Medical Policy



Subject: In-Vivo Analysis of Gastrointestinal Lesions
Document #: MED.00077 Current Effective Date:    03/29/2017
Status: Reviewed Last Review Date:    02/02/2017

Description/Scope

This document addresses in-vivo analysis of gastrointestinal (GI) lesions, which has been investigated as an adjunct to endoscopy and is intended to assist in the early detection and characterization of GI polyps, dysplasia and cancer.  Techniques include, but are not limited to chromoendoscopy (also known as as chromoscopy and chromocolonoscopy), electronic chromoendoscopy, confocal laser endomicroscopy (confocal fluorescent endomicroscopy), fiberoptic analysis, multi-band imaging and narrow band imaging.

Position Statement

Investigational and Not Medically Necessary:

In-vivo analysis, including but not limited to chromoendoscopy, electronic chromoendoscopy, confocal laser (fluorescent) endomicroscopy, fiberoptic analysis, multi-band imaging and narrow-band imaging of gastrointestinal lesions is considered investigational and not medically necessary for all indications.

Rationale

Endoscopic imaging of the GI tract is frequently conducted using white-light endoscopy.  However, standard white-light endoscopy may fail to identify lesions, especially within the colorectum, and may also contribute to a misinterpretation of findings.  Several in-vivo analysis techniques, including but not limited to chromoendoscopy, electronic chromoendoscopy, confocal laser endomicroscopy, fiberoptic analysis, multi-band imaging and narrow band imaging are being explored in an attempt to improve the detection of gastrointestinal lesions (Neumann, 2014).

Chromoendoscopy

Chromoendoscopy is being investigated as an adjunct to standard colonoscopy in several settings including the following:

General population screening

Kahi and colleagues (2010) randomized 660 average-risk individuals who had been referred for screening colonoscopy at four medical centers to undergo either high-definition chromocolonoscopy with indigo carmine dye (n=321) or high-definition white-light (standard) colonoscopy (n=339).  The primary outcomes were to compare adenoma detection between the two groups of individuals with at least one adenoma and the number of adenomas per participant.  The secondary outcome was to identify individuals with flat or depressed neoplasms, as defined by the Paris classification system.  Overall, the mean number of adenomas per subject was 1.2, the mean number of flat polyps per subject was 1.4, and the mean number of flat adenomas per subject was 0.5.  The number of individuals with at least 1 adenoma was somewhat higher in the chromocolonoscopy group (55.5%) than in the white-light colonoscopy group (48.4%).  The number of adenomas per individual was also slightly greater in the chromocolonoscopy group: 1.3 vs. 1.1.  However, neither of these differences was statistically significant.  Both methods were comparable in identifying advanced neoplasms.  One invasive cancer was detected in each group, neither of which was a flat adenoma.  Chromocolonoscopy identified more small (less than 5 mm) adenomas per participant (0.8 vs. 0.7) and more flat adenomas (0.6 vs. 0.4) than did white-light colonoscopy, but the absolute difference was small.  The authors concluded that based on the small magnitude and uncertain clinical significance of the differences, the routine usage of high-definition chromocolonoscopy for CRC screening in average-risk individuals is not supported.

In another study, Pohl and colleagues (2011) conducted a prospective, randomized, two-center study to determine whether pancolonic chromoendoscopy (PCC) using enhanced mucosal contrast (indigo carmine dye) results in higher rates of adenoma detection than standard colonoscopy.  The study included a mixed population, including individuals presenting for primary CRC screening (51%) and individuals presenting for diagnostic colonoscopy (49%).  Of the 1024 participants randomized to the study, 16 dropped out, leaving 496 subjects in the chromoendoscopy group and 512 subjects in the standard colonoscopy (control) group.  The demographic characteristics and indications for colonoscopy were similar in the two groups.  Individuals excluded from the study included those with known IBD, overt bleeding, polyposis syndromes or a history of surgical resection.  The histopathology of the lesions detected was confirmed by evaluating the endoscopic resection or biopsy specimens.  The proportion of participants with at least 1 adenoma was significantly higher in the PCC group (223 individuals [46.2%]) than in the control group (186 individuals [36.3%]).  The use of chromoendoscopy resulted in an increased overall detection rate for adenomas (0.95 vs. 0.66 per subject), flat adenomas (0.56 vs. 0.28 per subject) and serrated lesions (1.19 vs. 0.49 per subject) (p<0.001).  The authors also reported differences in lesion detection rate based on the size of lesion.  There were 151 (30.4%) subjects in the chromoendoscopy group and 119 (23.2%) subjects in the control group found to have at least 1 adenoma that was 5 mm or larger in size (p=0.012).  A total of 64 (12.9%) subjects in the chromoendoscopy group and 48 (9.4%) subjects in the control group were found to have at least one adenoma that was 10 mm or larger (p=0.092).  There was no significant difference in the detection of adenomas 10 mm or larger between the groups.  This study included a mixed population of subjects undergoing screening and diagnostic colonoscopy, and the authors do not report results separately for the screening and the diagnostic colonoscopy groups.

Symptomatic individuals and individuals at increased risk for CRC

In 2016, Brown and colleagues updated a systematic review which set out to determine whether the use of chromoscopy enhances the detection of neoplasia and polyps during endoscopic examination of the colon and rectum.  A total of seven  studies (2727 subjects) from 2002–2015 were included in the review of studies comparing chromoendoscopy and conventional colonoscopy.  Study subjects included individuals undergoing colonoscopy for the detection of polyps and also included those individuals undergoing endoscopy for any of the following: (1) investigation of gastrointestinal symptoms; (2) as part of a CRC screening program; (3) surveillance for colorectal neoplasia due to a family history of CRC; (4), previous polyp detection; or (5) a previous CRC resection. Individuals with IBD or polyposis syndromes were not included.  The primary outcome measures for each intervention included the number of polyps detected per subject, the number of neoplastic polyps detected per subject, the number of subjects with at least one polyp and the number of subjects with at least one neoplastic polyp.  Secondary outcomes included the number of diminutive neoplastic polyps per subject, the number of subjects with at least one diminutive neoplastic polyp, the number of subjects with three or more neoplastic polyps, the extubation time and the site of the lesion in the colon.  The results are summarized below:

Primary Outcomes Effect of Intervention Statistical Measure
Number of polyps (neoplastic and non-neoplastic) detected 0.89 (95% CI++, 0.74-1.04) WMD*
Number of neoplastic polyps detected 0.33 (95% CI++, 0.25-0.41) WMD* +
Number of subjects with at least one polyp (neoplastic and non-neoplastic) detected 1.87 (95% CI++, 1.51-2.30) OR+
Number of subjects with at least one neoplastic polyp detected 1.53 (95% CI++, 1.31-1.79) OR+

 

Secondary Outcomes Effect of Intervention Statistical Measure
Number of diminutive neoplastic lesion detected 0.21 (95% CI++, 0.10-0.32) WMD*
Number of subjects with at least one diminutive neoplastic lesion detected 151 (95% CI++, 1.19-1.92) OR+
Number of subjects with three or more diminutive neoplastic lesions detected 1.34 (95% CI++, 0.96-1.87) OR+
Site of lesions found (right vs. left) Trend supported enhanced detection  
Extubation time Heterogeneity precluded analysis  

++ CI = confidence interval     *WMD = weighted mean differences        +OR = odds ratios

Although there were some methodological drawbacks and differences in study design, the authors found that combining the results showed a significant difference in favor of chromoscopy for all detection outcomes.  Chromoscopy yielded more subjects with at least 1 neoplasm (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.31-1.79) and more subjects with 3 or more neoplastic lesions (OR, 1.34; 95% CI, 0.96-1.87).  The authors concluded that chromoscopy could theoretically be incorporated into routine practice but also cautioned that "the lack of data with respect to advanced adenoma detection and interval cancer rates and the time constraints involved in incorporating routine panchromoscopy suggest that at present selective use may be the only feasible practical application" (Brown, 2016).

