tumors of the small and large bowe

Question 1

epitdemiology of colorectal adenocarcinoma

Answer 1

colorectal adenocarcinoma is the most common malignancy of the GIT, compare to the small bowel where adenocarcinoma is very rare

10% of all cancer deaths
in the west
Demographics- mid age, M>F, Af am>whites, SES, fam history

Dietary- low carbs, red meat, tobacco, alcohol, metabolic syndrome

Heritable cancer syndromes (adenomatous polypposis coli, lynch syndrome)-
IBD- UC and Crohns disease

protective factors-increased physical activity, fruit and veggies, fiber, aspirin and NSAIDs

Question 2

APC/ Wnt? adenoma pathway (85% of colerectal adenocarcinoma)

Answer 2

1. Mutation in the gene, APC at 5 q21 ( adenomatous polyptosis coli). germline mutation of a cancer suppressor gene
2. Methylation abnormalities
3. Protooncogenes mutation (KRAS and TP53)

APC (adenomatous polyposis coli)- a tumor suppressor gene that negatively regulates Beta Catenin (a proto-oncogene). APC normally releases Beta catenin when WNT receptor is activated

Once released, beta catenin enters the cell nucleus and promotes cell proliferation

An APC mutation will result in uncontrolled proliferation

Many colorectal adenocarcinomas without APC mutations, will harbor beta catenin mutations instead

Question 3

RAS genes and the MAPK pathway- colorectal adenocarcinoma

Answer 3

RAS ( a group of proto oncogenes) are important regulators for many growth factor receptors

In the MAPK pathway, a membrane tyrosine kinase receptor will activate the RAS protein, which will activate the downstream pathway

There are 3 RAS genes in humans: HRAS, KRAS, and NRAS

Because RAS is immediately downstream of the initiating event in the pathway, RAS mutations can upregulate the entire pathway

Not many drugs that can target RAS, RAF proteins (BRAF) are downstream but serve a similar role as RAS

Question 4

P53: the guardian of the genome- colerectal adenocarcinoma

Answer 4

When theres a muation in P53, it cant tell the cell to die

P53 is one of the most important tumor suppressor genes

Activation of p53 is poorly understood, due to combination of oncogenic stress and hypoxia

P53 then acts as a transcription factor to activate neoplastic transformation, transient cell cycle arrest (allows DNA repair mechanisms to take effect), Permanent cell cycle arrest (senesence), or Apoptosis (cell death

Question 5

mismatch repair/microsatellite instability/ sessile serrated polyp pathway

Answer 5

MLH1 and MSH2 mutations, –> accumulation of messed up, BraF can also be mutated

Question 6

Microsatellite instability

Answer 6

Microsatellites are tandem repeats of 1 to 6 nucleotides and are found throughout the genome, AKA short tandem repeats, length remains contstant normally, called satellites becasue they separate from bult genomic DNA on centrifugation

Microsatellites occur anywhere in the genome, including coding regions and nn coding regions, they have high mutation rates and contribute to high genetic diversity
Widely used in genetics- Kinship analysis, paternity test and forensics

Question 7

CpG island hypermethylation pathway

Answer 7

the inciting event is hypermethylation of the promotor region of MLH1 resulting in microsatellite instability without mutations in the mismatch repair genes

BRAF mutations (but not Ras and p53) are common in these tumors

A small subset in these groups show hypermethylation without MSI , these tumors tend to contain KRAS mutations but not BRAF or p53

Question 8

Key genetic markers for prognosis

Answer 8

BRAF good, Microsatellite Unstabe- Good prognosis
BRAF good, Microsatellite stable- intermediate
Braf mutant, Microsatellite Unstable- intermediate
Braf mutant, microsatellite stable- Poor prognosis

Question 9

Key genetic markers for treatment (dont need to know a alt)

Answer 9

Targeted EGFR blockade: Panitumumab, cetuximuab
RAS or BRAF mutations poor response to EGFR directed therapies, Bevacizumab directly targets BRAF

MSI tumors poor response to 5FU alone, add oxaliplatin

MSI tumors show high response to antiPDL1 drugs, pembrolizumab, nivolumab

Question 10

Hyperplastic polyp (HP

Answer 10

No malignant potential..yay
sessile lesion (no stalk)
Serrated epithelium that does not extend into the muscularis mucosae
Elongated funnel shaped crypts
90% are in the distal colon and rectum

Asymptomatic

Question 11

Sessile serrated polyp

Answer 11

may progress to CRC (indolent for 10- 15 yrs)
Sessile lesions (no stalk)
Serrated epithelium
Flask or boot shaped crypts (Serrated architecture through full length of crypts)
More common in the proximal colon
Usually no dysplasia (presence of dysplasia, even low grade, is a concerning finding)

