objectives - american college of...

Carol A. Burke, MD, FACG, FASGE

Surveillance in Hereditary ColorectalCancer Syndromes

Carol A. Burke, MD, FACG, FASGESanford R Weiss MD Center for Hereditary Colorectal Neoplasia

Department of Gastroenterology and HepatologyCleveland Clinic, Cleveland, Ohio

Objectives

• Recognize molecular and phenotypic clues differentiating the most common hereditary colorectal cancer syndromes

• Formulate surveillance strategies for patients with Lynch Syndrome and FAP/MAP

2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology

of 12


Hereditary Colon Cancer SyndromesSyndrome Gene(s) Features

Lynch Syndrome MLH1, MSH2, MSH6, PMS2, EPCAM

Colon, endometrial, ovarian, gastric, urinary tract, small bowel cancers, brain tumors, sebaceous neoplasms

Li Fraumeni TP53 Childhood cancers, sarcoma, leukemia, brain tumors, breast cancer, CRC

Familial Adenomatous Polyposis

APC Adenomas, CRC, duodenal cancer, thyroid cancer, osteomas, soft tissue tumors, desmoid tumors

MYH-Associated Polyposis

MUTYH* Usually oligopolyposis, CRC, duodenal cancer, thyroid cancer

NTHL1- associated Polyposis

NTHL1 Oligopolyposis, CRC, endometrial cancer

Polymerase proofreading associated polyposis

POLE, POLD1 Oligopolyposis, endometrial cancer, brain cancer

Peutz-JeghersSyndrome

STK11 Mucocutaneous melanin spots, hamartomas, breast, CRC, SB, GI, pancreatic, and rare gyn cancers

CowdenSyndrome

PTEN Hamartomas, derm lesions, macrocephaly, breast, thyroid, endometrial, renal, CRC cancers

Juvenile Polyposis Syndrome

BMPR1A, SMAD4 Hamartomas, CRC, gastric cancer, HHT with SMAD4mutations

3

Pathways to CRC

Adenoma SessileSerrated Polyp

Sporadic CRC

MicrosatelliteStable (MSS)

MSS or

Microsatellite MSIInstability (MSI)

Lynch Syndrome

FAP MAP

BRAF mutationMLH1 methylation

MSI


of 12


Microsatellite Fidelity• Repeated nucleotide sequences called “microsatellites”• DNA fidelity maintained by Mismatch Repair Proteins (MMR)

Boland CR, Gastroenterology 2010;138:2073

MLH1 PMS2

MSH2 MSH6

Genes

Proteins

Evidence of Mismatch Repair Deficiency

2. Lack of MMR protein expression

T C T A C

A G C T G A G C A T G

T C G T A C

6

1. Microsatellite Instability NormalTissue

Colon Cancer

Etiology: MLH1 promoter methylationSomatic MMR gene mutationLynch Like SyndromeLynch Syndrome

MSH2 intact Lack of expression MLH1


of 12


Approach to Non-Polyposis Colorectal Cancer

CRC

MSI

No Germline Mutation

Lynch Like Syndrome

*Bi-allelic Somatic MMR

Germline MMR

Mutation

Lynch Syndrome

No MSI

Familial Colorectal Type X

*Mensenkamp, et al. Gastroenterology 2014;146:643–646

Sporadic CRC

Cancer Risk in Families MeetingAmsterdam Criteria I

Site of Cancer SIR (95% CI) P value

MSI(N=1855)

No MSI(N=1567)

Colorectum 6.1* 2.3* <0.001

Uterus 4.1* 0.8 <0.001

Stomach 4.6* 1.4 .008

Kidney 2.6* 0.9 .04

Ovary 2.0* 1.5 .60

Small Intestine 7.6* 1.6 .10

Ureter 9.0* 2.9 .29

161 families

* Compared to SEER Lindor N, JAMA. 2005;293:1979-1985


of 12


CRC: Lynch Syndrome vs Type X

Lindor, JAMA. 2005;293:1979-1985

Lynch

SEER

Type X

Management

• Tumor testing– CRC in non polyposis settings

• Genetic counseling – Risk assessment

– Germline testing• Based upon tumor testing in CRC patients/families

• To diagnoses cause of polyposis syndrome

• Surveillance– Based upon results of genetic testing


of 12


Multi-Society Task Force Recommendations for Surveillance in LS

Organ Age to Begin Method Interval

Colon 20-25 yrs* Colonoscopy 1-2 yrs

Uterus/Ovary 30-35 yrs TVUS, Endometrial Bx 1-2 yrs

After childbearing or age 40

TAH-BSO

Stomach/SB 30-35 yrs EGD-bx H pylori 2-3 yrs

Urothelium 30-35 yrs Urinalysis 1 yr

Giardiello FM, Am J Gastroenterol 2014;109(8):1159-79

*Or 10 years younger than the youngest age of the affected relative (2-5 yrs if relative < 25 yrs)

