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From the Department of Radiology, Gifu Central Hospital, 3-25 Kawabe, 501-1198 Gifu, Japan (H.W.); Departments of Radiology (H.W., M.K., S.G., H. Kondo, H. Kawada, Y.N., Y.T., N.K.) and Radiology Services (M.K.), Gifu University Hospital, Gifu, Japan; Departments of Surgical Oncology (K.T., S.O., K.Y.) and Tumor Pathology (H.T., A.H.), Gifu University Graduate School of Medicine, Gifu, Japan; and Research Center for Cancer Prevention and Screening, National Cancer Center Hospital, Tsukiji, Japan (N.M.). Received May 24, 2013; revision requested July 22; revision received August 6; accepted August 22; final version accepted September 4. Address correspondence to H.W. (e-mail: [email protected]).
Purpose:
To assess the potential value of magnetic resonance (MR) imaging in evaluating pancreatic fibrosis and predicting the development of postoperative pancreatic fistula.
Materials and Methods:
This retrospective study had institutional review board approval, and the requirement for informed consent was waived. MR images obtained in 29 consecutive patients (15 men, 14 women; mean age, 64.9 years; age range, 21–80 years) who underwent pancreatectomy were evaluated. The pancreas-to-muscle signal intensity (SI) ratio on unenhanced T1- and T2-weighted, dynamic contrast material–enhanced, and diffusion-weighted images and the apparent diffusion coefficient (ADC) of the pancreas were measured. MR imaging parameters were correlated with the degrees of pancreatic fibrosis and expression of activated pancreatic stellate cells (PSCs) by using univariate and multivariate regression analyses and receiver operating characteristic curve analysis. The relationships between the development of postoperative pancreatic fistula and the MR imaging measurements were examined by using logistic regression analysis and the Mann-Whitney U test.
Results:
Multiple regression analysis showed that pancreas-tomuscle SI ratios on T1-weighted images and ADC values were independently associated with pancreatic fibrosis (r2 = 0.66, P , .001) and with activated PSC expression (r2 = 0.67, P , .001). The mean pancreas-to-muscle SI ratio (6 standard deviation) on T1-weighted images was higher (P = .0029) for patients with postoperative pancreatic fistula (1.6 6 0.2) than for those without (1.2 6 0.2), and the odds ratio for postoperative pancreatic fistula was 21.3 in patients with an SI ratio of 1.41 and higher.
Conclusion:
The pancreas-to-muscle SI ratio on T1-weighted MR images of the pancreas may be a potential biomarker for assessment of pancreatic fibrosis and prediction of postoperative pancreatic fistula. RSNA, 2013
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Imaging
Haruo Watanabe, MD Masayuki Kanematsu, MD Kaori Tanaka, MD Shinji Osada, MD, PhD Hiroyuki Tomita, MD, PhD Akira Hara, MD, PhD Satoshi Goshima, MD Hiroshi Kondo, MD Hiroshi Kawada, MD Yoshifumi Noda, MD Yukichi Tanahashi, MD Nobuyuki Kawai, MD Kazuhiro Yoshida, MD, PhD Noriyuki Moriyama, MD
Original Research n Gastrointestinal
Fibrosis and Postoperative Fistula of the Pancreas: Correlation with MR Imaging Findings—Preliminary Results1
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P
ancreatic parenchyma becomes hardened because of fibrosis associated with chronic pancreatitis and pancreatic carcinoma, and the hardness of the pancreatic parenchyma is known to be associated with the development of postoperative pancreatic fistula after pancreatectomy (1,2). Several predisposing factors for development of postoperative pancreatic fistula have been suggested. Old age, a narrow pancreatic duct diameter, soft or normal pancreatic parenchyma, ampullary or duodenal disease, longer operation time, and greater intraoperative blood loss have been regarded as possible causes of postoperative pancreatic fistula (2). Postoperative pancreatic fistula is generally known as the most relevant complication after pancreatectomy because it potentially leads
Advances in Knowledge nn The pancreas-to-muscle signal intensity (SI) ratio on T1-weighted MR images and apparent diffusion coefficient (ADC) measured at diffusionweighted MR imaging decreased as pancreatic fibrosis progressed (Spearman rank correlation coefficient, r = 20.69 and 20.60, respectively) and pancreatic stellate cells (PSCs) were activated (r = 20.64 and 20.70, respectively). nn In our retrospective test set, for detection of pancreatic fibrosis of grade F2 and higher, a pancreasto-muscle SI ratio cutoff value of 1.15 on T1-weighted images yielded a sensitivity of 100% (eight of eight patients) and specificity of 95% (20 of 21 patients); for detecting the activated PSC expression grade A3, an ADC cutoff value of 1.30 yielded a sensitivity of 100% (six of six patients) and specificity of 96% (22 of 23 patients). nn The odds ratio for the development of postoperative pancreatic fistula was 21.3 (95% confidence interval: 2.9, 154.6) in patients with a pancreas-to-muscle SI ratio of 1.41 and higher. 792
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to deleterious secondary complications, such as peripancreatic fluid collection, abscess, or bleeding from adjacent major vessels (3). Thus, assessment of preoperative features of pancreatic parenchymal texture that are highly linked to occurrence of postoperative pancreatic fistula is a promising area of investigation. Pancreatic stellate cells (PSCs) are a-smooth muscle actin–expressing myofibroblast-like cells residing in exocrine areas of the pancreas that can switch between the quiescent and activated phenotypes. They are known to be an activator factor of fibrosis in pancreatic disease of various origins. PSCs are activated as a consequence of pancreatic injury; they participate in tissue repair activities and are abundant in areas of pancreatic fibrosis in pathologic conditions, such as chronic pancreatitis or pancreatic adenocarcinoma (4,5). Several investigators have attempted to use T1-weighted (2) or dynamic contrast material–enhanced magnetic resonance (MR) imaging to predict subsequent pancreatic anastomotic leakage (6,7). Demachi et al (8), who correlated dynamic computed tomographic findings and histopathologic features of pancreatic cancers, described that the degree of contrast enhancement was related to histologic features, such as dense fibrosis and increased cellularity, acinar tissue, or mucin. In addition, the apparent diffusion coefficient (ADC) has been shown to decrease as collagenous fibers proliferate with pancreatic cancers (9). However, our literature search failed to unearth any previous reports in which the relationships between MR imaging findings, PSC expression, pancreatic fibrosis progression, and postoperative pancreatic fistula development have been ascertained.
Implication for Patient Care nn The pancreas-to-muscle SI ratio on T1-weighted MR images may be a potentially useful biomarker for preoperatively assessing the progression of pancreatic fibrosis and predicting the development of postoperative pancreatic fistula.
Thus, the purpose of our study was to assess the potential value of MR imaging to help assess degrees of pancreatic fibrosis and expression of activated PSCs and predict development of postoperative pancreatic fistula.
Materials and Methods Patients Approval for this retrospective study was obtained from our institutional review board, and the requirement for informed consent was waived. From November 2007 to September 2010, 36 consecutive patients underwent excision of the pancreas to treat pancreatic or bile duct tumors in our hospital, and histopathologic diagnoses were assigned for the tumors. Among them, 32 consecutive patients underwent preoperative MR examination, including gadolinium-enhanced dynamic MR imaging. Three of the 32 patients were excluded because of inadequate specimens for assessment of nontumoral pancreatic parenchyma. Thus, the remaining 29 patients (mean age, 64.9 years; range, 21–80 years), including 15 men (mean age, 69.5 years; range, 42–80 years) and 14 women (mean age, 59.9 years; range, 21–73 years), were included in our study (Fig 1).
Published online before print 10.1148/radiol.13131194 Content codes: Radiology 2014; 270:791–799 Abbreviations: ADC = apparent diffusion coefficient PSC = pancreatic stellate cells ROC = receiver operating characteristic SI = signal intensity Author contributions: Guarantors of integrity of entire study, H.W., M.K., S.G.; 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, H.W., S.G., H. Kawada, Y.N., N.K., K.Y., N.M.; clinical studies, H.W., M.K., H. Kondo, Y.T., K.Y.; experimental studies, K.T., S.O., H.T., A.H.; statistical analysis, H.W., M.K., S.G.; and manuscript editing, H.W., M.K., S.G., K.Y. Conflicts of interest are listed at the end of this article.
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Table 1 Parameters Used in MR Sequences Parameter Respiratory control Sequence Fat suppression Repetition time (msec)/echo time (msec) Flip angle (degree) b values (mm2/sec) Field of view (cm) Matrix No. of signals acquired Parallel imaging factor Section thickness (mm) Intersection gap (mm) No. of sections Acquisition time
T1-weighted Imaging
T2-weighted Imaging
Diffusion-weighted Imaging
Dynamic Gadolinium-enhanced Imaging
Breath holding 2D Fast field echo Yes 160/4.1
Respiratory triggered 2D Turbo spin echo Yes 1200/80 (effective)
Free breathing 2D Single-shot echo planar Yes 1347/49 (effective)
Breath holding 3D Spoiled fast field echo Yes 4.7/2.3
75 NA 38 3 30 320 3 224 (512 3 512 reconstruction) 1 1.1 5 1 30 24-sec breath holding, repeated twice
90 NA 38 3 30 320 3 224 (512 3 512 reconstruction) 2 1.6 5 1 30 4 min
90 0 and 500 38 3 30 128 3 90 (256 3 256 reconstruction) 6 2 7 0 30 1 min 7 sec
12 NA 42 3 29 288 3 260 (512 3 512 reconstruction) 1 1.7 4 22 90 for each phase 20 sec for each phase
Note.—Imaging delays for the pancreatic parenchymal, portal venous, and equilibrium phases were 10, 45, and 160 seconds, respectively, after arrival of the contrast agent in the abdominal aorta. NA = not applicable, 2D = two dimensional, 3D = three dimensional.
fat-suppressed three-dimensional spoiled fast field-echo sequence. Gadolinium-enhanced images were obtained after an intravenous bolus injection of 0.1 mmol/kg of gadopentetate dimeglumine and a flush with 15 mL of sterile saline solution. Imaging delays for the pancreatic parenchymal, portal venous, and equilibrium phases were 10, 45, and 160 seconds, respectively, after arrival of the contrast agent in the abdominal aorta. The center of the k-space lines was filled immediately after the start of data acquisition. The other parameters are shown in Table 1.
