Neoplasia là gì

Introduction

Colorectal cancer (CRC) is the third most common cancer và the third leading cause of cancer–related deaths in the United States. It is estimated that approximately 135,000 new cases of CRC will be diagnosed in năm nhâm thìn & that 50,000 deaths from colorectal cancer will occur.1 CRC screening has been associated with a decrease in CRC incidence và mortality.2 Unfortunately, only 65% of eligible Americans are up–to–date with the recommended screening. Colorectal cancers detected on screening are more likely to be early stage và curable compared with cancers detected on an examination done for symptoms related to the tumor. Efforts should be focused on improving the rates of screening, recognizing and mitigating risk factors, adhering khổng lồ evidence based intervals for colonoscopic surveillance, & enhancing the chất lượng of colonoscopy.

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Pathophysiology

Molecular Pathways

Three well–established molecular pathways, the chromosomal instability (CIN), microsatellite CpG island methylator phenotype (CIMP), and microsatellite instability (MSI), have broadened our understanding of the pathogenesis of CRC. The majority of CRCs arise through the CIN pathway where by genetic alterations including loss of heterozygosity và progressive sầu mutations occur as the adenomas progress to lớn cancer. The activation of oncogenes (eg, Kirsten rat sarcoma KRAS, c–src and c–myc) & deactivation of tumor suppressor genes (eg, APC và p53) result in unchecked cellular proliferation và disordered apoptosis.3 Over time, the affected cells continue to lớn accumulate mutations, often altering the total number of chromosomes, until they transsize into an adenoma and eventually invasive sầu adenocarcinoma.

Up to lớn 30% of CRCs arise from sessile serrated polyps (SSP) through the CIMPhường pathway. The primary cause of cellular dysfunction in this pathway occurs through epigenetic or acquired modification to genes through methylation of the CG–rich promoter regions, which effect gen expression & function. Two commonly affected genes in the SSP–CRC pathway include mutations in the oncoren BRAF and methylation of the DNA mismatch repair gene MLH1.

The third pathway is characterized by defects in the DNA mismatch repair (MMR) apparatus, leading lớn replication errors in areas of the genome containing simple repeated nucleotide sequences, called MSI.4 CRCs that have sầu evidence of MSI may be the result of a germline mutation in one of the MMR genes, which is the sine qua non of Lynch Syndrome, due to bi–allelic somatic genetic alterations in the tumor MMR genes or due to tumor methylation of MLH1, which is a hallmark of CRCs arising from SSPs.

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Precursor Lesions and Natural History

CRC arises from neoplastic epithelial polyps including adenomatous và sessile serrated polyps. The most comtháng precancerous colon polyp is the adenoma, which is believed to be the precursor for about 80% of CRC. Studies of individuals of average risk of CRC and 50 years và older found 22% to 42% harbor adenomas.5

Adenomatous polyps can be further classified by histolô ghích features (tubular, tubulovillous, & villous) & the degree of dysplasia (low grade & high grade). Strong evidence demonstrates that the polyp features most strongly associated with the future risk of an advanced adenoma or CRC include large size (≥10 mm), number of polyps (>2), high-grade dysplasia và presence of villous features in the polyp (Table 1).6-8


Table 1: Adenoma Features Associated with Metachronous Risk of Advanced Colorectal Neoplasia Baseline adenoma featureOdds ratio (95% CI)
2 adenomas vs 1 adenoma 1.39 (1.17–1.66)
3 adenomas vs 1 adenoma 1.85 (1.46–2.34)
4 adenomas vs 1 adenoma 2.41 (1.71–3.40)
Proximal vs distal 1.68 (1.43–1.98)
5–9 milimet vs 1.17 (0.95–1.42)
10–19 milimet vs 2.27 (1.84–2.78)
Tubulovillous/villous vs tubular 1.28 (1.07–1.52)

CI = confidence interval.Data from Martinez et al.6.


Serrated polyps are those that have a saw tooth appearance microscopically. The 3 types of serrated polyps of the colon include the hyperplastic polyp (HP), sessile serrated adenoma (SSP), và the traditional serrated adenoma (TSA). SSPs are believed lớn be the precursor lớn CRC in 20% lớn 35% of the cases & are detected in 2% khổng lồ 10% of patients undergoing average risk screening colonoscopy.9,10 Their molecular characteristics include high levels of CIMP, a v600E BRAF mutation, & MSI due to methylation of MLH1.4,11 They are often in the proximal colon, flat và difficult khổng lồ detect. The distinction between SSPs & HPs is based upon the morphology of the glandular epithelial crypt base. Hyperplastic polyps are the most common serrated polyp & are found in about 25% of patients. They are most often small, và primarily found in the rectum and sigmoid. The small HPs in the recto–sigmoid colon are not believed khổng lồ have malignant potential. Traditional serrated adenomas are very rare (Bachồng to lớn Top

