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MRI features of pancreatic intraductal papillary mucinous neoplasms associated with invasive carcinoma
Clinical Radiology 73 (2018) 873e880
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MRI features of pancreatic intraductal papillary mucinous neoplasms associated with invasive carcinoma W. Xu a, 1, X. Liu b, 1, Z. Yu c, W. Zhang d, Q. Zheng a, Z. Liu a, * a
Department of Radiology, Dezhou People’s Hospital, 1751 XinHu Street, Dezhou, Shandong 253000, China Department of Pharmacy, Dezhou People’s Hospital, 1751 XinHu Street, Dezhou, Shandong 253000, China c Department of Medical Administration Division, Dezhou People’s Hospital, 1751 XinHu Street, Dezhou, Shandong 253000, China d Department of Medicine and Nursing, Dezhou University, 566 DaXue West Road, Dezhou, Shandong 253000, China b
art icl e i nformat ion Article history: Received 9 February 2018 Accepted 4 June 2018
AIM: To assess the correlation between the magnetic resonance imaging (MRI) characteristics and histopathology in pancreatic intraductal papillary mucinous neoplasms (IPMNs) associated with invasive carcinoma. MATERIALS AND METHODS: Thirty-two patients with pancreatic IPMN associated with invasive carcinoma treated at a regional hospital in Dezhou were enrolled and the MRI findings were analysed retrospectively. The patients were assigned to one of two groups based on the invasive component: invasive component of <50% (IPMC-I; group A; n¼17) and invasive component of 50% (pancreatic ductal adenocarcinoma-associated IPMN [PDAC-IPMN]; group B; n¼15). The MRI findings between the groups were compared. RESULTS: The groups did not significantly differ in lesion location, radiological type, apparent diffusion coefficient (ADC) value, main pancreatic duct diameter, mural nodule size, early arterial phase signal enhancement ratio (SEREAP), lymphatic metastasis, etc.; however, lesion size and tumour classifications significantly differed between the groups (p<0.05). Moreover, the positive enhancement integral (PEI), late arterial phase signal enhancement ratio (SERLAP), early portal venous phase signal enhancement ratio (SEREVP), late portal venous phase signal enhancement ratio (SERLVP), and delay phase signal enhancement ratio (SERDP) values were significantly greater in group A than in group B (p<0.05). CONCLUSION: Thus, the MRI features differed between IPMC-I and PDAC-IPMN. In particular, dynamic enhancement on preoperative MRI could be used for diagnosis and clinicopathological classification of pancreatic IPMN associated with invasive carcinoma. Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction * Guarantor and correspondent: Z. Liu, Department of Radiology, Dezhou People’s Hospital, 1751 XinHu Street, Dezhou, Shandong 253000, China. Tel.: þ86 15615188277. E-mail address: [email protected] (Z. Liu). 1 These authors contributed equally to this work and are joint first authors.
Due to the widespread use of sensitive abdominal imaging tests, such as multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI), pancreatic cysts are now being detected more frequently.1 Pancreatic cysts can be histopathologically classified as pseudocysts, neoplastic cysts, and non-neoplastic cysts.2 Among the
https://doi.org/10.1016/j.crad.2018.06.001 0009-9260/Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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various types of neoplastic cysts, intraductal papillary mucinous neoplasms (IPMNs) are the most common.3 Several clinical studies have reported the imaging criteria for discriminating malignant IPMNs from benign IPMNs.4e6 Kang et al.7 showed that the 5-year disease-free survival rate for surgically treated was 42.1% for invasive intraductal papillary mucinous carcinoma (IPMC-I) and 27.8% for pancreatic ductal adenocarcinoma-associated IPMN (PDACIPMN). PDAC-IPMN had a significantly lower disease-free survival rate compared with IPMC-I (P¼0.093), and was comparable to that of normal pancreatic ductal adenocarcinoma (PDAC). To explore the relationship between MRI and histopathology, a comparative study of IPMC-I and PDAC-IPMN based on tumour morphology and the invasive component was conducted. Jones et al. reported that the diagnostic sensitivity for identifying pancreatic cyst communication was superior at MRI (91.4%) than at MDCT (85.7%).8 MRI has the advantages of no radiation and multiparameter imaging, and hence, MRI was chosen as a research tool. The aim of the present study was to compare the MRI findings of surgically resected IPMC-I and PDAC-IPMN and determine whether MRI is an appropriate tool for screening purposes.
Materials and methods Patient population From March 2012 to April 2017, a total of 115 patients with pathological IPMNs were diagnosed at a local regional hospital in China. The inclusion criteria were as follows:
patients received surgery or palliative treatment, and underwent MRI examination within 6 months prior to surgery. Histopathological diagnosis of pancreatic specimens from the 115 patients following surgery was made by consensus between two gastrointestinal pathologists. Pancreatic IPMNs were characterised according to the World Health Organization (WHO) 20109 classification criteria as follows: low-grade and moderate-grade dysplasia (n¼54), high-grade dysplasia (n¼19), and IPMN associated with invasive carcinomas (n¼41; Fig 1). Five patients were excluded from the study because of incomplete data. Four other cases were excluded because the IPMN did not have continuity with the invasive carcinoma. Finally, 32 cases of pancreatic IPMN associated with invasive carcinoma were enrolled in the present study (18 men and 14 women; mean age, 63.5 years; range, 53e80 years). Pancreatic IPMNs associated with invasive carcinomas were subcategorised into IPMC-I and PDAC-IPMN, and patients with these conditions were assigned to groups A (n¼17) and B (n¼15), respectively (Fig 1). Tumours defined as IPMC-I had an invasive component of <50%, and most of the tumour in these cases exhibited intraductal components that formed tall true papilla structures containing a fibrovascular core. In contrast, tumours with an invasive component of >50% that had morphological characteristics of a tubular or colloid carcinoma and an intraductal component with a short micropapillary structure were classified as PDAC-IPMN.7 All the postoperative patients were followed for 6 months to 3 years after surgery, and no recurrence or metastasis occurred within this time period.
