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Single-operator pancreatoscopy is helpful in the evaluation of suspected intraductal papillary mucinous neoplasms (IPMN)
Pancreatology 14 (2014) 510e514
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Original article
Single-operator pancreatoscopy is helpful in the evaluation of suspected intraductal papillary mucinous neoplasms (IPMN) €rd a, Lars Enochsson a, Urban Arnelo a, *, Antti Siiki a, b, Fredrik Swahn a, Ralf Segersva € hr a Marco del Chiaro a, Lars Lundell a, Caroline S. Verbeke c, J.-Matthias Lo a b c
Centre for Digestive Diseases, Karolinska University Hospital and Division of Surgery, CLINTEC, Karolinska Institute, Stockholm, Sweden Dept. of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland Division of Pathology, Dept. of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history: Available online 27 September 2014
Background and objective: Even when advanced cross-sectional imaging modalities have been employed, endoscopic evaluation of intraductal papillary mucinous neoplasms (IPMN) is often required in order to assess the final character and extent of lesions. The current study addresses the use of SpyGlass singleoperator peroral pancreatoscopy in suspected IPMN. Design: A prospective, non-randomized exploratory cohort study. Setting: Single-center. Patients and intervention: A prospective study-cohort of 44 consecutive patients in a single tertiary referral center who underwent ERCP and peroral pancreatoscopy, was prospectively collected between July 2007 and March 2013 because of a radiological signs of IPMN. These IPMN-findings were discovered incidentally in 44% of the cases. Main outcome measurements: Diagnostic accuracy (specificity & sensitivity) and complications. Results: The targeted region of the pancreatic duct was reached with the SpyGlass system in 41 patients (median age 65 years, 41% female). Three patients were excluded from analysis because of failed deep cannulation of the pancreatic duct. Brush cytology was taken in 88% and direct biopsies in 41%. IPMN with intermediate or high-grade dysplasia was the main final diagnosis (76%) in 22 patients who had surgery. Out of the 17 patients with a final diagnosis of MD-IPMN, 76% were correctly identified by pancreatoscopy. Of the 9 patients with a final diagnosis of BD-IPMN, the pancreatoscopy identified 78% of the cases correctly.The incidence of post-ERCP pancreatitis was 17%. Pancreatoscopy was found to have provided additional diagnostic information in the vast majority of the cases and to affect clinical decision-making in 76%. Limitations: Single-center study. Conclusions: Single-operator peroral pancreatoscopy contributed to the clinical evaluation of IPMN lesions and influenced decision-making concerning their clinical management. The problem of postprocedural pancreatitis needs further attention. Copyright © 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: IPMN ERCP Single-operator Pancreatoscopy SpyGlass High-grade dysplasia
Introduction Increased use of cross-sectional advanced radiological abdominal imaging technologies has increased awareness of cystic lesions of the pancreas and has stimulated the development of diagnostic
* Corresponding author. Centre for Digestive Diseases, Karolinska University Hospital, K53, S-414 86 Stockholm, Sweden. E-mail address: [email protected] (U. Arnelo).
criteria and management algorithms [1e5]. Mucin-producing cystic neoplasms of the pancreas are divided into two separate entities: intraductal papillary mucinous neoplasia (IPMN) and mucinous cystic neoplasia. IPMN is a well-described entity characterized by papillary proliferation of mucin-producing neoplastic epithelium, which causes cystic dilatation of the pancreatic duct system [1,6,7]. IPMN is a condition with a malignant potential comprising a spectrum of dysplastic epithelial lesions with varying severity of dysplastic changes that eventually progress to invasive carcinoma [8,9]. IPMN can be sub-classified into main-duct IPMN
http://dx.doi.org/10.1016/j.pan.2014.08.007 1424-3903/Copyright © 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
U. Arnelo et al. / Pancreatology 14 (2014) 510e514
(MD-IPMN) and branch-duct type IPMN (BD-IPMN). This subdivision is traditionally based on imaging characteristics on CT or MRI, ultimately validated by the morphological findings in pancreatic resection specimens [10e15]. There is also a combined or mixed type of IPMN. The incidence of co-existence of synchronous or metachronous invasive carcinoma is substantially higher in MDIPMN than in BD-IPMN [9]. As a result, BD-IPMN has a significantly better prognosis. The investigational tools currently available for diagnosis, surveillance, and decision making in cases of suspected IPMN are clearly far from optimal [14]. However, the development of endoscopic equipment that can enter the biliary-pancreatic duct systems has made it possible to visually inspect the target region(-s) and to perform targeted tissue sampling for morphological diagnosis [16e18]. The diagnostic goal of surveillance of patients with suspected IPMN lesions is to distinguish between MD-IPMN and BD-IPMN and to determine the proper timing for and the extent of therapeutic intervention [4,5]. A series of case reports and smaller studies have reported that single-operator SpyGlass technology can be useful for evaluation of pancreatic duct lesions such as IPMN because it allows visualization of the pancreatic duct epithelium and directed biopsies [17e26]. Based on a considerably larger prospectively collected patient cohort, the present study aimed to address the diagnostic accuracy and yield when this new endoscopic technology was