Validation of the NICE Classification Using Pentax Chromoendoscopy
Condition: Colorectal Polyp
Study type: Observational

Summary: 
      Colorectal cancer (CRC) is the most frequent gastrointestinal tumor and the second cause of
      cancer related death. Colonoscopy is currently the recommended method for detection of polyps
      and cancers in the colon. Removal of all adenomatous polyps during colonoscopy has become
      worldwide a standard procedure as it has been demonstrated to significantly reduce colorectal
      cancer incidence and mortality. It is routine practice to remove all the detected polyps for
      pathological evaluation, due to the low accuracy (59% to 84%) to differentiate non-neoplastic
      from neoplastic colorectal lesions with white-light endoscopy. The development of electronic
      or virtual chromoendoscopy (CE) has aimed to reliably predict histology of colorectal lesions
      based on endoscopic features. This technology differentiates between neoplastic and
      non-neoplastic lesions base on the analysis of the neo-angiogenesis and the mucosal pit
      pattern. Optical endoscopic diagnosis allows the real-time evaluation of polyp histology
      during colonoscopy and to determine the appropriate therapeutic strategy. This is important
      in clinical practice, since adenomas or superficial invasive submucosal carcinoma lesions can
      be curatively treated by endoscopic removal, unlike deeply invasive carcinomas, which
      requires surgery. The Narrow-band imaging (NBI) international colorectal endoscopic (NICE)
      classification is validated classification system proposed as a valid tool for not only
      differentiating hyperplastic from adenomatous polyps, but also predicting submucosal deep
      (SM-d) carcinomas. It was developed based on NBI technology, leaving uncertainty on its
      applicability to other systems. It was previously evaluated the application of the NICE
      classification to Fujinon spectral Imaging Color Enhancement (FICE) technology founding
      suboptimal results (accuracy 77%, sensitivity 77% and specificity 75%) and moderate
      inter-observer agreement (kappa: 0.51).
    

Detailed description: 
      NBI technology uses a physical filter in order to exploit the capacity of hemoglobin to
      selectively absorb blue light. It is considered to be less useful in areas with a large
      lumen, such as the stomach and colon, as a result of insufficient light for wide-range
      observation of the full extent of the tissue surface, and because the images are dark. I-scan
      is a virtual chromoendoscopy, based on the principle of digital post-processing and consists
      of three different image algorithms. Mode 1 is for detection of lesions. This algorithm is
      used for surface enhancement (SE) and enhances light-dark contrast by obtaining luminance
      intensity data for each pixel and apply an algorithm that allows detailed observation of the
      mucosal surface structure and lesion borders without altering the brightness of the
      endoscopic picture. Mode 2 is for characterization of lesions. This algorithm combines SE and
      tone enhancement (TE). TE dissects and analyses the individual red-green-blue components of a
      normal endoscopic image in real time and then alters the color frequencies of each component
      and recombines the components to a single, new color image without visible delay for the
      examiner. It is used to enhance minute mucosal changes and vessel structures. Mode 3 adds
      contrast enhancement (CE) to the endoscopic image (in addition to SE and TE) and is for
      demarcation of lesions. It digitally adds blue color to dark areas within the endoscopic
      image. Recently an image-enhanced endoscopic technology using a pre-processor band-limited
      light called Optical Enhancement system (OE system™), was developed by HOYA Co. (Tokyo,
      Japan) and is now equipped with the latest endoscopy system (Pentax Video Processor
      EPK-i7010; HOYA Co.). This new technology combines digital signal processing with optical
      filters that overcomes the limit of the spectral characteristics of the illumination light.
      Previous i-scan technology uses white light alone as an illumination light and digital
      post-processing of the reflection afterwards creates images yielding the virtual
      chromoendoscopic image. Although accumulating evidence has shown the usefulness of i-scan in
      the clinical setting, emission of white light alone causes a potential limitation for the
      current i-scan technology to obtain higher contrast images of microvascular pattern on the
      mucosal surface as shown by Narrow Band Imaging (NBI). The basic concept of OE is to overcome
      the darkness of NBI, which results in less usefulness for detectability in wide-range
      observation in the full-extended gastrointestinal lumen. The new innovated optical filters
      achieve higher illumination intensity and overall transmittance by connecting the peaks of
      the hemoglobin absorption spectrum (415 nm, 540 nm and 570 nm) creating a continuous
      wavelength spectrum. There are two modes with different OE filters. Mode 1 is designed mainly
      to improve visualization of microvessels with a sufficient amount of light, and Mode 2 is
      designed to improve contrast of white-light observation by bringing the color tone of the
      overall image closer to that of natural color (white color tone). Due to the underlying
      differences between the NBI and Pentax technologies (i-scan and OE system), it remains
      uncertain whether the NICE classification may be translated to this technology. The aim of
      this study is to validate the NICE classification by applying i-scan and OE system with
      high-definition without optical magnification, to evaluate colorectal lesions.

