Colorectal cancer screening: today and tomorrow.
Abstract: Colorectal cancer colorectal cancer
Malignant tumour of the large intestine (colon) or rectum. Risk factors include age (after age 50), family history of colorectal cancer, chronic inflammatory bowel diseases, benign polyps, physical inactivity, and a diet high in fat. remains a disease with significant morbidity and mortality Morbidity and Mortality can refer to:
Key Words: colorectal cancer, screening, colonoscopy
Colorectal cancer (CRC (Cyclical Redundancy Checking) An error checking technique used to ensure the accuracy of transmitting digital data. The transmitted messages are divided into predetermined lengths which, used as dividends, are divided by a fixed divisor. ) remains a disease with significant morbidity and mortality in the United States. Early detection can improve prognosis, but the recognition that virtually all colorectal cancers arise from a discrete and accessible precursor lesion raises the prospect that cancer can essentially be prevented with appropriate screening. Patients who present with symptoms such as hematochezia, melena melena /me·le·na/ (me-le´nah) the passage of dark stools stained with altered blood.
n. , weight loss, or change in bowel habits require a prompt diagnostic workup work·up
n. Abbr. w/u
A thorough medical examination for diagnostic purposes. and must be considered separately. The primary goal today is to identify the most sensitive and cost-effective screening approaches that will maximize patient compliance. We review the current screening modalities and guidelines for patients at average, moderate, and high-risk for CRC, and then introduce new, experimental approaches that lie on the horizon.
It is estimated that there will be nearly 150,000 new cases of CRC in the United States in 2005. In addition, there will be over 56,000 deaths, making this the second leading cause of cancer-related death in men and women combined. The cumulative lifetime risk for the development of CRC in the general population is 6% Over the past several decades, a small but perceptible decline in the incidence and mortality for colon cancer colon cancer, cancer of any part of the colon (often called the large intestine). Colon cancer is the second most common cancer diagnosed in the United States. has been observed. Although there are many potential explanations for this phenomenon, this clearly coincides with the initiation of widespread CRC screening programs. (1)
Rationale For Screening
Adenomatous polyps are benign precursors to colorectal cancer. Elegant work by Vogelstein and colleagues (2) has shown that CRC carcinogenesis car·ci·no·gen·e·sis
The production of cancer.
production of cancer.
viruses and some parasites are capable of initiating neoplasia. occurs in a stepwise stepwise
incremental; additional information is added at each step.
stepwise multiple regression
used when a large number of possible explanatory variables are available and there is difficulty interpreting the partial regression fashion, characterized by the accumulation of mutations in specific genes such as APC (1) (American Power Conversion Corporation, West Kingston, RI, www.apcc.com) The leading manufacturer of UPS systems and surge suppressors, founded in 1981 by Rodger Dowdell, Neil Rasmussen and Emanual Landsman, three electronic power engineers who had worked at MIT. , K-ras, and p53. The "dwell time" between the initiation of a polyp polyp, in medicine, a benign tumor occurring in areas lined with mucous membrane such as the nose, gastrointestinal tract (especially the colon), and the uterus. Some polyps are pedunculated tumors, i.e. and development of an invasive cancer has been estimated to be as long as 10 years. This provides an ideal opportunity to intervene and alter the natural history of the disease. Proof of this principle was provided by the National Polyp Study National Polyp Study GI disease A 10-year study that found that colonoscopy was more effective than barium enema in detecting precancerous adenomas, reported in June 2000, NEJM. , which established that colonoscopic polypectomy colonoscopic polypectomy Removal of any polyp–hyperplastic, adenomatous, villous adenoma, or polypoid–eg lymphoid hyperplasia, lesion by colonoscopy. See Colon polyp. can dramatically reduce the incidence of colorectal cancer. (3) Unfortunately, compliance with CRC screening guidelines is only fair. Data from the 2000 National Health Interview Study revealed that only 29% of respondents had undergone either sigmoidoscopy Sigmoidoscopy Definition
Sigmoidoscopy is a procedure by which a doctor inserts either a short and rigid or slightly longer and flexible fiber-optic tube into the rectum to examine the lower portion of the large intestine (or bowel). in the previous 5 years or colonoscopy in the previous 10 years. (4)
Risk Stratification risk stratification Medical decision-making The constellation of activities–eg, lab and clinical testing used to determine a person's risk for suffering a particular condition and need–or lack thereof–for preventive intervention
As with any population-wide screening strategy, it is essential to stratify strat·i·fy
