GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 1 of 11
Colon CA and Polyps, Epidemiology of the Colon Carcinoma and Screening
 Epidemiology (old data from year 2000)
o These numbers are from 2000, the numbers aren’t updated each year
o Est. 130,200 new cases diagnosed in 2000
o 56,300 deaths expected for 2000
o 6% lifetime risk of developing CRC (colorectal cancer)
o 2.5% risk of death from CRC
o Second leading cause of cancer-related death in the U.S.
 In both men & women
o 5-year survival rate 62%
o Affects men and women equally
o Higher incidence and mortality in African-American
 Not sure why, probably due to genetics & environmental factors, access
to health care, socio-economic factors
 Colorectal Cancer (CRC)
o Sporadic (average risk) – no family history of CRC → 65-85%
o Positive family history → 10-30%
o Hereditary nonpolyposis colorectal cancer (HNPCC) → 5%
o Familial adenomatous polyposis (FAP) → 1%
o Rare syndromes → <0.1%
 Pathogenesis
o Most CRC arise from adenomatous polyps
 Sequence from adenoma to carcinoma takes 7-12 years
o All adenomas are dysplastic
 Abnormal growth
o 30-50% of adults will develop adenomatous polyp, only a small fraction will
become cancerous
o Roughly 7 to 12 years for normal mucosa to progress to an adenoma and then to
invasive cancer.
o Once cancer develops, an additional 2 years to pass through Duke’s stage A
 Adenomatous polyposis coli gene (APC)
o Region where deletion or mutation causes polyposis
o Exact role of APC gene is unknown, thought to be tumor suppressor gene
o On chromosome 5
 Pathogenesis
o Inactivation of APC allows tumor to grow into adenoma
o Inactivated p53 allows adenoma to progress to dysplasia, then to carcinoma
 Genetic Factors
Gene
Chromosome Sporadic Tumors
Class
Function
with Alterations
K-ras
12
60%
Proto-oncogene
Signal transduction
APC
5
60%
Tumor suppressor
?cell adhesion
DCC
18
70%
Tumor suppressor
?cell adhesion
P53
17
75%
Tumor suppressor
Cell cycle control
hMSH2 2
DNA mismatch repair Maintains DNA replication
hMLH1 3
DNA mismatch repair Maintains DNA replication
o hMSH2 & hMLH1 are involved in hereditary polyposis syndromes
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 2 of 11
 Location of Tumors
o Most of polyps and cancers on left side (about 2/3)
o Proximal colonic lesion
 36% of colon cancer
 34% of adenomatous polyps
o Distal colorectal lesions
 64% of colorectal cancer
 66% adenomatous polyps
 Rectosigmoid Lesions (part of distal colorectal lesions)
 28% of cancers
 5% adenomatous polyps
 Location
o Synchronous Lesions
 2 or more primary tumors separated by normal bowel and not due to
direct extension or metastasis (3-5%)
 All are primary tumors
o Metachronous Lesions
 Nonanastomotic new tumors developing at least 6 months after initial
diagnosis (1%)
 Average about 9 years after diagnosis of original lesion
 Recurrence of old tumor
 Cost-Effectiveness (Cost/Year Life Saved)
o Mandatory motorcycle helmets $2,000
o Colorectal cancer screening
$25,000 (very cost effective)
o Breast cancer screening
$35,000
o Dual airbags in cars
$120,000
o Smoke detectors in homes
$210,000
o School bus seat belts
$1,800,000
 Colorectal Screening Rates are Low (1997 survey of >50,000 adults)
Subjects Reporting FOBT (age >50) Flex Sig (age >50) Mammography (age>40)
Ever Completed
40%
42%
85%
Up to date
20%
30%
71%
o FOBT – fecal occult blood testing
o This table indicates that the screening rate for CRC is poor
 Case 1
o 55 CM presents for CRC screening after hearing about Jay Monahan’s (Katie
Couric’s husband) death from CRC. He is asymptomatic. You review his risks
for CRC.
o What are the risks of CRC?
o What questions do you want to ask him?
o What are the screening modalities available for screening?
