Extraintestinal Applications of Endoscopic Ultrasound Rayburn Rego, MD
Dr. Rego is Assistant Professor in the Division of Gastroenterology at the University of South Alabama, Mobile, Ala. Address correspondence to: Rayburn Rego, MD, Gastroenterology Academic Offices, USA Knollwood Pavilion 5600 Girby Rd., Mobile, AL 36693; Tel: 251-660-5555; Fax: 251-660-5559; E-mail: [email protected].
Abstract: Since the joining of ultrasonographic and endoscopic technologies in 1980, there has been tremendous advancement in the use of endoscopic ultrasound (EUS). Initially EUS was used mainly to study the anatomic appearance of digestive organs. In the 1990s, with the development of the charge-coupled device, thinner, more flexible scopes were developed that simplified imaging for the endosonographer and improved patient safety. With the development of linear array EUS scopes, biopsies could be performed utilizing fine needle aspiration. Currently, several therapeutic techniques, which were formerly performed through radiologic or surgical procedures, are being safely done with EUS. These include celiac plexus neurolysis and endoscopic drainage of pancreatic cysts. With the advent of miniprobe technology, better delineation of the wall of the gastrointestinal tract can be obtained, facilitating endoscopic mucosal resection. Novel therapeutic uses for EUS are constantly emerging. This article describes the various extraintestinal applications of EUS that have been developed in the last 25 years. More gastroenterologists need training in order to utilize this challenging technology and improve patient access in the local community setting.
E Keywords Endoscopic ultrasound, fine needle aspiration
ndoscopic ultrasound (EUS) was developed in the 1980s. Its main use at that time was in the staging of gastrointestinal tumors. Initially used as a diagnostic tool, since the early 1990s it has been increasingly utilized in intervention and therapy. Its uses have broadened such that it now has indications for extraintestinal pathology. Use of EUS will continue to grow as new technology, such as the thin miniprobe, dual-plane reconstruction (DPR), intraductal probes, and the new electronic radial echoendoscope, become available. Over the next few years, EUS is foreseen as becoming one of the most powerful gastroenterological, radiological, and therapeutic instruments, catalyzing significant changes in patient management. EUS has been shown to be safe1 and emerging studies indicate that it is cost effective when compared to modalities such as computed tomography (CT) scans, positron emission tomography
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(PET) scanning, magnetic resonance imaging (MRI), angiography, and surgery.2 Immunotherapy, radiofrequency ablation, injection of viruses, gene therapy, and DNA analysis could become established EUS applications in the near future and are currently at various stages of investigation.3 Equipment Radial Scanning Echoendoscope The radial scanning echoendoscope is the most commonly used endoscope. It has either a rotating mechanical transducer at the tip (Olympus Corp) or a fixed, phased-array electronic transducer (Pentax Corp). The mechanical transducer provides a 360-degree image, oriented perpendicularly to the shaft of the scope, whereas the fixed array produces a 270-degree view (Figure 1). The image provided is a cross-sectional view, similar to slices of a CT scan, and is therefore easier to interpret, especially for the novice. The ultrasound frequency ranges between 5 and 20 MHz. It should be noted, however, that higher frequency results in better resolution, but at the expense of depth of penetration, which is relationally decreased. Endosonographers usually use the 5 and 7.5 MHz frequencies to scan and the depth of penetration is usually around 5–6 cm. It should also be noted that Doppler cannot be performed with the mechanical transducer, but is possible with the electronic radial scope. Recently, an electronic, 360-degree radial scanning echoendoscope with Doppler capability and tissue harmonic imaging was introduced by Olympus. The endoscopic view of this scope is forward oblique. The key components of the transducer are the piezoelectric crystals that vibrate to produce ultrasonic waves. Acoustic coupling is usually achieved with a waterfilled balloon around the instrument tip. Linear Scanning Echoendoscope This echoendoscope provides a view parallel to the long axis of the scope, allowing for safe performance of EUSguided fine needle aspiration (FNA; Figure 2). These scopes are manufactured by both Olympus and Pentax and employ electronic, fixed-array technology. Doppler is available, and very useful in differentiating vessels from tissue, especially for FNA. The scope can switch between 5 and 7.5 MHz frequency. The needles commonly used are 19 and 22 gauge. Linear scanning is generally more difficult to learn than radial scanning. High-Frequency Miniprobe Miniaturization of the ultrasound transducer led to the development of the miniprobe. This high-frequency ultrasound probe (HFUP) or catheter is about 2–3 mm in diameter and is passed through the biopsy channel of
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Radial • • • •
360 degrees Similar to CT scan Good screening Ideal for circumferential lesions • Easier to learn • No biopsies
Figure 1. Radial scanning echoendoscope produces 360˚ or 270˚ images. CT = computed tomography.
Linear • Long axis of scope • Allows FNA • Some advantages for vascular staging • Harder to learn
Figure 2. Linear scanning echoendoscope produces images parallel to the scope. FNA = fine needle aspiration.
a regular upper endoscope. The probe has a mechanical rotating transducer at the tip and frequency ranges from 12 to 30 MHz. Recently, DPR probes have been made available for surface and volume rendering and three-dimensional reconstruction. These probes provide detailed imaging of the wall of the gastrointestinal tract and precise depth of penetration of tumor. In contrast to the five-layered wall structure obtained with conventional EUS, HFUP can delineate up to nine layers. Dedicated miniprobes for intraductal ultrasonography (IDUS) are also available from 12.5 to 30 MHz. Extraluminal Applications Pancreatic Adenocarcinoma Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. The 5-year survival rate after postoperative multimodality treatment
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Figure 3. Hypoechoiec lesion (arrows) in the head of the pancreas. Fine needle aspiration confirmed pancreatic adenocarcinoma.
