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131 Cards in this Set
- Front
- Back
What percent of the GI is the small intestine? What percent of tumors occur here?
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- SI is 75% of length
- But only 3-6% of tumors are here |
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What are the most common tumors in the small intestine? Others?
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- Most common: Adenoma (near ampulla)
- Others: carcinoid and adenocarcinoma have equal incidence - Rare: mesenchymal tumors, lipoma, GIST, lymphoma |
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What does this specimen show?
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Tumors in small intestine by the Ampulla of Vader (cause back up of bile and pancreatic juices)
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What are the risk factors for SI Adencarcinoma?
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- Crohn’s disease
- Adenomas - Celiac disease - Familial polyposis syndrome |
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What is the most common non-epithelial (soft tissue) tumor in the GI tract?
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Gastrointestinal Stromal Tumor (GIST)
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What is the origin of the tissues in Gastrointestinal Stromal Tumor (GIST)?
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Mesenchymal origin, derived from interstitial cells of Cajal (pacemaker cells)
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What is Gastrointestinal Stromal Tumor (GIST) seen in?
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- Carney triad
- Neurofibromatosis (no KIT or PDGFRA mutation) - Carney-Stratakis syndrome (succinate dehydrogenase) |
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What drug is clinically useful in Gastrointestinal Stromal Tumor (GIST)?
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Gleevac (Imatinib)
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What kind of tumor is this?
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Gastrointestinal Stromal Tumor (GIST)
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What are the most common locations of Gastrointestinal Stromal Tumors (GIST)?
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- Stomach (60%)
- Small intestine (30%) - Colon (4%) |
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What mutations are common in Gastrointestinal Stromal Tumor (GIST)?
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- C-Kit mutations (80%)
- PDGFRA mutations (5-10%) |
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What are the immunohistochemical identifications of Gastrointestinal Stromal Tumor (GIST)?
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- CD117 (C-Kit) - positive in 90-100% of cases
- DOG1 - specific marker - CD34 - positive in 85-95% of cases - Muscle markers - actin (25%), desmin (10%), and S-100 (5%) |
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What are the microscopic identifications of Gastrointestinal Stromal Tumor (GIST)?
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- Cells are EPITHELIOID
- More pleomorphic and with deeply acidophilic cytoplasm - Features of smooth muscle differentiation (at immunohistochemical level - see markers of actin, desmin, and S-100) |
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What are the immunohistochemical signs that are diagnostic for Gastrointestinal Stromal Tumor (GIST)?
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- Few cells show c-KIT immunoreactivity, rendering a
diagnosis of gastrointestinal stromal tumor not that secure. - Extensive positive staining for DOG1 supports the diagnosis |
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What kind of genes are c-kit (CD117) and PDGFRA?
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Cell surface receptors - Tyrosine Kinase types
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What kind of tumor is a Carcinoid Tumor? What does that mean?
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Neuroendocrine tumor:
- Secretes bioactive compounds (biogenic amines) - Elevated serotonin (5-HT) |
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What are the signs of Carcinoid Syndrome?
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- Vasomotor disturbances
- Intestinal hypermotility - Wheezing - Hepatomegaly - Cardiac involvement |
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How does a Carcinoid Tumor present?
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Submucosal nodule
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What does this slide show?
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Submucosal Nodule - this is how Carcinoid Tumors present
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What do you see in MALT Lymphoma in the small intestine?
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Colonization of the germinal centers by the tumor cells
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What is the term for an epithelium-derived tumor mass which protrudes into the gut lumen?
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Polyp
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What is a polyp? What are the types?
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- Epithelium-derived tumor mass which protrudes into the gut lumen
- Pedunculated polyps - Sessile polyps |
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What is a non-neoplastic polyp the result of? Prognosis?
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Abnormal mucosal maturation, inflammation, distorted architecture - no malignant potential
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What is a neoplastic polyp the result of? Prognosis?
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Arises as a result of proliferation and dysplasia (adenomas) - precursors of carcinoma
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What is this?
