Colorectal polyposis / CRC syndromes Flashcards
1
Q
Surveillance for Lynch syndrome
A
- colonoscopy q1yr from age 25 or earlier if fam member w CRC <35yrs
- OGD q2-4yrs from age 30-35
- annual endometrial sampling from age 30-35
- annual pelvic exam, CA125, pelvic USS
- at least 1 full skin exam
2
Q
Management of family members of those with Lynch
A
- test offspring after age 18 (but screening not usu recommended til 25 so many choose to wait til then)
- if decide not to get tested, col q2yrs
3
Q
Management of Lynch
A
- surveillance discussed elsewhere
- can discuss prophylactic surgery as alternative to colonoscopy screening
- subtotal colectomy & IRA or restorative proctocolectomy
- if former, flexi sig q12mo, risk of rectal ca 12% at 12yrs
- may be no advantages over good quality surveillance & aspirin; surveillance has greates QOL benefit
- treatment if malignancy
- segmental resection vs colectomy & IRA if colon
- segmental gives better function but need q12mo colonoscopy; risk of metachronous bowel ca 16% at 10yrs
- consider if older/sphincter dysfunction
- if rectal ca, proctocolectomy +/- ileoanal pouch
- segmental resection vs colectomy & IRA if colon
- medical
- consider aspirin
- MSI tumours (Lynch and non-Lynch) have poor response to 5-FU chemo
4
Q
Clinical features of FAP
A
Polyps of GI tract + A DOPE CT
- Hundreds of CR adenomatous polyps at young age (2nd/3rd decade); CRC av age 39 if untreated
- Duodenal adenomatous polyps (30-70%)
- predilection for ampullary & periampullary regions
- lifetime risk duo ca 4-10% (2nd most common cause of FAP death)
- Non-neoplastic gastric fundic gland polyps (50-80%)
- Gastric adenomas (10%, risk of gastric ca low)
- SB polyps w ca (less common pancreatic adenoca, hepatoblastoma)
- Adrenocortical adenoma
- Desmoids 10-15%
- Osteomas (mandibular)
- Papillary thyroid ca (2%)
- Epidermoid cysts
- CHRPE (Congential hyperplasia of the retinal pigment epithelium)
- Dental anomalies incl supranumerary teeth
5
Q
Surveillance and testing of family members for FAP
A
Surveillance of carriers:
- colonoscopy q1yr from 14
- gastrosocpy q1-5yrs from age 25-30 - frequency depends on Spigelman
- annual thyroid USS from 30
Who to test:
- offspring/other relevant family of affected at age 12-14
- mutation carriers as above
- if no specific mutation found to test for, relatives should still have colonoscopies, generally from teenage years; if no polyps by age 50 can stop
6
Q
Medical/Surgical management of FAP
A
- chemoprevention - sulindac (NSAID) - but side effects too from chronic nSAIDs
- things to consider re surgery:
- pt factors - what they want, able to screen, fertility, stage of life
- disease factors - rectal criteria below
- prophylactic surgery - if symptomatic or dense polyps offer asap, otherwise usu in late teens after finishing school
- RPC & IPAA - with mucosectomy & hand-sewn anastomosis or w stapled anastomosis
- stapled: cuff of anal transition zone/rectal mucosa left but better function than handsewn which also doesn’t fully protect against ca; stapled also easier to survey & can treat anal transition zone adenomas endoscopically/transannaly
- need to do this if rectal ca, large polyp burden (>20 synchronous adenomas or adenomas w HGD), large (>30mm) adenomas or severe familial phenotype (>1000 adenomas), also particular mutations at high risk of rectal ca, and if desmoids in the family bc want to avoid second surgery
- fertility/erectile/ejaculatory dyfn risks, pouch failure 10%
- colectomy + IRA - need longterm rectal surveillance, 30% risk metachronous rectal ca; ok option for milder phenotypes
- total proctocolectomy & end ileo (almost exclusively for those w low rectal ca)
- RPC & IPAA - with mucosectomy & hand-sewn anastomosis or w stapled anastomosis
- post surgery
- regardless of operation need q12mo flexi sig
7
Q
Desmoid tumours
A
- histologically benign but locally invasive fibromatous lesions consisting of clonal proliferations of myofibroblasts
- 10-15% of those w FAP, mortality 10%
- F>M
- Location
- half intra-abdominally, usu within SB mesentery
- 40% abdo wall
- extremities & trunk
- Aetiology - contributions from:
- trauma (incl operative)
- oestrogens
- specific APC gene mutations & modifier genes
- Clinical
- can manifest as flat, fibrous, sheet-like lesions or as defined discrete masses
- may cause discomfort and be unsightly
- most exhibit cycles of growth & resolution & may not cause significant problems
- within abdo can cause SB or ureteric obstruction, intestinal ischaemia or perforation
- Investigations
- CT = best re size & relationship to surroundign strucutres
- T2 MRI may provide useful info re cellularity & growth potential
- consider reg renal tract imaging if intra-abdo ones being non-operatively managed to monitor for ureteric obstruction
- Management
- challenge - identify minority that are rapidly & relentlessly progressive & avoid harming pts w unnecessarily aggressive attempts to treat the rest
- NSAIDs (eg sulindac) & high dose antioestrogens - eg raloxifene - anecdotal succses
- surgery
- first–line for abdo wall & extra-abdo desmoids but recurrence rates high
- usually avoid surgery for intra-abdo desmoids where possible; typically reserve this for small, well-defined tumours when a clear margin can be obtained - pharmacologic threapies w NSAIDs & antioestrogens showed similar outcomes to surgery
- combination chemo, incl doxorubicin seems to be best option for progressively growing intra-abdo demoids
- nat hx: regress spontaneously or relentlessly grow in minority
8
Q
What is MAP?
