Colonic Mucosal Biopsy in the Evaluation of Suspected Inflammatory Diseases

1. Overview and Clinical Importance

• Confirm the presence of mucosal inflammation
• Distinguish between the major forms of IBD (ulcerative colitis vs. Crohn's colitis)
• Exclude infectious, ischemic, drug-induced, and microscopic colitides
• Detect dysplasia and malignant transformation during surveillance
• Assess disease activity and response to therapy

2. Normal Colonic Histology as a Baseline

• Yamada's Textbook of Gastroenterology, 7th ed.

3. Ulcerative Colitis (UC)

Macroscopic/Endoscopic-Histologic Correlation

Histological Features of Active UC

Ulcerative colitis - basal plasmacytosis, a hallmark of chronic injury (Yamada's Textbook of Gastroenterology)

Ulcerative colitis - histopathology from colonic biopsy showing crypt distortion and lymphocytic infiltration (Goldman-Cecil Medicine)

• Yamada's Textbook of Gastroenterology, 7th ed.
• Goldman-Cecil Medicine, International Ed.

4. Crohn's Colitis

Distinguishing Features on Biopsy

• Fischer's Mastery of Surgery, 8th ed.
• Yamada's Textbook of Gastroenterology, 7th ed.

5. Differential Diagnosis on Biopsy

5a. Infectious Colitis

• Characterized by a predominance of neutrophils in the lamina propria rather than within the crypt epithelium
• Architectural preservation is supportive of infectious over ulcerative colitis
• Overall chronic inflammation (lymphocytes/plasma cells) is less prominent
• The initial episode of UC may histologically mimic infectious colitis; therefore, infectious etiologies must be excluded before confirming UC

5b. NSAID/Medication-Induced Colitis

• NSAID ulcers are typically abrupt with no significant inflammation in adjacent mucosa and minimal chronic inflammation
• Erosions of NSAID origin have negligible acute inflammation; typically only a few neutrophils
• NSAID strictures ("diaphragms") are circumferential; biopsies show fibrosis with minimal inflammation
• Medications (NSAIDs, statins, PPIs, SSRIs) may cause focal acute colitis or ulcers throughout the colon

5c. Ischemic Colitis

• Marked surface epithelial injury with mucin loss
• "Atrophic microcrypts" and crypt dropout
• Hyalinization of the lamina propria - the normal loose connective tissue is replaced by dense eosinophilic matrix ("lamina propria collapse")
• Residual glands become more closely spaced
• Lack of neutrophil-mediated crypt destruction (contrasts with UC)
• Chronic ischemic colitis can be mistaken for UC, but age, location, muscularis propria involvement, and absence of cryptitis help differentiate

Ischemic colitis - atrophic microcrypts, crypt dropout, and lamina propria hyalinization (Yamada's Textbook of Gastroenterology)

5d. Microscopic Colitis (Collagenous and Lymphocytic)

• Chronic watery diarrhea
• Normal colonoscopy and barium enema
• Specific microscopic features on biopsy despite a macroscopically normal colon

• Thickened subepithelial collagen band (>10 µm)
• Inflamed lamina propria and surface injury
• Predominantly affects middle-aged women (F:M = 6-8:1, median age 55 years)
• Associated with rheumatoid arthritis, thyroid disorders, celiac disease, diabetes mellitus, and NSAID use

• Increased intraepithelial lymphocytes (≥20 per 100 epithelial cells)
• Inflamed lamina propria similar to collagenous colitis
• Separated as a distinct entity by Lazenby et al. (1989)
• Similar clinical associations

• Yamada's Textbook of Gastroenterology, 7th ed.

