Colon CA and polyps Flashcards
1
Q
Risk factors of colonic polyps
A
- Age: <40 colon CA is rare, but incidence increases w/ age starting at 50-55
- Genetics: FAP, HNPCC (lynch syndrome), MutYH, but 65-85% of CRC is sporadic
- Diet: fat and red meat increase risk, fiber/complex carbs decrease risk
- Comorbidities: DM, metabolic syndrome, CAD, high BMI, smoking, etoh all increase risk
- Low serum selenium increases risk
- Decreases risk: Ca, vit D, NSAIDs/ASA, omega3 FAs
2
Q
Distribution of CRC
A
- 60% occur on L side, mostly involving rectum and sigmoid colon
- 50% occur in ascending or cecum
- 80% of CRC arises from an adenomatous polyp (usually villous), but only a small percentage of adenomatous polyps will develop into malignancy
3
Q
Benign colonic polyps 1
A
- Lesions arising from aberrant crypt foci (in epithelium of mucosa), they are masses that protrude into the lumen
- May be pedunculated (w/ stalk) or sessile (no stalk)
- Hyperplastic polyps (most common): hyperplastic cells w/ basal nuclei, increased mucin production and serrated gland lumen
- 90% are found in L colon, these have no risk for CRC
- Usually do not have an increased risk of CA, except in some R sided sessile serrated adenomas that can transform to CRC by loss of MMR (mismatch repair) machinery
4
Q
Benign colonic polyps 2
A
- Hamartomatous polyps: disorganized mass of nl epithelium, glands, and (!) SmM tissue (of the mucosa)
- Seen throughout intestine, usually not associated w/ CRC risk, seen in peutz-jeghers syndrome (can show adenomatous change in PJS)
- PJS: melanin deposit in mouth, nose, lips, buccal mucosa (looks like freckles), polyps in SI, and increased risk for ovarian (and other) malignancies
- Juvenile retention polyps: hamartomatous proliferation of lamina propria usually in rectum (often in children, but can be seen in all ages), no increased risk for CRC
- Can see cystically dilated mucus glands lined by flat epithelium surrounded by abundant lamina propria (usually inflamed/eroded)
5
Q
Clinical presentation of polyps
A
- Most are ASx
- Rectal bleeding/anemia
- Change in bowel habits
- Unexplained weight loss
- Pain and obstruction
6
Q
Adenomatous (precancerous) polyps 1
A
- First recognizable transition to CA, risk of transformaiton correlated w/ polyp size (>1 cm) and number, architecture and severity of dysplasia (villous>tubulovillous>tubular)
- Most are found in rectosigmoid colon (very rare in SI)
- Most important precancerous lesions (most sporadic CRC comes from adenomatous polyps)
- Flat adenoma (lynch syndrome) associated w/ rapid progression to CA
- Epithelial dysplasia: hyper chromatic and stratified epithelial cells w/ loss of mucin content but no invasion
7
Q
Adenomatous (precancerous) polyps 2
A
- Tubular adenoma: >90% of colonic adenomas (most important), can be pedunculate or sessile
- 1-3% risk of malignancy, but risk is associated w/ size, number, degree of dysplasia
- Histo: many neoplastic glands lined by stratified hyper chromatic cells w/ reduced mucin production
- Proliferating epithelium confined to mucosa
8
Q
Adenomatous (precancerous) polyps 3
A
- Villous adenoma: only 1% of colonic adenomas (usually older individuals), but carry a 40% risk of CA
- Usually are larger, solitary sessile legions, most commonly in sigmoid and rectum
- More likely to be symptomatic
- Histo: epithelial cells organized into long papillary projections
- Tubulovillous adenomas: 5-10% of adenomas, intermediate in CRC risk and histologically
9
Q
Molecular pathways involved in CRC pathogenesis
A
- Chromosomal instability (CIN): gains or losses of whole or large portion of chromosomes (65-70% of sporadic CRC), implicated in FAP by inactivating APC
- Microsatellite instability (MSI): addition of nucleotide repeats due to mutations in MMR gene function, implicated in lynch syndrome by inactivating MMR complex proteins
- CpG island methylator phenotype (CIMP): widespread hypermethylation in gene promoter regions of tumor suppressor genes silences them
- Inactivation of APC (tumor suppressor), MLH1/MSH/PMS2 (MMR complex), p53, activation of KRAS (oncogene) are all implicated in pathogenesis
10
Q
Familial adenomatous polyposis (FAP)
A
- Caused by a mutation in APC tumor suppressor gene (usually CIN)
- This leads to development of hundreds of colonic adenomas by 2nd decade, 100% risk of CRC if untreated
- Duodenal adenomas also seen
- Tumor initiation is accelerated, but progression is nl (CA around 40)
- Autosomal dominant inheritance, 30% have de novo germline mutations
- APC down-regulates beta-catenin activity, thus loss of APC leads to increase b-catenin
- Excess b-catenin activity leads to activation of c-myc and proliferation
11
Q
Gardner’s syndrome
A
- Syndrome among FAP pts that consist of extra-intestinal Sxs
- Congenital hyper pigmentation of retinal pigment epithelium (CHRPE) most common (>70%)
- Osteoma (mandible, long bones, skull) and soft tissue tumors
- Desmoid tumor
- Periampullary CA
- Papillary thyroid CA
- Adrenal adnoma
- Supranumerary teeth
12
Q
Turcot syndrome
A
- A variant of FAP or lynch syndrome
- Multiple colorectal adenomas and primary brain tumors (meduloblastoma and GBM)
- FAP variant (APC mutations) result in meduloblastomas
- Lynch variant (MLH1/PMS2) associated w/ GBM
13
Q
MutYH polyposis (MAP)
A
- Autosomal recessive (only polyposis w/ recessive inheritance), mutation in MYH leads to inactivation in adenine base excision repair
- Colonic features similar to FAP, but to lesser degree
14
Q
FAP/MAP management/screening
A
- Endoscopic surveillance and prophylactic colectomy improves survival
- Noncarriers can be spared anxiety and need for increased surveillance
15
Q
Lynch syndrome (HNPCC)
A
- Hereditary non-polyposis CRC, autosomal dominant
- CRC Dx at 40 yo, tumors usually in R colon (80% lifetime risk for CRC)
- Tumor initiation is nl, but progression is accelerated (CA around 40)
- Associated w/ extracolonic CA: GBM, endometrium, ovary, stomach, urinary tract, SI, bile ducts, skin
- Due to defects in MMR genes MLH1, MSH2/6, and/or PMS2 which lead to MSI and loss of tumor suppressor genes
- MLH1 and MSH2 are most common mutations
- Amsterdam criteria: 3 or more relatives w/ lynch-associated CA, 2 or more successive generations, 1 lynch associated CA by age 50, 0 FAP (excluded)
