Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by irreversible morphologic changes often associated with pain and impairment of exocrine and/or endocrine function (1, 2). The estimated prevalence of CP ranges from 5 to 12 per 100,000 (3, 4), with CP accounting for 19,724 hospitalizations and $172 million in aggregate costs in the United States in 2009 (5). Although the clinical presentation varies, chronic disabling abdominal pain, which poses a major detriment to the quality of life, is present in nearly 80–90% of patients with CP and is the inciting symptom in over 90% of admissions (6). An early and accurate diagnosis of CP in patients presenting with abdominal pain is critical as they are otherwise subjected to repeated imaging as well as unnecessary interventions (7, 8). Conversely, patients with minimal abnormalities on conventional imaging may have significant pain burden (9). It is also now known that severity of imaging abnormalities correlates poorly with pain burden and pattern (9, 10).
While diagnosing advanced calcific CP is fairly straightforward by standard imaging such as contrast-enhanced computed tomography, diagnosing non-calcific chronic pancreatitis (NCCP) in patients presenting with chronic abdominal pain is challenging and controversial (7). Currently, endoscopic ultrasound (EUS), endoscopic pancreatic function tests (ePFT), and magnetic resonance imaging (MRI) are used to establish the diagnosis of CP (1). It has been well established that the acquisition of MRCP sequences following intravenous administration of secretin (secretin-enhanced MRCP-sMRCP) permits a more accurate visualization of subtle ductal changes even during early stages of CP and an indirect estimation of the exocrine pancreatic reserve (11, 12, 13, 14). Correlation has been demonstrated between a spectrum of MRI/MRCP findings and fecal elastase as well as secretin-induced ePFT (15, 16).
While EUS and ePFT have been correlated with surgical histopathology of CP, to date no study has compared MRI/sMRCP with histopathology in patients with NCCP (17, 18, 19, 20). In this study, we aimed to assess the correlation of MRI/sMRCP with surgical histopathology in NCCP patients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for refractory pain.
This was a retrospective cohort study, approved by the University of Minnesota institutional review board. All NCCP patients who underwent TPIAT for chronic or acute recurrent pancreatitis with refractory pain between 2008 and 2013 were identified from the University of Minnesota transplant surgery database. Patients were selected for TPIAT by a multidisciplinary committee using established criteria (21). The primary indication for TPIAT was to treat intractable pain associated with impaired quality of life due to CP or recurrent acute pancreatitis, when medical, endoscopic, or prior surgical therapy had failed (21). To minimize the potential bias of disease progression, only patients with MRI/sMRCP within 1 year before TPIAT were included in our study. The demographic and etiologic characteristics were extracted from the electronic medical record using a standardized data-collection form. Smokers were classified as never or former/current smoker. Similarly, alcoholics were categorized as never or former/current alcoholic.
All patients underwent baseline MRI and MRCP together with sMRCP at the same session. MRI was performed with a 1.5-T MR scanner with the use of a four-element quadrature phased-array surface coil. The standard upper abdominal MRI protocol was followed and the following sequences and parameters were obtained and analyzed: T1-weighted spoiled gradient echo in/out phase (repetition time (TR)/echo time (TE)/flip angle, 103/5.19–2.38 msec/70), T1-weighted fat-saturated 3D spoiled gradient echo (TR/TE/flip angle 5.05/2.28 msec/10). MRCP consisted of respiratory triggered 3D T2 images (TR/TE 2,500/704 msec) and T2 2D half single-shot fast spin-echo coronal (TR/TE/slice thickness 1,240/457 msec/4 mm). For secretin MRCP, oral preparation was performed with 300 ml silicone-coated superparamagnetic iron oxide particle suspension (ferumoxsil, GastroMark, Mallinckrodt Medical, St Louis, MO) a few minutes before the examination. MRCP was then performed with Thick Slab T2 2D single-shot fast spin-echo (TR/TE/slice thickness 6,000/1,140 msec/60 mm) before and after administration of secretin (0.2 mg/kg) (ChiRhoStim; ChiRhoClin, Burtonsville, MD). Following injection, imaging was obtained every minute for 7 min, as well as at 10 min after administration.
All MRI/sMRCP were reviewed by a single expert body-imaging radiologist (SPW) who was blinded to the surgical histopathology and the clinical outcome. For analysis, the pancreas was divided into three segments: head, body, and tail. Pancreatic size was determined with the measurement of the anteroposterior diameter of the gland on axial T1-weighted fat saturated images on each segment and the mean anteroposterior diameter was calculated. Pancreatic gland atrophy was defined as mean anteroposterior diameter below the lower-limit of age-related mean size (22).
