Optimización de la detección de neoplasias de colon en un programa de cribado poblacional de cáncer colorrectal /

Esta tesis ha pretendido profundizar en la optimización de estrategias de detección de neoplasias de colon en el cribado del cáncer colorrectal. Sus hallazgos suponen una aportación importante en el campo del cribado del cáncer colorrectal. Consta de dos proyectos principales, el primero de ellos basado en el test de sangre oculta en heces (FIT) y en el que se analiza el impacto que tendrían diferentes puntos de corte del test según el grupo de población estratificado en función de edad y sexo. En este estudio se demuestra que los puntos de corte del FIT se podrían individualizar en función de edad y sexo para optimizar el uso del FIT en el cribado del CCR. Como se explica en la tesis, parece necesario establecer estrategias más personalizadas, y en este sentido este proyecto aporta información de gran utilidad a la hora de planificar un cribado y unas necesidades de estudios endoscópicos. El segundo proyecto se centra en la colonoscopia y analiza la presencia de pólipos serrados en una cohorte de cribado poblacional y su relación con neoplasia avanzada sincrónica. Este estudio demuestra que en población de riesgo medio, los pólipos serrados grandes son poco frecuentes, e independientemente de su localización proximal o distal, se asocian a neoplasia avanzada sincrónica. Además, este riesgo de neoplasia avanzada es similar al riesgo de tener 3 o más adenomas tubulares pequeños, lo que apoya la recomendación de seguimiento endoscópico a los 3 años. Además, a pesar de que son necesarios más estudiso, los pólipos hiperplásicos proximales se relacionan con la presencia de neoplasia avanzada sincrónica. Estos resultados enfatizan la importancia de la detección y resección de estas lesiones mediante endoscopia de cribado de alta calidad. Ambos estudios se han basado en el estudio COLONPREV, un estudio poblacional, multicéntrico, nacional, controlado y randomizado, diseñado para comparar la eficacia de una colonoscopia con el FIT de forma bienal en reducir la mortalidad por cáncer colorrectal. La fortaleza de ambos estudios es que al estar basados en un estudio controlado, aleatorizado, prospectivo y multicéntrico, los resultados tienen una alta fiabilidad. Por otro lado, ambos tienen limitaciones. En el primero, los datos se analizaron con una sola ronda del FIT, y por tanto no refleja el mundo real donde los participantes en el cribado realizan rondas consecutivas; son necesarios estudios prospectivos sobre rondas consecutivas para valorar si los resultados varían. Otra limitación es que se ha realizado en un único país, y no se han tenido en cuenta otras variables que también pueden afectar al resultado, como el índice de masa corporal o el consumo de tabaco. Por otro lado, únicamente se realizaron colonoscopia los individuos que tenían un FIT con resultado positivo, de manera que no se han podido calcular la sensibilidad, especificidad, y los falsos negativos. El segundo proyecto también tiene algunas limitaciones, la más relevante, es que los criterios patológicos para el diagnóstico de pólipos serrados no fueron revisados de forma centralizada, y dado que puede haber variabilidad interobservador, esto puede haber influido en los resultados. Otras limitaciones son no haber podido determinar la relación entre cada tipo de pólipo serrado no hiperplásico, y por otro lado, dado el bajo número de casos diagnosticados de cáncer colorrectal, no se ha podido establecer la relación entre pólipos serrados grandes y cáncer colorrectal. Ambos proyectos han sido publicados en revistas indexadas y con factor de impacto, con un total de 8.332, y la tesis se presenta como compendio de publicaciones. Esta tesis abre la puerta a futuros proyectos de investigación, tanto de cribado en población de riesgo medio como de vigilancia de las lesiones diagnosticadas a raíz del cribado.The objective of this doctoral thesis is to develop the knowledge on optimization in colon neoplasias detection strategies. The findings of the studies offer an important contribution to the knowledge in the field of the colorectal cancer screening. The thesis consists of two separate projects. The first of them is focused on the fecal immunochemical test (FIT) and its objective is to evaluate its performance at different positivity cut-off values in a population-based colorectal cancer screening program, stratified by age and sex. This study shows that FIT cut-off values could be individualized by age and gender to improve the performance of the test in CRC screening programs. The study gives useful information to optimize resources and to plan a screening program. The second project is focused on colonoscopy, and it analyses the prevalence of serrated polyps and its relationship with synchronous advanced neoplasia. This study shows that large serrated polyps have low prevalence in average-risk individuals and, independently of their proximal or distal location, they are associated with the presence of synchronous advanced neoplasia. Advanced neoplasm associated risk is of the same magnitude to the risk of having three or more small tubular adenomas. This reinforces the recommendation of surveillance after three years. Furthermore, proximal hyperplastic polyps are related to the presence of synchronous advanced neoplasia, although further studies are needed to determine definitely the risk of patients with proximal hyperplastic polyps. These results emphasize the importance of endoscopic detection of these lesions with high quality screening examination. Both projects are based on the COLONPREV study, a population-based, multicenter, nationwide, randomized controlled trial designed to compare the efficacy of one-time colonoscopy and biennial FIT in reducing CRC-related mortality. The strength of both projects is that they are based on a recent, large, nationwide, controlled randomized and multicenter trial, which ensures the reliability of the data. On the other hand, the projects have some limitations as well. In the first project, results were analysed based on one FIT screening round, which does not reflect real world practice, in which people urdergo repeated testing. Prospective studies conducted over consecutive rounds are needed to determine if results are altered. Another limitation is that the study was performed in one country only, and that other factors such as smoking status, or body mass index were not evaluated and could have an influence on the results. Finally, test sensitivity and specificity could not be determined because only FIT positive individuals underwent colonoscopy. The second project also has some limitations, the most important being that pathologic criteria for the diagnosis of serrated polyps were not centrally reviewed. Interobserver variation among pathologists could have therefore influenced the results. Other limitations are that the relationship between each type of non-hyperplastic serrated polyp could not be determined, and that the relationship between large serrated polyps and CRC could not be established due to the few cases of diagnosed CRC. Both projects have been published in indexed journals with a total impact factor of 8.332, and this thesis is presented as compendium of both publications. Finally, this thesis opens the door to future research projects, both in the area of average-risk individuals that undergo colorectal cancer screening and in the surveillance of CRC screening diagnosed lesions

