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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 325-329

Study of human epidermal growth factor receptor (HER2/neu) expression in primary colorectal carcinoma in a tertiary care hospital


Department of Pathology, MGM Medical College and Hospital, Aurangabad, Maharashtra, India

Date of Submission27-Oct-2021
Date of Acceptance22-Nov-2021
Date of Web Publication22-Dec-2021

Correspondence Address:
Dr. Suparna S Pingle
Department of Pathology, MGM Medical College and Hospital, N6, CIDCO, Aurangabad 431003, Maharashtra.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_83_21

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  Abstract 

Introduction: Colorectal cancer (CRC) mainly affects the middle-aged and elderly population with a gradual increase in its incidence. Various studies have found human epidermal growth factor receptor (HER2/neu) overexpression in CRC and its associated prognostic outcome. HER2/neu activates various signaling pathways which leads to cell proliferation and survival, and thereby its overexpression causes excessive tumor cell growth and migration. Aims and Objectives: The aim of this study was to determine the percentage of HER2/neu positive and negative cases and to correlate it with the grade and stage of the tumor. Materials and Methods: The study was carried out for 2 years in the Department of Pathology, MGM Medical College and Hospital, Aurangabad, and included 35 resected specimens of colorectal carcinoma. Histopathological examination was studied and for immunohistochemical (IHC) staining, paraffin wax-embedded tissues were immune stained for HER2/neu. Results: Of 35 cases, there were 18 women and 17 men. Approximately 28.57% cases were in the age group of 41–50 years with the mean age being 54 years. In 37.14% of cases, the tumor was located in the ascending colon. Approximately 77.14% cases were Grade 2. In total, 57.14% cases were at stage T3. Six cases were HER2/neu positive and 29 cases were HER2/neu negative. Conclusion: A significant correlation was found between HER2/neu expression with histologic grade and stage of the tumor. HER2/neu targeted therapeutic strategies have the potential to change treatment course and outcome. Hence, HER2/neu can be used as a biomarker in patients with CRC to assess their prognostic outcome.

Keywords: Colorectal cancer, HER2/neu, immunohistochemistry


How to cite this article:
Agrawal M, Pingle SS, Prabhakar Bhale C. Study of human epidermal growth factor receptor (HER2/neu) expression in primary colorectal carcinoma in a tertiary care hospital. MGM J Med Sci 2021;8:325-9

How to cite this URL:
Agrawal M, Pingle SS, Prabhakar Bhale C. Study of human epidermal growth factor receptor (HER2/neu) expression in primary colorectal carcinoma in a tertiary care hospital. MGM J Med Sci [serial online] 2021 [cited 2022 Jan 18];8:325-9. Available from: http://www.mgmjms.com/text.asp?2021/8/4/325/333330



The article has been transcribed out of a dissertation entitled “Study of Human Epidermal growth factor receptor (HER 2/neu) expression in Primary Colorectal Carcinoma in Tertiary care hospital” by Mausmi Agrawal, one of the authors submitted to the Department of Pathology, MGM Medical College and Hospital, Aurangabad, Maharashtra, India for the award of MD (Pathology) Degree. It is certified that neither the dissertation has been published in any format anywhere nor it will be published in the future. Permission has been obtained from the management of the college for the publication of the manuscript in the proposed journal.


  Introduction Top


Colorectal cancer (CRC) has been considered the commonest malignancy all over the world and its incidence is gradually increasing.[1] With the development of new cytotoxic drugs and surgical techniques, patients with CRC have shown improved survival. But, once a patient becomes resistant to these drugs, no other treatment options are available. Recently, monoclonal antibodies are developed against vascular endothelial and epidermal growth factor receptor (EGFR).[2]

Human epidermal growth factor receptor (HER2/neu) is located on chromosome 17q21 and it encodes 185 kD transmembrane glycoprotein receptor. This activation further initiates various signaling cascades such as mitogen-activated protein kinase (MAPK), phosphatidyl inositol 3 kinase (PI3K/AKT), and protein kinase C (PKC) pathways, which are responsible for cellular differentiation, proliferation, and survival. During the process of neoplasia, these pathogens get dysregulated and lead to HER2/neu overexpression, which causes excessive tumor cell growth and migration.[3]

Herceptin inhibits colony formation of the human colon adenocarcinoma (HCA-7) cell line and xenografts. Studies mention that trastuzumab (herceptin) can be tried for those cancers that show HER2/neu overexpression. Along with other prognostic factors such as tumor grade, stage, and metastasis, HER2/neu overexpression can also be used as a prognostic tool. Different studies have shown 0%–84% variability of HER2/neu overexpression in CRC.[4],[5] This study was carried out to estimate the HER2/neu positivity in CRCs which might prove a useful prognostic factor, worthy of targeted therapeutic chemotherapy for CRC in the future.