A
- MYH-associated Polyposis
- AR inherited syndrome caused by germline mutation of both alleles of MUTYH gene, located on chromosome 1p
- a form of adenomatous polyposis that has considerable clinical overlap w FAP but genetically distinct
- clinical features
- colorectal polyps - most adenomas but can have serrated or mixture
- lifetime risk CRC almost 100% by 60yrs
- number of polyps variable; usu moderate polyposis (<100 adenomas) but can have phenotype like classical FAP with >100
- distribution differs from FAP - higher proportion of right-sided cancers, which also develop slightly later at 47yrs
- UGI tract
- duo adenomas in 20-30% but later onset, less of a problem, also diff disease pattern to FAP
- also gastric fundic gland polyps but less common
- Others - ?increased risk of breast ca
- colorectal polyps - most adenomas but can have serrated or mixture
- Diagnosis
- suspect if individuals w ≥10 cumulative colorectal adenomas or a hx of multiple adenomas in combo w extracolonic features assoc w MAP eg duodenal/ampullary adenomas, desmoid tumours, thyroid ca, CHRPE, epidermal cysts, osteomas
- biallelic pathogenic germline variants in MUTYH gene required to establish dx
- Who to test
- b/c recessive should test siblings - have 25% chance
- children of those with MAP don’t need testing or screening bc heterozygotes have negligible increased risk
- Management
- similar to FAP but may be able to survey rather than prophylactically operate on some, usually don’t need to take rectum bc rectal ca uncommon and screening can start a bit later
- annual col from 18-20yrs
- UGI endoscopy (w side-viewing scope) from 25 - if normal q3-5yrs otherwise as per Spigelman
- insuff evidence to support breast screening
9
Q
What is Peutz Jeghers Syndrome? What are the clinical features?
A
An AD inherited condition characterised by multiple GI hamartomatous polyps and muocutaneous pigmentation
- gene responsible in some = STK11 on chr 19p13
- 50% inherited; remainder from spontaneous mutation
- Clinical features
- benign hamartomatous, primarily GI, polyps (nearly 90%)
- most common in SB > colon > stomach > rectum
- polyps – differ histologically from juvenile polyps in that they arise due to overgrowth of muscularis mucosa cf lamina propria
- mucocutaneous pigmentation (dark blue or brown macules in vermillion border of lips, buccal mucosa, hands & feet
- bowel obstruction
- commonest polyp-related complication = SBO often caused by intussusception w polyp at apex
- incidence of subsequent SBO can be decreased by intraop SB enteroscopy
- remove polyps at time of initial laparotomy
- cancer risk – 90% lifetime risk altogether, av age 42
- significant risk of GI malignancy but risk not well defined - ?39% CRC
- also gastric, panc, lung, breast, uterine, cervical, testicular, ovarian
- most common GIT malignancy = colon and pancreas; extraintestinal malignancy = breast
- benign hamartomatous, primarily GI, polyps (nearly 90%)
10
Q
How is Peutz-Jeghers Syndrome diagnosed and managed?