Identification of Lynch Syndrome Carriers among Patients with Small Bowel Adenocarcinoma

Lynch syndrome; Hereditary cancer; Small bowel adenocarcinomaSíndrome de Lynch; Cáncer hereditario; Adenocarcinoma de intestino delgadoSíndrome de Lynch; Càncer hereditari; Adenocarcinoma d'intestí primBackground: Small bowel adenocarcinoma (SBA) is a rare disease which can be associated with Lynch syndrome (LS). LS tumors are characterized by the presence of microsatellite instability (MSI) and/or the loss of mismatch repair (MMR) protein expression. In SBA, the frequency of MMR deficient (MMRd) tumors varies from 5% to 35%. This study aims to describe the prevalence of LS carriers among patients with MMRd small bowel adenocarcinomas. Methods: A multicenter retrospective study with identification and MMR testing of all consecutive SBA between 2004 and 2020 in a multicenter Spanish study. Demographical data, tumor characteristics, follow-up and survival information were collected. Germline testing was driven by identification of MMRd tumors. Results: A total of 94 individuals diagnosed with SBA were recruited. We observed 20 (21.3%) MMRd tumors. In 9/15 (60%) patients with MMRd tumors, a pathogenic variant was identified (three MLH1, four MSH2, one MSH6 and one PMS2). Accordingly, the prevalence of LS among all SBA cases was 10.1%. Conclusions: More than one-fifth of SBA display MMRd and in more than a half is due to LS. Our data supports the implementation of universal MMR tumor testing among SBA for the identification of LS families.This study was funded by the CERCA Program (Generalitat de Catalunya) and Agència de Gestió d’Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653). CIBEREHD is funded by the Instituto de Salud Carlos III

Cápsula endoscópica de colon versus colonoscopia en el cribado familiar de cancer colorrectal

