Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

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Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Original article / research
Year : 2022 | Month : September | Volume : 16 | Issue : 9 | Page : EC22 - EC26 Full Version

Significance of HER2/neu Expression in Oesophageal Carcinomas and its Association with the Histopathological Grading


Published: September 1, 2022 | DOI: https://doi.org/10.7860/JCDR/2022/54890.16851
Saranya, Suriya Prabha, Surekha Bantumilli, Megala Chandrasekar

1. Consultant, Department of Pathology, Royal Care Hospital, Coimbatore, Tamil Nadu, India. 2. Assistant Professor, Department of Pathology, Karur Medical College, Karur, Tamil Nadu, India. 3. Resident, Department of Pathology, North Carolina University, North Carolina, Chapel Hill, United States of America. 4. Assistant Professor, Department of Pathology, Vinayaka Mission’s Kirupananda Variyar Medical College, Salem, Tamil Nadu, India.

Correspondence Address :
Dr. Megala Chandrasekar,
Assistant Professor, Department of Pathology, Vinayaka Missions Kirupananda Variyar Medical College and Hospital, Seeragapadi-636308, Salem, Tamil Nadu, India.
E-mail: drmegala1151989@gmail.com

Abstract

Introduction: Oesophageal carcinomas are one of the most aggressive human malignancies which are associated with a poor prognosis because most of the cases are in stage 2 or 3 at the time of diagnosis with a high frequency of lymph node metastases. It is important to know the prognostic factors can help us on therapeutic decisions and improve the survival of these patients. A member of Epidermal Growth Factor Receptor (EGFR) family, Human Epidermal Growth Factor Receptor 2 (HER-2/neu) is a very useful antigenic marker expressed in oesophageal carcinomas which has increasing evidence of therapeutic significance.

Aim: To determine the immunological expression of HER2/neu in oesophageal carcinomas and associate it with the histopathological grading.

Materials and Methods: This cross-sectional study was conducted in Department of Pathology at Coimbatore Medical College, Coimbatore, Tamil Nadu, India, from January 2015 to February 2016. Total 30 cases of histologically proven oesophageal carcinomas were subjected for HER2/neu immunoexpression. Membranous staining was considered as positive and the intensity of staining was scored and compared with various histopathological parameters. The p-value<0.05 using a two-tailed test was taken as level of significance for all statistical tests.

Results: Among 30 cases, 24 were squamous cell carcinomas and six were adenocarcinomas. Out of 24 cases of squamous cell carcinomas, there were 20 males and four females. All the six adenocarcinoma cases were males. HER2/neu was positive in 10 cases(41.6%) of squamous cell carcinoma and 4 cases(66.6%) of adenocarcinoma. It was seen in 10% of well differentiated, 60% of moderately differentiated and 80% of poorly differentiated carcinomas. There was significant correlation with staging and lymph node metastases. Higher grade tumours had higher level of expression of HER2/neu.

Conclusion: The HER2/neu immunoexpression was significantly higher with progression of tumour grade. Hence, such patients with high grade oesophageal carcinomas and with lymph node metastases could be benefitted with targeted therapy.

Keywords

Adenocarcinoma, Human epidermal growth factor receptor 2, Membranous staining, Oesophageal carcinomas, Squamous cell carcinoma

Oesophageal carcinoma is the sixth most common cause of mortality due to cancer in the world. The two major histological types of oesophageal carcinomas are Squamous Cell Carcinoma (SCC) and Adenocarcinoma (ADC). However, it is the squamous cell carcinoma that predominates globally over adenocarcinoma but the frequency of occurrence of oesophageal adenocarcinoma has dramatically increased during the last few decades (1),(2). Owing to the elasticity of the oesophagus and aggressiveness of the tumour growth, oesophageal carcinomas usually proceed to the advanced stage prior to the diagnosis. The mortality rate still remains high despite the development of advanced therapeutic modalities apart from surgical resection (3).

In this aspect, amplification of Human Epidermal Growth Factor Receptor 2/neu (HER2/neu) gene and the overexpression of the HER2/neu protein has known to occur in oesophageal carcinoma as a part from adenocarcinomas of gastric and gastro oesophageal junction (4). With a very dismal survival rate, the study is carried on with an idea that patients with these cancers may stand to benefit the identification of certain possible molecular targets such as HER2/neu for both prognostic and therapeutic purposes (5),(6).

