Colorectal Cancer

Nam Deuk Kim, Ph.D.

Pusan National University

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Contents

• What are the colon & rectum?

• Colorectal Cancer?

• Risk factor

• Symptom

• Screening tests

• Diagnosis

• Stages of colorectal cancer

• Treatment

• Treatment by stage

• Treatment method

• Reference

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What are the colon and rectum ?

• They are located in the

abdomen between the small

intestine and the anus.

• The colon have two major

functions.

• The colon absorbs water and

minerals from food and

transports them into the

bloodstream.

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Colon Cancer?

• Approximately 5% of Americans develop this cancer during their lifetime.

• The 4th incidence rate in Korean after stomach, lung, and liver cancers.

• Although the widely used term colorectal implies a common biology, the differences

between cancers of the colon and rectum seem to be more fundamental than simple

location. For instance, whereas colon cancer is much more common in the United

States than in Japan, the incidence of rectal cancer in the two populations is nearly

the same.

• Colon carcinoma may occur anywhere in the large intestine- from the cecal valve to

the rectum.

• However, the majority of colon cancers appear to occur in the right (ascending)

colon.

• Colon cancers shows a slight female preponderance, whereas rectal cancer is

somewhat more common in men.

• In 85% of cases of colorectal carcinoma, it has been estimated that at least 8 to 10

mutational events must accumulate before an invasive cancer with metastatic

potential develops. 4

2011.9.3. 조선일보

InfoGraphics

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What is risk factor of colorectal cancer ?

1. Age: colon cancer can strike at any age. More than 9 in 10 new cases are in people aged 50 or older.

2. Gender: colon cancer affects both men and women: however, men are slightly more likely to develop colon cancer and die of the disease.

3. Race: African Americans are more likely to be diagnosed with colon cancer at later stage and more likely to die from the disease.

4. Personal history of disease : A personal history of colon cancer intestinal polyps.

• Personal history of colorectal cancer

• Personal history of polyps

• Family history

• Personal history of ovarian, endometrial, or breast cancer

5. Sedentary lifestyle, Diet, & Obesity

6. Inflammatory Bowel Disease (IBD):

diseases such as chronic ulcerative

colitis, Crohn’s disease.

7. Hereditary Syndromes [familial

adenomatous polyposis (FAP)]

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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

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• consumption of red meat

• animal and saturated fat

• refined carbohydrates

• alcohol

• increased risk by:

Dietary factors implicated in

colorectal carcinogenesis

Dietary factors implicated in

colorectal carcinogenesis

• dietary fiber

• vegetables

• fruits

• antioxidant vitamins

• calcium

• folate (Vitamin B12)

• decreased risk by:

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Family History

가족성 선종 용종증

(Familial adenomatous

polyposis)

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Molecular Genetics of Colorectal Cancer APC gene: As noted above, germline mutations in APC (adenomatous polyposis

coli), a putative tumor-suppressor gene, lead to familial adenomatous polyposis.

In most sporadic colorectal cancers, the same gene is mutated. Some tumors with

normal APC have mutations in the β-catenin gene (its product binds to the APC

protein). APC mutations are seen in normal colonic mucosa preceding

development of sporadic adenomas. These data suggest an important role for

APC in the early development of most colorectal neoplasms.

Ras oncogene: Activating mutations of the ras protooncogene occur early in

tubular adenomas of the colon.

DCC gene: A putative tumor-suppressor gene, DCC (“deleted in colon cancer”)

is located on chromosome 18 and is often missing in colorectal cancers.

p53 tumor-suppressor gene: In the most common type of adenocarcinoma of

the colon, mutation of p53 participates in the transition from adenoma to

carcinoma and is a late event in the carcinogenic pathway.

Mismatch repair associated genes: In 15% of colorectal cancers, DNA repair is

impaired, leading to deficient correction of spontaneous replication errors,

particularly in simple repetitive sequences (microsatellites).