Patients with histological proven IPMNs either by surgical resection or palliative treatment between March 2012 to April 2017;n=115
Characterized according to the WHO 2010 classification criteria
Low and moderate grade dysplasia; n=54
High dysplasia; n=19
grade
IPMNs associated with invasive carcinomas;n=41
Excluded:n=9 Incomplete data n=5 IPMNs apart from the invasive carcinoma n=4 Enrolled patients; n=32
Invasive IPMN; n=17
PDAC-associated IPMNs;n=15
Figure 1 Flowchart shows the process of patient selection.
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MRI Equipment Two GE machines were used to perform MRI; either a 1.5 T unit with an eight-channel phased-array torso coil (n¼20) or a 3 T unit with a 12-channel phased-array torso coil (n¼12) was used. The upper abdomen, entire liver, and pancreas were examined. The following basic sequences were used as follows: (1) rapid spin echo T2-weighted (W) sequence cross-section imaging; (2) positive and negative phase T1W of the gradient echo (GRE) stimulated with a quick and small angle; (3) diffusion-weighted imaging (DWI; b-values of 0 and 800 s/mm2), sequence thickness of 5e7 mm, and interval 2 mm; (4) magnetic resonance cholangiopancreatography (MRCP); and (5) dynamic MRI images obtained before and after the administration of gadolinium diethylenetetramine pentaacetic acid (GdDTPA; 0.1 mmol/kg), with an injection rate of 2 ml/s. Images were acquired before contrast material injection (mask) and at 17 seconds (early arterial phase), 27 seconds (late arterial phase), 55 seconds (early portal venous phase), 65 seconds (late portal venous phase), and 5 minute (delay phase) after contrast agent injection. Each volume interpolated GRE (LAVA) phase was completed during one breath-hold at the end of expiration.
Figure 2 Dynamic enhanced timeeintensity curves (TIC): abscissa 1e6 represent the mask, early arterial phase, late arterial phase, early portal venous phase, late portal venous phase, and delayed phase, respectively. The ordinate represents the signal intensity. Curve 1 represents the descending aorta, curve 2 represents pancreatic IPMN tumour tissue, and curve 3 represents normal pancreatic tissue.
Image processing and analysis Two gastrointestinal radiologists independently reviewed the MRI. They were blinded to the final diagnosis, but were informed that the individuals in the study population had undergone surgery. The recorded data included tumour location, tumour size, presence or absence of mural nodules and size, degree of enhancement, lymph node metastasis, vascular invasion, and diameter of the pancreatic duct. DWI images are automatically processed using the GE AW4.4 workstation. The apparent diffusion coefficient (ADC) was calculated by using a monoexponential function with the region of interest (ROI) size. The ROI was selected, and used the same ROI size, as the average value at three different lesion locations. The most significant enhanced region of enhanced solid components of lesions in early phase was selected, with an area of 12 mm2. For smaller lesions, the maximum section of the solid components of the lesions was selected, and the whole lesion was outlined along the edge of the tumour to avoid necrotic and vascular areas. The dynamic enhanced images were imported into Functol post-processing software and timeeintensity curves (TICs) were plotted (Fig 2). Both the two observers used Functol to plot TICs independently, and then recorded the signal intensity of each period. The average value of the signal intensity was taken when the value varied, and was determined in consensus when different opinions were observed. Two GE machines 1.5 and 3 T were used to perform MRI and the signal intensity between the two machines was different. As a result the enhanced signal enhancement ratio to reduce the statistical error. The following parameters were measured: positive enhancement integral (PEI), early
arterial phase signal enhancement ratio (SEREAP), late arterial phase signal enhancement ratio (SERLAP), early portal venous phase signal enhancement ratio (SEREVP), late portal venous phase signal enhancement ratio (SERLVP), and delay phase signal enhancement ratio (SERDP). The signal intensity at time t (SIt), as well as signal intensity at the early arterial phase (SIEA), late arterial phase (SILAP), early portal venous phase (SIEVP), late portal venous phase (SILVP), and delay phase (SIDP) were also measured. Furthermore, the plain scan signal intensity (SImask) was recorded. The values were estimated as follows: PEI¼
P SIt, SEREAP¼[(SIEA-SImask)/SImask]100%,
SERLAP¼ [(SILAP-SImask)/SImask]100%,
SEREVP¼[(SIEVP-SImask)/SImask]100%,
SERLVP¼[(SILVP-SImask) /SImask]100%, and
SERDP¼[(SIDP-SImask)/SImask]100%.
Tumour staging was performed according to the 7th edition of the American Joint Committee on Cancer.10 In the T1 stage, the maximum tumour diameter was <2 cm and it was confined to the pancreas, whereas in the T2 stage, the maximum tumour diameter was >2 cm and it was still confined to the pancreas. In the T3 stage, there was
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pancreatic tissue around the local tumour invasion site or tumour invasion occurred in the duodenum and/or common bile duct; however, there was no infringement of the coeliac and superior mesenteric artery. In the T4 stage, tumour invasion of the coeliac and/or duodenal artery was noted. Finally, progression to lymph node metastases was considered when the lymph short diameter was >5 mm, or in the presence of necrosis whatever lymph node size.
Ethics approval This retrospective study was approved by the hospital review board and by the research ethics committees. The analysis was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and later amendments. All patients provided written informed consent.
Statistical analysis The pathological characteristics and MRI results of the pancreatic IPMN were analysed using SPSS Statistics version 17.0. Continuous data were compared using Student’s t-test, whereas parametric data were compared using Fisher’s exact test. A p-value of <0.05 was considered to indicate statistical significance.
Results Clinical information The 32 patients were assigned to two groups based on the condition, including those with IPMC-I in group A (n¼17) and those with PDAC-IPMN in group B (n¼15). In group A, the mean age was 62.76 years, 11 cases exhibited upper abdominal discomfort and distension symptoms, five cases were diagnosed during occasional physical examination, and one case showed progressive weight loss. Three cases (17.6%) were misdiagnosed, including two cases misdiagnosed as mucinous cystadenoma and one case misdiagnosed as pancreatic ductal adenocarcinoma. In group B, the mean age was 63.5 years, 10 patients showed upper abdominal discomfort and distension symptoms, two patients were diagnosed during occasional physical examination, one patient developed refractory diarrhoea, and two patients were diagnosed with obstructive jaundice. Four cases (26.7%) were misdiagnosed preoperatively, including three cases misdiagnosed as pancreatic ductal adenocarcinoma and one case misdiagnosed as solid mucinous cystadenoma (Table 1).
