1. Management of Gastric Polyposis/IM/Early Gastric Cancer Jeffrey H. Lee, MD, MPH, FACG, FASGE, AGAF Professor and Director, Advanced Therapeutic Endoscopy Fellowship and Training MD Anderson Cancer Center

2. Gastric Lesions 1.Gastric Polyposis – Epithelial lesions Fundic gland polyps Hyperplastic polyps Adenomas – Subepithelial lesions Carcinoids Leiomyomas Lipomas Granular cell tumors Gastrointestinal stromal tumors Pancreatic rests Linitis plastica 2.Gastric Intestinal Metaplasia 3.Early Gastric Cancer

3. Diagnostic Tools EGD with biopsy EUS – Differentiate extramural from intramural growth – Determine layer of origin – Size the lesion – Evaluate for regional lymphadenopathy – Obtain tissue for diagnosis – Help determine appropriate management CT MRI CT-PET

4. Fundic Gland Polyps

5. Hyperplastic Polyps

7. Hyperplastic Polyp Characteristics – Frequency: 2 nd most common gastric polyp – Increases between ages 60-80 years – Arise from mucosal damage due to chronic inflammation – Single, multiple, sessile, or pedunculated – Most commonly found in the antrum – H. pylori, pernicious anemia, chronic atrophic gastritis, adjacent to ulcers, sites of gastroenterostomies, APC treatment of GAVE – CT: Multiple small, round, sessile polyps in the fundus or gastric body – EGD: Less than 1cm, smooth, dome- shaped, or stalked – Endoscopic finding of white opaque substance in a gastric hyperplastic polyp is suggestive of neoplastic transformation Dirschmid et al. Virchows Archiv 2006 Park and Lauwers. Archives of pathol and lab med 2008 Baudet et al. Endoscopy 2007

8. Hyperplastic Polyp Symptoms – Usually asymptomatic – Anemia, bleeding due to ulceration, dyspepsia, gastric outlet obstruction Malignant potential – 2 % malignant transformation – Mechanism of carcinogenesis is unknown Management – If polyp persists or dysplasia is present, polypectomy is recommended with repeat EGD in one year – Although polyps greater than 2cm should be removed, carcinoma can arise in polyps less than 2cm – No endoscopic guidelines for follow-up of hyperplastic gastric polyp without dysplasia Dirschmid et al. Virchows Archiv 2006 Park and Lauwers. Archives of pathol and lab med 2008 Baudet et al. Endoscopy 2007

9. Adenoma with HGD

15. Gastric Adenoma Characteristics – Frequency: 6-10 % of gastric polyps in the western populations – Increases with age – Solitary – Commonly found in the antrum – Associated with atrophic gastritis and intestinal metaplasia – Tubular, tumbulovillous, villous – Villous >2cm: 28-40% increased risk of malignancy – Low or high grade dysplasia Based on degree of mitotic activity, cytoplasmic differentiation, nuclear crowding, hyperchromasia, stratification, architectural distortion – FAP – CT may not be helpful Vieth et al. Virchows Archiv 2003 Kamiya et al. Cancer 1982 Iida et al. Cancer 1988

16. Gastric Adenoma Symptoms – Usually asymptomatic – Anemia, bleeding due to ulceration Malignant potential – High grade dysplasia predisposes to invasive cancer not only within the polyp but also in synchronous areas of the stomach Management – Polypectomy – EMR – Follow-up For gastric adenoma after incomplete polypectomy or for high grade dysplasia; in 6 months For all other polyps; in 1 year Vieth et al. Virchows Archiv 2003 Kamiya et al. Cancer 1982 Iida et al. Cancer 1988

17. Submucosal Lesions PathologyMuscularis mucosa SubmucosaMuscularis propria Serosa GIST ✔✔ Leiomyoma ✔✔ Lipoma ✔ Granular cell tumor ✔✔ Pancreatic rest ✔ Carcinoid ✔ Fibroid lesion ✔ Duplication cyst ✔✔✔✔ Varices ✔ Lymphangioma ✔ Schwannoma ✔✔

