Breast Tuberculosis in Iran: A Comprehensive Review.

ABSTRACT: Tuberculosis (TB) remains a significant global health concern and kills millions of people every year. While TB can affect any organ in the body, breast TB is relatively uncommon. This study presents a comprehensive review of literature spanning 23 years, with a focus on cases of breast TB in Iran. Among the 96 cases found, the majority (89.6%) fell within the age range of 20-60, with a striking prevalence among women (98.9%). Common symptoms included pain and palpable mass, each presenting in approximately 60.4% of cases. Notably, only a quarter of patients had a confirmed history of exposure to a known TB case. Left breast involvement was more prevalent (58.3%), with ipsilateral lymph node enlargement observed in 40.6% of cases. Given the clinical presentation of breast TB, which often leads to misdiagnosis, a significant proportion of cases (68.7%) were diagnosed through excisional biopsy. Following a standard 6-month regimen of anti-TB drugs, relapse occurred in only 4.2% of cases. This study highlights the need for heightened awareness and vigilance in diagnosing breast TB, especially in regions with a high burden. Although breast TB poses diagnostic challenges, with prompt identification and treatment, the prognosis is generally favorable, with a low incidence of relapse.

Intratumoral Microbiota: Unraveling their Oncogenic Impact on Cancer Progression With Focus on Breast Cancer Therapeutic Outcomes.

The gut microbiota has been implicated in many cancers through the secretion of blood-traveling metabolites or activation of oncogenic signaling. Currently, specific microbial signatures have been detected in the human breast, which are different from other microbial-rich compartments, such as the intestine and skin. Changes in the breast microbiome profile have been shown to positively or negatively correlate with breast cancer development, progression, and therapeutic outcomes. However, studies regarding the role and underlying mechanism of intratumoral microbiota in breast cancer have remained concealed. This review aimed to provide an overview of the role of the intratumoral microbiome in tumorigenesis and tumor progression, and how these intratumoral microbiota affect breast cancer. We also discuss the potential of using the intratumoral microbiome as a biomarker or treatment alternative in breast cancers.

The Emerging Role of the Microbiota in Breast Cancer Progression.

Emerging evidence suggests a profound association between the microbiota composition in the gastrointestinal tract and breast cancer progression. The gut microbiota plays a crucial role in modulating the immune response, releasing metabolites, and modulating estrogen levels, all of which have implications for breast cancer growth. However, recent research has unveiled a novel aspect of the relationship between the microbiota and breast cancer, focusing on microbes residing within the mammary tissue, which was once considered sterile. These localized microbial communities have been found to change in the presence of a tumor as compared to healthy mammary tissue, unraveling their potential contribution to tumor progression. Studies have identified specific bacterial species that are enriched within breast tumors and have highlighted the mechanisms by which even these microbes influence cancer progression through immune modulation, direct carcinogenic activity, and effects on cellular pathways involved in cell proliferation or apoptosis. This review aims to provide an overview of the current knowledge on the mechanisms of crosstalk between the gut/mammary microbiota and breast cancer. Understanding this intricate interplay holds promise for developing innovative therapeutic approaches.

The breast tissue microbiome, stroma, immune cells and breast cancer.

