The adult female breast is a modified sweat gland; located on the anterior chest wall, overlying the pectoralis major muscle; It typically extends from the second to the sixth rib vertically; and from the sternal edge to the midaxillary line horizontally; with an axillary tail (of Spence) projecting into the axilla

Gross Anatomy
─ Lobes Composed of 15-25 lobes; collections of lobules; embedded in fibrous and adipose tissue
─ Ductal System Each lobe drains via a lactiferous duct that opens onto the nipple; Lactiferous sinuses are dilatations of the ducts just beneath the nipple
─ Nipple-Areolar Complex The nipple is a pigmented projection containing lactiferous duct openings, smooth muscle fibers, sensory nerve endings; The areola is pigmented skin surrounding the nipple; containing Montgomery glands (sebaceous glands)

Histology
─ Terminal Duct Lobular Unit (TDLU) Functional unit of the breast; Each TDLU consists of a terminal duct (extralobular terminal duct) and a cluster of ductules or acini (intralobular terminal ductules) forming the lobule
─ Acini/Ductules Small, gland-like structures for milk production during lactation; In resting state, small with inconspicuous lumina
─ Ductal-Lobular System Lining Both ducts and acini lined by a bilayer of cells
─ Inner (Luminal) Epithelial Cells Cuboidal to low columnar cells; round to oval nuclei; eosinophilic cytoplasm; Responsible for milk production and secretion; Positive for keratins like CK7, CK8/18
─ Outer (Basal) Myoepithelial Cells Spindle-shaped or flattened cells; between luminal epithelial cells and basement membrane; Contain myofilaments; contractile, aiding milk ejection; Typically positive for smooth muscle actin (SMA), p63, calponin, CK5/6, S100 (variable)
─ Basement Membrane Continuous layer surrounding ducts and TDLUs; separating epithelial/myoepithelial cells from stroma; Contains type IV collagen and laminin; Transgression by neoplastic cells defines invasion
─ Stroma Connective tissue framework; divided into
─ Intralobular Stroma Specialized loose connective tissue within lobules; surrounding acini; Hormonally responsive; contains fibroblasts, lymphocytes, macrophages
─ Interlobular Stroma Denser, more collagenous connective tissue; surrounds TDLUs and larger ducts; contains fibroblasts, adipose tissue, blood vessels, lymphatics, nerves
─ Nipple-Areolar Complex Histology
─ Epidermis is stratified squamous epithelium; variably pigmented
─ Lactiferous ducts extend into nipple; lined by stratified cuboidal or squamous epithelium near orifice
─ Dense fibrous stroma with smooth muscle bundles
─ Montgomery glands are modified sebaceous glands
─ Toker cells (clear cells of mammary origin) may be present in nipple epidermis

Physiology
─ Proliferative (Follicular) Phase Lobules relatively small; intralobular stroma dense
─ Secretory (Luteal) Phase Acinar cells may show secretory activity; lumina more open; intralobular stroma may be edematous; Myoepithelial cells can appear vacuolated
─ Pregnancy and Lactation Marked glandular proliferation and differentiation; acini distended with milk; luminal cells show prominent secretory vacuoles, apical snouts; Stroma relatively compressed
─ Involution (Post-Lactational and Menopausal) Gradual atrophy of glandular elements (TDLUs); replacement by fibrous and adipose tissue; Ducts may dilate (duct ectasia)

Vascular and Lymphatic Supply
─ Arterial Supply Primarily from internal mammary artery; lateral thoracic artery; intercostal arteries
─ Lymphatic Drainage Crucial for staging breast cancer; Predominantly drains to axillary lymph nodes (Level I, II, III); Medial breast can drain to internal mammary nodes

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Fibrocystic Changes (FCC)

General term for common, benign, hormonally mediated breast tissue alterations; often presenting as mastalgia or lumpiness; "Fibrocystic disease" discouraged due to commonality and benign nature; FCC includes non-proliferative and proliferative (without atypia) lesions

Clinical ─ Very common; particularly women of reproductive age (20s-50s); Symptoms often fluctuate with menstrual cycle; May present as diffuse or focal breast pain, tenderness, nodularity, or discrete palpable "lumps"

Radiology ─

─ Mammography May show diffuse benign calcifications; cysts; increased fibroglandular density; or no specific findings
─ Ultrasound Useful for characterizing palpable lumps; differentiating cysts from solid masses; May show simple or complex cysts; dilated ducts; heterogeneous fibroglandular tissue

Macro ─ Varied appearance; May show ill-defined areas of firmness or nodularity; Cysts single or multiple; variable size; may contain clear, straw-colored, turbid, or dark (blue-dome cysts) fluid; Fibrous areas appear dense, white

Micro ─
Combination of following features often present
Cyst Formation (Microcysts and Macrocysts)
─ Dilated terminal duct lobular units (TDLUs) or ducts
─ Lined by cuboidal, flattened, or attenuated epithelial cells
─ Apocrine metaplasia of cyst lining common
─ Lumina may contain proteinaceous fluid, debris, foamy macrophages, or calcifications
─ Rupture of cysts can lead to inflammation, fibrosis
Apocrine Metaplasia
─ Replacement of normal luminal epithelial cells by cells with abundant granular eosinophilic cytoplasm; round nuclei; prominent nucleoli; Apical "snouts" or blebs characteristic
─ Can line cysts or occur in non-dilated ducts/lobules
─ Considered a non-proliferative change
Stromal Fibrosis
─ Increased collagenous stroma; can be dense, hyalinized
─ Contributes to firmness, nodularity of breast
Adenosis
─ Increase in number and/or size of acini within lobules
─ Acini lined by epithelial, myoepithelial cells; maintain lobulocentric arrangement
─ (Sclerosing adenosis specific type; stromal fibrosis distorts, compresses proliferating acini - covered separately)
Mild Usual Ductal Hyperplasia (UDH)
─ Increase in epithelial cells lining ducts (more than two cell layers; typically not filling, distending duct)
─ Heterogeneous cell population; irregular slit-like fenestrations
─ Considered non-proliferative or minimally proliferative; (Florid UDH proliferative lesion without atypia - covered separately)

Prognosis
─ Non-proliferative changes (eg, cysts, apocrine metaplasia, mild UDH, fibrosis, duct ectasia) Generally not associated with increased breast cancer risk
─ Proliferative changes without atypia (eg, moderate/florid UDH, sclerosing adenosis, papillomas) Associated with slightly increased breast cancer risk (relative risk ~1;5-2 times)
─ (Note Original notebook has separate detailed entries for some proliferative lesions like UDH, Sclerosing Adenosis; appropriate)

DDx ─
─ Fibroadenoma (distinct biphasic tumor)
─ Ductal Carcinoma In Situ (DCIS) or Invasive Carcinoma (esp if presenting with calcifications or mass; distinguished by cytologic atypia, architectural features, lack of myoepithelial cells in invasive disease)
─ Specific inflammatory conditions
─ Radial Scar / Complex Sclerosing Lesion (distinctive architecture)

Media ─ ─ Benign microcalcification and fibrocystic disease / columnar cell change (Breast) WSI ─ Fibrocystic change (Breast) H&E ─ Fibrocystic changes and secretory changes (Breast) H&E ─ Fibrocystic disease (Breast) rosai ─ Fibrocystic disease (Breast) rosai ─ Fibrocystic disease (Breast) rosai ─ Fibrocystic disease (Breast) rosai ─ Fibrocystic disease with extensive papillomatosis (Left breast) rosai ─ Papilloma and fibrocystic change (Breast) H&E Cyctic papillary apocrine metaplasia WSI WSI

Fat Necrosis

Benign, non-suppurative inflammatory process in adipose tissue; often secondary to trauma, surgery, or radiation therapy; Can clinically, radiologically mimic malignancy

Clinical ─ May present as firm, palpable mass; often painless, can be tender; Skin retraction, dimpling, or ecchymosis may occur; History of breast trauma (eg, seatbelt injury, biopsy, lumpectomy, reduction mammoplasty, flap reconstruction) or radiation common; but may be absent; More common in women with larger breasts

Radiology ─ Appearance varies with age of lesion
─ Mammography: Early Ill-defined spiculated mass or focal asymmetry; suspicious calcifications (pleomorphic, irregular); Later Characteristic lipid cysts (oil cysts); lucent, round masses; often with peripheral rim calcification ("eggshell" calcification); Dystrophic, coarse calcifications; Architectural distortion
─ Ultrasound Variable appearance; Can be solid-appearing hypoechoic mass with irregular margins, posterior acoustic shadowing (mimicking carcinoma); or complex cystic mass (oil cyst); Intralesional echogenic bands
─ MRI Can be helpful; Oil cysts show characteristic fat signal; Enhancing areas of fibrosis or inflammation can mimic malignancy

Macro ─
─ Early Ill-defined, hemorrhagic, or indurated fatty tissue; may appear yellowish or gray
─ Later Firm, nodular, yellow-gray or chalky white lesion; May contain cystic spaces filled with oily, yellowish fluid (oil cysts); Dense fibrosis can occur

Micro ─ Histologic appearance evolves over time
Early Stage (Hours to Days)
─ Necrotic adipocytes with loss of nuclei; surrounded by neutrophils, hemorrhage
─ Adipocytes may appear as anucleated "ghost cells"; preserved outlines
Intermediate Stage (Days to Weeks)
─ Influx of lipid-laden macrophages (lipophages or foamy histiocytes); engulfing necrotic fat
─ Lymphocytes, plasma cells
─ Formation of multinucleated foreign body-type giant cells
─ Cholesterol clefts, hemosiderin deposition may be seen
─ Early fibroblastic proliferation, vascular ingrowth
Late Stage (Weeks to Months/Years)
─ Progressive fibrosis, scarring
─ Formation of cystic spaces (oil cysts); lined by foamy histiocytes, fibrous tissue; often containing amorphous lipid material
─ Dystrophic calcification; often within walls of oil cysts or in fibrous areas
─ Hemosiderin-laden macrophages may persist
─ Lesion may become dense, hyalinized scar

DDx ─
─ Invasive Carcinoma (esp if presenting as spiculated mass or with suspicious calcifications)
─ Post-Surgical Scar (can overlap; fat necrosis has more prominent inflammatory, lipid components)
─ Lipoma (pure proliferation of mature adipocytes)
─ Silicone Granuloma (if history of silicone; shows silicone vacuoles)
─ Specific granulomatous mastitides

Prognosis ─ Benign lesion; no malignant potential; Main significance is ability to mimic malignancy; potentially leading to biopsy; May resolve, persist as scar, or form stable oil cysts

Media ─ ─ Fat necrosis (Breast) H&E

Mammary Duct Ectasia / Periductal Mastitis

Dilatation of major subareolar ducts associated with periductal inflammation and fibrosis.
Clinical ─ Often smokers; thick nipple discharge, nipple retraction, subareolar mass.
Radiology ─
─ Mammography: May show dilated retroareolar ducts, +/- microcalcifications (often linear, coarse within ducts)
─ Ultrasound: May show dilated ducts with echogenic debris or fluid, duct wall thickening
Macro ─ Dilated ducts containing thick, cheesy, or pasty material (inspissated secretions); surrounding tissue may be firm/fibrotic
Micro ─
─ Dilated large ducts, often filled with eosinophilic, proteinaceous secretions and foamy macrophages (lipid-laden)
─ Periductal chronic inflammation (lymphocytes, plasma cells - often prominent)
─ Periductal fibrosis, variable degrees
─ +/- Squamous metaplasia of duct lining
─ +/- Cholesterol clefts, calcifications within duct lumen or wall
─ +/- Granulomatous inflammation (foreign body reaction to secretions)
─ In later stages, ducts may be obliterated by fibrosis
DDx ─
─ DCIS (Comedo type) (Necrosis central, atypia present, lacks prominent plasma cells/foamy macrophages in duct)
─ Plasma Cell Mastitis (Term often used interchangeably or for cases dominated by plasma cells)
─ Invasive Carcinoma (Infiltrative growth pattern, cytologic malignancy)
─ Abscess (Acute inflammation, neutrophils predominate)
─ Specific granulomatous mastitis (e.g., TB, fungal) (Specific organisms, well-formed granulomas)
Prognosis ─ Benign inflammatory condition; may resolve, persist, or recur; main significance is mimicry of malignancy
Media ─ ─ Duct ectasia (Breast) H&E ─ Duct ectasia (Breast) WSI WSI ─ Duct ectasia (Breast) rosai ─ Mammary duct ectasia (Breast) WSI Breast mammary duct ectasia 1a.jpg

Acute Mastitis

Acute inflammation of the breast, typically bacterial, often associated with lactation.
Clinical ─ Lactating women (puerperal mastitis); pain, swelling, erythema, warmth, fever; may form abscess
Radiology ─
─ Ultrasound: ill-defined hypoechoic area with increased vascularity, skin thickening, +/- fluid collection/abscess
Macro ─ Affected area is indurated, erythematous; abscess appears as fluctuant mass with purulent material
Micro ─
─ Dense neutrophilic infiltrate within lobules and stroma
─ Tissue necrosis, edema, hemorrhage
─ Abscess formation (collection of pus)
─ +/- granulation tissue, reactive epithelial changes in later stages
DDx ─
─ Inflammatory Breast Carcinoma (Dermal lymphatic invasion by tumor cells, clinical presentation)
─ Other forms of mastitis (Granulomatous, Lymphocytic - different inflammatory infiltrate)
─ Mammary Duct Ectasia/Periductal Mastitis (Plasma cells prominent, duct dilation with foamy macrophages)
Prognosis ─ Benign inflammatory condition; usually resolves with antibiotics; abscess may require drainage
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Lymphocytic & Diabetic Mastitis

Uncommon condition, dense lymphocytic infiltrates and keloidal fibrosis, strongly associated with type 1 diabetes mellitus. Also known as Sclerosing Lymphocytic Lobulitis.
Clinical ─ Typically premenopausal women with long-standing type 1 diabetes (can also occur in type 2 DM or autoimmune thyroid disease); presents as hard, painless, often bilateral breast mass(es); may mimic malignancy clinically and radiologically
Radiology ─
─ Mammography: Ill-defined density or asymmetry
─ Ultrasound: Ill-defined hypoechoic mass with posterior acoustic shadowing, mimicking carcinoma
Macro ─ Ill-defined, very firm, rubbery, gray-white tissue
Micro ─
─ Dense keloidal fibrosis (thick, hyalinized collagen bundles)
─ Lobulocentric lymphocytic infiltrate (predominantly B-cells, some T-cells and plasma cells) surrounding atrophic ducts and lobules
─ Lymphocytic vasculitis (lymphocytes infiltrating vessel walls) may be present
─ Epithelioid stromal fibroblasts (plump fibroblasts with eosinophilic cytoplasm) may be seen
─ +/- Diabetic microangiopathy in adjacent tissue
DDx ─
─ Invasive Carcinoma (esp. Lobular) (Malignant cells present, lacks prominent keloidal fibrosis/lymphocytic vasculitis)
─ Fibromatosis (Lacks dense lobulocentric lymphoid infiltrate/vasculitis, β-catenin+)
─ Sclerosing Lobular Hyperplasia (Less inflammation, lacks keloidal fibrosis/vasculitis)
─ Nodular Sclerosis Hodgkin Lymphoma (Reed-Sternberg cells present, specific IHC)
─ Other forms of mastitis (Lack keloidal fibrosis and prominent B-cell rich infiltrate)
Prognosis ─ Benign inflammatory condition; tends to recur; increased risk of subsequent lymphoma not established
Media ─ ─ Diabetic mastopathy (Breast) H&E Cystic neutrophilic granulomatous mastitis
Rare form of granulomatous mastitis with cystic spaces containing neutrophils and associated with Corynebacterium species.
Clinical ─ Women of reproductive age, often history of smoking, parity, or nipple piercing; presents as tender, erythematous breast mass, may form abscess or fistula
Radiology ─
─ Ultrasound/Mammography: May show ill-defined mass, abscess formation, complex cystic structures
Macro ─ Ill-defined inflammatory mass, may show abscess/cyst formation
Micro ─
─ Lobulocentric inflammation
─ Characteristic feature: Clear lipid vacuoles/spaces within granulomas or suppurative areas
─ Vacuoles are lined by neutrophils and/or histiocytes
─ Gram-positive bacilli (Corynebacterium) often demonstrable within vacuoles (requires Gram stain)
─ Mixed inflammatory infiltrate (neutrophils, lymphocytes, plasma cells, histiocytes, giant cells)
─ +/- Duct ectasia, abscess formation, fibrosis
DDx ─
─ Idiopathic Granulomatous Mastitis (Lacks cystic spaces with neutrophils/Corynebacterium)
─ Other infectious granulomatous mastitis (TB, fungal - specific organisms identified)
─ Mammary Duct Ectasia (Plasma cells prominent, foamy macrophages in ducts, lacks vacuoles with neutrophils)
─ Fat Necrosis (History of trauma/surgery, different morphology)
Prognosis ─ Benign inflammatory condition; often requires prolonged antibiotics; may recur
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Idiopathic Granulomatous Mastitis (IGM)

A rare, benign, chronic inflammatory disease of the breast characterized by non-caseating granulomas and abscess formation, primarily affecting the lobules; etiology unknown

Clinical ─ Typically affects women of childbearing age, often with a history of recent pregnancy or lactation; Presents as a firm, tender, unilateral breast mass; may be associated with pain, skin erythema, nipple retraction, abscesses, or sinus tract formation; Can mimic breast carcinoma clinically and radiologically

Radiology ─

─ Mammography Nonspecific; may show ill-defined mass, focal asymmetry, or skin thickening; calcifications are uncommon
─ Ultrasound Variable; often ill-defined hypoechoic mass or multiple confluent hypoechoic areas with tubular extensions; may show abscess cavities or increased vascularity; can mimic malignancy
─ MRI May show enhancing masses, non-mass enhancement, or rim-enhancing abscesses; findings are nonspecific

Macro ─ Ill-defined, firm, indurated area; may be yellow-tan or grayish; Abscess cavities containing purulent material may be present

Micro ─

─ Lobulocentric chronic granulomatous inflammation
─ Non-caseating epithelioid granulomas centered on lobules, often with lymphocytes, plasma cells, and multinucleated giant cells (Langhans or foreign body type)
─ Neutrophils are often present within granulomas or forming microabscesses, especially around cystic spaces or vacuoles (features may overlap with Cystic Neutrophilic Granulomatous Mastitis)
─ Ducts and lobules may be distorted or destroyed by the inflammatory process
─ Variable degrees of fibrosis
─ Absence of specific microorganisms (fungi, mycobacteria) on special stains is a key feature for "idiopathic" designation, though some cases may be associated with Corynebacterium infection (see Cystic Neutrophilic Granulomatous Mastitis)
─ Caseous necrosis is characteristically absent

IHC ─ Generally not required for diagnosis; special stains for organisms are more critical
─ CD68 highlights histiocytes

DDx ─

─ Tuberculous Mastitis (caseating granulomas, positive AFB stain or culture)
─ Fungal Mastitis (fungal elements seen on GMS or PAS stains)
─ Cystic Neutrophilic Granulomatous Mastitis (prominent cystic spaces lined by neutrophils, often Corynebacterium identified)
─ Sarcoidosis (granulomas typically non-lobulocentric, systemic disease often present, diagnosis of exclusion in breast)
─ Foreign Body Granulomatous Reaction (history of surgery, trauma, injections; foreign material may be visible)
─ Invasive Carcinoma (malignant cells, desmoplasia; granulomatous reaction can rarely be seen around tumors)
─ Mammary Duct Ectasia (periductal inflammation, plasma cells prominent, foamy macrophages in dilated ducts)

Prognosis ─ Benign condition, but can have a prolonged and recurrent course; Spontaneous resolution can occur; Treatment may include observation, antibiotics (if secondary infection or Corynebacterium suspected), corticosteroids, immunosuppressants (eg, methotrexate), or surgical excision for persistent/refractory disease

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Silicone mastitis / Granuloma

Granulomatous inflammatory reaction to extravasated silicone, from rupture or direct injection.
Clinical ─ History of breast implants (ruptured or leaking) or direct silicone injection; presents as firm nodules, masses, or diffuse induration; may have pain, skin changes, lymphadenopathy
Radiology ─
─ Ultrasound: "Snowstorm" appearance (diffuse high echogenicity with obscured posterior structures)
─ MRI: Characteristic silicone signal; can identify intracapsular vs extracapsular rupture
Macro ─ Firm, nodular, or diffusely indurated tissue; glistening, refractile material (silicone)
Micro ─
─ Numerous cystic spaces/vacuoles of varying sizes within fibrous stroma or adipose tissue
─ Multinucleated giant cells engulfing silicone
─ Chronic inflammatory infiltrate (lymphocytes, plasma cells, histiocytes - some foamy)
─ Dense fibrosis common
─ Silicone material is refractile but non-birefringent
DDx ─
─ Fat Necrosis (Different type of vacuoles - adipocytes, lacks refractile material, often history of trauma/surgery)
─ Other forms of granulomatous mastitis (Lack silicone vacuoles/history)
─ Cystic Neutrophilic Granulomatous Mastitis (Neutrophils lining vacuoles, Corynebacterium)
Prognosis ─ Benign inflammatory reaction; can cause significant fibrosis and cosmetic deformity; silicone lymphadenopathy can occur
Media ─ ─ Granulomatous silicone mastitis (Breast) rosai

Tuberculous Mastitis

A rare form of extrapulmonary tuberculosis involving the breast parenchyma, characterized by necrotizing granulomatous inflammation caused by Mycobacterium tuberculosis

Clinical ─ More common in endemic regions; affects women predominantly, often of reproductive age or lactating; Presents as a firm, irregular, often painless breast lump, which may be fixed to skin or underlying tissue; Can mimic breast carcinoma; Skin changes like erythema, ulceration, sinus tract formation, and nipple retraction may occur; Axillary lymphadenopathy is common; Constitutional symptoms (fever, night sweats, weight loss) present in a minority of cases

Radiology ─

─ Mammography Nonspecific; may show ill-defined mass, focal asymmetry, skin thickening, or suspicious calcifications
─ Ultrasound Ill-defined hypoechoic mass, complex collection (abscess), or diffuse heterogeneity; thickened skin or fistulous tracts may be seen
─ MRI Can show enhancing lesions, abscess formation, or chest wall involvement

Macro ─ Ill-defined, firm, indurated mass or multiple nodules; Cut surface may show gray-white or yellowish tissue with characteristic caseous (cheese-like) necrosis; Abscess cavities or sinus tracts may be evident

Micro ─

─ Hallmark is necrotizing (caseating) granulomatous inflammation
─ Well-formed epithelioid granulomas composed of epithelioid histiocytes, lymphocytes, and Langhans-type multinucleated giant cells
─ Central caseous necrosis within granulomas is characteristic but not always present in biopsy material
─ Inflammatory infiltrate involves ducts, lobules, and stroma
─ Lymphocytic cuffing around granulomas
─ Variable fibrosis
─ Identification of Acid-Fast Bacilli (AFB) using Ziehl-Neelsen or Fite-Faraco stain is diagnostic, but bacilli may be sparse
─ Culture or PCR for Mycobacterium tuberculosis can confirm diagnosis

IHC ─ Generally not used for primary diagnosis; special stains for organisms are key