used in clinical practice. In addition, the present study focused on the impact of peroral pancreatoscopy on clinical decision-making. Patients and methods During the time period from July 2007 to March 2013, forty-four patients were investigated at Karolinska University Hospital, Stockholm, Sweden, because radiological findings suggested IPMN. All patients had been submitted to a dedicated MR and/or abdominal three phase CT and in some cases EUS had been added. The diagnostic criteria for MD and BD IPMN were those generally applied; BD-IPMN, meaning IPMN with cystic lesions originating from the branch ducts either without (ie, pure type) or with (ie, mixed type) main pancreatic duct dilatation [27]. We categorized any IPMNs accompanied by main pancreatic duct diameter greater than 10 mm as MD- IPMNs. The diagnosis of mixed type IPMN or main-duct IPMN was done in the setting of our multidisciplinary decision-making conference. Three patients were excluded due to failure to enter the main duct system. Seventeen of the patients were female; 24 were male. The median age was 60 (range 46e80) years. The findings suggestive of IPMN were discovered incidentally in 18 patients (44%) who had no symptoms of pancreatic disease. Seven patients presented with obstructive jaundice and/or weight loss. Table 1, summarizes demographics, clinical and radiological findings. All pancreatoscopy procedures were carried out under general anesthesia using a single operator peroral pancreatoscopy system (SpyGlass™, Boston Scientific, Natik, MA, USA) [28]. The SpyGlass probe (SpyScope™) was passed through a standard therapeutic ERCP duodenoscope. The 4-lumen, fully-steerable catheter allowed water irrigation while the SpyGlass optic probe was in position. A pancreatogram was obtained after successful cannulation of the papilla and fluoroscopically-guided positioning of a guidewire in the main pancreatic duct. The SpyGlass probe was carefully advanced into the duct, and low-flow, low-pressure saline was used for ductal irrigation and clearance. Biopsies were taken with a dedicated mini-forceps (SpyBite™). In 32 of the patients, a sphincterotomy was done at the time of pancreatoscopy in order to gain access into the ductal system. In another 6 patients, a sphincterotomy was performed prior to the pancreatoscopy
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Table 1 Clinical and diagnostic characteristics of 41 patients undergoing pancreatoscopy for radiological suspicion of IPMN. All patients (n ¼ 41)
Operated (n ¼ 22)
Patients and symptoms Age (median and range) 65 (46e80) 65 (46e74) Sex (F/M) 17/24 7/15 Weight loss or jaundice 7 (17%) 5 (24%) Incidental presentation 18 (44%) 7 (33%) Radiologic imaging modality (sum more than 100%) MRI þ MRCP 20 (49%) 11 (52%) MDCT 38 (93%) 21 (100%) Suggested IPMN location by radiology Head/neck 28 (68%) 15 (71%) Body/tail 9 (22%) 3 (14%) Head/tail 4 (10%) 3 (14%)
Follow-up (n ¼ 29) 68 (48e80) 10/9 2 (10%) 11 (55%) 9 (45%) 18 (90%) 13 (65%) 6 (30%) 1 (5%)
MRI ¼ magnetic resonance imaging; MRCP ¼ magnetic resonance cholangiopancreatography; MDCT ¼ multi detector computed tomography.
session. In three of the patients, the SpyGlass probe was introduced into the duct through a regular sphinterotome instead of the SpyScope because a device with a smaller diameter was needed for the size of the duct. The endoscopic diagnosis of IPMN used in the present series followed those previously described in detail elsewhere [29]. When discrete, circumscribed areas containing fingerlike protrusions, mucus, or tumor vessels were identified [30], several biopsy specimens were obtained from different parts of the lesion under direct vision. In the absence of such lesions, random samples were in some patients collected. All samples were sent to a pancreatic pathologist for examination. In addition, brush cytology, cytology on irrigation fluid from the pancreatic duct, in situ hybridization (FISH), DNA flow cytometry were also performed in some cases. The macroscopic assessments were confined to the main duct as side branches only rarely can be entered for endoscopic control. All patients were discussed at our routine multidisciplinary team conference during which the management strategy was decided. Comprehensive retrospective evaluations of the records from these conferences were made to determine whether the information provided by the SpyGlass system had been useful during the decision-making process. In patients in whom surgery was performed, the final diagnoses were based on a careful investigation of the surgical specimens. In patients who did not have an operation, final diagnoses were based on the outcome of the clinical follow-up. Results The part of the pancreatic duct that was of interest, based on radiological findings, was reached in all 41 cases. The median overall duration of the procedure was 90 min (range 40e150). EUS was performed at the time of pancreatoscopy procedure in 13 of the cases (42%). In total 26 patients had a final diagnosis of IPMN (MD-IPMN n ¼ 17, BD-IMPN n ¼ 9). Of the 19 patients who underwent surgery for IPMN, the WHO grade of dysplasia [31] was low in 2, intermediate in 10 and high in 7. Ductal adenocarcinoma was found in one patient but in a different part of the pancreas than the MD-IPMN. PanIn-2 changes were found in 3 patients who post-surgically were diagnosed as chronic pancreatitis. Figs. 1e3 show the diagnoses based on radiology and pancreatoscopy in relation to the final diagnoses, either obtained at surgery or during long term follow-up. The median time of followup in patients not undergoing surgery was 2.3 (range 0.6e6.5) years Fig. 4, shows typical IPMN changes in the main pancreatic duct.
