---

Classification of Breast Carcinoma

---

I. Broad Division: In Situ vs. Invasive

• Robbins & Kumar Basic Pathology, p. 719

---

II. Carcinoma In Situ (CIS)

A. Ductal Carcinoma In Situ (DCIS)

• SCHWARTZ'S Principles of Surgery 11th Ed., p. 592

B. Lobular Carcinoma In Situ (LCIS)

• LCIS is a marker of increased risk and a precursor lesion
• It is non-palpable, often an incidental finding
• Unlike DCIS, when invasive cancer develops after LCIS: 2/3 occur in the same breast, 1/3 in the contralateral breast
• Characterized by loss of E-cadherin expression (shared with invasive lobular carcinoma)
• Relative risk of subsequent invasive carcinoma: ~8-10x (25-30%)
• Robbins, Cotran & Kumar Pathologic Basis of Disease

---

III. Invasive Breast Carcinoma: Histologic Classification

1. Invasive Carcinoma of No Special Type (NST) / Invasive Ductal Carcinoma - 75-80%

• Most common histologic subtype
• Also called "scirrhous," "simplex," or formerly "invasive ductal carcinoma NOS"
• Presents as a hard, irregular, radiodense mass with desmoplastic stromal reaction
• Has a characteristic grating sound when cut due to chalky-white stroma and calcification foci
• Heterogeneous group with variable grade and receptor status
• 75% express estrogen receptor (ER)
• Generally worse prognosis than special-type cancers

2. Invasive Lobular Carcinoma - ~10%

• Most common special subtype
• Associated with LCIS; shows single-file (Indian file) infiltration pattern through stroma
• E-cadherin negative - loss is characteristic and diagnostic
• Tends to be multifocal and bilateral
• Metastasizes to unusual sites (peritoneum, retroperitoneum, GI tract, meninges)

3. Medullary Carcinoma - ~4%

• Soft, hemorrhagic gross appearance
• Histology: syncytial sheets of high-grade cells + dense lymphocytic infiltrate
• Associated with BRCA1 hereditary breast cancer
• Paradoxically, despite high grade, behavior can be relatively favorable
• Now reclassified in current WHO system as invasive carcinoma NST with "medullary pattern"

4. Mucinous (Colloid) Carcinoma - ~2%

• Islands of tumor cells floating in large pools of extracellular mucin
• Typically low grade, better prognosis
• More common in elderly women

5. Tubular Carcinoma - ~2%

• Well-formed tubular glands with open lumina
• Excellent prognosis; usually Grade 1
• Almost always ER/PR positive, HER2 negative

6. Papillary Carcinoma - ~2%

• Forms fibrovascular papillary fronds
• Includes encapsulated, solid, and invasive papillary subtypes

7. Paget's Disease of the Nipple

• Chronic eczematous eruption of nipple, may progress to ulceration
• Pathognomonic: Paget cells - large, pale, vacuolated cells in the rete pegs of nipple epithelium
• Almost always associated with underlying DCIS, and sometimes invasive carcinoma
• Distinguished from melanoma by: CEA positive (Paget's) vs S-100 positive (melanoma)

8. Inflammatory Breast Carcinoma

• Clinically defined: erythema, skin thickening, peau d'orange, warmth - mimics mastitis
• Pathologically: tumor emboli in dermal lymphatics
• Most aggressive presentation; often presents as locally advanced disease
• High-grade, often ER-negative

9. Rare Special Types

• Adenoid cystic carcinoma
• Squamous cell carcinoma
• Apocrine carcinoma
• Metaplastic carcinoma

Note: To qualify as a "special type," at least 90% of the tumor must show the defining histologic features. - Schwartz's Surgery 11th Ed.

---

IV. Histologic Grading (Nottingham System)

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 978

---

V. Molecular/Biologic Classification (Gene Expression Profiling)

• Most basal-like tumors are triple negative
• But many triple-negative tumors do NOT have basal-like features
• Quick Compendium of Clinical Pathology 5th Ed.; Robbins, Cotran & Kumar Pathologic Basis of Disease

---

VI. Clinical Biologic Grouping (AJCC 8th Edition)

1. ER-positive / HER2-negative (Luminal A/B) - most common ~70%
2. HER2-positive - ~15-20%
3. Triple Negative (ER/PR/HER2 negative) - ~15%

