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Original Research n Gastrointestinal
Intraductal Papillary Mucinous Neoplasms of the Pancreas: Evaluation of Malignant Potential and Surgical Resectability by Using MR Imaging with MR Cholangiography1 Purpose:
To evaluate the diagnostic performance of magnetic resonance (MR) imaging with MR cholangiopancreatography (MRCP) in determining the malignant potential and surgical resectability of pancreas intraductal papillary mucinous neoplasms (IPMNs).
Materials and Methods:
Institutional review board approval was obtained, and the requirement for informed consent was waived. Ninetyeight patients with pathologically proved pancreas IPMNs who underwent MR imaging with MRCP comprised the study population. MR images were analyzed for findings suggestive of high-risk stigmata or worrisome features, as proposed by the international consensus guidelines 2012. Interobserver agreement between two experienced observers (observers 1 and 2) and one inexperienced observer (observer 3) was assessed. Diagnostic performance of MR imaging in the evaluation of the malignant potential and surgical resectability of IPMNs was analyzed in these three observers by using receiver operating curve analysis.
Results:
MR imaging with MRCP showed sensitivity of 83% (35/42), 79% (33/42), and 90% (38/42); specificity of 80% (41/51), 51% (26/51), and 24% (12/51); and accuracy of 82% (76/93), 63% (59/93), and 54% (50/93) for observers 1, 2, and 3, respectively, in the evaluation of the malignant potential of pancreas IPMNs when at least one worrisome feature was present. Interobserver agreement in the detection of intramural nodules (k = 0.349–0.574), enhanced solid components (k = 0.318–0.574), and measurement of main pancreatic duct diameter (intraclass correlation coefficient = 0.9477) was fair to high. The respective sensitivity, specificity, and accuracy in determination of surgical resectability were 95% (81/85), 99% (84/85), and 88% (75/85); 69% (9/13), 69% (9/13), and 54% (7/13); and 92% (90/98), 95% (93/98), and 84% (82/98) for observers 1, 2, and 3.
Conclusion:
MR imaging with MRCP is a useful modality in the evaluation of the malignant potential and resectability of IPMNs, with high sensitivity and moderate specificity in the experienced radiologists but relatively low specificity in the inexperienced radiology trainee.
1
From the Department of Radiology (S.H.K., J.M.L., J.H.B., J.H.K., J.K.H., B.I.C.) and Institute of Radiation Medicine (J.M.L., J.H.K., J.K.H., B.I.C.), Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea; and Department of Radiology, Research Institute and Hospital of National Cancer Center, Goyang, Republic of Korea (E.S.L.). Received December 29, 2013; revision requested February 3, 2014; revision received April 13; accepted June 16; final version accepted August 12. Address correspondence to J.M.L. (e-mail: [email protected]). RSNA, 2014
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Online supplemental material is available for this article. 723
Imaging
Seong Ho Kim, MD Jeong Min Lee, MD Eun Sun Lee, MD Jee Hyun Baek, MD Jung Hoon Kim, MD Joon Koo Han, MD Byung Ihn Choi, MD
GASTROINTESTINAL IMAGING: Intraductal Papillary Mucinous Neoplasms of the Pancreas
I
ntraductal papillary mucinous neoplasm (IPMN) of the pancreas is defined as a tumor growing in the main duct or branch duct of the pancreas,
Advances in Knowledge nn MR imaging with MR cholangiopancreatography (MRCP) showed sensitivity of 83% (35/42), 79% (33/42), and 90% (38/42); specificity of 80% (41/51), 51% (26/51), and 24% (12/51); and accuracy of 82% (76/93), 63% (59/93), and 54% (50/93) in two experienced observers and one inexperienced observer, respectively, who were evaluating the malignant potential of pancreatic intraductal papillary mucinous neoplasms (IPMNs) when at least one worrisome feature was present. nn Interobserver agreement in the detection of intramural nodules (k = 0.349–0.574) and enhanced solid components infiltrating the parenchyma (k = 0.318–0.574) and for the measurement of main pancreatic duct diameter (intraclass correlation coefficient = 0.9477) and pancreatic cyst size (intraclass correlation coefficient = 0.6982) was fair to high, whereas interobserver agreement in the detection of enhanced cyst walls (k = 0.066–0.211) was relatively limited among the two experienced observers and the one inexperienced observer. nn Agreement for detection of abrupt caliber changes in the main pancreatic duct (k = 0.294– 0.612) was variable between the three observers. nn Overall accuracy of MR imaging with MRCP in determining surgical resectability was 92% (90/98), 95% (93/98), and 84% (82/98) in two experienced observers and one inexperienced observer, respectively, while showing a tendency toward underestimation of vascular encasement. 724
Kim et al
with differentiated papillary features and production of atypical mucin, as well as segmental or diffuse dilation of the main pancreatic duct (MPD), cystic dilation of the secondary branches, or both (1). It is clinically subcategorized into three types: main-duct IPMN, branch-duct IPMN, and mixed IPMN, and the malignant potential is known to be higher in main-duct IPMNs and mixed IPMNs (2,3). In recent years, the incidence and number of surgical resections for pancreatic IPMNs has increased significantly (4,5). However, this increase has come without a corresponding increase in IPMN-related or overall pancreatic cancer–related mortality. Thus, it is likely to have resulted from an increase in diagnostic scrutiny, particularly the expansive use of high-resolution cross-sectional imaging techniques, such as multidetector row computed tomography (CT) or magnetic resonance (MR) imaging, rather than from a greater incidence of patients with IPMNs (4). According to the 2010 World Health Organization classification, pancreatic IPMNs can be subcategorized into IPMNs with low- or moderate-grade dysplasia, which are considered benign, and IPMNs with high-grade dysplasia or those associated with invasive cancers, which are considered malignant (3,6–8). Previous studies have described the imaging criteria in the differentiation of malignant IPMNs from benign IPMNs (7,9–18), and partly on the basis of those studies, the international consensus guidelines 2012 for the management of IPMNs and mucinous cystic neoplasms of the pancreas have been issued (7,9–18). The new international consensus guidelines recommend multidetector row CT or MR imaging with
Implication for Patient Care nn MR imaging with MRCP is a useful modality in the evaluation of malignant potential and resectability of IPMNs, with high sensitivity and moderate specificity in the experienced radiologists, albeit with relatively low specificity in the inexperienced radiology trainee.
MR cholangiopancreatography (CP) in the evaluation of pancreatic cysts larger than 1 cm to check for high-risk stigmata or worrisome features. In cysts that show high-risk stigmata, surgical management is recommended. In cysts that show worrisome features or that are larger than 3 cm without worrisome features, endoscopic ultrasonography (US) is recommended (7). If no worrisome features are present, no further diagnostic work-up is recommended, although surveillance is still required. Even though CT is still a mainstay in the evaluation of the surgical resectability of pancreatic IPMNs with a strong preference among pancreatic surgeons, MR imaging with MRCP has come into wide acceptance in recent days (7,14,19–27). Thus, the aim of our study was to evaluate the diagnostic performance of MR imaging with MRCP in determining the malignant potential and surgical resectability of pancreatic IPMNs by using pathologic and surgical analyses as reference standards. In addition, we attempted to evaluate the interobserver agreement in applying the diagnostic criteria proposed by the international consensus guidelines 2012 for the management of malignant IPMNs by using MR imaging with MRCP in a larger sample size.
Published online before print 10.1148/radiol.14132960 Content code: Radiology 2015; 274:723–733 Abbreviations: CI = confidence interval ICC = intraclass correlation coefficient IPMN = intraductal papillary mucinous neoplasm MPD = main pancreatic duct MRCP = MR cholangiopancreatography 3D = three-dimensional Author contributions: Guarantors of integrity of entire study, S.H.K., J.M.L.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, S.H.K., J.M.L., E.S.L., J.H.K.; clinical studies, S.H.K., J.M.L.; statistical analysis, S.H.K.; and manuscript editing, all authors Conflicts of interest are listed at the end of this article.
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Figure 1
Materials and Methods Patients Institutional review board approval was obtained for this retrospective study, and the informed consent requirement was waived. Between May 2009 and February 2013, 616 patients underwent MR examinations for suspected IPMNs of the pancreas either at our institution or at an outside hospital. Among them, 123 patients underwent either surgery or US-guided biopsy at our institution after diagnosis of pancreatic IPMNs with a suspicion of at least borderline malignancy. We included (a) patients with pancreatic IPMNs who had undergone curative or palliative treatment at our hospital, (b) patients who had undergone a preoperative or preprocedure three-dimensional (3D) MRCP examination and a contrast material–enhanced 3D dynamic MR imaging examination within 3 months prior to surgery or biopsy, and (c) patients who had a diagnosis of pancreatic IPMN at pathologic examination. A total of 493 patients who did not undergo surgery or biopsy were excluded from the study. Thereafter, 25 patients were further excluded because of the absence of contrast-enhanced multiphasic MR imaging (n = 11) or subdiagnostic quality MR images or MRCP images due to severe motion artifacts from limited breath-holding capability or recent interventional procedures (n = 14). Finally, our retrospective analysis included 98 patients (mean age, 67.8 years; age range, 40–85 years), 93 of whom had undergone surgical resection and five of whom had received only nonsurgical palliative treatment because of the advanced stage of malignant IPMNs at preoperative MR examination, as determined by a consensus of two experienced abdominal radiologists (K.J.H., L.J.M.) with more than 20 years of experience, but had pathologically confirmed pancreatic IPMNs (Fig 1). Our study used two different sample sizes for the respective evaluation of the surgical resectability of pancreatic IPMNs and the malignant potential of IPMNs. For resectability assessment, all 98 patients, including five patients who
Kim et al
Figure 1: Flow diagram of enrolled patients. ∗Only patients who underwent surgical resection were enrolled in the evaluation of presumed malignant potential. ∗∗Five patients were included in addition to the 93 patients who underwent surgical resection to evaluate surgical resectability at MR imaging with MRCP.
had undergone only biopsy and who had been excluded from evaluation of tumor staging, were included. However, for evaluation of the diagnostic performance of MR imaging in determining the malignant potential of pancreatic IPMNs, only 93 patients who had undergone surgical resection were included, as the pathology reports of the five patients who underwent only biopsy were not sufficiently adequate to determine the malignancy of pancreatic IPMNs (Fig 1). Among the 93 patients who underwent surgical resection for pancreatic IPMNs, 51 had IPMNs with low- or moderate-grade dysplasia, 17 had IPMNs with high-grade dysplasia, and 25 had IPMNs associated with an invasive cancer. Mean interval between MR examinations and surgery was 25.8 days (range, 1–90 days).
