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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
Original article / research
Full Version
Peritumoural Mast Cell Density in Invasive Breast Carcinoma: Possible Antitumourigenic Effect with Potential Role for Immunotherapy
Correspondence Address :
Dr. G Shivashekar,
Professor, Department of Pathology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chennai, India.
E-mail: hod.pathology.ktr@srmist.edu.in
Introduction: The interaction of cancer cells and the host within the tumour microenvironment plays a major role in determining the outcome of cancers. Mast cells are part of the innate immune system that interact with tumour cells and known to have pro-tumourigenic and antitumourigenic action through their mediators. Their role in the outcome of invasive breast cancer is still not clear with studies showing both a beneficial role as well as a role in tumour progression.
Aim: To assess Mast Cell Density (MCD) in tissues of invasive carcinoma of breast and compare with clinicopathological parameters to infer their biological significance.
Materials and Methods: The study was a retrospective cross-
sectional study carried out in the Department of Pathology at SRM Medical College Hospital and Research Centre, Kattankulathur, Chennai, India on 51 cases of invasive carcinoma of breast received between January 2011 to July 2013 and the study conducted between August 2013 to November 2013. Clinical parameters and histopathological findings were recorded. Mast cells were clearly demonstrated in tissue using Toluidine Blue stain at pH 2.3. The MCD within primary malignant breast tumour tissue (mastectomy specimens, n=51) was assessed using an eyepiece grid and expressed as number of cells/per sq. mm. Statistical analysis of all parameters was performed using Statistical Package for the Social Science (SPSS) software (version 17.0) to analyse association of MCD with clinicopathological parameters.
Results: The MCD was significantly higher in malignant breast tissue compared to non neoplastic breast tissue (p-value <0.0001). No significant difference in MCD was observed between tumour size groups (T1, T2, and T3) (p-value=0.696). No statistically significant difference in MCD was observed between the four histological types observed (p-value=0.892). The majority of the tumours were of grade 2 category (n=37), followed by grade 3 (n=11) and grade 1 (n=3). No significant difference in MCD was observed between the three histological grades (p-value=0.785). The MCD was significantly higher in patients without lymphnode metastasis compared to the group with lymphnode metastasis (p-value=0.0023). The MCD in invasive carcinoma of breast, postchemotherapy group was significantly higher than that in invasive carcinoma of breast pre-chemotherapy group (p-value=0.0064).
Conclusion: The current study shows significantly increased MCD at the periphery of the carcinoma breast tissue in patients without lymphnode metastasis compared to those with lymphnode metastasis. Hence, a potential antitumourigenic and beneficial role of mast cells in invasive primary breast carcinoma could be inferred and may serve as one of the prognostic indicators for patient stratification for various treatment options including immunotherapy.
Metastasis, Toluidine blue, Tumour microenvironment
Breast cancer is the most common cancer and one of the leading causes of death among women in India and worldwide (1). It is a multifactorial, hormone-dependent process that can be initiated by a variety of risk factors and progress of the tumour varies from patient to patient. Breast cancer has been found to be more prevalent in Indian women at premenopausal stage with more aggressive, high grade, and treatment-resistant disease, the reasons for which are not well understood (2). Hence, it is imperative to understand the tumour biology in detail in breast cancer in Indian populations, especially the tumour-host interactions in the microenvironment. Mast cells are potent effector cells of the immune system that infiltrate the tumoural stroma and periphery of the tumours along with other inflammatory cells like cytotoxic T-cell subsets, macrophages, and fibroblasts (3),(4),(5). The diverse mediators derived from mast cells are reported to have both pro-tumourigenic and antitumourigenic effects. The balance between these opposing mechanisms determines their net effect on the progression or regression of the tumour at any given stage.
A pro-tumourigenic effect of mast cells has been found in prostatic adenocarcinoma melanoma, pancreatic adenocarcinoma, pulmonary adenocarcinoma, cholangiocarcinoma, hepatocellular carcinoma, thyroid cancers, basal cell carcinoma, and neurofibroma (6),(7),(8).
