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Background: The transcription factor p63 is a member of a family of transcription factors p53, which play a fundamental role in cell growth, multiplication, programming, differentiation and apoptosis, henceforth, aberrantly involved in the form of different variants in breast cancers. Objectives: The study aimed to determine if p63 could serve as a novel method for identifying nuclear myoepithelial cells in a normal growing cell setting for both breast cancer in situ and lesions. Methods: This study is a combination of retrospective and prospective case series analysis. It involved examining 86 samples of breast lesions obtained from private clinics and laboratories in Ninawa Province (Iraq). The study was done on the excisional biopsy, lumpectomy, and mastectomy specimens. We performed an immunohistochemical (IHC) analysis to examine the intensity of the p63 nuclear protein. The extent was scored based on the percentage of positive cells and assigned a score of negative (0%), score 1 (

Introduction: Ductal carcinoma in situ (DCIS), characterized by a proliferation of neoplastic cells confined within the mammary ducts, is distinctly isolated from the surrounding stroma by an almost uninterrupted layer of myoepithelial cells (MECs) and by the basement membrane. Heightened interactions within the adipose microenvironment, particularly in obese patients, may play a key role in the transition from DCIS to invasive ductal carcinoma (IDC), which is attracting growing interest in scientific research. Adipose tissue undergoes metabolic changes in obesity, impacting adipokine secretion and promoting chronic inflammation. This study aimed to assess the interactions between DCIS, including in situ cancer cells and MECs, and the various components of its inflammatory adipose microenvironment (adipocytes and macrophages). Methods: To this end, a 3D co-culture model was developed using bicellular bi-fluorescent DCIS-like tumoroids, adipose cells, and macrophages to investigate the influence of the inflammatory adipose microenvironment on DCIS progression. Results: The 3D co-culture model demonstrated an inhibition of the expression of genes involved in apoptosis (BAX, BAG1, BCL2, CASP3, CASP8, and CASP9), and an increase in genes related to cell survival (TP53, JUN, and TGFB1), inflammation (TNF-α, PTGS2, IL-6R), invasion and metastasis (TIMP1 and MMP-9) in cancer cells of the tumoroids under inflammatory conditions versus a non-inflammatory microenvironment. On the contrary, it confirmed the compromised functionality of MECs, resulting in the loss of their protective effects against cancer cells. Adipocytes from obese women showed a significant increase in the expression of all studied myofibroblast-associated genes (myoCAFs), such as FAP and α-SMA. In contrast, adipocytes from normal-weight women expressed markers of inflammatory fibroblast phenotypes (iCAF) characterized by a significant increase in the expression of LIF and inflammatory cytokines such as TNF-α, IL-1β, IL-8, and CXCL-10. These changes also influenced macrophage polarization, leading to a pro-inflammatory M1 phenotype. In contrast, myoCAF-associated adipocytes, and the cancer-promoting microenvironment polarized macrophages towards an M2 phenotype, characterized by high CD163 receptor expression and IL-10 and TGF-β secretion. Discussion: Reciprocal interactions between the tumoroid and its microenvironment, particularly in obesity, led to transcriptomic changes in adipocytes and macrophages, may participate in breast cancer progression while disrupting the integrity of the MEC layer. These results underlined the importance of adipose tissue in cancer progression. [ABSTRACT FROM AUTHOR]

Patients with breast cancer show altered expression of genes within the pectoralis major skeletal muscle cells of the breast. Through analyses of The Cancer Genome Atlas (TCGA)-breast cancer (BRCA), we identified three previously uncharacterized putative novel tumor suppressor genes expressed in normal muscle cells, whose expression was downregulated in breast tumors. We found that NEDD4 binding protein 2-like 1 (N4BP2L1), pleckstrin homology domaincontaining family A member 4 (PLEKHA4), and brain-enriched guanylate kinaseassociated protein (BEGAIN) that are normally highly expressed in breast myoepithelial cells and smooth muscle cells were significantly downregulated in breast tumor tissues of a cohort of 50 patients with this cancer. Our data revealed that the low expression of PLEKHA4 in patients with menopause below 50 years correlated with a higher risk of breast cancer. Moreover, we identified N4BP2L1 and BEGAIN as potential biomarkers of HER2-positive breast cancer. Furthermore, low BEGAIN expression in breast cancer patients with blood fat, heart problems, and diabetes correlated with a higher risk of this cancer. In addition, protein and RNA expression analysis of TCGA-BRCA revealed N4BP2L1 as a promising diagnostic protein biomarker in breast cancer. In addition, the in silico data of scRNA-seq showed high expression of these genes in several cell types of normal breast tissue, including breast myoepithelial cells and smooth muscle cells. Thus, our results suggest their possible tumor-suppressive function in breast cancer and muscle development. [ABSTRACT FROM AUTHOR]

Introduction: Breast carcinoma is leading cause of cancer death in women. Breast lesions constitute heterogeneous group of diseases with wide variety of etiologies ranging from inflammatory-benign- malignant lesions. There are several reported markers for immunohistochemical detection of myoepithelial cells. Smooth muscle specific proteins, such as smooth muscle actin, smooth muscle myosin heavy chain, calponin and h-caldesmon are used to highlight myoepithelium. p63 antibody is myoepithelial cell marker that selectively stains nuclei. It is negative in stromal, myofibroblastic and adipocytic cells. Aims and Objectives: The aim of this study was to establish role of p63 expression in distinguishing benign breast lesions, premalignant lesions and malignant tumors of breast. Materials and Methods: 30 cases were selected from core biopsy, lumpectomy and mastectomy specimens of breast received at department of Pathology, Chalmeda Anand Rao Institute of Medical Sciences during the period of January 2021 to December 2021 and were studied prospectively. All specimens were processed according to CAP protocol and reported . Immunohistochemistry was performed to determine p63 expression in those specimens. p63expression was evaluated as continuous positive/discontinuous positive/negative. Ethical Approval: This study was reviewed and approved by institute ethics committee, CAIMS, Karimnagar. Results: Among total 30 cases, 18 cases (60%) were benign lesions and all were positive for p63 expression. 3 cases (9.99%) were premalignant and were least positive for p63 expression. All malignant cases 9 cases (29.99%) were negative for p63 expression. Conclusion: The Positive correlation was seen between histomorphological features and p63 scoring in all the lesions, So p63 is good Immunohistochemical marker for evaluating breast lesions. [ABSTRACT FROM AUTHOR]