DDx ─

─ Idiopathic Granulomatous Mastitis (non-caseating granulomas, AFB negative)
─ Fungal Mastitis (fungal elements on GMS/PAS, AFB negative)
─ Sarcoidosis (non-caseating granulomas, systemic disease, AFB negative)
─ Invasive Carcinoma with granulomatous reaction (malignant cells present)
─ Fat Necrosis (different type of necrosis, foamy histiocytes, history of trauma/surgery)
─ Other specific infections (eg, actinomycosis, brucellosis)

Prognosis ─ Generally good with appropriate multi-drug anti-tuberculous therapy (ATT); Surgical intervention may be needed for drainage of abscesses or excision of refractory lesions; Untreated or inadequately treated disease can lead to significant local destruction and morbidity

Media ─ ─ Granulomatous mastitis (M. tuberculosis cultured) (Right breast) rosai

Developmental Disorders

Juvenile Papillomatosis

Benign proliferative lesion occurring in young women, with duct papillomatosis, cysts, epithelial hyperplasia, and sclerosing adenosis. AKA "Swiss cheese disease" due to cystic appearance.
Clinical ─ Adolescents and young women ( < 30 years); palpable, well-circumscribed mass
Radiology ─
─ Mammography/Ultrasound: ill-defined mass with multiple small cysts
Macro ─ Poorly circumscribed, firm mass with prominent small cysts ("Swiss cheese")
Micro ─
─ Florid duct papillomatosis (intraductal papillary proliferation)
─ Multiple cysts, often with apocrine metaplasia
─ Usual ductal hyperplasia (UDH), often florid
─ Sclerosing adenosis
─ Stroma may be fibrotic
─ Atypia (ADH/ALH) or DCIS can occasionally be present concurrently or arise later
DDx ─
─ Fibrocystic changes (Less florid papillomatosis/hyperplasia, usually older patients)
─ Multiple papillomas (Discrete papillary tumors, less background hyperplasia/sclerosis)
─ DCIS (Papillary/Cribriform) (Significant cytologic atypia, monomorphic population, lacks prominent cysts/sclerosis typical of JP)
─ Fibroadenoma (Juvenile) (More prominent stromal component, different architecture)
Prognosis ─ Benign, but considered a marker of increased risk for subsequent breast cancer development (both ipsilateral and contralateral), especially if associated with atypia or family history
Media ─ ─ Papillomatosis (Breast) rosai

Gynecomastia

Benign enlargement of the male breast due to proliferation of ducts and stroma.
Clinical ─ Can occur at any age (neonatal, puberty, older age); associated with hormonal imbalance (relative estrogen excess), medications (e.g., spironolactone, cimetidine, hormones), liver disease, Klinefelter syndrome, tumors (testicular, adrenal); presents as palpable, often tender, subareolar mass/disc, unilateral or bilateral
Radiology ─
─ Mammography: Typically shows retroareolar density, may be flame-shaped or nodular
Macro ─ Rubbery, firm, gray-white tissue in subareolar region
Micro ─
─ Variable proliferation of both ducts and stroma around the nipple
─ Florid phase (early): Epithelial hyperplasia within ducts (pseudomicropapillary tufts, UDH-like), periductal stromal edema, increased vascularity, mild inflammation
─ Fibrous phase (late): Dense stromal fibrosis, fewer ducts which may be atrophic or dilated, less epithelial hyperplasia
─ +/- Squamous metaplasia, apocrine metaplasia, pseudoangiomatous stromal hyperplasia (PASH)
─ Lobule formation is absent (key feature distinguishing from female breast)
DDx ─
─ Male Breast Carcinoma (Invasive or DCIS) (Cytologic atypia, infiltrative growth, necrosis, lacks lobular architecture)
─ Pseudogynecomastia (Adipose tissue deposition without ductal/stromal proliferation)
─ Other benign male breast lesions (rare - papilloma, fibroadenoma-like changes)
Prognosis ─ Benign; no increased risk for male breast cancer
Media ─ ─ Gynecomastia (Breast) rosai

Mammary hamartoma

Benign, circumscribed lesion composed of mature but disorganized breast tissue elements (lobules, ducts, adipose tissue, fibrous stroma). Also known as fibroadenolipoma.
Clinical ─ Adults (wide age range, mc > 40 years), F >> M; presents as painless, soft to firm, mobile mass; often well-circumscribed ("breast within a breast" on imaging)
Radiology ─
─ Mammography: Characteristically well-circumscribed, encapsulated mass containing mixed densities of fat and fibroglandular tissue ("breast within a breast")
─ Ultrasound: Heterogeneous encapsulated mass with mixed echogenicity
Macro ─ Well-encapsulated, round to oval mass; cut surface shows lobulated gray-white fibrous/glandular tissue admixed with yellow adipose tissue
Micro ─
─ Encapsulated (or sharply circumscribed) lesion
─ Disorganized mixture of benign breast elements:
─ Mature lobules and ducts (may show usual hyperplasia, cysts, apocrine metaplasia)
─ Fibrous stroma (often hypocellular)
─ Mature adipose tissue
─ Relative proportions of components vary widely
─ Pseudoangiomatous stromal hyperplasia (PASH) common within stroma
─ Myoid hamartoma variant contains smooth muscle
DDx ─
─ Fibroadenoma (Biphasic, lacks mature lobules/adipose tissue within the lesion proper, different stromal quality)
─ Lipoma (Pure adipose tissue)
─ Normal breast tissue (Lacks encapsulation/sharp circumscription and disorganized arrangement)
─ Phyllodes Tumor (Leaf-like architecture, increased stromal cellularity/atypia)
Prognosis ─ Benign; excision is curative
Media ─ ─ Mammary hamartoma (Breast) H&E

Benign Epithelial Lesions

Columnar Cell Change (CCC)

Alteration of terminal duct lobular units (TDLUs) with replacement of native cuboidal epithelium with one or two layers of taller columnar cells, often with apical snouts and intraluminal secretions/calcifications. Considered benign.
Clinical ─ Common incidental finding on biopsy, often associated with microcalcifications; wide age range
Radiology ─
─ Mammography: amorphous, punctate, or pleomorphic microcalcifications, typically grouped
Macro ─ Not grossly distinct
Micro ─
─ Enlarged TDLUs with dilated acini/ductules
─ Lined by 1-2 layers of columnar epithelial cells (taller than normal cuboidal cells)
─ Apical cytoplasmic snouts/blebs common
─ Intraluminal secretions (eosinophilic, proteinaceous)
─ Microcalcifications (calcium oxalate or phosphate) frequent within lumens
─ Minimal cytologic atypia (nuclei usually small, round/oval, normochromatic)
─ Myoepithelial layer intact
IHC ─ (+) ER (often strong/diffuse), PR (variable); (+/-) CK5/6 (may show mosaic pattern if >1 layer); (-) HER2
DDx ─
─ Apocrine metaplasia (Granular eosinophilic cytoplasm, prominent nucleoli, AR+, GCDFP-15+)
─ Columnar Cell Hyperplasia (CCH) (>2 cell layers)
─ Flat Epithelial Atypia (FEA) (Cytologic atypia present)
─ Atypical Ductal Hyperplasia (ADH) / DCIS (More complex architecture, cytologic atypia)
Prognosis ─ Benign; considered non-proliferative or mildly proliferative; minimal to no increased risk for breast cancer on its own
Media ─ ─ Benign microcalcification and fibrocystic disease / columnar cell change (Breast) WSI

Columnar Cell Hyperplasia (CCH)

Alteration of TDLUs with proliferation of columnar epithelial cells (>2 cell layers), often with tufting or micropapillations, but lacking significant cytologic atypia.
Clinical ─ Common incidental finding on biopsy, often associated with microcalcifications; wide age range
Radiology ─
─ Mammography: amorphous, punctate, or pleomorphic microcalcifications, typically grouped
Macro ─ Not grossly distinct
Micro ─
─ Similar to CCC (enlarged TDLUs, dilated acini, apical snouts, secretions, calcifications)
─ Epithelial lining is >2 cell layers thick
─ May show cellular crowding, stratification, tufting, or simple micropapillations projecting into lumen
─ Lacks significant cytologic atypia (nuclei generally bland, similar to CCC)
─ Myoepithelial layer intact
IHC ─ (+) ER (often strong/diffuse), PR (variable); (+/-) CK5/6 (often shows mosaic pattern); (-) HER2
Molecular ─ Clonal alterations reported but significance unclear
DDx ─
─ Columnar Cell Change (CCC) (≤2 cell layers)
─ Flat Epithelial Atypia (FEA) (Cytologic atypia present)
─ Usual Ductal Hyperplasia (UDH) (Different cytology - overlapping/streaming nuclei, indistinct borders, slit-like spaces; often mosaic CK5/6)
─ Atypical Ductal Hyperplasia (ADH) / DCIS (More complex architecture, cytologic atypia)
Prognosis ─ Benign proliferative lesion; may confer a small increased risk for breast cancer, similar to mild UDH
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Flat Epithelial Atypia (FEA)

An alteration of terminal duct lobular units (TDLUs) where native epithelium is replaced by one to several layers of monotonous, mildly atypical columnar to cuboidal cells, lacking complex architectural features like bridging or micropapillae. Considered a low-risk atypical lesion.
Clinical ─ Often an incidental finding associated with microcalcifications on mammography; wide age range, but more common in perimenopausal/postmenopausal women
Radiology ─
─ Mammography: associated with amorphous or punctate microcalcifications, often grouped
Macro ─ Not grossly distinct
Micro ─
─ Involves TDLUs, replacing native epithelium
─ One or more layers (often 1-3) of monotonous epithelial cells
─ Cells cuboidal to columnar, may have apical snouts
─ Cytologic atypia: Mildly enlarged, round to oval nuclei; hyperchromatic or vesicular chromatin; small nucleoli may be visible; minimal pleomorphism
─ Loss of polarity compared to normal epithelium
─ Lumens often contain secretions and calcifications
─ Lacks complex architecture (no significant bridging, micropapillae, or solid growth)
─ Myoepithelial layer intact
IHC ─ (+) ER (strong, diffuse); (+) CK8/18; (-) CK5/6 (negative or only scattered positive cells); (-) HER2
Molecular ─ alterations common (16q loss, 17p gain), overlap with low-grade DCIS and tubular carcinoma
DDx ─
─ Columnar Cell Change/Hyperplasia (CCC/CCH) (Lacks cytologic atypia)
─ Atypical Ductal Hyperplasia (ADH) (More complex architecture - micropapillae, rigid bridges, cribriform spaces)
─ DCIS, Low Grade (esp. cribriform/micropapillary) (More complex architecture, greater cytologic atypia)
─ Apocrine Metaplasia (Different cytology - eosinophilic granular cytoplasm, prominent nucleoli, AR+)
Prognosis ─ Considered a low-risk lesion, but associated with a slightly increased risk of subsequent breast cancer (similar to ADH); often found adjacent to ADH, DCIS, or invasive carcinoma (esp. tubular)
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Usual Ductal Hyperplasia (UDH)

Benign intraductal proliferation with an increased number of epithelial cells filling and distending ducts/lobules; shows architectural and cytologic heterogeneity.
Clinical ─ Very common finding, often incidental; may be associated with calcifications or palpable masses related to fibrocystic changes; wide age range, common in reproductive/perimenopausal years
Radiology ─
─ Mammography: benign-appearing calcifications (punctate, amorphous)
Micro ─
─ Increased number of cells (>2 layers) filling part or all of a duct or lobular unit lumen
─ Cells often arranged haphazardly, showing streaming and overlapping nuclei
─ Irregular, slit-like, peripherally located secondary lumens common ("fenestrated" pattern)
─ Mixed cell population: Epithelial cells, myoepithelial cells, metaplastic cells intermingled
─ Nuclei vary in size/shape, often oval or spindled, chromatin fine to slightly coarse, nucleoli inconspicuous
─ Indistinct cell borders
─ Lacks significant cytologic atypia or architectural monotony seen in ADH/DCIS
─ Myoepithelial layer surrounding involved duct/lobule is intact
IHC ─
─ (+) CK5/6 or other HMWK (shows characteristic "mosaic" or mixed staining pattern, highlighting heterogeneity)
─ (+) ER, PR (often heterogeneous/patchy staining intensity and distribution)
─ (-) HER2
─ (+) Myoepithelial markers (p63, SMA etc.) show intact peripheral layer
Molecular ─ polyclonal
DDx ─
─ Atypical Ductal Hyperplasia (ADH) (Monomorphic population, distinct architectural patterns like cribriform/micropapillary, lacks CK5/6 mosaicism, strong/diffuse ER)
─ DCIS, Low Grade (More pronounced atypia/monotony, distinct architecture, lacks CK5/6 mosaicism)
─ Intraductal Papilloma (True fibrovascular cores lined by epithelium and myoepithelium)
─ Normal Duct/Lobule (Only 1-2 cell layers)
Prognosis ─ Benign proliferative lesion; confers a small increased risk (relative risk ~1.5-2x) for subsequent development of breast cancer
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Microglandular Adenosis (MGA)

Rare type of adenosis with a haphazard proliferation of small, uniform, round glands lacking a myoepithelial layer, often containing eosinophilic secretions.
Clinical ─ Wide age range; may present as palpable mass, mammographic density, or calcifications
Radiology ─ Non-specific; may show density, distortion, or calcifications
Macro ─ Ill-defined, firm, gray-white area
Micro ─
─ Haphazard proliferation of small, round, open glands infiltrating stroma and adipose tissue
─ Glands lined by a single layer of cuboidal cells with bland nuclei, often clear or eosinophilic cytoplasm
─ Characteristic feature: Absence of myoepithelial layer (confirmed by IHC)
─ Lumens often contain dense, eosinophilic, colloid-like secretions (PAS+)
─ Intact basement membrane surrounds glands (collagen IV+, laminin+)
─ Minimal stromal response
IHC ─ (+) S100 (strong, diffuse in epithelial cells); (+) CK8/18; (-) ER, PR, HER2 (typically triple negative);(-) Myoepithelial markers (p63, SMA, etc.)
DDx ─
─ Tubular Carcinoma (Angulated/teardrop glands, infiltrative growth with desmoplasia, lacks S100, ER+, lacks eosinophilic secretions)
─ Sclerosing Adenosis (Retains myoepithelial layer, glands often compressed/distorted)
─ Apocrine Adenosis (Apocrine cytology, retains myoepithelial layer)
─ Secretory Carcinoma (Different cytology, intracellular/extracellular secretions, ETV6::NTRK3 fusion)
Prognosis ─ Benign itself, but considered non-obligate precursor for carcinoma (often triple negative invasive carcinoma can arise in MGA)
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Sclerosing Adenosis

Common type of adenosis with proliferation of acini and stromal fibrosis, leading to compression and distortion of the glandular elements, but maintaining a lobular architecture at low power.
Clinical ─ Common component of fibrocystic changes; may present as palpable mass or mammographic density/calcifications; wide age range
Radiology ─
─ Mammography: May show microcalcifications (often punctate, amorphous, sometimes pleomorphic), density, or architectural distortion; can mimic carcinoma
Macro ─ Firm, rubbery, ill-defined area
Micro ─
─ Lobulocentric proliferation (overall lobular shape maintained at low power)
─ Increased number of small acini/ductules, often compressed and distorted by dense fibrous stroma
─ Glands lined by epithelial and myoepithelial cells
─ Myoepithelial layer is intact, often prominent
─ Streaming and swirling of epithelial cells common
─ Microcalcifications frequent within lumens
─ May extend into surrounding stroma/fat ("adenosis tumor" - still benign)
IHC ─ Myoepithelial markers (p63, SMA, calponin, CK5/6) highlight intact myoepithelial layer, confirming benignity; ER/PR variable
DDx ─
─ Tubular Carcinoma (Infiltrative growth, angulated glands, lacks myoepithelial layer, desmoplastic stroma, ER+)
─ Invasive Lobular Carcinoma (Single file infiltration, lacks myoepithelial layer, E-cadherin-)
─ Microglandular Adenosis (Lacks myoepithelial layer, S100+, eosinophilic secretions)
─ Radial Scar (Different architecture - central fibroelastotic core)
Prognosis ─ Benign proliferative lesion; confers a minimal increased risk (relative risk ~1.5-2x) for subsequent breast cancer
Media ─ ─ Sclerosing adenosis (Breast) rosai ─ Sclerosing adenosis (Breast) rosai ─ Sclerosing adenosis (Breast) rosai ─ Sclerosing adenosis (Breast) rosai ─ Sclerosing adenosis (breast) rosai

Apocrine Adenosis

Adenosis (usually sclerosing type) in which the epithelial cells show prominent apocrine metaplasia.
Clinical ─ Component of fibrocystic changes; presentation similar to sclerosing adenosis
Radiology ─ Similar to sclerosing adenosis, often associated with calcifications
Macro ─ Not grossly distinct
Micro ─
─ Features of adenosis (increased acini, often compressed/distorted by fibrosis, lobulocentric)
─ Epithelial cells lining the acini show apocrine metaplasia (abundant granular eosinophilic cytoplasm, round nuclei, prominent nucleoli, apical snouts)
─ Myoepithelial layer intact
─ May show mild nuclear atypia ("atypical apocrine adenosis" - still considered benign if architecture is adenosis)
IHC ─ Epithelial cells (+) GCDFP-15, AR; (-) ER, PR; Myoepithelial markers (+)
DDx ─
─ Apocrine DCIS involving adenosis (Significant cytologic atypia and/or DCIS architecture within adenosis)
─ Invasive Apocrine Carcinoma (Infiltrative growth, lacks myoepithelial layer)
─ Sclerosing Adenosis without apocrine change (Lacks apocrine cytology)
Prognosis ─ Benign; risk similar to sclerosing adenosis
Media ─ ─ Apocrine adenosis with atypia, breast (Breast) WSI

Collagenous Spherulosis

Benign incidental finding with intraductal clusters of myoepithelial cells surrounding eosinophilic, acellular spherules of basement membrane material.
Clinical ─ Incidental microscopic finding, often within areas of sclerosing adenosis, papillomas, or other benign proliferative lesions
Radiology ─ May be associated with microcalcifications if occurring within other lesions
Macro ─ Not grossly visible
Micro ─
─ Intraductal or intra-acinar lesion
─ Clusters of bland myoepithelial-like cells arranged around eosinophilic, hyaline, acellular spherules
─ Spherules represent basement membrane material (PAS+, Collagen IV+)
─ Often forms cribriform-like pattern within the duct/acinus
─ May have admixed epithelial cells
─ No cytologic atypia or necrosis
IHC ─ Spindle cells surrounding spherules (+) myoepithelial markers (p63, SMA, calponin, SMMHC); Spherules (+) Collagen IV, Laminin; Luminal epithelial cells (if present) (+) CK7/8/18
DDx ─
─ Cribriform DCIS (Low Grade) (Malignant epithelial cells, lacks myoepithelial cells within cribriform spaces, lacks eosinophilic spherules, lacks myoepithelial markers within spaces)
─ Adenoid Cystic Carcinoma (Rare in breast; true cribriform spaces with basement membrane material, biphasic population, invasive)
Prognosis ─ Benign incidental finding; no associated increased risk
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Radial Scar / Complex Sclerosing Lesion (CSL)

Benign proliferative lesions with a central fibroelastotic core with entrapped ducts, from which ducts and lobules radiate outwards. Radial Scar < 1 cm, CSL ≥ 1 cm.
Clinical ─ Can occur at any age, more common > 40 years; often detected as mammographic abnormality (spiculated mass, distortion, calcifications), less often palpable
Radiology ─
─ Mammography: Characteristically shows spiculated density with central radiolucency, architectural distortion; may have associated calcifications; mimics invasive carcinoma
─ Ultrasound: Irregular hypoechoic mass with posterior shadowing
Macro ─ Ill-defined, firm, gray-white stellate lesion; central puckering may be visible
Micro ─
─ Central fibroelastotic core: Hyalinized collagen and elastic fibers, often acellular or paucicellular, containing small, entrapped, often atrophic ducts/tubules
─ Radiating ducts and lobules: Proliferative changes common in radiating elements, including cysts, UDH, apocrine metaplasia, sclerosing adenosis, columnar cell changes, +/- atypia (ADH/ALH) or DCIS
─ Overall stellate architecture at low power
─ Entrapped ducts within core retain myoepithelial layer
IHC ─ Myoepithelial markers useful to confirm benignity of entrapped ducts in core and distinguish from tubular carcinoma
DDx ─
─ Tubular Carcinoma (Invasive angulated glands lacking myoepithelial layer, desmoplastic stroma, lacks central elastotic core and radiating benign structures)
─ Invasive Carcinoma NOS with desmoplasia (Malignant cytology, lacks characteristic architecture)
─ Sclerosing Adenosis (Lobulocentric, lacks central fibroelastotic core)
Prognosis ─ Benign lesion itself, but associated with slightly increased risk of subsequent breast cancer (~2x); risk higher if atypia (ADH/ALH) or DCIS is found within the lesion
Media ─ ─ Radial scar (Breast) WSI WSI DCIS involving radial sclerosing lesion

Lactating Adenoma

Benign tumor-like lesion occurring during pregnancy or lactation, composed of hyperplastic secretory lobules.
Clinical ─ Pregnant or lactating women (mc breast mass in this group); presents as palpable, mobile, often rapidly growing mass
Radiology ─
─ Ultrasound: Typically circumscribed, hypoechoic or isoechoic mass, may be complex
Macro ─ Well-circumscribed, lobulated, soft, gray-white to tan mass
Micro ─
─ Well-circumscribed, lobulated proliferation of glands resembling lactating breast tissue
─ Acini markedly enlarged, lined by cuboidal cells with secretory changes (vacuolated cytoplasm, apical snouts, luminal secretions)
─ Nuclei may be enlarged with prominent nucleoli (lactational change), but bland overall
─ Minimal intervening stroma
─ Mitotic figures may be present but are not atypical
─ +/- Infarction (esp. post-partum)
IHC ─ Not typically required; epithelial cells (+) milk proteins (e.g., lactalbumin), ER/PR often negative during lactation
Molecular ─ Lacks MED12 mutations (unlike fibroadenoma)
DDx ─
─ Fibroadenoma with lactational changes (Has characteristic fibroadenoma stroma, MED12 mutated)
─ Secretory Carcinoma (Infiltrative growth, characteristic eosinophilic secretions, ETV6::NTRK3 fusion)
─ Invasive Carcinoma with secretory features (Malignant cytology, infiltrative)
Prognosis ─ Benign; often regresses after cessation of lactation; excision may be performed for diagnosis or if persistent
Media ─ ─ Lactating adenoma (Breast) WSI ─ lactating adenoma (Breast) rosai

Tubular Adenoma

Benign neoplasm of closely packed small tubules with minimal intervening stroma.
Clinical ─ young women; well-circumscribed, palpable mass
Radiology ─
─ Mammography/Ultrasound: well-circumscribed, round or oval, may resemble fibroadenoma
Macro ─ Well-circumscribed, firm, tan-white nodule
Micro ─
─ Sharply circumscribed or encapsulated
─ Composed of tightly packed, small, uniform, round tubules
─ Tubules lined by single layer of epithelial cells and outer layer of myoepithelial cells
─ Epithelial cells cuboidal, bland nuclei, minimal cytoplasm
─ Minimal intervening stroma
─ +/- Apocrine metaplasia, calcifications
IHC ─ Epithelial cells (+) CK7/8/18, ER/PR; Myoepithelial layer (+) p63, SMA, etc.
DDx ─
─ Fibroadenoma (Prominent stromal component, different architecture)
─ Sclerosing Adenosis (Distorted/compressed glands, more stroma, lobulocentric)
─ Tubular Carcinoma (Infiltrative, angulated glands, lacks myoepithelial layer, desmoplasia)
─ Microglandular Adenosis (Haphazard glands, lacks myoepithelial layer, S100+)
Prognosis ─ Benign; excision is curative
Media ─ ─ Tubular adenoma (Breast) H&E ─ Tubular adenoma (Breast) H&E

