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Human Pathology Apr 2017Colorectal medullary carcinoma, recognized by the World Health Organization as a distinct histologic subtype, is commonly regarded as a specific entity with an improved...
Colorectal medullary carcinoma, recognized by the World Health Organization as a distinct histologic subtype, is commonly regarded as a specific entity with an improved prognosis and unique molecular pathogenesis. A fundamental but as yet unaddressed question, however, is whether it can be diagnosed reproducibly. In this study, by analyzing 80 colorectal adenocarcinomas whose dominant growth pattern was solid (thus encompassing medullary carcinoma and its mimics), we provided a detailed description of the morphological spectrum from "classic medullary histology" to nonmedullary poorly differentiated histologies and demonstrated significant overlapping between categories. By assessing a selected subset (n=30) that represented the spectrum of histologies, we showed that the interobserver agreement for diagnosing medullary carcinoma by using 2010 World Health Organization criteria was poor; the κ value among 5 gastrointestinal pathologists was only 0.157 (95% confidence interval, 0.127-0.263; P=.001). When we arbitrarily classified the entire cohort into "classic" and "indeterminate" medullary tumors (group 1, n=19; group 2, n=26, respectively) and nonmedullary poorly differentiated tumors (group 3, n=35), groups 1 and 2 were more likely to exhibit mismatch repair protein deficiency than group 3 (P<.001); however, improved survival could not be detected in either group compared with group 3. Our findings suggest that the diagnosis of medullary carcinoma, as currently applied, may only serve as a morphological descriptor indicating an increased likelihood of mismatch-repair deficiency. Additional evidence including a more objective classification system is needed before medullary carcinoma can be regarded as a distinct entity with prognostic relevance. Until such evidence becomes available, caution should be exercised when making this diagnosis, as well as when comparing results across different studies.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Biopsy; Carcinoma, Medullary; Cell Differentiation; Colorectal Neoplasms; DNA Mismatch Repair; DNA Repair Enzymes; Female; Humans; Immunohistochemistry; Male; Middle Aged; Observer Variation; Predictive Value of Tests; Prognosis; Reproducibility of Results; Terminology as Topic; Young Adult
PubMed: 28034727
DOI: 10.1016/j.humpath.2016.12.013 -
Cells Jun 2020Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal... (Review)
Review
Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies target proliferating and mature cancer cells, while CSCs are mostly quiescent and poorly differentiated, thereby they can easily survive chemotherapeutic insults. The aberrant activation of Wnt/β-catenin, Notch, Hedgehog, Hippo/YAP (Yes-associated protein) and phosphatidylinositol 3-kinase/protein kinase B facilitates CSCs with excessive self-renewal and therapy resistance property in CRC. CSCs survive the chemo-radiotherapies by escaping therapy mediated DNA damage via altering the cell cycle checkpoints, increasing DNA damage repair capacity and by an efficient scavenging of reactive oxygen species. Furthermore, dysregulations of miRNAs e.g., miR-21, miR-93, miR-203, miR-215, miR-497 etc., modulate the therapeutic sensitivity of colorectal CSCs by regulating growth and survival signalling. In addition, a reversible quiescent G state and the re-entering cell cycle capacity of colorectal CSCs can accelerate tumour regeneration after treatment. Moreover, switching to favourable metabolic signatures during a therapeutic regimen will add more complexity in therapeutic outcomes against CSCs. Therapeutic strategies targeting these underlying mechanisms of CSCs' therapy resistance could provide a promising outcome, however, deep understanding and concerted research are necessary to design novel therapies targeting CSCs. To conclude, the understanding of these mechanisms of CSC in CRC could lead to the improved management of patients with CRC.
