Of 313 patients with PDAC who underwent EUS between January 2015 and November 2018 in our hospital, 60 patients underwent surgery without chemotherapy or radiotherapy and 58 in whom vascular invasion was pathologically evaluated. Of these, 14 patients with distant tumors from blood vessels were excluded and 44 patients were subjects of this study. The median age was 71 (range 44 - 84) years old and the male to female ratio was 30:14. The lesion sites were the pancreatic head in 19, pancreatic body in 12 and pancreatic tail in 13. The median tumor diameter was 20 (range 9 - 40) mm. Subtotal stomach-preserving pancreatoduodenectomy was performed in 17 subjects (of which 8 subjects were resected with portal vein, 1 subject was resected with right hepatic artery), 23 subject s were distal pancreatectomy, and 4 subject s were total pancreatectomy (Table 1). The ultrasound observation system used Arietta 850 in 10 subjects (a linear instrument /a radial instrument: 1/9), EU-ME2 Premier Plus in 2 subjects (all radial instrument), Hi Vision Ascendus in 8 subjects (all radial instrument), Sonart SU-1 in 24 subjects (a linear instrument /a radial instrument: 14/10).Of these 44 subjects, 40 and 4 had tumors that contacted one and two vessels, respectively, on dynamic CT findings. A total of 48 sites were assessed (Figure 3).
The assessed blood vessels were the portal vein (PV) in 11 sites, superior mesenteric vein (SMV) in 7, splenic vein (SPV) in 17, superior mesenteric artery (SMA) in 1, splenic artery (SPA) in 10, gastroduodenal artery (GDA) in 1, and right hepatic artery (RHA) in 1. Among them, pathological vascular infiltration was positive in 5 sites of PV, 10 sites of SMV, 7 sites of SPV, 0 sites of SMA, 2 sites of SPA, 1 site of GDA, 1 site of RHA (Table 1). In difficult diagnosis sites group, the assessed blood vessels were PV in 9 sites, SMV in 3, SPV in 9, SMA in 1, SPA in 5, GDA in 1, and RHA in 1, respectively. Dynamic CT using a pancreatic protocol was performed in all 44 subjects. Vascular invasion was assessed by EUS-B mode and EUS-EG in 44 and 27 subjects, respectively. 17 subjects did not undergo EUS-EG.
The interobserver agreements of EUS B-mode and EUS-EG findings for vascular invasion were moderate (κ=0.542) and substantial (κ=0.625). The results of discrepancies among observers were 11 sites out of 48 sites in B-mode and 6 sites out of 32 sites in EUS-EG.
The sensitivity, specificity, PPV, NPV, and accuracy (95% CI) for vascular invasion in the 44 subjects (48 sites) were 0.733 ( 0.525-0.880), 0.697 (0.602-0.763), 0.524 (0.375-0.628), 0.852 (0.736-0.933), and 0.708 (0.578-0.800) on dynamic CT ; 0.733 (0.524-0.882), 0.606 (0.511-0.673), 0.458 (0.327-0.511), 0.833 (0.702-0.926), and 0.646 (0.515-0.739) in EUS B-mode ; and 0.917 (0.723-0.983), 0.900 (0.784-0.940), 0.846 (0.667-0.908), 0.947 (0.825-0.990), and 0.906 (0.761-0.956) in EUS-EG (32 sites) (Table 2). In the radial instrument, the sensitivity, specificity, PPV, NPV, and accuracy for vascular invasion were 0.800 (0.544-0.937), 0.722 (0.585-0.798), 0.615 (0.426-0.721), 0.867 (0.703-0.958), and 0.750 (0.574-0.848) in B-mode (28 sites); 0.875 (0.632-0.965), 0.900 (0.706-0.972), 0.875 (0.632-0.965), 0.900 (0.706-0.972), and 0.889 (0.673-0.969) in EUS-EG (18 sites).In the linear instrument, the sensitivity, specificity, PPV, NPV, and accuracy for vascular invasion were 0.600 (0.260-0.873), 0.467 (0.353-0.558), 0.273 (0.118-0.397), 0.778 (0.589-0.929), and 0.500 (0.330-0.636) in B-mode (20 sites); 1.000 (0.610-1.000), 0.900 (0.744-0.900), 0.800 (0.488-0.800), 1.000 (0.826-1.000), and 0.929 (0.705-0.929) in EUS-EG (14 sites).