IntroductionDuctal carcinoma in situ (DCIS), characterized by a proliferation of neoplastic cells confined within the mammary ducts, is distinctly isolated from the surrounding stroma by an almost uninterrupted layer of myoepithelial cells (MECs) and by the basement membrane. Heightened interactions within the adipose microenvironment, particularly in obese patients, may play a key role in the transition from DCIS to invasive ductal carcinoma (IDC), which is attracting growing interest in scientific research. Adipose tissue undergoes metabolic changes in obesity, impacting adipokine secretion and promoting chronic inflammation. This study aimed to assess the interactions between DCIS, including in situ cancer cells and MECs, and the various components of its inflammatory adipose microenvironment (adipocytes and macrophages).MethodsTo this end, a 3D co-culture model was developed using bicellular bi-fluorescent DCIS-like tumoroids, adipose cells, and macrophages to investigate the influence of the inflammatory adipose microenvironment on DCIS progression.ResultsThe 3D co-culture model demonstrated an inhibition of the expression of genes involved in apoptosis (BAX, BAG1, BCL2, CASP3, CASP8, and CASP9), and an increase in genes related to cell survival (TP53, JUN, and TGFB1), inflammation (TNF-α, PTGS2, IL-6R), invasion and metastasis (TIMP1 and MMP-9) in cancer cells of the tumoroids under inflammatory conditions versus a non-inflammatory microenvironment. On the contrary, it confirmed the compromised functionality of MECs, resulting in the loss of their protective effects against cancer cells. Adipocytes from obese women showed a significant increase in the expression of all studied myofibroblast-associated genes (myoCAFs), such as FAP and α-SMA. In contrast, adipocytes from normal-weight women expressed markers of inflammatory fibroblast phenotypes (iCAF) characterized by a significant increase in the expression of LIF and inflammatory cytokines such as TNF-α, IL-1β, IL-8, and CXCL-10. These changes also influenced macrophage polarization, leading to a pro-inflammatory M1 phenotype. In contrast, myoCAF-associated adipocytes, and the cancer-promoting microenvironment polarized macrophages towards an M2 phenotype, characterized by high CD163 receptor expression and IL-10 and TGF-β secretion.DiscussionReciprocal interactions between the tumoroid and its microenvironment, particularly in obesity, led to transcriptomic changes in adipocytes and macrophages, may participate in breast cancer progression while disrupting the integrity of the MEC layer. These results underlined the importance of adipose tissue in cancer progression.

The aim of the present study is to investigate the role of c-Jun N-terminal kinase (JNK) and matrix metalloproteinase-2 (MMP-2) in mediating the effects of interleukin-1β (IL-1β) on the function of lacrimal gland myoepithelial cells (MECs). MECs isolated from an α-smooth muscle actin–green fluorescent protein (SMA-GFP) transgenic mouse were treated with IL-1β alone or in the presence of SP600125, a JNK inhibitor, or ARP100, an MMP-2 inhibitor. The GFP intensity and the cell size/area were measured, and on day 7, the SMA, calponin, and pro-MMP-2 protein levels and the MEC contraction were assessed. At baseline, the control and treated cells showed no differences in GFP intensity or cell size. Starting on day 2 and continuing on days 4 and 7, the GFP intensity and cell size were significantly lower in the IL-1β-treated samples, and these effects were alleviated following inhibition of either JNK or MMP-2. Compared with the control, the levels of SMA and calponin were lower in the IL-1β-treated samples, and both the JNK and MMP-2 inhibitors reversed this trend. The pro-MMP-2 protein level was elevated in the IL-1β-treated samples, and this effect was abolished by the JNK inhibitor. Finally, oxytocin-induced MEC contraction was diminished in the IL-1β-treated samples, and both the JNK and MMP-2 inhibitors reversed this effect. Our data suggest that IL-1β uses the JNK/MMP-2 pathways to alter MEC functions, which might account for the diminished tears associated with aqueous-deficient dry eye disease.

Patients with breast cancer show altered expression of genes within the pectoralis major skeletal muscle cells of the breast. Through analyses of The Cancer Genome Atlas (TCGA)-breast cancer (BRCA), we identified three previously uncharacterized putative novel tumor suppressor genes expressed in normal muscle cells, whose expression was downregulated in breast tumors. We found that NEDD4 binding protein 2-like 1 (N4BP2L1), pleckstrin homology domain-containing family A member 4 (PLEKHA4), and brain-enriched guanylate kinase-associated protein (BEGAIN) that are normally highly expressed in breast myoepithelial cells and smooth muscle cells were significantly downregulated in breast tumor tissues of a cohort of 50 patients with this cancer. Our data revealed that the low expression of PLEKHA4 in patients with menopause below 50 years correlated with a higher risk of breast cancer. Moreover, we identified N4BP2L1 and BEGAIN as potential biomarkers of HER2-positive breast cancer. Furthermore, low BEGAIN expression in breast cancer patients with blood fat, heart problems, and diabetes correlated with a higher risk of this cancer. In addition, protein and RNA expression analysis of TCGA-BRCA revealed N4BP2L1 as a promising diagnostic protein biomarker in breast cancer. In addition, the in silico data of scRNA-seq showed high expression of these genes in several cell types of normal breast tissue, including breast myoepithelial cells and smooth muscle cells. Thus, our results suggest their possible tumor-suppressive function in breast cancer and muscle development.