BACKGROUND: Stromal and immune cell composition alterations in benign breast tissue associate with future cancer risk. Pilot data suggest the innate microbiome of normal breast tissue differs between women with and without breast cancer. Microbiome alterations might explain tissue microenvironment variations associated with disease status. METHODS: Prospectively-collected sterile normal breast tissues from women with benign (n=16) or malignant (n=17) disease underwent 16SrRNA sequencing with Illumina MiSeq and Hybrid-denovo pipeline processing. Breast tissue was scored for fibrosis and fat percentages and immune cell infiltrates (lobulitis) classified as absent/mild/moderate/severe. Alpha and beta diversity were calculated on rarefied OTU data and associations analyzed with multiple linear regression and PERMANOVA. RESULTS: Breast tissue stromal fat% was lower and fibrosis% higher in benign disease versus cancer (median 30% versus 60%, p=0.01, 70% versus 30%, p=0.002, respectively). The microbiome varied with stromal composition. Alpha diversity (Chao1) correlated with fat% (r=0.38, p=0.02) and fibrosis% (r=-0.32, p=0.05) and associated with different microbial populations as indicated by beta diversity metrics (weighted UniFrac, p=0.08, fat%, p=0.07, fibrosis%). Permutation testing with FDR control revealed taxa differences for fat% in Firmicutes, Bacilli, Bacillales, Staphylococcaceae and genus Staphylococcus, and fibrosis% in Firmicutes, Spirochaetes, Bacilli, Bacillales, Spirochaetales, Proteobacteria RF32, Sphingomonadales, Staphylococcaceae, and genera Clostridium, Staphylococcus, Spirochaetes, Actinobacteria Adlercreutzia. Moderate/severe lobulitis was more common in cancer (73%) than benign disease (13%), p=0.003, but no significant microbial associations were seen. CONCLUSION: These data suggest a link between breast tissue stromal alterations and its microbiome, further supporting a connection between the breast tissue microenvironment and breast cancer.

Microbiome composition indicate dysbiosis and lower richness in tumor breast tissues compared to healthy adjacent paired tissue, within the same women.

BACKGROUND: Breast cancer (BC) is the most common malignancy in women, in whom it reaches 20% of the total neoplasia incidence. Most BCs are considered sporadic and a number of factors, including familiarity, age, hormonal cycles and diet, have been reported to be BC risk factors. Also the gut microbiota plays a role in breast cancer development. In fact, its imbalance has been associated to various human diseases including cancer although a consequential cause-effect phenomenon has never been proven. METHODS: The aim of this work was to characterize the breast tissue microbiome in 34 women affected by BC using an NGS-based method, and analyzing the tumoral and the adjacent non-tumoral tissue of each patient. RESULTS: The healthy and tumor tissues differed in bacterial composition and richness: the number of Amplicon Sequence Variants (ASVs) was higher in healthy tissues than in tumor tissues (p = 0.001). Moreover, our analyses, able to investigate from phylum down to species taxa for each sample, revealed major differences in the two richest phyla, namely, Proteobacteria and Actinobacteria. Notably, the levels of Actinobacteria and Proteobacteria were, respectively, higher and lower in healthy with respect to tumor tissues. CONCLUSIONS: Our study provides information about the breast tissue microbial composition, as compared with very closely adjacent healthy tissue (paired samples within the same woman); the differences found are such to have possible diagnostic and therapeutic implications; further studies are necessary to clarify if the differences found in the breast tissue microbiome are simply an association or a concausative pathogenetic effect in BC. A comparison of different results on similar studies seems not to assess a universal microbiome signature, but single ones depending on the environmental cohorts' locations.

Characterizing the breast cancer lipidome and its interaction with the tissue microbiota.

Breast cancer is the most diagnosed cancer amongst women worldwide. We have previously shown that there is a breast microbiota which differs between women who have breast cancer and those who are disease-free. To better understand the local biochemical perturbations occurring with disease and the potential contribution of the breast microbiome, lipid profiling was performed on non-tumor breast tissue collected from 19 healthy women and 42 with breast cancer. Here we identified unique lipid signatures between the two groups with greater amounts of lysophosphatidylcholines and oxidized cholesteryl esters in the tissue from women with breast cancer and lower amounts of ceramides, diacylglycerols, phosphatidylcholines, and phosphatidylethanolamines. By integrating these lipid signatures with the breast bacterial profiles, we observed that Gammaproteobacteria and those from the class Bacillus, were negatively correlated with ceramides, lipids with antiproliferative properties. In the healthy tissues, diacylglyerols were positively associated with Acinetobacter, Lactococcus, Corynebacterium, Prevotella and Streptococcus. These bacterial groups were found to possess the genetic potential to synthesize these lipids. The cause-effect relationships of these observations and their contribution to disease patho-mechanisms warrants further investigation for a disease afflicting millions of women around the world.

