Gastrointestinal Cancer Imaging: Deeper Than the Eye Can See

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Gastrointestinal Cancer Imaging: Deeper Than the Eye Can See RICHARD S. KWON,* DUSHYANT V. SAHANI,‡ and WILLIAM R. BRUGGE* *Gastrointestinal Unit and ‡Division of Abdominal Imaging and Intervention, Massachusetts General Hospital, Boston, Massachusetts

he management of patients with a gastrointestinal (GI) malignancy requires a precise diagnosis and accurate staging information. Traditionally, a diagnosis of GI malignancy is made through a tissue biopsy guided by conventional light endoscopy or radiological imaging. Although a histological diagnosis of malignancy remains the gold standard, increasingly sophisticated endoscopic and radiological imaging may enable physicians to diagnose malignancy less invasively. The staging of GI malignancies is traditionally performed with cross-sectional imaging and is more recently performed with endoscopic ultrasonography (EUS). Recent refinements in imaging have improved our ability to accurately determine the depth and locoregional invasion of early malignancy arising from hollow and solid organs of the GI tract. In this review, we will examine recent advancements in endoscopic and radiological imaging techniques and discuss how they have influenced patient management. The review will discuss the current standards for imaging malignancies of the esophagus, stomach, pancreas, small intestine, liver, and colon. Emerging imaging technology for each major GI malignancy will also be discussed.

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Advances in Radiological Imaging Recent improvements in computerized tomography (CT) and magnetic resonance (MR) technology have dramatically improved the quality of imaging of many GI malignancies (Table 1). The current standard for CT imaging of the abdomen is the multidetector row CT (MDCT), which provides a large volume of high-resolution images during a rapid scan time.1 The derived 2-dimensional images can be rendered by sophisticated software to produce planar imaging and 3-dimensional projections of the GI tract. Three-dimensional CT imaging along the axis of a hollow organ provides a unique and striking radiological perspective of hollow and solid organs, as well as associated vascular structures of the mesentery and portal system.2 Three-dimensional colonography or virtual colonoscopy (VC) is the most notable example of this new imaging modality. This technology is now being applied to the detection and staging of GI malignancies.

Positron emission tomography (PET) is a functional imaging modality with a potential for broad indications in the management of GI malignancies.3 Radiotracers are used as markers of metabolism, such as regional blood flow. One example is 18F-fluoro-deoxy-D-glucose, a radionuclide indicator of glycolysis. Because GI malignancies often show increased levels of glycolysis, known as the Warburg effect, increased focal uptake of 18F-fluorodeoxy-D-glucose can be shown with positron tomography scanning. PET scanning has been used to identify primary epithelial GI tumors, metastases, and neuroendocrine tumors of the GI tract. Although PET imaging has proven useful in the detection of distant metastases, it has not yet been accepted as a routine staging tool in GI malignancies.4 One of the major limitations of PET scanning, the lack of anatomic correlation, has recently been overcome by fusion of PET scans with cross-sectional imaging, such as CT and MR.5 The advantages of synchronous imaging include near-simultaneous data collection, a shorter duration for the PET-specific imaging, and the obvious anatomic/functional correlation. The technique has not yet been optimized and critically evaluated in patients with GI malignancies. It will likely help to localize malignancies, direct biopsies, and monitor responses to therapy in the future.6

Advances in Endoscopic Imaging Techniques There has been great progress in endoscopic technology designed to identify abnormal or dysplastic tissue (Table 2). These techniques have predominantly focused Abbreviations used in this paper: ALA, 5-aminolevulinic acid; CT, computerized tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; GI, gastrointestinal; HCC, hepatocellular carcinoma; IDUS, intraductal ultrasonography; IPCL, intrapapillary capillary loops; MDCT, multidetector row computerized tomography; MR, magnetic resonance; MRCP, magnetic resonance cholangiopancreatography; NBI, narrow band imaging; OCT, optical coherence tomography; PET, positron emission tomography; VC, virtual colonoscopy. © 2005 by the American Gastroenterological Association 0016-5085/05/$30.00 doi:10.1053/j.gastro.2005.03.034

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Table 1. Radiological and Endoscopic Imaging Used to Stage Gastrointestinal Malignancies Imaging modality

Device used

Agent used

Detection of malignant tissue

Dedicated echoendoscope; Water is used as a The vast majority of malignancies are high-frequency coupling agent; relatively less ultrasound probes can Levovista or echoic (hypoechoic) Definityb are be used through the intravenous compared with instrument channel; fineultrasound normal tissue needle aspiration device contrast agents can be used with linear rarely used in EUS EUS Optical coherence Laser infrared light source, None Changes in tomography (OCT) semiconductor optical architecture of amplifier, catheter probe tissue (eg, loss of goblet cells) are used as a sign of malignancy Computerized An x-ray beam is emitted in Intravenous and With ionized tomography (CT) a fan shape as the oral iodineradiation, the vast rotating frame spins the based contrast majority of x-ray tube and detector agents malignant tissues around the patient; have a different multidetector CT with attenuation, computer-generated accentuated by the images use of intravenous contrast Magnetic resonance Large cylindrical magnets Gadolinium-DTPA Tissues have imaging (MRI) produce a strong (oral and characteristic magnetic field that intravenous); signals, and aligns the protons of gadodiamide malignant tissue hydrogen atoms in (intravenous) has increased or tissue; receiver detects decreased signal signals from tissue intensity 18F-2-fluoro-deoxyPositron emission Circular gamma ray Increased uptake of tomography (PET) detector array with the D-glucose labeled glucose positron-emitting tissue produced on site and emission of in the center of the by a particlepositrons from detector accelerator malignant tissue device Endoscopic ultrasonography (EUS)

