Computerized tomography colonography (CTC), also referred

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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:497 502 CLINICAL IMAGING Computerized Tomography Colonography: A Primer for Gastroenterologists PERRY J. PICKHARDT and DAVID H. KIM Department of Radiology, University of Wisconsin Medical School, Madison, Wisconsin Computerized tomography colonography (CTC), also referred to as virtual colonoscopy, is a radiologic examination of the large intestine that was first introduced in the mid-1990s. Since that time, CTC has undergone rapid evolution resulting in greatly improved diagnostic capabilities. As such, CTC has recently joined optical colonoscopy as a front-line diagnostic tool for total colonic examination, including use as a primary screening tool. 1 This primer is intended to provide gastroenterologists with enough basic information about this novel imaging test to allow for rational clinical decision making. Following up a case example, this overview will cover fundamental technical aspects, image interpretation, performance characteristics, and indications for CTC in clinical practice. The status of reimbursement for screening CTC from third-party payers also is addressed briefly. The CTC techniques used at the University of Wisconsin, which have been validated clinically, 2,3 are emphasized herein. Case Example An asymptomatic, average-risk, 50-year-old woman underwent routine CTC examination for colorectal cancer screening. Two unsuspected colonic abnormalities were identified (Figure 1). In the distal ascending colon, a large eccentric 5-cm soft tissue was present, highly concerning for invasive adenocarcinoma. Within the midsigmoid colon, a segment of annular soft-tissue thickening was seen that was less bulky but resulted in marked luminal narrowing that persisted on both supine and prone views. There was no evidence of diverticular disease. The patient subsequently was referred to same-day optical colonoscopy, but the endoscope could not be passed beyond the sigmoid stricture. Given the likely cancer in the ascending colon by CTC, the patient was referred for surgical evaluation. For the sigmoid stricture, the combined virtual and optical colonoscopic features favored a benign etiology but a synchronous cancer could not be excluded. Despite the lack of tissue diagnosis, the patient underwent surgery on the basis of the CTC findings, which confirmed both lesions. Pathologic evaluation revealed stage I colonic adenocarcinoma at the hepatic flexure and endometriosis of the sigmoid colon, both of which were unsuspected diagnoses before CTC screening. This case shows the complementary value of CTC evaluation, which provided important diagnostic information that was unobtainable by optical colonoscopy. Technical Overview This section covers the technical aspects of performing CTC, including bowel preparation, colonic distention, and multidetector CT (MDCT) scanning. The basic concept behind CTC is straightforward and simply represents MDCT imaging of a patient with a properly prepared and gas-distended colon. 4 This portion of the examination lasts approximately 10 to 15 minutes, after which the patient can return to regular activities. The MDCT images then are sent to a dedicated CTC software system for interpretation. Robust bowel preparation is important for accurate polyp detection at CTC and requires both cleansing and tagging. Our current low-volume preparation has proven highly effective and combines 3 basic components: a laxative for catharsis, dilute (2%) barium for tagging of any solid residual stool, and watersoluble iodinated contrast (diatrizoate) for opacification of residual luminal fluid. 