5e. Focal Active Colitis (FAC)

• A precursor or early manifestation of Crohn's disease (particularly in pediatric patients - up to 27.6% went on to develop Crohn's in some series)
• Infectious diarrhea (most common in adults)
• Bowel preparation artifact

6. Dysplasia Surveillance in Long-standing IBD

• CRC risk in UC begins after 7 years of disease and rises approximately 10% per decade, reaching as high as 34% at 30 years in some series (more recent population data suggest 15-18% at 30 years)
• Risk correlates with duration and extent of disease - universal colitis carries the highest risk
• Crohn's ileocolitis carries a 4-20-fold increased risk over the general population

• Crypts reduced in number, irregularly branched, and crowded ("back-to-back" glands)
• Enlarged, hyperchromatic nuclei
• Increased mitoses
• Pseudostratification (nuclei at different levels, "picket-fence" appearance)
• Classified as low-grade or high-grade

• Sleisenger and Fordtran's Gastrointestinal and Liver Disease

7. Effects of Treatment on Biopsy Interpretation

• Treated UC may show areas of involved and uninvolved mucosa, mimicking the patchy pattern of Crohn's colitis
• Iatrogenic rectal sparing can occur in treated UC, removing the characteristic distal predilection
• Fulminant colitis (toxic UC or fulminant Crohn's): impossible to distinguish on mucosal biopsy alone, because many discriminating features (transmural lymphoid aggregates, granulomas) are deep to the mucosa
• Re-review of original pre-treatment material is essential before a definitive diagnosis of UC vs. Crohn's is made - this is especially important before ileal pouch-anal anastomosis (IPAA), since Crohn's disease is a relative contraindication

8. Biopsy Artifacts to Recognize

• Hypertonic enemas (pre-sigmoidoscopy) may cause flattened surface epithelium, mucin loss, or mild neutrophilic inflammation
• Sodium phosphate bowel prep creates aphthous-like endoscopic lesions that histologically may resemble early Crohn's disease
• Gas insufflation can produce submucosal "pseudolipomatosis" (clear bubble-like spaces)
• Biopsy forceps trauma causes mucosal hemorrhage, crush artifact that may mimic dysplasia, or empty crypts ("squeeze artifact") that may be mistaken for ischemia

9. Summary Table: Key Histological Differences

Recent Evidence

Colorectal Tumours - Short Answer Questions

Q1. What are the risk factors for colorectal cancer (CRC)?

• High animal fat and calorie intake ("Western diet") - associated with increased gut anaerobes (e.g., Fusobacterium nucleatum, Bacteroides fragilis) that convert bile acids into carcinogens
• Obesity and insulin resistance - elevated circulating IGF-I stimulates intestinal mucosal proliferation
• Physical inactivity
• Tobacco use (particularly after >35 years)
• Moderate to excessive alcohol consumption
• Vitamin D deficiency

• Inflammatory bowel disease (UC and Crohn's disease) - risk increases ~0.5-1% per year after the first 10 years; 8-30% of patients develop cancer
• Prior adenoma or carcinoma (3-5% lifetime risk of a second colorectal cancer)
• Family history of colorectal cancer
• Hereditary polyposis syndromes (FAP, MAP, Lynch syndrome)
• Streptococcus bovis bacteremia (associated with underlying colonic neoplasia)
• Age (risk increases significantly after 50 years, but screening is now recommended from age 45)

Q2. Classify colorectal polyps.

Neoplastic Polyps

Non-Neoplastic Polyps

• Size >2 cm
• Villous histology
• High-grade dysplasia
• Multiple polyps

Q3. Describe Familial Adenomatous Polyposis (FAP).

• Incidence: 1 in 10,000 births
• Accounts for <1% of all CRC
• Up to one-third of cases are de novo mutations (no family history)
• Median age of adenoma development: 17 years
• Untreated patients develop CRC at median age 40; death at mean age 44

• Mutations in the "mutation cluster region" of exon 15 produce a virulent phenotype (thousands of polyps, earlier CRC onset)
• Mutations at the 3' end produce a milder (attenuated) phenotype

• Prophylactic colectomy is indicated (total colectomy with ileal pouch anal anastomosis, or subtotal colectomy with ileorectal anastomosis)
• Patients should be followed for extracolonic tumors
• NSAIDs (sulindac, celecoxib) cause polyp regression but do not reliably prevent CRC

Q4. What is Lynch Syndrome (HNPCC)? How is it diagnosed?

