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Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018



Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dematolgy,
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

Important Notice

Original article / research
Year : 2023 | Month : April | Volume : 17 | Issue : 4 | Page : EC08 - EC12 Full Version

Utility of Prognostic Scoring System Based on Histomorphological Parameters in Low-grade Colorectal Carcinoma

Published: April 1, 2023 | DOI: https://doi.org/10.7860/JCDR/2023/60715.17727

Aneesha Asok Kumar, Faseela Kalayam Kulath, Asiq Sideeque, Nisha Thattamparambil Gopalakrishnan, Akhil Chandran

1. Assistant Professor, Department of Pathology, MES Medical College, Malapuram, Kerala, India. 2. Assistant Professor, Department of Pathology, Malabar Medical College and Research Center, Kozhikode, Kerala, India. 3. Professor, Department of Pathology, MES Medical College, Malapuram, Kerala, India. 4. Associate Professor, Department of Pathology, MES Medical College, Malapuram, Kerala, India. 5. Senior Resident, Department of Pathology, MES Medical College, Malapuram, Kerala, India.

Correspondence Address :
Nisha Thattamparambil Gopalakrishnan,
Associate Professor, Department of Pathology, MES Medical College, Malapuram, Kerala, India.
E-mail: nishatg33@gmail.com

Abstract

Introduction: Colorectal Carcinoma (CRC) is the third most common cancer worldwide. Percentage of gland formation is the only valid parameter for histologic grading of CRC. Tumour budding and Tumour-infiltrating Lymphocytes (TILs) are emerging prognostic factors in CRC. In recent years high grade CRC has become subject to more precise molecular grading strategies. However low grade cases show in homogenous outcome due to still insufficient categorisation. The focus of this study is to determine whether the combination of amount of gland formation, budding, and TILs will allow us to further characterise large in homogenous group of WHO low-grade cases into prognostically significant subgroups.

Aim: To estimate the significance of tumour budding and TILs in low-grade CRC and to categorise low-grade CRC into prognostic subgroups taking into account three histologic parameters-gland formation, tumour budding and TIL.

Materials and Methods: This was a descriptive cross-sectional study done in the Department of Pathology, MES Medical College, Malappuram, Kerala, India. It was an ambispective study (retrospective from January 2015 to December 2021 and prospective from December 2021 to March 2022) which analysed 105 World Health Organisation (WHO) low-grade CRC cases. The demographic data of the patients was collected and histopathological assessment of tumour grade, pT, pN, Lymphovascular Invasion (LVI), Tumour-infiltrating Lymphocytes (TIL) and Tumour Budding (TB) was done on Haematoxylin and Eosin (H&E) stained sections. A morphology-based risk score was developed taking into account three parameters- percentage of gland formation, budding, and TIL. For each parameter, 1 to 2 points were given, resulting in a sum score, dividing the CRC cases into a low-, an intermediate-, and a high-risk group. Statistical analysis was performed using SPSS 25.0. The results were expressed as numbers and percentage. Pearson Chi-square test was used to test the relationship.

Results: In the present study degree of budding significantly associated with pT stage (p=0.02), pN stage (p=0.042) and LVI (p=0.038). TIL also differed significantly with pT (p=0.001) pN (p=0.042) and LVI (p=0.004). Applying the prognostic scoring to 105 cases, 33 (31.4%) cases showed high score, 30 (28.6%) cases were of intermediate score and 42 (40%) cases showed low score. The three groups differs significantly with pT (p=0.027), pN (p=0.035) and LVI (p=0.015).

Conclusion: The present study showed combining different morphological parameters of tumour and tumour environment can help to further subdivide CRC into prognostically significant subgroups.