Figure 1
Figure 1: Flowchart shows patient selection process.
MR Imaging Techniques A 1.5-T superconducting system (Intera Achieva Nova Dual; Philips Medical Systems, Best, the Netherlands) with a six-channel torso array coil was used to perform MR imaging. The basic MR imaging protocol consisted of the following imaging sequences: breath-hold two-dimensional fat-suppressed axial T1-weighted
fast field-echo imaging; respiratory-triggered two-dimensional fat-suppressed axial T2-weighted turbo spin-echo imaging; free-breathing two-dimensional axial diffusion-weighted imaging with a single-shot echo-planar sequence; and breath-holding gadolinium-enhanced pancreatic parenchymal, portal venous, and equilibrium-phase imaging with a
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Reference Standard The interval between pancreatectomy and preoperative MR imaging ranged from 3 to 139 days, with a mean of 44 days. Among the 29 patients, the final diagnosis was adenocarcinoma in 20 patients, intraductal papillary mucinous carcinoma in two, endocrine tumor in one, mucinous cystic neoplasm in one, paraganglioma in one, solid pseudopapillary tumor of the pancreas in one, extrahepatic bile duct carcinoma in two, and pancreatic invasion from gallbladder cancer in one. Nineteen patients (adenocarcinoma, n = 12; intraductal 793
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papillary mucinous carcinoma, n = 2; endocrine tumor, n = 1; paraganglioma, n = 1; extrahepatic bile duct carcinoma, n = 2; and pancreatic invasion from gallbladder cancer, n = 1) underwent pancreatoduodenectomy with pancreaticojejunostomy reconstruction by using pancreatojejunoseroal anastomosis, and 10 patients (adenocarcinoma, n = 8; mucinous cystic neoplasm, n = 1; and solid pseudopapillary tumor of the pancreas, n = 1) underwent distal pancreatectomy (fish-mouth closure). All histopathologic features of the pancreatic surgical specimens were evaluated by two experienced pathologists (A.H. and H.T., with 27 and 15 years of experience in tumor pathology, respectively) and a pancreatobiliary surgeon (K.T., with 8 years of experience in surgical oncology) in consensus. Azan staining was performed to grade the proliferation of collagenous materials that consisted of pancreatic fibrosis, and immunohistochemical staining was performed to evaluate the proliferation of a-smooth muscle actin–expressing cells, which are indicative of expression of activated PSCs. Additionally, hematoxylin-eosin–stained specimens were used to grade the degrees of fat deposition and interstitial edema in pancreatic parenchyma. Grades for fibrosis, activated PSC expression, fat deposition, and interstitial edema in nontumoral pancreatic parenchyma were determined semiquantitatively. We used the grading criteria for pancreatic fibrosis described previously (3): F0 = normal pancreatic parenchyma, no fibrotic changes; F1 = mild fibrosis with thickening of periductal fibrous tissue; F2 = moderate fibrosis with marked sclerosis of interlobular septa and no evidence of architectural changes; and F3 = severe fibrosis with detection of architectural destruction. The grading criteria for activated PSC expression were as follows: A0 = no staining, A1 = mild staining of a part of the periductal or interlobular tissue, A2 = moderate staining of the whole periductal or interlobular tissue, and A3 = severe staining of the whole periductal or interlobular tissue. Grading criteria for fat deposition were as follows: L0 = 794
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0%–10% deposition, L1 = 10%–20%, L2 = 20%–30%, and L3 = greater than 31%; those for interstitial edema were as follows: E0 = no or slight interstitial edema, E1 = mild periductal or interlobular edema, E2 = moderate periductal or interlobular edema, and E3 = severe periductal or interlobular edema. The development of postoperative pancreatic fistula was defined according to the definition of the International Study Group for Pancreatic Surgery: a postoperative pancreatic fistula is present if amylase level of drainage fluid on or after postoperative day 3 exceeds three times the upper serum limit. All patients were followed up by the team of surgeons, and amylase level of drainage fluid, serum amylase level, C-reactive protein, and white blood cell count on days 1, 3, and 5 after surgery were evaluated. Three different grades of postoperative pancreatic fistula (grades A, B, and C) are defined according to the clinical effect on the patient’s hospital course: grade A does not need specific treatment, grade B requires prolonged drainage or specific medical treatment, and grade C requires invasive therapy (10).
Quantitative Image Analysis Operator-defined region of interest (50–150 mm2) measurements were used to obtain the signal intensity (SI) ratio of the pancreatic parenchyma to paraspinal muscle on unenhanced T1-weighted, T2-weighted, diffusionweighted, and gadolinium-enhanced MR images and the SI ratio of the pancreatic parenchyma to spinal cord on diffusion-weighted images. The ADC values of pancreatic parenchyma were measured as follows: ADC = 2[ln (SIb/ SI0)]/b, where SI0 is the SI on images with a b value of 0 sec/mm2, and SIb is the SI with a b value of 500 sec/mm2. The delayed enhancement index was calculated as the ratio of the SI ratio of the pancreas during the equilibrium phase to that during the pancreatic parenchymal phase. Region of interest measurements were performed in areas of nontumoral pancreatic parenchyma by matching the locations as closely as possible
with the surgical specimen that was evaluated histopathologically. Regions of interest were chosen to be devoid of dilated pancreatic duct, normal intrapancreatic vasculature, and focal lesions. The maximal diameter of the main pancreatic duct was measured by using an electronic caliper. A radiologist (H.W., with 6 years of posttraining experience in interpreting body MR images) who had no knowledge of the clinical or histopathologic patient information performed all measurements by using a commercially available Digital Imaging and Communications in Medicine viewer (IVimage VINS; Yokogawa Solutions, Tokyo, Japan). For all measurements, the size, shape, and position of the regions of interest were kept constant among all MR images by applying a copy-and-paste function on the viewer.
Statistical Analysis Commercially available software (MedCalc, version 12.3.0; MedCalc, Mariakerke, Belgium) was used to perform statistical analysis. The Spearman rank correlation test was used to explore correlations of MR imaging measurements with grades for pancreatic fibrosis, activated PSC expression, fat deposition, and interstitial edema. Stepwise multiple regression tests were conducted to examine relationships of MR imaging measurements with grades for pancreatic fibrosis, activated PSC expression, fat deposition, and interstitial edema. The Kruskal-Wallis method with post hoc tests as described by Conover (11) were used to compare predictor variables in multiple regression models among all grades for pancreatic fibrosis, activated PSC expression, fat deposition, and interstitial edema. Nonparametric receiver operating characteristic (ROC) curves were composed to assess the diagnostic performance of these variables in discriminating the grades for pancreatic fibrosis and activated PSC expression. Cutoff values, sensitivity, and specificity were calculated. Stepwise multiple logistic regression tests were also used to examine the relationships between the development of
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Table 2 Correlation of MR Imaging Parameters with Pancreatic Fibrosis and Activated PSC Expression Grades Activated PSC Expression Grade
Pancreatic Fibrosis Grade MR Imaging Parameter Pancreas-to-muscle SI ratio T1-weighted imaging T2-weighted imaging Diffusion-weighted imaging Pancreatic parenchymal-phase imaging Portal venous phase imaging Equilibrium-phase imaging Pancreas-to–spinal cord SI ratio at diffusion-weighted imaging ADC Delayed enhancement index
r Value
P Value
r Value
20.69 20.12 0.082 20.52 20.24 20.28 0.39
, .0001 .54 .67 .0037 .22 .14 .035
20.64 0.056 0.24 20.37 0.029 20.023 0.51
.0006 .0016
20.60 0.44
20.70 0.44
P Value .0002 .77 .22 .048 .88 .91 .0043 ,.0001 .017
Note.—The r values were obtained with the Spearman rank correlation coefficient.
