A 52-year-old Indian woman undergoes mastectomy for a 3.5 cm invasive ductal carcinoma of the breast. Histopathology reveals the tumour is grade 3 (Bloom–Richardson score 9/9) with 18 mitotic figures per 10 high-power fields, marked nuclear pleomorphism, and poor glandular differentiation. Immunohistochemistry shows ER/PR negative and HER2 3+ (FISH positive). Sentinel lymph node biopsy shows metastases in 4 out of 8 sampled nodes. What is the TNM stage and intrinsic subtype of this carcinoma?

Explanation

## TNM Staging and Molecular Subtyping of Breast Cancer ### TNM Stage Determination **Key Point:** Breast cancer TNM staging integrates tumour size (T), lymph node involvement (N), and distant metastases (M). Lymph node metastases are a major prognostic factor. #### T Stage (Tumour Size) | T Stage | Size | |---------|------| | T1 | ≤ 2 cm | | T2 | 2–5 cm | | T3 | > 5 cm | | T4 | Any size with chest wall/skin invasion | #### N Stage (Lymph Node Involvement) | N Stage | Definition | |---------|------------| | N0 | No regional lymph node metastases | | N1 | 1–3 axillary nodes | | N2 | 4–9 axillary nodes OR internal mammary nodes | | N3 | ≥ 10 axillary nodes OR supraclavicular nodes | #### Stage Grouping (TNM) | Stage | Criteria | |-------|----------| | **Stage IIIA** | **T0–T2, N2, M0** OR **T3, N1–N2, M0** | | Stage IIIB | T4, N0–N2, M0 | | Stage IIIC | Any T, N3, M0 | | Stage IV | Any T, Any N, M1 | ### Case Analysis: TNM Stage This patient has: - **T2**: Tumour 3.5 cm (between 2–5 cm) - **N2**: 4 out of 8 sentinel nodes involved (4–9 nodes = N2) - **M0**: No distant metastases documented - **Therefore: Stage IIIA (T2N2M0)** ### Molecular Subtyping of Breast Cancer **High-Yield:** Breast cancer molecular subtypes are defined by hormone receptor and HER2 status: | Subtype | ER | PR | HER2 | Ki-67 | Prognosis | |---------|----|----|------|-------|----------| | **Luminal A** | + | + | − | Low | Best | | Luminal B | + | ± | ± | High | Intermediate | | **HER2-enriched** | **−** | **−** | **+** | **High** | Intermediate | | Triple-negative | − | − | − | High | Worst | ### Case Analysis: Intrinsic Subtype This patient has: - **ER/PR negative** (hormone receptor negative) - **HER2 3+ (FISH positive)** (HER2 positive) - **Grade 3** (high Ki-67 expected) - **Therefore: HER2-enriched subtype** **Clinical Pearl:** HER2-enriched breast cancers are hormone receptor-negative but HER2-positive. They respond to HER2-targeted therapy (trastuzumab, pertuzumab, T-DM1). Combined with chemotherapy, HER2-directed therapy significantly improves outcomes in this aggressive subtype. **Mnemonic:** **TNBC = Triple-Negative Breast Cancer** (ER−/PR−/HER2−); **HER2-E = HER2-enriched** (ER−/PR−/HER2+). The key difference is HER2 positivity, which offers a targetable pathway. **Warning:** Do not confuse Luminal B (ER+ or PR+, HER2+ or high Ki-67) with HER2-enriched (ER−/PR−/HER2+). This patient is ER/PR negative, so Luminal B is excluded.