Keywords

Gland formation, Low grade colorectal carcinoma, Prognostic scoring, Tumour budding, Tumour-infiltrating lymphocytes

Introduction
Colorectal Carcinoma (CRC) is the third most common cancer worldwide, and second leading cause of cancer related death (1). Tumour heterogeneity is a hot topic in cancer research now. Tumour heterogeneity in colorectal cancer is very well-established (2). The Tumour Node Metastasis (TNM) staging and histological tumour grading are the gold standard for classification of CRC patients into prognostic subgroups for the current treatment regimes. Despite advancements in the treatment of CRC, survival rates remain highly variable for different patients even within the same TNM staging (2). CRC-grading according to the World Health Organisation (WHO) classification is still only based on the percentage of gland formation which is subjected to high inter observer variability (3),(4). So, additional histomorphological parameters like tumour budding (TB) and tumour infiltrating lymphocytes (TIL) are recommended in the diagnostic work up protocols of CRC in addition to routine TNM staging and grading for better disease stratification and for more personalised treatment (5),(6),(7),(8).

Tumour budding was first recognised in the 1950s as “sprouting” at the invasive edge of carcinomas that may reflect a more rapid tumour growth rate (9). Biologically tumour budding is closely related to epithelial mesenchymal transition. Tumour budding denotes single or small aggregates detached from the neoplastic gland at the invasive front. Recently, criteria for evaluating and reporting tumour budding in CRC have been well defined by the International Concensus Conference on Tumour Budding (ITBCC) (10). Many studies showed, that high budding is associated with lymph node positivity, vascular and lymphatic infiltration, local tumour recurrence, distant metastases and higher tumour aggressiveness (11)(12),(13),(14),(15),(16).

In all these years, for treatment stratification the main focus was on tumour cell component. Now, there is a shift of focus to Tumour Microenvironment (TME) (17). From the recent advancements in the understanding of TME now it’s evident that the crosstalk between the tumour and TME plays an important role in the tumour progression. TIL is an important immunological biomarker of TME. Besides its prognostic value it also helps for personalised treatment with checkpoint blockage therapy which has been well-established in cancers like melanoma [2,18,19]. Salgado et al had standardised the methodology for visual assessment of TIL in breast cancer on Haematoxylin and Eosin (H&E) sections (20).

Grading of CRC is based on the percentage of gland formation. Traditionally, it was 3-tiered: well-differentiated (grade 1) showing glandular differentiation in more than 95% of the tumour, moderately differentiated (grade 2) with 50% to 95% glandular differentiation and high-grade (grade 3) with less than 50% glandular differentiation (21). In the current 5th edition of World Health Organisation classification of Gastrointestinal tumour, well- and moderately differentiated CRCs are summarised as one low-grade group because of similar behaviour and better interobserver agreement (22).

So, it is important to pay special attention to tumour morphology and TME for additional information on tumour behaviour and prognosis.

The author focussed on whether current CRC grading system focusing only on gland formation or a grading system analogue to Elston and Ellis grading breast cancer or Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading in sarcoma combining different histomorphological parameters is better for getting better information regarding tumour behaviour of each CRC-case. In this study, the authors aimed to determine if the combination of the percentage of gland formation, tumour budding, and TILs allows us to further characterise the large, inhomogeneous group of low-grade CRC into prognostically significant subgroups.
Material and Methods
This descriptive cross-sectional single institutional study was conducted in the Department of Pathology, MES Medical College, Malappuram, Kerala, India. The study was ambispective in nature (January 2015 to November 2021: retrospective, and December 2021 to March 2022: prospective), which analysed 105 WHO low-grade CRC cases. The study was approved by the Institutional Ethics Committee (Ref. No.IEC/MES/47/2021).

Inclusion criteria: All H&E stained slides of low-grade CRC diagnosed in resection specimens during the time period of January 2015 to November 2021 were retrieved from department archives and were studied.

Exclusion criteria: Cases with neoadjuvant treatment , WHO high grade CRC, special subtypes, such as mucinous, serrated, medullary carcinoma, inflammatory bowel disease-related carcinoma were excluded.