Els objectius van ser avaluar prospectivament la capacitat diagnòstica de la càpsula endoscòpica en comparació amb la colonoscòpia en 30 pacients amb història familiar de CCR, i avaluar la neteja colònica amb preparació amb Moviprep. La prevalença de pòlips detectats amb càpsula i colonoscòpia va ser de 20,7% i 24,1%, respectivament. La sensibilitat i especificitat en detecció de pòlips va ser de 71, 4 i 95,4%, respectivament, amb VPP i VPN de 83,3 i 91,3%. Es conclou que la càpsula endoscòpica suposa una tècnica alternativa precisa, fiable, ben tolerada i segura pel cribatge familiar de CCR.Los objetivos fueron evaluar prospectivamente la capacidad diagnóstica de la cápsula endoscópica comparada con colonoscopia en 30 pacientes con historia familiar de CCR, y evaluar la limpieza colónica con preparación mediante Moviprep. La prevalencia de pólipos detectados por cápsula y colonoscopia fue de 20,7 % y 24,1%. La sensibilidad y especificidad en detección de pólipos fue de 71,4% y 95,4%, respectivamente, con VPP y VPN de 83,3 y 91,3%. Se concluye que la cápsula endoscopica ofrece una técnica alternativa precisa, fiable, bien tolerada y segura para el cribado familiar de CCR

Accuracy of colon capsule endoscopy in detecting colorectal polyps in individuals with familial colorectal cancer: could we avoid colonoscopies?

Background. Individuals with a family history of colorectal cancer (CRC) have an increased risk of CRC. We evaluated the diagnostic yield of CCE in the detection of lesions and also two different colon preparations. Methods. A prospective multicenter study was designed to assess CCE diagnostic yield in a cohort of asymptomatic individuals with a family history of CRC. CCE and colonoscopy were performed on the same day by 2 endoscopists who were blinded to the results of the other procedure. Results. Fifty-three participants were enrolled. The sensitivity, specificity, PPV, and NPV of CCE for detecting advanced adenomas were 100%, 98%, 67%, and 100%. Sensitivity, specificity, PPV, and NPV of CCE for the diagnosis of individuals with polyps were 87%, 97%, 93%, and 88%, respectively. CCE identify 100% of individuals with significant or advanced lesions. Overall cleanliness was adequate by 60.7% of them. The PEG-ascorbic boost seems to improve colon cleanliness, with similar colonic transit time. Conclusion. CCE is a promising tool, but it has to be considered as an alternative technique in this population in order to reduce the number of colonoscopies performed. More studies are needed to understand appropriate screening follow-up intervals and optimize the bowel preparation regimen

Clinical and Pathological Characterization of Lynch-Like Syndrome

Background & aims: Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins-this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features. Methods: We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ2 test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables. Results: We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC. Conclusions: Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC

Risk of cancer in family members of patients with lynch-like syndrome

Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56-2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67-4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44-2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26-5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk

Cápsula endoscópica de colon versus colonoscopia en el cribado familiar de cancer colorrectal

Els objectius van ser avaluar prospectivament la capacitat diagnòstica de la càpsula endoscòpica en comparació amb la colonoscòpia en 30 pacients amb història familiar de CCR, i avaluar la neteja colònica amb preparació amb Moviprep. La prevalença de pòlips detectats amb càpsula i colonoscòpia va ser de 20,7% i 24,1%, respectivament. La sensibilitat i especificitat en detecció de pòlips va ser de 71, 4 i 95,4%, respectivament, amb VPP i VPN de 83,3 i 91,3%. Es conclou que la càpsula endoscòpica suposa una tècnica alternativa precisa, fiable, ben tolerada i segura pel cribatge familiar de CCR.Los objetivos fueron evaluar prospectivamente la capacidad diagnóstica de la cápsula endoscópica comparada con colonoscopia en 30 pacientes con historia familiar de CCR, y evaluar la limpieza colónica con preparación mediante Moviprep. La prevalencia de pólipos detectados por cápsula y colonoscopia fue de 20,7 % y 24,1%. La sensibilidad y especificidad en detección de pólipos fue de 71,4% y 95,4%, respectivamente, con VPP y VPN de 83,3 y 91,3%. Se concluye que la cápsula endoscopica ofrece una técnica alternativa precisa, fiable, bien tolerada y segura para el cribado familiar de CCR