4,5 This preparation is taken the evening before the examination, in conjunction with a clear liquid diet. In our experience with more than 5000 examinations, we have yet to encounter any significant complications, preparationrelated or otherwise. Sodium phosphate is our standard laxative, used in nearly 90% of cases, and is given as a single 45-mL dose. For patients with renal or cardiac dysfunction, or for elderly patients with hypertension (especially if taking an angiotensin-converting enzyme inhibitor), magnesium citrate is substituted. Polyethylene glycol is reserved for the rare patient who cannot tolerate any relevant fluid shifts and is used in less than 1% of cases. Not only is polyethylene glycol associated with the lowest patient compliance (because of the large volume), it also results in more residual luminal fluid at CTC. 6 Regardless of which laxative is used, the dual oral-contrast regimen is held constant. The complementary actions of the dilute barium and diatrizoate provide for optimal bowel preparation for CTC. The basic rationale is that the laxative provides catharsis for the bulk removal of fecal material, the barium tags any residual solid stool that remains, and the diatrizoate serves the dual purpose of uniform fluid tagging and secondary catharsis. In our experience, the dilute 2% barium has never caused a significant problem at same-day colonoscopy, which includes well over 1500 procedures dating back to the Depart- Abbreviations used in this paper: CTC, computerized tomography colonography; 3D, 3-dimensional; 2D, 2-dimensional; MDCT, multidetector computerized tomography. 2008 by the AGA Institute 1542-3565/08/$34.00 doi:10.1016/j.cgh.2008.02.048

498 PICKHARDT AND KIM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 5

May 2008 CTC: A PRIMER 499 ment of Defense trial. Given the improved performance characteristics seen with the use of oral contrast tagging in CTC, it should be regarded as standard technique and used whenever possible. In our experience, false-positive interpretations from residual stool are rare. Adequate luminal distension of the colon, like proper bowel preparation, is a critical component of technical success in CTC. Our distention protocol has continued to evolve and improve, resulting in inadequate segmental distention in less than 1% of cases. 7 When short-segment collapse persists on all views in the same area, it almost always involves a portion of sigmoid colon affected by severe diverticular disease. As such, examination of the remainder of the colon is almost always diagnostic, resulting in much greater coverage than an incomplete optical colonoscopy owing to the same underlying process, where the endoscope cannot be advanced to the right colon. The use of large, rigid, retention balloon catheters designed for the barium enema rarely is needed for performing virtual colonoscopy. Rather, the small-caliber flexible catheters with low-pressure retention cuffs specifically designed for virtual colonoscopy generally are more appropriate. Automated carbon dioxide (CO 2 ) delivery represents the frontline distention technique in CTC, with manual room air insufflation serving as a seldom used back-up. Nearly all reported perforations at CTC have involved the use of manual staff-controlled room air insufflation in patients with significant colonic disease, whereas the risk of perforation with automated or patient-controlled distention methods is extremely low. 8 With regard to both the degree of colonic distention and postprocedural discomfort, automated CO 2 is superior to the manual room air technique. 7 In our opinion, spasmolytics generally are unnecessary and best avoided. If focal collapse persists at the same point on both supine and prone scans, a third set of images is obtained, typically in the right lateral decubitus position. Our MDCT scanning protocol is straightforward. Obtaining both supine and prone scanning is mandatory given the invaluable complementary data provided. Although 8- or 16-channel MDCT scanners are preferred, adequate CTC examinations can be performed with 4-channel MDCT scanners. 2 A typical 16- channel MDCT protocol uses 1.25-mm collimation and 120 kv p. Given the nature of the soft tissue air interface for polyp detection at CTC, the ma level can be lowered significantly relative to a standard intravenous contrast-enhanced CT examination. To optimally minimize the delivered dose, we prefer a tube-current modulation system, which generally results in an effective dose of approximately 5 msv. For MDCT scanners that are not equipped with a tube-current modulation system, one generally can use a technique in the range of 35 to 75 mas (effective), with individualized increases as necessary for morbidly obese individuals. Although dose reduction is a desirable goal for screening of asymptomatic adults, it is reassuring to note that the very small theoretic risk of low-dose radiation exposure clearly is outweighed by the actual risk of not being screened for colorectal cancer. 