Hereditary%20Colorectal%20Cancer%20Syndromes

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Hereditary Colorectal Cancer Syndromes

• Philip Kam
• Queen Elizabeth Hospital

2
Overview

• Features and genetics basis
• Screening
• Surveillance protocol
• Surgical management

3
Colorectal cancers

• Colorectal cancer (CRC) is commonest cancer in HK
  (4450 new cases in 2011)
• Worldwide incidence estimated 1 million annually
• about 20 has strong familial basis
• HK Cancer registry, 2013
• Lynch et al 2009

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Colorectal cancers

• 5 hereditary
• Hereditary forms of colorectal cancers strong
  penetrance among families with known genetic
  basis, i.e. germline mutations
• Amongst them
• Familial Adenomatous Polyposis (FAP)
• Lynch Syndrome (also known as Hereditary
  Non-Polyposis Colorectal Cancer, HNPCC)
• Rustgi 2007

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Familial Adenomatous Polyposis (FAP)

• Classical FAP
• Presence of 100 or more polyps, with
  extra-colonic manifestations
• Attenuated FAP
• Less than100 adenomas (average 30) frequent
  right sided distribution
• Presents with multiple colonic polyps since
  average of 16 year old
• By age 35, 95 FAP have polyps
• Mean age of Colon cancer is 39 (34-43)
• Extra-colonic involvement include
• stomach, duodenum, osteoma, thyroid, congenital
  hypertrophy of the retinal pigment epithelium
  (CHRPE), soft tissue tumor, desmoid tumor
• Jasperson and Burt 2014 Rustgi 2007

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FAP - Genetics

• Autosomal dominant
• Defect in gene APC (Adenomatous polyposis coli),
  on Chrm 5p22.2
• Pathogenic variants, with more than 1,500
  germline mutations found
• Detection by
• Sequence analysis 90
• Duplication / deletion analysis 8-12
• Hedge et al, 2014

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FAP - Surveillance

• Sigmoidoscopy / Colonoscopy every 1-2 years from
  age 10-12
• Annual colonoscopy once polyp found
• OGD before colectomy or age 25, then every 1-3
  years
• Annual cervical USG to screen for thyroid cancer
  from at 25-30
• CT or MRI abdomen as baseline to look for desmoid
  tumor if strongly family history
• Small bowel enema / CT with oral contrast
• NCCN 2014, Stoffel 2014

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FAP - Treatment

• For classic FAP, colectomy is recommended once
  adenoma emerge
• In presence of symptoms, or lesions with high
  grade dysplasia, colectomy should be as soon as
  possible
• Options
• Total Colectomy with ileorectal anastomosis
• if Attenuated FAP / rectum is spared of polyp
• Restorative proctocolectomy with ileal pouch-anal
  anastomosis (IPAA)
• Total procotcolectomy with permanent ileostomy
• Jasperson Burt 2014, Campos 2014

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FAP - Treatment options
Total Colectomy IRA Proctocolectomy IPAA Total proctocolectomy stoma
Risk of Ca rectum (5 in 10years) No risk of future Ca rectum Most definitive but not the first line
Lower complications risks Less re-operative rate Function might be poor more frequent bowel movement, incontinence and soiling Difficult for young patients
Quality of life better Still has risks of polyp formation in IPAA but risk of Ca rectum ? 48 pouch adenoma
For few polyps and rectum spared (lt20) Severe rectal adenoma (gt20) and severe colon load (gt1000) For tumor involving sphincter / presence of desmoid tumor
Church 2013 Guillem et al 2006
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Lynch Syndrome
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Lynch Syndrome - Presentation

• Fulfills clinical criteria with germline mutation
  found
• Major outcome is colorectal cancer, with mean age
  of diagnosis at 44-60 years old (vs. 69 in
  sporadic)
• Risk of CRC up to 75-80 in life
• Majority are right side tumor (60-80)
• High rate of metachronous tumor (16 in 10 years,
  41 in 20 years)
• Also a wide variety of extracolonic tumors
• Risks of CRC and other tumors depend on which
  mutation
• In HK, about 170 families of Lynch Syndrome
  identified thus far
• Giardiello et al 2014, Kohlmann 2014

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LS - Extracolonic involvements
Giardiello et al. 2014
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Lynch Syndrome - Genetics

• Autosomal dominant
• At least 4 genes found implicated
• MLH1, MSH2, MSH6, PMS2
• All are Mismatch Repair (MMR) gene mutations
• Leading to a loss of proofreading in DNA
  replication
• Results in point-mutations, known as
  Microsatellite Instability (MSI)
• Accumulation of mutations cause more rapid
  adenoma-carcinoma sequence ? earlier onset
• Kohlmann 2014

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What is MMR?
In areas of long, tandem repeats of nucleotides,
MMR can correct mismatch of single nucleotide!

