AssessmentsColorectal polyps and cancer: Pathology review
USMLE® Step 1 style questions USMLE
A 5-year-old boy is brought to the physician by his mother due to excessive fatigue over the past 2 months. The mother has occasionally noticed blood in the toilet bowl after the patient defecates. There is no significant family history of cancers. The patient's temperature is 37.0°C (98.6°F), pulse is 96/min, and blood pressure is 110/70 mmHg. Physical examination shows conjunctival pallor. No abnormal skin pigmentation is noted. Laboratory results are as follows:
|Mean corpuscular volume (MCV)||74 μm3|
Colonoscopy is performed and reveals seven polyps throughout the gastrointestinal tract; subsequent biopsy reveals hamartomatous mucosal polyps. Genetic testing is performed and reveals a mutation in the BMPR1A gene. Which of the following is the most likely diagnosis in this patient?
Content Reviewers:Yifan Xiao, MD
At the gastroenterology clinic, there is a 63-year-old Caucasian male, named Neil, who's complaining about progressive fatigue and weight loss in the last 6 months.
Laboratory findings reveal positive fecal occult blood test and iron-deficiency anemia.
At the same time, an 18-year-old Caucasian male, named Brendon came in for a colonoscopy screening.
He was concerned after learning that both his grandfather and uncle were diagnosed with colon cancer in their early thirties.
His doctor detected more than one hundred polyps on colonoscopy.
Now, both people have some form of colorectal polyps or cancer.
But first let’s start with colorectal polyps, which are overgrowths of epithelial cells in the colon or rectum.
They are subdivided into non-neoplastic polyps, such as hamartomatous polyps, hyperplastic polyps, inflammatory pseudopolyps, mucosal, and submucosal polyps; and neoplastic polyps, which include adenomatous and serrated polyps.
Hamartomatous polyps are solitary, disorganized masses that contain normal tissue found at the site of the polyp.
Next, hyperplastic polyps, are the most common polyps and they are small and typically located in the rectosigmoid region.
Usually, these polyps are benign lesions, but in rare cases, they can evolve into serrated polyps, which have malignant potential.
Inflammatory pseudopolyps are multiple benign pseudopolyps that occur during regenerative and healing phases in chronic inflammation, and they are most commonly seen in inflammatory bowel disease.
Mucosal polyps, which are clinically insignificant, are usually small, less than 5mm, and they look similar to surrounding normal mucosa.
On the flip side, submucosal polyps can include lipomas, leiomyomas, fibromas, or other lesions.
Now let’s switch focus to neoplastic polyps!
Adenomatous polyps are caused by a mutation in the tumor suppressor gene called adenomatous polyposis coli or APC for short, which is located on chromosome 5 and is responsible for the regulation of cell growth and cell adhesion.
Now let’s focus on adenoma-carcinoma sequence which includes three steps.
The first step is the mutation of one allele of the APC gene, which leads to the formation of a small polyp, also called early adenoma.
The second step occurs when the small polyp acquires mutation of protooncogene called KRAS, which is further followed by an increase in the size of adenoma and formation of the late adenoma.
Finally, the third step requires mutation of tumor suppressor genes p53 and DCC.
Now, adenomatous polyps less than 1cm, are less likely to acquire these mutations and undergo malignant transformation, in contrast to adenomatous polyps greater than 4cm which are more likely to progress to adenocarcinoma.
Furthermore, based on histological appearance, there are three types of adenomatous polyps: villous, which are cauliflower-like polyps that have the highest malignant potential; tubular, which are pedunculated polyps that protrude out in the lumen of the intestine, they have the lowest malignant potential; and tubulovillous, which have characteristics of both, tubular and villous polyps, and they have an intermediate malignant potential.
Usually, adenomatous polyps are asymptomatic, but in some cases, villous polyps can cause bleeding, secretory diarrhea, and partial intestinal obstruction.
Finally, serrated polyps are often flat or sessile and are characterized by saw-tooth appearance under the microscope.
They contain methylated CpG islands in their genes.
DNA methylation regulates gene expression, which can cause silencing of DNA-repair genes, eventually leading to more mutations and malignancy.
After polyps, let’s look at colorectal cancer which is the third most common cancer worldwide.
Most commonly it affects people older than 50 years old, and in 25% of the cases, there's a positive family history.
Risk factors for colorectal cancer include hereditary factors, such as familial adenomatous polyposis; adenomatous and serrated polyps; inflammatory bowel disease, such as ulcerative colitis; lifestyle factors, such as obesity, smoking, alcohol, and physical inactivity; and finally, dietary factors, which include high consumption of processed red meat and low consumption of fruits and vegetables.
And finally, increased cyclooxygenase-2 activity is linked to some forms of colon adenocarcinoma, so frequent use of inhibitors of this enzyme like aspirin can lower risks.
For your exam, you should remember that the most common form of colorectal cancer is adenocarcinoma and it’s most commonly located in the rectosigmoid, then ascending colon, and rarely in descending colon.
Initially, adenocarcinoma can be asymptomatic but as they grow, their location determines their manifestations.
Left-sided colon tumors are usually smaller, but as they infiltrate the wall of the colon, they encircle the lumen, eventually narrowing the lumen and causing obstruction.
A frequently tested concept is what is the presentation of an individual with left-sided colorectal cancer; therefore it’s important to know that these individuals present with obstruction and altered bowel habits, such as narrowing of stool, colicky pains, constipation, abdominal distension, but also hematochezia, nausea, and vomiting.
On the other hand, right-sided colon cancers grow as exophytic masses but they don’t tend to cause colon obstruction, because the right-sided colon has a larger diameter than the left.
Instead, right-sided tumors tend to cause chronic bleeding, eventually causing iron-deficiency anemia.
Other manifestations of right-sided colon cancers include progressive fatigue, malaise, and weight loss.
Now as far as screening goes, you should screen low-risk individuals at the age of 50; while individuals with a first-degree relative who has colon cancer, at the age of 40 or 10 years prior to their relative’s diagnosis.
Screening includes visualization methods, such as colonoscopy and flexible sigmoidoscopy; and laboratory findings, such as fecal occult blood test, which is further subdivided into guaiac fecal occult blood test, or FOBT, and fecal immunochemical test, or short FIT.
On the other hand, individuals with hereditary polyposis syndromes or inflammatory bowel disease have different guidelines for screening like earlier and more frequent colonoscopies.
Now, diagnosis of colorectal cancer, just like screening of colorectal cancer, includes visualization methods, such as colonoscopy and flexible sigmoidoscopy; but it also includes imaging methods, such as CT colonography and barium enema x-ray, which might show “apple core” lesions.
But don’t forget, diagnosis is confirmed with biopsy!
As far as treatment goes, colorectal cancer can be treated with surgical resection of the colon, colectomy, and chemotherapy.
What you have to know for your exam is that serum carcinoembryonic antigen levels, or CEA levels are increased in 60-90% of individuals with colon cancer.
But, the CEA level is not specific for colon cancer only, it’s also increased in pancreatic, gastric, breast malignancies, as well as in inflammatory bowel disease, cirrhosis, and pancreatitis; therefore it can be only used to monitor the recurrence of colorectal cancer.
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