In a prospective study by Li and colleagues (2010), researchers investigated whether the morphology of the depression area at the surface of colorectal neoplasia with depression can be used for predicting its invasive depth and histology.  A total of 228 individuals with a total of 296 colorectal lesions were studied.  Individuals with hereditary nonpolyposis, colonic IBD or familial adenomatous polyposis CRC were excluded from the study.  All of the lesions were assessed using magnifying chromocolonoscopy.  The surface depression of all lesions was documented and the depressive morphology was then classified as type I (star-shaped or branched) or type II (round with broad uneven bases).  When both types of depressions were noted, type II was considered the major type.  The surface pit pattern was also classified according to the Kudo criteria.  All of the lesions were resected and examined to determine their histological composition.  Of the 296 lesions examined, 66 (22.3%) contained an area of central depression, including 43 in nonpolypoid (flat and depressed) lesions (66%) and 23 in polypoid lesions (10%).  The overall accuracy of depressive morphology in distinguishing between low-grade dysplasia and high-grade dysplasia/invasive cancer was 86.4%.  The researchers concluded that chromocolonoscopy to determine morphology depression could be used as a complementary method to assess the degree of atypia and invasive depth in colorectal neoplasia.  The authors acknowledged that the clinical value of depression morphology is limited by the fact that most colorectal lesions do not contain a depression area.

Yamada and colleagues (2015) reported equivalency between the accuracy of magnifying chromoendoscopy (MC) and endoscopic ultrasonography (EUS) when diagnosing the depth of CRC lesions in a recent prospective study; however, it is still unclear whether these tools show diagnostic differences in categories such as tumor size and morphology.  Therefore, the researchers conducted a detailed subset analysis of the data from the prospective, multi-center, comparative trial that enrolled participants between February 2011 and December 2012.  A total of 70 participants with early, flat CRC lesions were enrolled and the results of 66 lesions were analyzed.  The participants were randomly allocated to primary MC followed by EUS or to primary EUS followed by MC.  Diagnoses of invasion depth by each tool were divided into two categories (intra-mucosal to slight sub-mucosal invasion [invasion depth less than 1,000 μm] and deep sub-mucosal invasion [invasion depth greater than or equal to 1,000 μm]) and then compared with the final pathological diagnosis by an independent, blinded pathologist.  MC and EUS demonstrated similar diagnostic outcomes, with no significant differences in prediction of invasion depth in subset analyses according to location, tumor size and morphology.  Lesions that were consistently diagnosed as Tis/T1-SMS or greater than or equal to T1-SMD with both tools revealed accuracy of 76 to 78%.  Accuracy was lower in borderline lesions with irregular pit pattern in MC and distorted findings of the third layer in EUS (MC, 58.5%; EUS, 50.0%).  The authors concluded that "the irregular pit pattern in MC, distorted findings to the third layer in EUS and inconsistent diagnosis between both tools were associated with low accuracy, further refinements or even novel methods are still needed for such lesions".

Identification and surveillance of dysplasia in individuals with inflammatory bowel disease (IBD)

IBD includes two major forms of chronic intestinal disorders, Crohn's disease and ulcerative colitis (UC).  Individuals with UC have a higher risk for the development of colitis-associated CRC.  Risk factors for the development of CRC in individuals with UC include the duration of the disease, the degree and extent of inflammation, as well as the presence of primary sclerosing cholangitis.  The identification of intraepithelial neoplasias and colitis-associated cancers during surveillance colonoscopy is challenging because abnormal changes in the mucosa may not be visible on a macroscopic level.  Chromoendoscopy is one of the emerging endoscopic imaging techniques proposed as a means to identify dysplasia in individuals with IBD (Neumann, 2011).

Kiesslich and colleagues (2003) conducted a randomized controlled trial to test whether chromoendoscopy might facilitate the early detection of intraepithelial neoplasias and colitis-associated colon carcinomas.  A total of 165 individuals with long standing UC were randomized in a 1:1 ratio to undergo conventional colonoscopy or colonoscopy with chromoendoscopy using 0.1% methylene blue.  Five mucosal biopsy specimens were taken every 10 cm between the rectum and cecum.  Circumscript lesions in the colon were evaluated according to a modified pit pattern classification.  Significantly more intraepithelial neoplasms were identified in the chromoendoscopy group compared to the conventional colonoscopy group (32 vs. 10, p=0.003).  The authors concluded chromoendoscopy permits more accurate diagnosis of the extent and severity of the inflammatory activity in UC compared with conventional colonoscopy, but acknowledge additional controlled studies are needed.

Rutter and colleagues (2004) carried out a comparative study to determine if routine pancolonic indigo carmine dye spraying would improve the macroscopic detection of dysplasia and reduce the dependence on non-targeted biopsies.  A total of 100 participants with long standing UC participated in the study.  During the first examination, visible abnormalities were biopsied, and quadrantic non-targeted biopsies were taken every 10 cm.  During the second colonoscopic examination, the entire mucosa was sprayed with indigo carmine (0.1%) and any additional visible abnormalities were biopsied.  There was a trend towards statistically increased dysplasia detection following dye spraying (7/100 subjects vs. 2/100 subjects, p=0.06).  The targeted biopsy protocol with pancolonic chromoendoscopy required fewer biopsies than taking multiple non-targeted biopsies (157 biopsies as opposed to2904 biopsies).  In addition, the targeted biopsy protocol identified dysplasia in significantly more individuals than the non-targeted protocol (7/100 subjects vs. 0/100 subjects, p=0.02).

In another study, (Kiesslich, 2007) researchers conducted a randomized controlled trial to assess the value of chromoendoscopy (0.1% methylene blue) combined with endomicroscopy for the in vivo diagnosis of intraepithelial neoplasia in individuals with UC.  A total of 161 subjects with long-term UC in clinical remission were randomized at a 1:1 ratio to undergo conventional colonoscopy or chromoscopy with endomicroscopy.  Eight subjects were excluded from the study due to insufficient bowel preparation.  In the conventional colonoscopy group (n=73), random biopsy examinations and targeted biopsy examinations were carried out.  In the endomicroscopy group (n=80), circumscribed mucosal lesions were identified by chromoscopy and evaluated for targeted biopsy examination by endomicroscopy.  The primary outcome analysis was based on the detection of neoplasias.  The authors reported that by using chromoscopy with endomicroscopy, 4.75-fold more neoplasias could be detected (p=0.005) than with conventional colonoscopy and 50% fewer biopsy specimens (p=0.008) were required.  The presence of neoplastic changes could be predicted by endomicroscopy with high accuracy (sensitivity, 94.7%; specificity, 98.3%; accuracy, 97.8%).

Marion and colleagues (2008) prospectively compared dye-spray technique using methylene blue to standard colonoscopic surveillance in detecting dysplasia in individuals over 18 years of age with either extensive UC, at least left sided, or Crohn's colitis involving at least one-third of the colon.  In this study, 115 individuals recruited from a single facility were screened.  Of those recruited for the study, 102 individuals (64 males, 38 females) were enrolled after meeting the inclusion criteria.  Following a standard bowel preparation, each participant was examined using standard office endoscopic equipment by three methods: (a) standard surveillance colonoscopy with 4 random biopsies every 10 cm (for a total of at least 32 samples); (b) a targeted biopsy protocol; and finally (c) methylene blue (0.01%) dye spray was segmentally applied throughout the colon and any pit-pattern abnormality or lesion rendered visible by the dye spray was targeted and biopsied.  Each participant had a single examination, which included two passes of the colonoscope.  Specimens were reviewed in a blinded manner by a single GI pathologist.  The three methods were then compared with each participant serving as his or her own control.  Targeted biopsies with dye spray identified more dysplasia (16 participants with low-grade and 1 participant with high-grade) than random biopsies (3 participants with low-grade dysplasia) (p=0.001) and more than targeted non-dye spray (8 participants with low-grade and 1 participant with high-grade dysplasia) (p=0.057).  Targeted biopsies with and without dye spray identified dysplasia in 20 participants compared with 3 using method (a) (p=0.0002).  There were no adverse events.  The authors concluded that colonoscopic surveillance of chronic colitis subjects using methylene blue dye-spray targeted biopsies results in improved dysplasia yield compared to conventional random and targeted biopsy methods.  The authors acknowledged that there is still controversy surrounding the natural history of dysplasia in colitis and state that a long-term follow-up of the participants in the study is planned. 