Prevalence và Risk Factors

Prevalence
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Men and women in the U.S. face a lifetime risk of developing CRC of nearly 5% (Table 2).1 Over 90% of cases occur in individuals older than 50 years.2 Blachồng men and women have the highest incidence of CRC & stage–adjusted CRC mortality (Figure 1).1 The lowest incidence of CRC occurs aước ao Asians/pacific islanders & in all races & ethnic groups, the incidence is lower in women compared with men.1 The prevalence of adenomas và CRC is about one–third higher in men than in women; the cause of this is unclear, however an interplay between sex–specific predisposition khổng lồ DNA–methylation in colonic mucosa, varying hormonal levels, & exposure to lớn dietary and lifestyle risk factors such as red meat and alcohol consumption, smoking, and physical activity may be factors.12 Interestingly, incidence rates also vary by geographic location in the U.S. with the highest rates in the Northeast và lowest in the Southwest và may be partly attributed to lớn sun exposure & Vitamin D levels.13


Table 2: Probability of Diagnosis of Invasive sầu Colorectal Cancer by Age Range & Gendera Birth to lớn 49 years, % 50–59 years, % 60–69 years, % 70 years & older, % Birth to death, %
Male 0.3 (1 in 300) 0.7 (1 in 149) 1.2 (1 in 82) 3.7 (1 in 27) 4.7 (1 in 21)
Female 0.3 (1 in 318) 0.5 (1 in 195) 0.9 (1 in 117) 3.4 (1 in 30) 4.4 (1 in 23)

aUS population, 2010–2012.Data from Siegel et al.1


Risk Factors

Epidemioxúc tích và ngắn gọn studies have implicated a number of factors associated with an increased risk of CRC including an unhealthy diet & lifestyle, blaông chồng race, advanced age, chronic colitis và a personal và family history of colorectal polyps & CRC (Table 3).14-16 The greater the number & younger age of relatives with polyps or CRC, & the closeness of the familial relationship affects an individual"s risk of CRC.17,18


Table 3: Select Modifiable Risk Factors Associated with Colorectal Cancer Risk factorRelative risk (95% CI)
Alcohol: heavy (140–257 g/week) vs non-drinker 1.56 (1.42–1.7)a
Obesity: BXiaoMI ≥30 vs ≤25 1.19 (1.11–1.29)a
Smoking: current vs never smoker 1.16 (1.09–1.24)a
Diabetes 1.23 (1.17–1.30)b
Red meat consumption (100 g/day increase) 1.17 (1.05–1.31)c
Processed meat consumption (50 g/day increase) 1.18 (1.10–1.28)c

CI = confidence interval; BMI = body mass index.aData from Huxley et al.14bData from Yuhara et al.15cData from Chan et al.16.


Individuals at highest risk for CRC are those with a hereditary CRC syndrome due khổng lồ a germline gene mutation. Nearly all of the hereditary CRC syndromes are inherited in an autosomal dominant fashion and account for approximately 10% of the CRC cases. The most comtháng CRC syndromes include familial adenomatous polyposis (FAP), MYH-associated polyposis (MAP) and Lynch syndrome. Patients & families with hereditary CRC syndromes should undergo genetic counseling & genetic testing and adhere khổng lồ recommended guidelines for intensive cancer surveillance và prophylactic surgery.19,20

Familial adenomatous polyposis is caused by a mutation in the tumor suppressor gen APC. By the second decade of life, individuals with FAPhường develop hundreds lớn thousands of colorectal adenomas. CRC develops in nearly all patients with FAP.. by age 40 years if prophylactic colectomy is not performed. In individuals with the subtype attenuated FAP.. (AFAP),fewer colonic polyps (usually less than 100) occur polyposis occurs at a later age, & the lifetime risk of CRC is lower than individuals with FAPhường The extracolonic manifestations of FAP/AFAPhường include duodenal adenomas associated with periampullary cancer, thyroid cancer, gastric polyposis và gastric cancer, benign soft tissue tumors (lipomas, fibromas, sebaceous cysts), osteomas, supernumerary teeth, adrenal adenomas, desmoid tumors, và congenital hypertrophy of the retinal pigment epithelium.

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MAP is caused by biallelic mutations of the MYH gen và is inherited in an autosomal recessive fashion. Individuals with MAP.. have sầu a 19% risk of CRC presenting by the age of 50 with a colorectal polyp phenotype mimicking attenuated FAP.. The extra–colonic manifestations of MAPhường. are similar although less prevalent than FAPhường.