Availability Widely available

Clinical applications Frequently used to stage esophageal, gastric, pancreatic, and rectal cancer

Not commercially Staging of superficial available; malignancies prototypes used in research centers Helical CT is Broad applications in widely available; staging of advanced MDCT will GI malignancies become widely distributed

Widely available

Broad applications in staging of advanced GI malignancies

Available in major centers

Used in the detection of distant metastases and recurrence of esophageal and colon cancer

DTPA, diethylenetriaminepentaacetic acid. Palmitate, Berlex Canada/Schering AG, Germany. bPerflutren lipid microspheres, Dupont Pharmaceuticals, Billerica, MA. aGalactose

on improving the ability of traditional endoscopy to detect dysplastic tissue. To provide imaging tools for staging, techniques have been developed that increase the resolution and depth of imaging of malignancies (Figure 1). Chromoendoscopy, an adjunctive endoscopic technique, uses specialized epithelial dyes to differentiate between normal and dysplastic mucosal tissue that may not be easily discernible with visible light endoscopy. Chromoendoscopy serves to improve detection and mapping of early mucosal malignancies, thus aiding the endoscopist in resection techniques.7 The dyes that are commonly used are either absorptive (methylene blue and Lugol’s) or contrast agents (indigo carmine). When sprayed onto the mucosa at the time of endoscopy, the surface staining highlights subtle mucosal changes (ei-

ther by contrast or staining) associated with dysplasia, many of which are still being catalogued. This technique is often used with magnification endoscopy, which provides enhanced and higher-resolution images, to maximize the characterization of abnormal mucosa. For example, chromoendoscopy and magnification endoscopy may improve the detection of Barrett’s esophagus and high-grade dysplasia.8 The use of these 2 techniques is more prevalent in Japan and is not in widespread use in United States because of a lack of perceived necessity, a lack of reimbursement, and the time required to perform the procedure.9 Methylene blue, the most common agent for chromoendoscopy, is a vital dye that is actively absorbed by the epithelial cells of the small intestine and colon. It is not absorbed by nonabsorptive epithelium such as the

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Table 2. Summary of Endoscopic Image-Enhancement Techniques Used for Detection of Gastrointestinal Malignancy Endoscopic technique

Agent or device used

High-resolution endoscopy

High-resolution endoscope with high pixel density (eg, 850,000)

Magnification endoscopy

Magnification endoscope with manual (lens change) or electronic control

Mechanism

Combined high-resolution See above and magnification endoscopy Chromoendoscopy Topical agents often used in conjunction with magnification endoscopy Lugol’s solution Contrast dye, staining glycogen in squamous epithelium Methylene blue Absorptive dye, staining absorptive epithelium (small intestine and colon), including Barrett’s Indigo carmine Acetic acid Narrow band imaging Fluorescence endoscopy

Confocal microscopy

Electronic light source with narrow-band filters Image-processing module that provides real-time fluorescence images; 5aminolevulinic acid (topical or systemic); hexaminolevulinate Dedicated combined endoscope and microscope image-processing unit; acriflavine hydrochloride or fluorescein sodium

gastric cardia and the normal esophageal squamous mucosa. Methylene blue, therefore, will stain the columnar epithelium of Barrett’s esophagus and leave areas of malignant tissue unstained (Figure 2). Methylene blue often requires pretreatment mucolysis with 10% acetylcysteine and vigorous washing of the mucosa. Staining is evident within 2–3 minutes and fades after 15–20 minutes. Other dyes used in endoscopic detection of GI malignancy include indigo carmine (demarcation of gastric cancer) and Lugol’s (depiction of squamous epithelium).10 Newly developed advanced endoscopic tissue imaging without the use of dyes may enable the endoscopist to detect early malignancy during real-time endoscopy. Fluorescent and light scatter spectroscopy have been recently supplemented by advanced imaging techniques that can provide the endoscopist with high-resolution images of epithelial structures. Narrow band imaging (NBI) is the most promising of these techniques. NBI merges images generated from the rotation of 3 separate wavelengths of light that have different degrees of tissue penetration. The end result is enhanced contrast between superficial vasculature and adjacent mucosa, thus im-

Clinical application

Increased resolution by the coupled Endoscopic identification of chip device on the endoscope surface details such as crypts, glands, and pit pattern Magnification of the endoscopic Endoscopic identification of image surface details enhanced with dyes See above See above