• Caused by germline mutation in one of the DNA mismatch repair (MMR) genes:
  • MLH1 (chromosome 3p22)
  • MSH2 (chromosome 2p21-16)
  • MSH6 (chromosome 2p16)
  • PMS2 (chromosome 7p22)
• Also caused by EPCAM gene deletion (causes loss of MSH2 expression)
• Inherited in autosomal dominant fashion
• MMR system failure results in microsatellite instability (MSI) - accumulation of ~1000-fold more mutations compared with MMR-proficient tumors

1. Universal tumor testing: All CRC specimens should be tested by immunohistochemistry (IHC) for MMR proteins OR by microsatellite instability PCR
2. Amsterdam Criteria / Revised Bethesda Criteria: Family history criteria used for patients without a cancer diagnosis
3. Germline testing: Recommended for all patients with deficient MMR on tumor sample or appropriate family history (with pre- and post-test genetic counseling)

Q5. Describe the pathology of colorectal adenocarcinoma.

• Right-sided tumors: often polypoid/exophytic, may grow large before becoming symptomatic (present with iron-deficiency anemia, occult bleeding)
• Left-sided tumors: often annular/constricting ("apple-core" lesion on barium enema), cause obstruction and change in bowel habit
• Sigmoid/rectal tumors: commonly cause rectal bleeding, tenesmus, pencil-thin stools

"Apple-core" lesion - highly suggestive of colorectal carcinoma (Harrison's Principles of Internal Medicine 22E)

• Over 90% are adenocarcinomas (mucin-secreting)
• Arise via the adenoma-to-carcinoma sequence (APC mutation → K-ras activation → loss of DCC/SMAD4 → TP53 mutation → invasive carcinoma) or via the serrated pathway (BRAF mutation → MLH1 silencing → MSI-H)
• Poorly differentiated histology, venous invasion, and perineural invasion worsen prognosis

• Direct: Longitudinally along the bowel wall and radially into pericolic fat, adjacent organs
• Lymphatic: Along lymphatics to regional nodes in orderly progression from paracolic to intermediate to central nodes
• Hematogenous: Most commonly to liver via portal vein (1/3 of patients have liver metastases at diagnosis; 50% develop them at some point)
• Transcoelomic/Peritoneal: Peritoneum, ovaries (Krukenberg tumour), omentum
• Lung is the next most common metastatic site after liver; brain, bone, kidney are less common

Q6. How is colorectal cancer staged?

Dukes' Classification (historical but widely known):

TNM Classification (AJCC - International Standard):

• Tumor penetration through bowel wall into pericolic fat
• Poorly differentiated histology
• Perforation and/or tumor adherence to adjacent organs
• Venous invasion
• <12 lymph nodes sampled (unreliable staging)
• MSI-High / deficient MMR tumors have an improved prognosis (enhanced anti-tumor immune response)
• Right-sided colon cancer has a worse prognosis than left-sided (molecular differences)
• Tumor size itself does not independently affect prognosis when adjusted for nodal status and differentiation

Q7. What is the role of CEA in colorectal cancer?

• Baseline preoperative level: Elevated levels at presentation are associated with worse prognosis
• Monitoring for recurrence: CEA measured at 3-month intervals for 5 years after curative resection. A rising CEA may detect occult recurrence before it becomes clinically apparent
• Assessing response to chemotherapy/targeted therapy
• Not suitable for screening in asymptomatic populations (low sensitivity and specificity; elevated CEA can occur in benign conditions such as liver disease, smoking, and pancreatitis)

Q8. How is screening for colorectal cancer performed?

• FAP: Annual flexible sigmoidoscopy from age 10-12; colectomy when polyps confirmed
• Lynch syndrome: Colonoscopy every 1-2 years from age 20-25 (or 10 years before youngest case in family)
• IBD with pancolitis >8 years: Annual colonoscopy with mapping biopsies

Q9. Describe the surgical management of colon cancer.

• Surgical resection is the standard of care for localized (non-metastatic) disease
• Aims: Wide resection with adequate margins, high ligation of feeding vessels, and removal of the draining lymph nodes
• A minimum of 12 lymph nodes must be harvested for adequate staging
• Laparoscopic/robotic approaches have largely replaced open surgery with equivalent oncologic outcomes

• Stage I: Surgery alone; considered cured
• High-risk Stage II and Stage III: Adjuvant chemotherapy with fluoropyrimidine ± oxaliplatin for 3-6 months
• MSI-high rectal cancers: Checkpoint inhibitors (PD-1 antibodies) may achieve cure without surgery, radiation, or chemotherapy

• Physical exam + CEA every 3 months for 5 years
• Colonoscopy at 1 year, then every 3 years
• CT chest/abdomen/pelvis semi-annually to annually for 3 years

Q10. Describe the management of rectal cancer.

