MR cholangiopancreatography; Predicting imaging findings for differentiation of malignant bile ductal obstruction versus benign lesion

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Keitaro Sofue 3,4, Takamichi Murakami 1 1 Department of Radiology, Kindai University Faculty of Medicine, Osaka, Japan 2 Department of Radiology, Okanami General Hospital, Mie, Japan 3 Division of

1 Acta Med Kindai Univ Vol.43, No.1 1-8, MR cholangiopancreatography; Predicting imaging findings for differentiation of malignant bile ductal obstruction versus benign lesion Shojiro Hidaka 1,2, Masakatsu Tsurusaki 1,3, Keitaro Sofue 3,4, Takamichi Murakami 1 1 Department of Radiology, Kindai University Faculty of Medicine, Osaka, Japan 2 Department of Radiology, Okanami General Hospital, Mie, Japan 3 Division of Diagnostic Radiology, National Cancer Center, Tokyo, Japan 4 Department of Diagnostic Radiology, Kobe University, Graduate School of Medicine, Hyogo, Japan Abstract The purpose of the current study was to evaluate the use of magnetic resonance imaging (MRI) in conjunction with a scoring system to differentiate between malignant and benign strictures of the common bile duct. MRI scans of 54 patients with indeterminate biliary strictures on prior imaging were reviewed, and non-enhanced MRI, magnetic resonance cholangiopancreatography (MRCP), and diffusion-weighted imaging were analyzed. Eight radiologic parameters were significantly associated with malignancy; luminal irregularity, high signal intensity on diffusionweighted MRI, luminal stenosis asymmetry, T2- weighted MRI signal intensity, abrupt stenosis, bile duct dilatation 12.5 mm, stenosis length 10.5 mm, and wall thickness 4.5 mm. A simple system scoring based on statistically significant findings was developed, where each of the above findings counts for one point. A score of 6 or higher was found only in patients with a malignant stricture of the common bile duct; 60% of patients with a benign stenosis had a score of 1, or 2, and all patients with benign lesions had scores of less than 5. This MRI scoring system can assist in the differential diagnosis of common bile duct stricture with high accuracy; to be widely applicable, the MRI score needs to be validated in a prospective patient population. Key words:benign, bile duct, bile duct cancer, MR cholangiopancreatography Introduction Despite rapid advances in diagnostic imaging modalities, noninvasive etiologic diagnosis of strictures of the common bile duct remains challenging in some cases. Noninvasive imaging is traditionally required to recognize dilatation of the biliary tree, the level of obstruction, and whenever possible the cause of the obstruction. Magnetic resonance imaging (MRI) plays a pivotal role due to its unsurpassed precision with regard to soft tissue contrast differentiation, multiplanar imaging capacity, the fact that direct visualization of biliary and pancreatic fluids is possible via magnetic resonance cholangiopancreatography (MRCP), and its capacity to facilitate identification of hypercellular lesions via diffusionweighted imaging (DWI). 1-5 Moreover, MRI demonstrates high accuracy with regard to local staging of patients with malignant stenosis. 1-3,5 The high sensitivity of MRCP for detecting strictures of the common bile duct may not translate to a concomitant improvement in specificity and positive predictive value. 1,6,7 Therefore, a comprehensive MRI approach to the diagnosis of bile duct stenosis is necessary, to minimize indeterminate cases via the identification of MRI findings characteristic of malignancy. 1,2 In particular, the Received July 11, 2017; Accepted September 21,