A
Diagnosis
- clinical – based on presence of any two of following:
- two or more Peutz-Jeghers-type hamartomatous polyps of GI tract
- mucocutaneous hyperpigmentation of mouth, lips, nose, eyes, genitalia or fingers
- fhx of PJS
- those who meet clinical criteria should be tested for a germline mutation in STK11 gene; genetic testing in an individual who meets clinical criteria for PJS serves to confirm dx of PJS and counsel at-risk family members
- but not all mutations assoc w PJS have been identified – so if no pathogenic STK11 mutation is found in someone who meets clinical criteria for PJS and there is no known mutation of PJS in family, this doesn’t exclude dx of PJS
Who to test
- first-degree relatives of pts w PJS – screen annually from birth for clinical features – history and physical exam looking for mucocutaneous pigmentation and signs of precocious puberty; and in addition male pts should be examined for signs of feminization (eg gynaecomastia) and for testicular tumours w testicular palpation
- predictive genetic testing for those in whom dx not already clinically apparent by age 8, provided a pathogenic STK11 mutation has been identified in an affected family member
Surveillance
- OGD, pillcam & col at age 8
- If no polyps, repeat at age 18 then 2-3yrly
- If polyps found, repeat 2-3yrly
- Genital tract cancers
- Testicular (Sertoli cell) – annual exam from age 10
- Cervical – annual screening from age 21
- Ovarian and endometrial ca – annual pelvic exam, cervical smear and pelvic USS (though some don’t recommend screening for endometrial ca)
- Breast ca
- Risk approaches that of BRCA mutation carriers
- Annual exam, breast MRI & mamm from age 30
- Pancreatic ca
- MRCP or EUA q1-2yrs from age 30-35
- Others – increased thyroid and lung ca risk but lack of evidence to support routine screening w/o other risk factors
Management
- GIT
- Asymptomatic UGI or colonic polyps >3mm detected endoscopically - polypectomy
- SB polyps >1cm or those that have grown rapidly – remove to prevent complications (surgically or balloon-assisted enteroscopy)
- Surgery indications:
- Inability to achieve endoscopic polyp control either due to polyp size or number and the presence of neoplasia
- Surgery may also be required in pts w SBO or intussusception
- Pts w PJS undergoing laparotomy should undergo intraop enteroscopy to identify and resect SB polyps
- Insufficient evidence to recommend chemoprevention
11
Q
What is Juvenile Polyposis, how is it diagnosed and how is it managed?
A
- Rare AD condition where multiple characteristic hamartomatous juvenile polyps occur, mostly in colon but also UGI tract
- (sporadic juvenile polyp = different, occur in up to 2% of children <10yrs, usu solitary and not assoc w increased ca risk)
- 40-50% have genetic mutation detected in
- SMAD4 gene (chromosome 18q)
- BMPR1A gene (chromosome 10q)
- (both related to TGF-beta signaling pathway)
- 75% have fhx of juvenile polyposis; 25% have de novo mutations
Clinical features
- polyps usu begin to appear in 1st decade of life; can develop five to hundreds of polyps in lifetime
- 98% colorectum, 14% stomach, 7% duo, 7% jej & ileum
- most pts symptomatic by 20yrs of age – 90% present w bleeding or anaemia from GI polyps; rectal bleeding most common; also abdominal pain from intussusception, diarrhea from protein-losing enteropathy, rectal prolapse of polyps
- Risk of CRC 68% by 60yrs; av age 34yrs
- risk gastric ca espec SMAD4 mutation
- JPS from SMAD4 mutations may also be assoc w hereditary hemorrhagic telangiectasis (most common clinical manifestations = telangiectasias of skin and buccal mucosa, epistaxis and IDA from GI telangiectasia; pulmonary, hepatic, cerebral and rare arteriovenous malformations
- Other associated conditions: cardiac (eg mitral valve prolapse), vascular (eg arterial aneurysms), skeletal, cranial abnormalities
Diagnosis
- Clinical:
- 5 or more juvenile polyps in colorectum
- multiple juvenile polyps throughout GI tract OR
- any number of juvenile polyps in a person w known fhx of juvenile polyps
- individuals who meet clinical criteria for JPS should undergo genetic testing for a germline mutation in the BMPR1A and SMAD4 genes; but 40% hhave no germline mutation
Surveillance
- annual physical exam incl cardiovascular, iron studies
- colonoscopy q1-3yrs from age 15
- gastroscopy from age 15 (or 25) q1-3yrs
Management
- indications for colectomy +IRA or proctocolectomy + IPAA include:
- severe sx related to colonic neoplasia (eg severe GI bleeding)
- colorectal ca, adenoma w HGD or multiple adenomas >6mm
- marked increases in polyp number on consecutive exams
- inability to adequately survey colon bc of multiple polyps
