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Normal at thenipple﬉. systems emptyontotheskin center. 15-20majorductal located slightlyinferiorto -areolar complex﬈is pectoralis muscles﬊.The chest wall,overlyingthe is locatedontheanterior (Left) muscle ﬈. Thepectoralismajor the terminalductlobularunits the largeductsystem﬉,and the nipple-areolarcomplex﬇, major breaststructuresare Breast Origin and Function Abbreviations intercostal muscles. the chestwallconnectedby minor ſtoverlietheribsstof Breast has 2 types of• epithelial cells, 2 types of Normal Breast (Rule of Twos) Many important differences• in comparison to other Breast is highly evolved• modified appendage Terminal ductal lobular• unit (TDLU) INTRODUCTION TERMINOLOGY Structures○ Stroma○ Epithelial cell types○ 2 main structures Undergoes continuous○ change over life cycle in res Provides source of ○ nourishment and immunologic Defining feature of○ class Mammalia Due to superficial ○ location, breast has social, se protection for different individual (infant) cultural significance to menarche, , , and menopause TDLU– Large ducts– Intralobular stroma– Interlobular stroma– Myoepithelial cells– Luminal cells– Patients are 1st to diagnose– their carcinomas in Result in broad range – of what is normal breast Target for variety– of that regulate The adultfemalebreast ﬈ Breast is only□ cancer with > 3,000 year populations without screening development and physiologic function andthepectoralis history of 1st person accounts by patients

(Right) The Histology of Normal Breast dl eaeBes BreastStructure Adult FemaleBreast stroma, and xual, and organs p o n s e Nipple-areolar complex• supported by subdermal laye N i p p l e Carcinoma involving these• ligaments results in ski Swelling and edema of• breast tissue around these Provide support and allow• for mobility Ligaments attach to • of skin and pectoralis Suspensory (Cooper) Ligaments rest on anterior• chest wall overlying pect Covered by pigmented • squamous 10-15 major lactiferous• orifices open on surf Positioned slightly medial• and inferior to center Anatomic Boundaries N i p p l e In some women, breast• tissue is present in subcuta GROSS MICROSCOPIC ANATOMY Arranged radially in○ nipple n i p p l e Deep margin of breast○ rests on fascia of pectorali Breast tissue often○ extends into (tail of S d'orange) ligaments causes orange peel appearance of skin (pe Toker cells are normal○ epidermal component Facilitates nipple ○ , function during nursi circumferential Superior border ~ at○ 2nd rib; inferior border at 6 major and minor muscles retraction &/or dimpling borders tissue and can extend beyond grossly evident breast of sternum lateral border at mid axillary line; medial border m u s c l e Usually present as single– cells near nipple orific Present in majority of– if identified by 7 studies of breast m u s c l e oralis pence) ace of n ng at edge th rib; neous s major es au r o f 5 Normal Breast ls lls d ion re LU sm s ins 7, ins t intain reas of reas ng tiple tional em , and , stem quadrant Luminal cells Luminal composed of both cell types (e.g., types cell both of composed carcinoma) cystic myoepitheliomas, □ Supported by occurrence of clonal neoplasms clonal of □occurrence by Supported or serial section reconstruction section serial or another duct orifice at nipple at orifice duct another anastomoses between ducts between anastomoses present – Sometimes referred to as intermediate or basal cel basal or intermediate as – to referred ce Sometimes myoepithelial and luminal – both to rise give May – May also express basal –basal express also May – Cannot be recognized grossly; requires duct inject duct requires –grossly; recognized be Cannot – DCIS grows into 2nd duct system by crossing into crossing by system –duct 2nd into grows DCIS reporte of 1 via system duct – 2nd into crosses DCIS – 2 separate clonal neoplastic populations of DCIS a DCIS of populations –neoplastic clonal