Neoplasms

Digestive System Diseases

All Conditions

Symptoms and General Pathology

Colonic Neoplasms

Adenoma

Colonic Polyps

Polyps

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Pathological Conditions, Anatomical

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Intestinal Polyps

Herbal and Botanical

All Drugs and Chemicals

Cola

Individuals scheduled for colonoscopy at Hospital Universitari i Politècnic La Fe, participating in the Valencian CRC screening program, will be recruited.

Polypectomy or biopsy will be performed if necessary (following current guidelines).

Specific molecular analysis of serrated lesions and CRC will be carried out.

A colonoscopy will be performed to all individuals.

Colonoscopy

All lesions will be removed or biopsied during the procedure

Polypectomy or biopsy

Molecular analysis will be performed in all colorectal cancers and in those polyps diagnosed with "serrated lesion"

Molecular analysis

Marco Bustamante, M.D.;Ph.D.

Different subtypes of serrated lesions have been recently described. Among them, both sessile serrated polyp/adenoma (SSP/A) and traditional serrated adenoma (TSA) could have malignant potential through the serrated pathway or CIMP. These lesions, as a potential source of interval cancer, should also be considered in colorectal cancer (CRC) population-based screening programs. It is believed that this new described pathway could be responsible for up to 30% of all CRC.

Unlike the traditional adenoma, serrated lesions are difficult to diagnose because of their particular endoscopic appearance and their still unclear histological criteria. Furthermore, they have specific molecular changes and, through them, they could evolve into CRC faster than the adenoma. The real prevalence of the serrated lesions and their specific risk for developing new synchronous/metachronous lesions, or even malignancy, remains unknown. For all these reasons, we don't know if these patients could constitute a different CRC-risk group and if specific recommendations are needed during their follow-up.

This is a prospective longitudinal study developed within the framework of the CRC-screening program in the Valencian Community (Spain). We expect to include a total of 700 individuals who will be followed during 10 years.

In our study, we will collect epidemiologic variables related to the patient, variables related to all the polyps, and mutational (BRAF, KRAS, MSI), and CpG-island methylation status of serrated lesions. Strict endoscopic and histological criteria will be applied for the diagnosis of serrated lesions. All lesions detected at the index colonoscopy and during follow-up will be evaluated.

The purpose of this study is to correlate epidemiologic data, histological characteristics and the molecular profile of the serrated lesions with findings during follow-up, in order to define stratified groups according to their risk of developing new lesions or CRC in the future.

BACKGROUND Colorectal cancer (CRC) is, by its frequency and consequences, a relevant public health problem that has led to the implementation of population screening programs in many countries. The purpose of these programs is to reduce the incidence and mortality of CRC by early diagnosis of the disease, in the so-called pre-symptomatic phase. That is, to identify and remove all precursor lesions, essentially colon adenomas.

However, there is increasing evidence that these programs are not fully effective in preventing CRC. Cancers that appear before the next scheduled endoscopic control, called interval cancer (IC), occur in up to 2.5 / 1000 patients / year of observation, and the cumulative probability of developing a CRC within the first 5 years after an adenoma removal could be up to 2%. Recent studies suggest that the cause of more than 50% of ICs is the failure detecting premalignant lesions in the colon, either due to a poor colon preparation, technical deficiencies in the performance of colonoscopy or the characteristics of the lesions that make them barely visible.

A possible origin of the ICs could be the serrated polyp (SP). This is actually not a single lesion, but a heterogeneous group of lesions, different from the conventional adenoma, and characterized by the serration of the crypts in the histology. Serrated lesions, especially some subgroups, have macroscopic features that make them particularly difficult to detect in conventional colonoscopy: indistinct borders, cloud-like appearance, often covered by a mucous cap and interruption of the underlying mucosal vascular pattern. But the true diagnosis of serrated lesions is made by morphological criteria with the microscopic examination of the sample obtained by biopsy. Although all lesions that showed these features were initially identified as hyperplastic polyps (HP), in the last decade three subtypes of serrated lesions with different clinical implications have been described \[HP, sessile serrated polyp/adenoma (SSA/P) and traditional serrated adenoma (TSA)\]. However, the histological criteria are not yet fully clarified, and there is confusion in the terms to be used. Therefore, the agreement among pathologists is generally poor.