MRI Among the 32 patients, the pancreatic head was the most common tumour location in both group A (13 cases; 76.5%) and group B (9 cases; 60%). Moreover, the main pancreatic duct was the most commonly affected site in both group A (14 cases; 82.4%) and group B (13 cases; 86.7%). There was no significant difference in tumour location or duct type between the groups. The two groups of patients showed high or slightly higher signal on DWI and decreased ADC
Table 1 Patient demographics and histopathological characteristics for cases with IPMN associated with invasive carcinoma.
Age Sex (male: female) Pancreatitis history, n (%) CEA >5, n (%) CA199 >37, n (%) Location, n (%) Head Body Tail Radiological type, n (%) Main duct type Branch duct type Mixed type ADC value (1010 m2/s) Main pancreatic duct diameter
IPMC-I (n¼17)
PDAC-IPMN (n¼15)
p-Value
62.766.79 2.4: 1 3 (17.6) 2 (11.8) 5 (29.4)
63.507.3 2.75: 1 1 (6.7) 2 (13.3) 9 (60.0)
0.558 0.589 0.603 0.65 0.153 0.58
13 (76.5) 3 (17.6) 1 (5.9)
9 (60.0) 4 (26.7) 2 (13.3)
14(82.4) 3(17.6) 0 5.092.08 9.724.67
13(86.7) 2(13.3) 0 3.861.12 8.283.06
0.563
0.165 0.305
Values indicate the results of a Student’s t-test (significant p-values are presented in bold; p<0.05). IPMC intraductal papillary mucinous carcinoma; PDAC-IPMN pancreatic ductal adenocarcinoma-associated intraductal papillary mucinous neoplasms; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
values (Figs 3 and 4); however, the ADC values did not significantly differ between the two groups (p>0.05). In addition, the main pancreatic duct was dilated to different degrees in both groups A and B, and although the main pancreatic duct dilatation appeared greater in group A (Fig 5), there was no significant difference in the main pancreatic duct diameter (Table 1). Lesion size significantly differed between groups A (48.8118.01 mm) and B (34.2414.15 mm), whereas the wall tumour nodule size did not significantly differ between groups A and B (Table 2). In the 17 patients in group A, dynamic scans showed moderate or slightly low signals in the wall nodules on unenhanced scans, and mild to moderate enhancement in the arterial phase and continuous enhancement in the venous phase and delayed phase on enhanced scans (Fig 6). In the 15 patients in group B, dynamic scans showed moderate or low signals in the wall nodules on unenhanced scans, and mild enhancement during the whole phase on enhanced scans, although the degree of enhancement was lower than that in the pancreas (Fig 7). Moreover, the PEI was significantly higher in group A (2253.6521.92) than in group B (2253.6521.92; p<0.01). The SEREAP did not significantly differ between groups A and B, although the SERLAP was significantly higher in group A (0.520.27) than in group B (0.270.19; p<0.05). The SEREVP significantly differed between group A (0.610.25) and group B (0.350.17; p<0.01), and the SERLVP was also significantly higher in group A (0.630.17) than in group B (0.360.28; p<0.01). Furthermore, the SERDP significantly differed between groups A (0.620.18) and B (0.310.29; p<0.01; Table 2). In group A, the tumour in 14 cases (82.4%) was classified as T1 or T2 stage, whereas the tumour in three cases (17.6%) was classified as T3 or T4 stage. In group B, the tumour in
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Figure 3 Invasive IPMC-I. (a) Diffusion-weighted imaging (DWI) shows an increased lesion signal. (b) A decrease in the signal in the solid part of the lesion is observed in the ADC map, which suggests limited diffusion.
Figure 4 PDAC-IPMN. (a), Diffusion-weighted imaging shows a significant increase in the lesion signal. (b) A significant decrease in the signal in the solid part of the lesion is observed in the ADC map, which suggests limited diffusion.
eight cases (53.3%) was classified as T1 and T2 stage and the tumour in the remaining seven cases (46.7%) was classified as T3 and T4 stage. Thus, the tumour classification significantly differed between the two groups (p<0.05). There was no significant difference in lymph node metastasis between groups A (two cases; 11.8%) and B (four cases; 26.7%; Table 3).
Discussion
Figure 5 MRCP of invasive IPMC-I, which shows apparent tortuous dilation of the pancreatic duct tail, confirmed as a mucus lake on pathological examination.
Pancreatic IPMNs comprise 3.6e7% of all diagnosed tumours in the pancreas,11,12 which account for 16% of all pancreatectomised tumours13 that themselves account for 24% of all pancreatic cystic tumours.14 Moreover, 50% of incidental cystic lesions are classified as IPMNs.12,15 Although IPMN is not considered as a rare disease, it is gradually being accepted as one of the most common cystic neoplasms of the pancreas, as the understanding of the condition grows. In fact, IPMNs are classified into three types, including the main pancreatic duct type, branch duct type, and mixed type. Of these, the main pancreatic duct type and mixed duct type IPMNs have a higher malignant potential, and should be removed.16
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Table 2 Differences in dynamic enhanced MRI findings between IPMC-I and PDAC-PIMN cases.
Tumour size, (mm) Wall size (mm) Positive enhancement integral (PEI) Early arterial phase signal enhancement ratio (SEREAP) Late arterial phase signal enhancement ratio (SERLAP) Early portal venous phase signal enhancement ratio (SEREVP) Late portal venous phase signal enhancement ratio(SERLVP) Delay phase signal enhancement ratio (SERDP)
IPMC-I (n¼17)
PDAC-IPMN (n¼15)
p-Value
48.8118.01 11.786.00 2253.6521.92 0.30.1 0.520.27 0.610.25 0.630.17 0.620.18
34.2414.15 14.716.60 1930.87194.49 0.220.14 0.270.19 0.350.17 0.360.28 0.310.29
0.016 0.240 0.000 0.078 0.005 0.002 0.003 0.001
Values indicate the results of a Student’s t-test (significant p-values are presented in bold; p<0.05). IPMC intraductal papillary mucinous carcinoma; PDAC-IPMN pancreatic ductal adenocarcinoma-associated intraductal papillary mucinous neoplasms.
Figure 6 Invasive IPMC-I. (a) Dynamic MRI image in the early portal venous phase, wherein the lesions show papillary structures and visible enhancement. (b) The pathological evaluation shows partial carcinogenesis.