Figure 4. Hypoechoiec lesion in the head of the pancreas obstructing the common bile duct (CBD) and pancreatic duct (PD).
is about 20%.4,5 In the 1980s and early 1990s, EUS was found to be the best modality to locally stage pancreatic cancer (Figures 3 and 4).6,7 With the advancement in technology of other radiological methods, especially multidetector triple-phase CT scanning, later studies report comparable sensitivities and specificities. Tumor staging accuracy ranges from 85% to 93% and nodal staging accuracy is approximately 72%.8 There have been four studies comparing EUS with helical CT for evaluating pancreatic cancer. Two of them9,10 found helical CT and EUS to be equivalent; the other two11,12 found EUS to be superior for tumor detection and staging. The discrepancies in the findings of these four studies have several causes and biases beyond the scope of this article. EUS and helical CT are complimentary. A helical CT should be employed for initial evaluation and EUS should be performed if no evidence of distant metastasis is found. EUS can also determine vas-
cular invasion. EUS is less accurate in evaluating invasion into the superior mesenteric vessels, but is very accurate in diagnosing portal vein invasion.13 Nevertheless, with the advent of surgical portal vein resection, portal vein invasion does not necessarily preclude resection. Detection of vascular invasion by EUS is being challenged by advances in CT technology. Multiplanar reconstruction of major vessels in proximity to tumors revealed a sensitivity of 50–75% and a specificity of 91–97% in a recent study.14 EUS is very sensitive in detecting small pancreatic tumors. Studies comparing EUS with helical CT suggest EUS is more sensitive for tumors smaller than 3 cm.15 Therefore EUS is also indicated when there is clinical suspicion of a pancreatic tumor and other imaging studies are either nondiagnostic or equivocal. Studies comparing EUS and MRI suggest that EUS is more sensitive.16-18 Studies comparing angiography and EUS have varied results, but suggest that EUS is as accurate for determining vascular invasion, except invasion of the superior mesenteric vessels.18-20 A study comparing EUS and PET scanning found a sensitivity of 93% for EUS and 87% for fluorodeoxyglucose-PET.11 PET scanning could have a higher false-positive rate as inflammatory masses cause a positive scan. Problems could arise in differentiating an inflammatory mass from a malignancy in a patient with chronic pancreatitis. The specificity varies from 46% to 93%.21,22 Newer techniques such as contrast-enhanced Doppler imaging could result in improvement in sensitivity and specificity, as adenocarcinomas are hypoperfused and inflammatory lesions are hyperperfused. The establishment of diagnosis can be accomplished by EUS-guided FNA. The complication rate is less than 1%.23 Multiple studies have demonstrated sensitivities between 75% and 90% and specificity between 94% and 100%, implying a false-negative rate between 10% and 25%. If EUS suggests resectability, EUS-guided FNA is not necessary, although this aspect remains controversial. Advantages of needle biopsy include alternative diagnoses such as lymphoma, islet cell tumors, and metastatic disease. The disadvantages include bleeding, pancreatitis, and tumor seeding, a first case of which was recently reported.24 Several studies have evaluated cost-effectiveness and concluded that EUS-guided FNA is a cost-effective strategy, with one study estimating a cost saving of $3,300 per patient based on avoidance of surgery.25,26 Neuroendocrine Pancreatic Tumors Neuroendocrine pancreatic tumors are rare tumors, with an incidence of less than 1 per 100,000 people. EUS is very sensitive in detecting these small tumors. Sensitivities vary from 82% to 93% and specificity is over 90%.27,28 EUS is
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Simple Cysts: These are usually small in size and are congenital. They are benign, with thin walls, filled with clear fluid, and without septation. Serous Cystadenomas: These are usually benign, seen mostly in women in the seventh decade of life. These tumors tend to be located in the body and tail of the pancreas. Up to 10% of serous cystadenomas have central calcification, causing a characteristic sunburst pattern. They can also have multiple microcysts, forming a honeycomb pattern (Figure 5). FNA reveals low-viscosity fluid with low tumor markers and glycogen-containing cuboidal cells. If these tumors cause symptoms, such as abdominal pain, they can be resected; otherwise they can be left alone.
Figure 5. Two images showing honeycomb pattern of serous cystadenoma with thin septae.
comparable to somatostatin receptor scintigraphy (SRS) for detecting pancreatic gastrinomas, and more accurate for insulinomas due to the low density of SRS receptors. Both tests are clearly superior to CT, which has a detection rate of about 60% at best. Both techniques, however, miss a significant proportion of duodenal gastrinomas.29 Because there is a more frequent incidence of extrapancreatic tumors, EUS is frequently used in conjunction with other modalities such as SRS and triple-phase CT. Screening for Pancreatic Cancer A recent study recommended screening for pancreatic cancer in familial pancreatic cancer kindreds. The diagnostic yield for detecting clinically significant pancreatic neoplasms was 5.3%.30 No recommendations are known for surveillance after initial screening. Cystic Lesions of the Pancreas There are five basic types of cystic lesions that are encountered in the pancreas.