Topics: Animals; Colorectal Neoplasms; DNA Damage; Drug Resistance, Neoplasm; Humans; MicroRNAs; Neoplastic Stem Cells; Signal Transduction
PubMed: 32503256
DOI: 10.3390/cells9061392 -
Archives of Pathology & Laboratory... Oct 2008Colorectal carcinoma is one of the most common types of cancer in Western countries and is consistently ranked among the top 3 causes of cancer-related deaths, with... (Review)
Review
CONTEXT
Colorectal carcinoma is one of the most common types of cancer in Western countries and is consistently ranked among the top 3 causes of cancer-related deaths, with approximately 150 000 new cases in the United States and 55 000 deaths in 2006. The pathologist's assessment of tumor stage and stage-independent morphologic features, such as vascular/lymphatic invasion, influences treatment strategies for the individual patient, such as the decision to offer adjuvant therapy after surgery. However, although the pathologist influences clinical care in colorectal cancer, certain aspects of staging and evaluation of prognostic factors remain challenging and confusing.
OBJECTIVES
To present the currently used colorectal cancer staging system; to address challenging areas in pathologic staging, including T category considerations and recommendations for the minimum number of lymph nodes sampled; and to discuss assessment of selected stage-independent prognostic factors, such as vascular/ lymphatic invasion.
DATA SOURCES
This review is based on the current staging manual from the American Joint Committee on Cancer, the College of American Pathologists Protocol for Examination of Specimens From Patients With Primary Carcinomas of the Colon and Rectum, and selected articles pertaining to colorectal carcinoma staging and prognostic factors accessible through Ovid Medline (National Library of Medicine, Bethesda, Md).
CONCLUSIONS
Proper assessment of pathologic staging for colorectal cancer and of morphologic prognostic factors requires a thorough understanding of staging guidelines and careful specimen dissection and sampling.
Topics: Adenocarcinoma; Colorectal Neoplasms; Humans; Lymphatic Metastasis; Neoplasm Staging; Prognosis; United States
PubMed: 18834218
DOI: 10.5858/2008-132-1600-CCSIIP -
Oncology Research and Treatment 2020Metastatic colorectal carcinoma (mCRC) is one of the most prevalent types of cancer worldwide. After tumor progression with first- and second-line treatment,... (Review)
Review
BACKGROUND
Metastatic colorectal carcinoma (mCRC) is one of the most prevalent types of cancer worldwide. After tumor progression with first- and second-line treatment, trifluridine (FTD) and tipiracil (TPI) has been shown to be a treatment option.
SUMMARY
Data from a pivotal phase 3 trial (RECOURSE) and an ongoing phase 3b trial (PRECONNECT) have shown that, in mCRC patients who experienced disease progression after 2 lines of standard therapy, treatment with FTD/TPI is safe and efficacious. Other third-line options include regorafenib, rechallenge with previous treatment lines or personalized approaches based on comprehensive molecular profiling. Randomized trials or sequential studies aiming for the right treatment sequence or predefined subtypes for FTD/TPI or regorafenib as well for rechallenge are missing. However, FTD/TPI as well as regorafenib are recommended by the current ESMO, German S3, and National Comprehensive Cancer Network (NCCN) guidelines in the same situation, thus offering physicians a number of alternatives for the treatment of mCRC patients after the second progression. Key Message: This narrative review summarizes published data and their impact for FTD/TPI as well for regorafenib and rechallenge chemotherapy in clinical practice settings of refractory situations of colorectal cancer.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease Progression; Drug Combinations; Humans; Neoplasm Metastasis; Phenylurea Compounds; Pyridines; Pyrrolidines; Survival Rate; Switzerland; Thymine; Treatment Outcome; Trifluridine; Uracil
PubMed: 32146471
DOI: 10.1159/000506080 -
Deutsches Arzteblatt International Oct 2009Colorectal carcinoma is the most common type of tumor in Western countries. The risk of developing colorectal carcinoma depends both on genetic factors (familial... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Colorectal carcinoma is the most common type of tumor in Western countries. The risk of developing colorectal carcinoma depends both on genetic factors (familial predisposition) and on lifestyle-related factors such as body-mass index, level of physical activity, and nutritional behavior. Regular physical activity is important in primary prevention, and there is also evidence that the prognosis after treatment of a colorectal carcinoma can be improved by exercise.
METHODS
The PubMed database was searched for relevant articles that appeared in the last 10 years, and selected articles were evaluated.