 Risk Factors
o Strong risk factors (RR>4.0)
 Advanced age (over 50)
 Country of birth (North America, Northern Europe vs. Asia & Africa)
 Asia has more gastric cancer
 Long-standing ulcerative colitis
o Moderate risk factors (RR 2.1-4.0)
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 3 of 11
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Previous adenoma or colon cancer
High red-meat diet
Pelvis irradiation
 Usually presents 10 yrs after irradiation
o Modest risk factors (RR 1.1-2.0)
 High-fat diet
 Alcohol
 Cigarette smoking
 Obesity
 Tall stature & acromegaly
 Cholecystectomy – due to bile acids in colon (irritating)
 High sucrose consumption
 Inc growth factor
 Risk Factors
o
o
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Risk of colon cancer increases with age
Peaks in 70’s
 Should begin screening at 50
Risk Factors (graph)
o Death rate (by colorectal cancer) of specific countries vs. total fat diet
o Chart shows that countries with a higher fat diet (US, Northern Europe) have a
higher death rate from CRC than countries with a low fat diet (Japan, Singapore)
Risk Factors (graph)
o Table shows that as the fat intake in America has increased since the 1950’s, the
mortality & incidence of colon and breast cancer have also risen
Risk Factors (graph)
o This graph shows that countries with a high daily red meat consumption (US,
New Zealand, Canada) have a higher incidence of colon cancer than countries
with low daily red meat in their diet (Japan, Nigeria)
Case 1
o Additional History
 Weight loss
 A 10-15% weight loss is significant
 Anemia – IDA (iron deficiency anemia)
 Prior History of Gastric or Colon Polyps
 Hx of IBD
 Hx Radiation exposure to abdomen/pelvis
 Family History of Colon polyps or CRC and other malignancy
Genetic Factors
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 4 of 11
o
Family history is important in patients with FAP and HNPCC
 Almost 100% of these patients will develop CRC in their lifetime
 Case 1
o After your interview, you determined that the patient has average risk for CRC.
His physical exam is unremarkable.
o Should the physical exam include DRE?
 You should do a DRE because the patient is over 40, and you want to
check out his prostate
 Testing for blood (hemocult testing) is not good for CRC screening
because it has a high false positive rate
o What lab data or Xrays do you need?
o What is recommendation for screening?
 Hemocult Testing
o Biochemical basis for guiac based fecal occult blood testing
o Alpha guaiaconic acid (phenol) is converted to guaiacum blue (quinine) if blood
is present (turns blue)
o Use peroxidase and hydrogen peroxide to test
 Hemocult Testing
o Performance of the slide guaiac test for fecal occult blood
 For 3 days prior to and during testing, patients should avoid
 Rare red meat
 Peroxidase-containg vegetables & fruits
 Certain medications
o Vitamin C
o Aspirin & NSAIDS
 2 samples of each of 3 consecutive stools should be tested
 High false positives with hemocult test
 Slides should be developed within 4-6 days
 Slides should not be rehydrated prior to developing
 Screening Modalities
o Fecal occult blood test (FOBT) X3 done annually
o Flexible sigmoidoscopy every 5 years
o FOBT + flexible sigmoidoscopy
 FOBT every year
 Flex Sig every 5 years
o Double-contrast barium enema (DCME) every 5 years
o Colonoscopy every 10 years
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 5 of 11
o
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There is no consensus as to which screening tool is the best
 You should go over the options with our patient and let them decide
o Future screening devices?
 Virtual colonoscopy
 More at end of lecture
 Stool DNA
 Test for colon cancer antigen & gene products
Recommendation Guidelines
o The table lists the screening guidelines for the Preventative Services Task Force,
Gastrointestinal Consortium, American College of Gastroenterology, & the
American Cancer Society
o Dr. Hoang said it doesn’t matter which guideline you follow, as long as you are
consistent and stick with the same guideline
Case 1 – Colonoscopy
o Shows pictures of the polyp from case 1
o The pedunculated polyp was resected
Case 1
o Path results revealed a tubullovillous adenoma with focal high-grade dysplasia
involving the stalk, but does not extend to the base
o What are the types of polyps?
o What is his risk of cancer if the polyp was not removed?
o Does he need surgical consultation?
o What do you recommend for surveillance?
