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BREAST PATHOLOGY - MUHS 2nd MBBS EXAM NOTES

Based on Robbins, Cotran & Kumar - Pathologic Basis of Disease

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PART 1 - FIBROADENOMA OF THE BREAST ⭐⭐

Definition

Pathogenesis / Etiology

• Two-thirds harbor driver mutations in MED12 gene (encodes a subunit of the Mediator complex, which regulates RNA Polymerase II-dependent transcription)
• ~1/3 also harbor mutations in RARA (retinoic acid receptor alpha - an estrogen target gene)
• Hormonally responsive tumor - grows under estrogen influence
• Note: The same MED12 mutation is found in uterine leiomyomas - a useful exam fact

GROSS FEATURES

Exam Tip: "Well-circumscribed rubbery gray-white nodule that BULGES above surrounding tissue with slit-like spaces" = Fibroadenoma gross

MICROSCOPIC FEATURES (Histopathology)

1. Pericanalicular Pattern

• Delicate myxoid stroma surrounds patent (open) ducts
• Ducts remain round/oval
• Stroma proliferates around the ducts

2. Intracanalicular Pattern

• Stroma compresses and distorts ductal elements into cleft-like or slit-like spaces
• Epithelial-lined clefts are compressed
• More common

Stroma

• Delicate, often myxoid - resembles normal intralobular stroma
• In older females: stroma becomes densely hyalinized and epithelium becomes atrophic

Epithelium

• Two-layered: inner luminal cells + outer myoepithelial cells
• No atypia in benign fibroadenoma

DIAGRAM - FIBROADENOMA MICROSCOPY:

 ┌─────────────────────────────────────────┐
 │  Pericanalicular:    Intracanalicular:  │
 │                                         │
 │  [Stroma]──┐         [Stroma]──────┐    │
 │     ┌──O──┘   vs.      ──[Slit]──  │    │
 │     │ DUCT             compressed  │    │
 │  (round/oval)          duct lumen  │    │
 └─────────────────────────────────────────┘

Clinical Features

• Age: 20s-30s (peak in reproductive age)
• Frequently multiple and bilateral
• Grow during pregnancy (may mimic carcinoma due to rapid growth)
• Regress after menopause
• Rare malignant transformation (<0.1%)
• Treatment: Excision (lumpectomy)

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PART 2 - CLASSIFICATION OF BREAST TUMOURS ⭐⭐

WHO Classification of Breast Tumours

A. Epithelial Tumours

I. In Situ Carcinoma

1. Ductal Carcinoma In Situ (DCIS)
   • Comedo type (with central necrosis)
   • Non-comedo type (cribriform, micropapillary, papillary, solid)
2. Lobular Carcinoma In Situ (LCIS)
   • Classic LCIS
   • Pleomorphic LCIS

II. Invasive Carcinoma

1. Invasive carcinoma of No Special Type (NST) - formerly Invasive Ductal Carcinoma (IDC) - 75% of all invasive carcinomas
2. Invasive Lobular Carcinoma (ILC) - 10-15%
3. Tubular Carcinoma
4. Cribriform Carcinoma
5. Mucinous (Colloid) Carcinoma
6. Papillary Carcinoma
7. Medullary Pattern Carcinoma (now classified as IDC-NST with medullary pattern)
8. Metaplastic Carcinoma
9. Inflammatory Carcinoma

B. Mesenchymal Tumours

1. Fibroadenoma (most common benign)
2. Phyllodes Tumor (benign/borderline/malignant)
3. Angiosarcoma
4. Myofibroblastoma
5. Lipoma
6. Fibromatosis

C. Nipple Tumours

1. Paget's Disease of Nipple
2. Nipple Adenoma

D. Lymphoma and Metastases

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Classification Diagram - Breast Cancer

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Clinical/Biomarker Classification (Most Important for Exams)

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PART 3 - CARCINOMA BREAST (DETAILED) ⭐⭐⭐

Epidemiology

• Most common malignancy globally in females
• Surpassed lung cancer as most common cancer overall in 2020 (2.3 million new cases)
• Lifetime risk: 1 in 8 for females living to age 90 years (USA)
• 75% diagnosed after age 50
• Leading cause of cancer death in females worldwide

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RISK FACTORS FOR BREAST CARCINOMA

High Risk (Relative Risk >4)

