Terminal Duct Lobular Units Research Articles

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1. Selenocysteine is coded by UGA UAG UAA AUG Ans: A. UGA Explanation Selenocysteine (SeCys/SeC) is the 21st amino acid and is found in thioredoxin reductase, glutathione peroxidase, 5’-deiodinase, and selenoprotein P. It is an exceptional case where a stop codon codes for an amino acid. The other stop codons are UAA and UAG. The ability of the protein synthetic apparatus to identify a selenocysteine-specific UGA codon involves the selenocysteine insertion element, a stem-loop structure in the untranslated region of the mRNA.[1] 2. A child with diarrhea for 2 days came to your out-patient department (OPD). On examination, the signs of dehydration were marked and the child was treated with oral rehydration solution (ORS). Glucose absorption was facilitated by which receptors? SGLT1 SGLT2 GLUT4 Sodium–hydrogen antiporter Ans: A. SGLT1 Explanation Absorption of glucose from the intestinal lumen to intestinal cells is by the cotransport mechanism. It is an active transport system and can transport against the concentration gradient.[2] 3. Skeletal derivative of the second pharyngeal arch is Malleus Incus Stapes Maxilla Ans: C. Stapes Explanation Maxilla, malleus, and incus are derived from the first arch.[3] 4. Blastocyst makes contact with a uterus on <3 days 5–7 days 8–11 days 15–16 days Ans: B. 5–7 days Explanation Contact of the blastocyst with endometrium occurs at the time of implantation. Implantation occurs at around 5-7 days.[4] 5. The father of antiseptic surgery is Louis Pasteur Robert Koch Julius Petri Joseph Lister Ans. D. Joseph Lister Explanation Louis Pasteur – the father of microbiology, Robert Koch – the father of microbiology (with Louis Pasteur), and the father of medical bacteriology, Julius Petri – invented the Petri dish.[5] 6. Following were the findings in a Glucose tolerance test (GTT). Fasting blood glucose <75 mg/dl; all blood samples show low blood glucose; urine glucose – nil. The possible diagnosis is Alimentary glycosuria Diabetes mellitus Hypopituitarism Diabetes insipidus Ans. C. Hypopituitarism Explanation In alimentary glycosuria, there will be a peak in the first sample after glucose load and sugar will appear in urine. In diabetes mellitus, fasting and the next two samples will show higher values than the normal reference range and the sample does not return to baseline at the end of the test. In hypopituitarism, there is hypoglycemia and the patient feels fatigued and stressed. In diabetes insipidus, GTT is mostly unaffected.[6] 7. A 10-year-old boy with a history of atopy presented with seasonal recurrent bilateral conjunctivitis and complained of blurred vision for the past 1 week. On lid eversion, giant papillae were seen. All of the following could be seen by slit-lamp examination except: Vascular pannus and punctate epithelial erosions involving the superior cornea. An oval epithelial ulceration with underlying stromal opacification in the central cornea Limbal follicles Conjunctival symblepharon Ans. D. Conjunctival symblepharon Explanation A conjunctival symblepharon is seen in the case of autoimmune disorders such as Sjogren’s syndrome, sarcoidosis, lichen planus, granulomatosis with polyangiitis, etc.[7] 8. Which of the following breast lesion is a noninvasive malignancy? Tubular carcinoma and mucinous carcinoma Intraductal carcinoma of the comedo type Infiltrating ductal carcinoma and lobular carcinoma Medullary carcinoma, including atypical medullary lesions Ans. B. Intraductal carcinoma of the comedo type Explanation A comedo-type ductal carcinoma in situ (DCIS), also known as comedocarcinoma insitu, is the high-grade subtype of DCIS. It completely fills and dilates the ducts and lobules in terminal duct lobular units with plugs of high-grade tumor cells with central necrosis “comedonecrosis.”[8] 9. In patients who develop a documented episode of deep-vein thrombosis, the most significant long-term sequelae are: Claudication Recurrent foot infections Development of stasis ulcer Pulmonary embolization Ans. C-Development of stasis ulcer Explanation Chronic symptoms may occur after 6 weeks or beyond. Pulmonary embolization is the most common complication but is seen as an acute complication.[9] 10. Identify the test from the diagram. Rothera’s test Benedict’s test Barfoed’s test Seliwanoff’s test Ans. A. Rothera’s testFigure 1: Purple permanganate coloured ring [Ferro-penta cyanine complex] at the junction of two fluidsExplanation Rothera’s test was done to identify the presence of ketone bodies in a urine sample. Benedict’s test will contain a green/yellow/orange/brick red precipitate at the bottom. Barfoed’s test has a red scum at the top of the fluid and a little red precipitate at the bottom. Seliwanoff’s test will have a cherry red color.[10] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Reliability of CD44, CD24, and ALDH1A1 immunohistochemical staining: Pathologist assessment compared to quantitative image analysis.

