A Clinical Review of Colon Cancer
Definition
Colorectal cancer (CRC) is a malignancy originating from the epithelial cells that line the colon or rectum (12). Specifically, colon cancer forms in the tissues of the colon, the longest part of the large intestine. The vast majority, over 95%, of these cancers are adenocarcinomas, which arise from the glandular cells of the colonic mucosa responsible for mucus production (17).
These adenocarcinomas can be further sub-classified based on their microscopic appearance, which has important prognostic implications. Notable variants include:
Mucinous Adenocarcinoma: Defined by the presence of large amounts of extracellular mucin (mucus).
Signet-Ring Cell Carcinoma: Characterized by cells filled with intracellular mucin that pushes the nucleus to the periphery, resembling a signet ring.
Both mucinous and signet-ring cell types are generally considered more aggressive and are associated with a poorer prognosis compared to conventional adenocarcinoma (24). While exceedingly rare, other tumors like neuroendocrine tumors (NETs), gastrointestinal stromal tumors (GISTs), and lymphomas can also occur in the colon, but they have different origins and require entirely different management strategies not covered by the standard CRC guidelines (11).
Epidemiology
In Malaysia, colorectal cancer represents a major and growing public health crisis. It is the second most common cancer overall and the most common cancer affecting men (1). The most critical issue from a public health perspective is that approximately 70-75% of Malaysian patients present at advanced stages (Stage III or IV). This late presentation is the primary driver of poorer survival outcomes when compared to high-income countries with robust, population-wide screening programs that detect the disease at an earlier, more curable stage (2, 7).
Incidence: The lifetime risk for a Malaysian man to develop CRC is a stark 1 in 44 (5). There is a significant ethnic disparity, with the Chinese population having the highest incidence, followed by Malays and then Indians. This highlights a complex interplay between genetic predisposition, dietary habits, and lifestyle factors within Malaysia's diverse population (2). A particularly alarming trend is the "worrisome" rise in CRC incidence among Malaysians under the age of 50, challenging the traditional view of CRC as a disease of the elderly (6).
Global Context: Globally, CRC is the third most commonly diagnosed cancer. While Malaysia's incidence rates are currently lower than those in Western nations, they are on a sharp upward trajectory, mirroring trends across Asia. This is largely attributed to the region's nutritional transition towards "Westernized" lifestyles, characterized by diets high in processed foods and red meat, and increased sedentary behavior (33, 36).
Survival: The impact of late-stage diagnosis is reflected in Malaysia's survival statistics. The overall 5-year relative survival for CRC is approximately 51.1%. This figure masks a dramatic drop-off based on stage: survival is a promising 75.8% for localized Stage I disease but plummets to a mere 17.3% for Stage IV metastatic disease (2). This gap between potential curability and actual outcomes underscores the urgent need for improved early detection.
Etiology
The development of CRC is a multifactorial process, resulting from a complex interplay between an individual's genetic makeup and their environmental or lifestyle exposures. Understanding these risk factors is fundamental for both primary prevention (lifestyle modification) and secondary prevention (screening).
Non-Modifiable Risk Factors
These are inherent characteristics that cannot be changed but are crucial for identifying individuals who require earlier or more intensive screening.
Age: This remains the single most significant risk factor. The incidence of CRC increases markedly after age 50. However, the rising incidence in younger individuals means that CRC should not be dismissed as a possibility in symptomatic patients under 50 (6, 15).
Personal History: A prior history of CRC or adenomatous polyps significantly elevates the risk of developing a new (metachronous) cancer. Similarly, a personal history of Inflammatory Bowel Disease (IBD), such as Ulcerative Colitis or Crohn's Disease, is a major risk factor due to chronic inflammation. The risk from IBD increases with the duration of the disease (especially after 8-10 years) and the extent of colonic involvement (14, 15).
Family History: Having a first-degree relative (parent, sibling, child) with CRC increases an individual's risk by two- to four-fold. The risk is even higher if the relative was diagnosed at a young age (<60 years) or if multiple relatives are affected (14).
Inherited Genetic Syndromes: These rare conditions account for 5-10% of all CRC cases but confer an extremely high lifetime risk.
Lynch Syndrome (HNPCC): The most common inherited syndrome, caused by germline mutations in DNA Mismatch Repair (MMR) genes. It predisposes individuals to early-onset CRC and also increases the risk of other cancers, notably endometrial cancer in women (14).
Familial Adenomatous Polyposis (FAP): Caused by mutations in the APC gene. Individuals with classic FAP develop thousands of polyps and have a near 100% lifetime risk of developing CRC by age 40 if a prophylactic colectomy is not performed (14).
Modifiable Risk Factors
These factors related to lifestyle are central to primary prevention, as they are thought to contribute to over 50% of CRC cases.
