1. Improving Outcomes in Hereditary Gastrointestinal Polyposis Syndromes in the Mediterranean Region Thomas M Attard MD FAAP FACG Associate Professor, Pediatrics, Gastroenterology, University of Malta, Malta. Consultant Gastroenterologist Children’s Mercy Hospital, Kansas MO, USA.

2. 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

3. Genotypic and Phenotypic Heterogeneity in Hereditary Colorectal Cancer Syndromes. AC-I, Amsterdam Criteria I MMR, mismatch repair FAP, familial adenomatous polyposis AFAP, attenuated familial adenomatous polyposis; HBCC, hereditary breast and colorectal cancer PJS, Peutz–Jeghers syndrome FJP, familial juvenile polyposis CD, Cowden’s disease BRRS, Bannayan- Ruvalcaba–Riley syndrome. Lynch et al. Cancer 2004;100:53–64

4. 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

5. 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)

6. Polyposis: Defining the syndrome (age) Polyp – Histology – Number – Distribution Associated Clinical features / findings Family History

7. 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

8. modified from Lynch HT, Attard TM, Gastroent. & Hepatology 2005 Hereditary Gastrointestinal Cancer Syndromes: Management FAPJPPJSPTEN – HS Before age 10 α Fetoprotein and abdominal ultrasound annually from birth to age 10years 10 – 20 years o Annual colonoscopy from age 10-12years  Colectomy when dx established o Annual 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) o Colonoscopy with polypectomy, annually if not all polyps removed, otherwise every 3 years from age 15 years o Upper endoscopy every 3 – 5 years from age 15 years; repeated annually if the patient is not polyp free o Annual clinical exam and baseline ultrasound of the thyroid from adolescence o Every 2-3 years, Upper endoscopy (EGD / EGD and enteroscopy), SBFT (? role of capsule endoscopy) o Annual testicular exam, ultrasound if clinically suspected o Every 2 year colonoscopy, upper endoscopy o SBFT (? enteroscopy) from age 15 years o Monthly breast self exam from age 18 years o Baseline thyroid US at age 18 years, annual neck exam

9. 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

10. PopulationChildren 0-14 FAP (1:8,000) FJP (1:50,000) PJS (1:60,000) ALBANIA 3.639.453714.250891412 ALGERIA 34.178.1888.696.3201,087173144 BOSNIA 3.842.566668.063831311 CROATIA 4.489.409698.458871311 EGYPT 78.866.63526.020.3073,252520433 FRANCE 64.057.79211.968.6541,496239199 GREECE 10.737.4281.530.9921913025 ISRAEL 7.233.7012.015.8592514033 ITALY 58.126.2127.870.226984157131 LEBANON 4.017.0951.034.8851292117 MALTA 403.53265.306811 MOROCCO 31.285.1748.967.5761,120179149 SLOVENIA 2.046.976287.2753545 SPAIN 40.525.0025.864.41973311798 TUNISIA 10.486.3392.377.0342974740 TURKEY 72.561.31218.859.3342,357377314 455.668.89797.930.67912,2411,9581,632

11. 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

12. 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

13. Hereditary Gastrointestinal Polyposis Syndromes: Healthcare Provider Training Pediatric residents overall knowledge of gastrointestinal syndromes; proportion of correct answers by syndrome: pathogenesis and clinical features Variation in percent correct response rate by level of training FAPPJSJPPTEN - HS Attard TM et. al submitted J Cancer Edu. 2008

14. 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.

15. 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

16. 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.

17. 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)

18. 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

19. 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

20. Questions Acknowledgements