University of Pisa
Department of Translational Research and New
Technologies in Medicine and Surgery
Residency program in Diagnostic Radiology
(2016-2020)
Chairman: Prof. D. Caramella
Diffusion-weighted MRI at 3T device in the evaluation of
pancreatic cystic neoplasms.
Supervisors Candidate
Prof. Davide Caramella
Dr.ssa Maria Teresa Casotti
Dr. Piero Boraschi
Abstract
Purpose
To evaluate the potential role of diffusion-weighted imaging (DW-MRI) in the characterization of pancreatic cystic neoplasms.
Materials and Methods
We retrospectively selected a total number of 223 patients (130 women and 93 men; age range: 16-88 years; mean age: 64 years; SD: 14) with neoplastic and non-neoplastic pancreatic cystic lesions. The lesions were mainly categorized in the following groups: serous cystoadenomas, mucinous cystoadenomas, IPMNs, degenerated IPMNs and pseudocysts. All patients underwent MR examination performed on superconductive system operating at 3T. MR imaging protocol included axial T1w/T2w sequences, MRCP, diffusion-weighted MR imaging with multiple b values in all diffusion directions and contrast-enhanced T1-weighted sequences. All ADC values measurements were obtained from the images with multiple-b values and were performed for each pancreatic cystic lesions.
Results
A statistically significant difference was observed between the ADC values of degenerated IPMNs (n=24) and the ADC of each other category (p<0,001), respectively non-degenerated IPMNs (n=121), serous cystoadenomas (n=42), mucinous cystoadenomas (n=14) and pseudocysts (n=9). The ADC value of non-degenerated IPMN was significantly higher than that of serous cystoadenomas (p=0,0024). A statistically significant difference was observed between the ADC values of the mucinous cystic tumors (IPMNs + mucinous cystoadenomas) and the ADC of serous cystoadenomas (p=0,014).
Conclusion
Our data suggest that diffusion-weighted imaging may be helpful in the differential diagnosis of pancreatic cystic neoplasms. In particular it could be useful for the differential diagnosis between mucinous and serous cystic tumors and between degenerated and non-degenerated IPMNs.
Introduction
Pancreatic cystic neoplasms represent a heterogenous group of lesions including both benign and malignant tumors. They are being reported more frequently as incidental findings at cross sectional imaging. Intraductal papillary mucinous neoplasms (IPMNs), serous and mucinous cystadenomas represent the most common histological types of cystic tumors. Cross-sectional imaging plays an important role in the diagnostic work-up of cystic lesions of the pancreas, allowing to recognize their typical features and helping in identifying or excluding signs of malignancy. In fact, both computed tomography (CT) and magnetic resonance imaging (MRI) are able to evaluate location, morphology, internal architecture and enhancement characteristics of pancreatic cystic lesions [1, 2] and are therefore indicated in all patients with cystic lesion of the pancreas for the differential diagnosis and for depicting signs suggestive of malignancy [2].
In particular, MRI with MR cholangiopancreatography (MRCP) combine the possibility to evaluate cysts features (morphology, content, wall thickening and/or internal septa) as well as their relationship to the pancreatic duct [3, 4].
However, definite lesion characterization remains challenging since radiologic and clinical features may overlap between benign and malignant lesions and even bioptic sampling may result inconclusive. Therefore, additional diagnostic approaches to the available ones are needed.
In this setting, diffusion-weighted magnetic resonance imaging (DW-MRI) including apparent diffusion coefficient (ADC) measurement could represent a useful tool in the differential diagnosis of pancreatic cystic neoplasms. In DW-MRI, the signal intensity is based on the intravoxel incoherent motion of the excited spins, reflecting the microscopic stochastic Brownian molecular motion which is influenced by the microscopic structure and organization of biological tissues [5, 6]. One of the most common used diffusion index is ADC, which measures the water molecules displacement in mm2 per second.
ADC is widely used in body applications to improve tissue characterization, differentiate recurrence from post-therapeutic effects and carry out tumor staging [7].
To the best of our knowledge ADC assessment in the study of cystic pancreatic lesions has been limited investigated, in particular at 3T device. Therefore, the aim of our study was to analyse the potential role of DWI-MRI with special attention to ADC evaluation for the quantification of diffusivity in the characterization of pancreatic cystic neoplasms.
Materials and methods
A written informed consent was gathered in all cases. This retrospective single-institution study was approved by our Institutional Review Board.
