Colorectal Carcinoma: An Overview

Introduction to Colorectal Carcinoma

• Colorectal carcinoma (CRC) makes up over 90% of malignant colorectal neoplasms.
• CRC is among the most common malignant tumors and leading causes of cancer deaths worldwide.

Epidemiology of CRC

• The incidence of CRC varies depending on geographical location.
• The highest rates are in North America, Australia, New Zealand, and Northern and Western Europe.
• Japan has a low rate despite a high standard of living.
• In the US, CRC is second only to lung cancer as a cause of cancer deaths.
• CRC is slightly more common in males.
• Women tend to have higher rates of right-sided neoplasms and develop CRC at an earlier age.
• Germ-line genetic abnormalities, like FAP and HNPCC, often lead to CRC at a younger age; the youngest living patient was diagnosed at 9 months old.

Aetiopathogenesis and Risk Factors

• CRC is rare before age 40; incidence increases steadily to age 50 and doubles with each subsequent decade, peaking at 75.
• It's estimated that 1 in 20 North Americans will develop CRC by age 75, with sporadic cases occurring over 50 years of age.
• Approximate percentages diagnosed at certain ages:
  • 1% between 20-34 years
  • 3.6% between 35-44 years
  • 11.1% between 45-54 years
  • 17.8% between 55-64 years
  • 25.7% between 65-74 years
  • 28.6% between 75-84 years

Diet and CRC

• Low fiber diets can lead to slower transit of fecal contents through the colon, increasing the risk of CRC.
• High animal fat intake increases endogenous production, bacterial degradation, and excretion of bile acids and natural steroids, which are carcinogens.
• Excess lipid increases the concentration of secondary bile acids, which then stimulate protein kinase C.
• Vegetables, fruits, and exogenous antioxidants are considered protective against CRC.

Familial Factors and CRC

• Family history is an important factor in patients younger than 50 years.
• Relatives of patients with CRC have an increased risk.
• Genetic factors play a significant role in at least 20% of CRC cases.
• About 5-10% of CRC cases are inherited as autosomal dominant traits.
• A history of cancer at other sites can factor into the risk of CRC.

Inflammatory Bowel Disease and Schistosomiasis

• The risk of CRC in ulcerative colitis (UC) is associated with the duration of active disease, the extent of colitis, the emergence of mucosal dysplasia, and the continuity of noticeable symptoms.
  • 3% in first decade
  • 20% in second decade
  • 30% in third decade
• An association exists between chronic schistosomiasis and CRC, especially in endemic areas.
• All species of schistosomiasis are related to CRC.
• Chronic inflammation may lead to dysplasia, then progressing to carcinoma.

Other Factors

• A history of prior colorectal cancer is a risk factor.
• Other factors include:
  • pelvic radiation for gynecologic cancer,
  • low parity or no pregnancies,
  • sedentary occupations,
  • previous blood transfusions.

Colorectal Carcinogenesis

• Most colorectal carcinomas occur sporadically.
• The majority develop from pre-existing adenomas.
• Adenomas are considered precursors to CRC, which establishes the adenoma-carcinoma sequence in the colorectum.

Adenoma-Carcinoma Sequence

• Adenomas and carcinomas share a similar distribution.
• CRC and adenoma can frequently coexist in the same lesion.
• There's a correlation between the frequencies of CRC and adenoma across countries.
• Similar anatomical distribution is seen for both adenomas and CRC.
• There is an increased frequency of carcinomas in patients with adenomas.
• Adenomas occur with increased frequency in colons that contain carcinoma.
• With increasing age, there are increasing degrees of atypia and areas of invasive cancer observed.
• Residual adenomas can be found in some patients with carcinoma.
• Both adenomas and carcinomas can be produced in laboratory animals.
• Endoscopic removal of adenomas can reduce the expected incidence of carcinoma by 85%.
• All patients with familial adenomatous polyposis (FAP) will develop cancer if the adenoma-bearing colon is not removed.
• There is an absence of carcinoma in situ outside the area of adenoma.
• Areas of direct transition between adenoma and carcinoma are identifiable.
• Patients who refuse therapy after adenomas are found endoscopically might eventually develop invasive carcinoma at the same site.
• The chromosomal constitution in adenomatous and carcinomatous conditions is similar.
• Similar oncogenes can be identified in some adenomas and carcinomas.
• The DNA content of benign adenomas is intermediate between a normal colon and cancerous tissues.
• The peak incidence of adenomas occurs some years before that of CRC.
• The risk of CRC is directly proportional to the number and size of adenomas.
• Programs that target and remove adenomas reduce the incidence of CRC.