Figure 7 PDAC-IPMN. (a) Dynamic MRI image in the early portal venous phase, wherein the lesions appear slightly enhanced. (b) The pathological evaluation shows mostly regional carcinogenesis.
The latest WHO classification system has classified IPMN lesions as malignant.17 Poultsides et al.18 summarised 312 cases of IPMN, and found that 42% developed into invasive cancer. In the present study, 115 cases of pancreatic IPMNs were extracted from the pathology database, and 41 (35.7%) of these cases included IPMN associated with invasive carcinoma (Fig 1).
With regard to the clinical aspect of the disease, IPMN has a higher incidence among those in their sixties and seventies, and the disease can affect the entire pancreas, with a higher likelihood in the pancreatic head. In the present study of 32 cases, the pancreatic head was the main tumour location site, and pancreatitis was also observed in a small number of patients. Some patients also exhibited
W. Xu et al. / Clinical Radiology 73 (2018) 873e880 Table 3 Tumour classification of IPMN associated with invasive carcinoma.
T stage, n (%) T1, T2 T3, T4 Lymphatic metastasis, n (%)
IPMC-I (n¼17)
PDAC-IPMN (n¼15)
14 (82.4) 3(17.6) 2 (11.8)
7 (46.7) 8 (53.3) 4 (26.7)
p-Value 0.04
0.267
Values indicate the results of a Student’s t-test (significant p-values are presented in bold; p<0.05). IPMC intraductal papillary mucinous carcinoma; PDAC-IPMN pancreatic ductal adenocarcinoma-associated intraductal papillary mucinous neoplasms.
increased preoperative levels of CA199, especially the patient with pancreatic IPMN associated with invasive carcinoma. Although the preoperative CA199 level did not significantly differ between the groups, it was useful for preoperative diagnosis. Apparent mucus secretion in the catheter cavity is a typical characteristic of IPMNs. When mucus is overproduced and the pressure in the cavity is high, the cavity could rupture.19 Moreover, dilated ductal growth, coupled with excessive mucus secretion, could lead to continuous pressure within the catheter (the lumen of which included the cystic capsule) and to the extrusion of the tissue surrounding the catheter, which may even extend to pancreatic fat tissue (Fig 5). The degree of pancreatic duct dilatation differed between the two groups. Although group B exhibited more extensive invasion than group A, the diameter of the main pancreatic duct in group A was greater than that in group B. This may presumably be due to decreased mucin formation in the invasive tumour. Moreover, although tumour growth may be intraductal, it does not cause the pancreatic duct to dilate.19 DWI has generally been used to detect and characterise various tumours,20,21 and has important diagnostic value for benign and malignant IPMNs.22,23 Sandrasegaran et al. reported that the ADC values of benign IPMNs were higher than those of malignant IPMNs, and suggested that the lower fluid viscosity in benign IPMNs compared with malignant IPMNs may lead to such differences.24 In the present study, both groups A and B exhibited high signals on DWI; in particular, the ADC value of the solid component was decreased, and although the ADC value was lower in group B than in group A, the difference was not significant. Some of the solid IPMN lesions were <1 cm or grew along the wall with a high b-value on DWI, which led to inaccurate ADC measurements. Hence, the DWI findings and ADC values may be beneficial for the diagnosis of IPMN, although they may not be useful for the identification of malignant grade, consistent with that reported in the literature.23 In patients with IPMNs, the pancreatic duct is dilated and the acinar protein content is reduced due to chronic pancreatitis in the pancreatic tail; hence, the T1W signal is decreased,25 which reduces the signal contrast between pancreatic tissue and tumour, and thus impairs the ability of tumour detection. As dynamic enhanced scans had apparent advantages, an appropriate scanning period was
879
chosen to obtain the best contrast between the pancreas and tumour, which enabled good imaging of the tumour. Thus, by measuring the signal enhancement in each period, the difference in the degree of invasion could be determined. On dynamic enhanced imaging in the present study, the PEI, SERLAP, SEREVP, and SERLVP were significantly higher in group A than in group B, which suggests that the tumours in group A have greater blood supply than those in group B. This is presumably because the normal pancreas is an organ with a rich blood supply and high microvessel density. The pancreatic malignant tumour destroyed the normal pancreatic tissue, and greater destruction led to a lower amount of normal pancreatic tissue and a consequent weaker degree of enhancement, consistent with that noted in the literature26,27; however, there was no significant difference in the early rate of arterial enhancement, which may be because both of the cases in the two groups consisted of rich fibre components and the arteries had weakened during the early disease stage. With regard to tumour classification, IPMC-I exhibited lower grade and lymph node metastasis as compared to PDAC-IPMN. Hence, PDAC-IPMN may be more invasive and may have a poorer prognosis, consistent with the literature.7 Previous studies have focused on benign and malignant pancreatic differentiation of IPMN.11,14,28 To the authors’ knowledge, this is the first study to compare the diagnostic performance of MRI for predicting the malignant potential of pancreatic IPMNs. The limitations of the current study include the insufficient number of cases required to represent all the features of IPMN in the pancreas, and hence, additional data should be collected to further expand on the sample study. Second, the solid components of some lesions are small, and inaccurate measurements may still occur despite the use of multiple measurement methods. Third, two GE machines 1.5 and 3 T were used to perform MRI and the signal intensity between the two machines was different. Although enhanced signal intensity ratio was used to reduce the statistical error, it was still possible to have little impact on the results. Fourth, the two observers reviewed the MRI images independently, and the results were determined in consensus when different opinions were observed, but determination of interobserver variation between the two observers was not undertaken. Fifth, the number of cases was small and the number of cases with long-term followup was even less, so the information on follow-up and disease-free survival for the 32 cases was not reviewed in this study. In conclusion, pancreatic IPMN associated with invasive carcinoma manifests with a wide array of symptoms, and preliminary dynamic enhanced MRI can determine the degree of invasion and preoperative classification. After a preoperative classification, physicians can obtain more information about the disease. As the classification was different, the prognosis of patients was not the same and their 5-year disease-free survival rate was also different. Once known, physicians can communicate with the patient more effectively, and can also develop more treatment
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options for patients to choose from; thus, guiding the clinical development of a more complete treatment plan.