Hlavaty and colleagues (2011) carried out a cohort study comparing white-light endoscopy and chromoendoscopy performance in the detection of intraepithelial neoplasia (IEN) in subjects with either UC or Crohn's colitis.  The study population included 30 subjects examined by standard colonoscopy, chromoendoscopy with 0.4% indigo carmine, and by a confocal laser endomicroscopy system during one examination.  An additional 15 individuals consented only to standard white-light colonoscopy.  Random biopsies and biopsies of all suspicious lesions (strictures, masses, and polyps) were collected.  The researchers compared the number of IENs detected by white-light endoscopy and chromoendoscopy and analyzed the predictive values of chromoendoscopy and confocal laser endomicroscopy for the histologic diagnosis.  There were 1584 random biopsies (35.2 per subject) collected and 78 targeted biopsies (1.7 per subject) collected in 24 of 45 subjects examined by white-light (standard) endoscopy and an additional 36 biopsies in 16 of 30 subjects examined by chromoendoscopy (1.17 additional per subject).  There were no IENs found on random biopsies versus six low-grade or high-grade IENs in 4 participants (2 detected by white-light endoscopy, 4 additional by chromoendoscopy) from targeted biopsies (p=0.02).  A total of 100 suspicious lesions were identified and analyzed by chromoendoscopy and histology.  Thirty-two of 100 lesions (2 of 30 flat vs. 30 of 70 pedunculated lesions) could not be examined by confocal laser endoscopy.  The sensitivity of chromoendoscopy and confocal laser endomicroscopy for low-grade or high-grade IEN was 100 and 100% respectively, the specificity 96.8 and 98.4%, positive predictive value was 62.5 and 66.7% and negative predictive value was 100 and 100%.  The authors concluded that chromoendoscopy increases the diagnostic yield of white-light endoscopy and that targeted biopsies are superior to random biopsies in the screening of IEN in individuals with IBD.  The authors also concluded that confocal laser endoscopy did not provide additional clinical benefits.  Limitations of the study include its small sample size, and the bias inherent in allowing participants to choose either conventional or chromoendoscopy.  Another potential bias for the study results is that the endoscopes used for white-light endoscopy, chromoendoscopy and confocal laser endoscopy were not the same.

Neumann and colleagues (2011) reviewed the endoscopic and histological characteristics of the dysplasia-associated lesion or mass (DALM) and non-colitis mucosa adenoma-like mass (ALM) in the context of therapeutic procedures and proposed seven basic rules for the detection of neoplasia.  While the authors concluded that emerging endoscopic imaging techniques (chromoendoscopy, magnification endoscopy, and confocal laser endomicroscopy) offer the potential for real time in vivo diagnosis of intraepithelial neoplasia, they did not include these technologies in their recommendations for the detection of dysplasia.

Wu and colleagues (2012) conducted a meta-analysis to investigate the diagnostic accuracy of chromoendoscopy for dysplasia in individuals with UC.  The inclusion criteria consisted of: (1) chromoendoscopy employed as the comparative group; (2) sufficient data for analysis; and (3) histological diagnosis used as the gold standard.  Studies excluded from the meta-analysis were those in which the individuals did not have histological confirmation, studies with fewer than 10 participants, those which did not contain sufficient data and reviews and meta-analyses.  A total of six randomized controlled trials met the inclusion criteria.  Of the six studies, a total of 1528 subjects were included, of whom 1505 had UC and 23 had Crohn's disease.  Indigo carmine dye spray was used in three studies and methylene blue in the other three.  The results of the meta-analysis demonstrated a pooled sensitivity of 83.3%, specificity of 91.3%, and diagnostic odds ratio of 17.54.  Although the researchers concluded that chromoendoscopy has medium to high sensitivity and high diagnostic accuracy for dysplastic lesions in UC, they also acknowledged that the studies included in the meta-analysis had several limitations including that the baseline characteristics of the participants varied in each of the included studies, no consideration was given to the experience of the endoscopist, or the characteristics of the medical facility.  The authors recommended that additional studies be conducted to further assess the cost-effectiveness, tolerance and application of this technique in the clinical setting.

In 2015, Mooiweer and colleagues published a retrospective analysis of data on 937 subjects with Crohn's disease or UC undergoing surveillance colonoscopy.  The study compared the detection of neoplasia between chromoendoscopy (440 procedures in 401 participants) and white-light endoscopy (1802 procedures in 772 participants).  Dysplasia was detected in 48 of 440 colonoscopies performed in conjunction with chromoendoscopy (11%), compared to 189 of 1802 procedures performed with white-light endoscopy (10%).  Targeted biopsies identified 59 dysplastic lesions in the chromoendoscopy group, compared to 211 dysplastic lesions identified in the white-light endoscopy group.  The authors did not find an increase in the rate of neoplasia detection after the implementation of chromoendoscopy when compared to conventional white-light endoscopy with random biopsies protocol.  The authors concluded that more studies are needed to confirm these results and caution that the study results may be biased due to the retrospective nature of the study.

Deepak and colleagues (2016) explored whether using chromoendoscopy in individuals with IBD and a history of colorectal dysplasia would detect additional dysplastic lesions that were not identified on the index colonoscopy with standard or high-definition (HD) white-light endoscopy (WLE).  By conducting a retrospective review of medical records, the researchers identified a cohort of individuals with IBD with colorectal dysplasia on white-light endoscopy who subsequently underwent chromoendoscopy between January 1, 2006 and August 31, 2013.  Endoscopic and histologic findings were compared among the index white-light endoscopy, the first chromoendoscopy, and subsequent chromoendoscopy.  Measures assessed included endoscopic lesion removal, surgery or repeat chromoendoscopy, and diagnosis of CRC.  A total of 95 index cases were identified.  The median duration of IBD was 18 years and 78 subjects had ulcerative colitis.  Dysplasia was identified in 55 participants during the index white-light endoscopy and 72 lesions underwent targeted biopsy.  The first chromoendoscopy identified dysplastic lesions in 50 subjects, including 34 new lesions (not revealed on the index examination).  Endoscopic resection was successfully performed on 43 lesions, most of which were in the cecum/ascending colon (n=20) with sessile morphology (n=33).  Subsequent to the first chromoendoscopy, 14 individuals underwent surgery that identified 2 cases of CRC and 3 cases of high-grade dysplasia.  Multiple chromoendoscopy were performed in 44 subjects.  Of these, 20 participants had 34 visualized lesions, 26 of which were new findings.  The authors concluded that both the initial and subsequent chromoendoscopy performed in individuals with IBD with a history of colorectal dysplasia on WLE frequently identified new lesions, most of which were responsive to endoscopic treatment.

Several specialty association and societies have issued statements regarding chromoendoscopy.  The National Comprehensive Cancer Network (NCCN) guidelines on CRC screening include chromoendoscopy as a surveillance modality for individuals with a history of IBD.  The authors also indicate that:

Biopsies can be better targeted to abnormal-appearing mucosa using chromoendoscopy or confocal endomicroscopy and several studies indicate increased sensitivity of chromoendoscopy in detecting dysplastic lesions, however, the natural history of these lesions is unclear.  Targeted biopsies have been found to improve detection of dysplasia, and should be considered for surveillance colonoscopies in patients with ulcerative colitis" (NCCN, 2016).

In 2015, the American Society for Gastrointestinal Endoscopy (ASGE) and American Gastroenterological Association (AGA) released the SCENIC International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease.  The document, a consensus opinion of an international multidisciplinary expert panel, reflects a movement towards using chromoendoscopy to better visualize colonic tissue during the screening and surveillance of individuals with IBD.  The consensus group includes the following recommendations regarding chromoendoscopy to detect dysplasia on surveillance colonoscopy:

When performing surveillance with standard-definition colonoscopy, chromoendoscopy is recommended rather than white-light colonoscopy (strong recommendation, moderate-quality evidence).
When performing surveillance with high-definition colonoscopy, chromoendoscopy is suggested rather than white-light colonoscopy (conditional recommendation, low-quality evidence) (Laine, 2015).

Although the SCENIC guidelines recommend the use of chromoendoscopy, the authors state the following in their acknowledgement of the limitation of chromoendoscopy:

Although chromoendoscopy increases the yield of dysplasia compared with standard-definition white-light colonoscopy, whether the additional lesions identified with chromoendoscopy are associated with the same increased risk for CRC as the visible and invisible dysplasia identified in older studies is not known (Laine, 2015).