Detection of early squamous cell carcinoma of the esophagus Detection of Barrett’s esophagus and early malignancy arising from Barrett’s (lack of staining) Detection and mapping of gastroduodenal malignancies Detection of Barrett’s epithelium

Contrast dye, outlining mucosal surface Reversible intracellular protein denaturation Enhancement of surface capillary Detection and mapping of early patterns, pits, and villi gastric and esophageal cancer Sensitizers accumulate selectively Detection of early gastric and in malignant lesions and induce colonic adenomas and fluorescence upon illumination malignancies with light of the appropriate wavelength Fluorescent agents are absorbed by Broad applications in detection tissue and provide cellular and of mucosal neoplasia histological details

proving the visualization of superficial capillaries—in particular, intrapapillary capillary loops (IPCLs).11 Fluorescence endoscopy makes use of fluorescence that is emitted by intracellular or exogenous fluorophores. Tissue fluorescence is achieved during exposure to UV light, resulting in electron excitation and relaxation. There are many intracellular autofluorophores within the human body, including collagen. One example of an exogenous fluorophore is 5-aminolevulinic acid (ALA), a rate-limiting precursor in the heme synthesis pathway. ALA is converted into protoporphyrin IX, which emits a characteristic fluorescence. Protoporphyrin IX accumulates in malignant tissue for reasons not well understood. The technique has several limitations, including a restricted imaging area, technical challenges associated with directed tissue sampling, and a lack of contextual information to distinguish between dysplastic and normal tissue. However, fluorescent endoscopy is an excellent example of advanced endoscopic imaging with great potential for detecting early malignancy.12 Other endoscopic techniques designed to better identify dysplastic tissue include light-scattering spectroscopy and Raman spectroscopy. Light-scattering spectros-

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Optical coherence tomography (OCT) is a promising new technique, analogous to B-scan ultrasonography, that uses low-coherence infrared light. The technique analyzes the back-reflection from the mucosal structures to produce a high-resolution image based on low-coherence interferometry.15–17 Infrared light is split between the tissue and a movable reference mirror. Reflected light from both is recombined in the beam-splitter and analyzed by a detector. An interference signal is produced only when the light from both the tissue and the mirror travels the same distance. The intensity of the signal is dependent on the tissue microstructure. Current probes are 2–2.4 mm in diameter and are designed to capture end-on, linear, or radial images. The image resolution is 5–10 times greater than high-frequency ultrasound, and villi, glands, crypts, and blood vessels have been identified. OCT has been used to diagnose Barrett’s esophagus,18 biliary malignancy,19 and Crohn’s disease20 (Figure 3). Confocal laser endoscopy is an exciting application of a technique used by basic scientists to examine in vivo tissue. Confocal microscopy uses pinholes with a confocally placed light source and detector to produce highresolution 2-dimensional images by point-by-point laser scanning in a raster pattern. By varying the axial position of the focal plane through the tissue, multiple optical slices are obtained and can be combined by using specialized software to produce 3-dimensional images. The advantage of this imaging modality is the elimination of out-of-focus light scattering from other focal planes. With this technique, basic scientists have used fluores-

Figure 1. The depths of resolution of confocal microscopy (CM), optical coherence tomography (OCT), and endoscopic ultrasonography (EUS) are progressively greater, but with a loss of resolution.

copy uses scattered light reflectance to provide structural information. Back-scattering signals over a wavelength spectrum can be analyzed to measure the size and density of signal scatterers or absorbers. Light-scattering spectroscopy imaging is a measure of nuclear crowding and enlargement associated with malignancy.13 Raman spectroscopy takes advantage of unique vibrational/rotational modes of molecular bonds of intracellular compounds. When near-infrared photons are scattered in tissue, a small number of these photons are inelastically scattered to produce characteristic Raman emission spectral patterns that distinguish normal from dysplastic tissue.14 The technology is limited by weak signals and remains experimental.

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Figure 2. Methylene blue–stained Barrett’s epithelium with a focal, superficial malignancy unstained by methylene blue (arrow)

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have added Doppler capabilities and the ability to direct fine-needle aspiration. The diagnosis of malignancy with fine-needle aspiration cytology has significantly improved the specificity of EUS imaging, particularly in the diagnosis of pancreatic malignancy and adenopathy associated with malignancy.25

Clinical Applications Esophageal Cancer The diagnosis of squamous cell carcinomas and adenocarcinomas of the esophagus is traditionally made by upper endoscopy and biopsy.26 In the setting of Barrett’s esophagus, 4 quadrant biopsies every 2 cm is the accepted standard for screening patients with Barrett’s associated dysplasia.27 Once a diagnosis of esophageal malignancy is made, EUS can establish tumor and nodal staging, with accuracy rates of 70%– 80%.28,29 The reported sensitivity of chest and abdominal CT scans ranges roughly from 44% to 90%.30 Figure 3. Optical coherence tomography radial image of Barrett’s epithelium with early esophageal cancer (arrow; image provided courtesy of Pieralberto Testoni, MD, Milan, Italy).