• Female sex (99% of cases)
• Increasing age
• Germline mutations - BRCA1 / BRCA2 (high penetrance)
• Strong family history (>1 first-degree relative, young age, multiple cancers)
• Personal history of breast cancer
• High breast density

Moderate Risk (Relative Risk 2.1-4.0)

• Germline mutations of moderate penetrance (PALB2, CHEK2, ATM)
• High-dose radiation to chest at young age (<18 years)
• Family history (1 first-degree relative)

Low Risk (Relative Risk 1.1-2.0)

• Early menarche (age <12 years)
• Late menopause (age >55 years)
• Late first pregnancy (age >35 years)
• Nulliparity
• Absence of breastfeeding
• Exogenous hormone therapy (OCP, HRT)
• Postmenopausal obesity
• Physical inactivity
• High alcohol consumption

Protective Factors

• Early pregnancy (<20 years)
• Prolonged breastfeeding
• Bilateral prophylactic mastectomy (reduces risk by ~90%)
• ER antagonists (chemoprevention in high-risk patients)

Exam Mnemonic for Hormonal Risk Factors: "NEON-M" - Nulliparity, Early menarche, Obesity (postmenopausal), No breastfeeding, Menopause (late)

BRCA Genes

• BRCA1 (chromosome 17q) - associated with TNBC/basal-like tumors; also increases risk of ovarian cancer
• BRCA2 (chromosome 13q) - associated with luminal tumors; also increases risk of male breast cancer
• Women with BRCA mutations have up to 80% lifetime risk of breast cancer

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PATHOGENESIS

LOW-GRADE PATHWAY:                    HIGH-GRADE PATHWAY:
Columnar cell lesions                 High-grade DCIS
      ↓                                     ↓
Flat epithelial atypia               High-grade invasive
      ↓                               carcinoma (HER2+, TNBC)
Atypical hyperplasia
      ↓                              Genetics: Loss 13q,
Low-grade DCIS/LCIS                  gain 11q13, 17q12
      ↓                              amplification
Low-grade ER+ invasive Ca
(Luminal A/B)
Genetics: Loss 16q, gain 1q

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CLASSIFICATION OF BREAST CARCINOMA (Exam Format)

A. In Situ Carcinomas

1. Ductal Carcinoma In Situ (DCIS)

• Most common type of in situ carcinoma
• Confined within ducts, basement membrane intact
• Detected by mammography as calcifications
• Subtypes:
  • Comedo type (most aggressive): Necrotic center + calcification; high-grade nuclei; HER2 amplification
  • Non-comedo: Cribriform, micropapillary, solid, papillary

2. Lobular Carcinoma In Situ (LCIS)

• Marker of increased risk + precursor lesion
• Loss of E-cadherin expression (key feature)
• Small loosely cohesive cells filling lobular acini
• When carcinoma develops in LCIS patients: 2/3 in same breast, 1/3 contralateral
• Management: Bilateral risk-reduction strategies

B. Invasive (Infiltrating) Carcinomas

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

2. Invasive Lobular Carcinoma (10-15%)

• Loss of E-cadherin - cells are dyscohesive
• Indian-file / single-file pattern of infiltration
• Contains signet ring cells (intracytoplasmic mucin)
• Minimal desmoplasia - difficult to detect on imaging
• Metastasizes to: peritoneum, retroperitoneum, leptomeninges, GI tract, ovaries, uterus

3. Mucinous (Colloid) Carcinoma

• Soft, rubbery, gelatinous with pushing/circumscribed borders
• Tumor cells in pools of extracellular mucin
• Good prognosis - ER+

4. Tubular Carcinoma

• Well-differentiated; small angulated tubules
• Excellent prognosis; ER+

5. Medullary Pattern Carcinoma

• Previously called Medullary carcinoma; now IDC-NST with "medullary pattern"
• Large pleomorphic cells, prominent TILs (tumor infiltrating lymphocytes), solid growth
• Often TNBC

6. Paget's Disease of Nipple

• Large, pale cells (Paget cells) in nipple epidermis
• Always associated with underlying DCIS or invasive carcinoma
• Presents as eczema-like rash of nipple

7. Inflammatory Breast Carcinoma

• Rapid onset, skin erythema, warmth, edema ("peau d'orange" without a palpable mass)
• Due to dermal lymphatic invasion by tumor emboli
• Very poor prognosis (Stage IIIB)

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PART 4 - INVASIVE DUCTAL CARCINOMA (IDC) - DETAILED ⭐⭐⭐

Definition

GROSS FEATURES of IDC

GROSS DIAGRAM OF IDC:

