-like breast and gastric cancers.[6],[7]

The role of HER-2 receptor in pathogenesis of oesophageal carcinoma is unclear. Data regarding their role is emerging, which could impact outcomes of patients with oesophageal carcinoma by targeted therapy. In view of high burden of oesophageal carcinoma in our institute, the present study aims to analyse the expression HER-2 receptors in oesophageal carcinoma.


   Methodology Top


Diagnosis and staging

Data of patients diagnosed with oesophageal cancer from September 2018 to September 2019 were prospectively analysed. The study was approved by institutional ethics committee. A total of 160 patients who had been diagnosed with oesophageal cancer during this period were identified, of which data regarding clinical features, diagnostic, and staging work up, HER-2 receptor status were collected in 133 patients as rest of patients lost follow-up in the initial evaluation phase.

The workup for all patients included a detailed history, physical examination, standard blood workup, upper gastrointestinal endoscopy with biopsy, contrast enhanced computed tomography of neck, chest, and abdomen. On an average five samples of tumour tissue from different locations were taken for biopsy. Staging was done according to the eighth of American joint committee on cancer for oesophageal cancer.

Dysphagia and functional assessment score

Dysphagia score was graded as (grade-1: able to swallow some solids, grade-2: able to swallow only semisolids, grade-3: able to swallow liquids only, and grade-4: unable to swallow anything or total dysphagia). Functional status of patients was assessed according to Eastern cooperative oncology group (ECOG) score as (ECOG-0: Fully active, able to carry all predisease activity. Grade-1: able to carry out light household work, Grade-2: unable to carry out any activities and about more than 50% waking hours, Grade-3: capable of limited self-care and confined to chair more than 50% of waking hours, Grade-4: completely disabled, and Grade-5: dead).

Tissue processing

All samples were of endoscopic biopsy tissue. After endoscopic biopsy, tumour tissue was placed in 10% of the neutral buffer solution as early as possible (within 10–15 min). Overnight fixation of tissue with formalin was done. Paraffin blocks were made and sectioning was done with microtome, which was used to study histology. The same tissue blocks were used for immunohistochemistry after deparaffinization, which were reacted with primary and secondary antibody. Diaminobenzediene[DAB] gives characteristic brown colour [Figure 1] and [Figure 2].
Figure 1: IHC slide images of Oesophageal carcinoma histology with HER2 positivity

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Figure 2: Panel of microphotographs of different types of oesophageal carcinoma

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Monoclonal SP-3 rabbit antibody was used. It is a prediluted antibody product that contains ready to use reagents. Prediluents consisted of Tris buffer with pH of 7.3–7.7, 1% BSA, and 0.1% sodium azide with a working dilution of 1:100 to 1:500.

Reporting of IHC

The scoring system for reporting of HER-2 positivity used was 0 = No staining of tumour cells membrane [negative], 1+ = Partial and weak staining of cell membrane tumour cells, 2+ = Circumferential staining of tumour cells membrane in =10% of tumour cells, the staining ring is thin and patchy [borderline], and 3+ = Circumferential thick membrane staining of =10% of tumour cells positive.

Statistical analysis

Collection of data was done from the patient's clinical records and hospital online reporting system. Data were statistically described as frequencies (number of cases) and percentages where appropriate. Chi-square and Fischer's exact tests were used to find out the association between categorical variables. A P value less than 0.05 was considered as statistical significant at 95% confidence interval. The statistical analysis was performed using SSPS (statistical package for the social sciences) software version 17.0.


   Results Top


From September 2018 to September 2019,160 patients were diagnosed with oesophageal cancer under single unit, of which 133 patients met criteria for study analysis. Summary of demographic, clinical presentation, and laboratory data are presented in [Table 1]. In brief among 133 patients studied, 96 were males with a mean age of 52 years. The mean haemoglobin of patients was 9.3 grams/decilitre (gm/dL) and mean albumin was 3.2 (gm/dL). Majority of patients (55.6%) had performance status of ECOG-1. Dysphagia grades 1, 2, 3, and 4 were seen in 28.6%, 40.6%, 24.8%, and 6% of patients, respectively [Table 1].
Table 1: Demographic, clinical presentation, and laboratory data (n=133)

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Staging was done according to AJCC 8th ed.ition for oesophageal cancer. The majority of patients (85%) had stage II-III disease, with squamous cell carcinoma being most common (85.8%) histology. Grades of differentiation, for both SCC and adenocarcinoma were well differentiated (24.1%), moderately differentiated (65.4%) and poorly differentiated (10.5%) tumours [Table 2].
Table 2: Histopathology and stage of patients (n=133)

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None of our patients had evidence of barrett's oesophagus as seen during endoscopy or on histology.