cent stains to produce highly complex 3-dimensional structural images that depict protein trafficking in cell culture lines.21 This technology has recently been adapted to endoscopy with the use of optic fibers as the pinholes. In vivo, endoscopic imaging of the colon with confocal laser microscopy has produced stunning 3-dimensional images of the mucosa, the subsurface, and cellular abnormalities seen in colonic dysplasia.22 The capabilities of traditional endoscopic imaging have steadily improved through the use of smaller-diameter and wireless imaging devices. Direct endoscopic visualization of the biliary tree and pancreatic duct is now possible through the use of small-diameter endoscopic video probes that are placed during endoscopic retrograde cholangiopancreatography (ERCP).23 Even greater reduction in the size of endoscopic probes has yielded single-fiber endoscopy with the possibility of increasing imaging resolution.24 The ability to transmit endoscopic images from a small remote device has produced capsule endoscopy, which offers a significant advance in small-intestinal imaging. EUS has established itself as the primary endoscopic tool for the staging of GI malignancies. Using highfrequency ultrasound probes located in the tip of endoscopes, EUS can provide highly accurate staging of mucosal malignancies and solid organ tumors. Radial endosonoscopes provide cross-sectional imaging of lesions arising from the GI tract wall, and linear devices

Advances and future trends in imaging of esophageal malignancy. Advances in endoscopic imaging

have significantly improved our ability to detect early squamous cell carcinoma and adenocarcinoma of the esophagus. NBI has been used with magnifying endoscopy to better characterize superficial squamous cell carcinoma.31 As mentioned previously, the main advantage of this technique is the improved visualization of the IPCL, a key feature for the diagnosis and staging of early squamous cell esophageal cancer.11 In malignant lesions, the IPCL undergoes changes such as dilation, weaving, and changes in caliber and shape.31 Lugol’s solution has been the dye of choice in patients with suspected squamous cell carcinoma in high-risk populations, such as regional areas ranging from Brazil32 and China33 to Japan,34 and in patients with achalasia.33,35,36 Kumagai et al36 recently reported using magnifying chromoendoscopy with a endocytoscopy system consisting of a 3.2mm-diameter endoscope that passes through a regular gastroscope to produce in vivo histological images (with magnification as high as 1125⫻) in patients with superficial squamous cell carcinomas. When compared with normal squamous epithelia, the cancerous epithelium was marked by a much higher cellular density and a marked heterogeneity of cell and nuclear morphology. A recent preliminary report described the use of MDCT and virtual endoscopy to identify esophageal malignancies in a manner similar to virtual colonography,37 but this technique remains investigational. Diagnosis of Barrett’s esophagus and dysplasia. A variety of chromoendoscopic techniques have

been used to diagnose specialized intestinal metaplasia or

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Barrett’s esophagus. Methylene blue sprayed on the esophageal mucosa is the most popular agent. Chromoendoscopy with methylene blue has been reported to improve the detection of dysplasia arising in long-segment Barrett’s esophagus.38 Use of this spray dye may assist the endoscopist in directing biopsies in the screening and diagnosing of Barrett’s esophagus8 (Figure 2). However, other studies have shown high rates of interobserver variation and a lack of enhanced detection.39 The use of high-resolution or magnification endoscopy in conjunction with chromoendoscopy may enhance the imaging of pit patterns, a key feature of Barrett’s esophagus.40,41 Similar results have been published by using several other mucosal dyes, including indigo carmine,8,42 Lugol’s solution,43 acetic acid,44 and even a combination of methylene blue and crystal violet.8 Mucosal surface pit classification has been an important research tool but may not be clinically useful.45 There are many experimental methods for the detection of dysplasia arising from Barrett’s esophagus. OCT has shown promise as a screening method for Barrett’s esophagus46 (Figure 4). However, limited clinical data are available for the use of OCT to detect dysplasia. Changes ascribed to dysplasia and carcinoma include irregular glandularity and altered light reflection by OCT.47 Fluorescent endoscopic imaging by using ALAinduced fluorescent and autofluorescent spectroscopy has been used to detect dysplasia, but these techniques remain experimental.48,49 Staging of esophageal cancer. Staging of esophageal cancer is performed with a combination of highresolution imaging of the primary lesion and radiological imaging for nodal and metastatic staging. EUS is the method of choice for the diagnosis and staging of mucosal and mural malignancies of the esophagus. Many

Figure 4. Optical coherence tomography linear image of Barrett’s epithelium with high-grade dysplasia. Note the absence of goblet cells (image provided courtesy of Norman Nishioka, MD, Massachusetts General Hospital).

