Cáncer colorrectal ­ diagnóstico y tratamiento: revisión bibliográfica / Colorectal cancer ­ diagnosis and treatment: literature review

Colorectal cancer (CRC) is the third most prevalent cancer worldwide. Although improvements in detection and treatment have been implemented; CRC incidence, prevalence, and mortality remain high, even in developed countries. The risk of developing this cancer is related to poor eating habits, smoking, inflammatory bowel disease, polyps, genetic factors, and aging. There are several methods for detecting colorectal cancer, including the guaiac test, stool immunochemical test, stool DNA test, sigmoidoscopy, colonoscopy, and barium enema. The stage at which the cancer is detected determines the patient's prognosis, survival, and treatment. Treatments include endoscopic and surgical local excision, preoperative radiation therapy and systemic downstage therapy, extensive surgery for locoregional and metastatic disease, local ablative therapies for metastases, and palliative, targeted chemotherapy and immunotherapy.

El cáncer colorrectal (CCR) es el tercer cáncer más prevalente a nivel mundial. A pesar de que se han implementado mejoras en la detección y el tratamiento; la incidencia, la prevalencia y la mortalidad del CCR siguen siendo altas, incluso en países desarrollados. El riesgo de desarrollar este cáncer está relacionado con malos hábitos alimentarios, tabaquismo, enfermedad inflamatoria intestinal, pólipos, factores genéticos y envejecimiento. Existen varios métodos para detectar el cáncer colorrectal, como la prueba de guayaco, la prueba inmunoquímica de heces, la prueba de ADN en heces, la sigmoidoscopia, la colonoscopia y el enema de bario. El estadio en el que se detecta el cáncer determina el pronóstico, la supervivencia y el tratamiento del paciente. Los tratamientos incluyen escisión local endoscópica y quirúrgica, radioterapia preoperatoria y terapia sistémica de reducción del estadio, cirugía extensa para enfermedad locorregional y metastásica, terapias ablativas locales para metástasis y quimioterapia paliativa, terapia dirigida e inmunoterapia.

Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability.

Molecular classification of colorectal cancer is difficult to implement in clinical settings where hundreds of genes are involved, and resources are limited. This study aims to characterize the molecular subtypes of patients with sporadic colorectal cancer based on the three main carcinogenic pathways microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN) in a Chilean population. Although several reports have characterized colorectal cancer, most do not represent Latin-American populations. Our study includes 103 colorectal cancer patients who underwent surgery, without neoadjuvant treatment, in a private hospital between 2008 and 2017. MSI, CIN, and CIMP status were assessed. Frequent mutations in KRAS, BRAF, and PIK3CA genes were analyzed by Sanger sequencing, and statistical analysis was performed by Fisher's exact and/or chi-square test. Survival curves were estimated with Kaplan-Meier and log-rank test. Based on our observations, we can classify the tumors in four subgroups, Group 1: MSI-high tumors (15%) are located in the right colon, occur at older age, and 60% show a BRAF mutation; Group 2: CIN-high tumors (38%) are in the left colon, and 26% have KRAS mutations. Group 3: [MSI/CIN/CIMP]-low/negative tumors (30%) are left-sided, and 39% have KRAS mutations; Group 4: CIMP-high tumors (15%) were more frequent in men and left side colon, with 27% KRAS and 7% presented BRAF mutations. Three percent of patients could not be classified. We found that CIMP-high was associated with a worse prognosis, both in MSI-high and MSI stable patients (p = 0.0452). Group 3 (Low/negative tumors) tend to have better overall survival compared with MSI-high, CIMP-high, and CIN-high tumors. This study contributes to understanding the heterogeneity of tumors in the Chilean population being one of the few characterizations performed in Latin-America. Given the limited resources of these countries, these results allow to improve molecular characterization in Latin-American colorectal cancer populations and confirm the possibility of using the three main carcinogenic pathways to define therapeutic strategies.

