Week 3: Colon cancer and polyps

Question 1

environmental links with colorectal cancer

Answer 1

highest associations for development of CRC

• high fat, high red meat diet
• tobacco smoke

Question 2

polyps and cancer risk

Answer 2

1. Benign
   - hyperplastic, juvenile, hamartomatous
   - typically left colon
   - except serrated hyper plastic polyps may be part of genetic syndrome with increased cancer
2. Precancerous: Adenomatous polyp
   - villous> tubulovillous> tubular
   - increased risk with: > 1cm (5%), > 2cm (10-20%)
   - flat adenoma: lynch syndrome- rapid progression

Question 3

Chromosomal instability- multi step carcinogenesis

Answer 3

1. APC/b catenin mutation: tumor suppressor gene
   - from normal mucosa to aberrant crypt focus
2. KRAS mutation -protooncogene
   - to early adenoma to late adenoma
3. TP53, PIK3CA, loss of 18q

Question 4

Microsatellite instability (MSI)

Answer 4

• another pathway of carcinogenesis
• defects in mismatch repair gene- leading to mismatch repair failure leads to MSI (MLH1 and MSH2)
• inconsistent number of microsatelite nucleotide repeats
• pathway in Lynch syndrome

Question 5

CpG island methylator phenotype (CIMP)

Answer 5

• widespread hypermethylation in gene promoter regions associated CG islands of tumor suppressor and DNA repair genes, which leads to transcriptional silencing of these genes,
• associated with serrated adenoma to cancer

Question 6

Familial adenomatous polyposis (FAP)

Answer 6

• 2nd most common inherited CRC syndrome
• autosomal dominant, mutation in APC gene on chromosome 5. APC downregulates b-catenin protein (involved in cell devision)
• many many colonic adenomas
• 100% risk of developing CRC by middle age if untreated. Need to remove colon.

Question 7

Gardner’s syndrome

Answer 7

Extra intestinal Features of FAP

• Congenital hyper pigmentation of the retinal pigment epithelium (CHRPE)
• desmoid tumors
• Periampullary carcinomas
• papillary thyroid carcinoma
• adrenal adenoma
• osteomas
• supernumerary teeth
• soft tissue tumors
• lipoma, fibroma, sebaceous cysts

Question 8

Turcot syndrome

Answer 8

• rare hereditary syndrome of multiple colorectal adenomas and primary brain tumors. 2 subtypes.
• APC mutations associated with meduloblastoma
• MLH1/PMS2 associated with glioblastoma multiforme

Question 9

MutYH

Answer 9

• autosomal recessive
• involved in base excision repair
• polyposis with recessive inheritance, colon features similar to FAP to a lesser degree

Question 10

Lynch syndrome (hereditary no n polyposis colorectal cancer)

Answer 10

• tumor site in proximal colon predominates. Right side of colon instead of left.
• extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors
• autosomal dominant. MLH1, MSH2, MSH6, PMS2 mutations in mismatch repair genes.
• defective DNA repair, microsatelite instability, loss of tumor suppressor genes, proliferation of mutant cell types, activation of oncogenes. Leads to carcinoma.

Question 11

Surveillance options for carriers of lynch associated mutations

Answer 11

• colorectal cancer: colonoscopy beginning at 20-25 years old, every 1-2 years
• endometrial cancer: transvaginal ultrasound, endometrial aspirate, annually starting at age 35

Question 12

Screening tests for CRC

Answer 12

1. CRC detection
   - FOBT: fecal occult blood test
   - FIT: fecal immunochemical test-detects globin, more sensitive
   - Fecal DNA
2. CRC prevention
   - colonoscopy: gold standard, diagnostic and therapetic. For age 50-75
   - flex sig
   - Ct colonograph

Question 13

Hyperplastic polyp

Answer 13

• most commonly in rectosigmoid colon
• small, sessile (no stalk) polyps
• hyperplastic colonic epithelial cells with basally located nuclei, increased cytoplasmic mucin, serrated lumen
• don’t have increased cancer risk except sessile serrated adenomas on right side of colon

Question 14

Hamartomatous polyp -intestional

Answer 14

• isolated lesions or in familial hamartomatous polyposis (Peutz-Jeghers syndrome)
• histologically normal tissue but disorganized
• proliferation of epithelium, glands, and SMOOTH MUSCLE
• usually not associated with an increase risk of carcinoma. PJ syndrome polyps may be associated with increased risk of malignancy.

