Colon and Rectum Flashcards
Describe Hirschsprungs disease
- Absence of ganglion cells in Meissner’s and Auerbach’s plexus
- Distal colon
Tissue sections show decreased ganglion cells and increased nerve fibers.
AKA Congenital aganglionic megacolon
- Suspect when a newborn fails to pass meconium in first 24-48hrs.
- 10% of all cases occur in Down syndrome
Physiology:
- Absence of ganglion cells (likely) due to fsilure to migrate from vagal neural crest.
- Unable to coordinate muscular activity
- Causes spasticity of the affected bowel segment
- Failure to coordinate peristaltic activity
- Results in functional obstruction
Investigation:
- Comfirm with full-thickness rectal biopsy
- There is a naturally occuring hypoganglionic zone at sphincter site near muco-cutaneous junction - Not suitable to diagnose HD!!
Molecular:
- RET gene mutation
Stains:
AChE stain (Acetylcholinesterase)
* Can only be done on frozen sections
* Increased number and thickness of AChE+ nerve fibres in stroma of lamina propria and muscularis mucosae
Calretinin
* Most widely used
* Absence of caslretinin staining in muscularis mucosae and lamina propria of aganglionic segment
Describe Amoebic Colitis
- Entamoeba histolytica
- Faeco-oral route
- Sexual contact (oral-anal)
- Seen in colon - Caecum is most common
- Terminsl ileum ususally spared
- Symptoms can range from mild diarrhoea (most common) to severe dysentery
Micro:
* Broad shaped ulcers
* Trophozoites resembles macrophages
* Seen at luminal surface/within debris
Investigation:
* Stool microscopy
* Nucleic acid amplification tests (NAATs)
* Serological testing for E. histolytica antibodies
Treatment:
* Invasive disease - Metronidazole or Tinidazole
* Luminal cysts - Paromomycin
Describe Intestinal Spirochaetosis
- Brachyspira species
Micro:
* Maintained crypt architecture
* Accentuation, fuzziness and increased basophilia of the lumina surface
* Lamina propria –> mild to moderate lymphoplasmacytic inflammation
Stains
* Warthin-Starry
* Steiner
* Treponema pallidum immunohistochemistry
Treatment
* MEtronidazole
Describe Pseudomembranous Colitis
- Clostridium difficile (25%)
- Clostridium perfringens
- Staphylococcus Aureus
- Presents as acute or chronic diarrhoea
- May cause toxic megacolon and perforation
Risk factors:
* Antibiotics prior to onset
* Typically hospitalised
* Advanced age
* Immunosuppression
Investigation:
* C diff enterotoxin in stool
Macro:
* Hyperaemic mucosa with yellow-green exudate.
Micro:
* Denuded epithelium
* Mucopurulent exudate erupting out of crypts to form a mushroom-like cloud
* Karyorrhectic debris
* Neutrophils adhere to surface
Treatment:
* Vancomycin or metronidazole
* 25% may relapse
Describe Crohn’s Disease
Clinical:
* Onset 20-40 years
* Second peak 50-60 years
* Small bowel involvment (80%)
* Ileocolic involvement (30-40%)
* Transmural
Extraintestinal manifestations
Eyes: Episcleritis, Uveitis
Mouth: Stomatitis, Apthus ulcers
Liver: Steatosis
Biliary: Gallstones, Sclerosing cholangitis
Kidneys: Stones, fistulae
Skin: Erythema nodosum, Pyoderma gangrenosum
Joints: Spondylitis, Sacroilitis
Macro:
* Segmental involvement of the bowel
* Creeping fat –> transmural inflammation
* Thickened/Fibrotic bowel
* Strictures
* Mucosal apthous ulcers –> surrounded by hyperemia
* Cobblestone mucosa –> inflammatory pseudopolyps
* Fissures, sinus, fistulous tracts, abscesses
Micro:
* Skip lesions
* Apthous ulcers and deep fissuring ukcers
* Granulomas (only present in 50%)
* Lymphoid aggregates in subserosal adipose tissue
* Sinus tracks/fistula formation
* Dysplasia may be present in long-standing disease
Describe Ulcerative Colitis
Clinical:
* Onset 15-30 years
* Second peak in 50-70 years
* Chronic active inflammation
* Starts in the rectum, proceeds prioximally
* Continuous diffuse pattern (pan-colitis)
* Changes limited to mucosa and superficial sub-mucosa
* Small bowel usually not involved, but…
* Can see mild inflammation in terminal ileum 20% (backwash ileitis)
* Toxic megacolon
Macro:
* Mucosal erythema
* Granularity, superficial ulceration
* Pseudopolyp formation - due to ulceration and intervening areas of preserved mucosa.