Optimización de la detección de neoplasias de colon en un programa de cribado poblacional de cáncer colorrectal

Esta tesis ha pretendido profundizar en la optimización de estrategias de detección de neoplasias de colon en el cribado del cáncer colorrectal. Sus hallazgos suponen una aportación importante en el campo del cribado del cáncer colorrectal. Consta de dos proyectos principales, el primero de ellos basado en el test de sangre oculta en heces (FIT) y en el que se analiza el impacto que tendrían diferentes puntos de corte del test según el grupo de población estratificado en función de edad y sexo. En este estudio se demuestra que los puntos de corte del FIT se podrían individualizar en función de edad y sexo para optimizar el uso del FIT en el cribado del CCR. Como se explica en la tesis, parece necesario establecer estrategias más personalizadas, y en este sentido este proyecto aporta información de gran utilidad a la hora de planificar un cribado y unas necesidades de estudios endoscópicos. El segundo proyecto se centra en la colonoscopia y analiza la presencia de pólipos serrados en una cohorte de cribado poblacional y su relación con neoplasia avanzada sincrónica. Este estudio demuestra que en población de riesgo medio, los pólipos serrados grandes son poco frecuentes, e independientemente de su localización proximal o distal, se asocian a neoplasia avanzada sincrónica. Además, este riesgo de neoplasia avanzada es similar al riesgo de tener 3 o más adenomas tubulares pequeños, lo que apoya la recomendación de seguimiento endoscópico a los 3 años. Además, a pesar de que son necesarios más estudiso, los pólipos hiperplásicos proximales se relacionan con la presencia de neoplasia avanzada sincrónica. Estos resultados enfatizan la importancia de la detección y resección de estas lesiones mediante endoscopia de cribado de alta calidad. Ambos estudios se han basado en el estudio COLONPREV, un estudio poblacional, multicéntrico, nacional, controlado y randomizado, diseñado para comparar la eficacia de una colonoscopia con el FIT de forma bienal en reducir la mortalidad por cáncer colorrectal. La fortaleza de ambos estudios es que al estar basados en un estudio controlado, aleatorizado, prospectivo y multicéntrico, los resultados tienen una alta fiabilidad. Por otro lado, ambos tienen limitaciones. En el primero, los datos se analizaron con una sola ronda del FIT, y por tanto no refleja el mundo real donde los participantes en el cribado realizan rondas consecutivas; son necesarios estudios prospectivos sobre rondas consecutivas para valorar si los resultados varían. Otra limitación es que se ha realizado en un único país, y no se han tenido en cuenta otras variables que también pueden afectar al resultado, como el índice de masa corporal o el consumo de tabaco. Por otro lado, únicamente se realizaron colonoscopia los individuos que tenían un FIT con resultado positivo, de manera que no se han podido calcular la sensibilidad, especificidad, y los falsos negativos. El segundo proyecto también tiene algunas limitaciones, la más relevante, es que los criterios patológicos para el diagnóstico de pólipos serrados no fueron revisados de forma centralizada, y dado que puede haber variabilidad interobservador, esto puede haber influido en los resultados. Otras limitaciones son no haber podido determinar la relación entre cada tipo de pólipo serrado no hiperplásico, y por otro lado, dado el bajo número de casos diagnosticados de cáncer colorrectal, no se ha podido establecer la relación entre pólipos serrados grandes y cáncer colorrectal. Ambos proyectos han sido publicados en revistas indexadas y con factor de impacto, con un total de 8.332, y la tesis se presenta como compendio de publicaciones. Esta tesis abre la puerta a futuros proyectos de investigación, tanto de cribado en población de riesgo medio como de vigilancia de las lesiones diagnosticadas a raíz del cribado.The objective of this doctoral thesis is to develop the knowledge on optimization in colon neoplasias detection strategies. The findings of the studies offer an important contribution to the knowledge in the field of the colorectal cancer screening. The thesis consists of two separate projects. The first of them is focused on the fecal immunochemical test (FIT) and its objective is to evaluate its performance at different positivity cut-off values in a population-based colorectal cancer screening program, stratified by age and sex. This study shows that FIT cut-off values could be individualized by age and gender to improve the performance of the test in CRC screening programs. The study gives useful information to optimize resources and to plan a screening program. The second project is focused on colonoscopy, and it analyses the prevalence of serrated polyps and its relationship with synchronous advanced neoplasia. This study shows that large serrated polyps have low prevalence in average-risk individuals and, independently of their proximal or distal location, they are associated with the presence of synchronous advanced neoplasia. Advanced neoplasm associated risk is of the same magnitude to the risk of having three or more small tubular adenomas. This reinforces the recommendation of surveillance after three years. Furthermore, proximal hyperplastic polyps are related to the presence of synchronous advanced neoplasia, although further studies are needed to determine definitely the risk of patients with proximal hyperplastic polyps. These results emphasize the importance of endoscopic detection of these lesions with high quality screening examination. Both projects are based on the COLONPREV study, a population-based, multicenter, nationwide, randomized controlled trial designed to compare the efficacy of one-time colonoscopy and biennial FIT in reducing CRC-related mortality. The strength of both projects is that they are based on a recent, large, nationwide, controlled randomized and multicenter trial, which ensures the reliability of the data. On the other hand, the projects have some limitations as well. In the first project, results were analysed based on one FIT screening round, which does not reflect real world practice, in which people urdergo repeated testing. Prospective studies conducted over consecutive rounds are needed to determine if results are altered. Another limitation is that the study was performed in one country only, and that other factors such as smoking status, or body mass index were not evaluated and could have an influence on the results. Finally, test sensitivity and specificity could not be determined because only FIT positive individuals underwent colonoscopy. The second project also has some limitations, the most important being that pathologic criteria for the diagnosis of serrated polyps were not centrally reviewed. Interobserver variation among pathologists could have therefore influenced the results. Other limitations are that the relationship between each type of non-hyperplastic serrated polyp could not be determined, and that the relationship between large serrated polyps and CRC could not be established due to the few cases of diagnosed CRC. Both projects have been published in indexed journals with a total impact factor of 8.332, and this thesis is presented as compendium of both publications. Finally, this thesis opens the door to future research projects, both in the area of average-risk individuals that undergo colorectal cancer screening and in the surveillance of CRC screening diagnosed lesions

