Hereditary Colorectal Cancer Syndromes

Philip KamQueen 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

Jasperson and Burt 2014; Rustgi 2007

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

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-Jasperson & Burt 2014, Campos 2014

FAP - Treatment optionsTotal 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 risksLess 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 (<20)

Severe rectal adenoma (>20) and severe colon load (>1000)

For tumor involving sphincter / presence of desmoid tumor

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

Giardiello et al 2014, Kohlmann 2014

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?

Vilar & Gruber 2010

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

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

Screening Algorithms

Amsterdam / Bethesda criteria met

Endometrial Ca < age 50

Known LS in Family

Mutation known

Positive Lynch Syndrome surveillance

Negative Average risk surveillance

Mutation NOT known

Tumor a/v

Test for MSI and IHC for mutations, diagnosis and screening strategy accordingly

Tumor NOT a/v

Positive = Lynch syndrome surveillance and screening for family members

NCCN guideline 2014Stoffel et al 2014

Genetic for 4 MMR genes

LS - Amsterdam Criteria

“3-2-1 rule”

Sensitivity 22%;

Specificity 98%

Giardiello et al. 2014

LS - Revised Bethesda

Developed to identify patients who need MSI-testing

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 - SurveillanceSurveillance 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

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 ColonIf 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 <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

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