Colon Pathology and Polyps Overview

Definitions

• Polyp: A mass protruding into the lumen.
• Neoplasm: Excessive, autonomous, and uncoordinated tissue growth.
• Dysplasia: Abnormal cells with malignant features but no invasive or metastatic potential.
• Adenocarcinoma: Invasive carcinoma with glandular differentiation, has metastatic potential.
• Hamartoma: An abnormal tissue arrangement native to the site, both neoplastic and non-neoplastic forms exist.

Normal Colon

• The colon is comprised of several layers: mucosa, subserosa, muscularis propria, serosa, crypt, lamina propria, and muscular mucosa.

Types of Polyps in Colon

• Epithelial: Most common, including hyperplastic polyps, adenomas, carcinomas, and neuroendocrine tumors.
• Non-Epithelial: Includes neoplastic (lipomas, gastrointestinal stromal tumors (GIST), neural and vascular tumors, lymphoma), inflammatory (e.g., chronic inflammatory bowel disease, rectal prolapse), and hamartomas.

Symptoms of a Polyp

• Asymptomatic: Many polyps have no noticeable symptoms.
• Frank bleeding: Especially if large or located on the left side.
• Occult bleeding: More common on the right side, detected through screening.
• Anemia: Can be caused by chronic blood loss.
• Metabolic changes: e.g., hypokalemia with villous adenomas (VA).
• Large polyps: May cause altered bowel habit, obstruction, or intussusception.

Intussusception

• Occurs when a part of the colon telescopes into an adjacent portion, caused by a mass.
• Leads to obstruction.

Hyperplastic Polyp

• Common, primarily in the recto-sigmoid region.
• Usually under 0.5 cm.
• Asymptomatic.
• Hyperplastic mucosa.
• Rarely has malignant potential.
• Removed at colonoscopy.

Sessile Serrated Lesion

• Type of hyperplastic polyp, found mainly on the right side.
• Serrated crypts with an asymmetric architecture at the base.
• No dysplasia present.
• May be a precursor for sporadic carcinomas.
• Removed at colonoscopy, no need for clear margins.

Adenomas

• Common in middle-aged adults.
• More frequently found on the left side of the colon.
• Contain dysplastic epithelium.
• Can be pedunculated or sessile.

Tubular Adenomas (TA)

• Pedunculated tubular adenoma is a common type.

Villous (Sessile) Adenomas

• Broad-based, sessile villous adenoma.

Villous Adenomas (VA)

• Characterized by finger-like projections.

Risk of Adenoma Progressing to Malignancy

• Increased size: Risk increases with size, especially for adenomas greater than 40 mm.
• High-grade dysplasia: Presence of high-grade dysplasia significantly increases the risk.
• Villous growth: Higher proportion of villous growth increases risk.
• Number of adenomas: Multiple adenomas increase risk.
• Molecular profile: Emerging importance in future risk prediction.

Management of Adenomas

• Removal at colonoscopy: TAs often completely excised, complete excision not always necessary for TAs without high-grade dysplasia (HGD).
• Clear margins: HGD necessitates complete excision with clear margins, large VAs may require surgery to obtain clear margins.
• Surveillance: Regular follow-up based on risk factors (e.g., number, type, and size of adenomas).

Hamartoma

• Uncommon, found throughout the gastrointestinal tract.
• Disorganized arrangement of normal structures.
• Typically solitary.
• Removed at colonoscopy.
• Can be part of a syndrome if multiple.

Colorectal Carcinoma: Epidemiology

• Third most common cancer and cause of cancer mortality.
• Peak age of diagnosis is 60-70s.
• Data available for Ireland shows cases, rates, and deaths between 2018-2020, broken down by gender.
• Prevalence varies based on age group for both males and females.

Colorectal Carcinoma: Risk Factors

• Dietary: High caloric diet, high fat and refined carbohydrates, low vegetable and fiber intake.
• Smoking: Increases risk.
• Sedentary lifestyle: Increases risk.
• Aspirin: Shown to be protective.
• Sporadic adenomas: Presence of adenomas increases risk.
• Family history: Risk increased with relatives with adenomas or CRC.
• Strong family history Risk x 2-3 with one first-degree relative with CRC, x 3-4 with multiple family members affected, and x 4 if cancer diagnosed at a young age (45-59 years).

### Carcinoma and CIBD

• Increased risk in long-standing ulcerative colitis with pancolitis.
• Overall incidence is low.
• Symptoms may be masked by underlying disease.
• Multiple carcinomas can occur without obvious masses.
• Mechanisms not fully understood, potentially involving oxidative stress.