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MR Technique Because of the retrospective nature of this study, various MR imagers were used. MR imaging was performed with either a 1.5-T MR unit (Signa Excite HDXT, GE Medical Systems, Milwaukee, Wis [n = 18]; Achieva, Philips Healthcare, Best, the Netherlands [n = 2]) with an eight-channel phased-array torso coil or a 3-T MR unit (Magnetom Verio or Trio, Siemens Medical Solutions, Erlangen, Germany [n = 74]; Ingenia or Achieva, Philips Healthcare [n = 4]) with a 32- or 12-channel phased-array torso coil. All MR images were obtained in the axial plane with a rectangular field of view of 380 3 380 mm that was adjusted for each patient. Baseline MR imaging examinations included breath-hold transverse 725
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1 12 4.8 300–350 320 3 224 1 11 3 300–380 384 3 278 1 90 2 256–320 320 3 320 69 130 0.9 380 384 3 366 1 90 50 260 320 3 256
* Data are for opposed-phase and in-phase sequences, respectively.
Note.—Imager 1 was a Magnetom Verio unit (Siemens Medical Solutions). Imager 2 was a Signa Excite HDXT unit (GE Medical Systems).
256 130 or 180 50 or 60 240 320 3 256 1 90 7 380 144 3 144 1 180 7 380 256 3 205 1 90 7 300–350 320 3 192 1 15 4.8 300–350 320 3 224 1 9 3 300–380 320 3 285
256 130 7 300–380 384 3 307
4.6/2.2 3.4/1.2 3750/820 2320/815 4000/1202 2500/909 3275/81.9 4500/52 905/159 6.6/2.1, 6.6/4.4* 4.0/1.3, 4.0/2.3*
Repetition time msec/echo time msec Echo train length Flip angle (degrees) Thickness (mm) Field of view (mm) Matrix
800/93
Imager 2
Dynamic Image
Imager 1 Imager 2
3D MRCP
Imager 1 Imager 2 Imager 1 Imager 2 Imager 1 Imager 2 Imager 1 Imager 2 Imager 1
Thick-Slab Single-Section MRCP Diffusion-weighted Imaging T2-weighted Imaging T1-weighted Imaging
MR Parameters
Table 1
Image Analysis Evaluation of the malignant potential of pancreas IPMNs.—Morphologic features of pancreatic IPMNs and parenchymal changes on MR images were independently evaluated by two experienced attending radiologists with a subspecialty
Parameter
T2-weighted imaging with a singleshot fast spin-echo sequence or a halfFourier acquisition single-shot turbo spin-echo sequence with or without fat saturation, transverse T1-weighted imaging with in-phase and opposedphase spoiled 3D gradient-echo sequences, and an unenhanced fat-suppressed 3D gradient-echo sequence (VIBE, Siemens Medical Solutions). Diffusion-weighted images were obtained with both 1.5- and 3-T MR units. The 3D MRCP data were then transferred to a dedicated 3D workstation (Advanced Workstation, GE Medical Systems) and reconstructed by using a maximum intensity projection algorithm to obtain oblique images rotating about the z-axis in 10° increments. Dynamic MR images were obtained before and after administration of 1.0-M gadobutrol (7.5 mL of Gadovist; Bayer Healthcare, Berlin, Germany) at a dose of 0.1 mmol per kilogram of body weight and an injection rate of 2 mL/ sec. Images were acquired before contrast material injection (precontrast) and 8 seconds (arterial phase), 60 seconds (portal venous phase), and 2, 3, and 5 minutes after contrast material arrival at the distal thoracic aorta. The timing of arterial phase imaging was determined by using the MR fluoroscopic technique, which allowed real-time visualization of the heart and aorta during repetitive measurements at the same coronal position as the T1-weighted gradient-echo sequence. Postcontrast subtracted images were obtained in all patients who underwent MR examinations at our institution. All parameters for the MR sequences of the two imagers are summarized in Table 1. The acquisition of 3D gradient-echo data in each phase was finished during one breath hold at the end of expiration (time range, 16–22 seconds; mean time, 18 seconds) (Table 1).
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Table 2 List of Criteria in the International Consensus Guideline 2012 and Scoring of Malignant Potential in Pancreatic IPMNs Classification High-risk stigmata Worrisome features
Findings
Score
Enhanced solid components infiltrating pancreas parenchyma and MPD size 10 mm MPD size of 5–9 mm, presence of intramural nodule, acute caliber change in the MPD, enhanced cyst walls, cystic mass size 30 mm, lymphadenopathy
5, presence of at least one finding of high-risk stigmata
in abdominal imaging (L.E.S., B.J.H.; 7 and 10 years of experience, respectively) and one inexperienced radiology trainee without any subspecialty (H.E.J., 4 years of experience in radiology) on a picture archiving and communication system workstation monitor (m-view; Marotech, Seoul, Korea). They were blinded to the patients’ histologic diagnosis, as well as to any clinical or laboratory information; however, they were aware that the study population had pancreatic IPMNs. They were requested to evaluate findings of high-risk stigmata and worrisome features on MRCP images (Table 2). Thereafter, to assess interobserver agreement among two experienced observers and one inexperienced observer, imaging findings were evaluated by using the criteria in Appendix E1 (online). In addition, consensus for individual MR findings was obtained to determine the most common individual findings that may suggest malignant pancreatic IPMNs. The two experienced radiologists and one inexperienced radiology trainee were then asked to determine the malignant potential and surgical resectability of pancreatic IPMNs. The presumed malignant potential of pancreatic IPMNs was evaluated with a five-point scale. First, they scored their diagnostic confidence in differentiating malignant IPMNs (IPMN with high-grade dysplasia and IPMN with an invasive cancer) from benign IPMNs (low-grade or moderate dysplasia) as follows: a score of 1 indicated a definitely benign IPMN; a score of 2, a probably benign IPMN; a score of 3, a possibly malignant IPMN; a score of 4, a probably malignant IPMN; and a score of 5, a definitely malignant IPMN. MR criteria for presuming the malignant
4, presence of two or more worrisome features; 3, presence of only one worrisome feature; 2, no worrisome feature with an unclear duct type; 1, no worrisome feature and a definite branch duct type
potential of pancreatic IPMNs were based on those recommended by the international consensus guidelines 2012 (7). The method of scoring is provided in Table 2. Interobserver agreement in determining the malignant potential of pancreatic IPMNs was also obtained. Evaluation of the surgical resectability of pancreatic IPMNs.—Surgical resectability of pancreatic IPMNs was evaluated by using the criteria used in previous studies of pancreatic adenocarcinoma or IPMN, including vascular encasement, regional or distant lymph node metastases, and metastases to other solid organs (7,15,28–32). Unresectable disease was defined as clearly identifiable distant metastases; overt lymphadenopathy at portocaval, retrocaval, paraaortic, and mesentery areas with the shortest diameter greater than 10 mm; tumor encasement (.180° of circumferential involvement) of arteries, such as the superior mesenteric artery, celiac trunk, common hepatic artery, or origin or long segment of the portal vein (.3 cm in length) or superior mesenteric vein; or complete occlusion of the portal vein (15,28). Thereafter, the two experienced readers and one inexperienced reader rated the possibility of resectability on a five-point scale: 1 for definitely unresectable, 2 for probably unresectable, 3 for possibly unresectable or undetermined, 4 for probably resectable, and 5 for definitely resectable. The observers were aware that a rating of 1–3 indicated an IPMN was unresectable and that a rating of 4–5 indicated an IPMN was resectable.
Surgical Resection One of two experienced pancreatobiliary surgeons (K.S.H. and J.J.Y., both
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with more than 20 years of experience) performed a number of different operations in 93 (95%) of 98 patients for pancreatic IPMNs according to the location of the tumor. These procedures included subtotal pancreatectomy (n = 26), pancreas head resection (n = 1), total pancreatectomy (n = 6), Whipple operation (n = 8), pylorus-preserving pancreaticoduodenectomy (n = 51), and choledochojejunostomy with excisional biopsy (n = 1) (Appendix E2, Table E1 [online]).
Histopathologic Analysis All resected IPMNs were reviewed by an experienced pathologist (L.K.B.) with more than 10 years of experience in the evaluation of hepatopancreatobiliary diseases. The pathologist described the following findings in the pathologic report: type of IPMN, location of tumor, size of tumor, presence of mural nodule, diameter of MPD, peripancreatic infiltration, vascular involvement, lymph node metastasis, perineural invasion, and involvement of adjacent solid organs. R0, R1, and R2 were recorded on either pathology or surgery reports with the following definitions: R0, no evidence of residual tumor at the resection margin both microscopically and macroscopically; R1, direct tumor growth (high-grade dysplasia or invasive carcinoma) up to or within 1 mm of the margin; and R2, macroscopic residual tumor tissue at the resection margin (33). In this study, R1 and R2 resection cases were classified as unresectable cases, and R0 resection cases were thought to be resectable. The incidence of unresectable cases is listed in Appendix E3 (online). 727
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Table 3 Frequency of MR Findings in Benign versus Malignant IPMNs with Statistical Significance and Their Interobserver Agreement on the Basis of the International Consensus Guidelines 2012 MR Finding Type of IPMN Main duct type Branch duct type Mixed type High-risk stigmata Enhanced solid component infiltrating parenchyma MPD diameter 10 mm Worrisome features Intramural nodule Abrupt caliber change in the MPD Enhanced cyst wall MPD diameter 5–9 mm Cystic mass 3 cm Measurement of MPD or tumor‡ Mean diameter of MPD (mm) Mean size of cystic mass (mm)
Benign IPMNs (n = 51)
Malignant IPMNs (n = 42)
2 (4) 37 (73) 12 (24)
Weighted k† or ICC Value P Value*
Observers 1 and 2
Observers 2 and 3
Observers 1 and 3
4 (10) 13 (31) 25 (60)
,.001
… … k = 0.394
… … k = 0.421
… … k = 0.594
1 (2)
14 (33)
,.001
k = 0.318
k = 0.398
k = 0.574
3 (6)
15 (36)
,.001
…
…
…
4 (8) 4 (8) 0 (0) 18 (35) 32 (63)
21 (50) 12 (29) 4 (10) 17 (40) 29 (69)
,.001 .012 .038 ,.001 NS
k = 0.574 k = 0.398 k = 0.195 … …
k = 0.449 k = 0.294 k = 0.211 … …
k = 0.349 k = 0.612 k = 0.066 … …
4.4 6 2.8 32.5 6 11.7
8.9 6 5.9 37.0 6 16.2
,.001 NS
ICC = 0.9477 ICC = 0.6982
Note.—Unless otherwise indicated, data are for all three observers in consensus. Data in parentheses are percentages. NS = not significant * P , .05 indicates a significant difference. †
Weighted k value of less than 0.20 indicates slight agreement; k value of 0.20–0.39, fair agreement; k value of 0.40–0.59, moderate agreement; k value of 0.60–0.79, substantial agreement; and
k value of 0.80 or greater, outstanding agreement. ICC value of 0.75 or higher indicates high agreement. ‡
Data are mean 6 standard deviation.
