Diagnosis of Pancreatic Disorders Using Contrast-Enhanced Endoscopic Ultrasonography and Endoscopic Elastography

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:S63 S67 Diagnosis of Pancreatic Disorders Using Contrast-Enhanced Endoscopic Ultrasonography and Endoscopic Elastography YOSHIKI HIROOKA,* AKIHIRO ITOH, HIROKI KAWASHIMA, EIZABURO OHNO, TAKUYA ISHIKAWA, HIROSHI MATSUBARA, YUYA ITOH, MASANAO NAKAMURA, RYOJI MIYAHARA,* NAOKI OHMIYA, YASUMASA NIWA, MASATOSHI ISHIGAMI, YOSHIAKI KATANO, and HIDEMI GOTO*, *Department of Endoscopy, Nagoya University Hospital, and Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya City, Japan Contrast-enhanced endoscopic ultrasonography (CE-EUS) and EUS-elastography are cutting-edge diagnostic modalities for pancreatic disorders. Each pancreatic disorder has characteristic hemodynamics. CE-EUS uses color Doppler flow imaging to classify pancreatic lesions into a spectrum of solid and cystic patterns. Although there is overlap in the patterns generated by specific types of tumors, some types of tumors tend to produce distinct flow images. EUS-elastography can assess tissue hardness by measuring its elasticity. This parameter appears to correlate with the malignant potential of the lesions. Tissue elasticity studies can provide information on both its pattern and distribution. The former is the conventional method of morphologic diagnosis, but it is restricted to observations made in a region of interest. The latter is an unbiased analysis that can be performed by image analysis software and is theoretically constant, regardless of regions of interest. The evolving modalities of CE-EUS and EUS-elastography might provide clinical utility in the diagnosis of pancreatic disorders. Endoscopic ultrasonography (EUS) is thought to be one of the most reliable and efficient modalities for diagnosing pancreatic disorders. Additions to EUS imaging have enhanced its diagnostic potential. For example, EUS that provides hemodynamics data might be more useful than EUS with only B-mode imaging ability. Many techniques have been introduced for pancreatic imaging that can complement the information obtained from standard EUS. For example, computed tomography (CT) and magnetic resonance imaging (MRI), often combining contrast and non-contrast imaging of the pancreas and the biliary tract, can provide important supplemental information. One of the newest modalities used to provide information about tissue structure is tissue elastography. Tissue elasticity imaging using ultrasonography has been clinically applied in the diagnosis of superficial organ disorders involving tissues such as the thyroid and breast. 1 3 Instrumentation is now available that combines EUS with real-time tissue elastography (Hitachi Co, Ltd., Tokyo, Japan); it can provide information of tissue elasticity on deep organ structures, including the pancreas. Here we will review our knowledge and preliminary experience with the use of contrast-enhanced EUS (CE-EUS) and EUS-elastography for the diagnosis of pancreatic disease. Contrast-Enhanced Endoscopic Ultrasonography Because of recent advances in ultrasonographic equipment and the clinical application of intravenous contrast agents in ultrasonography, CE-EUS is being gradually established as a new diagnostic imaging modality in the diagnosis of pancreatic disorders. 4 7 Our experience assessing the use of CE-EUS with color Doppler flow imaging (CDFI) will be summarized in this section. Patients and Methods Among patients who underwent CE-EUS in our hospital between February 2001 and November 2004, there were 145 patients with pancreatic disorders (92 men, 53 women), with a mean age of 64.0 years (range, years). Details of these subjects are shown in Table 1. A definitive diagnosis was made during surgery or by EUS fine-needle aspiration, and patients were followed clinically to ensure the diagnosis of a benign lesion. When imaging suggested the diagnosis of an operable malignancy, surgery was performed. For inoperable cases, we performed EUS fine-needle aspiration and histopathologic investigation to make a definitive diagnosis. In lesions that were considered benign, we performed EUS every 6 months to document absence of malignancy. The mean observation time in our series was 31.3 months (range, months). To perform CE-EUS and study tissue hemodynamics, we first imaged the pancreas with B-mode EUS and then administered Levovist (Nihon Schering Co, Ltd, Tokyo, Japan; 2.5 g) at 300 mg/ml through a peripheral vein at a rate of 1 ml/s (total dose, 8 ml). Levovist consists of galactose microbubbles (air microbubbles) containing a low concentration (0.1%) of palmitic acid, which, after injection into peripheral vein, leads to transiently enhanced ultrasound echoes that allow analysis of blood flow and vascular structures Abbreviations used in this paper: CDFI, color Doppler flow imaging; CE-EUS, contrast-enhanced endoscopic ultrasonography; CT, computed tomography; EUS, endoscopic ultrasonography; IPMN, intraductal papillary mucinous neoplasm; MRI, magnetic resonance imaging; ROI, region of interest by the AGA Institute /09/$36.00 doi: /j.cgh

