Abstract

Endoscopic ultrasound (EUS) was developed in part to improve the imaging of the pancreas. High quality images of the pancreas can be obtained as it lies close to the gastric and duodenal lumen. EUS is considered safer than endoscopic retrograde pancreatography (ERP) and can detect abnormalities suggestive of chronic pancreatitis (CP) in the pancreatic parenchyma and duct that are not visible on any other imaging modality. The diagnosis of CP via EUS relies on quantitative and qualitative parenchymal and ductal criteria found during examination of the pancreas. It is generally accepted that in the absence of any criteria, CP is unlikely, whereas in the presence of ≥5 criteria (out of 9) CP is likely although ERP and standard tests of pancreatic function may still be normal. The diagnostic significance of patients with fewer (1-4) features found on EUS is currently unclear, particularly when other diagnostic tests such as ERP and function testing are normal.

Introduction

Through early feasibility studies in the use of EUS for the imaging of the pancreas and the diagnosis of CP, several important observations were made ^1-4. EUS had significant technical advantages over transabdominal ultrasound (TUS), due to the lack of overlying bowel gas and higher resolution images obtained with high-frequency transducers. In addition, these high-quality images led to the detection of several new features of CP not previously seen on TUS or CT. These include hyperechoic margins of the pancreatic duct, lobularity of the parenchyma, small cystic changes in the parenchyma, and side branch duct ectasia. With the discovery of new subtle features, questions have been raised of whether EUS may actually be too sensitive.

EUS Features of a Normal Pancreas

In order diagnose CP via EUS, it is necessary to understand the "normal" features of the pancreas. Ikeda et al.⁵ reported the TUS features (using a 3.5 or 5mHz transabdominal probe) of the pancreas in 130,951 "screening" examinations performed in Japan. Although this data cannot be completely translated to EUS findings, several important conclusions can be made from this large population survey. Pancreatic duct diameter, which is measured similarly by TUS and EUS, was dilated (>3 mm) in only 0.49% of individuals and was more common in males and older individuals. In fact, there was a strong trend toward increasing duct diameter with age. Cystic lesions were detected in 0.21% and calcifications in 0.05% of individuals although TUS may underestimate the prevalence of these abnormalities compared with EUS.

Several studies have evaluated the pancreas in "control" populations, such as those undergoing EUS for nonpancreatic indications such as nonpancreatic tumor staging, submucosal tumors, or portal hypertension^6-8. Although important contributions, there may be important pancreatic changes in these populations due to similar risk factors (ethanol) or severe cachexia (nonpancreatic malignancies). Natterman et al.⁸ reported EUS findings in 20 patients without suspected pancreatic disease. They described the pancreatic parenchyma as a "homogeneous fine granular pancreas with smooth margins." The pancreatic duct diameter in the body was 1.9mm on average (range, 1.5-2.4) ⁸. Catalano et al.⁷ reported 25 patients without suspected pancreatic disease. They described the parenchyma as "homogeneous and finely reticulated without evidence of side-branch ectasia." (Figure 1) A ventral anlage (echogenic difference between the ventral and dorsal pancreas) was seen in 68% of controls. (Figure 2) No cysts/pseudocysts or stones were described. The main pancreatic duct was uniformly tubular in shape with anechoic walls and a mean diameter (in the pancreatic body at the portal vein confluence) of 1.7 mm (range, 1-3 mm). Side branches were visible in 32% (8 of 25 patients).

Figure 1		Figure 2

Wiersema et al. ⁹ evaluated the endosonographic criteria of a small group of healthy volunteers with no prior history of abdominal pain or alcohol abuse. The pancreatic parenchyma was "uniform" and more echogenic than liver. A ventral anlage was detected in 45%. No cysts/pseudocysts were seen. The main pancreatic duct diameter was 2.4 mm (range, 0.8-3.6) in the head, 1.8 mm (0.9-3.0) in the body, and 1.2 mm (range, 0.5-2.0) in the tail. Side branches were visible but narrow in normal individuals (mean diameter 0.8 mm, head; 0.5 mm, body; 0.3 mm, tail). These data from control populations and healthy volunteers provide important standards for the normal endosonographic appearance of the pancreas but are limited by their small numbers and potential biases in control populations. Video Clip 1

EUS Features of Chronic Pancreatitis Video Clip 2

Parenchymal Features (Table 1)

The 5 pancreatic parenchymal features of CP include: hyperechogenic foci, hyperechogenic strands, lobulation, cysts/pseudocysts, and calcification.