Acknowledgements This research was granted from Shandong Medical and Health Science Technology Development Project (2017WSA14047).
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MRI features of pancreatic intraductal papillary mucinous neoplasms associated with invasive carcinoma W. Xu a, 1, X. Liu b, 1, Z. Yu c, W. Zhang d, Q. Zheng a, Z. Liu a, * a
Department of Radiology, Dezhou People’s Hospital, 1751 XinHu Street, Dezhou, Shandong 253000, China Department of Pharmacy, Dezhou People’s Hospital, 1751 XinHu Street, Dezhou, Shandong 253000, China c Department of Medical Administration Division, Dezhou People’s Hospital, 1751 XinHu Street, Dezhou, Shandong 253000, China d Department of Medicine and Nursing, Dezhou University, 566 DaXue West Road, Dezhou, Shandong 253000, China b
art icl e i nformat ion Article history: Received 9 February 2018 Accepted 4 June 2018
AIM: To assess the correlation between the magnetic resonance imaging (MRI) characteristics and histopathology in pancreatic intraductal papillary mucinous neoplasms (IPMNs) associated with invasive carcinoma. MATERIALS AND METHODS: Thirty-two patients with pancreatic IPMN associated with invasive carcinoma treated at a regional hospital in Dezhou were enrolled and the MRI findings were analysed retrospectively. The patients were assigned to one of two groups based on the invasive component: invasive component of <50% (IPMC-I; group A; n¼17) and invasive component of 50% (pancreatic ductal adenocarcinoma-associated IPMN [PDAC-IPMN]; group B; n¼15). The MRI findings between the groups were compared. RESULTS: The groups did not significantly differ in lesion location, radiological type, apparent diffusion coefficient (ADC) value, main pancreatic duct diameter, mural nodule size, early arterial phase signal enhancement ratio (SEREAP), lymphatic metastasis, etc.; however, lesion size and tumour classifications significantly differed between the groups (p<0.05). Moreover, the positive enhancement integral (PEI), late arterial phase signal enhancement ratio (SERLAP), early portal venous phase signal enhancement ratio (SEREVP), late portal venous phase signal enhancement ratio (SERLVP), and delay phase signal enhancement ratio (SERDP) values were significantly greater in group A than in group B (p<0.05). CONCLUSION: Thus, the MRI features differed between IPMC-I and PDAC-IPMN. In particular, dynamic enhancement on preoperative MRI could be used for diagnosis and clinicopathological classification of pancreatic IPMN associated with invasive carcinoma. Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction * Guarantor and correspondent: Z. Liu, Department of Radiology, Dezhou People’s Hospital, 1751 XinHu Street, Dezhou, Shandong 253000, China. Tel.: þ86 15615188277. E-mail address: [email protected] (Z. Liu). 1 These authors contributed equally to this work and are joint first authors.
Due to the widespread use of sensitive abdominal imaging tests, such as multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI), pancreatic cysts are now being detected more frequently.1 Pancreatic cysts can be histopathologically classified as pseudocysts, neoplastic cysts, and non-neoplastic cysts.2 Among the
https://doi.org/10.1016/j.crad.2018.06.001 0009-9260/Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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various types of neoplastic cysts, intraductal papillary mucinous neoplasms (IPMNs) are the most common.3 Several clinical studies have reported the imaging criteria for discriminating malignant IPMNs from benign IPMNs.4e6 Kang et al.7 showed that the 5-year disease-free survival rate for surgically treated was 42.1% for invasive intraductal papillary mucinous carcinoma (IPMC-I) and 27.8% for pancreatic ductal adenocarcinoma-associated IPMN (PDACIPMN). PDAC-IPMN had a significantly lower disease-free survival rate compared with IPMC-I (P¼0.093), and was comparable to that of normal pancreatic ductal adenocarcinoma (PDAC). To explore the relationship between MRI and histopathology, a comparative study of IPMC-I and PDAC-IPMN based on tumour morphology and the invasive component was conducted. Jones et al. reported that the diagnostic sensitivity for identifying pancreatic cyst communication was superior at MRI (91.4%) than at MDCT (85.7%).8 MRI has the advantages of no radiation and multiparameter imaging, and hence, MRI was chosen as a research tool. The aim of the present study was to compare the MRI findings of surgically resected IPMC-I and PDAC-IPMN and determine whether MRI is an appropriate tool for screening purposes.
Materials and methods Patient population From March 2012 to April 2017, a total of 115 patients with pathological IPMNs were diagnosed at a local regional hospital in China. The inclusion criteria were as follows:
patients received surgery or palliative treatment, and underwent MRI examination within 6 months prior to surgery. Histopathological diagnosis of pancreatic specimens from the 115 patients following surgery was made by consensus between two gastrointestinal pathologists. Pancreatic IPMNs were characterised according to the World Health Organization (WHO) 20109 classification criteria as follows: low-grade and moderate-grade dysplasia (n¼54), high-grade dysplasia (n¼19), and IPMN associated with invasive carcinomas (n¼41; Fig 1). Five patients were excluded from the study because of incomplete data. Four other cases were excluded because the IPMN did not have continuity with the invasive carcinoma. Finally, 32 cases of pancreatic IPMN associated with invasive carcinoma were enrolled in the present study (18 men and 14 women; mean age, 63.5 years; range, 53e80 years). Pancreatic IPMNs associated with invasive carcinomas were subcategorised into IPMC-I and PDAC-IPMN, and patients with these conditions were assigned to groups A (n¼17) and B (n¼15), respectively (Fig 1). Tumours defined as IPMC-I had an invasive component of <50%, and most of the tumour in these cases exhibited intraductal components that formed tall true papilla structures containing a fibrovascular core. In contrast, tumours with an invasive component of >50% that had morphological characteristics of a tubular or colloid carcinoma and an intraductal component with a short micropapillary structure were classified as PDAC-IPMN.7 All the postoperative patients were followed for 6 months to 3 years after surgery, and no recurrence or metastasis occurred within this time period.
Patients with histological proven IPMNs either by surgical resection or palliative treatment between March 2012 to April 2017;n=115
Characterized according to the WHO 2010 classification criteria
Low and moderate grade dysplasia; n=54
High dysplasia; n=19
grade
IPMNs associated with invasive carcinomas;n=41
Excluded:n=9 Incomplete data n=5 IPMNs apart from the invasive carcinoma n=4 Enrolled patients; n=32
Invasive IPMN; n=17
PDAC-associated IPMNs;n=15
Figure 1 Flowchart shows the process of patient selection.