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studies have established that EUS is more sensitive and specific than CT scanning in the staging of squamous cell carcinoma and adenocarcinoma of the esophagus. Early adenocarcinoma limited to the mucosa can be identified and safely removed endoscopically.50 EUS-guided fineneedle aspiration has significantly increased the specificity of lymph node staging.25 Distant metastases are best detected through abdominal and chest CT scanning. PET scans may increase the detection of M1 disease but should not be used routinely at this time.4,51–54 Gastric Cancer The diagnosis of gastric cancer is traditionally established by visible light endoscopy and biopsy. Helical CT scans and EUS are the accepted staging modalities for gastric cancer. Helical CT scans have an accuracy of T staging of 51%– 67%. The limitations of CT scans include clarifying gastric wall involvement and identifying metastases in normal-sized lymph nodes.55 The accuracy of N staging by CT scans is reported to range from 51% to 73%. For local staging, EUS is superior to dynamic CT56 and helical CT,57,58 but CT is superior for the detection of distant metastases. Optical biopsy techniques for the early diagnosis of gastric cancer are particularly important because early gastric cancer is amenable to endoscopic resection. Early gastric cancers show significantly stronger or weaker fluorescence depending on whether they have more or less abundant stroma than the surrounding mucosa.59 Autofluorescence with a xenon lamp can induce a distinct fluorescent spectrum that can differentiate cancerous tissue from normal mucosa with a sensitivity of 84%, a specificity of 87%, and a likelihood ratio for a positive test of 6.5.49 Signet-cell carcinoma shows greater variability in autofluorescence, and this results in a lower sensitivity and specificity (55% and 85%). Kobayashi et al60 evaluated autofluorescence endoscopy in 52 patients with 33 early gastric cancers and 21 benign lesions. Tissue was illuminated with a blue and white light source, and red and green autofluorescence was measured. A total of 85% of cancerous lesions were correctly detected according to the fluorescence pattern. The sensitivity and specificity were noted to be 94% and 86%, respectively. The combination of chromoendoscopy and NBI has enabled endoscopists to identify candidate lesions for endoscopic resection61,62 (Figure 5). Fluorescence endoscopy has also been used to detect early gastric cancer, but the method lacks specificity.59,63 Dinis-Ribeiro et al,64 using methylene blue– enhanced, high-magnification endoscopy, were able to define a set of reproducible imaging criteria that were predictive of gastric metaplasia and

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Figure 5. Imaging of a superficial gastric carcinoma. (A) Before indigo carmine staining, minor mucosal changes were found. (B) After indigo carmine staining, converging folds to a depressed lesion ⬎20 mm were found. On pathology, there was a deep invasion of the submucosa. Because the depressed lesion was ⬎10 mm, surgery was indicated (image provided courtesy of Moises Guelrud, MD, New England Medical Center).

dysplasia. By using a pattern of color, pit morphology, and the presence of villi, the specificity and negative predictive values for the diagnosis of dysplasia were 81% and 99%, respectively. In the future, multidetector CT will likely be the imaging modality of choice for the staging of gastric cancer65 (Figure 6). A recent case series showed that MDCT had an accuracy of 88.9% in T staging and 70.4% accuracy in N staging.66 Three-dimensional reconstruction provided virtual gastroscopy and mapping of the gastric malignancy. MDCT with 3-dimensional reconstruction was compared with EUS and histopathology in 63 patients with 67 gastric cancers. The overall accuracy for detecting gastric cancer with the 3-dimen-

Figure 6. Multidetector CT of gastric cancer involving the antral wall (arrows).

sional MDCT was 94% with early-stage cancer and 100% for advanced-stage cancer. The sensitivities, specificities, and overall accuracy of depth of invasion (T stage) were comparable between MDCT and EUS (83.3%, 69.1%, and 94.4% and 87.5%, 82.4%, and 96%, respectively). The 3-dimensional MDCT can also provide vascular mapping, which may be useful to guide surgical therapy.67 Small-Bowel Cancers The role of endoscopy in the diagnosis of smallbowel malignancy has traditionally been rather limited. Capsule endoscopy is capable of detecting malignancies of the small intestine, but its role in cancer detection has not been well defined. Chromoendoscopy may enhance the detection of early, superficial smallbowel cancer by using traditional endoscopic imaging. In a study of 118 patients, indigo carmine increased the detection of duodenal lesions compared with conventional endoscopy but did not yield a significant increase in adenoma detection.68 Magnification endoscopy did not improve diagnostic yield in this study. The potential benefits of chromoendoscopy in patients with familial adenomatous polyposis and duodenal adenomas—in particular, ampullary adenomas— have not been studied. A recent case series examined the possibility of virtual duodenography with MDCT as a screening tool in patients with familial adenomatous polyposis and duodenal adenoma.69 MDCT reflected the maximal polyp size accurately but was inaccurate in determining the number of polyps. Experimental techniques