9,10 Furthermore, this theoretic risk from radiation also is outweighed by the well-documented actual procedural risks associated with colonoscopy, which is the current standard for total colonic examination. Because of the high diagnostic accuracy of CTC when oral contrast tagging and 3-dimensional (3D) polyp detection are used, the use of intravenous contrast is not indicated for asymptomatic screening. However, intravenous contrast can be valuable in the setting of incomplete colonoscopy from an occlusive carcinoma and occasionally for suspected submucosal lesions. This protocol entails obtaining a low-dose prone scan first, followed by a postcontrast supine scan with standard diagnostic technique. Image Interpretation An absolute prerequisite for successful CTC interpretation is a solid foundation in CT image interpretation, including the use of advanced visualization software. CTC interpretation requires frequent correlation between the 3D volume-rendered and 2-dimensional (2D) multiplanar reformat displays to ensure accurate results (Figure 2). Although the 3D endoluminal view is highly sensitive for polyp detection, this display is nonspecific and requires 2D correlation to distinguish true soft-tissue polyps from a host of false-positive pitfalls. 4 Therefore, CTC cannot be interpreted from the 3D display alone because the specificity would approach zero by rendering almost every negative examination (falsely) positive. Diagnostic redundancy is the key to accurate polyp detection at CTC. Our combined 3D-2D interpretive approach emphasizes 3D polyp detection but also retains the complementary value of 2D detection. The basic concept behind our interpretive approach is that the more sensitive but less specific display (3D endoluminal) is best for initial polyp detection, whereas the more specific but less sensitive display (2D) is used for confirmation of suspected lesions and for secondary polyp detection. Although the 2D display is vital for confirming the soft-tissue nature of polyps, it is a rather ineffective and tedious method for initially detecting them, largely because of their poor conspicuity among the colonic folds. 11 Primary 2D evaluation, however, can be quite useful for annular lesions, fluid-filled areas (assuming oral contrast tagging has been applied), and segments with partial or total luminal collapse. Continual software improvements with the CTC system we use have resulted in ever more efficient and accurate interpretations. Primary 3D endoluminal review entails automated centerline fly-through of the supine and prone models with manual navigation as needed for further inspection of suspicious areas. A 4 Figure 1. Low-dose screening CTC examination in an asymptomatic average-risk 50-year-old woman. (A) The 3D colonic map marks the location of 2 colonic abnormalities identified at CTC, one in the ascending colon near the hepatic flexure (arrows) and the other in the midsigmoid colon (arrowhead). (B) 3D endoluminal CTC image shows a large, lobulated mass in the distal ascending colon that measured 5 cm and was highly concerning for invasive cancer. (C) 2D transverse prone CTC image confirms the large, nonobstructive, soft-tissue mass (arrow) near the hepatic flexure. No definite metastatic disease was identified on this noncontrast examination or at subsequent intravenous contrast-enhanced CT (not shown). (D) 2D transverse prone CTC caudal to C shows an area of annular soft-tissue thickening and luminal narrowing involving the sigmoid colon (arrowheads), which had a similar appearance on the supine view (not shown). This strictured segment was less bulky than the mass in the ascending colon. (E) Curved reformatted 2D coronal CTC image simultaneously shows the distal ascending colon mass (arrow), which proved to be stage I adenocarcinoma, and the midsigmoid lesion (arrowheads), which proved to be endometriosis.

