Abstract
Neoadjuvant therapy is increasingly used to control local tumor spread and micrometastasis of pancreatic ductal adenocarcinoma (PDAC). Pathology assessments of treatment effects might predict patient outcomes after surgery. However, there are conflicting reports regarding the reproducibility and prognostic performance of commonly used tumor regression grading systems, namely College of American Pathologists (CAP) and Evans’ grading system. Further, the M.D. Anderson Cancer Center group (MDA) and the Japan Pancreas Society (JPS) have introduced other grading systems, while we recently proposed a new, simple grading system based on the area of residual tumor (ART). Herein, we aimed to assess and compare the reproducibility and prognostic performance of the modified ART grading system with those of the four grading systems using a multicenter cohort. The study cohort consisted of 97 patients with PDAC who had undergone post-neoadjuvant pancreatectomy at four hospitals. All patients were treated with gemcitabine and S-1 (GS)-based chemotherapies with/without radiation. Two pathologists individually evaluated tumor regression in accordance with the CAP, Evans’, JPS, MDA and ART grading systems, and interobserver concordance was compared between the five systems. The ART grading system was a 5-tiered system based on a number of 40× microscopic fields equivalent to the surface area of the largest ART. Furthermore, the final grades, which were either the concordant grades of the two observers or the majority grades, including those given by the third observer, were correlated with patient outcomes in each system. The interobserver concordance (kappa value) for Evans’, CAP, MDA, JPS and ART grading systems were 0.34, 0.50, 0.65, 0.33, and 0.60, respectively. Univariate analysis showed that higher ART grades were significantly associated with shorter overall survival (p = 0.001) and recurrence-free survival (p = 0.005), while the other grading systems did not show significant association with patient outcomes. The present study revealed that the ART grading system that was designed to be simple and more objective has achieved high concordance and showed a prognostic value; thus it may be most practical for assessing tumor regression in post-neoadjuvant resections for PDAC.
Highlights
Neoadjuvant therapy is increasingly used to control local tumor spread and micrometastasis of pancreatic ductal adenocarcinoma (PDAC)
As for the assessment of fibrosis, we evaluated a ratio of the residual tumor cells over the fibrous stroma for the College of American Pathologists (CAP) and Japan Pancreas Society (JPS) grading systems, as it was difficult to differentiate fibrosis secondary to NAC from pre-existing or cancer-related chronic pancreatitis
When a few tumor cells were scattered in the fibrous stroma, it was considered a moderate response based on the fraction of the residual tumor (Fig. 1D)
Summary
Neoadjuvant therapy is increasingly used to control local tumor spread and micrometastasis of pancreatic ductal adenocarcinoma (PDAC). Two pathologists individually evaluated tumor regression in accordance with the CAP, Evans’, JPS, MDA and ART grading systems, and interobserver concordance was compared between the five systems. Anderson Cancer Center (MDA)[12,16,17] and the Japan Pancreas Society (JPS) (Table 1)[18] Both the Evans’ and JPS grading systems are specific for PDAC and are commonly used in Japan[19,20]. Differentiating treatment-related fibrosis from cancer-associated fibrosis may be complex and subjective given that even treatment-naïve PDAC often exhibits prominent fibrosis—desmoplastic reaction and/or associated chronic p ancreatitis[23,24] Such difficulties in the interpretation may cause interobserver disagreement in the assessment of tumor regression
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