Patients
A retrospective revision of our radiological database including all patients who underwent 3T MRI examination at our Department between January 2013 and March 2020 and diagnosed with pancreatic cystic lesions was performed (n=549).
Among them, all patients with both neoplastic and non-neoplastic pancreatic cystic lesions of the pancreas were included in the database, but as in previous studies, only the ones measuring at least 1 cm were investigated [8].
From this cohort, we excluded all the patients with repeated follow-up MRI (only the most recent exam was included) and the patients in which the final diagnosis was not obtained. Final diagnosis was obtained with histopathology of surgical specimen, endoscopic ultrasound-guided fine needle-aspiration (EUS/FNA) and presuntively in the group of patients with IPMN [2].
A total number of 223 patients (130 women and 93 men; age range: 16-88 years; mean age: 64 years; SD: 14) represented our final study group of patients with cystic pancreatic lesions, as reported in the flow-chart of figure 1.
Imaging technique
All patients underwent MRI examination performed on superconductive system operating at 3T (GE Discovery MR750; GE Healthcare). The eight-channel phased-array body coil was used for both excitation and signal reception. Patients had to fast at least 6 hours and before starting the examination, scopolamine methyl-bromide was administered intramuscularly to avoid peristaltic artifacts.
MRI protocol included axial T1-weighted fat-suppressed sequences, axial and coronal T2-weighted sequences with and without fat-suppression, heavily T2-weighted MRCP and diffusion-weighted MR imaging with multiple b-values (0, 150, 500, 1000 and 1500 s/mm²) in all diffusion directions.
Contrast-enhanced T1-weighted sequences were not routinely obtained and gadolinium-chelates administration was performed only in selected cases, mostly when signs of degeneration was suspected. Post contrast images were obtained in the arterial, portal-venous and delayed phases, between 3 and 5 minutes. Our MR imaging protocol is reported in Table 1.
Sequence TR (ms) TE (ms) FA (D°) multiple b-values Bandwidth (Hz/pixel) Acceleration (Phase/Slice) Slice Thickness/Spacing BH/RTr* 2D-Axial and Coronal SS-FSE T2w 1600 95 90 62.50 2/1 5/0 BH 2D-Axial FRFSE-Propeller T2w 3500-6000 65-90 110 36* 2/1 5/0 RTr 2D-Axial SPGR-Dual Echo T1w 150 TE1=1.3 TE2=2.5 50 166.7 2/1 5/0 BH 3D-MRCP FRFSE T2w 3000-5000 600-700 90 83.33 2/1 2.4/-1.2 RTr 2D-Axial E-EPI Diffusion T2w 4500-7000 Minimum 90 0 150 500 1000 1500 250 2/1 5/0 RTr 3D-Axial LAVA T1w 4.3 TE1=1.3 TE2=2.6 12 166.7 2/1 3/-1.5 BH
TR, repetition time; TE, echo time; FA, flip angle; BH, breath holding; RTr, respiratory trigger; *Effect Bandwith
Image analysis
All ADC values were calculated on a workstation dedicated to imaging processing (Advantage Windows 4.3, GE Healthcare) by two radiologists in consensus with 20 and 5 years of experience in abdominal imaging. All ADC values measurements were obtained from the images with multiple-b values (from 0 to 1500 s/mm2).
Operator-defined region of interest (ROI) were used to measure signal intensities for ADC calculation. The ROI was centrally placed in the lesion, sizing as large as possible in order to avoid potential artifacts (i.e., due to the interference from surrounding vessels or tissues).
Each reader performed three different measurements and the values obtained were averaged.
In case of branch duct-type IPMNs with multiple lesions, ADC measurements were performed at the level of all lesions of at least 1 cm in diameter and values were averaged. In case of mixed-type IPMNs, ADC measurements were performed at the level of both main duct and branch-duct lesions; then, the values obtained were averaged.
Data analysis
All statistical computations were carried out by using SPSS software (version 26.0; IBM Corp., Armonk, NY, USA).
Continuous variables were reported as means ± standard deviation (SD).
Kruskal–Wallis test was performed in the comparison of mean ADC values in patients with different diagnosis, and multiple comparisons were performed with Bonferroni method.
P value of 0.05 was considered indicative of statistically significant difference.
Results
The final diagnosis of our study group included: serous cystoadenomas (n=42); mucinous cystoadenomas (n=14); IPMNs (n=121), all of them performed imaging follow-up; IPMNs with signs of malignancy at histopathologic examination (n=24); pseudopapillary neoplasms (n=2); cystic neuroendocrine tumors (n=5); ductal adenocarcinomas with cystic degeneration (n=2); acinar cell cystoadenomas (n=2); cystic acinar cell carcinomas (n=2) and pseudocysts (n=9).