v. strat·i·fied, strat·i·fy·ing, strat·i·fies
1. To form, arrange, or deposit in layers.
2. patients into risk groups for CRC. Patients at high risk include those with a hereditary colon cancer syndrome. Moderate risk individuals include those with 1) a personal history of adenomatous polyps or CRC, 2) a family history of adenomatous polyps or CRC, or 3) chronic inflammatory bowel disease inflammatory bowel disease
n. Abbr. IBD
Any of several incurable and debilitating diseases of the gastrointestinal tract characterized by inflammation and obstruction of parts of the intestine. . Average risk patients are those greater than 50 years old who do not have any of the risk factors listed above. The vast majority of the population (>70%) will fall into the average risk group. A description of the currently utilized modalities and recommendations for screening follows below. The guidelines are derived from consensus statements of several organizations including the American Gastroenterology Association, American Cancer Society American Cancer Society,
n.pr established in 1913, this national volunteer-based health organization is committed to the elimination of cancer through prevention and treatment and to diminishing cancer suffering through advocacy, scholarship, research, , and US Public Health Task Force. (5-7) The ultimate choice of the specific test should be based upon individual discussions between the patient and physician.
Average Risk Patients
Fecal Occult Blood Testing
Recommendation. Annually, two samples from each of three consecutive stools should be examined without rehydration rehydration /re·hy·dra·tion/ (-hi-dra´shun) the restoration of water or fluid content to a patient or to a substance that has become dehydrated.
1. using a guaiac-impregnated slide. Patients are to avoid ASA/NSAIDS, foods high in vitamin C vitamin C
or ascorbic acid
Water-soluble organic compound important in animal metabolism. Most animals produce it in their bodies, but humans, other primates, and guinea pigs need it in the diet to prevent scurvy. , and red meat for three days before the examination. Any positive test should be followed up with colonoscopy.
Rationale. Three large prospective, randomized controlled trials demonstrated that fecal occult blood testing (FOBT FOBT Fecal occult blood testing, see there. See Occult bleeding. ) decreased mortality from CRC by 15 to 33%. (8-10) A subsequent meta-analysis of multiple FOBT trials calculated an overall 23% reduction in mortality (relative risk of 0.77). (11) Although rehydration will increase the sensitivity of FOBT, a corresponding decrease in specificity would increase the false positive rate, resulting in unnecessary additional testing. In practice, a digital rectal examination Digital rectal examination
A routine screening test that is used to detect any lumps in the prostate gland or any hardening or other abnormality of the prostate tissue. often serves as the source of stool for the FOBT. A comparison of the "at-home" 6-sample FOBT to that from a single digital rectal examination revealed a sensitivity for the detection of advanced adenomas of 23.9% versus 4.9%, respectively. (12) Advanced adenomas are defined as: 1) a tubular adenoma adenoma: see neoplasm. > 10 mm in size, 2) an adenoma with villous villous /vil·lous/ (vil´us) villose.
vil·lous or vil·lose
Of, relating to, resembling, or covered with villi.
pertaining to or emanating from villi. histology or high grade dysplasia dysplasia
Abnormal formation of a bodily structure or tissue, usually bone, that may occur in any part of the body. Several types are well-defined diseases in humans. , or 3) invasive cancer. Potential explanations for these discrepant dis·crep·ant
Marked by discrepancy; disagreeing.
[Middle English discrepaunt, from Latin discrep results between the 6-sample FOBT and a single digital rectal examination include the intermittent nature of hemorrhage from tumors or the uneven distribution of blood throughout stool, resulting in sampling error. As such, the digital FOBT is not routinely recommended.
Recommendation. Flexible sigmoidoscopy every five years.