Correlation between Her-2 expression and clinicopathological features

HER-2 receptor positivity was seen in 6.01% of patients. The details are summarized in [Table 3]. Statistically significant correlation of Her-2 expression was seen with stage (p = 0.001) and pathology (p = 0.0001). Correlation of rest of variables like gender (p = 0.854), ECOG status (p = 0.166), and dysphagia grade (p = 0.306) did not show any statistical significance. Her-2 receptors were expressed in 6.25% of males and 5.4% of females (p = 0.854). Majority (80%) of patients with HER-2 receptor positivity had ECOG performance status of =2. Patients with ECOG-1 performance status had receptor positivity of 2.7%, whereas in ECOG-3 cases, percentage raised to 13.3%.
Table 3: Correlation between HER-2 expression and clinicopathological parameters and stage of the studied oesophageal carcinoma patients (n=133)

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Expression of HER-2 receptors was maximum in stage-IVB patients. Out of seven patients in stage-IVB, 42.85% had receptor positivity, whereas receptor positivity was seen only in 9.1% and 5.8% of stage II and stage III patients, respectively, with statistically significant P value (p = 0.001). Squamous cell carcinoma had receptor positivity of 2.6%. Three (23.10%) patients of adenocarcinoma had expression of HER-2 receptors (p = 0.0001) [Table 3].


   Discussion Top


Expression of HER-2 receptors was studied in all cases. Out of 133 cases, 6.01% of cases with oesophageal carcinoma showed HER-2 receptor positivity. When we compared various previous studies of expression of HER-2 receptors in oesophageal carcinoma, we found that expression was variable ranging from 11 to 30%.[8],[9],[10],[11]

Expression of HER-2 was seen in 13–30% of patients with oesophageal carcinoma in a study by M. Dreilich et al.[12] HER-2 positivity was associated with statistically significant poor survival in patients with squamous cell carcinoma. A study by M.J.D. Prins et al. in patients with oesophageal carcinoma has shown that the majority of expression was seen in patients with adenocarcinoma.[13] Overexpression of HER-2 receptor was independent factor for poor outcomes.

Squamous cell carcinoma of oesophagus is still predominant in North-East part of India. This could have resulted in lower expression of HER-2 receptors in our set of patients, which was in concordance with various previous studies.

On correlation of various factors with HER-2 expression [Table 3], including gender, ECOG status, grade, stage of tumour and pathology, stage and pathology of tumour had statistically significant association. In concordance with study of Hazem-AL-Momani et al., patients with HER-2 receptor overexpression had higher stage.[14] In our study, receptor positivity was seen in 42.85% of stage-IVB patients.

Overexpression of HER-2 is associated with poor outcomes as seen in various previous studies. Though correlation of survival outcomes with receptor positivity was not done in our study, it was seen that in our subset of patients receptor positivity was associated with more advanced stage at presentation, poor grades of differentiation, and higher dysphagia grades.

Due to high burden of oesophageal carcinoma in our region, with annual new case registration of around 22.7%, it is essential for us in linking of new pathways of pathogenesis involved in carcinogenesis. In our search for effective molecular therapies, detecting the presence of targetable receptors is believed to help in producing meaningful clinical response in solid tumours. In our population, knowledge of frequency of such markers is very important and this study is such an attempt.

As still squamous cell carcinoma of oesophagus predominates in our region, the rate of receptor positivity for HER-2/neu is low. Further large scale studies from our region might confirm these findings.

An advantage of our study was that all data required were prospectively maintained in our database. Disadvantages include analysis of treatment outcomes, and survival was not done in this study. A study regarding above is on-going, which will be presented in future studies from our institute.