Mast cells and invasive carcinoma of breast: Mast cell accumulation in mammary adenocarcinoma was first demonstrated in rats and was one of the earliest reports of mast cell association with cancers. The presence of stromal mast cells were found to have a favourable prognosis in some studies including a large study sample of more than 4000 cases of breast carcinoma (9),(10). A general correlation of stromal mast cells to lower histological grades have been found but correlation to hormone receptor expression has not been consistently observed (11),(12). A correlation between stromal mast cells and small size of the tumour, tubular differentiation and hormone receptor expression, molecular subtyping, and microvessel density has been reported (13),(14),(15),(16),(17).
However, the exact role of mast cells as part of the tumour microenvironment in breast cancer is not yet completely understood. Hence, this study was taken up as a novel effort to analyse the tumour microenvironment in breast cancers in Indian populations where there is an increasing incidence in younger populations and presentation as more aggressive tumours. Hence, it is imperative to understand the tumour biology in detail to identify and validate therapeutic targets and for patient stratification and personalised treatment. The study aimed (i) To objectively and quantitatively assess MCD in the tumoural compartment of invasive breast carcinoma in South Indian population, and (ii) To compare MCD with clinicopathological parameters and to infer their biological role in the tumour microenvironment and their prognostic and therapeutic significance.
The study was a retrospective cross-sectional study carried out in the Department of Pathology at SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chennai, India on cases of invasive carcinoma of breast received between January 2011 to July 2013 and study conducted between August to November 2013 after obtaining approval from the Institutional Ethics Committee (312/IEC/2012).
Inclusion criteria: (i) Cases represented by resection (mastectomy) specimens with tissue blocks and Haematoxylin and Eosin (H&E) slides representing invasive carcinoma of breast received in the laboratory between January 2011 to July 2013 were included in the study. (ii) Cases with adequate clinical and demographics data of the patient.
Exclusion criteria: (i) Cases without adequate representation of the tumour tissue in sections (ii) Cases with inadequate area of tissue sections for mast cell counting (iii) Cases with incomplete clinical and demographics data were excluded from the study.
A total of 51 cases of breast carcinoma were included in this study. The number of samples received as in the study period were analysed, which was above the sample size calculated as per statistical requirements for this study.
Study Procedure
Formalin Fixed Paraffin-embedded (FFPE) tissue blocks and H&E stained sections representing malignant tumour tissue from surgically resected mastectomy specimens were analysed. Clinical parameters including age, gender, history of chemotherapy etc., were obtained from the referring departments and retrieved from the Medical Records Department. Mastectomy specimens were routinely sampled for histopathology analysis. H&E stained tissue sections were evaluated microscopically (OLYMPUS-CX-21; Field area of 0.196 mm2). Routine microscopic parameters in carcinoma breast including the following were recorded: tumour size, histological type, histological grade, surgical margin involvement, and axillary lymphnode status. A summary of clinicopathological parameters is provided in (Table/Fig 1). Mast cells were demonstrated histochemically on tissue sections by staining with 1% acidified toluidine blue solution at pH 2.3 (18). Microscopy-grade toluidine (Loba Chemie; CI no: 52040; Lot no: S26701111; Dye content-80%; Solubility-0.1%) was used for preparing a water clear solution. An electronic pH meter (Eutech Instruments: Catalog No: 35624-02) was used to control the pH.
Control tissue: Tissues from non neoplastic breast tissue were used as controls (as baseline value), to assess significance of MCD within the tissue compartments of invasive carcinoma breast. Non neoplastic breast parenchyma 5 cm away from the outermost margin of the tumour was selected as control tissue. A total of 21 controls were used in the study.
Mast cells were identified on tissue sections due to the violet-purple metachromatic staining of their granules against the blue orthochromatic background. Mast cells were counted quantitatively in sections using an eyepiece grid (model WF-18) (Table/Fig 2). Each side of the large square represented one millimeter (mm) on the tissue section. A minimum of 10 high power fields were used for counting mast cells and the average density was expressed as: Mast cell density (MCD)=Number of mast cells/sq. mm area of the tissue section.
Statistical Analysis
Statistical analysis with SPSS software (version 17.0) was done to analyse association of MCD with clinicopathological parameters. For determining statistical significance between two groups, the p-value was obtained using the two-tailed Student t-test. One-way Analysis of Variance (ANOVA) was used when comparing across three or more groups. The statistical data was tabulated for analysis and inference. A p-value of less than 0.05 was considered significant.