The 2015 ASGE Standards Practice Committee makes the following recommendations regarding the use of chromoendoscopy:

Chromoendoscopy with pancolonic dye spraying and targeted biopsies is sufficient for surveillance in IBD; consider 2 biopsies from each colon segment for histologic staging.
or
Random biopsies with targeted biopsies of any suspicious lesions is a reasonable alternative if chromoendoscopy is not available or if the yield of chromoendoscopy is reduced by significant underlying inflammation, pseudopolyposis, or poor preparation (ASGE, 2015). 

While there is emerging evidence that chromoendoscopy may yield higher polyp detection rates, at this time it is not known if the additional polyps detected are clinically significant and whether a higher detection rate results in a meaningful clinical outcome benefit. 

Confocal Laser Endomicroscopy

Confocal laser endomicroscopy (also known as confocal fluorescent endomicroscopy) is an endoscopic technique that makes it possible to carry out microscopic examination of a smaller, focused spot of the mucosal layer during endoscopic procedures.  

Rasmussen and colleagues (2015) conducted a systematic review of the current indications and perspectives of confocal laser endomicroscopy (CLE) for IBD.  Only studies reporting original clinical data were included and analyzed on technique, clinical aim and definitions of outcomes.  The authors found that CLE has been used for a wide range of purposes in IBD including the assessment of the severity of inflammation, prediction of therapeutic response and relapse, and adenoma surveillance in individuals with UC.  Systems used to measure the histological changes ranged from subjective grading to objective quantification analyzed by computer-aided models.  The studies derived their conclusions from the evaluation of histological features such epithelial gaps and epithelial leakiness to fluorescein.  The authors concluded that CLE "can detect and grade inflammation in the intestinal mucosa that is not macroscopically visible without taking biopsies."  The authors also state that at the present time:

Confocal laser endomicroscopy remains an experimental but emerging tool for assessment of inflammatory bowel disease. I t is the only method that enables in vivo functional assessment of intestinal barrier function.  There is great heterogeneity in the literature and no single approach has been validated and reproduced to the level of general acceptance (Rasmussen, 2015).

In another systematic review, Ypsilantis and colleagues (2015) examined literature examining the role of CLE as a tool assuring the completeness of endoscopic mucosal resection of gastrointestinal lesions.  The authors found that the number of pertinent studies is very limited, including a single randomized controlled study and two prospective comparative case series.  Per-lesion meta-analysis indicated that the sensitivity of CLE for detection of residual neoplasia was 91% (95% CI, 82.5%-96%) with specificity of 69% (95% CI, 61%-77%), with significant heterogeneity noted in all outcomes.  Researchers concluded that the evidence supporting "the usefulness of CLE in ensuring adequate EMR of gastrointestinal neoplasia is currently very weak with limited promising results related to gastric and colonic polyp resection."

At least two confocal laser endomicroscopy systems have received U.S. Food and Drug Administration (FDA) clearance.  According to the FDA pre-market summary letter (K042740):

The Pentax Confocal Laser System is a required accessory for legally marketed video endoscopes equipped with a confocal laser imaging module. The system is intended to allow confocal laser imaging of the internal microstructure of tissues in the anatomical track assessed by the endoscope.  

The FDA premarket notification letter (K061666) for the F-600 System (Cellvizio® Confocal Miniprobe) indicates this device is a "confocal laser system that is intended to allow confocal laser imaging of the internal microstructure of tissues in the anatomical tract, that is, GI or respiratory, accessed by the endoscope."

In the 2014 Technology Status Evaluation Report on confocal laser endomicroscopy, the ASGE concluded that "CLE is an emerging technology that has the potential to significantly reduce the number of biopsies in BE and IBD and reduce the need for removal of non-neoplastic colorectal polyps compared with WLE."  However, the authors also note that the limitations of CLE include, but are not limited to, the high cost of the equipment and the lack of proven efficacy compared to other advanced imaging techniques.  The ASGE cautions that "before the technology can be widely accepted, many further studies are needed to determine its clinical efficacy and evaluate its cost-effectiveness and its utilization in both academic and community settings" (ASGE, 2014).

A more recent consensus guideline which includes the recommendations of the AGA and the ASGE states the following:

Confocal laser endomicroscopy, a technique allowing real-time histologic examination of colon mucosa during endoscopy that has been studied in IBD surveillance, was not included in the focused questions for guideline development because it cannot practically be used for primary examination of the entire surface area of the colon as required for IBD surveillance.  Rather, its potential role would be in characterization of lesions identified during surveillance (Laine, 2015).

The NCCN guidelines on CRC screening indicate confocal endomicroscopy may be an appropriate screening tool for individuals with a history of UC (NCCN, 2015). 

Confocal laser endomicroscopy is reported to provide enhanced visualization of the vascular networks of gastroesophageal mucosa and could potentially help to distinguish malignant from normal mucosa.  However, the peer-reviewed literature on this technology consists of predominantly small, nonrandomized, uncontrolled trials.  At the present time there is inadequate data to demonstrate that this technology clearly improves clinical outcomes as compared with standard endoscopy and biopsy. 

Electronic Chromoendoscopy

Electronic chromoendoscopy uses digital computer algorithms to modify the light reflected from the GI mucosa from conventional white-light to various other wavelengths.  This technology enables the endoscopic image to be reconstructed into virtual images in real time without any noticeable time delay.  Currently, there are at least two electronic chromoendoscopy techniques available: the Fujifilm Intelligent Color Enhancement (FICE) and i-SCAN™.  With both of these systems, the endoscopic image can be reconstructed into a virtual image by pushing a button on the handle of the endoscope.

The FICE system is manufactured by Fujifilm Medical System (Wayne, NJ).  According to the FDA 510(k) premarket approval letter:

The EPX-4400 and EPX-4400HD Digital Video Processors with FICE are used for endoscopic observation, diagnosis, treatment, and image recording.  The devices are intended to process electronic signals transmitted from a video endoscope (a video camera in an endoscope).  The devices may be used on all patients requiring endoscopic examination and when using a Fujinon/FUJIFILM medical endoscope, light source, monitor, recorder and various peripheral devices.  FICE is an adjunctive tool for gastrointestinal endoscopic examination which can be used to supplement FUJIFILM white light endoscopy.  FICE is not intended to replace histopathological sampling as a means of diagnosis.

The FDA premarket approval letter for the i-SCAN (Pentax of American, Montvale, NJ) indicates the i-SCAN device and the optical imaging enhancement technology are to be used as an optional adjunct following traditional white-light endoscopy and are not intended to replace histopathological sampling.

Peer-reviewed literature on the use of FICE or i-SCAN for detection of colonic neoplasia during colonoscopy is limited.  Pohl and colleagues (2009) conducted a prospective, randomized multicenter trial of colonoscopy comparing the FICE system to standard colonoscopy with targeted indigo carmine chromoscopy (control group) in consecutive individuals undergoing routine colonoscopy.  Histopathology of detected lesions was confirmed.  A total of 871 participants were enrolled and 764 subjects were included in the final analysis (368 in the FICE group, 396 in the control group).  In total, 236 adenomas were detected using the FICE group and 271 adenomas in the control group.  The study found that adenoma detection rates are not improved by employing the FICE system compared with white-light endoscopy with targeted indigo carmine spraying.

In another prospective randomized trial, Chung and colleagues (2010) compared the detection rate of adenoma between FICE and white-light endoscopy (WLE) in screening colonoscopy.  The study included a total of 359 average-risk adults undergoing screening colonoscopy at a single institution.  The study's primary outcome measure was the difference in adenoma miss rates, and the secondary endpoint measure was the overall adenoma detection rate.  The number of adenomas identified by FICE and WLE was 123 and 107, respectively.  The adenoma miss rate using FICE demonstrated no significant difference compared with that of WLE (6.6% vs 8.3%, p=0.59).  Characteristics of lesions missed using FICE were similar to those missed using WLE; 93% of overall missed polyps were less than or equal to 5 mm, and none were greater than or equal to 1 cm.  All missed adenomas were nonpedunculated and low grade.  The researchers concluded that FICE used at screening colonoscopy does not improve the adenoma detection rate or adenoma miss rate compared with white-light colonoscopy.    