separate 2 5/6 in epithelial hyperplasia supports hyperplasia epithelial in 5/6 type cytokeratins cells multiple of population mixed of presence special techniques are required for recognition for required are techniques special this architecture from malignant lesions that do no do that lesions malignant from architecture this change or produce produce or change inconspicuous nucleoli inconspicuous 8, 18, 19 18, 8, breast majority of carcinomas are thought to arise from TD from arise to thought are carcinomas of majority situations ○ Patchy immunoreactivity for high molecular weight molecular high for ○immunoreactivity Patchy acini) ma that lesions benign ○distinguishing in Important cells myoepithelial and present; be may cells stem or ○ Precursor/progenitor ○ Luminal cells in TDLU produce milk produce ○TDLU in cells Luminal lacta undergo not do ducts ○larger in cells Luminal rounded acini (TDLU) acini rounded production milk for breast ○ of unit Functional ○ Nuclei are small, round to oval, usually have usually oval, to ○round small, are Nuclei cytopla eosinophilic of amount ○moderate have Cells Luminal cell phenotype cell Luminal kerat weight molecular low ○luminal express Usually ○ Some large ducts branch and fill widely separate a separate widely fill and ○branch ducts large Some structures resembling ducts resembling structures adenosis sclerosing ○hyperplasia, epithelial Cysts, ○ Anastomoses between ductal systems may be present be may systems ductal ○between Anastomoses carcinoma breast for Significance sy duct single involves ○population; clonal is DCIS syst ductal follows generally ○DCIS of Distribution followi in involved be could ○systems duct Multiple EPITHELIAL CELLS EPITHELIAL • 2 types of epithelial cells are present in breast: in present are cells •epithelial of types 2 Cells Luminal acini and ducts lining • layer innermost Form Lobules multiple into branches duct • terminal when Formed mul by surrounded (duct •architecture Lobulocentric • Cells are cuboidal to columnar in shape in columnar •to cuboidal are Cells • Epithelial Cell Types Cell Epithelial • TDLU can unfold with coalescence of acini to form to acini of coalescence • with unfold can TDLU outer upper in located tissue • glandular all of 50% TDLU the from arise •lesions breast of Majority • on e ola re y ment

n in nd into nd oli rom with als t, often t, hery neath Histology of Normal Breast Normal of Histology cells cytoplasm pale or □clear with cells Bland receptors □for positive Usually of snouts that are pinched off to form to off pinched are that snouts apocrine of secretion) (decapitation secretions – Consists of type IV collagen and laminin and –collagen IV type of Consists – Cells can mimic cells of Paget disease Paget of – cells mimic can Cells – Appearance and immunoprofile are same as luminal as same are –immunoprofile and Appearance – Characterized by apocrine secretion due to presenc to due secretion –apocrine by Characterized around mammary ducts but not lobules not but ducts mammary around contents of extravasation allowing weaken, ductal/lobular system; separates epithelial cells f cells epithelial separates system; ductal/lobular stroma breast nipple orifice nipple ducts of lining luminal/myoepithelial prominent glycogenated cytoplasm glycogenated prominent cytoplasmic granules cytoplasmic smooth muscle, collagen, and elastic fibers elastic and collagen, muscle, smooth sweat sweat closely related to breast epithelial cells epithelial breast to related closely ○ With age, supporting structures of major ducts can ducts major of structures ○supporting age, With ○ Elastic fibers normally present in varying amounts varying in present ○normally fibers Elastic membrane of skin of membrane mammary entire ○surrounds membrane Basement ○ Abrupt transition from squamous cells to normal to cells squamous ○from transition Abrupt major ducts for 1-2 mm 1-2 for ducts major present be may plug ○lactation, of Outside ○ Clear cells of nipple epidermis are keratinocytes keratinocytes are epidermis ○nipple of cells Clear overlap quadrant single ○ to confined Rarely individu different in greatly ○vary extent and Size ○ Additional smaller ductal systems open onto onto open systems ductal ○ smaller Additional ○ Numerous sebaceous glands are present in areola in present are glands ○ sebaceous are Numerous of periphery at prominences ○ small through Open lactati and pregnancy during ○prominent more Become ○ Nuclei are large and round with large single nucle single large with round ○and large are Nuclei ○ Cytoplasm is abundant, eosinophilic, and often has often and eosinophilic, ○abundant, is Cytoplasm nipple b supported are and contours ○serrated have Sinuses ○ Present in axillary skin and areola and skin ○axillary in i Present cells of appearance same has ○metaplasia Apocrine ○ Present in breast dermis and skin and ○dermis breast in Present glands these from arise ○syringomas sites, other mo At are nipple of adenomas ○syringomatous breast, In • Keratin-producing squamous cells of epidermis exte epidermis of cells •squamous Keratin-producing • Ducts ramify until they form TDLUs form •they until ramify Ducts exten and size in •considerably vary systems Ductal • Ducts dilate to form lactiferous (milk) sinuses be sinuses (milk) lactiferous • form to dilate Ducts Large Duct System Duct Large nipple at empty •systems duct major 15-20 Skin Appendages Skin •tubercles Montgomery Areola perip at except hair and •units pilosebaceous Lacks present are endings • sensory Numerous • of ducts is continuous with base with continuous is ducts • of membrane Basement • Apocrine sweat glands and ducts and •glands sweat Apocrine • Eccrine sweat glands and ducts and • glands sweat Eccrine 6

Normal Breast Often flattened with • small, round nuclei Multiple functions• Cells form contractile• meshwork that does not cove • Cells look monomorphic• due to metaplasia Epithelial cells can • take on different appearances Metaplastic Changes Form outermost layer • between luminal cells and bas Myoepithelial Cells • Cytoplasm can be abundant○ and clear; may mimic lob Contract for milk ejection○ during breast feeding Inhibit angiogenesis○ Aid in luminal cell○ polarity Help produce and maintain○ basement membrane In cross section, myoepithelial cells○ (MEC) layer basement membrane With aging, cells can○ become prominent and spindle MEC associated with○ carcinoma in situ may diminish Do not express hormone○ receptors Also express p63, CD10,○ P-cadherin, S100, mapsin Express contractile○ proteins: Smooth muscle , membrane Usually express high○ molecular weight basal kerati phenotype Some but not all luminal○ cells express ERα &/or PR It can be very difficult○ to distinguish some cases Complete loss of MEC○ is useful diagnostic feature Luminal cells are thought○ to be precursor cells fo Some luminal cells ○ express mammaglobin &/or gross Cells express E-cadherin○ and other catenins injury, hormonal influences, or other unknown facto Squamous metaplasia May be precursors of○ some hormone receptor negativ incomplete neoplasia 1 4 , 1 7 calponin, smooth muscle myosin heavy chain shape (MEC atrophy) membrane number and become displaced from basement majority of breast carcinomas carcinomas cystic disease fluid protein 15 (GCDFP-15) given time appearance metaplasia from carcinomas with metaplastic recognize invasive carcinoma Lesions of myoepithelial– cells often associated wi May also express luminal– keratins Often fail to express – some MEC markers Many of these carcinomas– express proteins found in Basal used to describe– carcinomas that may arise f Receptor (+) cells are– present in both large duct Hormone receptors are – not expressed in normal matrix production M E C s MEC or MEC-like cell system and TDLU but may be more frequent in latter proliferating luminal cells Histology of Normal Breast due to is of r r entire rs