Periodontitis as a Risk Factor for Breast Cancer - What We Know Till Date?

A healthy microbiome is important for human health because it exhibits a variety of functions in the human body wherein the microbiome dysbiosis can lead to a variety of diseases, including cancer. Recent advances in technology and cost reduction of sequencing have made it possible and much easier for researchers to investigate the role of the microbiome in carcinogenesis. Furthermore, modulation of microflora may serve as an effective adjunct to conventional anticancer therapy that is very important to improve the patient's quality of life. Additionally, microbiome biomarkers can also be used as a diagnostic tool for cancer. So far the association between oral microbial consortia and their interactions with the host in maintaining the human health and the pathogenesis of multiple cancers has gained much popularity in the scientific research community. While the interactions of oral microflora are better established in cancer- like gastric cancer, it is far less understood in others like breast cancer. Therefore, this review briefly outlines the current information on the role of oral microbiota in breast cancer with emphasis on the mechanisms of oral microflora induced carcinogenesis and discusses the emerging role of periodontitis as a risk factor for breast cancer. Clinical relevance; Periodontitis is a very common disease that is characterized by chronic polymicrobial infection and inflammation of gingiva. It might be associated as a risk factor for breast cancer. If this association is validated in large cohort studies, it would serve as a non-invasive biomarker for breast cancer.

Microbiota of Breast Tissue and Its Potential Association with Regional Recurrence of Breast Cancer in Korean Women.

Recent studies have reported dysbiosis of the microbiome in breast tissue collected from patients with breast cancer and the association between the microbiota and disease progression. However, the role of the microbiota in breast tissue remains unclear, possibly due to the complexity of breast cancer and various factors, including racial and geographical differences, influencing microbiota in breast tissue. Here, to determine the potential role of microbiota in breast tumor tissue, we analyzed 141 tissue samples based on three different tissue types (tumor, adjacent normal, and lymph node tissues) from the same patients with breast cancer in Korea. The microbiota was not simply distinguishable based on tissue types. However, the microbiota could be divided into two cluster types, even within the same tissue type, and the clinicopathologic factors were differently correlated in the two cluster types. Risk of regional recurrence was also significantly different between the microbiota cluster types (p = 0.014). In predicted function analysis, the pentose and glucuronate interconversions were significantly different between the cluster types (q < 0.001), and Enterococcus was the main genus contributing to these differences (q < 0.01). Results showed that the microbiota of breast tissue could interact with the host and influence the risk of regional recurrence. Although further studies would be recommended to validate our results, this study could expand our understanding on the breast tissue microbiota, and the results might be applied to develop novel prediction methods and treatments for patients with breast cancer.

Biopsy bacterial signature can predict patient tissue malignancy.

Considerable recent research has indicated the presence of bacteria in a variety of human tumours and matched normal tissue. Rather than focusing on further identification of bacteria within tumour samples, we reversed the hypothesis to query if establishing the bacterial profile of a tissue biopsy could reveal its histology / malignancy status. The aim of the present study was therefore to differentiate between malignant and non-malignant fresh breast biopsy specimens, collected specifically for this purpose, based on bacterial sequence data alone. Fresh tissue biopsies were obtained from breast cancer patients and subjected to 16S rRNA gene sequencing. Progressive microbiological and bioinformatic contamination control practices were imparted at all points of specimen handling and bioinformatic manipulation. Differences in breast tumour and matched normal tissues were probed using a variety of statistical and machine-learning-based strategies. Breast tumour and matched normal tissue microbiome profiles proved sufficiently different to indicate that a classification strategy using bacterial biomarkers could be effective. Leave-one-out cross-validation of the predictive model confirmed the ability to identify malignant breast tissue from its bacterial signature with 84.78% accuracy, with a corresponding area under the receiver operating characteristic curve of 0.888. This study provides proof-of-concept data, from fit-for-purpose study material, on the potential to use the bacterial signature of tissue biopsies to identify their malignancy status.

