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Breast

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Histology

Authors: Indu Agarwal, M.D., Luis Blanco, Jr., M.D.

Editorial Board Members: Gary Tozbikian, M.D., Julie M. Jorns, M.D.

Last author update: 2 August 2021

Last staff update: 9 May 2022

Copyright: 2002-2024, PathologyOutlines.com, Inc.

PubMed Search: Breast histology

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Table of Contents

Cite this page: Agarwal I, Blanco L. Histology. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/breastnormal.html. Accessed April 24th, 2024.

Definition / general

Mammary glands located on the upper anterior thorax that produce and secrete milk in females

Essential features

Adult female breast consists of branching ducts and acini; the acini group together to form lobules
Ductal - lobular system: composed of ducts and acini lined by a dual inner (luminal) epithelial cell layer and outer (basal) myoepithelial cell layer, resting on a basement membrane, enveloped by stroma
Exhibits physiologic histomorphologic changes during menstrual cycle, pregnancy / lactation, menopause, exogenous hormone therapy

Embryology

Considered an epidermal gland, as it develops as diverticula of epidermis into dermis
Mammary gland development begins at week 5
Week 5:
- Ectodermal thickenings called mammary ridges develop along ventral embryo, extending from axilla to medial thigh
- Ridges eventually disappear, except at fourth intercostal space where mammary gland develops
Week 15 - 20:
- Mesenchyme condenses around epithelial stalk under testosterone influence
- Solid epithelial columns develop within mesenchyme
Week 20 - 32:
- Differentiation of mesenchyme into fat within collagenous stroma
- Stroma of reticular dermis forms suspensory ligaments of Cooper, attaching breast to skin and subdividing breast into lobes
- Areola formed by ectoderm
Week 32 - 40:
- Epithelial cords canalize and branch, forming lobuloalveolar structures
- Depression in epidermis forms at the convergence of lactiferous ducts: mammary pit
Near term birth: nipple formed by evagination of mammary pit
Reference: Mills: Histology for Pathologists, 4th Edition, 2012

Histology

Ductal - lobular system:
- Consists of large lactiferous ducts that open to the surface of the nipple via lactiferous sinuses, which branch into ducts and terminal ductules which terminate in acini
- Acini are grouped together in clusters to form lobules (terminal duct lobular unit)
- Ductal - lobular system is arranged in series of segments (5 - 10)
- Cellular lining of the ductal - lobular system is bilayered and consists of:
  - Inner (luminal) epithelial cells: cuboidal to columnar epithelium with pale eosinophilic cytoplasm
  - Outer (basal) myoepithelium: variably distinctive, varies in appearance from flattened cells with compressed nuclei to prominent epithelioid cells with abundant clear cytoplasm, can sometimes have myoid appearance
- Both epithelial and myoepithelial cells thought to arise from a bipotent progenitor cell (Oncotarget 2017;8:10675)
- Basement membrane surrounds mammary ducts, ductules and acini (Virchows Arch A Pathol Anat Histopathol 1992;421:323)
- Basement membrane contains type IV collagen and laminin, demarcates ductal - lobular system from the surrounding stroma
- Transgression of the myoepithelial layer and basement membrane by tumor cells defines invasion
Stroma:
- Consists of varying amounts of fibrous tissue and adipose tissue and can be divided into:
  - Interlobular stroma:
    - Surrounds large ducts and terminal duct lobular units (TDLUs), denser, more collagenous than intralobular connective tissue
    - Multinucleated giant cells of unknown significance are sometimes present (Virchows Arch 2001;439:768)
  - Intralobular stroma: surrounds acini within TDLUs, loose, contains fibroblasts, scattered inflammatory cells and histiocytes
Nipple - areolar complex: skin variably pigmented, contains numerous sebaceous glands
- Independent of hair follicles, except at periphery of areola; contains dense fibrous stroma with bundles of smooth muscle
- Montgomery tubercles: sebaceous glands sharing ostium with a lactiferous duct, more prominent during pregnancy and lactation
- Epidermis may contain occasional clear cells, either clear keratinocytes or Toker cells (epidermally located mammary duct epithelium)
  - Toker cells found in 10% of normal nipple (Histol Histopathol 2009;24:367)
- Stratified squamous epithelium extends into duct lumens for 1 - 2 mm (Clin Radiol 2012;67:e42)

Menstrual cycle related changes

Clinically manifested by changes in breast size and texture, varies between individuals
Proliferative phase (follicular) breast:
- Small lobules with few terminal duct structures, smaller acinar lumina, rare mitotic figures, condensed intralobular stroma
- Myoepithelial cells inconspicuous
- Absence of inflammatory infiltrate in the intralobular stroma
Secretory phase (luteal) breast:
- Larger lobules, more terminal duct structures, open acinar lumina, prominent apical snouting, stromal edema (breast fullness), increased mitotic figures
- Myoepithelial cells with prominent cytoplasmic vacuolization
- Mixed inflammatory infiltrate in the stroma
Perimenstrual breast:
- Distended acinar lumina with secretions, luminal cells with scant cytoplasm, less apical snouting
- Myoepithelial cells with extensive cytoplasmic vacuolization
- Increased inflammatory infiltrate in the stroma
References: Mills: Histology for Pathologists, 4th Edition, 2012, Mod Pathol 2002;15:1348

