Predictive Value of Localized Stenosis of the Main Pancreatic Duct for Early Detection of Pancreatic Cancer

Patients

We intentionally performed endoscopic retrograde pancreatography (ERP) in 689 patients from January 2008 to September 2018. From this population, we extracted data of patients who underwent ERP for examination of localized MPD stenosis that was detected during other examinations (Fig. 1, Table 1). To evaluate only slight changes in MPD that potentially indicated a tiny neoplasm, including an intraepithelial cancer, we excluded patients with a detectable mass (detected using imaging techniques other than ERP). Patients with abnormal MPD-related findings due to definite chronic pancreatitis, intraductal papillary mucinous neoplasms, and autoimmune pancreatitis were also excluded. In addition, patients with multiple stenoses were excluded because these findings indicate chronic inflammatory changes rather than neoplasms.

Fig. 1.

Study flow chart. AIP, autoimmune pancreatitis; CT, computed tomography; ERP, endoscopic retrograde pancreatography; EUS, endoscopic ultrasonography; FiCE, findings for indicating suspicious pancreatic cancer at an early stage; IPMN, intraductal papillary mucinous neoplasms; MPD, main pancreatic duct; MRI, magnetic resonance imaging.

Table 1.

Criteria for Defining Main Pancreatic Duct Findings for Indicating Suspicious Pancreatic Cancer at an Early Stage in This Study

The final diagnosis of the etiology of MPD stenosis was defined as being (1) malignant or benign on the basis of histological diagnosis in cases involving surgical resection, (2) malignant when an obviously malignant tumor appeared at the site during follow-up without resection, and (3) benign when the abnormality had improved or had not changed after the 5-year follow-up. When improvement or lack of change was difficult to determine, the patient was excluded. Patients who did not undergo endoscopic ultrasound (EUS), dynamic computed tomography (CT), magnetic resonance cholangiopancreatography, or ERP after the 5-year follow-up were not diagnosed with benign stenosis and were excluded from the study, even if clinical course, laboratory data, and transabdominal ultrasound (US) findings did not indicate an obvious malignancy in the pancreas.

We finally included 19 patients (mean age, 69.9±13.2 years; male, 10) who had a single, localized MPD stenosis without a detectable mass (detected using other imaging methods) in this study.

Outcome measurements

The main outcome was the predictive reliability of MPD findings for indicating suspicious pancreatic cancer at an early stage (FiCE). The criteria for a FiCE were (1) a single, localized stenosis of MPD without a mass on US, EUS, CT, or magnetic resonance imaging (MRI), and (2) the absence of clinical evidence for other MPD etiologies, such as intraductal papillary mucinous neoplasms, autoimmune pancreatitis, definite chronic pancreatitis, pancreatic stones, previous surgical intervention, and past physical injury (Table 1). Localized stenosis was defined as an obvious decrease in MPD diameter, compared with the diameters of both the ampullary and tail sides of the MPD. The predictive value was estimated using the percentage of patients with pancreatic neoplasms at the stenotic site among those with FiCE.

Secondary outcome measures were detailed findings related to the MPD, prevalence of tumor invasion on histological evaluation, stage of the malignancy, and diagnostic outcomes of cytology using pancreatic juice samples obtained during ERP examination.

The degree of MPD stenosis was estimated using ERP in which the contrast agent was injected from the ampullary side of the stenosis; the degree of MPD stenosis was classified into three groups: (1) complete obstruction (contrast agent could not be injected beyond the stenosis); (2) a severe thread-like stricture (contrast agent could advance beyond the stenosis); and (3) mild stenosis with a gentle change in MPD diameter. MPD diameter at the tail side of the stenosis was classified as follows: (1) “highly dilated”, diameter >2 times the MPD diameter at the ampullary side; (2) “moderately dilated”, diameter <2 times the MPD diameter at the ampullary side; and (3) “no dilation”, diameter less than that of the MPD on the ampullary side.

Pancreatic juice was obtained using a cannula for a 0.035-inch guidewire with a side hole (PR-104Q; Olympus Co., Tokyo, Japan) or a double lumen catheter for 0.035-inch and 0.025-inch guidewires (Uneven cannula; Piolax Medical Devices, Inc., Yokohama, Japan). Before aspiration of pancreatic juice, the stenotic site was rubbed with a guidewire to scratch off the epithelial cells. Lavage was performed with 40–60 mL saline while using a double lumen catheter. The obtained samples were prepared using the cell-block method and were evaluated with hematoxylin-eosin and periodic acid-Schiff/alcian blue staining; if necessary, additional immunohistochemistry, such as staining for p53, Ki67, and MUC1, was also performed. Histological diagnosis was confirmed by an expert pathologist specializing in pancreatobiliary pathology (YN) and by another experienced pathologist who worked as a consultant at our center at that time.

