1. Colorectal Cancer (CRC)
Epidemiology, Risk Factors
Symptoms, Stages, Therapy
3) Molecular Biology & Pathology
Screening

2. EPIDEMIOLOGY one of the most common cancers in the world
US: 4th most common cancer (after lung, prostate, and breast cancers)
2nd most common cause of cancer death (after lung cancer)
2001: 130,000 new cases of CRC ,500 deaths caused by CRC

3. Typical sites of incidence and sympoms of colon cancer

4. Colon cancers result from a series of pathologic changes that transform normal colonic
epithelium into invasive carcinoma. Specific genetic events, shown by vertical arrows,
accompany this multistep process. The various chemopreventive agents exert their
effects at different steps in this pathway, and this is depicted on the basis of the
available epidemiologic evidence, the results of studies in animals, and the known
mechanisms of action of the agents.

6. Risk factors for CRC Age Adenomas, Polyps
Sedentary lifestyle, Diet, Obesity
Family History of CRC
Inflammatory Bowel Disease (IBD)
Hereditary Syndromes
(familial adenomatous polyposis (FAP))

7. Development of CRC result of interplay between environmental and
genetic factors
Central environmental factors:
diet and lifestyle
35% of all cancers are attributable to diet
50%-75% of CRC in the US may be preventable
through dietary modifications

8. Dietary factors implicated in colorectal carcinogenesis
consumption of red meat
animal and saturated fat
refined carbohydrates
alcohol
increased risk

9. Dietary factors implicated in colorectal carcinogenesis
dietary fiber
vegetables
fruits
antioxidant vitamins
calcium
folate (B Vitamin)
decreased risk

12. There is a solitary mass attached via a long stalk to the colonic mucosa. It is discreet and does not involve the wall of the colon. The surface is dark red (hemorrhagic). The stool guaiac was positive.

14. Multiple adenomatous polyps of the cecum are seen here in a case of
familial polyposis.

15. This is familial polyposis in which the mucosal surface of the colon is essentially
a carpet of small adenomatous polyps. Of course, even though they are small
now, there is a 100% risk over time for development of adenocarcinoma, so a
total colectomy is done, generally before age 20.

16. An encircling adenocarcinoma of the rectosigmoid region is seen here
An encircling adenocarcinoma of the rectosigmoid region is seen here. There is a heaped up margin of tumor at each side with a central area of ulceration. This produces the bleeding that allows detection through a stool guaiac test. Normal mucosa appears at the right. The tumor encircles the colon and infiltrates into the wall. Staging is based upon the degree of invasion into and through the wall.

17. This is an adenocarcinoma of the cecum which demonstrates an exophytic growth pattern, as the bulk of the mass is within the bowel lumen. The patient had iron deficiency anemia.

19. The barium enema techniqu
instills the radiopaque barium
sulfate into the colon, producing
a contrast with the wall of the colon
that highlights any masses present.
In this case, the classic "apple core”
lesion is present, representing an
encircling adenocarcinoma that
constricts the lumen.

22. Symptoms associated with CRC
rectal bleeding
change in bowel habits
obstruction
abdominal pain & mass
iron-deficiency anemia
weight loss
loss of appetite
night sweats
fever

23. Staging of CRC TNM system Primary tumor (T) Regional lymph nodes (N)
Distant metastasis (M)
*Note: Tis includes cancer cells confined within the glandular basement membran
e (intraepithelial) or lamina propria (intramucosal) with no extension through the
muscularis mucosae into the submucosa.
**Note: Direct invasion in T4 includes invasion of other segments of the colorectum
by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the
cecum.

24. Staging of CRC Dukes staging system A Mucosa 80%
B Into or through M. propria 50%
C1 Into M. propria, + LN ! 40%
C2 Through M. propria, + LN! 12%
D distant metastatic spread <5%

25. Sites of metastasis Via blood Via lymphatics Per continuitatem Liver
Lung
Brain
Bones
Lymph nodes
Abdominal wall
Nerves
Vessels

26. This is an in-situ photograph of the
chest and abdominal contents. As
can be seen, the liver is the largest
parenchymal organ, lying just below
the diaphragm. The right lobe (at the
left in the photograph) is larger than
The left lobe. The falciform ligament is
the rough dividing line between the
two lobes.

28. The liver is filled with multiple masses of varying size
The liver is filled with multiple masses of varying size. The primary was a colonic adenocarcinoma. Some of the larger metastatic nodules have central necrosis.

