Colorectal Cancer, Polyps, and Diverticular Disease: CRC Screening Biology Treatment Polyps

0:00Welcome to Board Pearls. This is episode one of two of the Colorectal Cancer, Polyps, and Diverticular Disease chapter, in the Colorectal and Pelvic Floor Disorders module. This episode is the neoplastic colorectal pathway from screening through treatment to surveillance: average-risk screening starting at forty-five, the molecular subtypes that drive treatment, the stage-based management, and the polyp surveillance intervals.

0:25Colorectal cancer is the disease screening is supposed to prevent, and the reason it's preventable is the long, recognizable precursor: an adenoma sits in the wall for years before crossing into invasive cancer, and that window is what screening targets. The point of the modality menu isn't to find every polyp by colonoscopy, it's to give every average-risk patient a route in, because some will accept colonoscopy, some only a stool test, some only a blood draw, and any of these beats no screening by a large margin, with the residual disagreement being about which test buys how much benefit at what cost.

1:00Average-risk screening now starts at forty-five, moved down from fifty because early-onset colorectal cancer has risen meaningfully in adults under fifty and the old age-fifty anchor was leaving interceptable disease uncounted. Screening runs through seventy-five, with shared decisions from seventy-six to eighty-five, then stops, and the reason it stops is mechanistic: the lead time needed to benefit from finding an adenoma exceeds the remaining life expectancy past that age. The high-risk routes start earlier: a first-degree relative with colorectal cancer or an advanced adenoma moves the start to forty, or ten years before the youngest case, with five-year intervals, the hereditary syndromes start much earlier, and IBD patients enter dysplasia surveillance eight years after diagnosis or immediately at the diagnosis of primary sclerosing cholangitis.

1:50Colonoscopy every ten years is the cornerstone because it does both jobs in one procedure, detecting neoplasia and removing it in the same session, with high sensitivity for advanced adenoma in a well-prepped exam by a quality endoscopist, underwritten by the quality metrics in chapter thirty. The main non-invasive test is the fecal immunochemical test every year, an antibody assay for human hemoglobin in stool, so it's specific to lower-GI bleeding and doesn't pick up upper sources, with good sensitivity for cancer but poor sensitivity for advanced adenoma, which is exactly why it's repeated annually rather than every few years, since the repeated test accumulates cancer detection over time even though any single test misses most adenomas. Multi-target stool DNA every three years adds methylation and mutation markers to the antibody, raising sensitivity for cancer and somewhat for advanced adenoma, at the cost of more false positives, and the board-tested rule that follows is specific: an asymptomatic patient with a positive stool DNA test and a high-quality negative colonoscopy needs no further GI workup, because the false-positive rate doesn't justify chasing a cancer that hasn't been demonstrated. CT colonography every five years gives anatomic visualization without sedation but needs the same prep and involves radiation and extracolonic findings, and flexible sigmoidoscopy every five years is largely historical in US practice because it leaves the right colon out of reach, where the serrated lesions that drive interval cancer concentrate. The newest entry is a blood-based cell-free DNA test, with reasonable sensitivity for cancer but poor sensitivity for precancerous polyps, so its place is the patient who declines colonoscopy and stool testing, not a replacement for them.

3:28The principle that holds the menu together is that any positive non-invasive test is an indication for diagnostic colonoscopy. A positive stool or blood test isn't a result, it's an indication for colonoscopy, and the dominant failure in board vignettes is the patient who declines colonoscopy as the primary test and then declines it again when the alternative turns positive, so the screening conversation up front has to include the commitment to colonoscopy if the other test is abnormal, or the patient gets the interval without the prevention.

3:57That's the front end. The molecular biology decides what happens once a cancer is found, and the disease cleanly partitions into subtypes that drive treatment. Two pathways matter: the conventional adenoma-carcinoma pathway accounts for most sporadic cancer, and the serrated pathway for the rest, with Lynch syndrome sitting on top as the hereditary mismatch-repair-deficient subtype. The conventional cascade starts with loss of the APC brake on Wnt signaling to produce a dysplastic adenoma, then KRAS drives growth and loss of the tumor suppressors follows, over years to decades, with chromosomal instability as the genomic phenotype. The serrated pathway runs through a BRAF mutation in a sessile serrated lesion that drives a methylator phenotype, which silences the MLH1 gene, producing a microsatellite-unstable cancer, the same unstable phenotype seen in Lynch but arising sporadically through methylation. Lynch is the hereditary version of mismatch-repair deficiency from a germline mutation in one of the repair genes, and Lynch cancers are right-sided, occur younger, and carry that same unstable signature. So of all the microsatellite-unstable cancers, most are sporadic methylation-driven and a smaller share are Lynch.