Uncovering Microbial Composition in Human Breast Cancer Primary Tumour Tissue Using Transcriptomic RNA-seq.

Recent research studies are showing breast tissues as a place where various species of microorganisms can thrive and cannot be considered sterile, as previously thought. We analysed the microbial composition of primary tumour tissue and normal breast tissue and found differences between them and between multiple breast cancer phenotypes. We sequenced the transcriptome of breast tumours and normal tissues (from cancer-free women) of 23 individuals from Slovakia and used bioinformatics tools to uncover differences in the microbial composition of tissues. To analyse our RNA-seq data (rRNA depleted), we used and tested Kraken2 and Metaphlan3 tools. Kraken2 has shown higher reliability for our data. Additionally, we analysed 91 samples obtained from SRA database, originated in China and submitted by Sichuan University. In breast tissue, the most enriched group were Proteobacteria, then Firmicutes and Actinobacteria for both datasets, in Slovak samples also Bacteroides, while in Chinese samples Cyanobacteria were more frequent. We have observed changes in the microbiome between cancerous and healthy tissues and also different phenotypes of diseases, based on the presence of circulating tumour cells and few other markers.

Human breast microbiome correlates with prognostic features and immunological signatures in breast cancer.

BACKGROUND: Currently, over half of breast cancer cases are unrelated to known risk factors, highlighting the importance of discovering other cancer-promoting factors. Since crosstalk between gut microbes and host immunity contributes to many diseases, we hypothesized that similar interactions could occur between the recently described breast microbiome and local immune responses to influence breast cancer pathogenesis. METHODS: Using 16S rRNA gene sequencing, we characterized the microbiome of human breast tissue in a total of 221 patients with breast cancer, 18 individuals predisposed to breast cancer, and 69 controls. We performed bioinformatic analyses using a DADA2-based pipeline and applied linear models with White's t or Kruskal-Wallis H-tests with Benjamini-Hochberg multiple testing correction to identify taxonomic groups associated with prognostic clinicopathologic features. We then used network analysis based on Spearman coefficients to correlate specific bacterial taxa with immunological data from NanoString gene expression and 65-plex cytokine assays. RESULTS: Multiple bacterial genera exhibited significant differences in relative abundance when stratifying by breast tissue type (tumor, tumor adjacent normal, high-risk, healthy control), cancer stage, grade, histologic subtype, receptor status, lymphovascular invasion, or node-positive status, even after adjusting for confounding variables. Microbiome-immune networks within the breast tended to be bacteria-centric, with sparse structure in tumors and more interconnected structure in benign tissues. Notably, Anaerococcus, Caulobacter, and Streptococcus, which were major bacterial hubs in benign tissue networks, were absent from cancer-associated tissue networks. In addition, Propionibacterium and Staphylococcus, which were depleted in tumors, showed negative associations with oncogenic immune features; Streptococcus and Propionibacterium also correlated positively with T-cell activation-related genes. CONCLUSIONS: This study, the largest to date comparing healthy versus cancer-associated breast microbiomes using fresh-frozen surgical specimens and immune correlates, provides insight into microbial profiles that correspond with prognostic clinicopathologic features in breast cancer. It additionally presents evidence for local microbial-immune interplay in breast cancer that merits further investigation and has preventative, diagnostic, and therapeutic potential.

An unexpected link: The role of mammary and gut microbiota on breast cancer development and management (Review).