Diet: A "Western-style" diet is a major driver. High intake of red meat (beef, pork) and especially processed meats (sausages, bacon) is strongly linked to increased risk. Conversely, a diet rich in dietary fiber from fruits, vegetables, and whole grains is protective. Fiber helps by diluting carcinogens in the stool and promoting the growth of healthy gut bacteria (15).
Lifestyle: Obesity and physical inactivity are strongly and independently associated with an increased risk. Excess body fat can promote cancer growth through mechanisms like insulin resistance and chronic inflammation. Smoking and moderate to heavy alcohol consumption are also well-established and significant risk factors (15, 50).
Pathophysiology
Most CRCs develop via the adenoma-carcinoma sequence, a multi-step, multi-year process where normal colonic epithelium progressively accumulates genetic and epigenetic mutations, transforming it into an invasive tumor over 10-20 years (24, 52). This long latency period provides the critical window of opportunity for screening to be effective. This progression occurs via several distinct molecular pathways.
Classical Pathway (Chromosomal Instability - CIN): This is the most common pathway, underlying ~85% of sporadic CRCs. It is characterized by widespread numerical and structural chromosome changes. The sequence is typically initiated by a mutation in the APC "gatekeeper" gene, leading to uncontrolled cell proliferation. This is followed by an activating mutation in the KRAS proto-oncogene, which further fuels growth, and finally the loss of the TP53 "guardian of the genome" tumor suppressor gene, which allows damaged cells to evade cell death and become invasive (24, 57).
Microsatellite Instability (MSI) Pathway: Accounting for ~15% of CRCs, this pathway is defined by a dysfunctional DNA Mismatch Repair (dMMR) system. This system normally corrects errors during DNA replication. When it fails, mutations accumulate rapidly, a state known as high-level microsatellite instability (MSI-H). This hypermutable state leads to the production of many abnormal proteins (neoantigens), making these tumors highly visible to the immune system and thus highly responsive to immunotherapy. This is the hallmark of Lynch Syndrome but can also occur sporadically through epigenetic silencing of an MMR gene (25).
Serrated Pathway: This pathway originates from a different type of pre-cancerous lesion known as a serrated polyp. It is often initiated by an activating BRAF V600E mutation and is strongly associated with widespread epigenetic gene silencing (the CIMP phenotype). These tumors are most commonly found in the right side of the colon (52, 56).
Clinical Presentation
Early-stage colon cancer is notoriously insidious and often asymptomatic. Symptoms typically appear only once the tumor has grown large enough to cause obstruction or bleeding. The most common presenting symptoms in Malaysia are altered bowel habit (41.7%), blood in stool (35.5%), and abdominal pain (31.5%) (11).
Diagnostic Clues
There are no pathognomonic signs for colon cancer. The essential clinical skill is to recognize a constellation of "red flag" symptoms that mandate investigation, as they overlap with many benign conditions (69).
Right-Sided Tumors: The cecum and ascending colon have a wide lumen, so tumors here can grow to a large size without causing obstructive symptoms. They often present insidiously with systemic symptoms of chronic, occult blood loss, leading to fatigue, weakness, and pallor from iron-deficiency anemia. Unexplained iron-deficiency anemia in an older adult should be considered colon cancer until proven otherwise. A palpable mass in the right iliac fossa may be a late finding (21).
Left-Sided Tumors: The descending and sigmoid colon are narrower, so tumors here cause obstructive symptoms earlier. The classic presentation is with overt rectal bleeding (hematochezia), a change in bowel habits (new-onset constipation, "pencil-thin" stools), and tenesmus (a persistent, painful feeling of needing to pass stool even when the bowel is empty), which is highly suggestive of a rectosigmoid tumor (21).
⚠️ Red Flag Signs & Symptoms
Bolded features indicate clinical urgency and require immediate investigation in any patient, particularly those over 40:
Any rectal bleeding not attributable to a confirmed benign cause like hemorrhoids.
A persistent and unexplained change in bowel habit lasting for more than a few weeks.
Unexplained iron-deficiency anemia, especially in males and postmenopausal females.
Unexplained and unintentional weight loss.
A palpable abdominal or rectal mass on physical examination.
Complications
The complications of colon cancer can be life-threatening and often require urgent intervention.
Gastrointestinal:
Malignant Bowel Obstruction: The tumor grows to completely block the bowel lumen, leading to abdominal pain, distension, vomiting, and absolute constipation. This is a surgical emergency requiring either endoscopic stenting to relieve the blockage or emergency surgery (e.g., a diverting stoma or resection).
Perforation: The tumor can erode through the bowel wall, spilling fecal contents into the abdominal cavity. This leads to peritonitis and sepsis, which carries a high mortality rate and requires immediate surgery.
