To study the utility of tumor budding as a histopathological marker in comparison to various histopathological parameters and TNM staging in breast carcinoma

SOUMYA AGRAWAL; Sunita Vagha; Samarth Shukla

doi:10.12688/f1000research.142427.1

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To study the utility of tumor budding as a histopathological marker in comparison to various histopathological parameters and TNM staging in breast carcinoma

[version 1; peer review: 1 approved]

SOUMYA AGRAWAL ¹, Sunita Vagha¹, Samarth Shukla¹

PUBLISHED 15 Jan 2024

Author details Author details

¹ Pathology, Jawahar Lal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, Maharashtra, India

SOUMYA AGRAWAL
Roles: Conceptualization, Resources, Writing – Original Draft Preparation, Writing – Review & Editing

Sunita Vagha
Roles: Supervision, Validation, Writing – Review & Editing

Samarth Shukla
Roles: Supervision, Validation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Datta Meghe Institute of Higher Education and Research collection.

Abstract

Background

Breast cancer is the leading cause of death in Indian females. Detection of breast cancer in later stages leads to poorer prognosis and therefore decreases patient survival. Various new modalities such as mammography and USG guided FNACs are developed and many new markers are available to diagnose breast cancer; however, tumour budding is a cost-effective method which can be helpful in early diagnosis. Tumour buds are found to have a positive correlation with various histopathological prognostic markers in breast cancer. The present study will be conducted to evaluate tumour buds as a prognostic marker in breast cancer. This study aims to compare tumour budding with histopathological prognostic markers, TNM staging and IHC phenotypes.

Methods

The study will be observational, cross- sectional, and prospective, will include 60 cases and will be conducted at Jawaharlal Nehru Medical College (JNMC) Wardha in the Pathology Department.

Results

Data will be collected and combined together over a period of two years and will be analysed statistically for tumour budding as a marker and its correlation with breast prognosis.

Keywords

Breast cancer, Tumor budding, histopathological markers, TNM staging

Corresponding author: SOUMYA AGRAWAL

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2024 AGRAWAL S et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: AGRAWAL S, Vagha S and Shukla S. To study the utility of tumor budding as a histopathological marker in comparison to various histopathological parameters and TNM staging in breast carcinoma [version 1; peer review: 1 approved]. F1000Research 2024, 13:68 (https://doi.org/10.12688/f1000research.142427.1) First published: 15 Jan 2024, 13:68 (https://doi.org/10.12688/f1000research.142427.1) Latest published: 15 Jan 2024, 13:68 (https://doi.org/10.12688/f1000research.142427.1)

Introduction

Breast cancer is among the commonest cancers diagnosed in females.¹ Breast cancer is the main cause of death and is the most diagnosed cancer, exceeding lung cancer. Breast cancer is ranked first among Indian females,² and men contributes 0.5 to 1% of breast cancers.³ In 2020 breast cancer was diagnosed in 2.3 million women, and 6,85,000 related deaths were reported globally in the same year. Among all known cancers, breast cancer leads to loss of most DALYs (disability adjusted life years) in women. A total of 7.8 million women who diagnosed with breast cancer in the past 5 years were alive at the end of 2020.¹^,³ Breast cancer is a risk in both rural and urban India and it accounts for 14% cancers in India. A breast cancer case in Indian women is diagnosed every four minutes. Breast cancer stage 3 and 4 are present in more than 50% Indian women.

Breast cancer patients’ survival five years after diagnosis varies greatly –in high income countries it is higher than 90%, 66% in India, and 40% in South Africa.¹^,³ Women in their early 30s and 50s are at a higher risk of having breast cancer. Breast cancer incidence is at peak in the 50-64 years age range. One in 28 women in India is likely to develop breast cancer and it is more prevalent in urban populations than in rural populations. Approximately 30% of breast cancer patients have distant metastasis at first diagnosis.⁴

Early detection and treatment have led to reduce mortality in the last few decades and have proved to be successful in countries with higher incomes; therefore, they should also be made available to countries with limited resources. In later stages of cancer, chances of patient survival are lower. The presence of lumps or masses that suggest cancerous outgrowths can be diagnosed by women themselves by self-examination. Patients’ line of treatment is determined by various factors including clinical, pathological and genetic factors.⁵