Statistical Analysis Preoperative or preprocedural MR evaluation of imaging findings, malignant potential, and overall tumor resectability were compared with the surgical findings and the pathology reports. Statistical analyses were performed with commercially available software (MedCalc for Windows, version 12.7.0; MedCalc Software, Mariakerke, Belgium). The prevalence of each stigmata or worrisome MR finding in benign pancreatic IPMNs and malignant pancreatic IPMNs was analyzed by using the Fisher exact test. Interobserver agreement was evaluated with the weighted k statistic for noncontinuous scales and with the intraclass correlation coefficient (ICC) for continuous scales. Weighted k values of less than 0.20 indicated slight agreement; weighted k values of 0.20–0.39, fair agreement; weighted k values of 0.40–0.59, moderate agreement; weighted k values 728
of 0.60–0.79, substantial agreement, and weighted k values of more than 0.80, outstanding agreement. ICCs of more than 0.75 were considered to be in high agreement. Diagnostic performance of MR imaging with MRCP in the determination of malignant potential and its resectability was analyzed by using receiver operating characteristic curve analysis. Sensitivity, specificity, accuracy, and interobserver agreement were determined, and P , .05 was considered to indicate a significant difference.
Results Interpreting Individual MR Imaging Findings and Their Interobserver Variation Among the MR imaging findings of highrisk stigmata and worrisome features, the prevalence of all imaging findings except cyst size 3 cm in diameter or larger (mean size of the cystic mass) and
MPD diameter of 5–9 mm were higher in patients with malignant IPMNs than in those with benign IPMNs (Table 3). In addition, intramural nodule was the most common finding among the imaging criteria observed in malignant pancreatic IPMNs, while enhanced solid component was the second most common finding according to the consensus reading of the three reviewers (Table 3). Most of the high-risk stigmata and worrisome features proposed by the international consensus guidelines 2012 were shown to have fair to moderate or high interobserver agreement, except for the enhanced cyst wall (Table 3). The three observers showed high interobserver agreement (ICC = 0.9477) for measurement of MPD diameter and fair to moderate interobserver agreement for measurement of pancreatic cyst size (ICC = 0.6982), classification of IPMN type (k = 0.394–0.594), detection of enhanced solid components infiltrating the parenchyma (k = 0.318–0.574),
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Figure 2
Figure 2: Intraductal papillary mucinous neoplasm associated with an invasive carcinoma in an 85-year-old woman who underwent a 3-T MR examination shows both a high-risk stigmata and a worrisome feature of MPD 10 mm or larger in diameter and intramural nodules (score 5). (a) Axial T2-weighted half-Fourier acquisition single-shot turbo spin-echo MR image shows marked dilatation of the MPD larger than 10 mm in diameter and multiple intraluminal nodules showing lower signal intensity than that of the pancreatic duct fluid (arrow). (b) A 3D MRCP image obtained with T2-weighted half-Fourier acquisition single-shot turbo spin-echo sequence shows marked dilatation of the MPD with multiple filling defects (arrows), which is suggestive of multiple mural nodules. (c) Delayed contrast-enhanced 3D axial gradient-echo MR image shows enhancement of multiple mural nodules (arrows) filling in the dilated MPD. Both reviewers determined the mass did not abut any major vessel. The mass was confirmed as an invasive carcinoma without vascular encasement.
Figure 3
Figure 3: Images in a 70-year-old man who was confirmed to have pancreatic IPMN of high-grade dysplasia at 3-T MR imaging with three worrisome features of a cystic mass at least 3 cm in diameter, an enhanced cystic wall, and an MPD diameter of 5–9 mm on MR images (score 4). (a) Axial T2-weighted half-Fourier acquisition single-shot turbo spin-echo MR image shows a lobulated cystic mass (arrow) larger than 3 cm in diameter in the pancreas uncinate process. (b) Delayed contrast-enhanced 3D axial gradient-echo MR image shows a cystic mass with thickened enhanced cyst walls (arrow) at the uncinate process abutting and compressing the major portal vein but without vascular encasement. (c) A 3D MRCP image shows an irregularly shaped cystic mass (arrow) at the uncinate process with associated diffuse upstream pancreatic duct dilatation (5–9 mm in diameter). Both reviewers interpreted the mass as separate from major vessels and assigned a diagnosis of resectable malignant IPMN (score 4). The mass was confirmed as a pancreatic IPMN with high-grade dysplasia negative for vascular encasement.
and identification of intramural nodules (k = 0.349–0.574). However, the three observers showed slight interobserver agreement in the detection of an enhanced cyst wall (k = 0.066–0.211).
Diagnostic Performance of MR Imaging with MRCP in Detecting Malignant Potential When the presence of at least one worrisome feature or any high-risk
stigmata (score 3) was regarded as indicating the malignant potential of IPMNs or specifically high-grade dysplasia and invasive carcinoma, the sensitivity of MR imaging with MRCP was 83% (35/42), 79% (33/42), and 90% (38/42) for observers 1, 2, and 3, respectively; specificity was 80% (41/51), 51% (26/51), and 22% (12/51), respectively; and accuracy
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was 82% (76/93), 63% (59/93), and 54% (50/93), respectively (Figs 2, 3); Fig E1 [online]). The area under the receiver operating characteristic curve of MR imaging with MRCP was 0.843 (95% confidence interval [CI]: 0.753, 0.910) for observer 1, 0.778 (95% CI: 0.680, 0.857) for observer 2, and 0.823 (95% CI: 0.730, 0.894) for observer 3 in determining the malignant potential of 729
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unresectable cases, underestimated six (46%) of 13 truly unresectable cases, and correctly evaluated resectability in 75 (88%) of 85 truly resectable cases. The positive predictive value of MR imaging with MRCP for observers 1, 2, and 3 in determining whether IPMNs were unresectable was 69% (nine of 13), 90% (nine of 10), and 39% (seven of 18), respectively (Table 5).
Table 4 Diagnostic Performance of MR Imaging with MRCP in the Evaluation of the Malignant Potential of Pancreas IPMNs Score and Statistic Score 5 only Sensitivity Specificity Accuracy Score 4 Sensitivity Specificity Accuracy Score 3 Sensitivity Specificity Accuracy
Observer 1 (%)
Observer 2 (%)
Observer 3 (%)
33 (14/42) 98 (50/51) 69 (64/93)
26 (11/42) 100 (51/51) 67 (62/93)
57 (24/42) 98 (50/51) 80 (74/93)
62 (26/42) 96 (49/51) 81 (75/93)
62 (26/42) 96 (49/51) 81 (75/93)
83 (35/42) 65 (33/51) 73 (68/93)
83 (35/42) 80 (41/51) 82 (76/93)
79 (33/42) 51 (26/51) 63 (59/93)
90 (38/42) 24 (12/51) 54 (50/93)
Discussion
Note.—Numbers in parentheses are raw data. Worrisome features and high-risk stigmata are based on the international consensus guidelines 2012.
pancreatic IPMNs. However, when only the presence of any high-risk stigmata regardless of worrisome features (score 5) was regarded as a criterion indicating the malignant potential of pancreatic IPMNs, the sensitivity of MR imaging with MRCP was 33% (14/42), 26% (11/42), and 57% (24/42) for observers 1, 2, and 3, respectively; specificity was 98% (50/51), 100% (51/51), and 98% (50/51), respectively; and accuracy was 69% (64/93), 67% (62/93), and 80% (74/93), respectively (Table 4). The two experienced observers showed substantial interobserver agreement (k = 0.652), while agreement between the experienced observers and the inexperienced observer was moderate (k = 0.460 and 0.475) in scoring the malignant potential when the suggested criteria of the international consensus guidelines 2012 were applied.
Diagnostic Performance of MR Imaging with MRCP in Evaluating Surgical Resectability The sensitivity of MR imaging with MRCP in determining surgical resectability was 95% (81/85), 99% (84/85), and 88% (75/85), respectively, for observers 1, 2, and 3 (Table 5). However, specificity was 69% (nine of 13) for observers 1 and 2 but 54% (seven of 13) forn observer 3, showing a tendency 730
toward underestimation of vascular encasement (Fig 4). Overall accuracy of observers 1, 2, and 3 was 92% (90/98), 95% (93/98), and 84% (82/98), respectively. The area under the receiver operating characteristic curve was 0.859 (95% CI: 0.728, 0.990) in observer 1, 0.831 (95% CI: 0.688, 0.974) in observer 2, and 0.751 (95% CI: 0.654, 0.833) in observer 3. The two experienced readers showed outstanding interobserver agreement in the evaluation of surgical resectability (k = 0.870), while the inexperienced reader and the experienced readers showed substantial interobserver agreement in the evaluation of surgical resectability (k = 0.706 and 0.739). Both experienced observers correctly evaluated unresectability in nine (69%) of 13 unresectable cases, while both experienced observers underestimated four (31%) of 13 truly unresectable cases. Of these, three were underestimation of portal vein invasion, and one was underestimation of superior mesenteric artery invasion. Conversely, observer 1 correctly evaluated resectability in 81 (95%) of 85 truly resectable cases, and observer 2 correctly evaluated resectability in 84 (99%) of 85 truly resectable cases. The inexperienced observer correctly evaluated unresectability in seven (54%) of 13
The recently introduced international consensus guidelines 2012 for the management of IPMNs and mucinous cystic neoplasms of the pancreas gave us useful recommendations for the management of IPMNs. However, questions remained as to the diagnostic performance of MR imaging with MRCP in determining the malignant potential and surgical resectability of pancreas IPMNs with the new criteria. Our study results showed that MR imaging with MRCP showed acceptable diagnostic performance in the prediction of the malignant potential of IPMNs when using the image criteria of the international consensus guidelines 2012. Specifically, we observed that the diagnostic accuracy of MR imaging with MRCP ranged from 63% (59/93) to 82% (76/93) in experienced observers and was 54% (50/93) in an inexperienced observer when we considered the presence of at least one worrisome feature or any high-risk stigmata (score 3) as criteria for diagnosis of the malignant potential of IPMNs, with high sensitivity. Under these combined criteria, for observers 1, 2, and 3, respectively, sensitivity was 83% (35/42), 79% (33/42), and 90% (38/42); specificity was 80% (41/51), 51% (26/51), and 22% (12/51); and accuracy was 82% (76/93), 63% (59/93), and 54% (50/93). The low specificity of experienced observer 2 and inexperienced observer 3 and the substantial gap between the three observers may be explained by the low interobserver reliability in the evaluation of enhanced cyst walls and abrupt caliber changes in the MPD. The enhanced cyst wall is difficult to discriminate on MR images,
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Table 5 Surgical Resectability According to MR Imaging with MRCP Results in 98 Patients with IPMNs R1† or R2‡ Resection or Not Resected (n = 13)
R0 Resection* (n = 85) MR Result Resectable Not resectable
Observer 1
Observer 2
Observer 3
Observer 1
Observer 2
Observer 3
81 (95) 4 (5)
84 (99) 1 (1)
75 (88) 10 (12)
4 (31) 9 (69)
4 (31) 9 (69)
6 (46) 7 (54)
* R0 resection = no evidence of residual tumor at the resection margin both microscopically or macroscopically. †
R1 resection = direct tumor growth (high-grade dysplasia or invasive carcinoma) up to or within 1 mm of the margin.
