Download Hereditary Colorectal Cancer Syndromes

Hereditary Colorectal Cancer Syndromes
Philip Kam
Queen Elizabeth Hospital
Overview
-Features and genetics basis
-Screening
-Surveillance protocol
-Surgical management
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
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
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
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%
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
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
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
Quality of life better
Still has risks of polyp
formation in IPAA; but risk
of Ca rectum ?
~48% pouch adenoma
Difficult for young patients
Church 2013; Guillem et al 2006
Lynch Syndrome
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
LS - Extracolonic involvements
Giardiello et al. 2014
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
What is MMR?
In areas of long,
tandem repeats of
nucleotides, MMR can
correct mismatch of
single nucleotide!
Vilar & Gruber 2010
Lynch Syndrome - who to suspect?
Two major clinical guidelines have been developed to screen for Lynch
Syndrome
-Amsterdam
-Revised
Criteria
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
Screening Algorithms
Amsterdam /
Bethesda criteria met
Endometrial Ca < age 50
Positive
Lynch Syndrome surveillance
Negative
Average risk surveillance
Mutation
known
Known LS in Family
Tumor a/v
Mutation
NOT
known
Tumor
NOT a/v
NCCN guideline 2014
Stoffel et al 2014
Test for MSI and IHC for
mutations, diagnosis and
screening strategy accordingly
Genetic for
4 MMR
genes
Positive = Lynch
syndrome surveillance
and screening for family
members
LS - Amsterdam Criteria
“3-2-1 rule”
Sensitivity 22%;
Specificity 98%
Giardiello et al. 2014
LS - Revised Bethesda
Developed to identify
patients who need MSItesting
Sensitivity 82%;
Specificity 77%
Giardiello et al. 2014
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
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 3035
- 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
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
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 ileorectal anastomosis significantly reduced the risks to <3.4%
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
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
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
Thank you
References
•HK Cancer Registry 2013; available at http://www3.ha.org.hk/cancereg/Summary%20of%20CanStat%202011.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): 1–18
•Rustgi AK, The genetics of hereditary colon cancer. Genes & Dev. 2007; 21:2525–2538
•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 cancer—the 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.2014.58.1322)
•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 2003;46(8):1001-1012
•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; 60:950–957.
•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; 20:1829–1836.
•D.L. Edelstein, J.E. Axilbund, M. Baxter, et al., Rapid development of colorectal neoplasia in patients with lynch
syndrome, Clin Gastroenterol Hepatol 2011; 9:340–343.
•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; 225:1121–1125
•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.