2 S. Hidaka et al. etiologies of small periductal lesions and of lesions of the common bile duct wall have been difficult to distinguish noninvasively, despite improvements in MRI technology. 8,9 The purpose of the current retrospective study was to evaluate the capacity of MRI used in conjunction with a practical scoring system based on objective imaging parameters to differentiate between malignant and benign stenosis of the common bile duct. Materials and methods Patients The radiology records of all MRI investigations of the biliary system performed at our hospital between January 2008 and December 2010 were reviewed. Patients with an indeterminate stricture of the common bile duct, i.e., one that was not definitively diagnosed by abdominal sonography or computed tomography, were enrolled in the study. Patients with a prior history of biliary surgery and/or biliary radiologic or endoscopic procedures, common bile duct stones, acute pancreatitis, chronic pancreatitis, or overt neoplasms of the pancreatic head previously detected via ultrasound and/or computed tomography were excluded from the study. MRI examinations were reviewed by an experienced abdominal radiologist with 15 years of experience in abdominal MRI, who was unaware of the final diagnoses. The present retrospective study was approved by our institutional ethics committee review board. MRI MRI examinations of the upper abdomen were performed with a 1.5T magnet (Avanto, Siemens Healthcare, Erlangen, Germany) or a 3T magnet (Trio A Tim, Siemens Healthcare, Erlangen, Germany) using phased-array body surface coils. MRI results were displayed on a PACS workstation and the following sequences were reviewed: Coronal half-fourier-acquired singleshot turbo spin echo (HASTE) T2-weighted imaging; in-phase and out-of phase gradient echo T1 sequence; axial HASTE T2-weighted imaging with and without fat suppression; DWI; radial thick-slice fat-suppressed HASTE T2-weighted MRCP; and coronal thin-slice fat-saturated threedimensional T2-weighted MRCP. Assessment of MRI findings The categorical and ordinal variables scrutinized were as follows: (1) Magnetic field strength of MR machine that was used to image MRCP; (2) evidence of the double duct sign; (3) luminal irregularity; (4) tapering versus abrupt narrowing of the stricture; (5) asymmetry of the stenosis; (6) signal intensity (SI) on T2-weighted images relative to liver, expressed as low, iso, or high; (7) SI on DWI at b 800, expressed as low or iso-high; (8) stenosis length; (9) wall thickness of the stenosis; and (10) diameter of the common bile duct. SIs on T2-weighted and DWI scans were subjectively evaluated because the very small size of the lesions precluded a reliable measurement of the region of interest. For the same reason, the apparent diffusion coefficient was not estimated. Mean SI on T2-wighted images and DWI of bile ductal wall at the obstructive level were measured using an operator-defined region-of -interest (ROI). Mean SI of the liver were measured ROI of right anterior lobe of the liver. The size of the ROI was chosen to include a large representative portion of the object with an upper limit of 500 pixels. Reference standard of pathology A final pathologic diagnosis was made on the basis of histology of surgical or postmortem specimens, or when there was a lack of a surgical specimen, MRI follow-up studies were performed for at least 6 months to track the behavior of the lesion. 5-6,15,16 Statistics Statistical analysis was performed via χ 2 and Fisher s exact tests for comparing frequencies of categorical variables in benign and malignant cases. The Wilcoxon-Mann-Whitney test was used to assess correlations between continuous variables, and accuracy for predicting malignancy was evaluated by estimating the area under the characteristic receiver operator curve (ROC). The D2 test was also calculated to identify cut-off values for malignancy. After univariate regression analysis, the sensitivity and specificity values associated with all significant variables were calculated. A scoring system based on MRI findings significantly associated with malignancy was devised and retrospectively applied in both groups of patients. Statistical analysis was performed with the SPSS software package (IBM SPSS Statistics, release 20.0, USA), and p < 0.05 was considered statistically significant. 2

MR cholangiopancreatography; Predicting imaging findings for differentiation of malignant bile ductal ob-struction versus benign lesion Results During the study period, 54 patients (33 men and 21