The article has been transcribed out of a dissertation entitled “Study of human epidermal growth factor receptor (HER2/neu) expression in primary colorectal carcinoma in tertiary care hospital” by Mausmi Agrawal, one of the authors submitted to the Department of Pathology, MGM Medical College and Hospital, Aurangabad, Maharashtra, India for the award of MD (pathology) degree. It is certified that neither the dissertation has been published in any format anywhere nor it will be published in the future. Permission has been obtained from the management of the college for the publication of the manuscript in the proposed journal.

Aims and objectives

  1. To determine the percentage of HER2/neu positive and negative cases in primary colorectal carcinoma.


  2. To correlate HER2/neu expression with grade and stage of tumor in primary colorectal carcinoma.



  Materials and methods Top


The study was carried out for 2 years from November 1, 2018 to October 30, 2020 in the Department of Pathology, MGM Medical College and Hospital, Aurangabad. The study was carried out on 35 resected specimens of colorectal carcinoma.

For every patient, the details about clinical and pathological parameters were collected from medical section records, pathologist’s reports, and operation procedure data. After colectomy, specimens are formalin-fixed in neutral formalin (10%) and embedded in paraffin. Serial sections of 4 µm thickness are prepared from each tissue block, one of them is stained by hematoxylin and eosin (H&E) for histopathological re-evaluation. For immunohistochemical (IHC) staining by HER2/neu, the formalin-fixed, paraffin wax-embedded tissues are immune stained for HER2/neu, using standard methods. HER2/neu staining was performed with rabbit monoclonal antibodies obtained from the DAKO company. Antigen retrieval was performed using E-Z Retrieval System. For control, known HER2/neu positive breast tissue was used. Block selection for IHC staining was performed based on maximum tumor tissue found on H&E examination. Tumor staging was performed according to TNM American Joint Committee on Cancer (AJCC) criteria (8th edition) and Immuno Histo Chemistry (IHC) for HER2/neu was performed according to College of American Pathologists (CAP) guidelines. History of chemotherapy or radiation therapy before surgery and colonoscopic biopsy specimens were excluded from the study. The slides were screened by two pathologists, opinions were discussed and a conclusion was made.


  Results Top


In this study, 35 cases were examined. There were 18 (51.43%) women and 17 (48.57%) men. The majority of the cases (28.57%) were in the age group of 41–50 years. The mean age of colorectal carcinoma was 54 years.

The majority of the patients had tumors located in the ascending colon (37.14%), followed by the sigmoid colon (34.29%). Maximum 27 cases (77.14%) were Grade 2 (moderately differentiated) tumors. Grade 1 (well-differentiated) and Grade 3 (poorly differentiated) tumors comprised three cases (8.57%) and five cases (14.29%), respectively. We found that majority of the tumors (57.14%) were of stage T3. No cases were seen in stage T1. Tumors in stage T2 and T3 comprised 28.57% and 14.29%, respectively. In the study, we found that of 35 cases, 6 cases (17.14%) were HER2/neu positive and 29 cases (82.86%) were HER2/neu negative [Table 1].
Table 1: Human epidermal growth factor receptor (HER 2/neu) expression in colorectal cancers

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Of six HER 2/neu positive cases, three were of Grade 2, two were Grade 1, and only one was Grade 3. We found that the correlation between the histologic grade of the tumor and HER2/neu expression was statistically significant [Table 2].
Table 2: Correlation of human epidermal growth factor receptor (HER2/neu) with grade of tumor

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In this study, three cases of stage T4 were HER2/neu positive. In stage T3, two cases showed HER2/neu positivity and only one case of stage T2 was found to be HER2/neu positive. We observed a statistically significant association between tumor (T) stage and HER2/neu expression [Table 3]. No or incomplete membrane staining of tumor cells was considered negative [Figure 1]. Circumferential intense complete membrane staining of tumor cells was considered positive [Figure 2].
Table 3: Correlation of human epidermal growth factor receptor (HER2/neu) with primary tumor (T) stage

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Figure 1: Negative human epidermal growth factor receptor (HER2/neu) showing no membrane staining of tumor cells (immunohistochemical [IHC], 100×)