ement to help at any ns 5/6, in th d in rom u l a r e Breast stromal composition• depends on age, menstru Composition • • • • MAMMARY STROMA Composed of varying○ amount of fibrous connective a status, pregnancy history, and lactation Ratio of ductal/fibrous○ tissue to to adipose tissu Mammographic appearance○ Breast epithelial cells○ can take on squamous pheno Very common change ○ in cells lining cystic spaces a Apocrine metaplasia Different appearance○ can often raise concern for a Cytoplasm is abundant○ and eosinophilic Nuclei are large and○ round with prominent single Mixed apocrine and ○ nonapocrine populations favor Rare squamous carcinomas○ arise from areas of Can be present in either○ luminal cells or myoepith Nuclei often small,○ hyperchromatic, and round Cytoplasm is abundant○ and clear Clear cell change Luminal cells have ○ a tall columnar shape rather th Columnar cell change If more than 1 cell○ layer is present, termed colum Luminal cells have ○ brightly eosinophilic cytoplasm Paneth cell-like change Can be associated with○ microglandular adenosis Associatedand with eosinophilic○ colloid-like secretio between individuals and changes over time in response to injury or inflammation papillomas nucleoli benign lesion squamous metaplasia in cysts or neoplasia cells being cuboidal hyperplasia granules carcinomas In older women, breast– may be predominantly With age, fibrous stroma– is replaced by adipose ti In young women, breast– tissue is predominantly Important determinant – of mammographic density Apocrine cells often express– androgen receptor Resembleand apocrine sweat– glands Apocrine snouts common– Red cytoplasmic granules– often present Presence of spindled population– of epithelial cell May be related to apocrine– metaplasia has greater□ sensitivity as adipose tissue (radiolucent or black) Mammography has low□ sensitivity due to difficultyfibrous (radiodense or white) stroma is generally diagnostic of carcinoma show immunoreactivity for HER2 easily calcifications and small masses are detected more detecting lesions e varies ns nar cell an elial ic n d i n t y p i a type al s in ssue r a r e nd 7 Normal Breast troma mal , hemangioma, , are biphasic are cer Res Treat. 97(3):285- Treat. Res cer ipple: three-dimensional ipple: cts revisited. Cancer. revisited. cts ck ' hypothesis and hypothesis lobe' ck ts in . Breast cancer. breast in ts es Treat. 106(2):171-9, Treat. es plasia/Tumor smic granules in breast in granules smic oma, encapsulated papillary encapsulated oma, Epithelial hyperplasia, atypical hyperplasia, Epithelial carcinomas of majority hyperplasia, Myoepitheliomas, collagenous Myoepitheliomas, of subset possible spherulosis, carcinomas negative triple- Pseudoangiomatous stromal Pseudoangiomatous tumors, fibrous (PASH), hyperplasia fibromatosis, desmoid myofibroblastoma, tumors /phyllodes , leiomyoma, adenoma, Nipple Paget adenoma, syringomatous disease carcinoma, Fibroadenoma, phyllodes Fibroadenoma, Epithelial hyperplasia, sclerosing hyperplasia, Epithelial carcinomas adenosis, fibromatosis, nodular fascitis, nodular fibromatosis, myofibroblastoma, tumors, fibrous stromal pseudoangiomatous sarcoma hyperplasia, ctiferous – and phyllodes tumors –phyllodes and Fibroadenomas population that stimulates growth of nonclonal of growth stimulates that population epithelium and epithelium and ulomatous lobular , lobular ulomatous 101(9):1947-57, 2004 101(9):1947-57, intraductal approaches to breast cancer. Breast Can Breast cancer. breast to approaches intraductal 2006 91, patterns and clinical implications. Breast Cancer R Cancer Breast implications. clinical and patterns 2007 carcinoma. Ann Diagn Pathol. 15(2):84-92, 2011 15(2):84-92, Pathol. Diagn Ann carcinoma. Cancer Res Treat. 