      MATERIALS AND METHODS

      Study design: It will be a non-interventional, prospective, non-randomized, non-controlled
      and simple blind study, performed in the Ecuadorian Institute of Digestive Disease (IECED),
      OmniHospital Academic Tertiary Center Ecuador, with patients included from April 2017 to
      October 2017. The study protocol and consent form has been approved by the institutional
      review board and will be conducted according to the declaration of Helsinki. Written informed
      consent will be obtained from all subjects before the examination.

      Study Population: Consecutive adult patients between 18 and 80 years of age, referred for
      elective outpatient colonoscopy and in whom polypectomy or biopsy is performed will be
      enrolled. Exclusion criteria will be pregnancy, suspected colonic obstruction or history of
      previous obstruction, gastrointestinal bleeding, history colorectal surgery, inflammatory
      bowel disease, hereditary polyposis syndrome, diverticulitis, history of radiation therapy to
      abdomen or pelvis, history of severe cardiovascular, pulmonary, liver or renal disease,
      severe coagulation disorders or use of anticoagulants. Patients with polyps but in whom
      histopathology has not been evaluated or with a poor bowel preparation (Boston Bowel
      Preparation Scale ≤6) will be excluded from the analysis but included in the intention to
      treat.

      Intervention: endoscopic technique The procedures will be performed under propofol
      intravenous sedation, in left later or supine position. For bowel preparation, the
      participants will have to ingest 4 liters of polyethylene glycol solution in the evening the
      day before the procedure. The effectiveness of the bowel cleansing will be evaluated using
      the Boston Bowel Preparation Scale. Three colonoscopists (C.R.M., M.V., M.S.A.), with
      extensive experience in colonoscopy with i-scan and OE (>1000 cases) and familiar with the
      NICE classification, will perform the procedures using Pentax high definition colonoscopes
      without optical magnification (EC-3890Zi, PENTAX Medical, HOYA Co.) and EPK-i7010 processor
      with the ability to display i-scan and OE system™ images. The endoscopy images will be
      analyzed on a 27-inch, flat panel, high definition LCD monitors (Radiance™ ultra
      SC-WU27-G1520 model). All lesions initially detected by white light endoscopy will be
      intensively washed using a water ejection pump before recording the procedure and then the
      endoscopic features on the surface will be evaluated using the 3 i-scan modes and the 2 OE
      modes without magnification. The lesion size data (1-5/6-9/>10 mm), location (cecum/ right/
      transverse/ left/ sigmoid colon/ rectum) and macroscopic shape of the lesions based on the
      Paris classification will be recorded. The size will be estimated with biopsy forceps (2.2 mm
      closed; Radial Jaw 4, Boston Scientific, Marlborough, Massachusetts, USA) or polypectomy
      snare (13mm open; Captivator, Boston Scientific, Marlborough, Massachusetts, USA). Finally
      all lesions will be classified in real-time into 3 types based on NICE classification (NICE
      1, hyperplastic polyps; NICE 2, adenoma and superficial submucosal carcinoma; NICE 3, SM-d
      invasive carcinoma). A level of confidence (high or low) will be assign in each stage. A high
      confidence prediction will be considered when the endoscopist is 90% certain of the diagnosis
      and this condition will be consider when polyps have ≥1 features associated with one NICE
      type and no features associated to the others NICE type. If there are uncertainty regarding
      the features or if there are features from different NICE types the prediction will have low
      confidence. Polyp's images will be photographically and videotape recorded. Each
      high-definition video will consist of 30 to 60 seconds of white-light endoscopy followed by
      i-scan 1,2,3 and OE mode 1 and 2. For the purpose of this study, magnification was not
      allowed during recording. All polyps will be resected or biopsied for histopathological
      examination used as the criterion standard for the analysis. Two experienced pathologists,
      blind to the endoscopic diagnosis, will assess the histology according to the revised Vienna
      classification. Lesions identified histopathologically as serrated adenomas/ polyps or
      traditional serrated adenoma will be excluded from the analysis but included in the intention
      to treat, due to the lack of fully established evidence of NICE classification utility for
      the diagnosis of these lesions.