Tumor budding is defined as a small clusters of one to five cells which are present at the invasive edge of the tumor mass. Tumor buds undergo transition in the mesenchymal epithelium which is an early event in the process of metastasis⁶ and therefore considered as representation of Epithelial Mesenchymal Transition (EMT).⁷ In tumor buds, mesenchymal markers are upregulated and epithelial markers are downregulated. Tumor budding is a relative prognostic marker in carcinoma breast and is one of the mechanisms of distant metastasis and invasion.⁴ Presence of tumor buds is suggestive of progression in cancer and is an important risk factor in breast carcinoma.⁴ Tumor budding in colon cancer shows a positive correlation with lymph nodes and poor prognosis.⁴ Tumor budding as a risk factor can be diagnosed routinely and is therefore both cost and time- effective. As tumor budding is related with local and regional metastasis, it may also be used in therapeutic decision making.⁴ High magnification is preferred for diagnosing tumor buds and should not be confused with tumor border. Correlation between tumor budding and positive lymph nodes indicates a poor prognosis in breast carcinoma patients.⁶ Therefore tumor budding in breast carcinoma is a parameter suggestive of aggressive tumor behavior, growth and distant spread, predicting a poor outcome.⁸

The present study is proposed to explore tumor budding as a histopathological marker in breast cancer in correlation with other poor clinicopathological parameters, which include-lymphnode involvement, lymphovascular invasion, tumor size, ER, PR, and Her2 expression.

Rationale

Tumor buds may be peritumoral, which means they are near the tumor margin, or intratumoral, i.e., inside the tumor mass.⁵ Detecting tumor buds in early metastasis would be of immense clinical value which would lead to or provide better survival of the patient.

Tumor budding is associated with poor clinicopathological parameters and usually indicates a poor prognosis in patients diagnosed with breast cancer. Early evaluation of tumor budding will provide better outcome for the patient and is also a cost-effective diagnostic marker, as IHC markers are not affordable to everyone. Distant metastasis is linked with high- gradetumors budding, and therefore its evaluation, scoring and inclusion in Tumor, Node and Metastasis TNM grading will improve the diagnosis of the patient.

Objectives

1. To confirm histopathological diagnosis of breast malignancy.
2. To evaluate other histopathological prognostic markers as per CAP guidelines.
3. To determine the stage of breast carcinoma as per TNM classification by the American Joint Committee of Cancer (AJCC).
4. To assess the tumour bud status in carcinoma breast and histopathological examination.

Methods

This study will be conducted at JNMC Wardha in the Pathology Department, in coordination with Department of General Surgery, Acharya Vinoba Bhave Rural Hospital, Sawangi.

It will be an observational, cross-sectional, and prospective study, and has received clearance from the institutional ethics committee (approval no. DMIMS (DU)/IEC/2022/1058). It will be carried out during a two-year period (June 2022 to June 2024).

Inclusion criteria

1. Histopathologically- confirmed cases of breast carcinoma.
2. Specimens of all modified radical mastectomy specimens.
3. Females diagnosed with breast carcinoma.
4. Newly diagnosed cases of breast cancer.

Exclusion criteria

1. Patients diagnosed with lesions other than breast carcinoma-, e.g., myoepithelial tumors, fibroepithelial tumors, mesenchymal tumors, benign tumors and mastectomy specimens.
2. Patients with a history of -lobectomy and biopsy specimen including both Tru - cut biopsies and wedge biopsies.
3. Male patients diagnosed with breast cancer.
4. Patients with a history of neo adjuvant therapy, e.g. Trastuzumab, Pertuzumab.

Approach to the present study

Prior written informed consent will be taken from the patients participating in the study. Keeping in mind the inclusion and exclusion criteria of the study, new and previously diagnosed cases will be noted and for newly diagnosed cases clinical history and physical examination will be carried out. Modified radical mastectomy specimens of clinically confirmed breast carcinoma patients will be studied for histopathological diagnosis. The specimens will be initially kept for fixation followed by proper gross examination and dissection. Sections from soft tissue and skin margins, nipple areola complex, tumour mass and different levels of axillary lymph nodes will be taken. Sections will then be stained using standard haematoxylin and eosin stains.