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Pedunculated, Tubular Polyp
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What is this?
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Sessile, Villous Polyp
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What kind of polyps are the result of abnormal mucosal maturation, inflammation, and distorted architecture? Types? Malignant potential?
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Non-neoplastic polyps:
- Hamartomatous - Inflammatory - Lymphoid No malignant potential |
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Hamartoma:
- Benign or malignant - Structure - Characteristics - Cause - Location |
- Benign tumors
- Focal, mass of tissue resembling a tumor, pedunculated, 1-3 cm - Composed of mature, histologically normal elements from a site that grow in a disorganized manner - Due to developmental errors - Occur in many sites (80% in rectum) |
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What kind of polyp is composed of mature, histologically normal elements that grow in a disorganized manner?
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Hamartomas
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What are the types of / syndromes with Hamartomatous Polyps?
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- Juvenile Polyposis Syndrome
- Peutz-Jeghers Syndrome - Cowden Syndrome - Cronkhite-Canada |
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What is the cause of Hamartomas? Who gets them?
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- Due to developmental error
- Juvenile: kids <5 years |
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What is the most common location of Hamartomatous polyps? Appearance / size?
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- 80% occur in rectum
- Pedunculated, 1-3cm (this is large by polyp standards) |
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What happens to the components of the mucosa in Hamartomatous Polyps?
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- Expanded lamina propria with variable inflammation
- Lamina propria constitutes bulk of polyp - Abundant, cystically dilated, tortuous glands |
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What are the criteria of Juvenile Polyposis Syndrome? How is it inherited?
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- Multiple juvenile hamartomatous polyps (>5, 50-100)
- Found in stomach, small intestine, colon, and/or rectum - Increased risk of adenomas, 10-50% lifetime incidence of colon cancer, also gastric, small intestine, and pancreas - Autosomal dominant |
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How is Juvenile Polyposis Syndrome inherited? What genes are abnormal? What are these patients at increased risk for?
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Autosomal dominant:
- SMAD4 (20%) - BMPR1A (20%) - PTEN (0%) Increased risk of adenomas - 10-50% lifetime incidence of colon cancer - Also gastric, small intestine, and pancreas |
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What are the criteria of Peutz-Jeghers Syndrome? How is it inherited?
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- Multiple Hamartomatous GI Peutz-Jeghers polyps (non-malignant)
- Hyperpigmentation: mucosal (mouth) and cutaneous (fingers) - Large and pedunculated polyps containing CT and smooth muscle as well as abundant glands rich in Goblet cells - Autosomal dominant: STK11 |
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How is Peutz-Jeghers Syndrome inherited? What genes are abnormal? What are these patients at increased risk for?
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Autosomal dominant:
- STK11 Increased risk of: - Intussusception (inversion of one portion of the intestine within another) - Cancer of pancreas, breast, lung, ovary, and uterus (50% lifetime risk of all types of cancer) |
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What are the characteristics of Cowden Syndrome? How is it inherited?
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- Hamartomatous GI polyps (non-malignant)
- Facial trichilemmomas, oral papillomas, acral keratoses - Autosomal dominant |
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How is Cowden Syndrome inherited? What genes are abnormal? What are these patients at increased risk for?
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Autsomal dominant
Increased risk of: - Thyroid and breast cancer |
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What are the characteristics of Cronkhite-Canada? How is it inherited?
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- GI hamartomatous polyps
- Ectodermal abnormalities (nail atrophy, alopecia) - Non-hereditary |
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What are the other non-neoplastic polyps?
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- Inflammatory polyps (pseudopolyps)
- Lymphoid polyps |
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What are the characteristics of inflammatory polyps?
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- Non-neoplastic
- Pseudopolyps - regenerating mucosa adjacent to ulceration (severe IBD) |
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What are the characteristics of lymphoid polyps?
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- Non-neoplastic
- Mucosal bumps - Caused by intramucosal lymphoid follicles - normal |
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What are the types of Serrated Polyps?