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Mucinous Cystadenomas: These tumors have malignant potential, with approximately 25% harboring malignancy at the time of diagnosis. They are usually asymptomatic, but can cause abdominal pain, pancreatitis, diabetes, and jaundice. They are usually found in women in the fifth and sixth decades of life and are located in the body and tail of the pancreas. Mucinous cystadenomas contain multiple fluid-filled cavities with thin wall septae (Figure 6), the cavities being much larger (>1 cm) than the microcysts seen in serous cystadenomas. FNA is usually performed on the nearest and largest cavity, and the cavity is completely drained to prevent infection. Antibiotics are usually administered prior to FNA and for about a week after. Mucous and mucous-filled cuboidal or columnar cells are seen in about 30–50% of cases. The tumor marker that is particularly helpful in determining a mucinous tumor is the carcinoembryonic antigen (CEA) level in cyst fluid. A recent prospective study found that a CEA level of 192 ng/mL using the receiver-operating curve analysis provided a sensitivity of 75% and a specificity of 84%.31 All mucinous cystadenomas are potentially malignant and should be resected. Intraductal Papillary Mucinous Neoplasm: These tumors arise from the epithelium of the pancreatic duct and have malignant potential. They are usually diagnosed in men in the sixth and seventh decades of life. Blockage of the pancreatic duct with mucous or growth accounts for symptoms of abdominal pain, pancreatitis, weight loss, diabetes, and steatorrhea. EUS reveals a dilated pancreatic duct, segmental duct dilation, or side branch dilation in the presence of normal echotexture of the pancreas. EUS-guided FNA of the dilated pancreatic duct can be performed. IDUS and pancreatoscopy are other methods that can be used to aid in diagnosis. The recommendation is limited resection, if possible, and avoidance
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Figure 6. Mucinous cystadenoma with papillary projections from the cyst wall (arrows).
Figure 7. Large pancreatic pseudocyst with fine debris.
of total pancreatectomy as recurrence rates are comparable after partial or total pancreatectomy for invasive disease. This avoids the serious metabolic consequences of a total pancreatectomy. Pseudocysts: These benign cysts are inflammatory collections of fluid that stem from duct disruption. They are usually seen in patients with chronic alcoholic pancreatitis. Signs detected with EUS include a hyperechoic thick wall, lack of septations, and internal echoes representing debris (Figure 7). FNA usually reveals a fluid with low viscosity, high amylase levels, low tumor markers, and histiocytes. Pseudocysts can be drained using EUS as guidance, especially if they are symptomatic. The advantages of using EUS include gauging the distance between the cyst wall and the gut wall (which should be 1 cm, round, homogeneous echo pattern, sharp borders), sensitivity was 83% with a 98% specificity.65 Accuracy is increased to 98% with the addition of FNA.66 EUS-guided FNA is superior to CT scanning in detecting malignant celiac lymph nodes. A recent study indicated that CT detected only 30% of
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Trachea
Level 2 Level 4
Aorta Level 5 (AP Window) Level 7 (Subcarina)
Esophagus Level 8
Figure 10. American Joint Committee on Staging of Cancer; lymph node stations. AP = aortopulmonary.
malignant nodes diagnosed by EUS-guided FNA and that EUS-guided FNA significantly affected subsequent patient management.67 Left Adrenal Gland Lesions The left adrenal gland is visualized on EUS as “seagullshaped”; the right is not usually seen. Metastatic cancer to the adrenal gland carries a grave prognosis and precludes curative surgical resection. Eloubeidi and colleagues68 found that EUS-guided FNA of the left adrenal gland was safe and confirms or excludes malignant adrenal involvement in patients with thoracic or gastrointestinal malignancies. Mediastinal Lymphadenopathy EUS can accurately assess mediastinal lymphadenopathy. Lung cancer is the most common cause of cancer-related death in the West and about 80% of cases are due to non–small cell lung cancer (NSCLC). Unfortunately, nearly 50% of patients harbor mediastinal disease at presentation. Direct mediastinal invasion or spread to contralateral lymph nodes (N3) is staged as IIIB disease; it is unresectable and treated with chemoradiation. Metastasis to ipsilateral and subcarinal nodes (N2) is classified as stage IIIA disease. Management is controversial. Most centers treat with chemoradiation only, but some centers offer surgery after adjuvant therapy. EUS can visualize posterior lymph node stations only (5 and 7), as air in the trachea prevents visualization of the anterior stations (2 and 4; Figure 10). Mediastinoscopy can stage anterior lymphadenopathy, but is associated with a complication rate of 2–3% and requires general anesthesia and a longer hospital stay. It cannot evaluate posterior lymph-