Cytological diagnosis was classified as positive and negative. Cells judged as being definitely cancerous, those strongly suspected of being cancerous, and those that were difficult to judge but were consistent with cancer, i.e., results corresponding to Papanicolaou Class V, IV, and IIIb, were defined as being cytologically positive, whereas the others were defined as being cytologically negative.

The presence of a pancreatic mass was evaluated using EUS, enhanced dynamic CT, and MRI if the patient did not have a contraindication to the examination. EUS was performed using radial-arrayed (GF-UM2000, GF-UE260; Olympus) or convex-arrayed (GF-UCT260; Olympus) echoendoscopes by an expert endosonographer who had performed more than 1,000 examinations or by a trainee under an expert’s supervision.

Ethics

Written informed consent was obtained for surgery and examinations, such as enhanced CT, EUS, and ERP. This retrospective study was approved by the Institutional Review Board of Sendai City Medical Center.

Diagnostic yield of FiCE

Among the 19 enrolled patients with FiCE, 11 underwent surgical resection (#1–#11 in Table 2) and the other 8 were followed up without surgery (#12–#19).

Table 2.

Characteristics of the Patients Included in This Study

The final diagnosis of MPD stenosis was pancreatic cancer in 9 of the 11 patients who underwent surgery (Fig. 2) and a non-neoplastic change in the remaining 2 patients (Fig. 3A, B). Among the 9 patients who underwent surgery for malignant stenosis, 3 (#1, #4, and #5) did not undergo resection immediately after ERP (Fig. 3C–I). Patient #1 underwent resection for pancreatic cancer after a 14-month interval because she had previously undergone resection for simultaneously detected lung cancer. Patients #4 and #5 did not undergo immediate resection owing to negative cytology results; however, they underwent surgery 42 and 5 months later, respectively, because a mass detected at the stenosis site was diagnosed as malignant via EUS-guided fine needle aspiration cytology.

Fig. 2.

Endoscopic retrograde pancreatography in patients diagnosed with malignant main pancreatic duct (MPD) stenosis with (findings for indicating suspicious pancreatic cancer at an early stage) without masses that are detectable via other imaging examinations. (A-I) show cases #1–#9 (Table 2) in a sequential order. (B, E, F) (Cases #2, #5, and #6, respectively) were obtained after a catheter was advanced into the tail side of the MPD along a guidewire, although contrast was not injected into the tail side as the catheter could not be advanced beyond the stenosis. Arrowheads indicate stenosis of the MPD.

Fig. 3.

Endoscopic retrograde pancreatography and magnetic resonance cholangiopancreatography (MRCP) in patients diagnosed with benign main pancreatic duct (MPD) stenosis with (findings for indicating suspicious pancreatic cancer at an early stage) without masses that are detectable via other imaging examinations. (A-I) show Cases #10–#18 (Table 2) in a sequential order. Because neither contrast nor a catheter could be advanced to the tail side of the MPD in Case #12, MRCP is additionally shown to show tail-side pancreatography (C). (B, D, J) (Cases #11, #13, and #17, respectively) were obtained after a catheter was advanced into the tail side of the MPD along a guidewire, although contrast was not injected into the tail side before the catheter was advanced beyond the stenosis.

In the remaining 8 patients, MPD stenosis was judged as being non-neoplastic after clinical follow-up of >5 years (median follow-up period, 74 months; range, 62–102 months). No patients were found to have malignancies at the MPD stenosis site after clinical follow-up without resection.

Overall, MPD FiCE was finally diagnosed as a pancreatic cancer-related change in 9 patients (47%) and a non-neoplastic change in 10 patients. In other words, the predictive value of FiCE for prevalence of pancreatic cancer was 47%.

