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Lecture Syllabus on Endoscopic Ultrasound

Introduction

Individuals from Japan, Germany and the United States first developed Endoscopic Ultrasound (EUS) in the early 1980's. This technology grew out of the frustration of the limitations of transabdominal ultrasound. In the last 15 years, many technical hurdles have been overcome and EUS is now established as the most accurate preoperative staging procedure for gastrointestinal and pancreatic malignancies. Many other "benign" conditions such as submucosal lesions of the GI tract and thickened gastric folds as seen by UGI or EGD are areas where EUS is invaluable. EUS is presently evolving from a staging and diagnostic tool to an interventional procedure much like what was seen with ERCP and cardiac catheterization. Primary care physicians initially diagnose many of these tumors; therefore, understanding its role in clinical medicine will significantly affect the practices of those physicians with access to this technology.

TNM Staging

The American Joint Committee on Cancer (AJCC) and The International Union Against Cancer (UICC) have created evolving recommendations regarding tumor staging and stage groupings. The TNM system has now been established worldwide. Hopefully, this will lead to more accurate pre- and post-operative staging, which ultimately affects treatment, prognosis, and outcome. "T" is the depth of tumor extension through the wall of the GI tract, "N" is the presence of tumor in local lymph nodes, and "M" is distant metastasis or invasion of adjacent organs (Figure 1). Stage groupings are then determined by the TNM stage. (Figures 2). EUS can provide high quality images of the GI tract wall that roughly correlate with GI histological layers (Figure 4). A typical five layer image is obtained (figure 3) which correlates with the mucosa, muscularis mucosa, submucosa, muscularis propria and serosa (adventitia, if one is in the esophagus). This correlation forms the basis of EUS tumor staging utilizing the TNM system.

Equipment

There are two basic types of instruments utilized to perform EUS. The tool with the longest track record is the Olympus radial scanning instrument. There is a 360 degree image, which is generated perpendicular to the long shaft of the endoscope. There is a water filled balloon surrounding the tip to provide an acoustical interface with the wall of the GI tract. The second type is a sector scanner, utilizing linear array technology and providing a 100 degree field of view for the Pentax/Hitachi system (FG-36UA) and 180 degrees for the new Olympus/Acoustic imaging echoendoscope (GF-UC30P). Both of the latter instruments are capable of performing real-time ultrasound guided fine needle aspiration/biopsy (FNA) and have Doppler and color-flow capabilities They also use a water filled balloon surrounding the tip of the instrument. All of the instruments have oblique optics, which limits the endoscopic field of view. The radial scanning Olympus instrument has two frequencies, i.e. 7.5 and 12 MHz. The Pentax FNA scope has 5.0 and 7.5MHz frequencies, while the Olympus FNA instrument has only a 7.5 MHz frequency. Olympus also manufactures a non-Doppler FNA instrument called the GUMP scope, but its use is limited for FNA, given its lack of Doppler capabilities. Other EUS tools manufactured by the Olympus corporation include miniature ultrasound probes that can be passed through the biopsy channel of a endoscope and directed at the area of interest. They have now developed balloon covered sheaths which help form an acoustical interface with the lesion in question. These probes are especially helpful in cases of esophageal stenosis, whereby the dedicated instrument cannot be passed, and in very small lesions in the GI tract that can be difficult to find with dedicated EUS scope. They can also be passed through an ERCP scope and aid in staging of CBD and ampullary cancers. Their main limitation is lack of depth of penetration of the ultrasound beam given their high frequencies of 12 and 20MHz. Olympus also manufactures an echocolonoscope, which has front viewing optics and a 300 degree ultrasound image. This tool is presently being studied for its ability to predict which patients are suitable for laparoscopic colectomy versus a standard operation for colon cancer.