Signal intensity (SI) and the contrast enhancement of the pancreatic gland were measured with the placement of an elliptical region of interest in three segments without changing its size (23 mm2). The S1 of each pancreatic segment and the spleen was measured on T1-weighted fat saturated images after iron deposition of the spleen was ruled out on T1-weighted dual echo images with absence of signal decrease on in-phase images compared with shorter echo out-of phase images (16). The SI ratio between the pancreas and spleen/pancreas and paraspinal muscle was determined (Figure 1a and b). Mean SI ratio greater than 1 was considered as normal.
The diameter of the main pancreatic duct (MPD) before and at 3 and 10 min after secretin stimulation was measured to monitor variations in ductal size. The MPD was considered to be dilated if the basal diameter was greater than 3 mm in patients less than 60 years of age and greater than 3.5 mm in patients over 60 years of age (11, 23, 24). Other parameters measured before and after secretin were the presence of MPD stenosis (ductal narrowing), irregularity in the contour of the duct, visualization of side branches in body and tail of the pancreas, the presence or absence of cysts, and the presence of pancreatic divisum (Figure 2a and b) (24).
The volume of fluid filling the duodenum over time after secretin-stimulated secretion of pancreatic fluid was graded semi-quantitatively. Duodenal filling (DF) was graded as: grade 0, no fluid signal in the duodenum; grade 1, fluid limited to the duodenal bulb; grade 2, fluid filling up to the genu inferius; and grade 3, DF beyond the genu inferius (Figure 3a and b) (11). The spectrum of MRI/sMRCP findings used to correlate histopathology has been summarized in Table 1.
The original slides for each TPIAT were retrieved from the pathology archive maintained by the Department of Pathology at University of Minnesota. An expert pancreatic pathologist (YH) blinded to the MRI/sMRCP findings reviewed and scored the pathological specimen based on the system proposed by Ammann et al. (25). The Ammann system quantifies the degree of focal (1, mild; 2, moderate; 3, severe focal fibrosis) and diffuse (4, mild; 5, moderate; 6, severe) with respect to intralobular and perilobular fibrosis. An overall mean fibrosis score (FS) is calculated for the pancreatic head and body/tail. The calculated FS ranges from 0 to 12. A FS of 2 or more was considered as abnormal and 6 or more was considered as severe fibrosis.
Patients were classified into two groups according to the presence or absence of CP (outcome of interest), as determined by histology (criterion standard). Descriptive statistics were reported as frequencies and percentages for categorical data and means with standard deviation (s.d.) for continuous data. Multiple linear regression analysis (stepwise selection) was performed to check for significant predictors of FS. Two-by-two contingency tables were constructed to calculate sensitivity, specificity, predictive values, and likelihood ratios. A quantitative receiver operating characteristic (ROC) curve was plotted for the number of features of NCCP diagnosed by MRI/sMRCP by using sensitivity and 1−specificity. For this study, the correlation between MRI/sMRCP criteria and histology was evaluated using Spearman rank correlation coefficient. In all analyses, a P-value of <0.05 was considered as significant. Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC).
A total of 57 patients were eligible, all of whom had undergone TPIAT for NCCP or recurrent acute pancreatitis resulting in unremitting abdominal pain and necessitating frequent hospitalization. Majority were females (85.9%) and the age ranged from 19 to 63 years. Most patients (71.9%) had a documented history of acute pancreatitis requiring hospitalization. Forty-eight (84.2%) had abnormal histology, defined as FS of higher than or equal to 2. All nine patients with normal pancreatic histology had undergone TPIAT for recurrent acute pancreatitis with refractory interval pain. Median FS was 4.7 (range 0–10). The baseline demographic characteristics are shown in Table 2. A history of smoking was present in 47%, and alcohol consumption in 60%.
Diagnostic performance of MRI/sMRCP in relation to FS ≥2 is shown in Table 3. Diagnostic performance of MRI/sMRCP in relation to FS ≥6 is shown in Table 4. The correlation between the number of MRI/sMRCP features and the FS was strong (r=0.6) and statistically significant (P<0.0001) as shown in Figure 4. By the quantitative ROC curve analysis (Figure 5), ≥2 MRI/sMRCP features provided the best balance of sensitivity (65%, 95% confidence interval (CI) 49.5–77.8%) and specificity (89%, 95% CI 51.7–98.2%) for predicting abnormal histology (FS≥2). Although the positive predictive value was 100% with three or more criteria, the operating characteristics were more optimal when two or more criteria were considered.