Hyperechogenic foci are small distinct bright echoes and hyperechogenic strands are bright string-like structures. (Figure 3) These correlate histologically with focal and bridging fibrosis. When these hyperechogenic strands form a rounded homogeneous area, this is called lobulation. (Figure 4) A cyst (Figure 5) is an anechoic round or oval structure representing a fluid filled structure and calcification (Figure 6) is a hyperechoic lesion with acoustic shadowing.

Figure 3	Figure 4	Figure 5	Figure 6

Ductal Features [Table 1]

The 4 ductal features of CP include: dilated duct, irregular duct, hyperechogenic ductal margins, and visible side branch ducts.

The main pancreatic duct is considered to be dilated (Figure 7) if the size is greater than 3mm in the head, 2mm in the body and 1mm in the tail. An irregular duct correlates to focal stricturing and dilation of the main pancreatic duct. When the duct lining is hyperechoic, this is considered hyperechoic duct margins (Figure 3). Visible side branch ducts (Figure 8) are tubular anechoic structures seen outside the main pancreatic duct.

Figure 7	Figure 8

The threshold for diagnosing CP based on EUS can be varied (e.g., ≥3, ≥4, or ≥5 criteria). The "sensitivity" and "specificity" of EUS compared with ERP or histology depends on which threshold is chosen. A low threshold (>1-2 criteria) will produce a high sensitivity and negative predictive value, but a low specificity and positive predictive value. However, a higher threshold (>5-6 criteria) will produce a high specificity and positive predictive value, but a low sensitivity and negative predictive value. This relationship is best shown as a receiver operating characteristic (ROC) curve, which plots the sensitivity and specificity as the diagnostic threshold is changed. This also allows one to "choose" an appropriate threshold based on the question at hand. If the purpose of an EUS exam is to exclude disease, a low threshold will give the best negative predictive value. For example, a patient with only 0-1 criteria of CP by EUS has a >90% chance of having a normal ERP ¹⁰ (and presumably does not have CP). In such a case, further testing is unlikely to identify CP. If the purpose of an EUS is to establish the diagnosis with a high degree of certainty, a high threshold such as ≥6 EUS criteria gives a positive predictive value of >80% of having an abnormal ERP. Those with fewer criteria may require further evidence to establish the diagnosis of CP.

Two other factors must be taken into account when diagnosing CP based on EUS criteria. All criteria may not be equally important. For example, the presence of intraductal calcifications alone is highly suggestive of CP even in the absence of other criteria. In addition, there are age-related changes in the pancreas that may affect the diagnostic threshold. The pancreatic duct becomes progressively wider as individuals age. A 4-mm main pancreatic duct may be normal for a 70-year-old, but abnormal for a 30-year-old. Currently, there is no accepted scoring system that factors in these effects. One common practice is to require a higher threshold (e.g., ≥5 criteria for older individuals) and a lower threshold (e.g. ≥4 criteria for a younger individual).

Discrimination of CP from Pancreatic Cancer

A major challenge of EUS is the differentiation of cancer from an inflammatory mass in CP. Most commonly, an obstructive mass in the head of the pancreas is responsible for the typical changes of CP in the body-tail region of the gland, such as an irregularly dilated main pancreatic duct, lobulations, dilated branch ducts and a variable degree of pancreatic atrophy.

EUS-FNA typically is employed to ascertain the presence of malignancy in pancreatic masses. A retrospective experience of EUS-FNA of focal pancreatic lesions in patients with normal parenchyma and CP by Fritscher-Ravens et al. ¹¹ found the overall sensitivity for EUS-FNA in patients with normal parenchyma to be 89%. However, in patients with CP the sensitivity was only 54%. The authors concluded that the sensitivity of EUS-FNA in patients with CP was unacceptably low and resection of the tumor by standard surgical techniques was still required to confirm the correct diagnosis. In contrast, the specificity was 100% and EUS contributed to change in patients’ management in 44% of the total group. This study demonstrates the limitations of the EUS in discriminating CP from tumors, as pancreatic carcinoma and focal pancreatitis can have a similar appearance at EUS. Similarly, the cytopathologist faces equivalent challenges trying to discriminate inflammatory from neoplastic cells. In the future, translational research with application of specific molecular (or tumor) markers to FNA specimens could provide a significant aid in discriminating CP from tumors.

Conclusions

EUS has emerged as an important tool in the diagnosis of CP. EUS detects changes of mild CP that may not be detectable with other imaging modalities or functional testing but can be confirmed by histology. There is still a need to improve the definitions and terminology used for the EUS diagnosis of CP and to find better methods for distinguishing focal CP from malignancy. There is still controversy regarding the diagnosis of "early" CP based on EUS changes alone. Future studies will need to evaluate the ability of EUS to predict the causes of CP and the response to specific methods of therapy.

Table 1

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