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have used enzyme-sensing molecular beacons for detecting minute duodenal adenomas.70 Hepatobiliary Cancers Hepatocellular carcinoma (HCC) is a worldwide problem. Its increasing incidence has been attributed to chronic hepatitis B and hepatitis C infections.71 Patients at the highest risk for HCC include men with cirrhosis due to chronic viral hepatitis and alcohol use.72 Recent guidelines suggest screening with serum ␣-fetoprotein, ultrasound, or both every 6 months, despite marginal cost-effectiveness.73 Diagnostic criteria for HCC include a focal hepatic lesion ⬎2 cm in diameter that enhances with contrast as identified by 2 or more imaging modalities.74 ␣-Fetoprotein is used to supplement an imaging diagnosis, and a cutoff of ⬎20 ng/mL provides a modest sensitivity of 60%; higher diagnostic rates are observed in patients with hepatitis B.73 However, screening with ␣-fetoprotein alone should not be performed. The imaging modalities most often used include ultrasonography (usually as part of screening) and helical CT.75 The most challenging radiological diagnosis is identifying tumor within a nodular cirrhotic liver, and MR imaging is the study of choice in this scenario.76 In general, a tissue biopsy is not needed for confirmation unless the diagnostic criteria are not met or if the lesion is ⬍2 cm.77 PET scans have little role in the diagnosis of HCC but contribute to staging and to monitoring the clinical response to adjuvant therapy.78 MDCT coupled with 3-dimensional rendering is recognized as a noninvasive imaging test that provides highly detailed vascular mapping. MDCT of the liver is useful for preoperative evaluation,79 as well as for planning chemoembolization.80,81 Unfortunately, MDCT does not improve tumor detection in cirrhotic livers.82 Similar to CT scanning, MR technology can also obtain images with high resolution that can be rendered to produce detailed 3-dimensional images.15,83 Gadolinium-diethylenetriaminepentaacetic acid contrast has long been used to identify hypervascular HCC lesions,84 but recently, liver-specific contrast agents have been developed to diagnose a range of hepatic malignancies. Superparamagnetic iron oxide particles, including ferumoxide and ferucarbotran (Resovist; Ferrixan, Schering AG, Germany), are taken up by Kupffer cells. HCC lesions show hyperintensity on T2 images and hypointensity on T1 images. Detection of HCC has been reported with feruoxmide alone85 and when it is used in combination with gadolinium.86,87 However, other lesions, such as adenomas and focal nodular hyperplasia, also enhance with contrast, and this may limit its usefulness.88 Other contrast agents that have been studied

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include gadoxetic acid disodium,89 gadobenate dimeglumine,90 and mangafodipir trisodium.91–95 Recent studies suggested that a combination of superparamagnetic iron oxide– enhanced and gadolinium-enhanced MR images was more accurate than either alone.96 –98 Advances in ultrasound technology are also being investigated. When pulsed harmonic sound waves interact with intravenously administered microbubble contrast agents, the resulting images provide information about both the size and the vascularity of a lesion, thus producing so-called vascular volume images.99 This technique, termed pulsed inversion harmonics, has been shown to be capable of detecting differences in the vascularity of benign and malignant liver lesions. HCC lesions are relatively unique in showing decreased portal (afferent) flow and abnormally active arterial (efferent) flow,100 and these changes can be further characterized with the maximum velocity and pulsatility index.101 The screening and surveillance for HCC with imaging will continue to evolve with the introduction of new contrast agents. Cholangiocarcinoma The diagnostic test of choice for patients with suspected cholangiocarcinoma is cholangiography, as depicted by various imaging techniques. Magnetic resonance cholangiopancreatography (MRCP) has now replaced diagnostic percutaneous cholangiograms and diagnostic ERCPs as the initial imaging test for patients with suspected cholangiocarcinoma.102,103 MRCP has been shown to be as accurate as invasive cholangiography, which should be reserved for therapy and tissue sampling.104,105 Multiplanar thin-slice (0.5 mm) CT is the optimal technique for imaging of the biliary tree with CT.106 For high-resolution imaging of the biliary epithelium, intraductal ultrasonography (IDUS) provides unsurpassed views of bile duct strictures and intraductal masses.107,108 Although IDUS requires the use of ERCP, high diagnostic rates (sensitivity of 90%, specificity of 93%, and overall accuracy of 92%) have been achieved in the evaluation of patients with biliary strictures.109 Diagnostic tissue acquisition during ERCP remains a challenge, but fine-needle aspiration directed by EUS can provide diagnostic tissue from large, adjacent masses.110,111 Staging with CT scanning can be supplemented with MR angiography that often provides critical information regarding portal vein and hepatic artery invasion.112 The role of PET scans in the diagnosis and staging of cholangiocarcinoma is still being investigated.113,114 Pancreatic Cancer The diagnostic test of choice for pancreatic cancer remains contrast-enhanced helical CT scanning, as originally outlined in an American Gastroenterological As-

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pancreatic cancer.124 Focal hypoechoic masses, cystic lesions, and intraductal neoplasms have been shown. Pancreatic imaging with ultrasonography and EUS specifically has been enhanced with the use of intravascular contrast agents.125 By using coded phase inversion harmonic imaging, characteristic pancreatic tumor vascularity has been shown with transabdominal ultrasonography. The overall sensitivity of the technique for the detection of pancreatic malignancy was 95%, which compared favorably to the sensitivity of contrast CT (68%) and endosonography (95%). Cystic Pancreatic Neoplasms