‡
R2 resection = macroscopic residual tumor tissue at the resection margin.
Figure 4
Figure 4: Images in a 72-year-old woman with invasive cancer who underwent a 3-T MR examination and had an incomplete resection (R2 resection). (a) A 3D MRCP image shows a multiseptated cystic mass in the pancreas head with upstream pancreatic duct dilatation and segmental narrowing (arrow) of the distal common bile duct, suggesting possible common bile duct invasion. (b) Axial contrast-enhanced T1-weighted MR image shows the ill-defined enhancing solid portion (arrow) of the mass. (c) Coronal contrast-enhanced T1-weighted MR image shows segmental narrowing of the distal common bile duct with enhancing wall thickening (arrow), suggesting distal common bile duct invasion by the tumor. The observers interpreted this case as a resectable invasive cancer (score 5); however, during surgery, the mass was deemed to be not resectable owing to severe invasion into the main portal vein and the superior mesenteric vein.
even with the help of postcontrast subtraction sequences. Moreover, the evaluation of MPD strictures is relatively subjective, particularly when associated with pancreatitis; we did not count findings as strictures in such a situation. It was even more difficult for the inexperienced observer to discriminate such findings, and he had a tendency to overrate imaging findings of worrisome features or high-risk stigmata, probably owing to a lack of experience and a sense of self-preservation. This might have resulted in higher sensitivity and lower specificity in the inexperienced observer. Indeed, Barron et al (34) reported that it may not be possible to classify main duct-type IPMNs appropriately solely on the basis of imaging studies. Our results showed fair to moderate interobserver reliability
in the evaluation of duct-type IPMNs, which also may contribute to the low specificity in diagnosing the malignant potential of pancreatic IPMNs. Further refinement for enhanced cyst walls and abrupt caliber changes of the MPD may be required to improve specificity and the gap between different observers. Furthermore, we observed that specificity increased markedly (.96%) when we applied the criteria of a score of more than 4. In addition, among the findings of worrisome features and high-risk stigmata, intramural nodule was the most commonly detected finding in malignant pancreatic IPMNs, and an enhancing solid component was the second most common finding when considering only the proposed findings for high-risk stigmata and worrisome features.
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Interobserver agreement for worrisome features or high-risk stigmata was fair to high. Interobserver agreement was especially high in the measurement of MPD diameter. The two experienced observers and the one inexperienced observer exhibited fair to moderate interobserver agreement in the measurement of cystic mass size, detection of enhanced solid components infiltrating the parenchyma, and the presence of abrupt caliber change in the MPD, whereas they showed only slight interobserver agreement (k = 0.066–0.211) in the detection of the presence of enhanced cyst walls. In addition, moderate interobserver agreement was observed in the detection of the presence of mural nodules, which was in good agreement with the results of a previous study by Manfredi et al (14). The 731
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poor interobserver agreement observed in the detection of enhanced cyst walls in our study could be explained by the fact that IPMNs are composed of dilated pancreatic ducts; thus, it may have been difficult to differentiate enhanced cyst walls from enhanced pancreatic duct walls. To continue to improve interobserver agreement, further clarification and refinement of the criteria in the international consensus guidelines for multidetector row CT and MR imaging suggesting malignancy may be necessary. In our study, the sensitivity of the two experienced observers was quite high (95% [81/85] and 99% [84/85] for observers 1 and 2, respectively) in the evaluation of the surgical resectability of IPMN lesions, whereas specificity was moderate (69% [nine of 13] for both reviewers) and overall accuracy (92% [90/98] and 95% [93/98] for observers 1 and 2, respectively) was satisfactory. Sensitivity (88%, [75/85]), specificity (54% [seven of 13]), and accuracy (84% [82/98]) were slightly lower in the inexperienced observer. These results are considerably better than those reported by Vullierme et al (15), who reported that the overall accuracy of helical CT in determining the surgical resectability of malignant IPMNs with invasive cancer was 74% but that the positive predictive value of CT in determining unresectability was only 17%, mainly owing to overestimation of arterial invasion. Our study showed that the positive predictive value of MR imaging with MRCP for experienced observers 1 and 2 in determining whether IPMNs were unresectable was 69% (nine of 13) and 90% (nine of 10), respectively. One important difference between our study and a previous study (15), which showed that CT usually resulted in overestimation of tumor extent and misdiagnosis of unresectability even in resectable cases, was that our results showed that MR imaging with MRCP tended to result in underestimation of tumor extent and misdiagnosis of unresectable cases as resectable, even though this modality was accurate in the detection of resectable lesions. Our study had several limitations. First, as the evaluation of cases was 732
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retrospective, there was unavoidable selection bias and verification bias. However, as MR imaging with MRCP is one of the standard preoperative diagnostic modalities used in the evaluation of IPMNs at our institution, selection bias might not have been serious. In addition, verification bias may have been unavoidable, as we used a strict reference standard to assess resectability. Second, MR images were obtained from multiple institutions, resulting in use of a variety of MR machines, MR sequences, and contrast materials. These variations might have interfered with the interpretation of images during the retrospective image analyses. Third, to decrease selection bias in the evaluation of surgical resectability, we enrolled patients with lesions deemed to be unresectable by two experienced abdominal imaging radiologists in consensus. However, there is a possibility that the good results obtained in our study may be related to the inclusion of relatively advanced cases in our study population. Fourth, as multidetector row CT is the primary modality used to evaluate pancreativ IPMNs at our institution, many macroscopically unresectable cases were excluded on the basis of CT findings, without the need for an MR examination. Thus, only patients with difficult cases of unresectable IPMN that were equivocal in the determination of tumor resectability at CT and that required further MR examination were enrolled in our study. Further studies involving a direct comparison between multidetector row CT and MR imaging with MR CP in determining the surgical resectability of IPMNs with invasive cancer are warranted to better address this limitation. In conclusion, MR imaging with MR CP has high sensitivity in the diagnosis of malignant IPMNs when the presence of at least one worrisome feature or any high-risk stigmata (score 3) is used as a criterion for malignant IPMN, with high interobserver agreement. In addition, MR imaging with MRCP showed high sensitivity and diagnostic accuracy in the determination of surgical resectability, albeit with a relatively high rate of underestimating surgical unresectability.
Acknowledgments: We thank Eui Jin Hwang, MD, for his assistance in reviewing MR imaging findings. We also thank Chris Woo, BA, for his English editorial assistance. Disclosures of Conflicts of Interest: S.H.K. disclosed no relevant relationships. J.M.L. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received grants from Bayer Healthcare, GE Healthcare, CMS, Acuzen, and Guerbe Starmed; is on the board of Bayer Healthcare; gave lectures for Bayer Healthcare; is a consultant for Siemens Healthcare. Other relationships: disclosed no relevant relationships. E.S.L. disclosed no relevant relationships. J.H.B. disclosed no relevant relationships. J.H.K. disclosed no relevant relationships. J.K.H. disclosed no relevant relationships. B.I.C. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received a grant from Samsung Electronics. Other relationships: disclosed no relevant relationships.
References 1. Lim JH, Lee G, Oh YL. Radiologic spectrum of intraductal papillary mucinous tumor of the pancreas. RadioGraphics 2001;21(2):323–337; discussion 337–340. 2. Augustin T, Vandermeer TJ. Intraductal papillary mucinous neoplasm: a clinicopathologic review. Surg Clin North Am 2010;90(2):377–398. 3. Shi C, Hruban RH. Intraductal papillary mucinous neoplasm. Hum Pathol 2012; 43(1):1–16. 4. Klibansky DA, Reid-Lombardo KM, Gordon SR, Gardner TB. The clinical relevance of the increasing incidence of intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol 2012;10(5):555–558. 5. de Jong K, Bruno MJ, Fockens P. Epidemiology, diagnosis, and management of cystic lesions of the pancreas. Gastroenterol Res Pract 2012;2012:147465. 6. Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2004;28(8):977–987. 7. Tanaka M, Fernández-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12(3):183–197. 8. Bassi C, Sarr MG, Lillemoe KD, Reber HA. Natural history of intraductal papillary mucinous neoplasms (IPMN): current evidence and implications for management. J Gastrointest Surg 2008;12(4):645–650.
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9. Kimura W, Sasahira N, Yoshikawa T, Muto T, Makuuchi M. Duct-ectatic type of mucin producing tumor of the pancreas: new concept of pancreatic neoplasia. Hepatogastroenterology 1996;43(9):692–709. 10. Ogawa H, Itoh S, Ikeda M, Suzuki K, Naganawa S. Intraductal papillary mucinous neoplasm of the pancreas: assessment of the likelihood of invasiveness with multisection CT. Radiology 2008;248(3):876–886. 11. Kawamoto S, Horton KM, Lawler LP, Hruban RH, Fishman EK. Intraductal papillary mucinous neoplasm of the pancreas: can benign lesions be differentiated from malignant lesions with multidetector CT? RadioGraphics 2005;25(6):1451–1468; discussion 1468–1470. 12. Taouli B, Vilgrain V, Vullierme MP, et al. Intraductal papillary mucinous tumors of the pancreas: helical CT with histopathologic correlation. Radiology 2000;217(3):757–764. 13. Sugiyama M, Atomi Y. Intraductal papillary mucinous tumors of the pancreas: imaging studies and treatment strategies. Ann Surg 1998;228(5):685–691. 14. Manfredi R, Graziani R, Motton M, et al. Main pancreatic duct intraductal papillary mucinous neoplasms: accuracy of MR imaging in differentiation between benign and malignant tumors compared with histopathologic analysis. Radiology 2009;253(1): 106–115. 15. Vullierme MP, Giraud-Cohen M, Hammel P, et al. Malignant intraductal papillary mucinous neoplasm of the pancreas: in situ versus invasive carcinoma surgical resectability. Radiology 2007;245(2):483–490. 16. Uchiyama S, Chijiiwa K, Hiyoshi M, et al. Mucin-producing bile duct tumor of the caudate lobe protruding into the common hepatic duct. J Gastrointest Surg 2007;11(11): 1570–1572. 17. Sugiyama M, Izumisato Y, Abe N, Masaki T, Mori T, Atomi Y. Predictive factors for malignancy in intraductal papillary-muci-
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nous tumours of the pancreas. Br J Surg 2003;90(10):1244–1249.
the pancreas. Eur J Surg Oncol 2007;33(6): 678–684.
18. Sugiyama M, Atomi Y, Kuroda A. Two types of mucin-producing cystic tumors of the pancreas: diagnosis and treatment. Surgery 1997;122(3):617–625.