Steps for grossing a mastectomy specimen:

Identification of the carcinoma breast specimen will be done with the patient’s requisition form. Orientation of specimen will be done by the surgeon. If the specimen is not oriented it will be then oriented in accordance to its anatomical position. The specimen will then be incised and kept for fixation. Sectioning of the specimen is done and it is dissected into slices of 1 cm. Tumour examination will be done if the tumour is identified, dimensions are noted, its quadrant is identified and other features like consistency, haemorrhage and presence of necrosis will be identified. Longitudinal and coronal serial sections will be taken from the nipple areola complex. Other quadrants of the breast will be examined for micro calcification, satellite nodules and any other abnormalities. Axillary lymph node dissection will be conducted, the largest lymph node will be identified and its cut surface will be noted.

Identification of the carcinoma breast specimen with the patients requisition form.

Sample size

Sample size formula⁹:

n = \frac{{(Z \frac{α}{2})}^{2} \times p \times (1 - p)}{d^{2}}

where,

Z $\frac{α}{2}$ = level of significance at 5% = 1.96

p = incidence = 28.54% = 0.2854

d = desired error of margin = 7%

\begin{array}{c} n = \frac{n = \{1.96\} 2 * \{0.2854\} * \{1 - 0.2854\}}{{\{0.07\}}^{2}} \\ = 63.85 \\ = Approximative patient number = 60 \end{array}

Materials

The study will include approximately 60 confirmed breast carcinoma modified radical mastectomy specimens received from the Department of Histopathology, JNMC. Sections from the tumour mass of these specimens will then be fixed in formalin (10%) and embedded in paraffin blocks. Grossing instruments required includes- grossing tray, knife, scalpel, measuring tape, plain forceps and toothed forceps. Automated tissue processing assembly will be conducted, followed by staining with haematoxylin and eosin. Antibodies of ER/PR, Her2/neu of Brand-PATH NSIT2 will be used. Glass slides (Blue Star) with dimensions: 7.5 x 2.5 cm for microscopy assessment using binocular research microscope Magnus MLXi pro will be used.

Staining protocol: Haematoxylin and eosin staining

Staining protocols will be conducted by the following methods.¹⁰ Sections will be deparaffinised in three sets of xylene, 10 minutes for each set followed by dewaxing - and rehydration by decreasing grades of alcohol. They will then be watered and kept in Harris haematoxylin stain for 10 minutes. Sections will then be washed under running water for 2-3 minutes and then kept in 1% acid alcohol for a few seconds. They will then be washed in alkaline tap water for 5 minutes and then stained for 1 minute in 1% aqueous eosin. Finally, sections will be dehydrated by 90% alcohol and then mounted using Dibutylphthalate Polystyrene Xylene (DPX).

Immunostaining

Formalin- fixed paraffin- embedded tissue sections will be mounted on slides coated with Poly l- lysine followed by deparaffinization and rehydration. A pressure cooker will used for heat-induced epitope retrieval. Sections will then thrice rinsed with phosphate buffer saline (PBS). Then to block peroxidase activity, sections were kept in 3% hydrogen peroxide for 10 minutes for 30 – 40 minutes, ER/PR primary antibody will be placed on top and is kept for reacting at room temperature, followed by washing with PBS thrice. For the next 30 minutes it will be allowed to react at room temperature with the secondary antibody (streptavidin biotin), then sodium phosphate buffer, and for next 10 to 20 minutes they will be kept in DAB (3, 3-diaminobenzidine). After washing with tap water, it will then be kept in haematoxylin at room temperature for 2 minutes. Slides are mounted after clearing and drying.

Interpretation methodology

The tumour will be staged in accordance with TNM Classification determined by AJCC, eight edition.¹¹

Combined T, N and M Stage-

• Stage 0 - Tis
• Stage I - T1N0
• Stage II - T2N0, T3N0 T0N1, T1N1, or T2N1
• Stage III - Invasion into skin and/or ribs, matted lymph nodes, T3N1, T0N2, T1N2, T2N2, T3N2, any T N3, T4 any N, locally advanced breast cancer.
• Stage IV - M1, advanced breast cancer.