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- Hyperplastic Polyps
- Sessile Serrated Polyps |
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What are the smooth protrusions of mucosa usually at the tops of mucosal folds?
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Serrated Polyps
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What is the most common location of Serrated Polyps?
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Over half are found in the rectosigmoid colon
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What is the histological appearance of Serrated Polyps?
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Serrated lumina with increased numbers of goblet cells
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What is the size of Serrated Polyps?
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Very small - less than 5 mm in diameter
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What kind of polyp is this? Location? Malignant potential?
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Hyperplastic Serrated Polyp
- 60-90% of serrated polyps - Distal colon - No malignant potential |
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What kind of polyp is this? Location? Malignant potential?
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Sessile Serrated Polyp
- 10-30% of serrated polyps - Proximal colon - High malignant potential |
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What kind of mutations are seen in Serrated Polyps?
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- Hyperplastic: none discussed
- Sessile Serrated: BRAF V600E mutations |
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What is the progression of polyps to cancer?
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Benign
1. Starts as hyper-proliferation 2. Grows into small and large adenomatous polyps 3. Leads to severe dysplasia (pre-cancerous polyp) Malignant 4. Continues to grow into adenocarcinoma 5. Cancer progresses deep into tissues |
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What do Adenomatous Polyps (Adenomas) arise from?
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As a result of epithelial proliferative dysplasia
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What can Adenomatous Polyps progress to?
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Precursor lesion for adenocarcinoma (4x greater risk if you have adenomatous polyps)
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How common are Adenomatous Polyps? Who is at greatest risk?
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- Common: 40-50% after age 60 (20-30% before age 40)
- 4x greater risk if you have 1st degree relative with adenomas - 4x greater risk of carcinoma if you have adenoma - M = F |
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What are the types of Adenomatous Polyps?
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1. Tubular Adenoma
2. Villous Adenoma 3. Tubulovillous Adenoma |
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What is the morphological appearance of Tubular Adenomas? Location?
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- Tubular glands
- Often small, pedunculated - Can be single or multiple - Rarely >2.5 cm - Dysplastic epithelium - elongated, pseudostratified, hyperchromatic nuclei, w/ loss of mucin production - 90% found in colon |
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What is the morphological appearance of Villous Adenomas? Location?
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- Villous projections
- Often large and sessile - Up to 10 cm in diameter - Most common in older people in rectosigmoid colon |
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When invasive carcinoma is present, what is the appearance of the Villous Adenoma? Where does invasion occur?
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- When invasive carcinoma is present, there is no stalk to act as a buffer zone
- Cancer invasion occurs directly into the colon wall |
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When is the cancer risk rare in Adenomas?
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Tubular Adenomas < 1 cm
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When is the cancer risk increased in Adenomas?
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- 40% in patients with sessile, villous adenomas > 4cm
- High grade dysplasia is often found in the villous area - High grade dysplasia or carcinoma can be found in any polyp |
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What are the symptoms of Adenomatous Polyps?
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- May be asymptomatic
- May present with rectal bleeding or anemia |
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Where does intramucousal carcinoma invade? Metastatic potential?
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Invades lamina propria - no metastatic potential
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Where does invasive carcinoma in a pedunculated adenoma invade? Metastatic potential?
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- Invades through muscularis mucosa
- Metastatic potential |
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How should you treat an invasive carcinoma in a pedunculated adenoma?
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Endoscopic removal adequate if:
- Resection margins negative - No vascular or lymphatic invasion - Carcinoma is not poorly differentiated |
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How should you treat an invasive carcinoma in a sessile polyp?
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Polypectomy inadequate, requires partial colectomy
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How should you treat Adenomatous Polyps?
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- Regardless of whether carcinoma is present, the ONLY ADEQUATE TREATMENT is COMPLETE RESECTION
- If adenomatous epithelium remains int he patient, there is potential for carcinoma |
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What is the most common type of Colorectal Cancer?
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98% Adenocarcinoma (99% occur singly)
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What is the prognosis of Colorectal Cancer? When is the peak incidence? Who is at increased risk?