The data on the expression of stem cell markers CD44, CD24, and ALDH1A1 in the breast tissue of cancer-free women is very limited and no previous studies have explored the agreement between pathologist and computational assessments of these markers. We compared the immunohistochemical (IHC) expression assessment for CD44, CD24, and ALDH1A1 by an expert pathologist with the automated image analysis results and assessed the homogeneity of the markers across multiple cores pertaining to each woman. We included 81 cancer-free women (399 cores) with biopsy-confirmed benign breast disease in the Nurses' Health Study (NHS) and NHSII cohorts. IHC was conducted with commercial antibodies [CD44 (Dako, Santa Clara, CA, USA) 1:25 dilution; CD24 (Invitrogen, Waltham, MA, USA) 1:200 dilution and ALDH1A1 (Abcam, Cambridge, United Kingdom) 1:300 dilution]. For each core, the percent positivity was quantified by the pathologist and Definiens Tissue Studio. Correlations between pathologist and computational scores were evaluated with Spearman correlation (for categorical positivity: 0, >0-<1, 1-10, >10-50, and >50%) and sensitivity/specificity (for binary positivity defined with 1 and 10% cut-offs), using the pathologist scores as the gold standard. Expression homogeneity was examined with intra-class correlation (ICC). Analyses were stratified by core [normal terminal duct-lobular units (TDLUs), benign lesions] and tissue type (epithelium, stroma). Spearman correlation between pathologist and Definiens ranged between 0.40-0.64 for stroma and 0.66-0.68 for epithelium in normal TDLUs cores and between 0.24-0.60 for stroma and 0.61-0.64 for epithelium in benign lesions. For stroma, sensitivity and specificity ranged between 0.92-0.95 and 0.24-0.60, respectively, with 1% cut-off and between 0.43-0.88 and 0.73-0.85, respectively, with 10% cut-off. For epithelium, 10% cut-off resulted in better estimates for both sensitivity and specificity. ICC between the cores was strongest for CD44 for both stroma and epithelium in normal TDLUs cores and benign lesions (range 0.74-0.80). ICC for CD24 and ALDH1A ranged between 0.42-0.63 and 0.44-0.55, respectively. Our findings show that computational assessments for CD44, CD24, and ALDH1A1 exhibit variable correlations with manual assessment. These findings support the use of computational platforms for IHC evaluation of stem cell markers in large-scale epidemiologic studies. Pilot studies maybe also needed to determine appropriate cut-offs for defining staining positivity.

A Case Report of HER2-Amplification in the Breast Without Histological Abnormality.

Atypical ductal hyperplasia and low-grade ductal carcinoma in situ (DCIS) are regarded as precursor lesions of estrogen receptor (ER)-positive invasive breast cancer. In HER2-amplified invasive breast cancer, a precursor lesion before DCIS has not yet been described. Here we introduce a case of HER2-positive lobules in the breast without histological abnormality. A 39-year-old premenopausal woman visited a hospital due to identification of microcalcifications on screening mammography. The subsequent biopsy confirmed high-grade DCIS. She underwent wide excision, and a residual high-grade DCIS with a size of 1.4 cm was found. The tumor cells were hormone receptor positive and HER2 negative on immunohistochemical (IHC) staining. Around DCIS, there were terminal duct lobular units (TDLUs) showing strong HER2 positivity on IHC. These HER2-positive lobules were 7 mm away from the high-grade DCIS and was 1.1 mm in size. These HER2-positive lobules showed no histologic abnormality and had no difference compared with the surrounding normal TDLUs. Nevertheless, in addition to showing HER2 overexpression in IHC, HER2 amplification was also identified in HER2 silver in situ hybridization. HER2 amplification plays an important role in breast cancer development, and HER2 amplification is known to occur as an early event in cancer development. There have been studies identifying driver mutations in normal tissues of other organs. These findings suggest that HER2 amplification in the breast without histological abnormality could occur, and the HER2-positive lobules could be "at risk" for transformation into the precursor lesion of HER2-positive breast cancer, although the biological significance of these findings is unclear.