• Higher risk of local recurrence compared with colon cancer
• Proximity to sphincter complex, autonomic nerves, and pelvic structures

• TNM classification (same as colon cancer)
• Pelvic MRI is the preferred imaging modality for staging: determines T and N stage, circumferential resection margin (CRM) involvement, and tumor relation to the anterior peritoneal reflection
• CEA, contrast-enhanced CT chest/abdomen/pelvis for distant staging
• Complete colonoscopy to exclude synchronous lesions (~3% synchronous CRC, ~30% synchronous polyps)
• Multidisciplinary tumor board review is a central quality metric

• Low anterior resection (LAR): Sphincter-preserving; anastomosis above the dentate line; permanent colostomy avoided
• Abdominoperineal resection (APR): For tumors requiring resection of the anal sphincter; requires permanent colostomy; higher local recurrence risk
• Total Mesorectal Excision (TME): The cornerstone of modern rectal cancer surgery. Sharp dissection within the correct embryological TME plane preserves the fascia propria of the rectum and removes the entire mesorectal fat envelope with its lymph nodes. TME has dramatically reduced local recurrence rates and improved survival. For upper rectal tumors, a partial (tumor-specific) mesorectal excision with 5 cm distal mesorectal margin is acceptable.

• Hypogastric plexus (L1-L3): At risk during high ligation of IMA and posterior dissection; injury causes retrograde ejaculation
• Pelvic plexus/nervi erigentes (S2-S4): At risk during lateral dissection; injury causes erectile dysfunction and atonic bladder
• Periprostatic plexus: At risk during anterior dissection in men

• Stages II and III rectal cancer: Preoperative chemoradiation reduces local recurrence
• Combination long-course chemoradiotherapy (5-FU-based) followed by surgery at 6-8 weeks
• Short-course radiotherapy (5 x 5 Gy) is an alternative
• Total neoadjuvant therapy (TNT): Giving full systemic chemotherapy + radiation before surgery; achieves higher rates of complete pathological response
• Organ preservation ("watch-and-wait"): In patients achieving clinical complete response after chemoradiotherapy, surgery may be deferred. Risk of regrowth requires intensive surveillance.
• MSI-high rectal cancers: PD-1 inhibitor (dostarlimab/pembrolizumab) alone may achieve complete response without surgery

Q11. What are the clinical features of colorectal cancer?

• Usually asymptomatic for a long time
• Iron-deficiency anemia (chronic occult blood loss)
• Fatigue, weight loss
• Palpable right iliac fossa mass
• May present with right lower quadrant pain

• Change in bowel habit (alternating constipation and diarrhea)
• Rectal bleeding (fresh or altered blood mixed with stool)
• Abdominal colic
• Features of obstruction (abdominal distension, absolute constipation)
• Pencil-thin stools

• Fresh rectal bleeding
• Tenesmus (feeling of incomplete evacuation)
• Mucous discharge
• Sensation of rectal fullness

• Hepatomegaly (liver metastases)
• Jaundice (biliary obstruction from metastases)
• Ascites (peritoneal spread)
• Cachexia, anorexia, weight loss

Q12. What is the adenoma-to-carcinoma sequence?

1. APC mutation (chromosome 5q): Loss of APC function → accumulation of beta-catenin → dysregulated crypt cell proliferation → formation of an adenoma
2. K-ras mutation (chromosome 12p): Point mutation (codon 12 or 13) → constitutive activation of RAS signaling → promotes cell growth; occurs in the transition from small to large adenoma
3. Loss of DCC/SMAD4 (chromosome 18q): Loss of TGF-beta signaling; associated with intermediate-to-late adenoma
4. TP53 mutation (chromosome 17p): Loss of the "guardian of the genome"; enables transition from high-grade dysplasia to invasive carcinoma

• BRAF V600E mutation
• Widespread CpG island methylation (CIMP)
• MLH1 gene silencing by methylation → MSI-High tumors
• Associated with right-sided location, older women, better prognosis

Q13. What is the "apple-core" sign and what does it indicate?

Q14. Describe total mesorectal excision (TME).