Rationale. Two retrospective case-control studies in the early 1990s laid the foundation for endoscopically-based CRC screening by demonstrating a 60% reduction in mortality from colorectal cancer in those who had a screening flexible sigmoidoscopy. (13,14) The recommended five year interval is based on studies that demonstrated 1) a decrease in CRC mortality up to ten years after the initial screening flexible sigmoidoscopy and 2) a 0.6% incidence of advanced adenomas or cancer five years after a negative colonoscopy. (15,16) If an adenoma is identified on screening sigmoidoscopy, a full colonoscopy should be performed because synchronous proximal lesions are detected in as many as 30% of such cases. (17,18) Such a strategy based upon flexible sigmoidoscopy would be predicted to identify 70.3% of all advanced adenomas (adenomas > 1 cm in size, villous adenomas, adenomas with high grade dysplasia, or colon cancer) in men (19) but only 35.2% in women. (20)
Flexible Sigmoidoscopy And Fecal Occult Blood Testing
Recommendation. Annual FOBT coupled with flexible sigmoidoscopy every five years. FOBT should be performed first.
Rationale. It has been hypothesized that the combination of flexible sigmoidoscopy and FOBT would increase the overall detection rate of CRC. While this approach has not been rigorously tested, the sensitivity of this combined screening strategy was estimated by analyzing patients who had undergone both a full colonoscopy and FOBT. Lesions that would have been identified by flexible sigmoidoscopy were defined as those located in the portion of the examined colon up to the descending colon descending colon
The part of the colon extending from the left colic flexure to the pelvic brim. . FOBT, flexible sigmoidoscopy, and the combination of the two tests had a sensitivity for advanced adenomas of 23.9%, 70.3%, and 75.8%, respectively. (19) Thus, there was only an incremental increase in sensitivity by adding FOBT to screening sigmoidoscopy, and the majority of the benefit of this combined approach was achieved with the endoscopic en·do·scope
An instrument for examining visually the interior of a bodily canal or a hollow organ such as the colon, bladder, or stomach.
Double Contrast Barium Enema Barium Enema Definition
A barium enema, also known as a lower GI (gastrointestinal) exam, is a test that uses x-ray examination to view the large intestine. (DCBE DCBE Double Contrast Barium Enema
DCBE Data Control Block Extension )
Recommendation. DCBE every five years.
Rationale. In a direct comparison between DCBE and colonoscopy, the proportion of adenomas that were detected by barium enema was 32% for polyps Polyps
A tumor with a small flap that attaches itself to the wall of various vascular organs such as the nose, uterus and rectum. Polyps bleed easily, and if they are suspected to be cancerous they should be surgically removed. <0.5 cm, 53% for polyps 0.6 to 1.0 cm, and 48% for polyps > 1 cm. (21) As such, DCBE is considerably less sensitive than colonoscopy. Another unappealing feature is that patients with an abnormal study will require a subsequent colonoscopic examination for polypectomy. Nevertheless, this does represent another modality for visualization of the entire colon, particularly in those cases in which the cecum cecum (sē`kəm): see intestine. cannot be intubated or there are contraindications to colonoscopy.
Recommendation. Colonoscopy every ten years.
Rationale. To date, there are no studies that have demonstrated a benefit in mortality from screening colonoscopy screening colonoscopy GI disease The use of flexible colonoscopy to detect malignant or premalignant colorectal lesions; SC is most cost effective ≥ age 50. See Colonoscopy. . However, extrapolation (mathematics, algorithm) extrapolation - A mathematical procedure which estimates values of a function for certain desired inputs given values for known inputs.
If the desired input is outside the range of the known values this is called extrapolation, if it is inside then from the original studies of screening flexible sigmoidoscopy is reasonable. (13,14,16) Since colonoscopy visualizes the entire colon, it is likely that it would exhibit a comparable or greater reduction in CRC mortality. It has been convincingly demonstrated that colonoscopic polypectomy results in a decreased incidence of CRC, which is again likely to translate to a decrease in mortality from CRC. (3) Some of the potential shortcomings of colonoscopy include the higher cost, procedure-associated risks, discomfort of the colonic purge, and inconvenience secondary to time away from work. Recent studies have established the performance characteristics of screening colonoscopy. Although direct comparisons between colonoscopy and flexible sigmoidoscopy were not performed, estimates of the number of proximal lesions that would have been missed with a flexible sigmoidoscopy strategy were calculated. Two of these studies determined that 46 to 52% of patients with advanced proximal adenomas had no distal adenomas and therefore would have been missed by sigmoidoscopy. (22,23) A subsequent meta-analysis estimated that 2 to 5% of all patients undergoing screening colonoscopy may have isolated advanced proximal lesions. (24) Interestingly, women are twice as likely as men to have an isolated proximal neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. . (19,20) The complication rate of screening colonoscopy has been estimated to be 0.3%. (25) In a study of over 3,000 individuals, no perforations or deaths were attributed to colonoscopy, and lower GI bleeding was the most common adverse event.