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- 9% of all cancer deaths in US
- 90% diagnosed at age 50+ - 1-3% occur in familial syndromes or IBD |
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What are the potential locations of Colorectal Cancer? How common in each location?
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- Rectosigmoid colon (55%)
- Cecum and ascending colon (22%) - Transverse colon (11%) - Descending colon (6%) |
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Where are the highest death rates from Colorectal Cancer?
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- US
- Australia - New Zealand - Eastern Europe |
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What are the lifestyle risk factors for Colorectal Carcinoma?
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Dietary practices:
- Excess dietary caloric intake - Low fiber - High content of refined carbohydrates - Red meat - Decreased intake of micronutrients Obesity and physical inactivity |
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What are the clinical implications of right-sided Colon Cancer?
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- Non-obstructive
- Fatigue, weakness - Iron deficiency anemia - Polypoid, exophytic lesions |
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What are the clinical implications of left-sided Colon Cancer?
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- May be obstructive
- Occult bleeding - Changes in bowel habits - Abdominal discomfort - Annular "napkin ring" constrictions - Tend to be more infiltrative |
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Colorectal carcinoma on what side is more severe, may be obstructive, and tends to be more infiltrative?
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Left-sided lesions
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What is the most common clinical presentation of colorectal cancer?
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- Asymptomatic for years w/ insidious onset
- Iron deficiency anemia in an older male signifies colon cancer unless proven otherwise |
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If you have an older male that is presenting with iron deficiency anemia, what do you suspect?
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Colon cancer until proven otherwise
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How do adenomas relate to colorectal cancer?
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- Populations with a high prevalence of adenomas have a high prevalence of colorectal cancer, and vice versa
- Similar distribution of polyps and cancer in the colorectum - Peak age for adenomas precedes peak age for cancer - When cancer is identified at an early age, surrounding adenomatous tissue is often present - Cancer risk directly related to number of adenomas - Removal of polyps decreases cancer incidence |
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How can you decrease your risk of colorectal cancer?
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Remove any adenomatous polyps
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What can pretty much guarantee your development of colorectal cancer?
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FAP Syndrome: Familial Adenomatous Polyposis
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What is the molecular understanding of the adenoma-carcinoma relationship?
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- Multi-hit hypothesis
- Accumulation of mutations is more important that the specific order of mutations |
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What molecular findings are associated with the adenoma-carcinoma pathway?
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- >80% of colon cancers have inactivated APC
- 50% of cancers w/ APC mutations have β-catenin mutations (10% overall) - Loss of p53 occurs late in colon carcinogenesis |
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What are the implications of inactivated APC gene?
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Dysfunction of APC leads to:
- Increased WNT signaling - Decreased cell adhesion - Increased cellular proliferation >80% of colon cancers have inactivated APC |
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What genetic change occurs late in colon carcinogenesis?
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Loss of p53
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What pattern of Colorectal Cancer is associated with Ulcerative Colitis?
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Infiltrative Colorectal Cancer:
- Insidiously infiltrative - Difficult to identify grossly - Exceedingly aggressive - Spreads at early stage in evolution |
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How can you grade the depth of invasion of Colorectal Cancer?
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- T(in situ / IS) = just in mucosa
- T1 = invaded into submuocsa - T2 = invaded into muscularis propria - T3 = invaded through serosa - T4 = invades other organs or structures |
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How can you grade the lymph node involvement of Colorectal Cancer?
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- N0 = no LN metastasis
- N1 = metastasis in 1-3 LNs - N2 = metastasis in 4+ LNs |
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How can you grade the metastasis of Colorectal Cancer?
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- M0 = no distant metastasis
- M1 = distant metastasis |
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What does a Stage 0 colon carcinoma indicate?
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In situ carcinoma (tumor has not spread past the mucosa)
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What does a Stage 1 colon carcinoma indicate?
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- Tumor may have spread through submucosa (T1) or through muscularis propria (T2)
- No spread to lymph nodes or metastatic sites |
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What does a Stage 2 colon carcinoma indicate?