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MRI Equipment Two GE machines were used to perform MRI; either a 1.5 T unit with an eight-channel phased-array torso coil (n¼20) or a 3 T unit with a 12-channel phased-array torso coil (n¼12) was used. The upper abdomen, entire liver, and pancreas were examined. The following basic sequences were used as follows: (1) rapid spin echo T2-weighted (W) sequence cross-section imaging; (2) positive and negative phase T1W of the gradient echo (GRE) stimulated with a quick and small angle; (3) diffusion-weighted imaging (DWI; b-values of 0 and 800 s/mm2), sequence thickness of 5e7 mm, and interval 2 mm; (4) magnetic resonance cholangiopancreatography (MRCP); and (5) dynamic MRI images obtained before and after the administration of gadolinium diethylenetetramine pentaacetic acid (GdDTPA; 0.1 mmol/kg), with an injection rate of 2 ml/s. Images were acquired before contrast material injection (mask) and at 17 seconds (early arterial phase), 27 seconds (late arterial phase), 55 seconds (early portal venous phase), 65 seconds (late portal venous phase), and 5 minute (delay phase) after contrast agent injection. Each volume interpolated GRE (LAVA) phase was completed during one breath-hold at the end of expiration.
Figure 2 Dynamic enhanced timeeintensity curves (TIC): abscissa 1e6 represent the mask, early arterial phase, late arterial phase, early portal venous phase, late portal venous phase, and delayed phase, respectively. The ordinate represents the signal intensity. Curve 1 represents the descending aorta, curve 2 represents pancreatic IPMN tumour tissue, and curve 3 represents normal pancreatic tissue.
Image processing and analysis Two gastrointestinal radiologists independently reviewed the MRI. They were blinded to the final diagnosis, but were informed that the individuals in the study population had undergone surgery. The recorded data included tumour location, tumour size, presence or absence of mural nodules and size, degree of enhancement, lymph node metastasis, vascular invasion, and diameter of the pancreatic duct. DWI images are automatically processed using the GE AW4.4 workstation. The apparent diffusion coefficient (ADC) was calculated by using a monoexponential function with the region of interest (ROI) size. The ROI was selected, and used the same ROI size, as the average value at three different lesion locations. The most significant enhanced region of enhanced solid components of lesions in early phase was selected, with an area of 12 mm2. For smaller lesions, the maximum section of the solid components of the lesions was selected, and the whole lesion was outlined along the edge of the tumour to avoid necrotic and vascular areas. The dynamic enhanced images were imported into Functol post-processing software and timeeintensity curves (TICs) were plotted (Fig 2). Both the two observers used Functol to plot TICs independently, and then recorded the signal intensity of each period. The average value of the signal intensity was taken when the value varied, and was determined in consensus when different opinions were observed. Two GE machines 1.5 and 3 T were used to perform MRI and the signal intensity between the two machines was different. As a result the enhanced signal enhancement ratio to reduce the statistical error. The following parameters were measured: positive enhancement integral (PEI), early
arterial phase signal enhancement ratio (SEREAP), late arterial phase signal enhancement ratio (SERLAP), early portal venous phase signal enhancement ratio (SEREVP), late portal venous phase signal enhancement ratio (SERLVP), and delay phase signal enhancement ratio (SERDP). The signal intensity at time t (SIt), as well as signal intensity at the early arterial phase (SIEA), late arterial phase (SILAP), early portal venous phase (SIEVP), late portal venous phase (SILVP), and delay phase (SIDP) were also measured. Furthermore, the plain scan signal intensity (SImask) was recorded. The values were estimated as follows: PEI¼
P SIt, SEREAP¼[(SIEA-SImask)/SImask]100%,
SERLAP¼ [(SILAP-SImask)/SImask]100%,
SEREVP¼[(SIEVP-SImask)/SImask]100%,
SERLVP¼[(SILVP-SImask) /SImask]100%, and
SERDP¼[(SIDP-SImask)/SImask]100%.
Tumour staging was performed according to the 7th edition of the American Joint Committee on Cancer.10 In the T1 stage, the maximum tumour diameter was <2 cm and it was confined to the pancreas, whereas in the T2 stage, the maximum tumour diameter was >2 cm and it was still confined to the pancreas. In the T3 stage, there was
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pancreatic tissue around the local tumour invasion site or tumour invasion occurred in the duodenum and/or common bile duct; however, there was no infringement of the coeliac and superior mesenteric artery. In the T4 stage, tumour invasion of the coeliac and/or duodenal artery was noted. Finally, progression to lymph node metastases was considered when the lymph short diameter was >5 mm, or in the presence of necrosis whatever lymph node size.
Ethics approval This retrospective study was approved by the hospital review board and by the research ethics committees. The analysis was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and later amendments. All patients provided written informed consent.
Statistical analysis The pathological characteristics and MRI results of the pancreatic IPMN were analysed using SPSS Statistics version 17.0. Continuous data were compared using Student’s t-test, whereas parametric data were compared using Fisher’s exact test. A p-value of <0.05 was considered to indicate statistical significance.
Results Clinical information The 32 patients were assigned to two groups based on the condition, including those with IPMC-I in group A (n¼17) and those with PDAC-IPMN in group B (n¼15). In group A, the mean age was 62.76 years, 11 cases exhibited upper abdominal discomfort and distension symptoms, five cases were diagnosed during occasional physical examination, and one case showed progressive weight loss. Three cases (17.6%) were misdiagnosed, including two cases misdiagnosed as mucinous cystadenoma and one case misdiagnosed as pancreatic ductal adenocarcinoma. In group B, the mean age was 63.5 years, 10 patients showed upper abdominal discomfort and distension symptoms, two patients were diagnosed during occasional physical examination, one patient developed refractory diarrhoea, and two patients were diagnosed with obstructive jaundice. Four cases (26.7%) were misdiagnosed preoperatively, including three cases misdiagnosed as pancreatic ductal adenocarcinoma and one case misdiagnosed as solid mucinous cystadenoma (Table 1).