Nipple Adenoma / Florid Papillomatosis of the Nipple

Benign epithelial proliferation arising from the lactiferous ducts of the nipple, characterized by a variety of glandular and papillary patterns, often with florid hyperplasia; may clinically mimic Paget disease or carcinoma

Clinical ─ Typically presents in middle-aged women (can occur at any age, rarely in males) as nipple erythema, erosion, ulceration, crusting, induration, or a palpable nodule; Serosanguineous or bloody nipple discharge is common; Often unilateral

Radiology ─

─ Mammography/Ultrasound Often nonspecific or may not show a discrete lesion if superficial; May show a subareolar mass or ductal changes if extension occurs

Macro ─ Nipple may appear eroded, crusted, or ulcerated; A small, firm, ill-defined nodule may be palpable within the nipple substance; Cut surface can be grayish-white and granular

Micro ─

─ Complex proliferation of ductal structures within the nipple stroma, often connecting to the overlying epidermis or major collecting ducts
─ Variable architectural patterns often coexist
─ Papillary hyperplasia Florid intraductal papillary growths with fibrovascular cores lined by epithelial and myoepithelial cells
─ Ductal hyperplasia (usual type) Solid or fenestrated proliferation of epithelial cells filling and expanding ducts
─ Adenosis-like areas Small glandular proliferation
─ Sclerosis Stromal fibrosis can be prominent, sometimes distorting glands (sclerosing papillomatosis pattern)
─ Ducts are lined by a bilayer of inner epithelial cells and outer myoepithelial cells; myoepithelial layer is crucial for benign diagnosis
─ Epithelial cells are generally bland but can show some nuclear variability or apocrine metaplasia; significant atypia is usually absent
─ Squamous metaplasia or keratin-filled cysts can occur, especially near the skin surface
─ Overlying epidermis may show acanthosis, hyperkeratosis, or erosion due to underlying glandular proliferation extending to the surface
─ Pseudo-infiltrative pattern can occur due to stromal reaction, but true invasion is absent

IHC ─
─ Myoepithelial markers (eg, p63, SMA, calponin, CK5/6) Highlight the intact myoepithelial layer around glandular and papillary structures, confirming benignity
─ Epithelial cells Positive for luminal cytokeratins (eg, CK7, CK8/18)
─ ER/PR Often negative or weakly/patchily positive in epithelial cells
─ HER2 Usually negative

DDx ─

─ Paget Disease of the Nipple (intraepidermal adenocarcinoma cells; CK7+, HER2 often+, GCDFP-15+; S100-, p63-)
─ Ductal Carcinoma In Situ (DCIS) involving nipple ducts (monomorphic atypical cells, loss of myoepithelial layer within involved structures or specific DCIS architecture; nipple adenoma has benign hyperplasia)
─ Invasive Carcinoma (infiltrative growth, lack of myoepithelial layer, cytologic malignancy)
─ Syringomatous Tumor of the Nipple (infiltrative cords and tubules of bland cells, often with squamous differentiation and keratinous cysts; deeper dermal involvement)
─ Intraductal Papilloma (typically occurs in larger subareolar ducts rather than directly within nipple substance, though overlap exists; nipple adenoma is more complex and less circumscribed)

Prognosis ─ Benign lesion; Complete local excision is curative; Recurrence is rare if completely excised; No inherent increased risk for subsequent invasive carcinoma, but must be distinguished from DCIS or Paget disease

Media ─ ─ Adenoma of the Nipple (Breast) WSI ─ Nipple adenoma (Breast) H&E ─ Nipple adenoma (Breast) H&E ─ Nipple adenoma (Breast) H&E ─ Nipple adenoma (Breast) rosai ─ Nipple adenoma (Breast) rosai ─ Nipple adenoma (Breast) rosai ─ Nipple adenoma (Breast) rosai ─ Nipple adenoma (Breast) rosai ─ Nipple adenoma (Breast) rosai

Syringomatous Tumor of the Nipple / Syringomatous Adenoma

Rare, benign, locally infiltrative adnexal-type neoplasm of the nipple, thought to arise from sweat ducts or modified mammary ducts, characterized by small tubules and cords of epithelial cells in a sclerotic stroma

Clinical ─ Typically presents as a firm, indurated, sometimes tender, ill-defined nodule or plaque within the nipple or areola; May cause nipple distortion or retraction; Occurs in adults, more common in women

Radiology ─

─ Mammography/Ultrasound Often nonspecific; may show a small, irregular, or spiculated subareolar mass, potentially mimicking carcinoma

Macro ─ Ill-defined, firm, whitish, or yellowish lesion within the nipple dermis and subcutis; Usually small (often <2 cm)

Micro ─

─ Infiltrative proliferation of small, angulated, or comma-shaped tubules and narrow cords of bland epithelial cells embedded in a dense, sclerotic, or hyalinized fibrous stroma
─ Tubules are often lined by a double layer of cells (inner luminal epithelial, outer myoepithelial-like), but the outer layer can be attenuated or inconspicuous
─ Some tubules may show "tadpole" or "tear-drop" shapes
─ Squamous differentiation with keratin pearl formation or keratinous cysts is a characteristic feature within some tubules or cell nests
─ Luminal cells are typically small, cuboidal, with bland, uniform nuclei and scant cytoplasm
─ Perineural invasion can be seen but does not imply malignancy in this context
─ Mitotic activity is very low or absent; no significant cytologic atypia or necrosis
─ Deep infiltration into nipple stroma and smooth muscle is common

IHC ─
─ Epithelial cells Positive for cytokeratins (eg, CK7, AE1/AE3, CAM5;2)
─ Myoepithelial markers (p63, CK5/6, SMA) Often highlight an outer layer around tubules, though can be discontinuous or focal
─ CEA May be positive in luminal cells
─ S100 protein May be positive in some cells, reflecting sweat gland differentiation
─ ER/PR Usually negative

DDx ─

─ Tubular Carcinoma (invasive angulated tubules lacking myoepithelial layer, desmoplastic stroma, ER positive; syringomatous tumor has blander cytology, often squamous differentiation, and at least focal myoepithelial markers)
─ Microcystic Adnexal Carcinoma (MAC) of skin (similar infiltrative pattern and squamous differentiation, but typically more extensive, involves deeper structures, and more aggressive local behavior; rare in nipple)
─ Sclerosing Adenosis (lobulocentric, more rounded glands, myoepithelium more consistently prominent)
─ Nipple Adenoma (more florid papillary and glandular proliferation, less infiltrative stromal pattern)
─ Invasive Ductal Carcinoma, NST with desmoplasia (cytologic atypia, lacks characteristic syringomatous features)

Prognosis ─ Benign, but has a propensity for local recurrence if incompletely excised due to its infiltrative growth pattern; Complete excision with clear margins is recommended; Metastasis does not occur

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Epithelial-myoepithelial tumors

Pleomorphic adenoma

Benign biphasic tumor composed of epithelial/ductal elements and myoepithelial cells within a mesenchymal (often chondromyxoid) stroma. Rare in the breast, identical to its salivary gland counterpart. Also known as benign mixed tumor.
Clinical ─ Adults (wide age range); well-circumscribed, painless, mobile mass
Radiology ─
─ Mammography/Ultrasound: Typically shows well-circumscribed, lobulated mass; may have calcifications
Macro ─ Well-circumscribed, encapsulated, firm nodule; gray-white, glistening, cartilaginous cut surface
Micro ─
─ Biphasic tumor with epithelial and myoepithelial components embedded in stroma
─ Epithelial component: Ducts, tubules, or nests lined by cuboidal/columnar cells
─ Myoepithelial component: Spindle, plasmacytoid, or clear cells, often blending with stroma
─ Stromal component: Characteristically chondromyxoid (cartilage-like); may also be fibrous or hyalinized; osseous metaplasia possible
─ Well-circumscribed, often encapsulated
─ No significant atypia or mitoses
IHC ─
─ Epithelial cells: (+) Keratins (CK7, CAM5.2), EMA
─ Myoepithelial cells: (+) p63, CK5/6, S100, SMA, calponin, GFAP (variable)
─ Stroma: (+) S100 if chondroid
Molecular ─ PLAG1 gene rearrangements (chromosome 8q12) common, often involving HMGA2 fusion
DDx ─
─ Adenomyoepithelioma (Lacks chondromyxoid stroma, different architecture)
─ Metaplastic Carcinoma (esp. low-grade adenosquamous or matrix-producing) (Infiltrative growth, cytologic atypia, malignant features)
─ Phyllodes Tumor (Leaf-like architecture, lacks chondromyxoid stroma/true epithelial glands)
─ Fibroadenoma with stromal metaplasia (Different stromal quality, lacks prominent myoepithelial component)
Prognosis ─ Benign; recurrence rare if completely excised; rare malignant transformation (carcinoma ex pleomorphic adenoma)
Media ─ ─ Mixed tumor (Breast) rosai ─ Mixed tumor (Breast) rosai

Adenomyoepithelioma

Benign biphasic tumor with proliferation of both epithelial (luminal) cells and myoepithelial cells, typically arranged in a tubular pattern, lacking significant stromal component.
Clinical ─ Adults (often older women); presents as palpable, well-circumscribed mass
Radiology ─
─ Mammography/Ultrasound: Well-circumscribed, lobulated mass; may appear complex
Macro ─ Well-circumscribed, lobulated, firm, gray-white nodule
Micro ─
─ Well-circumscribed, often lobulated proliferation
─ Biphasic pattern with inner epithelial layer and outer myoepithelial layer
─ Predominantly tubular architecture most common; solid or spindle cell patterns also occur
─ Epithelial cells: Cuboidal to columnar, bland
─ Myoepithelial cells: Often prominent, surrounding tubules; may be spindled or clear; typically bland
─ Minimal intervening stroma (unlike pleomorphic adenoma)
─ +/- Apocrine metaplasia, squamous metaplasia, CCH/ADH in adjacent tissue
─ Mitoses rare, atypia minimal
IHC ─
─ Epithelial cells: (+) Keratins (CK7, CAM5.2), EMA
─ Myoepithelial cells: (+) p63, CK5/6, CK14, SMA, calponin, S100 (variable)
Molecular ─ Heterogeneous; PIK3CA, AKT1, HRAS, BRAF mutations reported; distinct from pleomorphic adenoma (PLAG1)
DDx ─
─ Tubular Adenoma (Myoepithelial layer less prominent, lacks clear/spindle myoepithelial cells)
─ Pleomorphic Adenoma (Has chondromyxoid stroma)
─ Myoepithelioma (Pure myoepithelial proliferation, lacks distinct ductal component)
─ Low-grade Adenosquamous Carcinoma / Syringomatous Tumor (Infiltrative growth, atypia)
─ Tubular Carcinoma (Infiltrative, lacks myoepithelial layer)
─ Malignant Adenomyoepithelioma / Adenomyoepithelioma with carcinoma (Malignant cytology in either component, infiltrative growth, necrosis, high mitoses)
Prognosis ─ Benign; low rate of local recurrence; rare malignant transformation
Media ─ ─ Adenomyoepithelioma (Breast) H&E ─ Adenomyoepithelioma (Breast) H&E

Papillary Lesions and Neoplasia

Intraductal papilloma

Benign papillary neoplasm arising within a duct, composed of fibrovascular cores lined by epithelial and myoepithelial cells.
Clinical ─ Wide age range, mc 40-50s; often presents with nipple discharge (serous or bloody); may be palpable subareolar mass (central papilloma) or incidental finding (peripheral papilloma)
Radiology ─
─ Mammography: May show solitary or multiple dilated ducts, well-circumscribed mass, or calcifications
─ Ultrasound: Intraductal mass, cystic lesion with mural nodule, or dilated duct with internal echoes
─ Ductography: Filling defect within a duct
Macro ─ Friable, tan-pink, papillary mass within a dilated duct lumen; often central/subareolar; peripheral papillomas are often smaller and multiple
Micro ─
─ Intraductal proliferation with distinct fibrovascular cores
─ Arborescent (branching) papillary fronds
─ Lined by two cell layers: inner epithelial (cuboidal/columnar) and outer myoepithelial
─ Myoepithelial layer must be present on stalks (key feature)
─ Epithelial component often shows usual ductal hyperplasia (UDH), apocrine metaplasia, or squamous metaplasia
─ Stroma may be fibrotic or hyalinized
─ +/- Associated duct ectasia, hemorrhage, inflammation, calcifications
─ Peripheral papillomas often arise in TDLUs, may show more sclerosis/adenosis features
IHC ─
─ Epithelial cells: (+) CK7, ER (variable)
─ Myoepithelial cells: (+) p63, CK5/6, SMA, calponin (highlighting presence on stalks)
─ (-) High molecular weight keratins in epithelial cells (unlike UDH sometimes)
Molecular ─ Clonal; recurrent PIK3CA and AKT1 mutations common
DDx ─
─ Usual Ductal Hyperplasia (UDH) (Solid or fenestrated growth, lacks true fibrovascular cores, streaming nuclei, mosaic CK5/6)
─ Papillary DCIS (Lacks myoepithelial layer on stalks, significant cytologic atypia, monomorphic population)
─ Encapsulated Papillary Carcinoma (Solid papillary carcinoma within fibrous capsule, lacks myoepithelial layer within papillae)
─ Solid Papillary Carcinoma (Solid growth pattern, neuroendocrine features common, lacks myoepithelial layer within tumor)
─ Invasive Papillary Carcinoma (Invasive growth pattern, lacks myoepithelial layer)
─ Adenomyoepithelioma (Different architecture, prominent myoepithelial proliferation around tubules)
Prognosis ─ Benign; solitary central papillomas without atypia have minimal increased risk; multiple peripheral papillomas confer a slightly higher risk; risk increases significantly if associated with ADH or DCIS
Media ─ ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai ─ Intraductal papilloma(tosis) (Breast) rosai WSI WSI + WSI & CK5/6 with UDH WSI with ADH WSI with DCIS

Papillary DCIS

Ductal carcinoma in situ (DCIS) with the formation of true papillae lined by neoplastic epithelial cells lacking a myoepithelial layer along the fibrovascular cores.
Clinical ─ Wide age range, often older women; may present with nipple discharge or as mammographic finding (calcifications, mass)
Radiology ─
─ Mammography: May show calcifications, intraductal mass, or duct dilatation
─ Ultrasound: May show intraductal mass or complex cystic lesion
Macro ─ Often involves large ducts; may form a friable mass within a duct or cyst
Micro ─
─ Intraductal proliferation forming papillae with fibrovascular cores
─ Papillae lined by neoplastic epithelial cells showing cytologic features of DCIS (usually low to intermediate grade atypia, but can be high grade)
─ Key feature: Absence of myoepithelial cell layer along the fibrovascular cores of the papillae (must confirm with IHC)
─ Myoepithelial layer is still present at the periphery of the involved duct
─ May coexist with other patterns of DCIS (e.g., cribriform, solid)
─ Necrosis may be present
IHC ─
─ Epithelial cells: (+) ER, PR (usually); (+) CK7; (-) Myoepithelial markers (p63, CK5/6, SMA, etc.) on papillary stalks
─ Peripheral myoepithelial layer: (+) Myoepithelial markers
Molecular ─ Similar genetic alterations to other forms of non-high grade DCIS
DDx ─
─ Intraductal Papilloma (Benign; has myoepithelial layer on stalks)
─ Intraductal Papilloma with ADH/DCIS (Atypical proliferation involves benign papilloma structure which retains focal myoepithelial cells on stalks)
─ Encapsulated Papillary Carcinoma (Lacks peripheral duct structure/myoepithelial layer; surrounded by fibrous capsule)
─ Solid Papillary Carcinoma (Predominantly solid growth, often neuroendocrine features, lacks true fibrovascular cores)
─ Invasive Papillary Carcinoma (Invasive growth into stroma)
Prognosis ─ Considered DCIS; prognosis excellent with complete excision; risk of recurrence/progression similar to other DCIS subtypes of comparable grade
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Solid Papillary Carcinoma (SPC)

Circumscribed papillary neoplasm with solid growth of monotonous, low-grade neuroendocrine-like epithelial cells arranged in nodules separated by delicate fibrovascular septa. Often considered a form of DCIS or low-grade invasive carcinoma depending on circumscription/invasion.
Clinical ─ Typically older women (postmenopausal); often presents as palpable mass or mammographic finding
Radiology ─
─ Mammography/Ultrasound: Usually well-circumscribed, round or lobulated mass; may appear complex cystic/solid
Macro ─ Well-circumscribed, fleshy, tan-gray nodule; may have cystic areas
Micro ─
─ Expansile, circumscribed nodules of solid epithelial proliferation
─ Separated by delicate fibrovascular septa (true papillae with cores are rare/absent)
─ Tumor cells: Monotonous, round to oval nuclei, often with neuroendocrine features (salt-and-pepper chromatin, inconspicuous nucleoli), eosinophilic/granular cytoplasm
─ Solid growth pattern predominates; may have pseudorosettes or pseudoacini
─ Myoepithelial cells are absent within the tumor nodules (present only at periphery if SPC is entirely intraductal/in situ)
─ +/- Mucinous production (intracytoplasmic or extracellular)
─ +/- Invasive component (usually low-grade invasive ductal carcinoma NOS) at periphery
IHC ─
─ Tumor cells: (+) ER, PR (often strong); (+) Synaptophysin, Chromogranin (neuroendocrine markers, variable); (+) CK7; (-) Myoepithelial markers within nodules
─ HER2 negative
Molecular ─ Frequent PIK3CA mutations
DDx ─
─ Encapsulated Papillary Carcinoma (More prominent papillary/cribriform architecture, lacks neuroendocrine features)
─ Papillary DCIS (True fibrovascular cores, lacks solid neuroendocrine-like growth)
─ Intraductal Papilloma (Benign; myoepithelial layer present on stalks)
─ Neuroendocrine Neoplasm (Metastatic or primary NET) (Different morphology, other neuroendocrine markers may be stronger, lacks ER/PR)
─ Invasive Ductal Carcinoma NOS (If invasive component present, need to assess SPC features)
Prognosis ─ Generally indolent course; if entirely circumscribed (in situ SPC), prognosis excellent; risk increases if associated invasive carcinoma is present
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Encapsulated Papillary Carcinoma (EPC)

Papillary carcinoma entirely enclosed within a fibrous capsule, lacking myoepithelial cells within the papillae and along the capsule boundary. Often considered a form of DCIS.
Clinical ─ Typically older women (postmenopausal); presents as palpable mass or mammographic finding
Radiology ─
─ Mammography/Ultrasound: Well-circumscribed, round or oval mass, often complex cystic/solid
Macro ─ Well-circumscribed, often cystic nodule containing papillary structures; surrounded by fibrous capsule
Micro ─
─ Papillary and/or cribriform proliferation of neoplastic epithelial cells
─ Cells typically show low to intermediate grade atypia
─ Contained entirely within a thick fibrous capsule
─ Key feature: Absence of myoepithelial cell layer both within the papillary stalks and at the periphery/capsule interface (must confirm with IHC)
─ True stromal invasion beyond the capsule is absent by definition
─ +/- Hemorrhage, hemosiderin, foamy macrophages within cystic spaces
IHC ─
─ Epithelial cells: (+) ER, PR (usually); (+) CK7; (-) Myoepithelial markers (p63, CK5/6, SMA, etc.) throughout the lesion including periphery
─ HER2 negative
Molecular ─ Similar alterations to low/intermediate grade DCIS
DDx ─
─ Intracystic Papilloma (Benign; has myoepithelial layer on stalks and/or periphery)
─ Papillary DCIS (Contained within a native duct structure with peripheral myoepithelial cells; lacks thick fibrous capsule)
─ Solid Papillary Carcinoma (Predominantly solid growth, neuroendocrine features)
─ Invasive Papillary Carcinoma (Invasion beyond capsule into stroma)
─ Invasive Cribriform Carcinoma (If predominantly cribriform; invasive component present)
Prognosis ─ Excellent prognosis, considered a form of non-invasive carcinoma (DCIS); risk of recurrence very low if completely excised
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Lobular Neoplasia

Atypical Lobular Hyperplasia (ALH)

A neoplastic proliferation of small, monotonous, discohesive cells within terminal duct lobular units (TDLUs), partially filling and involving <50% of the acini within an individual lobule. Considered part of the spectrum of lobular neoplasia (LN).
Clinical ─ Primarily premenopausal women; usually an incidental microscopic finding on biopsy performed for other reasons (e.g., calcifications, fibrocystic changes)
Radiology ─
─ No specific imaging features; often found in biopsies for calcifications which are usually related to adjacent benign changes (e.g., sclerosing adenosis)
Macro ─ Not grossly identifiable
Micro ─
─ Proliferation of small, uniform, round cells with scant cytoplasm and indistinct borders
─ Cells are discohesive, lacking cell-to-cell adhesion
─ Involves acini of TDLUs, partially filling them; defined as involving <50% of the acini within a lobule
─ Acini are generally not distended (unlike florid LCIS)
─ Nuclei round to oval, often with inconspicuous nucleoli; minimal pleomorphism
─ Intracytoplasmic lumina (mucin negative) may be present
─ Pagetoid spread (single cells undermining ductal epithelium) into terminal ducts can occur
─ Myoepithelial layer surrounding acini is intact
IHC ─
─ (-) E-cadherin (membranous loss is characteristic)
─ (+) p120 catenin (cytoplasmic staining pattern due to E-cadherin loss)
─ (+) ER, PR
─ (-) HER2
─ (-) CK5/6, HMWK (negative in neoplastic cells)
Molecular ─
─ Loss of CDH1 gene function (mutation or methylation)
─ Loss of heterozygosity (LOH) at 16q (location of CDH1) common
DDx ─
─ Lobular Carcinoma In Situ (LCIS) (Same cytology but involves ≥50% of acini in a lobule, often with distension)
─ Ductal Carcinoma In Situ (DCIS), Low Grade (Cohesive cells, different architecture (cribriform, micropapillary), E-cadherin+)
─ Usual Ductal Hyperplasia (UDH) (Polymorphous population, streaming/slit-like spaces, CK5/6 mosaic+, E-cadherin+)
─ Benign lobules/Acinar cells in adenosis (Cohesive, maintain polarity, E-cadherin+)
Prognosis ─ Considered a risk factor (marker) for subsequent development of invasive carcinoma (relative risk ~4-5x) in both breasts; risk is lower than for LCIS
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Lobular Carcinoma In Situ (LCIS)

