Grading System for Renal Cell Carcinoma
The WHO/ISUP nucleolar grading system is the standard for grading clear cell RCC and papillary RCC, based on nucleolar prominence at different magnifications, with grades 1-3 determined by nucleolar size and grade 4 defined by extreme pleomorphism, sarcomatoid, or rhabdoid features 1, 2.
Core Grading Principles
The 2012 ISUP consensus conference established a nucleolar-based grading system that correlates well with prognosis and demonstrates good interobserver reproducibility 3. This system has been formally adopted by WHO and is designated as the WHO/ISUP grading classification 1, 4.
Grade Definitions
The grading system operates as follows:
- Grade 1: Nucleoli are inconspicuous and basophilic at ×400 magnification
- Grade 2: Nucleoli are clearly visible and eosinophilic at ×400 magnification
- Grade 3: Nucleoli are clearly visible at ×100 magnification
- Grade 4: Extreme nuclear pleomorphism, tumor giant cells, sarcomatoid differentiation, or rhabdoid morphology 3, 1
Histologic Subtype-Specific Applications
Clear Cell RCC and Papillary RCC
Apply the WHO/ISUP nucleolar grading system to both clear cell and papillary RCC 1. Multiple validation studies confirm this system provides superior prognostic information compared to the older Fuhrman grading system 5. The WHO/ISUP system results in general down-grading compared to Fuhrman, with better discrimination between grades for cancer-free survival 5.
Chromophobe RCC
Do not apply WHO/ISUP grading to chromophobe RCC 3, 1. Instead, only report the presence of sarcomatoid features or anaplastic components 3. Validation studies failed to demonstrate correlation between grade and outcome for chromophobe RCC 6.
Novel RCC Variants
For novel variants with marked nucleolar atypia, the nucleolar grading system is only recommended for assessment of anaplastic areas 3.
Enhanced Grading Approaches
Incorporation of Necrosis
For clear cell RCC specifically, incorporating microscopic tumor necrosis into grading provides superior survival information 7. A proposed four-tier system combines ISUP grade with necrosis status:
- Grade 1: ISUP grade 1 + ISUP grade 2 without necrosis
- Grade 2: ISUP grade 2 with necrosis + ISUP grade 3 without necrosis
- Grade 3: ISUP grade 3 with necrosis + ISUP grade 4 without necrosis
- Grade 4: ISUP grade 4 with necrosis or sarcomatoid/rhabdoid tumors
This system demonstrates superior concordance index compared to ISUP grading alone for clear cell RCC 7.
Clinical Context and Prognostic Integration
Risk Stratification
The KEYNOTE-564 TNM-based classification is now the preferred risk classification for operable disease 2:
- Intermediate-high risk: pT2, grade 4 or sarcomatoid, N0, M0; or pT3, any grade, N0, M0
- High-risk: pT4, any grade, N0, M0; or any pT, any grade, node-positive, M0
This classification has direct therapeutic implications for adjuvant pembrolizumab eligibility 2.
Essential Pathology Reporting Elements
Pathology reports must include 1:
- Tumor histological subtype
- ISUP nucleolar grade (for clear cell and papillary RCC only)
- Presence of sarcomatoid and/or rhabdoid differentiation (defines grade 4)
- Presence of necrosis
- Microscopic vascular invasion
- pTNM staging
- Description of non-neoplastic renal tissue
Common Pitfalls
Avoid applying Fuhrman grading - it cannot be reliably applied in >20% of cases and provides inferior prognostic information compared to WHO/ISUP grading 5.
Do not grade chromophobe RCC using WHO/ISUP criteria - this provides misleading prognostic information as validation studies show no correlation with outcome 6.
Recognize grade heterogeneity - assign the highest grade present in the tumor, as this drives prognosis 8.
Document sarcomatoid percentage - the extent of sarcomatoid differentiation has prognostic significance and should be quantified when present 2.