• Vilar Gruber 2010

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Lynch Syndrome - who to suspect?

• Two major clinical guidelines have been developed
  to screen for Lynch Syndrome
• Amsterdam Criteria
• Revised Bethesda Guideline
• Guidelines help to initiate genetic testing in
  tumor specimen to confirm diagnosis of LS in a
  proband
• Microsatellite Instablity (MSI)
• Immunohistochemical stain (IHC)
• Germline sequence analysis

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Screening Algorithms
Lynch Syndrome surveillance
Positive
Amsterdam / Bethesda criteria met
Mutation known
Endometrial Ca lt age 50
Negative
Average risk surveillance
Known LS in Family
Test for MSI and IHC for mutations, diagnosis and
screening strategy accordingly
Tumor a/v
Mutation NOT known
Tumor NOT a/v
Positive Lynch syndrome surveillance and
screening for family members
Genetic for 4 MMR genes
NCCN guideline 2014 Stoffel et al 2014
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LS - Amsterdam Criteria

• 3-2-1 rule
• Sensitivity 22
• Specificity 98

Giardiello et al. 2014
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LS - Revised Bethesda
Developed to identify patients who need
MSI-testing Sensitivity 82 Specificity 77
Giardiello et al. 2014
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Lynch Syndrome - Genetics Testing

• The tumor specimen can be tested for
• MSI stability
• A panel of 5 markers used MSI-high, MSI-low, or
  MSI-stable
• Immunohistochemistry (IHC) staining
• To see which MMR gene protein is dysfunctional
• 90 of LS tumors are MSI-high. But 10-15 of
  sporadic cases are also MSI-H and abnormal IHC
• Germline molecular testing by sequence analysis
• When tumor specimen is not available
• Lynch 2009 Giardello 2014 NCCN guideline 2014

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Lynch Syndrome - Surveillance

• Surveillance strategy for extracolonic tumor once
  genetic test positive
• Colorectal Ca Colonoscopy every 1-2 years
  starting age 20-25 or 2-5 years before youngest
  age of CRC in family if diagnosed before 25yo
• Endometrial Ca Annual pelvic exam and
  endometrial sampling at age 30-35
• Ovarian Ca annual TV USG from age 30-35
• Consider prophylactic TAHBSO in women with LS at
  age 40 or finish child-bearing
• Giardello et al 2014 Stoffel et al 2014 NCCN
  2014

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Lynch Syndrome - Surveillance

• Surveillance strategy
• Gastric Ca OGD from age 30-35 with antral
  biopsy and H.pylori eradication FU OGD every 2-3
  years
• Small bowel Ca lacks evidence for use of small
  bowel enema / capsule endoscopy
• NCCN OGD with extended duodenoscopy
• Urinary Ca annual urinalysis from age 30-35
• CNS cancer annual neurological exam
• Giardello et al 2014 Stoffel et al 2014 NCCN
  2014

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LS - Treatment of Ca Colon

• If LS patient has CA colon or pre-malignant
  adenoma, colectomy is the choice
• If only partial colectomy, risks of 10-year CRC
  risks increases from 16-19 despite vigilant
  colonoscopy
• Prophylactic subtotal colectomy or total
  colectomy with ileo-rectal anastomosis
  significantly reduced the risks to lt3.4
• Win et al 2013, Edelstein et al 2011
• Retrospective review showed metachronous CRC
  reduced by 31 of every 10cm of large bowel
  resected
• Parry 2011

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LS - Treatment of Ca rectum

• LS with Ca rectum (up to 20 in LS)
• Total proctocolectomy with ileal pouch-anal
  anastomosis (IPAA) theoretically attains smaller
  risks of metachronous tumor
• Anterior resection with intensive surveillance
  is an option?
• risk of metachronous cancer / advanced neoplasia
  up to 51
• Kalady et al 2012

