Histology of Normal Breast TERMINOLOGY GROSS ANATOMY Abbreviations Anatomic Boundaries • Terminal ductal lobular unit (TDLU) • Breasts rest on anterior chest wall overlying pectoralis major and minor muscles Normal Breast INTRODUCTION ○ Superior border ~ at 2nd rib; inferior border at 6th rib; Breast Origin and Function lateral border at mid axillary line; medial border at edge of sternum • Breast is highly evolved modified skin appendage ○ Deep margin of breast rests on fascia of pectoralis major ○ Defining feature of class Mammalia muscle • Many important differences in comparison to other organs ○ Breast tissue often extends into axilla (tail of Spence) ○ Provides source of nourishment and immunologic • In some women, breast tissue is present in subcutaneous protection for different individual (infant) tissue and can extend beyond grossly evident breast ○ Undergoes continuous change over life cycle in response borders to menarche, pregnancy, lactation, and menopause – Target organ for variety of hormones that regulate Suspensory (Cooper) Ligaments development and physiologic function • Ligaments attach to fascia of skin and pectoralis muscle – Result in broad range of what is normal breast • Provide support and allow for mobility histology • Swelling and edema of breast tissue around these ○ Due to superficial location, breast has social, sexual, and ligaments causes orange peel appearance of skin (peau cultural significance d'orange) – Patients are 1st to diagnose their carcinomas in • Carcinoma involving these ligaments results in skin populations without screening retraction &/or dimpling □ Breast cancer is only cancer with > 3,000 year Nipple history of 1st person accounts by patients • Positioned slightly medial and inferior to center of breast Normal Breast (Rule of Twos) • 10-15 major lactiferous duct orifices open on surface of • Breast has 2 types of epithelial cells, 2 types of stroma, and nipple 2 main structures ○ Arranged radially in nipple ○ Epithelial cell types • Nipple-areolar complex supported by subdermal layer of – Luminal cells circumferential smooth muscle – Myoepithelial cells ○ Facilitates nipple erection, function during nursing ○ Stroma – Interlobular stroma MICROSCOPIC ANATOMY – Intralobular stroma Nipple ○ Structures • Covered by pigmented squamous epithelium – Large ducts ○ Toker cells are normal epidermal component – TDLU – Present in majority of nipples if identified by cytokeratin 7 studies – Usually present as single cells near nipple orifices Adult Female Breast Breast Structure (Left) The adult female breast is located on the anterior chest wall, overlying the pectoralis muscles ﬊. The nipple-areolar complex ﬈ is located slightly inferior to center. 15-20 major ductal systems empty onto the skin at the nipple ﬉. (Right) The major breast structures are the nipple-areolar complex ﬇, the large duct system ﬉, and the terminal duct lobular units ﬈. The pectoralis major muscle ﬈ and the pectoralis minor ſt overlie the ribs st of the chest wall connected by intercostal muscles. 4 Histology of Normal Breast Normal Breast – Appearance and immunoprofile are same as luminal ○ Some large ducts branch and fill widely separate areas of cells breast □ Bland cells with clear or pale cytoplasm – Cannot be recognized grossly; requires duct injection □ Usually positive for hormone receptors or serial section reconstruction ○ Clear cells of nipple epidermis are keratinocytes with ○ Anastomoses between ductal systems may be present prominent glycogenated cytoplasm • Significance for breast carcinoma – Cells can mimic cells of Paget disease ○ DCIS is clonal population; involves single duct system • Ducts dilate to form lactiferous (milk) sinuses beneath ○ Distribution of DCIS generally follows ductal system nipple ○ Multiple duct systems could be involved in following ○ Sinuses have serrated contours and are supported by situations smooth muscle, collagen, and elastic fibers – DCIS grows into 2nd duct system by crossing into • Basement membrane of ducts is continuous with basement another duct orifice at nipple membrane of skin – DCIS crosses into 2nd duct system via 1 of reported ○ Basement membrane surrounds entire mammary anastomoses between ducts ductal/lobular system; separates epithelial cells from – 2 separate clonal neoplastic populations of DCIS are breast stroma present – Consists of type IV collagen and laminin Lobules ○ Elastic fibers normally present in varying amounts around mammary ducts but not lobules • Formed when terminal duct branches into multiple ○ With age, supporting structures of major ducts can rounded acini (TDLU) weaken, allowing extravasation of contents ○ Functional unit of breast for milk production • Keratin-producing squamous cells of epidermis extend into • Lobulocentric architecture (duct surrounded by multiple major ducts for 1-2 mm acini) ○ Outside of lactation, keratin plug may be present in ○ Important in distinguishing benign lesions that maintain nipple orifice this architecture from malignant lesions that do not ○ Abrupt transition from squamous cells to normal • TDLU can unfold with coalescence of acini to form luminal/myoepithelial lining of ducts structures resembling ducts • 50% of all glandular tissue located in upper outer quadrant Areola • Majority of breast lesions arise from the TDLU • Lacks pilosebaceous units and hair except at periphery ○ Cysts, epithelial hyperplasia, sclerosing adenosis, and • Numerous sensory nerve endings are present majority of carcinomas are thought to arise from TDLU Skin Appendages EPITHELIAL CELLS • Montgomery tubercles ○ Numerous sebaceous glands are present in areola Epithelial Cell Types ○ Open through small prominences at periphery of areola • 2 types of epithelial cells are present in breast: Luminal cells ○ Become more prominent during pregnancy and lactation and myoepithelial cells • Eccrine sweat glands and ducts ○ Precursor/progenitor or stem cells may be present; ○ Present in breast dermis and skin special techniques are required for recognition ○ At other sites, syringomas arise from these glands – Sometimes referred to as intermediate or basal cells ○ In breast, syringomatous adenomas of nipple are more – May give rise to both luminal and myoepithelial cells closely related to breast epithelial cells □ Supported by occurrence of clonal neoplasms • Apocrine sweat glands and ducts composed of both cell types (e.g., ○ Present in axillary skin and areola myoepitheliomas, adenoid cystic carcinoma) ○ Apocrine metaplasia has same appearance of cells in ○ Patchy immunoreactivity for high molecular weight sweat glands cytokeratins 5/6 in epithelial hyperplasia supports – Characterized by apocrine secretion due to presence presence of mixed population of multiple cells types of apocrine snouts that are pinched off to form Luminal Cells secretions (decapitation secretion) • Form innermost layer lining ducts and acini ○ Nuclei are large and round with large single nucleoli ○ Luminal cells in TDLU produce milk ○ Cytoplasm is abundant, eosinophilic, and often has ○ Luminal cells in larger ducts do not undergo lactational cytoplasmic granules change or produce milk Large Duct System • Cells are cuboidal to columnar in shape • 15-20 major duct systems empty at nipple ○ Nuclei are small, round to oval, usually have ○ Additional smaller ductal systems open onto areola inconspicuous nucleoli • Ducts ramify until they form TDLUs ○ Cells have moderate amount of eosinophilic cytoplasm • Ductal systems vary considerably in size and extent, often • Luminal cell phenotype overlap ○ Usually express luminal low molecular weight keratins 7, ○ Rarely confined to single quadrant 8, 18, 19 ○ Size and extent vary greatly in different individuals – May also express basal keratins 5 Histology of Normal Breast ○ Some but not all luminal cells express ERα &/or PR at any ○ Breast epithelial cells can take on squamous phenotype given time in response to injury or inflammation – Hormone receptors are not expressed in normal ○ Different appearance can often raise concern for atypia proliferating luminal cells or neoplasia – Receptor (+) cells are present in both large duct ○ Rare squamous carcinomas arise from areas of Normal Breast system and TDLU but may be more frequent in latter squamous metaplasia in cysts ○ Cells express E-cadherin and other catenins – Presence of spindled population of epithelial cells in ○ Some luminal cells express mammaglobin &/or gross stroma is generally diagnostic of carcinoma cystic disease fluid protein 15 (GCDFP-15) • Apocrine metaplasia ○ Luminal cells are thought to be precursor cells for ○ Very common change in cells lining cystic spaces and in majority of breast carcinomas papillomas Myoepithelial Cells – Resemble apocrine sweat glands – Apocrine cells often express androgen receptor and • Form outermost layer between luminal cells and basement show immunoreactivity for HER2 membrane ○ Mixed apocrine and nonapocrine populations favor • Cells form contractile meshwork that does not cover entire benign lesion basement membrane ○ Nuclei are large and round with prominent single ○ In cross section, myoepithelial cells (MEC) layer is nucleoli incomplete ○ Cytoplasm is abundant and eosinophilic • Multiple functions – Red cytoplasmic granules often present ○ Help produce and maintain basement membrane – Apocrine snouts common – Lesions of myoepithelial cells often associated with • Clear cell change matrix production ○ Cytoplasm is abundant and clear ○ Aid in luminal cell polarity ○ Nuclei often small, hyperchromatic, and