27. Berland LL, Silverman SG, Gore RM, et al. Managing incidental findings on abdominal CT: white paper of the ACR incidental findings committee. J Am Coll Radiol 2010;7(10):754–773.
19. Waters JA, Schmidt CM, Pinchot JW, et al. CT vs MRCP: optimal classification of IPMN type and extent. J Gastrointest Surg 2008;12(1):101–109. 20. Song SJ, Lee JM, Kim YJ, et al. Differentiation of intraductal papillary mucinous neoplasms from other pancreatic cystic masses: comparison of multirow-detector CT and MR imaging using ROC analysis. J Magn Reson Imaging 2007;26(1):86–93. 21. Sahani DV, Kadavigere R, Blake M, Fernandez-Del Castillo C, Lauwers GY, Hahn PF. Intraductal papillary mucinous neoplasm of pancreas: multi-detector row CT with 2D curved reformations—correlation with MRCP. Radiology 2006;238(2):560–569. 22. Pedrosa I, Boparai D. Imaging consider ations in intraductal papillary mucinous neoplasms of the pancreas. World J Gastrointest Surg 2010;2(10):324–330. 23. Macari M, Eubig J, Robinson E, et al. Frequency of intraductal papillary mucinous neoplasm in patients with and without pancreas cancer. Pancreatology 2010;10(6): 734–741. 24. Kim JH, Hong SS, Kim YJ, Kim JK, Eun HW. Intraductal papillary mucinous neoplasm of the pancreas: differentiate from chronic pancreatits by MR imaging. Eur J Radiol 2012;81(4):671–676. 25. Kang KM, Lee JM, Shin CI, et al. Added value of diffusion-weighted imaging to MR cholangiopancreatography with unenhanced MR imaging for predicting malignancy or invasiveness of intraductal papillary mucinous neoplasm of the pancreas. J Magn Reson Imaging 2013;38(3):555–563. 26. Gourgiotis S, Ridolfini MP, Germanos S. Intraductal papillary mucinous neoplasms of
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28. Pezzilli R, Serra C, Calculli L, Ferroni F, Iammarino MT, Casadei R. Three-dimensional contrast-enhanced ultrasonography of intraductal papillary mucinous neoplasms of the pancreas: a comparison with magnetic resonance imaging. Pancreas 2013;42(7): 1164–1168. 29. Raman SP, Kawamoto S, Blackford A, et al. Histopathologic findings of multifocal pancreatic intraductal papillary mucinous neoplasms on CT. AJR Am J Roentgenol 2013;200(3): 563–569. 30. Diehl SJ, Lehmann KJ, Sadick M, Lach mann R, Georgi M. Pancreatic cancer: value of dual-phase helical CT in assessing resectability. Radiology 1998;206(2):373–378. 31. Hough TJ, Raptopoulos V, Siewert B, Matthews JB. Teardrop superior mesenteric vein: CT sign for unresectable carcinoma of the pancreas. AJR Am J Roentgenol 1999;173(6): 1509–1512. 32. O’Malley ME, Boland GW, Wood BJ, Fer nandez-del Castillo C, Warshaw AL, Mueller PR. Adenocarcinoma of the head of the pancreas: determination of surgical unresectability with thin-section pancreatic-phase helical CT. AJR Am J Roentgenol 1999;173(6):1513–1518. 33. Verbeke CS. Resection margins in pancre atic cancer. Surg Clin North Am 2013;93(3): 647–662. 34. Barron MR, Roch AM, Waters JA, et al. Does preoperative cross-sectional imaging accurately predict main duct involvement in intraductal papillary mucinous neoplasm? J Gastrointest Surg 2014;18(3):447–455; discussion 5455–5456.
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Original Research n Gastrointestinal
Intraductal Papillary Mucinous Neoplasms of the Pancreas: Evaluation of Malignant Potential and Surgical Resectability by Using MR Imaging with MR Cholangiography1 Purpose:
To evaluate the diagnostic performance of magnetic resonance (MR) imaging with MR cholangiopancreatography (MRCP) in determining the malignant potential and surgical resectability of pancreas intraductal papillary mucinous neoplasms (IPMNs).
Materials and Methods:
Institutional review board approval was obtained, and the requirement for informed consent was waived. Ninetyeight patients with pathologically proved pancreas IPMNs who underwent MR imaging with MRCP comprised the study population. MR images were analyzed for findings suggestive of high-risk stigmata or worrisome features, as proposed by the international consensus guidelines 2012. Interobserver agreement between two experienced observers (observers 1 and 2) and one inexperienced observer (observer 3) was assessed. Diagnostic performance of MR imaging in the evaluation of the malignant potential and surgical resectability of IPMNs was analyzed in these three observers by using receiver operating curve analysis.
Results:
MR imaging with MRCP showed sensitivity of 83% (35/42), 79% (33/42), and 90% (38/42); specificity of 80% (41/51), 51% (26/51), and 24% (12/51); and accuracy of 82% (76/93), 63% (59/93), and 54% (50/93) for observers 1, 2, and 3, respectively, in the evaluation of the malignant potential of pancreas IPMNs when at least one worrisome feature was present. Interobserver agreement in the detection of intramural nodules (k = 0.349–0.574), enhanced solid components (k = 0.318–0.574), and measurement of main pancreatic duct diameter (intraclass correlation coefficient = 0.9477) was fair to high. The respective sensitivity, specificity, and accuracy in determination of surgical resectability were 95% (81/85), 99% (84/85), and 88% (75/85); 69% (9/13), 69% (9/13), and 54% (7/13); and 92% (90/98), 95% (93/98), and 84% (82/98) for observers 1, 2, and 3.
Conclusion:
MR imaging with MRCP is a useful modality in the evaluation of the malignant potential and resectability of IPMNs, with high sensitivity and moderate specificity in the experienced radiologists but relatively low specificity in the inexperienced radiology trainee.
1
From the Department of Radiology (S.H.K., J.M.L., J.H.B., J.H.K., J.K.H., B.I.C.) and Institute of Radiation Medicine (J.M.L., J.H.K., J.K.H., B.I.C.), Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea; and Department of Radiology, Research Institute and Hospital of National Cancer Center, Goyang, Republic of Korea (E.S.L.). Received December 29, 2013; revision requested February 3, 2014; revision received April 13; accepted June 16; final version accepted August 12. Address correspondence to J.M.L. (e-mail: [email protected]). RSNA, 2014
q
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RSNA, 2014
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Online supplemental material is available for this article. 723
Imaging
Seong Ho Kim, MD Jeong Min Lee, MD Eun Sun Lee, MD Jee Hyun Baek, MD Jung Hoon Kim, MD Joon Koo Han, MD Byung Ihn Choi, MD
GASTROINTESTINAL IMAGING: Intraductal Papillary Mucinous Neoplasms of the Pancreas
I
ntraductal papillary mucinous neoplasm (IPMN) of the pancreas is defined as a tumor growing in the main duct or branch duct of the pancreas,
Advances in Knowledge nn MR imaging with MR cholangiopancreatography (MRCP) showed sensitivity of 83% (35/42), 79% (33/42), and 90% (38/42); specificity of 80% (41/51), 51% (26/51), and 24% (12/51); and accuracy of 82% (76/93), 63% (59/93), and 54% (50/93) in two experienced observers and one inexperienced observer, respectively, who were evaluating the malignant potential of pancreatic intraductal papillary mucinous neoplasms (IPMNs) when at least one worrisome feature was present. nn Interobserver agreement in the detection of intramural nodules (k = 0.349–0.574) and enhanced solid components infiltrating the parenchyma (k = 0.318–0.574) and for the measurement of main pancreatic duct diameter (intraclass correlation coefficient = 0.9477) and pancreatic cyst size (intraclass correlation coefficient = 0.6982) was fair to high, whereas interobserver agreement in the detection of enhanced cyst walls (k = 0.066–0.211) was relatively limited among the two experienced observers and the one inexperienced observer. nn Agreement for detection of abrupt caliber changes in the main pancreatic duct (k = 0.294– 0.612) was variable between the three observers. nn Overall accuracy of MR imaging with MRCP in determining surgical resectability was 92% (90/98), 95% (93/98), and 84% (82/98) in two experienced observers and one inexperienced observer, respectively, while showing a tendency toward underestimation of vascular encasement. 724
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with differentiated papillary features and production of atypical mucin, as well as segmental or diffuse dilation of the main pancreatic duct (MPD), cystic dilation of the secondary branches, or both (1). It is clinically subcategorized into three types: main-duct IPMN, branch-duct IPMN, and mixed IPMN, and the malignant potential is known to be higher in main-duct IPMNs and mixed IPMNs (2,3). In recent years, the incidence and number of surgical resections for pancreatic IPMNs has increased significantly (4,5). However, this increase has come without a corresponding increase in IPMN-related or overall pancreatic cancer–related mortality. Thus, it is likely to have resulted from an increase in diagnostic scrutiny, particularly the expansive use of high-resolution cross-sectional imaging techniques, such as multidetector row computed tomography (CT) or magnetic resonance (MR) imaging, rather than from a greater incidence of patients with IPMNs (4). According to the 2010 World Health Organization classification, pancreatic IPMNs can be subcategorized into IPMNs with low- or moderate-grade dysplasia, which are considered benign, and IPMNs with high-grade dysplasia or those associated with invasive cancers, which are considered malignant (3,6–8). Previous studies have described the imaging criteria in the differentiation of malignant IPMNs from benign IPMNs (7,9–18), and partly on the basis of those studies, the international consensus guidelines 2012 for the management of IPMNs and mucinous cystic neoplasms of the pancreas have been issued (7,9–18). The new international consensus guidelines recommend multidetector row CT or MR imaging with
Implication for Patient Care nn MR imaging with MRCP is a useful modality in the evaluation of malignant potential and resectability of IPMNs, with high sensitivity and moderate specificity in the experienced radiologists, albeit with relatively low specificity in the inexperienced radiology trainee.
MR cholangiopancreatography (CP) in the evaluation of pancreatic cysts larger than 1 cm to check for high-risk stigmata or worrisome features. In cysts that show high-risk stigmata, surgical management is recommended. In cysts that show worrisome features or that are larger than 3 cm without worrisome features, endoscopic ultrasonography (US) is recommended (7). If no worrisome features are present, no further diagnostic work-up is recommended, although surveillance is still required. Even though CT is still a mainstay in the evaluation of the surgical resectability of pancreatic IPMNs with a strong preference among pancreatic surgeons, MR imaging with MRCP has come into wide acceptance in recent days (7,14,19–27). Thus, the aim of our study was to evaluate the diagnostic performance of MR imaging with MRCP in determining the malignant potential and surgical resectability of pancreatic IPMNs by using pathologic and surgical analyses as reference standards. In addition, we attempted to evaluate the interobserver agreement in applying the diagnostic criteria proposed by the international consensus guidelines 2012 for the management of malignant IPMNs by using MR imaging with MRCP in a larger sample size.