Study Procedure

After applying inclusion and exclusion criteria, H&E slides of all histopathologically confirmed cases of low-grade CRC were retrieved and evaluated independently by two consultant pathologists in terms of gland formation, percentage of TIL, tumour budding and lymphovascular invasion (LVI). To receive higher interobserver concordance, a subset of the cases were viewed together by both observers on a multihead microscope.

The authors assessed tumour budding based on International Tumour Budding Consensus Conference (ITBCC) criteria. It defines tumour budding as a single tumour cell or a cluster of no more than four tumour cells and should be evaluated on H&E stained slides in one hotspot (in a field measuring 0.785 mm2) at the invasive front (10). In each case the authors selected slides with deepest invasion and then scanned 10 separate fields (20X objective) along the invasive front and a hotspot was identified. We counted the tumour bud in the hotspot (lens magnification 20X, ocular magnification 10X, eyepiece field number diameter 22) and adjusted it by dividing with normalisation factor (1.210) to get a field measuring 0.785 mm2. ITBCC recommended three-tiered system is used for further risk stratification- low budding, 0-4 buds; intermediate budding 5-9 buds; and high budding ≥10 buds (10).

The percentage of TILs was estimated according to the criteria defined by Salgado R et al., in breast cancer (20). The slide with the deepest invasion were scanned in a 200 fold magnification (ocular x10, objective x20) and the average percentage amount of stromal TILs within the border of invasion was assessed as high if >5% or low if ≤5% (23).

The gland formation based on grading according to three-tiered WHO grading system was done in each of these case. These parameters were then given score points of 1-2 to calculate a sum score and categorise them into three risk groups in a similar way Lang-Schwarz C, et al., did by using Bayreuth scoring system in their study (23) (Table/Fig 1).

Statistical Analysis

All the data collected were entered in Microsoft excel and analysis was done with the help of Statistical Package for the Social Sciences software version 25.0 (SPSS Inc., Chicago, USA). The results were expressed as numbers and percentage and statistical analysis was done using Pearson Chi-square test. A p-value of <0.05 was considered statistically significant.
Results
Summary of cases and tumour characteristics (Table/Fig 2).

Tumour budding: In this study, the authors found low budding in 43 (41%),intermediate budding in 31 (29.5%) (Table/Fig 3) and high budding in 31 (29.5%) cases (Table/Fig 4). In the present study degree of budding significantly associated with pT stage (p=0.02), pN stage (p=0.042) and LVI (p=0.03). High budding was associated with higher pT stage, pN stage and more chance for lymphovascular invasion (Table/Fig 5).

Tumour infiltrating lymphocytes: Out of 105 cases 70 cases (66.7%) showed high TIL (>5%) and 35 cases (33.3%) showed low TIL (≤5%). TIL differed significantly with pT (p=0.001) pN (p=0.042) and LVI (p=0.004) High TIL was associated with higher pTstage, pN stage and more chance for lymphovascular invasion when compared to low TIL with a significant p-value (Table/Fig 6),(Table/Fig 7).

Gland formation: Based on the percentage of gland formation, out of 105 low grade cases showed the following results: 57 (54.5%) of cases were well-differentiated and 48 (45.7%) of cases were of moderately differentiated.

Scoring: gland formation, budding and TIL: Applying the prognostic score described in (Table/Fig 1) to the 105 cases showed the following results: 33 (31.4%) cases showed high score, 30 (28.6%) cases showed intermediate score and 42 (40%) showed low score. High and intermediate scores associated significantly with high pT (0.027), high pN (0.035) and had more chance for lymphovascular invasion (0.015) (Table/Fig 8).
Discussion
Cancer is not a single disease. It is a heterogenous disease which involves complex interplay between the tumour and TME. Due to intertumoural heterogeneity CRC differs on various levels resulting in differences in prognosis and therapeutic response even for patients with the same stage and grade. So there is a need for a robust classification system for CRC which includes both molecular and histopathological parameters (2).