Table 3 SI Ratio and ADC for Pancreatic Fibrosis and Activated PSC Expression Grades Grade Pancreatic fibrosis grade F0 (n = 7) F1 (n = 13) F2 (n = 5) F3 (n = 4) P value* Activated PSC expression grade A0 (n = 10) A1 (n = 9) A2 (n = 4) A3 (n = 6) P value*
Pancreas-to-Muscle SI Ratio at T1-weighted Imaging
ADC
1.51 6 0.25 (1.16–1.91) 1.48 6 0.22 (1.21–1.98) 1.05 6 0.09 (0.95–1.15) 0.94 6 0.10 (0.85–1.08) .0004
1.85 6 0.23 (1.59–2.19) 1.73 6 0.36 (1.27–2.27) 1.44 6 0.27 (1.14–1.75) 1.19 6 0.13 (1.07–1.30) .0082
1.52 6 0.22 (1.16–1.91) 1.41 6 0.33 (0.95–1.98) 1.25 6 0.14 (1.09–1.41) 1.00 6 0.13 (0.85–1.15) .0046
1.90 6 0.31 (1.32–2.27) 1.66 6 0.32 (1.27–2.24) 1.59 6 0.19 (1.33–1.77) 1.19 6 0.11 (1.07–1.30) .0016
Note.—Data are mean 6 standard deviation. Numbers in parentheses are the range. * Kruskal-Wallis test.
postoperative pancreatic fistula and the MR imaging measurements, grades of pancreatic fibrosis, activated PSC expression, fat deposition, and interstitial edema. The Mann-Whitney U test was used to compare the response variables used in the logistic regression analysis between patients with and those without postoperative pancreatic fistula. In all comparisons, a P value of .05 was considered to indicate a significant difference.
Results The mean maximal diameter of the main pancreatic duct was 5.0 mm 6 3.3 (standard deviation) (range, 1–15 mm), and dilatation of the main pancreatic duct (mean, 6.0 mm 6 3.1; range, 3–15 mm) was found in 22 patients. A positive correlation was found between the pancreatic fibrosis grade and the activated PSC expression grade (r = 0.76, P , .0001). The Spearman rank
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correlation test indicated that the pancreas-to-muscle SI ratios on T1-weighted images and pancreatic parenchymalphase images, pancreas–spinal cord SI ratio on diffusion-weighted images, ADC, and delayed enhancement index were correlated with the pancreatic fibrosis grades and the activated PSC expression grades. The pancreas-tomuscle SI ratio on T1-weighted images and ADC value were correlated with the pancreatic fibrosis grade (r = 20.69 and 20.60, respectively) and with the activated PSC expression grade (r = 20.64 and 20.70, respectively) (Table 2). ADC value was correlated with the fat deposition grade (r = 0.43, P = .02), and pancreas-to–spinal cord SI ratio on diffusion-weighted images was correlated with the interstitial edema grade (r = 0.58, P = .001). Multiple regression analysis showed the following correlations: the pancreas-to-muscle SI ratio on T1weighted images (coefficient = 21.88, P , .0001) and ADC value (coefficient = 21.20, P = .0006) were independently associated with the pancreatic fibrosis grade (r2 = 0.66, P , .001). The pancreas-to-muscle SI ratio on T1weighted images (coefficient = 21.82, P = .0003) and ADC value (coefficient = 21.76, P , .0001) were independently associated with the activated PSC expression grade (r2 = 0.67, P , .001). The ADC value (coefficient = 1.23, P = .02) was independently associated with the fat deposition grade (r2 = 0.15, P = .02). The pancreas-to–spinal cord SI ratio on diffusion-weighted images (coefficient = 1.28, P = .006) was independently associated with the interstitial edema grade (r2 = 0.37, P = .006). The other MR imaging parameters showed no correlation. The pancreas-to-muscle SI ratio on T1-weighted images and ADC values for the pancreatic fibrosis grades and the activated PSC expression grades are summarized in Table 3. Box plots for the pancreas-to-muscle SI ratio on T1-weighted images for each histologic grade are illustrated in Figure 2. The mean pancreas-to-muscle SI ratio on T1-weighted images decreased constantly as the pancreatic fibrosis grade 795
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progressed (P , .05). The pancreasto-muscle SI ratio on T1-weighted images was lower for fibrosis grades F2 and F3 than for grades F0 and F1 (P , .05). The overlap between fibrosis grades F0 and F1 and grades F2 and F3 was minimal (Fig 2a). The mean pancreas-to-muscle SI ratio on T1weighted images for activated PSC expression grade A3 was lower than that for grades A0 and A1 (P , .05) (Fig 2b). Box plots for ADC values for each histologic grade are illustrated in Figure 3. The mean ADC value constantly decreased as the pancreatic fibrosis grade progressed, although there were large overlaps. The mean ADC value was lower for F3 than for F0 and F1 (P , .05) and lower for F2 than for F0 (P , .05). The mean ADC value for activated PSC expression grade A3 was lower than that for grades A0 to A2 (P , .05). Area under the ROC curve values in the detection of pancreatic fibrosis and activated PSC expression with pancreas-to-muscle SI ratio on T1weighted images and the ADC values, sensitivities, and specificities based on the most discriminating cutoff values are shown in Table 4. In detecting pancreatic fibrosis of grade F2 and higher, an SI ratio cutoff value of 1.15 on T1weighted images yielded a sensitivity of 100% (eight of eight patients) and a specificity of 95% (20 of 21 patients). In detecting the activated PSC expression grade A3, an ADC cutoff value of 1.30 yielded a sensitivity of 100% (six of six patients) and a specificity of 96% (22 of 23 patients). Ten patients (34%, 10 of 29) developed postoperative pancreatic fistula, and 19 did not. The postoperative pancreatic fistulas were grades A and B in five patients each (17%, five of 29). Multiple logistic regression analysis showed that the pancreas-to-muscle SI ratio on T1-weighted images alone was significantly associated with the occurrence of postoperative pancreatic fistula (P = .0094). The mean pancreas-to-muscle SI ratio on T1-weighted images in the patients with postoperative pancreatic fistula (1.6 6 0.2) was higher than that 796
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Figure 2
Figure 2: Box plots show the SI ratio on T1-weighted images for (a) pancreatic fibrosis and (b) activated PSC expression grades. The boundary of the box that is closest to zero represents the 25th percentile, the line in the box indicates the median, the boundary of the box that is farthest from zero represents the 75th percentile, and the error bar shows the smallest and largest values in 1.5 box lengths of the 25th and 75th percentiles. Horizontal brackets indicate the significant difference found with the Kruskal-Wallis method in the post hoc tests, as described by Conover (P , .05).
Figure 3
Figure 3: Box plots show the ADC value for (a) pancreatic fibrosis and (b) activated PSC expression grades. The boundary of the box that is closest to zero indicates the 25th percentile, the line in the box indicates the median, the boundary of the box that is farthest from zero represents the 75th percentile, and the error bar shows the smallest and largest values in 1.5 box lengths of the 25th and 75th percentiles. Horizontal brackets indicate the significant difference found with the Kruskal-Wallis method in the post hoc tests, as described by Conover (P , .05).
in the patients without (1.2 6 0.2) (P = .0029) (Figs 4–6). For predicting the development of postoperative pancreatic fistula, an SI ratio cutoff value of
1.41 yielded a sensitivity of 80% (eight of 10 patients), specificity of 84% (16 of 19 patients), positive predictive value of 73% (eight of 11 patients), and negative
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Table 4 Az Value, SI Ratio Cutoff, Sensitivity, and Specificity for Pancreatic Fibrosis and Activated PSC Expression Grades Pancreas-to-Muscle SI Ratio at T1-weighted Imaging Grade Pancreatic fibrosis grade F1 F2 F3 Activated PSC expression grade A1 A2 A3
Az Value
SI Ratio Cutoff Sensitivity (%)
0.60 (0.40, 0.77) 0.95 (0.80, 0.98) 0.98 (0.85, 1.00)
1.27 1.15 1.08
0.68 (0.48, 0.84) 0.82 (0.63, 0.94) 0.94 (0.79, 1.00)
1.35 1.31 1.15
ADC Az Value
SI Ratio Cutoff Sensitivity (%)
52 [11/21] (30, 74) 75 [6/8] (35, 97) 100 [8/8] (63, 100) 95 [20/21] (76, 100) 100 [4/4] (40, 100) 92 [23/25] (74, 99)
0.65 (0.45, 0.82) 0.85 (0.67, 0.96) 0.94 (0.79, 0.99)
1.48 1.33 1.30
52 [11/21] (30, 74) 88 [7/8] (47, 100) 75 [6/8] (35, 97) 81 [17/21] (58, 95) 100 [4/4] (40, 100) 88 [22/25] (69, 98)
67 [12/18] (41, 87) 73 [8/11] (39, 94) 89 [8/9] (52, 100) 70 [14/20] (46, 88) 100 [6/6] (54, 100) 87 [20/23] (66, 97)
0.77 (0.57, 0.90) 0.83 (0.65, 0.94) 0.98 (0.84, 1.00)
1.77 1.77 1.30
83 [15/18] (59, 96) 64 [7/11] (31, 89) 100 [9/9] (66, 100) 50 [10/20] (27, 73) 100 [6/6] (54, 100) 96 [22/23] (78, 100)
Specificity (%)
Specificity (%)
Note.—Numbers in parentheses are 95% confidence intervals; 95% confidence intervals for area under the ROC curve (Az) values were calculated by means of the binomial exact method. Confidence intervals for the sensitivity and specificity are bootstrapped 95% confidence intervals. Data in brackets were used to calculate the statistics.
Figure 4
predictive value of 89% (16 of 18 patients). The odds ratio for the development of postoperative pancreatic fistula was 21.3 (95% confidence interval: 2.9, 154.6) when using an SI ratio of 1.41 and higher.