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- Tumor may have spread through serosa (T3) or into adjacent structures/organs (T4)
- No spread to lymph nodes or metastatic sites |
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What does a Stage 3 colon carcinoma indicate?
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- Tumor may have spread through any layer of the colon wall
- SPREAD TO LYMPH NODES - No distant metastasis |
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What does a Stage 4 colon carcinoma indicate?
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- Tumor may have spread through any layer of the colon wall
- Tumor may have spread to any number of lymph nodes - DISTANT METASTASES |
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What is the most important prognostic indicator of colorectal carcinoma?
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Extent of the tumor (stage) at the time of diagnosis
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What is the prognosis for the different stages of Colorectal Cancer?
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5-year survival:
- Stage 1: 93% - Stage 2: 85% - Stage 3: 70% - spread to lymph nodes - Stage 4: 8% - distant metastasis |
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Where can Colon Cancer metastasize to?
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- Direct extension into adjacent structures
- Spread to lymph nodes and vessels - Goes to regional lymph nodes, liver, lungs, and bones |
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How common is metastatic spread of colon carcinoma upon presentation? Implications?
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25-30% have metastasis (Stage 4) which indicates an 8% 5-year survival
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What are the most common sites of metastasis of colon cancer?
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- Liver
- Lungs - Bones |
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What can we use to figure out the best therapy for a tumor and the prognosis of the cancer?
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Prognostic and Predictive Biomarker Assessment (look at molecular features of tumor)
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What is the utility of analyzing biomarkers on tumors?
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Helps determine prognosis and best treatment (surgery, surgery + chemo, or best supportive care)
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What are the traditional agents for treating Colorectal Cancer? Characteristics?
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- 5FU / LV
- Capecitabine - Irinotecan - Oxaliplatin - These cause all cells to die not just tumor cells; lots of side effects |
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What are the targeted agents for treating Colorectal Cancer? Characteristics?
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- Bevacizumab
- Cetuximab - Panitumumab - These only harm tumor cells, thus have a lot less side effects |
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What are the kinds of biomarkers used to guide adjuvant therapy for colorectal cancer? Functions?
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- Prognostic biomarkers - provide information about the patient's overall outcome, regardless of therapy (will it be more or less severe?)
- Predictive biomarkers - provide information about the effects of a particular therapeutic intervention (helps us figure out what drug to use) |
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What gene is important in Colorectal cancer?
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EGFR (ErbB1 / Her1)
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Activation of EGFR (ErbB1 / Her1) gene leads to what?
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Stimulates key processes involved in tumor growth and progression:
- Proliferation - Angiogenesis - Invasion - Metastasis |
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What 3 major pathways are activated when EGFR (ErbB1 / Her1) is activated?
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- RAS-RAF-MAP kinase
- PI3K-AKT - PLCγ |
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What is the structure of EGFR (ErbB1 / Her1)?
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Transmembrane receptor with:
- Ligand binding domain (extracellular) - Transmembrane domain - Tyrosine kinase domain (intracellular) |
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What drugs are being used to target EGFR (ErbB1 / Her1) = anti-EGFR?
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- Cetuximab
- Panitumumab |
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What percent of Colorectal Cancer cases benefit from EGFR monoclonal Ab therapy (cetuximab and panitumumab)?
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- Only 10-20% of cases benefit
- Patients who do not respond have mutations in signaling pathway further down (thus blocking the EGFR receptor does nothing) |
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What is the major negative predictor of efficacy in EGFR monoclonal Ab therapy? What other mutation correlates with poor prognosis and lack of response?
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- KRAS mutation = major negative predictor
- BRAF mutation = poor prognosis and lack of response |
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What are the hereditary syndromes involving the GI tract?
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- Peutz-Jeghers, Cowden disease, and Juvenile polyposis
- Familial adenomatous polyposis (Gardner's syndrome and Turcot's syndrome) - MYH Associated Polyposis (MAP) - Lynch Syndrome / HNPCC (hereditary non-polyposis colorectal carcinoma syndrome) |
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How are the hereditary syndromes involving the GI tract inherited?
