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    Lynch Synd

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    Ramez Antakia
    1. Lynch syndrome is the most common inherited colorectal cancer syndrome, accounting for 2% of colorectal cancers. It is characterized by right-sided colorectal tumors and increased risks of other cancers as well. 2. Familial adenomatous polyposis causes numerous colon polyps and a 100% risk of colorectal cancer. It is characterized by hundreds of colon polyps and increased risks of other polyps and cancers. 3. Several other polyposis syndromes exist that are associated with colon polyps and increased cancer risks, including MYH-associated polyposis and Peutz-Jeghers syndrome. They require specialized surveillance and management approaches.

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    Lynch Synd

    Uploaded by

    Ramez Antakia
    8 views4 pages
    1. Lynch syndrome is the most common inherited colorectal cancer syndrome, accounting for 2% of colorectal cancers. It is characterized by right-sided colorectal tumors and increased risks of other cancers as well. 2. Familial adenomatous polyposis causes numerous colon polyps and a 100% risk of colorectal cancer. It is characterized by hundreds of colon polyps and increased risks of other polyps and cancers. 3. Several other polyposis syndromes exist that are associated with colon polyps and increased cancer risks, including MYH-associated polyposis and Peutz-Jeghers syndrome. They require specialized surveillance and management approaches.

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    Lynch syndrome hereditary CRC

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    1. Lynch syndrome is the most common inherited colorectal cancer syndrome, accounting for 2% of colorectal cancers. It is characterized by right-sided colorectal tumors and increased risks of other cancers as well. 2. Familial adenomatous polyposis causes numerous colon polyps and a 100% risk of colorectal cancer. It is characterized by hundreds of colon polyps and increased risks of other polyps and cancers. 3. Several other polyposis syndromes exist that are associated with colon polyps and increased cancer risks, including MYH-associated polyposis and Peutz-Jeghers syndrome. They require specialized surveillance and management approaches.

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    © All Rights Reserved
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    8 views4 pages

    Lynch Synd

    Uploaded by

    Ramez Antakia
    1. Lynch syndrome is the most common inherited colorectal cancer syndrome, accounting for 2% of colorectal cancers. It is characterized by right-sided colorectal tumors and increased risks of other cancers as well. 2. Familial adenomatous polyposis causes numerous colon polyps and a 100% risk of colorectal cancer. It is characterized by hundreds of colon polyps and increased risks of other polyps and cancers. 3. Several other polyposis syndromes exist that are associated with colon polyps and increased cancer risks, including MYH-associated polyposis and Peutz-Jeghers syndrome. They require specialized surveillance and management approaches.

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    LYNCH SYNDROME (HNPCC)

    Commonest inherited CRC syndrome; 2% of CRCs; lifetime risk= 50%+; 45yo CRC onset
    Right-sided mucinous CR tumours
    Also uterine/renal/CNS tumours

    Genetics:
    Autosomal dominant ie 50% inheritance; expressed when solitary normal gene lost/mutated
    (a)MMR germline mutations hMLH1/hMSH2/hMSH6/hPMS2in 70% (b)Sporadic EPCAM
    Microsatellite: short(~5 nucleotide) DNA seq repeats in region ||MSI: MS mut. changes # of repeats/length of region (hallmark 50% and 15% sporadic cancers)
    MMR= TS gene by DNA mismatch repair (i)repairs base pair-matching errors in DNA rep (ii)apoptosis if damage beyond repair
    Defective TS gene  DNA mismatch repair + apoptosis lost  tumorigenesis

    Diagnosis:
    1.Pedigree (Amsterdam II criteria)
    3+relatives w/ Lynch-associated cancer (1FDR of other two)/2+ successive generations/1+ diagnosed <50y + exclude FAP
    50% families meeting criteria have Lynch; 50% of Lynch individuals from families not meeting criteria *FHx insufficient for Dx*
    Amsterdam +ive but MMR i-ve= Familial CRC syndrome X  3-5yrly scope
    2. Analysis of tumour tissue 5 MS markers to detect MSI: 2+=MSI high (IHC and genetic testing detect 90% Lynch individuals)
    3. Genetic testing (refer all): Identify at risk family members for surveillance/discharge non-carriers from surveillance

    Surveillance:
    1. Colonoscopy 1-2yrly from 25-75(or 5yrs younger than youngest relative) *63% CRC reduction*
    2. OGD 2yrly from 50
    3. Extracolonic surveillance if FHx of cancer at that site (uterine/renal/CNS)

    Intervention: *REFER TO GENETICS*


    1. SURGERY (i)Prophylactic colectomy (STC+IRA/RPC+pouch) ||TAHBSO
    (ii)Curative colectomy in Ca (segmental/STC+IRA/RPC+pouch for rectal ca)
    RPC: two-stage; higher ejaculatory/fertility/defecatory dysfunction; 10% pouch failure -> permanent EI;
    STC+IRA: one-stage; better sexual/reproductive/defecatory morbidity; rectal cancer 12%@12yrs--> annual anoscopy
    2. REFER TO GENETICS
    FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
    Less common than Lynch; 0.5% of CRCs; 100% lifetime risk of CRC
    Left-sided tumours and younger

    Features:
    1. Colorectal: (i)Severe >100 adenomas (ii) Attentuated <100 adenomas
    2. Extracolonic: Ectoderm - epidermoid cysts, pilomatrixioma, CNS tumours, cong. retinal pig hypertrophy
    Mesoderm - desmoid tumours, adhesions, osteoma, exostosis, dental cysts
    Endoderm - 80% fundic gland polyps, 90% duodenal adenomas, SI, biliary tract, thyroid, adrenal adenomas
    (non-adenomatous) (5% malignant change)

