There are four main pathways for the development of colorectal cancer: chromosomal instability, microsatellite instability, hypermethylation, and COX-2 overexpression. The risk factors include age over 40, family history, adenomas, inflammatory bowel disease, and diabetes. Protective factors include long-term aspirin or NSAID use. Symptoms depend on tumor location but may include bleeding, anemia, changes in bowel habits, abdominal pain or discomfort. Diagnostic tests include digital rectal exam, endoscopy, colonoscopy, imaging and blood tests. Treatment involves surgery to remove the tumor along with nearby lymph nodes and metastases if present, as well as chemotherapy, radiation, and biologic therapies.

1. Colorectal cancer
Etiology
1- Chromosomal instability pathway in colon cancer (KRAS), Tumor suppressor genes
(APC, TP53)
• APC gene mutation (loss of cellular adhesion and increased cellular proliferation)
→ KRAS gene mutation (unregulated cellular signaling and cellular proliferation)
→ TP53 and DCC gene mutation
• Most cases of sporadic ColoRectal Carcinoma develop via this pathway.
2- Microsatellite instability pathway in colon cancer (Mutations in mismatch repair genes
(MMR genes, e.g., MLH1 or MSH2)
3- Hypermethylation phenotype pathway in colon cancer
4- COX-2 overexpression
Risk factors
• Age > 40 years
• Family history
• Colorectal adenomas
• Inflammatory bowel disease
• Diabetes mellitus type 2
Protective factors
• Long-term use of aspirin and other NSAIDs
Clinical features
CRC can be asymptomatic, particularly during the early stages.
In General
• Weight loss
• Fever
• Night sweats
• Fatigue
• Abdominal discomfort
Rt-sided colon carcinomas
(Cecum, ascending, Transverse)
• Occult bleeding or melena
• Iron deficiency anemia
(due to chronic bleeding)
• Diarrhea
Lt-sided colon carcinomas (Splenic flexure, descending, sigmoid, or the rectosigmoid junction)
More common because (fecal matter is more liquid in the proximal colon, Lt-sided Ca tend to
obstruct the lumen more than right-sided Ca)
.
• Changes in bowel habits (size, consistency, frequency)
• Blood-streaked stools
• Colicky abdominal pain (due to obstruction)
• Lifestyle
◦ Smoking
◦ Alcohol
• Diet
◦ Obesity
◦ High-fat and low-fiber
adenocarcinoma (95%)

2. Rectal carcinomas (≤ 15 cm from the anal verge)
• Hematochezia
• ↓ Stool caliber (pencil-shaped stool)
• Rectal pain
• Tenesmus
Diagnostics
1- Digital rectal examination
• Distal rectal cancers may be palpable
2- Flexible sigmoidoscopy with or without anoscopy
• hematochezia
• Age < 40 years
3- Complete colonoscopy and biopsy
4- CT colonography & IV or oral contrast
5- Double-contrast barium enema (Apple core lesion)
6- Laboratory studies
• Carcinoembryonic antigen (CEA)
• CBC
Liver Metastases
Treatment
1- Surgery for colorectal cancer
A- Curative surgery
• Surgery of primary tumor
◦Complete resection with clear margins (R0 resection) is associated with the best prognosis.
• Regional lymph node dissection
• Resection of metastases (liver and/or lung metastases
B- Palliative surgery
2- Systemic therapy
A- Chemotherapy regimens
• FOLFOX
• FOLFIRI
• CAPOX
B- Biologics
• Anti-VEGF antibodies (e.g., bevacizumab)
• EGFR antibodies (e.g., cetuximab)
3- Radiation therapy
• Rectal cancer (standard treatment)
• Colon cancer (Not a standard modality because of adverse effects on the small intestine)

3. Typical surgeries for colon cancer
Type of resection Description Indication
Hemicolectomy
Right hemicolectomy
• Resection of part of the distal ileum, the ileocecal valve, cecum,
ascending colon, hepatic flexure, and proximal third of the transverse
colon
• Tumor in the cecum and ascending
colon
Extended right
hemicolectomy
• Right hemicolectomy and resection of the transverse colon
• Tumor near the hepatic flexure or in
the proximal or middle transverse
colon
Left hemicolectomy
• Resection of the distal third of the transverse colon, the splenic flexure,
descending colon, and sigmoid colon
• Tumor in the descending colon
Sigmoid colectomy • Resection of the sigmoid colon • Tumor in the sigmoid colon
Subtotal or total abdominal
colectomy
• Resection of most of or the entire colon
• Multifocal carcinomas
• Underlying colonic disease
Less commonly used techniques
• Extended left hemicolectomy
• Transverse colectomy
• Anterior resection
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