In the group of patients with serous cystoadenomas, the final diagnosis was proven on the basis of endoscopic ultrasound-guided fine needle aspiration (EUS/FNA), except for 4 patients who underwent open surgery.
In the group of patients with mucinous cystoadenomas, the final diagnosis was carried out through analysis of surgical specimen (n=12) and EUS/FNA (n=2).
In the group of 121 patients with IPMN lesions were subclassified into main-duct type (n=4), branch-duct type (n=97) and mixed-type (n=20). Of the four patients affected by IPMN-MD, presumed diagnosis was
based on typical MRI findings; in IPMN-BD, diagnosis was established using EUS/FNA (n=6), surgery (n=5) and typical MRI findings in the other cases; in mixed-type IPMN, diagnosis was established using EUS/FNA (n=2), surgery (n=10) and typical MRI findings in the remaining cases.
All patients with degenerated IPMNs were histopathologically diagnosed after surgical intervention.
The diagnosis of pseudocyst was based on typical clinical history, laboratory findings, MRI findings and clinical and radiologic follow-up.
In the group of patients affected by pseudopapillary neoplasms, cystic neuroendocrine tumors, ductal adenocarcinomas with cystic degeneration, acinar cell cystoadenomas and cystic acinar cell carcinomas, the final diagnosis was made on the basis of histopathologic examination after open surgery. However, this group was excluded from the statistical analysis due to the small sample size and the rarity of lesions.
Finally, statistical analysis was performed on the following categories: serous cystoadenomas, mucinous cystoadenomas, IPMNs, degenerated IPMNs and pseudocysts.
Mean ADC value was 2,57x10-3 mm2/s (range 1,10x10-3 - 3,32x10-3 mm2/s) for serous cystoadenomas and
2,73x10-3 mm2/s for mucinous cystoadenomas (range 1,13x10-3 - 3,24x10-3 mm2/s).
Mean ADC value was 2,72x10-3 mm2/s for IPMN-BD (range 1,71x10-3 - 3,70x10-3 mm2/s), 2,81x10-3 mm2/s for
IPMN-mixed type (range 2,09x10-3 - 3,35x10-3 mm2/s) and 2,84x10-3 mm2/s for IPMN-MD (range 2,29x10-3 -
3,11x10-3 mm2/s); therefore, no significant difference in terms of ADC values was identified between the
different types of IPMNs. Otherwise, mean ADC value of degenerated IPMNs was 1,83x10-3 mm2/s (range
1,02 and 3,20x10-3 mm2/s), a result that is significantly lower respect to the average ADC value of all the
benign IPMNs (2,79x10-3 mm2/s). Mean ADC value was 1,09x10-3 mm2/s (range 1,08x10-3-1,10x10-3 mm2/s)
for pseudopapillary neoplasms, 1,90x10-3 mm2/s (range 1,20x10-3-2,43x10-3 mm2/s) for cystic neuroendocrine
tumors, 1,62x10-3 mm2/s (range 1,44x10-3-1,79x10-3 mm2/s) for ductal adenocarcinomas with cystic
degeneration. The ADC values of acinar cell cystoadenomas ranged from 2,49 to 2,99x10-3 mm2/s with a mean
value of 2,74x10-3 mm2/s and mean ADC value was 1,70x10-3 mm2/s (range 1,22x10-3-2,18x10-3 mm2/s) for
cystic acinar cell carcinoma.
The ADC values of pseudocysts ranged from 1,09 to 3,18x10-3 mm2/s with a mean value of 2,67x10-3 mm2/s.
A statistically significant difference (p<0,001) was observed between the ADC values of degenerated IPMNs and the ADC of their benign counterpart (IPMNs) as well as each further category (serous cystoadenomas, mucinous cystoadenomas and pseudocysts).
The statistical analysis showed that the ADC value of IPMNs was significantly higher than the ADC of serous cystoadenomas (p=0,024). (Figure 2).
A statistically significant difference was observed between the ADC values of mucinous lesions (all subtypes of IPMNs and mucinous cystadenomas, the predominant pre-malignant disease) and serous cystoadenomas (p=0,014) [9]. (Figure 3).