Breast cancer (BC) impacts 2.3 million women each year, making it the most frequent cancer diagnosed among the female population. An unexpected link has been discovered between BC and alterations in the mammary and gut microbiota, suggesting their possible role in BC development, prevention and management. Studies suggest a distinct microbiome in healthy breast tissue compared to BC tissue. The healthy breast tissue has been found to be mostly enriched with bacteria of the phyla Proteobacteria, Firmicutes and Actinobacteria. However, certain bacteria are more abundant in cancerous tissues compared to adjacent non­cancerous tissues in BC women or compared to the breast tissues of healthy women. On the other hand, bacteria such as Lactococcus spp. are increased in the breast tissues of healthy women compared to the cancerous tissues of BC women and may therefore have potential protective effects against BC. Additionally, preliminary studies propose that the mammary microbiota is distinct in the different subtypes of BC, proposing a specific role of microbes in the development of BC and suggesting their possible use as biomarkers. Similarly, dysbiosis in the gut microbiota has been further linked to BC since certain gut bacteria can alter the production of beneficial metabolites and disrupt estrogen metabolism in the gut. While still at its infancy, such unexpected links between breast and gut microbiota and BC propose possible alternatives with regards to the prevention but also management of BC such as through the use of probiotics. The current review is focused on evaluating the recent evidence regarding the association between mammary and gut microbiota and BC and discusses the most important bacteria involved.

Use of Negative-Pressure Wound Therapy With Instillation and Dwell in Breast Reconstruction.

SUMMARY: The use of negative-pressure wound therapy (NPWT) has expanded over the last 3 decades, paralleled and documented by an increase in research. This article discusses the evolution and current applications of NPWT in modern breast reconstruction. Negative-pressure wound therapy with instillation and dwell (NPWTi-d) technology can be used to remove infectious material, facilitate salvaging compromised tissue, and stabilize the soft-tissue environment. Published consensus NPWTi-d guidelines can aid in treatment selection and implementation of this new technology. The therapeutic approach of simultaneously removing infectious material and actively improving mastectomy flap perfusion and thickness is a burgeoning concept, and illustrative cases are presented. NPWTi-d preliminary use has led to reconstruction salvage with reproducible early experience and outcomes, and it is hoped that it will raise interest and awareness of this promising application of the technology to improve breast reconstruction outcomes.

Effect of Microbiota in the Development of Breast Cancer.

Breast cancer is the most frequent cancer among women and causes the greatest number of cancer-related death among women all over the world. It approximately accounts for 15% of all cancer death. The human microbiota is the term applied to the aggregate of microbes that live in different habitats of living organisms 'bodies, including the gut, skin, vagina, and mouth, as well as nose, conjunctiva, pharynx, and urethra, among others. Increasing evidence is pointing to the role of the microbiome in the occurrence and development of a variety of cancers. Intestinal microbiome imbalance is related to the occurrence of gastrointestinal tumors, such as esophageal, gastric, colorectal, and gallbladder cancer. The present study aimed to identify the role of microbiota in the development of breast cancer. The women with breast cancer (n=130) in this study were in the age range of 25-75 years. The study was conducted in Kirkuk city of Iraq from September 10, 2019, to March 15, 2020. The control group included 20 women diagnosed with benign breast lesions in the age range 25-75 years, who matched the women in the patient group. Blood samples and breast tissue samples were taken from patients with breast cancer and benign breast lesions. Blood samples were examined through immunological methods, enzyme-linked immunosorbent assay (ELISA) was adopted for the detection of interleukin-19 (IL-19). Breast tissue samples were taken from breast cancer and benign breast lesions patients to isolate and identify bacteria. Based on the obtained results, only 6 out of 30 (20%) cultured breast tissue samples from women with breast cancer showed bacterial growth. In total, 4 (67%) and 2(33%) of these 6 positive cultures were Escherichia coli was and Staphylococcus aureus, respectively, and this relation was statistically significant. However, no bacterial growth was observed on the cultured breast tissue samples taken from women with benign breast lesions. Moreover, the difference between women with a positive and negative result of bacterial culture and stages of breast cancer was statistically non-significant. It is worth mentioning that 50 % of women with breast cancer and bacterial growth were within the age range of 40-49 year. The present study revealed that the difference between women with breast cancer and those with benign breast lesions was statistically highly significant according to the place of residence. In addition, the mean level of IL-19 among women with breast cancer was lower than that in women with benign breast lesions, and this relation was statistically highly significant.