     Skin dimpling
          ↓
    ___________
   /  Irregular/
  /  stellate  \   ← Spiculated margins
 |   HARD mass  |
  \  GRITTY    /   ← Chalky-white streaks
   \___(Ca)___/      (desmoplastic stroma)
         |
    Chest wall

MICROSCOPIC FEATURES (Histopathology) of IDC

Key Microscopic Findings:

1. Invasive nests, cords, tubules, or sheets of tumor cells infiltrating fibrous stroma
2. Desmoplastic stromal reaction - dense fibrous stroma surrounding tumor cell nests (hallmark)
3. No organized ductal/lobular architecture
4. Variable nuclear pleomorphism depending on grade
5. Mitotic figures present
6. Calcifications may be present
7. Some tumors have TILs (tumor infiltrating lymphocytes) - especially TNBC

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GRADING OF BREAST CARCINOMA - Nottingham Histologic Score (Elston-Ellis Modification of Bloom-Richardson) ⭐⭐⭐

Three Parameters (Each scored 1-3):

Total Score Interpretation:

• 3-5 = Grade 1 (Well differentiated) - Good prognosis
• 6-7 = Grade 2 (Moderately differentiated) - Intermediate prognosis
• 8-9 = Grade 3 (Poorly differentiated) - Poor prognosis

GRADING DIAGRAM:

Grade 1:          Grade 2:          Grade 3:
┌──────────┐      ┌──────────┐      ┌──────────┐
│ O  O  O  │      │ O Clust  │      │ ████████ │
│ Tubules  │  vs  │ Clusters │  vs  │ Solid    │
│ uniform  │      │ some     │      │ sheets,  │
│ nuclei   │      │ atypia   │      │ necrosis │
└──────────┘      └──────────┘      └──────────┘
  Score 3-5          Score 6-7         Score 8-9

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STAGING OF BREAST CARCINOMA - TNM System (AJCC 8th Edition) ⭐⭐⭐

TNM Categories:

• T = Primary Tumor size
  • Tis = In situ (DCIS/LCIS)
  • T1 = ≤2 cm
  • T2 = >2 cm but ≤5 cm
  • T3 = >5 cm
  • T4 = Any size with skin/chest wall involvement or inflammatory carcinoma
• N = Regional Lymph Nodes
  • N0 = No metastasis
  • N1 = 1-3 positive axillary nodes
  • N2 = 4-9 positive nodes
  • N3 = ≥10 positive nodes
• M = Distant Metastasis
  • M0 = Absent
  • M1 = Present

Stage Groups and Prognosis:

AJCC 8th Edition Update: The current staging also incorporates Grade + ER + PR + HER2 status to assign a PROGNOSTIC STAGE that may differ from the anatomic stage. For example, a TNBC may be "up-staged" because of its aggressive biology.

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PART 5 - PROGNOSTIC AND PREDICTIVE FACTORS ⭐⭐⭐

Key Definitions

• Prognostic factor: Indicates likely outcome (survival, recurrence) independent of therapy
• Predictive factor: Indicates likely response to specific treatment
• Note: Tumor biology factors (ER, HER2) are BOTH prognostic AND predictive; tumor extent factors (size, nodes) are primarily PROGNOSTIC

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MAJOR PROGNOSTIC FACTORS (In order of importance)

1. Distant Metastases (Most Important Overall)

• Once present, cure is unlikely
• Palliation still possible in ER+ and HER2+ tumors
• Common sites: bone, lung, liver, brain

2. Axillary Lymph Node Status (Most Important in Absence of Distant Mets)

• Sentinel lymph node biopsy: identifies first draining node with radiotracer/blue dye
• If sentinel node negative - no full axillary dissection needed

3. Tumor Size

• Smaller tumors = better prognosis
• Tumors ≤1 cm with no node involvement = excellent prognosis

4. Histologic Grade

• Grade 1 (well diff.) > Grade 2 > Grade 3 (poorly diff.) in terms of prognosis

5. Molecular/Biomarker Factors

ER (Estrogen Receptor)

• Prognostic + Predictive
• ER+ (≥1% nuclear staining) responds to endocrine therapy (Tamoxifen, Aromatase Inhibitors)
• Low ER (1-10%) = worse prognosis than high ER expression

PR (Progesterone Receptor)

