Colorectal Cancer (CRC): A Comprehensive Overview

Epidemiology

• Pye's Surgical Handicraft, 22nd Ed.
• Sabiston Textbook of Surgery, p. 2121

Types of Colorectal Cancer

By Histology

By Molecular/Genetic Pathway

Overlapping molecular pathways to colorectal carcinoma - Sabiston Textbook of Surgery

1. Chromosomal Instability (CIN) Pathway - Most common (65-70%). Initiated by APC gene mutation → Wnt/β-catenin activation → tubular adenoma → KRAS mutation → TP53/SMAD4 changes → invasive cancer. The classic adenoma-to-carcinoma sequence. Results in sporadic CIMP-MSS carcinoma (~60%).
2. Serrated/Methylator Pathway (CIMP+) - Initiated by BRAF mutation → CpG island methylator phenotype (CIMP) → silencing of tumor-suppressor genes. Accounts for ~15-20% of CRCs. Tumors tend to be right-sided, in older/female patients. Sporadic CIMP+MSI-H accounts for ~13%, and CIMP+MSS ~20%.
3. Microsatellite Instability (MSI) Pathway - Loss of mismatch repair (MMR) function (MLH1, MSH2, MSH6, PMS2 genes). Three etiologies: Lynch syndrome germline variant, MLH1 hypermethylation, or somatic MMR mutation. Lynch syndrome carcinoma (CIMP-MSI-H) accounts for ~5% of CRC.

• Sabiston Textbook of Surgery, pp. 2121-2122

By Location

• 50% in sigmoid colon and rectum
• Right colon (cecum/ascending): often occult, presents with iron-deficiency anemia
• Left colon/sigmoid: more likely to cause obstruction, change in bowel habits
• Rectal: rectal bleeding, tenesmus

Etiology & Risk Factors

Non-Modifiable Risk Factors

• Age >50 (risk increases sharply)
• Personal history of adenomatous polyps or CRC
• Family history of CRC or adenomas
• Hereditary syndromes (see below)
• Inflammatory bowel disease (UC > Crohn's; risk rises after 8-10 years of disease)
• Male sex (slightly higher risk)

Modifiable/Environmental Risk Factors

• Diet high in red/processed meat; low in fiber
• Obesity and physical inactivity
• Alcohol consumption
• Smoking
• Diabetes mellitus and insulin resistance

Hereditary Syndromes

Polyposis Syndromes

Nonpolyposis Syndromes

• Lynch Syndrome (HNPCC): Autosomal dominant; MMR gene pathogenic variant (MLH1, MSH2, MSH6, PMS2, EPCAM). Incidence: 1/279 in general population; ~3% of all CRCs. Cumulative CRC risk by age 80: 46-61% (MLH1), 33-52% (MSH2), 10-44% (MSH6), 8.7-20% (PMS2). Also at risk: endometrial, ovarian, gastric, urological, pancreatic, small bowel cancers. Amsterdam II criteria used for clinical diagnosis. Annual colonoscopy from age 20-25.
• Sabiston Textbook of Surgery, pp. 2122-2124

Clinical Features

Right-Sided Colon Cancer

• Iron-deficiency anemia (occult bleeding from cecal/ascending lesions)
• Fatigue, pallor
• Palpable right iliac fossa mass
• Vague abdominal discomfort
• Late obstruction (large lumen)

Left-Sided Colon / Sigmoid Cancer

• Change in bowel habit (most common symptom overall) - alternating constipation/diarrhea
• Bright red rectal bleeding or blood mixed with stool
• "Pencil-thin" stools
• Colicky abdominal pain
• Acute intestinal obstruction (narrower lumen)

Rectal Cancer

• Rectal bleeding (most common symptom)
• Tenesmus (feeling of incomplete evacuation)
• Mucous per rectum
• Pelvic/perineal pain (advanced)
• Palpable mass on digital rectal examination

Advanced/Systemic Features

• Weight loss
• Anorexia
• Hepatomegaly (liver metastases)
• Jaundice
• Malignant ascites
• Features of distant metastases (lung, bone, brain)
• Acute presentations: intestinal obstruction (~8-29% of cases), perforation, fistula
• Pye's Surgical Handicraft, 22nd Ed., p. 275

Investigations

Blood Tests

• FBC: Microcytic hypochromic anemia (iron deficiency from chronic blood loss)
• LFTs: May be deranged with liver metastases
• CEA (Carcinoembryonic antigen): Tumor marker; preoperative level >5 ng/mL predicts worse disease-free survival (DFS). Used primarily for post-treatment surveillance - not diagnostic
• CA 19-9: May be elevated
• LDH, ALP: Non-specific markers of metastatic disease

Stool Tests

• Fecal Occult Blood Test (FOBT) / Fecal Immunochemical Test (FIT): Screening tools
• Multi-targeted stool DNA test: Every 1-3 years as screening option

Endoscopy

• Colonoscopy: Gold standard - allows visualization, biopsy, and polypectomy of the entire colon. Preferred screening modality
• Flexible sigmoidoscopy: Visualizes distal colon only; combined with FOBT for screening
• CT colonography (virtual colonoscopy): Every 5 years as screening option; non-invasive