• Patient demographics
• Grade distribution
• Mutation profile
• Metastatic pattern
• Response to therapy
• Time to recurrence and prognosis
• Robbins, Cotran & Kumar Pathologic Basis of Disease; Robbins & Kumar Basic Pathology, p. 719

---

Summary Diagram

BREAST CARCINOMA
│
├── IN SITU
│   ├── DCIS (Ductal) → High/Intermediate/Low grade (Comedo / Non-comedo)
│   └── LCIS (Lobular) → Risk marker + precursor
│
└── INVASIVE
    │
    ├── HISTOLOGIC TYPE
    │   ├── No Special Type (NST) / IDC - 75-80%
    │   ├── Invasive Lobular Carcinoma - 10%
    │   ├── Medullary - 4%
    │   ├── Mucinous/Colloid - 2%
    │   ├── Tubular - 2%
    │   ├── Papillary - 2%
    │   ├── Paget's Disease of Nipple
    │   ├── Inflammatory Carcinoma
    │   └── Rare (adenoid cystic, squamous, apocrine)
    │
    ├── HISTOLOGIC GRADE (Nottingham)
    │   ├── Grade 1 (Well differentiated)
    │   ├── Grade 2 (Moderately differentiated)
    │   └── Grade 3 (Poorly differentiated)
    │
    └── MOLECULAR SUBTYPE
        ├── Luminal A (ER+, HER2-, low Ki67) → best prognosis
        ├── Luminal B (ER+, HER2+, high Ki67) → intermediate
        ├── HER2-enriched (ER-, HER2+) → treat with trastuzumab
        └── Triple Negative / Basal-like (ER-, PR-, HER2-) → worst prognosis

---

Classification of Breast Carcinoma - Robbins, Cotran & Kumar

Source: Robbins, Cotran & Kumar - Pathologic Basis of Disease (Latest Edition), Chapter 23

---

PART 1: IN SITU CARCINOMA

---

A. Ductal Carcinoma In Situ (DCIS)

• Comedo - high-grade cells with large central necrosis; calcifications linear/branching on mammogram
• Cribriform - rounded "cookie cutter" spaces filled with calcifying secretions
• Micropapillary - complex bulbous protrusions without fibrovascular cores
• Papillary - true papillae with fibrovascular cores, lacks myoepithelial layer
• Solid - sheets of cells fill and distend ducts

• Low-grade DCIS: ~1% per year risk of invasion (ipsilateral, same quadrant)
• High-grade or extensive DCIS: higher risk and faster progression
• Death from metastatic disease after DCIS diagnosis: only 1-3%

Paget Disease of the Nipple

• Presents as unilateral erythematous eruption with scale crust; pruritus is common
• Paget cells = large, pale, vacuolated malignant cells in nipple epidermis
• Underlying palpable mass: ~50% of cases → these usually have invasive carcinoma
• Without palpable mass: usually pure DCIS, staged as such
• Prognosis depends on features of any underlying invasive carcinoma

---

B. Lobular Carcinoma In Situ (LCIS)

• Clonal proliferation within lobules with characteristic dyscohesive cells
• Loss of E-cadherin expression - shared with invasive lobular carcinoma (diagnostic marker)
• Molecular features similar to low-grade ER-positive invasive carcinoma
• Acts as both a risk marker (increased risk both breasts) and precursor lesion
• Risk of invasive carcinoma: ~8-10x relative risk (25-30% lifetime)

---

PART 2: INVASIVE CARCINOMA

Histologic Subtype Classification

---

1. Invasive Carcinoma of No Special Type (NST) - ~75%

• Hard, irregular, radiodense mass with irregular margins
• Desmoplastic stromal reaction - produces characteristic grating sound when cut
• Chalky-white stroma with foci of calcification
• Less commonly: well-circumscribed mass with scant stroma, or scattered infiltrating glands

Note: High-grade NST tumors with prominent tumor-infiltrating lymphocytes (TILs) were previously called "medullary carcinoma" - this entity proved not to be diagnostically reproducible and is now classified as invasive carcinoma NST with medullary pattern.

Nottingham Histologic Grade (all invasive carcinomas graded this way):

---

2. Special Histologic Subtypes

Luminal (ER-positive / HER2-negative) Special Types

• Second most common invasive subtype (up to 15%)
• Loss of E-cadherin → dyscohesive cells
• CDH1 germline mutations increase risk of lobular breast carcinoma AND signet ring gastric carcinoma
• Unique metastatic sites: peritoneum, retroperitoneum, leptomeninges, GI tract, ovaries, uterus
• Difficult to detect on imaging due to minimal desmoplasia and diffuse infiltration

HER2-Positive Special Types

Triple-Negative (ER/PR/HER2-negative) Special Types

Note: The rare indolent TNBC subtypes (adenoid cystic, secretory, mucoepidermoid) are "salivary gland-like" tumors with an excellent prognosis despite being triple negative.