5:10Universal reflex testing for mismatch-repair status on every newly diagnosed cancer is now standard, because family-history criteria miss too many Lynch patients. The algorithm starts with mismatch-repair immunohistochemistry on the tumor, staining for the four repair proteins, or microsatellite instability testing. Intact proteins rule in sporadic disease and stop the workup. Loss of MSH2, MSH6, or isolated PMS2 goes straight to germline testing, because those aren't explained by sporadic methylation. Loss of MLH1 needs one more step first, because it usually pulls PMS2 down with it and that combined loss could be sporadic methylation or Lynch, so you reflex to BRAF mutation or MLH1 methylation testing on the tumor: a positive result supports sporadic disease and stops the workup, while a negative one pushes the patient to germline testing. So the board stem to recognize is MLH1 loss with a positive BRAF, which is the sporadic serrated path with no germline implication.

6:14For metastatic disease the profile expands. RAS and BRAF are tested because either mutation predicts non-response to anti-EGFR therapy, and HER2 amplification identifies a small targetable subset. Sidedness adds a layer: right-sided tumors more often carry BRAF, microsatellite instability, and serrated features, while left-sided tumors more often follow the conventional cascade and respond better to anti-EGFR therapy when RAS is wild-type.

6:45Staging uses the TNM system: the tumor invades progressively deeper, from submucosa, to muscularis propria, through it into pericolic tissue, then to the peritoneal surface, then into adjacent organs; nodes are one to three versus four or more positive; and metastasis is one organ, multiple organs, or peritoneum. At least twelve lymph nodes must be examined for adequate node staging, and there's no lower fallback minimum, which matters because a non-existent lower-node rule has appeared in test prep and is wrong. The workup at diagnosis is colonoscopy, a baseline CEA, and CT of the chest, abdomen, and pelvis, with rectal cancer adding pelvic MRI, because the circumferential margin and mesorectal fascia decide whether neoadjuvant therapy and the surgical approach change. Stage one is the tumor confined to the wall without nodes, stage two is deeper without nodes, stage three is any depth with positive nodes, and stage four is distant metastasis.

7:48Treatment runs by stage, then layers molecular profile onto stage four. Stage one is surgery alone, a segmental colectomy with lymphadenectomy, with endoscopic resection curative for the most superficial cancers with favorable histology, meaning well or moderately differentiated, no lymphovascular or perineural invasion, a clear deep margin, and shallow submucosal invasion. Stage two is surgery alone in most cases, because the absolute survival benefit of adjuvant therapy is small, with chemotherapy reserved for high-risk features, deep or perforated or obstructing tumors, inadequate node sampling, lymphovascular or perineural invasion, or poor differentiation, and the microsatellite-unstable stage two tumor is an explicit exception, because it doesn't benefit from single-agent fluorouracil and already has a favorable prognosis, so it's usually observed. Stage three is mandatory adjuvant chemotherapy because the benefit is substantial, with the standard oxaliplatin-based regimens for three to six months, and the reason the duration is shortened where possible is that oxaliplatin neuropathy is cumulative and dose-limiting, so the shorter course preserves efficacy in low-risk stage three with much less neurotoxicity, while six months stays preferred for high-risk disease.

9:06Stage four is where molecular profiling drives drug selection. First-line in fit patients is a chemotherapy triplet plus the VEGF inhibitor bevacizumab, giving the deepest tumor shrinkage at the cost of more toxicity, with a doublet plus bevacizumab for less-fit patients. Anti-EGFR therapy with cetuximab or panitumumab works only in RAS-wild-type tumors, because a RAS mutation bypasses the EGFR target and makes the antibody useless, and the board rule layers a second filter on top: it's used only in RAS-wild-type left-sided primaries, because right-sided tumors are more often BRAF-driven and unstable and less EGFR-dependent, which is a mechanistic reason, not an arbitrary one. BRAF-mutant metastatic disease is poor-prognosis and gets a BRAF inhibitor plus cetuximab, and the reason it needs the cetuximab partner is that BRAF inhibition alone fails in colon cancer because EGFR feedback reactivates the pathway, so blocking EGFR closes that escape route. Microsatellite-unstable metastatic disease gets the checkpoint inhibitor pembrolizumab first-line, which nearly doubled progression-free survival over chemotherapy, and the mechanism is that these tumors carry a high mutational burden and abundant neoantigens, so releasing the immune brake unleashes a strong T-cell response, with chemotherapy reserved for the mismatch-repair-proficient patients. And HER2 amplification opens a separate targeted door with a HER2-directed regimen after first-line.