A neoplastic proliferation of small, monotonous, discohesive cells filling and distending ≥50% of the acini within a TDLU. Considered part of the spectrum of lobular neoplasia (LN).
Clinical ─ Primarily premenopausal women (mean age ~50); usually an incidental microscopic finding; not typically associated with a palpable mass or specific imaging findings, though may be near calcifications
Radiology ─
─ No specific features; usually occult on imaging; may be found in biopsies for calcifications related to adjacent benign changes
Macro ─ Not grossly identifiable
Micro ─
─ Proliferation of small, uniform, round cells with scant cytoplasm and indistinct borders
─ Cells are discohesive, lacking cell-to-cell adhesion
─ Fills and often distends most or all (≥50%) of the acini within affected TDLUs
─ Nuclei round to oval, monotonous, often with inconspicuous nucleoli; minimal pleomorphism (Classic LCIS)
─ Intracytoplasmic lumina (mucin negative) may be present
─ Pagetoid spread (single cells undermining ductal epithelium) into terminal ducts and larger ducts is common
─ Myoepithelial layer surrounding involved acini/ducts is intact
─ Variants:
─ Florid LCIS: Marked expansion of TDLUs by classic LCIS cells, often with central necrosis/calcification, forming confluent sheets
─ Pleomorphic LCIS (PLCIS): Cells show greater nuclear pleomorphism (size ≥4x lymphocyte), larger nucleoli, more cytoplasm; often associated with necrosis/calcification; may mimic high-grade DCIS
IHC ─
─ (-) E-cadherin (membranous loss is characteristic)
─ (+) p120 catenin (cytoplasmic staining pattern)
─ (+) ER, PR (usually strong/diffuse in classic LCIS; may be weaker or negative in PLCIS)
─ (-) HER2 (may be amplified in PLCIS)
─ (-) CK5/6, HMWK (negative in neoplastic cells)
Molecular ─
─ Loss of CDH1 gene function (mutation or methylation)
─ Loss of heterozygosity (LOH) at 16q (location of CDH1) common
─ Complex alterations may be seen in PLCIS
DDx ─
─ Atypical Lobular Hyperplasia (ALH) (Same cytology but involves <50% of acini within a lobule, minimal/no distension)
─ Ductal Carcinoma In Situ (DCIS) (Cohesive cells, different architecture (cribriform, micropapillary, solid), E-cadherin+)
─ Invasive Lobular Carcinoma (Infiltration into stroma, lacks surrounding myoepithelial layer)
─ Lymphoma/Leukemia Infiltrate (LCA+, specific hematopoietic markers+)
─ Benign lobules/Acinar cells in adenosis (Cohesive, maintain polarity, E-cadherin+)
Prognosis ─ Considered a risk factor (marker) and non-obligate precursor for subsequent invasive carcinoma (relative risk ~8-10x) in both breasts. Risk is higher than for ALH. Pleomorphic and florid LCIS may have higher risk and are often managed similarly to DCIS (excision with margins).
Media ─ ─ Lobular carcinoma in situ (Breast) rosai ─ Lobular carcinoma in situ (Breast) rosai ─ Lobular carcinoma in situ (Breast) rosai Pleomorphic pathoutlines WSI WSI
Florid pathoutlines

Ductal Neoplasia

Atypical Ductal Hyperplasia (ADH)

A clonal intraductal proliferation of epithelial cells that resembles low-grade DCIS (architecturally and/or cytologically) but is quantitatively limited in extent (typically defined as involving ≤2 duct spaces or measuring ≤2 mm in linear extent).
Clinical ─ Usually an incidental microscopic finding, most often associated with mammographic calcifications biopsied for other reasons; peak age typically perimenopausal/postmenopausal
Radiology ─
─ Mammography: Frequently associated with microcalcifications (amorphous, punctate, or pleomorphic), often grouped; may be seen with architectural distortion or densities but often has no specific correlate itself
Macro ─ Not grossly identifiable
Micro ─
─ Proliferation of monotonous epithelial cells within ducts or TDLUs
─ Cells resemble those of low-grade DCIS (round nuclei, mild atypia, distinct cell borders)
─ Architectural patterns mimic low-grade DCIS:
─ Cribriform: Rigid bridges, punched-out secondary lumens
─ Micropapillary: Short, club-shaped projections without fibrovascular cores
─ Solid: Ducts partially filled with monotonous cells
─ Quantitative limitation is key for diagnosis: Involvement of only one or two duct spaces, AND/OR linear extent ≤ 2 mm
─ Myoepithelial layer surrounding involved spaces is intact
IHC ─
─ (+) ER, PR (usually strong and diffuse)
─ (+) E-cadherin (membranous)
─ (-) CK5/6 or HMWK (negative or only rare scattered positive cells within proliferation, unlike mosaic pattern in UDH)
─ (-) HER2 (typically)
─ (+) Myoepithelial markers (p63, etc.) highlight intact peripheral layer
Molecular ─
─ Clonal proliferation; often shows LOH at 16q and 17p, similar to low-grade DCIS
DDx ─
─ Usual Ductal Hyperplasia (UDH) (Heterogeneous population, streaming nuclei, slit-like spaces, mosaic CK5/6+, patchy ER)
─ DCIS, Low Grade (Qualitatively similar but exceeds size criteria for ADH - >2mm or >2 ducts involved)
─ Flat Epithelial Atypia (FEA) (Lacks complex architecture like cribriform/micropapillary patterns)
─ LCIS involving ducts (Pagetoid spread) (Discohesive cells, E-cadherin negative)
Prognosis ─ Considered a high-risk lesion, conferring a significantly increased risk (relative risk ~4-5x) for subsequent development of invasive carcinoma in both breasts; often warrants excision biopsy if found on core needle biopsy due to risk of upgrade to DCIS or invasive carcinoma
Media ─ ─ Myoid hamartoma with ductal hyperplasia (Breast) rosai WSI + stains WSI WSI WSI video H&E H&E video

Ductal Carcinoma In Situ (DCIS)

A neoplastic proliferation of epithelial cells confined to the ductal-lobular system, with cytologic atypia and specific architectural patterns.
Clinical ─ Wide age range, more common with increasing age; detected as calcifications; less commonly as palpable mass, discharge, or Paget disease of nipple
Radiology ─
─ Mammography: Microcalcifications (pleomorphic, linear, branching, casting) are the most common finding; may also present as mass, density, or architectural distortion
─ Ultrasound: May show duct dilatation, intraductal mass, or non-specific findings; less sensitive than mammography, especially for calcification-only DCIS
─ MRI: May show non-mass enhancement or clumped enhancement
Macro ─ Often grossly occult; may appear as firm, gray-white areas, dilated ducts with cheesy material (comedo type), or cystic lesion (papillary types)
Micro ─
─ Proliferation of neoplastic epithelial cells confined within ducts and/or lobules (cancerization of lobules)
─ Myoepithelial cell layer is present around involved ducts/lobules (though may be attenuated)
─ Cytologic atypia present, ranging from low to high grade
─ Various architectural patterns (often mixed):
─ Comedo: High-grade nuclei, central necrosis (often calcified), solid sheets peripherally
─ Cribriform: Rigid, punched-out, round secondary lumens within solid proliferation
─ Micropapillary: Finger-like projections lacking fibrovascular cores, attached to duct wall
─ Papillary: True fibrovascular cores lined by neoplastic cells, lacking myoepithelial layer on stalks (see Papillary DCIS outline)
─ Solid: Ducts completely filled by neoplastic cells
─ Flat: Resembles FEA but with higher grade nuclei or more extensive involvement (less common pattern)
─ Grading (typically 3-tiered: Low, Intermediate, High): Based primarily on nuclear pleomorphism and presence/absence of comedonecrosis
─ Low Grade: Monotonous nuclei (1.5-2x RBC), inconspicuous nucleoli, rare mitoses, necrosis usually absent (includes cribriform, micropapillary patterns)
─ Intermediate Grade: Moderate pleomorphism, visible nucleoli, +/- necrosis, moderate mitoses
─ High Grade: Marked pleomorphism (>2.5-3x RBC), prominent nucleoli, frequent mitoses, comedonecrosis characteristic
IHC ─
─ (+) ER, PR (Common in low/intermediate grade, often negative in high grade/comedo)
─ (+) E-cadherin (membranous, confirms ductal lineage)
─ (+) CK7, CAM5.2 (epithelial cells)
─ (-) Myoepithelial markers within neoplastic proliferation (e.g., p63, CK5/6, SMA); highlights intact peripheral myoepithelial layer
─ HER2 overexpression/amplification common in high-grade/comedo DCIS, rare in low grade
Molecular ─
─ Clonal proliferation with genetic alterations similar to invasive ductal carcinoma of corresponding grade
─ Low grade: Often 16q loss, 1q gain
─ High grade: More complex alterations, TP53 mutations, MYC amplification, HER2 amplification common
DDx ─
─ Atypical Ductal Hyperplasia (ADH) (Similar cytology/architecture to low-grade DCIS but quantitatively limited - typically <2 ducts involved or <2mm extent)
─ Usual Ductal Hyperplasia (UDH) (Heterogeneous population, streaming, slit-like spaces, mosaic CK5/6)
─ Flat Epithelial Atypia (FEA) (Less atypia, lacks complex architecture)
─ LCIS with ductal spread (Discohesive cells, E-cadherin negative)
─ Intraductal Papilloma (Benign; myoepithelial layer present on stalks)
─ Invasive Carcinoma (Breach of basement membrane/myoepithelial layer, stromal invasion)
Prognosis ─ Non-invasive precursor lesion; excellent prognosis with complete excision; main risk is local recurrence (as DCIS or invasive carcinoma) or development of new primary in either breast; risk of recurrence influenced by grade, size, margin status
Media ─ ─ Basal-like carcinoma + micropapillary high grade DCIS (Breast) H&E ─ High grade DCIS (ductal carcinoma in-situ) (Breast) H&E ─ High grade DCIS with cancerisation of lobules (Breast) WSI ─ Hypersecretory DCIS/ Grade 1 invasive ductal carcinoma (Breast) WSI ─ Intermediate grade solid, cribriform, comedo DCIS (Breast) H&E ─ Mixed invasive ductal carcinoma and micropapillary carcinoma with associated low grade DCIS (Breast) WSI ─ Widespread sclerosing adenosis with intermediate grade DCIS and a small number of tubules with no myosin staining representing an invasive ductal carcinoma grade 2. Micrometastasis in the lymph node (Breast) WSI

Invasive breast carcinoma

Invasive Breast Carcinoma of No Special Type (IBC-NST)

The most common type of invasive breast cancer, characterized by malignant epithelial cells invading beyond the basement membrane into the stroma, lacking features that would classify it as a special histologic type; formerly known as Invasive Ductal Carcinoma (IDC), Not Otherwise Specified (NOS)

Clinical ─ Most common invasive breast cancer (approx 70-80%); Can occur at any adult age, incidence increases with age, peak in postmenopausal women; May present as a palpable mass (often hard, irregular), mammographic abnormality (spiculated mass, calcifications, architectural distortion), nipple discharge, or skin changes (retraction, peau d'orange)

Radiology ─

─ Mammography Typically an irregular, spiculated mass; may have associated pleomorphic or linear microcalcifications; can also be a well-circumscribed mass or architectural distortion
─ Ultrasound Often an irregular, hypoechoic mass with posterior acoustic shadowing or enhancement; margins may be indistinct, spiculated, or microlobulated
─ MRI Variable appearance; typically an enhancing mass with irregular shape and margins; useful for assessing extent, multifocality, and response to neoadjuvant therapy

Macro ─ Variable; often a firm to hard, gray-white, gritty cut surface; Borders are typically infiltrative and irregular; Necrosis or hemorrhage may be visible in higher-grade tumors; Tumor size is a key prognostic factor

Micro ─

A diagnosis of exclusion; lacks specific architectural or cytological features of special type carcinomas
─ Growth Patterns Tumor cells infiltrate stroma in various patterns
─ Nests, cords, trabeculae, sheets, or individual cells
─ Glandular/tubular differentiation is variable (forms basis of histologic grade component)
─ Cytologic Features Variable depending on grade
─ Low grade Cells relatively uniform, small nuclei, inconspicuous nucleoli
─ Intermediate grade Moderate pleomorphism, visible nucleoli
─ High grade Marked pleomorphism, large vesicular nuclei, prominent/multiple nucleoli, coarse chromatin
─ Stroma Typically desmoplastic (fibrous, sclerotic); amount varies from minimal to abundant; May show elastosis
─ Tumor-Associated Lymphocytic Infiltrate (TILs) Variable numbers of lymphocytes and plasma cells in the stroma; high TILs can be prognostic/predictive in some subtypes (eg, triple negative, HER2+)
─ Lymphovascular Invasion (LVI) Presence of tumor cells within endothelial-lined spaces (lymphatics or blood vessels); important prognostic factor
─ Perineural Invasion Tumor cells infiltrating around nerve fibers
─ Associated DCIS Often present adjacent to or intermingled with the invasive component
─ Histologic Grade (Nottingham Histologic Score / Elston-Ellis modification of Scarff-Bloom-Richardson system)
─ Based on three morphologic features, each scored 1-3
─ Tubule formation (percentage of tumor forming tubules)
─ Nuclear pleomorphism (variation in nuclear size and shape)
─ Mitotic count (number of mitoses per 10 high-power fields in the most active area)
─ Total score determines grade
─ Grade 1 (Well-differentiated) Score 3-5
─ Grade 2 (Moderately-differentiated) Score 6-7
─ Grade 3 (Poorly-differentiated) Score 8-9

IHC ─
Essential for classification and guiding treatment
─ Estrogen Receptor (ER) Nuclear stain; positive in ~70-80%; predicts response to endocrine therapy
─ Progesterone Receptor (PR) Nuclear stain; positive in ~60-70%; also predicts endocrine therapy response
─ HER2 (Human Epidermal Growth Factor Receptor 2) Membrane stain (protein expression) and/or ISH (gene amplification); overexpressed/amplified in ~15-20%; predicts response to anti-HER2 therapy
─ Ki-67 Nuclear stain for proliferation; high levels indicate more aggressive tumor and may influence treatment decisions
─ E-cadherin Membranous stain; typically positive (helps distinguish from invasive lobular carcinoma)
─ Myoepithelial markers (eg, p63, SMA) Negative in invasive tumor cells; used to confirm absence of myoepithelial layer and distinguish from in situ disease or benign mimics
─ Cytokeratins (eg, CK7, CAM5;2) Positive in tumor cells, confirming epithelial origin

Molecular ─
Classified into intrinsic molecular subtypes (see separate section) based on gene expression profiles, often approximated by IHC surrogates (ER, PR, HER2, Ki-67)

DDx ─

─ Special Types of Invasive Carcinoma (eg, lobular, tubular, mucinous, medullary, metaplastic etc; these have specific defining features)
─ Metastatic Carcinoma to the breast (eg, from lung, ovary, melanoma; clinical history and specific IHC markers are key)
─ Benign Sclerosing Lesions (eg, radial scar, complex sclerosing lesion, sclerosing adenosis; retain myoepithelial layer, lack atypia)
─ Granulomatous Mastitis (inflammatory, granulomas present, no malignant cells)

Prognosis ─ Highly variable; depends on multiple factors including
─ Tumor stage (TNM size, nodal status, distant metastasis)
─ Histologic grade
─ Molecular subtype (ER/PR/HER2 status)
─ Lymphovascular invasion
─ Proliferation rate (Ki-67)
─ Response to therapy

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Inflammatory Breast Carcinoma (IBC)

A rare but aggressive clinicopathologic entity characterized by diffuse erythema, edema (peau d'orange), warmth, and induration of the breast, often without a discrete palpable mass; diagnosis requires these clinical signs and pathologic confirmation of invasive carcinoma

Clinical ─ Rapid onset of symptoms (typically < 6 months); Breast becomes enlarged, tender, warm, erythematous (often involving at least one-third of the breast); Skin may appear pitted like an orange peel (peau d'orange); Nipple retraction or discharge may occur; A discrete underlying mass may or may not be palpable; Axillary lymphadenopathy is common at presentation; Often affects younger women compared to non-IBC; High risk of early metastasis

Radiology ─

─ Mammography Often shows skin thickening, increased breast density, trabecular coarsening; A discrete mass may or may not be visible; Diffuse suspicious microcalcifications can be present
─ Ultrasound Skin thickening, diffuse stromal heterogeneity, dilated lymphatic channels, and disruption of normal tissue planes; May identify an underlying mass or axillary adenopathy
─ MRI Can be useful to assess the extent of disease, chest wall involvement, and response to therapy; often shows diffuse abnormal enhancement and skin thickening
─ PET/CT Often used for staging to detect regional and distant metastases

Macro ─ Affected breast is often enlarged, firm, and diffusely indurated; Skin is thickened and erythematous; A discrete tumor mass may not be apparent on gross examination, or there may be an ill-defined infiltrative lesion

Micro ─

─ Underlying invasive carcinoma is most commonly Invasive Breast Carcinoma of No Special Type (IBC-NST), usually high grade; Other histologic types can occur but are less common
─ The pathognomonic histologic finding, if present in a skin biopsy, is invasion of dermal lymphatics by tumor cells (tumor emboli)
─ However, dermal lymphatic invasion is NOT required for the diagnosis if the clinical signs of IBC are present and there is invasive carcinoma in the breast parenchyma
─ Conversely, incidental finding of dermal lymphatic invasion without clinical signs of IBC is not sufficient for an IBC diagnosis
─ Tumor cells within lymphatics are often poorly differentiated
─ Associated DCIS may or may not be present
─ The breast parenchyma itself shows features of the underlying invasive carcinoma type

IHC ─
─ Reflects the underlying invasive carcinoma subtype; Many IBCs are ER/PR negative and/or HER2 positive, or triple-negative, contributing to their aggressive behavior
─ E-cadherin is usually positive in tumor emboli (if ductal origin)
─ D2-40 or podoplanin can highlight lymphatic vessels containing tumor emboli

Molecular ─
─ Often associated with aggressive molecular profiles (eg, basal-like, HER2-enriched)
─ Overexpression of genes related to angiogenesis, lymphangiogenesis, and cell adhesion (eg, RhoC, E-cadherin) has been reported

DDx ─

Clinical DDx is crucial
─ Acute Mastitis / Breast Abscess (infectious; often responds to antibiotics; may have fever, leukocytosis; imaging can show collections)
─ Other causes of lymphedema or lymphatic obstruction
─ Locally advanced non-inflammatory breast cancer with extensive skin involvement (may overlap, but IBC has specific rapid onset and diffuse erythema/edema criteria)
─ Dermatologic conditions causing erythema and edema

Prognosis ─ Poor compared to non-inflammatory breast cancer of similar stage; IBC is considered at least T4d disease by AJCC staging; High rates of local recurrence and distant metastasis; Multimodal therapy (neoadjuvant chemotherapy, surgery, radiation, targeted therapy if applicable) has improved outcomes, but overall survival remains lower than for other breast cancer types

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Molecular Subtypes of Breast Cancer

Breast cancer is a heterogeneous disease classified into distinct molecular subtypes based on gene expression profiling, which have significant prognostic and therapeutic implications; These are often approximated in clinical practice using immunohistochemical (IHC) surrogates for ER, PR, HER2, and Ki-67

Intrinsic Molecular Subtypes (Perou/Sørlie et al;)
─ Luminal A
─ Characteristics Typically ER positive, PR positive, HER2 negative, low Ki-67 (low proliferation)
─ Gene Expression High expression of luminal cytokeratins (CK8, CK18), estrogen-regulated genes; low expression of proliferation-related genes
─ Histology Often lower grade IBC-NST, tubular, cribriform, classic invasive lobular carcinoma
─ Prognosis Generally the best prognosis among all subtypes; responsive to endocrine therapy
─ Luminal B
─ Characteristics Typically ER positive, HER2 negative, but with high Ki-67 (high proliferation) OR ER positive, PR low or negative, HER2 positive
─ Gene Expression High expression of luminal genes; higher expression of proliferation genes than Luminal A, or co-expression of HER2 pathway genes
─ Histology Often higher grade IBC-NST compared to Luminal A
─ Prognosis Generally worse prognosis than Luminal A; responsive to endocrine therapy, may benefit from chemotherapy; if HER2 positive, benefits from anti-HER2 therapy
─ HER2-Enriched
─ Characteristics ER negative, PR negative, HER2 positive
─ Gene Expression High expression of HER2 gene cluster and proliferation genes
─ Histology Often high-grade IBC-NST, sometimes micropapillary features
─ Prognosis Historically poor, but significantly improved with anti-HER2 targeted therapies (eg, trastuzumab, pertuzumab)
─ Basal-like
─ Characteristics Typically ER negative, PR negative, HER2 negative (Triple-Negative Breast Cancer, TNBC); often express basal/myoepithelial markers (eg, CK5/6, CK14, EGFR)
─ Gene Expression High expression of basal cytokeratins, proliferation genes; often associated with BRCA1 mutations
─ Histology Often high-grade IBC-NST, medullary features, metaplastic carcinoma
─ Prognosis Generally aggressive with higher rates of recurrence and metastasis, particularly in early years; does not respond to endocrine or anti-HER2 therapy; chemotherapy is main systemic treatment; PARP inhibitors may be used for BRCA-mutated cases
─ Normal-like (less well-defined and debated as a distinct tumor subtype; may represent contamination with normal tissue or a very low-grade tumor)

IHC Surrogate Classification (Clinical Practice)
Used to approximate intrinsic subtypes
─ Luminal A-like ER positive, PR positive (often ≥20%), HER2 negative, Ki-67 low (eg, <14% or <20% depending on lab cutoffs)
─ Luminal B-like (HER2 Negative) ER positive, HER2 negative, AND at least one of PR low/negative (eg, <20%) OR Ki-67 high (eg, ≥20%)
─ Luminal B-like (HER2 Positive) ER positive, HER2 positive (any PR, any Ki-67)
─ HER2-Enriched (Non-Luminal) ER negative, PR negative, HER2 positive
─ Triple-Negative (Ductal/NST) ER negative, PR negative, HER2 negative; often corresponds to Basal-like but not perfectly synonymous
─ Basal-like (by IHC) TNBC that is also positive for basal markers like CK5/6 or EGFR

Clinical Significance
─ Guides treatment decisions (endocrine therapy, chemotherapy, anti-HER2 therapy, PARP inhibitors)
─ Provides prognostic information
─ Helps in understanding tumor biology and heterogeneity

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Microinvasive carcinoma

Invasive carcinoma ≤ 1 mm in greatest dimension.
Clinical ─ Detected due to associated DCIS
Micro ─
─ Focus or foci of invasion measuring ≤ 1 mm in greatest dimension
─ Infiltration of neoplastic cells into stroma beyond basement membrane/myoepithelial layer
─ Single cells, small clusters, or tiny glands
DDx ─
─ DCIS extending into sclerosing adenosis/radial scar (Retains myoepithelial layer)
─ Extensive DCIS with tangential sectioning mimicking invasion
─ True invasive carcinoma > 1 mm
Prognosis ─ Excellent prognosis, similar to DCIS alone, guidelines for DCIS
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Invasive lobular carcinoma (ILC)