Imaging

• CT chest/abdomen/pelvis (staging): Primary modality for staging; detects liver, lung, lymph node metastases
• MRI pelvis: Critical for rectal cancer - assesses relationship to mesorectal fascia, circumferential resection margin (CRM), sphincter involvement, and depth of invasion (T staging)
• Endorectal ultrasound (ERUS): Accurate T and N staging for rectal cancer
• PET-CT: For equivocal metastatic lesions, recurrence assessment, or evaluating response to treatment

Histopathology & Molecular Testing

• Biopsy: Confirms diagnosis, histological grade
• MSI/MMR testing: All newly diagnosed CRC should be tested for Lynch syndrome screening
• KRAS/NRAS/BRAF mutation testing: Required before initiating anti-EGFR therapy (cetuximab, panitumumab)
• HER2 amplification, NTRK fusions: For targeted therapy eligibility in metastatic CRC
• Sabiston Textbook of Surgery, pp. 2128-2135
• Goldman-Cecil Medicine, p. 3962

Staging

TNM Staging (AJCC - 8th Edition)

Dukes' Classification (Historical, Still Referenced)

Poor Prognostic Factors

• High CEA (>5 ng/mL) pre- and post-op
• Lymphovascular invasion (LVI)
• Perineural invasion (PNI)
• High tumor budding
• Mucinous histology / signet ring cells
• BRAF and KRAS mutations (worse prognosis)
• MSI-H predicts better survival (~15% better than MSS)
• Sabiston Textbook of Surgery, pp. 2133-2135
• Pye's Surgical Handicraft, Table 18.3

Management

Screening (Asymptomatic Average-Risk Adults ≥45 years)

• Annual high-sensitivity FOBT or FIT
• Multi-targeted stool DNA test every 1-3 years
• CT colonography every 5 years
• Flexible sigmoidoscopy every 5 years (or every 10 years + annual FOBT)
• Colonoscopy every 10 years (preferred - combines detection and treatment)

Surgical Management

Colon Cancer

• Right hemicolectomy: Cecal, ascending, hepatic flexure cancers
• Transverse colectomy: Transverse colon tumors
• Left hemicolectomy: Descending colon tumors
• Sigmoid colectomy: Sigmoid tumors
• High anterior resection: Upper rectum/sigmoid junction

• Right-sided: segmental resection ± primary anastomosis
• Left-sided: options include Hartmann's procedure (resection + end colostomy) or primary anastomosis in stable patients. Endoscopic stenting as bridge to elective surgery is an option - reduces wound infection, increases laparoscopic completion, higher rates of primary anastomosis.

Rectal Cancer

• Low anterior resection (LAR): For upper and mid-rectal tumors with adequate distal margin; anastomosis with/without defunctioning stoma
• Abdominoperineal resection (APR): For very low rectal tumors where sphincter preservation is not possible; results in permanent colostomy
• Transanal endoscopic microsurgery (TEM)/Transanal minimally invasive surgery (TAMIS): For selected early T1-T2 rectal tumors

Neoadjuvant Therapy (Rectal Cancer)

• Neoadjuvant chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) or capecitabine + radiation: Standard for locally advanced rectal cancer (T3/T4 or N+). Downsizes tumor, increases R0 resection rates, reduces local recurrence.
• Short-course radiotherapy (SCRT): 25 Gy in 5 fractions, followed by surgery within 1 week.
• Total Neoadjuvant Therapy (TNT): Full chemotherapy + radiation delivered before surgery (increasingly used).

Adjuvant Chemotherapy

• Stage III (lymph node positive): FOLFOX (oxaliplatin + 5-FU + leucovorin) or CAPOX (capecitabine + oxaliplatin) for 6 months - standard of care
• Stage II high-risk (T4, LVI, PNI, <12 nodes examined, obstruction/perforation, poor differentiation): adjuvant chemotherapy considered
• Stage II standard-risk: Generally surveillance alone; MSI-H tumors have less benefit from 5-FU monotherapy
• Stage IV: Systemic chemotherapy is the primary modality (FOLFOX, FOLFIRI ± bevacizumab/cetuximab/panitumumab based on RAS/BRAF status)

Targeted & Biologic Therapy (Metastatic CRC)

Management of Liver Metastases

• ~15-25% of patients have synchronous liver metastases
• Surgical resection is the only potentially curative option; 5-year survival ~40% after R0 resection
• Neoadjuvant chemotherapy to downsize before surgery ("conversion chemotherapy")
• Ablation (radiofrequency or microwave) for non-resectable small lesions
• Hepatic arterial infusion pump for liver-predominant disease

Surveillance After Curative Resection

• CEA every 3-6 months for 2 years, then every 6 months for 3 years
• CT chest/abdomen/pelvis annually for 5 years
• Colonoscopy at 1 year post-resection, then every 3-5 years
• Regular history and physical examination
• Sabiston Textbook of Surgery, pp. 2133-2150

Key Summary Points