2 S64 HIROOKA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 11S Table 1. One Hundred Forty-five Cases of CE-EUS Pancreatic disorder No. of cases Invasive ductal carcinoma 36 (5, por; 2, pap) Acinar cell adenocarcinoma 5 IPMN 47 Chronic pancreatitis 25 Endocrine tumor 13 Serous cystadenoma 7 Solid pseudopapillary tumor 5 Simple cyst 7 por, poorly differentiated tubular adenocarcinoma; pap, papillary adenocarcinoma. The instruments used at our institution were the EG- 3630UR/EG-3670URK electronic radial type ultrasonographic endoscope (PENTAX Co, Ltd, Tokyo, Japan) and the EUB- 8500/HV-900 ultrasound (Hitachi Co, Ltd). We used the following instrument conditions: frequency, 7.5 MHz, and color Doppler mode with minimum detectable velocity range, 4.5 cm/s. We retrospectively investigated the color-enhanced patterns of the pancreatic disorders listed in Table 1. Figure 2. Invasive ductal carcinoma. Invasive ductal carcinoma of about 20 mm in diameter was seen in the pancreatic head. The tumor was demonstrated as a clearly delineated hypoechoic mass, with the spotted hyperechoic area in the center of the tumor. Plain CDFI (left panel) showed vessels near the duodenal lumen; CE-EUS depicted the hypoechoic tumor as hypovascular mass (right panel). Appearance is that of a solid mass pattern-3. Results The color-enhanced pancreatic images were classified into 3 patterns of solid masses and 5 patterns of cystic masses as shown in Figure 1. The 3 patterns of solid masses were defined as follows: (1) filled with color signals throughout the tumor; (2) color signals seen to the same degree as the normal parenchyma; and (3) scarcity of color signals or only color signals associated with involved vessels. The 5 patterns of cystic masses were defined as follows: (1) color signals in both papillary growths and septa; (2) color signals only in septa; (3) color signals filling microcystic regions; (4) color signals seen mainly in the surrounding wall or periphery of the mass; and (5) no color signals. As shown in Figure 1, there was a correlation between the color-enhanced pattern and the pancreatic pathology. All endocrine tumors were classified as solid mass pattern-1, and 81% of invasive ductal carcinomas were classified as solid mass pattern-3. Seven cases of invasive ductal carcinoma, 5 cases of acinar cell carcinoma, and 23 cases of chronic pancreatitis were classified as solid mass pattern-2. The diagnosis of invasive ductal carcinoma can be made when the mass shows solid mass pattern-3 (Figure 2). On the other hand, if the mass shows solid mass pattern-1 or -2, the differential diagnosis is broader. Conventional B-mode images might be helpful in making the final diagnosis when used in combination with CE-EUS. For the cystic masses, all cases of serous cystadenoma and solid pseudopapillary tumors were classified into cystic mass pattern-3 and -4, respectively. CE-EUS images of intraductal papillary mucinous neoplasm (IPMN) conformed to cystic mass pattern-1, -2, and -5. Malignant IPMN (intraductal papillary mucinous carcinoma) was seen only in cystic mass pattern-1. The pattern of CE-EUS might reflect the malignant potential of Figure 1. Schematic representations of each CE-EUS pattern and the pancreatic disorders that demonstrated features of each pattern. The important features of solid mass patterns are (1) filled with color signals throughout tumor; (2) color signals seen are similar to normal parenchyma; and (3) scarcity of color signals or only color signals. For cystic mass patterns, the important features are (1) color signals seen in both papillary growth and septa; (2) color signals seen only in septa; (3) filled with color signals in the microcystic area; (4) color signals seen mainly in the surrounding wall or periphery of the mass; and (5) no color signals.

