Pathology of Intestinal Polyps and Colorectal Carcinoma

Question 1

What is the definition of a polyp and what sessile vs pedunculated?

Answer 1

A mass of tissue that projects outwards from a mucosal surface

Sessile - broad-based polyp with no definable stalk (flat)

Pedunculated - base is a slender stalk

Question 2

What are the types of non-neoplastic polyps and which is most common?

Answer 2

Hyperplastic polyps - most common

Juvenile polyps - seen below age 5

Inflammatory polyp and pseudopolyp - i.e. ulcerative colitis

Question 3

What is the sequence of neoplastic polyps in the APC sequence? Which is most common?

Answer 3

1. Tubular adenoma - most common - low risk of cancer in it
2. Tubulovillous adenoma
3. Villous adenoma - worst - 40% chance of having cancer in it

“Villous is the villain”

Question 4

What is the most common type of polyp and what is it caused by? How does it appear grossly?

Answer 4

Hyperplastic polyp - caused by mucosal hyperplasia with slowed epithelial cell migration and shedding leading to overcrowding

Appear grossly as small, sessile polyps on mucosal folds -> must be biopsied because it cannot be told it’s noncancerous unless done so

Question 5

How does a hyperplastic polyp appear microscopically? Is it associated with malignancy?

Answer 5

Elongated regular glands and crypts with superficial “sawtooth” luminn borders by mature epithelial cells with no cytologic atypia
-> normal cells which are overcrowding

-not associated with malignancy

Question 6

What is a juvenile polyp and what symptoms is is associated with?

Answer 6

Hamartomatous mucosal polyp in children <5 years

Associated with bleeding, and autoamputation of polyp into stool is frequent and spooky

Question 7

How does a juvenile polyp appear microscopically?

Answer 7

Dilated and cystic glands filled with mucus and inflammatory debris (become irritated from sticking out into lumen), with fibrotic stroma. Ulceration is common -> causes bleeding

Question 8

What causes an inflammatory polyp?

Answer 8

Recurrent mucosal injury and repair, as in solitary rectal ulcer syndrome

-> mucosa prolapses into lumen, causes edema, superficial erosions, and acute / chronic inflammation

Question 9

What cuases an inflammatory pseudopolyp?

Answer 9

Chronic inflammatory bowel disease, especially ulcerative colitis

Polyp is due to presence of adjacent erosion or ulcer, but can sometimes grow beyond mucosa due to healing

Question 10

What causes Peutz-Jeghers syndrome and how can its polyps be told apart from juvenile polyps? Are they premalignant?

Answer 10

Autosomal dominant disorder

GI tract: Large, pedunculated, hamartomatous polyps

Major characteristic difference: Large bundles of smooth muscle within the polyps in PJS

They are NOT premalignant, although PJS is associated with increased risk of cancer

Question 11

What is seen throughout the body in PJS outside the GI tract and what cancers is it associated with?

Answer 11

Melanotic pigmented macules along cutaneous and mucosal surfaces, i.e. mouth, lips, hands

Cancers: increased risk of breast and GI carcinomas

Question 12

What is the lowest risk type of adenoma and what will be seen microscopically in the head vs the stalk?

Answer 12

Tubular adenoma

Head - dysplastic cells of interest -> Crowded, irregular glands with dysplastic lining epithelium

Stalk - normal mucosal epithelium

Question 13

What is the intermediate type of polyp in the adenoma-carcinoma sequence? What are its features?

Answer 13

Tubulovillous adenoma - some finger-like projections like villi, but also many tubular structures in the polyp

Question 14

How does a villous adenoma appear grossly and microscopically?

Answer 14

Grossly - Large, sessile, papillary polyp

Microscopic - long, finger-like projections covered by dysplastic glandular epithelium

Question 15

What are the clinical features of tubular adenoma vs villous adenoma?

Answer 15

Tubular - Usually asymptomatic, but some occult bleeding is possible

Villous - rectal bleeding is common. Cells are also so dysplastic that they release alot of protein -> hypoproteinemia due to protein-losing enteropathy. Can also secrete Cl- causing metabolic alkalosis -> hypokalemia

Question 16

Where are the majority of adenomas and polyps found and why? What is the exception to this rule?

Answer 16

Left side of the colon -> this is where the poop is the slowest moving, and highest the highest relative exposure to carcinogens

Exception to this rule: Sessile serrated adenoma - found in the right colon

Question 17

Other than being on the right side, how else is a sessile serrated adenoma different with respect to molecular genetics and microscopic appearance? How is it told apart from a hyperplastic polyp?