3 MR cholangiopancreatography; Predicting imaging findings for differentiation of malignant bile ductal ob-struction versus benign lesion Results During the study period, 54 patients (33 men and 21 women, mean age 69 years, range years) met the inclusion criteria. Of these, 12 (34%) had a prior history of cholecystectomy. The mean interval between MRCP and surgery was 42 days (range 7 60 days). The final diagnoses included 20 cases of benign pathology and 34 of malignancy. Three cases of benign biliary lesions were characterized with cytology/histology (one each of cholangitis, mucosal hyperplasia of the papilla of Vater, and primary sclerosing cholangitis), and all three of these cases were followed up with MRI, for a mean period of 185 days. The remaining 17 patients diagnosed with benign biliary stricture who did not undergo fine needle biopsy had a mean follow-up period of 285 days (range days), and the final diagnoses were secondary cholangitis in 12, and odditis in 5. The remaining 34 malignant biliary lesions included 26 cholangiocarcinomas of the common bile duct, 4 ductal carcinomas of the pancreatic head, 3 ampullary adenocarcinomas, and 1 periampullary duodenal carcinoma. Diagnoses of malignancies in all patients were confirmed by surgical pathology. At MRCP, typical benign strictures tend to have smooth and symmetric borders with tapered margins (Figure 1), whereas malignant common bile duct strictures tend to have irregular, asymmetric and abrupt strictures (Figure 2). Categorical variables (Table 1) identified significantly more frequently in malignant lesions were luminal irregularity, asymmetrical stenosis, abrupt stenosis, and signal intensity on T2- weighted images. Ordinal variables (lengths measured in mm) all differed significantly between malignant and benign lesions (Table 2). The ROC of continuous variables (Figure3) and corresponding thresholds for malignant stenosis are shown in Table 3. Luminal irregularity and high signal on DWI yielded the highest odds ratios in logistic regression analysis, as well as the highest sensitivity for the diagnosis of malignant lesions (Tables 4 and 5). Summation of the eight significant findings permitted a simple scoring system that was highly discriminative for malignant versus benign strictures. In the 20 patients with benign lesions, all but one case totaled four or fewer points; 16/20 (75%) of patients with benign lesions had three or fewer points. A single patient with a benign stricture had a total score of 5 points. Conversely, 27 of 34 patients with a histologically-proven malignant stricture had a score of 6 or higher; the other two patients had a score of 3 points or higher. A score of 5 or greater was diagnostic of a malignant stricture (p < 0.01) (Figure 4). Figure 1 55-year-old man with IgG4 related choledochitis. Thick slab MRCP shows dilatation of the biliary tree and the main bile duct with a tapering stenosis; the main bile duct measures 12 mm in diameter. 3

duct (arrow head) ; (b) DWI b 800 reveals a focal area of water diffusion restriction (arrow).

4 S. Hidaka et al. Figure 2 (a) Figure 2 (b) Figure 2 70-year-old woman with inferior ductal cancer (a) MRCP shows dilatation of the biliary tree due to an abrupt, eccentric stenosis of the lower of the common bile duct (arrow head) ; (b) DWI b 800 reveals a focal area of water diffusion restriction (arrow). Discussion MRCP provides noninvasive images comparable to those obtained by direct retrograde cholangiography, and can provide indirect evidence of a malignant lesion, such as irregularity of the inner border, abrupt stenosis, and stenosis length. Although these findings are highly sensitive, they are not specific for malignancy Dilatation of the biliary tree is an epiphenomenon of biliary strictures, and depends more on the duration and degree rather than the cause of the stenosis, although such dilatation is more frequently observed in cases of malignancy. 1,4,13 Therefore, this sign has ancillary value only, and should always be considered as part of a complete radiologic picture. MRI characterization of common bile duct stenosis relies on direct and secondary findings, none of which by themselves are pathognomonic for malignancy. 1,2,5,10,11 As previously reported, 12 MRI diagnosis is not affected by the magnetic field strength. 4

