Improving Outcomes in Hereditary Gastrointestinal Polyposis Syndromes in

the Mediterranean Region

Thomas M Attard MD FAAP FACGAssociate Professor, Pediatrics, Gastroenterology, University of Malta, Malta. Consultant Gastroenterologist Children’s Mercy Hospital, Kansas MO, USA.

Content:

• Overview: Hereditary Gastrointestinal Polyposis Syndromes in Childhood and Adolescence

• Polyposis Burden in Children in the Mediterranean Basin

• Obstacles for Management of Childhood Polyposis Syndromes

• Pilot Project to Improve Outcomes in Children with Hereditary Gastrointestinal Polyposis Syndromes in the Medicel Forum

Genotypic and Phenotypic Heterogeneity in Hereditary Colorectal Cancer Syndromes.

AC-I, Amsterdam Criteria IMMR, mismatch repairFAP, familial adenomatous polyposis AFAP, attenuated familial adenomatous polyposis; HBCC, hereditary breast and colorectal cancerPJS, Peutz–Jeghers syndromeFJP, familial juvenile polyposisCD, Cowden’s disease BRRS, Bannayan-Ruvalcaba–Riley syndrome.

Lynch et al. Cancer 2004;100:53–64

Hereditary Gastrointestinal Cancer Syndromes in Childhood

• ~ 5% of individuals with colorectal cancer will have a recognizable hereditary gastrointestinal cancer predisposing syndrome

• Polyposis syndromes frequently present in the first two decades of life with intestinal / extraintestinal manifestations

• Management of hereditary polyposis syndromes includes genetic testing, screening and in many cases surgery during childhood / adolescence

Hereditary Cancer Syndromes that present in childhood / adolescence

• Familial Adenomatous Polyposis – (FAP 1:8,000)

• Peutz-Jeghers Syndrome – (PJS, 1:15,000)

• Juvenile Polyposis Syndrome – (JPS, 1:35 – 50,000)

• HNPCC

• PTEN Hamartoma Syndrome (Cowden’s Syndrome, BRRS)

• Hereditary Mixed Polyposis Syndrome HMPS• MEN IIB• MYH-Associated Polyposis (MAP)

Polyposis: Defining the syndrome

• (age)

• Polyp – Histology– Number– Distribution

• Associated Clinical features / findings

• Family History

Familial Adenomatous

Polyposis

Peutz-Jeghers Syndrome

Juvenile Polyposis Syndrome

PTEN-Hamartoma Syndrome

Polyp distribution

Colorectal, most will develop gastric, small intestinal

Panintestinal (primarily small intestinal )

Colorectal, gastric

Colorectal

Polyp histology

Panintestinal Adenomatous and(Gastric) fundic gland polyps

Hamartomatous polyps¥ψ

Ψ a significant proportion of syndromic juvenile polyps will harbor areas of adenomatous transformation

¥ Peutz-Jeghers polyps have characteristic - prominent smooth muscle component in the submucosa

Hereditary Cancer Syndromes – polyps by anatomic localization & histology

modified from Lynch HT, Attard TM, Gastroent. & Hepatology 2005

Hereditary Gastrointestinal Cancer Syndromes: Management

FAP JP PJS PTEN – HS

Before age 10

α Fetoprotein and abdominal ultrasound annually from birth to age 10years

10 – 20 years

oAnnual colonoscopy from age 10-12years Colectomy when dx established oAnnual upper endoscopy*, as soon as colonic polyps appear or 15 years in AFAP†

o(no current consensus on thyroid screening but clinical examination and ultrasound of suspicious lesions needs to be part routine HCM visits)

oColonoscopy with polypectomy, annually if not all polyps removed, otherwise every 3 years from age 15 yearsoUpper endoscopy every 3 – 5 years from age 15 years; repeated annually if the patient is not polyp freeoAnnual clinical exam and baseline ultrasound of the thyroid from adolescence

oEvery 2-3 years, Upper endoscopy (EGD / EGD and enteroscopy), SBFT (? role of capsule endoscopy)oAnnual testicular exam, ultrasound if clinically suspected

oEvery 2 year colonoscopy, upper endoscopyoSBFT (? enteroscopy) from age 15 yearsoMonthly breast self exam from age 18 yearsoBaseline thyroid US at age 18 years, annual neck exam