ntroduction: Pleomorphic Adenoma (PA) histopathologically represents a heterogeneous lesion with a varying proportion of epithelial and mesenchymal components. Due to its morphological diversity, a diagnostic dilemma often arises when identifying its various patterns. This diverse morphology is considered to be a function of the neoplastic myoepithelium. Tumor protein 63 (p63) is expressed in stratified epithelia and in the basal cells of salivary glands. Aim: To investigate the immunoreactivity of p63 as a reliable myoepithelial marker in PA. Materials and Methods: A cross-sectional study was performed in the Department of Oral and Maxillofacial Pathology at PGIDS, Rohtak, Haryana, India. The duration of the study was 14 months, from March 2015 to April 2016. A total of 15 tissue blocks of histopathologically diagnosed cases of PA were included from departmental archives and subjected to Immunohistochemistry (IHC) using a monoclonal p63 antibody. The myoepithelium was classified as myoepithelial-like (abluminal and spindled), modified myoepithelium (myxoid and chondroid), and transformed myoepithelium (solid epithelioid, squamous, and basaloid cribriform). IHC for p63 was assessed in each myoepithelial component, as well as in non neoplastic Myoepithelial Cells (MEC) and inner tubular epithelial cells. Only nuclear staining for p63 was considered positive. The obtained data were subjected to statistical analysis, and the Chi-square test was applied. Results: The PA samples subjected to IHC showed 100% p63 reactivity. Transformed MEC, abluminal, and modified MEC revealed variable immunostaining with a significant difference (p=0.049). There was no immunostaining in luminal/inner layer cells in all cases of PA. p63 was also expressed in the nuclei of MEC of acini and intercalated ducts of normal salivary gland tissue. Conclusion: p63 is a sensitive and specific myoepithelial marker to identify MEC in PA. Additionally, the expression of MECassociated markers in acini and intercalated ducts of normal salivary glands has confirmed their role in the histogenesis of this tumour.

Introduction: Pleomorphic Adenoma (PA) histopathologically represents a heterogeneous lesion with a varying proportion of epithelial and mesenchymal components. Due to its morphological diversity, a diagnostic dilemma often arises when identifying its various patterns. This diverse morphology is considered to be a function of the neoplastic myoepithelium. Tumor protein 63 (p63) is expressed in stratified epithelia and in the basal cells of salivary glands. Aim: To investigate the immunoreactivity of p63 as a reliable myoepithelial marker in PA. Materials and Methods: A cross-sectional study was performed in the Department of Oral and Maxillofacial Pathology at PGIDS, Rohtak, Haryana, India. The duration of the study was 14 months, from March 2015 to April 2016. A total of 15 tissue blocks of histopathologically diagnosed cases of PA were included from departmental archives and subjected to Immunohistochemistry (IHC) using a monoclonal p63 antibody. The myoepithelium was classified as myoepithelial-like (abluminal and spindled), modified myoepithelium (myxoid and chondroid), and transformed myoepithelium (solid epithelioid, squamous, and basaloid cribriform). IHC for p63 was assessed in each myoepithelial component, as well as in non neoplastic Myoepithelial Cells (MEC) and inner tubular epithelial cells. Only nuclear staining for p63 was considered positive. The obtained data were subjected to statistical analysis, and the Chi-square test was applied. Results: The PA samples subjected to IHC showed 100% p63 reactivity. Transformed MEC, abluminal, and modified MEC revealed variable immunostaining with a significant difference (p=0.049). There was no immunostaining in luminal/inner layer cells in all cases of PA. p63 was also expressed in the nuclei of MEC of acini and intercalated ducts of normal salivary gland tissue. Conclusion: p63 is a sensitive and specific myoepithelial marker to identify MEC in PA. Additionally, the expression of MECassociated markers in acini and intercalated ducts of normal salivary glands has confirmed their role in the histogenesis of this tumour. [ABSTRACT FROM AUTHOR]

Abstract Over the past decades, luminal epithelial cell lineage has gained considerable attraction as the functionally milk-secreting units and as the most fruitful acreage for breast cancer launching. Recognition of the effective involvement of the myoepithelial cells in mammary gland development and in hampering tumorigenesis has renewed the interest in investigating the biological roles of this second main mammary lineage. The human breast is made up of an extensively branching ductal system intervening by copious lobular units. The ductal system is coated by a chain of luminal epithelial cells (LECs) situated on a layer of myoepithelial cells (MECs) and encompassed by a distinguished basement membrane. Ductal contractility during lactation is a well-known function delivered by the MECs however this is not the only assignment mediated by these cellular populations. It has been well appreciated that the MECs exhibit a natural paracrine power in defeating cancer development and advancement. MECs were found to express numerous proteinase inhibitors, anti-angiogenic factors, and tumour suppressors proteins. Additionally, MECs contributed effectively to maintaining the right luminal cells' polarization and further separating them from the adjacent stroma by making an integrated fence. Indeed, disruption of the MECs layer was reported to facilitate the invasion of the cancer cells to the surrounding stroma. Nonetheless, MECs were also found to exhibit cancer-promoting effects and provoke tumour invasion and dissemination by displaying distinct cancer chemokines. Herein in this review, we aimed to address the roles delivered by MECs in breast cancer progression and decipher the molecular mechanisms regulating proper MECs’ physiology, integrity, and terminal differentiation. Graphical Abstract

Breast adenomyoepithelioma is an unusual tumour characterized by a biphasic proliferation of epithelial and myoepithelial cells. Most of the breast adenomyoepitheliomas are considered to be benign and characterized by propensity for local recurrence. Malignant change can occur rarely in one or both cellular components. We here present a case of a 70-year-old previously healthy female who initially presented with a painless breast lump. The patient underwent wide local excision in view of suspicion of malignancy and sent for frozen section regarding the diagnosis and margins which surprisingly came as adenomyoepithelioma. Final histopathology came as low-grade malignant adenomyoepithelioma. The patient shows no sign of tumour recurrence in the follow up. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cytokeratins are non-contractile intermediate filaments engaged in anchoring and structural functions forming a network to support cytoplasm. Cytokeratin 7 (CK7) expression in human breast carcinomas has proved to be a useful differentiation marker, but its expression in canine mammary gland tumors is poorly understood. OBJECTIVES: Cytokeratin 7 (CK7) expression in human breast carcinomas has proved to be a useful differentiation marker, but its expression in canine mammary gland tumors is poorly understood. METHODS: This research was based on the immunohistochemical study of CK7 in 17 cases of canine mammary gland neoplasms obtained from the Department of Pathology, Faculty of Veterinary Medicine, University of Tehran. Masson’s trichrome staining was performed to differentiate between collagen fibers and smooth muscle. RESULTS: CK7 protein was detected in both epithelial (1 benign mixed tumor, 1 fibroadenoma, 1 complex carcinoma, and 1 carcinoma mixed type) and myoepithelial (1 fibroadenoma, 1 benign mixed tumor, 3 complex carcinomas, 1 ductal carcinoma, and 1 carcinoma mixed type) cells. Fine and thick collagen fibers were observed in the sections stained by Masson’s trichrome. CONCLUSIONS: Despite using CK7 as a differentiation marker in human breast cancer, CK7 had a controversial ex-pression in the epithelial and myoepithelial cells in canine mammary gland neoplasms. Based on the results, CK7 could not be considered as an independent marker for the canine mammary glands epithelial cell detection and a prognostic factor in canine mammary gland neoplasms