RESULTS
Cross-sectional studies have shown that regular physical activity (ca. 7 hours of brisk walking per week) lowers the risk of colon carcinoma by 40%. Physical activity also improves the outcome of patients already diagnosed with colorectal carcinoma: for example, patients with advanced disease (UICC stage II or III) have been found to survive significantly longer if they perform 4 hours of brisk walking per week, or the equivalent degree of physical exercise.
CONCLUSIONS
Cross-sectional studies show that physically active persons are less likely to develop colorectal carcinoma than physically inactive persons, and that they have better outcomes in the event that they do develop the disease. The positive findings with respect to secondary prevention still need to be confirmed in interventional trials, but in primary prevention, at least, physical activity should be actively promoted, along with other beneficial lifestyle habits and screening measures.
Topics: Clinical Trials as Topic; Colorectal Neoplasms; Exercise; Exercise Therapy; Humans; Incidence; Motor Activity; PubMed; Risk Assessment; Risk Factors; Risk Reduction Behavior; Survival Analysis; Survival Rate; Treatment Outcome
PubMed: 19997551
DOI: 10.3238/arztebl.2009.0722 -
Journal of Cellular and Molecular... 2007Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been... (Review)
Review
Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been revealed. High up in the list of colorectal cancer lesions are APC (adenomatous polyposis coli), K-ras, Smad4 (or DPC4-deleted in pancreatic cancer 4) and p53 genes. All these molecules are part of important pathways for the regulation of cell proliferation and apoptosis and as a result perturbation of these processes lead to carcinogenesis. The ubiquitin-proteasome system (UPS) is comprised of a multi-unit cellular protease system that regulates several dozens of cell proteins after their ligation with the protein ubiquitin. Given that among these proteins are regulators of the cell cycle, apoptosis, angiogenesis, adhesion and cell signalling, this system plays a significant role in cell fate and carcinogenesis. UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma. Cyclooxygenase-2 (Cox-2) is the inducible form of the enzyme that metabolizes the lipid arachidonic acid to prostaglandin H2, the first step of prostaglandins production. This enzyme is up-regulated in colorectal cancer and in several other cancers. Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population. NSAIDs have also Cox-independent anti-proliferative effects. Targeted therapies, the result of increasingly understanding carcinogenesis in the molecular level, have entered the field of anti-neoplastic treatment and are used by themselves and in combination with chemotherapy drugs. Combinations of targeted drugs have started also to be investigated. This article reviews the molecular pathogenesis of colorectal cancer, the roles of UPS and Cox-2 in it and puts forward a rational for their combined inhibition in colorectal cancer treatment.
Topics: Carcinoma; Colorectal Neoplasms; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Humans; Models, Biological; Proteasome Endopeptidase Complex; Ubiquitin
PubMed: 17488476
DOI: 10.1111/j.1582-4934.2007.00032.x -
Praxis Jan 2014Colitis-associated colorectal carcinoma (CRC) accounts for about 5% of all CRC and the risk for CRC in inflammatory bowel disease (IBD) patients - according to older... (Review)
Review
Colitis-associated colorectal carcinoma (CRC) accounts for about 5% of all CRC and the risk for CRC in inflammatory bowel disease (IBD) patients - according to older meta-analyses - is slightly increased when compared to normal population. Effective anti-inflammatory therapy seems to decrease this risk. Main risk factors for colitis-associated CRC are pancolitis, duration of colitis and presence of primary sclerosing cholangitis. In contrast to sporadic CRC, a characteristic adenoma-carcinoma sequence in the pathogenesis of colitis-associated CRC cannot be found. Nevertheless, numerous cell and gene defects occur. Reactive oxygen species also seem to play a pivotal role in the pathogenesis of colitis-associated CRC. Particularly patients with chronically active pancolitis should undergo regular surveillance colonoscopy, since prognosis of colitis-associated CRC is poor.
