Specialty Guide · Path-iQ Global Pathology Review
Breast pathology is the highest-volume subspecialty in surgical pathology at most cancer centres. It integrates diagnostic histology, biomarker IHC (ER, PR, HER2, Ki-67), molecular subtyping, genomic risk profiling, and the evolving WHO classification to guide surgery, systemic therapy, and radiation decisions for the world's most commonly diagnosed cancer.
| Tumour Type | Frequency | Histology | Key Molecular Feature |
|---|---|---|---|
| Invasive carcinoma of no special type (NST) — formerly IDC | ~70–75% of invasive breast cancers | Cords, nests, solid sheets; variable gland formation; Nottingham grade 1–3 | Heterogeneous; most luminal A, luminal B, or HER2-enriched; TP53 mutation common in high-grade |
| Invasive lobular carcinoma (ILC) | ~10–15% | Single file ("Indian file") infiltration; discohesive cells; targetoid pattern around ducts; signet ring cells in some | E-cadherin loss (CDH1 mutation or promoter methylation); ER strongly positive in >95%; HER2 positive rare |
| Tubular carcinoma | ~1–2% | Angular tubules with open lumina; apocrine snouts; low-grade nuclear features; desmoplastic stroma | ER+, HER2−, grade 1; excellent prognosis; may arise from flat epithelial atypia |
| Mucinous (colloid) carcinoma | ~2% | Islands of low-grade tumour cells floating in lakes of extracellular mucin; pushing border | ER+; HER2−; neuroendocrine differentiation in some; favourable prognosis with pure mucinous histology |
| Metaplastic carcinoma | ~1% | Squamous, spindle, chondroid, or osseous metaplasia within an otherwise carcinomatous tumour; PD-L1 frequently positive | Triple negative (ER−/PR−/HER2−) in ~90%; high grade; TP53, RB1, PTEN, PIK3CA mutations; poor prognosis; checkpoint inhibitor responsive |
| Micropapillary carcinoma | ~2% | Small morule-like clusters in retraction artefact spaces; "inside-out" polarity (EMA apical staining at outer surface) | High lymphovascular invasion; nodal metastasis more common than histological grade suggests; EMA reversal pattern diagnostic |
| Adenoid cystic carcinoma | <0.1% | Biphasic: basaloid cells + luminal cells; cylindromatous pattern; cribriform spaces with basement membrane material | MYB-NFIB fusion (t(6;9)); triple negative but excellent prognosis; low nodal spread; MYB IHC positive |
| DCIS (ductal carcinoma in situ) | ~20% of screen-detected breast cancer | Clinging, cribriform, micropapillary, solid, comedo subtypes; Van Nuys Prognostic Index (grade + margin + size + age) | HER2 amplification common in high-grade DCIS; ER positive in low/intermediate grade; comedo necrosis = high-grade |
| LCIS / lobular neoplasia | Incidental finding in ~1–2% of biopsies | Distension of lobular acini by discohesive cells; E-cadherin negative; classic vs pleomorphic (worse) | Risk marker for bilateral breast cancer (4–10× increased risk); pleomorphic LCIS may warrant excision; standard LCIS = observation |
The Nottingham Combined Histological Grade (Elston-Ellis modification of Scarff-Bloom-Richardson) assigns scores across three morphological features. It is the universal grading system for invasive breast carcinoma of NST and applies to most special types.
| Feature | Score 1 | Score 2 | Score 3 |
|---|---|---|---|
| Tubule / gland formation | >75% of tumour area forms tubules | 10–75% tubule formation | <10% tubule formation |
| Nuclear pleomorphism | Small, uniform nuclei; chromatin similar to normal breast epithelium | Moderate increase in size/variability | Marked variation; prominent nucleoli; vesicular chromatin |
| Mitotic count | Field-size dependent; calibrated per 10 HPF at 40× objective (varies by microscope field diameter) | Moderate mitotic activity | High mitotic rate; pathology laboratory must establish site-specific mitotic thresholds |
Per ASCO/CAP 2020 HR testing guideline: ER and PR are positive when ≥1% of tumour nuclei stain by IHC. The 1% threshold replaced the prior 10% threshold. Cases with 1–10% nuclear staining are classified as "ER/PR low positive" — they have uncertain benefit from endocrine therapy and should be discussed in multidisciplinary tumour board. Clinically negative cases have <1% nuclear staining. H-score (0–300) and Allred score (0–8) are semi-quantitative methods; both remain in clinical use.
HER2 testing uses IHC as first-line followed by ISH (FISH/CISH) for IHC 2+ (equivocal) cases. Per ASCO/CAP 2023 HER2 guideline:
| IHC Score | Definition | ISH Required? | Clinical Classification |
|---|---|---|---|
| 0 | No staining OR incomplete faint/barely perceptible staining in ≤10% of tumour cells | No | HER2-negative |
| 1+ | Incomplete faint/barely perceptible membranous staining in >10% of tumour cells | No (ISH optional for HER2-low consideration) | HER2-low (eligible for trastuzumab deruxtecan / T-DXd in metastatic setting) |
| 2+ | Incomplete weak-to-moderate complete membranous staining in >10% OR complete strong in ≤10% | Yes — mandatory reflex | Equivocal — ISH determines HER2 status |
| 3+ | Complete intense membranous staining in >10% of tumour cells | No | HER2-positive — anti-HER2 therapy (trastuzumab, pertuzumab, T-DM1) |
HER2-low and HER2-ultralow: The 2023 ASCO/CAP update introduced a framework for HER2-low (IHC 1+ or IHC 2+/ISH-negative) and HER2-ultralow (IHC 0 with faint, incomplete staining in ≥1% of cells). Both are eligible for trastuzumab deruxtecan (T-DXd) in the metastatic HR+/HER2-low setting (DESTINY-Breast04/06 data), dramatically expanding the eligible population beyond traditional HER2-positive (3+ or ISH-amplified) cases.
