Nottingham Histologic Grade in Breast Cancer
Definition and Clinical Significance
The Nottingham histologic grade (also called Nottingham combined histologic grade or Nottingham modification of the Bloom-Richardson system) is a mandatory prognostic marker that must be determined on all newly diagnosed invasive breast carcinomas, as it directly predicts survival and guides chemotherapy decisions. 1, 2
Grading System Components
The Nottingham system evaluates three distinct morphologic features, each scored 1-3 points: 2, 3
- Tubule/glandular formation: Degree of glandular differentiation present in the tumor 2
- Nuclear pleomorphism: Score 1 for small, regular uniform cells; Score 2 for moderate increase in size and variability; Score 3 for marked variation with large, irregular nuclei 2
- Mitotic count: Number of mitoses per standardized high-power field 2, 3
Final grade assignment: Grade 1 (3-5 points), Grade 2 (6-7 points), Grade 3 (8-9 points) 2, 3
Prognostic Impact on Survival
Survival worsens significantly as grade increases, with Grade 3 tumors showing hazard ratios of 2.27-4.07 compared to Grade 1 tumors. 4, 3 The prognostic value holds across both lymph node-negative and lymph node-positive disease, though the magnitude differs: 5
- Lymph node-negative patients: Hazard ratio of 1.437 per grade increase (p=0.045) 5
- Lymph node-positive patients: Hazard ratio of 1.651 per grade increase (p<0.001) 5
Treatment Decision-Making
Grade is essential for determining adjuvant chemotherapy benefit, particularly in ER-positive disease. 2 The treatment implications are grade-specific: 1, 5
- Grade 1 (Luminal A-like): Endocrine therapy alone is appropriate for the majority of cases; consider chemotherapy only if high tumor burden (≥4 positive lymph nodes, T3 or higher) 1
- Grade 2: Most require both chemotherapy and endocrine therapy if hormone receptor-positive 1
- Grade 3 (Luminal B-like): Chemotherapy plus endocrine therapy for the majority; Grade 3 lymph node-positive patients derive significantly greater benefit from prolonged versus perioperative chemotherapy (p=0.016 for overall survival) 1, 5
Integration with Risk Assessment Tools
The Nottingham Prognostic Index (NPI) combines grade with tumor size and lymph node status to provide excellent patient stratification. 1, 3 Additional tools that incorporate grade include: 1
- PREDICT score: Integrates age, tumor stage, ER/PgR expression, HER2 status, and histological grade 1
- Adjuvant! Online: Uses clinical parameters including grade to estimate recurrence and death probability 1
Reporting Requirements and Quality Assurance
All pathology reports must state the specific grading system used (Nottingham method) and assign a grade to all ordinary invasive carcinomas. 2 A cautionary statement should be added when histologic type contradicts grade assignment: 1
- Tubular, lobular, and mucinous histologic types or tumors with Nottingham score of 1 are almost always ER-positive; if testing negative, this discordance should be flagged 1
Special Considerations
For inflammatory breast cancer (IBC), determination of Nottingham grade is required before initiating primary systemic chemotherapy, as preoperative biopsy may be the only tissue available if pathological complete response is achieved. 1
For invasive lobular carcinoma specifically, a 2-tiered nuclear grading system (low grade = grade 1 nuclei; high grade = grades 2-3 nuclei) may reduce interobserver variability while maintaining prognostic value, as tubule formation and mitotic activity show minimal variation in this histologic subtype. 6
Reproducibility and Validation
Interobserver agreement for Nottingham grading is generally good, with 76-80% concordance between pathologists for combined grade assignment. 7 Recent deep learning models demonstrate equivalent prognostic performance to manual grading (HR 4.07 vs 3.58 for grade 3 vs 1), suggesting potential for improved standardization. 4