MRI Among the 32 patients, the pancreatic head was the most common tumour location in both group A (13 cases; 76.5%) and group B (9 cases; 60%). Moreover, the main pancreatic duct was the most commonly affected site in both group A (14 cases; 82.4%) and group B (13 cases; 86.7%). There was no significant difference in tumour location or duct type between the groups. The two groups of patients showed high or slightly higher signal on DWI and decreased ADC
Table 1 Patient demographics and histopathological characteristics for cases with IPMN associated with invasive carcinoma.
Age Sex (male: female) Pancreatitis history, n (%) CEA >5, n (%) CA199 >37, n (%) Location, n (%) Head Body Tail Radiological type, n (%) Main duct type Branch duct type Mixed type ADC value (1010 m2/s) Main pancreatic duct diameter
IPMC-I (n¼17)
PDAC-IPMN (n¼15)
p-Value
62.766.79 2.4: 1 3 (17.6) 2 (11.8) 5 (29.4)
63.507.3 2.75: 1 1 (6.7) 2 (13.3) 9 (60.0)
0.558 0.589 0.603 0.65 0.153 0.58
13 (76.5) 3 (17.6) 1 (5.9)
9 (60.0) 4 (26.7) 2 (13.3)
14(82.4) 3(17.6) 0 5.092.08 9.724.67
13(86.7) 2(13.3) 0 3.861.12 8.283.06
0.563
0.165 0.305
Values indicate the results of a Student’s t-test (significant p-values are presented in bold; p<0.05). IPMC intraductal papillary mucinous carcinoma; PDAC-IPMN pancreatic ductal adenocarcinoma-associated intraductal papillary mucinous neoplasms; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
values (Figs 3 and 4); however, the ADC values did not significantly differ between the two groups (p>0.05). In addition, the main pancreatic duct was dilated to different degrees in both groups A and B, and although the main pancreatic duct dilatation appeared greater in group A (Fig 5), there was no significant difference in the main pancreatic duct diameter (Table 1). Lesion size significantly differed between groups A (48.8118.01 mm) and B (34.2414.15 mm), whereas the wall tumour nodule size did not significantly differ between groups A and B (Table 2). In the 17 patients in group A, dynamic scans showed moderate or slightly low signals in the wall nodules on unenhanced scans, and mild to moderate enhancement in the arterial phase and continuous enhancement in the venous phase and delayed phase on enhanced scans (Fig 6). In the 15 patients in group B, dynamic scans showed moderate or low signals in the wall nodules on unenhanced scans, and mild enhancement during the whole phase on enhanced scans, although the degree of enhancement was lower than that in the pancreas (Fig 7). Moreover, the PEI was significantly higher in group A (2253.6521.92) than in group B (2253.6521.92; p<0.01). The SEREAP did not significantly differ between groups A and B, although the SERLAP was significantly higher in group A (0.520.27) than in group B (0.270.19; p<0.05). The SEREVP significantly differed between group A (0.610.25) and group B (0.350.17; p<0.01), and the SERLVP was also significantly higher in group A (0.630.17) than in group B (0.360.28; p<0.01). Furthermore, the SERDP significantly differed between groups A (0.620.18) and B (0.310.29; p<0.01; Table 2). In group A, the tumour in 14 cases (82.4%) was classified as T1 or T2 stage, whereas the tumour in three cases (17.6%) was classified as T3 or T4 stage. In group B, the tumour in
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Figure 3 Invasive IPMC-I. (a) Diffusion-weighted imaging (DWI) shows an increased lesion signal. (b) A decrease in the signal in the solid part of the lesion is observed in the ADC map, which suggests limited diffusion.
Figure 4 PDAC-IPMN. (a), Diffusion-weighted imaging shows a significant increase in the lesion signal. (b) A significant decrease in the signal in the solid part of the lesion is observed in the ADC map, which suggests limited diffusion.
eight cases (53.3%) was classified as T1 and T2 stage and the tumour in the remaining seven cases (46.7%) was classified as T3 and T4 stage. Thus, the tumour classification significantly differed between the two groups (p<0.05). There was no significant difference in lymph node metastasis between groups A (two cases; 11.8%) and B (four cases; 26.7%; Table 3).
Discussion
Figure 5 MRCP of invasive IPMC-I, which shows apparent tortuous dilation of the pancreatic duct tail, confirmed as a mucus lake on pathological examination.
Pancreatic IPMNs comprise 3.6e7% of all diagnosed tumours in the pancreas,11,12 which account for 16% of all pancreatectomised tumours13 that themselves account for 24% of all pancreatic cystic tumours.14 Moreover, 50% of incidental cystic lesions are classified as IPMNs.12,15 Although IPMN is not considered as a rare disease, it is gradually being accepted as one of the most common cystic neoplasms of the pancreas, as the understanding of the condition grows. In fact, IPMNs are classified into three types, including the main pancreatic duct type, branch duct type, and mixed type. Of these, the main pancreatic duct type and mixed duct type IPMNs have a higher malignant potential, and should be removed.16
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Table 2 Differences in dynamic enhanced MRI findings between IPMC-I and PDAC-PIMN cases.
Tumour size, (mm) Wall size (mm) Positive enhancement integral (PEI) Early arterial phase signal enhancement ratio (SEREAP) Late arterial phase signal enhancement ratio (SERLAP) Early portal venous phase signal enhancement ratio (SEREVP) Late portal venous phase signal enhancement ratio(SERLVP) Delay phase signal enhancement ratio (SERDP)
IPMC-I (n¼17)
PDAC-IPMN (n¼15)
p-Value
48.8118.01 11.786.00 2253.6521.92 0.30.1 0.520.27 0.610.25 0.630.17 0.620.18
34.2414.15 14.716.60 1930.87194.49 0.220.14 0.270.19 0.350.17 0.360.28 0.310.29
0.016 0.240 0.000 0.078 0.005 0.002 0.003 0.001
Values indicate the results of a Student’s t-test (significant p-values are presented in bold; p<0.05). IPMC intraductal papillary mucinous carcinoma; PDAC-IPMN pancreatic ductal adenocarcinoma-associated intraductal papillary mucinous neoplasms.
Figure 6 Invasive IPMC-I. (a) Dynamic MRI image in the early portal venous phase, wherein the lesions show papillary structures and visible enhancement. (b) The pathological evaluation shows partial carcinogenesis.
