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PA23.8 | Colorectal Carcinoma — SDL Guide (Part 2)

Polyposis Syndromes — FAP and HNPCC/Lynch

A four-panel medical diagram compares FAP and Lynch syndrome by polyp burden, genes, molecular pathways, extracolonic cancers, and screening methods. — **Panel A:** FAP colon with hundreds-thousands of colorectal adenomatous polyps, APC mutation at chromosome 5q21, autosomal dominant inheritance, second-decade onset, CRC risk by age 40 if untreated, prophylactic colectomy, duodenal/periampullary polyps, desmoid tumour, CHRPE, osteomas.. **Panel B:** HNPCC/Lynch colon with few polyps and right-sided ascending colon carcinoma, MMR gene mutations MLH1, MSH2, MSH6, PMS2, autosomal dominant inheritance, younger-onset CRC, mucinous or poorly differentiated histology.. **Panel C:** Molecular pathway showing MMR defect causing microsatellite instability with insertion/deletion errors, accumulated mutations, carcinoma formation, and separate APC loss adenoma-carcinoma pathway for FAP.. **Panel D:** Lynch extracolonic cancer associations including endometrial, ovarian, gastric, and urinary tract carcinomas; universal CRC screening with MMR immunohistochemistry and MSI PCR; Peutz-Jeghers contrast note with STK11/LKB1 mutation, hamartomatous polyps, and mucocutaneous melanin spots..

Two major hereditary syndromes account for most familial CRC:

1. Familial Adenomatous Polyposis (FAP)
- Inheritance: Autosomal dominant; germline APC mutation (chromosome 5q21).
- Phenotype: Hundreds to thousands of colorectal adenomatous polyps, typically appearing in the second decade; if untreated, CRC is virtually inevitable by age 40.
- Extracolonic: Duodenal/periampullary polyps, desmoid tumours (Gardner syndrome variant), congenital hypertrophy of retinal pigment epithelium (CHRPE), osteomas.
- Management: Prophylactic colectomy.

2. Hereditary Non-Polyposis Colorectal Cancer (HNPCC) / Lynch Syndrome
- Inheritance: Autosomal dominant; germline mutations in mismatch repair (MMR) genes — most commonly MLH1, MSH2, MSH6, PMS2.
- Molecular consequence: Microsatellite instability (MSI) — repetitive DNA sequences (microsatellites) accumulate insertion/deletion errors.
- Phenotype: Fewer polyps than FAP; CRC often right-sided, arising at younger age (~45 years); mucinous or poorly differentiated histology.
- Extracolonic: Endometrial, ovarian, gastric, urinary tract carcinomas (Amsterdam II criteria).
- Screening: MMR immunohistochemistry ± MSI PCR on all CRC tissue (universal screening).

Peutz-Jeghers syndrome (STK11/LKB1 mutation) causes hamartomatous polyps + mucocutaneous melanin spots; CRC risk elevated but pathway is non-adenomatous.

SELF-CHECK

A 44-year-old woman is found to have a right-sided colon carcinoma. Immunohistochemistry shows absent MLH1 and PMS2 protein expression. Which molecular pathway is most likely driving this tumour?

A. APC/β-catenin chromosomal instability pathway

B. Mismatch repair deficiency with microsatellite instability

C. RAS/RAF serrated pathway

D. TP53 loss with aneuploidy

Reveal Answer

Answer: B. Mismatch repair deficiency with microsatellite instability

Loss of MLH1 and PMS2 by IHC indicates mismatch repair (MMR) deficiency. Absent MMR protein leads to microsatellite instability (MSI-H). This is the hallmark of the Lynch syndrome/HNPCC pathway, and MSI-H CRCs characteristically arise on the right side of the colon, at a younger age, and show mucinous or poorly differentiated histology. MSI-H CRCs also respond to PD-1/PD-L1 immune checkpoint inhibitors.

Molecular Pathways — CIN vs MSI

Side-by-side diagram comparing colorectal carcinogenesis through the CIN pathway with APC, KRAS, SMAD4/DCC and TP53 mutations versus the MSI pathway with mismatch repair loss and microsatellite frameshift mutations. — **Panel A:** CIN pathway: APC loss, β-catenin activation, KRAS activation, DCC/SMAD4 loss on 18q, TP53 loss on 17p, aneuploidy, MSS, left-sided colorectal cancer, conventional adenocarcinoma, sporadic or FAP-associated.. **Panel B:** MSI pathway: MMR gene loss, MLH1 methylation in sporadic cancer, germline MMR mutation in Lynch syndrome, frameshift mutations at microsatellites, diploid or near-diploid tumour, MSI-H, right-sided colorectal cancer, mucinous or medullary histology, pembrolizumab response..

Two principal molecular mechanisms drive colorectal carcinogenesis:

Pathway 1 — Chromosomal Instability (CIN): APC/β-catenin
- Accounts for ~85% of sporadic CRC.
- Initiating event: loss of APC tumour suppressor → unrestrained β-catenin transcription → increased cell proliferation.
- Sequential mutations: APC → activating KRAS → loss of SMAD4/DCC (18q) → loss of TP53 (17p).
- Result: widespread chromosomal gains and losses (aneuploidy), microsatellite stable (MSS).
- Clinically: left-sided predominance, conventional adenocarcinoma, sporadic or FAP-associated.