500 PICKHARDT AND KIM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 5 Figure 2. Screen capture of the CTC software system used for interpretation at the University of Wisconsin. This system allows for automated 3D endoluminal fly-through along a predetermined centerline, with immediate 2D correlation for suspicious findings. Secondary 2D evaluation for polyps can supplement 3D evaluation. In addition, there are a number of useful diagnostic tools that increase both the accuracy and diagnostic confidence for interpretation. tool for rapidly reviewing any missed areas ensures proper coverage of the colonic mucosa. 12 Seamless interrogation of polypoid lesions detected on 3D can be accomplished by the usual 2D multiplanar reformations correlation or with 3D translucency rendering, which provides information on the internal density of a lesion. 13 Although the CTC software system that we use allows for electronic cleansing of the opacified residual luminal fluid, 14 we have kept this function disabled because we believe that the artifacts that are introduced currently outweigh the potential benefits. 15 A CTC examination is considered positive when one or more polyps 6 mm or greater in size are detected. However, the primary goal of CTC screening is actually detection of large polyps ( 1 cm), which represent an effective surrogate for advanced neoplasms. 16,17 For a number of reasons, isolated diminutive lesions are not reported at CTC. The main reason is that the risks and costs of polypectomy referral for a diminutive polyp outweigh the almost negligible health risks related to the polyp itself. 18 Additional reasons include the fact that CTC specificity for diminutive lesions is quite low, and there is a low concordance rate at colonoscopy. Furthermore, such reporting may unnecessarily increase anxiety in patients and referring physicians, who likely do not have a firm understanding of the risk-benefit ratio for polypectomy. Performance Results The test performance characteristics of CTC for lesion detection have been derived by using optical colonoscopy as the reference standard, preferably with segmental unblinding of results to minimize the number of discordant cases. The early single-center CTC trials involving small, polyp-rich cohorts 19 21 provided encouraging initial results, which showed feasibility of the concept and led the way to larger multicenter trials evaluating low-prevalence populations. Two early multicenter trials by Cotton et al 22 and Rockey et al, 23 which included approximately 600 subjects each, reported a per-patient sensitivity for large polyps of only 55% and 59%, respectively. However, these 2 studies did not evaluate true screening populations, nor did they apply the now preferred techniques of oral contrast tagging, automated CO 2 for bowel distention, and primary 3D polyp detection. The Department of Defense multicenter screening trial (NEJM 2003), which evaluated 1233 asymptomatic adults and introduced the techniques of stool tagging and primary 3D polyp detection, reported a 94% sensitivity for large adenomas, with a per-patient sensitivity for adenomas 6 mm or greater of 89%. Since then, a number of additional CTC trials have either been completed or still are ongoing. Preliminary results from smaller 3D screening trials by Cash et al 24 and Graser et al 25 have shown performance characteristics similar to that of the Department of Defense trial, providing a measure of independent validation for this screening technique. A retrospective review of CTC cases from the Department of Defense, performed by experienced radiologists using a primary 2D approach, recapitulated the poor sensitivities seen in the previous 2D trials. 26 This provides direct evidence of the clear benefit of 3D endoluminal polyp detection over 2D approaches. Also of interest is the recently completed American College of Radiology Imaging Network Study 6664 trial, which involved a screening cohort of approximately 2500 patients across 15 institutions. Preliminary findings suggest adequate performance for polyp detection, including a per-patient sensitivity of 90% for large adenomas. The ability of CTC to detect invasive colorectal cancer has been uniformly high (Figure 1), with one meta-analysis showing an overall sensitivity of 96%, which is comparable with optical colonoscopy. 27 Beyond validation in clinical trials, we recently showed the efficacy of CTC screening in actual clinical implementation. 3 By comparing primary screening with either virtual colonoscopy or