Molecular Carcinogenesis

• Histologic progression of CRC involves alterations in key genes and their protein products, including oncogenes, tumor suppressor genes, and DNA mismatch repair (MMR) genes.
• Specific genes mutate at specific times during neoplastic progression to colon cancer.
• The accumulation of a critical number of genetic alterations, rather than their specific order, determines neoplasm appearance.
• Three pathways involved in CRC development:
  • Chromosomal instability pathway (similar to FAP)
  • Microsatellite instability pathway (similar to HNPCC)
  • Epigenetic or methylator pathway

Chromosomal Instability Pathway

• CRCs arise through multistep progression in the adenoma-carcinoma sequence.
• In 85% of cases, a minimum of 8 to 10 mutational events accumulate before invasive cancer develops with metastatic potential.
• Progression occurs from normal mucosa through an adenomatous precursor to invasive adenocarcinoma.
• The following genes are involved: - APC gene: Germline mutations responsible for FAP; sporadic CRC also harbors mutation in APC, playing an important role in early development of colorectal neoplasm. - K-ras oncogene (12p): Mutational activation occurs early in tubular adenomas of the colon. - DCC gene: Deleted in colon cancer, 18q, missing in CRC. - MCC gene: Mutated in colon cancer, 5q. - p53 gene: Mutation in p53 participates in the transition from adenoma to carcinoma and is therefore a late event.

Microsatellite Instability Pathway

• MMR genes act in concert with other genes to remove mismatches, stabilize the DNA strand, and resynthesize a new DNA strand.
• This process is essential for stabilizing the genome.
• At least 6 different human MMR genes exist: MLH1, MSH2, MSH3, MSH6, PMS1, and PMS2.
• Defective DNA mismatch repair seen in HNPCC is usually associated with alteration in MLH1 and MSH2 genes.
• Microsatellite instability is found in 15% of CRC cases.

Screening Methods

• CRC is attractive for screening strategies.
• Individuals are divided into high-risk and average-risk groups.
• High-risk groups include individuals with:
  • FAP
  • HNPCC
  • UC
  • Positive family history (i.e., first-degree relatives)
• Available screening methods include:
  • Fecal occult blood testing
  • Digital rectal examination: A substantive number of colorectal carcinomas are within reach via examining finger.
  • Rigid and flexible sigmoidoscopy
  • Barium enema, including air contrast barium enema
  • Colonoscopy, CT colonoscopy
• The age at onset of screening and the frequency of screening are determined by the risk of CRC.

Morphology of Colorectal Carcinoma

• Gross appearance: Ulcerating and/or stenosing tumors occur in about 75% of cases (usually left-sided), while fungating tumors occur in about 25% (frequently right-sided).
• Histology: Approximately 90% are adenocarcinomas.
• Mucinous adenocarcinoma is characterized by a large amount of extracellular mucin.
• In signet ring cell carcinoma, the cells contain a large quantity of intracellular mucin, more common in young females.
• The signet ring cell variant often presents when the disease is advanced (stage III & IV) and has a poor prognosis.

Modes of Spread

• Direct extension
• Lymphatic spread
• Venous invasion
• CRCs may also present as periumbilical nodules (Sister Mary Joseph nodules).

Staging

• Three main staging systems:
  • Duke’s
  • Astler-Coller’s
  • TNM/AJCC.
• Duke's Staging:
  • Stage A: Tumor does not grow beyond the muscularis propria.
  • Stage B: Tumor grows beyond the muscularis propria.
  • Stage C: Lymph node metastases with the tumor.
  • Stage D (added by Turnbull): Distant metastases.
• Astler-Coller's Staging:
  • A: Tumor confined to the mucosa.
  • B1: Through the muscularis mucosae but not through the muscularis propria.
  • B2: Beyond the muscularis propria to involve the serosa.
  • C1: B1 with regional lymph node metastases.
  • C2: B2 with regional lymph node metastases.
  • D: Distant metastases.

Clinical Presentation

• Symptoms depend on the anatomical region involved:
  • Left-sided cancers: Constipation alternating with diarrhea, decrease in stool caliber (pencil stool), abdominal pain, and obstructive symptoms.
  • Right-sided cancers: Vague abdominal pain (unlike colicky pains in obstructive left-sided lesions), palpable abdominal mass, anemia from chronic blood loss.
  • Rectal cancers: Change in bowel movement, rectal fullness, urgency, rectal bleeding, tenesmus.

Prognosis

• Prognosis is predicted significantly by the pathologic stage rather than the size of the tumor.
• Other factors include histologic grade, histologic type (mucinous, small cell carcinoma, and signet ring cell carcinomas demonstrate worse prognosis than adenocarcinoma), tumor location, gross growth pattern, 18q loss, and preoperative level of carcinoembryonic antigen (CEA).

Hereditary Nonpolyposis Colon Cancer

• This is an autosomal dominant familial syndrome (Lynch syndrome).
• It results from mutations in DNA repair genes, resulting in microsatellite instability.
• It is characterized by an increased risk of CRC, particularly in the cecum and proximal colon, along with extraintestinal cancer (mainly endometrium and ovary).
• Colonic malignancies are usually multiple and not usually associated with pre-existing adenomas.