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Fig. 1. Outcome of pancreatoscopy in patients with radiological signs of main-duct IPMN (MD-IPMN). BD-IPMN ¼ branch-duct IPMN; CP ¼ chronic pancreatitis; SCN ¼ serous cystic neoplasia; Final ¼ diagnosis after surgery or follow-up. The number of cases are shown in parentheses.
Four of the 25 patients with radiological signs of MD-IPMN were classified as BD-IPMN after pancreatoscopy by exclusion of lesions in MPD (Fig. 1). BD-IPMN was confirmed following surgery in one of these and supported by the follow-up in two others. MD-IPMN was found postoperatively in another, during surgery two years after the pancreatoscopy procedure. In 11 patients, pancreatoscopy supported the radiological diagnosis of MD-IPMN (Fig. 1). The postoperative histological diagnoses in this group were MD-IPMN (n ¼ 8), BD-IPMN (n ¼ 1), and chronic pancreatitis (n ¼ 1). Surgery for MD-IPMN was recommended during follow-up for the other patient, which was refused. Another 10 patients classified as MD-IPMN by radiology, were diagnosed as non-IPMN by endoscopy (Fig. 1). The final diagnoses in those patients were chronic pancreatitis (n ¼ 2), serous cystic neoplasia (SCN) (n ¼ 1), MD-IPMN (n ¼ 3), BD-IPMN (n ¼ 1), other benign (n ¼ 2), and unknown (operation refused - n ¼ 1). Radiology suggested BD-IPMN in 8 cases (Fig. 2). The pancreatoscopy diagnosis was also BD-IPMN in 4 of these by exclusion of lesions in the MPD. This diagnosis was later confirmed in 3 of these patients, but one patient presented with metastasized pancreatic adenocarcinoma two years later. In one patient with a radiology-based diagnosis of BD-IPMN, the pancreatoscopy diagnosis was MD-IPMN, subsequently confirmed by surgery. Three patients with a radiology-based diagnosis of BD-IPMN were categorized as non-IPMN by endoscopy. The final diagnoses in these three patients were chronic pancreatitis (n ¼ 1), SCN (n ¼ 1) and indeterminate (n ¼ 1).
In eight cases, radiology did not allow a definite characterization of the duct abnormalities (Fig. 3). The pancreatoscopy diagnosis was MD-IPMN in three of those patients, which later was confirmed postoperatively from the resected specimens. The endoscopic diagnosis of BD-IPMN in one patient was also confirmed histologically. The other 4 patients were diagnosed by pancreatoscopy as non-IPMN; their final diagnoses were chronic pancreatitis (n ¼ 3) and indeterminate (n ¼ 1). Pancreatoscopy was judged to have provided additional diagnostic information in 39 of the 41 cases (95%). In 76% of the cases, pancreatoscopy findings were considered to have affected the clinical decisions made during the multidisciplinary team conferences. The final diagnosis in 26 patients was IPMN. Out of the 17 patients with a final diagnosis of MD-IPMN, 76% were correctly identified by both radiology and pancreatoscopy. Of the 9 patients with a final diagnosis of BD-IPMN, the radiologically-based diagnosis was correct in 33% of the patients, while pancreatoscopy identified 78% of the cases correctly. With the operated cases as a reference, the sensitivity for SpyGlass was 84% (16/19) and the specificity was 75% (9/12). The post-procedural course was uneventful in 34 patients. However, post-ERCP pancreatitis developed in seven patients (17%), six of them having a MPD of normal width or slightly dilated or irregular MPD and only one patient with dilated MPD developed a mild post-ERCP pancreatitis. Two of the seven post-ERCP pancreatitis cases were mild and 4 were moderate according to Cotton [32]. The other pancreatitis patient died due to the development of respiratory failure later during the course.
Fig. 2. Outcome of pancreatoscopy in patients with radiological signs of branch-duct IPMN (BD-IPMN). MD-IPMN ¼ main-duct IPMN; CP ¼ chronic pancreatitis; Cancer ¼ pancreatic cancer; Final ¼ diagnosis after surgery or follow-up. The number of cases is shown in parentheses.
Fig. 3. Outcome of pancreatoscopy in patients with undefined lesions by radiology. MD-IPMN ¼ main-duct IPMN; BD-IPMN ¼ branch-duct IPMN; CP ¼ chronic pancreatitis; Final ¼ diagnosis after surgery or follow-up. The number of cases is shown in parentheses.
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Fig. 4. A-B. Endoscopic retrograde pancreatography (A) and intraductal pancreatoscopy (B) images from a 64-year-old female with main-duct IPMN. Pictures are taken from the video (see online).
Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.pan.2014.08.007 At the time of duodenoscopy, a classic fish-eye papilla was seen in 6 (14%) of the 41 patients, representing only 35% of the patients in whom the final diagnosis was MD-IPMN. Oozing of mucus was observed in an additional 8 patients (7 MD-IPMN final diagnosis, 1 BD-IPMN final diagnosis). Brush cytology was taken in 36 patients and pancreatic fluid cytology was performed in 22. Malignancy was shown in 3% of the brush cytology aliquots and in 5% of the patients from whom pancreatic fluid was collected. Benign morphology was found in 9 of the 17 patients in whom forceps biopsies were taken. High grade dysplasia was found in biopsies of 4 (24%) patients and confirmed postoperatively in 3 patients; the other patient refused surgery. There were 4 patients in which the SpyBite biopsies could not be used for histological diagnosis because of inadequate size and quality. In situ hybridization (FISH) was performed in 3 patients and DNA flow cytometry in 27. Discussion Diagnosis of intraductal papillary mucinous neoplasms of the pancreas has increased markedly during recent years, primarily due to the widespread use of high-resolution abdominal imaging [4,13]. The patient downside of this development is that substantial numbers of IMPN lesions are found incidentally in asymptomatic individuals thereby introducing huge diagnostic dilemmas [2,33]. Therapeutic decisions for IMPN can also be very challenging because of the malignant potential of the lesions and their broad spectrum of morphological manifestations [4,5,7,34]. The main objective of this study was to investigate the additional clinical value of single operator pancreatoscopy with the SpyGlass system in patients in whom IPMN was suspected on the basis of MDCT and/ or MRI. The current series of 41 consecutive patients is relevant since it represents the largest number of unselected cases published to date [17e26]. The current data confirmed previous findings that “fish-eye” papillae and oozing of mucus are not seen consistently in patients with MD-IPMN [19e22]. In our series, a fish-eye papilla was seen
during the procedure in only 35% of the patients in whom diagnosis of MD-IPMN was eventually confirmed by surgery and/or histology. The data from the current study provides evidence that pancreatoscopy is feasible in cases with suspicion of IPMN. This is consistent with data presented in previous smaller series and case reports [17e26]. While it is easy to diagnose IPMN with mucus protruding from the papilla and relatively easy to find papillary tumorous lesions located in the MPD in case of MD-IPMN, the role of pancreatoscopy in BD-IPMN is merely to exclude MD-IPMN or mixed-type IPMN. However, the diagnosis of BD-IPMN can sometimes be made by observing mucus in (dilated) first-degree side branches of the MPD. Taken together, pancreatoscopy and its associated investigations (pancreatography ± EUS) provided additional information to support or contradict the radiologic findings in 95% of our 41 cases, and in 76% of the cases, the pancreatoscopy findings were judged to significantly have affected the clinical decisions made during the multidisciplinary team conferences. In some patients, surgery that had been proposed was avoided based on the information provided by pancreatoscopy. In a recent study, evaluating peroral pancreatoscopy on 17 IPMN patients, the investigators presents astonishingly high figures on specificity for the use of irrigation fluid cytology and targeted biopsy material [26]. Despite the suggested and apparent advantages of peroral pancreatoscopy we have to conclude that we could not reach similar levels of specificity for a variety of reasons. An increased rate of post-procedural pancreatitis was seen in our patients, which is in accordance previous reports [16,17,35]. This finding is potentially problematic and might hinder a wider clinical use of this technology. The level of experience of the endoscopist appears to be an important factor, since six of our seven cases of pancreatitis, including the fatal case, occurred during the first three years of our experience with the procedure. One measure we took was to reduce the flow rate of the irrigation fluid during the SpyGlass procedure. It is our impression that particular care is needed in those patients with non dilated MPD as 6 out of the 7 post-ERCP pancreatitis occurred in those patients. The data from our series suggest that pancreatoscopy using the SpyGlass system still is justified in patients in whom robust and
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comprehensive information is needed for the subsequent complex clinical decisions. However, the high rate of post-ERCP pancreatitis in the series even at specialized centers indicates the need for special caution. Further development of pancreatoscopy equipment and strict indications is required to increase the diagnostic ability of the technique. Optics with better resolution and a video chip instead of fiber optics could improve the visual inspection of the ductal system. Improved steerability could also help reduce the number of missed lesions. In conclusion, peroral pancreatoscopy with directed biopsies contributes to the clinical evaluation of IPMN cases and the sometimes delicate decision to the proper timing of and sometimes avoidance of surgical intervention. A predefined protocol for prospective collection of data to determine the contributions of pancreatoscopy to decision making is warranted to further clarify its role in the assessment of IPMNs with or without irrigation cytology and biopsies. Strategies for minimizing the risk of post-procedural pancreatitis also need to be investigated.
[13]
[14] [15]
[16]
[17]
[18]
[19]
[20]
Acknowledgments [21]
We thank Professor Margery Herrington for valuable discussions and constructive comments in the preparation of the manuscript. We thank our endoscopy nurses, Inger Sahlgren, Susanne €ck, Ann-Helen Stensro €d, Sari Kallija €rvi and Manuel Jimenez Stenba for their skilful assistance. The study was supported by a grant through a regional agreement on clinical research between Stockholm County Council and Karolinska Institutet (ALF 20130512).