---

PART 3: MOLECULAR/BIOLOGIC CLASSIFICATION

• Luminal A vs. B: differ mainly in proliferative rate (Ki67)
• HER2 cancers: defined by HER2 overexpression due to gene amplification; respond well to HER2 inhibitors
• TNBC: often associated with BRCA1 silencing or TP53 mutation; typically high-grade solid tumors with necrosis and very high proliferation
• A small subset of low-grade TNBC exists with excellent prognosis (e.g., secretory carcinoma, adenoid cystic) - these are biologically distinct

"Basal-like" and "triple negative" are not synonymous - most basal-like tumors are TNBC, but many TNBCs do not have basal-like features.

---

PART 4: STAGING - AJCC 8th Edition

---

Summary Flowchart (Robbins Framework)

BREAST CARCINOMA (all from TDLU)
│
├── IN SITU (basement membrane intact)
│   ├── DCIS ──── Low-grade (ER+, HER2−, 16q loss)
│   │             High-grade (ER−/HER2+, genomic instability)
│   │             Patterns: comedo, cribriform, micropapillary, papillary, solid
│   │             + Paget disease of nipple (DCIS → nipple skin)
│   └── LCIS ──── E-cadherin negative; risk marker + precursor
│
└── INVASIVE (basement membrane breached)
    │
    ├── NO SPECIAL TYPE (NST) ~75% ── Graded I, II, III (Nottingham)
    │
    ├── SPECIAL TYPES (organized by molecular group)
    │   ├── Luminal (ER+/HER2−): Lobular, Mucinous, Tubular, Cribriform, Papillary
    │   ├── HER2+: Apocrine, Micropapillary
    │   └── TNBC: Metaplastic (aggressive); Adenoid cystic/Secretory (favorable)
    │
    └── MOLECULAR GROUPS
        ├── Luminal A (ER+, low Ki67) ── best prognosis
        ├── Luminal B (ER+, high Ki67) ── intermediate
        ├── HER2-enriched (HER2 amp) ── trastuzumab-sensitive
        └── TNBC / Basal-like (ER−PR−HER2−) ── worst prognosis

• Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 23, pp. 966-984

---

Breast Carcinoma - Complete Pathology

Robbins, Cotran & Kumar - Pathologic Basis of Disease, Chapter 23

---

OVERVIEW

---

EPIDEMIOLOGY & RISK FACTORS

Age & Incidence Patterns

• Rare before age 25; increases rapidly after age 30
• Luminal (ER+) cancer: incidence continues to rise with age and peaks late in life
• TNBC & HER2 cancer: incidence plateaus in middle age (~40 years)
• Therefore, TNBC/HER2 cancers account for nearly half of breast cancers in young females vs. <20% in older females

Hormonal Risk Factors

• Prolonged estrogenic stimulation (early menarche, late menopause, nulliparity, late first pregnancy, exogenous postmenopausal hormones)
• Hormone receptor-positive tumors are especially susceptible to estrogen-driven proliferation

Genetic/Familial Risk

---

PATHOGENESIS

Cell of Origin

Two Major Pathways of Breast Cancer Evolution (Low-grade vs. High-grade)

• Progression: Columnar cell lesions → Flat epithelial atypia → Atypical ductal hyperplasia → Low-grade DCIS → Low-grade invasive carcinoma
• Molecular hallmarks: 16q deletion, 1q gain
• Phenotype: ER-positive/HER2-negative (Luminal A)
• Slow, stepwise accumulation of mutations

• More complex, often arising de novo or from high-grade DCIS
• Molecular hallmarks: TP53 mutation, genomic instability, chromosomal changes
• Phenotypes: HER2-enriched, TNBC/basal-like
• More aggressive biological behavior

Tumor Microenvironment

• Cancer-associated fibroblasts (CAFs) facilitate adhesion, ECM remodeling, and immunosuppression
• Myoepithelial cell loss creates gaps in the basement membrane, predisposing to stromal invasion
• Tumor cells upregulate PD-L1 (immune checkpoint) to evade host immune response