- surveillance of remaining rectum or pouch q12mo post colectomy (~50% those w IRA will eventually require proctectomy)
- Genital tract cancers
- Testicular (Sertoli cell) – annual exam from age 10
- Cervical – annual screening from age 21
- Ovarian and endometrial ca – annual pelvic exam, cervical smear and pelvic USS (though some don’t recommend screening for endometrial ca)
- Breast ca
- Risk approaches that of BRCA mutation carriers
- Annual exam, breast MRI & mamm from age 30
- Pancreatic ca
- MRCP or EUA q1-2yrs from age 30-35
- Others – increased thyroid and lung ca risk but lack of evidence to support routine screening w/o other risk factors
An AD condition where multiple characteristic hamartomatous juvenile polyps occur, mostly in colon but also UGI tract (isolated juvenile polyp = different and low if any malignant potential)
- 40-50% have genetic mutation detected in
- SMAD4 gene (chromosome 18)
- BMPRIA (chromosome 10q)
- Clinical
- risk of CRC up to 40%; av age 34yrs
- increased risk gastric ca espec w SMAD4 mutation
- sx related to polyps - acute/chronic bleeding, IDA, propased rectal polyps, abdo pain or diarrhoea
- Diagnosis
- 5 or more juvenile polyps in colorectum
- multiple juvenile polyps throughout GI tract
- any number of juvenile polyps w fhx juvenile polyposis
- Screening
- colonoscopy from age 15
- gastroscopy from age 25
- Management
- occasionally require prophylactic colectomy or gastrectomy
- if polyp burden can’t be effectively managed endoscopically
- poor surveillance compliance
- fhx CRC
- or if HGD or ca
- options:
- subtotal colectomy & IRA
- segmental colectomy
- total colectomy & IPAA
- occasionally require prophylactic colectomy or gastrectomy
12
Q
Cowden’s syndrome
A
- mutations in PTEN gene
- GI hamartomas + cancers + high risk of ca of:
- thyroid
- breast
- endometrium, cervix
- benign mucocutanoeus lesions espec tricholemmomas (benign tumour of outer sheath of har follicle), oral fibromas, punctate palmoplantar keratoses
Think of a COW (Cowden) in a PEN (PTEN)
- spots of cow = hamartomas of skin and mucosa especially tricholemmoooomas
- bell = thyroid ca
- udder = breast (and endometrium, cervix)
- cowpat = colon ca risk
13
Q
Genetics of juvenile polyposis
A
- Rare AD condition where multiple characteristic hamartomatous juvenile polyps occur, mostly in colon but also UGI tract
- (sporadic juvenile polyp = different, occur in up to 2% of children <10yrs, usu solitary and not assoc w increased ca risk)
- 40-50% have genetic mutation detected in
- SMAD4 gene (chromosome 18q)
- BMPR1A gene (chromosome 10q)
- (both related to TGF-beta signaling pathway)
- 75% have fhx of juvenile polyposis; 25% have de novo mutations
14
Q
Describe management of Desmoid Tumours
A
- Surveillance for other tumours if found in FAP (15% of patients with FAP get desmoids)
- Identify current or anticipated complications and operate only on those, if at all
- Trial Oestrogen (Tamoxifen 80-120mg OD) and/or NSAIDS (Sulindac 150-200mg BD)
- Cytotoxic chemotherapy has a limited role for a minority of desmoids (locally aggressive tumours)
- first-line for abdo wall & extra-abdo desmoids but recurrence rates high
- usu avoid surgery for intra-abdo desmoids where possible; typically reserve this for small, well-defined tumours when a clear margin can be obtained
- combination chemo, incl doxorubicin seems to be beest option for progressively growing intra-abdo desmoids
Natural history: regress spontaneously or relentlessly grow in minority
15
Q
Describe the genetics of Lynch Syndrome / HNPCC
A
- Autosomal dominant – germline mutation in one of MMR genes (germ-line mutation on chromosome 2p (whose role it is to correct errors in base-pair matching during replication of DNA or to initiate apoptosis when DNA is beyond repair)
- Mutations in MLH1 or MSH 2 = ~90% of Lynch
- Also MSH6, PMS2 (MLH3, PMS1)
- Recently, transmissible epimutations in non-MMR gene EPCAM have been identified as a cause of Lynch à hypermethylation of adjacent MSH2 gene which silences MSH2 expression (up to 6% Lynch)
- Hallmark of tumours with defective MMR = microsatellite instability
- Microsatellites = non-coding segments of DNA that contain repetitive sequences of 1-6 nucleotides; when errors aren’t repaired due to MMR deficiency, length of microsatellite regions are altered
- MSI found in >90% of colon malignancies in Lynch pts
- NB ~1/2 sporadic CRCs show MSI = most occur in older pts & are due to inactivation of MMR gene MLH1 by promoter methylation, which isn’t related to any inherited factor
- Sporadic mutation in BRAF noted in 15% sporadic CRCs but not in Lynch – ie presence of BRAF mutations in MSI CRC = evidence against presence of Lynch
