Download Colon Polyps and Polyposis Syndromes

7/24/2012
Colon Polyps and Polyposis Syndromes
Douglas K Rex
Two histologies account for 99% of colorectal polyps
• Adenomas and adenomas with invasive carcinoma
• Serrated polyps
– Hyperplastic polyps
– Sessile serrated adenomas (SSAs)
– Traditional serrated adenomas (TSAs)
1
7/24/2012
Polyp classifications
• Shape • Size
• Histology
Shape – Paris Classification
2
7/24/2012
Shape classification
• Type 1 – the “polyps”
– Pedunculated (1p) – about 5% of all polyps
– Sessile (1s)‐ about 50% of all polyps
• Type 2 – 40‐50% of all precancerous lesions – also called “flat and depressed lesions” or “Non‐
polypoid colorectal neoplasia”
– Flat • IIa ‐very common and not scary
• IIb‐ rare and not scary
– Depressed (IIc, IIa+IIc,IIc+IIa)‐ very uncommon and very bad histology
Features indicating adenomas – red headed pedunculated polyps
3
7/24/2012
Sessile Polyps – Shape 1s
Flat Lesions – Paris Classification
IIa IIb
4
7/24/2012
IIa (flat) lesions in white light
Depressed
5
7/24/2012
Polyp shape
• Lateral spreading tumor (essentially a large IIa lesion: often called “carpet lesion” in U.S.)
– Granular (most common, least worrisome)
– Non‐granular( less common, worse histology)
Lateral Spreading Tumor
6
7/24/2012
• Any given endoscopic technique is more likely to miss flat and depressed lesions than polypoid lesions
Polyp size
• Usual groupings
– Diminutive (1‐5mm) – about 80% of all polyps
– Small (6‐9) – about 10% of all polyps
– Large (≥ 10 mm) – about 10% of all polyps
7
7/24/2012
Polyp size vs histology
Size %adenoma % serrated
1‐5 mm 50% 50%
6‐9 mm 60% 40%
≥ 10 mm 85% 15% Adenomas
• All adenomas are dysplastic
• Atypia is an improper term in the description of adenomas
• Dysplasia should be classified as low grade or high grade
– Mild,moderate,severe: too much interoberserver
variation
• Most adenomas have LGD
• Pathologists may use different definitions of HGD
– Morphologic criteria: lower rates of HGD
– Cytologic criteria: higher rates of HGD
8
7/24/2012
Discouraged (outdated) terms
• Carcinoma‐in‐situ: severe dysplastic changes confined to the epithelium
• Intramucosal carcinoma: dysplasia is present in the lamina propria but not the mucosa
• Both “carcinoma‐in‐situ” and “intramucosal
carcinoma” should be designated HGD
– Both are benign – patients with completely resected polyps are cured 100% of the time
9
7/24/2012
Definition of cancer in the colon
• Invasion of dysplastic elements into the submucosa
– Why this definition? Because there are no lymphatics in the mucosa: lesions confined to the mucosa have no chance of metastasis
10
7/24/2012
Villous vs Tubular
• Villous: greater risk of HGD and invasive cancer
11
7/24/2012
Tubular vs Villous
• Tubular: > 75% tubular
• Villous: > 75% villous
• Tubulovillous: < 75% of both
– Polyps with either villous or tubulovillous histology are often said to have “villous elements”
• Marked variation in pathologic interpretation: up to 6 fold differences between pathologists
12
7/24/2012
Advanced adenoma
• Concept developed as a surrogate marker of risk in post‐polypectomy studies
• Most common definition is an adenoma with any of the following:
– Size ≥ 10 mm
– HGD
– Villous elements
Impact of variable interpretation of HGD
• Randomized controlled trials of diffuse dye‐
spraying (chromoendoscopy) • Sheffield, U.K. (Hurlstone‐260 pts) and St Mark’s London,U.K. (Brooker – 259 pts)
13
7/24/2012
Impact of variable interpretation of HGD
• Adenoma cohort RCTs colonoscoped at 1 and 3‐4 years
• National Polyp Study and rofecoxib trial
When is endoscopic resection of a malignant polyp adequate?
