Colon Cancer Screening – Uses, Indications, Procedure

Pathogenesis of Colon Cancer Screening

Most CRCs begin as protuberances tethered to the inner surface of the colon or rectum, clinically knows as “polyps.” These are mainly of two types: flat or raised, relative to the inner-epithelial lining.

Raised polyps show two distinctive growth patterns of mushroomed growth:

• With a stalk (pedunculated polyps)
• Without a stalk (sessile polyps)

About 10 percent of CRC patients carry one or more pathogenic “non-Lynch syndrome mutations,”  including mutations in high-penetrance genes such as APC, bi-allelic MUTYH, BRCA1, BRCA2, PALB2, CDKN2A, and TP53.[rx]

Right-sided CRCs tend to be diagnosed in advanced stages compared to left-sided, as the cecum and right colon have a larger caliber, and stool is more liquid, causing symptoms of partial obstruction such as pain, swelling, and constipation. Blood in stools (hematochezia or melena) isn’t readily observed and comes much later as compared to the left side, making screening tools pivotal in management for early detection and therapy.[rx][rx]

Risk factors for CRC and Colon cancer screening

Risk factor assessment helps to categorize the patient as high, average, or low-risk. Aggressive multiple interval-based testing starts as early as the teenage years[rx] in patients with a positive family history or co-existing genetic cancer syndromes. A relaxed approach towards screening and further management can be seen in the majority of cases that are at average risk.[rx]

1.) Family history (especially first degree relatives)

• Colorectal carcinoma
• Pre-cancerous adenomas

2.) Genetic cancer syndromes

• Familial adenomatous polyposis (FAP and its variants Gardner and Turcot syndrome)
• Lynch syndrome
• Hereditary non-polyposis colorectal cancer (HNPCC)
• Peutz-Jeghers syndrome
• Juvenile polyposis

3.) Medical history

• Previously resected or diagnosed adenomatous colorectal polyps; or any of the above mentioned genetic-cancer syndromes
• Cystic fibrosis[rx]
• Inflammatory bowel diseases like Crohn disease or ulcerative colitis
• Diabetes mellitus and insulin resistance[rx]
• Abdomino-pelvic radiation for an earlier cancer, in childhood or adolescence (as suggested by Children Oncology Group- COG)
• HIV infection in men[rx]

4.) Personal history

• Chronic alcoholism
• Smoking
• Physical inactivity
• Obesity
• Poor diet (low fiber; high amounts of red and processed meat consumption)

 5.) Race

• Higher incidence and mortality among African-Americans, particularly men. CRC occurrence is higher in African-Americans less than 50 years of age, hence earlier screening, starting from age 45 years, is recommended by USPSTF.[rx]

Clinical Significance of Colon Cancer Screening

Screening Tools

The various modalities for early detection of CRCs are as follows:

Stool-based Tests

• Fecal immuno-chemical test (FIT)
• Guaiac fecal occult blood test (gFOBT), also known as HSgFOBT (high-sensitivity guaiac-based fecal occult blood test)
• Stool DNA test (FIT-DNA): also known as MT-sDNA test (Multi-targeted-stool DNA test)

Visualization-based Tests

• Sigmoidoscopy

• Colonoscopy

  • Optical- standard
  • Virtual- Radiological: CTC and Capsule colonoscopy.
• Barium enema

Blood-based Test

• Methylated SEPT-9

Age to Initiate Screening

The U.S. Preventive Services Task Force (USPSTF) and many other expert councils recommend 50 years of age to initiate screening for average-risk patients. In African-Americans, it can be lowered to 45 years of age due to high early-onset incidence.[1] For those with high-risk attributes (positive family history or cancer syndromes), screening can be initiated from as early as the teenage years.[9] Screening for those with a positive family history is recommended to start 10 years before the age of diagnosis of the family member. USPSTF doesn’t recommend routine CRC screening in adults 86 years and older.

Contraindications for Screening

Contraindications might vary depending upon the screening method. Most stool-based tests can be carried out easily. However, other screening methods involve sedation, consumption of contrast, and further instrumentation of the colon. Bowel preparation is a vital pre-requisite, using either a laxative or non-laxative method. The type of bowel preparation should be determined based on the patient’s medical conditions. Colonoscopy should generally be avoided if there is a concern for bowel perforation. Care should be taken for the following conditions:

• Active colonic inflammation (e.g., acute diarrhea, active inflammatory bowel disease)
• Symptomatic colon-containing abdominal wall hernia
• Recent acute diverticulitis
• Recent colorectal surgery
• Recent deep endoscopic biopsy/polypectomy/mucosectomy
• Known or suspected colonic perforation
• Symptomatic or high-grade bowel obstruction
• The patient is unwilling to give consent
• The patient is uncooperative or unable to achieve sedation
• Risk of colonic perforation in patients undergoing colonoscopies such as those with toxic mega-colon and fulminant colitis[rx]
• Other contraindications limited to colonoscopy include- inadequate bowel preparation, recent myocardial infarction, arrhythmias, or medically unstable patients.

