Karsinoma Kolorektal

01Pathophysiology

Colorectal carcinoma arises predominantly through the adenoma-to-carcinoma sequence, a well-characterized stepwise accumulation of genetic mutations that transforms normal colonic epithelium into invasive carcinoma over a period of approximately 10 to 15 years. The initiating event is typically a loss-of-function mutation in the APC tumor suppressor gene (chromosome 5q), which disrupts the regulation of beta-catenin and Wnt signaling, leading to uncontrolled epithelial proliferation. This produces a small adenomatous polyp. Subsequent activating mutations in the KRAS oncogene drive further clonal expansion and dysplasia. Finally, loss of TP53 (chromosome 17p) and deletion of DCC/SMAD4 (chromosome 18q) permit the transition from high-grade dysplasia to frank invasive carcinoma. This pathway accounts for roughly 80% of sporadic colorectal cancers and is the molecular basis of FAP, where patients inherit one defective APC allele and develop hundreds to thousands of polyps by adolescence.
The second major pathway is the microsatellite instability (MSI) pathway, which results from defective DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. When MMR function is lost, repetitive DNA sequences (microsatellites) accumulate uncorrected replication errors, leading to genomic instability and rapid tumor progression. This pathway underlies Lynch syndrome (the most common hereditary colorectal cancer syndrome) and also occurs in roughly 15% of sporadic cases through epigenetic silencing (MLH1 promoter hypermethylation). Tumors arising through this pathway tend to be right-sided, poorly differentiated, mucinous, and paradoxically carry a somewhat better prognosis stage-for-stage compared to microsatellite-stable tumors.
The clinical presentation links directly to anatomy. Right-sided (cecum and ascending colon) tumors grow as large, polypoid, exophytic masses into a wide-caliber lumen. Because the cecal diameter is large and the stool is still liquid, obstruction is uncommon. Instead, these tumors bleed insidiously, producing chronic occult blood loss that manifests as iron deficiency anemia (fatigue, pallor, low MCV, low ferritin) without visible bleeding. This is the classic vignette clue: an older patient presenting with unexplained iron deficiency anemia.
Left-sided (descending and sigmoid colon) tumors tend to be annular, constricting ("napkin-ring") lesions that encircle the lumen. Because the left colon has a smaller diameter and the stool is more formed, these tumors cause obstructive symptoms: change in bowel habits (alternating constipation and diarrhea), decreased stool caliber, colicky pain, and frank hematochezia. Rectal tumors present similarly but with added tenesmus and a feeling of incomplete evacuation.

02Classification and Clinical Manifestation

Polyp Types and Malignant Potential

Remember the rule: malignant potential increases with size greater than 2 cm, villous histology, and degree of dysplasia. Villous adenomas are the highest yield polyp to know. They also classically secrete a protein-rich mucoid fluid that can cause secretory diarrhea with hypokalemia.

Hereditary Colorectal Cancer Syndromes

TNM Staging and Corresponding Dukes Classification

03Diagnostic Workup

The best initial diagnostic test when colorectal carcinoma is suspected (for example, an older patient with iron deficiency anemia, hematochezia, or change in bowel habits) is colonoscopy with biopsy. It serves double duty: it visualizes the entire colon and provides tissue for histopathologic confirmation. It is also the most accurate test (gold standard) because no other modality can both detect and biopsy a lesion in a single procedure.
Do not confuse screening with diagnosis. Screening tests such as FOBT/FIT and stool DNA testing are for asymptomatic average-risk individuals. A positive screening test always requires follow-up colonoscopy. In a patient who is already symptomatic, you skip the screening step and proceed directly to colonoscopy.
Once the diagnosis is confirmed histologically, the next step is staging with CT of the chest, abdomen, and pelvis. This identifies the local extent of disease, lymph node involvement, and the most common sites of distant metastasis: the liver (via portal venous drainage) and the lungs. For rectal cancers, MRI of the pelvis is added because it provides superior soft-tissue resolution to determine the depth of invasion into the rectal wall and involvement of the mesorectal fascia, which directly dictates whether neoadjuvant therapy is needed before surgery.
CEA is one of the most commonly tested concepts. It is drawn at baseline before surgery and followed serially after resection. A rising postoperative CEA is a sentinel marker for recurrence. However, CEA is neither sensitive nor sufficiently reliable to be used as a screening tool. It can also be elevated in smokers, pancreatitis, hepatitis, and other gastrointestinal conditions. The exam will test you on this distinction: CEA is for monitoring, never for diagnosis or screening.
Molecular testing has become increasingly relevant. All colorectal cancers should be tested for MSI status or MMR protein expression. MSI-high or MMR-deficient tumors respond exceptionally well to checkpoint inhibitor immunotherapy (pembrolizumab). For metastatic disease, KRAS/NRAS mutation testing is required before initiating anti-EGFR antibodies because these agents are only effective in RAS wild-type tumors.