5 MR cholangiopancreatography; Predicting imaging findings for differentiation of malignant bile ductal ob-struction versus benign lesion Table 1 Statistics of categorical variables. Benign Lesion % Malignant lesion % P Magnetic field strength (1.5T vs 3T) 3/17 15/85 10/ /70.6 NS Double duct sign NS Luminal irregularity < 0.01 Stenosis asymmetry < 0.01 Abrupt stenosis < 0.01 T2W SI Hypointense Iso/hyperintense SI in DWI b800 Hypointense ±Hyperintense < 0.01 Abbreviations: SI: signal intensity; NS: not significant. Table 2 Statistics of ordinal variables. MRI findings Benign lesion Malignant lesion P Bile duct dilatation (mm ± SD) 11.5 ± ± 5.32 < 0.01 Stenosis length (mm ± SD) 8.1 ± ± 7.02 < 0.01 Stenosis wall thickness (mm ± SD) 3.6 ± ± 6.5 < 0.01 Abbreviations: SD: standard deviation. Table 3 ROC analysis of ordinal variables and discriminating values for malignancy. MRI findings Area under ROC curve SE Cut-off (mm) Bile duct dilatation ± Stenosis length ± Stenosis wall thickness ± Abbreviations: SE: standard error. Table 4 Logistic regression analysis. MRI findings Odds Ratio (95% CI) P Luminal irregularity 73.6 ( ) < 0.01 DW-MRI hyperintensity 49.0 ( ) < 0.01 Stenosis asymmetry 18.0 ( ) < 0.01 Abrupt stenosis 14.7 ( ) < 0.01 Stenosis length 10.5mm 12.4( ) < 0.01 T2 Iso/hyperintenisity 9.0 ( ) 0.01 Wall thickness 4.5mm 7.1 ( ) < 0.01 Bile duct dilatation 12.5mm 6.8 ( ) < 0.01 Abbreviations: CI: confidence interval. 5

6 S. Hidaka et al. Table 5 Sensitivity and specificity of variables predicting for malignancy. MRI findings Sensitivity IC 95% Specificity IC 95% Luminal irregularity DW-MRI hyperintensity Stenosis asymmetry T2 Iso/hyperintenisity Abrupt stenosis Bile duct dilatation 12.5mm Stenosis length 10.5mm Wall thickness 4.5mm Abbreviations: CI: confidence interval benign malignant Figure3 Graph shows ROC of continuous variables in separating benign and malignant bile ductal obstructions. Area under curve is 0.86 for stenosis wall thickness (thick solid line) and 0.76 for bile duct dilatation (dotted line) and 0.80 for stenosis length (thin solid line). Morphologic and signal characteristics of biliary lesion stenosis may differentiate between benign and malignant pathology. Although high SI on T2-weighted images of the biliary lesion is correlated with malignancy, this finding has a weak predictive diagnostic value. Bile duct cancer may be hyperintense relative to the liver due to increased interstitial fluid, 2 but it may also show a low signal due to a desmoid component that mimics a fibrotic stenosis. Conversely, high signal intensity of a benign stricture may be observed when marked inflammation is present. In any event, the evaluation of SI should be undertaken cautiously in most cases, due to the very Figure 4 MRI scoring of benign and malignant strictures of the bile duct. small tumor size of these infiltrating lesions. DWI at high b values is a reliable predictor of a malignant bile stricture, and can improve the sensitivity of MRCP due to its sensitivity with regard to hypercellularity 5,11,14 16 ; nevertheless, care must be taken because inflammatory processes can also be hyperintense on DWI. 15, 16 Moreover, DWI may not be discriminatory in cases of well-differentiated neoplasms or small tumors, and image quality may suffer from artifacts that induce signal loss. 11 As the above-described MRI findings are not individually pathognomonic for malignant bile duct stenosis, a constellation of MRI findings 6