As a consequence, many serrated lesions are misdiagnosed and incorrectly classified. This has clinical relevance since some of them have malignant capacity. Both SSA/P and TSA can evolve to CRC through the so-called serrated pathway or cytosine-phosphate-guanosine (CpG) island methylator phenotype (CIMP), which could be responsible for up to 30% of all CRC. In this pathway, an aberrant hypermethylation of the genome is produced, which leads to transcriptional silencing and inhibition of expression in some genes promoter regions (epigenetic modification). CRCs that arise from a SP are not homogeneous and may have different molecular and histological characteristics depending on whether the origin mutation in the precursor lesion occurs in BRAF or Kirsten rat sarcoma (KRAS) gene, which leads to the development of SSA/P or TSA. And depending on if a mutL homolog 1 (MLH1) gene methylation is produced thereafter, a unstable (MSI) or stable (MSS) CRC will develop. The presence of a high CIMP rate also depends on the initial mutation. Therefore, serrated lesions could originate MSI/CIMP-H CRC (11%), MSS/CIMP-H CCR (4%) and MSS/CIMP-L CRC (15%). It is thought that some of the ICs may be directly related to the SP because they share morphological and molecular characteristics. The evolution from SSP/SSA to invasive carcinoma has been described to occur in only eight months.

This theoretical risk of developing advanced premalignant lesions and IC and its clinical significance has not been clearly shown in clinical practice because data on the prevalence of serrated lesions are limited and there is also a lack of longitudinal follow-up studies in patients with serrated lesions. The prevalence described is very variable and ranges from 0.6% to 13%, depending on the study, and the data are even scarcer in fecal occult blood test (FOBT) -based screening population. The presence of serrated lesions (other than HP) has been associated with the development of advanced synchronous adenomas in the colon, but also with advanced metachronous lesions during follow-up. This situation could place these patients in a special risk group. Patients with large SP may have a similar risk to develop a future CRC to those patients with advanced adenomas. Most Scientific Societies recommend endoscopic follow-up of serrated lesions, but the evidence is weak and specific intervals are proposed based only on expert recommendations.

In summary, there are still many unresolved questions about serrated polyps and their importance in CRC screening programs. Their prevalence on CRC screening population is not fully clarified because of the lack of prospective trials and the difficulty in diagnosis and histological classification. Their malignant potential is not clarified either because of the uncertainty about the prevalence of dysplasia in serrated lesions, and the lack of well-designed longitudinal studies for the detection of metachronic lesions. The current criteria for classifying these lesions seem weak to define the CRC risk for a specific patient, thus the proposed follow-up intervals are not based on strong scientific evidence. A thorough study of serrated lesions relating their molecular and histological characteristics with lesions found on colonoscopic follow-up could establish a new molecular classification aimed to design a patient-oriented follow-up strategy.

HYPOTHESIS The correlation of epidemiological data of the patient, histological characteristics and molecular alterations of SP of the colon, along with findings in the endoscopic follow-up, would allow to identify stratified groups of patients according to their risk of developing advanced lesions and CRC in the future.

OBJECTIVE

* To deepen the knowledge of histology and genetic alterations of SP and thereby try to establish a molecular classification that may serve as a basis for new endoscopic follow-up guidelines. These recommendations would be more reliable and adjusted to the patient's individual risk profile.
* To establish the prevalence of serrated lesions, especially SSP/SSA and SSP with dysplasia, in the FOBT positive CRC screening population.

colonic polyp or colorectal cancer samples

Molecular and Histological Characteristics of Serrated Lesions of the Colon

Molecular and Histological Characteristics of Serrated Lesions of the Colon: Development of an Individual Risk Profile Applicable to Population-based Colorectal Cancer Screening Programs

To assess the risk of developing metachronous advanced lesions or cancers in FOBT screening population

Analysis of molecular changes in colorectal cancer and serrated lesions in FOBT screening population

To assess the prevalence of serrated lesions in FOBT screening population

Hospital Universitario La Fe

Gastrointestinal Endoscopy Consultant

Syndrome

Two tandem colonoscopies: first inspection was on high-resolution white-light endoscopy from the cecum/ileo-colonic anastomosis to the rectum, followed by a second inspection also on HR-WLE.

two tandem colonoscopies: first inspection was on HR-WLE from the cecum/ileo-colonic anastomosis to the rectum, followed by a second inspection with panchromoendoscopy on indigo carmine.

the lumen of the colon is sprayed in a segmental fashion using 0.4% indigo carmine delivered via a specially designed dye spray catheter (Olympus PW-5V1) or via the accessory channel with a 50cc syringe filled with indigo carmine and air.