Tumour budding has been a hot topic in cancer research for many years. In the recent (June 2022) CAP (College of American Pathologist) protocol for reporting primary carcinomas of colon and rectum recommends reporting of tumour budding in stage I and II cases and for cancers arising from polyp, but it’s not considered as a required element. In a study conducted by Hase K et al., in 1993 they found out that more severe budding in CRC is associated with worst outcome and also suggested meticulous follow-up and possibly neoadjuvant chemotherapy for such patients irrespective of the stage (24). Sadek SA et al., in 2020 assessed TB in H&E and Cytokeratin (CK) stained sections and found it is significantly associated with adverse prognostic variables including vascular invasion, lymph node metastasis, advanced Dukes and TNM stages and inversely associated with TIL which is known to be a good prognostic indicator (25). The present study also found that high budding is associated with high pT, pN and more chance for LVI.

Cancer immunoediting is a dynamic process that consists of immunosurveillance and tumour progression. TIL is an important factor in cancer immunoediting and has not only prognostic significance but also emerging as an important biomarker in predicting the efficacy and treatment outcome (17). In the study conducted by Lang-Schwarz C et al., in 2019, TILs ≤5% versus >5% showed significant advantages for the higher TILs group concerning the parameters pT stage , pN stage, M stage, TNM stage, lymphatic vessel invasion and also venous invasion (8). In 2020 Fuchs TL et al., studied the prognostic significance of TIL in 1034 CRC patients and found out that TIL is a powerful predictor of survival in CRC (26). In the present study also TIL differed significantly with pT, pN and LVI.

There are a very few studies which combines different aspects of tumour and TME to create a prognostically significant grading system in CRC. In 2009, Lugli A et al., proposed a CD8+ lymphocytes/tumour budding index which they found to have prognostic significance in CRC (27).

Lang-Schwarz C, et al., in 2018 studied 501CRC cases and found Budding/TIL –score correlates with most clinicopathological parameters (8). In 2019 the same group of pathologist combined budding, TIL, and gland formation in low grade CRCs and proposed Bayreuth score that enables separating the large group of WHO low-grade CRC cases into subgroups, which differ significantly in outcome and survival (23). This study was first of its kind that integrates budding and TILs with traditional grading parameter-gland formation.

Combining different histomorphological parameters along with molecular markers for therapeutic stratification is nothing new in tumour diagnostics. We have been using Ellston-Ellis grading system which combines three different histomorphological parameters along with molecular markers for patient stratification in breast cancer (28).

Limitation(s)

Impact of prognostic scoring system in long term survival is not analysed in this study. Molecular biomarkers were not used in this study.
Conclusion
In the present study the authors found out that budding and TIL are independent prognostic factors in CRC and combining these parameters along with the well-established prognostic factor tumour grade could be a clue to better understanding of tumour behaviour. Assessing budding and TIL is a simple, cost-effective, time saving and reproducible method for routine practice. Even in the age of molecular pathology it is still worthy to pay attention to H&E based tumour morphology. For better disease stratification, in addition to TNM staging and grading, additional histomorphological factors like budding and TIL along with Microsatellite Instability Analysis (MSI), KRAS, BRAF and NRAS mutation analysis are recommended in CRC. More studies are required to analyse whether a prognostic scoring system combining different histopathological parameters will be effective in CRC which will lead to more unified and simplified reporting system in CRC.
Acknowledgement
We are extremely thankful to Dr. Jane Mary, Soumya Shinu, Menshi Joseph, Jisha K.
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DOI and Others
DOI: 10.7860/JCDR/2023/60715.17727

Date of Submission: Oct 13, 2022
Date of Peer Review: Nov 22, 2022
Date of Acceptance: Dec 19, 2022
Date of Publishing: Apr 01, 2023

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? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Oct 15, 2022
• Manual Googling: Nov 22, 2022
• iThenticate Software: Dec 08, 2022 (11%)

ETYMOLOGY: Author Origin
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