Evidence of Effectiveness of Various Screening Tests:

1.) Guaiac FOBT (gFOBT) vs. Fecal Immune-chemical Test (FIT)

Evidence of Effectiveness

• FIT is more sensitive than gFOBT for colon lesions.[rx]
• High-sensitivity gFOBT has a sensitivity of 62% to 79% and a specificity of 87% to 96% for detecting colorectal cancer.[rx]
• FIT has a sensitivity of 79% to 88% and a specificity of 91% to 93%.
• Evidence suggests a decline in the mortality rate by 15% to 33% when gFOBT/FIT is performed every 1- 2 years in people aged 50 to 80 years.[rx]
• FIT has high sensitivity (80%) for detecting CRC, while only 25% to 56% sensitivity for detecting advanced adenomas.[rx][rx]

2.) Stool DNA Test

Evidence of Effectiveness

• Its sensitivity and specificity were 92% to 95% and 84% to 95%, respectively. Its sensitivity to detect advanced precancerous lesions such as advanced adenomas and sessile serrated polyps measuring less than 1 cm was 42% and its specificity to detect “all nonadvanced findings,” including non-neoplastic findings, was 87%.[rx]
• It displays a higher sensitivity than FIT, (92% vs. 74%) with more false positives. However, it detected less than half of advanced adenomas (42%), limiting its preventive role, due to its low specificity (87% to 90%).[rx]
• No evidence of mortality reduction currently exists.

3.) Sigmoidoscopy

Evidence of Effectiveness

1. Evidence suggests that regular screening with sigmoidoscopy alone after 50 years of age (55 to 64 years) significantly lowers mortality related to rectal or lower colonic cancer by 60% to 70%.[rx][rx]
2. There is a reduction of CRC incidence by 33 to 42 percent through various randomized controlled trials.[rx][rx]

4.) Colonoscopy

Evidence of Effectiveness

• Reduction in CRC incidence and mortality was 31% and 46%, respectively, as established by six observational studies, which further suggested strong evidence of a reduction in incidence and mortality of both distal and proximal colorectal cancers. Sigmoidoscopy only helps in curtailing distal CRC-related mortality and incidence.[rx]
• Colonoscopy is very effective in preventing left-sided CRC than right-sided CRCs, which could also contribute to a shift in the distribution of cancers in the colon.[rx]
• The sensitivity of colonoscopy after bowel preparation to detect adenomas 6 mm or larger ranged from 75% to 93%, and specificity ranged from 89% to 91%.[rx]
• For adenomatous polyps 6 mm or larger, a systematic review reported the sensitivity of colonoscopy for detection varied from 75 percent to 93 percent. The miss rate for polyps of any size was 22 percent, with rates increasing inversely with the size of the lesion. Adenomas smaller than 5 mm were missed in as many as 25% of patients.[rx][rx]

5.) Colon Capsule Endoscopy

Evidence of Effectiveness

• Studies showed that in asymptomatic patients using high-quality optic colonoscopy as the standard, capsule endoscopy identified subjects with more than one adenoma of greater than or equal to 6 mm with a sensitivity of 88 percent and specificity 82 percent, and even higher rates in larger adenomas.[rx]

6.) Computed Tomography Colonography

Evidence of Effectiveness

• Even though it’s a sophisticated modality when compared to colonoscopy, multiple studies demonstrate a fluctuating sensitivity for CRC lesions, between 67 and 94 percent, while colonoscopy is 92% sensitive. However, CT colonography (CTC) has a very high specificity at 96 to 98 percent.[rx]
• Patients who underwent both colonoscopy and CTC saw a surge of 14 to 15 non-rectal neoplasms, missed by colonoscopy, which was located on mucosal folds.[rx][rx]
• It can still miss some flattened and small polyps (less than 8 mm).[rx]

7.) Methylated SEPT-9

Evidence of effectiveness

• It can detect advanced CRC; however, relevance in early-stage detection is yet to be established. The methylated SEPT-9 DNA assay has a sensitivity for CRC of 75 percent and specificity of 87 percent, with increasing detection rates in advanced cancers.[rx]
• Due to poor sensitivity, its role as a primary screening tool is questionable. It also has a false positive rate of 4.7 percent.[rx][rx]
• There is no evidence yet that this test can reduce CRC deaths. However, as a non-invasive testing option, it can have significantly increased compliance and participation among high-risk groups.[rx]