Published online before print 10.1148/radiol.14132960 Content code: Radiology 2015; 274:723–733 Abbreviations: CI = confidence interval ICC = intraclass correlation coefficient IPMN = intraductal papillary mucinous neoplasm MPD = main pancreatic duct MRCP = MR cholangiopancreatography 3D = three-dimensional Author contributions: Guarantors of integrity of entire study, S.H.K., J.M.L.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, S.H.K., J.M.L., E.S.L., J.H.K.; clinical studies, S.H.K., J.M.L.; statistical analysis, S.H.K.; and manuscript editing, all authors Conflicts of interest are listed at the end of this article.
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Figure 1
Materials and Methods Patients Institutional review board approval was obtained for this retrospective study, and the informed consent requirement was waived. Between May 2009 and February 2013, 616 patients underwent MR examinations for suspected IPMNs of the pancreas either at our institution or at an outside hospital. Among them, 123 patients underwent either surgery or US-guided biopsy at our institution after diagnosis of pancreatic IPMNs with a suspicion of at least borderline malignancy. We included (a) patients with pancreatic IPMNs who had undergone curative or palliative treatment at our hospital, (b) patients who had undergone a preoperative or preprocedure three-dimensional (3D) MRCP examination and a contrast material–enhanced 3D dynamic MR imaging examination within 3 months prior to surgery or biopsy, and (c) patients who had a diagnosis of pancreatic IPMN at pathologic examination. A total of 493 patients who did not undergo surgery or biopsy were excluded from the study. Thereafter, 25 patients were further excluded because of the absence of contrast-enhanced multiphasic MR imaging (n = 11) or subdiagnostic quality MR images or MRCP images due to severe motion artifacts from limited breath-holding capability or recent interventional procedures (n = 14). Finally, our retrospective analysis included 98 patients (mean age, 67.8 years; age range, 40–85 years), 93 of whom had undergone surgical resection and five of whom had received only nonsurgical palliative treatment because of the advanced stage of malignant IPMNs at preoperative MR examination, as determined by a consensus of two experienced abdominal radiologists (K.J.H., L.J.M.) with more than 20 years of experience, but had pathologically confirmed pancreatic IPMNs (Fig 1). Our study used two different sample sizes for the respective evaluation of the surgical resectability of pancreatic IPMNs and the malignant potential of IPMNs. For resectability assessment, all 98 patients, including five patients who
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Figure 1: Flow diagram of enrolled patients. ∗Only patients who underwent surgical resection were enrolled in the evaluation of presumed malignant potential. ∗∗Five patients were included in addition to the 93 patients who underwent surgical resection to evaluate surgical resectability at MR imaging with MRCP.
had undergone only biopsy and who had been excluded from evaluation of tumor staging, were included. However, for evaluation of the diagnostic performance of MR imaging in determining the malignant potential of pancreatic IPMNs, only 93 patients who had undergone surgical resection were included, as the pathology reports of the five patients who underwent only biopsy were not sufficiently adequate to determine the malignancy of pancreatic IPMNs (Fig 1). Among the 93 patients who underwent surgical resection for pancreatic IPMNs, 51 had IPMNs with low- or moderate-grade dysplasia, 17 had IPMNs with high-grade dysplasia, and 25 had IPMNs associated with an invasive cancer. Mean interval between MR examinations and surgery was 25.8 days (range, 1–90 days).
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MR Technique Because of the retrospective nature of this study, various MR imagers were used. MR imaging was performed with either a 1.5-T MR unit (Signa Excite HDXT, GE Medical Systems, Milwaukee, Wis [n = 18]; Achieva, Philips Healthcare, Best, the Netherlands [n = 2]) with an eight-channel phased-array torso coil or a 3-T MR unit (Magnetom Verio or Trio, Siemens Medical Solutions, Erlangen, Germany [n = 74]; Ingenia or Achieva, Philips Healthcare [n = 4]) with a 32- or 12-channel phased-array torso coil. All MR images were obtained in the axial plane with a rectangular field of view of 380 3 380 mm that was adjusted for each patient. Baseline MR imaging examinations included breath-hold transverse 725
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726
1 12 4.8 300–350 320 3 224 1 11 3 300–380 384 3 278 1 90 2 256–320 320 3 320 69 130 0.9 380 384 3 366 1 90 50 260 320 3 256
* Data are for opposed-phase and in-phase sequences, respectively.
Note.—Imager 1 was a Magnetom Verio unit (Siemens Medical Solutions). Imager 2 was a Signa Excite HDXT unit (GE Medical Systems).
256 130 or 180 50 or 60 240 320 3 256 1 90 7 380 144 3 144 1 180 7 380 256 3 205 1 90 7 300–350 320 3 192 1 15 4.8 300–350 320 3 224 1 9 3 300–380 320 3 285
256 130 7 300–380 384 3 307
4.6/2.2 3.4/1.2 3750/820 2320/815 4000/1202 2500/909 3275/81.9 4500/52 905/159 6.6/2.1, 6.6/4.4* 4.0/1.3, 4.0/2.3*
Repetition time msec/echo time msec Echo train length Flip angle (degrees) Thickness (mm) Field of view (mm) Matrix
800/93
Imager 2
Dynamic Image
Imager 1 Imager 2
3D MRCP
Imager 1 Imager 2 Imager 1 Imager 2 Imager 1 Imager 2 Imager 1 Imager 2 Imager 1
Thick-Slab Single-Section MRCP Diffusion-weighted Imaging T2-weighted Imaging T1-weighted Imaging
MR Parameters
Table 1
Image Analysis Evaluation of the malignant potential of pancreas IPMNs.—Morphologic features of pancreatic IPMNs and parenchymal changes on MR images were independently evaluated by two experienced attending radiologists with a subspecialty
Parameter
T2-weighted imaging with a singleshot fast spin-echo sequence or a halfFourier acquisition single-shot turbo spin-echo sequence with or without fat saturation, transverse T1-weighted imaging with in-phase and opposedphase spoiled 3D gradient-echo sequences, and an unenhanced fat-suppressed 3D gradient-echo sequence (VIBE, Siemens Medical Solutions). Diffusion-weighted images were obtained with both 1.5- and 3-T MR units. The 3D MRCP data were then transferred to a dedicated 3D workstation (Advanced Workstation, GE Medical Systems) and reconstructed by using a maximum intensity projection algorithm to obtain oblique images rotating about the z-axis in 10° increments. Dynamic MR images were obtained before and after administration of 1.0-M gadobutrol (7.5 mL of Gadovist; Bayer Healthcare, Berlin, Germany) at a dose of 0.1 mmol per kilogram of body weight and an injection rate of 2 mL/ sec. Images were acquired before contrast material injection (precontrast) and 8 seconds (arterial phase), 60 seconds (portal venous phase), and 2, 3, and 5 minutes after contrast material arrival at the distal thoracic aorta. The timing of arterial phase imaging was determined by using the MR fluoroscopic technique, which allowed real-time visualization of the heart and aorta during repetitive measurements at the same coronal position as the T1-weighted gradient-echo sequence. Postcontrast subtracted images were obtained in all patients who underwent MR examinations at our institution. All parameters for the MR sequences of the two imagers are summarized in Table 1. The acquisition of 3D gradient-echo data in each phase was finished during one breath hold at the end of expiration (time range, 16–22 seconds; mean time, 18 seconds) (Table 1).
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Table 2 List of Criteria in the International Consensus Guideline 2012 and Scoring of Malignant Potential in Pancreatic IPMNs Classification High-risk stigmata Worrisome features
Findings
Score
Enhanced solid components infiltrating pancreas parenchyma and MPD size 10 mm MPD size of 5–9 mm, presence of intramural nodule, acute caliber change in the MPD, enhanced cyst walls, cystic mass size 30 mm, lymphadenopathy
5, presence of at least one finding of high-risk stigmata
in abdominal imaging (L.E.S., B.J.H.; 7 and 10 years of experience, respectively) and one inexperienced radiology trainee without any subspecialty (H.E.J., 4 years of experience in radiology) on a picture archiving and communication system workstation monitor (m-view; Marotech, Seoul, Korea). They were blinded to the patients’ histologic diagnosis, as well as to any clinical or laboratory information; however, they were aware that the study population had pancreatic IPMNs. They were requested to evaluate findings of high-risk stigmata and worrisome features on MRCP images (Table 2). Thereafter, to assess interobserver agreement among two experienced observers and one inexperienced observer, imaging findings were evaluated by using the criteria in Appendix E1 (online). In addition, consensus for individual MR findings was obtained to determine the most common individual findings that may suggest malignant pancreatic IPMNs. The two experienced radiologists and one inexperienced radiology trainee were then asked to determine the malignant potential and surgical resectability of pancreatic IPMNs. The presumed malignant potential of pancreatic IPMNs was evaluated with a five-point scale. First, they scored their diagnostic confidence in differentiating malignant IPMNs (IPMN with high-grade dysplasia and IPMN with an invasive cancer) from benign IPMNs (low-grade or moderate dysplasia) as follows: a score of 1 indicated a definitely benign IPMN; a score of 2, a probably benign IPMN; a score of 3, a possibly malignant IPMN; a score of 4, a probably malignant IPMN; and a score of 5, a definitely malignant IPMN. MR criteria for presuming the malignant
4, presence of two or more worrisome features; 3, presence of only one worrisome feature; 2, no worrisome feature with an unclear duct type; 1, no worrisome feature and a definite branch duct type
potential of pancreatic IPMNs were based on those recommended by the international consensus guidelines 2012 (7). The method of scoring is provided in Table 2. Interobserver agreement in determining the malignant potential of pancreatic IPMNs was also obtained. Evaluation of the surgical resectability of pancreatic IPMNs.—Surgical resectability of pancreatic IPMNs was evaluated by using the criteria used in previous studies of pancreatic adenocarcinoma or IPMN, including vascular encasement, regional or distant lymph node metastases, and metastases to other solid organs (7,15,28–32). Unresectable disease was defined as clearly identifiable distant metastases; overt lymphadenopathy at portocaval, retrocaval, paraaortic, and mesentery areas with the shortest diameter greater than 10 mm; tumor encasement (.180° of circumferential involvement) of arteries, such as the superior mesenteric artery, celiac trunk, common hepatic artery, or origin or long segment of the portal vein (.3 cm in length) or superior mesenteric vein; or complete occlusion of the portal vein (15,28). Thereafter, the two experienced readers and one inexperienced reader rated the possibility of resectability on a five-point scale: 1 for definitely unresectable, 2 for probably unresectable, 3 for possibly unresectable or undetermined, 4 for probably resectable, and 5 for definitely resectable. The observers were aware that a rating of 1–3 indicated an IPMN was unresectable and that a rating of 4–5 indicated an IPMN was resectable.