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Pancreatology journal homepage: www.elsevier.com/locate/pan
Original article
Single-operator pancreatoscopy is helpful in the evaluation of suspected intraductal papillary mucinous neoplasms (IPMN) €rd a, Lars Enochsson a, Urban Arnelo a, *, Antti Siiki a, b, Fredrik Swahn a, Ralf Segersva € hr a Marco del Chiaro a, Lars Lundell a, Caroline S. Verbeke c, J.-Matthias Lo a b c
Centre for Digestive Diseases, Karolinska University Hospital and Division of Surgery, CLINTEC, Karolinska Institute, Stockholm, Sweden Dept. of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland Division of Pathology, Dept. of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history: Available online 27 September 2014
Background and objective: Even when advanced cross-sectional imaging modalities have been employed, endoscopic evaluation of intraductal papillary mucinous neoplasms (IPMN) is often required in order to assess the final character and extent of lesions. The current study addresses the use of SpyGlass singleoperator peroral pancreatoscopy in suspected IPMN. Design: A prospective, non-randomized exploratory cohort study. Setting: Single-center. Patients and intervention: A prospective study-cohort of 44 consecutive patients in a single tertiary referral center who underwent ERCP and peroral pancreatoscopy, was prospectively collected between July 2007 and March 2013 because of a radiological signs of IPMN. These IPMN-findings were discovered incidentally in 44% of the cases. Main outcome measurements: Diagnostic accuracy (specificity & sensitivity) and complications. Results: The targeted region of the pancreatic duct was reached with the SpyGlass system in 41 patients (median age 65 years, 41% female). Three patients were excluded from analysis because of failed deep cannulation of the pancreatic duct. Brush cytology was taken in 88% and direct biopsies in 41%. IPMN with intermediate or high-grade dysplasia was the main final diagnosis (76%) in 22 patients who had surgery. Out of the 17 patients with a final diagnosis of MD-IPMN, 76% were correctly identified by pancreatoscopy. Of the 9 patients with a final diagnosis of BD-IPMN, the pancreatoscopy identified 78% of the cases correctly.The incidence of post-ERCP pancreatitis was 17%. Pancreatoscopy was found to have provided additional diagnostic information in the vast majority of the cases and to affect clinical decision-making in 76%. Limitations: Single-center study. Conclusions: Single-operator peroral pancreatoscopy contributed to the clinical evaluation of IPMN lesions and influenced decision-making concerning their clinical management. The problem of postprocedural pancreatitis needs further attention. Copyright © 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: IPMN ERCP Single-operator Pancreatoscopy SpyGlass High-grade dysplasia
Introduction Increased use of cross-sectional advanced radiological abdominal imaging technologies has increased awareness of cystic lesions of the pancreas and has stimulated the development of diagnostic
* Corresponding author. Centre for Digestive Diseases, Karolinska University Hospital, K53, S-414 86 Stockholm, Sweden. E-mail address: [email protected] (U. Arnelo).
criteria and management algorithms [1e5]. Mucin-producing cystic neoplasms of the pancreas are divided into two separate entities: intraductal papillary mucinous neoplasia (IPMN) and mucinous cystic neoplasia. IPMN is a well-described entity characterized by papillary proliferation of mucin-producing neoplastic epithelium, which causes cystic dilatation of the pancreatic duct system [1,6,7]. IPMN is a condition with a malignant potential comprising a spectrum of dysplastic epithelial lesions with varying severity of dysplastic changes that eventually progress to invasive carcinoma [8,9]. IPMN can be sub-classified into main-duct IPMN
http://dx.doi.org/10.1016/j.pan.2014.08.007 1424-3903/Copyright © 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
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(MD-IPMN) and branch-duct type IPMN (BD-IPMN). This subdivision is traditionally based on imaging characteristics on CT or MRI, ultimately validated by the morphological findings in pancreatic resection specimens [10e15]. There is also a combined or mixed type of IPMN. The incidence of co-existence of synchronous or metachronous invasive carcinoma is substantially higher in MDIPMN than in BD-IPMN [9]. As a result, BD-IPMN has a significantly better prognosis. The investigational tools currently available for diagnosis, surveillance, and decision making in cases of suspected IPMN are clearly far from optimal [14]. However, the development of endoscopic equipment that can enter the biliary-pancreatic duct systems has made it possible to visually inspect the target region(-s) and to perform targeted tissue sampling for morphological diagnosis [16e18]. The diagnostic goal of surveillance of patients with suspected IPMN lesions is to distinguish between MD-IPMN and BD-IPMN and to determine the proper timing for and the extent of therapeutic intervention [4,5]. A series of case reports and smaller studies have reported that single-operator SpyGlass technology can be useful for evaluation of pancreatic duct lesions such as IPMN because it allows visualization of the pancreatic duct epithelium and directed biopsies [17e26]. Based on a considerably larger prospectively collected patient cohort, the present study aimed to address the diagnostic accuracy and yield when this new endoscopic technology was used in clinical practice. In addition, the present study focused on