* Toxic megacolon - marked dilation and wall thinning
Micro:
* Crypt architecture distortion –> widespread crypt branching/atrophy/irregular spacing/shortening.
* Inflammatory expansion of lamina propria with basal lymphoplasmacytosis
* Neutrophilic inflammation with cryptitis/abscess
Activity:
* neutrophils
* abscesses
* ulceration
Chronicity
* architectural distortion
* inflammatory expansion of lamina propria
* paneth cell metaplasia or hyperplasia
Dysplasia in IBD
Inflammation –> DNA oxidative damage –> Cancer
- Risk proportion to severity and duration of inflammation
- Cancer risk in inflammatory bowel disease (2% risk)
Screening:
- First 8-10 years after diagnosis –> no increased screening
- Years 10-20 –> every 1-3 years (shorter if severe disease or PSC)
- Years 20 and onwards –> 1-2 years
If indefinite for dysplasia:
- Usually because of inflammation –> reactive vs dysplastic
- Treat active disease
- Repeat biopsy in 3-12 months
Intervention:
- Resection endoscopically (if seen)
- Needs meticulous colonoscopic follow up
- Proctocolectomy –> if endoscopic resection not possible, non-visible HG dysplasia or adenoCa found.
Describe Ischaemic Colitis
- Leading cause of acute abdomen in the elderly
Site:
* Watershed areas –> splenic flexure and rectosigmoid
Micro:
* Prominent hyalinization of lamina propria
* Haemorrhage
* Withered or atrophic crypts
* Surface epithelium my show regenerative changes
Microscopic Colitis
Two Types:
* Lymphocytic colitis
* Collagenous colitis
Clinical:
* Cause of chronic non-bloody, watery diarrhoea
* Some are asymptomatic
* Associated with autoimmune disorders –> Thyroiditis, Coeliac disease, Diabetes, Psoriasis, Rheumatoid
- Colon, Right > Left, Rectum
- Females > Males
Causes:
* Idiopathic
* Viral infections
* Medications –> NSAIDS, Olmesartan, antidepressants
Lymphocytic Colitis:
* Colonic intraepithelial lymohocytosis (>20 per 100 enterocytes
* Diffuse increase in lamina propria inflammatory cells
* Preserved/Intact crypt architecture
Collagenous Colitis:
* Strong female predominance
* Strong association with certain medications –> NSAIDs, aspirin, PPI, H2 receptor agonists, SSRI
- Subepithelial collagen band
- Intraepithellial lymphocytosis
- Mixed inflammation in the lamina propria
- Surface mucosal damage
- Preserved crypt architecture
Diversion Colitis
- AKA Defunctionalised bowel
- Due to dietary deprivation of short chain fatty acids niormally produced by colonic bacteria
- Mild colitis with crypt abscesses
- Marked lymphoid hyperplasia –> initially in lamina propria, but later transmural
**Later in disease: **
* Muscularis mucosa hypertrophy
* Fatty and fibrous infiltration of submucosa
* Thickened muscularis propria and narrow lumen
Mucosal prolapse syndrome/Solitary rectal ulcer syndrome
- Stupid name
- Not always solitary, not always rectal, not always ulcerated, not really a syndrome
- Solitary or multiple uklcerated or polypoid lesions
- 4-10cm from anal margin
- More common in women
- Rare
Cause:
* Abnormal function of anal and pelvic floor musculature during defication
* Causes rectal mucosal prolapse or intussusception
Micro:
* Polypoid
