Characteristics of the Cases
The characteristics of the cases are summarized in . Briefly, the mean age (±std. deviation) of the patients was 66.0±10.5 years. Mean tumor size was 3.3±1.4 cm (range, 1.5–9.5 cm). Of the 209 cases included in this study, 140 (50.2%) were men, 185 (88.5%) were Caucasians, 176 (84%) were located in the pancreatic head, 149 (71.3%) had lymph node metastasis, 93 (44.5%) were >3cm, 137 (65.6%) were T3 classification, 85 (40.7%) were poorly differentiated, 49 (23.4%) had positive margins, and 189 (90.4%) had perineural invasion. Twenty-three of the patients had received neoadjuvant therapy prior to resection. The follow-up period ranged from 0.2 to 73.2 months (mean, 16.3 months). 133 (63.6%) of the 209 patients were followed to death. The overall median survival was 16.7 months and 8.7% of patients were alive after 5 years of follow-up.
Clinicopathologic characteristics of the cases with ductal adenocarcinoma of the pancreas. The table is also stratified based on vascular invasion status.
Microscopic Vascular Invasion
Microscopic vascular invasion was observed in 136 (65.1%) of the 209 cases. The associations of microscopic vascular invasion with clinicopathologic characteristics are summarized in . Microscopic vascular invasion was more frequently observed in patients with larger tumors (≥3cm, 72%, 86/120 cases) than those with smaller tumors (<3cm, 57%, 50/87 cases; p=0.04, Chi-square and Fisher`s exact tests).
Because of the small number of pT1 and pT4 cases, we merged pT1 with pT2 cancers and classified this merged group as localized cancer (pT1+pT2). Similarly, we merged stage pT3 with pT4 cancers under the umbrella term advanced cancer (pT3+pT4). Microscopic vascular invasion was more commonly demonstrated in patients with advanced cancer (pT3+pT4, 72%, 105/145) than those with localized cancer (pT1+pT2, 50%, 32/64; p=0.003). Microscopic vascular invasion was more commonly observed in patients with lymph node metastasis (76%, 114/149 cases) than those without lymph node metastasis (38%, 23/60; p<0.0001) and was more frequent in those with perineural invasion (69%, 130/189 cases) than those without perineural invasion (35%, 7/20 cases; p=0.005). The cancers resected from patients who had received neo-adjuvant therapy were less likely to have microscopic vascular invasion (30%, 7/23 cases) than were those resected from patients who did not receive neoadjuvant therapy (70%, 130/186 cases; p<0.0001). Also, because of the small sample size of well-differentiated cancers, we merged well and moderately differentiated cancers into the group well-moderately differentiated cancer in our analyses of associations between vascular invasion and differentiation. There was no association between microscopic vascular invasion and gender and ethnicity of the patients, location of the tumor, and differentiation.
In addition to identifying microscopic intraluminal vascular invasion, we also examined the histopathologic changes in the adjacent uninvolved blood vessels. These results are summarized in . When peritumoral blood vessels showed intimal lymphocytic infiltration with more than 5 lymphocytes (80%, 56/70 cases; p=0.002), intimal fibrosis (73%, 92/127 cases; p=0.007) or medial fibrosis (78%, 68/87 cases; p=0.001), or cancer cells within the vascular wall but not within the lumen (86%, 66/77 cases; p<0.0001), these features were highly associated with presence of microscopic vascular invasion elsewhere in the case. Representative examples of each of these features are depicted in . Other histologic features, such as fibrous luminal occlusion, more than 5 of lymphocytes within blood vessel lumen or in the medial wall, were not associated with presence of microscopic vascular invasion nearby blood vessels.
Associations between vascular invasion status and histologic characteristics of blood vessels around present vascular invasion
PanIN-like Microscopic Vascular Invasion
Vascular invasion with PanIN-like features were observed in 94 of 136 cases (69.1%) with vascular invasion. Representative images of vascular invasion with PanIN-like features are depicted in . The clinicopathologic characteristics of the patients with microscopic vascular invasion with PanIN-like features are summarized in . Microscopic vascular invasion with PanIN-like features was more commonly observed in patients with pancreatic head cancer (50.0%, 88/176) than those in body or tail cancer (18.2%, 6/33, p=0.001). Microscopic vascular invasion with PanIN-like features was more commonly demonstrated in patients with advanced cancer (pT3+pT4, 51.0%, 74/145) than those with localized cancer (pT1+pT2, 31.3% 20/64; p=0.01). Microscopic vascular invasion with PanIN-like features was more commonly seen in patients with lymph node metastasis (55.7%, 83/149 cases) than it was in patients without lymph node metastasis (18.3%, 11/60; p<0.0001).
Figure 3 Representative images of PanIN-like vascular invasion. Like PanIN, the neoplastic cells form papillary structures and have nuclear and cytologic atypia. However, these PanIN-like structures are surrounded by smooth muscle layer. Therefore, these represent (more ...)
Vascular invasion with PanIN-like features and clinicopathologic characteristics in pancreatic ductal adenocarcinoma patients
Patients Survival and Vascular Invasion
Kaplan-Meyer survival analysis comparing patients with and without vascular invasion is summarized on . The median survival for patients with any form of vascular invasion (N=137) was significantly shorter (median survival, 12.9 months; 1-year survival rate, 66.0%; 3-year survival rate, 14.2%) than for patients without vascular invasion (N=72; median survival time, 17.6 months; 1-year survival rate, 67.8%; 3-year survival rate, 31.7%; log-rank test, p=0.01).
Figure 4 Kaplan-Meyer survival analysis comparing patients with and without vascular invasion. The median survival for patients with vascular invasion (N=137) was significantly shorter (median survival, 12.9 months; 1-year survival rate, 66.0%; 3-year survival (more ...)
We further compared the survival of the patients with different histologic types of vascular invasion (). The median survival for patients with PanIN-like features of vascular invasion was 15.7 months. The median survival for patients with conventional vascular invasion was 14.6 months, while that for patients without vascular invasion was 25.1 months. There was a significant survival difference among 3 groups (p=0.036, log-rank test, overall comparison). When compared in a pair-wise manner, there was a significant survival difference between patients with PanIN-like vascular invasion and those without vascular invasion (p=0.015). There was a marginal significance between patients with conventional vascular invasion and those without vascular invasion (p=0.059). There was no difference in survival between patients with PanIN-like and conventional vascular invasion (p=0.96).
Figure 5 Kaplan-Meyer survival analysis according to the histologic type of vascular invasion. The median survival for patients with PanIN-like features of vascular invasion was 15.7 months. The median survival for patients with conventional vascular invasion (more ...)
Univariate Analysis for Other Clinicopathologic Factors
By univariate survival analysis, the following clinicopathologic factors were associated with shorter patient survival (): poor tumor differentiation, advanced stage (pT3+pT4), the presence of lymph node metastasis, and the presence of microscopic vascular invasion.
Univariate analysis of clinicopathologic factors
Multivariate analyses were performed to assess which factors remained independent predictors of survival after adjusting for factors that were significant by univariate analyses. Differentiation of tumor (p=0.001, Cox regression model) and pT classification were independently prognostic in our model (). Vascular invasion (p=0.07) showed marginal significance.
Multivariate analysis for prognosis