Discussion
Figure 4: Box plots show the SI ratios on T1-weighted images for patients with postoperative pancreatic fistula and those without. The boundary of the box that is closest to zero indicates the 25th percentile, the line within the box indicates the median, and the boundary of the box that is farthest from zero indicates the 75th percentile. The error bar indicates the smallest and largest values within 1.5 box lengths of the 25th and 75th percentiles. A significant difference was found with the Mann-Whitney U test (P = .0029). POPF(2) = absence of postoperative pancreatic fistula, POPF(+) = presence of postoperative pancreatic fistula.
In previous studies, investigators have described some relationships between MR imaging parameters and activated stellate cell expressions in organs (12,13) and have indicated that MR imaging might be used to help assess the degree of liver steatosis (12), liver fibrosis (14), or renal fibrosis (13). With regard to liver fibrosis, it has been reported that collagen cross-linking by members of the lysyl oxidase protein family increases the stiffness of the liver before activated hepatic stellate cell expression (15). In addition, ADC measurement on diffusionweighted MR images was an efficient technique for detecting and monitoring abnormal histopathologic changes, including fibroblast expression during the progression of renal fibrosis (13). PSCs are the principal source of fibrosis in the pancreatic stroma, and it has been reported that pancreatic cancer cells induce fibrosis by way of the stimulation of proliferation and matrix synthesis of PSCs, which strongly supports tumor growth and results in
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increased deposition of connective tissue (16). Our histologic examination also showed that the expression of activated PSCs correlated with the progression of pancreatic fibrosis. The ADC value of the pancreatic parenchyma correlated highly with the expression of activated PSCs. These results suggested that the ADCs reflected the changes in molecular diffusion property related to the process of pancreatic fibrogenesis. The strong correlations between ADCs and both pancreatic fibrosis and activated PSC expression were shown in our study. However, the relationship between the ADCs and fibrogenesis is thought to be complex and controversial. It is widely accepted that increased cell density causes a reduction of ADC (17). High cellularity causes an increase in the density of cell membranes, which is the dominant mechanism that restricts water molecule movement (18,19). In addition, high cell density causes a decrease in extracellular water fraction and, reciprocally, an increase in intracellular water fraction, which in turn exhibits a lower ADC (20). On the other hand, inflammatory cell infiltration, progressive destruction of pancreatic parenchyma, and retention of pancreatic exocrine products secondary to obstructive pancreatitis of different severities in the course of pancreatic fibrosis might increase the ADC measurements. 797
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Figure 5
Figure 5: Images show pancreatic adenocarcinoma in the pancreatic body in a 42-year-old man who subsequently developed postoperative pancreatic fistula. Histopathologic examination demonstrated the pancreatic fibrosis grade of F0 and an activated PSC expression grade of A0. (a) SI ratio at T1-weighted MR imaging was 1.91, and (b) ADC measured on an ADC map in the pancreatic body that corresponds to the surgical specimen was 1.77 3 1023 mm2/sec. The region of interest was located in areas of nontumoral pancreatic parenchyma, and it was matched with the location of the surgical resection margin (circles). On the ADC map (b), pancreatic adenocarcinoma (arrow) is seen as the region with decreased ADC in the pancreatic body.
Figure 6
Figure 6: Images show pancreatic adenocarcinoma in the pancreatic head in a 70-year-old woman without subsequent postoperative pancreatic fistula. Histopathologic examination showed the pancreatic fibrosis grade of F2 and an activated PSC expression grade of A2. (a) SI ratio on a T1-weighted image was 1.09, and (b) ADC measured on an ADC map in the pancreatic head that corresponds to the surgical specimen was 1.33 3 1023 mm2/sec. The region of interest was located in areas of nontumoral pancreatic parenchyma, and it was matched with the location of the surgical resection margin (circles). The pancreatic duct (arrow in a) and common bile duct (arrowhead in a) were dilated upstream from the known adenocarcinoma of the pancreatic head on the T1-weighted image.
Multiple regression analysis showed that the SI ratios on T1-weighted images and ADCs were associated with the degrees of pancreatic fibrosis and 798
activated PSC expression. Fat-suppressed T1-weighted imaging is sensitive for focal pancreatic disease because a normal pancreas exhibits relatively
high signal intensity on T1-weighted images compared with other abdominal organs owing to its short T1-relaxation time, which is attributed to the abundant protein and rough endoplasmic reticulum contained within it (21). On the other hand, SI of abnormal pancreatic parenchyma on fat-suppressed T1weighted images may decrease, owing to pancreatic atrophy, fibrosis, edema, or fat deposition. However, our findings suggest that the decrease in SI ratio on fat-suppressed T1-weighted images with the progression of pancreatic fibrosis is more attributable to an increase in pancreatic fibrosis or activated PSC proliferation than to fat deposition or edema caused by inflammatory changes in association with pancreatic fibrosis or obstructive pancreatitis. Although there was significant overlap in the SI ratios on T1-weighted images and ADCs between grades of pancreatic fibrosis and activated PSC expression, the most discriminating SI and ADC cutoff value settings based on ROC analyses of our retrospectively derived test set potentially yielded sufficiently high sensitivities and specificities for detecting, in particular, severe pancreatic fibrosis and advanced activated PSC expression. Further, the mean SI ratio on T1-weighted images was significantly higher in patients with postoperative pancreatic fistula than in those without postoperative pancreatic fistula, and the odds ratio for the development of postoperative pancreatic fistula was fairly high at 21.3 in patients with a pancreas-to-muscle SI ratio of 1.41 and higher. Accordingly, we believe that the SI ratio on T1-weighted images and ADCs may be useful in the detection of advanced pancreatic fibrosis, and preoperative assessment with MR imaging may help act preemptively against occurrence of postoperative pancreatic fistula. Our study had some limitations. First, our study cohort was not large. The relatively small sample size may have potentially caused selection bias. Thus, our results should be considered preliminary and require confirmation in a multiinstitutional study that could provide a large sample size. Second, correlations
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between MR imaging findings and longterm postoperative courses or pancreatic fibrosis and exocrine function are yet to be determined. Third, we calculated SI ratio and ADC cutoff values on the basis of retrospective data; therefore, our results need to be validated in future clinical studies as they likely include overestimations of diagnostic performance. Finally, diffusion-weighted images obtained with free breathing were evaluated in our retrospective study. However, the presence of respiratory motion-related artifacts may have introduced a certain degree of errors in ADC measurements. In conclusion, our results suggest that T1-weighted and diffusion-weighted MR imaging with concomitant SI ratio and ADC measurements could serve as preoperative noninvasive biomarkers to efficiently detect advanced pancreatic fibrosis, which is highly linked to the occurrence of postoperative pancreatic fistula. We believe that the measurement of these simple parameters at routine unenhanced MR imaging may enhance the value of pancreatic MR imaging. Disclosures of Conflicts of Interest: H.W. No relevant conflicts of interest to disclose. M.K. No relevant conflicts of interest to disclose. K.T. No relevant conflicts of interest to disclose. S.O. No relevant conflicts of interest to disclose. H.T. No relevant conflicts of interest to disclose. A.H. No relevant conflicts of interest to disclose. S.G. No relevant conflicts of interest to disclose. H. Kondo No relevant conflicts of interest to disclose. H. Kawada No relevant conflicts of interest to disclose. Y.N. No relevant conflicts of interest to disclose. Y.T. No relevant conflicts of interest to disclose. N.K. No relevant conflicts of interest to disclose. K.Y. No relevant conflicts of interest to disclose. N.M. No relevant conflicts of interest to disclose.
References 1. Hashimoto Y, Sclabas GM, Takahashi N, et al. Dual-phase computed tomography for assessment of pancreatic fibrosis and
anastomotic failure risk following pancreatoduodenectomy. J Gastrointest Surg 2011;15(12):2193–2204. 2. Kim Z, Kim MJ, Kim JH, et al. Prediction of post-operative pancreatic fistula in pancreaticoduodenectomy patients using preoperative MRI: a pilot study. HPB (Oxford) 2009;11(3):215–221. 3. Wellner UF, Kayser G, Lapshyn H, et al. A simple scoring system based on clinical factors related to pancreatic texture predicts postoperative pancreatic fistula preoperatively. HPB (Oxford) 2010;12(10):696–702. 4. Cyriac J, Mahadevan P, Augustine P, Ramesh H, Koshy A. Stellate cell activation in tropical calcific pancreatitis compared to alcoholic pancreatitis, adenocarcinoma of pancreas and normal pancreas. JOP 2012;13(4):376–386. 5. Haber PS, Keogh GW, Apte MV, et al. Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am J Pathol 1999;155(4):1087–1095. 6. Dinter DJ, Aramin N, Weiss C, et al. Prediction of anastomotic leakage after pancreatic head resections by dynamic magnetic resonance imaging (dMRI). J Gastrointest Surg 2009;13(4):735–744. 7. Tajima Y, Kuroki T, Tsutsumi R, et al. Risk factors for pancreatic anastomotic leakage: the significance of preoperative dynamic magnetic resonance imaging of the pancreas as a predictor of leakage. J Am Coll Surg 2006;202(5):723–731. 8. Demachi H, Matsui O, Kobayashi S, et al. Histological influence on contrast-enhanced CT of pancreatic ductal adenocarcinoma. J Comput Assist Tomogr 1997;21(6):980–985.