Figure 7. EUS of pancreatic cancer with color Doppler imaging enhancement of the adjacent portal vein.

sociation position statement.115 MDCT with multiplanar vascular reconstruction may enhance the rates of diagnosis and staging of pancreatic neoplasms.1 Providing even higher diagnostic rates, EUS should be used in patients with CT findings suggestive of malignancy or pancreatic/ biliary obstruction115,116 (Figure 7). EUS can also supplement diagnosis and local tumor staging by MDCT, but its role as a frontline staging tool remains controversial.117,118 When a tissue diagnosis is required, EUSguided fine-needle aspiration has many advantages over CT-guided biopsy.119 MR imaging may offer more accurate staging of pancreatic cancer while eliminating the risk of radiation exposure. Its main limitations are its high cost and low availability. Recently in Europe, the hepatobiliary-specific contrast agent mangafodipir trisodium has shown promise in detecting small tumors or tumor-simulating lesions in patients with equivocal CT findings.120 However, this use of contrast-enhanced MR has not yet been shown to be superior to helical or MDCT, and further studies should clarify the utility of this technique.121 The role of PET scans in the management of pancreatic cancer is still under debate. PET scanning does not provide information regarding tumor size or local invasion. It is most useful for detecting distant metastases, to monitor tumor response to treatment, and to assess tumor viability.122 A recent study reported that the combined modality of PET/CT increased the sensitivity of detection of malignant pancreatic lesions. A small number of occult metastatic lesions were discovered by using fusion imaging, but there was a decrease in specificity compared with CT alone.123 Pancreatic imaging with EUS and fine-needle aspiration can be used to screen high-risk individuals for

With improvements in cross-sectional imaging techniques of the pancreas, there has been increasing discovery of cystic neoplasms.126 The vast majority of cystic lesions in the pancreas are pseudocysts, serous cystadenoma, mucinous cystadenoma, and intraductal papillary mucinous tumors (Figure 8). MDCT can show many of the features of serous cystadenomas, which are benign, microcystic lesions that do not necessitate surgical intervention, in contrast to the malignant or premalignant macrocystic mucinous lesions.127 MRCP, a form of MR imaging that uses T2-weighted images, is very sensitive for the presence of cystic and intraductal tumors of the pancreas. The imaging findings may be used diagnostically when classic morphologies, such as the microcystic morphology of a serous cystadenoma, are shown. Although cross-sectional imaging is very sensitive in detecting cystic lesions of the pancreas, cyst fluid analysis with carcinoembryonic antigen concentrations will improve the specificity for differentiating between mucinous and nonmucinous lesions.128 EUS and cyst fluid analysis should be used to aid in the selection of patients with lesions at high risk for malignancy.

Figure 8. A CT image reformatted along the pancreatic duct to show a main-duct IPMN in the head of the pancreas is shown. There is segmental dilatation of the main pancreatic duct in the head (arrows), with normal-appearing pancreatic parenchyma and a normal-caliber distal duct.

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IDUS and peroral pancreatoscopy have been used to improve visualization of the pancreatic duct in patients with suspected intraductal papillary mucinous tumors.129 Mapping of intraductal papillary mucinous tumors with IDUS or pancreatoscopy before surgery or using frozen section during surgical resection is critical for minimizing positive resection margins. In a recent large retrospective study, the combination has been reported to distinguish between malignant and benign lesions with a sensitivity of 91%, a specificity of 82%, and an overall accuracy of 88%.130 The IDUS findings that suggest malignancy include lesions protruding more than 4 mm and fish egg–like, villous, and vegetative protrusions (by pancreatoscopy).130 Colorectal Cancers The vast majority of colorectal cancers have a highly characteristic appearance with light endoscopy. Colonoscopy-directed biopsies can readily confirm the diagnosis for mass lesions and remove polyps, which are often associated with colon malignancies. Although most sporadic colon cancers and cancers arising in the setting of hereditary polyposis are readily identified by colonoscopy, there are increasing reports of malignancies with an atypical appearance. Challenges also arise for gastroenterologists when identifying dysplasia amongst flat or polypoid lesions, particularly in the setting of inflammatory bowel disease. The advent of VC has introduced an alternative screening test.131 Impressive results for the detection of adenomatous polyps have been reported by several centers132,133 (Figure 9). Although CT colonography is more