Colon Cancer Cases Arising in Various Family Risk Settings

• Sporadic cases: Majority of cases.
• Familial risk: 10% to 30% of cases.
• Lynch Syndrome: 2% to 3% of cases.
• Hamartomatous polyposis syndromes: Less than 0.1% of cases.
• Familial adenomatous polyposis: Less than 1% of cases.

Common Polyposis Syndromes

• Adenomas: FAP, Attenuated FAP, Gardner, Turcot, MYH-associated Polyposis (MAP).
• Hamartomas: Peutz-Jeghers, Juvenile Polyposis.

Polyposis Syndromes: FAP

• Autosomal dominant inheritance.
• Germline mutation in the APC gene.
• APC is a tumor suppressor gene.
• More than 100 adenomas in the large bowel.
• Adenomas and carcinoma in the small bowel and stomach.
• 100% risk of progression to colorectal carcinoma.
• Extra-GI manifestations: fibromatosis, cysts, CHRPE, carcinoma of thyroid, adrenal, pancreas, bile duct, etc.

Lynch Family Syndrome (HNPCC)

• Autosomal dominant.
• Mutations in DNA mismatch repair (MMR) genes.
• 80% lifetime risk of CRC.
• Onset around 45 years.
• Rapid growth.
• Predominantly on the right side, multiple tumors, mucinous subtype, dense lymphocytic infiltrate.
• Also linked to carcinoma of the small bowel and endometrium.

Molecular basis of CRC: Pathways that Drive Colonic Neoplasia

• Chromosomal Instability (CIN): Sporadic and hereditary (e.g., FAP).
• Microsatellite Instability (MSI): Sporadic methylation and Lynch Family/HNPHCC.

Chromosomal Instability (CIN) Pathway

• Mechanism for cancers arising in FAP and 80% of sporadic carcinomas.
• Stepwise accumulation of genetic aberrations.
• Number of mutations is more important than the sequence, generally 4-5 molecular events in key pathways are needed.
• Tumors show aneuploidy and chromosomal losses.
• CIN effectively leads to the loss of wild-type alleles of tumor suppressor genes.

CIN (APC) Pathway

• Shows the progression from normal epithelium to small adenoma, large adenoma, and carcinoma.
• Key genes involved are APC, RAS, PI3K, Cell Cycle/Apoptosis, and TGF-β.

Microsatellite Instability (MSI) Pathway

• Found in 10-15% of sporadic cancers and tumors arising in HNPCC/Lynch Family Syndrome.
• Loss of mismatch repair (MMR) protein function.
• Morphological sequence not fully understood compared to CIN pathway.

Microsatellite Instability (MSI) Pathway Role of Mismatch Repair Proteins

• Shows MMR proteins (MLH1, PMS2, MSH2, MSH6) involved in DNA mismatch repair during replication.
• MMR proteins form heterodimer pairs.

Role of Mismatch Repair Proteins in CRC

• Epigenetic hypermethylation in sporadic cases.
• Defects in MMR coding genes lead to reduced repair of specific DNA damage.
• Germline mutations in MMR genes (Lynch Syndrome/HNPCC) drastically increase mutation rate in microsatellite DNA, leading to colorectal carcinoma.

Microsatellite Instability (MSI) Pathway

• Germline or somatic mutations in mismatch repair genes.
• Alteration of the second allele by LOH, mutation, or promoter methylation.
• Microsatellite instability ("mutator phenotype").
• Accumulated mutations in genes regulating growth, differentiation, and/or apoptosis.
• TGFbR, BAX, BRAF are often affected (not p53, KRAS).

Classic Presentation: Right-Sided carcinoma

• Symptoms: Subtle, related to occult blood loss (fatigue, pallor, iron deficiency anemia).
• Signs: Vague mass in the right iliac fossa, possible altered bowel habit.
• FOB test: Positive.
• Differential Diagnosis: Other causes of IDA, appendiceal mass, adenoma or other tumor, ovarian mass.

Classic Presentation: left-sided tumor

• Symptoms: Altered bowel habit (constipation or diarrhea), rectal bleeding, possible abdominal pain.
• Signs: Left iliac fossa mass.
• Differential Diagnosis: Adenoma, colitis (e.g., CIBD), diverticular disease, rectal prolapse, other tumors.

Diagnosis of CRC requires tissue obtained at colonoscopy

• Microscopy: Biopsy shows adenocarcinoma in over 90% of cases.
• Cytokeratin Profile Characteristic profile of CK20+, CK7-, CDX2+.

Mucinous adenocarcinoma is more common in MSI-positive CRC

• Shows microscopic images of colonic adenocarcinoma including pools of extra-cellular mucin and intra-cellular mucin (signet ring cells).

Staging

• CRC spreads through direct extension, lymphatics, and blood.
• Staging is performed by radiology.