There are some reported cases of carcinomas which express HER2/neu having poorer prognosis and fail to respond to the conventional chemotherapy. Such tumours respond well to specific targeted therapy with HER2/neu antibody (trastuzumab) thereby prolonging the survival of the patients (7). Hence, this study has been focused on the importance of expression of HER2/neu protein in the different grades of differentiation of oesophageal carcinomas and thereby any positive result could be used for further treatment of the patient via anti-HER2/neu monoclonal antibodies (Herceptin) as a molecular targeted therapy for the increased survival of the patients.

Material and Methods

This cross-sectional study was conducted in Department of Pathology at Coimbatore Medical College, Coimbatore, in Tamil Nadu, India, from January 2015 to February 2016. Ethical clearance was obtained from Government Coimbatore Medical College committee experts (dated: 15/7/2014). Total 30 oesophagectomy specimens received were appropriately fixed in 10% neutral buffered formalin and processed for routine Hematoxylin and Eosin (H&E) staining. The H&E stained sections were observed under light microscope and the histopathological types and grades were assessed based on American Joint Committee on Cancer Staging (AJCC) manual (8). According to this AJCC 7th edition, staging for both SCC and ADC, prognosis of the patient depends on level of tumor infiltration in the wall of esophagus(T), Nodal metastasis(N), metastasis to other organs(M), Grading of tumor(G). But in SCC, location of the tumor in the oesophagus is also considered for staging.

Inclusion criteria: All histopathologically proven epithelial oesophageal malignancies were taken included in the study.

Exclusion criteria: Benign tumours, neuroendocrine tumours and lymphomas are excluded from the study.

The immunohistochemical technique used was a two-step indirect technique based on the antigen detection in the cells and the tissues. The HER2/neu expression by immunohistochemistry was evaluated qualitatively and quantitatively by intensity of staining and percentage of cells showing positive expression criteria used in the Trastuzumab for GAstric cancer (ToGA) (9) trial 6 for scoring HER2 expression by Immunohistochemistry (IHC) pattern as in (Table/Fig 1) and correlated with the histological grade of the tumour (10),(11). Finally the percentage of HER2/neu expression in the entire sample was calculated quantitatively.

Statistical Analysis

The datas were reported as the mean and standard deviation or the median, depending on their distribution. The differences in quantitative variables between groups were assessed by means of the unpaired t-test. Comparsion between groups was made by the non parameteric Mann-Whitney test. A Chi-square test was used to assess the differences in categoric variables between the groups. The p-value <0.05 using a two-tailed test was taken as being of significance for all statistical tests. All datas were analysed with a Statistical Package for Social Sciences (SPSS) version 16.0. Data and results were obtained, coded and entered into Microsoft excel spread sheet and were analysed.

Results

A total of 30 cases were studied, that included all oesophageal carcinomas for which surgical resection of oesophagus was done. Among 30 cases, 24 were squamous cell carcinomas and six were adenocarcinomas. Out of 24 cases of squamous cell carcinomas, there were 20 males and four females. All the six adenocarcinoma cases were males. Out of total, 16 cases (53%) had carcinoma in the middle third of the oesophagus/thoracic oesophagus extending from suprasternal notch above to diaphragm and 14 cases (47%) had involvement of lower third of the oesophagus/abdominal oesophagus extending from diaphragm to gastric cardia. The incidence of oesophageal carcinoma was high 43% (13 cases) in the age group of 51-60 years followed by 36.6% (11 cases) in 61-70 years,10% (three cases) in <50 years and 10% (three cases) in >70 years of age.

Histological grades assessed are as depicted in (Table/Fig 2). Maximum number of cases were of grade II morphology. Out of 24 cases of squamous cell carcinomas, 50% of cases were grade II tumours and 13% cases were of grade III morphology. Among 6 adenocarcinoma cases, 50% cases were grade II and 33.3% cases were of grade III tumours. Immunohistochemical assessment was done and results are as depicted in (Table/Fig 3). Out of total, 10 cases (41.6%) of squamous cell carcinoma and 4 cases (66.6%) of adenocarcinoma showed HER2/neu positivity.