MCD in non neoplastic and malignant breast tissues: Controls representing non neoplastic breast tissue were used to compare with cases of carcinoma breast included in the study. Mast cells were visualised and density assessed in tissue sections representing primary breast carcinoma and correlated with histopathological features (Table/Fig 3),(Table/Fig 4),(Table/Fig 5). MCD in breast carcinoma tissue was found to be significantly higher compared to MCD in non neoplastic breast tissue (p-value <0.0001; (Table/Fig 6).
MCD and age: The age of patients with breast carcinoma ranged from 26 to 69 years with a mean age of 49.65 years. No statistically significant difference was noted between the two groups in our study (p-value=0.523).
MCD and tumour size: When the tumors were grouped based on their size using TNM staging parameters, most cases of invasive breast carcinoma belonged to the T2 group (n=33; 64.7% of cases) and 18 cases belonged to T3 (35.3% of cases). None of the cases were reported as T1. No significant difference in MCD was observed between these two groups (Table/Fig 7).
MCD and histological types: Invasive Ductal Carcinoma- Not Otherwise Specified (NOS) accounted for the majority of the tumours (n=48; 94.1%). One case each of invasive lobular carcinoma, mucinous carcinoma and metaplastic carcinoma (1.96% each) were also diagnosed. No significant difference in MCD was observed between the four histological types (Table/Fig 8).
MCD and histological grade: Histological grading of Invasive ductal carcinoma-NOS was performed based on Nottingham’s modification of Bloom-Richardson’s system (11). The majority of the tumours were of grade 2 category (n=37; 72.5%), followed by grade 3 (n=11; 21.6% and grade 1 (n=3; 5.9%) (Table/Fig 9). No statistically significant difference in MCD was observed between the three histological grades.
MCD and surgical margin involvement by tumour: Only three cases (5.88%) out of 51 cases showed involvement of surgical margins (deep resected margin) by tumour cells (Table/Fig 1). No statistically significant difference in MCD was observed between the two groups (p-value=0.782).
MCD and regional lymphnode status: Total 28 out of 51 cases showed metastatic deposits from breast carcinoma to regional axillary lymphnodes. The mean MCD as measured in the primary breast tumours of patients without axillary node metastasis was significantly higher compared to mean MCD in primary breast tumours with axillary node metastasis. This difference was found to be statistically significant (p-value=0.0023) (Table/Fig 10). When lymphnode positive cases were grouped as pN1, pN2, and pN3 according to the number of positive lymphnodes, no statistically significant difference in MCD of primary tumours was observed between the groups pN1, pN2, and pN3 (p-value=0.294) (Table/Fig 11).
MCD in Postchemotherapy cases: MCD in seven cases of invasive breast carcinoma, post-chemotherapy status (Table/Fig 12),(Table/Fig 13) was significantly higher than MCD in invasive carcinoma of breast prechemotherapy (p-value=0.0064). This was an observation being reported here towards the understanding of mast cell biology and not included in the correlation to clinicopathological parameters.
Mast cells were clearly demonstrated in tissue sections using toluidine blue staining method and MCD was found to be significantly higher in the malignant tumour compartment compared to normal breast tissue tissue, the difference being statistically significant. This highlights their potential interaction with tumour cells and the stroma in the tumour microenviroment.
Mast cell density and invasive carcinoma of breast: Dabiri S et al., (9) and Rajput AB et al., (10) have shown that the presence of mast cells in stroma is associated with a favourable prognosis in carcinoma breast and that the presence of mast cells and not necessarily a high MCD is necessary to render this favourable outcome. Fakhrjou A et al., (11) have shown the interaction of mast cells in breast cancer and Tamma R et al., (12) have reported the importance of spatial distribution of mast cells and clinicopathological parameters.
Age: A previous study by Sang J et al., (17) has analysed MCD within two age groups (<50 and >50 years) and observed a higher MCD in patients <50 years compared to patients >50 years. Sang J et al., (17) have described that the demarcation of 50 years of age was to differentiate premenopausal reproductive age group and postmenopausal group. In the present study, no statistically significant difference in the mean MCD between patients in these two age groups was found (p-value=0.523).
Histological type: Variations in MCD between histological types was observed in previous studies by Fakhrjou A et al., (11) and Glajcar A et al., (14). In the present study there was no statistically significant difference between the mean MCD in different histologic types of breast carcinoma. However, it needs to be noted that the present study had only one case each of metaplastic carcinoma, mucinous carcinoma, and invasive lobular carcinoma. All the other cases were of invasive ductal carcinoma-NOS. Dabiri S et al., (9) have reported a lower number of mast cells in metaplastic carcinoma, which was not observed in the present study.