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adenopathy. Nevertheless, both investigations should be regarded as complementary. EUS is highly accurate with a sensitivity of approximately 93% and a specificity of nearly 100%.69 EUS has been found to be superior to CT and PET scanning.70 In a recent large study EUS-FNA detected mediastinal disease in 10 of 24 patients (42%) without mediastinal adenopathy on CT.71 Another study by Wallace and associates72 in patients with NSCLC with nodes less than 1 cm by CT revealed advanced disease in 25% of patients by EUS-guided FNA. Transbronchial node aspiration (TBNA) performed during bronchoscopy is usually a blind procedure limited to pretracheal, paratracheal, and subcarinal areas, with yield varying from 20% to 70%. Recently, Krasnik and associates73 reported promising experience with a prototype realtime endobronchial ultrasound (EBUS)-TBNA bronchoscope. The same investigators in a later study combined transesophageal EUS-guided FNA and EBUSTBNA biopsy in the evaluation of mediastinal masses. They were found to be complementary and the accuracy for diagnosis of mediastinal cancer was 100%. The investigators concluded that the combined approach may be able to replace more invasive methods for evaluation of mediastinal cancer.74 Currently, EBUS is being performed at select centers in the United States and Europe. EUS is also very accurate in diagnosing other diseases affecting the mediastinum, such as sarcoidosis, histoplasmosis, tuberculosis, lymphoma, and metastasis from other primary tumors.75 Conclusion EUS is a new endoscopic tool that has revolutionized how gastrointestinal diseases are managed, particularly gastrointestinal tumors. It has numerous diagnostic and therapeutic indications, which continue to expand. There is a steep learning curve and a need for more gastroenterologists to be trained in this advanced procedure. It usually takes a dedicated year of training to become reasonably skilled in the technique. Parada and colleagues,76 in a resource utilization projection study, concluded that current EUS resources are not sufficient to meet the demand in the United States. If more gastrointestinal programs offered advanced fellowships in EUS, this potential problem could be averted. Higher reimbursement for the procedure could make the sacrifice of an additional year of fellowship worthwhile. Reduced equipment costs (currently between $300,000 and $350,000) could also help mainstream EUS into community practices. The ultimate goal is to make EUS easily accessible to all gastroenterologists, so that patients do not have to travel great distances and the most effective management options are available at home.
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66. Eloubeidi M, Wallace M, Reed C, et al. The utility of EUS and EUS-guided fine needle aspiration in detecting celiac lymph node metastasis in patients with esophageal cancer: a single-center experience. Gastrointest Endosc. 2001;54:714-719. 67. Parmar KS, Zwischenberger JB, Reeves AL, et al. Clinical impact of endoscopic ultrasound-guided fine needle aspiration of celiac axis lymph nodes (M1a disease) in esophageal cancer. Ann Thorac Surg. 2002:73:916-920. 68. Eloubeidi M, Seewald S, Tamhane A et al. EUS-guided FNA of the left adrenal gland in patients with thoracic or GI malignancies. Gastrointest Endosc. 2004;59:627-633. 69. Wallace M, Fritscher-Ravens A, Savides TJ. Endoscopic ultrasound for the staging of non small-cell lung cancer. Endoscopy. 2003;35:606-610. 70. Fritscher-Ravens A. Endoscopic ultrasound evaluation in the diagnosis and staging of lung cancer. Lung Cancer. 2003;41:259-267. 71. Wallace NB, Silvestri GA, Sahai AV, et al. Endoscopic ultrasound guided fine needle aspiration for staging patients with carcinoma of the lung. Ann Thorac Surg. 2001;72:1861-1867. 72. Wallace MB, Ravenel J, Block MI, et al. Endoscopic ultrasound in lung cancer patients with normal mediastinum on computed tomography. Ann Thorac Surg. 2004;77:1763-1768. 73. Krasnik M, Vilmann P, Larsen SS, et al. Preliminary experience with a new method of endoscopic transbronchial real-time ultrasound guided biopsy for diagnosis of mediastinal and hilar lesions. Thorax. 2003;58:1083-1086. 74. Villmann P, Krasnik M, Larsen SS, et al. Transesophageal endoscopic ultrasound-guided fine-needle aspiration(EUS-FNA) and endobronchial ultrasoundguided transbronchial aspiration(EBUS-TBNA)biopsy: a combined approach in the evaluation of mediastinal lesions. Endoscopy. 2005;37:833-839. 75. Fritscher-Ravens A, Sriram PVJ, Topalidis T, et al. Diagnosing sarcoidosis using endosonography-guided fine needle aspiration. Chest. 2000;118:928-935. 76. Parada K, Peng R, Erickson R, et al. A resource utilization projection study of EUS. Gastrointest Endosc. 2002;55:328-334.
Dr. Rego is Assistant Professor in the Division of Gastroenterology at the University of South Alabama, Mobile, Ala. Address correspondence to: Rayburn Rego, MD, Gastroenterology Academic Offices, USA Knollwood Pavilion 5600 Girby Rd., Mobile, AL 36693; Tel: 251-660-5555; Fax: 251-660-5559; E-mail: [email protected].
Abstract: Since the joining of ultrasonographic and endoscopic technologies in 1980, there has been tremendous advancement in the use of endoscopic ultrasound (EUS). Initially EUS was used mainly to study the anatomic appearance of digestive organs. In the 1990s, with the development of the charge-coupled device, thinner, more flexible scopes were developed that simplified imaging for the endosonographer and improved patient safety. With the development of linear array EUS scopes, biopsies could be performed utilizing fine needle aspiration. Currently, several therapeutic techniques, which were formerly performed through radiologic or surgical procedures, are being safely done with EUS. These include celiac plexus neurolysis and endoscopic drainage of pancreatic cysts. With the advent of miniprobe technology, better delineation of the wall of the gastrointestinal tract can be obtained, facilitating endoscopic mucosal resection. Novel therapeutic uses for EUS are constantly emerging. This article describes the various extraintestinal applications of EUS that have been developed in the last 25 years. More gastroenterologists need training in order to utilize this challenging technology and improve patient access in the local community setting.