To understand the development of the mucous preglottal salivary gland in Coturnix japonica (Japanese quail), morphological and histochemical studies were performed on 20 healthy Japanese quail embryos (aging from 10th to 17th incubation days) and 25 healthy quail chicks (aging from 0th to 60th days). The primordia of preglottal salivary gland were observed as an epithelial bud at the early embryonic stage, which then elongated and differentiated into secretory units by the end of this stage. In Japanese quails, the preglottal salivary gland was a mucous polystomatic tubuloalveolar unpaired gland composed of two lateral portions and a middle one embedded into the submucosa of the lingual root. The gland openings accompanied taste pore (8.17 μm) of taste buds associated salivary glands type; some skeletal muscle fibers embedded among secretory lobules extended from muscle cricohyoideus at 14th day‐old quail chick. Also, both herbts corpuscles and secretory motor plexus could be detected among secretory lobules. Based on our investigations, the development of the preglottal salivary gland could clearly be distinguished in the embryonic stage into pre bud and bud stages at 10th day old, cord and branching stages ended by cavitation at 11th day old, canalization stage at 13th day old, lobulation and secretory stages by the 17th day old. The secretory materials showed different histochemical reactions ended with highly alcinophilic mucous indicated highly sialomucin (acidic) content. Myoepithelial cells could be demonstrated at a 17‐day old quail embryo and thereafter surrounded the secretory endpieces of the preglottal salivary gland. [ABSTRACT FROM AUTHOR]

Abstract Cancer‐associated fibroblasts are essential modifiers of the tumor microenvironment. The collagen‐binding integrin α11β1 has been proposed to be upregulated in a pro‐tumorigenic subtype of cancer‐associated fibroblasts. Here, we analyzed the expression and clinical relevance of integrin α11β1 in a large breast cancer series using a novel antibody against the human integrin α11 chain. Several novel monoclonal antibodies against the integrin α11 subunit were tested for use on formalin‐fixed paraffin‐embedded tissues, and Ab 210F4B6A4 was eventually selected to investigate the immunohistochemical expression in 392 breast cancers using whole sections. mRNA data from METABRIC and co‐expression patterns of integrin α11 in relation to αSMA and cytokeratin‐14 were also investigated. Integrin α11 was expressed to varying degrees in spindle‐shaped cells in the stroma of 99% of invasive breast carcinomas. Integrin α11 co‐localized with αSMA in stromal cells, and with αSMA and cytokeratin‐14 in breast myoepithelium. High stromal integrin α11 expression (66% of cases) was associated with aggressive breast cancer features such as high histologic grade, increased tumor cell proliferation, ER negativity, HER2 positivity, and triple‐negative phenotype, but was not associated with breast cancer specific survival at protein or mRNA levels. In conclusion, high stromal integrin α11 expression was associated with aggressive breast cancer phenotypes.

The aim of the present study is to investigate the role of c-Jun N-terminal kinase (JNK) and matrix metalloproteinase-2 (MMP-2) in mediating the effects of interleukin-1β (IL-1β) on the function of lacrimal gland myoepithelial cells (MECs). MECs isolated from an α-smooth muscle actin-green fluorescent protein (SMA-GFP) transgenic mouse were treated with IL-1β alone or in the presence of SP600125, a JNK inhibitor, or ARP100, an MMP-2 inhibitor. The GFP intensity and the cell size/area were measured, and on day 7, the SMA, calponin, and pro-MMP-2 protein levels and the MEC contraction were assessed. At baseline, the control and treated cells showed no differences in GFP intensity or cell size. Starting on day 2 and continuing on days 4 and 7, the GFP intensity and cell size were significantly lower in the IL-1β-treated samples, and these effects were alleviated following inhibition of either JNK or MMP-2. Compared with the control, the levels of SMA and calponin were lower in the IL-1β-treated samples, and both the JNK and MMP-2 inhibitors reversed this trend. The pro-MMP-2 protein level was elevated in the IL-1β-treated samples, and this effect was abolished by the JNK inhibitor. Finally, oxytocin-induced MEC contraction was diminished in the IL-1β-treated samples, and both the JNK and MMP-2 inhibitors reversed this effect. Our data suggest that IL-1β uses the JNK/MMP-2 pathways to alter MEC functions, which might account for the diminished tears associated with aqueous-deficient dry eye disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Morokuma, Gárriz, Toribio, Pagni and Zoukhri.)

Introduction: Breast carcinoma demands attention as it causes high morbidity and mortality. It is important to recognise benign lesions to distinguish them from in situ and invasive breast cancer and to assess a patient’s risk of developing breast cancer, so that the most appropriate treatment modality for each case can be established. The p63 has been characterised as a reliable marker of myoepithelial cells of lactiferous duct. It is exclusively expressed in myoepithelial cells of normal breast tissue. Hence, p63 can be of great help in the differential diagnosis involving benign lesions. Also, p63 may aid in distinguishing benign from malignant lesions. Aim: To study the Immunohistochemistry (IHC) expression of p63 in benign and malignant breast lesions. Materials and Methods: The prospective study was conducted on 76 breast specimens for a period of one year, from 1st December 2018 to 30th November 2019 in the Department of Pathology, Bhagat Phool Singh, Government Medical College for Women, Khanpur Kalan, Sonepat, Haryana, India. IHC assessment for p63 nuclear protein was performed. The intensity of p63 expression was evaluated as continuous positive, discontinuous positive and negative. The extent was scored on the basis of percentage of positive cells and assigned a score of negative (0%), 1 (<25%), 2 (26-90%) and 3 (91-100%). Results: Out of 76 cases, 38 cases were diagnosed as benign and 38 cases as malignant. IHC staining with p63 showed nuclear positivity in all benign lesions. Among malignant lesions, four were positive and 34 were negative. Conclusion: According to the above results, p63 is a very useful IHC marker in diagnosing difficult cases, cases of carcinoma in situ, borderline cases and cases with inconclusive histomorphological diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: Breast carcinoma demands attention as it causes high morbidity and mortality. It is important to recognise benign lesions to distinguish them from in situ and invasive breast cancer and to assess a patient’s risk of developing breast cancer, so that the most appropriate treatment modality for each case can be established. The p63 has been characterised as a reliable marker of myoepithelial cells of lactiferous duct. It is exclusively expressed in myoepithelial cells of normal breast tissue. Hence, p63 can be of great help in the differential diagnosis involving benign lesions. Also, p63 may aid in distinguishing benign from malignant lesions. Aim: To study the Immunohistochemistry (IHC) expression of p63 in benign and malignant breast lesions. Materials and Methods: The prospective study was conducted on 76 breast specimens for a period of one year, from 1st December 2018 to 30th November 2019 in the Department of Pathology, Bhagat Phool Singh, Government Medical College for Women, Khanpur Kalan, Sonepat, Haryana, India. IHC assessment for p63 nuclear protein was performed. The intensity of p63 expression was evaluated as continuous positive, discontinuous positive and negative. The extent was scored on the basis of percentage of positive cells and assigned a score of negative (0%), 1 (

