Tumour necrosis is a postoperative prognostic marker for pancreatic cancer patients with a high interobserver reproducibility in histological evaluation

Abstract

Background: Tumour necrosis reflects the presence of hypoxia, which can be indicative of an aggressive tumour phenotype. The aim of this study was to investigate whether histological necrosis is a useful predictor of outcome in patients with pancreatic ductal carcinoma (PDC).

Methods: We reviewed histopathological findings in 348 cases of PDC in comparison with clinicopathological information. We counted small necrotic foci (micronecrosis) as necrosis, in addition to massive necrosis that had been only defined as necrosis in previous studies. The reproducibility of identifying histological parameters was tested by asking five independent observers to blindly review 51 examples of PDC.

Results: Both micronecrosis and massive necrosis corresponded to hypoxic foci expressing carbonic anhydrase IX detected by immunohistochemistry. Multivariate survival analysis showed that histological necrosis was an independent predictor of poor outcome in terms of both disease-free survival (DFS) and disease-specific survival (DSS) of PDC patients. In addition, metastatic status, and lymphatic, venous, and intrapancreatic neural invasion were independent prognostic factors for shorter DFS and metastatic status, margin status, lymphatic invasion, and intrapancreatic neural invasion were independent prognostic factors for DSS. The interobserver reproducibility of necrosis identification among the five independent observers was 'almost perfect' (κ-value of 0.87).

Conclusion: Histological necrosis is a simple, accurate, and reproducible predictor of postoperative outcome in PDC patients.

Figure 1

Representative histology of massive necrosis (upper columns) and micronecrosis (lower columns). Arrows indicate necrotic area. Left, centre, and right columns are in low ( × 6.25), middle ( × 20), and high magnification ( × 100), respectively. High power view of histology in right columns corresponds to the rectangle (solid line) in left or middle column. Middle power view of histology in centre columns corresponds to the rectangle (dotted line) in left columns.

Figure 2

Hypoxia is reflected by the presence of massive necrosis or micronecrosis. Expression of CAIX is immunohistochemically detectable in both cancer cells and stromal cells within or around areas of massive necrosis (upper columns) and micronecrosis (lower columns). Carbonic anhydrase IX is expressed in plasma membrane. Arrows indicate necrotic area. Low power view (left columns) and high power view (right columns).

Figure 3

Kaplan–Meier survival curves showing the comparison of disease-free survival between high and low expression of CAIX (P-values obtained from log-rank test) (left columns). Kaplan–Meier survival curves showing the comparison of disease-specific survival between high and low expression of CAIX (P-values obtained from log-rank test) (right columns).

Figure 4

Kaplan–Meier survival curves showing a comparison of disease-free survival between cases in which histological necrosis was present and absent (P-values obtained by log-rank test) (left columns). Kaplan–Meier survival curves showing a comparison of disease-specific survival between cases, in which histological necrosis was present and absent (P-values obtained by log-rank test) (right columns).