Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03089268 |
| Other study ID # |
PSC-01A |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2017 |
| Est. completion date |
January 1, 2028 |
Study information
| Verified date |
September 2023 |
| Source |
Hospital Universitario La Fe |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
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.
Description:
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.