Hemorrhage: While chronic occult bleeding is common, tumors can sometimes erode into a major blood vessel, causing acute, massive hemorrhage and hemodynamic instability.
Metastatic Disease: Symptoms depend on the organ involved.
Liver Metastases (most common): Jaundice, right upper quadrant pain, nausea, and ascites (fluid in the abdomen).
Lung Metastases: Persistent cough, shortness of breath (dyspnea), or coughing up blood (hemoptysis).
Bone Metastases: Can cause severe, localized bone pain, fractures from minimal trauma (pathological fractures), or spinal cord compression if in the vertebrae, which is a neurological emergency.
Prognosis
Prognosis is directly and powerfully tied to the stage at diagnosis. The late presentation of most Malaysian patients is the primary driver of the nation's poor overall outcomes.
The overall 5-year survival in Malaysia is 51.1% (2).
This rate plummets from a hopeful 75.8% for Stage I disease to a grim 17.3% for Stage IV metastatic disease (2).
Other key prognostic factors include the tumor's molecular profile. Tumors with MSI-High (MSI-H) status generally have a better prognosis in non-metastatic stages but respond differently to chemotherapy (24). In contrast, the presence of a BRAF V600E mutation is a marker of aggressive biology and is associated with a poorer prognosis (20).
Differential Diagnosis
Given the non-specific symptoms, a broad differential diagnosis must be considered.
Irritable Bowel Syndrome (IBS): This is a key differential for altered bowel habits in younger patients. However, IBS is a diagnosis of exclusion and importantly, does not cause bleeding, weight loss, or anemia. The absence of these red flag symptoms points towards IBS (67).
Hemorrhoids: A very common cause of bright red rectal bleeding seen on toilet paper. However, attributing bleeding to hemorrhoids without investigation is a common and dangerous pitfall, especially in patients over 40 or with other red flags, as CRC and hemorrhoids can coexist.
Diverticular Disease: Can cause lower abdominal pain and rectal bleeding. Diverticulitis (inflammation of diverticula) can even mimic the obstructive symptoms of a left-sided cancer.
Inflammatory Bowel Disease (IBD): Crohn's disease and ulcerative colitis present with chronic diarrhea, abdominal pain, and rectal bleeding. Colonoscopy with biopsy is essential to differentiate IBD from cancer, although IBD itself is a major risk factor for developing CRC over time.
Investigations
The workup follows a structured path: Screen → Diagnose → Stage → Surveil, guided by the Malaysian CPG.
Immediate & Bedside Tests
Full Blood Count (FBC): Essential to identify anemia resulting from chronic occult blood loss, which is a key diagnostic clue, and to establish a baseline hemoglobin before treatment (79).
Digital Rectal Examination (DRE): A mandatory part of the physical exam. It can detect a palpable low rectal mass and identify melena (black, tarry stools) or fresh blood.
Diagnostic Workup
First-Line (Screening): For average-risk individuals aged 50-75, the Malaysian CPG recommends an annual immunochemical Faecal Occult Blood Test (iFOBT). This simple stool test is cost-effective for population screening. A positive result is not a diagnosis of cancer but is an absolute indication for a follow-up colonoscopy (1).
Gold Standard (Diagnosis): Colonoscopy with biopsy is the definitive investigation. It is the only test that allows for both direct visualization of the entire colon and the ability to take tissue samples (biopsy) from any suspicious lesion for histopathological confirmation of adenocarcinoma (78, 81).
Monitoring & Staging
Carcinoembryonic Antigen (CEA): This blood tumor marker is not for screening or diagnosis. Its crucial role is to establish a pre-operative baseline and for post-treatment surveillance. A rising CEA after surgery is highly suspicious for disease recurrence and mandates further imaging (1).
Staging Imaging (Colon Cancer): A contrast-enhanced CT scan of the Thorax, Abdomen, and Pelvis is the standard. This single scan effectively assesses the primary tumor, regional lymph nodes, and the most common sites of distant metastases (liver and lungs) (1).
Staging Imaging (Rectal Cancer): In addition to a staging CT scan, a high-resolution pelvic MRI is mandatory for local staging. MRI provides superior soft-tissue detail to assess the tumor's depth and its relationship to the critical mesorectal fascia, information that is essential for planning pre-operative (neoadjuvant) therapy (1).
Pathological Staging: The final, most accurate stage is determined from the resected surgical specimen. The pathology report is critical. The CPG emphasizes that a minimum of 12 lymph nodes must be harvested and examined to confidently declare a patient as node-negative (N0) and provide an accurate prognosis (11).
Management
Management is highly individualized based on stage, location, and molecular profile, and all cases should be discussed by a Multidisciplinary Team (MDT) (1).
Management Principles
The management of colon cancer focuses on curative surgical resection for localized disease and systemic therapy to control disease, manage symptoms, and prolong life in the metastatic setting.