Case series on variable presentations of tuberculosis of the breast.

Tuberculosis (TB) of the breast is extremely rare and is often mistaken for benign or malignant lesions of the breast. They are rare even in countries which are endemic for TB, like India. The most common type of clinical presentation is a vague lump in the breast, but there are even other types of presentations which are documented. In olden days, there was a lot of dilemma and challenge in diagnosing TB of the breast, but thanks to improved pathological knowledge and the advent of investigations such as QuantiFERON-TB gold and GeneXpert, TB can be diagnosed early nowadays and treated accordingly. In this study series, we report 10 cases of TB of the breast with variable clinical presentations as fibroadenosis, breast abscess, duct ectasia and breast lump on evaluation, and the challenges encountered in establishing the diagnosis.

Recurrent bilateral breast abscess due to Mycobacterium abscessus in an immune-competent woman.

Mycobacterium abscessus is a rapidly growing, non-tubercular mycobacteria, often associated with skin and soft tissue infections. We report a case of 57-year-old immune-competent woman who suffered recurrent bilateral breast infection for 6 years. She did not benefit from repeated surgical interventions and multiple courses of antibiotics, and one course of empirical antitubercular therapy. Chronicity of the presentation and non-response to varied treatment interventions prompted further microbiological investigations. The patient was diagnosed with M. abscessus and treated with rifabutin, clarithromycin daily for 6 months and injection amikacin for 1 month. Amikacin was replaced with oral levofloxacin due to bilateral sensory-neural hearing loss for higher frequencies after 6 months. Suspicion and identification of NTM are important as the treatment involves long-term combination antibacterial therapy along with surgical debridement for extensive infection or when implants are involved.

The human tumor microbiome is composed of tumor type-specific intracellular bacteria.

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.

Imaging and clinical features of breast tuberculosis: a review series of 62 cases.

AIM: To outline the disease burden of breast tuberculosis (TB) as a quantitative analysis amongst three tertiary hospitals in South Africa, with correlation to their clinical, demographic, and imaging features. MATERIALS AND METHODS: A retrospective analysis was undertaken over an 18-month period (01/01/2017-30/06/2018) of all patients undergoing laboratory investigations for breast disease at the mammography departments of these three tertiary centres. RESULTS: The prevalence of breast TB was 2.5% (n=62) of 2,516 patients. The median age of presentation was 38.5 years (interquartile range [IQR] 33-45). HIV status was known in 45 patients, of whom 36 were HIV infected (80%, 95% CI: 0.65-0.90, p<0.0001). Based on the ultrasound and/or mammogram findings, the patients were classified into five categories: TB breast abscess (40.3%), inflammatory/disseminated (24.2%), isolated TB lymphadenitis (22.6%), nodular (11.3%), and sclerosing form (1.6%). Histology demonstrated necrotising granulomatous inflammation in 57 cases (92%). Acid-fast bacilli (AFB) were positive in 8.1% (n=5) of the cytology and 16.1% (n=10) of the histology specimens. Culture for Mycobacterium tuberculosis was positive in 27% (17 cases), and in 12.9% (n=8). AFB were detected histologically using polymerase chain reaction (PCR) testing. CONCLUSION: Knowledge of the varied clinical and radiological features is necessary to maintain a high degree of suspicion to prevent misdiagnoses, inappropriate management, and complications. Ultrasound-guided core biopsy rather than fine-needle aspiration (FNA) is advocated as the first-line intervention in diagnosing or excluding this disease, as it yields a better tissue sample and more often a positive diagnosis.