**6. Chronic pancreatitis**

Chronic pancreatitis (CP) is a pathologic fibroinflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathologic response to parenchymal injury or stress.

CP is most commonly caused by toxins such as alcohol or tobacco, genetic polymorphisms and recurrent attacks of acute pancreatitis.

### *Imaging of Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.106764*

Early diagnosis of CP is fundamental because early CP is the stage in which target therapy is likely to be most effective.

According to American College of Gastroenterology 2020 guidelines, in patients with clinical symptoms of a pancreatic inflammatory disorder and/or in patients with a suggestive gene–environment risk assessment, cross-sectional imaging, in particular, CT or MRI with MRCP, should be the first-line tests for the diagnosis of CP, because they are valid, reproducible, widely available and non-invasive. Because of its invasiveness and minor reproducibility and availability, EUS should be used after cross-sectional imaging when the diagnosis is still in doubt, or if there is a concern about "minimal changes" that cannot be visualized on cross-sectional imaging. If CT, MRI with MRCP and EUS do not confirm the diagnosis of CP and the suspicion is still high, S-MRCP is suggested because it allows better visualization of the main pancreatic duct and side branches and allows to obtain a semiquantitative measurement of duodenal filling [39].

In CP impaired outflow of pancreatic juice induces inflammation and fibrotic replacement of pancreatic parenchyma; fibrosis is responsible for reduced ductal compliance and ductal anomalies (such as side branches ectasia in early-stage and dilatations, strictures and irregularities of the main pancreatic duct in advances stages), while inflammation causes intraductal and parenchymal calcifications.

At imaging, in early chronic pancreatitis morphology and dimensions of the pancreas are normal, but impairment of pancreatic juice outflow drives mild fibrosis; in overt CP, the main pancreatic duct is dilatated and distorted, pancreatic parenchyma is thinned and may contain cysts, and intraductal and parenchymal calcifications are present.

The role of the radiologist in the early stage is to make a diagnosis of CP and look for its causes (so that they can be removed if possible), while in the advanced phase the role of the radiologist is to confirm the diagnosis, look for its causes, identify complications, monitor the disease and early detect pancreatic adenocarcinoma (PDAC) for which these patients are at increased risk [40]. The most valid radiological techniques to diagnose and monitor CP are CT, MRI with MRCP and S-MRCP.

CT and MRI have similar sensitivity and specificity in diagnosing CP, respectively 75% and 91% for CT and 78% and 98% for MRI [41]. CT is cheaper, easily available, allows rapid visualization and characterization of calcifications and is much faster, thus can be used also in uncooperative patients; on the other hand, MRI allows better identification of early parenchymal alteration and subtle ductal changes so it is the best technique to diagnose early CP; moreover, it is the best technique to monitor disease progression, to early detect pancreatic ductal adenocarcinoma (for which patients with CP are at increased risk) and is useful in differentiating focal CP from PDAC and CP from IPMN. In any case, the two techniques may be considered complementary.

### **6.1 MRI imaging**

MRI is the best technique to early diagnose and follow up CP, thanks to its intrinsic high contrast resolution because it provides optimal visualization of the pancreatic ductal system.

MRCP are key sequences for evaluating the pancreatic ductal system and are acquired using 2D and/or 3D heavily T2 weighted sequences in which structures containing static fluid appear markedly hyperintense while surrounding solid structures display very low signal and appear markedly hypointense (**Figures 8–12**).

The best sequence to evaluate pancreatic borders and pancreatic parenchyma is GRE T1 fat-sat (either with Dixon technique), because of the intrinsic signal differences between the high signal intensity of the pancreatic parenchyma and the suppressed signal of the peri-pancreatic fat. With this sequence, the healthy pancreas, whose cells are rich in proteins, appears homogeneously hyperintense while the fibrotic replacement of acinar cells leads to a progressive decrease in signal intensity, and this signal loss correlates with the decrease in exocrine function (**Figures 13** and **14**) [42, 43].

Moreover with "T1 mapping", a novel advanced MRI technique, pancreatic T1 signal intensity may be reliably assessed and could be used as a practical and sensitive biomarker to monitor CP and to diagnose mild CP, even earlier than ductal anomalies become appreciable, as the fibrotic replacement of acinar cells precedes ductal alterations (**Figure 15**). T1 mapping is a quantitative MR imaging technique that allows measuring the tissue-specific T1 relaxation time. The T1 relaxation time of pancreatic parenchyma is significantly increased in patients with mild CP [44] and, given the quantitative nature of the data, T1 mapping may be a more reliable method compared to traditional T1 weighted imaging, allowing ready comparison across longitudinal time points and permitting a more meaningful interpretation of intensity changes, so it could become a biomarker. However, more studies are required to transform these potential benefits into clinical practice.