Multi-Society Task Force Recommendations for Surveillance in LS

Organ Age to Begin Method Interval

Colon 20-25 yrs* Colonoscopy 1-2 yrs

Uterus/Ovary 30-35 yrs TVUS, Endometrial Bx 1-2 yrs

After childbearing or age 40

TAH-BSO

Stomach/SB 30-35 yrs EGD-bx H pylori 2-3 yrs

Urothelium 30-35 yrs Urinalysis 1 yr

Giardiello FM, Am J Gastro 2014;109(8):1159-79

*Or 10 years younger than the youngest age of the affected relative (2-5 yrs if relative < 25 yrs)


of 12


ACG Guidelines on LS SurveillanceOrgan Method Interval Starting

AgeEvidence

Colorectum Colonoscopy 1-2 yrs 20 -25 Strong; Moderate

Uterus/Ovary Endometrial biopsy & transvaginal ultrasound

1-2 yrs 30 - 35 Conditional, v. low

Hysterectomy and BSO When childbearing

complete

40–45 Conditional, Low

UGI EGD with H. pylori bx 3-5 yrs* 30-35 Conditional, v. low

Syngal S, Am J Gastroenterol 2015; 110:223–262

Surveillance in LS Non-Polyposis CRC

CRC

MSI

No Germline Mutation

Lynch Like Syndrome

*Bi-allelic Somatic MMR

Germline MMR

Mutation

Lynch Syndrome

No MSI

Familial Colorectal Type X Sporadic CRC

Colonoscopy every 3-5 yrs

Macaron C, et al. Curr Gastroenterol Rep 2015; 17: 39


of 12


FAP and MYH Associated PolyposisColorectal Phenotype and Genotype

Grover S, et al. JAMA. 2012;308(5):485-492

Familial Adenomatous Polyposis• Prevalence: 1:10,000

– Dominant mutation in APC gene

• Phenotypes– Profuse or classic

• Diffuse adenomas, >100 • Onset 10-12 yrs• 100% risk of CRC

– Attenuated• Proximal adenomas, <100 • Onset early adulthood• 60% risk of CRC


of 12


Extra-intestinal features of FAP

• Desmoid tumors (15%)• Thyroid carcinoma (2-17%)• Adrenal adenoma (7-13% )• Osteomas (50-90%)• Supernumerary teeth (11-27%)• CHRPE (70-80%)• Soft tissue tumors (50%)

– Lipoma, fibroma, sebaceous cysts

• Hepatoblastoma (<2%)

Gastric features of FAP

• Fundic gland polyposis– Prevalence: 88%– Location: Fundus/Body– Mean Number polyps: 30

• 41% have LGD• 3% have HGD

– Resect >10 mm

• Gastric adenomas– Prevalence: 10%– Location: antrum- resect– Number: Solitary, few

• Gastric Cancer: Rare

Bianchi L, Burke CA, et al. Clin Gastro Hep 2007;6:180


of 12


Duodenal features of FAP

• Duodenal adenomas– Prevalence: 100%

• Adenomatous papilla1

– 54% if papilla appears normal – 89% if papilla appears abnormal

• Periampullary/Duodenal cancer– Prevalence: 2-36%2

– Cancer risk based upon stage of duodenal polyposis

2Groves C Gut 2002;50:6361Burke C, GIE 1999;49:358

Staging of Duodenal Polyposis

1 point 2 points 3 points

No. of polyps 1-4 5-20 >20

Polyp size (mm) 1-4 5-10 >10

Histology Tubular TVA Villous

Dysplasia Mild Moderate Severe

Spigelman AD. Lancet 1989;2: 783

Stage Points Cancer Risk EGD Interval*

I 1-4 0% 2-3 y

II 5-6 2.3% 1-3 y

III 7-8 2.4% 6 -12 m

IV 9-12 36% 3-6 mGroves C Gut 2002;50:636 Syngal S, Am J Gastroenterol 2015; 110:223–262

NCCN Genetic /Familial High Risk Assessment: Colorectal version 2.2015


of 12


MYH Associated Polyposis

Age of Diagnosis 45 yrs

Colon Phenotype Attenuated (80%)

Pathology Adenoma, Serrated, lymphoid

Polyp distribution Proximal (40%)

Age at CRC 48 yrs

• Autosomal recessive• Bi-allelic MYH mutations• Extra-colonic features ~ FAP

Aretz S. Int J Ca 2006;119:807

MYH mutation No Polyps < 3 polyps > 3 polyps

Mutation/Mutation 29% 29% 42%

Mutation/WT 75% 19% 7%

WT/WT 79% 15% 6%

Synchronous Polyps in Patients with CRC

Lubbe S, et al. J Clin Oncol 27:3975-3980.

ACG Guidelines on FAP/MAP Surveillance

Organ Method Interval StartingAge

Evidence

ColorectumClassic FAP

Colonoscopy or FS

1 yr Puberty Strong; moderate

AFAP/MAP Colonoscopy 1-2 yrs 18-20

Post operative FS/ileoscopy 1 / 2 yrs Strong, low

Thyroid Ultrasound 1 yr ND Conditional, low

UGI EGD withduodenoscopy

Based on duodenal polyposis stage

25–30 Strong, low

Hepatoblastoma AFP and US 6 months Infancy to age 7

Conditional, v low

Syngal S, Am J Gastroenterol 2015; 110:223–262


of 12



of 12

objectives - american college of...

Documents