Figure 7 PDAC-IPMN. (a) Dynamic MRI image in the early portal venous phase, wherein the lesions appear slightly enhanced. (b) The pathological evaluation shows mostly regional carcinogenesis.
The latest WHO classification system has classified IPMN lesions as malignant.17 Poultsides et al.18 summarised 312 cases of IPMN, and found that 42% developed into invasive cancer. In the present study, 115 cases of pancreatic IPMNs were extracted from the pathology database, and 41 (35.7%) of these cases included IPMN associated with invasive carcinoma (Fig 1).
With regard to the clinical aspect of the disease, IPMN has a higher incidence among those in their sixties and seventies, and the disease can affect the entire pancreas, with a higher likelihood in the pancreatic head. In the present study of 32 cases, the pancreatic head was the main tumour location site, and pancreatitis was also observed in a small number of patients. Some patients also exhibited
W. Xu et al. / Clinical Radiology 73 (2018) 873e880 Table 3 Tumour classification of IPMN associated with invasive carcinoma.
T stage, n (%) T1, T2 T3, T4 Lymphatic metastasis, n (%)
IPMC-I (n¼17)
PDAC-IPMN (n¼15)
14 (82.4) 3(17.6) 2 (11.8)
7 (46.7) 8 (53.3) 4 (26.7)
p-Value 0.04
0.267
Values indicate the results of a Student’s t-test (significant p-values are presented in bold; p<0.05). IPMC intraductal papillary mucinous carcinoma; PDAC-IPMN pancreatic ductal adenocarcinoma-associated intraductal papillary mucinous neoplasms.
increased preoperative levels of CA199, especially the patient with pancreatic IPMN associated with invasive carcinoma. Although the preoperative CA199 level did not significantly differ between the groups, it was useful for preoperative diagnosis. Apparent mucus secretion in the catheter cavity is a typical characteristic of IPMNs. When mucus is overproduced and the pressure in the cavity is high, the cavity could rupture.19 Moreover, dilated ductal growth, coupled with excessive mucus secretion, could lead to continuous pressure within the catheter (the lumen of which included the cystic capsule) and to the extrusion of the tissue surrounding the catheter, which may even extend to pancreatic fat tissue (Fig 5). The degree of pancreatic duct dilatation differed between the two groups. Although group B exhibited more extensive invasion than group A, the diameter of the main pancreatic duct in group A was greater than that in group B. This may presumably be due to decreased mucin formation in the invasive tumour. Moreover, although tumour growth may be intraductal, it does not cause the pancreatic duct to dilate.19 DWI has generally been used to detect and characterise various tumours,20,21 and has important diagnostic value for benign and malignant IPMNs.22,23 Sandrasegaran et al. reported that the ADC values of benign IPMNs were higher than those of malignant IPMNs, and suggested that the lower fluid viscosity in benign IPMNs compared with malignant IPMNs may lead to such differences.24 In the present study, both groups A and B exhibited high signals on DWI; in particular, the ADC value of the solid component was decreased, and although the ADC value was lower in group B than in group A, the difference was not significant. Some of the solid IPMN lesions were <1 cm or grew along the wall with a high b-value on DWI, which led to inaccurate ADC measurements. Hence, the DWI findings and ADC values may be beneficial for the diagnosis of IPMN, although they may not be useful for the identification of malignant grade, consistent with that reported in the literature.23 In patients with IPMNs, the pancreatic duct is dilated and the acinar protein content is reduced due to chronic pancreatitis in the pancreatic tail; hence, the T1W signal is decreased,25 which reduces the signal contrast between pancreatic tissue and tumour, and thus impairs the ability of tumour detection. As dynamic enhanced scans had apparent advantages, an appropriate scanning period was
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chosen to obtain the best contrast between the pancreas and tumour, which enabled good imaging of the tumour. Thus, by measuring the signal enhancement in each period, the difference in the degree of invasion could be determined. On dynamic enhanced imaging in the present study, the PEI, SERLAP, SEREVP, and SERLVP were significantly higher in group A than in group B, which suggests that the tumours in group A have greater blood supply than those in group B. This is presumably because the normal pancreas is an organ with a rich blood supply and high microvessel density. The pancreatic malignant tumour destroyed the normal pancreatic tissue, and greater destruction led to a lower amount of normal pancreatic tissue and a consequent weaker degree of enhancement, consistent with that noted in the literature26,27; however, there was no significant difference in the early rate of arterial enhancement, which may be because both of the cases in the two groups consisted of rich fibre components and the arteries had weakened during the early disease stage. With regard to tumour classification, IPMC-I exhibited lower grade and lymph node metastasis as compared to PDAC-IPMN. Hence, PDAC-IPMN may be more invasive and may have a poorer prognosis, consistent with the literature.7 Previous studies have focused on benign and malignant pancreatic differentiation of IPMN.11,14,28 To the authors’ knowledge, this is the first study to compare the diagnostic performance of MRI for predicting the malignant potential of pancreatic IPMNs. The limitations of the current study include the insufficient number of cases required to represent all the features of IPMN in the pancreas, and hence, additional data should be collected to further expand on the sample study. Second, the solid components of some lesions are small, and inaccurate measurements may still occur despite the use of multiple measurement methods. Third, two GE machines 1.5 and 3 T were used to perform MRI and the signal intensity between the two machines was different. Although enhanced signal intensity ratio was used to reduce the statistical error, it was still possible to have little impact on the results. Fourth, the two observers reviewed the MRI images independently, and the results were determined in consensus when different opinions were observed, but determination of interobserver variation between the two observers was not undertaken. Fifth, the number of cases was small and the number of cases with long-term followup was even less, so the information on follow-up and disease-free survival for the 32 cases was not reviewed in this study. In conclusion, pancreatic IPMN associated with invasive carcinoma manifests with a wide array of symptoms, and preliminary dynamic enhanced MRI can determine the degree of invasion and preoperative classification. After a preoperative classification, physicians can obtain more information about the disease. As the classification was different, the prognosis of patients was not the same and their 5-year disease-free survival rate was also different. Once known, physicians can communicate with the patient more effectively, and can also develop more treatment
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options for patients to choose from; thus, guiding the clinical development of a more complete treatment plan.
Acknowledgements This research was granted from Shandong Medical and Health Science Technology Development Project (2017WSA14047).
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