### **Figure 13.**

*T1w GRE fat-sat MRI scan comparing a normal pancreas (a), a mild CP (b) and an advanced CP (c), where the non-enhanced T1 intensity of the gland is gradually reduced according to the severity of CP.*

### **Figure 14.**

*M, 70 yo. Evolution of CP few months (up) and few years (down) after necrotizing pancreatitis recovery in T2w HASTE sequence (a), unenhanced T1w GRE fat-sat (b), delayed-phase T1w GRE fat-sat (c) and MRCP (d). The progressive upstream dilatation of the ductal system is accompanied by a progressive reduction of T1 intensity of the parenchyma which is increasingly replaced by fibrosis.*

### **Figure 15.**

*M, 73 yo. Early-stage of CP in T1 mapping sequence (a), S-MRCP (b), T2w HASTE sequence c), unenhanced T1w GRE fat-sat (d). T1-mapping shows an increased T1 relaxation time of the gland even before the appearance of marked classic signs of chronic pancreatitis. S-MRCP visualization of side branches at body-tail after secretin is a sign of early CP.*

After contrast injection, while a healthy pancreas typically displays strong enhancement in the arterial phase and homogeneously decreasing enhancement in the venous phase, in CP fibrotic tissue causes heterogeneously reduced enhancement in the arterial phase, followed by a delayed enhancement in the venous and equilibrium phase, related to the fibrotic changes of the pancreatic parenchyma (**Figure 14**) [28, 43].

The ductal abnormalities are well depicted on MRCP images. In particular, in the early-stage CP side branches get mildly dilatated and become visible, while in advanced stages are depicted more severe alterations of side branches (such as ectasia or sacculation) and alterations of the main duct such as irregular profiles, dilatation, focal strictures and filling defects (due to stones and protein plugs). Ductal abnormalities of CP can be scored according to the Cambridge Classification modified for MRCP (**Table 2**) [45].

The overall sensitivity of MRCP for diagnosing CP increases from 77–89% using S-MRCP [46], which adds both morphological and functional information. Secretin infusion induces transitory hypertension in the ductal system improving the morphological evaluation of the main pancreatic duct and side branches and making eventual ducts anatomical variants (such as pancreas divisum), obstructions, stenosis, dilatations and irregular contours easier detectable.

In a healthy pancreas, ductal response to secretin stimulation determines an increase in the main duct caliber of approximately 1 mm with a peak at 3 min with


### **Table 2.**

*Grading of chronic pancreatitis.*

the return to baseline caliber at 10 min. In CP periductal fibrosis causes a decrease in ductal compliance and leads to an abnormal and persistent main duct dilatation with visibility of the side branches. Thus, visualization of side branches at the body-tail after secretin is a sign of early CP (**Figure 15**) [47]. Moreover, in early stages of CP, secretin-induced hypertension may result in acinar filling with a progressive hydrographic enhancement of the pancreatic parenchyma, the so-called "S-MRCP parenchymogram" which is a sign of pancreatic outlet obstruction (**Figure 16**) [43, 48].

Finally, S-MRCP allows to obtain a semiquantitative assessment of the duodenal filling which correlates with pancreatic exocrine function, with diagnostic performance comparable to that of invasive tests such as endoscopic pancreatic function testing [49]. The semiquantitative assessment is performed by applying a grading system to duodenal filling from grade I (filling limited to the duodenal bulb, indicating severely reduced duodenal filling), to grade II (filling visible as far as the second portion of the duodenum, indicating reduced duodenal filling),

to grade III (filling beyond the second portion of the duodenum, indicating normal duodenal filling); a reduced duodenal filling suggests a decrease in pancreatic exocrine reserve. However, the normal duodenal filling does not exclude impairment of pancreatic exocrine function; so reduced duodenal filling is a specific but not sensitive sign of CP.

In some cases, CP can be focal and thus simulates PDAC and differential diagnosis is very difficult, even for the pathologist, because PDAC is characterized by a rich desmoplastic component.

To make a correct diagnosis, the radiologist can rely both on morphological criteria (in the particular relationship between the lesion and the dilatated ducts, the

### **Figure 16.**

*M, 45 yo, Recurrent episodes of pain and increase of pancreatic enzymes. Pre-secretin MRCP (a) shows no significant changes. Just 2 minutes after secretin injection (b), an increase in signal intensity of the parenchyma can be observed and persists for the full 17 minutes of the exam (c). This phase shows a good passage of pancreatic juice in the duodenum due to adequate exocrine function.*

**Figure 17.**

*M, 65 yo. CP with evidence of two ductal strictures at MRCP sequences (arrows) at diagnosis (a) and a few months later (b). CT (c) performed two years later discovers multiple gross calcifications of pancreatic parenchyma, typical of CP.*

relationship between the lesion and calcifications and enhancement criteria) and on functional criteria (in particularly advanced DWI techniques and S-MRCP).