Screening Protocols and Algorithms (Image 1)

1.) Fecal Occult Blood Test

• Since polyps and CRCs have a high propensity to bleed, FOBT can detect occult blood.[rx]
• Sample collection: The patient is given a stool collection kit or asked to get one from the pharmacy (as per local protocols) and is asked to bring in stool samples (sometimes by mail) within 24 hours of collection, as sensitivity to test declines proportionally to delay.[rx][rx]
• Sample processing: Don’t rehydrate samples, as it may falsely increase sensitivity, leading to an increased number of false positives.[rx]

Guaiac FOBT (gFOBT)

• Consists of guaiac as the main reagent derived from a plant that exclusively grows in the Caribbean. It detects organic heme by oxidation. Therefore, the presence of dietary heme from red meat, peroxidase from some plants, and anti-oxidants like vitamin C or E can lead to false positives. Fasting is advised before the test.

Fecal Immune-Chemical Test (FIT)

Employs antibodies to specifically detect human heme-based globin. Dietary and medication restrictions prior to tests aren’t required. The test is very specific for detecting colonic/rectal bleeding.

2.) Stool DNA Test

• Also known as the FIT-DNA test, it comes as an FDA-approved kit. It’s a multi-target test that detects occult blood along with nine DNA biomarkers of three genes associated with CRC and advanced adenoma.[rx][rx]
• Sample collection: Like FOBTs, the patient is provided a stool collection kit and asked to collect a stool sample, which can be delivered via mail or can be delivered personally to a laboratory/office, ideally within 72 hours.

3.) Sigmoidoscopy

• Examination of the rectum and sigmoid colon using a sigmoidoscope, an instrument consisting of a flexible tube with a lens and light source for visualization and a tool for removing tissues (polyp/adenoma) or taking biopsy samples.
• The sigmoidoscope is inserted through the anus up to the splenic flexure, after insufflating carbon dioxide for better visualization.

4.) Colonoscopy

• A colonoscope is inserted through the anus and through the entire colon ending in the cecum.
• Abnormal growths can be visualized and can be either removed (polypectomy) in whole, or a small sample can be taken for biopsy in a single procedure.
• Since the procedure is more invasive than sigmoidoscopy, it requires rigorous bowel preparation and dietary modifications.[rx]

5.) Colon Capsule Endoscopy

• Approved by the US Food and Drug Administration (FDA) to be used only in patients who had an incomplete colonoscopy. The patient swallows a capsule containing tiny wireless cameras that take images as the capsule traverses the colon.

6.) Computed Tomography Colonography

• The procedure isn’t invasive and doesn’t require sedation. However, bowel preparation and carbon dioxide insufflation are still needed for better visualization.
• It may additionally require an intravenous catheter for glucagon administration for bowel relaxation. Images are then obtained during a single 32-second breath-hold.[rx]

7.) Fecal Tagging

• It’s a laxative-free CTC approach, done by oral administration of a contrast agent over several days before the procedure, making fecal material in the colon distinct from colon tissue by “tagging” it.
• Radiographs of the colon are then obtained.
• Sensitivity is somewhat lower than conventional CTC with laxative bowel preparation.[rx]

8.) Barium Enema

• Either single or double-contrast is rarely used, and neither is recommended by any other expert group, due to its poor screening indices and because of the advent of better endoscopic and CTC procedures with better results.

Screening Frequencies and Ideal Intervals for Surveillance and Follow-up (Image 2)

1.) Guaiac FOBT (gFOBT) & Fecal Immune-chemical Test (FIT)

• Frequency of testing: Experts recommend sigmoidoscopy every 5 years for people at average risk who have had negative test results.[rx]

2.) Stool DNA Test

• Frequency of testing: The current recommendation is once every three years. If positive on any of the occasions, endoscopic studies such as colonoscopy and sigmoidoscopy are recommended.[rx]

3.) Sigmoidoscopy

• Screening frequency: Sigmoidoscopy should be performed at five-year intervals from baseline intervention, with gFOBT/FIT every three years.[rx][rx]

3.) Colonoscopy

• Screening frequency: Patients undergoing colonoscopy should have a 10-year interval between screening colonoscopies if the examination is negative and of adequate quality.[rx][rx]

4.) Computed Tomography Colonography

• Screening frequency – Current USPSTF recommends CTC every five years from baseline CTC or optical colonoscopy.