Answer 17

Sessile serrated adenoma looks like a hyperplastic polyp

• > Arises from the satellite instability pathway rather than Lynch syndrome
• > Epithelium does not have significant dysplasia like a hyperplastic polyp

-Major different from hyperplastic: base of crypts is flat (extends horizontally along muscularis mucosae)

Question 18

What causes FAP? What is the function of the lost gene? Wat chromosome?

Answer 18

Autosomal dominant (first hit) mutation of APC causes familial adenomatous polyposis

APC is a tumor suppressor on chromosome 5 which binds Beta-catenin when it is not associated with E-cadherin. Loss of APC allows beta-catenin to induce transcriptional activation of cell proliferation and decreased apoptosis
-> 100s of polyps are easily formed

Question 19

When do polyps start to form in FAP and what is the treatment?

Answer 19

Tubular adenomas develop by the second decade -> progression to colorectal carcinoma is 100% if not treated by colectomy

Question 20

What extraintestinal manifestation of FAP is useful for screening first degree relatives of affected individuals?

Answer 20

Congenital hypertrophy of the retinal pigment epithelium

Question 21

What FAP variant is assocatied with osteomas (benign tumors of bone)? What else is it associated with?

Answer 21

Gardner syndrome

Also associated with soft tissue tumors: fibromatosis of retriperitoneum (fibroblast proliferation), and dental abnormalities

Question 22

What is Turcot syndrome?

Answer 22

An FAP variant also associated with malignant CNS tumors

Think Turcot = Turban (head)

Question 23

What is Lynch syndrome also called? What causes it?

Answer 23

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Autosomal dominant mutation of DNA mismatch repair genes with microsatellite instability

Question 24

What GI and extra-GI manifestations are a part of Lynch syndrome?

Answer 24

GI: increased incidence of sessile serrated adenomas (1st hit in this pathway) which are in right colon, and development of adenocarcinoma

Extra-GI: Endometrial, ovarian, and stomach cancers

Question 25

What are the risk factors for colorectal adenocarcinoma?

Answer 25

Family history of adenomas or carcinoma (not necessarily the syndromes)

IBD

Diet which is low in fiber and high in fat -> bile production is carcinogenic + low transit speed

Question 26

What are the steps of the adenoma-carcinoma sequence?

Answer 26

1. 2-hits to APC
2. KRAS mutations - Ras becomes GTPase-activating protein (GAP) resistant
3. Loss of TGF-beta signalling (important inhibitor of epithelial proliferation)
4. TP53 knockout - DNA repair checkpoint is lost
5. Additional mutations and acquisition of telomerase

Question 27

What are the steps in the microsatellite instability pathway?

Answer 27

Knockout of both DNA mismatch repair genes -> genomic microsatellite instability -> increased genetic abnormalities affecting regulation of cell-growth and survival

Question 28

How does colon cancer in the left colon appear and why? What pathway does it use? What symptoms does it cause?

Answer 28

Left colon - most common, via APC pathway - appears as an annular, ulcerated mass with heaped up margins (apple-core or napkin-ring constriction) -> poop is tightly packed so it doesn’t have much room to reach into the lumen

Causes obstruction and bowel habit changes / discomfort. May cause hematochezia

Question 29

How does colon cancer in the right colon appear and why? What pathway does it use? What symptoms does it cause?

Answer 29

Right colon - less common, via the DNA mismatch repair pathway - appears as exophytic, polyploid mass branching into lumen, as the diameter is larger and the poop is fast-moving (tumor less likely to obstruct lumen)

Causes occult, rectal bleeding from sessile carcinoma (occult blood + iron deficiency anemia is common presentation)

Question 30

How does colon adenocarcinoma appear microscopically in general vs other adenocarcinomas and how can you track recurrence in some patients?

Answer 30

Appears with a profound inflammatory infiltrate and desmoplasia, with LOTS of luminal necrosis / necrotic tumor cells

Recurrence can be tracked by carcinoembryonic antigen (CEA) marker. If it was high before tumor removal and then becomes low, recurrence of cancer can be tracked via this marker

Question 31

What are the stages of colorectal carcinoma?

Answer 31

0 = CIS before invasion thru muscularis mucosa (no lymphatics in mucosa)
1 = no deeper than muscularis propria
2 = Through muscularis propria
3 = lymph node metastases
4 = distant metastases (most commonly liver, then elsewhere)