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.
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.
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.
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.
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 &quot;apple core” lesion is present, representing an encircling adenocarcinoma that constricts the lumen.
*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.
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.
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.
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.
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.
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.
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.
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.
EPIDEMIOLOGY one of the most common cancers in the world US: 4 th most common cancer (after lung, prostate, and breast cancers) 2 nd most common cause of cancer death (after lung cancer) 2001: 130,000 new cases of CRC 56,500 deaths caused by CRC
Typical sites of incidence and sympoms of colon cancer
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))
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 Development of CRC
consumption of red meat animal and saturated fat refined carbohydrates alcohol increased risk Dietary factors implicated in colorectal carcinogenesis
Symptoms associated with CRC weight loss loss of appetite night sweats fever rectal bleeding change in bowel habits obstruction abdominal pain & mass iron-deficiency anemia
TNM system Primary tumor (T) Regional lymph nodes (N) Distant metastasis (M) Staging of CRC
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
Sites of metastasis Liver Lung Brain Bones Via blood Lymph nodes Abdominal wall Nerves Vessels Via lymphatics Per continuitatem
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
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
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 Types of Screening
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 Current Screening Guidelines
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
Mutations in the APC pathway cause increased proliferation
MMR defects give rise to TGF-beta RII mutations, which prevent cell cycle inhibitor (p15) and protease inhibitor (PAI-1) expression
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
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)
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
“ Sign up to receive an e-mail message reminding you to have your colon screened at www.wewantthebestforyou.com ” CRC and the Internet
CRC is a leading cause of death Early stages are detectable Screening can prevent CRC Katie Couric: http://www.nccra.com/about/videos.htm Summary
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