Pathway 2 — Microsatellite Instability (MSI): MMR deficiency
- Accounts for ~15% of sporadic CRC + most Lynch syndrome.
- Initiating event: loss of MMR genes (MLH1 silenced by methylation in sporadic cases; germline mutation in Lynch).
- Result: frameshift mutations accumulate at microsatellites throughout genome; diploid or near-diploid tumours.
- Clinically: right-sided predominance, mucinous/medullary histology, better prognosis stage-for-stage, respond to immunotherapy (MSI-H = predictive biomarker for pembrolizumab).

IMPORTANT: These pathways are not mutually exclusive but are conceptually distinct; knowing which pathway is active guides molecular testing, hereditary counselling and therapy selection.

Two-column diagram comparing CIN and MSI pathways of colorectal carcinoma with molecular steps, tumor sidedness, ploidy, MSI status, and clinical testing implications. — **Panel A:** CIN pathway showing APC loss, KRAS activation, DCC / SMAD4 loss, TP53 loss, aneuploidy, MSS status, and left-sided colorectal carcinoma association.. **Panel B:** MSI pathway showing mismatch repair loss, MLH1 / MSH2 / MSH6 / PMS2 testing, microsatellite instability, frameshift mutations, diploidy, MSI-H status, right-sided colorectal carcinoma, and better prognosis.. **Panel C:** Clinical correlates showing universal MMR testing, checkpoint inhibitor responsiveness of MSI-H CRC, and the caution that high-grade morphology may still have favorable MSI-H prognosis..

CLINICAL PEARL

Universal MMR testing is now recommended for all newly diagnosed CRC tissue. This single IHC panel (MLH1, MSH2, MSH6, PMS2) identifies Lynch syndrome candidates, guides immunotherapy eligibility (MSI-H CRCs respond dramatically to checkpoint inhibitors), and provides prognostic information. A tumour that is MSI-H has better stage-adjusted survival — but paradoxically tends to be higher grade on morphology. Never assume high grade = poor prognosis without knowing MSI status.

Gross Pathology — Right-Sided vs Left-Sided CRC

Side-by-side pathology diagram comparing right-sided colorectal carcinoma as a polypoid exophytic mass in a wide lumen with left-sided colorectal carcinoma as an annular napkin-ring lesion causing early obstruction. — **Panel A:** Right colon: caecum, ascending colon, wide lumen, polypoid/fungating/exophytic mass, haemorrhagic surface, soft necrotic centre, non-encircling growth.. **Panel B:** Right colon cut-section: wide calibre lumen, liquid faeces, patent lumen, late/uncommon obstruction, occult gastrointestinal bleeding, iron-deficiency anaemia, fatigue, palpable RIF mass.. **Panel C:** Left colon: descending colon, sigmoid colon, rectum, annular constricting carcinoma, napkin-ring lesion, circumferential encirclement, narrowed slit-like lumen.. **Panel D:** Left colon cut-section: narrow calibre lumen, formed/solid faeces, near-complete luminal obliteration, early/common obstruction, colicky LIF pain, altered bowel habit, pencil-thin stools, frank rectal bleeding..

The anatomical side of the colon profoundly influences gross morphology and clinical presentation, because luminal calibre and faecal consistency differ markedly between caecum/ascending colon and descending/sigmoid colon.

Right-sided CRC (caecum, ascending colon)
- Gross form: Polypoid / fungating / exophytic mass — grows into the wide lumen without encircling it.
- Lumen: Wide; liquid faeces → obstruction is late and uncommon.
- Clinical presentation: Occult gastrointestinal bleeding → iron-deficiency anaemia, fatigue, palpable RIF mass. No visible rectal bleeding, no obstruction.
- Cut surface: Soft, haemorrhagic tumour tissue; necrotic centre common.

Left-sided CRC (descending colon, sigmoid, rectum)
- Gross form: Annular / constricting / "napkin-ring" lesion — encircles the narrow lumen circumferentially.
- Lumen: Narrow; solid/formed faeces → obstruction is early and common.
- Clinical presentation: Colicky LIF pain, altered bowel habit (constipation alternating with diarrhoea), pencil-thin stools, rectal bleeding (frank).

Side-by-side diagram comparing a right-sided caecal polypoid fungating colorectal carcinoma with a left-sided sigmoid annular napkin-ring carcinoma causing luminal obstruction. — **Panel A:** Right colon/caecum with wide lumen, polypoid fungating exophytic mass, haemorrhagic friable surface, and anaemia association.. **Panel B:** Left colon/sigmoid with narrow lumen, circumferential annular constricting carcinoma, napkin-ring stricture, near-complete luminal obliteration, obstruction, and pencil-thin stools..

SELF-CHECK

A 70-year-old man presents with progressive obstruction and pencil-thin stools. Colonoscopy reveals a circumferential annular lesion at the sigmoid colon. Which gross morphological pattern does this represent?

A. Polypoid / fungating / exophytic

B. Annular / constricting / napkin-ring

C. Ulcerating with raised edges

D. Diffuse infiltrating (linitis plastica pattern)

Reveal Answer

Answer: B. Annular / constricting / napkin-ring

The sigmoid colon has a narrow lumen and carries formed stool — carcinomas here encircle the wall circumferentially, producing the classic annular 'napkin-ring' stricture that causes obstruction and alters stool calibre. The polypoid/fungating pattern is characteristic of right-sided (caecum/ascending) CRC, which presents with anaemia rather than obstruction. Linitis plastica is a diffuse gastric pattern, not typical of the colon.