Clinical and pathological characterization of Lynch-Like Syndrome

Background & aims: Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins-this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features. Methods: We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ2 test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables. Results: We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, Immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC. Conclusions: Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC

Cápsula endoscópica de colon versus colonoscopia en el cribado familiar de cancer colorrectal

Els objectius van ser avaluar prospectivament la capacitat diagnòstica de la càpsula endoscòpica en comparació amb la colonoscòpia en 30 pacients amb història familiar de CCR, i avaluar la neteja colònica amb preparació amb Moviprep. La prevalença de pòlips detectats amb càpsula i colonoscòpia va ser de 20,7% i 24,1%, respectivament. La sensibilitat i especificitat en detecció de pòlips va ser de 71, 4 i 95,4%, respectivament, amb VPP i VPN de 83,3 i 91,3%. Es conclou que la càpsula endoscòpica suposa una tècnica alternativa precisa, fiable, ben tolerada i segura pel cribatge familiar de CCR.Los objetivos fueron evaluar prospectivamente la capacidad diagnóstica de la cápsula endoscópica comparada con colonoscopia en 30 pacientes con historia familiar de CCR, y evaluar la limpieza colónica con preparación mediante Moviprep. La prevalencia de pólipos detectados por cápsula y colonoscopia fue de 20,7 % y 24,1%. La sensibilidad y especificidad en detección de pólipos fue de 71,4% y 95,4%, respectivamente, con VPP y VPN de 83,3 y 91,3%. Se concluye que la cápsula endoscopica ofrece una técnica alternativa precisa, fiable, bien tolerada y segura para el cribado familiar de CCR