Moderate Risk Patients
Personal History Of Adenomatous Polyps
Recommendation. Patients with an advanced adenoma (> 1 cm, villous histology, high-grade dysplasia, or cancer) or [greater than or equal to] 3 adenomas should have a follow-up colonoscopy in three years. Patients with 1 or 2 small ([less than or equal to] 1 cm) tubular adenomas should have a follow-up colonoscopy in five years.
Rationale. The adenoma recurrence rate 3 years after removal of adenomatous polyps ranges from 35-50%. (26) However, the recurrence rate of adenomas with advanced histologic features at 3 years ranges from 4 to 11%. (26) Risk factors for recurrence of advanced adenomas at 3 years include [greater than or equal to] 3 adenomas, age at diagnosis > 60 years, and a family history of CRC. (27) Patients with only 1 or 2 small ([less than or equal to] 1 cm) adenomas without villous features are at low risk for a significant finding after three years. (28)
Personal History Of CRC
Recommendation. Patients with CRC should have a complete colonoscopy at the time of diagnosis to rule out synchronous lesions. Follow-up colonoscopy should be performed at three years and if normal, again at five years.
Rationale. After a surgical cure of CRC, patients are at increased risk for the development of metachronous CRC. (29,30) The cumulative incidence of a second case of primary colon cancer at 5 years ranges from 1.5% to 5.3%. (30,31)
Family History Of Adenomatous Polyps Or CRC
1. Patients with one 1st degree relative with CRC or adenomatous polyps diagnosed at < 60 years old or two 1st degree relatives with CRC diagnosed at any age should start screening colonoscopy at 40 years old or 10 years before the earliest diagnosis in the family. This should be repeated every five years.
2. Patients with one 1st degree relative with CRC or adenomatous polyps diagnosed at > 60 years old or two 2nd degree relatives with CRC should begin screening at 40 years old. If normal, examinations should be repeated every 10 years.
Rationale. Approximately 20% of all cases of colon cancer arise in conjunction with a family history of the disease. For patients with one 1st degree relative with adenomatous polyps, the relative risk is 1.9, and for those with a 1st degree relative with CRC, the relative risk increases to 2.25. If the initial diagnosis was before 45 years old, the relative risk increases even further to 3.87. If there is more than one 1st degree relative with CRC, the relative risk jumps to 4.25. (32) In those with familial risks, the rate of progression of CRC is similar to the general population, but the age of onset The age of onset is a medical term referring to the age at which an individual acquires, develops, or first experiences a condition or symptoms of a disease or disorder.
Diseases are often categorized by their ages of onset as congenital, infantile, juvenile, or adult. of polyp formation may be as much as 10 years earlier. (33) The majority of these familial cancers are polygenic polygenic /poly·gen·ic/ (pol?e-jen´ik) pertaining to or determined by several different genes.
adj. in nature. However, there are several specific hereditary colon cancer syndromes that are caused by a germline alteration in a single gene. These syndromes require more intensive surveillance and will be discussed below.
Inflammatory Bowel Disease
Recommendation. Surveillance colonoscopy is recommended every 1 to 2 years after 8 years of disease in patients with pancolitis and after 15 years in those with left-sided disease. Four-quadrant biopsies should be taken every 10 cm throughout the colon. Additional biopsies should be taken of any suspicious lesions.
Rationale. Chronic inflammatory bowel disease is associated with an increased risk of CRC. In patients with panulcerative colitis, there is an approximately 30% risk of CRC after 35 years. (34) A similar risk has been noted in patients with Crohn colitis. (35) Patients with biopsies demonstrating low- or high-grade dysplasia that have been independently verified by two expert pathologists should be advised to undergo colectomy colectomy /co·lec·to·my/ (ko-lek´tah-me) excision of the colon or of a portion of it.
