Colorectal cancer refers to malignancies of the colon and rectum, typically encompassing colorectal adenocarcinoma, which accounts for approximately 95% of all colorectal malignancies. Colon cancer and rectal cancer are among the most common cancers worldwide, ranking third in incidence and second in cancer-related mortality globally.
Etiology and Pathogenesis
Environmental Factors
Excessive intake of high-fat or red meat diets and insufficient dietary fiber are significant environmental factors contributing to colorectal cancer. Additional factors include smoking, environmental carcinogens and mutagens, heme iron-containing foods, heterocyclic amines (produced by grilling or frying meats and fish), reduced consumption of fruits and non-starchy vegetables, and gut microbiota dysbiosis.
Imbalances in the gut microbiota, such as the accumulation of pathogenic bacteria like Fusobacterium nucleatum on the intestinal mucosa, also play a role in the development and progression of colorectal cancer and may even influence its prevention and treatment.
Genetic Factors
From a genetic perspective, colorectal cancer can be categorized into hereditary (familial) and non-hereditary (sporadic) types. Hereditary types include familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC, also known as Lynch syndrome). Sporadic colorectal cancer is primarily caused by gene mutations induced by environmental factors, although genetic factors also contribute to its development.
In sporadic colorectal cancer, abnormalities in key genes are involved, including inactivation of genes such as APC, DCC, and TP53; mutations and overexpression of genes like KRAS, PIK3CA, and even BRAF; and loss of DNA mismatch repair genes.
High-Risk Factors
Colorectal Adenomas
Colorectal adenomas are the most significant precancerous lesions. Adenomas meeting any of the following three criteria are considered high-risk advanced adenomas:
- Diameter ≥10 mm
- Villous or mixed adenomas with a villous component exceeding 25%
- Presence of high-grade intraepithelial neoplasia
Other Polypoid Neoplasms
These include serrated lesions (such as hyperplastic polyps, sessile serrated adenomas/polyps [SSA/P], traditional serrated adenomas [TSA], and hyperplastic polyposis syndrome), as well as hamartomas (associated with conditions like juvenile polyposis syndrome, Peutz-Jeghers syndrome, multiple hamartoma syndromes, Gardner syndrome, Turcot syndrome, and Cronkhite-Canada syndrome). These lesions also carry a risk of malignant transformation.
Inflammatory Bowel Disease (IBD)
Colorectal cancer may develop in patients with IBD, particularly those with ulcerative colitis. This is more common in cases with early-onset disease, extensive colonic involvement, long disease duration, or concurrent primary sclerosing cholangitis.
Other High-Risk Populations or Factors
Additional high-risk groups or factors include:
- Positive fecal occult blood tests
- Family history of colorectal cancer
- Personal history of cancer
- Long-term smoking, excessive alcohol consumption, obesity, physical inactivity, and age >50 years
- Presence of at least two of the following six conditions: chronic diarrhea, chronic constipation, mucopurulent bloody stools, history of chronic appendicitis or appendectomy, history of chronic cholecystitis or cholecystectomy, and prolonged psychological stress
- History of pelvic radiotherapy
Colorectal cancer develops through three main pathways: the adenoma-carcinoma sequence (including the serrated pathway), the de novo pathway, and the inflammation-cancer pathway, with the adenoma-carcinoma sequence being the most common.
Pathology
Pathological Morphology
Early colorectal cancer is defined as cancer confined to the mucosa and submucosa, while advanced colorectal cancer involves invasion of the muscularis propria. Advanced colorectal cancer is classified macroscopically into three types: mass-forming, infiltrative, and ulcerative.
Histological Classification
Common histological types include adenocarcinoma, adenosquamous carcinoma, spindle cell carcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Adenocarcinoma is the most prevalent type and includes six subtypes: cribriform comedo adenocarcinoma, medullary carcinoma, micropapillary carcinoma, mucinous adenocarcinoma, serrated adenocarcinoma, and signet-ring cell carcinoma.
Clinical and Pathological Staging
The TNM staging system proposed by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) is used for pathological staging of colorectal cancer. The modified Dukes staging system divides colorectal cancer into four stages: A, B, C, and D.
Metastatic Pathways
The metastatic pathways of colorectal cancer include direct extension, lymphatic metastasis, and hematogenous dissemination.
Clinical Manifestations
The incidence of colorectal cancer is higher in males than in females. The incidence of colorectal tumors (including colorectal cancer and adenomas) begins to increase significantly after the age of 50, peaks between 75 and 80 years old, and then gradually declines. However, colorectal cancer in individuals under 30 years of age is not uncommon.
Colorectal cancer has an insidious onset, with early stages often presenting only as positive fecal occult blood tests. Over time, the following clinical manifestations may appear:
Changes in Bowel Habits and Stool Characteristics
These are often the earliest symptoms of the disease. They typically present as hematochezia (blood in the stool) or positive fecal occult blood tests. The amount of hemorrhage depends on factors such as tumor size and ulceration depth. Persistent constipation may occur, with stools becoming thinner in shape. Diarrhea or alternating diarrhea and constipation may also manifest, with stools typically lacking significant mucus or pus, a presentation more common in right-sided colorectal cancer.