• Introduced by Bill Heald in the 1980s
• Reduced local recurrence rates from ~30-40% to <10%
• Ensures adequate circumferential resection margin (CRM)

• For mid and lower rectal tumors: Full TME down to the level of the levator ani
• For upper rectal tumors: Tumor-specific/partial mesorectal excision with at least 5 cm distal mesorectal clearance

Q15. What are the complications of colorectal cancer surgery?

• Hemorrhage
• Ureteric injury
• Nerve injury (autonomic nerves - retrograde ejaculation, erectile dysfunction, atonic bladder)
• Bowel injury

• Anastomotic leak (5-15%; more common in low pelvic anastomoses)
• Wound infection
• Ileus
• Deep vein thrombosis / pulmonary embolism
• Urinary retention

• Anastomotic stricture
• Adhesion-related bowel obstruction
• Incisional hernia
• Anterior resection syndrome (urgency, frequency, fecal incontinence after LAR)
• Tumor recurrence (local recurrence more common in rectal vs. colon cancer)
• Colostomy complications (prolapse, parastomal hernia, retraction)

Colorectal Tumours - A Comprehensive Discussion

1. Introduction and Epidemiology

2. Classification of Colorectal Tumours

Benign

• Adenomatous polyps (neoplastic, with malignant potential):
  • Tubular adenoma (most common, ~75%)
  • Villous adenoma (highest malignant potential)
  • Tubulovillous adenoma (intermediate)
  • Serrated/sessile serrated lesions (distinct pathway)
• Non-neoplastic polyps (no direct malignant potential):
  • Hyperplastic polyps
  • Hamartomatous polyps (Peutz-Jeghers, juvenile polyps)
  • Inflammatory pseudopolyps (seen in IBD)

Malignant

• Adenocarcinoma (>90% of CRC)
• Squamous cell carcinoma (anal canal, rare)
• Carcinoid/Neuroendocrine tumour
• Lymphoma (rare)
• Gastrointestinal stromal tumour (GIST)
• Kaposi sarcoma (immunocompromised patients)

3. Aetiology and Risk Factors

• High animal fat and red/processed meat intake - increases gut anaerobes (Fusobacterium nucleatum, Bacteroides fragilis) that convert bile acids into carcinogens
• Haem and N-nitroso compounds in meat products
• Obesity and insulin resistance - elevated IGF-I stimulates mucosal proliferation
• Sedentary lifestyle
• Cigarette smoking (especially after >35 years)
• Moderate-to-excessive alcohol intake
• Cholecystectomy (marginally increases right-sided colon cancer risk)

• Inflammatory bowel disease - risk increases at ~0.5-1% per year after 10 years of disease; 8-30% of patients may develop CRC
• Prior adenoma or colorectal carcinoma (3-5% lifetime risk of second CRC)
• Streptococcus bovis bacteremia (strong association with colonic neoplasia)
• Vitamin D deficiency

• Dietary fibre (reduces transit time, reduces carcinogen exposure)
• Aspirin/NSAIDs (inhibit prostaglandin synthesis via COX-2, associated with polyp regression and reduced incidence in cohort studies)
• Calcium and magnesium intake
• Oestrogen replacement therapy (reduces incidence but not mortality in women)

4. Molecular Pathogenesis

4a. The Adenoma-Carcinoma Sequence (Chromosomal Instability Pathway - ~85% of CRC)

1. APC mutation (chromosome 5q21) - occurs in 2/3 of colonic adenomas; earliest event. Loss of APC function allows beta-catenin to accumulate, enter the nucleus, and drive transcription of growth factors (WNT pathway activation)
2. K-ras mutation (codon 12 or 13) - activation of cell signalling pathways; more common in larger lesions, suggesting it is a later event in mutagenesis
3. Loss of DCC/SMAD4 (chromosome 18q) - loss of TGF-beta signalling; associated with intermediate adenoma
4. TP53 mutation (chromosome 17p) - loss of the "guardian of the genome"; transition from high-grade dysplasia to invasive carcinoma

• Distribution of adenomas is similar to that of cancers (70% left-sided)
• Larger adenomas are more likely to be dysplastic
• Majority of early cancers have adjacent adenomatous tissue
• Adenomas are found in one-third of specimens resected for CRC
• CRC incidence decreases within screening programmes that include colonoscopy and polypectomy