A threshold of ≥2 MRI/sMRCP features the best cutoff for diagnosing severe fibrosis (FS≥6), with a sensitivity of 88% (95% CI 61.6–98.1%) and specificity of 78% (95% CI 62.4–89.4%), as shown in Figure 6. No individual criterion or group of criteria appeared to predict FS, given the small sample size.
Making an accurate diagnosis of CP is increasingly crucial as CP carries with it certain social, financial (insurability), and psychological repercussions (7). An early diagnosis potentiates early aggressive behavioral modifications (such as smoking cessation and abstinence from alcohol), which may alter the natural course of the disease (7, 8, 26). It also permits timely referral to appropriate sub-specialties (such as endocrine, pain, and nutrition management) for prevention and management of long-term complications of CP (8). Furthermore, TPIAT is emerging as a viable treatment option for patients with intractable painful CP refractory to other therapies (21, 27).
MRI/sMRCP provides a noninvasive diagnostic imaging modality without ionizing radiation which can detect subtle abnormalities in the pancreatic parenchyma and ductal morphology. In contrast to EUS, the MRI/MRCP literature does not propose a scoring system such as standard criteria or Rosemont classification for diagnosis of CP (28, 29). The spectrum of potential MRI findings has not been validated against a gold standard for CP. MRI/MRCP findings may precede pancreatic exocrine insufficiency as measured by fecal elastase (15). Patients with clinical suspicion for CP and negative ePFT can have MRI/MRCP changes consistent with CP (30). Similarly, sMRCP has been correlated with fecal elastase 1 levels and ePFT (16, 31, 32, 33, 34). It was concluded that both good correlation and discrepancies exist between standard MRI/sMRCP findings and ePFTs, as some patients with chronic abdominal pain consistent with CP but normal ePFTs had severe pancreatic ductal changes (16, 33). All these studies clearly established that although ePFT is a reliable maker for exocrine insufficiency, is not the “holy grail” for diagnosis of CP as it appears to occur relatively late in the disease process. These observations underscore the need for validation of standard MRI/sMRCP findings with a more reliable gold-standard such as histopathology.
In our study, two or more features of MRI/sMRCP provided the best balance of sensitivity and specificity to make a diagnosis of NCCP as shown by the ROC (Figure 5). As with any cutoff on a linear scale, higher cutoffs are more specific, with three or more features showing 100% specificity and positive predictive value (as shown in Table 3). A cutoff of three or more features may be relevant in instances where establishing a clear diagnosis is imperative, as when surgeries such as TPIAT are contemplated. Based on Figures 5 and 6, we can conclude that MRI/sMRCP appeared better for predicting the presence vs. absence of fibrosis (Area under Receiver Operating Characteristic curve 0.88 and accuracy of 84.2%) when compared to distinguishing severe disease from non-severe disease.
“Asymptomatic” fibrosis is known to occur in patients without pancreatic endocrine or exocrine insufficiency (1). It however remains unclear if this fibrosis represents an early stage of CP or a separate entity unrelated to pancreatitis (35). Such asymptomatic fibrosis is known to occur in the presence of certain patient related factors such as age, sex, and obesity, as well as certain environmental exposure such as smoking and alcohol exposure. A linear regression was therefore performed to identify independent predictors of CP after taking age, sex, body mass index (BMI), smoking, and alcohol exposure into consideration in our patients. MPD irregularity, T1 SI ratio between the pancreas and paraspinal muscle, and DF after secretin administration were established as independent predictors of CP (Table 5).
Despite improved resolution, it is difficult to delineate minimally dilated side branches by MRCP, in contrast to endoscopic retrograde pancreatography, in which the collapsed MPD and branches are distended by contrast administration. However, concurrent administration of secretin causes a transient increase in the tone of the sphincter of Oddi which enables delineation of the pancreatic ductal morphology in both healthy and patients with CP (11, 36, 37). Secretin facilitates detection of subtle changes of early CP, even when no abnormalities can be demonstrated by MRCP under physiologic conditions. Normally, the MPD has a smooth contour which tapers gradually toward the tail (37). MPD irregularity was found to be an independent predictor of CP in our study. The degree of MPD irregularity and periductal fibrosis correlated closely with pancreatic fibrosis in a retrospective study by Kloppel et al. (38). More recently, Leblanc et al. (20) reported that MPD irregularity was an important EUS criterion in predicting fibrosis and ductal changes may be a direct consequence of parenchymal fibrosis. Secretin administration causes an increase in caliber of the MPD by 1 mm or more in normal patients followed by a recovery of the duct diameter to the baseline typically at 10 min after IV secretin injection (1). Loss of compliance of the MP due to peri-ductal fibrosis and ductal strictures are other abnormalities seen in CP (37). Pancreatic side branches are distended with bicarbonate-rich pancreatic enzymes after secretin administration, which along with impaired steam into the MPD causes side-branch ectasia in the setting of CP (1, 16).