ER/PR status assessment -¹²

Proportion score

Score	Percentage of stained cells
0	No staining
1	<1 or 1 nuclei staining
2	1-10 nuclei staining
3	11-33 nuclei staining
4	34-66 nuclei staining
5	67-100 nuclei staining

Intensity score

Score	Intensity of staining
0	Negative
1	Weak
2	Intermediate
3	Strong

Allred score (total score) = Proportion score + Intensity score

Allred score (total score)	Effect on hormone therapy
0-1	No effect
2-3	Small (20%) chance of benefit
4-6	Moderate (50%) chance of benefit
7-8	Good (75%) chance of benefit.

Her2 scoring¹³

Score	HER2 expression and staining pattern
0	Negative, not stained or membrane stained in < 10% of tumor cells
1+	Negative, Membrane stained faintly in > 10% of tumor cells (only a part of membrane shows positivity)
2+	Weakly positive, Membrane in its entirety is weak to moderately stained in > 10% of tumor cells
3+	Strongly positive, entire membrane is strongly stained in >10% of the tumor cells.

Grading of tumor budding¹⁴

≤ 4/10 HPF – low tumor budding

> 4/10HPF – high tumor budding

Ethical considerations

The present study received approval from the institutional ethics committee (IEC) with the reference number DMIMS (DU)/IEC/2022/1058, dated 27 June 2022.

Informed written consent will be taken from the patients participating in this study.

Statistics

Statistical analysis will be carried out ‘using Chi square’ test to analyse the relationship between tumour budding grading and clinicopathological, histopathological indices and immunohistochemical markers. Multiple linear regression analysis will be used to clarify the relative factors for metastasis. A value of P<0.05 considered to indicate statistical significance.

Discussion

Breast cancer is a considerably heterogenous disease.⁴ A range of factors – are considered, such as- disease development, treatment and patient survival. Breast cancer is the major cause of death linked to cancer in females. There are many different subtypes of breast cancer, and they present with various different clinicopathological and biological features which leads to different prognosis.⁷ Early metastasis leads to poor prognosis in patients with breast carcinoma although many advances have been made in treatment. Approximately 30% patients are diagnosed with distant metastasis in their first breast carcinoma diagnosis.⁴ Interpretation of tumor buds is made difficult in breast carcinoma due to many interstitial reactions as these reactions leads to tumor A necrosis, fibroblast, proliferation, inflammatory cell infiltration-, among others.⁴

Tumor buds are defined as cells which are detached from the main tumor mass. Tumor bud can be a single cell or cluster of upto 5 cells.⁷ It easy to evaluate in routine diagnosis and is both time and cost effective.⁵ Tumor budding is one of the parameter that might help in decision making therapeutically.⁵ Tumor buds are invasive cells that migrate through peritumoral connective tissue, evade the host defense mechanism leading to invasion of lymphatics and blood vessels which leads to local and distant metastasis. Tumor budding is also linked with various different cancers like cancers of head and neck, colorectal, lung, gastric and esophageal.⁶ Raised tumor bud count is related with shortened survival in breast cancer and various other cancer cells. Tumor buds that have undergone epithelial mesenchymal transition are more invasive and prone to metastasize. Tumor budding is therefore the first step of metastasis. Tumor buds during EMT lose their epithelial characteristics and acquire mesenchymal characteristics which also includes expression of mesenchymal proteins and therefore becomes motile. EMT is a dynamic process in which loss of epithelial characteristics and acquired mesenchymal characteristics are not permanent but temporary.⁴

Below are discussed a few studies that were conducted in the last few years which showed tumor budding as a histopathological prognostic marker in early stages of breast cancer, and its association with poor clinicopathological characteristics and worst clinical outcome. These studies showed that early detection of tumor budding would be helpful in treating patients diagnosed with breast cancer.

Huang et al., carried out a study titled “Tumor budding is a novel marker in breast cancer: the clinical application and future prospects” in the year 2022. The study showed that tumor buds which have an invasive behavior biologically provides tumor cells an increased ability to migrate and invade. The tumor buds can help predict patients’ prognosis as they are associated with lymph node involvement and lymphatic invasion.⁴

Mohamed Gabal et al., conducted a -study titled “Tumor budding and MMP-2 expression in Breast Invasive Ductal carcinoma” in 2018. It was a cross-sectional, observational study in which specimens of 61 cases of either mastectomy or conservative breast surgery were taken from females diagnosed with invasive ductal breast carcinoma aged from 22 to 82 years. The study emphasized the prediction of poor outcomes in patients as tumor budding is a parameter which denotes the aggressiveness, growth and distant spread of tumor. It also showed positive correlation of tumor budding with ill-defined border, low mitotic count, expression of MMP- 2 and positive metastasis of lymph nodes.⁸