In the 27 subjects (29 sites) in difficult diagnosis sites group, the sensitivity, specificity, PPV, NPV, and accuracy for vascular invasion were 0.556 (0.303-0.772), 0.750 (0.636-0.847), 0.500 (0.273-0.694), 0.789 (0.670-0.892), and 0.690 (0.533-0.824) on dynamic CT; 0.667 (0.400-0.863), 0.700 (0.580-0.788), 0.500 (0.300-0.647), 0.824 (0.682-0.927), and 0.690 (0.524-0.811) in EUS B-mode; and 0.889 (0.635-0.979), 0.850 (0.736-0.890), 0.727 (0.520-0.801), 0.944 (0.818-0.989), and 0.862 (0.705-0.918) in EUS-EG, respectively. These results show that EUS-EG had the best diagnostic performance (Table 3). For PV (9 sites), SMV (3 sites), and SMA (1 site), the sensitivity, specificity, PPV, NPV, and accuracy for vascular invasion were 0.250 (0.050-0.449), 0.889 (0.800-0.977), 0.500 (0.099-0.898), 0.727 (0.654-0.800), and 0.692 (0.569-0.815) on dynamic CT; 0.500 (0.171-0.817), 0.667 (0.520-0.808), 0.400 (0.136-0.654), 0.750 (0.585-0.909), and 0.615 (0.413-0.811) in EUS B-mode; and 1.000 (0.613-1.000), 0.889 (0.717-0.889), 0.800 (0.490-0.800), 1.000 (0.806-1.000), and 0.923 (0.685-0.923) in EUS-EG, respectively. The diagnoses of all three modalities matched in 12 sites and the diagnostic accuracy was 100% (12/12) in this situation. Meanwhile, the diagnoses of either two out of three modalities (CT and EUS B-mode, CT and EUS-EG, or EUS B-mode and EUS-EG) matched in 5 sites, 7 sites, and 5 sites, and the diagnostic accuracy for each situation was 40% (2/5), 85.7% (6/7), and 80% (4/5), respectively.In difficult diagnosis site group, 9 sites had "an abnormal vessel missing a hyperechoic layer vascular surface" on EUS B-mode. Of these, pathological vascular invasion was positive in 4 sites and negative in 5 sites. EUS-EG successfully diagnosed 8 of the 9 sites (One example was false negative).
The 29 sites were divided into arterial (8 sites) and portal groups (21 sites). In the arterial group, the sensitivity, specificity, PPV, NPV, and accuracy for vascular invasion were 1.000 (0.418-1.000), 0.500 (0.306-0.500), 0.400 (0.167-0.400), 1.000 (0.612-1.000), and 0.625 (0.334-0.625) on dynamic CT; 1.000 (0.413-1.000), 0.833 (0.638-0.833), 0.667 (0.275-0.667), 1.000 (0.765-1.000), and 0.875 (0.581-0.875) in EUS B-mode; and 1.000 (0.413-1.000), 0.833 (0.638-0.833), 0.667 (0.275-0.667), 1.000 (0.765-1.000), and 0.875 (0.581-0.875) in EUS-EG, respectively. In the portal group, these results were 0.429 (0185-0.619), 0.857 (0.735-0.952), 0.600 (0.258-0.866), 0.750 (0.643-0.833), and 0.714 (0.552-0.841) on dynamic CT; 0.571 (0.290-0.806), 0.714 (0.573-0.832), 0.500 (0.253-0.705), 0.769 (0.617-0.896), and 0.667 (0.479-0.823) in EUS B-mode; and 0.857 (0.567-0.971), 0.857 (0.712-0.914), 0.750 (0.496-0.850), 0.923 (0.767-0.985), and 0.857 (0.664-0.933) in EUS-EG, respectively (Table 4).Discussion
Vascular invasion in PDAC is a factor in staging that is important for determining the therapeutic strategy and surgical procedure. Elastography has been shown to be useful for qualitative diagnosis of PDAC, but there has been no study of this technique for staging diagnosis. This is the first study that has shown the usefulness of elastography for diagnosis of vascular invasion in patients with PDAC.