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sensitive (81%) than double-contrast barium enema (45%), CT colonography is slightly less specific.134 Advances in software may enable radiologists to differentiate between stool and polyps, perhaps eliminating the need for colonic purging before CT colonography.135,136 VC has a high sensitivity for polypoid lesions ⬎1 cm, but despite methods to eliminate movement artifacts, VC still lacks sensitivity for lesions ⬍1 cm and flat lesions. Its role in screening, however, will likely be dictated by what is defined to be a positive finding137 and its cost.138 Colorectal cancer is staged by using CT scans to look for regional disease, lymph nodes, and distant metastases. For rectal cancer, MR with rectal coils or EUS provides images that display the relationship between the tumor and the rectal wall to determine whether there is evidence of transmural invasion.139 For recurrent disease, PET scans are superior to CT scans in identifying recurrent disease or metastases.140 –142 In the management of colorectal cancers, chromoendoscopy and magnification endoscopy have been investigated as means of differentiating hyperplastic and adenomatous polyps,143,144 increasing detection of flat adenomas and cancers during screening colonoscopy,22,145–149 ensuring complete tissue resection during endoscopic mucosal resection,150 and, perhaps most notably, identifying dysplastic lesions in the setting of inflammatory bowel disease.151 One of the most quoted pit pattern classifications has recently been found to have high interobserver and intraobserver reproducibility.15 Despite the ability to visualize polypoid lesions in detail,

Figure 9. Screening CT colonography images in a 57-year-old man are shown. On the endoluminal view, a pedunculated polyp in the right colon is seen, and a well-defined soft tissue abnormality is seen as a projection into the lumen (arrow).

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Figure 10. Confocal microscopic image of early colon cancer: (A) normal rectum; (B) rectal cancer (image provided courtesy of Ralph Kiesslich, MD, Mainz, Germany).

it is not possible to accurately differentiate between adenomatous and hyperplastic polyps with chromoendoscopy,150 and, as such, this technique has not been widely used by Western physicians. Although chromoendoscopy may not be indicated for differentiating various types of colon polyps, chromoendoscopy may have a role in improving the detection of early neoplasia arising in the colon of ulcerative colitis.152 Current guidelines recommend annual colonoscopies with 4 quadrant biopsies every 10 cm for patients with chronic (8 –10 years), inactive pancolitis.153 Small, flat adenomas arising in the inflamed mucosa of ulcerative colitis have been shown by using high-resolution colonoscopy enhanced with indigo carmine chromoendoscopy.154 Recently a randomized, controlled study showed a greater number of neoplasias detected by chromoendoscopy compared with conventional endoscopy in patients with ulcerative colitis.155 Chromoendoscopy with methylene blue also provided enhanced detection of

neoplasia, coupled with better correlation between endoscopic and histopathologic findings of the extent and degree of inflammation.156 The sensitivity and specificity for differentiating benign and neoplastic lesions was 93%. Although it is not yet the standard of care, chromoendoscopy with magnification could become the technique of choice in patients with long-standing ulcerative colitis if the results of this study can be reproduced.157 Fluorescent endoscopy may provide an alternative method for dysplasia detection in the setting of ulcerative colitis. A recent study in 37 patients with ulcerative colitis showed that sensitivity for dysplasia detection was 87% and 100% after local administration of 5-ALA by enema or spray catheter, respectively, as compared with 43% by systemic administration.12 The negative predictive value of nonfluorescent mucosa was 89% and 98%–100% in enema-administered or spray catheter–administered 5-ALA, respectively. Further studies will be required to clarify the possible roles for fluores-

Figure 11. PET/CT image of recurrent rectal cancer in a 52year-old man operated on 7 months previously. Selected images in 3 rows are shown. The top row shows axial CT, fused PET/CT, and PET images, with the corresponding coronal image shown in the bottom row. A soft tissue abnormality on CT in the presacral space shows increased 18Ffluoro-deoxy-D-glucose uptake (arrows). This was confirmed as tumor recurrence on biopsy.

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cent endoscopy in the detection of malignant and premalignant colonic lesions. One of the most dramatic demonstrations of fluorescent imaging has used a new imaging technology, confocal laser microscopic endoscopy, in the colon to provide surface and subsurface images.22 The striking in vivo images, obtained with a dedicated, investigational confocal microscope, of visible neoplastic lesions rivaled histopathology of tissue biopsies (Figure 10). In a wide range of colonic histology, the accuracy rate was 99.2%. Real-time confocal microscopic endoscopy may be able to provide histopathologic diagnoses in a wide range of lesions, diseases, and endoscopic procedures. The use of multiple fluorescent dyes could further enhance the abilities of this technology to provide histological diagnoses. PET scans have an established role in the detection of recurrent colorectal cancers158 (Figure 11). The fusion of PET/CT imaging has increased the specificity, sensitivity, and overall accuracy when compared with PET scans alone.159 –161 The combined modality of PET/CT scanning has improved the localization of positive PET signals and decreased the false-positive PET uptake. A limitation of the PET/CT scan is a decrease in the detection rate of liver lesions on CT because of a lack of use of intravenous contrast and obscuring background noise.159

Conclusions These are exciting times for developments in endoscopic and radiological imaging of GI malignancies. Many new technologies are going to be applied to a spectrum of malignancies. These techniques should improve the prognosis of patients with GI malignancies through earlier diagnosis and more accurate staging.

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Received December 9, 2004. Accepted February 7, 2005. Address requests for reprints to: William R. Brugge, MD, Massachusetts General Hospital, Blake 452c, 55 Fruit Street, Boston, Massachusetts 02114; e-mail: [email protected]; fax: (617) 724-5997.