Gastric Neoplasia: Subtypes, Staging, and Ancillary testing Rish K. Pai MD, PhD Professor of Laboratory Medicine & Pathology Mayo Clinic Arizona Florida Society of Pathology Summer 2019 [email protected] ©2017 MFMER | slide-1 1 Session Outline • Gastric Epithelial Polyps, including Unusual Types • An Update on the Classification and Staging of Gastric Carcinoma • Ancillary Testing in Gastric Carcinoma 2 2 Gastric Epithelial Polyps Most Common Polyp Types • Fundic gland polyp (~75%) • Gastric hyperplastic polyp (~20%) • Polypoid adenocarcinoma (~2%) Infrequently Encountered Polyp Types • Adenoma (~1%) – Intestinal type, foveolar type, oxyntic gland adenoma, pyloric gland adenoma • Hamartomatous polyp (<<1%) – Juvenile polyp, Peutz‐Jegher polyp, Cowden syndrome • All fairly indistinguishable from sporadic gastric hyperplastic polyp 3 1. Carmack SW et al. Am J Gastroenterol 2009;104:1524-1532. 3 Fundic Gland Polyp • Most common gastric polyp (~75% of all polyps). Sporadic Syndromic Fundic Gland Polyp Fundic Gland Polyp Increasing incidence due to proton pump inhibitor Familial adenomatous polyposis (FAP) therapy and GERD GAPPS (Gastric adenocarcinoma and proximal polyposis syndrome) Women > Men Women = Men Solitary or multiple (40%) Typically multiple (90%) Mean age ~50 years Mean age ~40 years (any fundic gland polyp in a child should prompt evaluation for FAP) CTNNB1 (ß‐catenin) mutation (90%) >>> APC (10%) APC mutation >> CTNNB1 (ß‐catenin) Low risk of dysplasia (<1%) High risk of dysplasia (~50%) (most studies indicate FAP patients do not develop adenocarcinoma) 4 1. Arnason T et al. Histopathology 2014;65:353-362. 4 Fundic Gland Polyp with Low‐Grade Dysplasia in FAP Patient 5 5 Fundic Gland Polyp in FAP Patient 6 6 Fundic Gland Polyp with Low‐Grade Dysplasia in FAP Patient 7 7 Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) • Early onset presentation (youngest 10 years, earliest gastric cancer at age 33 years). • Autosomal dominant inherited fundic gland polyposis of the body and fundus (>100 polyps in index patient or >30 in first degree relative). • No colorectal or duodenal polyposis. • High rate of progression to intestinal‐type gastric adenocarcinoma. • Due to point mutations in the promoter 1B of the APC gene. 1. Worthley DL et al. Gut 2012;61:774-779. 2. Li J et al. Am J Hum Genet 2016;98:830-842 8 3. McDuffie LA et al. J Clin Pathol 2016;69:826-833. 8 Gastrectomy Specimen from ~39 year old woman (no known prior genetic disorder) subsequently found to have point mutation in APC promoter 1B 9 9 GAPPS: Proximal Fundic Gland Polyposis 10 10 GAPPS: Proximal Fundic Gland Polyposis 11 11 Oxyntic Gland Polyp/Adenoma • Rare, usually solitary, and exclusively located in the gastric fundus or body. • Histologic Features: – Crowded glands or irregular anastomosing cords of oxyntic epithelial cells involving the deep mucosal glands. – Mixture of chief cells (predominate), parietal cells, and mucous neck cells. – MUC6 positive, MUC5AC negative, MUC2 negative. – Pitfall: synaptophysin can be positive (Don’t mistake for a neuroendocrine tumor!) • Prognosis – Most studies indicate that these do not progress to invasive adenocarcinoma, although literature is limited. 1. Singhi A et al. Am J Surg Pathol 2012;36:1030-1035. 2. Hidaka Y et al. Hum Pathol 2013;44:2438-2448. 12 3. Chan K et al. Histopathology 2016;Histopathology 68:825-833. 