Topics: Anti-Inflammatory Agents; Cell Transformation, Neoplastic; Colonoscopy; Colorectal Neoplasms; Early Diagnosis; Humans; Inflammatory Bowel Diseases; Mass Screening; Observation; Reactive Oxygen Species; Risk Factors
PubMed: 24468454
DOI: 10.1024/1661-8157/a001548 -
Disease Markers 2015Colorectal carcinoma is the third most prevalent cancer in the world. In the most advanced stages, the use of chemotherapy induces a poor response and is usually... (Review)
Review
Colorectal carcinoma is the third most prevalent cancer in the world. In the most advanced stages, the use of chemotherapy induces a poor response and is usually accompanied by other tissue damage. Significant progress based on suicide gene therapy has demonstrated that it may potentiate the classical cytotoxic effects in colorectal cancer. The inconvenience still rests with the targeting and the specificity efficiency. The main target of gene therapy is to achieve an effective vehicle to hand over therapeutic genes safely into specific cells. One possibility is the use of tumor-specific promoters overexpressed in cancers. They could induce a specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several promoters have been assayed into direct suicide genes to cancer cells. This review discusses the current status of specific tumor-promoters and their great potential in colorectal carcinoma treatment.
Topics: Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Genetic Therapy; Humans; Promoter Regions, Genetic
PubMed: 26648599
DOI: 10.1155/2015/390161 -
Journal of Cancer Research and... Oct 2016Helicobacter pylori infection and colorectal cancer risk are not clear. We perform this meta-analysis to further evaluate the association between H. pylori infection and... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Helicobacter pylori infection and colorectal cancer risk are not clear. We perform this meta-analysis to further evaluate the association between H. pylori infection and colorectal cancer susceptibility.
METHODS
The databases of CNKI, Wanfang, PubMed, Medline, EMBASE, and HighWire Press were electronic searched by two reviewers independently. The case-control study or cohort study about H. pylori infection and colorectal cancer risk were included in this meta-analysis. The association between H. pylori infection and colorectal cancer risk was evaluated by odds ratio (OR) and corresponding 95% confidence interval (95% CI).
RESULTS
Fourteen case-control studies related to H. pylori infection and colorectal cancer risk were eventually include in this meta-analysis. The pooled results showed that H. pylori infection slight increase the risk of developing colorectal carcinoma (OR = 1.33, 95% CI: 1.01-1.77, P = 0.05). Moreover, Begg's funnel plot demonstrated no significant publication bias.
CONCLUSION
Colorectal carcinoma is associated with H. pylori infection. However, for significant heterogeneity across the studies, this results should be further confirmed by large sample size cohort study.
Topics: Case-Control Studies; Colorectal Neoplasms; Helicobacter Infections; Helicobacter pylori; Humans; Publication Bias; Risk
PubMed: 27721244
DOI: 10.4103/0973-1482.191621 -
BMC Research Notes Jan 2018A rising frequency of colorectal carcinoma has been noted in recent years in Pakistan. In the present study, we aimed to evaluate clinicopathologic features of...
OBJECTIVES
A rising frequency of colorectal carcinoma has been noted in recent years in Pakistan. In the present study, we aimed to evaluate clinicopathologic features of colorectal carcinoma in our population so that protocols could be developed to stratify patients that may require further biomarker/molecular testing. Furthermore, histological features which predict higher T and N stage were also evaluated.
RESULTS
Median age at diagnosis was 54.5 (19-85) years. 79% cases were of conventional adenocarcinoma while 13% cases were of mucinous carcinoma. Most of the cases were at T3 stage (81%), while 27 and 68% of cases revealed lymphovascular invasion and nodal metastasis respectively. Mucinous and signet ring tumors were associated with a higher N stage. Pre-existing polyp was associated with lower T and N stage. We found a high proportion of our cases to present at advanced T-stage. Tumor grade and lymphovascular invasion were found to be associated with higher N-stage while tumor infiltrating lymphocytes was associated with lower T and N-stage. Moreover, a high frequency of mucinous differentiation may be linked to microsatellite instability in our cases of colorectal carcinoma; therefore, we suggest that microsatellite instability testing in colorectal carcinoma should be evaluated in our setup.
Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Female; Humans; Lymphatic Metastasis; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Pakistan; Prognosis; Young Adult
PubMed: 29351808
DOI: 10.1186/s13104-018-3183-2