3 November 2009 CE-EUS AND EUS-ELASTOGRAPHY S65 IPMNs; recently we reported that the combination of B-mode images and CE-EUS images was clinically useful for differentiating between benign IPMNs and malignant IPMNs. 7 Representative Cases Figure 2 shows an invasive ductal carcinoma of about 20 mm in diameter in the pancreatic head. The tumor was clearly delineated as a hypoechoic mass with a spotted hyperechoic region in the center of the tumor. Plain CDFI showed vessels near the duodenal lumen, and CE-EUS depicted the hypoechoic tumor as hypovascular mass (solid mass pattern-3). An endocrine tumor of about 10 mm in diameter in the pancreatic body is shown in Supplementary Figure 1. The tumor was hypoechoic, with tumor vessels visible by using plain CDFI imaging. The tumor was filled with color signals on the CE-EUS image and showed a solid mass pattern-1. An intraductal papillary mucinous carcinoma (which was minimally invasive) in the pancreatic body with internal papillary structures is demonstrated in Supplementary Figure 2. The papillary growth-like structure is the most important initial characteristic for differentiating between malignant and benign lesions. CE-EUS revealed numerous color signals in the papillary-like structure consistent with cystic mass pattern-1; this led to the diagnosis of a malignant IPMN. In Supplementary Figure 3, a serous cystadenoma involving the pancreatic head is shown. There were a few color signals in the tumor on the plain EUS image, whereas on the CE-EUS image, the tumor was filled with color signals (cystic mass pattern-3). Endoscopic Ultrasonography Elastography In addition to B-mode observation, the diagnosis of pancreatic disorders can be also aided by evaluating tissue hemodynamics. Elastography has the potential to provide new information that differs from B-mode image or hemodynamic information, but without the need for contrast medium. Generally, tissue hardness is thought to correlate with malignant potential; malignant tumors are harder than those that are benign. 11 On the basis of this concept, several techniques to evaluate the tissue hardness, also called tissue elastic imaging, have been developed Tissue elastic imaging with MRI or CT has been introduced for clinical use, but in this review we will focus on tissue elastic imaging with an ultrasonographic approach that is named real-time tissue elastography (Hitachi Co, Ltd) and combined with EUS. 15,16 Instrumentation CE-EUS and EUS-elastography use the same instrumentation. In this system, the tissue is imaged by using electronic radial EUS ( MHz); B-mode and elastography mode images are simultaneously acquired and visualized on a dual screen. Elasticity in the region of interest (ROI) is expressed by transparent color (hard, blue; soft, red) superimposed on conventional gray-scale B-mode images. Principles of Real-time Tissue Elastography The principles of elastography can be explained by using a spring model (Figure 3). Thus, when a one-dimensionally connected hard spring and soft spring are compressed, the hard spring is negligibly deformed, but the soft spring is compressed. This difference in deformation results in differences in Figure 3. Principles of real-time tissue elastography. When a model in which hard springs and soft springs are one-dimensionally connected is compressed, the hard springs are negligibly deformed, but the soft springs are markedly deformed. The same type of information is provided when a sound wave passes through tissues that vary in hardness. This difference in deformation results in differences in displacement among areas, and the amount of distortion obtained by spatial differentiation of this displacement distribution provides elasticity information. displacement among areas, and the amount of distortion obtained by spatial differentiation of this displacement distribution provides elasticity information (Figure 3). Supplementary Figure 4 shows elastography with a model in which a high elastic gel is buried in low elastic gel. In B-mode image we cannot visualize the target, because they have the same echo intensity (or the same acoustic impedance). However, in elastography-mode image, the differences in elasticity are distinct. Interpretation of Real-time Tissue Elastography One should appreciate that real-time tissue elastography provides information about distributed pattern of tissue hardness as well as hardness at a specific point. The information regarding hardness of a specific point is classified further into 2 categories: (1) pattern recognition and (2) quantitative assessment (strain ratio). Hardness of the Specific Point Pattern recognition is the conventional method for making a morphologic diagnosis in gastroenterology. Figure 4 shows the typical pattern of invasive ductal carcinoma. EUSelastography shows a markedly hard region at the site of the low-echo tumor area and distribution of slightly soft spots in its interior. Histopathologic examination confirmed that the hard area contained a large amount of fibrous tissue, and the internal soft spots were aggregates of variously sized atypical ducts. Strain ratio was developed to add quantitative diagnostic information to pattern recognition. Strain ratio is expressed as the ratio of lesion hardness to connective tissue or fatty tissue hardness. Strain ratio is based on the assumption that the hardness of connective tissue or fatty tissue does not vary between individuals. Supplementary Figure 5 shows the same image as in Figure 4, but in this case the strain ratio has been calculated and is 6.26.