Postnatal exposure to a glyphosate-based herbicide interferes with the development and growth of the mammary gland of pre-pubertal Ewe lambs

The aim of the present study was to evaluate whether early postnatal exposure to a glyphosate-based herbicide (GBH) alters pre-pubertal mammary development in Friesian lambs. To this end, from postnatal day 1–14, ewe lambs were exposed subcutaneously or orally to GBH (2 mg/kg bw/day) or vehicle (control) and mammary gland biopsies were obtained at 45 days of age. GBH-exposed lambs exhibited larger mammary ducts and less area occupied by terminal duct lobular units than controls, accompanied by an increase in the area of adipocytes in the mammary stroma. Lambs subcutaneously exposed to GBH showed increased protein expression of estrogen receptor alpha; however, both GBH-exposed groups had decreased mRNA expression of this receptor. Control lambs showed nuclear progesterone receptor (PR) protein expression, whereas GBH-exposed animals showed cytoplasmic PR expression; both GBH-exposed groups exhibited decreased mRNA expression of PR. GBH-exposed lambs also had decreased epithelial cell proliferation. Regarding insulin-like growth factors, both groups showed similar IGF-1 mRNA and protein expression but decreased expression of its receptor, and increased IGFBP5 expression. In addition, phosphorylated AKT was only observed in the mammary gland of control lambs. Our results show that early postnatal exposure to GBH, regardless of the exposure route, affects the IGF-1 system and the AKT/protein kinase B pathway, interfering with steroid hormone receptor expression and cell proliferation. This consequently modifies the growth and development of the pre-pubertal mammary gland of Frisian lambs.

Dimorphic cells: a common feature throughout the low nuclear grade breast neoplasia spectrum

Columnar cell lesions (CCLs) are recognized precursor lesions of the low nuclear grade breast neoplasia family. CCLs are cystic enlarged terminal duct lobular units with monotonous (monoclonal) columnar-type luminal cells. CCLs without atypia are regarded as benign and CCLs with atypia as true precursor lesions with clonal molecular changes, a certain progression risk, and an association with more advanced lesions. However, reproducibility of designating atypia in CCL is not optimal, and no objective markers of atypia have been identified, although 16q loss seems to be associated with atypical CCLs. Dimorphic (“pale”) cell populations have been described in low nuclear grade ductal carcinoma in situ (DCIS) but not in CCLs and atypical ductal hyperplasia (ADH). Therefore, we searched for pale cells in CCL (N = 60), ADH (N = 41), and DCIS grade 1 (N = 84). Diagnostic criteria were derived from the WHO, and atypia was designated according to the Schnitt criteria. Pale cells occurred in 0% (0/30), 73% (22/30), 56% (23/41), and 76% (64/84) of CCLs without atypia, CCLs with atypia, ADH, and DCIS grade 1, respectively. Pale cells expressed ERα, E-cadherin and p120 and variably cyclin D1, and lacked expression of CK5 and p63. In conclusion, dimorphic “pale” cells occur throughout the low nuclear grade progression spectrum, increasing in frequency with progression. Interestingly, CCL lesions without atypia do not seem to bear showed pale cells, indicating that the presence of pale cells may serve as a diagnostic morphological feature of atypia in CCLs.

Are Columnar Cell Lesions the Earliest Non-Obligate Precursor in the Low-Grade Breast Neoplasia Pathway?

Columnar cell lesions (CCLs) of the breast comprise a spectrum of morphologic alterations of the terminal duct lobular unit involving variably dilated and enlarged acini lined by columnar epithelial cells. The World Health Organization currently classifies CCLs without atypia as columnar cell change (CCC) and columnar cell hyperplasia (CCH), whereas flat epithelial atypia (FEA) is a unifying term encompassing both CCC and CCH with cytologic atypia. CCLs have been increasingly recognized in stereotactic core needle biopsies (CNBs) performed for the assessment of calcifications. CCLs are believed to represent the earliest non-obligate precursor of low-grade invasive breast carcinomas as they share molecular alterations and often coexist with entities in the low-grade breast neoplasia pathway. Despite this association, however, the risk of progression of CCLs to invasive breast carcinoma appears low and may not exceed that of concurrent proliferative lesions. As the reported upgrade rates of pure CCL/FEA when identified as the most advanced high-risk lesion on CNB vary widely, the management of FEA diagnosed on CNB remains controversial. This review will include a historical overview of CCLs and will examine histologic diagnostic criteria, molecular alterations, prognosis and issues related to upgrade rates and clinical management.