E Keywords Endoscopic ultrasound, fine needle aspiration
ndoscopic ultrasound (EUS) was developed in the 1980s. Its main use at that time was in the staging of gastrointestinal tumors. Initially used as a diagnostic tool, since the early 1990s it has been increasingly utilized in intervention and therapy. Its uses have broadened such that it now has indications for extraintestinal pathology. Use of EUS will continue to grow as new technology, such as the thin miniprobe, dual-plane reconstruction (DPR), intraductal probes, and the new electronic radial echoendoscope, become available. Over the next few years, EUS is foreseen as becoming one of the most powerful gastroenterological, radiological, and therapeutic instruments, catalyzing significant changes in patient management. EUS has been shown to be safe1 and emerging studies indicate that it is cost effective when compared to modalities such as computed tomography (CT) scans, positron emission tomography
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(PET) scanning, magnetic resonance imaging (MRI), angiography, and surgery.2 Immunotherapy, radiofrequency ablation, injection of viruses, gene therapy, and DNA analysis could become established EUS applications in the near future and are currently at various stages of investigation.3 Equipment Radial Scanning Echoendoscope The radial scanning echoendoscope is the most commonly used endoscope. It has either a rotating mechanical transducer at the tip (Olympus Corp) or a fixed, phased-array electronic transducer (Pentax Corp). The mechanical transducer provides a 360-degree image, oriented perpendicularly to the shaft of the scope, whereas the fixed array produces a 270-degree view (Figure 1). The image provided is a cross-sectional view, similar to slices of a CT scan, and is therefore easier to interpret, especially for the novice. The ultrasound frequency ranges between 5 and 20 MHz. It should be noted, however, that higher frequency results in better resolution, but at the expense of depth of penetration, which is relationally decreased. Endosonographers usually use the 5 and 7.5 MHz frequencies to scan and the depth of penetration is usually around 5–6 cm. It should also be noted that Doppler cannot be performed with the mechanical transducer, but is possible with the electronic radial scope. Recently, an electronic, 360-degree radial scanning echoendoscope with Doppler capability and tissue harmonic imaging was introduced by Olympus. The endoscopic view of this scope is forward oblique. The key components of the transducer are the piezoelectric crystals that vibrate to produce ultrasonic waves. Acoustic coupling is usually achieved with a waterfilled balloon around the instrument tip. Linear Scanning Echoendoscope This echoendoscope provides a view parallel to the long axis of the scope, allowing for safe performance of EUSguided fine needle aspiration (FNA; Figure 2). These scopes are manufactured by both Olympus and Pentax and employ electronic, fixed-array technology. Doppler is available, and very useful in differentiating vessels from tissue, especially for FNA. The scope can switch between 5 and 7.5 MHz frequency. The needles commonly used are 19 and 22 gauge. Linear scanning is generally more difficult to learn than radial scanning. High-Frequency Miniprobe Miniaturization of the ultrasound transducer led to the development of the miniprobe. This high-frequency ultrasound probe (HFUP) or catheter is about 2–3 mm in diameter and is passed through the biopsy channel of
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Radial • • • •
360 degrees Similar to CT scan Good screening Ideal for circumferential lesions • Easier to learn • No biopsies
Figure 1. Radial scanning echoendoscope produces 360˚ or 270˚ images. CT = computed tomography.
Linear • Long axis of scope • Allows FNA • Some advantages for vascular staging • Harder to learn
Figure 2. Linear scanning echoendoscope produces images parallel to the scope. FNA = fine needle aspiration.
a regular upper endoscope. The probe has a mechanical rotating transducer at the tip and frequency ranges from 12 to 30 MHz. Recently, DPR probes have been made available for surface and volume rendering and three-dimensional reconstruction. These probes provide detailed imaging of the wall of the gastrointestinal tract and precise depth of penetration of tumor. In contrast to the five-layered wall structure obtained with conventional EUS, HFUP can delineate up to nine layers. Dedicated miniprobes for intraductal ultrasonography (IDUS) are also available from 12.5 to 30 MHz. Extraluminal Applications Pancreatic Adenocarcinoma Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. The 5-year survival rate after postoperative multimodality treatment
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Figure 3. Hypoechoiec lesion (arrows) in the head of the pancreas. Fine needle aspiration confirmed pancreatic adenocarcinoma.
Figure 4. Hypoechoiec lesion in the head of the pancreas obstructing the common bile duct (CBD) and pancreatic duct (PD).
