A 40-year-old woman underwent colonoscopy for investigation of anaemia. It showed numerous polyps as well as a malignant-looking mass in the descending colon.
a.i. List the polyposis syndromes associated with an increased risk of colon cancer.
1 mark
Model answer
Familial adenomatous polyposis (FAP) — classic, plus Gardner and Turcot variants; attenuated FAP
MUTYH-associated polyposis (MAP)
Peutz–Jeghers syndrome (STK11/LKB1)
Juvenile polyposis syndrome (SMAD4 / BMPR1A)
PTEN hamartoma tumour syndrome / Cowden
Serrated polyposis syndrome
Lynch syndrome (HNPCC) is the commonest hereditary CRC but is not a polyposis syndrome — mention only if hedging.
FAP and MAP produce adenomatous polyps and carry the highest CRC risk through the classic adenoma–carcinoma sequence. Peutz–Jeghers and juvenile polyposis are hamartomatous — lower polyp-for-polyp malignant potential, but cumulative lifetime risk is still substantially raised, partly via accompanying adenomatous change.
b. For Familial Polyposis Coli (classic form): inheritance & molecular abnormality; clinical features; extracolonic manifestations (≥4, two with malignant potential).
3 marks
Model answer
i. Inheritance & molecular: Autosomal dominant (~20–30% de novo). Germline inactivating mutation of the APC tumour-suppressor gene on chromosome 5q21. APC normally promotes β-catenin degradation in the Wnt pathway; loss → β-catenin accumulation and unchecked proliferation.
ii. Clinical features: Hundreds–thousands (>100) of colorectal adenomatous polyps developing from the 2nd decade; essentially 100% lifetime risk of colorectal cancer (mean ~age 35–40) if untreated → prophylactic proctocolectomy.
iii. Extracolonic manifestations:
Duodenal / periampullary adenomas → adenocarcinoma (malignant potential — leading cause of death post-colectomy)
APC is the gatekeeper of colorectal neoplasia and the first hit in the adenoma–carcinoma sequence; FAP follows a two-hit model where the germline mutation is inherited and the second allele is lost somatically. The position of the APC mutation correlates with phenotype — mutations around codons 1250–1450 give profuse (>1000 polyp) disease, while 5' and 3' mutations tend to produce attenuated FAP. Duodenal/periampullary carcinoma is now the leading cause of cancer death after prophylactic colectomy, which is why upper-GI surveillance continues lifelong.
c. Node-negative adenocarcinoma NOS, AJCC Stage II. List the adverse clinicopathologic features that would guide adjuvant chemotherapy.
Poorly differentiated / high grade (excluding MSI-high tumours)
Lymphovascular invasion
Perineural invasion
Clinical bowel obstruction or perforation at presentation
Inadequate nodal yield (<12 lymph nodes examined)
Positive / close circumferential or radial margin
Elevated pre-operative CEA
MMR/MSI status modifies the decision: MSI-high tumours have a favourable prognosis and derive no benefit from (and may be harmed by) single-agent 5-FU — so high-risk features matter most in MMR-proficient/MSS disease.
The absolute survival benefit of adjuvant chemotherapy in stage II is modest (~3–5%), so the decision balances these adverse features against MSI status, age, comorbidity and patient preference (QUASAR). T4 disease and obstruction/perforation carry the greatest weight. When chemo is given it is usually a fluoropyrimidine ± oxaliplatin; benefit of adding oxaliplatin in stage II is unproven and reserved for the highest-risk cases.
d. Two years later: multiple liver lesions, percutaneous biopsy. (i) Microscopic appearance & IHC confirming metastatic colon adenocarcinoma. (ii) Molecular mutations to request and their significance.
3 marks
Model answer
i. Microscopy: Infiltrating glands — complex/cribriform and angulated, lined by tall columnar cells with elongated, hyperchromatic, pseudostratified nuclei; central "dirty" necrosis (necrotic debris/karyorrhexis within gland lumina); desmoplastic stroma. IHC profile:CK20 +, CDX2 +, SATB2 +, CK7 −; nuclear β-catenin. (CK20+/CK7−/CDX2+ is the classic colorectal signature; helps exclude cholangiocarcinoma and upper-GI/pancreatobiliary primaries.)
ii. Molecular testing:
RAS (KRAS & NRAS, exons 2/3/4): mutation predicts lack of benefit from anti-EGFR antibodies (cetuximab/panitumumab); only RAS wild-type respond.
Mismatch repair / MSI (MLH1, MSH2, MSH6, PMS2): dMMR/MSI-high predicts response to immune checkpoint inhibitors (e.g. pembrolizumab) and flags possible Lynch syndrome.
HER2 amplification: emerging therapeutic target in RAS/BRAF wild-type disease.
SATB2 is highly specific for colorectal/appendiceal origin and is the most useful discriminator when CK20 is weak or focal; CDX2 confirms intestinal differentiation but is not site-specific (also positive in upper-GI and some pancreatobiliary tumours). RAS and BRAF mutations are essentially mutually exclusive; testing can be performed on either the primary or the metastasis as the key drivers are usually concordant. Anti-EGFR benefit is also greater in left-sided primaries — relevant here as the tumour is in the descending colon.