Surgical Resection One of two experienced pancreatobiliary surgeons (K.S.H. and J.J.Y., both
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with more than 20 years of experience) performed a number of different operations in 93 (95%) of 98 patients for pancreatic IPMNs according to the location of the tumor. These procedures included subtotal pancreatectomy (n = 26), pancreas head resection (n = 1), total pancreatectomy (n = 6), Whipple operation (n = 8), pylorus-preserving pancreaticoduodenectomy (n = 51), and choledochojejunostomy with excisional biopsy (n = 1) (Appendix E2, Table E1 [online]).
Histopathologic Analysis All resected IPMNs were reviewed by an experienced pathologist (L.K.B.) with more than 10 years of experience in the evaluation of hepatopancreatobiliary diseases. The pathologist described the following findings in the pathologic report: type of IPMN, location of tumor, size of tumor, presence of mural nodule, diameter of MPD, peripancreatic infiltration, vascular involvement, lymph node metastasis, perineural invasion, and involvement of adjacent solid organs. R0, R1, and R2 were recorded on either pathology or surgery reports with the following definitions: R0, no evidence of residual tumor at the resection margin both microscopically and macroscopically; R1, direct tumor growth (high-grade dysplasia or invasive carcinoma) up to or within 1 mm of the margin; and R2, macroscopic residual tumor tissue at the resection margin (33). In this study, R1 and R2 resection cases were classified as unresectable cases, and R0 resection cases were thought to be resectable. The incidence of unresectable cases is listed in Appendix E3 (online). 727
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Table 3 Frequency of MR Findings in Benign versus Malignant IPMNs with Statistical Significance and Their Interobserver Agreement on the Basis of the International Consensus Guidelines 2012 MR Finding Type of IPMN Main duct type Branch duct type Mixed type High-risk stigmata Enhanced solid component infiltrating parenchyma MPD diameter 10 mm Worrisome features Intramural nodule Abrupt caliber change in the MPD Enhanced cyst wall MPD diameter 5–9 mm Cystic mass 3 cm Measurement of MPD or tumor‡ Mean diameter of MPD (mm) Mean size of cystic mass (mm)
Benign IPMNs (n = 51)
Malignant IPMNs (n = 42)
2 (4) 37 (73) 12 (24)
Weighted k† or ICC Value P Value*
Observers 1 and 2
Observers 2 and 3
Observers 1 and 3
4 (10) 13 (31) 25 (60)
,.001
… … k = 0.394
… … k = 0.421
… … k = 0.594
1 (2)
14 (33)
,.001
k = 0.318
k = 0.398
k = 0.574
3 (6)
15 (36)
,.001
…
…
…
4 (8) 4 (8) 0 (0) 18 (35) 32 (63)
21 (50) 12 (29) 4 (10) 17 (40) 29 (69)
,.001 .012 .038 ,.001 NS
k = 0.574 k = 0.398 k = 0.195 … …
k = 0.449 k = 0.294 k = 0.211 … …
k = 0.349 k = 0.612 k = 0.066 … …
4.4 6 2.8 32.5 6 11.7
8.9 6 5.9 37.0 6 16.2
,.001 NS
ICC = 0.9477 ICC = 0.6982
Note.—Unless otherwise indicated, data are for all three observers in consensus. Data in parentheses are percentages. NS = not significant * P , .05 indicates a significant difference. †
Weighted k value of less than 0.20 indicates slight agreement; k value of 0.20–0.39, fair agreement; k value of 0.40–0.59, moderate agreement; k value of 0.60–0.79, substantial agreement; and
k value of 0.80 or greater, outstanding agreement. ICC value of 0.75 or higher indicates high agreement. ‡
Data are mean 6 standard deviation.
Statistical Analysis Preoperative or preprocedural MR evaluation of imaging findings, malignant potential, and overall tumor resectability were compared with the surgical findings and the pathology reports. Statistical analyses were performed with commercially available software (MedCalc for Windows, version 12.7.0; MedCalc Software, Mariakerke, Belgium). The prevalence of each stigmata or worrisome MR finding in benign pancreatic IPMNs and malignant pancreatic IPMNs was analyzed by using the Fisher exact test. Interobserver agreement was evaluated with the weighted k statistic for noncontinuous scales and with the intraclass correlation coefficient (ICC) for continuous scales. Weighted k values of less than 0.20 indicated slight agreement; weighted k values of 0.20–0.39, fair agreement; weighted k values of 0.40–0.59, moderate agreement; weighted k values 728
of 0.60–0.79, substantial agreement, and weighted k values of more than 0.80, outstanding agreement. ICCs of more than 0.75 were considered to be in high agreement. Diagnostic performance of MR imaging with MRCP in the determination of malignant potential and its resectability was analyzed by using receiver operating characteristic curve analysis. Sensitivity, specificity, accuracy, and interobserver agreement were determined, and P , .05 was considered to indicate a significant difference.
Results Interpreting Individual MR Imaging Findings and Their Interobserver Variation Among the MR imaging findings of highrisk stigmata and worrisome features, the prevalence of all imaging findings except cyst size 3 cm in diameter or larger (mean size of the cystic mass) and
MPD diameter of 5–9 mm were higher in patients with malignant IPMNs than in those with benign IPMNs (Table 3). In addition, intramural nodule was the most common finding among the imaging criteria observed in malignant pancreatic IPMNs, while enhanced solid component was the second most common finding according to the consensus reading of the three reviewers (Table 3). Most of the high-risk stigmata and worrisome features proposed by the international consensus guidelines 2012 were shown to have fair to moderate or high interobserver agreement, except for the enhanced cyst wall (Table 3). The three observers showed high interobserver agreement (ICC = 0.9477) for measurement of MPD diameter and fair to moderate interobserver agreement for measurement of pancreatic cyst size (ICC = 0.6982), classification of IPMN type (k = 0.394–0.594), detection of enhanced solid components infiltrating the parenchyma (k = 0.318–0.574),
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Figure 2
Figure 2: Intraductal papillary mucinous neoplasm associated with an invasive carcinoma in an 85-year-old woman who underwent a 3-T MR examination shows both a high-risk stigmata and a worrisome feature of MPD 10 mm or larger in diameter and intramural nodules (score 5). (a) Axial T2-weighted half-Fourier acquisition single-shot turbo spin-echo MR image shows marked dilatation of the MPD larger than 10 mm in diameter and multiple intraluminal nodules showing lower signal intensity than that of the pancreatic duct fluid (arrow). (b) A 3D MRCP image obtained with T2-weighted half-Fourier acquisition single-shot turbo spin-echo sequence shows marked dilatation of the MPD with multiple filling defects (arrows), which is suggestive of multiple mural nodules. (c) Delayed contrast-enhanced 3D axial gradient-echo MR image shows enhancement of multiple mural nodules (arrows) filling in the dilated MPD. Both reviewers determined the mass did not abut any major vessel. The mass was confirmed as an invasive carcinoma without vascular encasement.
Figure 3
Figure 3: Images in a 70-year-old man who was confirmed to have pancreatic IPMN of high-grade dysplasia at 3-T MR imaging with three worrisome features of a cystic mass at least 3 cm in diameter, an enhanced cystic wall, and an MPD diameter of 5–9 mm on MR images (score 4). (a) Axial T2-weighted half-Fourier acquisition single-shot turbo spin-echo MR image shows a lobulated cystic mass (arrow) larger than 3 cm in diameter in the pancreas uncinate process. (b) Delayed contrast-enhanced 3D axial gradient-echo MR image shows a cystic mass with thickened enhanced cyst walls (arrow) at the uncinate process abutting and compressing the major portal vein but without vascular encasement. (c) A 3D MRCP image shows an irregularly shaped cystic mass (arrow) at the uncinate process with associated diffuse upstream pancreatic duct dilatation (5–9 mm in diameter). Both reviewers interpreted the mass as separate from major vessels and assigned a diagnosis of resectable malignant IPMN (score 4). The mass was confirmed as a pancreatic IPMN with high-grade dysplasia negative for vascular encasement.
and identification of intramural nodules (k = 0.349–0.574). However, the three observers showed slight interobserver agreement in the detection of an enhanced cyst wall (k = 0.066–0.211).
Diagnostic Performance of MR Imaging with MRCP in Detecting Malignant Potential When the presence of at least one worrisome feature or any high-risk
stigmata (score 3) was regarded as indicating the malignant potential of IPMNs or specifically high-grade dysplasia and invasive carcinoma, the sensitivity of MR imaging with MRCP was 83% (35/42), 79% (33/42), and 90% (38/42) for observers 1, 2, and 3, respectively; specificity was 80% (41/51), 51% (26/51), and 22% (12/51), respectively; and accuracy
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was 82% (76/93), 63% (59/93), and 54% (50/93), respectively (Figs 2, 3); Fig E1 [online]). The area under the receiver operating characteristic curve of MR imaging with MRCP was 0.843 (95% confidence interval [CI]: 0.753, 0.910) for observer 1, 0.778 (95% CI: 0.680, 0.857) for observer 2, and 0.823 (95% CI: 0.730, 0.894) for observer 3 in determining the malignant potential of 729
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unresectable cases, underestimated six (46%) of 13 truly unresectable cases, and correctly evaluated resectability in 75 (88%) of 85 truly resectable cases. The positive predictive value of MR imaging with MRCP for observers 1, 2, and 3 in determining whether IPMNs were unresectable was 69% (nine of 13), 90% (nine of 10), and 39% (seven of 18), respectively (Table 5).
Table 4 Diagnostic Performance of MR Imaging with MRCP in the Evaluation of the Malignant Potential of Pancreas IPMNs Score and Statistic Score 5 only Sensitivity Specificity Accuracy Score 4 Sensitivity Specificity Accuracy Score 3 Sensitivity Specificity Accuracy
Observer 1 (%)
Observer 2 (%)
Observer 3 (%)
33 (14/42) 98 (50/51) 69 (64/93)
26 (11/42) 100 (51/51) 67 (62/93)
57 (24/42) 98 (50/51) 80 (74/93)
62 (26/42) 96 (49/51) 81 (75/93)
62 (26/42) 96 (49/51) 81 (75/93)
83 (35/42) 65 (33/51) 73 (68/93)
83 (35/42) 80 (41/51) 82 (76/93)
79 (33/42) 51 (26/51) 63 (59/93)
90 (38/42) 24 (12/51) 54 (50/93)
Discussion
Note.—Numbers in parentheses are raw data. Worrisome features and high-risk stigmata are based on the international consensus guidelines 2012.
pancreatic IPMNs. However, when only the presence of any high-risk stigmata regardless of worrisome features (score 5) was regarded as a criterion indicating the malignant potential of pancreatic IPMNs, the sensitivity of MR imaging with MRCP was 33% (14/42), 26% (11/42), and 57% (24/42) for observers 1, 2, and 3, respectively; specificity was 98% (50/51), 100% (51/51), and 98% (50/51), respectively; and accuracy was 69% (64/93), 67% (62/93), and 80% (74/93), respectively (Table 4). The two experienced observers showed substantial interobserver agreement (k = 0.652), while agreement between the experienced observers and the inexperienced observer was moderate (k = 0.460 and 0.475) in scoring the malignant potential when the suggested criteria of the international consensus guidelines 2012 were applied.
