Neoplasm of Lower GI

Question 1

State the basic facts about neoplastic polyps, the concept of cytologic dysplasia, and what features confer increased risk for malignancy

Answer 1

• Polyp - sessile vs. pedunculated, neoplastic vs non-neoplastic
• Adenoma (precursor to malignancy)
• Adenocarcinoma (invasive)
• Hyperplastic polyps are considered non-neoplastic
• Dysplastic polyps (esp. high grade dysplasia) are considered neoplastic or pre-malignant. May be considered carcinoma in situ
• Morphologic and molecular changes (ie: step-wise mutation process) may convert adenomas into adenocarcinoma

•Size of polyp matters (size is the most important characteristic that correlates with risk of malignancy overall in the patient)

Question 2

List the four main molecular/pathway aberrations associated with colon cancer

Answer 2

• WNT/APC/Beta-catenin pathway
• KRAS—MAP Kinase pathway
• KRAS—PI3 Kinase pathway
• Microsatellite instability (MSI)—result of defect in mismatch repair

Question 3

State the important risk factors for colorectal carcinoma

Answer 3

• Advanced age
• Obesity
• FAP/HNPCC
• Long-standing ulcerative colitis
• Excessive alcohol
• Smoking

Question 4

Explain the basis for the hereditary cancer syndromes of FAP and HNPCC

Answer 4

FAP= familial adenomatous polyposis (the name says it all–inherited syndrome characterized by early and numerous adenomas (polyps)

• Autosomal dominant mutation in the APC gene
• APC= adenomatous polyposis coli (again the name is descriptive—adenomatous polyps in the colon—named for the discovery of this gene as the cause of FAP)
• APC is a component of the WNT signaling pathway, part of the “destruction complex” that turns over Beta-catenin in the absence of WNT ligand signaling (see figure below)
• A mutation in APC results in constitutive activity of B-catenin in the colonic crypt, which in turn results in polyp formation
• WNT/B-catenin should be shut off when cells reach the top of the crypt in order for colonic villus cells to differentiate; if it does not, cells continue to proliferate, exhibit undifferentiated progenitor phenotype= adenoma (see figure below)
• Eventually, 100% of these will go on to develop adenocarcinomas
• Recall from Dr. Kaplan’s lecture that APC/WNT mutations have also been observed in stomach cancer (gastric adenocarcinomas)

Question 5

Describe the various ways colorectal carcinoma can present an the tools we use to screen and diagnose cancer

Answer 5

Presentation:
Early colon carcinoma
•usually asymptomatic
•non-specific: fatigue; weight loss; anemia

Advanced CRC (fairly straightforward and logical)
•changes in bowel habits; constipation
•blood loss; anemia; blood in stool or bleeding from rectum
•cramping, abdominal pain
•unexplained weight loss

Screening and Diagnostic Tools:
•visual—colonoscopy—best (seeing is believing!) May or may not include biopsy
•barium enema
•occult blood stool detection
•stool tumor cell/mutation detection

Question 6

Describe the importance of KRAS mutational status in the treatment of colon cancer with EGFR inhibitors

Answer 6

• KRAS (Kirsten isoform of RAS; pronounced K-RAS) is a key signaling molecule (GTPase) downstream of the EGFR tyrosine kinase receptor
• Activating mutations in KRAS are seen in 50-60% of colon cancers
• EGFR inhibitors (ie: cetuximab, gefitinib) are approved for colon cancer but are only effective in KRAS wildtype tumors. This is logical: if KRAS is constitutively activated, and is downstream of EGFR, inhibiting EGFR will have little if any effect.
• Demonstrates the importance of knowledge of molecular pathways in CRC oncogenesis–all CRC patients are now screened for KRAS mutations to best guide therapy

Question 7

What are the important histological and prognostic features of colorectal carcinoma?

Answer 7

• Invasion of dysplastic epithelial cells into and beyond the lamina propria
• Recall that dysplasia describes carcinoma in situ

•Adenomas at risk (size matters—rule of thumb: the bigger the tumor the greater likelihood of distant metastases)
4 cm: high risk (~40% in one study) of identification of invasive component within lesion

Question 8

Describe the staging and grading of colorectal carcinoma

Answer 8

• TNM grading helps determine Stage
• T stands for Tumor; numerical value based on size and degree of invasiveness into muscularis and/or surrounding organs (a bit subjective by pathologist)
• N stands for Node; number of lymph nodes involved

•M stands for Metastasis; binary, 0 or 1 patient either has them or not (non-detectable)—automatically places patient in Stage IV;
NOTE #1: we don’t count the number of metastases. Positive lymph nodes are not considered metastases (for reasons I don’t fully understand!)