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11. Conover WJ. Practical Nonparametric Statistics. 3rd ed. New York, NY: Wiley; 1999. 12. Salameh N, Larrat B, Abarca-Quinones J, et al. Early detection of steatohepatitis in fatty rat liver by using MR elastography. Radiology 2009;253(1):90–97. 13. Togao O, Doi S, Kuro-o M, Masaki T, Yorioka N, Takahashi M. Assessment of renal fibrosis with diffusion-weighted MR imaging: study with murine model of unilateral ureteral obstruction. Radiology 2010; 255(3):772–780. 14. Ehman RL. Science to practice: can MR elastography be used to detect early steatohepatitis in fatty liver disease? Radiology 2009;253(1):1–3. 15. Georges PC, Hui JJ, Gombos Z, et al. Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am J Physiol Gastrointest Liver Physiol 2007;293(6):G1147–G1154. 16. Bachem MG, Schünemann M, Ramadani M, et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005;128(4):907–921. 17. Lyng H, Haraldseth O, Rofstad EK. Measurement of cell density and necrotic fraction in human melanoma xenografts by diffusion weighted magnetic resonance imaging. Magn Reson Med 2000;43(6):828–836. 18. Takahashi M, Hackney DB, Zhang G, et al. Magnetic resonance microimaging of intraaxonal water diffusion in live excised lamprey spinal cord. Proc Natl Acad Sci U S A 2002;99(25):16192–16196. 19. Szafer A, Zhong J, Gore JC. Theoretical model for water diffusion in tissues. Magn Reson Med 1995;33(5):697–712.
9. Muraoka N, Uematsu H, Kimura H, et al. Apparent diffusion coefficient in pancreatic cancer: characterization and histopathological correlations. J Magn Reson Imaging 2008;27(6):1302–1308.
20. Chin CL, Wehrli FW, Hwang SN, Takahashi M, Hackney DB. Biexponential diffusion attenuation in the rat spinal cord: computer simulations based on anatomic images of axonal architecture. Magn Reson Med 2002;47(3):455–460.
10. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 2005;138(1):8–13.
21. Winston CB, Mitchell DG, Outwater EK, Ehrlich SM. Pancreatic signal intensity on T1-weighted fat saturation MR images: clinical correlation. J Magn Reson Imaging 1995;5(3):267–271.
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From the Department of Radiology, Gifu Central Hospital, 3-25 Kawabe, 501-1198 Gifu, Japan (H.W.); Departments of Radiology (H.W., M.K., S.G., H. Kondo, H. Kawada, Y.N., Y.T., N.K.) and Radiology Services (M.K.), Gifu University Hospital, Gifu, Japan; Departments of Surgical Oncology (K.T., S.O., K.Y.) and Tumor Pathology (H.T., A.H.), Gifu University Graduate School of Medicine, Gifu, Japan; and Research Center for Cancer Prevention and Screening, National Cancer Center Hospital, Tsukiji, Japan (N.M.). Received May 24, 2013; revision requested July 22; revision received August 6; accepted August 22; final version accepted September 4. Address correspondence to H.W. (e-mail: [email protected]).
Purpose:
To assess the potential value of magnetic resonance (MR) imaging in evaluating pancreatic fibrosis and predicting the development of postoperative pancreatic fistula.
Materials and Methods:
This retrospective study had institutional review board approval, and the requirement for informed consent was waived. MR images obtained in 29 consecutive patients (15 men, 14 women; mean age, 64.9 years; age range, 21–80 years) who underwent pancreatectomy were evaluated. The pancreas-to-muscle signal intensity (SI) ratio on unenhanced T1- and T2-weighted, dynamic contrast material–enhanced, and diffusion-weighted images and the apparent diffusion coefficient (ADC) of the pancreas were measured. MR imaging parameters were correlated with the degrees of pancreatic fibrosis and expression of activated pancreatic stellate cells (PSCs) by using univariate and multivariate regression analyses and receiver operating characteristic curve analysis. The relationships between the development of postoperative pancreatic fistula and the MR imaging measurements were examined by using logistic regression analysis and the Mann-Whitney U test.
Results:
Multiple regression analysis showed that pancreas-tomuscle SI ratios on T1-weighted images and ADC values were independently associated with pancreatic fibrosis (r2 = 0.66, P , .001) and with activated PSC expression (r2 = 0.67, P , .001). The mean pancreas-to-muscle SI ratio (6 standard deviation) on T1-weighted images was higher (P = .0029) for patients with postoperative pancreatic fistula (1.6 6 0.2) than for those without (1.2 6 0.2), and the odds ratio for postoperative pancreatic fistula was 21.3 in patients with an SI ratio of 1.41 and higher.
Conclusion:
The pancreas-to-muscle SI ratio on T1-weighted MR images of the pancreas may be a potential biomarker for assessment of pancreatic fibrosis and prediction of postoperative pancreatic fistula. RSNA, 2013
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Haruo Watanabe, MD Masayuki Kanematsu, MD Kaori Tanaka, MD Shinji Osada, MD, PhD Hiroyuki Tomita, MD, PhD Akira Hara, MD, PhD Satoshi Goshima, MD Hiroshi Kondo, MD Hiroshi Kawada, MD Yoshifumi Noda, MD Yukichi Tanahashi, MD Nobuyuki Kawai, MD Kazuhiro Yoshida, MD, PhD Noriyuki Moriyama, MD
Original Research n Gastrointestinal
Fibrosis and Postoperative Fistula of the Pancreas: Correlation with MR Imaging Findings—Preliminary Results1
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P
ancreatic parenchyma becomes hardened because of fibrosis associated with chronic pancreatitis and pancreatic carcinoma, and the hardness of the pancreatic parenchyma is known to be associated with the development of postoperative pancreatic fistula after pancreatectomy (1,2). Several predisposing factors for development of postoperative pancreatic fistula have been suggested. Old age, a narrow pancreatic duct diameter, soft or normal pancreatic parenchyma, ampullary or duodenal disease, longer operation time, and greater intraoperative blood loss have been regarded as possible causes of postoperative pancreatic fistula (2). Postoperative pancreatic fistula is generally known as the most relevant complication after pancreatectomy because it potentially leads
Advances in Knowledge nn The pancreas-to-muscle signal intensity (SI) ratio on T1-weighted MR images and apparent diffusion coefficient (ADC) measured at diffusionweighted MR imaging decreased as pancreatic fibrosis progressed (Spearman rank correlation coefficient, r = 20.69 and 20.60, respectively) and pancreatic stellate cells (PSCs) were activated (r = 20.64 and 20.70, respectively). nn In our retrospective test set, for detection of pancreatic fibrosis of grade F2 and higher, a pancreasto-muscle SI ratio cutoff value of 1.15 on T1-weighted images yielded a sensitivity of 100% (eight of eight patients) and specificity of 95% (20 of 21 patients); for detecting the activated PSC expression grade A3, an ADC cutoff value of 1.30 yielded a sensitivity of 100% (six of six patients) and specificity of 96% (22 of 23 patients). nn The odds ratio for the development of postoperative pancreatic fistula was 21.3 (95% confidence interval: 2.9, 154.6) in patients with a pancreas-to-muscle SI ratio of 1.41 and higher. 792
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to deleterious secondary complications, such as peripancreatic fluid collection, abscess, or bleeding from adjacent major vessels (3). Thus, assessment of preoperative features of pancreatic parenchymal texture that are highly linked to occurrence of postoperative pancreatic fistula is a promising area of investigation. Pancreatic stellate cells (PSCs) are a-smooth muscle actin–expressing myofibroblast-like cells residing in exocrine areas of the pancreas that can switch between the quiescent and activated phenotypes. They are known to be an activator factor of fibrosis in pancreatic disease of various origins. PSCs are activated as a consequence of pancreatic injury; they participate in tissue repair activities and are abundant in areas of pancreatic fibrosis in pathologic conditions, such as chronic pancreatitis or pancreatic adenocarcinoma (4,5). Several investigators have attempted to use T1-weighted (2) or dynamic contrast material–enhanced magnetic resonance (MR) imaging to predict subsequent pancreatic anastomotic leakage (6,7). Demachi et al (8), who correlated dynamic computed tomographic findings and histopathologic features of pancreatic cancers, described that the degree of contrast enhancement was related to histologic features, such as dense fibrosis and increased cellularity, acinar tissue, or mucin. In addition, the apparent diffusion coefficient (ADC) has been shown to decrease as collagenous fibers proliferate with pancreatic cancers (9). However, our literature search failed to unearth any previous reports in which the relationships between MR imaging findings, PSC expression, pancreatic fibrosis progression, and postoperative pancreatic fistula development have been ascertained.
Implication for Patient Care nn The pancreas-to-muscle SI ratio on T1-weighted MR images may be a potentially useful biomarker for preoperatively assessing the progression of pancreatic fibrosis and predicting the development of postoperative pancreatic fistula.
Thus, the purpose of our study was to assess the potential value of MR imaging to help assess degrees of pancreatic fibrosis and expression of activated PSCs and predict development of postoperative pancreatic fistula.
Materials and Methods Patients Approval for this retrospective study was obtained from our institutional review board, and the requirement for informed consent was waived. From November 2007 to September 2010, 36 consecutive patients underwent excision of the pancreas to treat pancreatic or bile duct tumors in our hospital, and histopathologic diagnoses were assigned for the tumors. Among them, 32 consecutive patients underwent preoperative MR examination, including gadolinium-enhanced dynamic MR imaging. Three of the 32 patients were excluded because of inadequate specimens for assessment of nontumoral pancreatic parenchyma. Thus, the remaining 29 patients (mean age, 64.9 years; range, 21–80 years), including 15 men (mean age, 69.5 years; range, 42–80 years) and 14 women (mean age, 59.9 years; range, 21–73 years), were included in our study (Fig 1).
