What are the main types of colonic polyps?
What are main histologic types of colonic polyps?
adenomatous (70%)- include tubular, villous, tubulovillous, and sessile serrated adenomas (these CAN develop into cancer)
non aenomatous (30%)- include hyperplastic, hamatomatous (Peutz-Jeghers syndrome), and Juvenile poylps (very low risk of developing into cancer)
What kind of polyp is this?
Non-adenomatous hyperplastic polyp
Describe Non-adenomatous hyperplastic polyps
These are the most common non-neoplastic polyp, usually diminutive in size, and located usually in the rectum or sigmoid colon (No malignant potential in small distal hyperplastic polyps)
How do hamartomatous polyps form?
Hamartomatous polyps occur sporadically or as components of various genetically determined or acquired syndromes (Peutz-Jeghers syndrome)
Describe Peurz-Jeghers Syndrome
This is an AD syndrome that presents around 11 y/o with multiple GI hamartomatous polyps in the small intestine and mucocutanoeus lesions on the buccal mucosa (below)
What mutation is common in Peutz-Jeghers Syndrome?
loss of function in gene STK11
Peutz-Jeghers syndrome is associated with a markedly increased risk of several malignancies. Name some.
•sex cord tumors of the testes;
•late childhood for gastric and small intestinal cancers; and the second and third decades of life for colon, pancreatic, breast, lung, ovarian, and uterine cancers
•Regular surveillance is recommended beginning at birth
What is this?
When and where do juvenile poylps most commonly occur?
In the rectum of children under 5 y/o (presents with rectal bleeding)
How do juvenile polyps form?
Morphogenesis incompletely understood. It has been proposed that mucosal hyperplasia is the initiating event
What are some complications of juvenile polyps?
•Intussusception, intestinal obstruction, or polyp prolapse (through the anal sphincter) may occur. Some malignant potential as well
How common is dysplastic transformation of a juvenile polyp?
Rare in sporadic polyps, but in contrast juvenile polyposis syndrome, 30% to 40% of patients with juvenile polyposis develop colonic adenocarcinoma by age 45
•Individuals with the autosomal dominant syndrome can have from 3 to as many as 100 hamartomatous polyps. A minority can undergo malignant transformation.
What is the most common mutation seen in juvenile polyps?
What are the risk factors for adenomatous polyp formation?
Age, abdominal obesity, male sex, and African American race are risk factors (Prevalence of 25-30 % at age 50)
Remember that adenomatous polyps can appear grossly as sessile, pedunculated, flat, or even depressed and
histologically can be tubular (80%), villous (5-15%), or mixed
Which types of adenomatous polyps have the most malignant potential?
villous is more likely than tubular due to typically being larger and Villous are usually sessile and more likely to infiltrate (larger= more likely to transform)
What is the difference between sessile serrated adenomas (SSAs) and hyperplastic polyps?
SSAs have some histological features of hyperplastic polyps but have malignant potential
Below: Narrow-band imaging to enhance vascular pattern to ID SSA polyp
T or F. SSAs are more common in the right/ascending colon
SSAs are most likely to have ____ or ____ mutations
MSI-H or BRAC
Tx for a polyp?
What is the most common GI malignancy?
What are the risk factors for CRC?
-age is most important
-fam Hx, chronic colitis, adenoma, previous colorectal neoplasia
-living in a developing country (high fat, low fiber diet)
-lack of physical activity
-red meat consumption
-cigs and alcohol
What things decrease the risk of CRC?
-multivitamins containing folic acid
-aspirin and other NSAIDs
-postmenopausal hormone use
-calcium and folate
-veggies, fruits, and fiber
•Incidence of CRC has declined by 30% in last decade in patients> age 50
Age is the most common risk factor for colon cancer*****
Need to start screening at age 50 (AA may be earlier-screen at age 45)
How is CRC in the right/ascending colon most likely to present?
The right colon has a larger lumen and thus is less likely to cause obstruction than the descending colon so the main presenting symptoms are most commonly:
-anemia (decreased hemoglobin)
-changed bowel habits
-rarely rectal bleeding (21%)
How is CRC in the left/descending colon most likely to present?