29. Therapy Surgical resection the only curative treatment
Likelihood of cure is greater when disease is
detected at early stage
Early detection and screening is of pivotal
importance

30. Screening What is screening? a public health service in which members
of a defined population are examined to
identify those individuals who would benefit
from treatment
to benefit:
to reduce the risk of a disease or its
complications

31. Types of Screening fecal occult blood test (FOBT)
chemical test for blood in a stool sample.
annual screening by FOBT reduces colorectal cancer deaths by 33%
Flexible sigmoidoscopy can detect about 65%–75% of polyps and 40%–65% of colorectal cancers.
rectum and sigmoid colon are visually inspected

32. Current Screening Guidelines
regular screening for all adults aged 50 years or
older is recommended
FOBT every year
flexible sigmoidoscopy every 5 years
total colon examination by colonoscopy
every 10 years or by barium enema every
5–10 years

36. The concept of differentiation is demonstrated by this small adenomatous polyp of the
colon. Note the difference in staining quality between the epithelial cells of the adenoma
at the top and the normal glandular epithelium of the colonic mucosa below.

37. At high magnification, the normal colonic epithelium at the left contrasts with the atypical
epithelium of the adenomatous polyp at the right. Nuclei are darker and more irregularly
sized and closer together in the adenomatous polyp than in the normal mucosa. However, the overall difference between them is not great, so this benign neoplasm
mimics the normal tissue quite well and this, therefore, well-differentiated.

38. This neoplasm is so poorly differentiated that it is difficult to tell
what the cell of origin is. It is probably a carcinoma because
of the polygonal nature of the cells. Note that nucleoli are numerous
and large in this neoplasm. Neoplasms with no differentiation are
said to be anaplastic.

39. A mitotic figure is seen in the center, surrounded by a poorly differentiated squamous cell carcinoma with pleomorphic cells and minimal pink keratinization. In general, mitoses are more likely to be seen in malignant neoplasms. Remember, though, that normally cells are actively dividing in bone marrow, gonads and gastrointestinal tract.

40. This gastric adenocarcinoma is positive for cytokeratin by immunoperoxidase.
This is a typical staining reaction for carcinomas and helps to distinguish carcinoma from sarcomas and lymphomas. Immunoperoxidase staining is helpful to determine the cell type of a neoplasm when the degree of differentiation, or morphology alone, does not allow an exact classification.

41. Changes resulting in colon cancer

42. Molecular Biology & Pathology
CRCs arise from a series of histopathological and
molecular changes that transform normal epithelial cells
Intermediate step is the adenomatous polyp
Adenoma-Carcinoma-Sequence (Vogelstein & Kinzler)
Polyps occur universally in FAP,
but FAP accounts for only 1% of CRCs
Adenomatous Polyps in general population:
33% at age 50
70% at age 70

43. Mutations in the APC pathway cause increased proliferation

44. MMR defects give rise to TGF-beta RII mutations, which prevent
cell cycle inhibitor (p15) and protease inhibitor (PAI-1) expression

45. Cyclooxygenase (COX) cell membrane lipids Phospholipase A2
arachidonic acid (aa)
aspirin
ibuprofen
indomethacin
COX -1 -2
prostaglandins

46. COX and CRC COX-2 not detectable in normal colon but in 90% of
CRCs and 40% of adenomas
Animal models: COX-inhibition results in 50%
reduction of carcinomas and >90% reduction of
adenomas
Epidemiological studies: patients regularly taking
aspirin showed 40-50% reduced risk of CRC
But: minimal effective dose and duration of treatment
have not yet been determined

47. Microenvironment Control mechanisms of mitosis & apotosis lost
High metabolic rates, glycolysis (Warburg),
high lactic acid output
Result: hostile microenvironmental conditions
(Hypoxia, low pH, low glucose,
free oxygen radicals)

48. Hypoxia Central factor for tumor growth and spread
Correlated to tumor hypoxia:
Therapy outcome & probablility of metastasis
Hypoxia exerts selective pressure
genetic instability results in survival of cells
better adapted to lack of oxygen
Evolution of highly aggressive tumor cells

50. CRC and the Internet
“Sign up to receive an
message reminding you to have
your colon screened at

51. CRC is a leading cause of death Early stages are detectable
Summary
CRC is a leading cause of death
Early stages are detectable
Screening can prevent CRC
Katie Couric: