Neoplasms of Lower GI Tract (use ppt for pics, chart @ end) Flashcards
Right sided mass
stool semi-liquid, so might not detect mass
left sided mass
stool progressively well formed/solid, so more likely to get stuck/be detected if mass present
Where are epithelial stem cells?
base of crypts
Polyp
- sessile vs. pedunculated, neoplastic vs non-neoplastic
adeoma
precurtsor to malignancy
adenocarcinoma
invasive
Pedunculated vs sessil
pedunculated has stalk
Inflammatory polyps
Often present with bleeding
Often due to mucosal prolapse (very common in the rectum)
Cycles of injury and healing result in “polyp” formation = inflamed colonic mucosa with ulceration/erosion, epithelial hyperplasia
Hamartomatous polyps
Most occurring in childhood (pre-pubertal)
Hamartoma: “tumor-like” over-growth / mature tissue / developing where it is normally present (e.g. colonic tissue developing in the colon)
Juvenile (sporadic and syndromic) and Peutz-Jeghers (syndromic)
Key Points
Polyps: Variable locations in lower GI system
Benign features histologically but syndromic juvenile polyps often have foci of dysplasia
May portend:
Risk of future GI carcinoma (increase frequency of screening)
Both Peutz-Jeghers and Juvenile polyposis = 40% cumulative risk for CA
Extra-GI manifestations
Need to consider familial screening (genetic counseling) in some cases
Types
Juvenile
Peutz-Jeghers
Others: Cowden, Cronkhite-Canada
Extra-GI manifestations of Peutz Jeghers
Mucocutaneous pigmented lesions; increased risk of thyroid, breast, lung, pancreas, gonadal, and bladder cancers
Extra-GI Manifestations of juvenile polyposis
Pulmonary arteriovenous malformations, digital clubbing
Hyperplastic Polyps
Location: left colon including rectum (90%)
increases w/ age
small (
Hyperplastic polyp histology
Smooth, nodular lesion with flat base sessile Need microscopic evaluation to definitively distinguish Hyperplastic polyp Adenomatous polyp
composed of mixed absorptive and goblet cells; cells are crowded, possibly due to delayed shedding of epithelium “hyperplastic.” A serrated architecture results. This is a benign, usually non-neoplastic lesion to be distinguished from SSPs
Serrated polyps
Not pre-malignant: hyperplastic (left sided)
Crypts with “star-shaped” / “serrated” appearance- Cytology: Not dysplastic
- Have been considered for decades “non- neoplastic
Premalignant:
Sessile Serrated Polyps/Adenoma (tend to be right sided) –> alternate pathways to carcinoma than the usual adenomatous polyp
Microsatellite Instability pathway
DNA hypermethylation pathway (CpG island methylation)
Architecture: looks like “serrated” knife
- Cytology: Dysplastic epithelium may or may not be present
Pre-neoplastic = DEFINITELY can progress to adenocarcinoma
Adenomas
Size is variable – range from a few mm to several cm (10 cm or more)
In nearly 50% of Western adults by age 50
Present throughout the colon
Have epithelial cytologic dysplasia ranging from low grade to high grade (carcinoma in situ)
Villous adenomas contain foci of invasion more frequently than tubular adenomas but SIZE MATTERS (correlates with risk of malignancy )
Presence of high grade dysplasia increases risk of malignant transformation in that polyp but not in the rest of the colon
Adenomatous changes on histology
- Cells
- Piling up on each other (no respect!)