-abdominal pain (84%)
-changed bowel habits (86%)
rectal bleeding (44%)
How is CRC in the rectum most likely to present?
rectal bleeding (80%)
-abdominal pain (60%) and changed bowel habits
Bairum enemas arent used as much anymore
What are the main goals of CRC screening?
1) Decrease mortality from colon cancer
2) Prevent colon cancer by removing adenomatous polyps
What are the main barriers to CRC screening?
1)Limited access to medical care or colonoscopy
2)Patient preference-bowel prep, time off from work for colonoscopy
3) Risk and expense of screening tests
** Best test for individual patient is test that gets done
**Only 60 % of patients currently get screening between age of 50 and 75
What are the screening options for average risk CRC pts?
Avergae pt= no GI symptoms or bleeding. Start screening at 50 and options include 10 yr colonoscopy for screening, a CT colography every 5 yrs, a sigmoidoscopy + barium enema. IF any are positive, move to colonoscopy
What are the screening options for high risk CRC pts?
High risk can ONLY do a colonoscopy, not any alternatives for screening
What are the main stool based CRC screening tests?
FOBT (Fecal Occult Blood Test)
FIT (Fecal Immunochemistry Test)
Requires 3 stool samples done yearly using a stool card that can be stained for occult blood. Positive test has 20% chance of having large polyp or cancer
•80% false positive rate (Low sensitivity for detecting CRC)
•Responds to only human hemoglobin (doesnt depend on diet)
•Does not detect UGI bleeding
•Requires 1 or 2 stool samples
•May detect as little as 0.3gmHb/gm stool
•More expensive than Guiac and More sensitive and specific than Guiac tests
•Done yearly for screening
As shown, the majority of CRC is sporadic with age being the predominant risk factor
What does this image most likely show?
Hereditary non-polyposis colon carcinoma/ Lynch syndrome (note how the cecum is not covered in polyps like in FAP)
Describe Hereditary non-polyposis colon carcinoma/ Lynch syndrome
AD condition that accounts for 2% to 4% of all colorectal cancers, making it the most common syndromic form of colon cancer.
When does Hereditary non-polyposis colon carcinoma/ Lynch syndrome present?
•Tend to occur at younger ages than sporadic colon cancers and are often located in the right colon.
•Compared to familial adenomatous polyposis (FAP), in HNPCC there are fewer polyps and an older age for development of carcinoma.
What causes Lynch syndrome?
faulty DNA mismatch repair genes, and most HNPCC tumors demonstrate microsatellite instability (variations in dinucleotide repeat sequences).
What criteria is used for clinical diagnosis of Lynch syndrome?
What are the Bethesda criteria?
NOTE: Currently most GI pathology leaders are screening every colorectal adenocarcinoma for MSI
1. CRC diagnosed in individual under 50 years of age.
2. Presence of other HNPCC-associated tumors*, regardless of age.
3. CRC with the MSI-H histology, in patient <60 years of age.
4. CRC in 1 or more first-degree relatives with an HNPCC-related tumor, with 1 of the cancers being diagnosed under age 50 years.
5. CRC diagnosed in 2 or more 1st or 2nd degree relatives with HNPCC-related tumors, regardless of age.
* endometrial, ovarian, gastric, hepatobiliary, small bowel, transitional cell carcinoma of the renal pelvis or ureter.
What is this?
FAP, familial adenomatous polyposis
Syndrome characterized by almost complete carpeting of the of the mucosal surface of the colon with small adenomatous polyps with tubular-like adenoma microscopic appearances
Are the polyps of FAP confined to the colon?
No, Adenomas may develop elsewhere in the GI tract, particularly adjacent to the ampulla of Vater and in the stomach
What causes FAP?
germline mutations of the APC gene in every cell of the colon in one allele, and then polyp growth begins when the second allele is somatically mutated
How is FAP managed?
This AD syndrome is managed by total prophylatic colectomy (generally before age 20)
NOTE: Colorectal adenocarcinoma develops in 100% of untreated FAP patients, often before age 30 and nearly always by age 50
What are the clinical variants of FAP?