• ER+/PR+ = best outcome
• ER+ but PR-low = worse outcome

HER2 (Human Epidermal Growth Factor Receptor 2)

• Prognostic + Predictive
• HER2 positivity = aggressive behavior
• Responds to HER2-targeting agents: Trastuzumab (Herceptin), Pertuzumab, T-DM1
• Assessed by IHC (3+ = positive) or FISH (gene amplification)

6. Molecular Subtype

7. Tumor Infiltrating Lymphocytes (TILs)

• Prominent TILs = better prognosis and better response to neoadjuvant chemotherapy
• Especially important in HER2+ and TNBC

8. Proliferation Rate (Ki-67)

• Low Ki-67 = slower growing = better prognosis
• High Ki-67 = high-grade, aggressive

9. Gene Expression Profiling

• Oncotype DX, MammaPrint, Prosigna
• Used mainly to identify ER+/HER2- patients who can safely avoid chemotherapy

10. Response to Neoadjuvant Chemotherapy

• Pathologic Complete Response (pCR) = no residual invasive disease after pre-surgery chemo
• pCR in TNBC and HER2+ = significantly better prognosis

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Recurrence Patterns by Molecular Subtype

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PREDICTIVE FACTORS (Summary)

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QUICK SUMMARY TABLE FOR MUHS EXAM

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IMPORTANT EXAM DIAGRAMS - DRAWN

Diagram 1: IDC Histopathology Schema

LOW POWER (IDC - Scirrhous type):          HIGH POWER:

 Fat     Tumor nests                    Nuclear pleomorphism
  O     ╔══╗  ╔═╗                        Large irregular
  O  ══╪══╪══╪═╪══  Dense fibrous        nuclei, prominent
  O     ╚══╝  ╚═╝   stroma               nucleoli
        ↑ Invasive  (desmoplasia)
        tumor clusters                  Mitotic figures:
                                        │ │
  Lymphatics                            (⊗)← Mitosis
  invaded──→ ══                         
  (LVI)                                 Gland formation:
                                        minimal (Grade 3)

Diagram 2: Fibroadenoma Histopathology

PERICANALICULAR:          INTRACANALICULAR:
                               
 ~Stroma~Stroma~           ~~Stroma~~
 ~~( O )~~( O )~~   vs.   ~~[  ─  ]~~
 ~Stroma~Stroma~           ~~[cleft]~~
 ~~( O )~~( O )~~          ~~Stroma~~

Round patent ducts        Compressed slit-like 
surrounded by stroma      epithelial spaces
                          (CLEFTS)
Stroma: Myxoid/loose

Diagram 3: DCIS Types

COMEDO DCIS:              CRIBRIFORM DCIS:

 ┌──────────────┐          ┌──────────────┐
 │▓▓▓Necrosis▓▓▓│          │ ○ ○ ○ ○ ○  │
 │▓(calcific.)▓▓│          │○ ○ Sieve- ○ │
 │  High-grade  │          │  like holes  │
 │  nuclei ring │          │  Low-grade   │
 └──────────────┘          └──────────────┘
 Most aggressive           Good prognosis
 HER2 amplification        ER+

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ONE-LINERS FOR VIVA / SHORT ANSWERS

1. Most common benign tumor of breast = Fibroadenoma
2. Most common malignant tumor of breast = IDC-NST (Invasive ductal carcinoma)
3. Grading system used = Nottingham Histologic Score (Bloom-Richardson modified by Elston & Ellis)
4. Three parameters of Nottingham grading = Tubule formation + Nuclear pleomorphism + Mitotic count
5. Sentinel node biopsy uses = Radiotracer or blue dye
6. Most important prognostic factor overall = Distant metastases
7. Most important prognostic factor in absence of mets = Axillary lymph node status
8. Loss of E-cadherin = Invasive lobular carcinoma / LCIS
9. Indian file pattern = Invasive lobular carcinoma
10. Skin dimpling in breast cancer = Cooper's ligament involvement by tumor fibrosis
11. Paget cells = Large pale cells in nipple epidermis, always indicating underlying carcinoma
12. ER+ breast cancer responds to = Tamoxifen (premenopausal), Aromatase Inhibitors (postmenopausal)
13. HER2+ responds to = Trastuzumab (Herceptin)
14. TNBC = ER-, PR-, HER2- ; associated with BRCA1 mutation, basal-like subtype
15. Fibroadenoma mutation = MED12 (same as uterine leiomyoma)

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