• Rules developed for pedunculated malignant polyps:
– Clear margin
– Well or moderately differentiated
– No lymphatic or vascular invasion
– Endoscopist confident of complete resection
14
7/24/2012
Serrated polyps
• Hyperplastic polyps in distal colon – Mostly diminutive and mostly clinically insignificant
• In proximal colon these lesions share molecular features with a group of cancers in the proximal colon
– CpG Island Methylator Phenotype (CIMP)
– Sometimes with MSI (hypermethylation of MLH1)
– BRAF mutations
Typical proximal colon serrated polyps
15
7/24/2012
Serrated Polyps
• TSAs are more obvious endoscopically
• SSAs can have cytologic dysplasia and can be endoscopically very subtle
• Marked interobserver variation between pathologists in interpretation of SSA vs
hyperplastic
• Risk for individual patients should consider number, size, location and histology of serrated polyps
Sessile serrated adenomas
16
7/24/2012
SSAs
Follow up of proximal colon serrated polyps
• New recs coming for surveillance
• Problems:
– Miss rate unknown
– Interobserver variation in pathologic interpretation
– Significance of histology uncertain: sessile serrated polyp (adenoma) > hyperplastic polyp 17
7/24/2012
Serrated polyposis syndrome
• WHO definition (not yet validated)
– ≥ 5 serrated polyps proximal to sigmoid of which ≥ 2 are > 1 cm in size
– 1 serrated polyp proximal to the sigmoid in patient with FDR who has SPS
– > 20 serrated polyps “throughout the colon”
• Many patients with SPS do not have a family history of SPS or CRC
• Associated with smoking
• Genetic basis not yet established
Follow up of proximal colon serrated polyps
• Aggressively search for and resect • Consider number, size, and histology of lesions in considering follow up intervals (clinical judgment)
18
7/24/2012
Other histologies – inflammatory
• Often has exudate on surface
• Reflects prior injury to colon
• Common in IBD but occur sporadically also
• Vascular – brisk venous bleeding with resection or biopsy – rarely clinically significant
Hamartomas – and hamartoma
syndromes
• 3 hamartomatous polyp syndromes
– JPS (juvenile polyposis syndrome): SMAD4 or BMPR1A
– PJS (Peutz‐Jeghers syndrome): STK11 (also called LKB1
– Cowden syndrome: (PTEN)
19
7/24/2012
Juvenile polyp
• Synonymous with “retention polyp”
– Distended mucus filled glands, multiple blood vessels, cystic dilation (hamartomas)
• Prevalence of 1‐2 % in children age 4‐14y
– 70% of patients have only 1 polyp; most others have 2 or 3
• Sporadic juvenile polyps not associated with CRC risk
Juvenile polyposis syndrome (JPS)
• Mutations in SMAD4 or BMPR1A
• Increase risk of CRC, stomach, small bowel (if polyps present) • No physical exam clues
• Consider if ≥ 3 JPs in colon, JPs in stomach or small bowel, JPs with + FH of JPS
20
7/24/2012
Screening in JPS (www.nccn.org)
• Colonoscopy q 2‐3 y when sx begin or in late teens
• EGD q 1‐3 y
Peutz‐Jeghers Syndrome
• STK11(LKB1) mutations
• Oral and buccal mucosal hyperpigmentation
• Colorectal cancer, breast, stomach, small bowel, pancreas, testis, cervix, uterus, ovary, lung
21
7/24/2012
Screening in PJS (www.nccn.org)
• Colonoscopy q 2‐3y
• Annual mammogram and breast MRI;biannual
breast exam beginning at age 25 y
• MRCP or EUS q 1‐2y beginning at age 30 y
• EGD and small bowel imaging q 2‐3y beginning at age 10
• Annual pelvic, Pap smear, and transvaginal
ultrasound beginning at age 18 y
