GI Polyps and Carcinoma Flashcards
Sessile polyp vs pedunclulated polyp
Pedunculated: has a stalk
Sessile: no stalk
Non-Neoplastic Polyps
Inflammatory Polyps
Hamartomatous Polyps: Juvenile, Peutz-Jeghers, Others: Cowden, Cronkhite-Canada
Hyperplastic Polyps
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
Tissue that does belong there but is overgrown and a little disorganized
Most occur in childhood
Think about syndromes
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
Peutz-Jeghers syndrome
Mucocutaneous pigmented lesions; increased risk of thyroid, breast, lung, pancreas, gonadal, and bladder cancers
Juvenile polyposis
Pulmonary arteriovenous malformations, digital clubbing
Hyperplastic Polyps
Delayed maturation with overgrowth of epithelium (SERRATED appearance)
Increasing incidence with age
Small in size
No dysplasia but need to distinguish from “sessile serrated polyp/adenoma” (SSP) which ARE pre-malignant
Serrated Polyps
NOT pre-malignant: Hyperplastic Polyps (generally)
Pre-malignant: Sessile serrated polyps/adenoma (alternate pathways to carcinoma than the usual adenomatous polyp).
Adenomas (non-serrated)
Size is variable – range from a few mm to several cm (10 cm or more)
Present 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 (size is the most important characteristic that correlates with risk of malignancy overall in the patient)
Presence of high grade dysplasia increases risk of malignant transformation in that polyp but not in the rest of the colon
Adenomatous Changes
- 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
Adenoma to cancer progression
APC mutations, beta-catenin (also APC), KRAS mut, loss of p53 and/or SMAD 2 and 4
Risk factors for colorectal cancer
High-risk: Age Country of birth FAP/HNPCC Long-standing ulcerative colitis
Moderate-risk:
HIgh-red mean diet
previous denoma or cancer
pelvic irradiation
Mild risk: High fat diet smoking and alcohol Obesity Cholecystectomy
Protective factors for colorectal cancer
Exercise
NSAID use
High-fiber diet
Main Molecular Pathways for colorectal cancer
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
Also: epigenetic events such as methylation-induced gene silencing…enhances progression along these pathways
The WNT Pathway
APC and beta-catenin are part of WNT pathway
Wnt protein ligands are critical for development
Animals lacking Wnt homologs fail to develop entire organs. The fly homolog of human wnt-1 is wingless
Wnt ligands drive proliferation of their target tissues/organs
The Wnt pathway regulates the levels of cytoplasmic beta-catenin
Without WNT signaling: Phosphorylated beta-catenin is ubiquitylated and degraded in proteasome
With WNT signaling: unphosphorylated beta-catenin accumulates, migrates to nucleus, and displaces groucho causing transcription of WNT-responsive genes
Adenoma formation
There is no increase in the rate of cell proliferation in
the early stage of polyp formation.
Polyps represent an increase in the size of the proliferating crypt compartment
FAP: Familial Adenometous Polyposis
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
Colon Carcinoma: Symptoms / Presentation
Early Colon Carcinoma: No symptoms most often Nonspecific findings Fatigue Weight loss Anemia
Advancing 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
cetuximab
Monoclonal antibody against EGFR
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
Definition of carcinoma and what adenomas are at risk
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
Staging of colorectal cancer
TNM
T: tumor size and degree of invasion
N: Lymph node involvement
M: metastasis
Most important prognostic factors
Depth of invasion
Presence or absence of lymph node metastasis
Distant metastasis
Most common location of metastasis of colorectal cancer
liver
Therapy for colorectal 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
Sporadic colon cancer: pathway involved, target molecule, and histology
APC/WNT pathway (80%)
APC target molecule
Histology: Tubular, villous; typical adenocarcinoma
DNA mismatch repair (10-15%)
Target genes: MSH2, MLH1
Histology: Sessile serrated adenoma; mucinous adenocarcinoma
Familial Adenomatous Polyposis: pathway involved, target molecule, and histology
APC/WNT pathway (70%)
Target gene: APC
HIstology: Tubular, villous; typical adenocarcinoma
DNA mismatch repair (
Hereditary Nonpolyposis Colorectal Cancer
(HNPCC) / Lynch Syndrome: mechanism, target molecule, and histology
DNA mismatch repair
Target genes: MSH2, MLH1
Histology: Sessile serrated adenoma; mucinous adenocarcinoma