In PDAC both pancreatic dilatated ducts and calcifications are displaced at the periphery of the lesion, while in focal CP calcification and dilatated ducts are part of the lesion and so are located within it.

Both focal CP and PDAC are hypointense in T1 fat-sat and hypovascular in the pancreatic arterial phase, but while PDAC most of the time persists hypovascular, in focal CP a delayed enhancement is often detected.

Both focal CP and PDAC cause stenosis of the main duct, however, while in focal CP the stenoses reduce or resolve after secretin stimulation (duct penetrating sign), it does not change in PDAC (**Figure 17**) [50].

As the risk of pancreatic cancer is significantly elevated in patients with CP (cumulative risk at 10 and 20 years after the diagnosis of pancreatitis, respectively 1.8 and 4% [40]), this population needs to be followed up also to early detect PDAC, when the lesion is still resectable. MRI with MRCP and eventually with s MRCP is the best technique to early detect PDAC since very often the first sign of PDAC onset is focal stenosis of the main duct that does not resolve after secretin stimulation.

In advanced CP, the aspect of the pancreatic ductal system may mimic that of the main duct intraductal papillary mucinous neoplasm (MD-IPMN); however in MD-IPMN the dilatation of the main duct is more homogeneous with regular margins and without strictures, usually associated with bulging ampulla, sometimes with grape-like secondary duct dilatation and with a solid nodule in a duct, while specific findings of CP are ductal dilatation with strictures, the presence of a stone and side branches ectasia with non-cystic appearance (**Figure 18**) [51].

### **Figure 18.**

*CP with multiple calcifications at CT scan (a) and diffuse dilatation of ductal system at MRCP (b), compared to a mixed IPMN with main duct IPMN component clearly visible at MRCP (c).*

In conclusion, nowadays MRI is the best technique to early detect and monitor CP, to early detect PDAC in patients with CP and make a differential diagnosis between PDAC and focal CP and between MD-IPMN and CP. In the future MRI with T1 mapping could provide a biomarker to detect and monitor CP [52].

### **6.2 CT imaging**

CT has been a cornerstone for evaluating CP, thanks to its availability and reliability. Even if MRI has superior accuracy for imaging the ductal system, CT with its high spatial can well depict both the parenchyma and the dilatated ducts in a few minutes and provides good-quality morphological information even in uncooperative patients; moreover, CT is the best technique to detect and study the structure of parenchymal and intraductal calcifications, and to identify CP complications such as pseudocysts, vascular thrombosis and pseudoaneurysm [52].

Unenhanced CT may be considered complementary to MRI and MRCP because it allows to easily identify and precisely localize both pancreatic parenchymal and ductal calcifications (important information for treatment planning) (**Figure 19**), and permits to study the structure of stones, in order to identify features suggestive of gene mutations associated with CP. In particular stones with a hypodense central core, with the so-called "bull's eye" appearance, are detected in 67% of patients with a gene mutation associated CP [53] and identifying these patients is important because they have an even higher risk of developing PDAC and thus require strict surveillance, genetic counseling and family testing.

During the pancreatic parenchymal phase (a late arterial phase acquired approximately 40 s after the initiation of intravenous contrast injection) parenchymal enhancement is typically reduced in CP, due to fibrotic changes. Moreover, complications such as fluid collection and vascular abnormalities like pseudoaneurysms are detected. In the portal venous phase (70–90 s after intravenous contrast medium injection) venous vessels can be adequately studied and complications such as fluid collection and vascular abnormalities like thrombosis are detected [43].

Although CT represents a reliable technique to study patients with CP, it has some important limits. First of all, CT has low sensitivity to detect minimal pancreatic and ductal changes, thus a negative CT does not rule out an early/mild CP [54]. Moreover, CT causes patient exposure to ionizing radiations, which raises concerns for longitudinal monitoring in particular for younger patients, and finally it has rather low

### **Figure 19.**

*M, 48 yo. Chronic calcific pancreatitis with multiple gross calcifications in the dilatated ductal system (a), invisible at MRCP sequence (b).*

sensitivity (58–77%) to detect small iso-attenuating PDAC because of its non-optimal contrast resolution [55, 56].