Breast cancer is the most common cancer among women worldwide. Overweight and obesity are now recognized as established risk factors for this pathology in postmenopausal women. These conditions are also believed to be responsible for higher recurrence and mortality rates. Reciprocal interactions have been described between adipose and cancer cells. An adipose microenvironment favors a greater proliferation of cancer cells, their invasion and even resistance to anti-cancer treatments. In addition, the chronic low-grade inflammation observed in obese individuals is believed to amplify these processes. Among the cell types present in the breast, myoepithelial cells (MECs), located at the interface of the epithelial cells and the stroma, are considered “tumor suppressor” cells. During the transition from ductal carcinoma in situ to invasive cancer, disorganization or even the disappearance of MECs is observed, thereby enhancing the ability of the cancer cells to migrate. As the adipose microenvironment is now considered as a central actor in the progression of breast cancer, our objective was to evaluate if it could be involved in MEC functional modifications, leading to the transition of in situ to invasive carcinoma, particularly in obese patients. Through a co-culture model, we investigated the impact of human adipose stem cells from women of normal weight and obese women, differentiated or not into mature adipocytes, on the functionality of the MECs by measuring changes in viability, apoptosis, gene, and miRNA expressions. We found that adipose cells (precursors and differentiated adipocytes) could decrease the viability of the MECs, regardless of the original BMI. The adipose cells could also disrupt the expression of the genes involved in the maintenance of the extracellular matrix and to amplify the expression of leptin and inflammatory markers. miR-122-5p and miR-132-3p could also be considered as targets for adipose cells. The metabolite analyses revealed specific profiles that may be involved in the growth of neoplastic cells. All of these perturbations could thus be responsible for the loss of tumor suppressor status of MECs and promote the transition from in situ to invasive carcinoma.

BACKGROUND: Adenoid cystic carcinoma of the breast is a rare malignant infiltrating neoplasia with a morphological spectrum similar to its salivary gland counterpart. Characterized by proliferation of epithelial and myoepithelial cells in a solid, tubular or cribriform pattern. It can be subclassified according to its architecture and cytology into classic, solid-basaloid and with high-grade transformation. CLINICAL CASE: A 69-year-old woman who came to the clinic with nine months of a painful tumor lesion on the right breast. Breast ultrasound reported a single radiodense nodular image, 1.9 x 1.8 x 1.5 cm, with well-defined contours, with multiple thick echoes in its interior, located in the superior external quadrant, compatible with a complex cyst, category BIRADS-IVA. The diagnosis of adenoid cystic carcinoma was established, classified as histological grade 1 classic subtype, with positive hormone receptors and HER2/neu negativity, without lymph node involvement or relapse one year later. CONCLUSIONS: The current case corresponds to a classic manifestation of adenoid cystic carcinoma of the breast, treated with radical surgery and satisfactory evolution. Due to the low probability of local, regional, and distant metastasis, current evidence does not recommend lymph node dissection or routine systemic therapy with chemo or radiation therapy. [ABSTRACT FROM AUTHOR]

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Introduction: Early and correct diagnosis is the key to provide appropriate and timely treatment in breast cancer. It is important to distinguish between benign and malignant lesions, and also invasive and non-invasive lesions. The foci of micro-invasion lack myoepithelial (ME) cells and this is the major histological criterion for the diagnosis of invasiveness in breast carcinomas. In this study, we compare the results of immunohistochemistry (IHC) with the observation made on Haematoxylin and Eosin (H&E) staining to reconsider the diagnosis and to assess the utility of IHC for identification of myoepithelial cells. Materials & Method: In this observational study, surgical specimens, which included mastectomy, quadrantectomy, excisional biopsies, and incisional biopsies, received in histopathology laboratory were grossed and H&E staining was done. The cases were re-analyzed for presence and absence of myoepithelial cells after immuno-staining for α-smooth muscle actin. Results: Of 194 specimens, 186 (95.88%) were from female patients. Malignant lesions were the commonest with 110 (59.14%) cases. Fibro adenoma was the most common benign lesion (73.44%). In-situ lesions were seen associated with 37 cases-35 Ductal carcinoma in situ (DCIS) and 2 Lobular carcinoma in situ. Of these, the ME cell layer was circumferential in 11, absent in 8 and discontinuous in 18 on H&E staining. On IHC, 32 cases showed circumferential staining for ME cell, partial staining was noted in 3 cases and lack of staining in 2 cases. 21 (56.75%) cases were re-categorized from invasive to non-invasive lesions. Conclusion: It is not always possible to detect ME cells on routine H&E staining and IHC can be of immense help, especially when it is essential to rule out or confirm invasion. Correlating ME cell staining with H&E also is important to avoid misinterpretation because of false positive results due to stromal staining, and taking help of other markers in difficult cases is recommended. The usefulness will be further recognized in future when we will come across more cases of in situ carcinomas due to patient awareness and routine use of mammographic screening. [ABSTRACT FROM AUTHOR]

ABSTRACT Adenomyoepithelioma (AME) is an uncommon tumour of breast, which is common in middle aged and older adults (>60 years). It is characterised by dual differentiation of cells into luminal as well as myoepithelial cells. Herein we report a case of a 22-year-old female who presented with a solitary swelling in the upper outer quadrant of the left breast, diagnosed as fibrocystic breast disease on Fine Needle Aspiration Cytology (FNAC). Excisional biopsy and histopathologic examination showed features suggestive of AME, which was confirmed on Immunohistochemistry (IHC) staining. On retrospective review of the cytology slides, a biphasic appearance was discerned; the myoepithelial cells probably having been masked by the cystic degeneration. AMEs are generally benign. However, in view of substantial reports of local recurrences, malignant transformations and metastases, accurate distinction of this lesion is crucial. Here, the authors report this rare case, to emphasise the importance of considering this entity in the differential diagnosis of a focal solid lesion in the breast, and to underline the accompanying diagnostic pitfalls.