Different colon polyp types
o The graph shows the percentage of invasive cancer versus size & type of the
adenoma
o There are 5 different polyp types
 Tubular
 Villotubular
 Villous – highest risk of cancer, risk of cancer goes up with size
 Hyperplastic – benign, won’t become cancer
 Juvenile – benign, won’t become cancer
Types of Colon Polyps
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 6 of 11
 Surveillance Recommendations
 Protective Factors
o There are only weak studies on protective factors of CRC
 Modest protective factors
 High vegetable/fruit diet
 High fiber diet (20-30g)
 High folate/methionine intake
o Takes 15 years to reduce chance of CRC
 High calcium diet (3g a day)
 Postmenopausal hormone replacement therapy
o 20% decreased risk of CRC
 Moderate protective factors
 High protective activity
 Aspirin/NSAIDS
o For patients with FAP, they decrease the number of
polyps
o Main idea of decreasing risk of CRC is to increase the transit time in the colon,
increase the absorption, decrease the contact time, and provide antioxidants
 Case 2
o You are in rural clinic when a 45 HF presents with abdominal cramping,
bloating, and constipation.
o Wt loss of 5 lbs over last 3 months.
o CBC and iron studies consistent with IDA.
o Hemocult + times 3
o She report a Hx of cancer in the family but can’t remember any details.
o What is your next step for evaluation?
 Colonoscopy & barium enema
 Barium Enema
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 7 of 11
o Shows an apple core lesion in the top left hand corner of the image
o Associated with CRC
 Colonoscopy
o 3 different images of different appearances of adenocarcinomas
 Exophytic, polypoid, circumferential (apple core lesion)
 Case 2
o Path results reveals a poorly differentiated invasive adenocarcinoma
o She had a right hemicolectomy.
o Staging of her cancer is complete
 Duke’s Stage C, TNM Stage III
o Post-operative adjuvant chemotherapy
 5-FU and Leucovorin
 Post-op chemo is recommended for Duke Stage C, TNM stage III
 Colon cancer spreads to the liver via the portal system
 Rectal cancer can spread to the lungs because it is not drained by the
portal system (use chemoradiation for therapy)
o Baseline CEA 250
o What is her prognosis?
o What are your recommendations for follow-up?
 Surgical stage & survival in colorectal cancer (don’t have to know specifics)
 Duke Stage (for our own information)
o Carcinoma in situ
 No invasion
 5 year survival = 100%
o Stage A(I)
 Penetrates to the muscularis mucosa, invades the submucosa but extends
no further than the muscularis propria
 5 year survival = 95-100%
o Stage B(II)
 Penetrates muscularis propria and may extend through the serosa into
pericolic fat
 BI – into muscularis
 BII – through serosa
 5 year survival = 80-85%
o Stage C(III)
 Regional lymph node metastasis
 5 year survival = 60-70%
o Stage D(IV)
 Distant mets
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 8 of 11
 5 year survival = 5-10%
 TNM Staging (for our own information)
o Stage 0
 CIS, above muscularis mucosa
o Stage I
 T1 – through muscularis mucosa into submucosa, above muscularis
propria
 T2 – into muscularis propria, above pericolic fat
o Stage II
 T3 – through muscularis propria into subserosa or perirectal tissue
 T4 – through serosa or invasion into adjacent organs & tissure
o Stage III
 Any T, N1 – 1-3 positive regional lymph nodes
 Any T, N2 – 4 or more positive regional lymph nodes
 Any T, N3 – any positive lymph node along a named blood vessel
o Stage IV
 Any M – presence of distant Mets
 Surveillance After CRC Resection
o Stage I – not warrented (>95% are cured)
o Follow-up visits Q 3-6 months for the first 3 yrs then annually
o Include DRE for low anterior resection
o Serum CEA Q3months for first 2 yrs
o Complete Colonoscopy prior to resection or within 2-3 months post-op to “clear”
colon
o Pts with multiple polyps should have colonoscopy 1 yr after resection,
otherwise at 3 yrs, then Q 3-5 yrs
 Have colonoscopy at 1 year, 3 years, & 5 years
o Pts with low anterior resection without radiation therapy, Flexible
Sigmoidoscopy annually for 2 yrs, then colonoscopy at 3 yr
 Case 2
o You obtained some additional family history.
 PGF > Prostate CA
 PGM > Colon CA age?
 PAunt > Colon CA 42yo
 PUncle > Colon CA 48 yo
 Father > Colon CA 56 yo
 MGM > Renal cell CA age?