7 MR cholangiopancreatography; Predicting imaging findings for differentiation of malignant bile ductal ob-struction versus benign lesion may be considered, to improve diagnostic reliability. Kim et al. 2 reported that higher specificity may be achieved by combining a large number of MRI findings (maximum six), but unfortunately this was at the expense of a concomitant reduction in sensitivity. They achieved the best performance with a combination of three signs (sensitivity 100%, specificity 87.5%). In the present study, we identified eight radiological findings that were statistically significantly associated with malignancy, and identified some predictors for differential diagnosis between benign and malignant lesions. In the context of the current study, MRI was extremely effective for ruling out malignant neoplasm, and facilitated noninvasive imaging follow-up over a period of time, without the need for biopsy in all cases of common bile duct stenosis. The present study had some limitations. First, because our patient selection was retrospective there may have been inherent biases that went undetected. Specifically, heterogeneity of a malignant group can affect the evaluation of SI on T2- weighted MRI and DWI. Second, statistical analysis may have been affected by the low sample size. A prospective study with more patients included will be required to validate our design. Third, we did not evaluate enhancing pattern on contrast-enhanced MRI between benign and malignant lesions, because the diagnostic value of contrast-enhanced MRI has been reported and is characterized by an ability to delineate thickness and outer borders of a bile duct wall or a periductal lesion, both of which are predictors of malignancy. 2,4 Fourth, a lack of histologic confirmation in all diagnosed benign lesions raised the possibility of inaccuracy of the imaging findings; however, we feel this limitation was mitigated by the sufficiently long follow-up period. For follow-up observation, ERCP, CT, EUS and so on will be used for follow-up at intervals of 1 month, 3 months, 6 months, and over 1 year. 17 In conclusion, MRI investigation of common bile duct stricture requires an accurate technique relying on all available sequences to arrive at a definitive diagnosis. This comprehensive diagnostic approach can reduce uncertainty with regard to differentiating between malignant and benign causes of common bile duct stricture. Radiologic findings can assist in the differential diagnosis of common bile duct lesions with high accuracy, and the method is easy to apply. This comprehensive diagnostic approach can benefit from the application of our MRI score. There is no financial support and no relationship that poses a conflict of interest. References 1.Park MS, et al. (2004) Differentiation of extrahepatic bile duct cholangiocarcinoma from benign stricture: Findings at MRCP versus ERCP. Radiology 233(1): Kim JY, et al. (2007) Contrast-enhanced MRI combined with MR cholangiopancreatography for the evaluation of patients with biliary strictures: Differentiation of malignant from benign bile duct strictures. J Magn Reson Imaging 26(2): Yeh BM, et al. (2009) MR imaging and CT of the biliary tract. Radiographics 29(6): Yu XR, et al. (2014) Differentiation of infiltrative cholangiocarcinoma from benign common bile duct stricture using three-dimensional dynamic contrast-enhanced MRI with MRCP. Clin Radiol 69(6): Park HJ, et al. (2014) The role of diffusion-weighted MR imaging for differentiating benign from malignant bile duct strictures. Eur Radiol 24(4): Rösch T, et al. (2002) A prospective comparison of the diagnostic accuracy of ERCP, MRCP, CT, and EUS in biliary strictures. Gastrointest Endosc 55(7): Sai JK, et al. (2009) Early detection of extrahepatic bile-duct carcinomas in the nonicteric stage by using MRCP followed by EUS. Gastrointest Endosc 70(1): Topazian M (2012) Endoscopic ultrasonography in the evaluation of indeterminate biliary strictures. Clin Endosc 45(3): Victor DW, et al. (2012) Current endoscopic approach to indeterminate biliary strictures. World J Gastroenterol 18(43): Chung YE, et al. (2011) Differentiation of benign and malignant ampullary obstructions on MR imaging. Eur J Radiol 80(2): Cui XY, et al. (2012) Diffusion-weighted MR imaging for detection of extrahepatic cholangiocarcinoma. Eur J Radiol 81(11): Onishi H, et al. (2009) MR cholangiopancreatography at 3.0 T: Intraindividual comparative study with MR cholangiopancrea-tography at 1.5 T for clinical patients. Invest Radiol 44(9): Wu DS, et al. (2012) Pancreaticobiliary duct changes of periampullary carcinomas: quantitative analysis at MR imaging. Eur J Radiol 81(9): Cui XY, Chen HW (2010) Role of diffusion-weighted magnetic resonance imaging in the diagnosis of extrahepatic cholangio-carcinoma. World J Gastroenterol 16(25): Lee NK, et al. (2012) Diffusion-weighted imaging of biliopancreatic disorders: Correlation with conventional magnetic reso-nance imaging. World J Gastroenterol 18(31):

8 S. Hidaka et al. 16.Lee NK, et al. (2013) Diffusion-weighted MR imaging for the differentiation of malignant from benign strictures in the peri-ampullary region. Eur Radiol 23(5): Takao I (2012) Treatment for difficult cases of differential diagnosis in patients with middle to lower biliary strictures. Tando 26 (2):

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