Diagnostic Performance of MR Imaging with MRCP in Evaluating Surgical Resectability The sensitivity of MR imaging with MRCP in determining surgical resectability was 95% (81/85), 99% (84/85), and 88% (75/85), respectively, for observers 1, 2, and 3 (Table 5). However, specificity was 69% (nine of 13) for observers 1 and 2 but 54% (seven of 13) forn observer 3, showing a tendency 730
toward underestimation of vascular encasement (Fig 4). Overall accuracy of observers 1, 2, and 3 was 92% (90/98), 95% (93/98), and 84% (82/98), respectively. The area under the receiver operating characteristic curve was 0.859 (95% CI: 0.728, 0.990) in observer 1, 0.831 (95% CI: 0.688, 0.974) in observer 2, and 0.751 (95% CI: 0.654, 0.833) in observer 3. The two experienced readers showed outstanding interobserver agreement in the evaluation of surgical resectability (k = 0.870), while the inexperienced reader and the experienced readers showed substantial interobserver agreement in the evaluation of surgical resectability (k = 0.706 and 0.739). Both experienced observers correctly evaluated unresectability in nine (69%) of 13 unresectable cases, while both experienced observers underestimated four (31%) of 13 truly unresectable cases. Of these, three were underestimation of portal vein invasion, and one was underestimation of superior mesenteric artery invasion. Conversely, observer 1 correctly evaluated resectability in 81 (95%) of 85 truly resectable cases, and observer 2 correctly evaluated resectability in 84 (99%) of 85 truly resectable cases. The inexperienced observer correctly evaluated unresectability in seven (54%) of 13
The recently introduced international consensus guidelines 2012 for the management of IPMNs and mucinous cystic neoplasms of the pancreas gave us useful recommendations for the management of IPMNs. However, questions remained as to the diagnostic performance of MR imaging with MRCP in determining the malignant potential and surgical resectability of pancreas IPMNs with the new criteria. Our study results showed that MR imaging with MRCP showed acceptable diagnostic performance in the prediction of the malignant potential of IPMNs when using the image criteria of the international consensus guidelines 2012. Specifically, we observed that the diagnostic accuracy of MR imaging with MRCP ranged from 63% (59/93) to 82% (76/93) in experienced observers and was 54% (50/93) in an inexperienced observer when we considered the presence of at least one worrisome feature or any high-risk stigmata (score 3) as criteria for diagnosis of the malignant potential of IPMNs, with high sensitivity. Under these combined criteria, for observers 1, 2, and 3, respectively, sensitivity was 83% (35/42), 79% (33/42), and 90% (38/42); specificity was 80% (41/51), 51% (26/51), and 22% (12/51); and accuracy was 82% (76/93), 63% (59/93), and 54% (50/93). The low specificity of experienced observer 2 and inexperienced observer 3 and the substantial gap between the three observers may be explained by the low interobserver reliability in the evaluation of enhanced cyst walls and abrupt caliber changes in the MPD. The enhanced cyst wall is difficult to discriminate on MR images,
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Table 5 Surgical Resectability According to MR Imaging with MRCP Results in 98 Patients with IPMNs R1† or R2‡ Resection or Not Resected (n = 13)
R0 Resection* (n = 85) MR Result Resectable Not resectable
Observer 1
Observer 2
Observer 3
Observer 1
Observer 2
Observer 3
81 (95) 4 (5)
84 (99) 1 (1)
75 (88) 10 (12)
4 (31) 9 (69)
4 (31) 9 (69)
6 (46) 7 (54)
* R0 resection = no evidence of residual tumor at the resection margin both microscopically or macroscopically. †
R1 resection = direct tumor growth (high-grade dysplasia or invasive carcinoma) up to or within 1 mm of the margin.
‡
R2 resection = macroscopic residual tumor tissue at the resection margin.
Figure 4
Figure 4: Images in a 72-year-old woman with invasive cancer who underwent a 3-T MR examination and had an incomplete resection (R2 resection). (a) A 3D MRCP image shows a multiseptated cystic mass in the pancreas head with upstream pancreatic duct dilatation and segmental narrowing (arrow) of the distal common bile duct, suggesting possible common bile duct invasion. (b) Axial contrast-enhanced T1-weighted MR image shows the ill-defined enhancing solid portion (arrow) of the mass. (c) Coronal contrast-enhanced T1-weighted MR image shows segmental narrowing of the distal common bile duct with enhancing wall thickening (arrow), suggesting distal common bile duct invasion by the tumor. The observers interpreted this case as a resectable invasive cancer (score 5); however, during surgery, the mass was deemed to be not resectable owing to severe invasion into the main portal vein and the superior mesenteric vein.
even with the help of postcontrast subtraction sequences. Moreover, the evaluation of MPD strictures is relatively subjective, particularly when associated with pancreatitis; we did not count findings as strictures in such a situation. It was even more difficult for the inexperienced observer to discriminate such findings, and he had a tendency to overrate imaging findings of worrisome features or high-risk stigmata, probably owing to a lack of experience and a sense of self-preservation. This might have resulted in higher sensitivity and lower specificity in the inexperienced observer. Indeed, Barron et al (34) reported that it may not be possible to classify main duct-type IPMNs appropriately solely on the basis of imaging studies. Our results showed fair to moderate interobserver reliability
in the evaluation of duct-type IPMNs, which also may contribute to the low specificity in diagnosing the malignant potential of pancreatic IPMNs. Further refinement for enhanced cyst walls and abrupt caliber changes of the MPD may be required to improve specificity and the gap between different observers. Furthermore, we observed that specificity increased markedly (.96%) when we applied the criteria of a score of more than 4. In addition, among the findings of worrisome features and high-risk stigmata, intramural nodule was the most commonly detected finding in malignant pancreatic IPMNs, and an enhancing solid component was the second most common finding when considering only the proposed findings for high-risk stigmata and worrisome features.
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Interobserver agreement for worrisome features or high-risk stigmata was fair to high. Interobserver agreement was especially high in the measurement of MPD diameter. The two experienced observers and the one inexperienced observer exhibited fair to moderate interobserver agreement in the measurement of cystic mass size, detection of enhanced solid components infiltrating the parenchyma, and the presence of abrupt caliber change in the MPD, whereas they showed only slight interobserver agreement (k = 0.066–0.211) in the detection of the presence of enhanced cyst walls. In addition, moderate interobserver agreement was observed in the detection of the presence of mural nodules, which was in good agreement with the results of a previous study by Manfredi et al (14). The 731
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poor interobserver agreement observed in the detection of enhanced cyst walls in our study could be explained by the fact that IPMNs are composed of dilated pancreatic ducts; thus, it may have been difficult to differentiate enhanced cyst walls from enhanced pancreatic duct walls. To continue to improve interobserver agreement, further clarification and refinement of the criteria in the international consensus guidelines for multidetector row CT and MR imaging suggesting malignancy may be necessary. In our study, the sensitivity of the two experienced observers was quite high (95% [81/85] and 99% [84/85] for observers 1 and 2, respectively) in the evaluation of the surgical resectability of IPMN lesions, whereas specificity was moderate (69% [nine of 13] for both reviewers) and overall accuracy (92% [90/98] and 95% [93/98] for observers 1 and 2, respectively) was satisfactory. Sensitivity (88%, [75/85]), specificity (54% [seven of 13]), and accuracy (84% [82/98]) were slightly lower in the inexperienced observer. These results are considerably better than those reported by Vullierme et al (15), who reported that the overall accuracy of helical CT in determining the surgical resectability of malignant IPMNs with invasive cancer was 74% but that the positive predictive value of CT in determining unresectability was only 17%, mainly owing to overestimation of arterial invasion. Our study showed that the positive predictive value of MR imaging with MRCP for experienced observers 1 and 2 in determining whether IPMNs were unresectable was 69% (nine of 13) and 90% (nine of 10), respectively. One important difference between our study and a previous study (15), which showed that CT usually resulted in overestimation of tumor extent and misdiagnosis of unresectability even in resectable cases, was that our results showed that MR imaging with MRCP tended to result in underestimation of tumor extent and misdiagnosis of unresectable cases as resectable, even though this modality was accurate in the detection of resectable lesions. Our study had several limitations. First, as the evaluation of cases was 732
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retrospective, there was unavoidable selection bias and verification bias. However, as MR imaging with MRCP is one of the standard preoperative diagnostic modalities used in the evaluation of IPMNs at our institution, selection bias might not have been serious. In addition, verification bias may have been unavoidable, as we used a strict reference standard to assess resectability. Second, MR images were obtained from multiple institutions, resulting in use of a variety of MR machines, MR sequences, and contrast materials. These variations might have interfered with the interpretation of images during the retrospective image analyses. Third, to decrease selection bias in the evaluation of surgical resectability, we enrolled patients with lesions deemed to be unresectable by two experienced abdominal imaging radiologists in consensus. However, there is a possibility that the good results obtained in our study may be related to the inclusion of relatively advanced cases in our study population. Fourth, as multidetector row CT is the primary modality used to evaluate pancreativ IPMNs at our institution, many macroscopically unresectable cases were excluded on the basis of CT findings, without the need for an MR examination. Thus, only patients with difficult cases of unresectable IPMN that were equivocal in the determination of tumor resectability at CT and that required further MR examination were enrolled in our study. Further studies involving a direct comparison between multidetector row CT and MR imaging with MR CP in determining the surgical resectability of IPMNs with invasive cancer are warranted to better address this limitation. In conclusion, MR imaging with MR CP has high sensitivity in the diagnosis of malignant IPMNs when the presence of at least one worrisome feature or any high-risk stigmata (score 3) is used as a criterion for malignant IPMN, with high interobserver agreement. In addition, MR imaging with MRCP showed high sensitivity and diagnostic accuracy in the determination of surgical resectability, albeit with a relatively high rate of underestimating surgical unresectability.
Acknowledgments: We thank Eui Jin Hwang, MD, for his assistance in reviewing MR imaging findings. We also thank Chris Woo, BA, for his English editorial assistance. Disclosures of Conflicts of Interest: S.H.K. disclosed no relevant relationships. J.M.L. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received grants from Bayer Healthcare, GE Healthcare, CMS, Acuzen, and Guerbe Starmed; is on the board of Bayer Healthcare; gave lectures for Bayer Healthcare; is a consultant for Siemens Healthcare. Other relationships: disclosed no relevant relationships. E.S.L. disclosed no relevant relationships. J.H.B. disclosed no relevant relationships. J.H.K. disclosed no relevant relationships. J.K.H. disclosed no relevant relationships. B.I.C. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received a grant from Samsung Electronics. Other relationships: disclosed no relevant relationships.
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