Masilamani et al., carried out a study titled “-Evaluation of clinicopathological significance of tumor budding in breast carcinoma” 2018. They conducted a retrospective observational study in which 107 surgically resected specimens of breast carcinoma were collected. Whole tissue sections were taken from specimens and analysed using hematoxylin and eosin staining. The study concluded that tumor buds are associated with poor prognosis in breast cancer and that further standardization, proper framing of scoring parameters and cut off criteria for tumor budding is required prior to its inclusion in the histopathological reports.⁶

Sriwidyani et al., conducted a study titled “-Tumor budding in breast carcinoma: relation to E-cadherin, MMP-9 expression and metastasis risk” in 2016. It was a cross -sectional nested case control type study in which 35 cases of breast cancer with metastasis and 35 cases of breast cancer without metastasis were selected during a period from January 2012 to June 2015, with a mean age of 48.6 years (ranging from 23-74 years). The study concluded that tumor budding had no correlation with E-cadherin expression, while it was related to the level of MMP-9 expression. It showed high grade tumor budding is an independent risk factor of metastasis in breast cancer and shows features of EMT.⁷

Salhia et al., conducted a study titled “High tumor budding stratifies breast cancer with metastatic properties” in 2015. It was a retrospective study over a period of seven years from January 2005 to December 2011, in which tumor budding was analyzed in patients with known status of lymph nodes. The study included 148 cases resected surgically and 99 core biopsies. A correlation between tumor budding in breast cancer and invasion of lymphatics and positive lymph node status was found in the study.⁵

Association between tumor budding and breast cancer prognosis is suggested by the above- mentioned studies. In the present study we will observe consistent correlation of tumor budding with lymph node involvement, lymphovascular invasion, ER, PR, and tumor size.

Study dissemination

We intend to publish the study in a peer reviewed journal. The data will be prepared in excel sheet without patient identifiers and will be shared as and when requested by concerned journal/publishers/statistians. If required these data files will be uploaded in open data repository like Zenodo.

Study status

Recruitment has started, with currently 24 patients enrolled in the study.

Data availability

No data are associated with this article.

Reporting guidelines

Zenodo: STROBE checklist for protocol ‘To study the utility of tumor budding as a histopathological marker in comparison to various histopathological parameters and TNM staging in breast carcinoma’. DOI: 10.5281/zenodo.8337107.

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Acknowledgments

I would like to sincerely thank and acknowledge all the patients that participated in my study, all my teachers, technical staff and department of Oncology surgery without whom this study would not be possible.

References

1. Breast cancer: Who.int.2022 [cited 7 June 2022].
2. Malvia S, Bagadi SA, Dubey US, et al.: Epidemiology of breast cancer in Indian women. Asia Pac. J. Clin. Oncol. 2017 Aug; 13(4): 289–295. Publisher Full Text
3. Breast cancer: Who.int.2022 [cited 7 June 2022].
4. Huang T, Bao H, Meng YH, et al.: Tumour budding is a novel marker in breast cancer: the clinical application and future prospects. Ann. Med. 2022 Dec 31; 54(1): 1303–1312. PubMed Abstract | Publisher Full Text | Free Full Text
5. Salhia B, Trippel M, Pfaltz K, et al.: High tumor budding stratifies breast cancer with metastatic properties. Breast Cancer Res. Treat. 2015 Apr; 150(2): 363–371. PubMed Abstract | Publisher Full Text | Free Full Text
6. Masilamani DS, Kanmani P: Evaluation of clinicopathologic significance of tumor budding in breast carcinoma. Int. J. Clin. Diagn. Pathol. 2019; 2(1): 171–173. Publisher Full Text
7. Sriwidyani NP, Manuaba IB, Alit-Artha IG, et al.: Tumor budding in breast carcinoma: relation to E-Cadherin, MMP-9 expression, and metastasis risk. Bali. Med. J. 2016 Jan 1; 5(3): 150. Publisher Full Text
8. Gabal SM, Bassam AM, Sedqi ME, et al.: Tumour Budding and MMP-2 Expression in Breast Invasive Ductal Carcinoma. J. Clin. Diagn. Res. 2018 May 1; 12(5). Publisher Full Text
9. Chada V: Sample size determinant in health studies. NTI bulletin. 2006; 42/3 and 4: 55–62.
10. Bancroft JD, Gamble M: Theory and practice of histological techniques. Elsevier Health Sciences; 2008.
11. 1 greene f, edge s, schilsky r, gaspar l. ajcc cancer staging manual 8th edition. 8th ed. springer; 2018.
12. Rai PD, Vagha S, Shukla S, et al.: Comparison of various scoring systems by immunohistochemistry for evaluating hormone receptors (Estrogen receptor and progesterone receptor) in carcinoma of breast. Journal of Datta Meghe Institute of Medical Sciences University. 2020 Apr 1; 15(2): 202. Publisher Full Text
13. Cornolti G, Ungari M, Morassi ML, et al.: Amplification and overexpression of HER2/neu gene and HER2/neu protein in salivary duct carcinoma of the parotid gland. Archives of otolaryngology–head & neck surgery. 2007 Oct 1; 133(10): 1031–1036. PubMed Abstract | Publisher Full Text
14. Salhia B, Trippel M, Pfaltz K, et al.: High tumor budding stratifies breast cancer with metastatic properties. Breast Cancer Res. Treat. 2015 Apr; 150(2): 363–371. PubMed Abstract | Publisher Full Text | Free Full Text