Invasive carcinoma of small, discohesive cells, often infiltrating in single-file strands or targetoid patterns, associated with loss of E-cadherin.
Clinical ─ Often postmenopausal; ill-defined mass; higher incidence of bilaterality
Radiology ─
─ Mammography: ill-defined density, distortion, asymmetry; calcifications less common
─ Ultrasound: ill-defined hypoechoic mass with posterior shadowing or no discrete lesion
─ MRI: non-mass enhancement; more sensitive for detecting extent and multifocality
Macro ─ may lack a discrete mass
Micro ─
─ Infiltrative proliferation of small, relatively uniform, discohesive cells
─ Cells round to oval with scant cytoplasm, round nuclei, inconspicuous nucleoli (classic)
─ Single-file strands ("Indian files") infiltrating stroma, minimal desmoplasia
─ Targetoid pattern (concentric rings around benign ducts or lobules)
─ Intracytoplasmic lumina (mucin negative) common
─ Signet-ring cell features (intracytoplasmic mucin) may be present
─ Minimal tubule formation
─ Variants: Classic, solid, alveolar, pleomorphic (larger cells, more atypia/mitoses)
IHC ─
─ (-) E-cadherin (membranous loss)
─ (+) p120 catenin (cytoplasmic)
─ (+) ER, PR
─ (-) HER2 (amplification can occur in pleomorphic variant)
─ (+) CK7; (-) CK5/6
Molecular ─
─ Loss of CDH1
─ PIK3CA, TBX3, FOXA1 mutations common
─ ERBB2 (HER2) amplification in pleomorphic variant
DDx ─
─ Invasive Ductal Carcinoma NOS (Cohesive, tubule formation, E-cadherin+)
─ DCIS or LCIS with infiltration artifact (myoepithelial layer around in situ component)
─ Lymphoma/Leukemia
─ Metastatic carcinoma (esp. gastric signet ring)
Prognosis ─ ~IDC NOS; Pleomorphic worse than classic.
Media ─ ─ Invasive lobular carcinoma (Breast) WSI ─ Invasive lobular carcinoma (Breast) rosai ─ Invasive lobular carcinoma (Breast) rosai ─ Invasive lobular carcinoma (Breast) rosai ─ Invasive lobular carcinoma (Breast) rosai ─ Invasive lobular carcinoma (Breast) rosai ─ Invasive lobular carcinoma (Breast) rosai ─ Invasive lobular carcinoma (Breast) rosai

Tubular Carcinoma

Well-differentiated invasive carcinoma composed predominantly (≥90%) of single-layered tubules infiltrating stroma; low-grade malignancy.
Clinical ─ Often perimenopausal/older women; frequently detected mammographically as small spiculated density (≤1 cm), may have microcalcifications; can be palpable.
Radiology ─
─ Mammography: Small (<2cm), irregular or spiculated mass; often associated microcalcifications.
─ Ultrasound: Hypoechoic, irregular mass with posterior acoustic shadowing.
─ MRI: Irregular enhancing mass, useful for extent if needed.
Macro ─ Small (often ≤1 cm), firm, gritty, irregular/stellate borders; may be difficult to identify grossly.
Micro ─
─ Infiltrating, well-formed, open tubules; haphazardly arranged, often angulated/teardrop-shaped.
─ Key: Tubules lined by a single layer of epithelial cells (no myoepithelial layer).
─ Epithelial cells: Small, uniform, cuboidal; low-grade nuclei (round, regular, inconspicuous nucleoli, rare mitoses).
─ Apical snouts (decapitation secretion) characteristic and prominent.
─ Minimal cytologic atypia or pleomorphism.
─ Stroma: Desmoplastic/fibroelastotic.
─ Purity: ≥90% tubular pattern required for diagnosis; <90% is IDC NST with tubular features.
─ Often associated with low-grade DCIS, columnar cell lesions, LCIS (Rosen Triad).
IHC ─
─ (+) ER, PR
─ (-) HER2
─ (+) E-cadherin (Membranous)
─ (-) Myoepithelial markers (p63, SMA, Calponin, SMMHC) around invasive tubules.
─ (-) Basal Cytokeratins (CK5/6)
Molecular ─ Consistent with Luminal A subtype (ER+/PR+/HER2-). Specific recurrent mutations less defining than IHC profile.
DDx ─
─ Sclerosing Adenosis: Benign; compressed glands retain myoepithelial layer (IHC+).
─ Microglandular Adenosis: Benign; round glands lack myoepithelial layer but have basement membrane; ER/PR(-), S100(+).
─ Radial Scar/Complex Sclerosing Lesion: Benign; entrapped glands retain myoepithelial layer.
─ Invasive Cribriform Carcinoma: Well-differentiated; distinct cribriform architecture.
─ Tubulolobular Carcinoma: Features of both tubular and lobular carcinoma.
Prognosis ─ Excellent; significantly better than IDC NST. Low rate of lymph node metastasis (~10-15%); distant metastasis rare.
Media ─ ─ Tubular carcinoma (Breast) H&E ─ Tubular carcinoma (Breast) H&E ─ Tubular carcinoma (Breast) rosai ─ Tubular carcinoma (Breast) rosai ─ Tubular carcinoma (one focus of in situ duct carcinoma) (Right breast) rosai

Tubulolobular Carcinoma

Invasive carcinoma showing mixed features of both tubular carcinoma (tubules) and classic invasive lobular carcinoma (single file cells)
Clinical ─ Similar to tubular or lobular carcinoma; often small irregular mass on mammography
Radiology ─
─ Mammography: Small irregular or spiculated mass; possibly calcifications
─ Ultrasound: Irregular hypoechoic mass; possibly shadowing
─ MRI: Mixed features; useful for determining extent
Macro ─ Small (less than 2 cm), firm, gray-white, infiltrative borders
Micro ─
─ Mixture: infiltrating tubules (single layer, angulated, apical snouts) plus infiltrating single file strands or discohesive cells
─ Absent myoepithelial cells surrounding tubules
─ Cells are small, uniform, low-grade nuclei (similar to classic lobular and tubular carcinoma)
─ Intracytoplasmic lumina possible
─ Minimal stromal reaction surrounding single files; variable surrounding tubules
─ Tubular and lobular mixture varies
IHC ─
─ (+) E-cadherin (Membranous; key difference from classic lobular carcinoma)
─ (+) p120 catenin (Membranous)
─ (+) ER, PR
─ (-) HER2
─ (-) Myoepithelial markers (p63, SMA, Calponin) surrounding invasive components
Molecular ─
─ Absent CDH1 loss (unlike classic lobular carcinoma)
─ Luminal A subtype (ER/PR+/HER2 negative)
DDx ─
─ Tubular Carcinoma: Greater than 90% tubules; no significant single file component
─ Classic Lobular Carcinoma: Mostly single file cells; no tubules; E-cadherin negative
─ Invasive Ductal Carcinoma NST with Tubular and Lobular Features: Does not meet strict criteria; E-cadherin+
─ Invasive Cribriform Carcinoma: Cribriform architecture; E-cadherin+
Prognosis ─ Favorable; better than classic lobular carcinoma and invasive ductal carcinoma NST; possibly slightly worse than pure tubular carcinoma; depends on mixture and grade; low lymph node metastasis
media ─ placeholder ─ pathoutlines WSI

Invasive Cribriform Carcinoma

Invasive carcinoma with cribriform growth pattern similar to cribriform DCIS
Clinical ─ Similar presentation to invasive carcinoma NST
Radiology ─ Nonspecific mass or calcifications
Macro ─ Nonspecific firm mass
Micro ─
─ Infiltrating nests of cells with fenestrated rounded or angulated gland-like spaces (cribriform pattern)
─ Tumor cells usually low to intermediate nuclear grade
─ Mucinous secretion or microcalcifications sometimes present in lumens
─ Stroma often fibroblastic
─ Pure form has greater than 90% cribriform morphology
─ Tubular growth pattern commonly seen as minor component (less than 50%)
─ Other patterns present denote mixed type
IHC ─
─ (+) ER, PR
─ (-) HER2
─ (+) E-cadherin
─ (-) Myoepithelial markers around invasive nests
Molecular ─ Consistent with Luminal A subtype ((+)ER/PR positive/HER2 negative)
DDx ─
─ Cribriform DCIS: Retains myoepithelial layer (check with IHC)
─ Adenoid Cystic Carcinoma: Biphasic (epithelial/myoepithelial); distinct pseudolumens with basal lamina material; often CD117 positive
─ Tubular Carcinoma: Predominantly well-formed single-layered tubules; lacks cribriform pattern
─ Invasive Carcinoma NST with Cribriform Features: Less than 90% cribriform pattern
Prognosis ─ Favorable; better than invasive carcinoma NST
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Mucinous Carcinoma

Invasive carcinoma with extracellular mucin production
Clinical ─ Typically affects older postmenopausal women; often presents as palpable mass
Radiology ─
─ Mammography: circumscribed, lobulated; isodense or hyperdense; calcification uncommon
─ Ultrasound: complex cystic and solid mass; may be isoechoic or hypoechoic
─ MRI: Variable appearance; often high signal on T2-weighted images
Macro ─ Well-circumscribed gelatinous or mucoid mass; gray-blue cut surface
Micro ─
─ Nests clusters or islands of tumor cells floating in abundant extracellular mucin pools
─ Tumor cells typically small uniform low-grade nuclei; may show neuroendocrine features
─ Pure mucinous carcinoma: Greater than 90% mucinous pattern
─ Mixed mucinous carcinoma: 10–90% mucinous pattern admixed with non-mucinous invasive carcinoma (usually NST)
─ Micropapillary variant: Small clusters of cells with reversed polarity within mucin pools; more aggressive behavior
─ Cellular variant: More cellular nests with less abundant mucin
─ Signet-ring cells may be present
IHC ─
─ (+) ER, PR
─ (-) HER2
─ (+) E-cadherin
─ (+) Chromogranin/Synaptophysin
─ Mucin stains (Alcian blue PAS mucicarmine) positive for extracellular mucin
Molecular ─
─ Consistent with Luminal A subtype ((+)ER/PR positive/HER2 negative)
─ Lower frequency of TP53 mutations compared to invasive carcinoma NST
─ Specific molecular alterations not well-defined for pure type
DDx ─
─ Mucocele-like lesion: Benign; lacks atypia; often associated with ADH or DCIS; extravasated mucin lacks floating epithelial cells
─ Invasive Carcinoma NST with Mucin Production: Less than 90% mucinous pattern
─ Metastatic Mucinous Carcinoma (e g GI tract ovary): Check clinical history; use organ-specific IHC markers (e g CDX2 SATB2 PAX8 CK20)
─ Signet Ring Cell Carcinoma (Lobular variant): Predominantly intracellular mucin; E-cadherin negative
Prognosis ─ Pure mucinous carcinoma generally has a favorable prognosis; better than invasive carcinoma NST; low rate of lymph node metastasis Mixed type has prognosis similar to the non-mucinous component Micropapillary variant is more aggressive
Media ─ ─ Mucinous carcinoma (Breast) rosai ─ Mucinous carcinoma (Breast) rosai ─ Mucinous carcinoma (Breast) rosai ─ Mucinous carcinoma (Breast) rosai ─ Mucinous carcinoma (Breast) rosai ─ Mucinous carcinoma (Breast) rosai ─ Mucinous carcinoma (Breast) rosai ─ Mucinous carcinoma (breast) H&E

Invasive Carcinoma with Medullary Features

Poorly differentiated carcinoma with prominent lymphoplasmacytic infiltrate syncytial growth and pushing margins (Note: True "Medullary Carcinoma" is no longer a distinct WHO category; now termed "Invasive Carcinoma with Medullary Features")
Clinical ─ Younger age group often; may be associated with BRCA1 mutation; presents as palpable mass
Radiology ─ Typically well-circumscribed round or oval mass; may mimic benign lesion like fibroadenoma; calcifications uncommon
Macro ─ Well-circumscribed soft fleshy gray-white mass; may show hemorrhage or necrosis
Micro ─
─ Syncytial growth pattern (>75%): Broad sheets of cells with indistinct borders
─ High nuclear grade: Large pleomorphic nuclei vesicular chromatin prominent nucleoli
─ High mitotic rate often atypical forms
─ Prominent diffuse lymphoplasmacytic infiltrate within and surrounding tumor nests
─ Pushing non-infiltrative microscopic border
─ No glandular differentiation
─ Minimal associated DCIS if present
IHC ─
─ (-) ER, PR, HER2
─ (+) Basal cytokeratins (CK5/6 CK14 CK17)
─ (+) EGFR
─ (+) p53 due to mutation
Molecular ─
─ Frequently associated with BRCA1 germline mutations
─ Basal-like molecular subtype by gene expression profiling
─ High frequency of TP53 mutations
DDx ─
─ Poorly Differentiated Invasive Carcinoma NST: Lacks the combination of syncytial growth diffuse prominent lymphoid infiltrate and pushing borders
─ Metastatic Carcinoma (e g melanoma lymphoma): Clinical history and specific IHC markers needed
─ Lymphoma
Prognosis ─ Historically considered better than typical high-grade invasive carcinoma NST when strict criteria met; however prognosis is similar to other high-grade triple-negative/basal-like carcinomas when matched for stage
Media ─ ─ Medullary carcinoma (Breast) rosai ─ Medullary carcinoma (Breast) rosai ─ Medullary carcinoma (Breast) rosai ─ Medullary carcinoma (Breast) rosai ─ Medullary carcinoma (Breast) rosai

Papillary Carcinoma (Invasive)

Invasive carcinoma forming papillae lined by neoplastic cells (Note: Includes several entities like invasive solid papillary carcinoma invasive papillary carcinoma NST invasive encapsulated papillary carcinoma)
Clinical ─ Often older women; may present as mass or nipple discharge
Radiology ─ Well-circumscribed or complex cystic/solid mass; may have calcifications
Macro ─ Often well-circumscribed; may be solid or cystic with papillary projections
Micro ─
─ Invasive component shows papillary architecture: Fibrovascular cores lined by neoplastic epithelium invading stroma
─ Neoplastic cells typically low to intermediate grade; may show neuroendocrine features (especially in solid papillary carcinoma)
─ Encapsulated Papillary Carcinoma (EPC): Papillary proliferation within a cyst-like space surrounded by thick fibrous capsule; lacks myoepithelial cells at periphery; invasion often occurs beyond capsule as tubular carcinoma or IDC NST
─ Solid Papillary Carcinoma (SPC): Expansile solid nodules of monotonous cells arranged around delicate fibrovascular cores; often neuroendocrine differentiation; invasion often associated usually low grade
─ Invasive Papillary Carcinoma NST: True fibrovascular cores lined by malignant cells directly invading stroma; rare
IHC ─
─ (+) ER, PR
─ (-) HER2
─ (+) Neuroendocrine markers in SPC
─ (-) Myoepithelial markers absent around invasive papillae and at periphery of EPC/SPC invasion fronts
Molecular ─
─ Generally Luminal type
─ PIK3CA mutations common in some papillary lesions
DDx ─
─ Intraductal Papilloma: Benign; has myoepithelial layer around papillae and periphery
─ Intraductal Papillary Carcinoma (DCIS): Confined to ducts; myoepithelial layer present at periphery
─ Invasive Micropapillary Carcinoma: Lacks true fibrovascular cores; distinct morphology and IHC profile
─ Metastatic Papillary Carcinoma (e g ovary thyroid): Clinical history and organ-specific IHC needed
Prognosis ─ Generally favorable especially for invasive SPC and EPC when invasion is low grade/limited; Invasive papillary carcinoma NST prognosis depends on grade/stage

Invasive Micropapillary Carcinoma

Invasive carcinoma with small hollow clusters (morules) of neoplastic cells lying within clear stromal spaces resembling dilated lymphatics
Clinical ─ Similar age and presentation to invasive carcinoma NST; may be multifocal
Radiology ─ Often spiculated mass; frequently associated calcifications; may show extensive lymphadenopathy
Macro ─ No specific features; often ill-defined firm mass
Micro ─
─ Small tight clusters or morules of neoplastic cells arranged around a central lumen or as solid balls
─ Clusters situated within clear empty stromal spaces that mimic vascular channels
─ Characteristic "inside-out" growth pattern: Cells at periphery of clusters show reversed polarity (apical surface faces stroma)
─ Cells usually intermediate to high nuclear grade
─ Frequent lymphovascular invasion often extensive
─ Pure form (>90% micropapillary pattern) is rare; usually mixed with invasive carcinoma NST or other types
IHC ─
─ (+) ER, PR
─ (+) HER2 (~40-70%)
─ (+) EMA shows distinct "inside-out" staining pattern (membranous staining on stromal-facing/peripheral surface of cell clusters)
─ (-) CD34/D2-40 negative staining of stromal spaces confirms they are not true vascular channels (pseudo-lymphovascular spaces)
Molecular ─
─ Often Luminal B molecular subtype ((+)ER/HER2) or HER2-enriched subtype
─ TP53 mutations common
DDx ─
─ Lymphovascular Invasion by other Carcinoma types: True endothelial lining (CD34/D2-40+); tumor cells lack reversed polarity and characteristic morule formation
─ Mucinous Carcinoma Micropapillary Variant: Tumor clusters float in extracellular mucin pools not clear stromal spaces
Prognosis ─ Generally considered aggressive; high frequency of lymph node metastasis even with small primary tumor size; worse prognosis compared to invasive carcinoma NST when matched for stage
Media ─ ─ Invasive micropapillary carcinoma (Breast) H&E ─ Invasive micropapillary carcinoma (Breast) H&E ─ Invasive micropapillary carcinoma (Breast) WSI

Invasive Carcinoma with Apocrine Differentiation

Invasive carcinoma no special type showing focal apocrine features (typically >10% of tumor cells)
Clinical ─ Similar age and presentation to invasive carcinoma no special type
Radiology ─ Nonspecific findings similar to invasive carcinoma no special type
Macro ─ Nonspecific features similar to invasive carcinoma no special type
Micro ─
─ Invasive carcinoma no special type architecture (glands nests cords sheets)
─ Focal population (>10%) of cells with apocrine morphology: abundant eosinophilic granular cytoplasm large nuclei prominent nucleoli
─ Nuclear grade often intermediate to high in apocrine areas
─ Background carcinoma is typically invasive carcinoma no special type
IHC ─
─ Apocrine areas: (-) ER PR (+) AR (+) GCDFP-15
─ Non-apocrine areas: Variable ER PR HER2 status similar to invasive carcinoma no special type overall
─ HER2 status can be positive or negative
Molecular ─
─ Reflects the underlying invasive carcinoma no special type component
─ Apocrine component often shows molecular features similar to pure apocrine carcinoma (e g PIK3CA/AKT/mTOR pathway alterations)
DDx ─
─ Apocrine Carcinoma (Pure): >90% of tumor shows apocrine morphology
─ Invasive Carcinoma NST: Lacks significant apocrine features (<10%)
─ Benign Apocrine Metaplasia/Adenosis: Lacks invasion; retains myoepithelial layer (may be attenuated); lacks significant atypia
Prognosis ─ Generally determined by the grade stage and biomarker status of the overall tumor (invasive carcinoma no special type component); significance of focal apocrine differentiation itself is debated
Media ─ ─ Apocrine carcinoma (Breast) H&E ─ Apocrine carcinoma (Breast) rosai ─ Apocrine carcinoma (Breast) rosai ─ Invasive Apocrine carcinoma (Breast) H&E

Apocrine Carcinoma

Invasive carcinoma composed almost exclusively (>90%) of cells with apocrine differentiation
Clinical ─ Similar age and presentation to invasive carcinoma no special type; may occur in older women
Radiology ─ Nonspecific mass often circumscribed or irregular; calcifications may be present
Macro ─ Nonspecific firm mass gray-white tan cut surface
Micro ─
─ Infiltrating cells with distinct apocrine morphology: abundant eosinophilic granular cytoplasm large round nuclei prominent eosinophilic nucleoli distinct cell borders
─ Architectural patterns variable: solid nests tubules trabeculae sometimes papillary
─ Nuclear grade usually intermediate to high (grade 2 or 3)
─ Mitotic figures often present
─ May be associated with apocrine ductal carcinoma in situ
IHC ─
─ (-) ER, PR (or weak/focal)
─ (+) AR
─ (+) GCDFP-15
─ (+) HER2 (~30-50%)
─ (+) CK7 CK8/18
─ (-) CK5/6
Molecular ─
─ Often HER2 enriched or molecular apocrine subtype
─ Frequent PIK3CA AKT1 and TP53 mutations
─ HER2 (ERBB2) amplification common
─ Androgen receptor pathway activation
DDx ─
─ Invasive Carcinoma with Apocrine Differentiation: <90% apocrine morphology
─ Oncocytic Carcinoma: Cells packed with mitochondria (ultrastructure or specific stains); lacks prominent nucleoli of apocrine carcinoma; AR negative
─ Histiocytoid Carcinoma: Variant of lobular carcinoma; E-cadherin negative; cells resemble histiocytes
─ Granular Cell Tumor: Benign neural tumor; S100+; lacks true glandular differentiation
─ Metastatic Carcinoma (e g kidney liver): Clinical history and organ-specific markers needed
Prognosis ─ Controversial; often considered similar to invasive carcinoma no special type when matched for grade and stage; HER2 status is a key prognostic/predictive factor
Media ─ ─ Apocrine carcinoma (Breast) H&E ─ Apocrine carcinoma (Breast) rosai ─ Apocrine carcinoma (Breast) rosai

Metaplastic Carcinoma

Heterogeneous group of carcinomas showing differentiation towards squamous cells spindle cells mesenchymal elements (chondroid osseous) or a mixture
Clinical ─ Wide age range often presents as large palpable rapidly growing mass; less frequent lymph node metastasis compared to invasive carcinoma no special type but higher risk of distant metastasis
Radiology ─ Often well-circumscribed dense mass on mammography; may appear cystic on ultrasound; MRI features variable
Macro ─ Typically well-circumscribed or lobulated firm mass; may have cystic areas hemorrhage or necrosis; cut surface can be fleshy gray-white or show cartilaginous/bony areas
Micro ─ Highly variable depending on subtype:
─ Squamous Cell Carcinoma: Pure squamous differentiation or mixed with adenocarcinoma; keratinization intercellular bridges
─ Spindle Cell (Sarcomatoid) Carcinoma: Predominantly atypical spindle cells often in fascicles; may have epithelioid areas; minimal glandular component
─ Carcinoma with Mesenchymal Differentiation (Carcinosarcoma): Admixture of carcinomatous (ductal squamous or spindle) and malignant mesenchymal elements (chondrosarcoma osteosarcoma rhabdomyosarcoma fibrosarcoma)
─ Matrix-Producing Carcinoma: Carcinoma cells within an abundant chondromyxoid matrix
─ Low-Grade Adenosquamous Carcinoma: Infiltrating small glands and solid squamous nests in a fibrous/spindle cell stroma; low-grade cytology
─ Fibromatosis-like Metaplastic Carcinoma: Bland spindle cells infiltrating in long fascicles mimicking fibromatosis; low-grade cytology
─ Associated ductal carcinoma in situ may be present but often minimal or absent
IHC ─
─ (-) ER, PR, HER2 (Typically triple-negative >90%)
─ (+) Cytokeratins (variable often including high-molecular-weight CK5/6 34betaE12 CK14) confirms epithelial nature even in spindle/mesenchymal areas; positivity may be focal
─ (+) p63/p40 (squamous and spindle cell)
─ (+) EGFR
─ Mesenchymal markers (S100 desmin SMA) may be positive in areas with corresponding differentiation
Molecular ─
─ Predominantly basal-like or claudin-low molecular subtypes
─ High frequency of TP53 mutations
─ Frequent alterations in Wnt and PI3K pathways
─ Epithelial-mesenchymal transition (EMT) pathway activation common
DDx ─
─ Phyllodes Tumor (Malignant): Biphasic tumor with benign epithelial component and malignant stroma; lacks diffuse cytokeratin positivity in stroma; CD34 often positive in stroma
─ Primary Sarcoma (e g angiosarcoma fibrosarcoma): Exceedingly rare; lacks epithelial component/cytokeratin positivity
─ Fibromatosis: Bland spindle cells; nuclear beta-catenin positivity; lacks cytokeratin positivity
─ Nodular Fasciitis: Reactive spindle cell proliferation; lacks cytokeratin positivity
─ Invasive Carcinoma NST with Spindle Cell Change: Focal spindle cells within conventional adenocarcinoma
Prognosis ─ Generally poor compared to invasive carcinoma no special type; prognosis varies by subtype (low-grade variants better); high risk of hematogenous metastasis (lung brain) despite lower rate of nodal involvement
Media ─ ─ Metaplastic carcinoma (Breast) H&E ─ Metaplastic carcinoma (Breast) rosai ─ Metaplastic carcinoma (Breast) rosai ─ Metaplastic carcinoma (Breast) rosai ─ Metaplastic carcinoma (Breast) rosai