What is Turcot Syndrome?
FAP + CNS tumors, often medulloblastomas
What is Gardner Syndrome?
FAP + desmoid tumors, osteoms, dental anomalies, soft tissue skin tumors, and/or congenital hypertrophy of the retinal pigment epithelium (CHRPE)
What is this?
Hyperplastic colonic polyp
•Well-formed, elongated glands and crypts with saw tooth or star-shaped appearance - due to decreased epithelial cell turnover, delayed shedding of surface cells and piling up of cells
•Mixture of goblet cells (with abundant mucin) and absorptive cells
Bland cytology with eosinophilic cytoplasm
What is this?
Sessile Serrated Adenoma - Appears similar to hyperplastic poylps, but are marked by:
serrated architecture throughout the full length of the glands, including the crypt base,
crypt dilation, and
lateral growth (boot shaped crypts)
SSAs are most common in the _____ colon
NOTE: These have malignant potential but lack typical cytologic features of dysplasia
What is this?
Polyps seen in Peutz-Jeghers Syndrome. These are large and pedunculated, with characteristic arborizing (tree-like) networks of CT, as well as smooth muscle, lamina propria, and glands lined by normal-appearing intestinal epithelium
Describe juvenile poylps
•Most are less than 3 cm in diameter and are pedunculated, smooth-surfaced, reddish lesions with characteristic cystic spaces.
How do juvenile polyps appear histologically?
-Dilated glands filled with mucin and inflammatory debris
-Lamina propria expanded by mixed inflammatory infiltrates.
Bottom right: Inspissated mucous, neutrophils, and inflammatory debris can accumulate within dilated crypts
What is this?
Tubular Adenoma - tend to be small, pedunculated polyps composed of rounded, or tubular, glands
What is this?
Tubulovillous adenomas have a mixture of tubular and villous elements
1-20% villous component, higher rate of p53 and Kras mutation and MGMT loss
What is this?
Villous adenomas, which are often larger and sessile, are covered by slender villi
These have cauliflower-like appearance is due to the elongated glandular structures covered by dysplastic epithelium
Note about adenomatous poylps
These categories have little clinical significance in isolation.
Although villous adenomas contain foci of invasion more frequently than tubular adenomas, villous architecture alone does not increase cancer risk when polyp size is considered
What is the most important characteristic of polyps that correlates with risk of malignancy?
Note the two main types of colonic adenocarcinoma
What is a unique characteristic of metastatic CR adenocarcinoma?
Dirty necrosis, sloughing of material into the glands
Although poorly differentiated and mucinous colonic adenocarcinoma histologies are associated with poor prognosis, the two most important prognostic factors are what?
depth of invasion and the presence of lymph node metastases (to the subcapsular sinuses most commonly).
Where does CRC like to MET to?
liver, lung, and peritoneum
NOTE: With the exception of brain metastasis, liver metastasis had the worst prognosis (median survival time, 9 months).
What is the classic (80% of sporadic colon cancers) pathway for CRC development?
Normal epithelium - APC - small tubular adenoma - KRAS - intermediate adenoma - SMAD2/4 - advanced adenoma - p53 - adenocarcinoma
What is the MSI/Lynch Syndrome pathway for CRC development?
Normal epithelium - Failure of MMR - small tubular adenoma - MSI (DNA mismatch repair) - adenocarcinoma
What is the Epigenetic/CpG island hypermethylation pathway for CRC development?
Normal epithelium - BRAF mutation/hypermethylation MLH1 - hyperplastic polyp - MSI - SSA - MSI - adenocarcinoma
BRAF mutation is almost exclusively seen in sporadic MSI tumors that are presumed to develop through the serrated tumorigenic pathway, but has never been reported in Lynch syndrome.
What does APC normally do?
bind to and degrade B-catenin
What happens when APC is mutated in FAP?
Steps with loss of APC function:
1.β-catenin accumulates and translocates to the nucleus (stain positive in the nucleus),
2. where it forms a complex with the DNA-binding factor TCF and activates the transcription of genes, including MYC and cyclin D1, that
3. promote proliferation.