    Genetics:
    GERMLINE: APC C5q(TS gene regulates B-catenin in Wnt signalling pathway) mutation identified in 80%
    SPORADIC: de novo mututation in 20%
    Autosomal dominant (50% inheritance)  expressed when normal APC gene lost/mutated

    Diagnosis:
    1. Adenomas *FAP v Lynch: (i) Microadenomas in FAP/MAP, not Lynch (ii)MSI in 50% lynch but not in FAP/MAP*
    2. Predictive genetic test: affected family member  80% gene detection  at risk members blood test from age 12

    Surveillance:
    Colon: Alternating flexi/colonoscopy annually from 13-15  offer surgery from 16
    UGI: 3yrly OGD from 30
    *after surgery: 30% rectal Ca by 60  12mthly DRE+ flexi if pouch; UGI surveillance ongoing*

    Management:
    LARGE BOWEL
    (a)Prophylactic (STC+IRA/RPC+pouch/PPC+EI)
    (b)Therapeutic: same but (i)v. low cancerPPC+EI (ii)APC codon 1309 mutation/rectal ca/rectal polyposisRPC
    Surveillance after surgery in all (12 monthly DRE + flexisig)
    *main M&M after surgery is duodenal/dermoid lesions*

    UPPER GI
    Duodenal adenomas in 90%  malignant transformation in 5%
    Surveillance: 6mth-5yrly OGD from 20 years (Spiegelman Stage)
    Management: no chemoprevention/endotx in stage 4/surgery by PPPD or PD in stage 5
    *high rate of progression/invasive cancer has poor prognosis  consider surgery early despite high morbidity

    SCORE 1 2 3
    No. of polyps 1-4 5-20 >20
    Size (mm) 1-4 5-10 >10
    Architecture Tubular Tubulovillous Villous
    Dysplasia Mild Moderate High
    0: 5yrly/1-4: 5yrly/5-6:3yrly/7-8:1yrly +endo therapy/9+:surgery

    DESMOID TUMOURS:
    Fibromatous tumours composed of clonal proliferation of myofibroblasts ->growth/resolution cycles
    15% of FAP; 10% mortality
    Histo: benign
    Features: obstruction/ischaemia of small bowel/ureter
    Management: (i)only rapidly progressive+ relentless  surgery (otherwise anti-E2/cytotoxic chemo)
    (ii)surgery for abdominal wall/extra-abdominal desmoids
    Outcomes: high recurrence rates

    MAP: MYH-ASSOCIATED POLYPOSIS


    FAP phenotype but no APC gene mutation identified; lifetime CRC risk 100% by age 60
    Genetics: MYH C1p biallelic mutation; autosomal recessive (hets only marginally increased CRC risk) *AR, FAP is AD*
    May have no family history as AR
    Features:
    LARGE BOWEL: colonic adenomas/carcinomas *tend to be right-sided and older; FAP left/younger*
    UGI: gastric fundic polyps/duodenoal adenomas (30%) *fewer duodenal adenomas*
    OTHER: breast cancer/osteomas/dental cysts *no desmoids*
    Management: as for FAP  annual colonoscopy/OGD from 25 in homozygotes but not for heterozygotes

    PEUTZ-JEGHERS
    Autosomal dominant (STK11/LKB1 C19p13); not identified in all families
    Features: (i)SBO (intussusception from hamartomas) (ii)muco-cutaneous pgimentation
    Cancers: SB/breast/ovaries/cervix/testes/pancreas
    Surveillance: U+L endoscopy 2-3yrly + capsule/MRI enterography from age 8
    Breast: annual MRI 25-50  enter NHSBSP
    Cervix: routine screening
    Testes: self-exam *no evidence for ovarian/pancreatic surveillance*
    Management: Laparotomy + intraop enteroscopy + comprehensive polypectomy

    JUVENILE POLYPOSIS
    Autosomal dominant (germline SMAD4/BMPR1A) Multiple hamartomas (colon w/40% CRC risk + UGI)
    Surveillance: regular U+L endoscopy from age 15-18  70
    Management: prophylactic surgery

    COWDEN DISEASE
    PTEN C10q22  GI hamartomas/cancers + other Ca(breast/thyroid/uterus/cervix) + benign (breast/thyroid/mucocutaenous lesions ie oral papilloma/acral keratosis)
    50% 75%/75%

    OTHER POLYPOSIS SYNDROMES


    APC variant C5q E1317Q  CRC risk
    C15q gene for CRC susceptibility (esp Ashkenazis so don’t discharge after negative genetic testing for above conditions)

    COLONOSCOPIC SURVEILLANCE OF INHERITED BOWEL CANCER

    NO RISK
    1 FDR>60

    LOW RISK
    No personal CRC hx/no FHx CRX/no FDR with CRC/1 FDR>50
    2x average risk but not >colonoscopy
    Mx: BCS

    MODERATE RISK
    Low moderate: 1 FDR <50/2FDR >60  3x average risk  one off colonoscopy at 55 + genetics referral
    High moderate: 3FDR >50/2 FDR <60  6x average risk  5yr colonoscopy from 50-75 + genetics referral
    HIGH RISK
    1. Member of known FAP family
    2. Member of known Lynch family
    3. Pedigree suggests MYH-associated polyposis
    4. Pedigree suggests autosomal dominant cancer
    50% chance of inheriting 50% CRC risk  genetics referral and phenotypic diagnosis  surveillance/prophylactic treatment

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