Published online before print 10.1148/radiol.13131194 Content codes: Radiology 2014; 270:791–799 Abbreviations: ADC = apparent diffusion coefficient PSC = pancreatic stellate cells ROC = receiver operating characteristic SI = signal intensity Author contributions: Guarantors of integrity of entire study, H.W., M.K., S.G.; 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, H.W., S.G., H. Kawada, Y.N., N.K., K.Y., N.M.; clinical studies, H.W., M.K., H. Kondo, Y.T., K.Y.; experimental studies, K.T., S.O., H.T., A.H.; statistical analysis, H.W., M.K., S.G.; and manuscript editing, H.W., M.K., S.G., K.Y. Conflicts of interest are listed at the end of this article.
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Table 1 Parameters Used in MR Sequences Parameter Respiratory control Sequence Fat suppression Repetition time (msec)/echo time (msec) Flip angle (degree) b values (mm2/sec) Field of view (cm) Matrix No. of signals acquired Parallel imaging factor Section thickness (mm) Intersection gap (mm) No. of sections Acquisition time
T1-weighted Imaging
T2-weighted Imaging
Diffusion-weighted Imaging
Dynamic Gadolinium-enhanced Imaging
Breath holding 2D Fast field echo Yes 160/4.1
Respiratory triggered 2D Turbo spin echo Yes 1200/80 (effective)
Free breathing 2D Single-shot echo planar Yes 1347/49 (effective)
Breath holding 3D Spoiled fast field echo Yes 4.7/2.3
75 NA 38 3 30 320 3 224 (512 3 512 reconstruction) 1 1.1 5 1 30 24-sec breath holding, repeated twice
90 NA 38 3 30 320 3 224 (512 3 512 reconstruction) 2 1.6 5 1 30 4 min
90 0 and 500 38 3 30 128 3 90 (256 3 256 reconstruction) 6 2 7 0 30 1 min 7 sec
12 NA 42 3 29 288 3 260 (512 3 512 reconstruction) 1 1.7 4 22 90 for each phase 20 sec for each phase
Note.—Imaging delays for the pancreatic parenchymal, portal venous, and equilibrium phases were 10, 45, and 160 seconds, respectively, after arrival of the contrast agent in the abdominal aorta. NA = not applicable, 2D = two dimensional, 3D = three dimensional.
fat-suppressed three-dimensional spoiled fast field-echo sequence. Gadolinium-enhanced images were obtained after an intravenous bolus injection of 0.1 mmol/kg of gadopentetate dimeglumine and a flush with 15 mL of sterile saline solution. Imaging delays for the pancreatic parenchymal, portal venous, and equilibrium phases were 10, 45, and 160 seconds, respectively, after arrival of the contrast agent in the abdominal aorta. The center of the k-space lines was filled immediately after the start of data acquisition. The other parameters are shown in Table 1.
Figure 1
Figure 1: Flowchart shows patient selection process.
MR Imaging Techniques A 1.5-T superconducting system (Intera Achieva Nova Dual; Philips Medical Systems, Best, the Netherlands) with a six-channel torso array coil was used to perform MR imaging. The basic MR imaging protocol consisted of the following imaging sequences: breath-hold two-dimensional fat-suppressed axial T1-weighted
fast field-echo imaging; respiratory-triggered two-dimensional fat-suppressed axial T2-weighted turbo spin-echo imaging; free-breathing two-dimensional axial diffusion-weighted imaging with a single-shot echo-planar sequence; and breath-holding gadolinium-enhanced pancreatic parenchymal, portal venous, and equilibrium-phase imaging with a
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Reference Standard The interval between pancreatectomy and preoperative MR imaging ranged from 3 to 139 days, with a mean of 44 days. Among the 29 patients, the final diagnosis was adenocarcinoma in 20 patients, intraductal papillary mucinous carcinoma in two, endocrine tumor in one, mucinous cystic neoplasm in one, paraganglioma in one, solid pseudopapillary tumor of the pancreas in one, extrahepatic bile duct carcinoma in two, and pancreatic invasion from gallbladder cancer in one. Nineteen patients (adenocarcinoma, n = 12; intraductal 793
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papillary mucinous carcinoma, n = 2; endocrine tumor, n = 1; paraganglioma, n = 1; extrahepatic bile duct carcinoma, n = 2; and pancreatic invasion from gallbladder cancer, n = 1) underwent pancreatoduodenectomy with pancreaticojejunostomy reconstruction by using pancreatojejunoseroal anastomosis, and 10 patients (adenocarcinoma, n = 8; mucinous cystic neoplasm, n = 1; and solid pseudopapillary tumor of the pancreas, n = 1) underwent distal pancreatectomy (fish-mouth closure). All histopathologic features of the pancreatic surgical specimens were evaluated by two experienced pathologists (A.H. and H.T., with 27 and 15 years of experience in tumor pathology, respectively) and a pancreatobiliary surgeon (K.T., with 8 years of experience in surgical oncology) in consensus. Azan staining was performed to grade the proliferation of collagenous materials that consisted of pancreatic fibrosis, and immunohistochemical staining was performed to evaluate the proliferation of a-smooth muscle actin–expressing cells, which are indicative of expression of activated PSCs. Additionally, hematoxylin-eosin–stained specimens were used to grade the degrees of fat deposition and interstitial edema in pancreatic parenchyma. Grades for fibrosis, activated PSC expression, fat deposition, and interstitial edema in nontumoral pancreatic parenchyma were determined semiquantitatively. We used the grading criteria for pancreatic fibrosis described previously (3): F0 = normal pancreatic parenchyma, no fibrotic changes; F1 = mild fibrosis with thickening of periductal fibrous tissue; F2 = moderate fibrosis with marked sclerosis of interlobular septa and no evidence of architectural changes; and F3 = severe fibrosis with detection of architectural destruction. The grading criteria for activated PSC expression were as follows: A0 = no staining, A1 = mild staining of a part of the periductal or interlobular tissue, A2 = moderate staining of the whole periductal or interlobular tissue, and A3 = severe staining of the whole periductal or interlobular tissue. Grading criteria for fat deposition were as follows: L0 = 794
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0%–10% deposition, L1 = 10%–20%, L2 = 20%–30%, and L3 = greater than 31%; those for interstitial edema were as follows: E0 = no or slight interstitial edema, E1 = mild periductal or interlobular edema, E2 = moderate periductal or interlobular edema, and E3 = severe periductal or interlobular edema. The development of postoperative pancreatic fistula was defined according to the definition of the International Study Group for Pancreatic Surgery: a postoperative pancreatic fistula is present if amylase level of drainage fluid on or after postoperative day 3 exceeds three times the upper serum limit. All patients were followed up by the team of surgeons, and amylase level of drainage fluid, serum amylase level, C-reactive protein, and white blood cell count on days 1, 3, and 5 after surgery were evaluated. Three different grades of postoperative pancreatic fistula (grades A, B, and C) are defined according to the clinical effect on the patient’s hospital course: grade A does not need specific treatment, grade B requires prolonged drainage or specific medical treatment, and grade C requires invasive therapy (10).
Quantitative Image Analysis Operator-defined region of interest (50–150 mm2) measurements were used to obtain the signal intensity (SI) ratio of the pancreatic parenchyma to paraspinal muscle on unenhanced T1-weighted, T2-weighted, diffusionweighted, and gadolinium-enhanced MR images and the SI ratio of the pancreatic parenchyma to spinal cord on diffusion-weighted images. The ADC values of pancreatic parenchyma were measured as follows: ADC = 2[ln (SIb/ SI0)]/b, where SI0 is the SI on images with a b value of 0 sec/mm2, and SIb is the SI with a b value of 500 sec/mm2. The delayed enhancement index was calculated as the ratio of the SI ratio of the pancreas during the equilibrium phase to that during the pancreatic parenchymal phase. Region of interest measurements were performed in areas of nontumoral pancreatic parenchyma by matching the locations as closely as possible
with the surgical specimen that was evaluated histopathologically. Regions of interest were chosen to be devoid of dilated pancreatic duct, normal intrapancreatic vasculature, and focal lesions. The maximal diameter of the main pancreatic duct was measured by using an electronic caliper. A radiologist (H.W., with 6 years of posttraining experience in interpreting body MR images) who had no knowledge of the clinical or histopathologic patient information performed all measurements by using a commercially available Digital Imaging and Communications in Medicine viewer (IVimage VINS; Yokogawa Solutions, Tokyo, Japan). For all measurements, the size, shape, and position of the regions of interest were kept constant among all MR images by applying a copy-and-paste function on the viewer.