Histological grade of invasive ductal carcinoma-NOS: Rajput AB et al., (10) and Keser SH et al., (15) found significantly higher number of mast cells in low grade invasive ductal carcinoma-NOS compared to high grade tumours. In the present study, no significant difference in MCD was observed across grades 1, 2, and 3 tumours.
Surgical margins’ involvement by tumour: Only three out of 51 cases showed involvement of surgical margins (deep resected margins) by tumour cells. No statistically significant difference in MCD was observed between the two groups (p-value=0.782). Previous studies by Rajput AB et al., (10) and Sang J et al., (17) have not found significant difference between MCD and surgical margin status.
Regional lymphnode status: Axillary lymphnode metastasis is a significant prognostic factor in carcinoma breast. Our results indicate that a higher MCD within the primary breast tumour is seen in patients without lymphnode metastasis compared to those with lymphnode metastasis (Table/Fig 10); (p-value=0.0023). This was a significant finding correlating with many previous studies including Dabiri S et al., (9), Rajput AB et al., (10), and Pal S et al., (16) suggesting an antitumourigenic role of mast cells in invasive carcinoma breast.
Number of lymphnodes involved by tumour: Fakhrjou A et al., (11) have shown an inverse correlation of MCD to the number of lymphnodes involved by tumour. The present study did not reveal statistically significant difference of MCD between cases with pN1, pN2, and pN3 status.
MCD in carcinoma breast: Postchemotherapy induced changes in tissue. The present study included seven cases of carcinoma of breast, postneoadjuvant chemotherapy to assess their density and distribution pattern (and not included for clinicopathological correlation). The mean MCD was 3-4 folds higher compared to that of cases who did not receive chemotherapy. Mast cells were also distributed equally within the intratumoural and peritumoural areas whereas they were distributed mostly in the peritumoural areas, in those who did not receive chemotherapy.
A variety of inflammatory cells including mast cells are recruited to the breast parenchyma following neoadjuvant chemotherapy. It has been postulated that some of these cells may play a role in rendering chemoresistance. Ruffell B et al., (19) demonstrated that mast cells and neutrophils first infiltrate the tumour cells in higher number compared to those cases who did not receive neoadjuvant chemotherapy. Recent advances in tumour immunobiology have shown a role of antimast cell therapy for tumours where they play a pro-tumorigenic role (20) and a role for immunotherapy for some cancers where augmentation of antitumour immune response could limit the progression of cancers (21),(22).
Limitation(s)
The study has a few limitations including a relatively smaller sample size of breast cancer patients who have undergone mastectomy (n=51) and found to be adequate for statistical analysis; however, can be expanded into one with a larger sample size. More diversity of various histological types and tumour size and could shed more light on association of MCD with those clinicopathological parameters and their significance. Immunohistochemical (IHC) staining could be more advantageous to differentiate between functional mast cell subsets (chymase and tryptase positive) to infer their role.
Our study on the differential distribution of mast cells within the tumour microenvironmemnt in breast carcinoma in a South Indian population with relation to clinicopathological parameters has shown a statistically significant level of higher MCD within the peritumoural area in the patient group without regional lymphnode metastasis compared to the group with regional lymphnode metastasis. This would suggest an antitumorigenic or beneficial role of mast cells in breast carcinoma compared to other solid organ cancers and could serve as a positive prognostic indicator for patient stratification and specific treatment. Diligent clinical follow-up of these patients and survival rates are required to determine the exact prognostic significance of these findings. The function of mast cells, being a key component of the innate immune system could also be augmented by immunotherapy in cancers where they have an antitumorigenic role. This study could be extended with functional in-vitro studies and IHC analysis of mast cell subsets (tryptase and chymase positive) could further help to establish their exact function at a particular stage of tumour development and help identify mast cell-derived or associated molecular biomarkers, which could serve as new therapeutic targets for breast cancer in the era of personalised
medicine.
DOI: 10.7860/JCDR/2022/56975.16785
Date of Submission: Apr 09, 2022
Date of Peer Review: Apr 23, 2022
Date of Acceptance: Jun 28, 2022
Date of Publishing: Aug 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? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes
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