Pregnancy / lactation

Dramatic increase in the number of lobules, as well as acinar units
Increased epithelial cell proliferation and lobuloalveolar differentiation
Decrease in intralobular and interlobular stroma
Second and third trimester:
- Increase in size of epithelial cells and cytoplasmic vacuolization, myoepithelial cells difficult to discern
Lactation:
- Abundant secretory material and prominent cytoplasmic vacuoles, epithelial cells may have bulbous or hobnail appearance
- Myoepithelial cells remain inconspicuous
- Rarely areas of infarction (Exp Ther Med 2015;10:1888)

Menopause

Reduction of estrogen and progesterone causes involution and atrophy of TDLUs
Reduction in size and complexity of acini, loss of specialized intralobular stroma
Hyalinized stroma with relative increase in fat
Reference: Mills: Histology for Pathologists, 4th Edition, 2012

Neonatal breast

Identical in males and females at birth
Breast enlargement due to neonatal prolactin production, caused by falling maternal estrogen
Associated with production of colostrum
Extramedullary hematopoiesis may be seen (J Pediatr Hematol Oncol 2012;34:229)

Male breast

Composed of ductal structures only within collagenized stroma, with no / rare acini

Transsexual breast

Female to male conversion results from prolonged androgen administration, starting prior to mastectomy
- Reduction in glandular tissue and prominence of stroma (J Histochem Cytochem 2006;54:905)
- Calcifications more frequent (J Pathol 1993;170:37)
Male to female conversion involves prolonged estrogen therapy and chemical castration with progestational agents
- Changes include well developed lobular structures and pregnancy related changes

Clinical features

Gross anatomy:
- Lies on the anterior chest wall over the pectoralis major muscle, extends from second to sixth rib vertically and from sternal edge to midaxillary line horizontally
- Also projects into the axilla as the tail of Spence
- Microscopic foci of glandular tissue may extend through the pectoral fascia
- Clinical relevance: total mastectomy does not remove all glandular breast tissue
Arterial supply, lymphatic flow:
- Principal arterial supply by the internal mammary and lateral thoracic arteries
- Lymphatic drainage: > 90% to axillary lymph nodes, remaining to internal mammary and posterior intercostal nodes
- Relevance to staging, as metastasis to internal mammary node is higher nodal stage
Breast tissue is typically less nodular, late follicular phase is the optimal time for mammography (Radiol Phys Technol 2018;11:20)
Loss of myoepithelium is usually considered evidence of invasion, with the exception of microglandular adenosis, encapsulated papillary carcinoma and solid papillary carcinoma
Transsexual breast may develop any benign or malignant process seen in nontranssexual breast (Hoda: Rosen's Breast Pathology, 4th Edition, 2014)

Gross description

Mastectomy attempts to remove all breast tissue
Different types of mastectomies: simple, modified radical, prophylactic, skin sparing, nipple sparing and radical
Axillary dissections performed for the staging of invasive carcinoma
- Number of lymph nodes with metastases is the most important prognostic factor for breast carcinoma
Reference: Lester: Manual of Surgical Pathology, 3rd Edition, 2010

Gross images

Images hosted on other servers:

Mastectomy specimen, anterior view

Microscopic (histologic) images

Contributed by Indu Agarwal, M.D.

Terminal duct lobular unit (TDLU)

Extralobular and TDLU

Myoepithelial cells

Myoid appearance

Clear cell change

Cross section of nipple

Lactiferous duct

Lactational changes

Immunostain ER

Immunostain p63

Positive stains

Basement membrane: laminin, type IV collagen and reticulin
Epithelium / luminal cells:
- Usually express luminal cytokeratins: LMWCK, CK7, CK8, CK18, CK19 (J Pathol 2004;203:661)
- Also express mammaglobin, gross cystic disease fluid protein (GCDFP)
- Most express ER alpha or PR in a heterogeneous pattern
- E-cadherin, p120, beta catenin in membranous pattern
Myoepithelial cells:
- Basal cytokeratins: HMWCK, CK5/6, CK14 (Front Biosci (Landmark Ed) 2010;15:226)
- P-cadherin, calponin, smooth muscle myosin heavy chain (SMMHC), smooth muscle actin, CD10, S100 (Arch Pathol Lab Med 2008;132:349)
- At least 2 markers, 1 with a nuclear staining pattern (e.g. p63) and 1 with cytoplasmic staining (e.g. SMMHC) recommended
Toker cells: CK7, EMA and usually positive for ER and PR

Negative stains

HER2 / neu overexpression or amplification not seen in normal breast, restricted to carcinomas (J Clin Oncol 2000;18:267)

Electron microscopy images

Images hosted on other servers:

Acini

Glandular and myoepithelial cells

Videos

Shotgun histology inactive breast

Additional references

Schnitt: Biopsy Interpretation of the Breast, 3rd Edition, 2017

Board review style question #1

From the image above, what is the most likely diagnosis?

Atypical apocrine adenosis
Lactational changes
Microglandular adenosis
Secretory carcinoma

Board review style answer #1

B. Lactational changes. During lactation, epithelial cells are enlarged and have a bulbous or hobnail appearance with attenuated myoepithelial cells. These florid changes seen can be alarming and can be mistaken for atypia or malignancy.

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Reference: Breast - Histology

Board review style question #2

Myoepithelial cells are always retained in which of the following?

Atypical ductal hyperplasia
Encapsulated papillary carcinoma
Invasive tubular carcinoma
Microglandular adenosis

Board review style answer #2

A. Atypical ductal hyperplasia. Myoepithelium is retained in atypical ductal hyperplasia and most benign and in situ lesions, with the exception of microglandular adenosis and a few in situ lesions, e.g. encapsulated papillary carcinoma.

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Reference: Breast - Histology

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