Rectal cancer Locally advanced mid-rectal adenocarcinoma
A fit 51-year-old male presents with a 2-month history of rectal bleeding and recent cramping abdominal pain. Sigmoidoscopy and biopsy confirm an adenocarcinoma of the mid rectum through which the scope cannot pass.
a. Discuss your initial evaluation of this patient.
2 marks
Model answer
History & examination: performance status, comorbidities, family history; symptoms of obstruction. Digital rectal examination — distance from anal verge, fixity, sphincter/circumferential involvement.
Confirm histology (biopsy already done).
Local staging — pelvic MRI (rectal protocol): T stage, mesorectal fascia / CRM threat, extramural venous invasion (EMVI), nodal status, height from anal verge. (Endorectal US not feasible — scope can't pass.)
Distant staging: CT chest/abdomen/pelvis for metastatic disease.
Baseline CEA; FBC, renal & liver function.
Complete colonoscopy to exclude synchronous lesions (defer / CT colonography given obstruction).
MDT discussion.
MRI is the cornerstone of local staging: MRI-defined CRM involvement and EMVI are the strongest predictors of local and distant relapse respectively and directly drive the intensity of neoadjuvant therapy. "Mid rectum" (~6–10 cm) matters because tumour height determines sphincter-preservation feasibility and whether the peritoneal reflection is crossed.
b. cT3N2M0 mid rectum — tumour involves the mesorectal fascia, multiple mesorectal & internal iliac nodes, inferior edge 6 cm above anal verge. Discuss your preferred management plan and justify.
2 marks
Model answer
This is high-risk locally advanced rectal cancer: threatened/involved MRF (CRM+) and N2 → high risk of both local and distant relapse.
Preferred: neoadjuvant therapy → TME surgery. Favour total neoadjuvant therapy (TNT) — systemic chemotherapy plus long-course chemoradiotherapy, then total mesorectal excision (low anterior resection).
Long-course CRT is preferred over short-course here because the MRF is involved — downstaging is needed to achieve a clear circumferential margin.
Justify: RAPIDO and PRODIGE-23 show TNT increases pCR and improves disease-free survival / reduces distant metastases; involved MRF mandates downstaging for R0 resection; N2 disease carries high micrometastatic risk warranting up-front systemic therapy.
The two TNT trials differ in design: RAPIDO used short-course RT (25 Gy/5) followed by consolidation chemotherapy, whereas PRODIGE-23 used induction FOLFIRINOX followed by long-course CRT then surgery. Both improve DFS over standard CRT, so the choice hinges on the dominant problem — when the CRM is threatened (as here), long-course CRT is favoured for reliable downstaging; when distant relapse risk dominates, up-front systemic therapy is prioritised. TNT also raises the chance of a complete response, opening the door to organ preservation (part d).
c. A decision is made to proceed with pelvic radiation therapy. Describe a suitable RT technique and dose/fractionation. Justify.
3 marks
Model answer
Simulation: CT planning, prone on a belly board (or supine) with comfortably full bladder to displace small bowel; anal verge marker; IV ± rectal contrast.
Technique: IMRT/VMAT (or 3D conformal). CTV = primary tumour + mesorectum, presacral space, internal iliac and obturator nodes (external iliac if anterior organ involvement); GTV = primary + involved nodes; PTV margin ~0.7–1 cm.
Dose/fractionation:45 Gy in 25 fractions to the elective pelvis with a sequential or integrated boost to 50.4 Gy in 28 fractions to primary + involved nodes (1.8 Gy/fraction), with concurrent capecitabine.
Alternative (within TNT/RAPIDO): short-course 25 Gy in 5 fractions followed by consolidation chemotherapy.
OAR: small bowel, bladder, femoral heads — respect dose constraints.
Justify: concurrent capecitabine radiosensitises and improves local control; long-course schedule allows downstaging of the involved MRF before surgery.
Prone on a belly board lifts small bowel out of the pelvis through the cut-out; a full bladder displaces it further superiorly — together they reduce small-bowel dose and acute diarrhoea. IMRT/VMAT spares small bowel, bladder and pelvic bone marrow versus 3D conformal, but depends on reproducible bladder filling and daily image guidance. Capecitabine is the practical oral equivalent of infusional 5-FU (NSABP R-04 showed equivalence) and avoids a central line.
d. Complete radiological response after neoadjuvant treatment; patient declines definitive surgery. How would you counsel them and what is your subsequent management? Justify.
3 marks
Model answer
Watch-and-wait (non-operative management) is a recognised option for a clinical complete response (cCR), supported by Habr-Gama, the OPRA trial and the International Watch & Wait Database.
Counsel: radiological response ≠ pathological complete response. ~25–30% develop local regrowth, the majority within the first 2 years, and most are salvageable by surgery provided intensive surveillance is maintained. Avoids the morbidity of TME / permanent stoma, but requires commitment to close follow-up and acceptance of regrowth and small distant-metastasis risk.