Surgical removal of part or all of the colon. . Differentiation between dysplasia-associated mass lesions (DALMs) and sporadic adenomas requires the combination of endoscopic appearance and histologic examination histologic examination The study of a tissue specimen by staining it and examining it by LM. See Light microscopy. of the neighboring mucosa. It has been shown that adenoma-like DALMs can be treated with simple polypectomy followed by surveillance. (36)
High Risk Patients
Hereditary Colon Cancer Syndromes
Approximately 5% of all colorectal cancers occur in association with a hereditary colon cancer syndrome. Three of the most common and best understood are the Hereditary Nonpolyposis Colorectal Cancer Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is characterized by an increased risk of colorectal cancer and other cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. (HNPCC HNPCC Hereditary Nonpolyposis Colorectal Cancer
HNPCC Hereditary non-polyposis colon cancer ), Familial Adenomatous Polyposis familial adenomatous polyposis Familial polyposis An AD condition affecting ±50,000–US, characterized by progressive development of hundreds of adenomatous colorectal polyps; progression to cancer Molecular pathology APC (FAP (language) FAP - The assembly language for Sperry-Rand 1103 and 1103A.
[Listed in CACM 2(5):16 (May 1959)]. ), and MYH-Associated Polyposis polyposis /pol·yp·osis/ (pol?i-po´sis) the formation of numerous polyps.
familial polyposis , familial adenomatous polyposis (MAP) syndromes.
A model for CRC carcinogenesis has been proposed in which a specific
mutation is required for each progressive stage along the adenoma-carcinoma sequence. Mutations in the Adenomatous Polyposis Coli adenomatous polyposis coli Familial adenomatous polyposis, see there. See APC gene, APC protein. (APC) gene are the critical initiating step in most cases of FAP and sporadic cancers. This is followed by the progressive acquisition of mutations in the Ki-ras oncogene oncogene
Gene that can cause cancer. It is a sequence of DNA that has been altered or mutated from its original form, the proto-oncogene (see mutation). Proto-oncogenes promote the specialization and division of normal cells. and loss of heterozygosity Loss of heterozygosity (LOH) in a cell represents the loss of one parent's contribution to part of the cell's genome. LOH can arise via several pathways, including deletion, gene conversion, mitotic recombination and chromosome loss. (LOH LOH Loss of Heterozygosity
LOH Ladies Of Harley
LOH Line Overhead
LOH Light Observation Helicopter
LOH Legion of Honor
LOH Lay on Hands (Paladin ability; Everquest game)
LoH Loop of Henle (kidney nephron) ) on chromosome 18q. Mutations in p53 are believed to be a late event, as advanced adenomas become invasive carcinomas. (2) HNPCC results from germline mutations in DNA mismatch repair Any mutational event that disrupts the superhelical structure of DNA carries with it the potential to compromise the genetic stability of a cell. Mismatch repair is a system for recognising and repairing the erroneous insertion, deletion and mis-incorporation of bases that can arise (MMR MMR measles-mumps-rubella (vaccine); see measles, mumps, and rubella vaccine live, under vaccine.
measles, mumps, rubella vaccine ) enzymes, including MLH MLH Mellieha (postal locality, Malta)
MLH Mint, Lightly Hinged
MLH Major League Hockey
MLH Michigan League of Handweavers
MLH Mulhouse, France - Mulhouse (Airport Code) 1, MSH MSH melanocyte-stimulating hormone.
n See hormone, melanocyte-stimulating.
melanocyte-stimulating hormone. 2, and MSH6. These enzymes repair mismatched nucleotide errors that occur during DNA replication. (37) A mutated enzyme is unable to correct these mismatch errors, as well as base insertions and deletions at polynucleotide polynucleotide /poly·nu·cleo·tide/ (-noo´kle-o-tid) any polymer of mononucleotides.
n. repeats (microsatellites). This phenomenon of expansion and contraction of these repeats results in microsatellite instability (MSI MSI: see integrated circuit.
(1) (MicroSoft Installer) See Windows Installer.
(2) (Medium Scale Integration) Between 100 and 3,000 transistors on a chip. See SSI, LSI, VLSI and ULSI. ). All tumors associated with HNPCC and 15% of sporadic cases of CRC exhibit MSI. Thus, testing a tumor for MSI is a useful screening tool when HNPCC is suspected. The remaining 85% of sporadic cases and those associated with FAP do not show this behavior and are termed microsatellite See miniaturized satellite. stable (MSS).
Genetic Testing Genetic Testing Definition
A genetic test examines the genetic information contained inside a person's cells, called DNA, to determine if that person has or will develop a certain disease or could pass a disease to his or her offspring.