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Schematic of the morphologic and molecular changes in the adenoma-carcinoma sequence. It is

postulated that loss of one normal copy of the tumor suppressor gatekeeper gene APC occurs

early. Indeed, individuals may be born with one mutant allele of APC, rendering them extremely

likely to develop colon cancer. This is the "first hit," according to Knudson's hypothesis. The loss

of the normal copy of the APC gene follows ("second hit"). Mutations of the oncogene K-RAS

seem to occur next. Additional mutations or losses of heterozygosity inactivate the tumor

suppressor gene p53 (on chromosome 17p) and SMAD2 and SMAD4 on chromosome 18q, leading

finally to the emergence of carcinoma, in which additional mutations occur. It is important to

note that while there seems to be a temporal sequence of changes, as shown, the accumulation of

mutations, rather than their occurrence in a specific order, is more important. 11

Typical sites of incidence and symptoms of colon cancer

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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.

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Multiple adenomatous polyps of the

cecum are seen here in a case of

familial polyposis.

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.

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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.

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.

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Adenocarcinoma of the colon.

A. A resected colon shows an

ulcerated mass with enlarged,

firm, rolled borders.

B. Microscopically, this colon

adenocarcinoma consists of

moderately differentiated glands

with a prominent cribriform

pattern and frequent central

necrosis.

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What is the symptom of colorectal cancer ?

• Initially, colorectal cancer is clinically silent.

•A change in bowel habits

• Diarrhea or constipation

• Feeling that the bowel does not empty completely

• Vomiting, blood in the stool

- occult blood in the feces from cancer in the proximal portions of the colon

- bright red blood: cancer in the distal colorectum

• Abdominal discomfort (e.g., gas, bloating, cramps)

• Constant tiredness

• Unexplained anemia (e.g., iron-deficiency anemia)

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Diagnosis

• Colonoscopy. In this procedure a long flexible tube is inserted through the

rectum into the colon, and the whole inner lining of the colon is examined.

Small pieces of abnormal areas are removed and looked at under the

microscope.

• A barium enema may be done. In this procedure barium is inserted into the

rectum and x-ray pictures are taken.

• Computerized tomographic (CT) scan. This is a special kind of x-ray that

produces detailed pictures of the inner aspects of the body.

• Magnetic Imaging scans (MRI) or PET scans. These special tests may

sometimes be done to obtain detailed pictures of the body.

• Blood tests are done including blood count, kidney and liver function tests. A

special blood test called a CEA level may be done, as this is sometimes

increased in people with colorectal cancer.

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Screening tests for colorectal cancer

1. Fecal Occult Blood Test

Special cards are coated with a stool sample and returned to the physician

or lab. This test examines a patient's solid waste (stool) for occult (hidden)

blood. Studies show that a fecal occult blood test performed every 1 or 2

years in people between the ages of 50-80 years decreases the number of

deaths due to colorectal cancer. 20

2. Sigmoidoscopy

Sigmoidoscopy is an examination in which a doctor uses a thin, flexible tube

with a light to look inside the rectum and colon for polyps, tumors, or

abnormal areas. Studies suggest that fewer people may die of colorectal

cancer if they have regular screening by sigmoidoscopy after the age of 50

years.

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3. Digital Rectal Examination

A digital rectal examination is performed during an office visit or prior to

sigmoidoscopy or colonoscopy. For this examination, the doctor or nurse inserts a

lubricated gloved finger into the rectum and feels for lumps or abnormal areas. The

evidence available does not suggest that digital rectal examination is effective in

decreasing mortality from colorectal cancer.

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4. Barium Enema

Barium enema is a procedure in which a liquid containing barium is

put into the rectum and colon by way of the anus. Barium is a silver-

white metallic compound that helps to show the image of the lower

gastrointestinal tract on an x-ray. Barium enema may be effective in

detecting large polyps. 23

5. Colonoscopy

Colonoscopy is an examination of the inside of the colon and rectum

using a thin, lighted tube (called a colonoscope) inserted into the rectum.