---

PART I: CARCINOMA IN SITU

A. Ductal Carcinoma In Situ (DCIS)

• Comedo: High-grade cells + large central necrosis; linear/branching calcifications on mammogram
• Cribriform: "Cookie-cutter" rounded spaces filled with calcifying secretions
• Micropapillary: Bulbous protrusions without fibrovascular cores
• Papillary: True papillae with fibrovascular cores; lacks myoepithelial layer
• Solid: Sheets of cells filling and distending ducts

• Females with small, low-grade DCIS: ~1% per year invasion risk
• Invasive cancer in the same breast quadrant with same grade/receptor profile as DCIS
• Death from metastatic disease after DCIS: only 1-3%
• Overall death rate after DCIS diagnosis is lower than the general population (partly reflects better access to care)

Paget Disease of the Nipple

• Rare manifestation (1-4% of cases)
• DCIS extends via lactiferous ducts into nipple skin WITHOUT crossing the basement membrane
• Paget cells: Large, pale, vacuolated malignant cells within nipple epidermis
• Presentation: Unilateral erythematous eruption with scale crust; pruritus; may be mistaken for eczema
• ~50% have a palpable mass (usually invasive carcinoma underneath)
• Without palpable mass: usually pure DCIS, staged as such
• Prognosis depends on features of underlying invasive carcinoma (if present)

---

B. Lobular Carcinoma In Situ (LCIS)

• Clonal proliferation of dyscohesive cells within lobules
• Loss of E-cadherin (CDH1) expression - shared with invasive lobular carcinoma
• Molecular features overlap with low-grade ER-positive invasive carcinoma
• Serves as both a risk marker (both breasts) and direct precursor (ipsilateral)
• Risk of invasive carcinoma: ~8-10x relative risk (~25-30% lifetime risk)

---

PART II: INVASIVE CARCINOMA

A. Histologic Classification

---

1. Invasive Carcinoma of No Special Type (NST) - ~75%

• Hard, irregular, radiodense mass with irregular margins on mammography
• Stellate, fibrotic cut surface with desmoplastic stroma
• Characteristic grating sound when cut - due to chalky-white stroma and calcifications

• Most common: small clusters/nests/glands infiltrating stroma with desmoplastic reaction
• Less common: well-circumscribed mass with scant stroma (sheets of cells)
• Rare: scattered single cells infiltrating fibrofatty tissue (mimics lobular)
• High-grade NST with prominent tumor-infiltrating lymphocytes (TILs) = "medullary pattern" (previously called medullary carcinoma - no longer a reproducible entity)

---

Nottingham Histologic Grading (applies to all invasive carcinomas)

---

2. Special Histologic Subtypes

Luminal (ER+/HER2-) Special Types

HER2-Enriched Special Types

Triple-Negative (ER-/PR-/HER2-) Special Types

These rare TNBC subtypes (adenoid cystic, secretory, mucoepidermoid) are called "salivary gland-like carcinomas" - they are biologically distinct and have excellent prognosis despite being triple-negative.

Inflammatory Carcinoma (Clinical Presentation, not a histologic type)

• NOT a special histologic type - it is a clinical presentation
• Caused by extensive plugging of dermal lymphovascular spaces by carcinoma cells
• Results in: diffuse breast erythema, swelling, skin thickening, peau d'orange (skin tethered by Cooper ligaments)
• Mimics infection/mastitis → delayed diagnosis
• The name "inflammatory" is a misnomer - typically NO actual inflammation is present
• Underlying carcinoma: usually high-grade, diffusely infiltrative, no discrete palpable mass
• Very poor prognosis: 3-year survival rate only 3-10%

---

PART III: MOLECULAR SUBTYPES

• Normal-like: Gene expression resembles normal breast tissue
• Claudin-low: Low expression of cell-cell junction proteins; enriched for mesenchymal/stem cell features; associated with TNBC

---

PART IV: CLINICAL FEATURES

• Luminal cancers: More often detected by mammographic screening as small masses; limited to breast
• HER2+ and TNBC: More aggressive; more likely to present as palpable masses

• Fixed to pectoralis muscle / chest wall (skin/muscle invasion)
• Skin dimpling or retraction (dermal invasion)
• Nipple retraction (central breast involvement)
• Peau d'orange (dermal lymphatic blockage → inflammatory carcinoma)
• Rare: presents first as axillary lymph node metastasis before breast primary is found

---

PART V: PROGNOSTIC FACTORS

---

PART VI: TARGETED THERAPIES (Summary)

• Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 23, pp. 966-984