chromoendoscopy with indigo carmine

Jorge Lopez Vicente

Serrated polyposis syndrome (SPS) is the most common colorectal polyposis syndrome and is characterized by the combination of large and/or numerous serrated lesions (SLs) throughout the colorectum. SLs are classified into sessile serrated polyps (SSP) with or without dysplasia, hyperplastic polyps (HP) and traditional serrated adenomas (TSA). In 2010 the World Health Organization (WHO) defined this syndrome by any one of the following conditions: criterion I, at least 5 SLs proximal to the sigmoid colon with 2 or more of these being \>10mm in size; criterion II, any SLs proximal to the sigmoid colon in a first-degree relative with SPS; criterion III, more than 20 SLs of any size distributed throughout the colon. It has been demonstrated that 11.8-28.5% of patients with SPS present with colorectal cancer (CRC) at diagnosis. Tandem colonoscopy studies have demonstrated that a significant number of lesions are missed during conventional colonoscopy. This finding is even more evident when focusing SLs where a 31% miss rate has been reported. SLs are often overlooked due to their typical appearance: flat morphology, similar colour to the surrounding mucosa, subtle and indistinctive borders. Chromoendoscopy (dye spraying onto the surface of the colon) enhances the detection of subtle and flat polyps in the colon. Until the date no studies have assessed the use of dye-based chromoendoscopy in SPS patients.

The aim of this trial was to evaluate the usefulness of panchromoendoscopy with indigo carmine for the detection of polyps in the colon in patients with SPS. Secondary aims were to estimate the SLs and adenoma miss rates in these patients.

Patients were randomized in a 1:1 distribution to one of the two arms of the study by a list of random numbers distributed by the coordinator center. After randomization, patients were submitted to tandem colonoscopies by the same endoscopist:

* In group A (HR-WLE) the first inspection was on high-resolution white-light endoscopy from the cecum/ileo-colonic anastomosis to the rectum, followed by a second inspection also on HR-WLE.
* In group B (HR-CE) the first inspection was on HR-WLE from the cecum/ileo-colonic anastomosis to the rectum, followed by a second inspection with panchromoendoscopy. For this, the lumen was sprayed in a segmental fashion using 0.4% indigo carmine delivered via a specially designed dye spray catheter (Olympus PW-5V1) or via the accessory channel with a 50cc syringe filled with indigo carmine and air. After allowing a few seconds for the dye to settle onto the mucosal surface, excess pools of indigo carmine were suctioned and the mucosa was then scrutinised.

Time to withdrawal from the cecum was measured using a stopwatch excluding time needed for polypectomy and biopsies.

Lesions detected during each inspection were described and then removed. Size (measured in comparison with an open biopsy forceps), morphology (using the Paris classification), location and polypectomy technique were recorded before removal. Histology was used as gold standard.

Serrated polyposis syndrome (SPS) is the most common colorectal polyposis syndrome and is characterized by the combination of large and/or numerous serrated lesions (SLs) throughout the colorectum. SLs are classified into sessile serrated polyps (SSP) with or without dysplasia, hyperplastic polyps (HP) and traditional serrated adenomas (TSA). In 2010 the World Health Organization (WHO) defined this syndrome by any one of the following conditions: criterion I, at least 5 SLs proximal to the sigmoid colon with 2 or more of these being \>10mm in size; criterion II, any SLs proximal to the sigmoid colon in a first-degree relative with SPS; criterion III, more than 20 SLs of any size distributed throughout the colon. It has been demonstrated that 11.8-28.5% of patients with SPS present with colorectal cancer (CRC) at diagnosis. Tandem colonoscopy studies have demonstrated that a significant number of lesions are missed during conventional colonoscopy. This finding is even more evident when focusing SLs where a 31% miss rate has been reported. SLs are often overlooked due to their typical appearance: flat morphology, similar colour to the surrounding mucosa, subtle and indistinctive borders. Chromoendoscopy (dye spraying onto the surface of the colon) enhances the detection of subtle and flat polyps in the colon. Until the date no studies have assessed the use of dye-based chromoendoscopy in SPS patients.

The aim of this trial was to evaluate the usefulness of panchromoendoscopy with indigo carmine for the detection of polyps in the colon in patients with SPS. Secondary aims were to estimate the SLs and adenoma miss rates in these patients.