If the doctor sees polyps or other abnormal tissue during the procedure,

they can be removed and further examined under a microscope. Studies

suggest that colonoscopy is a more effective screening method than

barium enema.

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Study: Virtual colonoscopy as good as optical colonoscopy

(CNN, October 18, 2006)

"Virtual" colonoscopies done using a computer-assisted X-ray are nearly as

accurate as the standard kind and may entice reluctant patients into having the embarrassing procedure, U.S. researchers say.

The first study into results of virtual colonoscopies paid for by insurance showed that only 6.4 percent of patients required follow-up with optical colonoscopy, which involves threading a tiny camera on a tube through the rectum and into the colon.

"Our positive experience with virtual colonoscopy screening covered by health insurance demonstrates its enormous potential for increasing compliance for colorectal cancer prevention and screening," said Dr. Perry Pickhardt of the University of Wisconsin Medical School in Madison.

Pickhardt's team used three-dimensional computed tomography colonography, commonly known as virtual colonoscopy, to screen 1,110 adults with an average age of 58. The virtual procedure is noninvasive and involves passing the patient through a scanning machine.

They found large or medium polyps in 10 percent of the patients. Seventy-one, or 6.4 percent, of the patients had a second, standard colonoscopy, most on the same day.

The standard colonoscopy findings were the same as the virtual colonoscopy findings in 65 of the 71 patients, the researchers reported in the journal Radiology.

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• CT, MR, & MRI

Transition of colon

cancer into liver

Red color is colon

cancer

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• Simple chest X-ray

metastasis cancer

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• Anal rectum ultrasonic wave

• Other tests Computer scaning

CTAP, PEP

Black color is

colon cancer and

transition

Colon cancer

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Stages of cancer of the colon

• Stage 0 Stage 0 cancer of the colon is very early cancer. The

cancer is found only in the innermost lining of the colon.

• Stage I ( Duke A)

The cancer has spread beyond the innermost lining of the

colon to the second and third layers and involves the inside

wall of the colon, but has not spread to the outer wall of the

colon or outside the colon.

• Stage II ( Duke B)

Cancer has spread outside the colon to nearby tissue, but it has

not gone into the lymph nodes. (Lymph nodes are small, bean-

shaped structures that are found throughout the body. They

produce and store cells that fight infection.)

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Cancer has spread to nearby lymph nodes, but it has not

spread to other parts of the body.

• Stage III (Duke C)

• Stage IV ( Duke D)

Cancer has spread to other parts of the body.

• Recurrent Recurrent cancer of the colon is often found in the

liver and/or lungs.

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Staging of CRC

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%

Dukes staging system

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Sites of metastasis

Liver

Lung

Brain

Bones

Via blood

Lymph nodes Abdominal wall

Nerves

Vessels

Via lymphatics Per continuitatem

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Treatment • Some treatments are standard

(currently used treatment), and some are being tested in clinical trials.

• Before starting treatment, patients may want to think about taking part in a clinical trial.

• A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer.

• When clinical trials show that a new treatment is better than the "standard" treatment, the new treatment may become the standard treatment.

• 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.

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Treatment by stage • Stage 0 Colon Cancer

Treatment of stage 0 (carcinoma in situ) may include the

following types of surgery:

• Local excision (surgery to remove the tumor without cutting through

the abdominal wall) or simple polypectomy (surgery to remove the

cancer from a small bulging piece of tissue).

• Resection/anastomosis (surgery to remove the cancer and join the cut

ends of the colon). This is done when the cancerous tissue is too large

to remove by local excision.

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• Stage I Colon Cancer

Treatment of stage I colon cancer is usually the following:

• Resection/anastomosis (surgery to remove the cancer

and join the cut ends of the colon).

• Standard treatment options: Wide surgical resection and

anastomosis.