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Usually autosomal dominant
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Familial Adenomatous Polyposis:
- Inheritance pattern - Number of lesions - Presence of adenocarcinoma - Treatment - Other |
- Autosomal dominant
- Typically 500-2500 colonic adenomas (minimum of 100) - Colon adenocarcinoma occurs in ~100% - Treat with prophylactic colectomy |
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What is this syndrome?
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Familial Adenomatous Polyposis:
- Autosomal dominant - Typically 500-2500 colonic adenomas (minimum of 100) - Colon adenocarcinoma occurs in ~100% - Treat with prophylactic colectomy |
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What causes Familial Adenomatous Polyposis?
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- Inheritance (autosomal dominant) of germline mutation in the APC gene
- ~25% of FAP patients have no family history (new mutations in APC gene) - Tumors result when the second normal allele is mutated in a cell during life ("somatic mutation") |
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What is the age of onset of polyps in Familial Adenomatous Polyposis? Onset of colorectal cancer?
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Polyps:
- Median age 16 years - Range 5-38 years - Increasing number are detected with age Colorectal Cancer: - Late 30s, early 40s |
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What are the variants of Familial Adenomatous Polyposis?
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- Attenuated FAP (<100 polyps)
- Gardner's syndrome - Turcot syndrome |
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How does Attenuated Familial Adenomatous Polyposis differ from Classical FAP?
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<100 polyps
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How does Gardner's Syndrome differ from Classical Familial Adenomatous Polyposis?
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- Adenomatous polyposis with osteomas
- Epidermoid cysts - Desmoid tumors |
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How does Turcot Syndrome differ from Classical Familial Adenomatous Polyposis?
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Adenomatous polyposis with medulloblastoma
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MYH Associated Polyposis (MAP):
- Inheritance pattern - Number of lesions - Other |
- Autosomal recessive
- Typically 20-100 adenomatous polyps (can be >100) - Phenotypic overlap with FAP (mostly attenuated FAP), but present at older age than for FAP |
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What causes MYH Associated Polyposis (MAP)?
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- Mutations in MYH gene (1p34.3-p32.1) inherited in autosomal recessive pattern
- MYH protein is important for DNA repair (base excision repair and repairs oxidation induced DNA damage by removing A mis-paired with G) |
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What kind of cancer are patients with Lynch Syndrome at increased risk for?
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- Colorectal Cancer
- Extra-Intestinal Cancer (endometrial cancer in females, also small intestine, ureter, and renal pelvis) |
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What happens in Lynch Syndrome / Hereditary Non-Polyposis Colorectal Cancer?
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- Adenomas occur considerably earlier than in the normal population, but in low numbers
- Increased risk of colorectal cancer and extra-intestinal cancer (endometrial cancer in females, small intestine, ureter, and renal pelvis cancer too) - Colonic carcinomas are often multiple and not necessarily associated with the adenomas |
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What is the cause of Lynch Syndrome / Hereditary Non-Polyposis Colorectal Cancer?
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Genetic defect involves DNA mismatch repair genes (microsatellite instability pathway)
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How long does it take an adenoma to progress to carcinoma in Lynch Syndrome / Hereditary Non-Polyposis Colorectal Cancer? Normally?
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- Lynch syndrome: accelerated to 2-3 years
- Sporadic CRC: 8-10 years |
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How common is Lynch Syndrome in Colorectal Carcinoma patients?
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1 in 35 have Lynch Syndrome
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What is the risk for a second primary cancer in Lynch Syndrome?
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16% in 10 years
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What is the risk for new cancer in first/second degree relative of patient with Lynch syndrome?
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35%-45% by age 70
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What is a variant of Lynch Syndrome?
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Muir-Torre Syndrome - associated with multiple sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas
|
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What is the average age of presentation of the different types of cancer associated with Lynch Syndrome?
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- Colon ~44 years
- Endometrial ~46 years - Stomach ~56 years - Ovarian ~43 years |