In a 2015 technology Status Evaluation Report, the American Society for Gastrointestinal Endoscopy (ASGE) concludes the following with regards to electronic chromoendoscopy:

Electronic chromoendoscopy technologies provide image enhancement and may improve the diagnosis of mucosal lesions.  Although strides have been made in standardization of image characterization, especially with NBI, further image-to-pathology correlation and validation are required. There is promise for the development of a resect and discard policy for diminutive adenomas by using electronic chromoendoscopy; however, before this can be adopted, further community-based studies are needed.  Further validated training tools for NBI, FICE, and i-SCAN will also be required for the use of these techniques to become widespread (ASGE, 2015).

Currently there is insufficient evidence that electronic chromoendoscopy improves detection of clinically significant adenomas or health outcomes when compared to standard WLE or chromoendoscopy. 

Fiberoptic Analysis

One device for fiberoptic analysis of colorectal polyps has received FDA pre-market approval, the Optical Biopsy System™, SpectraScience, Minneapolis, MN.  According to the FDA Summary of Safety and Effectiveness Data, this device should be used as an aid to lower gastrointestinal endoscopy as follows:

For the evaluation of polyps less than 1 cm in diameter that the physician has not already elected to remove.  The device is only to be used in deciding whether such polyps should be removed (which includes submission for histological examination). 

The FDA approval for this device was based in part on the results of a prospective study of 101 individuals undergoing colonoscopy that evaluated the sensitivity and specificity of the fiberoptic system compared to physician assessment alone.  While fiberoptic analysis may identify additional adenomatous polyps that the physician considered to be hyperplastic based on visual assessment, it is difficult to determine the clinical significance of these findings.  It is not clear how the physician decided to select additional polyps for fiberoptic analysis, or whether the same results could be obtained by simply randomly taking a biopsy of a subset of polyps that were considered hyperplastic on visual assessment.  

Multi-band Imaging

Multi-band imaging (MBI) is a real time, on demand digital image processing technique that enhances the appearance of mucosal surface structures by using selected wavelengths of light to create reconstituted virtual images.  MBI can also be used in combination with electronic or optical magnification for better visualization of the mucosa.  Similar to narrow band imaging (NBI), MBI is being investigated as an imaging technique to enhance visualization of the vascular network and surface texture of the mucosa in an effort to improve tissue characterization, differentiation, and diagnosis.  MBI is being investigated as a tool to enhance the diagnosis of several conditions, including but not limited to high grade dysplasia and esophageal cancer and for differentiation of subtypes of gastric metaplasia and colorectal lesions.

The ASGE Technology Status Evaluation Report on NBI and multiband imaging (ASGE, 2008) includes MBI as one of the emerging technologies that may improve the diagnosis and characterization of mucosal lesions of the GI tract, in particular as an adjunctive technique to magnification endoscopy.  The report notes that some of the limitations of MBI include, but are not limited to the fact that while a classification of multi-band mucosal patterns has been described for various conditions (for example, Barrett's esophagus and colon polyps), it has not yet been standardized or validated sufficiently to establish guidelines for routine practice.  Also, the optimal MBI preset(s) for tissue diagnosis or differentiation have not been determined and may be dependent upon the location or type of lesion being examined.  The authors state that there is a need for randomized, controlled, multicenter trials assessing these new imaging modalities (NBI and MBI) against conventional white-light endoscopy and other techniques (for example, chromoendoscopy) for various GI conditions.  As in the case of NBI, the authors concluded that MBI may improve the diagnosis and characterization of mucosal lesions of the GI tract, especially when used as an adjunctive technique to magnification endoscopy.  However, more research addressing the standardization of image characterization, further image-to-pathology correlation and validation, and the impact of MBI on individual outcomes are necessary before endorsing its use can be considered routine practice of GI endoscopy.

Narrow Band Imaging

Narrow band imaging, which utilizes optical filters to narrow the band width of white light to blue light, is another illumination technology developed to enhance visualization of the mucosal microvasculature and to improve identification of vascular alterations indicative of pathologic conditions (ASGE, 2008).  NBI is being investigated as a tool to enhance the identification of lesions associated with several conditions, including but not limited to gastroesophageal reflux disease (GERD), Barrett's esophagus, chronic UC, and GI cancer.  NBI received FDA clearance through the 510(K) pre-market process, which included NBI with the existing EVIS EXERA 160A System (Olympus Medical Systems Corp) endoscopic equipment and indicates the technology is appropriate for endoscopic diagnosis, treatment and video observation.

Chiu and colleagues (2007) carried out a comparative study evaluating the diagnostic efficacy of NBI in differentiating neoplastic from non-neoplastic colorectal lesions.  In this prospective study, 180 colorectal lesions from 133 subjects were observed with conventional colonoscopy, low-magnification and high-magnification NBI and chromoendoscopy.  Endoscopic images were stored electronically and randomly allocated to two readers for evaluation.  The sensitivity, specificity and diagnostic accuracy of each endoscopic modality were assessed by reference to histopathology.  The researchers reported that NBI and chromoendoscopy scored better under high magnification than under low magnification in comparison with conventional colonoscopy.  The diagnostic accuracy of NBI with low or high magnification was significantly higher than that of conventional colonoscopy (low magnification: p=0.04 for reader 1 and p=0.004 for reader 2; high magnification: p<0.001 for both readers) and was comparable to that of chromoendoscopy.  The authors concluded that both low-magnification and high-magnification NBI can distinguish neoplastic from non-neoplastic colorectal lesions; the diagnostic accuracy of NBI was better than that of conventional colonoscopy and equivalent to that of chromoendoscopy.  The authors also acknowledged that the role of NBI in screening colonoscopy needs further evaluation.

Ignjatovic and colleagues (2009) carried out a prospective study to evaluate the accuracy of polyp characterization using optical diagnosis compared with histopathology.  Four endoscopists at a single facility evaluated consecutive individuals with positive fecal occult blood test results or previous adenomas.  Of the 363 polyps that were less than 10 mm (identified in 130 individuals), 278 had both histopathologic and endoscopic diagnoses.  The histopathological examination revealed 198 of these polyps to be adenomas and 80 non-neoplastic lesions, of which 62 were hyperplastic.  Endoscopic diagnosis using NBI had a sensitivity of 94%, a specificity of 89%, and an overall accuracy of 93%.  This diagnostic method allowed for assignment of a surveillance interval immediately after colonoscopy in 82 of the 130 individuals who had polyps less than 10 mm.  Assignment accuracy was 95% according to the U.S. Multisociety Guidelines and 98% according to United Kingdom (U.K.) guidelines.  The researchers acknowledged that this study had several limitations including the following: (1) colonoscopists had different levels of experience; (2) study took place in an academic training area; and (3) equipment used (Lucera, Olympus, Japan) was only available in the U.K. and Japan.

Another study (Tischendorf, 2010) evaluated the diagnostic accuracy of NBI endoscopy with and without high magnification to differentiate neoplastic from non-neoplastic colorectal polyps.  A total of 200 colorectal polyps from 131 individuals were evaluated.  Half of these lesions (n=100) were classified using NBI endoscopy with high optical magnification and the remaining 100 lesions were classified using high-definition endoscopy without high magnification.  An assessment of the clarity of the vessel network and a histologic examination were completed on all lesions.  The sensitivity and specificity of NBI endoscopy with high magnification to differentiate neoplastic versus non-neoplastic lesions was 92.1% and 89.2% respectively.  Comparable in performance, high-definition NBI endoscopy without high magnification resulted in a sensitivity of 87.9% and specificity of 90.5%. However, visualization of the capillary network was better with NBI endoscopy with optical magnification compared with high-definition NBI endoscopy without high magnification.  When compared with NBI endoscopy, white-light endoscopy, with or without magnification, resulted in inferior discrimination between neoplastic and non-neoplastic polyps.  The researchers conceded that one limitations of the study was the relatively low number of polyps that were included and stated that "definitive conclusions cannot be drawn and larger studies are warranted to determine whether or not smaller but statistically significant differences between NBI-based endoscopy with and without high magnification exist."