• Stage II Colon Cancer

Treatment of stage II colon cancer may include the following:

• Resection/anastomosis (surgery to remove the cancer and

join the cut ends of the colon).

• Clinical trials of chemotherapy, radiation therapy, or

biological therapy after surgery.

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• Stage III Colon Cancer

Treatment of stage III colon cancer may include the following:

• Resection/anastomosis (surgery to remove the cancer and

join the cut ends of the colon) with chemotherapy.

• Clinical trials of chemotherapy, radiation therapy,

and/orbiological therapy after surgery.

• Stage IV Colon Cancer

Treatment of stage IV colon cancer may include the following:

• Resection/anastomosis (surgery to remove the cancer and join

the cut ends of the colon or to bypass the tumor).

• Surgery to remove parts of other organs such as the liver,

lungs, and ovaries where the cancer may have spread.

• Clinical trials of chemotherapy or biological therapy.

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• Recurrent Colon Cancer

Treatment of recurrent colon cancer depends on where the cancer

has recurred (come back) and the general health of the patient.

Treatment for recurrent colon cancer may include the following:

• Surgery to remove cancer that may have spread to the liver, lungs, or

ovaries.

• Surgery to remove cancer cells that have recurred (come back) in the colon.

• Radiation therapy as palliative therapy (to relieve symptoms , 완화치료요법).

• Chemotherapy as palliative therapy (to relieve symptoms).

• Clinical trials of biological therapy or chemotherapy.

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Treatment method

• Surgery

• Local excision: If the cancer is found at a very early stage, the

doctor may remove it without cutting through the abdominal wall.

Instead, the doctor may put a tube through the rectum into the colon

and cut the cancer out. This is called a local excision. If the cancer

is found in a polyp (a small bulging piece of tissue), the operation

is called a polypectomy

Surgery (removing the cancer in an operation) is the most common

treatment for all stages of colon cancer. A doctor may remove the

cancer using one of the following types of surgery:

• Resection: If the cancer is larger, the doctor will perform

colectomy (removing the cancer and a small amount of healthy tissue

around it). The doctor may then perform an anastomosis (sewing the healthy

parts of the colon together). The doctor will also usually remove lymph nodes

near the colon and examine them under a microscope to see whether they

contain cancer. 39

• Chemotherapy

• Chemotherapy is the use of drugs to kill

cancer cells. Chemotherapy may be taken by

mouth, or it may be put into the body by

inserting a needle into a vein or muscle.

• Either type of chemotherapy is called systemic treatment

because the drugs enter the bloodstream, travel through the body,

and can kill cancer cells throughout the body.

• Common drugs for chemotherapy: 5-FU, Leucovorin, 5-FU is

given in combination with leucovorin

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Node-Positive colon cancer survival rates

The graph shows the survival rate of 4.768 patients 65 years of age

and older with node-positive colon cancer. Approximately half

recived surgery; the other half surgery and 5-FU. The surgery and 5-

Fu group did significantly better.

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• Radiation therapy

• Radiation therapy is the use of x-ray or other types of radiation to kill

cancer cells and shrink tumors.

• Radiation therapy may use external radiation (using a machine outside the

body) or internal radiation.

• Internal radiation involves putting radioisotopes (materials that produce

radiation) through thin plastic tubes into the area where cancer cells are

found. Colon cancer may be treated with external radiation.

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• Biological therapy

• Biological therapy is treatment to stimulate the

ability of the immune system to fight against

cancer.

• Substances made by the body or made in a

laboratory are used to boost, direct, or restore

the body's natural defenses against disease.

• Biological therapy is sometimes called biological

response modifier (BRM) therapy or immunotherapy.

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References

Essentials of Rubin’s Pathology by E. Rubin and H.M.

Reisner, Lippincott Williams & Wilkins, 2009

www. Mayoclinic.com

www. Cancer.gov

www. Cancerbacup.org.uk

www. Koreacancer.com

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