04Management and Treatment

Surgical principles. The standard curative operation for colon cancer is a segmental colectomy with removal of the regional lymphatic drainage basin. A minimum of 12 lymph nodes must be harvested and examined to ensure accurate staging. For rectal cancer, the gold-standard operation is total mesorectal excision (TME), which removes the rectum with an intact mesorectal envelope to minimize local recurrence. Tumors of the very low rectum (within 5 cm of the anal verge) that cannot achieve a distal margin of at least 1 to 2 cm typically require an abdominoperineal resection (APR) with a permanent colostomy.
Adjuvant chemotherapy. The decision to give adjuvant chemotherapy hinges on nodal status. Stage III (node-positive) disease receives adjuvant FOLFOX: 5-fluorouracil (bolus and continuous infusion), leucovorin (folinic acid, potentiates 5-FU by stabilizing thymidylate synthase inhibition), and oxaliplatin (platinum agent causing DNA crosslinks). The standard duration is 6 months, though recent evidence supports 3 months of FOLFOX for low-risk Stage III (T1-T3 N1) as noninferior while reducing oxaliplatin-related neuropathy. Stage II patients generally do not benefit from adjuvant chemotherapy unless high-risk features are present.
Neoadjuvant therapy for rectal cancer is a distinction you must remember. Unlike colon cancer, locally advanced rectal cancer (T3/T4 or node-positive on MRI) receives chemoradiation before surgery. The standard regimen is 5-FU-based chemotherapy with concurrent pelvic radiation (approximately 50.4 Gy delivered over 5 to 6 weeks). Surgery follows 6 to 8 weeks later. This sequence reduces local recurrence rates and may achieve a pathologic complete response in some patients, sometimes allowing a "watch and wait" approach in select cases.
Targeted therapy in metastatic disease. Bevacizumab (anti-VEGF monoclonal antibody) can be combined with any chemotherapy backbone. Anti-EGFR agents (cetuximab, panitumumab) are reserved exclusively for KRAS/NRAS wild-type, left-sided tumors, as right-sided tumors and RAS-mutant tumors do not respond. This is a frequently tested pharmacology point.
Surveillance after curative resection follows a structured protocol: CEA every 3 to 6 months for the first 2 years, then every 6 months for a total of 5 years. CT of chest, abdomen, and pelvis annually for up to 5 years. Colonoscopy at 1 year post-resection, then at 3 years, then every 5 years if normal.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common way students lose points on colorectal carcinoma questions is failing to recognize iron deficiency anemia as the presenting sign of a right-sided colon cancer. The vignette will describe an older male (or a postmenopausal female) with fatigue, pallor, low hemoglobin, low MCV, and low ferritin. There will be no overt GI bleeding mentioned. The trap is choosing a benign cause such as dietary deficiency or chronic disease anemia, when the correct next step is colonoscopy. Any iron deficiency anemia in a male of any age or a postmenopausal female must be investigated with colonoscopy to exclude malignancy until proven otherwise.
A second high-yield trap involves the role of CEA. Vignettes will try to get you to select CEA as a diagnostic or screening test. It is neither. CEA is drawn before surgery to establish a baseline and then followed serially to detect recurrence. A rising CEA after initially successful resection should prompt CT imaging and possible colonoscopy to search for recurrent disease.
The third trap concerns adjuvant chemotherapy decisions. Students may incorrectly recommend chemotherapy for all Stage II patients. Standard-risk Stage II colon cancer is treated with surgery alone. Chemotherapy is added only when high-risk features are present (T4, perforation, obstruction, poorly differentiated, inadequate lymph node harvest). By contrast, all Stage III patients receive adjuvant FOLFOX, and this distinction between Stage II and Stage III management is tested repeatedly.
For rectal cancer, students often forget that the treatment sequence is reversed: neoadjuvant chemoradiation comes before surgery, not after. Colon cancer goes surgery first, then adjuvant chemotherapy. Rectal cancer (when locally advanced) goes neoadjuvant chemoradiation first, then surgery, then adjuvant chemotherapy. Mixing these sequences up is one of the most common errors.
Finally, remember the targeted therapy rule: anti-EGFR agents (cetuximab, panitumumab) require RAS wild-type status and are preferentially used in left-sided tumors. Selecting these agents for a KRAS-mutant or right-sided tumor is a built-in distractor in pharmacology-based questions. Bevacizumab (anti-VEGF) has no such molecular restriction and can be paired with any chemotherapy backbone regardless of RAS status or tumor sidedness.