 MUncle > Stomach CA 55 yo
 Sister > Uterine CA 45 yo
 Other 3 sibs no cancer Hx
 Hereditary Nonpolyposis Colorectal Cancer Syndrome
o Lynch Syndromes – 1 & 2
o Autosomal dominant
o Mutation of DNA mismatch repair genes on chromosomes 2, 3, or 7
o Proximal and multiple lesions are common
o Early onset ~ 40 yo
o Associated with extracolonic cancers (Lynch syndrome 2)
o Genetic testing available
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 9 of 11
o Amsterdam Criteria
 Amsterdam Criteria
o This table shows the clinical criteria for hereditary non-polyposis colon cancer
o Testing for FAP: Protien truncation testing
o Testing for HNPCC: MSI Testing (microsatellite instability)
 Case 3
o 18 CM presents for evaluation of FAP. His brother was recently diagnosed with
FAP. He is 22. His brother tested negative for the FAP gene.
o What is your recommendation?
 Colonoscopy
o Does he need genetic testing?
 No, since his brother tested negative, it is most likely that the patient will
also test negative
o Does he need colectomy?
 Don’t know yet
 Management Guidelines II (for our own information)
 FAP
o Picture of FAP – shows thousands of polyps in the colon
 Barium enema
o Barium enema of FAP
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 10 of 11
 Management Guidelines I
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Perform a total colectomy because 100% of the patients with FAP with
eventually develop CRC (by age 17-20)
Management Guidelines Table (for our own information)
o This is a table that goes over the surgical guidelines for patients with FAP
Extracolonic manifestations of FAP
o Gardner’s syndrome (a variant of FAP)
 Colonic polyposis
 Bone tumors
 Soft tissue tumors
o Frequency 1:8000 to 1:12,000
o No gene mutation to distinquish FAP from Gardner’s
Extracoelomic manifestations of Gardner’s Syndrome
o Picture of the human body and it shows all the areas that can be affected when a
patient has Gardner’s Syndrome
Congenital Hypertrophy of Retinal Pigment Epithelium (CHRPE)
o 90% of the patients with Gardner’s Syndrome get CHRPE
Osteomas & Lipoma/Fibroma
o Shows X-rays of osteomas
o Shows a patient’s back with lipoma & fibromas
Osteoma of Skull and Supernumerary teeth
o Shows 2 x-rays, 1 is an osteoma of the skull, the other shows supernumary teeth
in the mandible
Desmoid Tumor
o Fibromastoid tumor of the mesentery (8-13% patients with Gardner’s Syndrome)
o These patients get huge abdominal masses
Case 4
o 47 CM with pan-ulcerative colitis for 11 years in remission on Asacol. His family
doctor refer him for Colonoscopy. He is asymptomatic currently.
o Does he need a colonoscopy?
 Yes. The patient has prolonged pan-ulcerative colitis for 11 years
GI2 #31
Monday 3/1/04 10am
Dr. Hoang
K. Stancoven for M. Ellsworth
Page 11 of 11
 Surveillance Recommendations
o Same recommendations as page 6
 Surveillance for IBD
o Begin surveillance after 7-10 yrs of pancolitis or 15 yrs if left-sided colitis
o Colonoscopy with Bx every 10 cm, Bx raised or mass lesions
o No dysplasia: Repeat Q2-3 yrs; after 20 yrs of disease, repeat annually
o Indefinite dysplasia: Repeat in 6-12 months
o Recommend colectomy for high-grade dysplasia or dysplasia associated with a
lesion or mass
o Consider colectomy for low-grade dysplasia
o Consider colonoscopy for patients with extensive Crohn’s colitis after 10 yrs of
disease
 American Cancer Society Guidelines for Screening & Surveillance for Early Detection of
Colorectal Polyps & Cancer
o For our own info (not on test)
 Virtual Colonoscopy
o Computer-simulated endoluminal perspective of the air-filled distended colon
 Patient still undergoes the usual preparations as a colonoscopy
o Spiral or Helical CT scan or MRI
o Clinical trials in progress – not widely available
o Sensitivity
 90 % for polyps > 10 mm
 70-80 % for polyps < 10 mm
 55 % for polyps < 5 mm
 Colonoscopy is better to pick up small polyps
o Cost comparable to colonoscopy – no financial advantages
 Virtual Colonoscopy
o Shows 2 images of computer generated virtual colonoscopy
 Virtual Colonoscopy Websites
 www.cs.sunysb.edu/~vislab/animations/colonoscopy
 www.vec.wfubmc.edu/gallery/colon/colon.html