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VERSION 1 PUBLISHED 15 Jan 2024

Author details Author details

¹ Pathology, Jawahar Lal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, Maharashtra, India

SOUMYA AGRAWAL
Roles: Conceptualization, Resources, Writing – Original Draft Preparation, Writing – Review & Editing

Sunita Vagha
Roles: Supervision, Validation, Writing – Review & Editing

Samarth Shukla
Roles: Supervision, Validation, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (1)

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Published: 15 Jan 2024, 13:68

https://doi.org/10.12688/f1000research.142427.1

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© 2024 AGRAWAL S et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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AGRAWAL S, Vagha S and Shukla S. To study the utility of tumor budding as a histopathological marker in comparison to various histopathological parameters and TNM staging in breast carcinoma [version 1; peer review: 1 approved]. F1000Research 2024, 13:68 (https://doi.org/10.12688/f1000research.142427.1)

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Reviewer Report 07 Feb 2024

Vivek Gupta, Jawaharlal Nehru Medical College, Sawangi, India; Pathology, Government Institute of Medical Sciences, Greater Noida, Greater Noida, Uttar Pradesh, India

Approved

https://doi.org/10.5256/f1000research.155981.r239730

The rationale for the study is well-defined and has clarity. It highlights the gap in the literature and the research question. The objectives are in sequence and lead to clarity in assessing the tumor bud in breast carcinoma.
... Continue reading

The rationale for the study is well-defined and has clarity. It highlights the gap in the literature and the research question. The objectives are in sequence and lead to clarity in assessing the tumor bud in breast carcinoma.
Objective 4 needs to be reframed to “Assessing the tumor bud status in carcinoma breast.” The histopathological examination may be removed as the same has already been mentioned in earlier objectives.

The study design is apt for study. It mentions inclusion and exclusion. They have graded tumor budding as ≤ 4/10 HPF – low tumor budding and > 4/10 HPF – high tumor budding. However, it can be graded as ≤ 4/10 HPF, 4 – 9/10 HPF, and >10/10 HPF. An optimal cut-off for the number of tumor budding and lymph node metastasis can also be correlated.

The protocol provides sufficient details for the evaluation of tumor budding. Microscopic pictures of high and low tumor buds can be more effective.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable

References

1. Kim JK, Rhee YY, Bae JM, Kim JH, et al.: Composite scoring system and optimal tumor budding cut-off number for estimating lymph node metastasis in submucosal colorectal cancer.BMC Cancer. 2022; 22 (1): 861 PubMed Abstract | Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: General Pathology, Surgical Pathology, Molecular Pathology, Oncopathology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Vivek Gupta, Jawaharlal Nehru Medical College, Sawangi, India; Government Institute of Medical Sciences, Greater Noida, Greater Noida, India

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07 Feb 2024 | for Version 1

Vivek Gupta, Jawaharlal Nehru Medical College, Sawangi, India; Pathology, Government Institute of Medical Sciences, Greater Noida, Greater Noida, Uttar Pradesh, India

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Approved

The rationale for the study is well-defined and has clarity. It highlights the gap in the literature and the research question. The objectives are in sequence and lead to clarity in assessing the tumor bud in breast carcinoma.
Objective 4 needs to be reframed to “Assessing the tumor bud status in carcinoma breast.” The histopathological examination may be removed as the same has already been mentioned in earlier objectives.