is about 20%.4,5 In the 1980s and early 1990s, EUS was found to be the best modality to locally stage pancreatic cancer (Figures 3 and 4).6,7 With the advancement in technology of other radiological methods, especially multidetector triple-phase CT scanning, later studies report comparable sensitivities and specificities. Tumor staging accuracy ranges from 85% to 93% and nodal staging accuracy is approximately 72%.8 There have been four studies comparing EUS with helical CT for evaluating pancreatic cancer. Two of them9,10 found helical CT and EUS to be equivalent; the other two11,12 found EUS to be superior for tumor detection and staging. The discrepancies in the findings of these four studies have several causes and biases beyond the scope of this article. EUS and helical CT are complimentary. A helical CT should be employed for initial evaluation and EUS should be performed if no evidence of distant metastasis is found. EUS can also determine vas-
cular invasion. EUS is less accurate in evaluating invasion into the superior mesenteric vessels, but is very accurate in diagnosing portal vein invasion.13 Nevertheless, with the advent of surgical portal vein resection, portal vein invasion does not necessarily preclude resection. Detection of vascular invasion by EUS is being challenged by advances in CT technology. Multiplanar reconstruction of major vessels in proximity to tumors revealed a sensitivity of 50–75% and a specificity of 91–97% in a recent study.14 EUS is very sensitive in detecting small pancreatic tumors. Studies comparing EUS with helical CT suggest EUS is more sensitive for tumors smaller than 3 cm.15 Therefore EUS is also indicated when there is clinical suspicion of a pancreatic tumor and other imaging studies are either nondiagnostic or equivocal. Studies comparing EUS and MRI suggest that EUS is more sensitive.16-18 Studies comparing angiography and EUS have varied results, but suggest that EUS is as accurate for determining vascular invasion, except invasion of the superior mesenteric vessels.18-20 A study comparing EUS and PET scanning found a sensitivity of 93% for EUS and 87% for fluorodeoxyglucose-PET.11 PET scanning could have a higher false-positive rate as inflammatory masses cause a positive scan. Problems could arise in differentiating an inflammatory mass from a malignancy in a patient with chronic pancreatitis. The specificity varies from 46% to 93%.21,22 Newer techniques such as contrast-enhanced Doppler imaging could result in improvement in sensitivity and specificity, as adenocarcinomas are hypoperfused and inflammatory lesions are hyperperfused. The establishment of diagnosis can be accomplished by EUS-guided FNA. The complication rate is less than 1%.23 Multiple studies have demonstrated sensitivities between 75% and 90% and specificity between 94% and 100%, implying a false-negative rate between 10% and 25%. If EUS suggests resectability, EUS-guided FNA is not necessary, although this aspect remains controversial. Advantages of needle biopsy include alternative diagnoses such as lymphoma, islet cell tumors, and metastatic disease. The disadvantages include bleeding, pancreatitis, and tumor seeding, a first case of which was recently reported.24 Several studies have evaluated cost-effectiveness and concluded that EUS-guided FNA is a cost-effective strategy, with one study estimating a cost saving of $3,300 per patient based on avoidance of surgery.25,26 Neuroendocrine Pancreatic Tumors Neuroendocrine pancreatic tumors are rare tumors, with an incidence of less than 1 per 100,000 people. EUS is very sensitive in detecting these small tumors. Sensitivities vary from 82% to 93% and specificity is over 90%.27,28 EUS is
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Simple Cysts: These are usually small in size and are congenital. They are benign, with thin walls, filled with clear fluid, and without septation. Serous Cystadenomas: These are usually benign, seen mostly in women in the seventh decade of life. These tumors tend to be located in the body and tail of the pancreas. Up to 10% of serous cystadenomas have central calcification, causing a characteristic sunburst pattern. They can also have multiple microcysts, forming a honeycomb pattern (Figure 5). FNA reveals low-viscosity fluid with low tumor markers and glycogen-containing cuboidal cells. If these tumors cause symptoms, such as abdominal pain, they can be resected; otherwise they can be left alone.
Figure 5. Two images showing honeycomb pattern of serous cystadenoma with thin septae.
comparable to somatostatin receptor scintigraphy (SRS) for detecting pancreatic gastrinomas, and more accurate for insulinomas due to the low density of SRS receptors. Both tests are clearly superior to CT, which has a detection rate of about 60% at best. Both techniques, however, miss a significant proportion of duodenal gastrinomas.29 Because there is a more frequent incidence of extrapancreatic tumors, EUS is frequently used in conjunction with other modalities such as SRS and triple-phase CT. Screening for Pancreatic Cancer A recent study recommended screening for pancreatic cancer in familial pancreatic cancer kindreds. The diagnostic yield for detecting clinically significant pancreatic neoplasms was 5.3%.30 No recommendations are known for surveillance after initial screening. Cystic Lesions of the Pancreas There are five basic types of cystic lesions that are encountered in the pancreas.
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Mucinous Cystadenomas: These tumors have malignant potential, with approximately 25% harboring malignancy at the time of diagnosis. They are usually asymptomatic, but can cause abdominal pain, pancreatitis, diabetes, and jaundice. They are usually found in women in the fifth and sixth decades of life and are located in the body and tail of the pancreas. Mucinous cystadenomas contain multiple fluid-filled cavities with thin wall septae (Figure 6), the cavities being much larger (>1 cm) than the microcysts seen in serous cystadenomas. FNA is usually performed on the nearest and largest cavity, and the cavity is completely drained to prevent infection. Antibiotics are usually administered prior to FNA and for about a week after. Mucous and mucous-filled cuboidal or columnar cells are seen in about 30–50% of cases. The tumor marker that is particularly helpful in determining a mucinous tumor is the carcinoembryonic antigen (CEA) level in cyst fluid. A recent prospective study found that a CEA level of 192 ng/mL using the receiver-operating curve analysis provided a sensitivity of 75% and a specificity of 84%.31 All mucinous cystadenomas are potentially malignant and should be resected. Intraductal Papillary Mucinous Neoplasm: These tumors arise from the epithelium of the pancreatic duct and have malignant potential. They are usually diagnosed in men in the sixth and seventh decades of life. Blockage of the pancreatic duct with mucous or growth accounts for symptoms of abdominal pain, pancreatitis, weight loss, diabetes, and steatorrhea. EUS reveals a dilated pancreatic duct, segmental duct dilation, or side branch dilation in the presence of normal echotexture of the pancreas. EUS-guided FNA of the dilated pancreatic duct can be performed. IDUS and pancreatoscopy are other methods that can be used to aid in diagnosis. The recommendation is limited resection, if possible, and avoidance
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Figure 6. Mucinous cystadenoma with papillary projections from the cyst wall (arrows).