* Crypt hyperplasia
* Cystic dilation
* Haphazardly arranged benign crypts
* Fibroblasts and smooth muscle proliferation
Angiodysplasia
- Arteriovenous malformation
- Angiodysplasia describes distinct GI mucosal vascular ectasias
- Not associated with cutaneous lesions, systemic vascular disease or familial syndrome
- Usually right colon
- Can occur anywhere in small intestine or colon
- Colon > Small intestine > Stomach
Clinical:
* Melena/bright red bloody stool
* May be associated with aortic stenosis or **von willebrand disease **
Micro:
* Numerous thin and thick walled dilated blood vessels
* Throughout the colonic submucosa and mucosa
GVHD
- Graft vs Host Disease
- Complication of allogenic stem cell transplantation
- T Cells from the donor recognise recipient tissue as foreign
- Cytokine storm
- Leads to organ damage
Site:
Skin > GI tract > Liver
Micro:
* Crypt apoptosis
* Crypt dropout
* Ulceration
* Inflammation tends to be sparse
Grading:
LERNER system
I: Crypt apoptosis without crypt dropout
II: Single crypt dropout
III: Contiguous crypt dropout
IV: Diffuse crypt dropout with ulceration
Conventional colorectal adenoma
Subtypes:
* Tubular adenoma
* Tubulovillous adenoma
* Villous adenoma
Risk of malignancy depends on:
* Higher number of lesions
* Larger Size –> 0.5% risk if <1cm, 10% risk if >2cm
* Higher proportion of villous architecture
* Extent of high-grade dysplasia
- Polyps with HG dysplasia are pTis
Tubular –> 2-3% cancer risk
Tubulovillous –> 6-8% risk
Villous –> 18% risk
Molecular:
Chromosomal Instability Pathway (Most Common)
APC –> KRAS –> p53 (also beta catenin and SMAD4)
Lynch Microsatellite Instability Pathway
Germline MMR mutation –> Loss of heterozygosity –> Microsatellite instability
Tubular Adenoma
- 80-85% of all adenomas
- At least 75% tubular component
- All tubular adenomas show dysplasia
- More commonly in the left colon
- When multiple (>10) —> may indicate FAP
Macro:
Small, round, pedunculated
Micro:
Round or oval glands
Molecular:
KRAS
P53
MGMT loss
APC
Beta Catenin
IHC:
BCL2
CEA
Tubulovillous and Villous Adenoma
Tubulo-villous adenoma
- Mix of both tubulae and villous architecture
- Villous architecture must compire at least 25% of the adenoma
Villous adenoma
- Finger-like, leaflike epithelial fronds
- Fronds contain vascular cores lined by dysplastic epithelium
- Villous architecture comprises >75% adenoma
- KRAS activation
- tumour suppressor genes APC, SMAD4 and P53 inactivation
Villous and tubulovillous is associated with increased risk of colorectal neoplasia
16.8% versus 9.7% in tubular adenoma
Serrated Polyps
- Columnar cells with mucin depleted, eosiniphilic cytoplasm
- May show dysplasia
- Ectopic crypts
- Contain either BRAF or KRAS mutation
- BRAF-mutated MMR-deficient carcinoma
- BRAF-mutated MMR-proficient carcinoma
- KRAS-mutated MMR-proficient carcinoma
Hyperplastic Polyp
- Most common colonic polyp
- Small, <10mm
- Usually sessile
- Usually left side of colon
- Non significant potential for malignant degeneration
BRAF gene mutations –> Microvesicular variant
KRAS gene mutations –> Goblet cell rich variant
If found in the right side of colon… consider SSL