18. GIST Characteristics – Originates from the interstitial cells of Cajal – A gain of function mutation in the KIT gene that codes for the c-kit protein, a tyrosine kinase receptor – IHC stain: CD117 positive in nearly 95% of cases – EUS: Hypoechoic lesion arising from the MP layer – EUS FNA not sufficient for assessment of mitotic count Symptoms – Iron deficiency anemia – GI bleeding Malignant potential – Potential malignant transformation and distant metastasis – Size of the lesion – Number of cells undergoing mitosis at pathology Management – <2 cm: Observation with annual EGD and/or EUS, resection if growing per NCCN – >2 cm: Consider surgical resection Endoscopic resection only possible with full-thickness resection and suturing – High risk lesions: Referral to medical oncology for consideration of adjuvant therapy with a tyrosine kinase inhibitor (e.g. Imatinib) A type of interstitial cells found in the GI Involved in the stimulation of smooth muscle cells Neurotransmitters act through them Grotz and Donohue. Surgical Oncol 2011 Hirota et al. Science 1998 Menon and Buscaglia. Ther Adv Gastroenterol 2014

19. GIST Risk of malignancySizeMitotic count Very low<2 cm<5/50 HPF Low2-5 cm<5/50 HPF Moderate<5cm6-10/50 HPF >5cm<5/50 HPF High>5cm6-10/50 HPF Any size>10/50 HPF

20. Leiomyoma Characteristics – Originates from the muscular layer, commonly MP – Most commonly in mid or distal esophagus – IHC staining is negative for CD117, CD34, s100 – IHC positive desmin, α-smooth muscle actin protein Symptoms – Usually asymptomatic – Bleeding Malignant potential – Malignant transformation to leiomyosarcoma is rare Management – > 1cm: EUS to confirm diagnosis – < 2cm: Surveillance EGD and/or EUS; if from MM layer, EMR Lee et al. J Am Coll Surg 2004

21. Lipoma Characteristics – Originates from the submucosal layer – Most commonly in the gastric antrum and colon – Yellow hue – Soft when prodded with a biopsy forceps, ‘pillow’ sign 98% specificity Symptoms – Usually asymptomatic Malignant potential – Essentially no malignant potential Management – Jumbo biopsies reveal yellow adipose tissue – Bleeding after biopsy may require clipping – Once confirmed as lipoma, no surveillance is needed Hwang et al. Gastrointest Endosc 2005

22. Granular Cell Tumors Characteristics – Subepithelial lesions of Schwann cell origin – Arise from the submucosal layer and grow toward the mucosa – Most occur within the esophagus Symptoms – Usually asymptomatic Malignant potential – Extremely low (one study, 2-4% and all were >4 cm) Management – <1 cm: Annual EGD surveillance – 1-2 cm: Annual surveillance vs. EMR – >2 cm: Surgical resection Orlowska et al. Am J Gasgtroenterol 1993

23. Pancreatic Rest Characteristics – 1-2% of patients in autopsy series – Nearly all within the stomach (90%), most often in the antrum – Arises from the submucosal layer – Central area of umbilication – On deep biopsy, pancreatic acinar tissue Symptoms – Usually asymptomatic – Ulceration, pain, bleeding, acute pancreatitis, gastric outlet obstruction Malignant potential – Benign – Rare cases of malignant transformation Management – No surveillance or removal needed Sadeghi et al. Gastroenterol and Hepatol 2008

24. Gastric Carcinoid

27. Carcinoid Tumors Characteristics – Slight female predominance (M:F; 1:1.6) – Gastric carcinoid tumors: 9% of all carcinoid tumors – Arise from the deep mucosal layer and penetrate into the submucosal layer – Type I: Atrophic gastritis, pernicious anemia, hypergastrinemia – Type II: hypergastrinemia due to ZE Syndrome or MEN-1 – Type III: Sporadic, without hypergastrinemia Symptoms – Usually asymptomatic – Ulceration, pain, bleeding, acute pancreatitis, gastric outlet obstruction Malignant potential – Type I: Very low malignant potential; fewer than 2 % are metastatic – Type II: Intermediate malignant potential; metastasize in 30% of cases – Type III: High malignant potential; lymph node metastasis in 71% of cases measuring more than 2 cm Kulke et al. NCCN 2012 Martinez-Ares et al. Rev Esp Enferm Dig 2004