Pancreatic signal on T1-weighted fat-saturated images is enhanced in relation to the surrounding retroperitoneal fat, and T1 SI ratio when compared with surrounding organs and tissue such as the spleen or paraspinal muscles is greater than 1 in normal pancreatic parenchyma (39, 40). Normal pancreatic parenchyma demonstrates a high T1-SI ratio because of the rich proteins in the acinar cells (enzymes and hormones) (39, 40, 41). In conditions such as CP, there is loss of aqueous proteins in the acini induced by chronic inflammation and fibrosis, which is represented as a segmental or diffuse decrease in the T1-SI of the pancreas (39, 40, 41). In our study, the T1-SI ratio between the pancreas and paraspinal muscle was a significant predictor after linear regression, although the T1-SI ratio between the pancreas and the spleen was not a significant predictor in our study, for unknown reasons.
The volume of fluid filling the duodenum over time after secretin-stimulated secretion of pancreatic fluid was graded semi-quantitatively and has been shown to be a reliable modality to estimate the exocrine insufficiency (11, 13, 36, 42, 43). It is believed that even in the absence of changes in ductal morphology, decreased DF after secretin administration would reflect early CP (11). Decreased DF was a significant predictor of fibrosis in our study. However, the volume of fluid excreted in the duodenum or the peak flow rate was not assessed in our study.
We correlated our findings with Ammann’s system, which correlates with the functional damage and years with disease, but is not a universally agreed-upon histologic grading system. There is no consensus on the minimum FS threshold defined as CP, with some studies using a more conservative threshold (2 of 12 on Ammann’s classification) (17, 19) when compared with others (6 of 12) (18). We re-analyzed our data considering a FS of 4 or more as diagnostic of CP, and found that two or more MRI/sMRCP features still provided the best balance of sensitivity (68%) and specificity (71%) with Area under Receiver Operating Characteristic curve of 0.81 (P<0.001).
To date, this is the first study to evaluate the correlation between MRI/sMRCP features and histopathology of NCCP. Since the diagnosis of advanced calcific CP is fairly straightforward, we intentionally included only patients with NCCP in our study cohort. CP can be a focal “patchy disease” especially in the early stages (44). By obtaining wedge biopsy from head, body, and tail, we procured histological samples representative of the entire gland and thus minimized the risk of sampling bias. We also assessed the impact of age, sex, BMI, smoking, and alcohol in the MRI/sMRCP diagnosis of CP by performing a multivariate analysis.
There are some limitations to this study. This is a retrospective study and should be considered as hypothesis-generating. The sample size was relatively small since only patients with NCCP who had undergone TPIAT were available for histopathological comparison. Additionally, our sample included predominantly female patients (84%), which might introduce unintentional skewing of data. MRI/MRCP and histopathology were reviewed in a blinded manner, but only by single experts each in body imaging and pancreatic histopathology. There would likely be substantial inter-observer variation by multiple reviewers. We were unable to assess the correlation between individual MRI features and histopathology because of the sample size.
There has been a considerable debate among pancreatologists if histopathology, and particularly fibrosis, is indeed the most appropriate “gold standard” for CP (8, 44, 45). It is also unclear whether the Ammann scoring system is an ideal standard for quantifying fibrosis. However, currently there is no alternate validated scoring system, and previous studies that compared EUS with surgical pathology have all used this scoring system (17, 18, 19, 20). Finally, our study, like many others, suffers from an obvious selection bias, as only patients with severe symptomatic disease refractory to conventional management and undergoing TPIAT were included. It is questionable if we can extrapolate the results to the typical patient with chronic “pancreatitis type” abdominal pain. However because of ethical considerations, it may not be feasible to obtain multiple pancreatic biopsies in consecutive patients presenting with chronic abdominal pain, so that true diagnostic accuracy and histological correlation may never be clearly defined (46).
In conclusion, MRI/sMRCP findings correlated fairly well with histopathology in patients with NCCP who underwent TPIAT. In the appropriate clinical context, two or more MRI/sMRCP features provide ideal threshold for making a diagnosis of NCCP. MPD irregularity, T1-SI ratio between pancreas and paraspinal muscle, and DF following secretin administration were independent predictors of CP after taking patient characteristics (age, sex, and BMI) and environmental factors into consideration. A multicenter, prospective study with long-term follow up would be crucial to validate the findings of our study.
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