Rare and salivary gland-type tumors

Acinic Cell Carcinoma

Rare invasive carcinoma showing serous acinar differentiation
Clinical ─ Nonspecific
Radiology ─ Nonspecific, often well-circumscribed
Macro ─ Well-circumscribed mass
Micro ─
─ Infiltrating cells in solid sheets microcystic acinar or glandular patterns
─ Cells have abundant granular cytoplasm due to zymogen-like granules
─ Nuclei round, uniform, eccentrically located; nucleoli inconspicuous
─ Mitotic activity low
IHC ─
─ (+)Cytokeratins (CK7 CK8/18)
─ (+)Amylase, Lysozyme, Chymotrypsin (acinar differentiation)
─ (+)S100, DOG1
─ (-)ER, PR, HER2
Molecular ─
─ None, does not share the genomic rearrangement of salivary ACC
DDx ─
─ Secretory Carcinoma: intracellular and extracellular secretions; ETV6::NTRK3
─ Apocrine Carcinoma: eosinophilic granular cytoplasm but prominent nucleoli; (-)ER/PR (+)AR, (+)GCDFP-15
─ Mucinous Carcinoma: Extracellular mucin pools
─ Metaplastic Carcinoma: Higher grade and associated with other metaplastic elements
─ Microglandular Adenosis: lacks atypia; (+)S100 but (-)ER/PR negative
Prognosis ─ indolent with favorable prognosis
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Adenoid Cystic Carcinoma

Invasive carcinoma morphologically identical to adenoid cystic carcinoma of salivary glands with dual epithelial and myoepithelial cell population
Micro ─
─ Infiltrating nests and islands with characteristic patterns
─ Cribriform: pseudolumens with eosinophilic hyaline or basophilic mucoid material
─ Tubular: small tubules lined by inner epithelial and outer myoepithelial cells
─ Solid: sheets of basaloid cells with minimal gland formation (worse prognosis)
─ Two cell types: Small basaloid myoepithelial cells, larger epithelial cells lining true lumens
─ Perineural invasion common and characteristic
IHC ─
─ Epithelial cells: (+) CK7 EMA CD117
─ Myoepithelial cells: (+) p63 p40 SMA Calponin S100
─ Basal lamina material in pseudolumens: (+) Collagen IV
─ (-)ER, PR, HER2
Molecular ─
─ MYB::NFIB (similar to salivary gland)
DDx ─
─ Invasive Cribriform Carcinoma: Lacks biphasic population; lacks basement membrane material in lumens; (+)ER; lacks MYB fusion
─ Collagenous Spherulosis: myoepithelial cells surrounding eosinophilic spherules
─ Solid Papillary Carcinoma: Neuroendocrine features common; (+)ER; not biphasic
─ Metastatic Adenoid Cystic Carcinoma
Prognosis ─ indolent, low metastatic potential; late recurrence; solid pattern worse
Media ─ ─ Adenoid cystic carcinoma (Breast) H&E ─ Adenoid cystic carcinoma (Breast) H&E ─ Adenoid cystic carcinoma (Breast) H&E ─ Adenoid cystic carcinoma (Breast) H&E ─ Adenoid cystic carcinoma (Breast) H&E ─ Adenoid cystic carcinoma (Breast) H&E H&E ─ Adenoid cystic carcinoma (Breast) rosai

Secretory Carcinoma

Rare carcinoma with abundant intracellular and extracellular eosinophilic secretions forming vacuoles and microcysts; previously known as juvenile secretory carcinoma
Clinical ─ Historically described in children/adolescents but occurs across all ages including adults; usually presents as well-defined palpable mass
Radiology ─ Typically well-circumscribed mass; may be complex cystic/solid
Macro ─ Well-circumscribed firm tan-white or gray mass; may have cystic areas
Micro ─
─ Infiltrating tumor cells arranged in solid microcystic glandular and sometimes papillary patterns
─ Abundant intracellular and extracellular eosinophilic secretions resembling thyroid colloid or milk
─ Secretions (+)PASD
─ Cells are generally bland with low-grade vesicular nuclei small nucleoli and vacuolated cytoplasm
─ Mitotic figures rare
IHC ─
─ (+) S100
─ (+) CK7 EMA Mammaglobin GCDFP-15 (variable)
─ (+) E-cadherin
─ (-) ER, PR, HER2
─ (-) Myoepithelial markers around invasive component
Molecular ─
─ ETV6::NTRK3 gene fusion resulting from t(12;15) translocation (same fusion found in infantile fibrosarcoma and congenital mesoblastic nephroma)
DDx ─
─ Mucinous Carcinoma: Extracellular mucin is pale basophilic not eosinophilic granular; lacks ETV6 fusion
─ Acinic Cell Carcinoma: Granular cytoplasm; lacks prominent secretions/vacuoles
─ Lipid-Rich Carcinoma: Cytoplasmic lipid vacuoles; lacks eosinophilic secretions
─ Glycogen-Rich Clear Cell Carcinoma: Abundant clear cytoplasm due to glycogen (PAS+ diastase sensitive); lacks eosinophilic secretions
─ Apocrine Carcinoma: Granular eosinophilic cytoplasm prominent nucleoli; AR+
Prognosis ─ Generally excellent prognosis especially in children; considered indolent with very low metastatic potential although recurrences and rare metastases can occur particularly in adults
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Mucoepidermoid Carcinoma

Invasive carcinoma composed of a mixture of mucin-producing, squamous, and intermediate cells, similar to salivary gland mucoepidermoid carcinoma
Clinical ─ Rare, wide age range, nonspecific presentation usually palpable mass
Radiology ─ Nonspecific mass, may be cystic or solid
Macro ─ Variable, often cystic or solid mass, gray-white cut surface
Micro ─
─ Triad of cell types: mucin-producing cells (glandular or signet ring), squamous cells (may show keratinization), and intermediate cells (undifferentiated)
─ Cells arranged in solid nests, cysts, and glandular structures
─ Variable amounts of extracellular and intracellular mucin
─ Stroma often fibrous, may have prominent lymphoid infiltrate
─ Classified into low, intermediate, and high grades based on proportion of cystic structures, neural invasion, necrosis, anaplasia, and mitotic rate (similar to salivary gland grading)
IHC ─
─ Epithelial cells: (+) Cytokeratins (CK7, CK8/18, CK5/6, CK14, p63, p40 especially in squamous/intermediate cells)
─ Mucin stains (+) (PAS, Alcian blue, mucicarmine)
─ (-) ER, PR, HER2 (Typically triple-negative)
─ (-) S100 protein, SMA (helps distinguish from some salivary gland type tumors)
Molecular ─
─ Characteristic MAML2 gene rearrangement (resulting from t(11;19) translocation) found in a subset of cases, similar to salivary gland counterpart
─ Often basal-like phenotype
DDx ─
─ Metaplastic Carcinoma with Squamous Differentiation: Lacks significant mucinous or intermediate cell component; may have spindle/mesenchymal elements
─ Adenoid Cystic Carcinoma: Biphasic population, distinct cribriform pattern with basement membrane material; (+) CD117; MYB fusion common
─ Secretory Carcinoma: Characteristic secretions; ETV6::NTRK3 fusion common
─ Metastatic Mucoepidermoid Carcinoma: Check clinical history for primary elsewhere (salivary gland, lung)
Prognosis ─ Variable, depends on histologic grade; low-grade tumors generally have favorable prognosis, high-grade tumors are more aggressive with potential for metastasis
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Neuroendocrine Neoplasms of the Breast

A heterogeneous group of tumors showing morphologic and immunohistochemical evidence of neuroendocrine differentiation; includes well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs), including small cell and large cell types; primary breast origin must be established by excluding metastasis

Clinical ─ Rare as primary breast tumors; Can occur over a wide age range; Presentation is often a palpable mass, similar to other breast carcinomas; Carcinoid syndrome is exceptionally rare with primary breast NETs

Radiology ─

─ Mammography Often a well-circumscribed or lobulated mass; may have irregular margins or calcifications, especially in higher-grade lesions
─ Ultrasound May show a solid, hypoechoic mass; features can be nonspecific
─ MRI Variable appearance; can show enhancing mass
─ Somatostatin receptor scintigraphy (Octreoscan) or PET (eg, Ga-DOTATATE PET/CT) May be useful for staging and detecting somatostatin receptor-expressing tumors, especially for well-differentiated NETs

Macro ─ Tumors are often well-circumscribed, fleshy, tan-gray to yellowish nodules; Larger or higher-grade lesions may show necrosis or hemorrhage

Micro ─

Spectrum of differentiation
Well-Differentiated Neuroendocrine Tumor (NET), Grade 1 and Grade 2 (formerly "carcinoid tumor")
─ Architectural patterns include insular (nests), trabecular, glandular, or solid sheets
─ Cells are relatively uniform, polygonal or spindle-shaped, with moderate amounts of eosinophilic granular cytoplasm
─ Nuclei are round to oval with characteristic "salt-and-pepper" stippled chromatin; nucleoli are usually inconspicuous
─ Mitotic activity is low (NET G1 <2 mitoses/2 mm² and Ki-67 ≤2%; NET G2 2-20 mitoses/2 mm² or Ki-67 3-20%)
─ Necrosis is typically absent or minimal in G1, may be focal in G2
Neuroendocrine Carcinoma (NEC), Grade 3
─ Small Cell Carcinoma
─ Sheets of small, round, blue cells with scant cytoplasm, finely granular chromatin, inconspicuous or absent nucleoli
─ High nuclear-to-cytoplasmic ratio
─ Nuclear molding, crush artifact, and Azzopardi effect (DNA encrustation of blood vessels) are common
─ Numerous mitoses and extensive necrosis are characteristic
─ Morphologically identical to small cell carcinoma of the lung
─ Large Cell Neuroendocrine Carcinoma
─ Large polygonal cells with more abundant cytoplasm, vesicular nuclei, and often prominent nucleoli
─ Organoid nesting, trabecular, or diffuse growth patterns
─ High mitotic rate and frequent necrosis
─ Also morphologically similar to its pulmonary counterpart
─ An in situ component (DCIS with neuroendocrine features) or association with other types of invasive breast carcinoma may sometimes be identified, supporting primary breast origin

IHC ─
Diagnosis requires demonstration of neuroendocrine differentiation by IHC
─ Synaptophysin Diffuse cytoplasmic staining; most consistent neuroendocrine marker in breast NETs/NECs
─ Chromogranin A Cytoplasmic granular staining; may be focal or absent, especially in poorly differentiated tumors
─ CD56 (NCAM) Membrane staining; sensitive but less specific
─ INSM1 Nuclear stain; emerging as a sensitive and specific marker for neuroendocrine differentiation
─ Hormone Receptors ER and PR are often positive in well-differentiated NETs of the breast, less commonly in NECs
─ HER2 Typically negative
─ TTF-1 Usually negative in primary breast NETs/NECs (important for excluding lung primary, though some breast cancers can be TTF-1 positive)
─ GATA3 Often positive in primary breast NETs/NECs, supporting breast origin
─ Ki-67 Essential for grading NETs (G1, G2, G3/NEC) based on proliferative index

Molecular ─
─ Well-differentiated NETs are often genomically stable, may have alterations similar to luminal breast cancers (eg, PIK3CA mutations)
─ Small Cell NECs often show TP53 and RB1 mutations, similar to pulmonary small cell carcinomas

DDx ─

─ Metastatic Neuroendocrine Neoplasm (from lung, pancreas, GI tract, etc;) Clinical history and imaging are crucial; IHC panel (TTF-1, CDX2, Islet-1, PAX6, GATA3) can help determine origin
─ Invasive Carcinoma with Neuroendocrine Differentiation (IBC-NST or special types like mucinous or solid papillary carcinoma showing focal neuroendocrine marker positivity but lacking dominant neuroendocrine morphology)
─ Solid Papillary Carcinoma (often shows neuroendocrine features and ER positivity; distinct architecture)
─ Lymphoma/Leukemia (especially for small cell NEC; lymphoid markers positive, neuroendocrine markers negative)
─ Melanoma (can mimic NEC; S100, SOX10, specific melanoma markers positive)

Prognosis ─
─ Well-differentiated NETs (G1, G2) Generally have a more indolent course and better prognosis compared to IBC-NST of similar stage, but metastatic potential exists, especially for G2 tumors
─ Neuroendocrine Carcinomas (Small Cell and Large Cell) Highly aggressive malignancies with poor prognosis, similar to their counterparts in other organs; prone to early and widespread metastasis

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Mesenchymal Tumors

Hemangioma

Benign vascular neoplasm composed of proliferating blood vessels; various subtypes exist based on vessel size and architecture; most are incidental findings in the breast

Clinical ─ Usually asymptomatic and found incidentally on imaging or in surgical specimens; Rarely palpable as a soft mass; Can occur at any age

Radiology ─

─ Mammography May appear as a well-circumscribed, lobulated, non-calcified or sometimes calcified (phleboliths) mass; often small
─ Ultrasound Typically a well-circumscribed, hypoechoic, isoechoic, or complex echogenic solid mass; Doppler may show vascularity

Macro ─ Usually small (<2 cm), well-circumscribed, soft, red-brown to purple, spongy nodule; Larger lesions may be more ill-defined

Micro ─

Composed of a proliferation of benign endothelial-lined vascular channels
─ Endothelial cells are bland, flattened, without atypia or significant mitotic activity
─ Lumen may contain red blood cells; thrombosis or phleboliths (calcified thrombi) can be present
─ Stroma is typically scant fibrous tissue
Subtypes include
─ Capillary Hemangioma Proliferation of small, capillary-sized vessels, often arranged in lobules; common type
─ Cavernous Hemangioma Composed of larger, dilated, thin-walled vascular channels resembling cavernous spaces
─ Venous Hemangioma Features thick-walled venous channels
─ Perilobular Hemangioma Small capillary hemangiomas (often <2mm) located in the intralobular or interlobular stroma, characteristically clustered around lobules; very common incidental finding
─ Angiomatosis Diffuse proliferation of benign vessels involving a large area of breast tissue, poorly circumscribed (covered as a separate entity in your notebook)

IHC ─
─ Endothelial cells positive for vascular markers CD31, CD34, ERG, Factor VIII-related antigen
─ Myoid markers (SMA, Calponin) may highlight pericytes
─ Negative for cytokeratins

DDx ─

─ Angiosarcoma (low-grade) More infiltrative growth, anastomosing vascular channels, mild to moderate endothelial atypia, mitoses may be present; crucial distinction
─ Pseudoangiomatous Stromal Hyperplasia (PASH) Anastomosing slit-like spaces lined by bland spindle cells (myofibroblasts), not true endothelial cells; spaces are CD34 positive but CD31/ERG negative in lining cells
─ Lymphangioma Composed of lymphatic channels, often containing proteinaceous lymph fluid rather than blood; D2-40 positive endothelial cells
─ Vascular Malformation (eg, Arteriovenous Malformation) Contains abnormal thick-walled arteries and veins, not just capillary/cavernous channels

Prognosis ─ Benign; excellent prognosis; Excision is curative; Perilobular hemangiomas are incidental and require no further action

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Lymphangioma

Benign malformation of lymphatic vessels, characterized by dilated lymphatic channels; rare in the breast

Clinical ─ May present as a soft, compressible, painless mass or swelling; Often congenital or presents in childhood, but can occur in adults; Breast involvement is usually an extension from axillary or chest wall lesions

Radiology ─

─ Mammography/Ultrasound May show a multicystic or sponge-like lesion with thin septations; can be ill-defined

Macro ─ Typically a poorly circumscribed, soft, spongy lesion composed of multiple thin-walled cysts containing clear, serous, or chylous fluid; May be infiltrative

Micro ─

─ Proliferation of dilated, thin-walled lymphatic channels of varying sizes
─ Channels are lined by a single layer of flattened, bland endothelial cells
─ Lumina often contain proteinaceous lymph fluid, sometimes with lymphocytes; red blood cells are typically sparse or absent (helps distinguish from hemangioma)
─ Intervening stroma is loose connective tissue, may contain lymphoid aggregates
─ Smooth muscle may be present in the walls of larger channels
Types
─ Lymphangioma Simplex (Capillary Lymphangioma) Small, capillary-sized lymphatic channels
─ Cavernous Lymphangioma Larger, dilated lymphatic spaces
─ Cystic Lymphangioma (Cystic Hygroma) Large, macroscopic cystic spaces; more common in neck/axilla

IHC ─
─ Endothelial cells lining lymphatic channels are positive for D2-40 (podoplanin) and LYVE-1, in addition to general vascular markers like CD31 and ERG

DDx ─

─ Hemangioma (especially cavernous) Contains blood-filled vascular channels; D2-40 negative or only focally positive in endothelial lining
─ Simple Cysts (fibrocystic change) Lined by cuboidal or apocrine epithelium, not endothelium; D2-40 negative lining
─ Angiosarcoma (low grade) More infiltrative, anastomosing channels, endothelial atypia; D2-40 may be positive but atypia is key
─ Fat Necrosis (oil cysts) Different wall characteristics, associated inflammation and foamy histiocytes

Prognosis ─ Benign; Complete excision is curative but may be difficult if infiltrative, leading to potential for local recurrence; No malignant potential

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Lipoma

Benign mesenchymal tumor composed of mature adipose tissue; common in soft tissues, relatively common in the breast

Clinical ─ Presents as a soft, usually painless, mobile, well-circumscribed mass; Can occur at any age, more common in adults

Radiology ─

─ Mammography Typically a well-circumscribed, radiolucent (fat-density) mass, often with a thin capsule; Diagnostic when purely fat-density
─ Ultrasound Usually a well-circumscribed, uniformly hyperechoic mass (compared to adjacent glandular tissue), or isoechoic to surrounding fat; may be compressible

Macro ─ Well-circumscribed, encapsulated, soft, lobulated, yellow mass composed of mature adipose tissue; Size is variable

Micro ─

─ Composed entirely of mature adipocytes (fat cells) with abundant clear cytoplasm and small, eccentric, bland nuclei
─ Adipocytes are uniform in size and shape, arranged in lobules separated by delicate fibrous septa containing thin-walled capillaries
─ No lipoblasts, significant atypia, or increased mitotic activity
─ A thin fibrous capsule is usually present
Variants (rare in breast) include spindle cell lipoma, pleomorphic lipoma, angiolipoma (see separate entry)

IHC ─ Not typically required for diagnosis
─ S100 protein is positive in adipocytes

DDx ─

─ Normal Breast Adipose Tissue (lipoma is a discrete, circumscribed mass)
─ Hamartoma (fibroadenolipoma) Contains glandular and fibrous stromal elements in addition to fat, often disorganized
─ Fat Necrosis (oil cyst stage) May appear cystic and contain necrotic fat, inflammation, and fibrosis; lacks the uniform adipocyte proliferation of lipoma
─ Well-Differentiated Liposarcoma / Atypical Lipomatous Tumor Extremely rare as primary in breast; shows variation in adipocyte size, atypical stromal cells, hyperchromatic nuclei, and possibly lipoblasts; MDM2/CDK4 amplification is characteristic
─ Angiolipoma (contains a prominent capillary vascular component, often with fibrin thrombi)

Prognosis ─ Benign; Excellent prognosis; Excision is curative; Recurrence is rare if completely excised

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Angiolipoma

Benign mesenchymal tumor composed of mature adipose tissue and a proliferation of small capillary-sized blood vessels, often containing fibrin thrombi; rare in the breast

Clinical ─ Typically presents as a small, well-circumscribed, often tender or painful subcutaneous nodule; More common in young adults, M>F; Multiple lesions can occur; Breast involvement is uncommon

Radiology ─

─ Mammography/Ultrasound May appear as a well-circumscribed, echogenic mass, similar to lipoma but potentially with more internal heterogeneity or vascularity on Doppler

Macro ─ Small (usually <2 cm), well-circumscribed, encapsulated, yellowish nodule, may have a reddish tinge due to vascularity

Micro ─

─ Composed of mature adipocytes admixed with a prominent network of small, capillary-sized blood vessels
─ Vessels are often clustered, particularly at the periphery or within septa
─ Characteristic feature Fibrin thrombi (small, eosinophilic, hyaline plugs) within the lumina of many capillaries
─ Endothelial cells lining capillaries are bland, without atypia
─ Adipocytes are mature and uniform
─ Cellular variant has a higher proportion of vascular component relative to fat

IHC ─ Not usually required
─ Vascular channels positive for CD31, CD34
─ Adipocytes positive for S100

DDx ─

─ Lipoma Lacks the prominent capillary proliferation and fibrin thrombi
─ Hemangioma (capillary type) Predominantly vascular, minimal or no mature adipose tissue component intermixed in the same way
─ Angiosarcoma (low grade) Infiltrative, anastomosing vessels, endothelial atypia; lacks mature adipocyte component and fibrin thrombi typical of angiolipoma
─ Kaposi Sarcoma Spindle cell proliferation, slit-like vascular spaces, extravasated red cells, HHV8 positive; different morphology

Prognosis ─ Benign; Excision is curative; No risk of recurrence or malignant transformation

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Leiomyoma

Benign mesenchymal tumor composed of smooth muscle cells; rare in the breast, typically arising from smooth muscle of the nipple-areolar complex, blood vessel walls, or undifferentiated stromal cells

Clinical ─ Most commonly presents as a small, firm, well-circumscribed, sometimes painful or tender nodule in the subareolar or nipple region; Can occur in deeper breast parenchyma (parenchymal leiomyoma), often larger and less symptomatic; Wide age range

Radiology ─

─ Mammography/Ultrasound Nonspecific; may appear as a well-circumscribed, solid, hypoechoic mass

Macro ─ Well-circumscribed, firm, gray-white to tan nodule with a whorled or trabeculated cut surface; Size is variable, usually small for nipple lesions, can be larger for parenchymal ones

Micro ─

─ Composed of intersecting fascicles of bland spindle cells with elongated, cigar-shaped nuclei (blunt-ended) and eosinophilic, fibrillary cytoplasm
─ Minimal to no cytologic atypia
─ Low mitotic activity (typically <1-2 mitoses/10 HPF)
─ Necrosis is absent
─ Hyalinization or myxoid change may be present in the stroma
─ Nipple leiomyomas arise in the dermis and are associated with nipple smooth muscle (arrector pili)
─ Parenchymal leiomyomas are rarer, may arise from vessel walls or stroma

IHC ─
─ Smooth Muscle Actin (SMA) Strong and diffuse positivity
─ Desmin Positive (often strong)
─ H-caldesmon Positive
─ ER/PR May be positive, especially in parenchymal lesions
─ S100 protein Negative
─ Cytokeratins Negative

DDx ─

─ Myofibroblastoma (can have overlapping features; often CD34 positive, desmin can be positive; shares 13q deletion with some leiomyomas)
─ Fibromatosis (infiltrative, lacks prominent whorling, nuclear beta-catenin positive, desmin usually negative)
─ Spindle Cell Metaplastic Carcinoma (cytokeratin positive, p63 positive; more atypia and mitoses)
─ Leiomyosarcoma (malignant; shows significant cytologic atypia, increased mitotic activity often >5-10/10 HPF, and/or tumor necrosis)
─ Schwannoma (S100 positive, wavy nuclei, Verocay bodies)
─ Solitary Fibrous Tumor (CD34 positive, STAT6 positive, characteristic staghorn vessels)