Opciones terapéuticas en el cáncer de recto inferior. Actualización / Therapeutic options in lower rectal cancer. Upgrade

Motiva esta presentación el hecho que desde el Relato "Opciones terapéuticas del Cáncer de Recto Inferior" en el año 2008 han pasado 10 años y por supuesto aparecieron algunos progresos y cambios. Se conoce gran heterogeneidad genética debido que puede desarrollarse por diferentes vías. Nuevos fármacos han aparecido para lograr terapia eficiente. La clasificación clínica TNM fue actualizada en el año 2018. Los métodos de diagnóstico siguen teniendo vigencia. La resección local endoanal se presenta como una conducta factible con resultados favorables debido al progreso instrumental. Combinado con R/T y Q mostró excelentes resultados ("Watch and Wait"). La escisión total de mesorecto sigue ocupando un lugar importante. En la amputación abdomino perineal debemos incluir la resección de ambos músculos elevadores del ano. La cirugía laparoscópica ocupa cada vez más lugar siendo tan segura como la convencional. Se adjuntan los algoritmos terapéuticos. Continuarán las investigaciones para mejorar los resultados. (AU)

The aim of this presentation is to update the one written in 2008 "Low rectal cancer therapeutic options" since some progress and changes have appeared after ten years. Great genetic heterogeneity is known because it can develop in different pathways. New drugs have appeared to achieve efficient therapy. The TNM clinical classification was updated in 2018. The diagnosis methods are still in effect. Endoanal local resection is presented as feasible behavior with favorable results due to instrumental progress. Combined with R/T and Ch showed excellent results (Watch and Wait). The total mesorectal continues to occupy an important place. The resection of both elevator muscles of anus must be included in the abdominoperineal amputation. Laparoscopic surgery is increasingly in place, being as safe as the conventional. Therapeutic algorithms are attached. Research will continue to improve results. (AU)

Aberrant expression of miRNAs predicts recurrence and survival in stage-II colorectal cancer patients from Egypt

Background: Patients with stage II CRC have a varying survival outcome. Therefore, it is critical to identify prognostic biomarkers that can define more aggressive forms of the disease. We assessed the expression levels of five miRNAs that have been previously addressed in relation to the development and progression of solid and hematological tumors. Methods: We measured the expression levels of miR-21, miR-137, miR-145, miR-320 and miR-498in stage II CRC patients from Egypt (124 tissues and 41 blood samples) by quantitative real time PCR (qPCR). The results were correlated with relevant clinicopathological factors, response to treatment and survival rates of the patients. Results: miR-137, miR-145 and miR-320 were significantly reduced in 39.5%, 48.4% and 52.4%; respectively whereas miR-21 and miR-498 were significantly overexpressed in 48.4% and 40.3% of the CRC tissues compared to the control group. In patients' blood, miR-137, miR-145 and miR-320 were significantly reduced in 46.3%, 46.3% and 51. 2%; respectively whereas mir-21 and miR-498 were significantly overexpressed in 46.3% and 43.9% of the cases, respectively. The concordance between tissue and blood was weak for miR-320 and miR-145 (kappa 40-65%), intermediate for miR-498 and miR-137 (kappa 65-75%) and strong for miR-21 (kappa 75-85%). In univariate analysis performance status, over-expression of miR-21 and miR-498 and reduced miR-137, miR-145, and miR-320 associated significantly with reduced DFS and OS. However, in multivariate analysis, miR-498 and miR-320 were independent prognostic factors for DFS whereas miR-21 was independent prognostic factors for OS. Conclusions: miRNAs play an important role in the development and progression of stage II CRC. A five markers panel (miR-21, miR-498, miR-137, miR-145 and miR-320) can predict recurrence and survival in stage II CRC patients from Egypt (AU)

[Development of malignant tumors in patients with inflammatory bowel disease]. / Desarrollo de neoplasia en pacientes con enfermedad inflamatoria intestinal.

BACKGROUND: The chronic inflammation of the intestinal mucosa, the extra-intestinal manifestations of the disease and the immunosuppressive treatment of inflammatory bowel disease may increase cancer risk. AIM: To report the demographic and clinical features of patients with IBD who developed a malignant tumor. MATERIAL AND METHODS: Retrospective analysis of an IBD patient registry of a private clinic, diagnosed between 1976 and 2014. RESULTS: 437 subjects were included, aged 15-88 years (58% women). Seventy two percent of patients had ulcerative colitis. The median time of follow up was 6 years. Ten patients (2.3%) developed a malignant tumor. In four, the tumor could be related to IBD (two colorectal cancers, one cholangiocarcinoma and one chronic myeloid leukemia (CML)). Two of 45 patients treated with biological therapy developed a tumor (CML and hypernephroma). Three of 170 patients on immunosuppressive treatment developed tumors. Only one had a tumor possibly related with the use of azathioprine (non-melanoma skin cancer). In only two patients, the treatment was changed at the time of their cancer diagnosis, from immunosuppressive medications to mesalamine. CONCLUSIONS: Only a small proportion of these patients with IBD developed a malignant tumor. The treatment of IBD has to be determined by the severity of the disease and not by the fear of developing a neoplasia. Following recommendations is fundamental to decrease the possibility of developing this complication.