4 S66 HIROOKA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 11S Figure 4. Invasive ductal carcinoma. EUS-elastography (left side) shows a markedly hard area at the site of the low-echo tumor area (right side) and distribution of slightly soft spots in its interior. Histopathologic examination confirmed that the hard area contained a large amount of fibrous tissue, and the internal soft spots were aggregations of atypical (various sizes of) ducts. What we must keep in mind is that represented colors in this system are relative in each ROI. In this context, the relationship between the color patterns and that of surrounding tissue sometimes provides the most meaningful data. Distributed Pattern of Tissue Hardness EUS-elastography provides additional important information relating to hardness, that is, its distributed pattern. Regardless of ROIs, the distributed pattern is theoretically a constant. The distributed pattern of hardness in a case of chronic pancreatitis is analyzed in Supplementary Figure 6. The prototype image analysis software used here extracts various features from real-time tissue elastography images. It converts the red-green-blue value inside the ROI of the elastography image into relative strain value and calculates other features of elastography image, such as the mean of relative strain value, the standard deviation of relative strain value, and the proportion of blue (low strain) region in analysis region, and determines the complexity of blue (low strain) region in analysis region ((Perimeter of blue region) 2 /(Area of blue region)). With this software (produced in cooperation with Hitachi Co, Ltd), we can demonstrate the uniformity, or lack thereof, of a target lesion and quantify a number of objective parameters of the distribution of hardness described above. Summary of Our Experience We have reported the pattern of pancreatic disorders by using transabdominal US. 17 For elastography, our experience for pancreatic disorders is summarized as follows. (1) Invasive ductal carcinoma showed a markedly hard area at the site of the hypoechoic tumor area and distribution of slightly soft spots in its interior. Histopathologic examination confirmed that the hard area contained a large amount of fibrous tissue, and the internal soft spots were aggregations of atypical ducts. (2) Chronic pancreatitis was characterized by pancreatic parenchyma with a mixture of various colors, indicating various degrees of hardness. (3) Pancreatic endocrine tumors were visualized as lesions with uniform hardness comparable to or slightly higher than that of the pancreatic parenchyma. Histopathologic examination showed a high cell density in the tumor and slight fibrosis. From our experience, findings obtained from transabdominal US might apply to those of EUS-elastography. Findings of invasive ductal carcinoma (Figures 2 and 4) and chronic pancreatitis (Supplementary Figure 6) agree with the typical pattern of US elastography stated above. Supplementary Figure 7 shows a case of endocrine tumor. A hypoechoic 10 mm tumor in diameter is depicted at the pancreatic body. In this subject, the EUS-elastography revealed a uniform hardness comparable to that of surrounding parenchyma. Discussion In this review, we have described the potential of CE- EUS and EUS-elastography to be used as cutting-edge diagnostic modalities and summarized our experience. The performance of EUS depends on both the efficiency of an endoscope and ultrasonographic technologies. In 2003 we first developed the endosonoscope with electronic radial scanning in cooperation with PENTAX (PENTAX Co, Ltd, Tokyo, Japan) to combine the ultrasound techniques that were being used for transabdominal US An electronic scanning method made it possible for us to perform CE-EUS and EUS-elastography. Tissue characterization by EUS was made by only B-mode image before the advent of CE-EUS or EUS-elastography. CE- EUS can now provide hemodynamic analysis of pancreatic disorders at the same level as CT or MRI. In this article, we reviewed enhanced CDFI, but recently, with the arrival of socalled second generation contrast media, the enhancement of B-mode images has become possible. 6 Our preliminary experience with the latter approach suggests that it might provide greater detail than CDFI for hemodynamics studies, but clinical usefulness of this method is still under investigation. EUS-elastography has introduced a new form of pathologic analysis, that is, tissue elasticity. Tissue elasticity as detected by this system can be divided into 2 major categories. One is pattern recognition, which has been the conventional method of morphologic diagnosis. Importantly, the image of EUSelastography indicates the relative value in a ROI, so the same lesion might display different colors in a different ROI. This is a limitation of EUS-elastography. The other is the distribution of tissue elasticity. With the prototype image analysis software, we can now capture and analyze features of real-time tissue elastography by using computer software. Theoretically, this will limit interpretation bias and provide a measure of pattern distribution that is constant and independent, regardless of ROIs. CE-EUS and EUS-elastography have the potential to provide clinical utility for the diagnosis of pancreatic disorders, but more studies and greater experience are needed before their place in our diagnostic armamentarium can be fully understood. Supplementary Data Note: to access the supplementary materials accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at

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