The diagnosis of a hereditary colon cancer syndrome can be established either clinically or through genetic testing. Clinical diagnoses are based upon a constellation of disease characteristics in the index patient and/or related family members. It is fairly straightforward to recognize syndromes with dramatic phenotypes, as seen in FAP. However, a diagnosis can be problematic in syndromes that present with more subtle features or that require extensive family histories, as seen with HNPCC (see Table 1). Genetic diagnoses are based on identification of germline mutations in a proband proband /pro·band/ (pro´band) an affected person ascertained independently of relatives in a genetic study.
n. . Genetic testing is performed by analyzing the DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. from white blood cells White blood cells
A group of several cell types that occur in the bloodstream and are essential for a properly functioning immune system.
Mentioned in: Abscess Incision & Drainage, Bone Marrow Transplantation, Complement Deficiencies in the peripheral blood peripheral blood Cardiology Blood circulating in the system/body , and can be particularly helpful in cases where the clinical phenotype is atypical. Furthermore, the identification of a mutation in a proband then makes it possible to offer testing to asymptomatic family members for cancer risk assessment. In this manner, only those relatives who carry the same genetic alteration will require intensive cancer screening, and those who do not carry the family mutation will be spared the intensive screening. If a genetic mutation cannot be identified in the proband, all family members must be considered "at-risk." The benefits of genetic testing must be considered in the context of potential risks. As genetic testing identifies high-risk individuals before disease is clinically apparent, it raises several concerns. These include psychological stress and potential discrimination in terms of employment and health insurance. Legal protections have been established in most states. Nevertheless, genetic counseling Genetic Counseling Definition
Genetic counseling aims to facilitate the exchange of information regarding a person's genetic legacy. It attempts to:
Purpose and informed consent are essential components of genetic testing.
A list of hereditary colon cancer syndromes and their clinical and genetic features is provided in Table 2. The critical first step in the identification of a hereditary cancer syndrome hereditary cancer syndrome Any of a group of often AD conditions characterized by tumors that are often site-specific, of early onset and multiple and/or bilateral; HCSs include nevoid basal cell carcinoma syndrome, dysplastic nevus–B-K mole syndrome, Cowden is to obtain a careful family history of cancer. Some general guidelines that should trigger a referral to a specialist are listed in Table 3. Specific cancer screening guidelines for patients with FAP and HNPCC are outlined in Table 4.
New Screening Modalities
Virtual Colonoscopy virtual colonoscopy
A screening examination of the colon in which x-rays obtained by CAT scan are used to generate computerized three-dimensional images of the colonic mucosa.
CT colonography, also referred to as "virtual colonoscopy," is a rapidly emerging technique. Images are obtained with a thin-section, helical CT and sophisticated computer algorithms generate three-dimensional reconstructions of the colon. Although this is a noninvasive procedure performed without sedation, a standard colonic purge and bowel insufflation insufflation /in·suf·fla·tion/ (-sah-fla´shun)
1. the act of blowing a powder, vapor, or gas into a body cavity.
2. finely powdered or liquid drugs carried into the respiratory passages by such devices as aerosols. are still required. One of the first studies of 100 patients at high risk for colorectal cancer demonstrated that virtual colonoscopy detected all cancers, 91% of polyps > 1 cm, 82% of polyps 6 to 9 mm, and 55% of polyps < 6 mm. (38) A larger study of asymptomatic adults determined the sensitivity of virtual colonoscopy to be 93.8% for polyps > 1 cm, 93.9% for polyps > 8 mm, and 88.7% for polyps > 6 mm, suggesting that virtual colonoscopy compares favorably with optical colonoscopy for clinically relevant lesions. (39) However, an independent study of 614 patients revealed a far lower sensitivity: for lesions > 1 cm, the sensitivity of CT colonography was only 59% and for lesions 6 to 9 mm in size, the sensitivity was 51%. (40) Thus, virtual colonoscopy exhibits promise as an alternative screening tool, but its specific role remains to be determined.