Sessile Serrated Lesion
- Premalignant lesion of the colorectum
- Most frequently in right colon
- Lesions >10mm or with HG dysplasia –>manage like high risk adenoma
Molecular:
- BRAF (V600E) mutation
- CpG island methylator phenotype (CIMP)
- These lead to microsatellite instability due to promotor hypermethylation of MLH1
Micro:
- Dilation/lateral spread of crypts at base of the lesion
- Sawtooth appearance
Traditional Serrated Adenoma
- Least common
- Neoplastic precursor lesion –> Aggressive BRAF mutated microsatellite instability (MSI) stable subtype of colorectal carcinoma
- More often in rectosigmoid
Macro:
* Pedunculated
* Villiform architecture
* Resemble tubulovillous adenomas
Micro:
* Villiform architecture
* Columnar cells with abundant mucin-depleated eosinophillic cytoplasm
* Hypochromatic nuclei
* Minimal atypia
* Ectopic crypts
Treatment:
* Endoscopic removal of the adenoma
Haggitt and Kikuchi Classifications
Haggitt Classification
* Depth of invasion in malignant **pedunculated **and sessile polyps
* Level 1: confined to head of polyp
* Level 2: at junction of head and stalk
* Level 3: confined to anywhere in the stalk
* Level 4: Invasion into the submucosa
Note: a sessile polyp has no stalk, so it automatically classified as Haggit level 4
Kikuchi Classification
* Depth of invasion into the submucosa of a malignant sessile polyp
* Sm1: upper 1/3 of submucosa
* Sm2: upper 2/3 of submucosa
* Sm3: lower 1/3 of submucosa
What are the major hamartomatous polyposis syndromes
- Juvenile polyposis syndrome
- Peutz-Jeghers syndrome
- Cowden disease
- Bannayan-Riley-Ruvalcaba syndrome
- Cronkite-Canada syndrome
Juvenile Polyp
- AKA retention polyps
- 70% occur in children <10 years
- Majority are solitary
- Multiple may indicate a premalignant syndrome –> juvenile polyposis or juvenile polyposis syndrome
Prognosis:
* Extremely low risk of malignancy, unless syndromic
* Recurrence is common
Macro:
* Single pedunculated cherry-red polyps
* Smooth surface and contour
Micro:
* Surface shows ulceration and granulation tissue with regenerating epithelium
* Maybe mistaken for dysplasia
* Cystic spaces –> abundant mucin and inflammatory debris
* Glands are separated by expanded oedematous lamina propria containing inflammatory cells
Juvenile Polyposis Syndrome:
* 3-5 juvenile polyps in the colorectum OR
* Juvenile polyps throughout the GI tract OR
* Any number of juvenile polyps with a positive family history of juvenile polyposis
Autosomal dominant
Mutation:
* SMAD4
* BMPR1A
Peutz-Jeghers Polyp/Syndrome
Autosomal dominant
Mutation:
* LKB1
* STK11
* On chromosome 19p
* Encodes serine/Threonine kinase
Clinical:
* Hamartomatous polyps throughout GI tract
* Small intestine > Colon > Stomach
* Mucocutaneous hyperpigmentation and macules on gentalia and palms/soles
* Marked increase in several malignancies –> Colon, Breast, Ovary, Cervix, Lung, Pancreas, Thyroid
* 1/3 of patients with sex cord tumor with annular tubules have Peutz-Jeghers syndrome.
* Almost all women with Peutz-Jeghers syndrome develop sex-cord tumor with annular tubules.
* Men may get calcifying sertoli cell tumors.