Ki-67 IHC (MIB1 or SP6 clone) quantifies the proliferating fraction of tumour cells and is used to distinguish luminal A (Ki-67 low, <20%) from luminal B (Ki-67 high, ≥20%) in ER+/HER2− tumours. The 20% threshold is a guideline consensus, not an absolute biological boundary. Ki-67 results from IHC are not standardised between laboratories — interpretation requires internal validation and NordiQC/UKNEQAS participation. The International Ki-67 in Breast Cancer Working Group (IKWG) recommends global scoring (not hot-spot counting) of at least 500 tumour cells on a representative area.
| Subtype | IHC Surrogate | Ki-67 | Frequency | Prognosis | Treatment |
|---|---|---|---|---|---|
| Luminal A | ER+ and/or PR+, HER2− | <20% | ~40% | Best; low recurrence risk | Endocrine therapy; low chemotherapy benefit |
| Luminal B (HER2−) | ER+ and/or PR+, HER2− | ≥20% | ~20% | Intermediate | Endocrine ± chemotherapy; Oncotype DX guides decision |
| Luminal B (HER2+) | ER+ and/or PR+, HER2+ | Any | ~10% | Intermediate-poor | Anti-HER2 + endocrine + chemotherapy |
| HER2-enriched | ER−, PR−, HER2+ | High | ~10% | Poor without targeted therapy; excellent with anti-HER2 | Anti-HER2 (trastuzumab/pertuzumab/T-DM1) + chemotherapy |
| Triple negative (TNBC) | ER−, PR−, HER2− | High | ~15% | Worst overall; but pCR predicts long-term survival | Chemotherapy ± immunotherapy (pembrolizumab for PD-L1 CPS≥10) ± PARP inhibitor (BRCA1/2) |
| Test | Indication | Output | Evidence |
|---|---|---|---|
| Oncotype DX (Genomic Health) | ER+/HER2−, node-negative or 1–3 node-positive (post-menopausal); FFPE primary tumour | Recurrence Score (RS) 0–100; RS <26 = endocrine therapy alone; RS ≥26 = chemotherapy benefit (premenopausal RS 16–25 also benefits) | TAILORx (N0) and RxPONDER (N1–3) prospective randomised trials; highest level evidence |
| MammaPrint (Agendia) | ER+/HER2−, node-negative; also node-positive in MINDACT-eligible patients; fresh or FFPE | Low risk / High risk; MammaPrint low risk → consider endocrine therapy alone even if clinically high risk | MINDACT trial — 46% of clinically high-risk / genomically low-risk patients spared chemotherapy without OS detriment |
| Prosigna / PAM50 (Veracyte) | ER+/HER2−, post-menopausal, node-negative or node-positive; FFPE | Intrinsic subtype + Risk of Recurrence (ROR) score; ROR predicts distant recurrence at 10 years | Validated in ABCSG-8, TransATAC cohorts; CE-marked; preferred assay in some European guidelines |
| EndoPredict (Myriad) | ER+/HER2−, node-negative or 1–3 positive; post-menopausal; FFPE | EP score + EPclin score (incorporates tumour size and nodal status); dichotomised low/high risk | Validated in ABCSG-6/8 and TransATAC; CE-marked; endorsed in Austrian and some German guidelines |
Sentinel lymph node (SLN) pathological examination uses intraoperative frozen section or imprint cytology (for immediate results) and/or permanent sections with IHC. Per ASCO guidelines and ACOSOG Z0011 trial data: patients with 1–2 positive SLNs undergoing breast conservation and whole-breast radiation do not require axillary lymph node dissection (ALND). Key pathological distinctions:
World authority on DCIS margins and management. Lead author on SSO-ASTRO-ASCO margin guideline for DCIS. Expert on lobular neoplasia, flat epithelial atypia, and the pathological spectrum of low-grade breast neoplasia.
Editor-in-chief of Histopathology; expert on breast tumour subtyping, the WHO 2022 breast classification, and novel molecular markers in breast pathology. Champion of standardised pathological reporting for breast cancer clinical trials.
Editor of Diagnostic Immunohistochemistry; leading authority on ER/PR/HER2 standardisation and the ASCO/CAP breast biomarker testing guidelines. Expert in predictive biomarker IHC for breast cancer treatment selection.
Co-editor of WHO Classification of Breast Tumours (5th edition, 2019). International authority on the pathology of BRCA1/2-associated breast cancers, lobular carcinoma, and familial breast tumour syndromes.
Leader in translational breast cancer genomics — including molecular portraits of triple-negative breast cancer, intratumoural heterogeneity, and liquid biopsy in breast cancer. Co-author on ASCO/CAP HER2 2023 updates and HER2-low evidence framework.
One of Asia's foremost breast pathologists; Editor of Breast Pathology (Cambridge University Press); co-editor of the WHO breast tumours volume. Expert on special histological subtypes, fibroepithelial lesions, and pathology in the Asian breast cancer context.