   Conclusion Top


Squamous cell carcinoma of oesophagus still predominates in North-eastern part of India. For studying the role of effective targeted therapies, knowledge of frequency of HER-2 receptor positivity is of utmost importance in our population, and our study aims to answer this question. The present study shows low prevalence of HER-2 neu overexpression in our community, probably due to disproportionately high incidence of SCC compared to adenocarcinoma. Patients with HER-2 receptor positivity presented in advanced stage with poor functional status and poor grades of differentiation. Further large-scale studies are essential to confirm these findings.

Acknowledgements

The authors thank to all of the patients and all departments of Dr. B. Borooah Cancer Institute.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Lambert R, Hainaut P. The multidisciplinary management of gastrointestinal cancer. Epidemiology of esophago-gastric cancer. Best Pract Res Clin Gastroenterol 2007;21:921-45.  Back to cited text no. 2
    
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Lee PC, Port JL, Paul S, Stiles BM, Altorki NK. Predictors of long-term survival after resection of esophageal carcinoma with nonregional nodal metastasis. Ann Thorac Surg 2009;88:186-92.  Back to cited text no. 3
    
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Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82.  Back to cited text no. 4
    
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Yu GZ, Chen Y, Wang JJ. Overexpression of Grb2/HER2 signaling in Chinese gastric cancer: Their relationship with clinicopathological parameters and prognostic significance. J Cancer Res Clin Oncol 2009;135:1331-9.  Back to cited text no. 6
    
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Liang Z, Zeng X, Gao J, Wu S, Wang P, Shi X, et al. Analysis of EGFR, HER2, and TOP2A gene status and chromosomal polysomy in gastric adenocarcinoma from Chinese patients. BMC Cancer 2008;8:363.  Back to cited text no. 7
    
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Fleoju JF, Paraf F, Muzeau F, Fekete F, Henin D, Jothy S, et al. Expression of c-erb-2 Oncogene product in Barretts adenocarcinoma: Pathological and prognostic implications. J Clin Pathol 1994;47:23-6.  Back to cited text no. 8
    
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Radu OM, Foxwell TJ, Cieply KM, Navina S, Dacic S, Nason KS, et al. Her-2 amplification in gastroesophageal adenocarcinoma. Correlation of two antibodies using gastric cancer scoring criteria, H score, and digital image analysis with fluorescence in situ hybridization. Am J Clin Pathol 2012;137:583-94.  Back to cited text no. 9
    
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Boers JE, Meeuwissen H, Methorst N. HER2 status in gastroesophageal adenocarcinomas assessed by two rabbit monoclonal antibodies (SP3 and 4B5) and two insitu hybridization methods (FISH and SISH). Histopathology 2011;58:383-94.  Back to cited text no. 10
    
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Yoon HH, Shi Q, Sukov WR, Wiktor AE, Khan M, Sattler CA, et al. Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas. Clin Cancer Res 2012;18:546-54.  Back to cited text no. 11
    
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Dreilich M, Wanders A, Brattstorm D, Bergstrom S, Hesselius P, Wagenius G, et al. Her-2 overexpression (3+) in patients with squamous cell oesophageal carcinoma correlates with poorer survival. Dis Esophagus 2006;19:224-31.  Back to cited text no. 12
    
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Prins MJD, Ruurda JP, Van Diest PJ, Van Hillegersberg R, ten Kate FJW. The significance of the HER-2 status in esophageal adenocarcinoma for survival: An immunohistochemical and in situ hybridization study. Ann Oncol 2013;24:1290-7.  Back to cited text no. 13
    
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Al-Momani H, Barnes R, El-Hadi A, Shah R, Lewis WG, Edwards P. Human epidermal growth factor receptor-2 in oesophageal cancers: An observational study. World J Gastroenterol 2012;18:6447-51.  Back to cited text no. 14
    

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Correspondence Address:
Srinivas Bannoth
Dr. B. Borooah Cancer Institute, Unit of Tata Memorial Centre Mumbai, A.K. Azad Road, Gopinath Nagar, Guwahati, Assam
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_406_20

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