Prognosis ─ Benign; Excellent prognosis; Local excision is curative; Recurrence is rare

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Schwannoma (Neurilemmoma)

Benign peripheral nerve sheath tumor composed of Schwann cells; rare in the breast

Clinical ─ Typically presents as a solitary, slow-growing, painless, well-circumscribed, mobile mass; Can occur at any age, but most common in adults; Not usually associated with neurofibromatosis type 1 (NF1); if multiple or plexiform, consider NF2 or schwannomatosis

Radiology ─

─ Mammography/Ultrasound Often a well-circumscribed, round or oval, hypoechoic solid mass; may show cystic changes or internal heterogeneity

Macro ─ Encapsulated, firm, rubbery, gray-white, tan, or yellowish nodule; Cut surface may be solid, cystic, or show myxoid change or hemorrhage

Micro ─

─ Encapsulated tumor composed of differentiated Schwann cells
─ Characteristic biphasic pattern with two main components
─ Antoni A areas Densely cellular areas composed of spindle cells with wavy, buckled, or tapered nuclei, arranged in short fascicles or storiform patterns; Nuclear palisading (nuclei aligned in rows) forming Verocay bodies (acellular eosinophilic zones between palisades) is highly characteristic
─ Antoni B areas Less cellular, loose, myxoid, or edematous areas with haphazardly arranged spindle or stellate cells and microcystic changes; blood vessels are often prominent and hyalinized
─ Blood vessels are often thick-walled and hyalinized
─ Degenerative changes like cyst formation, hemorrhage, calcification, and nuclear atypia ("ancient change" with large, hyperchromatic, pleomorphic nuclei but no increased mitoses) can occur
─ Mitotic activity is typically very low or absent

IHC ─
─ S100 protein Strong and diffuse nuclear and cytoplasmic positivity in tumor cells (hallmark)
─ SOX10 Nuclear positivity
─ GFAP Variable positivity
─ CD34 May be positive in scattered stromal cells or capsule, but tumor cells are negative
─ Cytokeratins Negative
─ SMA Negative

DDx ─

─ Neurofibroma (not encapsulated, more heterogeneous cell population including fibroblasts and perineurial-like cells, less organized Antoni A/B areas, S100 often less diffuse and strong, CD34+ stromal cells)
─ Malignant Peripheral Nerve Sheath Tumor (MPNST) Shows overt malignancy (cellularity, atypia, mitoses, necrosis, infiltrative growth); S100 positivity may be lost or focal; rare, often arises in NF1 context or from pre-existing neurofibroma
─ Myofibroblastoma (CD34+, desmin+, S100-)
─ Leiomyoma (SMA+, desmin+, S100-)
─ Fibromatosis (nuclear beta-catenin+, S100-)
─ Spindle Cell Metaplastic Carcinoma (cytokeratin+, p63+, S100-)

Prognosis ─ Benign; Excellent prognosis; Local excision is curative; Malignant transformation is exceptionally rare in conventional schwannomas

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Neurofibroma

Benign peripheral nerve sheath tumor composed of a mixture of Schwann cells, perineurial-like cells, fibroblasts, mast cells, and interspersed axons, all within a collagenous or myxoid stroma; rare in the breast, more common in the skin/subcutis of the breast

Clinical ─ May present as a solitary, soft, painless, palpable nodule or as part of neurofibromatosis type 1 (NF1), where lesions can be multiple and plexiform; Most breast neurofibromas are localized and sporadic; Skin lesions may be pedunculated

Radiology ─

─ Mammography/Ultrasound Nonspecific; may appear as a well-circumscribed or ill-defined, hypoechoic solid mass

Macro ─
─ Localized Neurofibroma Typically a well-circumscribed but unencapsulated, soft, rubbery, gray-white to tan nodule
─ Diffuse Neurofibroma Ill-defined, plaque-like thickening of skin and subcutis
─ Plexiform Neurofibroma Pathognomonic for NF1; "bag of worms" appearance, involving multiple nerve fascicles, causing diffuse enlargement of affected nerves and surrounding tissue

Micro ─

─ Unencapsulated, relatively hypocellular to moderately cellular proliferation of bland spindle cells with wavy, slender, pointed or comma-shaped nuclei, set in a loose, collagenous, or myxoid stroma
─ Heterogeneous cell population
─ Schwann cells (S100 positive)
─ Fibroblasts (produce collagen)
─ Perineurial-like cells (EMA positive, often subtle)
─ Mast cells are often scattered throughout
─ Axons (neurofilament positive) can be seen traversing the lesion, though may be sparse
─ Stroma is often pale, myxoid, or finely collagenous ("shredded carrot" collagen)
─ Blood vessels are usually delicate
─ No significant cytologic atypia or mitotic activity in conventional neurofibromas
─ Plexiform neurofibroma shows expansion of multiple nerve fascicles by the neurofibromatous proliferation

IHC ─
─ S100 protein Positive in Schwann cells, often in a diffuse but sometimes patchy or less intense manner compared to schwannoma
─ SOX10 Positive in Schwann cells
─ CD34 Often positive in scattered stromal spindle cells (fibroblasts)
─ EMA May highlight perineurial-like cells, often focally
─ Neurofilament Highlights interspersed axons
─ Mast cell tryptase Highlights mast cells

DDx ─

─ Schwannoma (encapsulated, biphasic Antoni A/B pattern, Verocay bodies, diffuse strong S100+)
─ Myxoid lesions (eg, myxoma, myxoid liposarcoma if atypia present; different IHC profile)
─ Fibromatosis (more cellular, fascicular, nuclear beta-catenin+)
─ Low-grade Spindle Cell Sarcomas (eg, MPNST-low grade, fibrosarcoma; show atypia, mitoses, infiltrative growth)
─ Dermatofibroma (storiform pattern, entrapped collagen, Factor XIIIa+)

Prognosis ─ Benign; Solitary localized neurofibromas have excellent prognosis with low recurrence rate after complete excision; Risk of malignant transformation to Malignant Peripheral Nerve Sheath Tumor (MPNST) is very low for solitary lesions but is significantly increased in individuals with NF1, particularly in plexiform neurofibromas

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Tall Cell Carcinoma with Reversed Polarity (Pattern)

(Note: Not a distinct WHO entity, but a specific architectural and cytological pattern, most commonly seen as a component of Invasive Micropapillary Carcinoma, but also described in other carcinoma types)
Invasive carcinoma pattern characterized by cells with tall columnar morphology and reversed polarity, often within stromal spaces
Clinical ─ Associated with underlying carcinoma type (often Invasive Micropapillary Carcinoma)
Radiology ─ Reflects underlying carcinoma type
Macro ─ Reflects underlying carcinoma type
Micro ─
─ Tumor cells are distinctly tall, columnar, with eosinophilic cytoplasm
─ Nuclei often located towards the apical (luminal-facing) aspect of the cell
─ Basal aspect of the cell faces the stroma, showing "reversed polarity"
─ Cells often form clusters, tubules, or micropapillae lying within clear, retraction-like stromal spaces (similar to Invasive Micropapillary Carcinoma)
─ May be admixed with conventional Invasive Micropapillary Carcinoma or other carcinoma types
IHC ─
─ Reflects underlying carcinoma type (often (+)ER, (+)PR, frequently (+)HER2 if associated with Invasive Micropapillary Carcinoma)
─ (+) EMA shows staining on the stromal-facing (basal) surface, highlighting the reversed polarity (similar to Invasive Micropapillary Carcinoma)
Molecular ─ Reflects underlying carcinoma type
DDx ─
─ Invasive Micropapillary Carcinoma: TCCRP is often considered a variant pattern within this; distinction may be academic if classic IMPC is also present
─ Columnar Cell Lesions/FEA: Benign/atypical intraductal lesions; lack invasion; lack reversed polarity EMA staining
─ Apocrine Carcinoma: Apocrine cytologic features (granular cytoplasm, prominent nucleoli); typically (+)AR; lacks characteristic reversed polarity pattern
Prognosis ─ Likely driven by the associated carcinoma type and overall grade/stage; pattern itself associated with aggressive features like lymphovascular invasion and nodal metastasis, similar to Invasive Micropapillary Carcinoma
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Paget Disease of the Nipple

A rare form of breast cancer characterized by the intraepidermal infiltration of malignant glandular epithelial cells (Paget cells) within the nipple and areolar epidermis; Almost always associated with an underlying in situ (DCIS) or invasive carcinoma in the breast parenchyma

Clinical ─ Presents as a chronic, eczematous, or psoriatic-like lesion of the nipple and/or areola; Symptoms include itching, burning, redness, scaling, crusting, oozing, or ulceration; Nipple may be flattened or retracted; A palpable breast mass may or may not be present; Typically unilateral; Most common in postmenopausal women

Radiology ─

─ Mammography May be normal, show nipple/areolar thickening, suspicious microcalcifications, or an underlying breast mass (DCIS or invasive carcinoma)
─ Ultrasound Can show nipple-areolar changes, ductal abnormalities, or an underlying mass
─ MRI Often used to evaluate the extent of underlying disease if mammography/ultrasound are inconclusive or show extensive DCIS

Macro ─ Nipple and areola show eczematoid changes with erythema, scaling, crusting, thickening, or ulceration; The appearance can be subtle initially

Micro ─

─ Presence of Paget cells within the epidermis of the nipple and areola
─ Paget cells are large, atypical cells with abundant pale, vacuolated, or eosinophilic cytoplasm and large, pleomorphic, hyperchromatic nuclei, often with prominent nucleoli
─ Cells occur singly or in clusters, nests, or glandular formations, typically scattered throughout all layers of the epidermis, often prominent along the basal layer
─ Paget cells may show intracytoplasmic mucin (PAS-diastase positive, Alcian blue positive)
─ Underlying epidermis often shows acanthosis, parakeratosis, and chronic inflammation in the dermis
─ Lactiferous ducts in the nipple are frequently involved by DCIS, with Paget cells extending from the ductal system into the overlying epidermis
─ An underlying invasive carcinoma is present in many cases

IHC ─
Paget cells are typically
─ CK7 Positive (strong and diffuse cytoplasmic staining; key marker)
─ EMA (Epithelial Membrane Antigen) Positive (membranous)
─ HER2 Overexpressed/amplified in a significant proportion of cases (correlates with HER2 status of underlying carcinoma)
─ GATA3 Positive (nuclear)
─ GCDFP-15 Variable positivity
─ ER/PR Often negative in Paget cells, even if underlying carcinoma is ER/PR positive (though can be positive)
─ S100 protein Negative
─ Melan-A/HMB-45 Negative (helps distinguish from melanoma)
─ p63 Negative (Paget cells are not myoepithelial or squamous)
─ CK20 Negative (helps distinguish from extramammary Paget disease of GI/urothelial origin if location is ambiguous, though mammary Paget is typically CK20-)

DDx ─

─ Eczema/Dermatitis of the nipple (inflammatory cells, spongiosis, no Paget cells)
─ Melanoma in situ or invasive melanoma of the nipple (S100+, Melan-A+, HMB-45+; CK7-)
─ Bowen Disease (Squamous Cell Carcinoma in situ) of the nipple (atypical keratinocytes, p63+, CK5/6+; CK7-)
─ Toker Cell Hyperplasia (benign clear cells in nipple epidermis; bland cytology, CK7+, ER+, S100 variable; no atypia)
─ Nipple Adenoma (glandular proliferation beneath epidermis, may erode surface; lacks intraepidermal Paget cells)

Prognosis ─ Depends primarily on the presence, type, grade, and stage of the underlying breast carcinoma (DCIS or invasive); If no underlying invasive carcinoma is found (Paget disease with DCIS only), prognosis is generally excellent after treatment; If an underlying invasive carcinoma is present, prognosis is similar to that of other invasive breast cancers of the same stage and subtype

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Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL)

A rare type of T-cell non-Hodgkin lymphoma that develops in association with breast implants, typically presenting as a late seroma or, less commonly, a mass adjacent to the implant

Clinical ─ Typically presents years after implant placement (median ~8-10 years); Most common symptom is a spontaneous, delayed peri-implant fluid collection (seroma); May also present as a palpable mass, capsular contracture, pain, swelling, or skin rash; Strongly associated with textured-surface implants rather than smooth-surface implants

Radiology ─

─ Ultrasound Often shows a peri-implant fluid collection (seroma); may identify a mass associated with the capsule
─ MRI Can delineate the extent of fluid, capsular thickening, or an associated mass
─ PET/CT Useful for staging if a mass is present or if systemic spread is suspected

Macro ─
─ Seroma Fluid is often straw-colored or serosanguineous
─ Capsule The fibrous capsule surrounding the implant may be thickened, irregular, or contain a discrete tumor mass
─ Tumor Mass (less common) Fleshy, gray-white, or tan mass adherent to or invading the capsule

Micro ─

─ Proliferation of atypical large lymphoid cells with anaplastic morphology
─ Cells are large, with irregular, often horseshoe-shaped or kidney-shaped nuclei (hallmark cells)
─ Prominent nucleoli and abundant, often eosinophilic or clear cytoplasm
─ Mitotic figures are usually present, can be frequent
─ In most cases (seroma-confined), the lymphoma cells are found predominantly in the seroma fluid and lining the inner surface of the fibrous capsule, often in a non-invasive manner or as a thin layer
─ In mass-forming cases, tumor cells form solid sheets or clusters invading the capsule and potentially adjacent breast tissue
─ Background may show chronic inflammation, fibrosis, and sometimes foreign body giant cells related to the implant material

IHC ─
Tumor cells are characteristically
─ CD30 Strong and uniform membranous and Golgi pattern positivity (hallmark)
─ ALK (Anaplastic Lymphoma Kinase) Negative (this distinguishes BIA-ALCL from systemic ALK+ ALCL)
─ T-cell markers Often positive for some pan-T-cell markers like CD2, CD3 (can be variable or lost), CD4, CD5, CD43; loss of some T-cell antigens is common
─ CD8 Usually negative
─ Cytotoxic markers (eg, TIA-1, Granzyme B, Perforin) Often positive
─ EMA (Epithelial Membrane Antigen) Can be positive in a subset of cases
─ Ki-67 High proliferation index
─ B-cell markers (eg, CD20, PAX5) Negative
─ Cytokeratins Negative

Molecular ─
─ Clonal T-cell receptor gene rearrangements are present
─ No ALK gene rearrangement
─ Recurrent mutations in JAK/STAT pathway genes (eg, STAT3, JAK1) are common

DDx ─

─ Benign reactive T-cell infiltrates/atypia (less cohesive, lack strong/uniform CD30, no anaplastic morphology, polyclonal T-cells)
─ Other T-cell lymphomas involving the breast (rare; immunophenotype and clinical context differ)
─ Systemic ALK-negative ALCL with secondary breast involvement (clinically different presentation, BIA-ALCL is localized to implant capsule/seroma initially)
─ Hodgkin Lymphoma (CD30+ but also CD15+, PAX5 weak+; different morphology of Reed-Sternberg cells)
─ Inflammatory reactions to implant (eg, synovial metaplasia, granulomatous inflammation; lack atypical lymphoid infiltrate and specific IHC profile)

Prognosis ─ Generally good, especially for seroma-confined (in situ) disease treated with complete capsulectomy and implant removal; Five-year overall survival is high for localized disease; Mass-forming or invasive disease has a more guarded prognosis and may require chemotherapy in addition to surgery; Systemic spread is rare but can occur, particularly with invasive disease

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Myoepithelioma and Myoepithelial Carcinoma

Myoepithelioma is a benign neoplasm composed predominantly or exclusively of myoepithelial cells; Myoepithelial carcinoma is its malignant counterpart, showing overtly malignant cytologic features and/or infiltrative growth; these are rare in the breast

Clinical ─
─ Myoepithelioma Typically presents as a palpable, well-circumscribed mass; wide age range
─ Myoepithelial Carcinoma May arise de novo or from a pre-existing adenomyoepithelioma or myoepithelioma; often presents as a larger, sometimes rapidly growing mass; can occur at any age, mean often in 50s

Radiology ─

─ Myoepithelioma Often well-circumscribed mass on mammography and ultrasound; may be lobulated
─ Myoepithelial Carcinoma May appear as a well-circumscribed or irregular, infiltrative mass; imaging features are often nonspecific and can mimic other benign or malignant lesions

Macro ─
─ Myoepithelioma Typically a well-circumscribed, firm, gray-white to tan nodule
─ Myoepithelial Carcinoma Can be well-circumscribed or infiltrative; often larger than benign counterpart; may show areas of necrosis or hemorrhage

Micro ─

Myoepithelioma
─ Composed predominantly of myoepithelial cells, which can be spindle-shaped, epithelioid, plasmacytoid, or clear cells, often arranged in sheets, fascicles, or a vaguely lobulated pattern
─ Stroma can be myxoid, hyalinized, or chondromyxoid (less common in pure myoepithelioma than pleomorphic adenoma)
─ Minimal to no ductal epithelial component (distinction from adenomyoepithelioma)
─ Bland cytology, low mitotic activity, no necrosis
Myoepithelial Carcinoma
─ Shows overt features of malignancy in the myoepithelial cell population
─ Cytologic atypia (pleomorphism, hyperchromasia, prominent nucleoli)
─ Increased mitotic activity, often including atypical mitoses
─ Infiltrative growth into surrounding tissues
─ Necrosis may be present
─ Can exhibit various cell morphologies similar to benign myoepithelioma but with malignant features
─ Some consider it a form of metaplastic carcinoma

IHC ─

Myoepithelial cells (benign and malignant) are typically positive for
─ Cytokeratins (eg, CK5/6, CK14, AE1/AE3, CAM5;2)
─ Myoepithelial markers (eg, p63, p40, SMA, calponin, S100 protein, CD10)
─ Note Not all markers are positive in every case, and expression can be variable
Myoepithelial Carcinoma
─ May show loss or aberrant expression of some myoepithelial markers compared to benign lesions
─ Often negative for ER, PR, and HER2

Molecular ─
─ Myoepitheliomas and myoepithelial carcinomas can show rearrangements involving genes like EWSR1, PLAG1 (especially if arising from pleomorphic adenoma-like areas), or other less common fusions

DDx ─

Myoepithelioma
─ Adenomyoepithelioma (has a distinct benign epithelial/ductal component)
─ Pleomorphic Adenoma (has prominent chondromyxoid stroma and distinct epithelial glands)
─ Fibromatosis (lacks myoepithelial markers, nuclear beta-catenin positive)
─ Nodular Fasciitis (different morphology, lacks diffuse myoepithelial marker expression)
Myoepithelial Carcinoma
─ Metaplastic Carcinoma (spindle cell, squamous, or matrix-producing types; distinction can be challenging as myoepithelial carcinoma is sometimes classified within this group; relies on demonstrating myoepithelial differentiation)
─ Malignant Phyllodes Tumor (biphasic with epithelial component, stromal malignancy)
─ Primary Sarcoma of the breast (eg, leiomyosarcoma, fibrosarcoma; lacks epithelial/myoepithelial markers)
─ Invasive Ductal or Lobular Carcinoma with spindle cell features (will retain expression of epithelial markers like GATA3 or ER/PR in ductal/lobular types, and lack diffuse myoepithelial profile)

Prognosis ─
─ Myoepithelioma Benign; local recurrence can occur, especially if incompletely excised
─ Myoepithelial Carcinoma Malignant with potential for local recurrence and distant metastasis (lungs, bone, brain); Prognosis is variable, generally guarded; larger size, high grade, and necrosis may be adverse factors

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Fibroepithelial & Mesenchymal Tumors

Fibroadenoma

Benign biphasic tumor composed of proliferating glandular epithelium and specialized mammary stroma
Clinical ─ Most common benign breast tumor, typically young women (20s-30s), often presents as palpable, mobile, rubbery mass
Radiology ─
─ Mammography: Well-circumscribed, oval or lobulated mass, iso- or slightly hyperdense; coarse "popcorn" calcifications common in involuting fibroadenomas
─ Ultrasound: Well-circumscribed, oval, hypoechoic or isoechoic mass, may have gentle lobulations, posterior acoustic enhancement common
Macro ─ Sharply circumscribed, encapsulated, firm, rubbery, gray-white nodule; cut surface often bulges and may show slit-like spaces
Micro ─
─ Biphasic proliferation of benign ductal/glandular epithelium and bland fibrous/myxoid stroma
─ Intracanalicular pattern: Stroma compresses ducts into elongated clefts and slits
─ Pericanalicular pattern: Stroma surrounds open, rounded ducts/glands
─ Often mixed intracanalicular and pericanalicular patterns
─ Stroma typically low to moderate cellularity, bland spindle cells, no significant atypia, rare mitoses (<3/10 HPF)
─ Epithelium usually simple cuboidal/columnar, may show usual ductal hyperplasia, apocrine metaplasia, cysts; rarely atypical hyperplasia or carcinoma in situ
─ Variants: Juvenile (more cellular stroma/epithelium, younger age), Myxoid (abundant myxoid stroma), Complex (cysts >3mm, sclerosing adenosis, epithelial calcifications, or papillary apocrine change)
IHC ─
─ Epithelium: (+)CKs (e g, CK7, CK8/18), (+)ER/PR (variable), (-)myoepithelial markers in luminal cells
─ Myoepithelium: (+)p63, (+)SMA, (+)calponin, (+)S100 (variable)
─ Stroma: (+)CD34, (+)vimentin, (+)ER/PR/AR (variable), (-)CKs
Molecular ─ MED12 gene mutations common in stromal component
DDx ─
─ Phyllodes Tumor (Benign): Increased stromal cellularity (esp subepithelial), leaf-like architecture more prominent, may have >3 mitoses/10 HPF
─ Tubular Adenoma: Predominantly closely packed small tubules, minimal stroma
─ Hamartoma: Admixture of mature adipose tissue, fibrous stroma, and benign glands/lobules, often less circumscribed
Prognosis ─ Benign, excellent prognosis; very low risk of malignant transformation (usually carcinoma arising in epithelial component, rarely sarcoma in stroma); complex fibroadenoma associated with slightly increased breast cancer risk
media ─ placeholder ─ pathoutlines intracanalicular WSI hyalinized WSI cellular WSI
WSI WSI video video