Desarrollo de neoplasia en pacientes con enfermedad inflamatoria intestinal / Development of malignant tumors in patients with inflammatory bowel disease

Background: The chronic inflammation of the intestinal mucosa, the extra-intestinal manifestations of the disease and the immunosuppressive treatment of inflammatory bowel disease may increase cancer risk. Aim: To report the demographic and clinical features of patients with IBD who developed a malignant tumor. Material and Methods: Retrospective analysis of an IBD patient registry of a private clinic, diagnosed between 1976 and 2014. Results: 437 subjects were included, aged 15-88 years (58% women). Seventy two percent of patients had ulcerative colitis. The median time of follow up was 6 years. Ten patients (2.3%) developed a malignant tumor. In four, the tumor could be related to IBD (two colorectal cancers, one cholangiocarcinoma and one chronic myeloid leukemia (CML)). Two of 45 patients treated with biological therapy developed a tumor (CML and hypernephroma). Three of 170 patients on immunosuppressive treatment developed tumors. Only one had a tumor possibly related with the use of azathioprine (non-melanoma skin cancer). In only two patients, the treatment was changed at the time of their cancer diagnosis, from immunosuppressive medications to mesalamine. Conclusions: Only a small proportion of these patients with IBD developed a malignant tumor. The treatment of IBD has to be determined by the severity of the disease and not by the fear of developing a neoplasia. Following recommendations is fundamental to decrease the possibility of developing this complication.

Vascular endothelial growth factor gene polymorphisms and colorectal cancer risk: a meta-analysis.

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen involved in a number of pathologic processes, including angiogenesis, tumor growth and metastasis. Polymorphisms of the VEGF gene have been associated with susceptibility to colorectal cancer (CRC). However, the specific association still remains controversial. We made a meta-analysis of the association between VEGF gene polymorphisms and CRC risk. Only eight case-control studies were retrieved, with a total of 2337 CRC patients and 2032 healthy controls. Six VEGF gene polymorphisms were addressed in all studies included, +936C>T (rs3025039), -2578C>A (rs699947), -1154G>A (rs1570360), -634G>C (rs2010963), -460C>T (rs833061), and +405C>G (rs2010963). There was a significant association between -2578C>A polymorphism and susceptibility to CRC in the comparison of C allele carriers (CC + CA) versus AA (odds ratio = 0.77, 95% confidence interval = 0.62-0.96, P = 0.02). No association was found between +936C>T, -1154G>A, -634G>C, -460C>T, and +405C>G with susceptibility to CRC. We conclude that the C allele carrier (CC + CA) of VEGF -2578C>A polymorphism appears to be a protective factor for CRC.

Endoscopic classification of the capillary-vessel pattern of colorectal lesions by spectral estimation technology and magnifying zoom imaging.

BACKGROUND: Colonoscopy with spectral estimation technology and magnifying zoom imaging allows the characterization of the fine superficial capillary pattern of normal mucosa and of colorectal lesions. The endoscopic distinction of the capillary pattern of colorectal lesions might contribute to the differential diagnosis among normal, hyperplastic, and neoplastic lesions. OBJECTIVE: By means of these latest technologic advances, the objective is to define a classification of the capillary-vessel pattern of colorectal lesions diagnosed during routine colonoscopy. DESIGN: A total of 309 colorectal lesions endoscopically or surgically resected were prospectively examined. The capillary pattern was divided into 5 subtypes according to the number, morphology, and distribution of the fine blood vessels. Capillary patterns types I and II were characterized by a few short, straight, and sparsely distributed vessels; types III to V were of numerous, elongated, and tortuous capillaries irregularly distributed. RESULTS: The overall accuracy of the capillary-vessel classification in determining the neoplastic or non-neoplastic nature of the colorectal lesions was 98.3% (304/309 lesions). Among 59 non-neoplastic lesions, 56 (94.9%) that showed patterns I or II were diagnosed as normal, inflammatory, or hyperplastic polyps. Of the 250 neoplastic lesions, 248 (99.2%) that had capillary pattern types III, IV, and V were diagnosed as adenomatous or carcinoma. The sensitivity of the capillary pattern classification for distinguishing neoplasia was 99.2% (95% CI, 98.2%-100%), and the specificity was 94.9% (95% CI, 92.5%-97.4%). LIMITATION: A single-center study. CONCLUSION: The endoscopic classification of the superficial capillary-vessel pattern of colorectal lesions is an accurate method of predicting the histopathologic findings.

