Flashcards in 25. Tumors of the Small and Large Bowel Deck (123):
Though the small intestine makes up 75% the length of the GI tract, what % of the tumors are found there?
What is the most common tumor of the SI?
Adenoma near the ampulla
What are four RFs for small intestine adenocarcinoma?
Familial polyposis syndrome
What is the most common non-epithelial tumor in the GI tract? What is it derived from?
Mesenchymal origin, from interstitial cells of Cajal (pacemaker cells)
What are three syndromes associated with GIST?
1. Carney triad: GIST, pulmonary chondroma, extra-adrenal paragnaglioma
3. Carney-Stratakis syndrome
What can be used to treate GIST and CML?
Where is GIST most commonly located?
What % of GIST tumors have a c-kit mutation?
What are three specific markers for GIST?
What are three muscle markers that can be used for GIST but are not necessarily specific?
What two tyrosine kinase receptors can get mutated in GIST, and in what region of the receptor?
C-kit: juxtamembrane domain
PDGFRA: tyrosine kinase II domain
What are neuroendocrine tumors of the GI that secrete bioactive compounds?
What are components of carcinoid syndrome?
Intestinal hypermotility (diarrhea)
What condition can lead to MALT lymphoma?
H. pylori gastritis
What is a polyp?
Epithelium-derived tumor mass which protrudes into the gut lumen
What are the two main types of polyp by shape?
A non-neoplastic polyp is a result of:
Abnomal mucosal maturation, inflammation, architectural distortion
**no malignant potential
Neoplastic polyps arise from:
Proliferation and dysplasia (adenomas)
**precursor for carcinoma
What are the three main types of non-neoplastic polyps?
What is a hamartoma?
Benign tumor that is composed of mature, histologically normal elements that grow in a disorganized manner due to developmental error
What is a choistoma?
Like a hamartoma, but in an abnormal location
Where do 80% of juvenile, hamartomatous polyps occur? Shape?
Pedunculated (1-3 cm)
Histologic appearance of juvenile, hamartomatous polyps
Expanded lamina propria with variable inflammation
Abundant cystically dilated and tortuous glands
What is Juvenile polyposis syndrome?
Over 5 juvenile polyps in the stomach, SI, colon, rectum
What mutations are associated with juvenile polyposis syndrome?
Juvenile polyposis syndrome is associated with risk for:
10-50% lifetime incidence of colon cancer
What mutation is Peutz-Jeghers syndrome associated with (hamartomatous polyps)
What is seen in Peutz-Jeghers syndrome?
Multiple GI hamartomatous polyps
Hyperpigmentation--mucosal and cutaneous (fingers)
What is there an increased risk for with Peutz-Jeghers syndrome?
Cancer of the pancreas, breast, lung, ovary, uterus (50% cumulative lifetime risk for cancer)
What are the characteristics of Peutz-Jeghers Polyp?
Large and pedunculated
Connective tissue and smooth muscle extends into the polyp
Abundant glands rich in goblet cells
What is Cowden syndrome?
AD condition with:
- Hamatomatous GI polyps
- Facial trichilemmomas
- Oral papillomas
- Acral keratoses
What is Cowden syndrome associated with a risk for?
Thyroid and breast cancer
**polyps themselves have no malignant potential
What is Cronkhite Canada syndrome?
Non-herediatry syndrome with
- GI hamartomatous polyps
- Nail atrophy and alopecia (ectodermal abnormalities)
What are inflammatory polyps?
Psuedopolyps that form from regenerating mucosa adjacent to ulceration (usually with severe IBD)
What are lymphoid follicles?
Mucosal bumps that are caused by intramucosal lymphoid follicles (normal)
What are the two serrated polyps?
What are the two types of polyps with malignant potential?
Hyperplastic and sessile serrated polyps
Sessile serrated polyps and adenomatous polyps
What are serrated polyps?
Smooth protrusions of mucosa, usually at the tops of mucosal folds
Serrated lumnia and increased numbers of goblet cells
Where are most serrated polyps found?
What is the prevelance of the two types of serrated polyps?
Hyperplastic 60-90% (MC)
Sessile serrated 10-30%
What kind of mutation is associated with sessile serrated polyps?
BRAF V600E mutations
What do adenomas/adenomatous polyps arise from?
Arise from epithelial proliferative dysplasia
Precursor lesions for adenocarcinoma
What are the three architectural types of adenomas/adenomatous polyps?
Prevalence of adenomas?