Figure 7. Large pancreatic pseudocyst with fine debris.
of total pancreatectomy as recurrence rates are comparable after partial or total pancreatectomy for invasive disease. This avoids the serious metabolic consequences of a total pancreatectomy. Pseudocysts: These benign cysts are inflammatory collections of fluid that stem from duct disruption. They are usually seen in patients with chronic alcoholic pancreatitis. Signs detected with EUS include a hyperechoic thick wall, lack of septations, and internal echoes representing debris (Figure 7). FNA usually reveals a fluid with low viscosity, high amylase levels, low tumor markers, and histiocytes. Pseudocysts can be drained using EUS as guidance, especially if they are symptomatic. The advantages of using EUS include gauging the distance between the cyst wall and the gut wall (which should be 1 cm, round, homogeneous echo pattern, sharp borders), sensitivity was 83% with a 98% specificity.65 Accuracy is increased to 98% with the addition of FNA.66 EUS-guided FNA is superior to CT scanning in detecting malignant celiac lymph nodes. A recent study indicated that CT detected only 30% of
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Trachea
Level 2 Level 4
Aorta Level 5 (AP Window) Level 7 (Subcarina)
Esophagus Level 8
Figure 10. American Joint Committee on Staging of Cancer; lymph node stations. AP = aortopulmonary.
malignant nodes diagnosed by EUS-guided FNA and that EUS-guided FNA significantly affected subsequent patient management.67 Left Adrenal Gland Lesions The left adrenal gland is visualized on EUS as “seagullshaped”; the right is not usually seen. Metastatic cancer to the adrenal gland carries a grave prognosis and precludes curative surgical resection. Eloubeidi and colleagues68 found that EUS-guided FNA of the left adrenal gland was safe and confirms or excludes malignant adrenal involvement in patients with thoracic or gastrointestinal malignancies. Mediastinal Lymphadenopathy EUS can accurately assess mediastinal lymphadenopathy. Lung cancer is the most common cause of cancer-related death in the West and about 80% of cases are due to non–small cell lung cancer (NSCLC). Unfortunately, nearly 50% of patients harbor mediastinal disease at presentation. Direct mediastinal invasion or spread to contralateral lymph nodes (N3) is staged as IIIB disease; it is unresectable and treated with chemoradiation. Metastasis to ipsilateral and subcarinal nodes (N2) is classified as stage IIIA disease. Management is controversial. Most centers treat with chemoradiation only, but some centers offer surgery after adjuvant therapy. EUS can visualize posterior lymph node stations only (5 and 7), as air in the trachea prevents visualization of the anterior stations (2 and 4; Figure 10). Mediastinoscopy can stage anterior lymphadenopathy, but is associated with a complication rate of 2–3% and requires general anesthesia and a longer hospital stay. It cannot evaluate posterior lymph-
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adenopathy. Nevertheless, both investigations should be regarded as complementary. EUS is highly accurate with a sensitivity of approximately 93% and a specificity of nearly 100%.69 EUS has been found to be superior to CT and PET scanning.70 In a recent large study EUS-FNA detected mediastinal disease in 10 of 24 patients (42%) without mediastinal adenopathy on CT.71 Another study by Wallace and associates72 in patients with NSCLC with nodes less than 1 cm by CT revealed advanced disease in 25% of patients by EUS-guided FNA. Transbronchial node aspiration (TBNA) performed during bronchoscopy is usually a blind procedure limited to pretracheal, paratracheal, and subcarinal areas, with yield varying from 20% to 70%. Recently, Krasnik and associates73 reported promising experience with a prototype realtime endobronchial ultrasound (EBUS)-TBNA bronchoscope. The same investigators in a later study combined transesophageal EUS-guided FNA and EBUSTBNA biopsy in the evaluation of mediastinal masses. They were found to be complementary and the accuracy for diagnosis of mediastinal cancer was 100%. The investigators concluded that the combined approach may be able to replace more invasive methods for evaluation of mediastinal cancer.74 Currently, EBUS is being performed at select centers in the United States and Europe. EUS is also very accurate in diagnosing other diseases affecting the mediastinum, such as sarcoidosis, histoplasmosis, tuberculosis, lymphoma, and metastasis from other primary tumors.75 Conclusion EUS is a new endoscopic tool that has revolutionized how gastrointestinal diseases are managed, particularly gastrointestinal tumors. It has numerous diagnostic and therapeutic indications, which continue to expand. There is a steep learning curve and a need for more gastroenterologists to be trained in this advanced procedure. It usually takes a dedicated year of training to become reasonably skilled in the technique. Parada and colleagues,76 in a resource utilization projection study, concluded that current EUS resources are not sufficient to meet the demand in the United States. If more gastrointestinal programs offered advanced fellowships in EUS, this potential problem could be averted. Higher reimbursement for the procedure could make the sacrifice of an additional year of fellowship worthwhile. Reduced equipment costs (currently between $300,000 and $350,000) could also help mainstream EUS into community practices. The ultimate goal is to make EUS easily accessible to all gastroenterologists, so that patients do not have to travel great distances and the most effective management options are available at home.