10:34Rectal cancer adds neoadjuvant therapy and total mesorectal excision, because the rectum sits in a fixed bony pelvis with limited margins, so local recurrence risk is higher and the circumferential margin matters more. Locally advanced rectal cancer, deeper or node-positive disease, gets neoadjuvant therapy then total mesorectal excision, and giving all the chemotherapy and radiation before surgery rather than splitting it has become the preferred approach, raising the rate of a pathologic complete response enough to open the door to organ preservation in patients who achieve a complete clinical response, the watch-and-wait approach where surgery is deferred and the patient followed closely. And microsatellite-unstable locally advanced rectal cancer has its own evolving option, where upfront checkpoint inhibitor therapy has produced complete responses that allow surgical avoidance. Surveillance after curative resection is a CEA every few months for two years then less often to five years, annual CT for five years in stage two and three, and colonoscopy at one year, then three, then five, with local excision of rectal cancer adding closer anastomotic surveillance because its local recurrence is higher.

11:42That closes the cancer side. The polyp side is the precursor the screening is hunting, and the histology decides both the cancer risk and the surveillance interval. Sporadic polyps split into the conventional adenomas of the conventional pathway and the serrated polyps of the serrated pathway, and the histology matters more than the appearance, because the two can share morphology, especially in the right colon where the sessile serrated lesion can look deceptively like a hyperplastic polyp. Conventional adenomas come as tubular, the most common, tubulovillous with a mixed pattern, and villous with mostly finger-like fronds and the highest cancer risk, and the risk grades by histology, size, and number, with the probability that a polyp already harbors cancer rising sharply with size and high-grade dysplasia the immediate predecessor of invasive cancer. The unifying clinical term is advanced adenoma, defined as ten millimeters or larger, or villous or tubulovillous histology, or high-grade dysplasia, any one of which is sufficient, and it's worth knowing because it sets the surveillance interval.

12:44The serrated pathway accounts for the rest and has been under-recognized because its precursor is flat, mucus-capped, and right-sided. Its three members are the hyperplastic polyp, the sessile serrated lesion, and the traditional serrated adenoma. Hyperplastic polyps are the most common serrated lesion, usually small and left-sided, considered nonpremalignant when diminutive and left-sided, with the board caveat that any proximal hyperplastic polyp ten millimeters or larger is treated as a sessile serrated lesion for surveillance. Sessile serrated lesions are the molecularly distinct precursor, carrying the BRAF mutation and the methylation that drives instability, predominantly right-sided, flat or slightly elevated, and often mucus-capped, with the histologic discriminator from a hyperplastic polyp being distorted crypts at the base, requiring only a single unequivocally abnormal crypt for the diagnosis, and most lack cytologic dysplasia, but when dysplasia develops the cancer risk steps up, concentrating in lesions over ten millimeters. Traditional serrated adenoma is the rarest, with uniform eosinophilic dysplasia, often bulky, predominantly left-sided, and KRAS-mutated rather than BRAF, treated as an advanced lesion by default.

13:56The clinical translation is the post-polypectomy surveillance intervals, graded by number, size, and histology, and the principle behind them is that risk-stratified follow-up assumes a high-quality index exam, so the intervals aren't portable to a poorly prepped colonoscopy. The headline intervals: one or two small tubular adenomas with low-grade dysplasia get seven to ten years, three or four small adenomas get three to five years, five to ten get three years, and more than ten get one year plus an evaluation for a hereditary polyposis syndrome. Any advanced adenoma, meaning ten millimeters or larger, villous histology, or high-grade dysplasia, gets three years. One or two small sessile serrated lesions get five to ten years, while a sessile serrated lesion ten millimeters or larger, or any with cytologic dysplasia, or any traditional serrated adenoma, gets three years. And a piecemeal endoscopic resection of a lesion twenty millimeters or larger gets a six-month look at the resection site first, then a year, then standard intervals. Serrated polyposis syndrome sits at the intersection of the serrated pathway and the polyposis syndromes, defined by either five or more sessile serrated lesions proximal to the rectum with at least two larger than ten millimeters, or more than twenty serrated polyps of any size with at least five proximal to the rectum, with an elevated lifetime cancer risk managed by annual colonoscopy with aggressive clearance.

15:24So the thread that ties the whole episode together is mechanism. Screening starts at forty-five because of the early-onset incidence, not a round number. MLH1 loss reflexes to BRAF testing to distinguish sporadic methylation from germline Lynch. RAS-mutant patients don't get cetuximab because downstream RAS activation bypasses the EGFR target. Microsatellite-unstable metastatic disease gets pembrolizumab because of the neoantigen load from its mutational burden. And post-polypectomy surveillance grades by histology and size because the risk does too.

16:00The next episode turns to diverticular disease, which shares the chapter but not the biology: the false-diverticulum mechanism, uncomplicated diverticulitis with selective rather than universal antibiotics in the immunocompetent outpatient, complicated disease graded by Hinchey, and the elective surgery indications that no longer rely on a fixed episode count.

16:23For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode one of two of chapter fifteen, and I'll see you in the next one.