Acute Stabilisation (The First Hour)
This applies to patients presenting with acute complications like obstruction or perforation.
Circulation: Secure two large-bore IV cannulas and begin aggressive fluid resuscitation with crystalloids to correct dehydration and hypotension.
Decompression: Insert a nasogastric tube on free drainage to decompress the stomach and prevent aspiration, especially in a patient with bowel obstruction.
Antibiotics: Administer broad-spectrum IV antibiotics covering gut flora as per local guidelines if perforation or sepsis is suspected.
Action: An urgent surgical consultation is mandatory for definitive management.
Definitive Therapy
Stage 0-I: Surgery alone is typically curative. This may be a simple polypectomy during colonoscopy for cancers confined to a polyp, or a formal partial colectomy (surgical resection of the cancerous segment and regional lymph nodes) (85).
Stage II: The standard treatment is a partial colectomy. The key decision is whether to offer adjuvant (post-operative) chemotherapy. This is considered only for high-risk cases (e.g., T4 tumors invading through the bowel wall, presentation with obstruction or perforation, or an inadequate lymph node yield of <12 nodes) after a thorough discussion of risks and benefits (3, 11).
Stage III (Node-Positive): The risk of recurrence after surgery alone is high. Therefore, the standard of care is partial colectomy followed by a course of adjuvant chemotherapy to eradicate microscopic cancer cells.
First-Line Treatment: Standard regimens are FOLFOX (intravenous 5-FU, Leucovorin, and Oxaliplatin) or CAPEOX (oral Capecitabine and intravenous Oxaliplatin) for a duration of 3 to 6 months (11, 85).
Stage IV (Metastatic): The goal shifts from cure to palliation.
First-Line Treatment: Systemic therapy is the mainstay, and the choice is critically guided by molecular testing of the tumor:
All Patients: Combination chemotherapy (e.g., FOLFOX or FOLFIRI) is the backbone, often combined with an anti-VEGF agent like Bevacizumab, which inhibits tumor blood vessel growth (11).
RAS Wild-Type Tumors: For tumors without a mutation in the RAS gene, anti-EGFR agents like Cetuximab can be added to chemotherapy to block a key cancer growth pathway (11).
MSI-High/dMMR Tumors: This ~5% of metastatic tumors are highly responsive to immunotherapy. Immune checkpoint inhibitors like Pembrolizumab are the preferred first-line treatment and are superior to chemotherapy for this specific subgroup (62).
Supportive & Symptomatic Care
Pain Management: Follow the WHO analgesic ladder, from simple analgesics to strong opioids. Palliative radiotherapy is highly effective for managing pain from localized bone metastases (98).
Nutritional Support: Ensure adequate hydration and nutrition. A consultation with a dietitian is often necessary, especially for patients with weight loss or poor appetite.
Palliative Care: It is a common misconception that palliative care is only for the end of life. Early integration of a palliative care team is crucial for all patients with advanced disease. This specialized care is delivered alongside active cancer treatment to expertly manage symptoms (pain, nausea, fatigue) and provide vital psychosocial and spiritual support, which has been shown to significantly improve quality of life (98, 104).
Key Nursing & Monitoring Instructions
Strict input/output chart monitoring, especially post-operatively or in patients with obstruction, to guide fluid management.
Monitor vital signs closely for signs of surgical complications (fever, tachycardia, increasing abdominal pain) or sepsis.
For patients on chemotherapy, educate them on and monitor for common side effects like nausea, diarrhea, and the signs of a low white blood cell count (neutropenic sepsis), such as fever.
Inform the medical team immediately if systolic BP drops below 90 mmHg, urine output is <0.5mL/kg/hr, or if there are any new, concerning symptoms like confusion or severe pain.
When to Escalate
A house officer must recognize when to call for senior help promptly.
Call Your Senior (MO/Specialist) if:
The patient shows clinical signs of acute bowel obstruction (vomiting, distension, absolute constipation), perforation, or peritonitis.
The patient on chemotherapy develops a fever (febrile neutropenia), which is a medical emergency.
There is hemodynamic instability (hypotension, persistent tachycardia) or evidence of significant active bleeding.
The patient develops new, focal neurological signs, which could suggest the development of brain or spinal cord metastases and requires urgent imaging and intervention.
Referral Criteria
All newly diagnosed cancer cases must be discussed at a formal Multidisciplinary Team (MDT) meeting to formulate a comprehensive treatment plan.
Refer to the Clinical Genetics Service for any patient with a personal or family history suggestive of an inherited syndrome (e.g., FAP, Lynch syndrome) for counseling and testing (1).
Refer to the Palliative Care Team early in the course of metastatic disease to run concurrently with active treatment, not just at the end of life (98).
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