Ductal keratin 15+ luminal progenitors in normal breast exhibit a basal-like breast cancer transcriptomic signature

Normal breast luminal epithelial progenitors have been implicated as cell of origin in basal-like breast cancer, but their anatomical localization remains understudied. Here, we combine collection under the microscope of organoids from reduction mammoplasties and single-cell mRNA sequencing (scRNA-seq) of FACS-sorted luminal epithelial cells with multicolor imaging to profile ducts and terminal duct lobular units (TDLUs) and compare them with breast cancer subtypes. Unsupervised clustering reveals eleven distinct clusters and a differentiation trajectory starting with keratin 15+ (K15+) progenitors enriched in ducts. Spatial mapping of luminal progenitors is confirmed at the protein level by staining with critical duct markers. Comparison of the gene expression profiles of normal luminal cells with those of breast cancer subtypes suggests a strong correlation between normal breast ductal progenitors and basal-like breast cancer. We propose that K15+ basal-like breast cancers originate in ductal progenitors, which emphasizes the importance of not only lineages but also cellular position within the ductal-lobular tree.

Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence

BackgroundBreast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described.MethodsUsing validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors ≤ 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean “capillary” area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher’s exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: ≤ 5 years versus remote birth: > 5 years]) using multivariable regression models.ResultsNormal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked ≤ 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration.ConclusionsOur study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

Idiopathic Granulomatous Mastitis with Incidental Lobular Carcinoma In Situ: A Case Report

Background: Lobular carcinoma in situ (LCIS) is a type of lobular neoplasia within the terminal duct lobular unit, involving more than half of acini. It is mostly diagnosed incidentally and although it is not a malignant lesion, it has an association with malignancy in the future. Idiopathic granulomatous mastitis (IGM) is a benign granulomatous disease with few simultaneous reports of malignant lesions in the literature. In this case report, we present a case with LCIS and IGM in a single breast.Case Presentation: A 35-year-old female presented to the breast clinic with complaints of pain and a palpable mass in the right breast. The past medical history, habitual history, drug history, and family history of cancer were negative. Physical examinations showed a palpable mass in the right breast without nipple discharge and retraction and lymphadenopathy and the left breast was intact. Breast imaging showed a right UOQ mass. A core needle biopsy was performed showing LCIS and IGM on the right side with a positive cytoplasmic reaction for P120 catenin. E-cadherin was negative in LCIS. P63 and CK5/6 immunostainings revealed the presence of myoepithelial cells around ductal and glandular structures. The patient developed erythema nodosum at the time of diagnosis. She was put on prednisolone 50 mg per day and NSAID, and after improvement was maintained on 25 mg daily prednisolone for about 7 months, combined with 3 months of hydroxychloroquine 200 mg twice a day. At the 12-month follow-up, both breasts were completely normal in the physical examination without any mass or skin changes and the right breast mass decreased in size.Conclusion: Radiologic findings of IGM can be suggestive of other possible causes and silent etiologies like the primary phase of breast cancer and LCIS should not be overlooked.

Breast cancers originating from the major lactiferous ducts and the process of neoductgenesis: Ductal Adenocarcinoma of the Breast, DAB