• Annual testis exam beginning at age 10 y
Cowden’s syndrome
• PTEN
• Hamartomas in all sections of the bowel including esophagus
• Not a clear increased risk of CRC
• Very high risk of thyroid and breast cancer
22
7/24/2012
Inherited Adenoma Syndromes
23
7/24/2012
FAMILIAL ADENOMATOUS POLYPOSIS
•
•
•
•
•
•
•
•
•
<1% of all CRC
autosomal dominant
>95% penetrance
hundreds of adenomas
cancers in duodenum
desmoid tumors
Germline mutations in APC gene
screening: sigmoidoscopy or colonoscopy
commercial genetic testing available
24
7/24/2012
25
7/24/2012
Screening in FAP
• Colonoscopy q 1‐2 y beginning at age 10
• Screening can be delayed to late teens in AAFP
• Prophylactic colectomy when polyps unmanageable
• EGD q 1‐3 y beginning age 25y
• Annual physical exam including thyroid
• If remaining rectum or ileal pouch, screen every 6 mo to 2 y
26
7/24/2012
UGI tract polyps, cancer in FAP
• Gastric fundic gland polyps
– Can be dysplastic but rarely become malignant
• Duodenal adenomas
– Most cancers arise at papilla
– Spigelman score predicts non papilla risk
Modified Spigelman score
Points
1 2 3
# polyps 1‐4 5‐20 >20
Polyp size,mm
1‐4 5‐10 >10
Histology Tub TV Villous Dysplasia LGD ‐
HGD
Stage 0:no polyps; Stage 1: 1‐4 points Stage 2: 5‐6 points; Stage 3:7‐8 points; Stage 4: 9‐12 points 27
7/24/2012
MUTYH‐Associated Polyposis: MAP
• Autosomal recessive
• Due to germline mutations in MYH genes
• MUTYH defends against oxidative DNA damage (helps prevent G:C to T:A transversions)
• Phenotype mimics FAP especially AAPC (increase in adenomas) but also increase in serrated polyps
• Duodenal polyposis
Screening in MAP
• Colonoscopy q 2‐3 years beginning at age 25 y
• EGD q 1‐3 y beginning at age 20‐25y
28
7/24/2012
Lynch Syndrome
HEREDITARY NON POLYPOSIS COLORECTAL CANCER (LYNCH SYNDROME)
•
•
•
•
•
•
•
•
•
•
•
2‐5% of all CRC
Germline Mutation in Mismatch repair genes: MLH1, MSH2, MSH6, PMS1
Patients usually have only a few adenomas
Autosomal dominant
70% penetrance
Cancers at young age
Rightward distribution
Cancers at other sites: endometrium, small bowel, renal pelvis,ureter, brain, ovary, stomach Microsatellite instability
Screening: colonoscopy Commercial genetic testing available
29
7/24/2012
Amsterdam II
• Cancers can be at any of following sites:
– Colorectum
– Endometrium
– Small bowel
– Ureter – Renal pelvis
30
7/24/2012
31
7/24/2012
32
7/24/2012
Revised Bethesda Guidelines
• CRC in patient < 50 y • Synchronous, metachronous or other LS tumor
• CRC in patient < 60y with MSI‐H
• CRC with ≥ 1 FDR with LS tumor with ≥ 1 diagnosed at age < 50 y
• CRC and ≥ 2 FDR or SDR with LS tumor regardless of age
33
7/24/2012
Alternative to MSI testing
• Immunostaining for MMR gene protein products – Easier to do – More widely available
General Approach to Lynch Syndrome
• Test tumor for MSI or perform immunostaining
• Follow with BRAF test or hypermethylation assay if MHL1 mutated
• If tumor positive (but BRAF negative or hypermethylation negative) then proceed with genetic testing
• OR: MSI or immunostaining of all CRCs
34
7/24/2012
CRC Syndromes
• Muir‐Torre Syndrome
– HNPCC (sebaceous carcinomas)
• Turcot’s syndrome
– HNPCC (indolent glioblastoma multiforme)
– FAP (medulloblastoma)
Familial Colon Cancer Syndrome X
• Clinical features
– High risk of colorectal cancer (mimics HNPCC)
– Little evidence of rapid conversion
– Not at increased risk of extracolonic cancers
• Genetic basis
– Not yet determined
35