Hereditary colorectal Cancer Syndromes in the Mediterranean Basin

• Population specific data is lacking for most countries

• InSIGHT membership incl. Italy, Spain*, Israel, Serbia*

• Multiple observations on unique disease manifestations and natural history

• No significant participation in pediatric chemopreventive trials

*Adult Gastroenterology Programs

Population Children

0-14FAP

(1:8,000)FJP

(1:50,000)PJS

(1:60,000)

ALBANIA 3.639.453 714.250 89 14 12

ALGERIA 34.178.188 8.696.320 1,087 173 144

BOSNIA 3.842.566 668.063 83 13 11

CROATIA 4.489.409 698.458 87 13 11

EGYPT 78.866.635 26.020.307 3,252 520 433

FRANCE 64.057.792 11.968.654 1,496 239 199

GREECE 10.737.428 1.530.992 191 30 25

ISRAEL 7.233.701 2.015.859 251 40 33

ITALY 58.126.212 7.870.226 984 157 131

LEBANON 4.017.095 1.034.885 129 21 17

MALTA 403.532 65.306 8 1 1

MOROCCO 31.285.174 8.967.576 1,120 179 149

SLOVENIA 2.046.976 287.275 35 4 5

SPAIN 40.525.002 5.864.419 733 117 98

TUNISIA 10.486.339 2.377.034 297 47 40

TURKEY 72.561.312 18.859.334 2,357 377 314

455.668.897 97.930.679 12,241 1,958 1,632

Obstacles for Management of Childhood Polyposis Syndromes

• individually these are rare conditions → very different, complex management algorithms: – Genetic testing / Endoscopy / Surgery/ Chemoprevention /

Surveillance

• need for team approach: – Gastroenterology / Surgery / Adult GI services / Genetic

Counseling / Psychology

• changing / unclear management algorithms– access to research protocols / chemoprevention

Obstacles for Management

• Recognizing symptoms and family history at risk.

• Access and timely referral for comprehensive services

• Long term surveillance planning and follow-up including family screening

• Lack of medical guidelines / discrepancy in provider competence

Hereditary Gastrointestinal Polyposis Syndromes: Healthcare Provider Training

Pediatric residents overall knowledge of gastrointestinal syndromes; proportion of correct answers by syndrome: pathogenesis and clinical features

PGY I PGY II PGY III0

20

40

60

80

100

Variation in percent correct response rate by level of training

Series10.15

0.25

0.35

0.45

0.55

0.65

0.75

0.85

0.95

FAP PJS JP PTEN - HS Attard TM et. al submitted J

Cancer Edu. 2008

Hereditary Colorectal Cancer Registries

• National, institutional, regional entity that serves as repository of expertise and academic interest on the group of diseases

• Demonstrable patient benefit from belonging to a registry → earlier recognition and treatment

• Registries as the only resource able to liase and effect drug (egs. chemoprevention) trials

Järvinen Hj et al. Gastroenterology. 2000 May;118(5):829-34.

Informational / Educational Cooperation

Coordination of Epidemiologic / Observational Studies

Registry Based Family based recommendations

Registry Based prospective Chemopreventive Studies

STEPWISE MODEL OF THE DEVELOPMENT OF A REGIONAL HEREDITARY GASTROINTESTINAL CANCER REGISTRY

Step 1: Informational / Educational Cooperation

• Initial development of a network for individual case consultation

• Commitment toward timely, comprehensive – structured consultation

• Academic network to pool, study, publish interesting cases

• Identification – development of regional / national resources toward Step 2.

Step 1: Informational / Educational Cooperation

• Multidisciplinary team:– pediatric gastroenterologists + trainee (fellow) based in UoM

(Malta, EU), Children’s Mercy Kansas City (MO, USA)– Genetic counselor– Psychologist

• e-mail based structured consultation with management plan

• De-identified clinical outline retained in dedicated database / Children’s Mercy Hospital, Kansas City (pending IRB approval)

Step 1: Informational / Educational Cooperation

• structured consultation: – Summary of salient clinical, endoscopic, +/-

genetic testing findings

– Outline of differential Dx, current diagnostic testing recommendations

– Outline long term management incl. surveillance planning

Preparing for Step 2 and beyond

• How did step 1 go?• Is there a perceived need for more structured

resources? • Are communication channels adequate?

Does the model work?

• Coordinating epidemiologic and observational studies in regional heterogeneity of disease

QuestionsAcknowledgements