The majority of patients with pancreatic cancer are not eligible for surgery at presentation because the disease only becomes symptomatic at late stages. Therefore, predictive factors for patients presenting with unresectable, locally recurrent or metastatic disease should be considered when selecting appropriate treatment for each individual patient [6, 21–23, 25].
The prognostic value of DNA ploidy in pancreatic carcinoma has been studied in the past and results have been disappointing . The first reported evaluation of DNA nuclear pattern in pancreatic cancer was in 1987 by Weger et al who used flow cytometry to examine 77 cases of ductal carcinoma . There were no diploid tumor tumors and all patients (n = 16) with triploid neoplasms died within 18 months. In contrast, of 15 patients with near tetraploid tumors, 8 were alive at 70 months after the time of diagnosis. Since then, a number of studies have reported conflicting results in terms of prognostic value of these techniques in pancreatic cancer. Bottger et al examined DNA content in 41 cases following resection using image cytometry .
Hypotriploid (n = 1), triploid (n = 7), hypertriploid (n = 21), and tetraploid (n = 12) patterns were noted. Tetraploid tumors had a significantly improved survival versus non-tetraploid tumors (p = 0.0037). They found that DNA ploidy was the strongest independent prognostic factor for survival in these patients by multivariate analysis. Yeo et al determined DNA content by image cytometry and found that 43% of 119 tumors were diploid and 57% were aneuploid. Patients with diploid tumors had a median survival of 24 months and 5-year survival of 39%, significantly better than the median survival of 11.5 months and 5-year survival of 8% observed in patients with aneuploid tumors; p = 0.0002. In multivariate analysis DNA content was one of the strongest independent predictors of favourable outcome in pancreatic cancer . Porschen et al determined DNA content by flow cytometry and found that 29 of 56 (52%) pancreatic ductal adenocarcinomas were diploid, while 27 (48%) were aneuploid. The median survival of those with diploid tumors was 6.9 months as compared to 4.5 months for aneuploid tumors (p = 0.013), but this survival benefit was seen mostly in patients who underwent nonradical surgical intervention. In multivariate analysis, the only factors associated with survival were radicality of surgery and DNA ploidy. The authors concluded that DNA ploidy adds valuable information which is distinct from other clinico-pathological variables . Similar results have been reported by others [35–39]. In contrast, Baisch et al using flow cytometry analysis did not find DNA ploidy to be a prognostic factor for survival . They did note that aneuploidy (15%) of their cases was associate with advanced stage and tended to be more common in high grade tumors. Herrera et al examined a cohort of 72 patients who underwent radical resection at the Mayo Clinic between 1951 and 1980 . The patients with short (mortality within 12 months) and long term survival (>3 years) were examined. No difference in the DNA nuclear histograms, the fraction of cells in the S phase or DNA index was noted between these two groups. Similarly, in a recently published study, Stoecklein et al reported their results of DNA ploidy in conjunction to HER2 amplification and chromosome 17 copy number analysis in patients with pancreatic ductal adenocarcinoma after radical operation (R0 resection). Tumor ploidy levels correlated with prognosis of patients with pancreatic ductal adenocarcinoma, in contrast, to the absence of a prognostic effect on patient outcome regarding HER2 gene amplification or p185 (HER2) overexpression . Berczi et al also concluded using flow cytometry analysis that DNA ploidy status had no significant effect on survival of patients with carcinoma of the pancreatic head region . To some extend, disparate results in DNA ploidy studies have been ascribed to the differing techniques employed, and the heterogeneity in the nuclear DNA content in pancreatic tumor cells, hence image cytometry has generally been considered superior to flow cytometry as only tumor cells are used for DNA measurement . Subsequently, the clinical utility of DNA ploidy has been limited and its role in staging and treatment is still under investigation .
In the present study all factors under investigation were significantly related to survival time except gender, age, and CA-19.9, which is largely in accordance with results previously published by our group and others . We distinguished three groups of factors that influence survival. The first group of factors relates to the presence of disease. Patients with distant metastasis and/or locally extensive disease had a worse prognosis. Patients with increased ploidy score and/or increased levels of the marker CEA, which represent increased tumor burden, were also associated with a worse prognosis. The second group of factors relates to the clinical characteristics of the patient and the immune response such as poor PS at the time of diagnosis, weight loss, severity of pain, steatorrhoea, and anaemia under epoetin-A therapy. Each of these factors was related to a negative influence on survival. The third group of factors relates to therapeutic modalities: patients given only supportive care had the worst survival in comparison to those who underwent chemotherapy and better with the combination of chemotherapy and surgery.
According to the significance of the examined factor, survival was improved mainly by the combination of surgery and chemotherapy, and by a low DNA ploidy score. Secondary factors are the performance status (performance status and weight loss) and expansion of cancer (local extension and distant metastases). Considerable factors are pain, anemia, steatorrhoea, and CEA value.
The present study represents a comprehensive analysis regarding the prognostic significance of microscopically assessed DNA ploidy in the context of additional patient- and treatment-related known prognostic factors in a large cohort of advanced inoperable ductal pancreatic adenocarcinoma. Our analysis demonstrated that DNA ploidy, together with chemotherapy or surgery or surgery plus chemotherapy carry the most significant independent effect on outcome of advanced pancreatic adenocarcinoma.