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11 Diagnosis:? Diagnosis: Juvenile Polyposis with BMPR1A Mutation 36
12 Juvenile Polyposis Syndrome Rare Autosomal Dominant Disorder with Multiple Juvenile Polyps in GI Tract Juvenile Polyposis Syndrome > 5 Polyps in Large Bowel, Throughout the GI Tract or Any Number of Polyps and a Family History of Juvenile Polyps Germline Mutation in SMAD4 (18q21) or BMPR1A (10q23.2) in 50 to 60% Increased Risk for Colorectal Carcinoma Sporadic Solitary Juvenile Polyps 2% of Pediatric Population without Increased Risk of Colorectal Carcinoma Juvenile Polyposis of Infancy Infantile Generalized Form with Polyps in Stomach, Small Bowel, and Colon Sessile and Pedunculated Polyps (1 to 30mm) Diarrhea, Hemorrhage, Malnutrition, Intussusception Congenital Anomalies: Macrocephaly, Hypotonia Contiguous Deletion of BMPR1A (10q23.2) and PTEN (10q23.3) Suggested Death at Early Age 37
13 Juvenile Polyposis Syndrome Juvenile Polyposis Syndrome Syndromic Juvenile Polyps Frond-Like Growth Pattern Less Stroma Fewer Dilated Glands More Proliferative & Smaller Glands Neoplastic Changes Cytologic Atypia & Some with Dysplasia Also Polyps in Stomach, Duodenum, Jejunum and Ileum 38
14 BMPR Type IA Receptor & SMAD4 In MAP Kinase & BMP-TGF-Beta Pathways: JPS Juvenile Polyposis Syndrome: Genetics Germline Mutations in SMAD4 of BMPR1A Genes in 50 to 60% Most Point Mutations or Small Base Pair Deletions in Coding Regions Deletions in One or More Exons or Entire Coding Sequence (15%) Additional 10% with Previously Unknown Mutations in BMPR1A Promoter Region Candidate Genes in Remaining 30-40% TGF-Beta, Endoglin, SMAD1, 2, 3, 5, 6 and 7, BMPR2, BMPR1B, ACVRL1, TGF-Beta Receptor II, and CDX2 PTEN (Cowden's and Bannayan-Riley-Ruvalcaba Syndromes) on 10q
15 BMPR1a SMAD4 Classic JPS-BMPR1a Type A Epithelial JPS SMAD4 Type B SMAD4 IHC 40
16 Cancer Risk in JPS Cumulative Life-Time Risk For Colorectal Carcinoma of 39% Conservative Estimate Because Some Patients Have Undergone Prophylactic Colectomy St. Mark s Hospital Registry (Jass, 1990) Reported Cumulative Colorectal Cancer Risk of 68% Small Bowel Carcinoma in 11% Gastric and Small Bowel Carcinoma Occur at One- Fifth the Frequency of Colorectal Cancer. Cases of Gastric, Duodenal and Pancreatic Cancer Described in Literature 41
17 Treatment in JPS At Risk Patients: Endoscopic Screening of Colon and Upper GI Tract at Age 15 Years or at 1 st Symptom At Diagnosis of JPS, Entire GI Tract Examined for Polyps Genetic Testing for BMPR1a and SMAD4 Germline Mutations Upper & Lower GI Endoscopic Exam Every 2 to 3 Years Treatment in JPS Prophylactic Colectomy if: Unmanageable Polyp Load ( Polyps) Severe GI Bleeding or Diarrhea Dysplastic Polyps Family History of Colorectal Cancer Recurrence of Rectal Polyps with Subtotal Colectomy in about 50% - Require Proctectomy Endoscopic Surveillance for Polyps in Remnant Rectum and Pouch 42
18 Treatment in JPS JPS with SMAD4 Germline Mutations Screening for Hereditary Hemorrhagic Telangiectasia Chest X-ray for AVM, MRI of Brain and Liver Ultrasound Digital Clubbing and Pulmonary Osteoarthropathy Frequent COX2 Expression High in JPS Polyps COX Inhibitors for Treatment and Chemoprevention Value of NSAIDs Requires Further Study Case History 16 year-old Male with Vague Abdominal Pain Guaiac Positive Stools and Iron Deficiency Barium Swallow Revealed Stricture in Ileum Evaluated for Crohn s Disease Endoscopic Biopsies Nonspecific Findings Laparoscopic Examination at Surgery Small Intestinal Mass 43
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24 Clear Cell Sarcoma of Soft Tissue Involving Gastrointestinal Tract 49
25 Gastrointestinal Clear Cell Sarcoma-Like GI Tumor Most Common Sites: Small Intestine & Stomach; Rarely in Colon Clinical Presentation Mimics GIST Highly Aggressive with Metastatic Disease to Nodes & Liver 100% DOD <36 Months Mural Mass of 3-6cm Located Below Mucosa Gray to Pink Tan Cut Surface Round to Ovoid Cells & Osteoclastic Giant Cells Fibrous Septa Gastrointestinal Clear Cell Sarcoma-Like GI Tumor Lack Melanin Pigmentation S100, NSE, Synaptophysin, CD56, CD57 Positive Melanocytic Markers Negative (HMB-45, MITF, A103, Tyrosine Kinase) in About 70% c-kit, CD34, Chromogranin A, Keratins, & Myogenic Markers Negative Rare Melanosomes by EM 50
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