Lynch syndrome (LS) is defined as an individual who carries a germ-line mutation in one of the four DNA mismatch repair genes or the EPCAM ren. The lifetime risk of CRC is reported lớn be up to 74% though varies by genotype and can be mitigated by colonoscopy surveillance. Endometrial, ovarian, small bowel, urothelial, skin, gastric and brain cancer occur in patients with LS. Early onphối & frequent screening for endometrial and ovarian cancers and prophylactic total hysterectomy and bilateral salpingo-oopherectomy is recommended for women with LS. Historically, the diagnosis of LS was based upon the Amsterdam Criteria I và II & the revised Bethesdomain authority criteria.đôi mươi The criteria bởi not have sầu sufficient diagnostic sensitivity or specifiđô thị for the identification of patients with LS. Since MSI is the hallmark of CRC due to lớn LS, testing all patients with CRC for evidence of MSI or MMR deficiency, known as universal testing, is currently recommended to assist in identifying patients who may have LS.20

Chronic colonic inflammation due lớn inflammatory bowel disease (IBD) including ulcerative colitis và Crohn’s disease is associated with an increased risk of CRC. The risk is related to the anatomic extent of affected colon (above the sigmoid colon), severity of inflammation, & duration of disease (>8 years).21 Concurrent primary sclerosing cholangitis (PSC) và IBD is a svào risk factor for CRC with a nearly fivefold increased risk compared with patients with IBD without PSC.22

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Prevention và Screening

The incidence of CRC has significantly decreased in the last 3 decades in adults over the age of 50 years, mainly attributed to lớn an increased CRC screening. Several professional societies have recommendations on colorectal cancer screening. The U.S. Preventive Services Task Force (USPSTF) has recently published updated CRC screening guidelines endorsing a variety of available screening modalities for individuals aged 50 to 75 years (Table 4).23 Individuals aged 76 khổng lồ 85 years who have sầu previously been screened derive sầu less benefit than those who have never been screened. Thus screening those 76 khổng lồ 85 years of age who have sầu been previously screened & individuals less than 50 years should be an individualized decision. The American College of Gastroenterology recommends screening at the age of 45 in African Americans because of the increased incidence and earlier age of onset of CRC in this population.24

Available screening tests can be divided inlớn those that detect cancer and those that prevent CRC by detection và treatment of precancerous colonic lesions. High chất lượng colonoscopy is often recommended as the preferred screening modality. Advantages include a long interval between normal exams, direct mucosal visualization, và ability to remove lesions.


Table 4: U.S. Preventive Services Task Force Recommendations for Colorectal Cancer Screening of Adults 50 to 75 Years of Age MethodScreening Interval
High sensitivity gFOBT or FIT Annually
Stool DNA 1 or 3 years
Computed tomography colonography Every 5 years
Flexible sigmoidoscopy Every 5 years or every 10 years with annual FIT
Colonoscopy Every 10 years

gFOBT = guaiac fecal occult blood test; FIT = fecal immunochemical thử nghiệm.Data from U.S. Preventive Services Task Force.23.


CRC Screening Modalities Fecal Occult Blood Tests

Fecal occult blood tests (FOBTs) detect bleeding from large adenomas and CRC. There are 2 types of FOBTs, a guaiac–based chạy thử and an immunochemical-based demo. Guaiac FOBTs (gFOBT) take advantage of the peroxidase activity of hemoglobin that can be detected in the stool by a color change when it catalyzes the oxidation of guaiac by a peroxide reagent. Three randomized controlled trials found that the use of annual gFOBTs decreased the mortality from CRC by up to 33% compared with unscreened patients.25 In a trial of 46,551 participants aged 50 to 80 years through 30 years of follow–up, annual screening và biannual screening to a lesser extent reduced the risk of dying from CRC compared with usual care.26 The only gFOBT approved by the U.S. Food & Drug Administration (FDA) is the Hemoccult Sensa (Beckman Coulter). Pseudoperoxidases in foods may cause false positive sầu guaiac tests; therefore, a special diet (eg, meat–không tính phí, high–residue diet without vegetables with peroxidase activity such as turnips & horseradish) is recommended for at least 24 hours before 3 separate stool specimens are collected each 1 day apart. The USPSTF guidelines endorse an option of high sensitivity gFOBT annually. Any individual with a positive sầu gFOBT demo should be evaluated with a colonoscopy.

Immunochemical–based FOBTs, known as fecal immunochemical tests (FIT) use antibodies to lớn human globin to lớn detect blood in the stool. The advantage of the FIT includes an increase in compliance as only one sample is needed & no dietary restrictions are required because FIT antibodies vày not cross–react with nonhuman hemoglobin or peroxidase from food sources. Hemoglobin does not survive sầu passage through the upper gastrointestinal tract, therefore the kiểm tra is specific for colorectal bleeding. FIT can be both qualitative sầu và quantitative. The fecal hemoglobin threshold for a positive chạy thử can be altered. When a cutoff of ≥75 ng/mL is used, the CRC detection sensitivity is 94% and the specifiđô thị is 87.5% and the clinically significant neoplasm sensitivity is 67% and the specificity is 91.4%.