4b. Mismatch Repair Deficiency / Microsatellite Instability Pathway (~15%)

• Lynch syndrome (HNPCC): Germline mutation in one MMR gene (MLH1, MSH2, MSH6, or PMS2) plus somatic "second hit." MSH2 and MLH1 each account for ~30% of cases. Autosomal dominant inheritance. Predisposes to CRC arising in the cecum/proximal colon.
• Sporadic MSI-H CRC: Usually due to epigenetic silencing of MLH1 by promoter methylation (CIMP-high) rather than somatic mutation. Often associated with BRAF V600E mutation.

• MSI-H tumours have an improved prognosis (enhanced immune surveillance)
• MSI-H rectal cancers can be treated for cure with PD-1 checkpoint inhibitors alone (without surgery, radiation, or chemotherapy) - a paradigm shift in management
• Universal tumour testing for MMR deficiency (IHC for MMR proteins or MSI PCR) is now recommended for all CRC specimens

4c. Consensus Molecular Subtypes (CMS)

• CMS1: MSI-high (Lynch-type or sporadic); right-sided
• CMS2: WNT and MYC signalling activation
• CMS3: Metabolic dysregulation
• CMS4: TGF-beta activation; worst prognosis

5. Pathology

5a. Distribution by Site

Distribution of colorectal cancer by site (Bailey & Love's Short Practice of Surgery, 28th Ed.)

5b. Gross Morphology

• Right-sided tumours (caecum/ascending colon): Predominantly polypoid/exophytic masses that grow into the lumen. They bleed easily, causing chronic occult blood loss and iron-deficiency anaemia. Obstruction is less common as the stool is still liquid.
• Left-sided tumours (descending/sigmoid colon): Tend to grow in an annular, constricting ("apple-core" or "napkin ring") pattern. Cause obstruction and change in bowel habit because stool is more solid in the left colon.
• Rectal tumours: May be polypoid, ulcerating, or annular. Cause fresh rectal bleeding and tenesmus.

5c. Microscopy

5d. Spread

• Local (direct): Longitudinally along the bowel wall; radially into pericolic fat, adjacent organs (bladder, uterus, posterior abdominal wall, duodenum)
• Lymphatic: Orderly progression from paracolic nodes → intermediate nodes → central/aortic nodes along the course of feeding vessels
• Haematogenous: Via portal vein to liver (most common; one-third of patients have liver metastases at diagnosis; 50% develop them at some point). Lung is the next most common site. Ovary, brain, kidney, bone are less common.
• Transcoelomic/Peritoneal: Spread along the peritoneal surface; may involve ovaries (Krukenberg tumour), omentum, peritoneum

6. Clinical Features

Right-sided Colon Cancer

• Iron-deficiency anaemia (occult bleeding, often without visible blood)
• Fatigue, weakness, pallor
• Palpable right iliac fossa mass
• Right-sided abdominal discomfort or pain
• Weight loss, anorexia (in advanced disease)
• The unexplained presence of iron-deficiency anaemia in any adult mandates endoscopic/radiographic visualisation of the entire large bowel

Left-sided Colon Cancer

• Change in bowel habit (alternating constipation and diarrhoea)
• Dark or altered rectal bleeding mixed with stool
• Abdominal cramping and colic
• Features of obstruction (abdominal distension, absolute constipation, vomiting)
• Radiological "apple-core" lesion on barium enema or CT colonography

Rectal Cancer

• Fresh rectal bleeding (most common presenting symptom)
• Tenesmus (sensation of incomplete evacuation)
• Mucous discharge per rectum
• Sensation of rectal fullness or mass
• Narrow/pencil-thin stools
• Note: rectal bleeding must never be attributed to haemorrhoids without a thorough examination

Features of Advanced/Metastatic Disease

• Hepatomegaly, jaundice (liver metastases)
• Ascites (peritoneal involvement)
• Supraclavicular lymphadenopathy (Virchow's node)
• Cachexia, anorexia, night sweats

7. Investigations

• FBC (iron-deficiency anaemia)
• LFTs, ALP (liver metastases)
• Serum CEA - baseline must be obtained preoperatively; used for monitoring recurrence