PurposeTo call attention to a highly fatal breast cancer subtype arising from the major lactiferous ducts that is currently underdiagnosed as ductal carcinoma in situ (DCIS) with or without microinvasion. MethodAll breast cancers diagnosed at the Department of Mammography, Falun Central Hospital, Sweden, since 1977 have been classified according to their mammographic tumour features (imaging biomarkers) and followed up at regular intervals for the past four decades. The imaging biomarkers characteristic of breast cancers apparently arising from the major lactiferous ducts have been correlated with large format thin and thick section histopathology and long-term patient outcome. ResultsBreast cancers arising within the major lactiferous ducts propagate intraductally and produce continuously branching neoducts through epithelial-mesenchymal transformation (EMT), an invasive process termed neoductgenesis, which eventually forms a massive tumour burden. The high fatality of this breast cancer subtype indicates its truly invasive nature, although it is conventionally termed ductal carcinoma in situ, DCIS, terminology which is at odds with its poor long-term patient outcome. The neoducts are filled with multiple layers of malignant cells, have no attached lobules, and propagate by forming multiple invasive side branches. These newly formed duct-like structures are surrounded by a desmoplastic reaction (cancer associated fibroblasts, CAFs) and periductal lymphocytic infiltration. The neoducts are tightly packed together in irregular formations bearing no resemblance to the paniculate branching structure of normal lactiferous ducts. Cancers originating from the major ducts have six imaging biomarkers which can be easily recognized at breast imaging. These are described in detail in an accompanying article. ConclusionsNeoductgenesis in the breast, DAB, is similar in appearance and prognosis to ductal adenocarcinoma of the prostate, DAP. We propose the term ductal adenocarcinoma of the breast, DAB, to facilitate its recognition as a distinct invasive breast cancer subtype. The high fatality rates associated with neoductgenesis reflect the failure of current histopathologic diagnostic criteria to effectively guide therapeutic practice. When the neoducts are associated with small stellate/spiculated or spherical/oval-shaped invasive cancers arising from the terminal ductal lobular units (TDLUs), the prognosis and management are erroneously estimated according to the smaller invasive tumour(s), giving a false sense of security often resulting in undertreatment. Recognition that neoductgenesis is an invasive malignancy is a prerequisite for preventing treatment failure.

The ultrasound diagnosis of breast atypical ductal hyperplasia type with pseudo-invasive growth (clinical observation)

Atypical ductal hyperplasia is a proliferation of monomorphic, evenly placed epithelial cells involving terminalduct lobular units. The term atypical ductal hyperplasia identifies a group of lesions with a combination of specifically defined architectural and cytological features that predict an increased risk of subsequent breast cancer. Our case described the visualization of breast atypical ductal hyperplasia with architectural distortion seen in a form of “radiance” phenomenon in a patient with burdened obstetric and gynecological anamnesis by a tridimensional breast ultrasound examination on the system Siemens Acuson S2000 with mammalogical device ABVS (Automated Breast Volume Scanner).

Breast cancers originating from the terminal ductal lobular units: In situ and invasive acinar adenocarcinoma of the breast, AAB

PurposeTo use mammographic tumour features (imaging biomarkers) to identify and investigate breast cancers originating from the terminal ductal lobular units (TDLUs) of the breast in order to overcome the confusion arising from the current histopathology terminology, which calls cancers arising from the TDLUs either “ductal” or “lobular”. MethodProspectively collected data from a randomized controlled mammography screening trial with more than four decades of follow up, and data from the subsequent population-based service screening program in Dalarna County, Sweden, provided the database necessary for studying nonpalpable, primarily screen-detected breast cancer cases in their earliest detectable phases. Large format thick (subgross) and thin section histopathologic images of breast cancers originating from the TDLUs were correlated with their mammographic tumour features (imaging biomarkers) and long-term patient outcome. ResultsThis systematic correlation indicates that imaging biomarkers can reliably determine the site of origin of breast cancers arising from the terminal ductal lobular units (TDLUs). This breast cancer subgroup has four specific mammographic tumour features: the in situ carcinomas developing from the TDLUs appear as powdery or crushed stone-like calcifications, while the invasive carcinomas appear as stellate/spiculated or circular/oval shaped tumour masses. These features are easily identified with breast imaging, either alone or in combination, unifocal or multifocal. We propose calling breast cancers of TDLU origin acinar adenocarcinoma of the breast (AAB). ConclusionsThe era of early detection necessitates rectifying the current, confusing histopathological nomenclature to one that is based on the anatomical site of origin of breast cancers. Invasive cancers originating from the TDLUs are either stellate/spiculated or circular, irrespective of the complex WHO histopathologic terminology. The mortality reduction accomplished by participation in mammography screening is mostly accomplished by identifying and treating the AABs in their non-palpable, early phase. AABs detected when < 15 mm diameter with no associated carcinoma originating from the major lactiferous ducts (ductal adenocarcinoma of the breast, DAB) have a good to excellent long-term outcome, irrespective of the current terminology, which tends to lead to overtreatment of these early invasive tumours. The conventionally used prognostic factors, including immunohistochemical biomarkers, fail to identify those 1–14 mm invasive AABs tumours that are eventually fatal. This identification can be made preoperatively by including the characteristic mammographic tumour features, imaging biomarkers, in primary diagnosis, treatment planning, and predicting long-term patient outcome. Forthcoming articles will address breast malignancies originating from structures of the breast other than the TDLUs.

