Academe Learn
CBME Curriculum Preview

Page 8 of 19

PA30.2 | Carcinoma of the Breast — SDL Guide (Part 4)

Histological Grading: Nottingham (Bloom-Richardson) System

Histological grade is one of the strongest independent prognostic factors in breast carcinoma and is reported for every invasive carcinoma. The Nottingham Grading System (modified Bloom-Richardson) evaluates three morphological parameters, each scored 1–3.

Six-panel composite histology diagram comparing Score 1 versus Score 3 for each of the three Nottingham grading parameters: tubule formation, nuclear pleomorphism, and mitotic count, with annotated labels and grade summary footer.

Nottingham Grading System — Composite Histological Scoring Panel

Panel A-left (Score 1): Well-formed glandular tubules with clear lumina; >75% tubule formation; Score 1 badge. Panel A-right (Score 3): Solid tumour cell nests; absent lumina; <10% tubule formation; Score 3 badge. Panel B-left (Score 1): Uniform small round nuclei; inconspicuous nucleolus; minimal size variation; Score 1 badge. Panel B-right (Score 3): Markedly pleomorphic large nuclei; irregular nuclear membrane; prominent nucleolus; Score 3 badge. Panel C-left (Score 1): Rare mitotic figures (1–5 per 10 HPF); counting box overlay; Score 1 badge. Panel C-right (Score 3): Numerous mitoses (>10 per 10 HPF); atypical/multipolar mitosis labelled; Score 3 badge.
ParameterScore 1Score 2Score 3
Tubule formation>75% of tumour forms tubules10–75% tubules<10% tubules
Nuclear pleomorphismUniform small nuclei (similar to normal breast nuclei)Moderate size variationMarked variation, prominent nucleoli
Mitotic countLow (1–5 per 10 HPF)Intermediate (6–10)High (>10)

HPF = high-power fields (40× objective, field diameter 0.44 mm — count must be calibrated to microscope field area)

Total score → Grade:
• 3–5 → Grade 1 (well-differentiated) — best prognosis
• 6–7 → Grade 2 (moderately differentiated) — intermediate
• 8–9 → Grade 3 (poorly differentiated) — worst prognosis

Grade correlates strongly with molecular subtype: Luminal A tumours are usually Grade 1–2; triple-negative and HER2-enriched carcinomas are almost always Grade 3. Grade is a histological parameter (not molecular) but aligns with biology.

Staging (TNM), Prognostic Factors, and Routes of Spread

TNM Staging (AJCC 8th edition — anatomic stage):

T (Primary Tumour):
• Tis — In situ (DCIS or LCIS)
• T1 — ≤2 cm (T1a ≤0.5 cm, T1b 0.5–1 cm, T1c 1–2 cm)
• T2 — >2 cm to ≤5 cm
• T3 — >5 cm
• T4 — Any size with chest wall/skin extension; T4d = Inflammatory carcinoma

N (Regional Nodes — axillary):
• N0 — No nodal metastasis
• N1 — 1–3 axillary nodes; or internal mammary node(s) by sentinel biopsy
• N2 — 4–9 axillary nodes; or internal mammary nodes clinically
• N3 — ≥10 axillary; or infraclavicular; or supraclavicular nodes

M (Distant Metastasis): M0 = absent; M1 = present → Stage IV

Three-panel diagram showing routes of spread of breast carcinoma: a central body silhouette with teal arrows to axillary and internal mammary lymph nodes and red arrows to bone, lung, liver, and brain; a detail panel of axillary lymph node levels I–III with sentinel node; and a comparison panel of osteolytic versus osteosclerotic bone metastasis.

Routes of Spread of Breast Carcinoma

Panel A: Primary breast carcinoma mass; (A) Axillary lymph nodes with Level I/II/III progression and lateral drainage label; (B) Internal mammary nodes along sternal edge with medial/central drainage label; dotted supraclavicular N3 extension; (C) Bone — commonest distant site, osteolytic + osteosclerotic sub-label; (D) Lung/Pleura in thoracic region; (E) Liver right hypochondrium; (F) Brain with HER2+/Triple-negative annotation; teal vs red arrow legend with frequency notes. Panel B: Axillary lymph node Levels I, II, III relative to pectoralis minor muscle; breast tumour at lower left; SLNB sentinel node dotted arrow; 'if SLNB negative → skip axillary dissection' note. Panel C: Left half — osteolytic vertebral cross-section (radiolucent, moth-eaten trabeculae); Right half — osteosclerotic vertebral cross-section (radio-opaque, dense trabeculae); shared footer label: Hypercalcaemia / Pathological Fracture risk.

Routes of Spread:

Lymphatic (most important clinically):
• Axillary lymph nodes — most common; upper outer quadrant tumours → Level I/II axillary nodes
• Internal mammary nodes (medial/central tumours)
• Supraclavicular nodes (advanced disease, N3)
• Sentinel lymph node biopsy (SLNB) samples the first draining node — if negative, skip axillary dissection

Haematogenous:
• Bone — most common distant site (osteolytic or osteosclerotic; causes hypercalcaemia, pathological fracture)
• Lungs — pulmonary nodules, malignant pleural effusion
• Liver — hepatomegaly, jaundice
• Brain — particularly in HER2+ and triple-negative carcinoma (also leptomeninges in ILC)

Direct extension:
• Skin (ulceration, peau d'orange, satellite nodules)
• Chest wall (pectoral muscles, ribs) — fixation on clinical exam
• Cooper's ligament tethering → skin dimpling
• Nipple retraction (central tumours pulling lactiferous ducts)

Key Prognostic and Predictive Factors:

Prognostic (predict outcome regardless of treatment):
• Axillary nodal status — single most important prognostic factor
• Tumour size — T stage inversely correlates with survival
• Histological grade (Nottingham 1–3)
• Lymphovascular invasion (LVI) — independent predictor of nodal involvement
• Molecular subtype (Luminal A → best; TNBC → worst)
• Ki-67 proliferation index

Predictive (predict response to a specific treatment):
• ER/PR status — predicts response to tamoxifen/aromatase inhibitors
• HER2 amplification — predicts response to trastuzumab (Herceptin), pertuzumab, TDM1
• BRCA1/2 mutation — predicts response to PARP inhibitors
• PD-L1 expression — predicts response to immunotherapy (pembrolizumab in TNBC)

SELF-CHECK

A breast carcinoma shows: tubule formation 20% of tumour (score 2), moderately pleomorphic nuclei (score 2), and 8 mitoses per 10 HPF (score 2). What is the Nottingham grade and total score?

A. Score 6, Grade 2 (moderately differentiated)

B. Score 7, Grade 2 (moderately differentiated)

C. Score 8, Grade 3 (poorly differentiated)

D. Score 5, Grade 1 (well-differentiated)

Reveal Answer

Answer: A. Score 6, Grade 2 (moderately differentiated)

Tubule score 2 + nuclear score 2 + mitotic score 2 = total 6. Score 6–7 = Nottingham Grade 2 (moderately differentiated). Note: mitoses 6–10/10 HPF = score 2, which fits '8 per 10 HPF'. Total score 6 is the lower end of Grade 2.