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Conclusion

• Lynch syndrome and FAP should be suspected in
  young patients with cancer / multiple colonic
  adenoma
• Clear family history important
• Clinically should screen for other organ
  involvement
• Genetically should arrange appropriate genetic
  testing
• Surgically should tailor-made appropriate
  operation for curative and prophylactic purpose
• Hopefully involving surgeons, oncologist, and
  geneticist

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Thank you
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References

• HK Cancer Registry 2013 available at
  http//www3.ha.org.hk/cancereg/Summary20of20CanS
  tat202011.pdf
• Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch
  JF, Boland CR. Review of the Lynch syndrome
  history, molecular genetics, screening,
  differential diagnosis and medicolegal
  ramifications. Clin Genet. 2009 76(1) 118
• Rustgi AK, The genetics of hereditary colon
  cancer. Genes Dev. 2007 2125252538
• Giardello FM, Allen JI, Axibund JE, Boland CR. et
  al. Guidelines on genetic evaluation and
  management of Lynch syndrome a consensus
  statement by the US Multi-Society Task Force on
  Colorectal Cancer. Dis Colon Rectum 2014 57
  1025-1048
• Kohlmann W. Lynch Syndrome. GeneReviews, NCBI
  Bookshelf, last updated May 22, 2014. Available
  at http//www.ncbi.nlm.nih.gov/books/NBK1211
• Vilar E, Gruber SB, Microsatellite instability
  in colorectal cancerthe stable evidence. Nature
  Review Cliincal Oncology, 2010 7(3)153-62
• Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, et
  al. Hereditary Colorectal Cancer Syndromes
  American Society of Clinical Oncology clinical
  practice guideline endorsement of the familial
  risk-colorectal cancer European Society for
  Medical Oncology clinical practice guidelines. J
  Clin Oncol 2014 (ahead of print available at
  http//jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.5
  8.1322)
• Church J, Simmang C, The Standards Task Force The
  American Society of Colon and Rectal Surgeons.
  Treatment of patients with dominantly inherited
  colorectal cancer (Familial Adenomatous Polyposis
  and Hereditary Nonpolyposis Colorectal Cancer)
  Diseases of the Colon Rectum 200346(8)1001-101
  2
• S. Parry, A.K. Win, B. Parry, et al.,
  Metachronous colorectal cancer risk for mismatch
  repair gene mutation carriers the advantage of
  more extensive colon surgery. Gut 2011
  60950957.
• K. Win, S. Parry, B. Parry, et al., Risk of
  metachronous colon cancer following surgery for
  rectal cancer in mismatch repair gene mutation
  carriers, Ann Surg Oncol 2013 2018291836.
• D.L. Edelstein, J.E. Axilbund, M. Baxter, et al.,
  Rapid development of colorectal neoplasia in
  patients with lynch syndrome, Clin Gastroenterol
  Hepatol 2011 9340343.
• M.F. Kalady, J. Lipman, E. McGannon, et al., Risk
  of colonic neoplasia after proctectomy for rectal
  cancer in hereditary non- polyposis colorectal
  cancer, Ann Surg 2012 22511211125
• Hedge M, Ferber M, Mao R, et al. ACMG technical
  standards and guidelines for genetic testing for
  inherited colorectal cancer (Lynch syndrome,
  familial adenomatous polyposis, and
  MYH-associated polyposis) Genetics in Med 2014
  16(1)101-116
• Jasperson KW and Burt RW APC-associated polyposis
  condition.. GeneReviews, NCBI Bookshelf, last
  updated March 27, 2014. Avaialble at
  http//www.ncbi.nlm.nih.gov/books/NBK1345
• Campos FG Surgical treatment of familial
  adenomatous polyposis dilemmas and current
  recommendations. World J Gastroenterol 2014
  20(44) 16620-16629
• Aziz O, Athanasiou T, Fazio VW, Nicholls RJ,
  Darzi AW, Church J, Phillips RK, Tekkis PP.
  Meta-analysis of observational studies of
  ileorectal versus ileal pouch-anal anastomosis
  for familial adenomatous polyposis. Br J Surg
  2006 93 407-417
• Pommaret E, Vienne A, Lefevre JH, et al.
  Prevalence and risk factors for adenomas in the
  ileal pouch and the afferent loop after
  restorative proctocolectomy for patients with
  familial adenomatous polyposis Surg Endosc 2013
  27 3816-3822
• Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO
  Review of current risk-reducing surgery in common
  hereditary cancer syndromes. J Clin Onco 2006
  24(28) 4642-4660