Scientific paper
Analysis of Ki-67 antigen expression, DNA proliferative fraction, and survival in resected cancer of the pancreas

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Abstract

Background

Prognostic markers for pancreas cancer, such as CEA, CA19-9, ploidy analysis, and S-phase determination using flow cytometry, have not been consistently predictive. We chose to evaluate nuclear proliferation, as measured by the MIB-1 monoclonal antibody and digital image analysis, as a prognostic marker in pancreatic carcinoma, and compare the findings with DNA ploidy and S-phase analysis. MIB-1 identifies the Ki67 antigen present in nuclei of cells in all phases of the cell cycle except G0.

Methods

We retrospectively reviewed 33 patients with pancreatic adenocarcinoma resected for cure between 1989 and 1994 with available fixed tissue. Sectioned tissue was stained with MIB-1, and the number of positively stained nuclei determined and expressed as a MIB-1 labeling index (LI) by quantitative image analysis. Disaggregated nuclei were analyzed by flow cytometry using standard techniques.

Results

MIB-1 LI for pancreas cancers was heterogeneous within and between cancers. The MIB-1 LI for the cancers was 28 ± 15 (median 29). There was no correlation between survival and MIB-1 expression (R2 = 0.03). Likewise, there was no correlation between MIB-1 LI and percentage of cells in S-phase, G2/M, or total proliferating cells (S+G2/M; R2 = 0.01), nor was there a difference between MIB-1 LI and ploidy (P = 0.88).

Conclusions

We conclude that in our patient population, nuclear proliferation in pancreatic cancer, as determined by expression of Ki67 nuclear antigen, does not appear to correlate with survival and is not a useful prognostic marker. Despite intuitive thoughts to the contrary, there is no correlation between cell cycle analysis as determined by flow cytometry and Ki67 expression in pancreas cancer. Current methods of assessing prognosis after curative resection of cancer of the pancreas, including lymph node and margin status, tumor size, and possibly DNA ploidy as determined by flow cytometry, are not augmented by the assessment of nuclear proliferation by image analysis using the MIB-1 monoclonal antibody.

Section snippets

Patient population

Between 1989 and 1994, 43 patients underwent pancreaticoduodenectomy or total pancreatectomy with curative intent for presumed adenocarcinoma of the head of the pancreas at the Indiana University Medical Center. Four patients were ultimately excluded from the analysis after review revealed a nonpancreatic malignancy (3 patients) or proven hepatic metastases at the time of surgery (1 patient). Thus, 39 patients were available for analysis (20 female and 19 male). Archival specimens were

Patient demographics

Table 1summarizes the demographics of patients who had curative resections for cancer of the head of the pancreas. Our previous multivariate analysis revealed only the presence of lymphatic invasion as a statistically significant predictor of poor survival with estimated 5-year survival rates for patients without lymphatic invasion being 23% and with lymphatic invasion being 0% (P = 0.015 by Cox survival analysis) [23]. In the current study, actual overall 2-year survival was 27%, 5-year

Comments

Pancreas cancer has a dismal prognosis with overall 5-year survival rates of well under 5%. Only a small minority of patients benefit from aggressive surgery, attaining at best 20% to 25% predicted 5-year survival. Certain properties of pancreatic tumors themselves, such as tumor size, site, clinical stage, presence of nodal metastases and histologic lymphovascular invasion have been demonstrated to correlate with survival. On the other hand, investigations of operative factors and their

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