Question 15

Juvenile (retention) polyp

Answer 15

• common, in rectum of young children, but can be also found in adults
• hamartomatous proliferation, mainly of lamina propr.
• cystically dilated mucous glands, lined by flat epithelium, abundant lamina propria
• often with erosion and inflammation
• not associated with increased risk of carcinoma.

Question 16

Neoplastic epithelial polyps (colonic adenomas)

Answer 16

• more common in rectosigmoid colon (left)
• epithelial proliferation with dysplasia
• majority of sporadic invasive colorectal adenocarcinomas arise from preexisting adenomatous polyps
• malignant risk correlates with: size and number, histologic architecture, severity of dysplasia
• villous>tubulovillous>tubular

Question 17

Tubular adenoma

Answer 17

> 90% of colonic adenomas

• multiple, pedunculate or sessile
• glands lined with epithelial cells that are hyper chromatic, stratified and show loss of normal mucin content

Question 18

Villous adenomas

Answer 18

• 1% of colonic adenomas
• older individuals, solitary, larger, sessile lesion. commonly in rectum and rectosigmoid colon
• papillary growths that project into lumen
• histo: neoplastic proliferation of colonic epithelial cells organized into long fingerlike papillary or villous processes
• up to 40% incidence of carcinoma

Question 19

Tubulovillous adenoma

Answer 19

-5-10% of colonic adenomas
-mixed tubular and villous features
-

Question 20

familial polyposis syndromes- pathology

Answer 20

• autosomal dominant
• colonic adenomas at young age, 100s-1000s carpet mucosa surface
• most polyps are tubular adenomas
• also have duodenal adenomas
• risk of colonic cancer is 100% unless colectomy performed

Question 21

Colorectal carcinomas

Answer 21

• mostly adenocarcinomas
• most commonly in rectosigmoid
• right colon: tends to be large, polypoid, exophytic mass
• left colon: annular, whole circumference, napkin ring/apple core
• rectal carcinomas: commonly ulcerated with raised everted edges

Question 22

Carcinoma of the anal zone

Answer 22

• rare
• can be squamous carcinoma or busload carcinoma from the transitional zone of anorectal unction
• present with rectal discomfort, discharge, bleeding, mass

Question 23

Adenocarcinoma of the small intestine

Answer 23

• very rare
• most commonly preambulary region of duodenum
• pathologically similar to colon adenocarcinoma

Question 24

GI lymphomas

Answer 24

• 1-4% of GI malignancies
• primary lymphomas: no evidence of liver, spleen, bone marrow disease at diagnosis
• intestine is common site of extra nodal malignant lymphoma. Most common is non hodgkin lymphoma from MALT tissue
• increased incidence in AIDS (high grade B cell lymphoma) and Celiac (t cell lymphoma)

Question 25

GI stromal tumors (GIST)

Answer 25

• most common mesenchymal neoplasms
• somatic mutation in c-KIT (CD117), encodes tyrosine kinase receptor
• gross: submucosal polypoid, intramural, subserosal masses.
• histo: spindle cells

Question 26

Carcinoid tumors of GI

Answer 26

• < 2% of colorectal malignancies
• from neuroendocrine cells of mucosa
• most common: tip of appendix, ileum
• mostly benign and incidental findings
• gross: firm, yellow nodules, may be multiple.
• histo: nests, trabeculate, strands or cords of small uniform round cells.
• diagnosis can be confirmed by immunohistochemical stains