What is the Combined histologic grading (Nottingham/Bloom-Richardson) system for breast cancer?

Combined Histologic Grading (Nottingham/Bloom-Richardson) System

The Nottingham modification of the Bloom-Richardson grading system (also called the Elston-Ellis modification) is the standard histologic grading method for invasive breast carcinoma that should be used in all pathology reports, as it provides critical prognostic information by evaluating three morphologic features: tubule formation, nuclear pleomorphism, and mitotic count. 1

System Components and Scoring

The grading system evaluates three distinct histologic features, each scored on a scale of 1-3 points 1, 2:

Tubule Formation (Glandular Differentiation)

• Score 1: >75% of tumor showing tubule/gland formation
• Score 2: 10-75% tubule formation
• Score 3: <10% tubule formation 2

Nuclear Pleomorphism

• Score 1: Small, regular uniform cells
• Score 2: Moderate increase in size and variability
• Score 3: Marked variation with large, irregular nuclei 2

Mitotic Count

• Score 1,2, or 3: Based on number of mitoses per 10 high-power fields (specific thresholds vary by microscope field diameter and must be calibrated for each laboratory) 1, 3
• Critical point: The mitotic count is the single most important prognostic component of the grading system and the only factor significantly associated with metastasis-free survival in multivariate analysis 3

Final Grade Assignment

The three component scores are summed to produce a total score of 3-9 points 1, 2:

• Grade 1 (well-differentiated): 3-5 points
• Grade 2 (moderately differentiated): 6-7 points
• Grade 3 (poorly differentiated): 8-9 points 1, 2

Prognostic Significance

Histologic grade is one of the strongest independent prognostic factors in breast cancer, with survival worsening significantly as grade increases. 4, 2 The grade directly impacts treatment decisions and is incorporated into integrated prognostic scoring systems 1:

• Nottingham Prognostic Index (NPI): Combines tumor size, grade, and lymph node status 1, 4
• PREDICT score: Incorporates age, tumor stage, ER/PgR expression, HER2 status, and histological grade 1

Grade is particularly important because it helps identify patients at risk for adverse outcomes who may benefit from adjuvant therapies 5

Critical Technical Requirements

Specimen Handling

• Optimal fixation is essential: B5 fixation provides superior nuclear morphology preservation compared to buffered formalin, resulting in better interobserver agreement (83.3% vs 73.5% complete agreement) 6
• Proper tissue processing directly affects mitotic count accuracy, which is the most prognostic component 3

Pathologist Training and Standardization

• Precise grading guidelines and experience significantly improve reproducibility, with kappa values of 0.73 for optimally fixed specimens when pathologists use standardized criteria 6
• Training sets and comparison with expert consensus improve agreement rates to approximately 80% 6
• Common pitfall: Inconsistent interpretation of cribriform or complex gland patterns can lead to systematic bias in tubule scoring 6

Mitotic Count Standardization

• The microscope field diameter must be calibrated and documented, as mitotic count thresholds are field-size dependent 3
• Tissue processing, microscopic observation technique, and threshold values must be well-standardized and controlled 3
• The uneven distribution of high mitotic counts between grading systems can affect prognostic stratification (2% high mitotic index in Nottingham vs 10% in original SBR) 3

Clinical Application and Reporting

All ordinary invasive carcinomas (ductal, no special type) must be assigned a histologic grade; the specific grading system used should be stated in the pathology report. 1 Special histologic types (tubular, mucinous, papillary) are generally considered low grade by definition 1, 7

Integration with Treatment Decisions

• Grade is essential for determining adjuvant chemotherapy benefit, particularly in ER-positive disease 1
• When pathologists disagree on grade, consensus assessment is valuable, as patient outcomes for borderline scores (e.g., scores 5-6) fall between established grade categories 8
• Grade 1 tumors, especially when small (≤0.5 cm), have such favorable prognosis that adjuvant systemic therapy provides minimal incremental benefit 4, 9

Quality Assurance Considerations

Histologic grading must be performed accurately on properly fixed specimens by adequately trained dedicated pathologists who diligently follow protocol methodology. 5 When adequately carried out, histologic grading remains of important prognostic value despite the availability of gene expression profiles 5

Avoid the pitfall of inconsistent grading methodology across cases or institutions, as this undermines the prognostic value and can lead to inappropriate treatment decisions 3, 8