Statistical Analysis Commercially available software (MedCalc, version 12.3.0; MedCalc, Mariakerke, Belgium) was used to perform statistical analysis. The Spearman rank correlation test was used to explore correlations of MR imaging measurements with grades for pancreatic fibrosis, activated PSC expression, fat deposition, and interstitial edema. Stepwise multiple regression tests were conducted to examine relationships of MR imaging measurements with grades for pancreatic fibrosis, activated PSC expression, fat deposition, and interstitial edema. The Kruskal-Wallis method with post hoc tests as described by Conover (11) were used to compare predictor variables in multiple regression models among all grades for pancreatic fibrosis, activated PSC expression, fat deposition, and interstitial edema. Nonparametric receiver operating characteristic (ROC) curves were composed to assess the diagnostic performance of these variables in discriminating the grades for pancreatic fibrosis and activated PSC expression. Cutoff values, sensitivity, and specificity were calculated. Stepwise multiple logistic regression tests were also used to examine the relationships between the development of
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Table 2 Correlation of MR Imaging Parameters with Pancreatic Fibrosis and Activated PSC Expression Grades Activated PSC Expression Grade
Pancreatic Fibrosis Grade MR Imaging Parameter Pancreas-to-muscle SI ratio T1-weighted imaging T2-weighted imaging Diffusion-weighted imaging Pancreatic parenchymal-phase imaging Portal venous phase imaging Equilibrium-phase imaging Pancreas-to–spinal cord SI ratio at diffusion-weighted imaging ADC Delayed enhancement index
r Value
P Value
r Value
20.69 20.12 0.082 20.52 20.24 20.28 0.39
, .0001 .54 .67 .0037 .22 .14 .035
20.64 0.056 0.24 20.37 0.029 20.023 0.51
.0006 .0016
20.60 0.44
20.70 0.44
P Value .0002 .77 .22 .048 .88 .91 .0043 ,.0001 .017
Note.—The r values were obtained with the Spearman rank correlation coefficient.
Table 3 SI Ratio and ADC for Pancreatic Fibrosis and Activated PSC Expression Grades Grade Pancreatic fibrosis grade F0 (n = 7) F1 (n = 13) F2 (n = 5) F3 (n = 4) P value* Activated PSC expression grade A0 (n = 10) A1 (n = 9) A2 (n = 4) A3 (n = 6) P value*
Pancreas-to-Muscle SI Ratio at T1-weighted Imaging
ADC
1.51 6 0.25 (1.16–1.91) 1.48 6 0.22 (1.21–1.98) 1.05 6 0.09 (0.95–1.15) 0.94 6 0.10 (0.85–1.08) .0004
1.85 6 0.23 (1.59–2.19) 1.73 6 0.36 (1.27–2.27) 1.44 6 0.27 (1.14–1.75) 1.19 6 0.13 (1.07–1.30) .0082
1.52 6 0.22 (1.16–1.91) 1.41 6 0.33 (0.95–1.98) 1.25 6 0.14 (1.09–1.41) 1.00 6 0.13 (0.85–1.15) .0046
1.90 6 0.31 (1.32–2.27) 1.66 6 0.32 (1.27–2.24) 1.59 6 0.19 (1.33–1.77) 1.19 6 0.11 (1.07–1.30) .0016
Note.—Data are mean 6 standard deviation. Numbers in parentheses are the range. * Kruskal-Wallis test.
postoperative pancreatic fistula and the MR imaging measurements, grades of pancreatic fibrosis, activated PSC expression, fat deposition, and interstitial edema. The Mann-Whitney U test was used to compare the response variables used in the logistic regression analysis between patients with and those without postoperative pancreatic fistula. In all comparisons, a P value of .05 was considered to indicate a significant difference.
Results The mean maximal diameter of the main pancreatic duct was 5.0 mm 6 3.3 (standard deviation) (range, 1–15 mm), and dilatation of the main pancreatic duct (mean, 6.0 mm 6 3.1; range, 3–15 mm) was found in 22 patients. A positive correlation was found between the pancreatic fibrosis grade and the activated PSC expression grade (r = 0.76, P , .0001). The Spearman rank
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correlation test indicated that the pancreas-to-muscle SI ratios on T1-weighted images and pancreatic parenchymalphase images, pancreas–spinal cord SI ratio on diffusion-weighted images, ADC, and delayed enhancement index were correlated with the pancreatic fibrosis grades and the activated PSC expression grades. The pancreas-tomuscle SI ratio on T1-weighted images and ADC value were correlated with the pancreatic fibrosis grade (r = 20.69 and 20.60, respectively) and with the activated PSC expression grade (r = 20.64 and 20.70, respectively) (Table 2). ADC value was correlated with the fat deposition grade (r = 0.43, P = .02), and pancreas-to–spinal cord SI ratio on diffusion-weighted images was correlated with the interstitial edema grade (r = 0.58, P = .001). Multiple regression analysis showed the following correlations: the pancreas-to-muscle SI ratio on T1weighted images (coefficient = 21.88, P , .0001) and ADC value (coefficient = 21.20, P = .0006) were independently associated with the pancreatic fibrosis grade (r2 = 0.66, P , .001). The pancreas-to-muscle SI ratio on T1weighted images (coefficient = 21.82, P = .0003) and ADC value (coefficient = 21.76, P , .0001) were independently associated with the activated PSC expression grade (r2 = 0.67, P , .001). The ADC value (coefficient = 1.23, P = .02) was independently associated with the fat deposition grade (r2 = 0.15, P = .02). The pancreas-to–spinal cord SI ratio on diffusion-weighted images (coefficient = 1.28, P = .006) was independently associated with the interstitial edema grade (r2 = 0.37, P = .006). The other MR imaging parameters showed no correlation. The pancreas-to-muscle SI ratio on T1-weighted images and ADC values for the pancreatic fibrosis grades and the activated PSC expression grades are summarized in Table 3. Box plots for the pancreas-to-muscle SI ratio on T1-weighted images for each histologic grade are illustrated in Figure 2. The mean pancreas-to-muscle SI ratio on T1-weighted images decreased constantly as the pancreatic fibrosis grade 795
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progressed (P , .05). The pancreasto-muscle SI ratio on T1-weighted images was lower for fibrosis grades F2 and F3 than for grades F0 and F1 (P , .05). The overlap between fibrosis grades F0 and F1 and grades F2 and F3 was minimal (Fig 2a). The mean pancreas-to-muscle SI ratio on T1weighted images for activated PSC expression grade A3 was lower than that for grades A0 and A1 (P , .05) (Fig 2b). Box plots for ADC values for each histologic grade are illustrated in Figure 3. The mean ADC value constantly decreased as the pancreatic fibrosis grade progressed, although there were large overlaps. The mean ADC value was lower for F3 than for F0 and F1 (P , .05) and lower for F2 than for F0 (P , .05). The mean ADC value for activated PSC expression grade A3 was lower than that for grades A0 to A2 (P , .05). Area under the ROC curve values in the detection of pancreatic fibrosis and activated PSC expression with pancreas-to-muscle SI ratio on T1weighted images and the ADC values, sensitivities, and specificities based on the most discriminating cutoff values are shown in Table 4. In detecting pancreatic fibrosis of grade F2 and higher, an SI ratio cutoff value of 1.15 on T1weighted images yielded a sensitivity of 100% (eight of eight patients) and a specificity of 95% (20 of 21 patients). In detecting the activated PSC expression grade A3, an ADC cutoff value of 1.30 yielded a sensitivity of 100% (six of six patients) and a specificity of 96% (22 of 23 patients). Ten patients (34%, 10 of 29) developed postoperative pancreatic fistula, and 19 did not. The postoperative pancreatic fistulas were grades A and B in five patients each (17%, five of 29). Multiple logistic regression analysis showed that the pancreas-to-muscle SI ratio on T1-weighted images alone was significantly associated with the occurrence of postoperative pancreatic fistula (P = .0094). The mean pancreas-to-muscle SI ratio on T1-weighted images in the patients with postoperative pancreatic fistula (1.6 6 0.2) was higher than that 796
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Figure 2
Figure 2: Box plots show the SI ratio on T1-weighted images for (a) pancreatic fibrosis and (b) activated PSC expression grades. The boundary of the box that is closest to zero represents the 25th percentile, the line in the box indicates the median, the boundary of the box that is farthest from zero represents the 75th percentile, and the error bar shows the smallest and largest values in 1.5 box lengths of the 25th and 75th percentiles. Horizontal brackets indicate the significant difference found with the Kruskal-Wallis method in the post hoc tests, as described by Conover (P , .05).