FIT has been shown in case–control studies lớn reduce CRC mortality of up to 80%. A large retrospective sầu study demonstrated that programmatic annual FIT testing in an organized health system remained highly sensitive sầu at 78% for CRC over 4 years of screening. Adherence to annual FIT in the 48% of participants participating in the first round of screening ranged from 75% lớn 86% over the screening period.28

The accuracy of a one–time FIT for the detection of CRC & advanced adenomas is higher than with gFOBT. CRC sensitivity with FIT has been reported khổng lồ be 87.5% & 82% compared with gFOBT reported to be 54.2% & 64.3%.29,30 The sensitivity for the detection of advanced adenomas is nearly double with FIT at 42.6% versus 23% for gFOBT.29 The specifiđô thị of each modality is greater than 98%. Annual FIT is endorsed by the USPSTF. Any positive sầu chạy thử should be followed by a colonoscopy.

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Stool DNA Testing

Cells slough from the epithelial lining of the GI tract and pass in the stool daily. Exfoliated neoplastic cells harboring genetic alterations from tumors may be detected in stool by stool DNA testing. Currently, 1 stool DNA test is commercially available, Cologuard (Exact Sciences). It combines a FIT with an assay for a variety of genetic alterations known to lớn be associated with colorectal neoplasia. In the hallmark trial comparing the stool DNA–FIT demo with FIT using colonoscopy as the gold standard, the accuracy of a one-time stool DNA–FIT thử nghiệm for CRC was 92.3% versus FIT at 73.8%. The sensitivity for the detection of advanced neoplasms with stool DNA–FIT was 42.4% & with FIT was 23.8%.31 Stool DNA–FIT detected 42.4% of patients with sessile serrated polyps 1cm or larger whereas FIT detected 5.1%. The number needed to screen to lớn detect 1 CRC with FIT was 208, with stool DNA-FIT was 166, và with colonoscopy was154. The năm 2016 USPSTF endorses an option of stool DNA–FIT testing every 1 or 3 years.23 A positive sầu thử nghiệm requires colonoscopy.

Serum–Based Tests

The FDA approved a CRC screening chạy thử in năm nhâm thìn that detects circulating methylated DNA in plasma. Cthảm bại lớn 8,000 individuals 50 & older and eligible for CRC screening in Germany and the U.S., had plasma serum drawn prior lớn colonoscopy. Compared with the 53 cases of CRC discovered on colonoscopy, detection with methylated plasma DNA sensitivity was 48% and specifiđô thị was 91.5%. The sensitivity was best for stage IV CRC at 77.4%, but as low as 35% for stage I CRC và 11.2 % for advanced adenomas.32 With limited evidence and a low sensitivity, the USPTF does not provide formal recommendations on serum based testing và does not danh sách it as one of the preferred screening strategies.

Computed Tomography Colonography (CTC)

Over the last decade, significant advances have occurred in computed tomography colonography (CTC) công nghệ allowing improved detection of adenomatous polyps. No data is available khổng lồ determine the impact of CTC on CRC mortality. Trials comparing CTC with colonoscopy for the detection of adenomatous polyps ≥6mm report sensitivities ranging from 73% to lớn 98% & specificities from 89% to lớn 91%.23 CTC is less invasive sầu than colonoscopy, may increase CRC screening rates, does not require sedation, và may not require bowel preparation although lesion detection rates are improved with bowel preparation.33 Unfortunately, CTC is less effective in detecting SSPs. Recent data show 0.8% of patients undergoing CTC were diagnosed with 1 or more SSPs compared with 4.3% of patients undergoing colonoscopy.34 The difference was significant for flat SSPs, SSPs with dysplasia, & SSPs in the right colon. CTC every 5 years is endorsed as a screening option by the USPTF, though the task force found insufficient evidence khổng lồ evaluate the harms of detecting incidental findings or radiation exposure. CTC as a CRC screening option may not be covered by insurance. Colonoscopy is required for the removal lesions detected on CTC.

Flexible Sigmoidoscopy

Flexible sigmoidoscopy (FS) allows for visualization of the distal third of the colon. Three large European and one U.S. randomized controlled trial have recently shown that FS reduces CRC incidence và in most of the trials a decrease in CRC mortality over more than a decade of follow–up (Table 5).35-38 The USPSTF guidelines recommkết thúc the use of flexible sigmoidoscopy alone every 5 years or every 10 years coupled with yearly FIT testing. Computer prediction models show improved patient life–years saved with annual FIT combined –with flexible sigmoidoscopy every 10 years screening strategy.23


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