Fecal DNA Analysis
Because of the invasive nature of endoscopy endoscopy
Examination of the body's interior through an instrument inserted into a natural opening or an incision, usually as an outpatient procedure. Endoscopes include the upper gastrointestinal endoscope (for the esophagus, stomach, and duodenum), the colonoscope (for the , poor patient compliance, and limited endoscopic resources, a highly sensitive and specific noninvasive screening method to preselect pre·se·lect
tr.v. pre·se·lect·ed, pre·se·lect·ing, pre·se·lects
To select beforehand, usually according to a specific criterion.
pre those individuals who require colonoscopy would be desirable. One possible approach is fecal DNA analysis. As described previously, colorectal carcinogenesis is dependent upon the accumulation of multiple mutations in specific oncogenes oncogenes
1. genes carried by tumor viruses that are directly and solely responsible for the neoplastic transformation of host cells. Many oncogenes function after integration into the DNA of the host cell and some up-regulate normal downstream host cell genes to cause neoplasia. and tumor suppressor genes. (2) This screening test is based on the hypothesis that abnormal cells from polyps or cancers are sloughed off and admixed into stool. DNA can be isolated from stool and analyzed for mutations in APC, K-ras and p53. In an early study, the sensitivities for adenomas > 1 cm and cancer were 82% and 91%, respectively, with a specificity of 93%. (41) A subsequent prospective study compared fecal DNA analysis with FOBT in a cohort of over 2,500 patients undergoing screening colonoscopy. The fecal DNA panel detected only 51.6% of invasive cancers, and the sensitivity of FOBT was even lower at 12.9%. (42) While this approach did demonstrate superior sensitivity to FOBT for the detection of colon cancer, its sensitivity for the detection of advanced adenomas was low (18.2%).
Proteomics involves the separation and identification of peptides and proteins in complex mixtures of biologic samples. Identification of cancer-specific proteins can be utilized to develop novel diagnostic tests. For optimal clinical use, a CRC biomarker should be present in a readily accessible fluid such as blood. Past efforts have employed labor-intensive approaches to study a single marker protein that is over-expressed by tumors. However, recent advances in mass spectrometry technology now enable us to take an unbiased look at the complex mixture of proteins as a whole in the plasma compartment. (43,44) This approach is based on the general hypothesis that the pattern of proteins in the blood will reflect the underlying disease state of an organ.
Multiple groups have used proteomics-based approaches to develop screening tools for cancer. In these studies, surface enhanced laser desorption Desorption
A process in which atomic and molecular species residing on the surface of a solid leave the surface and enter the surrounding gas or vacuum. and ionization-time of flight (SELDI-TOF SELDI-TOF Surface-Enhanced Laser Desorption/Ionization Time-Of-Flight ) mass spectrometry is used to generate proteomic spectra from patient sera. (43-45) A training set of spectra is generated from patients with cancer and healthy controls. Using iterative artificial intelligence searching algorithms, a subset of mass spectral peaks is identified that discriminates cancer patients from healthy controls. This mass spectral pattern is then used to classify a masked population of cancer-bearing and healthy controls. In an initial study, ovarian cancer patients were identified with a sensitivity and specificity of 100% and 95%, respectively. (46) In another initial study on prostate cancer patients, a mass spectral signature was discovered that correctly identified 95% of patients with cancer and 78% of patients with benign disease. (47) SELDI-TOF mass spectrometry has also been used in the study of 182 serum samples from patients with colorectal cancer. A set of seven potential biomarkers was identified that could differentiate carcinomas from adenomas with a sensitivity of 89% and a specificity of 83%, and from healthy controls with a sensitivity of 89% and a specificity of 92%. (48) Clearly, a proteomic approach holds much promise.
Screening can be an effective strategy to prevent colon cancer. A variety of screening modalities are available, and the choice of the specific approach should be individualized. Unfortunately, rates of compliance with established guidelines for colorectal cancer screening remain low. Effective application of these guidelines depends upon accurate risk stratification, and a careful family history is one of the most important risk factors to consider. Advances in our understanding of the molecular basis of colon cancer have led to the development of genetic tests for the diagnosis and management of hereditary colon cancer syndromes. Although colonoscopy remains the mainstay of colorectal cancer screening today, newer molecular approaches are poised to transform clinical practice in the future.
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MHE materials handling equipment (US DoD)
MHE Multiple Hereditary Exostoses
MHE Ministry of Higher Education (Philippines)
MHE Multiple Headspace Extraction , et al. Randomised Adj. 1. randomised - set up or distributed in a deliberately random way
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adj. Chiefly British
Variant of fecal.