      In a second phase, endoscopists with less experience (<1000 procedures) using i-scan and OE
      will be selected. After a formal instruction on the NICE classification based on theoretical
      background and a series of i-scan/OE-polyp images, each of them will have to reviewed all the
      videos and applied the NICE classification in order to predict the histology. Each of the
      three criteria of the NICE system (colour/vessel/surface pattern) will be individually scored
      as well as the overall level of confidence (high/low).

      Statistical analysis

      Base line characteristics will be expressed as percentage or mean +/- standard deviation. It
      will be calculated the accuracy, sensitivity, specificity, negative and positive predictive
      values with the 95% of Confidence Interval (95% CI), for each component of the classification
      and for the overall prediction by using the classification. Using multilevel logistic
      regression, the sensitivity and specificity of the different criteria, will be compared.
      Diagnostic values of the criteria used in combination (combination of "at least 1 criterion
      being positive" versus "all combined criteria being positive") will be assessed and compared.
      The criterion standard for validation of predictions will be the lesions histology. Presence
      of adenomatous feature at each criterion will be defined as a positive result. The sample
      size was calculated assuming that 80% of predictions will be made with high confidence, and
      that the real accuracy will be 90%. A data set containing 30 random-selected videos will be
      presented after 2 months to the three main investigators (C.R.M, M.V, M.S.A.) in order to
      assess intra and inter-observer reproducibility. The endoscopists will have classified again
      the polyps according to the three types on the NICE classification. To examine inter and
      intra observer agreement, kappa values will be calculated. Kappa coefficients below 0.4
      indicate "poor agreement," values between 0.4 and 0.8 represent "moderate to good agreement,"
      and values greater than 0.8 indicate "excellent agreement." A P value of less than 0.05 will
      be considered to be statistically significant. All the statistical analysis will be performed
      using SPSS software suite v.22.
    

Intervention name(s): Pentax chromoendoscopy (i-scan and Optical Enhancement)
Intervention type(s): Device
Intervention description(s): All lesions will be evaluated using the 3 i-scan modes and the 2 OE modes without magnification. The lesion size data, location and macroscopic shape of the lesions based on the Paris classification will be recorded. Finally all lesions will be classified in real-time into 3 types based on NICE classification (NICE 1, hyperplastic polyps; NICE 2, adenoma and superficial submucosal carcinoma; NICE 3, SM-d invasive carcinoma). A level of confidence (high or low) will be assign in each stage. Polyp's images will be photographically and videotape recorded. All polyps will be resected or biopsied for histopathological examination used as the criterion standard for the analysis.
Observational model: Case-Crossover
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Consecutive adult patients between 18 and 80 years of age, referred for elective outpatient
        colonoscopy and in whom polypectomy or biopsy is performed will be enrolled.
      
Biospecimen description: 
      colorectal polyps will be resected y biopsed