Of the 9 patients with pancreatic cancer, 3 were diagnosed with intraepithelial adenocarcinoma (high-grade pancreatic intraepithelial neoplasia [HG-PanIN]) and the remaining 6 with invasive ductal adenocarcinoma, based on examination of resected specimens. Mean size of the invasive region was 12.7±8.8 mm in the 6 patients with invasive cancer. The final cancer stages were as follows: 0, 3 patients; IA, 2 patients; IB, 2 patients; and IIB, 2 patients. Although no patients had distal metastases, Stage IIB cancers were accompanied by metastases to a pancreatic regional lymph node. Although EUS, dynamic CT, and MRI were performed for all enrolled patients, no masses were identified, even during retrospective review. In the 2 patients who showed invasive regions sized >20 mm, the invasive regions were not reported to be round, dense, or well-demarcated, possibly due to the difficulty in detection during imaging examinations (Fig. 4).

Fig. 4.

Cancer invasion, with the invasive region being 27 mm in size (Case #9 in Table 2). (A) Mapping through divided faces; (B) Mapping through cutting lines; (C) Microscopic examination of hematoxylin-eosin-stained specimen (×10) showing a whitish, hard region, indicating that invasive cancer was not identified macroscopically on the divided faces. Microscopic evaluation shows that the invasive region (red color) was not round, dense, or well-demarcated, possibly due to the difficulty in detection during imaging examinations. The invasive region is indicated in red and the high-grade pancreatic intraepithelial neoplasia is indicated in yellow. The white box in (A) indicates the location of (C). The blue arrow indicates the main pancreatic duct near the stenosis.

MPD findings

MPD stenosis was located at the pancreatic head, body, and tail in 2, 6, and 1 patients with cancer and in 1, 7, and 2 patients without cancer, respectively (no statistical difference) (Table 2). Moreover, degree of stenosis and tail-side dilation did not differ between patients with and without cancer. Lengths of the stenosis were also similar in both groups.

Other clinical findings

Abdominal examinations, through which MPD findings were detected, were performed due to acute pancreatitis in 5 patients and abdominal pain in 3 patients. The remaining 11 patients, including 4 in whom abnormalities were detected via screening US, did not have any symptoms.

Serum carcinoembryonic antigen (CEA) levels were within the normal limit (<5.0 ng/mL) in all patients except two whose CEA levels were slightly elevated due to smoking. Elevated serum carbohydrate antigen 19-9 (CA19-9) levels (normal limit, <37.0 U/mL) were observed in two patients with invasive cancer (#7 and #9), but serum CA19-9 levels decreased to normal after resection.

No patients exhibited any clinical features indicative of pancreatic cancer, including anorexia, weight loss, new-onset diabetes, indigestion, and pyrexia.

Accuracy of pancreatic juice cytology

The sensitivity, specificity, and accuracy of pancreatic cytology performed on samples from 18 patients were 67%, 100%, and 83%, respectively. The sample obtained from a patient with a HG-PanIN (#3 in Table 2) was not sufficient for histological evaluation. Excluding this sample, the sensitivity, specificity, and accuracy of cytology were 75%, 100%, and 88%, respectively. Two patients received false-negative diagnoses (#4 and #7); in these patients, the investigated cells were judged as only having mild atypia that could not be defined as malignant change. Five patients, who did not have neoplastic cells in their pancreatic juice samples (#3, #4, #7, #10, and #11) desired and underwent surgical resection after giving full informed consent. Pancreatic juice cytology was not performed for one patient (#12) because the procedure was ceased before obtaining sufficient pancreatic juice due to patient’s non-cooperation.

Post-procedural pancreatitis with mild severity, according to Consensus Criteria [11,12], was observed in 3 patients (16%).

Prognosis

All 10 patients who underwent surgery for neoplastic stenosis were still alive during the median follow-up period of 9 months (range, 3–68 months), which lasted till the last checkup before this analysis. However, one Stage-IA cancer patient who showed an invasive region of 8 mm developed metastatic recurrence in the lung, although he has been alive for 18 months after surgery without chemotherapy (#4 in Tables 2, 3). Another patient showed metachronous pancreatic cancer in the remnant pancreatic head (#6). This patient underwent surgical resection of the remnant pancreas for the Stage-IA cancer 39 months after the first surgery and has be alive for 17 months post-second surgery without recurrence.

Table 3.

Characteristics of the Patients Who Were Diagnosed with Malignant Main Pancreatic Duct Stenosis Based on Evaluation of the Resected Specimen

The 2 patients who underwent distal pancreatectomy despite a non-neoplastic stenotic change are alive without surgery-related sequelae 280 (#10) and 75 (#11) days, respectively, post-surgery. All 8 patients who did not undergo surgery are alive after a median follow-up period of 74 months.