The study design is apt for study. It mentions inclusion and exclusion. They have graded tumor budding as ≤ 4/10 HPF – low tumor budding and > 4/10 HPF – high tumor budding. However, it can be graded as ≤ 4/10 HPF, 4 – 9/10 HPF, and >10/10 HPF. An optimal cut-off for the number of tumor budding and lymph node metastasis can also be correlated.

The protocol provides sufficient details for the evaluation of tumor budding. Microscopic pictures of high and low tumor buds can be more effective.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable

References

1. Kim JK, Rhee YY, Bae JM, Kim JH, et al.: Composite scoring system and optimal tumor budding cut-off number for estimating lymph node metastasis in submucosal colorectal cancer.BMC Cancer. 2022; 22 (1): 861 PubMed Abstract | Publisher Full Text

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

General Pathology, Surgical Pathology, Molecular Pathology, Oncopathology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

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[1] 1. Breast cancer: Who.int.2022 [cited 7 June 2022].

[2] 2. Malvia S, Bagadi SA, Dubey US, et al.: Epidemiology of breast cancer in Indian women. Asia Pac. J. Clin. Oncol. 2017 Aug; 13(4): 289–295. Publisher Full Text

[3] 3. Breast cancer: Who.int.2022 [cited 7 June 2022].

[4] 4. Huang T, Bao H, Meng YH, et al.: Tumour budding is a novel marker in breast cancer: the clinical application and future prospects. Ann. Med. 2022 Dec 31; 54(1): 1303–1312. PubMed Abstract | Publisher Full Text | Free Full Text

[5] 5. Salhia B, Trippel M, Pfaltz K, et al.: High tumor budding stratifies breast cancer with metastatic properties. Breast Cancer Res. Treat. 2015 Apr; 150(2): 363–371. PubMed Abstract | Publisher Full Text | Free Full Text

[6] 6. Masilamani DS, Kanmani P: Evaluation of clinicopathologic significance of tumor budding in breast carcinoma. Int. J. Clin. Diagn. Pathol. 2019; 2(1): 171–173. Publisher Full Text

[7] 7. Sriwidyani NP, Manuaba IB, Alit-Artha IG, et al.: Tumor budding in breast carcinoma: relation to E-Cadherin, MMP-9 expression, and metastasis risk. Bali. Med. J. 2016 Jan 1; 5(3): 150. Publisher Full Text

[8] 8. Gabal SM, Bassam AM, Sedqi ME, et al.: Tumour Budding and MMP-2 Expression in Breast Invasive Ductal Carcinoma. J. Clin. Diagn. Res. 2018 May 1; 12(5). Publisher Full Text

[9] 9. Chada V: Sample size determinant in health studies. NTI bulletin. 2006; 42/3 and 4: 55–62.

[10] 10. Bancroft JD, Gamble M: Theory and practice of histological techniques. Elsevier Health Sciences; 2008.

[11] 11. 1 greene f, edge s, schilsky r, gaspar l. ajcc cancer staging manual 8th edition. 8th ed. springer; 2018.

[12] 12. Rai PD, Vagha S, Shukla S, et al.: Comparison of various scoring systems by immunohistochemistry for evaluating hormone receptors (Estrogen receptor and progesterone receptor) in carcinoma of breast. Journal of Datta Meghe Institute of Medical Sciences University. 2020 Apr 1; 15(2): 202. Publisher Full Text

[13] 13. Cornolti G, Ungari M, Morassi ML, et al.: Amplification and overexpression of HER2/neu gene and HER2/neu protein in salivary duct carcinoma of the parotid gland. Archives of otolaryngology–head & neck surgery. 2007 Oct 1; 133(10): 1031–1036. PubMed Abstract | Publisher Full Text

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To study the utility of tumor budding as a histopathological marker in comparison to various histopathological parameters and TNM staging in breast carcinoma

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