May 2008 CTC: A PRIMER 501 optical colonoscopy in more than 6000 patients at our institution, we found strikingly similar detection rates for advanced neoplasia. However, the total number of polyps removed was more than 4 times greater in the optical colonoscopy group (2434 vs 561) and there were 7 perforations in the optical colonoscopy group compared with none in the CTC group. These findings suggest that CTC can achieve the same goal of advanced neoplasia detection in a safer and more cost-effective manner than optical colonoscopy. Flat lesions represent a potential concern for both virtual and optical colonoscopic evaluation. Although flat lesions generally are less conspicuous than typical polypoid lesions, the overall detection rate at CTC does not appear to be significantly lower. 28 Furthermore, most flat lesions are hyperplastic in our experience and, according to the National Polyp Study, flat adenomas do not carry a higher risk for high-grade dysplasia. 29 Clinical Indications The appropriate clinical indications for performing CTC continue to evolve. In general, CTC may be divided into 2 main clinical categories, namely, diagnostic and screening examinations. A wide variety of clinical indications exist for diagnostic CTC, including recent incomplete optical colonoscopy, evaluation of a suspected submucosal lesion, a pre-existing condition that renders colonoscopy unsuitable, a complicated prior colonoscopy, and surveillance of small unresected colorectal polyps. Noninvasive CTC surveillance of previously detected 6- to 9-mm polyps may be a reasonable alternative to immediate polypectomy for some patients, 30,31 but a broad consensus has yet to be reached on this controversial issue. 32 Examples of pre-existing conditions that make optical colonoscopy more risky include patients who are debilitated or elderly, on anticoagulation or with a bleeding diathesis, or at significant risk for sedation. Diagnostic CTC for postpolypectomy surveillance and after colorectal cancer resection are potential indications that remain unproven. Diagnostic indications aside, screening of asymptomatic adults represents the greatest potential indication for CTC. Although colorectal carcinoma is largely preventable through effective screening, it remains the second-leading cause of cancer-related death in the United States primarily because so many adults are not being screened. 33,34 CTC has been shown to represent a very effective screening tool when properly performed. However, CTC should not be viewed as a replacement for optical colonoscopy screening, but rather as an additional effective option that has the potential to significantly increase overall compliance rates for screening. The introduction of a parallel CTC screening program at our institution has not had a negative impact on referrals for optical colonoscopy screening, 35 which implies that we are bringing in new individuals off the screening sidelines rather than exchanging one test for another. As with any colorectal screening test, there are relative advantages and disadvantages of CTC that should be taken into consideration. Relative benefits of CTC compared with colonoscopy include that it is less invasive and does not require intravenous sedation or pain control. For asymptomatic screening, the risk of complications such as perforation or bleeding likely approaches zero. A survey of the Working Group on Virtual Colonoscopy revealed no cases of perforation among 11,707 adults undergoing screening CTC. 8 Furthermore, patients are able to immediately drive themselves home or back to work without a chaperone. In the event that polypectomy is needed, which occurs in less than 10% of our screening population, 3 same-day or next-day therapeutic colonoscopy can be arranged, which avoids the need for a second bowel preparation. In our experience, CTC screening is a highly cost-effective practice, particularly when diminutive lesions are ignored. 31,36 The major drawbacks of CTC are that a cathartic bowel preparation still is needed and that polypectomy is not possible. Noncathartic CTC, however, may not be the holy grail examination, 37 as some have suggested. Status of Reimbursement Backed by our clinically proven technique, we successfully lobbied for third-party reimbursement for CTC screening examinations performed at the University of Wisconsin, with initiation of coverage in April 2004. 38,39 Unfortunately, at the time of this writing, no other program in the United States has achieved a similar status in the ensuing 4 years. However, now that the validation phase for CTC screening finally is concluding, it is likely that more widespread coverage is on the horizon. In December 2007, Representative Barbara Cubin (R-Wyoming) introduced legislation to the US House of Representatives that calls for Medicare coverage of CTC screening (H.R. 4879, the Virtual Screening for Cancer Act (VSCA) of 2007). In parallel developments, a national coverage determination and category I current procedural terminology (CPT) code from the American Medical Association conceivably could happen in the near future as well. Of note, diagnostic indications for performing CTC such as an incomplete optical colonoscopy already are covered in nearly every state in the United States. Conclusions CTC has evolved rapidly and now shows enormous potential for helping to address the major challenges facing colorectal cancer screening. 