- Nuclei
- Darker
(hyperchromasia) - Progressive loss of basal-orientation
- Darker
- Cytoplasm - Reduced compared to nucleus
(increased N:C ratio)- Reduced mucin production
- Mitotic Figures - Increased mitotic activity
Villous adenoma
Lesion is sessile – No stalk
Architecture: multiple, slender villi (finger-like projections)
Adenomatous(dysplastic)
histologic features
Colorectal cancer
3rd most common in men and women
Common mutation in Adenoma
APC @ 5q21
Later events: Beta catenin, K-RAS, loss of p53/SMAD2 and 4 tumor suppressor genes
RFs/ PRotective factors for colorectal cancer
age
country of birth
FAP/HNPCC
longstanding UC
moderate:
high red meat diet
previous adenoma or cancer
pelvic irradiation
modest high fat diet smoking/alc obesity cholecystectomy
Protective
phys activity
aspirin/NSAIDs
fruit/veg/fiber/folate methionine
Ca
Postmenopausal hormone therapy
Main molecular pathways
WNT/APC/beta-catenin – classical adenoma-carcinoma sequence
K-Ras/MAP kinase/PI3 kinase signaling pathways—activating mutations
Microsatellite Instability – defects in mismatch repair proteins
methylation induced gene silencing enhances progression along pathway
most CR cancers are
sporadic (followed by familial)
WNT signaling altered in what % of CRC pts?
92%
WNT pathway
Wnt protein ligands are critical for development
Animals lacking Wnt homologs fail to develop entire organs. (fly wnt-1 mut =wingless)
Wnt ligands drive proliferation of their target tissues/organs
The Wnt pathway regulates the levels of cytoplasmic beta-catenin
***WNT pathwayd involves APC and Beta-catenin (made often, degraded fast) Need all components in “destruction complex”: APC, Beta catenin, axin, etc. (Dishevelled activated and allows Beta catenin to escape destruction and act on genes)
Where is beta-catenin turned off
@ top of crypt (if stays on, accumulation of cells @ site of future polyp formation)
Polyps represent An increase in the size of the proliferating crypt compartment
FAP
Familial Adenometous Polyposis (Aut dom)
APC mutations can run in families, producing Familial Adenomatous Polyposis (FAP)
FAP patients have increased risk of colon cancer, but these account for a small fraction of the total cases of colon cancer (~5%)
Most people who acquire colon cancer without FAP acquire spontaneous somatic mutations in APC
In FAP: 100% will develop invasive adenocarcinoma, often before age 30
Cetuximab
EGFR inhibitor (monoclonal antibody)
Hereditary Non-Polyposis Colorectal Cancer aka Lynch Syndrome
Develop colon cancer at an earlier age than sporadic forms
Tend to be right-sided
Inherit mutation of mismatch repair gene allele, acquire the second allele mutation over time leading to microsatellite instability
Advancing vs early colon carcinoma
Change in bowel habits and indicators Constipation Urgency Narrowing of stool Cramping / pain Blood Loss Blood in stool or bleeding from rectum (BBBPR) Anemia (iron-deficiency) Unexplained weight loss
Early Colon Carcinoma No symptoms most often Nonspecific findings Fatigue Weight loss Anemia
Detection of neoplasms
Visualization +/- Biopsy
= Colonoscopy
= Barium enema
= Other options
Blood Detection in Stool
- Hemorrhage of ulcerated lesion
DNA / Mutation Detection in Stool
- Shed neoplastic cells vs. normal colonic epithelial cells
Carcinoma
Invasion of dysplastic epithelial cells into and beyond the lamina propria
Adenomas at risk:
4 cm: high risk (~40% in one study) of identification of invasive component within lesion
typical adenocarcinoma histology
gland formation
mucin production
Neoplastic glands (adenocarcinoma) invading into muscularis propria, inciting a “desmoplastic” (fibrotic) response. There is “dirty necrosis” in the lumen of some of the glands (arrow), a fairly common finding in colon carcinoma.
Prognosis
Most important prognostic factors:
Depth of invasion
Presence or absence of lymph node metastasis
Distant metastasis
Where does colon cancer most commonly metastasize to?
LIVER
Therapy for colon cancer
Surgery
Local excision – e.g. polypectomy
Colonic resection
Radiofrequency ablation
Cryosurgery
Chemotherapy
-Only treatment = palliative
-Adjunctive treatment
Pre or Post-Operative
Radiation therapy
Targeted Therapy
- Monoclonal antibodies
- Angiogenesis inhibitors