With adenomas, __fold greater risk for developing carcinoma
Common, 40-50% after 60
Morphology and location of tubular adenomas
Small and pedunculated from dysplastic epithelium (elongated, psuedostratified, hyperchromatic nuclei with loss of mucin production)
90% in the colon
Morphology and location of villous adenoma?
Villous projections that are large and sessile
Retrosignoid colon of older people
Why does invasion occur more readily with villous adneoma than tubular?
No stalk to act as a buffer zone--cancer invasion occurs directly into the colon wall, lymphatics
While cancer is rare in TAs under 1 cm, the risk of cancer approaches __% in sessile, villous adenomas over 4 cm
Clinical presentation of adenomatous polyps
Present with rectal bleeding or anemia
When is endoscopic removal of pendunculated adenomatous polyps sufficient?
- Resection margins negative
- No vascular or lymphatic invasion
- Carcinoma not poorly differentiated
Colon and rectum cancer is the ___ deadliest cancer
98% of colorectal cancer is what type?
Where are the most common locations for colorectal cancer?
Rectosigmoid colon (55%)
Cecum and ascending colon (22%)
Transverse colon (11%)
Descending colon (6%)
In what geographic locations are the highest death rates from colorectal cancer?
**linked to diet
What dietary practices are risk factors for colorectal carcinoma?
Excess dietary intake
High content of refined carbs
Decreased intake of nicronutrients
Obesity and physical inactivity
Presentation of right sided colon cancer? Type of lesions?
Fatigue, weakenss, IDA
**Polypoid, exophytic lesions
Presentation of left sided colon cancer? Type of lesions?
Occult bleeding, changes in BMs, abdominal discomfort
Annular "napkin ring" constrictions
What classic presentation is colon cancer until proven otherwise?
IDA in a older male
What is the idea behind the 'adenoma-carcinoma sequence'?
Populations with a high prevalence of adenomas have a high prevalence of colon cancer, and vice versa
Distribution of the two is similar
What is typically the first mutation to occur in the multi-hit devo of adenoma-carcinoma?
Inactivating mutation in APC (5q11)
**also beta catenin
What is the result of dysfunction of APC?
Increased WNT signaling, which leads to decreased cell adhesion and increased cell proliferation
What mutation occurs late in the multi-hit development of adeomas and carcinoma?
Loss of p53
Along with p53, APC, and beta catenin, what are other mutations involved in the development of colorectal cancer?
SMAD2 and 4
When colorectal cancer is insidiously infiltrative and difficult to identify grossly, what is this usually associated with?
What does that T of TMN classification represent?
Depth of invasion
What are the T stages of the TMN classification?
Tis: In situ (LP invasion)
T1: Invasion of submucosa
T2: Invasion of muscularis propria
T3: Penetration of muscularis propria into serosa
T4: Invasion into other structures/organs
What are stages 0-IV of colon carcinoma
Stage 0: in situ
Stage I: T1 or T2, N0, M0
Stage II: T3 or T4, N0, M0
Stage III: Any T, + nodes, M0
Stage IV: Any T, any N, M1
What is the difference between N1 and N2 in stage III?
N1: 1-3 positive LNs
N2: 4 or more positive LNs
What is the most important prognostic factor for colorectal carcinoma?
Stage of the tumor at the time of diagnosis
What is the 5 yr survival for stage I, II, III, IV?
What are the different ways the colon carcinoma can metastasize?
What % of patients have mets at the time of dx?
- Direct extension into adjacent structures
- Met through LNs and vessels
What are the four non-specific agents that can be used for colorectal carcinoma (more SEs)
What are the three drugs that can be used for targeted therapy of colorectal cancer (picked based on the mutation prolife of the cancer present)
What are the two types of biomarkers with respect to their function?
Prognostic: info about the patient's overall outcome, regardless of therapy
Predictive: info about the effects of a particular therapeutic intervention
What receptor stimulates key processes involved with tumor growth and progression--proliferation, angiogenesis, invasion, and metastasis?
**overexpressed in a range of solid tumors
What 3 major pathways are activated by EGFR?
1. RAS-RAF-MAP kinase
What are the three domains of EGFR?
Intracellular domain (tyrosine kinase)
What are the 4 subsets of EGFR?
What subset of EGFR is expressed in COLON cancer, lung, and head and neck cancers?
What are the two monoclonal antibodies to EGFR?
It is not the EGFR expression that dictates response to anti-EGFR therapy, but rather:
Constituativly active proteins downstream of EGFR, like K-RAS, B-Raf, PI3K, and PTEN
What is the major negative predicator of efficiency of EGFR monocloncal antibody tx (cetuximab and reanitumab)?