Ezoe and colleagues (2011) carried out a multicenter, prospective, randomized trial that compared the real-time diagnostic yield of conventional white-light imaging (C-WLI) for small, depressed gastric mucosal cancers with that of magnifying narrow-band imaging (M-NBI) in individuals with undiagnosed depressed lesions less than or equal to 10 mm in diameter identified by endoscopy.  Of the 1351 participants, 362 individuals (27%) had newly detected, small (10 mm), depressed gastric lesions and were randomized to diagnostic evaluation with C-WLI  (n=176) or M-NBI (n=177). Individuals diagnosed using C-WLI were immediately evaluated with M-NBI.  The histopathologic findings of biopsy samples were used as the diagnostic gold standard.  Cancer was diagnosed in 40 of 353 participants.  The diagnostic accuracy, sensitivity, and specificity for C-WLI and M-NBI were 65%, 40%, and 68% and 90%, 60%, and 94%, respectively.  Combining M-NBI with C-WLI increased accuracy to 97%, sensitivity to 95%, and specificity to 97%.  The researchers concluded that C-WLI in combination with M-NBI is better than using either modality alone.  The study suggests that M-NBI may enhance the ability to diagnose subtle characteristics of mucosal cancers better than C-WLI in a select, high-risk population.  Use of both modalities was statistically superior to C-WLI alone but not to M-NBI alone.

Nagorni and colleagues (2012) conducted a meta-analysis which compared standard or high-definition white-light colonoscopy with NBI colonoscopy for detection of colorectal polyps.  Eight randomized controlled trials (3673 participants) were included in the analyses.  The authors found there was no convincing evidence that NBI is significantly better than high-definition white-light colonoscopy for the identification of subjects with colorectal polyps or colorectal adenomas.  However, the authors did conclude that NBI may be better than standard definition white-light colonoscopy and equal to high-definition white-light colonoscopy for identification of subjects with colorectal polyps, or colorectal adenomas.

Researchers (Ignjatovic, 2012) conducted a multicenter study comparing NBI with high-definition white-light endoscopy.  The randomized, controlled trial included 112 participants with chronic UC who underwent colonoscopic surveillance with either procedure.  Fifty-six subjects were allocated to the NBI group and the other half were included in the white-light endoscopy group.  Targeted biopsies of suspicious areas and quadrantic random biopsies every 10 cm were obtained from both groups.  The primary outcome measure was the proportion of participants with at least one area of dysplasia detected.  In a prespecified mid-point analysis, the criteria for trial discontinuation were met and the trial was stopped and analyzed at this point.  The researchers found no difference in the primary outcome between the two groups with 5 subjects in each group having at least one dysplastic lesion.  The yield of dysplasia from random nontargeted biopsies was 1/2707 (0.04%).  Random background biopsies were ineffective in detecting dysplasia.

In another study, researchers conducted a meta-analysis to determine whether use of NBI enhances the detection of adenomas.  A total of six studies were included in the analyses.  When the data was analyzed, the authors found there was no statistically significant difference in the overall adenoma detection rate with the use of NBI or white-light colonoscopy and there was no statistically significant difference in polyp detection rate using NBI or white-light colonoscopy.  The researchers concluded NBI did not increase adenoma or polyp detection rates (Dinesen, 2012).

Sakamoto and colleagues (2012) compared interpretation times between NBI and magnifying chromoendoscopy (MCE) techniques in distinguishing between neoplastic and non-neoplastic small colorectal lesions.  A total of 693 consecutive participants who underwent colonoscopy at a single medical facility in Japan were enrolled.  When the first lesion was detected by conventional white-light observation, the participant was randomly assigned to undergo a sequence of NBI and MCE observations (group A: NBI-MCE, group B: MCE-NBI).  The time to diagnosis with each modality (NBI, from changing to NBI until diagnosis; MCE, from the start of indigo carmine solution spraying until diagnosis) was recorded by an independent observer.  The sensitivity, specificity, and diagnostic accuracy of the first modality used in each group (NBI or MCE) were assessed by referring to the histopathological data.  Seventy-one participants (137 lesions) were randomized to group A, and 80 participants (163 lesions) to group B.  The median interpretation times were 12 seconds (interquartile range [IQR], 7-19 seconds) in group A, and 17 seconds (IQR, 12-24 s) in group B, the difference being significant (p<0.001).  The authors reported no significant differences were observed between NBI and MCE in terms of sensitivity, specificity, and diagnostic accuracy and concluded NBI reduces the interpretation times for distinguishing between neoplastic and non-neoplastic small lesions during colonoscopies, without loss of diagnostic accuracy. 

Kobayashi and colleagues (2012) conducted a meta-analysis comparing the diagnostic test performance of chromoendoscopy and NBI for colonic neoplasms.  Twenty-seven of the 1342 articles screened met the inclusion criteria.  Pooled sensitivity for chromoendoscopy and NBI was 0.94 (95% CI, 0.92-0.95) and 0.94 (95% CI, 0.91-0.97), and specificity was 0.82 (95% CI, 0.77-0.88) and 0.86 (95% CI, 0.83-0.89), respectively.  There were no differences in sensitivity (p=0.99) or specificity (p=0.54) between the two methods.  In the secondary analysis, pooled sensitivity for chromoendoscopy and NBI was 0.93 (95% CI, 0.90-0.97) and 0.96 (95% CI, 0.93-0.99) and specificity was 0.80 (95% CI, 0.73-0.87) and 0.85 (95% CI, 0.78-0.92) respectively.  Overall, the pooled false-negative rate was 0.057 (95% CI, 0.040-0.73) for chromoendoscopy and 0.057 (95% CI, 0.028-0.085) for NBI.  The authors concluded that chromoendoscopy and NBI had similar diagnostic test characteristics in the assessment of colonic neoplasms; however, the false-negative rate for both methods of 5.7% is an unacceptably high rate and currently neither method can be considered ready for general use.

Dutta and colleagues (2013) explored whether NBI is superior to conventional white-light gastroscopy (WLG) in detecting potentially premalignant gastric lesions.  In a randomized prospective crossover, 200 individuals above 45 years of age with dyspepsia and no alarming symptoms (weight loss, vomiting, hematemesis, melena, dysphagia), underwent gastric mucosal examination.  Both WLG and NBI were performed during the same session by different endoscopists who were blinded to each other's endoscopy findings.  Biopsy was taken if required at the end of the second gastroscopy after a third observer reviewed reports of both endoscopists.  The yield of gastric potentially premalignant lesions (adenomatous polyp, dysplasia, intestinal metaplasia and atrophic gastritis) was compared for both procedures.  Thirty-two participants were diagnosed to have potentially premalignant lesions using both modalities.  No participants had early gastric cancer.  WLG detected lesions in 17 individuals (atrophic gastritis in 12, atrophic gastritis with intestinal metaplasia in 5) and NBI in 31 participants (atrophic gastritis in 22, atrophic gastritis with intestinal metaplasia in 9). The sensitivity of lesion detection by NBI was significantly higher than WLG (p=0.001).  The authors concluded that NBI was superior to WLG for detection of atrophic gastritis and intestinal metaplasia.

The American Cancer Society (ACS) and the U.S. Multi-Society Task Force on Colorectal Cancer jointly published a guideline regarding colonoscopy surveillance after polypectomy which indicates that there is currently insufficient evidence that the evolving technology of NBI should be part of routine post-polypectomy surveillance at this time (Winawer, 2006).

The ASGE Technology Status Evaluation Report on NBI and multiband imaging. (ASGE, 2008) includes NBI as one of the emerging technologies that may improve the diagnosis and characterization of mucosal lesions of the GI tract, in particular as an adjunctive technique to magnification endoscopy.  However, additional studies addressing the standardization of image characterization, further image-to-pathology correlation and validation, and the impact of this technology on individual outcomes are necessary before endorsing the use of NBI in the routine practice of GI endoscopy.

The American Gastroenterological Association (AGA) Institute technology assessment on image-enhanced endoscopy (AGA, 2008) includes NBI in the category of "imaged-enhanced endoscopy (IEE)" which "encompasses various means of enhancing contrast during endoscopy using dye, optical, and/or electronic methods."  The technology assessment states that "equipment-based IEE is increasingly reported to aid in the detailed visualization of the microvessels and surface structures of neoplastic, metaplastic, and hyperplastic tissues."  However, "IEE is not routinely used in the management of diseases of the small intestine."