• Colonoscopy: Gold standard; allows visualisation of entire colon, biopsy, and polypectomy. Must identify synchronous cancers (~3%) and synchronous polyps (~30%).
• Flexible sigmoidoscopy: If full colonoscopy not possible

• CT chest/abdomen/pelvis (contrast-enhanced): Standard for staging, assessment of lymph nodes, liver metastases
• Pelvic MRI: Mandatory for all rectal cancers - assesses T and N stage, circumferential resection margin (CRM), relationship to anterior peritoneal reflection
• Endorectal ultrasound: Useful for T-staging in rectal cancer; less accurate for nodal involvement
• CT colonography (virtual colonoscopy): Alternative when full colonoscopy not possible
• PET scan: Not routinely recommended for primary staging; useful for suspected recurrence

• MMR protein immunohistochemistry (or MSI testing by PCR) on all resected CRC specimens
• Minimum 12 lymph nodes must be sampled for adequate staging

8. Staging

Dukes' Classification (historical, widely recognised)

TNM Classification (AJCC - International Standard)

TNM staging system and associated 5-year survival rates for colorectal cancer (Harrison's Principles of Internal Medicine 22E)

• Depth of tumour invasion (T stage)
• Number of positive lymph nodes (minimum 12 must be harvested)
• Histological grade (poorly differentiated = worse prognosis)
• Venous invasion, perineural invasion
• Circumferential resection margin (CRM) in rectal cancer
• MSI-H status - associated with improved prognosis despite right-sided location
• Perforation or obstruction at presentation (worse prognosis)
• Tumour size alone does not independently predict prognosis when adjusted for nodal status and differentiation

9. Screening

10. Treatment

10a. Surgical Management of Colon Cancer

• Wide resection with clear margins
• High ligation of the feeding vessel (ensures adequate lymph node clearance)
• Harvest of ≥12 lymph nodes
• Minimally invasive approaches (laparoscopic/robotic) have largely replaced open surgery

10b. Surgical Management of Rectal Cancer

• Higher risk of local recurrence compared with colon cancer
• Anatomic constraints of the pelvis (ureters, bladder, prostate/vagina, iliac vessels, sacrum) make achieving negative radial margins more difficult
• Proximity of autonomic nerves

1. Low anterior resection (LAR): Sphincter-preserving resection; anastomosis proximal to the sphincter; a defunctioning loop ileostomy is usually fashioned temporarily
2. Abdominoperineal resection (APR): Combined abdominal and perineal approach; required when the tumour invades the sphincter; results in permanent colostomy. Historically associated with high local recurrence rates.
3. Local excision (transanal/TEM/TAMIS): Suitable only for select T1 tumours (<3 cm, well/moderately differentiated, no LVI); does not allow nodal assessment; local recurrence rates high (20-40%)

• Sharp dissection within the embryological avascular plane between the visceral fascia propria of the rectum and the parietal presacral fascia
• Removing the entire mesorectal fat envelope (with its blood vessels, lymphatics, and lymph nodes) as an intact, undisturbed package
• This ensures removal of all potential micrometastatic disease and a clear circumferential resection margin (CRM)
• For upper rectal tumours, a partial/tumour-specific mesorectal excision with at least 5 cm distal mesorectal clearance is acceptable
• TME reduces local recurrence from ~30-40% to <10% and improves long-term survival

• Hypogastric plexus (L1-L3): At risk during high IMA ligation and posterior dissection over the sacral promontory - injury causes retrograde ejaculation
• Pelvic plexus/nervi erigentes (S2-S4): At risk during lateral dissection - injury causes erectile dysfunction and atonic bladder
• Periprostatic plexus: At risk during anterior dissection - erectile dysfunction

10c. Adjuvant and Neoadjuvant Therapy

• Stage I: Surgery alone; patients considered cured
• High-risk Stage II and Stage III: Adjuvant chemotherapy (fluoropyrimidine ± oxaliplatin for 3-6 months) improves survival by ~30%
• CEA surveillance every 3 months for 5 years post-resection
• Colonoscopy at 1 year, then every 3 years

Diagnostic and treatment algorithm for rectal adenocarcinoma (Schwartz's Principles of Surgery, 11th Ed.)