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49. Vasen HFA HFA Harvard Film Archive (Harvard University)
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50. Jo WS, Chung DC. Genetics of hereditary colorectal cancer. Semin Oncol 2005;32:11-23.</p> <pre> No one is useless in this world who lightens the burdens of another. --Charles Dickens </pre> <p>Kenneth E. Hung, MD, PHD and Daniel C. Chung, MD
From the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital Massachusetts General Hospital Health care The major teaching hospital for Harvard Medical School, widely regarded as one of the best health care centers in the world , Harvard Medical School Harvard Medical School (HMS) is one of the graduate schools of Harvard University. It is a prestigious American medical school located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts. , Boston, MA.
Reprint requests to Daniel C. Chung, MD, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Email: firstname.lastname@example.org
Dr. Chung is a consultant for Myriad Genetics. Dr. Hung has no disclosures to declare.
Accepted December 21, 2005.
RELATED ARTICLE: Key Points
* Everyone over age 50 should be screened for colon cancer.
* Patients with 1) a personal history of adenomas and/or colorectal cancer, 2) a family history of adenomas and/or colorectal cancer, or 3) chronic inflammatory bowel disease are considered to be at moderate risk and require more frequent screening.
* A careful family history is necessary to recognize hereditary colon cancer syndromes, and a genetic evaluation can establish the diagnosis.
Table 1. Amsterdam II criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) (49) Three or more relatives with HNPCC-related cancers (colon, uterine, stomach, ovarian, small bowel, and urinary tract). One affected relative is a 1st degree relative of the other two. Affected relatives span two different generations. One of the cancers must be diagnosed before age 50 years old. Table 2. Hereditary colorectal cancer syndromes (50) Syndrome Genetic Mutation Inheritance Familial Adenomatous APC Autosomal Dominant Polyposis (FAP) Attenuated Familial APC Autosomal Dominant Adenomatous Polyposis (AFAP) MYH-associated Polyposis MYH Autosomal Recessive Hereditary Non-Polyposis MLH1, MSH2, MSH6 Autosomal Dominant Colon Cancer (HNPCC) Peutz-Jegher Syndrome LKB1 Autosomal Dominant Juvenile Polyposis MADH4, BMPR1A Autosomal Dominant Syndrome Syndrome Clinical Characteristics Familial Adenomatous Hundreds to thousands of adenomatous polyps in Polyposis (FAP) colon, fundic gland polyps, duodenal/ ampullary adenomas, desmoid tumors, osteomas, thyroid, and brain tumors Attenuated Familial Fundic gland polyps, duodenal, ampullary Adenomatous Polyposis adenomas, <100 colonic polyps (AFAP) MYH-associated Polyposis 3-100 colonic adenomatous polyps Hereditary Non-Polyposis Tumors of stomach, small intestine, colon, Colon Cancer (HNPCC) genitourinary tract, biliary tree, and skin Peutz-Jegher Syndrome Characteristic mucocutaneous pigmentation, tumors of breast, lungs, uterus, reproductive organs, pancreas, and gallbladder Juvenile Polyposis Tumors of stomach and duodenum Syndrome Table 3. General guidelines that should trigger further evaluation by a specialist in hereditary colorectal cancer syndromes 1. Two or more close family members with colon cancer or related cancers (gastric, uterine, ovarian, urinary tract, biliary). 2. A personal history of two or more colon cancers or related cancers (gastric, uterine, ovarian, urinary tract, biliary). 3. A personal or family history of young onset colon cancer (before age 50 yrs). 4. A personal or family history of multiple adenomatous polyps (> 10 cumulatively). Table 4. Screening recommendations for patients with familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) FAP HNPCC Screening guidelines Annual sigmoidoscopy Colonoscopy every 1-2 years for CRC starting at 10-12 starting at age 20-25 years old years or 10 years earlier In attenuated FAP, than the youngest case of full colonoscopy CRC diagnosis in the should be performed family. Annual annually starting colonoscopy after age 40 at age 25 years. years. Screening guidelines 1. Upper endoscopy 1. Annual transvaginal for other cancers every 1-3 years, ultrasound, endometrial including a side biopsy, and pelvic exam viewing endoscope to screen for 2. Annual thyroid endometrial and ovarian ultrasound cancer 3. Annual alpha 2. Upper endoscopy every 2 fetoprotein and years starting at age liver ultrasound 30-35 or 5 years earlier during 1st decade than the youngest case of life of gastric cancer 3. Annual renal ultrasound, urinalysis, and urine cytology