[Tendency of the colorectal cancer in a zone of northern Spain]. / Tendencia del cáncer colorectal en una zona del norte de España.

BACKGROUND: The colorectal cancer incidence rates have been rapidly increasing. In order to investigate trends in colorectal cancer incidence rates we analyzed incidence data between 1992 and 2005 in the North of Spain. METHODS: Using Joinpoint models, we evaluated the effects of time period on colon and rectal cancer incidence. RESULTS: The analysis found a significant annual percentage of change (APC) (7.34) on female colon cancer incidence, and a significant APC (10.10) in male incidence. For incidence rectal cancer significant cohort effect was found comparing males and females. CONCLUSIONS: Our study shows a significant continuous increase incidence ofcolon cancer in Spain. We suggest to follow monitoring of cancer incidence and assessing risk factors.

Tendencia del cáncer colorectal en una zona del norte de España / Tendency of the Colorectal Cancer in a zone of northern Spain

Introducción: Las tasas de cáncer colorectal están aumentando en varios países. Para investigar este hecho hemos analizado las tasas de incidencia en una zona del Norte de España entre 1992 y 2005. Métodos: hemos calculado las tasas de incidencia del cáncer de colon y recto, así como la tendencia por el método de Joinpoint. Resultados: Se observa un porcentaje anual de cambio (APC) de 7.34 en mujeres y 10.10 en hombres, ambos estadísticamente significativos. En cambio no se encuentra variación en el cáncer de recto. Conclusiones: también en España se están encontrando notables incrementos de cáncer de colon, aunqueno de recto. Es preciso seguir monitorizando esta tendencia y evaluar los factores de riesgo para esta enfermedad.

Background: The colorectal cancer incidence rates have been rapidly increasing. In order to investigate trends in colorectal cancer incidence rates we analyzed incidence data between 1992 and 2005 in the North of Spain. Methods: Using Joinpoint models, we evaluated the effects of time period on colon and rectal cancer incidence. Results: The analysis found a significant annual percentage of change (APC) (7.34) on female colon cancer incidence, and a significant APC (10.10) in male incidence. For incidence rectal cancer significant cohort effect was found comparing males and females. Conclusions: Owr study shows a significant continuous increase incidence of colon cancer in Spain. We suggest to follow monitoring of cancer incidence and assessing risk factors.

Tendencia del cáncer colorectal en una zona del norte de España / Tendency of the Colorectal Cancer in a zone of northern Spain

Introducción: Las tasas de cáncer colorectal están aumentando en varios países. Para investigar este hecho hemos analizado las tasas de incidencia en una zona del Norte de España entre 1992 y 2005. Métodos: hemos calculado las tasas de incidencia del cáncer de colon y recto, así como la tendencia por el método de Joinpoint. Resultados: Se observa un porcentaje anual de cambio (APC) de 7.34 en mujeres y 10.10 en hombres, ambos estadísticamente significativos. En cambio no se encuentra variación en el cáncer de recto. Conclusiones: también en España se están encontrando notables incrementos de cáncer de colon, aunqueno de recto. Es preciso seguir monitorizando esta tendencia y evaluar los factores de riesgo para esta enfermedad.(AU)

Background: The colorectal cancer incidence rates have been rapidly increasing. In order to investigate trends in colorectal cancer incidence rates we analyzed incidence data between 1992 and 2005 in the North of Spain. Methods: Using Joinpoint models, we evaluated the effects of time period on colon and rectal cancer incidence. Results: The analysis found a significant annual percentage of change (APC) (7.34) on female colon cancer incidence, and a significant APC (10.10) in male incidence. For incidence rectal cancer significant cohort effect was found comparing males and females. Conclusions: Owr study shows a significant continuous increase incidence of colon cancer in Spain. We suggest to follow monitoring of cancer incidence and assessing risk factors.(AU)

Molecular genetics of colorectal cancer.

Colorectal tumours constitute an excellent system to study carcinogenesis and the molecular events implicated in the development of cancer. Attending to the way it is transmitted, colorectal cancer may appear in one of three forms: sporadic, familial, and hereditary. The sporadic form is most common and has no familial or hereditary associated factor thus far, while familial and hereditary forms show the same inheritance pattern. Hereditary colorectal cancers develop by means of defined stages that go from lesions in the crypt of the colon through adenomas to manifest cancer. They are characterised by the accumulation of multiple mutations in tumour suppressor genes and oncogenes that affect the balance between cell proliferation and apoptosis. The colorectal carcinogenesis pathway is not unique and there are probably several ways for the initiation, development and progression of colorectal tumours.