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27. Rosch T, Lightdale CJ, Botel JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasound. N Engl J Med. 1992;326:1721-1726. 28. Anderson MA, Carpenter S, Thompson NW, et al. Endsocopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol. 2001;95:2271-2277. 29. Cadiot G, Lebtahi R, Sorda L, et al. Prospective detection of duodenal gastrinomas and peripancreatic nodes by somatostatin receptor scintigraphy. Gastroenterology. 1996;111:845-854. 30. Canto IM, Goffons M, Yeo CJ, et al. Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol Hepatol. 2004;2:606-621. 31. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. The diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology. 2004;126:1330-1336. 32. Giovannini M, Bernardini D, Seitz JF. Cystogastrostomy entirely performed under endosonography guidance for pancreatic pseudocyst-results in six patients. Gastrointestinal Endosc. 1998;48:200-203. 33. Seifert H, Wehrmann T, Schmitt T, et al. Retroperitoneal endoscopic debridement for infected peripancreatic necrosis. Lancet. 2000;365:653-655. 34. Sahai AV. EUS and chronic pancreatitis. Gastrointest Endosc. 2002;56(suppl): S76-S81. 35. Catalano MF, Lohati S, Geenan JE, Hogan WJ. Prospective evaluation of endoscopic ultra-sonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointestinal Endosc. 1998;48:11-17. 36. Wallace MB, Hawes RH, Durkalski V, et al. The reliability of EUS for the diagnosis of chronic pancreatitis: interobserver agreement among experienced endosonographers. Gastrointestinal Endosc. 2001;53:294-299. 37. Hollerbach S, Klamann A, Topalidis T, Schmiegel WH. Endoscopic ultrasonography (EUS) and fine-needle aspiration (FNA) cytology for diagnosis of chronic pancreatitis. Endoscopy. 2001;33:824-831. 38. Farrell JJ, Garber J, Sahani D, Brugge W. EUS findings in patients with autoimmune pancreatitis. Gastrointestinal Endosc. 2004;60:927-936. 39. Draganov P, Forsmark CE. “Idiopathic” pancreatitis. Gastroenterology. 2005;128:756-763. 40. Chen R, Hawes R, Wallace M, Hoffman B. Diagnosing pancreas divisum in patients with abdominal pain and pancreatitis: Is endoscopic ultrasound (EUS) accurate enough? [abstract] Gastrointest Endosc. 2002;55: Abstract 578. 41. Bhutani MS, Hoffman BJ, Hawes RH. Diagnosis of pancreas divisum by endoscopic ultrasonography. Endoscopy. 1999;32:167-169. 42. Gunaratnam NT, Sarma AV, Norton ID, Weirsema MJ. A prospective study of EUS-guided celiac plexus neurolysis for pancreatic cancer pain. Gastrointestinal Endosc. 2001;54:316-324. 43. Gress F, Schmitt C, Sherman S, et al. A prospective randomized comparison of endoscopic ultrasound and computed tomography-guided celiac plexus block for managing chronic pancreatitis pain. Am J Gastroenterol. 1999;94:900-905. 44. Penman I, Henry E. EUS guided celiac plexus neurolysis. Digestive Endoscopy. 2004;16(suppl):S206-S208. 45. Amouyal P, Amouyal G, Levy P, et al. Diagnosis of choledocholithiasis by endoscopic ultrasonography. Gastroenterology. 1994;106:1062-1067. 46. Palazzo L, Girollet P, Salmeron M, et al. Value of endoscopic ultrasonography in the diagnosis of common bile duct stones: comparison with surgical exploration and ERCP. Gastrointesy Endosc. 1995;42:225-231. 47. Prat E, Amouyal G, Amouyal P, et al. Prospective controlled studey of endoscopic ultrasonography and endoscopic retrograde cholangiography in patients with suspected common bile duct lithiasis. Lancet. 1996;347:75-79. 48. Norton SA, Alderson D. Prospective comparison of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in the detection of bile duct stones. Br J Surg. 1997;84:1366-1369. 49. Canto MI, Chak A, Stellato T, Sivak MV Jr. Endoscopic ultrasonography versus cholangiography for the diagnosis of choledocholithiasis. Gastrointestinal Endosc. 1998;47:439-448. 50. de Ledinghen V, Lecesne R, Raymond J, et al. Diagnosis of choledocholithiasis: EUS or magnetic resonance cholangiography? A prospective controlled study. Gastrointest Endosc. 1999;49:26-31. 51. Scheiman JM, Carlos RC, Barnett JL, et al. Can endoscopic ultrasound or magnetic resonance cholangiopancreatography replace ERCP in patients with suspected biliary disease? A prospective and cost analysis. Am J Gastroenterol. 2001;96:2900-2904. 52. Dahan P, Andant C, Levy P, et al. Prospective evaluation of endoscopic ultrasonography and microscopic examination of duodenal bile in the diagnosis of cholecystolithiasis in 45 patients with normal conventional ultrasonography. Gut. 1996;38:277-281.
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