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Figure 2: Positive human epidermal growth factor receptor (HER2/neu) showing circumferential intense complete membrane staining of tumor cells (immunohistochemical [IHC], 400×)

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  Discussion Top


CRC forms a major cause of cancer-related morbidity and mortality and it accounts for about 5,00,000 deaths every year worldwide.[6],[7] It is the third most common cancer in men and the second most common cancer in women worldwide.[8] Immunohistochemistry (IHC) is a method for localizing specific proteins in tissues or cells placed on antigen–antibody reaction. The main advantages of IHC are easily available, cost-effective, consumes lesser time, is easy to preserve, and requires routine microscopes.[9] HER2/neu can be used as a useful marker to assess the prognostic outcome of patients having colorectal carcinoma. It can be used to select patients for immunotherapy with targeted monoclonal antibody therapy.[10],[11] It has been found that overexpression of HER2/neu correlates with a poorer prognosis.[12],[13] Various studies have reported overexpression of HER2/neu in CRCs and thus, it is the most promising targeted therapy for the treatment of these patients.[14]

In this study, 35 cases of colorectal carcinoma were examined. Histopathological examination was performed to assess the grade and stage of the tumor. HER2/neu expression was evaluated using immunohistochemistry. In our study, the age group of patients presenting with colorectal carcinoma was from 21 to 90 years. This finding was in agreement with the study conducted by Gill et al.[9] and Seo et al.[15] The mean age of patients with CRC observed was 54 years. This finding was similar to the study conducted by Gill et al.[9] Slightly male preponderance (51.43%) was seen in our study. Our finding is very similar to the study conducted by Heppner et al.[16] and Heidari et al.[17]

In our study, the majority of the tumors (37.14%) were located in the ascending colon. This finding was in agreement with the study conducted by Mohamed and Temimi,[13] who observed that 37.43% of tumors were located in the ascending colon. We observed 77.4% of the tumors were Grade 2 (moderately differentiated). This finding was consistent with the study conducted by Heppner et al.[16] and Fazeli et al.,[18] who observed that 78.5% and 79.13% of the tumors were Grade 2, respectively. We found that 57.14% of the tumors were of stage T3. Similar findings were observed by Heppner et al.[16] We found that of 35 cases of colorectal carcinoma, 6 cases (17.14%) were HER2/neu positive. This was similar to the studies conducted by Tavangar et al.,[19] and Li et al.[20]

In our study, the majority of the tumors that showed HER2/neu positivity were moderately differentiated (Grade 2). We found a statistically significant correlation between HER2/neu expression and the histological grade of the tumor (P = 0.015). Among the tumor (T) stage, the majority of the tumors that showed HER2/neu positivity were of stage T4. Thus, higher stage tumors showed more HER2/neu expression. A statistically significant correlation was found between HER2/neu expression and tumor (T) stage in our study (P = 0.023). Tavangar et al.[19] and Sun et al.[21] found that majority of the tumors that showed HER2/neu positivity were Grade 2. Heppner et al.,[16] Deng et al.,[22] and Kountourakis et al.[23] observed in their study that higher stage tumors showed more HER2/neu positivity.

Thus, we found a significant correlation between the grade of the tumor and HER2/neu expression. This result was consistent with the study conducted by Tavangar et al.,[19] Sun et al.,[21] Deng et al.,[22] Shabbir et al.,[24] Madani et al.,[25] and Half et al.[26]. Also, we found a significant correlation between stage of tumor and HER2/neu expression. This is in agreement with the study conducted by Heppner et al.,[16] Tavangar et al.,[19] Sun et al.,[21] Deng et al.,[22] and Kapitanovic et al.[27]

In our study, 17.14% of the cases were HER2/neu positive. Tavangar et al.[19] and Li et al.[20] found 21.8% and 15.5% positive cases in their study.


  Conclusion Top


A significant correlation was found between HER2/neu expression with histologic grade and stage of the tumor. HER2/neu expression was greater with a higher grade of tumors. Monoclonal antibodies like trastuzumab (herceptin) can be used in these HER2/neu overexpressed colorectal carcinoma patients as they are the potential candidates and might get benefitted from the therapy.

Ethical policy and institutional review board statement

Institutional Ethics Committee for Research on Human Subjects (ECRHS) of MGM Medical College and Hospital, Aurangabad, India has approved to conduct of the “Study of Human Epidermal Growth Factor Receptor (HER2/neu) Expression in Primary Colorectal Carcinoma in a Tertiary Care Hospital” vide their letter no. MGM-ECRHS/2018/11 dated October 5, 2018.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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