Histopathological grade and HER2/neu positivity were associated and the results were as in (Table/Fig 4). Out of 30 cases, 10 cases were grade I, 15 cases were grade II and 5 cases were grade III. Grade I tumours showed10% HER2/neu positivity. Grade II tumours showed 60% HER2/neu positivity. Grade III tumours showed 80% HER2/neu positivity (Table/Fig 5), (Table/Fig 6), (Table/Fig 7), (Table/Fig 8), (Table/Fig 9), (Table/Fig 10). The p-value was statistically significant (p-value <0.05). In the present study, out of 15 cases with stage 2 (advanced disease with lymph node metastasis at the initial time of clinical presentation), only 4 cases showed HER-2/neu positivity (26.6%). Out of 15 cases with stage T3, 10 cases showed HER-2/neu positivity (66.6%) and it was statistically significant (p-value <0.05). In the present study, 11 out of 30 cases had lymph node metastasis of which 72.7% cases showed HER2\neu positivity. Variables were statistically significant (p-value <0.05).

Discussion

Oesophageal carcinoma has been rated as the sixth most frequent cause of cancer deaths worldwide. Carcinoma oesophagus is generally associated with a poor prognosis, the reason being that most of these tumours present with stage T2 or T3 with lymphnode metastasis at the initial time of clinical presentation. Thus, it is essential to know the molecular pathogenesis for targeted therapy (12).

Even though the tumor can be assessed by histopathology in terms of tumor grading and staging which are strong prognostic indicators, invention on newer prognostic markers such as expression of various immunological markers have come under lime light nowadays. The expression of these proteins was known to alter the impact of the survival rate in these patient.

Regarding this aspect, there are several molecular proteins that regulate the pathogenesis of oesophageal carcinomas. One of them is the HER2/neu family of receptor tyrosine kinases which play an important role in modulating cell proliferation, cell survival and differentiation (13).

Recent ongoing trials have been successful enough to prove that HER2/neu expression has a huge significance in oesophageal carcinomas apart from a variety of human cancers such as breast cancer, colorectal cancer, gastric, lung and prostrate tumours (14).

Many strategies directed against epidermal growth factor receptor and HER2/neu were developed such as monoclonal anti-HER2/neu antibodies and small molecule kinase inhibitors. There is sufficient data from the clinical trials demonstrating the positive effects of applying epidermal growth factor receptor tyrosine kinase inhibitors to oesophageal squamous cell carcinomas and adenocarcinomas. These facts indicate that HER2/neu is a very useful molecular marker with a range of therapeutic implications in the overall survival rates of oesophageal squamous cell carcinoma and adenocarcinomas (15),(16),(17),(18).

In the present study, the frequency of HER2/neu expression in oesophagectomy specimens and an analysis of its correlation with the histopathological grading of the tumour was done. Thirty cases of oesophageal carcinomas were included in the study and the age wise distribution was studied. Out of 30 cases, age of the patients ranges from 45 to 72 years with a mean age of 60.5 years. A similar study conducted by Reichelt U et al., showed the mean age of the patients to be 62 years ranging from 34 to 92 years and Sato-Kuwabara Y et al., showed the mean age of occurrence of 54.5 years (19),(20).

In the present study, out of 24 cases of squamous cell carcinomas 20 were males and four were females with a male: female ratio being 5:1 and all the six cases of adenocarcinoma were males. These results were in accordance with a study done by Sato-Kuwabara Y et al., which also showed a male preponderance of 4:1 for squamous cell carcinomas and 100% preponderance for males in adenocarcinomas (20).

Regarding the location of the tumour 51% cases were in the middle third of the oesophagus and 47% cases were in the lower third of the oesophagus and none in the upper third. According to study done by Mimura K et al., out of 66 cases, 56% were in the lower third of the oesophagus, 25% cases were in the middle third and 20% cases were involving the upper third of the oesophagus (21). In a similar study by Sato-kuwabara Y et al., 52.3% of the cases were found in the middle third, 25% in the lower third and 17% cases in the upper third of the oesophagus (20).

In the present study, 80% cases were reported as SCC. Remaining 20% cases were as adenocarcinoma. The ratio of SCC to adenocarcinoma was found to be 4:1. Among the 24 cases of SCC, nine cases were of grade I morphology (38%), 12 cases were grade II tumours (50%) and three cases were grade III tumours (12.5%). Among six cases of adenocarcinoma, one case was grade I, three cases were grade II and two cases were grade III. Similarly, study by Hardwick RH et al., 36% of the ADC cases were grade I tumours, 52% grade II and 12% cases under grade III morphology (22). The present study was also in consistent with the results obtained from study done by Lam KY et al., where in 26% cases were grade I, 58% of the oesophageal SCC were grade II tumours and 25% belonged to grade III category (23).