According to the American College of Gastroenterology (ACG) Guidelines for Colorectal Cancer Screening 2008 (Rex 2009):

Narrow band imaging does not enhance mucosal inspection by endoscopists with high adenoma detection rates, but may be a useful teaching tool for enhancement of flat lesion detection by endoscopists with low adenoma detection rate.  The ACG recommends that clinical gastroenterologists follow actively the technical developments pertaining to mucosal inspection enhancement techniques and incorporate such techniques into practice, as they are proven to be both effective and practical.  However, endoscopists should understand that no enhancement technique replaces the need for a meticulous inspection.

The US Multi-Society Task Force on Colorectal Cancer released updated consensus guidelines for colonoscopy surveillance after screening and polypectomy.  According to the consensus group:  

Chromoendoscopy and narrow band imaging may enable endoscopists to accurately determine if lesions are neoplastic, and if there is a need to remove them and send material to pathology. At this point, these technologies do not have an impact on surveillance intervals (Lieberman, 2012).

As mentioned above, the SCENIC International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease, published by the ASGE and the AGA, represents the consensus opinions of an international multidisciplinary expert panel.  With regards to NBI, the consensus group does not recommend that NBI be used in place of white-light colonoscopy when performing surveillance with either standard-definition, high-definition or imaged-enhanced high-definition colonoscopy (Laine, 2015).

It has been proposed that NBI may assist in the distinction between normal and abnormal GI mucosa.  While these image enhancing technologies may increase visibility of the GI mucosa and may therefore enable the physician to identify additional suspicious lesions, additional studies on this technology are needed to demonstrate that this technology improves clinical outcomes over standard practices.

Background/Overview

Colonoscopy is the gold standard for detecting and removing polyps from the colon.  During colonoscopy, an endoscope is inserted into the rectum and slowly advanced into the colon.  As the endoscope is advanced, the practitioner closely examines the walls of the colon.  Small, suspicious polyps are removed at this time and sent to a laboratory to be analyzed.  The laboratory pathologist makes the determination whether or not a polyp is benign (non-cancerous), precancerous or malignant (cancerous). 

Conventional chromoendoscopy utilizes contrast dyes to heighten visualization of the colonic mucosa and surface contours.  In conventional pancolonic chromoendoscopy, a catheter is used to apply dye (for example, methylene blue or indigo carmine) directly through the working channel of the endoscope onto the mucosa.

The Optical Biopsy System consists of a laser, an optical fiber, analytical software, and a user-interface console.  The laser light is directed at a suspicious polyp.  The polyp absorbs the light and redirects it through the fiber to a computer.  The software determines whether the polyp has the potential to become malignant.  The Optical Biopsy System is not intended to be used as a stand-alone device or as a diagnostic test to be done instead of colonoscopy.  The Optical Biopsy System is designed to be used as an additional tool during colonoscopy to assist the physician in determining whether certain colon polyps are potentially cancerous and should be removed.  As with the standard colonoscopy, after the endoscopic examination is complete, the biopsy samples are sent to the pathology department for evaluation.  

During colonoscopy, the endoscope normally emits a white light.  NBI converts the white light to a narrower wave length, which results in a bluish light.  The blue light increases the contrast of the surface structures of the colon.  Combining the narrow band image with video processing equipment further enhances the anatomical structures of the colon.  The EVIS EXERA 160A System (Olympus Medical Systems Corp) is one example of a NBI system.

Confocal laser (fluorescent) endomicroscopy is also being investigated as a tool to enhance the in vivo analysis of the GI tract.  The confocal laser endomicroscope combines a confocal laser microscope mounted in the distal tip of a conventional video endoscope.  According to the ASGE:

CLE is based on tissue illumination with a low-power laser with subsequent detection of the fluorescence light reflected from the tissue through a pinhole.  The term confocal refers to the alignment of both illumination and collection systems in the same focal plane.  The laser light is focused at a selected depth in the tissue of interest and reflected light is then refocused onto the detection system by the same lens.  Only returning light refocused through the pinhole is detected.  The light reflected and scattered at other geometric angles from the illuminated object or refocused out of plane with the pinhole is excluded from detection (ASGE, 2014). 

This dramatically increases the spatial resolution of CLE, thus providing an 'optical biopsy' - histological examination of the superficial layer of the GI tract.  This enables the practitioner to view the GI tract without making a surgical incision (endoscopy), and to magnify the area being examined using a microscope.  A fluoroscopic agent is also used to enhance tissue visibility.  Practitioners have the option of storing images either digitally or on video, so that if necessary, they may be viewed later.  

Electronic chromoendoscopy employs imaging technologies to augment visualization of the mucosal surface of the GI tract.  Several electronic chromoendoscopy devices have been developed, including but not limited to FICE and i-SCAN.

Definitions

Chromoendoscopy (chromoscopy and chromocolonoscopy): The application of pigments or stains by spraying them through a catheter, onto the tissue, during endoscopy. 

Colonoscope: An elongated endoscope specifically designed to be used to view the interior walls of the colon.

Colonoscopy: Visual examination of the inner walls of the colon by means of a colonoscope.

Confocal laser endomicroscopy: An examination based on tissue illumination with a low-power laser with subsequent detection of the fluorescence light reflected from the tissue through a pinhole. This dramatically increases the spatial resolution of confocal endomicroscopy, thus providing an 'optical biopsy' - histological examination of the superficial layer of the GI tract.

Electronic chromoendoscopy: any endoscopic imaging technology that provides a detailed contrast enhancement of the mucosal blood vessels and surface and is used as an alternative to dye-based chromoendoscopy. 

Endoscope: A small, lighted, flexible tube used to view internal body structures.

Fiberoptic analysis: Based on the observation that benign and malignant tissues emit different patterns and wavelengths of fluorescence after exposure to a laser light, fluorescent signals are measured and analyzed by a proprietary system such that lesions can be classified as suspicious (adenomatous) or not suspicious (hyperplastic). 

In vivo: Within a living organism.

Multi-band imaging (MBI): A digital image processing technique that enhances the appearance of mucosal surface structures by using selected wavelengths of light to create reconstituted virtual images. Multi-band imaging can also be used in combination with electronic or optical magnification for better visualization of the mucosa. Multi-band imaging differs from narrow band imaging in that it is software driven and uses an image processing algorithm.

Narrow band imaging: An illumination technology which employs light with wavelengths of narrow bands to enhance the visibility of veins, capillaries and other subtle tissue structures of the GI tract. 

Polyps: Small masses of tissue found in the GI tract: a polyp may either be benign, precancerous, or cancerous.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When Services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT  
43206 Esophagoscopy, flexible, transoral; with optical endomicroscopy
43252 Esophagogastroduodenoscopy, flexible, transoral; with optical endomicroscopy
43499 Unlisted procedure, esophagus [when specified as in vivo analysis of gastrointestinal lesions (e.g., fiberoptic analysis, narrow band imaging or multi-band imaging)]
43999 Unlisted procedure, stomach [when specified as in vivo analysis of gastrointestinal lesions (e.g., fiberoptic analysis, narrow band imaging or multi-band imaging)]
45399 Unlisted procedure, colon [when specified as in vivo analysis of gastrointestinal lesions (e.g., fiberoptic analysis, narrow band imaging, multi-band imaging, chromoendoscopy or electronic chromoendoscopy, or confocal laser endomicroscopy)]
45999 Unlisted procedure, rectum [when specified as in vivo analysis of gastrointestinal lesions (e.g., fiberoptic analysis, narrow band imaging, multi-band imaging chromoendoscopy or electronic chromoendoscopy, or confocal laser endomicroscopy)]
88375 Optical endomicroscopic image(s), interpretation and report, real-time or referred, each endoscopic session
0397T Endoscopic retrograde cholangiopancreatography (ERCP), with optical endomicroscopy
   