K-RAS mutation **
What are the uncommon and autosomal dominant herediatary syndromes that involve the GI tract?
1. Peutz-Jeghers, Cowden disease, Juvenile
2. FAP- Gardner's and Turcot's syndromes
3. MYH associated polyposis (MAP)
4. Lynch syndrome
Inheritance and penetrance of familial adenomatous polyposis
How many colonic adenomas are typically present in FAP?
500-2,500 (minimum of 100)
Tx for FAP?
Prophylactic colectomy, because colon adenocarcinoma occurs in 100%
FAP is due to inheritance of germline mutations in:
APC gene in chrom 5q11
What % of people with FAP have no fam hx (de novo, somatic mutations)
What is the age of onset for FAP?
Range 5-38 years
Colorectal cancer in late 30s early 40s
What is attenuated FAP
Some residual low level of APC resulting in fewer polyps
What is Gardner syndrome?
What is Turcot syndrome?
Where in the chromosome coding for APC are mutation leading to classical FAP? Attenuated? Garner?
Near N terminal
Near C terminal
Between (causes desmoids)
What is a herediatary colorectal cancer syndrome that looks like attenuated FAP (20-100 adenomatous polyps) but is caused by a different mutation (not APC)
MYH associated polyposis (MAP)
Inheritance pattern for MYH associated polyposis. Age of presentation
Older age of presentation
MAP is due to mutations in the MYH gene, which encodes what kind of protein?
DNA repair protein involved in base excision repair (repairs oxidation-induced DNA damage by removing A mis-paired with G)
What are the two common mutations in MYH associated polyposis?
**present in 85-90%
What is lynch syndrome associated with an increased risk for?
Extra-intestinal cancer: endometrial cancer, ureter, renal pelvis)
What is the genetic defect in lynch syndrome?
DNA mismatch repair genes (microsatellite instability pathway)
What is Muir-Torre syndrome?
Subtype of Lynch syndrome
Associated with multiple sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas
What are two histological presentation of Lynch syndrome tumors?
Mucinous features and chronic inflammation
Mucionous faatures and signet ring features
What is the role of MSH2 and MSH6? PMS2 and MLH1
Find the mismatch
Read the mismatch and remove mutant strand
What is the dominant protein in the MSH2/6 relationship?
What happens with a sporadic (12%) or hereditary (3%) loss of mismatch repair (MMR) function?
Random accumulation of mutations during cell divisions
Mutant in important oncogenes/tumor suppressor genes
Further acceleration of tumor devlopment
What is negative IHC with a MSH2 mutation?
What is negative with a MSH6 mutation?
What is negative with a PMS2 mutation?
What is negative with a MLH1 mutation?
Interpretation of a tumor that is + for MSH2, MSH6, MLH1, PMS2
Sporadic cancer, LS unlikely
Interpretation of a tumor that is - for MLH1, PMS2? Etiology?
LS or sporadic caner
MLH1 mutation or MLH1 hypermethylation
Interpretation of a tumor that is - for MSH2 and MSH6? Etiology
Interpretation of a tumor that is - for MSH6? Etiology
Interpretation of a tumor that is - for PMS2? Etiology
What are sensitive markers for defective function of mismatch repair?
Microsatellites: with DNA slippage, MMR should repair the loss of DNA. Failure of system leads to variation in the size of microsatellites
What are the three outcomes of microsatellite testing?
Microsatellite stable (MSS): no markers show MSI
Microsatellite instability-LOW (MSI-L): one marker shows MSI
Microsatellite instability-HIGH (MSI-H): at least 2 markers show MSI
What is the difference in the response of MSI-L vs MSI-H to adjuvant chemo?
MSI-L have better outcomes with adjuvant chemo
MSI-H have better outcomes without adjuvant chemo
What mutation has never been reported in a patient with lynch syndrome, but it present in 68% of patients with MSI CRC that is not related to lynch syndrome?
Do must people with MSI phenotypes and CRC have sporadic mutations or lynch syndrome?
What are the types of cancer that can occur in the anal canal?
Squamous cell carcinoma
What is the MC tumor of the appendix?
Carcinoid (20-39 yrs)
What is a mucocele?
Obstructed appendix containing insipissated mucin (not truely a tumor)
What is a mucinous cystadenoma of the appendix?
Mucus secreting epithelial tumor of the appendix
Where in the appendix are carcinoid tumors found?
At the distal tip