The immunohistochemical expression of HER2/neu in both SCC and ADC was evaluated (Table/Fig 4), (Table/Fig 5), (Table/Fig 6), (Table/Fig 7), (Table/Fig 8), (Table/Fig 9), (Table/Fig 10). and graded accordingly by new revised CAP protocol. From the results obtained, out of 24 SCC 10 cases showed HER2/neu positivity (41.6%), three cases with 1+, three cases with 2+ and four cases with 3+ score. Among six adenocarcinoma, 66.6% positivity was shown (one case with 1+, one case with 2+ and two cases with 3+ score) (Table/Fig 3). This was similar to the study by Reichelt U et al., which showed 37% of SCC and 28% of ADC showed positive HER2/neu immunostaining (19).

In the present study, out of 30 cases grade I tumours showed 10% HER2/neu positivity, grade II tumours had 60% positivity and grade III tumours showed 80% HER2/neu positivity as shown in (Table/Fig 4). These results were consistent with study done by Dreilich M et al., which showed 45% positivity rate for poorly differentiated oesophageal adenocarcinoma compared to 28% positivity rate with well and moderately differentiated tumours (24). In the study by Mimura K et al., 4.5% of SCC cases had 3+ staining score, 9% cases showed 2+ scoring and 16.7% cases had 1+intensity of scoring 8% cases had 2+ score and 45% cases showed 3+ score (21). According to these results, Chi-square analysis was done and it was found to be statistically significant (p-value <0.05). These results were similar to the study done by Mimura K et al., wherein there was 100% HER2/neu positivity in metastatic lymphnodes (21).

In present study, it was observed that 11 out of 30 cases had lymph node metastases of which 72.7% of the cases showed HER2/neu positivity and 31.5% of the cases with reactive follicular hyperplasia showed HER2/neu positivity. From this it was concluded that the variables were statistically significant. In a second study by Dreilich M et al., HER2/neu expression was found to be correlated with the cases with lymphnode metastases (24).

The HER2/neu expression was analysed with the stage of the tumour. Four out of 15 cases of stage II tumours were positive with HER2/ neu. Whereas, 10 out of 15 cases of stage III tumours showed positive HER2/neu expression. These results were found to be statistically significant (p-value <0.05) by Chi-square analysis. This can be compared with the results from the study by Mori S et al., which showed 49% positivity with HER2/neu in stage III tumours and only 16% positivity in stage II tumours (25).

Limitation(s)

As like any research study, this study too have some limitations. Present study sample size was 30 which eventually represents only a small population of patients with oesophageal carcinoma. A larger sample size would have given a better overall representation of the parameters of this study. Manual Immunohistochemical method authors used may have some limitations in standardisation when compared with automated immunohistochemistry technique. Nowadays molecular study using fluorescent insitu hybridization techniques for HER2/neu expression is available which will give more promising results. Only the expression of HER2/neu in oesophageal resection specimens was seen and graded in present study, but patients were not followed-up.

Conclusion

The HER2/neu over-expression indicate the higher grade and stage of the tumor. Such patients could be benefitted with targeted therapy such as anti-HER2/neu monoclonal antibody for a better prognosis. However, due to variability in expression by IHC method, further ancillary studies such as Fluorescent In Situ Hybridization (FISH) for gene amplification involving larger number of patients should be used to synergise the positivity of HER2/neu expression for a greater sensitivity and to develop targeted therapy in such patients.

Acknowledgement

Authors would like to acknowledge and express gratitude to Dr.Arjunan, Retired Professor, Department of Pathology, Coimbatore Medical College (Coimbatore), for his expert guidance and motivation throughout the completion of this study.

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DOI and Others

DOI: 10.7860/JCDR/2022/54890.16851

Date of Submission: Jan 11, 2022
Date of Peer Review: Feb 04, 2022
Date of Acceptance: May 10, 2022
Date of Publishing: Sep 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Jan 15, 2022
• Manual Googling: May 09, 2022
• iThenticate Software: Aug 18, 2022 (6%) [Excluding Repository]

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