Figure 4. Serous cystoadenoma confirmed by surgery. Axial T2-weighted (A), MRCP (B), pre- (C) and post-contrast T1-weighted (D) images exhibit a voluminous microcystic lesion in the pancreatic head. This formation causes compression and dislocation of the duodenum and inferior vena cava. After DW-MRI (E), ADC value of the lesion is 2,06x10-3 mm2/s (F).
Figure 5. Mucinous cystoadenoma confirmed by surgery. Axial T2-weighted (A), MRCP (B), pre- (C) and post-contrast T1-weighted (D) images show a unilocular cystic lesion with thick and slighty irregular wall in the pancreatic tail. After DW-MRI (E), ADC value of the pancreatic lesion is
Figure 6. Patient with IPMN-branch duct type at the level of pancreatic tail performed MRI follow-up. Axial T2-weighted (A), MRCP (B), pre- (C) and post-contrast T1-weighted (D) images demonstrate a cystic bilobed dilation of the secondary pancreatic ducts without dilation of main
Figure 7. Degenerated IPMN in the body/tail of the pancreas. Axial T2-weighted (A), MRCP (B), pre- (C) and post-contrast T1-weighted (D) images show a structural alteration with loss of normal glandular lobulation, with slower enhancement than the normal pancreas; dila tions of secondary ducts and of Wirsung are associated. Patient underwent surgery and final diagnosis was pancreatic cancer. On DW imaging (E), ADC
Figure 8. Two different pseudocysts in the same patient diagnosed on the basis of typical clinical history, laboratory findings and imaging findings. Axial T2-weighted (A), MRCP (B), pre- (C) and post-contrast T1-weighted (D) images exhibit respectively a fluid-filled pseudocyst in the
pancreatic head and a hemorrhagic pseudocyst at the level of the pancreatic tail. DW imaging (E) reflects the variability of the content. ADC value of the fluid-filled pseudocyst was 2,77x10-3 mm2/s and 8,25x10-3 mm2/s in the hemorrhagic one.
Discussion
Several efforts have been made to non-invasively characterize pancreatic cystic neoplasms, which are diagnosed with increasing frequency and represent common incidental findings discovered at autopsy or on imaging studies performed for other reasons. The reported prevalence of pancreatic cystic lesions is 13,5-44,7 % when MR is the imaging modality.
The accuracy for identifying the specific type of pancreatic cystic neoplasm is variable, ranging between 40% and 95% for MRI/MRCP and between 40% and 81% for CT [10].
Although MRI plays a vital role in this scenario, its accuracy remains unsatisfactory for characterizing a specific type of pancreatic cystic neoplasm, for differentiating small pancreatic cystic tumor from non-neoplastic or non-epithelial cysts, or for connection to the ductal system [11, 12].
To our knowledge, limited studies in literature were focused on the role of DW-MRI in evaluation of cystic pancreatic lesions, with controversial results.
Irie et al. [13] reported that it is difficult to differentiate between mucin-producing and other cystic lesions by ADC measurements while Mottola et al. [14] reported that even though DW-MRI may be helpful in differentiating mucinous and non-mucinous or neoplastic and non-neoplastic cystic pancreatic lesions, the possibility to reach a definite characterization remain limited. On the other hand, some Authors noticed that some differences exist in DW-MRI for mucin-producing cysts compared with serous ones, with divergent results relative to ADC values. Inan et al. [15] reported significantly lower ADC values and ratios of neoplastic cysts than those of simple cysts and pseudocysts, but significant differences in terms of signal intensity ratios between pancreatic cysts were found only on images with a b factor of 1,000 s/mm2. Schraibman et al. [16]
reported higher ADC values for non-mucinous cysts while other Authors reported higher ADC values for mucin-producing lesions [5, 17]. Our experience, obtained utilizing a multiple b-value diffusion-weighted sequences at 3T device, outlined higher ADC values in mucinous lesions (IPMNs and mucinous cystadenomas) compared to serous cystadenomas as just reported in previous papers [5, 18]. It is well known that cystic lesions demonstrate different diffusivity with regard to the cyst contents (fluid, serous, mucinous or hemorrhagic) and size of the cyst compartment [19]. Mucinous lesions were expected to have lower ADC values due to their viscous content, however a possible explanation of higher ADC values in mucinous lesions might be represented by the multiloculate and multiseptate nature of serous cysts, including both fluid and solid components that may restrict the movement of water molecules. A further contribution to restricted diffusion might come from the presence of glicogen-rich epithelium and proteinaceus fluid [5, 18]. Fatima et al. [19] also found a significant difference in ADC values between mucinous cystic neoplasms from IPMNs and attributed the higher ADC of IPMNs to the possibility of cyst fluid content to move more freely given their
connection with the pancreatic ductal system. On the contrary, in our experience mean ADC values of mucinous cystoadenomas and IPMNs are substantially overlapping, without significant differences between the two groups.