Technical Considerations

Standard transcutaneous ultrasonography has become popular due to its safety, low cost, availability and non-invasive nature. However, its overall utility for GI disorders has been hampered due to the presence of intestinal gas and bone, both of which US is incapable of penetrating. The mediastinum cannot be seen due to the air filled lungs, ribs and spine. Also, the depth of penetration needed to visualize many GI tract organs cannot be reached with traditional ultrasound transducers. A standard principle of ultrasound is that as frequency increases the depth of penetration decreases but the image quality and resolution improve and visa versa. Therefore, to image the pancreas transcutaneously (if it can be completely seen through bowel gas), one must utilize frequencies of 1-3MHz. EUS bypasses many of these limitations by allowing the ultrasound transducer to be adjacent to the organ in question. One can then utilize a water-filled balloon and/or water-filling of the organ in question then apply high frequencies to investigate lesions in the wall or of surrounding organs such as the pancreas.

Technique

A standard upper or lower endoscopy is almost always performed prior to EUS to accurately localize the area in question. For instance, in esophageal cancer, given the fact the optics are oblique, the location of the tumor is first established by EGD then the centimeter markings from the distal and proximal margins are utilized to guide complete visualization of the tumor throughout its length. In the esophagus, the water filled balloon technique is most often utilized given the risk of aspiration, but for lesions in the stomach, duodenum, and rectum a combination of water in the lumen and the balloon can be used. The endosonographer must be careful to avoid oblique scanning which can overstage tumors and must be sure (if technically possible) to scan the tumor and its associated lymph nodes throughout its length. In the esophagus it is also critical to evaluate the area of the Celiac trunk since nodes found in this area carry the same poor prognosis as do distant metastasis. Standard positions are scanned in the esophagus, stomach, and duodenum to evaluate extraluminal and retroperitoneal structures.

Clinical Utility of Endoscopic Ultrasound

Submucosal Lesions

The differential diagnosis of submucosal tumors of the GI tract are listed in Table I. Many of these lesions are found on routine endoscopy, UGI series, or rectal examination. Often they are simply other organs pressing on the wall of the GI tract but not always. Up to 10% of all esophageal and 50% of all gastroduodenal tumors are benign "submucosal" lesions. The term submucosal is confusing since it could be interpreted as meaning the lesion arises in the submucosa. However, most do not, and in fact, 50% are Leiomyomas arising from the muscularis propria or less often from the muscularis mucosa. Until the advent of EUS, most of these lesions remained undiagnosed due the fact they cannot be readily seen on traditional US, CT, or MRI. EUS allows for the most accurate assessment of the layer of origin, size, shape, echotexture, and whether they are cystic, solid, vascular or non-vascular, extramural or intramural. For example, Leiomyomas are classically round or ovoid, hypoechoic (dark) or heterogeneous in its echotexture (Figure 5) and almost always arise from the fourth hypoechoic layer corresponding to the muscularis propria. Although EUS can strongly suggest that a lesion is a Leiomyoma, differentiating a benign from a malignant tumor remains difficult. Controversy exists in calling these lesions malignant even when the entire specimen has been removed, therefore the addition of EUS-FNA may not add much to standard EUS. Esophageal and gastric varices can sometimes mimic "submucosal tumors" and biopsy of such lesions would be potentially disastrous. EUS can clearly identify these as varices and avoid unnecessary complications. Lipomas are the next most common submucosal tumor or the GI tract. They are easy to differentiate from Leiomyomas due to the fact they arise in the true submucosal layer, and are echogenic (bright).