• Stage I: Radical resection; local excision only for selected low-risk T1 lesions
• Stage II-III: Neoadjuvant chemoradiation (5-FU-based long-course CRT or short-course 5×5 Gy radiotherapy) before surgery:
  • Reduces local recurrence rates significantly
  • Allows downsizing/downstaging, potentially enabling sphincter preservation
  • Pre-operative approach preferred over post-operative due to better tumour radiosensitivity, lower toxicity, and improved compliance
• Total Neoadjuvant Therapy (TNT): Full systemic chemotherapy + radiation before surgery achieves higher complete response rates
• Watch-and-wait (organ preservation): Patients with complete clinical response after CRT may have surgery deferred; requires intensive endoscopic and MRI surveillance. Tumour regrowth occurs in ~25-30%.
• MSI-H rectal cancer: PD-1 checkpoint inhibitors (pembrolizumab, dostarlimab) achieve clinical complete response in a significant proportion, potentially avoiding surgery altogether

• FOLFOX (5-FU + leucovorin + oxaliplatin) or FOLFIRI (5-FU + leucovorin + irinotecan) ± bevacizumab (anti-VEGF) or cetuximab/panitumumab (anti-EGFR, only for RAS wild-type)
• Resection of isolated liver or lung metastases can be curative in selected patients
• Palliative: colonic stenting, defunctioning stoma, laser ablation, best supportive care

11. Hereditary Colorectal Cancer Syndromes (Detailed)

Familial Adenomatous Polyposis (FAP)

• Gene: APC (chromosome 5q21); autosomal dominant; 1 in 10,000 births; up to 1/3 are de novo mutations
• APC function: Forms a complex that degrades beta-catenin (WNT pathway). Loss of APC → beta-catenin accumulates → nuclear translocation → drives cell proliferation
• Phenotype: Hundreds to thousands of colonic adenomas by late teenage years; 100% risk of CRC if untreated (median age 40)
• Extracolonic: Desmoid tumours, congenital hypertrophy of retinal pigment epithelium (CHRPE), osteomas (Gardner's syndrome), brain tumours (Turcot's syndrome)
• Management: Prophylactic colectomy (total colectomy + IPAA, or subtotal colectomy + ileorectal anastomosis). NSAIDs (sulindac, celecoxib) cause polyp regression but do not reliably prevent CRC. Follow-up for extracolonic manifestations.

Lynch Syndrome (HNPCC)

• Most common inherited CRC predisposition; ~3% of all CRC; up to 17-fold increased risk
• Gene: Germline mutation in MMR genes - MLH1 (Chr 3p22), MSH2 (Chr 2p21), MSH6 (Chr 2p16), PMS2 (Chr 7p22); also EPCAM deletion causing MSH2 loss
• MMR failure → microsatellite instability → ~1000-fold more mutations than MMR-proficient tumours
• Extracolonic cancers: Endometrium (most common), ovary, stomach, small bowel, urinary tract, pancreaticobiliary, brain (Turcot), skin (Muir-Torre)
• Diagnosis: Amsterdam II Criteria (3 affected relatives including 1 first-degree relative, 2 successive generations, one diagnosis <50 years, FAP excluded). Universal tumour testing by MMR IHC or MSI PCR. Germline testing with genetic counselling.
• Surveillance: Colonoscopy every 1-2 years from age 25 (MLH1/MSH2) or 35 (MSH6); every 5 years from 35 for PMS2. Gynaecological screening per 2019 Manchester Consensus.
• Surgery: Extended colectomy (rather than segmental) recommended when cancer develops, to reduce risk of metachronous CRC

12. Prognosis and Follow-up

• The liver represents the most frequent visceral site of metastasis (via the portal vein); one-third of patients have liver metastases at diagnosis, and 50% eventually develop them
• The majority of recurrences occur within the first 5 years after resection
• Anastomotic recurrences are infrequent when margins are adequate
• After curative resection, patients with a previous CRC have a 3-5% risk of a second colorectal carcinoma and a >15% risk of new adenomatous polyps during their lifetime
• Post-resection surveillance: CEA every 3 months × 5 years; CT chest/abdomen/pelvis semi-annually to annually × 3 years; colonoscopy at 1 year then every 3 years

13. Summary of Key Points