Abstract Background The microenvironment and stress factors like glucocorticoids have a strong influence on breast cancer progression but their role in the first stages of breast cancer and, particularly, in myoepithelial cell regulation remains unclear. Consequently, we investigated the role of glucocorticoids in ductal carcinoma in situ (DCIS) in breast cancer, focusing specially on myoepithelial cells. Methods To clarify the role of glucocorticoids at breast cancer onset, we evaluated the effects of cortisol and corticosterone on epithelial and myoepithelial cells using 2D and 3D in vitro and in vivo approaches and human samples. Results Glucocorticoids induce a reduction in laminin levels and favour the disruption of the basement membrane by promotion of myoepithelial cell apoptosis in vitro. In an in vivo stress murine model, increased corticosterone levels fostered the transition from DCIS to invasive ductal carcinoma (IDC) via myoepithelial cell apoptosis and disappearance of the basement membrane. RU486 is able to partially block the effects of cortisol in vitro and in vivo. We found that myoepithelial cell apoptosis is more frequent in patients with DCIS+IDC than in patients with DCIS. Conclusions Our findings show that physiological stress, through increased glucocorticoid blood levels, promotes the transition from DCIS to IDC, particularly by inducing myoepithelial cell apoptosis. Since this would be a prerequisite for invasive features in patients with DCIS breast cancer, its clinical management could help to prevent breast cancer progression to IDC.

Background and Objectives: Myoepithelial cells (ME) are known to contribute in the patterning of salivary gland neoplasms (SGN) and possess cytoplasmic smooth muscle actin (SMA) revealed by alpha SMA (α-SMA). The present study aimed to assess the expression of α-SMA in selected benign and malignant SGN (pleomorphic adenoma [PA], mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and polymorphous low-grade adenocarcinoma (PLGA). Materials and Methods: The intensity and pattern of expression of α-SMA were studied in 25 cases of SGN's ACC (n = 7), MEC (n = 8), PA (n = 8), and PLGA (n = 2), and correlated with the histological patterns. Results: Maximum expression of α-SMA in the epithelial compartment was seen in ACC, followed by PA, whereas MEC and PLGA showed completely negative staining. The connective tissue expression was mild in ACC and MEC. The myxoid stroma of PA with “melting” pattern was weakly positive for α-SMA. The stroma in PLGA showed complete negativity. In ACC, α-SMA-positive cells were lining the cribriform spaces, small islands, and dispersed within large islands. Small nests showed complete positivity for α-SMA. Interpretation and Conclusion: In ACC, α-SMA expression supports the involvement of ME in epithelial organization explaining the histological patterns seen. In PA, the expression correlates with the predominantly secretory nature of ME. The absence of epithelial positivity in MEC and PLGA suggest that ME has less role to play in their histogenesis. The weak stromal positivity observed in MEC and ACC may be attributed to the positive immunoreactivity of myofibroblasts playing a role in modulating the course of SGN's.

Background. The expression of terminal deoxynucleotidyl transferase (TdT) in myoepithelial cells (MECs) within the breast was recently incidentally observed in our routine practice. This study aimed to elucidate the expression of TdT in MECs. Methods. TdT immunostaining was performed on 180 mammary, 89 cutaneous, and 94 salivary tissues or lesions. Other myoepithelial markers, including P63, calponin, and SMA as well as double staining for TdT and calponin, were also evaluated in some cases. Selected lesions with basal or myoid differentiation were also included in the investigation. Results. MECs were positive for TdT in mammary lesions that contained MECs (132/135) but negative when they did not contain MECs (45/45). MECs in sweat glands (24/30) and their neoplastic counterparts, including those in hidradenoma papilliferum (2/9), spiradenoma (6/6), and cutaneous mixed tumor (9/9), showed weak to moderate TdT positivity. MECs were variably immunolabeled for TdT in salivary or salivary gland–type tumors with myoepithelial differentiation (pleomorphic adenoma, 24/25; basal cell adenoma, 6/7; adenoid cystic carcinoma, 7/7; Warthin tumor, 0/6; mucoepidermoid carcinoma, 0/8; acinic cell carcinoma, 0/4), but MECs in normal salivary gland barely stained for TdT (30/32). Conclusions. Our findings indicate that TdT may be eligible as an additional auxiliary immunohistochemical marker as P63, but not a surrogate, to identify the MECs in the breast with limited cross-reactivity, particularly in lesions with a prominent proportion of MECs. Positivity for TdT, along with other relevant markers, in a subset of sweat gland lesions and salivary tumors may contribute to their diagnosis. [ABSTRACT FROM AUTHOR]

Background: Mammary neoplasms are common tumors in intact female dogs. Fine‐needle aspiration cytology (FNAC) is a valuable diagnostic tool and has gained some credibility in the diagnosis of mammary tumors in dogs. Prompt classification of canine mammary tumors using cytology would enhance feasibility as a prognostic tool and guide clinical and surgical management. Objectives: We aimed to examine background elements to differentiate mammary tumors using FNAC. We proposed to distinguish simple from complex and mixed tumors by identifying myoepithelial (ME) cells and different types of extracellular matrix. Additionally, we determined the accuracy of FNAC to differentiate benign from malignant tumors. Methods: One hundred and one mammary tumors from female dogs were included in this study. We compared FNAC using histopathology as the gold standard. Cellular and background components were evaluated and identified. The cytologic accuracy, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignancy were determined, excluding inadequate samples. Results: The cytologic‐histologic agreement was 92.5% for simple carcinomas, 57.9% for complex‐type carcinomas, 57.1% for mixed‐type carcinomas, 27.3% for carcinosarcomas, and 100% for osteosarcomas. Myoepithelial cells were successfully identified using FNAC. Myxoid and chondroid/osteoid matrix were satisfactorily recognized. Cytologic accuracy, Se, Sp, PPV, and NPV for diagnosing malignancy were 99%, 100%, 83%, 99%, and 100%, respectively. Conclusions: Chondroid/osteoid matrix was noted in mixed tumors but not in complex tumors. Myxoid matrix, often associated with ME cells, was noted in complex and mixed tumors. Mesenchymal cells were differentiated from ME cells, allowing the distinction of simple carcinomas with scirrhous reaction from complex and mixed tumors. [ABSTRACT FROM AUTHOR]