Phyllodes Tumor

Biphasic fibroepithelial neoplasm characterized by increased stromal cellularity and architectural features resembling intracanalicular fibroadenoma, with potential for recurrence and metastasis (borderline/malignant)
Clinical ─ Less common than fibroadenoma, typically older women (mean age 40s-50s), usually presents as palpable mass, often larger and may grow more rapidly than fibroadenoma
Radiology ─
─ Mammography/Ultrasound: Often large, well-circumscribed, oval or lobulated mass, may have cystic spaces; frequently indistinguishable from fibroadenoma
Macro ─ Usually well-circumscribed (benign/borderline) or infiltrative (malignant), gray-white, fleshy, firm mass; cut surface shows characteristic leaf-like clefts and protrusions; may have cystic degeneration, hemorrhage, or necrosis, especially in larger/higher-grade tumors
Micro ─
─ Biphasic tumor with benign epithelial component lining elongated, compressed ducts and clefts, and a stromal component showing a spectrum of changes
─ Characteristic leaf-like architecture (stromal fronds protruding into cystic spaces)
─ Stromal cellularity increased compared to fibroadenoma, often with subepithelial condensation (cambium layer)
─ Graded based on combination of stromal features (WHO 2012):
─ Benign: Mild stromal hypercellularity and atypia, <5 mitoses/10 HPF, pushing margins, no stromal overgrowth
─ Borderline: Moderate stromal hypercellularity and atypia, 5–9 mitoses/10 HPF, pushing or focally infiltrative margins, stromal overgrowth usually absent or focal
─ Malignant: Marked stromal hypercellularity and atypia, ≥10 mitoses/10 HPF, infiltrative margins, stromal overgrowth often present; diagnosis also made if malignant heterologous elements (e g, liposarcoma, chondrosarcoma, osteosarcoma) present
─ Stromal overgrowth: Presence of stroma without epithelium in at least one low-power field (x4 objective)
─ Epithelial component usually benign, may show hyperplasia, rarely atypia or carcinoma in situ
IHC ─
─ Epithelium: (+)CKs
─ Stroma: (+)Vimentin, (+)CD34 (often patchy, may be lost in higher grades/stromal overgrowth), variable (+)SMA, (+)desmin, (+)ER/PR/AR; usually (-)CKs, (-)p63 (may be focal); p53 overexpression common in borderline/malignant
Molecular ─ More complex and numerous genetic alterations than fibroadenoma, especially in borderline/malignant grades; includes gains (e g, 1q) and losses (e g, 9p21, 13q), TP53/RB1 mutations, EGFR/IGF1R amplification; MED12 mutations less frequent than in fibroadenoma
DDx ─
─ Fibroadenoma (esp Cellular): Less stromal cellularity/atypia/mitoses, lacks significant stromal overgrowth or infiltrative margins
─ Metaplastic Carcinoma (esp Spindle Cell/Sarcomatoid): Malignant spindle cells express CKs and/or p63/p40; lacks typical leaf-like architecture; often triple-negative
─ Primary Sarcoma: Purely mesenchymal, lacks epithelial component, very rare in breast
─ Periductal Stromal Tumor: Similar stroma but infiltrative growth around open ducts, lacks leaf-like pattern
─ Pseudoangiomatous Stromal Hyperplasia (PASH): Anastomosing slit-like spaces in fibrous stroma, lacks leaf-like architecture and stromal atypia/mitoses
Prognosis ─ Related to grade and margin status; wide excision with negative margins crucial
─ Benign: Local recurrence ~10–20%, metastasis exceptionally rare
─ Borderline: Local recurrence ~15–30%, metastasis rare (~<5%)
─ Malignant: Local recurrence ~20–30%, distant metastasis (hematogenous, typically lung/bone) ~10–25%
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Benign WSI WSI WSI WSI Borderline WSI WSI WSI Malignant WSI WSI WSI

Mesenchymal Tumors

Hemangioma

Benign vascular neoplasm composed of proliferating blood vessels; various subtypes exist based on vessel size and architecture; most are incidental findings in the breast

Clinical ─ Usually asymptomatic and found incidentally on imaging or in surgical specimens; Rarely palpable as a soft mass; Can occur at any age

Radiology ─

Macro ─ Usually small (<2 cm), well-circumscribed, soft, red-brown to purple, spongy nodule; Larger lesions may be more ill-defined

Micro ─

IHC ─
─ Endothelial cells positive for vascular markers CD31, CD34, ERG, Factor VIII-related antigen
─ Myoid markers (SMA, Calponin) may highlight pericytes
─ Negative for cytokeratins

DDx ─
─ Angiosarcoma (low-grade) More infiltrative growth, anastomosing vascular channels, mild to moderate endothelial atypia, mitoses may be present; crucial distinction
─ Pseudoangiomatous Stromal Hyperplasia (PASH) Anastomosing slit-like spaces lined by bland spindle cells (myofibroblasts), not true endothelial cells; spaces are CD34 positive but CD31/ERG negative in lining cells
─ Lymphangioma Composed of lymphatic channels, often containing proteinaceous lymph fluid rather than blood; D2-40 positive endothelial cells
─ Vascular Malformation (eg, Arteriovenous Malformation) Contains abnormal thick-walled arteries and veins, not just capillary/cavernous channels

Prognosis ─ Benign; excellent prognosis; Excision is curative; Perilobular hemangiomas are incidental and require no further action

Media ─ ─ Hemangioma (Breast) rosai

Angiomatosis

Diffuse proliferation of benign vascular channels
Clinical ─ diffuse breast enlargement or ill-defined mass
Radiology ─ Nonspecific
Macro ─ Poorly defined, spongy area involving parenchyma and adipose tissue
Micro ─
─ Diffuse, proliferation of vascular channels permeating breast stroma and adipose tissue
─ Vessels vary in size, often capillary or cavernous type, lined by bland endothelial cells
─ No significant endothelial atypia or mitotic activity
─ Interspersed normal breast ducts and lobules
IHC ─
─ Endothelial cells: (+)CD31, CD34, ERG
─ (-)Cytokeratins
DDx ─
─ Angiosarcoma (Low-grade): Although diffuse, typically shows more infiltrative pattern with anastomosing channels and at least mild endothelial atypia
─ Hemangioma: Well-circumscribed lesion, not diffuse
─ Vascular Malformation (e g, Arteriovenous Malformation): Contains abnormal thick-walled arteries and veins
Prognosis ─ Benign, but may recur locally if incompletely excised due to diffuse nature
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Lymphangioma

Benign malformation of lymphatic vessels, characterized by dilated lymphatic channels; rare in the breast

Radiology ─

─ Mammography/Ultrasound May show a multicystic or sponge-like lesion with thin septations; can be ill-defined

Macro ─ Typically a poorly circumscribed, soft, spongy lesion composed of multiple thin-walled cysts containing clear, serous, or chylous fluid; May be infiltrative

Micro ─

IHC ─
─ Endothelial cells lining lymphatic channels are positive for D2-40 (podoplanin) and LYVE-1, in addition to general vascular markers like CD31 and ERG

DDx ─

Prognosis ─ Benign; Complete excision is curative but may be difficult if infiltrative, leading to potential for local recurrence; No malignant potential

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Lipoma

Benign mesenchymal tumor composed of mature adipose tissue; common in soft tissues, relatively common in the breast

Clinical ─ Presents as a soft, usually painless, mobile, well-circumscribed mass; Can occur at any age, more common in adults

Radiology ─

Macro ─ Well-circumscribed, encapsulated, soft, lobulated, yellow mass composed of mature adipose tissue; Size is variable

Micro ─

IHC ─
─ S100 protein is positive in adipocytes

DDx ─

Prognosis ─ Benign; Excellent prognosis; Excision is curative; Recurrence is rare if completely excised

media ─ placeholder ─ pathoutlines (general lipoma)

Angiolipoma

Benign mesenchymal tumor composed of mature adipose tissue and a proliferation of small capillary-sized blood vessels, often containing fibrin thrombi; rare in the breast

Radiology ─

─ Mammography/Ultrasound May appear as a well-circumscribed, echogenic mass, similar to lipoma but potentially with more internal heterogeneity or vascularity on Doppler

Macro ─ Small (usually <2 cm), well-circumscribed, encapsulated, yellowish nodule, may have a reddish tinge due to vascularity

Micro ─

IHC ─ Not usually required
─ Vascular channels positive for CD31, CD34
─ Adipocytes positive for S100

DDx ─

Prognosis ─ Benign; Excision is curative; No risk of recurrence or malignant transformation

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Leiomyoma

Benign mesenchymal tumor composed of smooth muscle cells; rare in the breast, typically arising from smooth muscle of the nipple-areolar complex, blood vessel walls, or undifferentiated stromal cells

Radiology ─

─ Mammography/Ultrasound Nonspecific; may appear as a well-circumscribed, solid, hypoechoic mass

Macro ─ Well-circumscribed, firm, gray-white to tan nodule with a whorled or trabeculated cut surface; Size is variable, usually small for nipple lesions, can be larger for parenchymal ones

Micro ─

DDx ─

Prognosis ─ Benign; Excellent prognosis; Local excision is curative; Recurrence is rare

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Schwannoma (Neurilemmoma)

Benign peripheral nerve sheath tumor composed of Schwann cells; rare in the breast

Radiology ─

─ Mammography/Ultrasound Often a well-circumscribed, round or oval, hypoechoic solid mass; may show cystic changes or internal heterogeneity

Macro ─ Encapsulated, firm, rubbery, gray-white, tan, or yellowish nodule; Cut surface may be solid, cystic, or show myxoid change or hemorrhage

Micro ─

DDx ─

Prognosis ─ Benign; Excellent prognosis; Local excision is curative; Malignant transformation is exceptionally rare in conventional schwannomas

Media ─ ─ Schwannoma (neurilemmoma), benign (Breast) H&E

Neurofibroma

Radiology ─

─ Mammography/Ultrasound Nonspecific; may appear as a well-circumscribed or ill-defined, hypoechoic solid mass

Micro ─

DDx ─

media ─ placeholder ─ pathoutlines (general neurofibroma)

Atypical Vascular Lesion (AVL)

Benign endothelial proliferation, typically small, occurring after radiation therapy or chronic lymphedema, distinct from angiosarcoma
Clinical ─ Usually develops in skin of previously irradiated breast or arm with lymphedema, presents as small red papules or vesicles
Radiology ─ Usually not imaged, skin lesion
Macro ─ Small (<1 cm) red or violaceous papules, vesicles, or plaques on the skin
Micro ─
─ Dermal proliferation of small, simple, thin-walled vascular channels
─ May dissect collagen bundles
─ Lined by bland endothelial cells, minimal or no atypia, often hobnail appearance
─ Mitoses typically absent
─ Usually confined to superficial dermis, may extend deeper
IHC ─
─ Endothelial cells: (+)CD31, (+)CD34, (+)ERG
─ (-)Cytokeratins
─ (-)MYC amplification/overexpression (key distinction from post-radiation angiosarcoma)
DDx ─
─ Angiosarcoma (Low-grade, especially post-radiation): More infiltrative, anastomosing channels, greater endothelial atypia, possible mitoses, often (+)MYC amplification/overexpression
─ Hemangioma: More circumscribed, less likely in post-radiation setting
─ Lymphangioma Circumscriptum: Dilated lymphatic channels in dermis
Prognosis ─ Benign, but requires complete excision due to potential for local recurrence and the critical need to exclude angiosarcoma; some consider it a potential precursor to angiosarcoma
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Angiosarcoma

Malignant neoplasm of endothelial cells forming vascular channels
Clinical ─ May be primary (younger women, palpable mass, often large) or secondary (older women, post-radiation or chronic lymphedema, often skin lesions)
Radiology ─ Nonspecific, may be ill-defined mass or skin thickening; MRI may show heterogeneous enhancement
Macro ─ Ill-defined, hemorrhagic, spongy mass or violaceous skin lesions
Micro ─
─ Spectrum from low-grade (resembling hemangioma) to high-grade (solid, epithelioid, or spindle cell areas)
─ Low-grade: Well-formed, anastomosing vascular channels infiltrating stroma and fat, mild endothelial atypia, scant mitoses
─ Intermediate-grade: Increased cellularity, endothelial tufting, papillary formations, occasional mitoses
─ High-grade: Solid sheets of atypical endothelial cells, spindle cell areas, prominent papillary formations, necrosis, hemorrhage, frequent mitoses
─ Epithelioid variant: Large cells with abundant eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, mimicking carcinoma
─ Post-radiation angiosarcoma often starts in skin, may be multifocal
IHC ─
─ Endothelial cells: (+)CD31, (+)CD34, (+)ERG, (+)Factor VIII (variable)
─ (+)FLI1
─ Epithelioid variant often (+)Cytokeratins (potential pitfall)
─ Post-radiation angiosarcoma: (+)MYC amplification/overexpression (highly specific)
─ (-)ER, PR, HER2
DDx ─
─ Hemangioma/Atypical Vascular Lesion: Less infiltration, lack significant atypia/mitoses; AVL lacks MYC amplification
─ Metaplastic Carcinoma (esp Spindle Cell): (+)Cytokeratins, (+)p63; lacks diffuse vascular marker positivity
─ Phyllodes Tumor (Malignant): Biphasic, stromal atypia, lacks diffuse vascular marker positivity
─ Other Sarcomas: Specific lineage markers (e g, desmin, S100)
Prognosis ─ Generally poor, high risk of local recurrence and distant metastasis (lung, liver, bone, skin); grade may correlate with prognosis in primary but not secondary angiosarcoma; post-radiation type often aggressive
Media ─ ─ Angiosarcoma (Breast) H&E ─ Angiosarcoma (Breast) H&E ─ Angiosarcoma (Breast) rosai ─ Angiosarcoma (Breast) rosai ─ Angiosarcoma (Breast) rosai ─ Angiosarcoma (Breast) rosai ─ Angiosarcoma (Right breast) rosai ─ angiosarcoma (Breast) H&E WSI WSI WSI WSI H&E w stains video

Nodular Fasciitis

Benign, reactive proliferation of myofibroblasts, often rapidly growing
Clinical ─ Uncommon in breast, usually young adults, presents as rapidly growing, sometimes tender, palpable mass
Radiology ─ Nonspecific mass, may be ill-defined
Macro ─ Usually small (<3 cm), circumscribed or ill-defined, firm, gray-white nodule
Micro ─
─ Cellular proliferation of plump, immature-appearing spindle cells (myofibroblasts) arranged in short fascicles or haphazardly
─ Characteristic "tissue culture" appearance
─ Stroma is typically loose, myxoid, with extravasated red blood cells and scattered lymphocytes
─ Mitotic figures often numerous but typically normal morphology
─ No significant nuclear atypia
─ May show infiltrative borders into adjacent fat or stroma
IHC ─
─ Spindle cells: (+)SMA, (+)MSA (variable), (+)Vimentin
─ (-)Desmin, (-)S100 protein, (-)Cytokeratins, (-)CD34, (-)Beta-catenin (nuclear)
Molecular ─ Characteristic USP6 gene rearrangement often present
DDx ─
─ Fibromatosis: More infiltrative, less cellular, less myxoid, lacks tissue culture appearance, (+)nuclear Beta-catenin
─ Myofibroblastoma: More organized fascicles of bland spindle cells, thick collagen bundles, (+)CD34, (+)Desmin
─ Spindle Cell Metaplastic Carcinoma: (+)Cytokeratins, (+)p63/p40; usually older patients
─ Low-grade Fibromyxoid Sarcoma/Myxofibrosarcoma: Rare in breast, different morphology and IHC
─ Phyllodes Tumor (stromal component): Leaf-like architecture, lacks tissue culture appearance
Prognosis ─ Benign, self-limited process; may regress spontaneously; local excision is curative, recurrence is rare
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Myofibroblastoma

Benign mesenchymal tumor composed of myofibroblasts
Clinical ─ Uncommon, typically older men, but also occurs in women (often postmenopausal); presents as painless, well-circumscribed, mobile mass
Radiology ─ Well-circumscribed mass, may mimic fibroadenoma or carcinoma
Macro ─ Well-circumscribed, firm, rubbery, gray-white nodule, usually <4 cm
Micro ─
─ Spindle cells arranged in clusters or short fascicles separated by hyalinized collagen bundles
─ Cells have oval to spindle nuclei, inconspicuous nucleoli, scant eosinophilic cytoplasm
─ Low mitotic activity, minimal to no atypia
─ Variable amount of interspersed mature adipose tissue
─ Variants: Cellular, collagenized/fibrous, lipomatous, epithelioid, deciduoid-like, palisaded/Schwannian-like
IHC ─
─ Spindle cells: (+)CD34, (+)Desmin, (+)SMA (variable), (+)ER, (+)PR, (+)AR (variable), (+)Bcl2
─ (-)Cytokeratins, (-)S100 protein, (-)HMB45
Molecular ─ Loss of chromosome 13q14 region (includes RB1 gene) characteristic
DDx ─
─ Fibromatosis: Infiltrative borders, lacks circumscription, (+)nuclear Beta-catenin, (-)CD34, (-)Desmin
─ Spindle Cell Lipoma: Morphologically similar, often more prominent adipose tissue, shares 13q deletion; distinction may be academic
─ Solitary Fibrous Tumor: Staghorn vessels, (+)CD34, (+)STAT6, (-)Desmin
─ Spindle Cell Metaplastic Carcinoma: (+)Cytokeratins, (+)p63/p40; usually triple-negative
─ Nodular Fasciitis: More myxoid, "tissue culture" appearance, lacks thick collagen bundles, (-)CD34, (-)Desmin
Prognosis ─ Benign, excellent prognosis; local excision is curative, recurrence is very rare
Media ─ ─ Myofibroblastoma (Breast) H&E ─ Myofibroblastoma (Breast) H&E ─ Myofibroblastoma (Breast) H&E ─ Myofibroblastoma (Breast) WSI

Fibromatosis (Desmoid Tumor)

Locally aggressive, non-metastasizing fibroblastic/myofibroblastic proliferation
Clinical ─ Uncommon, wide age range, presents as firm, irregular, fixed mass; may be associated with prior surgery/trauma or Gardner syndrome
Radiology ─ Irregular, spiculated mass, often suspicious for carcinoma
Macro ─ Ill-defined, very firm, gray-white, fibrous mass with infiltrative borders
Micro ─
─ Infiltrative proliferation of bland, slender spindle cells arranged in sweeping fascicles
─ Cells have uniform, elongated nuclei, pale cytoplasm, indistinct cell borders
─ Collagenous stroma, variable cellularity
─ Mitoses rare or absent, no significant atypia
─ Characteristic infiltration into adjacent breast parenchyma and adipose tissue, entrapping ducts and lobules
IHC ─
─ Spindle cells: (+)Vimentin, (+)SMA (variable), (+)MSA (variable)
─ (+)Nuclear Beta-catenin (characteristic, ~80% of cases)
─ (+)ER beta (variable), (-)ER alpha, (-)PR
─ (-)CD34, (-)Desmin, (-)S100 protein, (-)Cytokeratins
Molecular ─ CTNNB1 (Beta-catenin) gene mutations common in sporadic cases; APC gene mutations in Gardner syndrome associated cases
DDx ─
─ Low-grade Fibromatosis-like Metaplastic Carcinoma: (+)Cytokeratins (may be focal), (+)p63/p40; lacks nuclear Beta-catenin
─ Scar Tissue: Less cellular, more hyalinized collagen, history of prior procedure
─ Nodular Fasciitis: More cellular, myxoid stroma, "tissue culture" appearance, lacks nuclear Beta-catenin
─ Myofibroblastoma: Well-circumscribed, (+)CD34, (+)Desmin, lacks nuclear Beta-catenin
─ Phyllodes Tumor (Low-grade): Biphasic, leaf-like architecture, (+)CD34
Prognosis ─ Benign (does not metastasize), but high rate of local recurrence (20–30%) if incompletely excised; requires wide local excision
Media ─ ─ Fibromatosis (Breast) H&E ─ Fibromatosis (Breast) WSI ─ Fibromatosis (Breast) rosai ─ Fibromatosis (Breast) rosai

Granular Cell Tumor

Benign neural tumor of Schwann cell origin with granular cytoplasm
Clinical ─ Rare in breast (~6% of all GCTs), wide age range (peak 40s-50s), more common in women of African descent; presents as firm, often fixed mass, may mimic carcinoma clinically and radiologically
Radiology ─ Often irregular or spiculated mass, may mimic carcinoma
Macro ─ Usually small (<3 cm), firm, ill-defined, gray-white or yellowish nodule
Micro ─
─ Infiltrating nests, cords, or sheets of large polygonal cells with abundant, intensely eosinophilic, granular cytoplasm (due to lysosomal accumulation)
─ Small, central, round to oval, darkly stained nuclei, minimal atypia
─ Indistinct cell borders
─ Often infiltrates adjacent stroma and fat, may entrap benign ducts/lobules causing pseudoepitheliomatous hyperplasia of overlying skin or duct epithelium
─ Mitoses rare
─ Malignant variant exceedingly rare (criteria: necrosis, spindling, vesicular nuclei with large nucleoli, increased mitoses >2/10 HPF, high N/C ratio, pleomorphism)
IHC ─
─ Tumor cells: (+)S100 protein (strong, diffuse), (+)CD68 (lysosomal marker), (+)PAS-diastase resistant granules, (+)Inhibin (variable), (+)Calretinin (variable), (+)SOX10
─ (-)Cytokeratins, (-)EMA, (-)SMA, (-)Desmin, (-)ER, (-)PR, (-)HER2, (-)GCDFP-15
DDx ─
─ Invasive Carcinoma (esp Apocrine or Histiocytoid Lobular): (+)Cytokeratins; Apocrine is (+)AR, (+)GCDFP-15; Histiocytoid Lobular is (-)E-cadherin; both (-)S100
─ Fat Necrosis with Histiocytes: Foamy macrophages, lipid vacuoles, associated inflammation; histiocytes (+)CD68 but (-)S100
─ Benign Histiocytic Proliferations: Lack S100 positivity
─ Alveolar Soft Part Sarcoma (metastatic): Distinct alveolar pattern, PAS+ crystalline material, TFE3+
Prognosis ─ Benign, excellent prognosis; requires complete excision as infiltrative borders can lead to local recurrence if margins positive; malignant GCT is rare but aggressive
Media ─ ─ Granular cell tumor (Breast) rosai ─ Granular cell tumor (myoblastoma) (breast) rosai

Pseudoangiomatous Stromal Hyperplasia (PASH)

Benign stromal proliferation characterized by complex, anastomosing slit-like spaces within dense collagenous stroma, mimicking a vascular proliferation
Clinical ─ Wide age range (premenopausal > postmenopausal), often incidental microscopic finding, may present as palpable mass (tumorous PASH)
Radiology ─ Nonspecific, may be well-circumscribed mass, focal asymmetry, or no abnormality
Macro ─ Usually incidental finding; tumorous form presents as firm, rubbery, well-circumscribed, gray-white mass
Micro ─
─ Proliferation of bland, slender spindle cells (myofibroblasts) within dense, collagenous stroma
─ Formation of complex, anastomosing, empty slit-like spaces lined by spindle cells, mimicking vascular channels
─ Spaces lack red blood cells
─ Spindle cells have scant cytoplasm, uniform nuclei, no atypia or mitoses
─ May entrap benign ducts and lobules
─ Often associated with fibrocystic changes or fibroadenomas
IHC ─
─ Spindle cells lining spaces: (+)CD34, (+)Vimentin, (+)PR (variable), (+)Actin (variable)
─ (-)CD31, (-)ERG (confirming spaces are not true vascular channels)
─ (-)Cytokeratins, (-)S100 protein
DDx ─
─ Low-grade Angiosarcoma: True vascular channels lined by endothelial cells ((+)CD31, (+)ERG), often contain red blood cells, infiltrative growth, endothelial atypia
─ Fibroadenoma/Phyllodes Tumor: Biphasic lesions with epithelial component, distinct stromal patterns
─ Myofibroblastoma: Discrete tumor composed of fascicles of spindle cells and collagen bundles, (+)Desmin
─ Fibromatosis: More cellular fascicles, infiltrative, (+)nuclear Beta-catenin
Prognosis ─ Benign, no increased risk of malignancy; tumorous PASH may recur locally (~15–20%) if incompletely excised, but recurrence is benign
Media ─ ─ Pseudoangiomatous stromal hyperplasia (PASH) (Breast) H&E

Neuroendocrine Neoplasms

Radiology ─

Macro ─ Tumors are often well-circumscribed, fleshy, tan-gray to yellowish nodules; Larger or higher-grade lesions may show necrosis or hemorrhage

Micro ─

DDx ─

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