Esophagus

Endosonography is utilized for a number of different disorders of the esophagus but most often for staging of esophageal and esophagogastric cancers. EUS has been shown to be unequivocally the single best method for establishing accurate TNM staging and predicting survival base on this preoperative data. (Figure 6). When compared to Computerized tomography (CT) overall accuracy is 85-90% versus 60% for T stage and 84% versus 60% for N staging. However, given the fact EUS cannot fully evaluate the lungs and liver, CT is superior to EUS for overall M status (presence of distant metastasis) 90% versus 70%. The celiac axis is an area of difficulty for many imaging modalities but easily seen in 95-100% of all patients by EUS. As mentioned earlier if EUS suggest their are metastatic lymph nodes in this area using standard EUS criteria for malignant nodes (round, dark, sharp margins, greater than 1cm in size) or it is definitively proven via EUS-FNA this precludes the use of surgery as a curative procedure. In addition, recent studies have shown the utility of EUS for identifying early recurrences while patients were still asymptomatic done on 6 month intervals post resection for esophageal or gastric cardia cancer. Other uses for EUS in the esophagus also include the differentiating of primary from secondary achalasia in cases where the later is suspected but a tissue diagnosis cannot be established. It has also been studied in Barrett's esophagus, but its utility at the present frequencies has not been clearly established. EUS guided injections of Botulinum toxin for the treatment is also being evaluated.

Stomach

EUS has been utilized for many benign disorders of the stomach. These include varices, submucosal tumors, and for the complete evaluation of enlarged gastric folds. Many times UGI or EGD reveals thickened folds are but the exact nature of why they are thickened remains unclear. The differential diagnosis of thickened gastric folds includes H. Pylori, Menetrier's disease, Hypertrophic hypersecretory gastropathy, amyloidosis, syphilis, lymphoma, and linitis plastica. Certain EUS patterns can help narrow the differential and provide a tissue diagnosis or recommend surgery even if a tissue diagnosis has not been established. This is especially true in cases of linitis plastica where the fourth layer is thickened and mucosal biopsies are often negative. The TNM staging of gastric cancer is again best accomplished by a combination of EUS plus CT for distant metastasis. For T staging EUS is more accurate than CT i.e. 92% versus 42% and for N staging 78% versus 48%. EUS can also help predict resectability. As for esophageal cancer, one can asses for recurrences at the anastomotic site post-operatively. Gastric lymphoma staging has clearly been established as an indication for EUS due to its excellent T and N staging accuracy (91% and 82% respectively. It is also quite useful in assessing the response to chemotherapy and possibly the risk of perforation sometimes seen during treatment.

Pancreas

When a pancreatic lesion is suspected by history or physical exam the first order of business is to image the pancreas. This can be accomplished by a number of methods including CT, MRI, and ultrasound. Although standard US is often the first test, a CT is almost inevitable if the clinical scenario fits or of the patient has had an abnormal ERCP. If the lesion is greater than 3cm most of the above technologies should be able to provide useful information. A CT is very important for ruling out distant metastasis and for detection of advanced local invasion, which helps to define "operability" versus "resectability. Unfortunately, most pancreatic cancers are far advanced by the time they present clinically and therefore we need to better define who will or will not benefit from surgery. EUS alone, or now in combination with EUS-FNA (fine needle aspiration), has been shown in many large studies to be the most accurate method for preoperative staging of pancreatic cancer. The smaller the pancreatic lesion the larger the difference. In a recent study by T Rosch et al looking specifically at detecting tumors less than 3cm EUS had a sensitivity an specificity of 100%/100% versus 90%/73% for ERCP, 55%/53% for CT, and 50%/40% for US. EUS has high accuracy in predicting true resectability do to its ability to image vascular invasion of the splenic and portal vein along with the superior mesenteric vein and artery. It has been shown to be superior to all other imaging studies including angiography. This has been accomplished without Doppler. Therefore, if one encounters a patient with obstructive jaundice and is found to have a pancreatic tumor by another imaging study and there is no CT evidence of that would preclude surgery, the next test of major importance is the EUS with or without FNA. (Figure 7). If vascular invasion is identified attempts at curative resection will be futile. EUS is also superior to other imaging studies for the localization of pancreatic endocrine tumors. EUS in combination with nuclear medicine studies designed to localize neuroendocrine tumors are the most accurate test available. This is likely so because most of the endocrine tumors are less than 3cm making the accuracy of traditional imaging decrease significantly. EUS and its superiority for local staging also hold true for ampullary carcinoma.

