How is tumor regression grade measured?

How to Measure Tumor Regression Grade

Tumor regression grade (TRG) is measured using standardized pathological scoring systems that evaluate the proportion of residual viable tumor cells versus treatment-induced fibrosis and necrosis in surgical specimens after neoadjuvant therapy, with specific systems varying by cancer type.

Pathological Assessment Methods

For Rectal and Esophageal Cancer

The most widely recommended approach uses a modified 4-tier or 5-tier grading system based on the percentage of residual cancer cells:

• Grade 0 (Complete Response): 0% residual cancer cells - complete pathological response with no viable tumor identified 1
• Grade 1 (Marked Response): 1-10% residual cancer cells with extensive fibrosis 1
• Grade 2 (Moderate Response): 11-50% residual cancer cells 1
• Grade 3 (Poor/Minimal Response): >50% residual cancer cells or gross residual carcinoma 1

The pathology report should include assessment of the entire tumor bed, requiring thorough sampling of the primary tumor site, particularly when no grossly obvious residual tumor is present 1. For complete pathological response designation, both the primary site (ypT0) and lymph nodes (ypN0) must be free of viable tumor 1.

For Gastric Cancer

The pathology report after neoadjuvant therapy must document tumor regression grade as a core element 1. A multidisciplinary judgment involving both pathologist and radiologist is recommended for optimal assessment 1.

For Soft Tissue Sarcomas

No validated TRG system currently exists for soft tissue sarcomas, unlike osteosarcoma and Ewing sarcoma 1. The pathology report should include a descriptive assessment of histological response, but no specific percentage of residual viable cells has established prognostic significance 1. This limitation stems from several factors including pre-existing non-treatment-related necrosis, hemorrhage, and heterogeneity of post-treatment changes 1. A multidisciplinary judgment involving pathologist and radiologist is recommended 1.

MRI-Based Tumor Regression Grading (mrTRG)

MRI tumor regression grading provides complementary prognostic information and can identify treatment responders, though it shows only fair agreement with pathological TRG:

• mrTRG uses T2-weighted imaging to assess fibrosis versus residual tumor, with diffusion-weighted imaging (DWI) improving interobserver agreement 1, 2
• mrTRG grades 1-3 indicate complete or near-complete response and can predict pathological complete response with 94% sensitivity in rectal cancer 3
• The agreement between mrTRG and pathological TRG is limited (κ=0.24-0.25), so mrTRG cannot serve as a surrogate for pathological assessment 4
• mrTRG may predict overall survival and disease-free survival comparably or better than pathological TRG in some studies 2

Sequential MRI comparison provides better discrimination between good and poor responders than single post-treatment imaging 1.

Critical Technical Considerations

Timing of Assessment

• Pathological TRG assessment requires the entire tumor bed to be processed histologically, especially when complete response is suspected 1
• For rectal cancer, median time from neoadjuvant treatment completion to pre-operative MRI is approximately 4 weeks, with surgery at 6-7 weeks 4

Important Limitations and Pitfalls

Grading cannot be reliably assigned after preoperative treatment in certain contexts:

• For sarcomas, tumor tissue undergoes major therapy-related changes that prevent standard malignancy grading using systems like FNCLCC 1
• MRI may both underestimate response (difficulty distinguishing residual tumor from radiation-induced fibrosis) and overestimate response (tumor fragmentation) 1
• Interobserver variability exists even among expert pathologists, requiring standardized protocols 1

Complementary Assessment Tools

• Reduction in tumor diameter and area on MRI correlates with pathological TRG, with diameter reduction being convenient and reliable 5
• Signal intensity ratio changes on MRI (absolute SI ratio reduction rate) significantly predict favorable pathological response 5
• PET/CT combined with MRI increases accuracy for predicting complete response to 94.7% compared to MRI alone at 76% 1

The pathological assessment of margins should be performed in collaboration with the surgeon to ensure accurate evaluation of treatment response 1.