132(2):555-64, 2012 132(2):555-64, Treat. Res Cancer ○ Neoplasias are due to proliferation of clonal stro clonal of proliferation to ○ due are Neoplasias ○ Hyperplasias are due to increased growth of both s both of growth increased to ○due are Hyperplasias interlobular stroma interlobular ○appearance in myxoid be May SELECTED REFERENCES SELECTED at necrosis, bacterial infection bacterial necrosis, at angiolipoma Lipoma, 5. Love SM et al: Anatomy of the nipple and breast du breast 5.and nipple the of Anatomy al: et SM Love 4. Going JJ et al: Human breast duct anatomy, the 'si the 4.anatomy, duct breast Human al: et JJ Going 3. Rusby JE et al: Breast duct anatomy in the human n human the 3.in anatomy duct Breast al: et JE Rusby 2. Huo L et al: Paneth cell-like eosinophilic cytopla 2.eosinophilic cell-like Paneth al: et L Huo 1. Twelves D et al: The anatomy of fluid-yielding duc 1.fluid-yielding of anatomy The al: et D Twelves Luminal keratins 7, 8, 18, E- 18, 8, 7, keratins Luminal and estrogen cadherin, receptor Basal keratins 5/6, 14, 17, P- 17, 14, 5/6, keratins Basal p63, markers, muscle cadherin, (D2-40) podoplanin CD10, CD34 (majority), muscle markers muscle (majority), CD34 and estrogen (), receptors progesterone (myofibroblasts) • Looser more cellular appearance compared with compared appearance • cellular more Looser cells plasma and •lymphocytes scattered has Often and breast to specific are •stroma this of Lesions ducts (SMOLD) ducts lymphocytic mastopathy lymphocytic Cysts (rupture), granulomatous (rupture), Cysts lymphocytic mastitis, lobular mastopathy s sels f breast f e to e ilk production; ilk Histology of Normal Breast Normal of Histology Conduit for milk for Conduit maintenance of luminal cell luminal of maintenance milk for contraction polarity, ejection Support of epithelial cells, provide cells, epithelial of Support volume breast of majority myoepithelial cells: Contraction for Contraction cells: myoepithelial ejection milk to maintain breast tissue density tissue breast maintain to □ Obesity and postmenopausal hormone use can act can use hormone □postmenopausal and Obesity can be seen and may be due to degenerative changes degenerative to due be may and seen be can understood hemangioma, nodular fasciitis, fibromatosis fasciitis, nodular hemangioma, angiosarcoma (PASH) – Majority of fibroblasts and myofibroblasts CD34(+) myofibroblasts and –fibroblasts of Majority PR(+) &/or ER –are myofibroblasts Some cell stromal multinucleated –hyperchromatic, Large, – Hormonal influences on this stroma are poorly are stroma this –on influences Hormonal – Breast and other sites: Lipoma, angiolipoma, Lipoma, –sites: other and Breast and Myofibroblastoma –breast: in common Most hyperplasia stromal –Pseudoangiomatous breast: Only increase in interlobular stroma interlobular in increase myofibroblasts, adipocytes, blood and lymphatic ves lymphatic and blood adipocytes, myofibroblasts, arise from this stroma this from arise Cell Types of Breast of Types Cell Anatomic Structures and Associated Lesions Associated and Structures Anatomic Interlobular stroma Interlobular volume breast of ○majority for du Responsible primarily is at size ○ breast in Increase ○ Variety of lesions that can occur in and outside o outside and in occur can that ○ lesions of Variety ○ Cellular components of stroma include fibroblasts, include stroma of ○components Cellular Cell Types Cell FunctionExpression Protein Lesions Anatomic Structure Anatomic FunctionLesions Inflammatory Hyper Luminal cells Luminal Ducts: production; Milk TDLU: Myoepithelial cells Myoepithelial membrane, basement Support Nipple/areolaejection Milk la of metaplasia Squamous Stromal fibroblasts and fibroblasts Stromal myofibroblasts Large duct system duct Large milk for Conduit ectasia Duct Papill Terminal ductal lobular unit (TDLU) unit lobular M ductal cells: Terminal Luminal Interlobular stroma Interlobular breast of motility shape, Size, F Intralobular stroma Intralobular TDLU of support and Function Gran • Surrounds and supports acini of TDLU of acini •supports and Surrounds Intralobular Stroma Intralobular •