Colorectal cancer staging: reappraisal of N/PN classification.

PURPOSE: Current American Joint Committee on Cancer and the Union Internationale Contre le Cancer TNM classification disregards location of positive nodes, discontinuing N3 category, which constitutes a major modification to 1987 version. This study was designed to assess the impact of the recategorization of former N3 cases and the reliability of the current N1-N2 subcategorization of Stage III patients. METHODS: Prospectively collected data from 1,391 patients (55.8 percent males; median age, 64 (range, 21-97) years), operated on with curative intent between 1980 and 1999, were analyzed. The median follow-up was 60 (interquartile range, 27-97) months with 129 cases lost to follow-up. RESULTS: Of positive node cases, 25.3 percent were former N3. Among them, 30.5 percent migrated to the N1 group and 69.5 percent to the N2 group. The proportions of former N3 cases in N1 and N2 groups were 12.5 percent and 46.1 percent, respectively (P<0.001). Node-positive patients had an actuarial five-year survival rate of 56.7 percent (95 percent confidence interval, 53-59), with a significant difference between N1/N2 categories (63.6 vs. 44.1 percent, respectively; P<0.001). Although apical node involvement and more than three positive nodes were associated with poorer outcomes in univariate analysis, only the number of positive nodes had independent association (hazard ratio, 1.6 (range, 1.2-2.2); P<0.001). Integration of former N3 cases did not modify outcomes. CONCLUSIONS: The recategorization of former N3 involved a high proportion of positive node cases. Current N1/N2 categories clearly defined different outcomes and were not modified by the integration of former N3.

[Detection of micrometastases of colorectal carcinoma in lymph nodes]. / Detección de micrometástasis de carcinoma de colon en ganglios linfáticos.

Dissemination of lymph nodes is a known prognostic factor in colorectal carcinoma. Micrometastases in lymph nodes can be missed when studied by routine techniques. We analyzed 162 lymph nodes from 30 patients with colonic carcinoma and using routine techniques, they were classified as follows: two Dukes A; nineteen Dukes B; and nine Dukes C. A patient with benign colon disease served as negative control. Lymph nodes were all sectioned in halves, with one of the halves stored in liquid nitrogen for molecular biology examination by carcinoembryonic antigen expression. The other formalin-fixed and paraffin embedded halves were saved for both pathologic and immunohistochemical examination. For Dukes A and Dukes B tumors, reverse transcriptase-polymerase chain reaction (RT-PCR) had a 50% higher sensitivity in the detection of micrometastases. The expression of carcinoembryonic antigen (CEA) was detected in all Dukes C cases, which were considered as positive controls. These results showed that RT-PCR has a higher sensitivity in the detection of micrometastases than routine techniques, including immunohistochemistry.

Deteccion de micrometastasis de carcinoma de colon en glanglios linfaticos / Detection of micrometastases of colorectal carcinoma in lymph nodes

En el carcinoma colorrectal Ia diseminación a los ganglios linfáticos es un factor pronóstico reco nocido. La presencia de ganglios linfáticos con micrometástasis en muchos casos no puede ser detectada por técnicas rutinarias. Se estudiaron prospectivamente 162 ganglios linfáticos de 30 pacientes con carcinoma de colon, los cuales según los resultados de Ias técnicas rutinarias fueron clasificados como Dukes A (2), Dukes B (19) y Dukes C (9). Un paciente con enfermedad colónica benigna se uso como control negativo. Todos los ganglios se seccionaron en mitades, una de Ias cuales se almacenó en nitrógeno líquido para su ulterior estudio por técnicas de biología molecular, mediante Ia expresión dei antígeno carcinoembrionario (CEA). La otra mitad fue fijada en formaldehído e incluída en parafina para su estudio anatomopatológico e inmunohistoquímico. Dei total de los casos se detectó un aumento dei 50% de Ia sensibilidad en Ia detección de micrometástasis mediante Ia reacción en cadena de Ia polimerasa con transcriptasa reversa (RT PCR) para los Dukes A B y se detectó Ia expresión de dicho antígeno en el total de ]os casos Dukes C. Estos resultados evidencian una mayor sensibilidad en Ia detección de micrometástasis utilizando RT PCR en comparación con Ias técnicas rutinarias, incluyendo Ia inmunohistoquímica.(AU)