Rectum/Anal Sphincter

Rectal cancer is accurately staged by EUS. It has been shown to be superior to all other imaging modalities with a overall T stage accuracy of 89% and 79% for N stage. This highly accurate staging can help the clinician and patient choose the appropriate preoperative treatment depending on the TNM stage. (Figure 8). It is often times utilized to help the gastroenterologist or surgeon decide if snare polypectomy of a sessile lesion or transanal resection of a superficial cancer (T1orT2) can be employed instead of a much larger operation possibly requiring colostomy with AP resection. Anal sphincter EUS has also been employed to help the colorectal surgeon in guiding sphincter repair after injuries from previous surgery or obstetrical injury in patients complaining of incontinence.

Miscellaneous

Other less frequent uses for EUS include, evaluation of perirectal abscess, assessing motility disorders, and investigating the Gallbladder, bile duct, and pancreas without ERCP. In a recent study, Dill et al studied 66 patients with "Gallbladder-like" symptoms and a negative transabdominal ultrasound and found 86% of the patients had sludge or small stones by EUS. Approximately 90% of these patients underwent cholycystectomy and most remained pain free at one year. There are presently in development EUS criteria to aid in the diagnosis of chronic pancreatitis. EUS assisted drainage of pancreatic pseudocyst into the stomach is not infrequently performed.

EUS Guided-FNA

Although EUS is the best staging tool for all GI malignancies there has still been some reluctance on the part of physicians to avoid surgery because of the small chance a lymph node called positive by EUS is really a false positive. Similarly, the oncologist or radiation therapist will not introduce more or less aggressive chemotherapy or radiation without tissue to prove it is necessary. EUS-FNA provides the information needed for all individuals involved in these difficult cases. EUS-FNA is also helping the pulmonologist and chest surgeons avoid unnecessary surgery inpatients with non-small cell cancer of the lung. This procedure, utilizing a linear array instrument, which enables one to monitor the passage of the needle into the mediastinum, pancreas, adrenal gland, celiac axis, and pararectal area, has advanced our abilities to obtain tissue and further improve staging accuracy. This in turn helps patients avoid unnecessary, painful, and costly surgery and will help oncologists choose more accurately their treatment plans. Hopefully, this will lead to prolonged survival or cures for these dreadful diseases. Not only can lymph nodes be sampled, but fluid collections in the chest or abdomen can be aspirated, cytology performed, and if positive, this precludes surgery as a viable treatment option. EUS-guided Celiac axis ganglion blocks are also possible for patients with intractable pain from pancreatic cancer. In a recent study, Chang et al described how EUS-FNA would affect treatment decisions and found that out of 50 patients, 25 avoided unnecessary surgery. Other studies have confirmed that EUS alone or in combination with FNA can markedly alter treatment decisions for many different diseases. There is also tremendous cost saving provided by avoidance of unnecessary surgery.

Conclusions

Endoscopic ultrasonography has been a major advancement in the management of both benign and malignant gastrointestinal diseases. It allows us to visualize individual wall layers of the GI tract and adjacent structures making it superior to other imaging modalities. The primary care physician, with access to a center where EUS and EUS-FNA are performed, can now raise the level of care he/she provides by helping patients avoid surgery if the likelihood of benefit is nil or direct the patient toward surgery if the staging is favorable. Patients with benign diseases, such as unexplained abdominal pain, can now benefit from less invasive testing to determine if GB removal may be useful or if unsuspected pathology in the CBD or Pancreas is the source. EUS will continue to improve and evolve in a similar fashion to ERCP and steadily increase its role in our everyday practices.

Table 1

Differenetial Diagnosis of Submucosal Tumors of the GI Tract

Brunner's Gland Hyperplasia	Leimyoblastomas
Carcinoid	Leimyoma
Duplication Cys	Leimyosarcomas
Fibroid Polyp	Lipoma
Fibrovascular Polyp	Lynphangioma
Glomus Tumor	Neural Tumor
Granular Cell Tumor	Pancreatic Rest
Hemangioma

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