Grading of Sarcoma: Prognostic and Treatment Implications
Histologic grading is the single most important prognostic factor in soft tissue sarcomas and serves as the primary determinant for metastatic risk assessment and adjuvant treatment decisions. 1, 2, 3
Why Grading Matters
Grading must be provided in all feasible cases because it has both prognostic and predictive meaning that directly influences treatment intensity. 1 The grade determines:
- Risk of distant metastasis - the primary outcome that grading predicts 4, 3
- Overall survival - higher grades correlate with worse mortality 5, 6
- Selection for adjuvant chemotherapy - high-grade tumors are candidates for systemic therapy 7
- Radiation therapy decisions - high-grade, deep tumors >5 cm typically require postoperative radiation 2
The FNCLCC Grading System
The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system is the standard grading method and distinguishes three malignancy grades based on three parameters. 1, 8
Scoring Parameters:
Tumor Differentiation:
- Score 1: Well-differentiated (closely resembles normal tissue)
- Score 2: Moderately differentiated
- Score 3: Poorly differentiated (markedly abnormal appearance) 1, 8
Necrosis (macro and microscopic):
- Score 0: Absent
- Score 1: <50%
- Score 2: ≥50% 1
Mitotic Count (per 10 high-power fields):
- Score 1: <10 mitoses
- Score 2: 10-19 mitoses
- Score 3: ≥20 mitoses 1
Final Grade Assignment:
- Grade 1 (low grade): Total score 2-3 points
- Grade 2 (intermediate grade): Total score 4-5 points
- Grade 3 (high grade): Total score 6-8 points 1, 8
The FNCLCC system demonstrates superior prognostic performance compared to other systems, with higher predictive weight for metastasis development and tumor mortality. 5
Integration with Staging Systems
The UICC/AJCC staging system emphasizes histologic grade as the primary determinant, combined with tumor size, depth, and presence of metastases. 1, 2 The staging hierarchy places grade above size and depth in prognostic importance. 2, 6
Beyond traditional staging, nomograms incorporating grade along with clinical and demographic factors provide more personalized risk assessment for treatment decisions. 1, 2
Critical Limitations and Pitfalls
When Grading Cannot Be Applied:
Grading should NOT be used for certain sarcoma subtypes where it provides no incremental prognostic information: 4, 3
- Well-differentiated liposarcoma/atypical lipomatous neoplasm (always low-grade by definition)
- Ewing's sarcoma (uniformly high-grade)
- Traditionally "ungradable" tumors: epithelioid sarcoma, clear cell sarcoma, angiosarcoma
- Dedifferentiated liposarcoma (grade does not correlate with outcome)
- Malignant peripheral nerve sheath tumors (recent evidence shows poor grade-outcome correlation) 4
Post-Treatment Limitations:
Grading CANNOT be assigned after preoperative medical treatment because therapy-related changes (necrosis, hemorrhage, cellular alterations) obscure the original tumor characteristics and make assessment unreliable. 1, 8 This represents a major limitation when neoadjuvant therapy is planned.
Biopsy Underestimation:
Core needle biopsies may underestimate the true malignancy grade due to sampling error and tumor heterogeneity. 1 When preoperative treatment is considered, radiological imaging (including PET) should complement pathology to estimate grade features like necrosis. 1
Current three-tier grading systems are not optimally suited for core needle biopsies and may require simplified two-tier assessment (low versus high grade) with close clinical dialogue. 4
Practical Implementation Algorithm
1. Obtain adequate tissue: Multiple core needle biopsies (not fine-needle aspiration) under imaging guidance 2
2. Ensure expert pathology review: Pathological expert validation is required when original diagnosis was made outside a reference center 1
3. Apply FNCLCC grading: Score all three parameters (differentiation, necrosis, mitoses) and calculate total 1
4. Report mitotic rate independently: Whenever possible, provide the actual mitotic count separately 1
5. Integrate with other prognostic factors: Combine grade with tumor size, depth, and site for comprehensive risk assessment 1, 2
6. Use nomograms for treatment decisions: Particularly for adjuvant/neoadjuvant therapy selection 1, 2
Quality Assurance
The mitotic rate should be recorded with improved reliability, and external quality assurance programs are strongly encouraged for laboratories performing grading assessments. 1 The pathological assessment should be made in collaboration with the surgeon and discussed at specialized sarcoma multidisciplinary team meetings. 1, 2