Serum hormone levels and normal breast histology among premenopausal women.

Breast terminal duct lobular units (TDLUs) are the main source of breast cancer (BC) precursors. Higher serum concentrations of hormones and growth factors have been linked to increased TDLU numbers and to elevated BC risk, with variable effects by menopausal status. We assessed associations of circulating factors with breast histology among premenopausal women using artificial intelligence (AI) and preliminarily tested whether parity modifies associations. Pathology AI analysis was performed on 316 digital images of H&E-stained sections of normal breast tissues from Komen Tissue Bank donors ages ≤ 45years to assess 11 quantitative metrics. Associations of circulating factors with AI metrics were assessed using regression analyses, with inclusion of interaction terms to assess effect modification. Higher prolactin levels were related to larger TDLU area (p < 0.001) and increased presence of adipose tissue proximate to TDLUs (p < 0.001), with less significant positive associations for acini counts (p = 0.012), dilated acini (p = 0.043), capillary area (p = 0.014), epithelial area (p = 0.007), and mononuclear cell counts (p = 0.017). Testosterone levels were associated with increased TDLU counts (p < 0.001), irrespective of parity, but associations differed by adipose tissue content. AI data for TDLU counts generally agreed with prior visual assessments. Among premenopausal women, serum hormone levels linked to BC risk were also associated with quantitative features of normal breast tissue. These relationships were suggestively modified by parity status and tissue composition. We conclude that the microanatomic features of normal breast tissue may represent a marker of BC risk.

Association of Genetic Ancestry With Terminal Duct Lobular Unit Involution Among Healthy Women.

Reduced age-related terminal duct lobular unit (TDLU) involution has been linked to increased breast cancer risk and triple-negative breast cancer. Associations of TDLU involution levels with race and ethnicity remain incompletely explored. Herein, we examined the association between genetic ancestry and TDLU involution in normal breast tissue donated by 2014 healthy women in the United States. Women of African ancestry were more likely than European women to have increased TDLU counts (odds ratio [OR]trend = 1.36, 95% confidence interval [CI] = 1.07 to 1.74), acini counts per TDLU (OR = 1.47, 95% CI = 1.06 to 2.03), and median TDLU span (ORtrend = 1.44, 95% CI = 1.08 to 1.91), indicating lower involution, whereas East Asian descendants were associated with decreased TDLU counts (ORtrend = 0.52, 95% CI = 0.35 to 0.78) after controlling for potential confounders. These associations are consistent with the racial variations in incidence rates of triple-negative breast cancer in the United States and suggest opportunities for future work examining whether TDLU involution may mediate the racial differences in subtype-specific breast cancer risk.

Myoepithelial progenitors as founder cells of hyperplastic human breast lesions upon PIK3CA transformation

The myoepithelial (MEP) lineage of human breast comprises bipotent and multipotent progenitors in ducts and terminal duct lobular units (TDLUs). We here assess whether this heterogeneity impacts on oncogenic PIK3CA transformation. Single cell RNA sequencing (scRNA-seq) and multicolor imaging reveal that terminal ducts represent the most enriched source of cells with ductal MEP markers including α-smooth muscle actin (α-SMA), keratin K14, K17 and CD200. Furthermore, we find neighboring CD200high and CD200low progenitors within terminal ducts. When sorted and kept in ground state conditions, their CD200low and CD200high phenotypes are preserved. Upon differentiation, progenitors remain multipotent and bipotent, respectively. Immortalized progenitors are transduced with mutant PIK3CA on an shp53 background. Upon transplantation, CD200low MEP progenitors distinguish from CD200high by the formation of multilayered structures with a hyperplastic inner layer of luminal epithelial cells. We suggest a model with spatially distributed MEP progenitors as founder cells of biphasic breast lesions with implications for early detection and prevention strategies.