the impact of peroral pancreatoscopy on clinical decision-making. Patients and methods During the time period from July 2007 to March 2013, forty-four patients were investigated at Karolinska University Hospital, Stockholm, Sweden, because radiological findings suggested IPMN. All patients had been submitted to a dedicated MR and/or abdominal three phase CT and in some cases EUS had been added. The diagnostic criteria for MD and BD IPMN were those generally applied; BD-IPMN, meaning IPMN with cystic lesions originating from the branch ducts either without (ie, pure type) or with (ie, mixed type) main pancreatic duct dilatation [27]. We categorized any IPMNs accompanied by main pancreatic duct diameter greater than 10 mm as MD- IPMNs. The diagnosis of mixed type IPMN or main-duct IPMN was done in the setting of our multidisciplinary decision-making conference. Three patients were excluded due to failure to enter the main duct system. Seventeen of the patients were female; 24 were male. The median age was 60 (range 46e80) years. The findings suggestive of IPMN were discovered incidentally in 18 patients (44%) who had no symptoms of pancreatic disease. Seven patients presented with obstructive jaundice and/or weight loss. Table 1, summarizes demographics, clinical and radiological findings. All pancreatoscopy procedures were carried out under general anesthesia using a single operator peroral pancreatoscopy system (SpyGlass™, Boston Scientific, Natik, MA, USA) [28]. The SpyGlass probe (SpyScope™) was passed through a standard therapeutic ERCP duodenoscope. The 4-lumen, fully-steerable catheter allowed water irrigation while the SpyGlass optic probe was in position. A pancreatogram was obtained after successful cannulation of the papilla and fluoroscopically-guided positioning of a guidewire in the main pancreatic duct. The SpyGlass probe was carefully advanced into the duct, and low-flow, low-pressure saline was used for ductal irrigation and clearance. Biopsies were taken with a dedicated mini-forceps (SpyBite™). In 32 of the patients, a sphincterotomy was done at the time of pancreatoscopy in order to gain access into the ductal system. In another 6 patients, a sphincterotomy was performed prior to the pancreatoscopy
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Table 1 Clinical and diagnostic characteristics of 41 patients undergoing pancreatoscopy for radiological suspicion of IPMN. All patients (n ¼ 41)
Operated (n ¼ 22)
Patients and symptoms Age (median and range) 65 (46e80) 65 (46e74) Sex (F/M) 17/24 7/15 Weight loss or jaundice 7 (17%) 5 (24%) Incidental presentation 18 (44%) 7 (33%) Radiologic imaging modality (sum more than 100%) MRI þ MRCP 20 (49%) 11 (52%) MDCT 38 (93%) 21 (100%) Suggested IPMN location by radiology Head/neck 28 (68%) 15 (71%) Body/tail 9 (22%) 3 (14%) Head/tail 4 (10%) 3 (14%)
Follow-up (n ¼ 29) 68 (48e80) 10/9 2 (10%) 11 (55%) 9 (45%) 18 (90%) 13 (65%) 6 (30%) 1 (5%)
MRI ¼ magnetic resonance imaging; MRCP ¼ magnetic resonance cholangiopancreatography; MDCT ¼ multi detector computed tomography.
session. In three of the patients, the SpyGlass probe was introduced into the duct through a regular sphinterotome instead of the SpyScope because a device with a smaller diameter was needed for the size of the duct. The endoscopic diagnosis of IPMN used in the present series followed those previously described in detail elsewhere [29]. When discrete, circumscribed areas containing fingerlike protrusions, mucus, or tumor vessels were identified [30], several biopsy specimens were obtained from different parts of the lesion under direct vision. In the absence of such lesions, random samples were in some patients collected. All samples were sent to a pancreatic pathologist for examination. In addition, brush cytology, cytology on irrigation fluid from the pancreatic duct, in situ hybridization (FISH), DNA flow cytometry were also performed in some cases. The macroscopic assessments were confined to the main duct as side branches only rarely can be entered for endoscopic control. All patients were discussed at our routine multidisciplinary team conference during which the management strategy was decided. Comprehensive retrospective evaluations of the records from these conferences were made to determine whether the information provided by the SpyGlass system had been useful during the decision-making process. In patients in whom surgery was performed, the final diagnoses were based on a careful investigation of the surgical specimens. In patients who did not have an operation, final diagnoses were based on the outcome of the clinical follow-up. Results The part of the pancreatic duct that was of interest, based on radiological findings, was reached in all 41 cases. The median overall duration of the procedure was 90 min (range 40e150). EUS was performed at the time of pancreatoscopy procedure in 13 of the cases (42%). In total 26 patients had a final diagnosis of IPMN (MD-IPMN n ¼ 17, BD-IMPN n ¼ 9). Of the 19 patients who underwent surgery for IPMN, the WHO grade of dysplasia [31] was low in 2, intermediate in 10 and high in 7. Ductal adenocarcinoma was found in one patient but in a different part of the pancreas than the MD-IPMN. PanIn-2 changes were found in 3 patients who post-surgically were diagnosed as chronic pancreatitis. Figs. 1e3 show the diagnoses based on radiology and pancreatoscopy in relation to the final diagnoses, either obtained at surgery or during long term follow-up. The median time of followup in patients not undergoing surgery was 2.3 (range 0.6e6.5) years Fig. 4, shows typical IPMN changes in the main pancreatic duct.