Cancer‐associated fibroblasts are essential modifiers of the tumor microenvironment. The collagen‐binding integrin α11β1 has been proposed to be upregulated in a pro‐tumorigenic subtype of cancer‐associated fibroblasts. Here, we analyzed the expression and clinical relevance of integrin α11β1 in a large breast cancer series using a novel antibody against the human integrin α11 chain. Several novel monoclonal antibodies against the integrin α11 subunit were tested for use on formalin‐fixed paraffin‐embedded tissues, and Ab 210F4B6A4 was eventually selected to investigate the immunohistochemical expression in 392 breast cancers using whole sections. mRNA data from METABRIC and co‐expression patterns of integrin α11 in relation to αSMA and cytokeratin‐14 were also investigated. Integrin α11 was expressed to varying degrees in spindle‐shaped cells in the stroma of 99% of invasive breast carcinomas. Integrin α11 co‐localized with αSMA in stromal cells, and with αSMA and cytokeratin‐14 in breast myoepithelium. High stromal integrin α11 expression (66% of cases) was associated with aggressive breast cancer features such as high histologic grade, increased tumor cell proliferation, ER negativity, HER2 positivity, and triple‐negative phenotype, but was not associated with breast cancer specific survival at protein or mRNA levels. In conclusion, high stromal integrin α11 expression was associated with aggressive breast cancer phenotypes. [ABSTRACT FROM AUTHOR]

A decreased saliva production occurs in primary Sjögren’s syndrome (pSS), an autoimmune disease characterized by oral and ocular dryness due to dysfunction of the lacrimal and salivary glands (SGs). Since water movement is involved in saliva secretion, the expression, localization, and function of the water channels aquaporins (AQPs) have been extensively studied in SGs. To date, the presence of AQP4 remains controversial and ambiguous in human SGs. We investigated by immunohistochemistry, high-resolution confocal microscopy and quantitative image analysis, Western blot and real-time RT-PCR, the presence of the AQP4 gene, and the distribution of AQP4 protein in healthy controls and pSS SG biopsies. Through the immunohistochemical analysis, we demonstrated that AQP4 presence is confined to the basal region of acini, to the lateral and apical membrane of intercalated and striated ducts in both control and pSS glands. The most striking observation was the discovery of AQP4 localization in myoepithelial cells (MECs) that surround acini lobules and intercalated ducts, and the demonstration of AQP4-downregulated immunoreactivity in pSS MECs. Our studies suggest that the capacity for water flow across the membrane of MECs may be altered in pSS, identifying AQP4 as a promising new therapeutic agent to treat xerostomia.

Abstract Background The breast tumor microenvironment regulates progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). However, it is unclear how interactions between breast epithelial and stromal cells can drive this progression and whether there are reliable microenvironmental biomarkers to predict transition of DCIS to IDC. Methods We used xenograft mouse models and a 3D pathomimetic model termed mammary architecture and microenvironment engineering (MAME) to study the interplay between human breast myoepithelial cells (MEPs) and cancer-associated fibroblasts (CAFs) on DCIS progression. Results Our results show that MEPs suppress tumor formation by DCIS cells in vivo even in the presence of CAFs. In the in vitro MAME model, MEPs reduce the size of 3D DCIS structures and their degradation of extracellular matrix. We further show that the tumor-suppressive effects of MEPs on DCIS are linked to inhibition of urokinase plasminogen activator (uPA)/urokinase plasminogen activator receptor (uPAR)-mediated proteolysis by plasminogen activator inhibitor 1 (PAI-1) and that they can lessen the tumor-promoting effects of CAFs by attenuating interleukin 6 (IL-6) signaling pathways. Conclusions Our studies using MAME are, to our knowledge, the first to demonstrate a divergent interplay between MEPs and CAFs within the DCIS tumor microenvironment. We show that the tumor-suppressive actions of MEPs are mediated by PAI-1, uPA and its receptor, uPAR, and are sustained even in the presence of the CAFs, which themselves enhance DCIS tumorigenesis via IL-6 signaling. Identifying tumor microenvironmental regulators of DCIS progression will be critical for defining a robust and predictive molecular signature for clinical use.

Sialadenoma papilliferum-like intraductal papillary tumour (SP-IPT) is a recently described salivary gland tumour that shows identical morphology to sialadenoma papilliferum (SP) except for the lack of an exophytic papillary component. However, the immunohistochemical phenotypes and molecular profiles of SP-IPT remain unclear. This study aims to report new cases of SP-IPT and to determine its cellular differentiation and molecular basis. After histopathological review, four cases of SP-IPT were retrieved. Immunohistochemical staining was performed to analyse the expression patterns of cytokeratin 7 (CK7), p63, smooth muscle actin (SMA), vimentin, S100, mammaglobin, androgen receptor, SOX10, BRAF V600E-mutated protein, and phosphorylated ERK. Sanger sequencing was performed to determine the mutation status of the BRAF, KRAS, NRAS, and HRAS genes. All four cases affected the posterior mandible with a mean age of 62 years and a male-to-female ratio of 3:1. Histologically, all cases consisted of multiple tubular and cystic structures with varying sizes and shapes. The tubulocystic components were lined by a double or few-layered epithelium frequently showing a micropapillary pattern. The outer layer consisted of a rim of myoepithelial cells, which were CK7+/p63+/SMA+/vimentin+/S100+/SOX10+. The inner ductal cells were CK7+/S100+/SOX10+, consistent with intercalated duct differentiation. All cases harboured BRAF V600E mutations, but no other mutations were detected. The BRAF V600E-mutated protein and phosphorylated ERK were expressed in both ductal and myoepithelial cells. These findings demonstrate the immunohistochemical and molecular similarities between SP-IPT and SP and the role and extent of MAPK pathway activation in the pathogenesis of SP-IPT., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Salivary gland myoepithelial cells regulate salivary secretion and have been implicated in the histological diversity of salivary gland tumors. However, isolation of myoepithelial cells has been difficult owing to a lack of detailed functional analysis and cell surface markers. Therefore, we aimed to isolate myoepithelial cells from adult mouse submandibular glands using the epithelial marker EpCAM and cell adhesion factor CD49f as indicators and characterize them via sphere-forming culture. Functional analysis of specific gene expression in myoepithelial cells is possible via cell transfection experiments using the piggyBac transposon vector system. Here, we describe detailed methods and tips for the isolation and functional analysis of myoepithelial cells., (© 2023. Springer Science+Business Media, LLC.)