Figure 3
Figure 3: Box plots show the ADC value for (a) pancreatic fibrosis and (b) activated PSC expression grades. The boundary of the box that is closest to zero indicates the 25th percentile, the line in the box indicates the median, the boundary of the box that is farthest from zero represents the 75th percentile, and the error bar shows the smallest and largest values in 1.5 box lengths of the 25th and 75th percentiles. Horizontal brackets indicate the significant difference found with the Kruskal-Wallis method in the post hoc tests, as described by Conover (P , .05).
in the patients without (1.2 6 0.2) (P = .0029) (Figs 4–6). For predicting the development of postoperative pancreatic fistula, an SI ratio cutoff value of
1.41 yielded a sensitivity of 80% (eight of 10 patients), specificity of 84% (16 of 19 patients), positive predictive value of 73% (eight of 11 patients), and negative
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Table 4 Az Value, SI Ratio Cutoff, Sensitivity, and Specificity for Pancreatic Fibrosis and Activated PSC Expression Grades Pancreas-to-Muscle SI Ratio at T1-weighted Imaging Grade Pancreatic fibrosis grade F1 F2 F3 Activated PSC expression grade A1 A2 A3
Az Value
SI Ratio Cutoff Sensitivity (%)
0.60 (0.40, 0.77) 0.95 (0.80, 0.98) 0.98 (0.85, 1.00)
1.27 1.15 1.08
0.68 (0.48, 0.84) 0.82 (0.63, 0.94) 0.94 (0.79, 1.00)
1.35 1.31 1.15
ADC Az Value
SI Ratio Cutoff Sensitivity (%)
52 [11/21] (30, 74) 75 [6/8] (35, 97) 100 [8/8] (63, 100) 95 [20/21] (76, 100) 100 [4/4] (40, 100) 92 [23/25] (74, 99)
0.65 (0.45, 0.82) 0.85 (0.67, 0.96) 0.94 (0.79, 0.99)
1.48 1.33 1.30
52 [11/21] (30, 74) 88 [7/8] (47, 100) 75 [6/8] (35, 97) 81 [17/21] (58, 95) 100 [4/4] (40, 100) 88 [22/25] (69, 98)
67 [12/18] (41, 87) 73 [8/11] (39, 94) 89 [8/9] (52, 100) 70 [14/20] (46, 88) 100 [6/6] (54, 100) 87 [20/23] (66, 97)
0.77 (0.57, 0.90) 0.83 (0.65, 0.94) 0.98 (0.84, 1.00)
1.77 1.77 1.30
83 [15/18] (59, 96) 64 [7/11] (31, 89) 100 [9/9] (66, 100) 50 [10/20] (27, 73) 100 [6/6] (54, 100) 96 [22/23] (78, 100)
Specificity (%)
Specificity (%)
Note.—Numbers in parentheses are 95% confidence intervals; 95% confidence intervals for area under the ROC curve (Az) values were calculated by means of the binomial exact method. Confidence intervals for the sensitivity and specificity are bootstrapped 95% confidence intervals. Data in brackets were used to calculate the statistics.
Figure 4
predictive value of 89% (16 of 18 patients). The odds ratio for the development of postoperative pancreatic fistula was 21.3 (95% confidence interval: 2.9, 154.6) when using an SI ratio of 1.41 and higher.
Discussion
Figure 4: Box plots show the SI ratios on T1-weighted images for patients with postoperative pancreatic fistula and those without. The boundary of the box that is closest to zero indicates the 25th percentile, the line within the box indicates the median, and the boundary of the box that is farthest from zero indicates the 75th percentile. The error bar indicates the smallest and largest values within 1.5 box lengths of the 25th and 75th percentiles. A significant difference was found with the Mann-Whitney U test (P = .0029). POPF(2) = absence of postoperative pancreatic fistula, POPF(+) = presence of postoperative pancreatic fistula.
In previous studies, investigators have described some relationships between MR imaging parameters and activated stellate cell expressions in organs (12,13) and have indicated that MR imaging might be used to help assess the degree of liver steatosis (12), liver fibrosis (14), or renal fibrosis (13). With regard to liver fibrosis, it has been reported that collagen cross-linking by members of the lysyl oxidase protein family increases the stiffness of the liver before activated hepatic stellate cell expression (15). In addition, ADC measurement on diffusionweighted MR images was an efficient technique for detecting and monitoring abnormal histopathologic changes, including fibroblast expression during the progression of renal fibrosis (13). PSCs are the principal source of fibrosis in the pancreatic stroma, and it has been reported that pancreatic cancer cells induce fibrosis by way of the stimulation of proliferation and matrix synthesis of PSCs, which strongly supports tumor growth and results in
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increased deposition of connective tissue (16). Our histologic examination also showed that the expression of activated PSCs correlated with the progression of pancreatic fibrosis. The ADC value of the pancreatic parenchyma correlated highly with the expression of activated PSCs. These results suggested that the ADCs reflected the changes in molecular diffusion property related to the process of pancreatic fibrogenesis. The strong correlations between ADCs and both pancreatic fibrosis and activated PSC expression were shown in our study. However, the relationship between the ADCs and fibrogenesis is thought to be complex and controversial. It is widely accepted that increased cell density causes a reduction of ADC (17). High cellularity causes an increase in the density of cell membranes, which is the dominant mechanism that restricts water molecule movement (18,19). In addition, high cell density causes a decrease in extracellular water fraction and, reciprocally, an increase in intracellular water fraction, which in turn exhibits a lower ADC (20). On the other hand, inflammatory cell infiltration, progressive destruction of pancreatic parenchyma, and retention of pancreatic exocrine products secondary to obstructive pancreatitis of different severities in the course of pancreatic fibrosis might increase the ADC measurements. 797
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Figure 5
Figure 5: Images show pancreatic adenocarcinoma in the pancreatic body in a 42-year-old man who subsequently developed postoperative pancreatic fistula. Histopathologic examination demonstrated the pancreatic fibrosis grade of F0 and an activated PSC expression grade of A0. (a) SI ratio at T1-weighted MR imaging was 1.91, and (b) ADC measured on an ADC map in the pancreatic body that corresponds to the surgical specimen was 1.77 3 1023 mm2/sec. The region of interest was located in areas of nontumoral pancreatic parenchyma, and it was matched with the location of the surgical resection margin (circles). On the ADC map (b), pancreatic adenocarcinoma (arrow) is seen as the region with decreased ADC in the pancreatic body.
Figure 6
Figure 6: Images show pancreatic adenocarcinoma in the pancreatic head in a 70-year-old woman without subsequent postoperative pancreatic fistula. Histopathologic examination showed the pancreatic fibrosis grade of F2 and an activated PSC expression grade of A2. (a) SI ratio on a T1-weighted image was 1.09, and (b) ADC measured on an ADC map in the pancreatic head that corresponds to the surgical specimen was 1.33 3 1023 mm2/sec. The region of interest was located in areas of nontumoral pancreatic parenchyma, and it was matched with the location of the surgical resection margin (circles). The pancreatic duct (arrow in a) and common bile duct (arrowhead in a) were dilated upstream from the known adenocarcinoma of the pancreatic head on the T1-weighted image.
Multiple regression analysis showed that the SI ratios on T1-weighted images and ADCs were associated with the degrees of pancreatic fibrosis and 798
activated PSC expression. Fat-suppressed T1-weighted imaging is sensitive for focal pancreatic disease because a normal pancreas exhibits relatively
high signal intensity on T1-weighted images compared with other abdominal organs owing to its short T1-relaxation time, which is attributed to the abundant protein and rough endoplasmic reticulum contained within it (21). On the other hand, SI of abnormal pancreatic parenchyma on fat-suppressed T1weighted images may decrease, owing to pancreatic atrophy, fibrosis, edema, or fat deposition. However, our findings suggest that the decrease in SI ratio on fat-suppressed T1-weighted images with the progression of pancreatic fibrosis is more attributable to an increase in pancreatic fibrosis or activated PSC proliferation than to fat deposition or edema caused by inflammatory changes in association with pancreatic fibrosis or obstructive pancreatitis. Although there was significant overlap in the SI ratios on T1-weighted images and ADCs between grades of pancreatic fibrosis and activated PSC expression, the most discriminating SI and ADC cutoff value settings based on ROC analyses of our retrospectively derived test set potentially yielded sufficiently high sensitivities and specificities for detecting, in particular, severe pancreatic fibrosis and advanced activated PSC expression. Further, the mean SI ratio on T1-weighted images was significantly higher in patients with postoperative pancreatic fistula than in those without postoperative pancreatic fistula, and the odds ratio for the development of postoperative pancreatic fistula was fairly high at 21.3 in patients with a pancreas-to-muscle SI ratio of 1.41 and higher. Accordingly, we believe that the SI ratio on T1-weighted images and ADCs may be useful in the detection of advanced pancreatic fibrosis, and preoperative assessment with MR imaging may help act preemptively against occurrence of postoperative pancreatic fistula. Our study had some limitations. First, our study cohort was not large. The relatively small sample size may have potentially caused selection bias. Thus, our results should be considered preliminary and require confirmation in a multiinstitutional study that could provide a large sample size. Second, correlations
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between MR imaging findings and longterm postoperative courses or pancreatic fibrosis and exocrine function are yet to be determined. Third, we calculated SI ratio and ADC cutoff values on the basis of retrospective data; therefore, our results need to be validated in future clinical studies as they likely include overestimations of diagnostic performance. Finally, diffusion-weighted images obtained with free breathing were evaluated in our retrospective study. However, the presence of respiratory motion-related artifacts may have introduced a certain degree of errors in ADC measurements. In conclusion, our results suggest that T1-weighted and diffusion-weighted MR imaging with concomitant SI ratio and ADC measurements could serve as preoperative noninvasive biomarkers to efficiently detect advanced pancreatic fibrosis, which is highly linked to the occurrence of postoperative pancreatic fistula. We believe that the measurement of these simple parameters at routine unenhanced MR imaging may enhance the value of pancreatic MR imaging. Disclosures of Conflicts of Interest: H.W. No relevant conflicts of interest to disclose. M.K. No relevant conflicts of interest to disclose. K.T. No relevant conflicts of interest to disclose. S.O. No relevant conflicts of interest to disclose. H.T. No relevant conflicts of interest to disclose. A.H. No relevant conflicts of interest to disclose. S.G. No relevant conflicts of interest to disclose. H. Kondo No relevant conflicts of interest to disclose. H. Kawada No relevant conflicts of interest to disclose. Y.N. No relevant conflicts of interest to disclose. Y.T. No relevant conflicts of interest to disclose. N.K. No relevant conflicts of interest to disclose. K.Y. No relevant conflicts of interest to disclose. N.M. No relevant conflicts of interest to disclose.
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