Abdominal Pain
Abdominal pain is more common in right-sided colorectal cancer. It often presents as dull pain in the right abdomen, which may also involve the right upper abdomen or the epigastric region. Postprandial abdominal pain may occur due to enhanced gastrocolic reflexes caused by the lesion. In cases where colorectal cancer leads to bowel obstruction, the pain may intensify or present as colicky pain.
Rectal or Abdominal Masses
In many patients with rectal cancer, a rectal mass can be detected during a digital rectal examination. The mass is typically hard, nodular in texture, and may cause local narrowing of the intestinal lumen. Blood-stained mucus may be observed on the examining glove after the procedure. Abdominal masses, which suggest advanced disease, are localized depending on the tumor's location.
Systemic Symptoms
Anemia and low-grade fever are common, particularly in right-sided colorectal cancer. In advanced stages, patients may experience progressive emaciation, cachexia, ascites, and other systemic symptoms. Right-sided colorectal cancer is often characterized by systemic symptoms, anemia, and abdominal masses, while left-sided colorectal cancer primarily presents with hematochezia, diarrhea, constipation, and bowel obstruction. Complications in advanced stages include bowel obstruction, gastrointestinal hemorrhage, and complications related to peritoneal metastasis.
Laboratory and Other Examinations
Fecal Occult Blood Test (FOBT)
Although FOBT lacks specificity and is not a definitive diagnostic tool, it is simple and convenient. It can serve as a screening method or an early diagnostic clue.
Colonoscopy
Colonoscopy is highly valuable for the definitive diagnosis of colorectal cancer. It allows direct visualization of the entire colorectal mucosa and lumen, enables determination of the tumor's location and size, and provides an initial assessment of the depth of invasion. Biopsies can confirm the diagnosis. Early colorectal cancer appears as either elevated or flat lesions under endoscopy.
Chromoendoscopy during colonoscopy significantly improves the detection of small lesions, particularly flat lesions. Techniques such as magnifying chromoendoscopy combined with pit pattern analysis can help determine the nature and depth of the lesion. Endoscopic ultrasonography (EUS) is useful for assessing the depth of invasion in colorectal cancer, offering high accuracy in T staging and aiding in determining the suitability for endoscopic treatment.
Barium Enema X-ray
Barium enema can serve as an auxiliary examination for colorectal tumors, although its diagnostic value is inferior to colonoscopy. It is currently used in patients unwilling to undergo colonoscopy, those with contraindications to colonoscopy, or in cases where luminal narrowing prevents the endoscope from passing but visualization of the proximal colon is required. Barium enema may reveal filling defects, luminal narrowing, and mucosal fold destruction, indicating the tumor's location and extent.
CT Colonography
CT colonography is primarily used to assess the extent of colorectal cancer invasion into the bowel wall and surrounding tissues, as well as metastasis. It aids in clinical staging, treatment planning, and postoperative follow-up. However, its value in early diagnosis is limited, as it cannot provide biopsies and may yield false negatives for small or flat lesions. False positives may also occur due to interference from stool.
Diagnosis and Differential Diagnosis
Individuals with high-risk factors who develop symptoms such as changes in bowel habits or stool characteristics, abdominal pain, or anemia should undergo colonoscopy promptly. Diagnosis primarily relies on colonoscopy and pathological examination of mucosal biopsies. Early colorectal cancer is characterized by lesions confined to the mucosa or submucosa, regardless of local lymph node involvement. Pathologically, these lesions often present as high-grade intraepithelial neoplasia or adenocarcinoma.
Right-sided colorectal cancer should be differentiated from conditions such as intestinal amebiasis, intestinal tuberculosis, schistosomiasis, appendiceal diseases, and Crohn's disease. Left-sided colorectal cancer should be distinguished from hemorrhoids, functional constipation, chronic bacterial dysentery, schistosomiasis, ulcerative colitis, Crohn's disease, colorectal polyps, and diverticulitis.
When abdominal masses are detected, differentiation from benign mucosal or submucosal tumors, endometriosis, and inflammatory masses is necessary. In cases of obstruction, differentiation from Crohn's disease and radiation-induced injury is required. Lower gastrointestinal hemorrhage should be distinguished from inflammatory bowel disease (IBD), hemorrhoids, infectious colitis, and ischemic colitis. Abdominal pain should prompt consideration of diverticulitis, IBD, irritable bowel syndrome (IBS), and ischemic bowel disease. Changes in bowel habits should be differentiated from infectious diarrhea, IBD, IBS, or side effects of medication.
Treatment
The key to treatment lies in early detection and diagnosis, which facilitate curative interventions.
Surgical Treatment
Surgical resection in the early stages is the only curative method for colorectal cancer. For patients with extensive metastases where the affected intestinal segment cannot be resected, palliative surgery may be performed to relieve bowel obstruction. For patients with liver metastases who have undergone radical resection of the primary tumor and show no evidence of extrahepatic disease, partial hepatectomy may also be considered.
Given that some patients with colorectal cancer may not have undergone a complete preoperative examination of the entire colon, there is a risk of synchronous colorectal cancer (a second primary tumor). For these patients, a follow-up colonoscopy is recommended within 3 to 6 months after surgery.
Endoscopic Treatment
Adenomas with malignant transformation and early-stage cancers confined to the mucosa can be removed via colonoscopy using high-frequency electrocautery, endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD). The resected tissue is sent for pathological examination. If the cancer does not involve the base of the lesion, the treatment is considered complete. If the base is involved, additional surgery is required to ensure complete removal of the cancerous tissue.
For left-sided colorectal cancer causing bowel obstruction, endoscopic stent placement can be performed to relieve the obstruction. This not only alleviates symptoms but also reduces intraoperative contamination and increases the likelihood of primary anastomosis in a single-stage surgery.
Chemotherapy
Colorectal cancer generally shows limited sensitivity to chemotherapy. Early-stage cancers that have been radically resected typically do not require chemotherapy, while chemotherapy is often used as an adjuvant treatment following surgery for advanced-stage cancers. Neoadjuvant chemotherapy can reduce the clinical stage of the tumor and facilitate surgical resection. Common chemotherapeutic agents include 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (used in the mFOLFOX6 regimen).
Radiation Therapy
Radiation therapy is primarily used for rectal cancer. Preoperative radiation can improve resection rates and reduce postoperative recurrence. Postoperative radiation is reserved for cases where radical resection was not achieved or in cases of local recurrence. A combination of preoperative and postoperative radiation therapy, referred to as the "sandwich therapy," can reduce the risk of local recurrence in stage II or III rectal and rectosigmoid cancers. It also increases resection rates in cases of large tumors or tumors fixed to pelvic organs.
Targeted Therapy
Monoclonal antibodies targeting vascular endothelial growth factor (VEGF), such as bevacizumab, and those targeting epidermal growth factor receptor (EGFR), such as cetuximab, can regulate key pathways in tumor growth. Both drugs have been approved for the treatment of advanced colorectal cancer.
Immune Checkpoint Inhibitor Therapy
The efficacy of immune checkpoint inhibitors is limited and is primarily used in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) subtypes, which account for approximately 15% of all colorectal cancers and 5% of metastatic colorectal cancers. Pembrolizumab has been approved for use as monotherapy in patients with wild-type KRAS, NRAS, and BRAF genes. Treatment regimens may include monotherapy, dual therapy, combinations with chemotherapy, or combinations with targeted therapies.
Prognosis
Prognosis depends on factors such as clinical staging, histopathological characteristics, early diagnosis, and the feasibility of achieving a curative resection. Patients with exophytic or polypoid tumors generally have a better prognosis compared to those with ulcerative or infiltrative tumors. The depth of tumor invasion through the intestinal wall and the extent of lymph node involvement are critical factors influencing prognosis. Poorly differentiated tumors have a worse prognosis compared to well-differentiated tumors.
Prevention
Colorectal cancer has well-defined precancerous conditions and a relatively long progression period from early to advanced stages, providing opportunities for effective prevention.
Screening and Early Detection
High-risk populations should undergo screening to detect early lesions. High-risk individuals can be identified through questionnaires and fecal occult blood tests, followed by further examinations such as digital rectal examination, sigmoidoscopy, or full colonoscopy. Interval colorectal cancer (CRC), which refers to cancers diagnosed after a negative screening test but before the next scheduled screening, is an important indicator of the quality and effectiveness of colorectal cancer screening programs.
Primary and Secondary Prevention of Adenomas
Measures for prevention include:
- Lifestyle Modifications: Increasing physical activity, reducing red meat consumption, increasing dietary fiber intake, and quitting smoking.
- Chemoprevention: High-risk individuals (e.g., those over 50 years old, particularly men, or those with a family history of colorectal tumors or other cancers, smokers, overweight individuals, or those with a history of gallbladder surgery or schistosomiasis) may consider the use of aspirin or COX-2 inhibitors (e.g., celecoxib) for prevention. Long-term use requires monitoring for adverse effects. Supplementation with vitamins A, C, and E, folic acid, calcium, vitamin D, selenium, fish oil, or statins may also have some preventive effects.
- Regular Colonoscopic Surveillance: Removal of colorectal adenomas via colonoscopy can prevent the development of colorectal cancer. Post-polypectomy, regular follow-up colonoscopies should be performed based on the patient's condition to detect and remove recurrent adenomas promptly.
- Management of Inflammatory Bowel Disease: Controlling the extent and severity of the disease and promoting mucosal healing can help reduce the risk of malignant transformation.