This study is the first to evaluate the efficacy of PJC using LBC with a large number of surgically resected IPMN cases. In our study, LBC increased the accuracy of PJC for a malignant IPMN diagnosis (smear method: 56% vs. LBC: 76%; P = 0.044) and proved to be a significant factor influencing an accurate diagnosis of PJC in the multivariate analysis (odds ratio [OR]: 3.52; P = 0.021). Second, LBC increased the accuracy of PJC particularly for diagnosing malignant IPMN in WF patients (smear method: 66% vs. LBC: 93%; P = 0.043).
The smear method has been used generally due to its convenience and low cost. However, issues associated with this method include the fact that the amount of cells placed on the slide glass varies depending on the skill of the operator, and dry denaturation causes poor cell preservation. Previous studies have reported that these issues accounted for two-thirds of cytological false negatives.26-28
With LBC, all collected cells are placed in the fixative, and the cells required to make a diagnosis are mainly collected using separation reagents. The cell suspension is smeared uniformly onto two spots of a glass slide, with few overlapping cells, so the cell findings at the margin of the cluster can be analyzed. In addition, the background of inflammatory cells and mucus is removed, so the tumor cells scattered solitarily can be evaluated. Furthermore, because the scope of the speculum is narrowed, the speculum time is reduced. For these reasons, almost all cells can be efficiently analyzed. The LBC method is thus superior to the smear method with regard to assessing both the cellularity and cytomorphology. For the diagnosis of malignant IPMN, PJC has low sensitivity due to inadequate cellularity in most cases.29 Using LBC, an increased sensitivity (21% to 40%) and negative predictive value (NPV) (51% to 72%) contributed to the increased accuracy of PJC.
Both the BD SurePath (Nippon Becton Dickinson Company, Tokyo, Japan) and ThinPrep (Hologic Japan, Tokyo, Japan) are commonly used LBC technologies in cervical cytology. These technologies differ by their methods of producing thin‐layer slides. The BD SurePath uses no filters and employs a proprietary cell enrichment process that separates and reduces mucus, blood and inflammatory cells. The unnecessary debris is then trapped in a gradient density material that is removed. In contrast, the ThinPrep uses a membrane that controls the collection and transfer of diagnostic cells. Kenyon et al. reported that the addition of mucus did not reduce the cellularity with the BD SurePath; however, the cellularity was significantly reduced with ThinPrep.30 They showed that direct obstruction of the filtration membrane of the ThinPrep due to excess mucus caused a reduction in the number of diagnostic cells. We therefore considered that the BD SurePath might be suitable for the diagnosis of malignant IPMN with rich mucus.
In patients with HRS, LBC showed a tendency toward an improved accuracy, although not to a significant degree (smear method: 43% vs. LBC: 65%; P = 0.139). The median diameter of the MPD was larger in HRS patients than in WF patients (10.0 mm vs. 5.0 mm; P < 0.001). Because MPD dilatation without obstruction in IPMN has been generally considered to be the result of mucus hypersecretion,31 HRS patients are expected to have more mucus than WF patients. Even using LBC with the BD SurePath, the improving effect of LBC was inadequate in cases rich in mucus, such as in HRS patients. However, in the clinical setting, it is important to detect malignant IPMNs in WF patients.
Enhancing MN > 5 mm negatively contributed to the accuracy of PJC (OR 0.23; P = 0.013). Of the 31 and 59 patients with and without enhancing MN > 5 mm, an accurate diagnosis was obtained in 17 (55%) and 41 (69%), respectively. The pathological diagnoses were as follows: L-IGD, 12; HGD, 5; and IC, 14 in patients with MN >5 mm, and L-IGD, 35; HGD, 10; and IC, 14 in patients without MN >5 mm. The proportion of malignant IPMN (HGD or IC) was larger in patients with enhancing MN > 5 mm than in those without enhancing MN > 5 mm (61% vs. 41%; P = 0.063). There was a bias between populations, and the sensitivity of PJC was low (28%) while the NPV was relatively high (60%). The accuracy was thus decreased in the patients with enhancing MN > 5 mm. However, enhancing MN > 5 mm itself is associated with malignant IPMN, so surgery should be recommended for patients with HRS, regardless of the results of PJC.
An elevated serum level of CA19-9 contributed to the accuracy of PJC (OR 0.24; P = 0.019). Of the 22 patients with an elevated level of CA19-9, an accurate diagnosis was obtained in 8 (36%). In contrast, of the 68 patients with normal levels of CA19-9, an accurate diagnosis was obtained in 50 (74%). Among the patients with elevated levels of CA19-9, 18 had malignant IPMN (HGD: 3 [14%], IC: 15 [68%]). In contrast, among the patients with normal levels of CA19-9, 25 had malignant IPMN (HGD: 12 [18%], IC: 13 [19%]). The proportion of IC was significantly larger in the patients with elevated levels of CA19-9 than in those with normal levels of CA19-9 (P < 0.0001). The sensitivity of PJC was low, but the NPV was high. Because of the bias between populations, the accuracy was decreased in the group with elevated levels of CA19-9. However, in the 22 patients with elevated levels of CA19-9, LBC improved the accuracy, although not to a significant degree (29% to 50%; P = 0.315). CA19-9 itself was also a useful marker for detecting IC derived from IPMN.
Yamakawa et al. reported that the sensitivity and accuracy of PJC for a malignant IPMN diagnosis were increased by a SPACE in IPMN patients.15 Our study similarly showed that the sensitivity and accuracy of PJC were increased by a SPACE, although not to a significant degree (sensitivity: 26% to 50%; P=0.301, accuracy: 62% to 83%; P=0.142). Only 12 patients (13%) underwent a SPACE. Statistically significant differences might have been obtained if more patients had undergone a SPACE. Furthermore, of the 12 patients who underwent a SPACE, 11 were diagnosed by LBC, so it is necessary to consider the possibility of confounding by LBC.
Even using LBC methods, the sensitivity of PJC for malignant IPMN was not sufficient (40%), a PEP occurred in 12.5% of cases. Although the severity of PEP was only mild or moderate and there were no patients who needed to cancel or delay their surgery, we should consider the indication of PJC for surgical candidates. In this study, among 46 patients with HRS, 30 (65%) had malignant IPMN. Thus, the findings of HRS are an adequate indication for surgery, and PJC for patient with HRS may be unnecessary. Among patients with WF, all of patients with lymphadenopathy and a majority with increasing serum levels of CA19-9 were malignant IPMN (100%, 82%). In contrast, 37% (15/41) of patients with a cyst size ≥3 cm had malignant lesions, and the cyst size was associated with the accuracy of PJC (OR: 4.41, P = 0.009). Given these results, patients with a cyst size of ≥3 cm without the above 2 WF factors are considered well-indicated for PJC with LBC.
This study has several limitations. First, this was a retrospective study. Not all procedures were performed by the same endoscopists, and not all cytology specimens were evaluated by the same pathologists. Second, this study had a selection bias, as the indications of PJC depended in part on the discretion of the attending physician. Third, the efficacy of SPACE was not evaluated sufficiently because of the lack of patients who underwent a SPACE. Fourth, there were relatively few patients with LBC among the WF patients.