28. Carcinoid Tumors Management – EUS can help in identifying the blood vessel near the carcinoid, which can potentially help prevent bleeding during endoscopic resection – For type I and II <2 cm: EMR >2 cm: Surgical resection – Antrectomy to remove G cell mass burden – Fundectomy to remove ECL cell mass burden – Post-surgical resection: EGD q 6-12 months for 3 years and annually thereafter – For type III Surgical resection with lymph node dissection Follow-up EGD Monitor chromogranin A, serum tumor marker, for recurrence Monitor 5-HIAA, a metabolite of serotonin, for treatment response Kulke et al. NCCN 2012 Ramage et al. Gut 2005

29. Carcinoid Tumors Management – For hepatic metastasis Hepatic artery ligation or embolization – Decreases symptoms and improves survival Octreotide, Somatostatin analogue – Decreases the symptoms of carcinoid syndrome – For Metastatic carcinoids Chemotherapy – Streptozocin, flurouracil, doxorubicin, cyclophosphamide – Tumor response rate of 20-40% Kulke et al. NCCN 2012 Ramage et al. Gut 2005

30. Gastric Carcinoid

32. Linitus Plastica

35. Linitis Plastica Characteristics – Frequency: 3-19% of gastric adenocarcinoma – Diffuse type of gastric cancer characterized by diffuse thickening – Asymptomatic but symptomatic at advanced stage – Metastasis from breast should be excluded as infiltrative lobular breast cancer tends to metastasize to stomach – CT scan findings: Thickened stomach wall, diffuse gastric wall thickening, perigastric stranding, lung nodules, mediastinal lymphadenopathy, local lymphadenopathy and liver metastasis – Usually the lower third of the mucosa; sometimes the biopsy of the mucosa can be negative as the mucosa is not infiltrated – Multiple biopsies at the same site or diathermic snare – CT: Diffuse mural thickening with or without ulceration – EGD: Prominent gastric folds Thickened area of irregular gastric mucosa at the greater curvature Circumferential thickening of the proximal stomach Hwang et al. Gastrointest Endosc 2005

36. Linitis Plastica Symptoms – Early satiety, abdominal discomfort, weight loss, dysphagia, dyspepsia, vomiting – Most common; regurgitation of food due to decreasing volume of the stomach Malignant potential – Malignant – Peritoneal seeding, extension to surrounding organs and metastasis to lymph nodes Management – Complete resection but only 20% benefit from total gastrectomy – Post-operative radiation with or without chemotherapy should be evaluated in future studies since complete resection is not possible in the majority of cases Hwang et al. Gastrointest Endosc 2005

37. Gastric Intestinal Metaplasia Characteristics – The most frequently encountered precancerous lesion – The sequence of gastric adenocarcinoma of intestinal type Nonatrophic gastritis Multifocal atrophic gastritis Metaplasia and dysplasia – More common in populations at high risk for gastric cancer; Eastern Asia, Eastern Europe, and Andean Latin America (Bolivia, Columbia, Ecuador, and Peru) – High-risk populations in US; African Americans, Native Americans, and immigrants from Asia and Latin America – Risk factors: Helicobacter pylori infection, high salt intake, smoking, alcohol consumption, and chronic bile reflux – Complete type IM Contains the small bowel enzymes Resemble small intestinal epithelium with eosinophil enterocytes, goblet cells, and paneth cells – Incomplete IM Contains no or little amount of small bowel enzymes Resemble colonic epithelium with absent brush border Lee et al. J Am Coll Surg 2004

38. Gastric Intestinal Metaplasia Symptoms – Usually asymptomatic – Nausea – Dyspepsia Malignant potential – Several studies showed that there is progression of IM to adenocarcinoma in incomplete IM Management – Incomplete IM Endoscopic mapping to identify multifocal areas of IM Typically, biopsy is obtained from the antrum, corpus, incisura angularis, and any visible lesion – Complete IM Endoscopic surveillance is not indicated unless there are other risk factors for gastric cancer Lee et al. Am Coll Surg 2004