Disease conditions associate with Colon Cancer Screening

• Inflammatory polyps (pseudopolyps) – There is a well-defined association between identifying pseudopolyps and the spectrum of inflammatory bowel disease. However, a variety of other infectious and non-infectious colitis, including amoebic, ischemic, and schistosomal colitis might be attributed. The larger lesions with greater than 1.5 cm diameter, classifying as giant pseudopolyps, might present as an extensive polyposis syndrome.[rx]
• Familial juvenile polyposis – is inherited via an autosomal dominant pattern. Colon and rectum are most commonly involved. Malignant degeneration through the adenoma and carcinoma transformation is possible. Due to the high malignant yield, annual screening should merit consideration from the age of 10 to 12 years. Although it is an uncommon polyposis syndrome in adults, it has a remarkable significant percentage of polyposis syndrome in the pediatric population.[rx]
• Hyperplastic polyps – The colon is most commonly affected by hyperplastic polyps. Although the hyperplastic polyps do not classify as premalignant lesions, due to the similarities with adenomatous polyps in colonoscopy, once diagnosed, they require removal. They may occur as a polyposis syndrome with multiple/ giant polyps harboring a significantly increased risk of malignancy.[rx]
• Familial polyposis coli – Familial adenomatous polyposis (FAP) or familial polyposis coli is considered as one of the rare causes of colorectal adenocarcinomas. Specific mutation of APC and positive family history are evident in the majority of patients. There is already an extremely significant value of timely screening and surveillance in positive family and personal history of FAP, respectively. Among those affected with FAP, the risk of colorectal cancer goes way up to 100% by the age of 50.[rx]
• Turcot syndrome – Familial colorectal adenocarcinomas, including FAP and HNPCC, may accompany with a variety of central nervous system tumors known as Turcot syndrome. Moreover, Turcot syndrome categorizes according to the type of CNS tumor and number of colonic polyps in a couple of subgroups; type I, attributes to the glial tumors and a small number of colonic polyps, while a significant number of polyps and greater risk of medulloblastoma have been well-documented in type II.[rx]
• Cowden syndrome and PTEN hamartoma – PTEN acts as a tumor suppressor gene. Cowden syndrome, as an autosomal dominant syndrome and related to PTEN hamartoma tumor syndrome (PHTS), has a broad range of clinical manifestations including trichilemmomas in the face, malignant pathologies in the breast, thyroid, and gastrointestinal polyps. Obtaining timely screening schedules to exclude malignancies in these patients is crucial. Traditionally, there was a remarkable 80% germline PTEN mutation in patients affected by Cowden syndrome; however, recently, the specificity of these criteria has been questioned.[rx]
• Peutz-Jeghers syndrome – Peutz-Jeghers syndrome, or mucocutaneous pigmentation and polyposis syndrome, is classified as an autosomal dominant hamartomatous polyposis. Although evidence of the remarkable malignant potential is lacking, stepwise screening plans are generally the recommended approach to evaluate not only the GI tract but also other possible sites for malignancies, including breast, upper gastrointestinal tract, pancreas, cervix, ovaries, and testicles.[rx]
• Cronkite-Canada syndrome – Cronkite-Canada syndrome is a rare non-inherited disorder in which patients develop gastrointestinal polyposis in correlation with alopecia, cutaneous pigmentation, and fingernail/toenail atrophy. Diarrhea is a prominent symptom, and malabsorption, vomiting, and protein-losing enteropathy may occur. Most patients die of this disease despite maximal medical therapy, and surgery is only for complications of polyposis such as obstruction. Cowden syndrome is an autosomal dominant disorder with hamartomas of all three of the embryonal cell layers. Facial trichilemmomas, breast cancer, thyroid disease, and gastrointestinal polyps are typical of the syndrome. Patients should have screening for cancers.[25]
• Attenuated familial adenomatous polyposis (AFAP) – is a recognized variant of FAP. Patients present later in life with fewer polyps (usually 10–100) predominantly located in the right colon, when compared to classic FAP. Colorectal carcinoma develops in more than 50% of these patients but occurs later (average age, 55 years). Patients are also at risk for duodenal polyposis. However, in contrast to FAP, APC gene mutations are present in only about 30% of patients with AFAP. When present, these mutations express in an autosomal dominant pattern. Mutations in MYH, a gene involved in the repair of DNA, also result in the AFAP phenotype but are expressed in an autosomal recessive pattern.[rx]
• Serrated polyps – including sessile serrated adenomas and traditional serrated adenomas, are a recently recognized, histologically distinct group of neoplastic polyps. Endoscopically they are flat lesions and frequently difficult to visualize. These lesions were long thought to be similar to hyperplastic polyps with minimal malignant potential. However, it has become clear that some of these polyps will develop into invasive cancers. Additionally, research has described a familial serrated polyposis syndrome.[rx]

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