40 CTC should not be viewed as a replacement for optical colonoscopy but rather as an effective complement to improve patient care. In addition to screening, there are a number of diagnostic indications for which CTC can provide valuable information. Regardless of the specific indication, clinical success with CTC requires careful attention to all facets of the examination, including proper bowel preparation, colonic distention, CT scanning, and image interpretation. Close collaboration among radiologists, gastroenterologists, and colorectal surgeons will be critical to maximize the potential yield from this powerful imaging test. Supplementary Data Note: to access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology www.cghjournal.org. References 1. Levin B, Lieberman DA, McFarland B, et al. Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 2008 (Epub March 5, 2008). 2. Pickhardt PJ, Choi JR, Hwang I, et al. Computed tomographic

502 PICKHARDT AND KIM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 5 virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med 2003;349:2191 2200. 3. Kim DH, Pickhardt PJ, Taylor AJ, et al. CT colonography versus colonoscopy for the detection of advanced neoplasia. N Engl J Med 2007;357:1403 1412. 4. Pickhardt PJ. Screening CT colonography: how I do it. AJR Am J Roentgenol 2007;189:290 298. 5. Kim DH, Pickhardt PJ, Hinshaw JL, et al. Prospective blinded trial comparing 45-mL and 90-mL doses of oral sodium phosphate for bowel preparation before computed tomographic colonography. J Comput Assist Tomogr 2007;31:53 58. 6. Macari M, Lavelle M, Pedrosa I, et al. Effect of different bowel preparations on residual fluid at CT colonography. Radiology 2001;218:274 277. 7. Shinners TJ, Pickhardt PJ, Taylor AJ, et al. Patient-controlled room air insufflation versus automated carbon dioxide delivery for CT colonography. AJR Am J Roentgenol 2006;186:1491 1496. 8. Pickhardt PJ. Incidence of colonic perforation at CT colonography: review of existing data and implications for screening of asymptomatic adults. Radiology 2006;239:313 316. 9. Radiation risk in perspective: position statement of the Health Physics Society. Adopted January 1996, revised August 2004. Mclean, VA: Health Physics Society, 2004. 10. Brenner DJ, Georgsson MA. Mass screening with CT colonography: should the radiation exposure be of concern? Gastroenterology 2005;129:328 337. 11. Pickhardt PJ, Lee AD, Taylor AJ, et al. Primary 2D versus primary 3D polyp detection at screening CT colonography. AJR Am J Roentgenol 2007;189:1451 1456. 12. Pickhardt PJ, Taylor AJ, Gopal DV. Surface visualization at 3D endoluminal CT colonography: degree of coverage and implications for polyp detection. Gastroenterology 2006;130:1582 1587. 13. Pickhardt PJ. Translucency rendering in 3D endoluminal CT colonography: a useful tool for increasing polyp specificity and decreasing interpretation time. AJR Am J Roentgenol 2004;183:429 436. 14. Pickhardt PJ, Choi JHR. Electronic cleansing and stool tagging in CT colonography: advantages and pitfalls with primary three-dimensional evaluation. AJR Am J Roentgenol 2003;181:799 805. 15. Pickhardt PJ. Differential diagnosis of polypoid lesions seen at CT colonography (virtual colonoscopy). Radiographics 2004;24: 1535 1556. 16. Kim DH, Pickhardt PJ, Taylor AJ. Characteristics of advanced adenomas detected at CT colonographic screening: implications for appropriate polyp size thresholds for polypectomy versus surveillance. AJR Am J Roentgenol 2007;188:940 944. 17. Kim DH, Pickhardt PJ. CT colonography versus colonoscopy for the detection of advanced neoplasia reply. N Engl J Med 2008;358:90. 18. Pickhardt PJ, Hassan C, Laghi A, et al. 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Building a CT colonography program: necessary ingredients for reimbursement and clinical success. Radiology 2005;235:17 20. 39. Pickhardt PJ, Taylor AJ, Kim DH, et al. Screening for colorectal neoplasia with CT colonography: initial experience from the 1st year of coverage by third-party payers. Radiology 2006;241:417 425. 40. Pickhardt PJ, Kim DH. CT colonography (virtual colonoscopy): a practical approach for population screening. Radiol Clin North Am 2007;45:361 375. Address requests for reprints to: Perry J. Pickhardt, MD, Department of Radiology, University of Wisconsin Medical School, E3/311 Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 53792-3252. e-mail: pj.pickhardt@hosp.wisc.edu; fax: (608) 263-0140. Drs Pickhardt and Kim have served as consultants for Viatronix and Fleet.