Confirm a true cCR before committing: DRE (no palpable tumour), endoscopy (white flat scar, telangiectasia, no ulcer/mass) and MRI (mrTRG1, no residual tumour/node).
Surveillance: DRE + endoscopy every ~3 months for 1–2 years, regular pelvic MRI, serial CEA, and CT chest/abdomen for distant disease; lengthen intervals after 2–3 years.
If regrowth: proceed to salvage TME with curative intent. Document the informed, shared decision at MDT.
In the OPRA trial roughly half of patients achieved sustained organ preservation, and salvage TME for regrowth did not compromise oncological outcomes provided surveillance was rigorous. cCR tended to be more durable when chemotherapy was given as consolidation (after CRT) rather than induction. Be explicit with the patient that watch-and-wait trades the morbidity and stoma risk of TME for a lifelong commitment to intensive surveillance — it is appropriate only for a motivated, reliable patient.
Anal cancer Node-positive anal canal SCC
A 39-year-old woman presents with PR bleeding and a 4 cm mass in the anal canal.
a. How would you further evaluate this patient? Justify.
Fertility counselling / ovarian transposition before pelvic RT (age 39).
MDT discussion.
Justify: accurate T and N staging (MRI + PET) defines RT volumes and dose; HIV status and fertility affect the whole treatment plan; histology confirms SCC suitable for definitive chemoradiation.
PET-CT upstages nodal disease in ~15–20% of anal cancers and frequently changes the RT volume and dose-painting. The whole anogenital tract is an HPV "field", so synchronous cervical/vulvar dysplasia is common — hence cervical screening. At 39, ovarian transposition before pelvic RT can preserve ovarian function and should be discussed early, before treatment planning, as it changes the simulation.
b. Biopsy-proven SCC of the distal anal canal, 2 cm right internal iliac node; treat with concurrent chemoradiation. Describe a suitable RT technique and dose/fractionation.
4 marks
Model answer
Simulation: supine, comfortably full bladder, immobilisation, arms up; CT planning; radio-opaque wire marking anal verge, palpable tumour and any nodes; consider bolus over perineum/inguinal nodes.
Technique:IMRT/VMAT with simultaneous integrated boost — RTOG 0529 showed reduced acute GI/skin/haematological toxicity vs 3D conformal.
Concurrent chemotherapy:5-FU + mitomycin C (MMC day 1 ± 29, infusional 5-FU weeks 1 & 5), or capecitabine + MMC.
OAR: small bowel, bladder, femoral heads, external genitalia, iliac crest / pelvic bone marrow.
Definitive chemoradiation is organ-preserving and is the standard of care — surgery is reserved for salvage, since the landmark Nigro work showed up-front APR is unnecessary. Mitomycin C cannot be omitted: ACT II and RTOG 98-11 confirm 5-FU/MMC is superior to 5-FU alone or cisplatin-based regimens, and induction/maintenance chemo adds nothing. Elective inguinal irradiation is mandatory even when nodes are clinically negative because of the high rate of occult involvement and the morbidity of inguinal relapse. Avoid treatment gaps — prolonged overall treatment time worsens local control.
c. Outline your follow-up program for this patient.
1 mark
Model answer
Clinical review with DRE, anoscopy and inguinal node palpation.
First response assessment at ~8–12 weeks; regression can be slow, so allow up to 26 weeks before declaring treatment failure.
Then every 3–6 months for 2–3 years, 6-monthly to 5 years.
Pelvic MRI and/or CT for surveillance; consider PET-CT at ~3 months to confirm complete metabolic response.
The key principle is that regression is slow — a meaningful proportion of complete responders only declare after 3–6 months (ACT II assessed response at 26 weeks). Premature biopsy of irradiated tissue risks anal necrosis and false positives, so serial clinical assessment, not early biopsy, is the mainstay. Most local relapses occur within the first 2–3 years, justifying frequent early review.
d. Residual disease palpable on DRE at the first post-treatment review — how would you manage this?
2 marks
Model answer
Do not rush to salvage surgery — regression after chemoradiation is often slow and may continue for up to 26 weeks.
Reassess with serial examination and re-imaging (pelvic MRI ± PET-CT). If regressing, continue close observation and re-review in 4–8 weeks.
Biopsy only if disease is clearly persistent or progressive — biopsy of irradiated tissue risks necrosis/poor healing and false positives.
If biopsy-proven persistent/progressive disease at ~26 weeks → restage to exclude distant metastases, then salvage abdominoperineal resection (APR) with curative intent.
Manage at MDT.
The trap in this question is the instinct to biopsy or operate immediately — persistence at the first review is not failure if disease is still regressing. Failure is defined by clear persistence or progression confirmed at ~26 weeks. Salvage APR achieves long-term control in roughly 50–60% of those with isolated local persistence/recurrence, but carries significant perineal-wound morbidity, so confirmation of true persistent disease before committing is essential.