Previous studies have shown the sensitivity and specificity is 0.72-0.87 and 0.89-0.93 using EUS, and is 0.58-0.63 and 0.92-0.95 using CT for diagnosis of vascular invasion in PDAC [22-24]. In addition, there is a report showing that the contrast-enhanced EUS using Sonazoid® (Daiichi-Sankyo, Tokyo, Japan) in evaluation of portal vein infiltration has sensitivity of 1.00 and specificity of 0.726-1.00 [25]. Based on these results, the diagnostic results for vascular invasion using EUS are similar or better than those with CT; however, it is sometimes difficult to interpret the EUS findings in the same way among the reviewers because EUS is more subjective compared to CT. In this study, vascular invasion was assessed based on easy-to-read colored band using EUS-EG, which showed a high diagnostic ability with sensitivity of 0.917, specificity of 0.900, and accuracy of 0.906. Regarding the interobserver agreement, EUS-EG showed higher κ-coefficients than EUS B-mode (κ=0.542 vs. κ=0.625) with sufficient agreement. These results suggest that evaluating colored band in EUS-EG is an easy and reliable method to diagnose vascular invasion in PDAC.
In the group of difficult diagnosis sites, use of colored band in EUS-EG gave good results for arterial and portal invasion, although there were only a few cases with arterial invasion. The number of subjects in the arterial system is small, it is because a case with suspected invasion of the SMA or celiac artery was assessed as borderline resectable or unresectable.
There are few reports on the difference in diagnostic performance between radial and linear EUS, but it is reported that there is no difference in the accuracy rate [23]. In this study, the results of the radial instrument in B-mode were better than those of the linear type, but the diagnostic ability was improved by adding the EG findings in both types of the EUS scope.
The vascular invasion diagnostic ability of EUS-EG in both artery and portal vein was superior to those of EUS B-mode alone; therefore, the EUS-EG vascular invasion diagnosis using colored band was considered to be objective and useful for assessment of arterial and portal vascular invasion. However, it is difficult to use EUS-EG to assess a tumor that is shown not to be in contact with vessels using CT or EUS B-mode, and lesions in which a tumor and vessel cannot be imaged on the same cross-section by EUS B-mode. Therefore, it is not meaningful to use EUS-EG vascular invasion diagnosis in such cases. The NCCN Guidelines specify that EUS should be performed for selected patients [1]. It is preferable to perform EUS-EG proactively in cases in which diagnosis of vascular invasion using CT is difficult (those with slight contact of the tumor with vessels), such as those defined as difficult diagnosis site in this study. In particular, if the diagnoses of the three modalities coincide, it is highly possible to predict the presence or absence of vascular infiltration.
This study has several limitations. First, it was a retrospective study at a single center. The elastography technique used was not standardized for all patients, and some EUS-EG images mainly performed for tumor characterization were retrospectively reviewed for the evaluation of vascular invasion. Further prospective studies with standardized elastography techniques may be required. Second, endoscopists and devices differed among patients. In our study, we have used 6 different combinations of ultrasound systems and EUS probes, and the use of different machines may have impacted the results. However, it is difficult to evaluate the diagnostic performances for each ultrasound system or probe because of the small number. There have been several reports using different machines in the same study to evaluate the usefulness of EUS-EG [26,27]. Considering these previous reports and the fact that multiple EUS modalities can be used in the real-world practice, we think it is reasonable to include multiple machines in the present study. Within these limitations, our results may show that EUS-EG is useful for diagnosis of vascular invasion. Further studies and an accumulation of cases are needed to validate EUS-EG for diagnosis of vascular invasion in PDAC.