Laminin N-terminus α31 is upregulated in invasive ductal breast cancer and changes the mode of tumour invasion.

Laminin N-terminus α31 (LaNt α31) is an alternative splice isoform derived from the laminin α3 gene. The LaNt α31 protein is enriched around the terminal duct lobular units in normal breast tissue. In the skin and cornea the protein influences epithelial cell migration and tissue remodelling. However, LaNt α31 has never been investigated in a tumour environment. Here we analysed LaNt α31 in invasive ductal carcinoma and determined its contribution to breast carcinoma invasion. LaNt α31 expression and distribution were analysed by immunohistochemistry in human breast tissue biopsy sections and tissue microarrays covering 232 breast cancer samples. This analysis revealed LaNt α31 to be upregulated in 56% of invasive ductal carcinoma specimens compared with matched normal tissue, and further increased in nodal metastasis compared with the tumour mass in 45% of samples. 65.8% of triple negative cases displayed medium to high LaNt α31 expression. To study LaNt α31 function, an adenoviral system was used to induce expression in MCF-7 and MDA-MB-231 cells. 2D cell migration and invasion into collagen hydrogels were not significantly different between LaNt α31 overexpressing cells and control treated cells. However, LaNt α31 overexpression reduced the proliferation rate of MCF-7 and MDA-MB-231 cells. Moreover, LaNt α31 overexpressing MDA-MB-231 cells displayed a striking change in their mode of invasion into laminin-containing Matrigel; changing from multicellular streaming to individual cellular-invasion. In agreement with these results, 66.7% of the tumours with the highest LaNt α31 expression were non-cohesive. Together these findings indicate that breast cancer-associated changes in LaNt α31 expression could contribute to the processes involved in tumour invasion and may represent a new therapeutic target.

Abstract P2-11-14: Pathology AI features and immune biomarkers of postpartum involution: Implications for postpartum breast cancer

Abstract Breast cancer risk is increased in parous women in the period following childbirth, peaking at five years. After weaning or in the absence of lactation, the breast undergoes postpartum involution (PPI), a process characterized by epithelial cell death and tissue remodeling that returns the mammary gland to a baseline state, and has previously been associated with increased inflammation and breast cancer development and progression in preclinical models. Features of PPI and determinants of related inflammation have been incompletely characterized among women. In this study, we performed visual and AI analysis of 725 digitized H&amp;E images of normal breast tissues donated to the Komen Tissue Bank (KTB) by parous and nulliparous women ≤45 years, and further investigated the immune microenvironment in specimens from 23 women (also from KTB, 13 parous, 10 nulliparous) using NanoString RNA immuno oncology (IO) 360 panels and immune protein biomarkers by NanoString GeoMx Digital Spatial Profiling (DSP). We found that recently parous women (≤5 years of a last birth) had higher numbers of terminal duct lobular units (TDLUs), immune cells, and plasma cells as compared with nulliparous women, and that beyond 5 years of a last birth, TDLU numbers were still higher in parous women, but the immune and plasma cell content of the breast of parous and nulliparous women were not significantly different. Our gene expression analysis revealed differential expression of genes that clustered according to parity status, with interferon stimulated genes; STAT1 and IFITM1, and interferon alpha receptor 1 (IFNAR1), and MHC class II genes (HLA-DMA, HLA-DPA,HLA-DPB1, and HLA-DRA) elevated in parous women. Our DSP analysis revealed that immune biomarkers with immunosuppressive functions, including ARG1, VISTA, CTLA-4, and CD68 were significantly higher in parous women as compared with nulliparous women. Breast tissues of parous women show lobular expansion and alterations in immune cell components compared with nulliparous tissues. Further research is needed to assess how these alterations may impact risk. Citation Format: Joshua Were Ogony, Thomas De Bel, Derek Radisky, Jeroen VanderLaak, Mark Sherman. Pathology AI features and immune biomarkers of postpartum involution: Implications for postpartum breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-11-14.