An 11-year-old female miniature Dachshund dog presented with a solid, soft, gray mass on the hepatic lateral left lobe. Histologically, the mass consisted of neoplastic proliferation of cells with round nuclei and eosinophilic and vacuolated cytoplasm arranged in alveolar, trabecular, and solid patterns. Immunohistochemically, the neoplastic cells were positive for pancytokeratin (CK AE1/AE3), CK5, CK14, vimentin, Sox9, and myoepithelial markers (α–smooth muscle actin, p63, and calponin). The morphological and immunohistochemical findings indicated a diagnosis of myoepithelial carcinoma. We conducted immunohistochemical studies on other representative canine hepatic tumors. Although the myoepithelial phenotype was not observed in the hepatocellular carcinoma, some tumor cells in cholangiocarcinoma showed immunohistochemical features of myoepithelium, suggesting that some neoplastic cells in cholangiocarcinoma may have the potential to differentiate into myoepithelial cells. To our knowledge, this is the first report in veterinary medicine of a hepatic carcinoma with a myoepithelial phenotype. [ABSTRACT FROM AUTHOR]

The human salivary gland (SGs) develops as a highly branched structure designed to produce and secrete saliva indispensable to maintain the health of the oral cavity and for carry out physiological functions like mastication, taste perception and speech. Here we review the anatomy and cytoarchitecture of SGs and the most recent literature that has enabled a better understanding of the molecular signalling pathways of SGs development to translate this basic research towards therapy for patients suffering from salivary hypo function. [ABSTRACT FROM AUTHOR]

Nipple adenoma is a very uncommon, benign proliferative process of lactiferous ducts of the nipple. Clinically mimic the presentation of mammary Paget’s disease and histopathologically with carcinoma or precursor lesions. Therefore, the histological and immunophenotypic analysis is essential for the differential diagnosis. The present study describes the characteristics of a clinical case of Nipple adenoma, as well as review of the literature. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 4‐phosphate 5‐kinase (PIP5K), which is composed of three isozymes (α, β and γ), catalyzes the production of phosphatidylinositol bisphosphate (PIP2). This phospholipid functions in membrane trafficking, as an anchor for actin cytoskeletons and as a regulator of intramembranous channels/transporters. It is also a precursor of such second messengers as diacylglycerol, inositol triphosphate and phosphatidylinositol (3,4,5)‐triphosphate. In the present study, the expression and localization of endogenous PIP5Ks were examined in the three major salivary glands of young adult mice in situ. In western blotting of normal control glands, immunoreactive bands for individual PIP5Ks were detectable, with the highest density in the parotid gland and the weakest density in the submandibular gland. In immuno‐light microscopy under non‐stimulated condition, weak immunoreactivity for PIP5Kα was confined to the apical plasmalemma in parotid, but not sublingual or submandibular, acinar cells. Immunoreactivity for PIP5Kβ was weak to moderate and confined to ductal cells but not acinar cells, whereas that for PIP5Kγ was selectively and intensely detected in myoepithelial cells but not acinar cells, and it was weak in ductal cells in the three glands. In western blot of the parotid gland stimulated by isoproterenol, a β‐adrenoceptor agonist, no changes were seen in the intensity of immunoreactive bands for any of the PIP5Ks. In contrast, in immuno‐light microscopy, the apical immunoreactivity for PIP5Kα in parotid acinar cells was transiently and distinctly increased after the stimulation. The increased immunoreactivity was ultrastructurally localized on most apical microvilli and along contiguous plasma membrane, where membranous invaginations of various shapes and small vesicles were frequently found. It was thus suggested that PIP5Kα is involved in post‐exocytotic membrane dynamics via microvillous membranes. The present finding further suggests that each of the three isoforms of PIP5K functions through its product PIP2 discretely in different cells of the glands to regulate saliva secretion. [ABSTRACT FROM AUTHOR]

Encapsulated papillary carcinoma (EPC) is a relatively rare form of breast cancer. To date, no evidence-based guidelines for the treatment of EPC have been established. Between January 2015 and December 2021, patients with histologically confirmed EPC of the breast were recorded in a database by The Third Hospital of Nanchang City (Nanchang, China). A total of 46 patients with EPC were retrieved from the database. Age at diagnosis ranged from 41–88 years (median age, 62 years). A total of 21 of these patients had pure EPC, 6 patients had EPC associated with ductal carcinoma in situ and 19 patients had EPC associated with invasive carcinoma. The majority of EPC cases were low nuclear grade, hormone receptor-positive and human epidermal growth factor receptor-2-negative. Additionally, myoepithelial cells were always absent in the papillae of the EPC. All patients underwent lumpectomy or mastectomy with sentinel lymph node biopsy, and almost all of the patients received adjuvant hormonal therapy. Adjuvant chemotherapy was only suggested to 4 patients who were diagnosed with axillary lymph node involvement. Subsequently, the clinicopathological features of non-invasive EPC were compared with invasive EPC. The results indicated that larger tumor sizes and axillary lymph node metastases were more common in invasive tumors. During the follow-up, only 2 patients with invasive EPC experienced recurrence or metastasis. In conclusion, a substantial proportion of invasive EPC cases display aggressive characteristics and metastatic potential, despite it being considered a subtype of carcinoma in situ with excellent prognosis, and local surgical resection is the initial method of treatment. Therefore, adjuvant endocrine therapy, radiotherapy and chemotherapy should be considered in select patients, especially in those diagnosed with invasive EPC tumors. [ABSTRACT FROM AUTHOR]