Micro:
* Complex glandular architecture
* Normal appearing epithelium
* Lamina propria with arbourising smooth muscle fascles
* Paneth cells may also be present
* Dysplasia is rare
Cronkhite-Canada Syndrome
Non-Hereditary Syndrome
Currently considered idiopathic
- Multiple polyps of the digestive tract
- Anomalies of ectodermal tissues
GI manifestations:
* Polyps found in Stomach > Large intestine > Small intestine > Oesophagus
* Non-malignant
* Strawberry like
Other manifestations:
* Ectodermal tissues
* Alopecia
* Atrophy of nails
* Skin pigmentation
Cowden syndrome/ Multiple Hamartoma syndrome
Autosomal dominant
Mutation:
* PTEN
* Tumour suppressor gene
* 10q22
Characterisation:
* Non-cancerous tunour like growths (hamartomas)
* Skin
* Mucous membranes –> mouth, nasal membranes, GI tract
* Thyroid
* Breast
At risk to certain forms of cancer:
* Breast carcinoma
* Thyroid carcinoma
* Endometrial carcinoma
* Kidney carcinoma
Bannayan-Riley-Ruvalcaba Syndrome
Autosomal dominant
- Overgrowth/hamartomatous disorder
- Multiple subcutaneous lipomas
- Macrocephaly
- Haemangiomas
- Dark penis freckles on penis
Mutation:
PTEN
Adenomatous polyposis syndromes
- Familial Adenomatous Polyposis (FAP)
- Gardner’s
- Turcot’s
- Hereditary Nonpolyposis Colon Cancer HNPCC (Lynch’s Syndrome)
FAP
Autosomal dominant
* 20-25 years of age
* 1% all colorectal cancers
- Germline mutation
- APC gene (5q21)
- > 100 colorectal adenomatous polyps
- Left colon/Rectum
- Can develop fundic gland polyps and small intestinal polyps
- 100% lifetime risk of colorectal adenoCa
Diagnostic Criteria:
- 100 or more colorectal adenomatous polyps OR
- Germline mutation in APC OR
- Family Hx of FAP with colorectal adenomas (age <30)
- Family Hx of FAP with at least one epidermoid cyst, osteoma or desmoid tumour
Variants
- Gardner syndrome
- Turcot syndrome
- Attenuated familial adenomatous polyposis (AFAP)
AFAP –> fewer, more prox colonic distribution and later onset polyps and cancer
Gardner’s Syndrome
- Varient of FAP
- Prominent extraintestinal manifestations
Extracolonic tumours:
* Osteomas of the skull
* Thyroid cancer
* Epidermoid cysts
* Fibromas
* Desmoid tumours
Turcot’s Syndrome
Either:
- **APC mutation **–> FAP and usually medulloblastoma
OR
- MMR gene mutation –> Lynch syndrome with glioblastoma multiforme
HNPCC
- Autosomal dominant
- 44 years onwards
- 5% all colorectal cancers
- Right colon
- Mutation of DNA mismatch repair (MMR) gene
- Most commonly germline mutation in MSH2 or MLH1
- Less frequently due to MSH6 or PMS2
MLH1 partners with PMS2
MSH2 partners with MSH6.
Tumors that are MMR deficient have a better prognosis, are not prone to metastasis, and require less aggressive treatment.
MLH1 and MSH2 are the dominant partners, so if one of these is lost, it’s partner will be lost too.
If the non-dominant partner is lost, the dominant partner will remain.
It is much more likely to have the loss of one protein due to mutation than two proteins.
HNPCC Increased risk of cancers:
- Endometrial carcinoma (33%)
- Ovarian carcinoma (5%)
- Small bowel
- Stomach
- Upper urinary tract
- Brain
Muir Torre Syndrome –> Clinical variant
Diagnostic Criteria:
* Amsterdam
* Revised Bethesda Criteria
Colon carcinoma
Risk factors:
* Older age
* Obesity
* Physical inactivity
* Alcohol
* IBD
* Schistosomiasis
* Family Hx
Polyposis Syndromes:
* FAP –> APC gene
* Lynch Syndrome –> MLH1, MSH2, MSH6, PMS2 genes
* Juvenile Polyposis –> SMAD4, PTEN genes
* Peutz-Jeghers Syndrome –> STK11 gene
Dietary risk factors:
* Low veg fibre
* High refined carbs
* Increased beef consumption
* Decreased vitamin A, C, E
Prognostic factors:
* Stage is most important prognostic factor
* Signet ring –> poorer prognosis
* Mucinous histology –> poorer prognosis
* Microsatellite instability better prognosis than stability
Medullary AdenoCa
- Usually right sided
- High degree of microsatellite instability –> loss of normal DNA repair gene
- Often better outcome independent of stage
- 5-FU not as effective as with other MSI tumours
Micro:
* Sheets of poorly differentiated cells
* Pleomorphic
Molecular:
* Associated with MSI —> can be sporadic or Lynch Syndrome
* BRAF mutations common
Markers:
* CK7 +
* Calretinin +
- CDX2 -ve
- CD20 -ve
- Weird for intestinal differentiation
Mucinous AdenoCa
- Usual Right sided
- Same or worse prognosis than standard AdenoCa
- Typically presents at more advanced stage
- Greater nodal involvement than standard AdenoCa
Molecular:
* KRAS more common
* TP53 less common