Patients were randomized in a 1:1 distribution to one of the two arms of the study by a list of random numbers distributed by the coordinator center. After randomization, patients were submitted to tandem colonoscopies by the same endoscopist:

* In group A (HR-WLE) the first inspection was on high-resolution white-light endoscopy from the cecum/ileo-colonic anastomosis to the rectum, followed by a second inspection also on HR-WLE.
* In group B (HR-CE) the first inspection was on HR-WLE from the cecum/ileo-colonic anastomosis to the rectum, followed by a second inspection with panchromoendoscopy. For this, the lumen was sprayed in a segmental fashion using 0.4% indigo carmine delivered via a specially designed dye spray catheter (Olympus PW-5V1) or via the accessory channel with a 50cc syringe filled with indigo carmine and air. After allowing a few seconds for the dye to settle onto the mucosal surface, excess pools of indigo carmine were suctioned and the mucosa was then scrutinised.

Time to withdrawal from the cecum was measured using a stopwatch excluding time needed for polypectomy and biopsies.

Lesions detected during each inspection were described and then removed. Size (measured in comparison with an open biopsy forceps), morphology (using the Paris classification), location and polypectomy technique were recorded before removal. Histology was used as gold standard. Biopsies were processed and stained using standard methods, and were subsequently evaluated by experienced gastrointestinal pathologists in each center according to Vienna criteria of gastrointestinal epithelial neoplasia. Serrated lesions were classified according to the WHO 2010 classification into hyperplastic polyps, sessile serrated polyps, and traditional serrated adenomas. Cytological dysplasia among serrated polyps was analyzed both as presence/absence of dysplasia, as well as the presence of low-grade and high-grade dysplasia. Neoplastic extension vertically into the submucosal layer or beyond was classified as invasive cancer.All the procedures were done under superficial sedation (midazolam and/or fentanyl or pethidine) or under deep sedation with propofol at the discretion of the endoscopist. Procedures were performed with high definition systems \[i.e: 180/190 series in combination with EVIS EXERA II-III processors (Olympus, Tokyo, Japan), EC 390 LI scope in combination with Pentax processor (Pentax, Tokyo, Japan) or 590 WL and 580 ZW endoscopes in combination with Fujinon 4400/4450 processors (Fujifilm medical systems, USA)\].

Quality of bowel cleansing was graded by each endoscopist following the Boston Bowel Preparation Scale. Adequate preparation was defined as a total score ≥6 with no segments \<2. Procedures in which the quality of preparation was inadequate were excluded.

Sample size calculation: a polyp miss rate of 29% with HR-WLE was described previously in a Dutch multicenter study with SPS patients. Estimating a power of 80% and a significance level of 0.05, the investigators calculated 516 lesions would be required to measure a difference of 15% on HR-CE. In a previous study a median of 6 polyps was found on annual surveillance4. The investigators calculated a simple size of 86 patients for the study, 43 on each group.

Statistical analysis was performed with SPSS version 15.0 for windows. Numeric variables are presented as mean and standard deviation in case of a normal distribution and compared with a Student´s t test. Categorical variables are presented as frequencies and compared with the Chi Square test. Polyp miss rates were compared with chi square test. Logistic regression analysis was used to compare polyp characteristics and miss rates and was expressed as Odds ratio with the confidence intervals (95% CIs) to quantify the magnitude of the associations.

Patients are randomized into two groups with tandem explorations: in the group A or white light group (HR-WLE) where inspection is performed with white light in both colonoscopies, and in the group B or chromoendoscopy group (HR-CE) where a first inspection is performed with white light and the second with panchromoendoscopy with indigo carmine.

Chromoendoscopy for Serrated Polyposis Syndrome

Panchromoendoscopy for the Surveillance of Serrated Polyposis Syndrome, a Multicenter, Prospective and Randomized Trial.

number of polyps detected during the second inspection divided by the total number of polyps detected during the first and the second examination

number of serrated lesions detected during the second inspection divided by the total number of serrated lesions detected during the first and the second examination

number of adenomas detected during the second inspection divided by the total number of adenomas detected during the first and the second examination

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Molecular and Histological Characteristics of Serrated Lesions of the Colon	NCT03089268	Colonic Neoplas... Colorectal Canc... Sessile Serrate... Polyp of Colon	Colonoscopy Polypectomy or ... Molecular analy...	50 Years - 75 Years	Hospital Universitario La Fe
Chromoendoscopy for Serrated Polyposis Syndrome	NCT03476434	Colonic Polyp Colonic Neoplas... Colonic Cancer	chromoendoscopy...	18 Years - 90 Years	Hospital Universitario de Móstoles
Chromoendoscopy for Serrated Polyposis Syndrome	NCT03476434	Colonic Polyp Colonic Neoplas... Colonic Cancer	chromoendoscopy...	18 Years - 90 Years	Hospital Universitario de Móstoles

Spots Global Cancer Trial Database for sessile serrated polyp