Furthermore in our study the mean ADC value of degenerated IPMNs was significantly lower than that of benign IPMNs (p<0,001) and this result closely agreed with the ones emerged in previous studies. Kang et al. [20] analysed a series of 52 patients with surgically resected IPMNs and found that the mean ADC value of malignant IPMNs was significantly lower than that of benign IPMNs and among the malignant IPMNs, invasive IPMCs (intraductal mucinous carcinomas) showed a significantly lower mean ADC than that of noninvasive IPMCs. In this retrospective study, DW-MRI was performed with three b factors (0, 500 and 1000 mm2/s).
Similar results were also obtained by Ogawa et al. [21]; they investigated the effectiveness of DW-MRI in the evaluation of the histological degree of malignancy in a series of 35 patients with IPMNs. Applying only a b value of 1000 mm2/s they found a mean ADC value of malignant IPMNs (IPMN with high-grade dysplasia and
IPMN with an associated invasive carcinoma) was significantly lower than that of the benign counterpart (IPMN with low- or intermediate grade dysplasia). Our data regarding degenerated IPMNs could be explained by the presence of many factors that determine the restriction of diffusivity and the lower ADCs of malignant tumors: increased cellularity and cell density, higher water and protein content, tissue disorganization and extracellular space tortuosity [22, 23]. Moreover, in the process of de-differentiation of pancreatic cancer there is a progressive loss of glandular formation with dense fibrotic reaction and reported lower ADCs [24]. The interpretation of the mean ADC values relative to pseudocysts appeared more problematic. Our data did not show any statistically significant differences in ADCs between mucin producing neoplasms, pseudocysts and serous cystoadenomas. However, our results agreed to that reported in previous papers by Irie et al. [13] et Inan et al. [15]. They obtained a rather wide range of ADC values (our range 1,09-3,18x10-3 mm2/s, Irie’s
range 1,8-5,5 mm2/s) that could be justified by the wide variability of pseudocysts’s content. A pancreatic
pseudocyst is a unilocular or multilocular fluid-filled lesion, encapsulated by fibrous tissue and usually form after inflammation, necrosis or hemorrhage related to acute pancreatitis. It can evolves by shape, morfology and content over short interval; older cysts tend to have thicker walls that may contain calcium [25]. It therefore seemed quite intuitive that ADC values varied following the natural evolution of the pancreatitic process; moreover, the relatively low ADC value of pseudocyst found in our work could be ascribed to their content, since necrotic tissue and haemorrhage are known to decrease the ADC value [5]. Possible explanations of the divergent data in literature might be attributed to some methodological differences between the previous studies, mainly related to the sample size, heterogeneity of pathologic entities investigated in the study groups and b values chosen.
Regarding the choice of b values, three or more b values are recommended and should include b = 0 s/mm2,
optimal for ADC calculation because of a lower signal-to-noise ratio. The choice of almost three b values should enable calculation of perfusion-insensitive ADC values. The degree of perfusion bias in ADC measurement increases with volume fraction of flow and decreases b-value range [22]. By using a high b value (i.e. b = 1000 s/mm2) the signal from normal tissue is suppressed as much as possible and it is easily to detect highly cellular lesion [5].
Our study had a number of limitations. First, the retrospective design of the study. Second, the number of patients was relatively small for all types of lesion except for IPMNs, which might have influenced the results. In addition, in some cases pathological confirmation was lacking and diagnosis relied only on clinical and/or imaging features. However, the diagnosis of IPMN’s has been presumptive in many cases, although this is supported by the European guidelines on pancreatic cystic neoplasms [2]. Besides, a homogeneus distribution of patients by neoplasm type is not possible since IPMNs are the most frequent cystic tumor. Finally, ADC was calculated not on the volume of the entire lesion but in the largest axial image.
In conclusion our data suggest that DWI-MRI with ADC evaluation may be helpful in the differential diagnosis of pancreatic cystic neoplasms and should always be performed as a part of conventional MRI protocol, since it could improve diagnostic assessment of pancreatic cystic neoplasms with particular regards of differential diagnosis between mucinous and serous cystic tumors and between degenerated and non-degenerated IPMNs.
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