ICD-10 Diagnosis  
  All diagnoses
   
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  38. Rutter MD, Saunders BP, Schofield G, et al. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut. 2004; 53(2):256-260.
  39. Sakamoto T, Matsuda T, Aoki T, et al. Time saving with narrow-band imaging for distinguishing between neoplastic and non-neoplastic small colorectal lesions. J Gastroenterol Hepatol. 2012; 27(2):351-355.
  40. Singh R, Kaye PV, Ragunath K. Distinction between neoplastic and non-neoplastic colorectal polyps utilizing narrow band imaging with magnification: a novel technique to increase the efficacy of colorectal cancer screening? Scand J Gastroenterol. 2008; 43(3):380-381.
  41. Su MY, Hsu CM, Ho YP, et al. Comparative study of conventional colonoscopy, chromoendoscopy, and narrow-band imaging systems in differential diagnosis of neoplastic and nonneoplastic colonic polyps. Am J Gastroenterol. 2006; 101(12):2711-2716.
  42. Tischendorf JJ, Schirin-Sokhan R, Streetz K, et al. Value of magnifying endoscopy in classifying colorectal polyps based on vascular pattern. Endoscopy. 2010; 42(1):22-27.
  43. Tischendorf JJ, Wasmuth HE, Koch A, et al. Value of magnifying chromoendoscopy and narrow band imaging (NBI) in classifying colorectal polyps: a prospective controlled study. Endoscopy. 2007; 39(12):1092-1096.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Society for Gastrointestinal Endoscopy (ASGE). Report on emerging technology. Confocal laser endomicroscopy. Gastrointest Endosc. 2009; 70(12):197-200. 
  2. Annese V, Daperno M, Rutter MD, et al. European evidence based consensus for endoscopy in inflammatory bowel disease. J Crohns Colitis. 2013; 7(12):982-1018.
  3. ASGE Standards of Practice Committee, Shergill AK, Lightdale JR, Bruining DH, et al. The role of endoscopy in inflammatory bowel disease. Gastrointest Endosc. 2015; 81(5):1101-21.e1-e13.
  4. ASGE Technology Committee. Chromoendoscopy. Gastrointest Endosc. 2007; 66(4):639-649.
  5. ASGE Technology Committee. Confocal laser endomicroscopy. Gastrointest Endosc. 2014; 80(6):928-933.
  6. ASGE Technology Committee. Song LM, Adler DG, Conway JD, et al. Narrow band imaging and multiband imaging. Gastrointest Endosc. 2008; 67(4):581-589.
  7. ASGE Technology Committee, Manfredi MA, Abu Dayyeh BK, Bhat YM, et al. Electronic chromoendoscopy. Gastrointest Endosc. 2015; 81(2):249-261.
  8. Centre for Clinical Practice at NICE (UK). Colonoscopic Surveillance for Prevention of Colorectal Cancer in People with Ulcerative Colitis, Crohn's Disease or Adenomas. London: National Institute for Health and Clinical Excellence (UK); 2011 Mar. (NICE Clinical Guidelines, No. 118.) Available from: http://www.ncbi.nlm.nih.gov/books/NBK82209/. Accessed on December 17, 2016.
  9. Farraye FA, Odze RD, Eaden J, et al. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 2010; 138(2):738-745.
  10. Kaltenbach T, Sano Y, Friedland S, et al. American Gastroenterological Association (AGA) Institute technology assessment on image-enhanced endoscopy. Gastroenterology. 2008; 134(1):327-340.
  11. Laine L, Kaltenbach T, Barkun A, et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastrointest Endosc. 2015; 81(3):489-501.e26.
  12. Leighton JA, Shen B, Baron TH, et al.; Standards of Practice Committee, American Society for Gastrointestinal Endoscopy. ASGE guideline: endoscopy in the diagnosis and treatment of inflammatory bowel disease. Gastrointest Endosc. 2006; 63(4):558-565.
  13. Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012; 143(3):844-857.
  14. NCCN Clinical Practice Guidelines in Oncology. © 2016 National Comprehensive Cancer Network, Inc. Colorectal Cancer Screening. V2.2016. Revised October 20, 2016. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on December 17, 2016.
  15. Rex DK, Johnson DA, Anderson JC, et al. American College of Gastroenterology guidelines for colorectal cancer screening 2008. Am J Gastroenterol. 2009; 104(3):739-750.
  16. U.S. Food and Drug Administration 510(k) Premarket Approval. EPX-4400 and EPX-4400 HD with FICE: No. K150221. Rockville, MD: FDA. October 1, 2015. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf15/k150221.pdf. Accessed on December 17, 2016.
  17. U.S. Food and Drug Administration 510(k) Premarket Approval. Optical Biopsy System: Summary of Safety and Effectiveness. No. 990050. Rockville, MD: FDA. November 19, 1999. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf/P990050b.pdf. Accessed on December 17, 2016.
  18. U.S. Food and Drug Administration 510(k) Premarket Approval. Pentax Medical EPK-i7010 Video Processor with GI Family. No. K150618. Silver Spring, MD: FDA. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf15/k150618.pdf. Accessed on December 17, 2016.
  19. U.S. Food and Drug Administration Premarket Notification Special 510(k) Summary. The Cellvizio® (GI, -LUNG) with Confocal Miniprobe™ (Coloflex, Gastroflex, Alveoflex). No. K061666. Rockville, MD: FDA. August 24, 2006. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf6/K061666.pdf. Accessed on December 17, 2016.
  20. U.S. Food and Drug Administration 510(k) Summary. EVIS EXERA 160A System. No.K051645. Rockville, MD: FDA. October 13, 2005. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf5/K051645.pdf. Accessed on December 17, 2016.
  21. U.S. Food and Drug Administration 510(k) Summary. Pentax Confocal Laser System. No. K042740. Rockville, MD: FDA. October 19, 2004. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf4/k042740.pdf. Accessed on December 17, 2016.
  22. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology. 2006; 130(6):1872-1885.
Index

Cellvizio® Confocal Miniprobe (Coloflex)
Chromocolonoscopy
Chromoendoscopy
Chromoscopy
Colorectal Polyps
Confocal fluorescent endomicroscopy
Confocal laser endomicroscopy
Electronic chromoendoscopy
EVIS EXERA 11 160A System
Fiberoptic Analysis of Colorectal Lesions
Fujinon intelligent color enhancement (FICE)
Flexible spectral imaging color enhancement
i-SCAN
Multi-band Imaging
Narrow Band Imaging
Optical Biopsy™ System
Virtual chromoendoscopy
WavSTAT™ Optical Biopsy System

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Review date, Description/Scope, Rationale, References and History sections of the document.
Revised 02/04/2016 MPTAC review. Revised investigational and not medically necessary position statement to include electronic chromoendoscopy. Updated Review date, Description, Rationale, Definitions, Background/Overview, References, History and Index sections of the document.
  01/01/2016 Updated Coding section with 01/01/2016 CPT and HCPCS changes, removed G6021 deleted 12/31/2015; also removed ICD-9 codes.
Reviewed 02/05/2015 MPTAC review. Updated Review date, Rationale, References, and History sections of the document.
  01/01/2015 Updated Coding section with 01/01/2015 CPT and HCPCS changes; removed 44799 (no longer applicable).
Reviewed 02/13/2014 MPTAC review. Updated Review date, Rationale, References, and History sections of the document.
  01/01/2014 Updated Coding section with 01/01/2014 CPT descriptor changes.
Reviewed 02/14/2013 MPTAC review. Updated Review date, Rationale, References, and History sections of the document.
  01/01/2013 Updated Coding section with 01/01/2013 CPT changes.
Revised 02/16/2012 MPTAC review. The term "in vivo" changed to "in-vivo" in title and throughout the document. Revised the position statement to include chromoendoscopy as investigational and not medically necessary for all indications. Updated Review date, Description/Scope, Rationale, Definitions, References, History and Index sections of the document.
Revised 02/17/2011 MPTAC review. Title and scope of policy changed to address gastrointestinal lesions. Updated Review date, Rationale, Coding, References and History sections of the document.
Reviewed 08/19/2010 MPTAC review. Updated Review date, Rationale, References and History sections of the document.
Reviewed 08/27/2009 MPTAC review. Updated rationale, review date, references and history sections.
Revised 08/28/2008 MPTAC review.  Scope of document expanded to address narrow band imaging, and confocal fluorescent endomicroscopy. Title changed to "In Vivo Analysis of Colorectal Polyps." Review date, description, rationale, background/overview, references, history and index sections updated.
  02/21/2008 The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Reviewed 08/23/2007 MPTAC review. Review date, references and history sections updated.
Reviewed 09/14/2006 MPTAC review. References and coding updated.
Revised 09/22/2005 MPTAC review. Revisions based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger Organizations Last Review Date Document Number Title
Anthem, Inc.     No prior document
WellPoint Health Networks, Inc. 04/28/2005 2.06.18 Fiberoptic Analysis of Colorectal Polyps