A new approach to breast cancer terminology based on the anatomic site of tumour origin: The importance of radiologic imaging biomarkers

PurposeTo use mammographic tumour features (imaging biomarkers) to classify breast cancer according to its apparent anatomic site of origin in the new era where tumours are found at their nonpalpable, earliest detectable phase. MethodLarge format, subgross, three-dimensional histopathologic images of breast cancer subtypes and their corresponding imaging biomarkers were correlated with large format thin section histopathology and long-term patient outcome. ResultsThis systematic correlation indicates that breast cancers arise from three separate fibroglandular tissue components: the terminal ductal lobular units (TDLUs), the major lactiferous ducts, and in the stem cells of the mesenchyme. The resulting three cancer subgroups have distinctly different clinical, histopathological and mammographic presentations and different long-term outcomes. The relative frequency of these three breast cancer subgroups is approximately 75%, 20% and 5%, respectively. Classification of breast cancers according to their anatomic site of origin, as demonstrated with breast imaging and confirmed by subgross histopathology, correlates closely with the long-term patient outcome. ConclusionsClassification of breast cancers according to their site of origin helps overcome the inconsistencies in the current histopathologic terminology with its ductal-lobular dichotomy. The ability of the imaging biomarkers to determine the site of tumour origin and serve as a prognostic indicator emphasizes the increasingly crucial role of breast imaging in the management of breast cancer. Basing breast cancer management upon anatomically relevant terminology challenges the conventional mindset. Our proposals are based on research results from an unprecedented number of prospectively collected nonpalpable breast cancers diagnosed at their earliest detectable phases and followed up for several decades. This article is a general introduction to a series of forthcoming articles describing in detail the breast malignancies originating from the three sites of origin.

Automated quantification of levels of breast terminal duct lobular (TDLU) involution using deep learning

Convolutional neural networks (CNNs) offer the potential to generate comprehensive quantitative analysis of histologic features. Diagnostic reporting of benign breast disease (BBD) biopsies is usually limited to subjective assessment of the most severe lesion in a sample, while ignoring the vast majority of tissue features, including involution of background terminal duct lobular units (TDLUs), the structures from which breast cancers arise. Studies indicate that increased levels of age-related TDLU involution in BBD biopsies predict lower breast cancer risk, and therefore its assessment may have potential value in risk assessment and management. However, assessment of TDLU involution is time-consuming and difficult to standardize and quantitate. Accordingly, we developed a CNN to enable automated quantitative measurement of TDLU involution and tested its performance in 174 specimens selected from the pathology archives at Mayo Clinic, Rochester, MN. The CNN was trained and tested on a subset of 33 biopsies, delineating important tissue types. Nine quantitative features were extracted from delineated TDLU regions. Our CNN reached an overall dice-score of 0.871 (±0.049) for tissue classes versus reference standard annotation. Consensus of four reviewers scoring 705 images for TDLU involution demonstrated substantial agreement with the CNN method (unweighted κappa = 0.747 ± 0.01). Quantitative involution measures showed anticipated associations with BBD histology, breast cancer risk, breast density, menopausal status, and breast cancer risk prediction scores (p < 0.05). Our work demonstrates the potential to improve risk prediction for women with BBD biopsies by applying CNN approaches to generate automated quantitative evaluation of TDLU involution.

Determination of Risk Factors for DCIS Ductal in-situ Carcinoma of Mammary Gland

Mammary gland is altered gland present in skin whose main function in females is that it acts as a lactating gland while in males it is non-functional. When the sample of tissue of mammary gland is observed under microscope it was found that there are 2 major types of tissues which are present. These tissues are epithelial and stromal tissues. The epithelial component of the breast consists of 2 major parts: terminal duct-lobular unit (TDLU) which performs the main secretory function during lactation, and large duct system which performs the function of collection and drainage of secretions; both are interconnected to each other. During the menstrual age of a female patient there are different number of tissues (connective and adipose) is present in the mammary gland these tissues mainly perform as the support system for the mammary gland. Acini, ducts, and lobule are enclosed in intralobular stroma and is mainly formed of connective tissue(loose) myxomatous stroma and some dispersed lymphocyte. The ductal carcinoma is very serious Pathology of breast which is now a major concern in developed country and to a certain extent in developing countries also. There are many major risk factors which are responsible for the same. Some may be of lifestyle based or of genetic based. The treatment for the disease is now possible with advancement in the medical science.&#x0D; Purpose for this review article is: Determine the cause affecting factors influencing factors and pathos physiological background of development of DCIS also to describe the gene involved in alteration of cell to enhance tumorous growth and the treatment therapy involved alongside the disease.