Are All HR+ Breast Tumors Low Grade and All TNBC High Grade?
No, this is a dangerous oversimplification that can lead to clinical errors—while there are strong associations between receptor status and grade, significant exceptions exist that must be recognized.
The Reality of HR+ Breast Cancer Grading
Luminal A tumors are typically low grade, but Luminal B tumors are frequently high grade despite being hormone receptor-positive. 1, 2
- Luminal A breast cancers are characterized by strong ER/PgR expression, low Ki67 (<20%), and typically low histologic grade (grade I or II) 1, 2
- However, Luminal B breast cancers, which are also ER-positive, demonstrate higher grade (26% are grade III) and higher proliferative fraction 1, 3
- Luminal B tumors may have variable degrees of ER/PgR expression and are characterized by either high Ki67 (>20%) or low PgR, distinguishing them from Luminal A 1, 3
Clinical Pitfall to Avoid
Do not assume all ER-positive tumors behave the same way. The distinction between Luminal A and Luminal B is critical because Luminal B requires chemotherapy despite hormone receptor positivity, whereas endocrine therapy alone suffices for most Luminal A cases. 3
The Reality of Triple-Negative Breast Cancer Grading
While most TNBCs are high-grade tumors, well-characterized low-grade TNBCs exist with indolent clinical behavior. 4
- The majority of TNBCs are indeed high-grade tumors with aggressive features 1, 5, 6
- However, secretory carcinomas and adenoid cystic carcinomas are histologic types of TNBC that are low-grade with indolent clinical behavior 4
- These low-grade TNBCs have distinct molecular features, are underpinned by specific fusion genes, and their natural history and optimal therapy vastly differ from high-grade TNBCs 4
- Other special histological types classified as triple-negative include carcinoma with rich lymphocytic stroma (former medullary), low-grade metaplastic carcinoma, and tumors arising from microglandular adenosis 1, 4
The Heterogeneity Problem
TNBC is merely a descriptive term encompassing vastly heterogeneous disease with marked genetic, transcriptional, histological, and clinical differences. 4 There is approximately 80% overlap between 'triple-negative' and intrinsic 'basal' subtype, but the remaining 20% includes these special low-grade histological types. 1
Key Clinical Implications
- Always assess Ki67 and PgR levels in HR+ tumors—do not rely solely on ER status, as this is critical for distinguishing Luminal A from Luminal B and determining whether chemotherapy is needed 3
- Recognize special histologic types of TNBC that may have favorable prognosis despite triple-negative status 1, 4
- Quality control is essential: standardized assays and meticulous quality control are prerequisites for accurate surrogate assessment of breast cancer subtypes 2, 3
- Ki67 interpretation must be standardized in light of local laboratory values, with suggested cut-offs around 20% (values ≥30% clearly high, ≤10% clearly low) 1, 2, 3