39. Early Gastric Cancer (EGC) Characteristics – Confined to the mucosa or submucosa regardless lymph node metastasis – EGC accounts for 50 % of gastric cancer incidence in Japan – Paris classification – Kudo pit pattern – 5-year survival over 90 % Symptoms – Feeling bloated after eating – Nausea – Stomach pain Saito et al. Surgical Endoscopy 2010Minami et al. Gastrointestinal Endoscopy 2006 Takizawa et al. Endoscopy 2008 Catalano et al. Surgical Endoscopy 2009Oda et al. Digestive Endoscopy 2013Ferlay et al. Int J Cancer 2010 Maruyama et al. Gastric Cancer 1991 Ono et al. Gut 2001

40. Paris Classification Paris I: Protruded lesions Paris 2: – Paris 2a : Slightly elevated, – Paris 2b: Completely flat – Paris 2c: Depressed Paris 3: Ulceration of the mucosa Yada et al. Diagnostic and Therapeutic Endoscopy 20 13

41. Kudo Pit Pattern Type 1: Round Type 2: Stellar or papillary, nonneoplastic Type 3: Tubular or small roundish Type 4: Branch-like or gyrus-like Type 5: Irregular or nonstructural pits, neoplastic – Usually involves the submucosal layer and there is a high rate of lymph node metastasis

42. ESD Devices Distal attachment – Assorted size, transparent – Helps to open up the submucosal area by mechanical stretching technique Injection needle – Upper or lower case – Right gauge for easy injection Coag grasper – Used with soft coag setting to control bleeding – Can be used underwater Grounding pad – No metal such as plates, screws, or joint replacements – Across a large muscle area Electrical surgical unit – Generator providing modulated current options – Settings are different for different stages of the procedure and different models of generators ESD knives

44. Meta-analysis on EMR vs. ESD 15 nonrandomized studies; 7 articles and 8 abstracts ESD when compared with EMR – Higher en bloc and curative resection rates for esophageal, gastric, and colorectal neoplasms and for lesions of size 20 mm – Lower local recurrent rate (OR 0.09, 95%CI 0.04-0.18) – More time-consuming Complications – Higher procedure-related bleeding and perforation rates than in general procedures (OR 2.20, 95% CI 1.58-3.07; OR 4.09, 95%CI 2.47- 6.80) – Bleeding: 93/1596 (6%) in EMR vs. 80/868 (9%) in ESD – Perforation: 19/1982 (1%) in EMR vs. 57/1255 (5%) in ESD Recurrence – Local recurrence: 118/2254 (5%) in EMR vs. 5/1484 (0.3%) in ESD Cao Y et al. Endoscopy Lancet 2009;41:751-757

45. Early Gastric Cancer Management – EUS To assess depth of invasion (T-stage) To identify lymph node metastasis (N-stage) – Endoscopic mucosal resection (EMR) – Endoscopic submucosal dissection (ESD) – Post EMR/ESD metachronous cancer; a 3-year cumulative incident rate of 5.9% with average time until detection of 3.1 +1.7 years – Italian study of 45 patients En-bloc resection: 26/36(72%) in EMR and 11/12(92%) in ESD Curative resection: 20/36(56%) in EMR vs. 11/12(92%) in ESD No recurrence or distant metastasis in mean follow-up of 31 months Complications of EMR vs. ESD – Bleeding (8% vs. 8%) – Stenosis (3% vs. 0) – Perforation (0 vs. 8%) Saito et al. Surgical Endoscopy 2010Minami et al. Gastrointestinal Endoscopy 2006 Takizawa et al. Endoscopy 2008 Catalano et al. Surgical Endoscopy 2009Oda et al. Digestive Endoscopy 2013

46. Take-home Message Weigh the benefits and risks Have a thorough discussion with the patient before the planned procedure For invasive procedures – EMR/ESD team needed – Arrange surgical support Surveillance is important for some of the lesions