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Fig. 1. Outcome of pancreatoscopy in patients with radiological signs of main-duct IPMN (MD-IPMN). BD-IPMN ¼ branch-duct IPMN; CP ¼ chronic pancreatitis; SCN ¼ serous cystic neoplasia; Final ¼ diagnosis after surgery or follow-up. The number of cases are shown in parentheses.
Four of the 25 patients with radiological signs of MD-IPMN were classified as BD-IPMN after pancreatoscopy by exclusion of lesions in MPD (Fig. 1). BD-IPMN was confirmed following surgery in one of these and supported by the follow-up in two others. MD-IPMN was found postoperatively in another, during surgery two years after the pancreatoscopy procedure. In 11 patients, pancreatoscopy supported the radiological diagnosis of MD-IPMN (Fig. 1). The postoperative histological diagnoses in this group were MD-IPMN (n ¼ 8), BD-IPMN (n ¼ 1), and chronic pancreatitis (n ¼ 1). Surgery for MD-IPMN was recommended during follow-up for the other patient, which was refused. Another 10 patients classified as MD-IPMN by radiology, were diagnosed as non-IPMN by endoscopy (Fig. 1). The final diagnoses in those patients were chronic pancreatitis (n ¼ 2), serous cystic neoplasia (SCN) (n ¼ 1), MD-IPMN (n ¼ 3), BD-IPMN (n ¼ 1), other benign (n ¼ 2), and unknown (operation refused - n ¼ 1). Radiology suggested BD-IPMN in 8 cases (Fig. 2). The pancreatoscopy diagnosis was also BD-IPMN in 4 of these by exclusion of lesions in the MPD. This diagnosis was later confirmed in 3 of these patients, but one patient presented with metastasized pancreatic adenocarcinoma two years later. In one patient with a radiology-based diagnosis of BD-IPMN, the pancreatoscopy diagnosis was MD-IPMN, subsequently confirmed by surgery. Three patients with a radiology-based diagnosis of BD-IPMN were categorized as non-IPMN by endoscopy. The final diagnoses in these three patients were chronic pancreatitis (n ¼ 1), SCN (n ¼ 1) and indeterminate (n ¼ 1).
In eight cases, radiology did not allow a definite characterization of the duct abnormalities (Fig. 3). The pancreatoscopy diagnosis was MD-IPMN in three of those patients, which later was confirmed postoperatively from the resected specimens. The endoscopic diagnosis of BD-IPMN in one patient was also confirmed histologically. The other 4 patients were diagnosed by pancreatoscopy as non-IPMN; their final diagnoses were chronic pancreatitis (n ¼ 3) and indeterminate (n ¼ 1). Pancreatoscopy was judged to have provided additional diagnostic information in 39 of the 41 cases (95%). In 76% of the cases, pancreatoscopy findings were considered to have affected the clinical decisions made during the multidisciplinary team conferences. The final diagnosis in 26 patients was IPMN. Out of the 17 patients with a final diagnosis of MD-IPMN, 76% were correctly identified by both radiology and pancreatoscopy. Of the 9 patients with a final diagnosis of BD-IPMN, the radiologically-based diagnosis was correct in 33% of the patients, while pancreatoscopy identified 78% of the cases correctly. With the operated cases as a reference, the sensitivity for SpyGlass was 84% (16/19) and the specificity was 75% (9/12). The post-procedural course was uneventful in 34 patients. However, post-ERCP pancreatitis developed in seven patients (17%), six of them having a MPD of normal width or slightly dilated or irregular MPD and only one patient with dilated MPD developed a mild post-ERCP pancreatitis. Two of the seven post-ERCP pancreatitis cases were mild and 4 were moderate according to Cotton [32]. The other pancreatitis patient died due to the development of respiratory failure later during the course.
Fig. 2. Outcome of pancreatoscopy in patients with radiological signs of branch-duct IPMN (BD-IPMN). MD-IPMN ¼ main-duct IPMN; CP ¼ chronic pancreatitis; Cancer ¼ pancreatic cancer; Final ¼ diagnosis after surgery or follow-up. The number of cases is shown in parentheses.
Fig. 3. Outcome of pancreatoscopy in patients with undefined lesions by radiology. MD-IPMN ¼ main-duct IPMN; BD-IPMN ¼ branch-duct IPMN; CP ¼ chronic pancreatitis; Final ¼ diagnosis after surgery or follow-up. The number of cases is shown in parentheses.
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Fig. 4. A-B. Endoscopic retrograde pancreatography (A) and intraductal pancreatoscopy (B) images from a 64-year-old female with main-duct IPMN. Pictures are taken from the video (see online).
Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.pan.2014.08.007 At the time of duodenoscopy, a classic fish-eye papilla was seen in 6 (14%) of the 41 patients, representing only 35% of the patients in whom the final diagnosis was MD-IPMN. Oozing of mucus was observed in an additional 8 patients (7 MD-IPMN final diagnosis, 1 BD-IPMN final diagnosis). Brush cytology was taken in 36 patients and pancreatic fluid cytology was performed in 22. Malignancy was shown in 3% of the brush cytology aliquots and in 5% of the patients from whom pancreatic fluid was collected. Benign morphology was found in 9 of the 17 patients in whom forceps biopsies were taken. High grade dysplasia was found in biopsies of 4 (24%) patients and confirmed postoperatively in 3 patients; the other patient refused surgery. There were 4 patients in which the SpyBite biopsies could not be used for histological diagnosis because of inadequate size and quality. In situ hybridization (FISH) was performed in 3 patients and DNA flow cytometry in 27. Discussion Diagnosis of intraductal papillary mucinous neoplasms of the pancreas has increased markedly during recent years, primarily due to the widespread use of high-resolution abdominal imaging [4,13]. The patient downside of this development is that substantial numbers of IMPN lesions are found incidentally in asymptomatic individuals thereby introducing huge diagnostic dilemmas [2,33]. Therapeutic decisions for IMPN can also be very challenging because of the malignant potential of the lesions and their broad spectrum of morphological manifestations [4,5,7,34]. The main objective of this study was to investigate the additional clinical value of single operator pancreatoscopy with the SpyGlass system in patients in whom IPMN was suspected on the basis of MDCT and/ or MRI. The current series of 41 consecutive patients is relevant since it represents the largest number of unselected cases published to date [17e26]. The current data confirmed previous findings that “fish-eye” papillae and oozing of mucus are not seen consistently in patients with MD-IPMN [19e22]. In our series, a fish-eye papilla was seen
during the procedure in only 35% of the patients in whom diagnosis of MD-IPMN was eventually confirmed by surgery and/or histology. The data from the current study provides evidence that pancreatoscopy is feasible in cases with suspicion of IPMN. This is consistent with data presented in previous smaller series and case reports [17e26]. While it is easy to diagnose IPMN with mucus protruding from the papilla and relatively easy to find papillary tumorous lesions located in the MPD in case of MD-IPMN, the role of pancreatoscopy in BD-IPMN is merely to exclude MD-IPMN or mixed-type IPMN. However, the diagnosis of BD-IPMN can sometimes be made by observing mucus in (dilated) first-degree side branches of the MPD. Taken together, pancreatoscopy and its associated investigations (pancreatography ± EUS) provided additional information to support or contradict the radiologic findings in 95% of our 41 cases, and in 76% of the cases, the pancreatoscopy findings were judged to significantly have affected the clinical decisions made during the multidisciplinary team conferences. In some patients, surgery that had been proposed was avoided based on the information provided by pancreatoscopy. In a recent study, evaluating peroral pancreatoscopy on 17 IPMN patients, the investigators presents astonishingly high figures on specificity for the use of irrigation fluid cytology and targeted biopsy material [26]. Despite the suggested and apparent advantages of peroral pancreatoscopy we have to conclude that we could not reach similar levels of specificity for a variety of reasons. An increased rate of post-procedural pancreatitis was seen in our patients, which is in accordance previous reports [16,17,35]. This finding is potentially problematic and might hinder a wider clinical use of this technology. The level of experience of the endoscopist appears to be an important factor, since six of our seven cases of pancreatitis, including the fatal case, occurred during the first three years of our experience with the procedure. One measure we took was to reduce the flow rate of the irrigation fluid during the SpyGlass procedure. It is our impression that particular care is needed in those patients with non dilated MPD as 6 out of the 7 post-ERCP pancreatitis occurred in those patients. The data from our series suggest that pancreatoscopy using the SpyGlass system still is justified in patients in whom robust and
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comprehensive information is needed for the subsequent complex clinical decisions. However, the high rate of post-ERCP pancreatitis in the series even at specialized centers indicates the need for special caution. Further development of pancreatoscopy equipment and strict indications is required to increase the diagnostic ability of the technique. Optics with better resolution and a video chip instead of fiber optics could improve the visual inspection of the ductal system. Improved steerability could also help reduce the number of missed lesions. In conclusion, peroral pancreatoscopy with directed biopsies contributes to the clinical evaluation of IPMN cases and the sometimes delicate decision to the proper timing of and sometimes avoidance of surgical intervention. A predefined protocol for prospective collection of data to determine the contributions of pancreatoscopy to decision making is warranted to further clarify its role in the assessment of IPMNs with or without irrigation cytology and biopsies. Strategies for minimizing the risk of post-procedural pancreatitis also need to be investigated.
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[14] [15]
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Acknowledgments [21]
We thank Professor Margery Herrington for valuable discussions and constructive comments in the preparation of the manuscript. We thank our endoscopy nurses, Inger Sahlgren, Susanne €ck, Ann-Helen Stensro €d, Sari Kallija €rvi and Manuel Jimenez Stenba for their skilful assistance. The study was supported by a grant through a regional agreement on clinical research between Stockholm County Council and Karolinska Institutet (ALF 20130512).
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