Question 12

traditional serrated adenoma

Answer 12

Rare, hyper serrated architecture with ectopic crypt formation, abundant eosinophilic cytoplasm

At least low grade dysplasia by definition (compare to SSP)
Can progress to CRC

Question 13

conventional adenomas

Answer 13

May progress to CRC, classified as tubular tubulovillous, or villous- All show dysplasia (at least low grade by definition, but may contain high grade dysplasia or intramucosal adenocarcinoma)

Pedunculated polyps (have a stalk)
Found in 25% of the screening colonoscopies

High risk…>1 cm, presence of high grade dysplasia, villous component

usually asymptomatic but larger lesions can bleed

Question 14

Prolapse polyps

Answer 14

non neoplastic polyps, do not progress to CRC
Thought to arise from chronic cycles of mucosal injury and healing… solitary rectal ulcer syndrome: impaired of the anorectal sphincter may cause a sharp angle of teh anterior rectal shelf leading to recurrent abrasion and ulceration

Similar appearing polyps may occur throughout the colon

Question 15

Colorectal adenocarcinoma: Clinical symptoms

Answer 15

Anemia, constipation, diarrhea, hematochezia, weight loss, left sided lesions are more likely to cause symptoms of obstruction
Right sided lesions more likely to be asymptomatic

Question 16

Tumor pT stage

Answer 16

Tumor size
Is- epithelim
T1- musculatis tto submucosa
t20 Musculatis propria
T30 subseros
T4- Serosa

Question 17

Node and Metastiasis staging, pN and p M

Answer 17

N0- no nodal mets– N20 more than 3 nodes,

Mx- no distant mets, M10 distaant mets

Question 18

Familail adenomatous polyposis (FAP)

Answer 18

autosomal dominant disorder resulting from germline mutation in the APC gene
APC is a key negative regulator of the WNT signaling pathway

1/4 is denovo
Hundred of colon polyps, 100% of pats will develop CRC before 30 , prophylactic colectomy prevents CRC, but cancer can dev at otehr sites

Question 19

hereditary non polyposis colerectal cancer

Answer 19

Lynch syndrome, caused by germline mutation in mismatch repair genes, most commonly MLH1 or MSH2

Autosomal dominant inheritance
Most common cause of inherited colorectal cancer (2-4% of all colorectal cancer)

Causes multiple sessile serrated polyps

Like APC, pts are also at risk for other neoplasms (endometrioid carcinoma, ovarian carcinoma, ACC, glioblastoma)

Question 20

hamartomas polyps

Answer 20

abnormal growth of normal tissue, generally related to a systemic genetic condition, not a clonal proliferation

Can occur sporadically in the GIT

Can also be part of an inherited syndrome

pts with hamartomatous polyposis syndrome may be at risk for malignant neoplasia

Question 21

juvenile polyp/ juvenile polyposis syndrome

Answer 21

Hamartoma with inflamed edematous lamina propria and dilated epithelial cysts

Juvenile polyposis syndrome: multiple juvenile polyps

most commonly results from a mutation in SMAD4 which is a member of the TGF B1 signaling pathway

Associaions with juvnile polyposis syndrome

Question 22

Peutz Jeghers syndrome

Answer 22

Hamartomatous polyposis with mucocutaneous hyperpigmention

Most common genetic defect is STK 11 ( a tumor suppressor)
AD inheritance, 25% of cases occur denovo

Polyps have characteristic arborizing with bundles of smooth muscle forming the trunk and branches

Sporadic with associated cancers

Question 23

Cowden syndrome (PTEN hamartoma)

Answer 23

Multiple hamartomas of the skin, GIT and other organs, increased risk of breast, thyroid and endometrial cancer

PTEN is a tumor suppressor that encodes a lipid phosphatase which regulates PI3K and AKT signaling ( from Ras)

Colonic hamartomas are stroma rich

There may be overlap with juvenile polyps but less inflammation

Question 24

Cronkhite Canada Syndrome

Answer 24

Rare hamatromatous polyposis, not hereditary, unknown cause

Presentation is multiple hamartomatous polyps of the stomach, small intestine, and large intestine along with mucinous hyperplasia of the mucosa

Protein losing enteropathy, diarrhea, and weight loss

55% mortality

Question 25

Appendiceal neuroendocrine neoplasms aka Carcinoid

Answer 25

Well differentiated, poorly differentiated, very rare in the appendix, SCC, large cell carcinoma

PT with it will differentiated neuroendocrine tumors of the appendix, appendectomy

Neuroendocrine carcinoma has a poor outcome similar to its counter parts elsewhere in the GIT