12 Oxyntic Gland Polyp / Adenoma: Chief cell predominant 13 13 Oxyntic Gland Polyp / Adenoma: Crowded Deep Glands 14 14 Oxyntic Gland Polyp / Adenoma: Chief cell predominant 15 15 Gastric Hyperplastic Polyp • Most often in older patient (6th to 7th decade) with equal gender distribution. • Clinical Associations: – Helicobacter gastritis (if non‐polypoid mucosa is not sampled, I order Helicobacter IHC to evaluate if there is active inflammation with abundant plasma cells). – Chemical gastritis / reactive gastropathy (bile reflux). – Gastroesophageal reflux disease (GERD) if located in the cardia • Histologic Features: – Cystically dilated glands with elongated foveolar epithelium with “corkscrew” appearance. – Stromal edema and chronic inflammation. – Surface erosion and ulceration is common. – Intestinal metaplasia and dysplasia can occur. 16 1. Horvath B et al. Int J Surg Pathol 2016;24:704-708. 16 Gastric Hyperplastic Polyp with Low‐Grade Dysplasia 17 17 Gastric Hyperplastic Polyp with Low‐Grade Dysplasia 18 18 Gastric Hyperplastic Polyp with Low‐Grade Dysplasia 19 19 Differential Diagnosis of Gastric Hyperplastic Polyp Polypoid foveolar hyperplasia • Smaller than hyperplastic polyps. • Foveolar elongation and corkscrewing without cystic change to the glands or stromal edema. Mucosal prolapse type polyp • Antral/pylorus location. • Foveolar elongation with mild cystic change, prominent vertical smooth muscle hyperplasia, and thick walled vessels within the mucosa. 20 Gonzalez-Obeso E et al. Am J Surg Pathol 2011;35:670-677. 20 Juvenile Polyposis • Juvenile polyps can be virtually indistinguishable from gastric hyperplastic polyps. • ~40% cumulative lifetime risk of developing colorectal cancer and 10‐15% cumulative lifetime risk of gastric cancer. • “Hyperplastic” polyp in young patients, especially if multiple, should be evaluated for the possibility of a hamartomatous polyposis syndrome. • Due to germline mutation in genes involved in the transforming growth factor (TGF) β signalling pathway: – SMAD4 • Increased propensity for polyps in upper GI tract, particularly the stomach. • Polyps with epithelial component >> stromal component. • More likely to develop carcinoma. – BMPR1A 21 Gastrectomy Specimen from 32 year old woman (no known prior genetic disorder) 22 Epithelial Predominant Juvenile Polyp 23 Epithelial Predominant Juvenile Polyp 24 Loss of SMAD4 by Immunohistochemistry: Juvenile Polyposis due to germline SMAD4 mutation 25 Am J Clin Pathol 2017;147:390-398. Histopathology 2017;70:918-928 • Combined total of 31 patients presenting with massive gastric juvenile‐ type polyposis. • Median age 48 years (range 13 to 79 years). • Loss of SMAD4 expression in 25 of 29 cases (86%). • High frequency of gastric epithelial neoplasia: – 7 of 31 (23%) with gastric carcinoma. – 9 of 31 (29%) with dysplasia. • 18 of 31 patients had a known history of juvenile polyposis. • Of the patients without a history of juvenile polyposis, five of six patients had germline testing demonstrating a SMAD4 germline mutation. 26 Gastric Adenoma • Rare (~1% of all gastric polyps). • Intestinal‐type adenoma (more common) – Arise in a background of intestinal metaplasia. – Often have intermixed Paneth cells (which may be prominent) and endocrine cells. – MUC2 positive (IHC not necessary for diagnosis). • Foveolar‐type adenoma (less common) – Characteristic apical mucin cap within the cytoplasm. – MUC5AC positive, MUC6 negative, MUC2 negative. • Therapy: Complete endoscopic removal. 27 27 Gastric Adenoma, Intestinal Type, with Low‐Grade Dysplasia 28 28 Gastric Adenoma, Intestinal Type, with Low‐Grade Dysplasia 29 29 Gastric Adenoma, Foveolar Type, with Low‐Grade Dysplasia 30 30 Gastric Adenoma, Foveolar Type, with Low‐Grade Dysplasia: Note the characteristic apical mucin cap 31 31 Gastric Adenoma, Foveolar Type, with High‐Grade Dysplasia 32 32 Pyloric Gland Adenoma • Occur in the stomach (all sites) and duodenum. • Women >> men for gastric lesions; mean age 73 years. • Histologic features: – Closely packed glands with a monolayer of cuboidal epithelial cells. – Pale to eosinophilic “ground glass” cytoplasm. – No apical mucin cap (in contrast to gastric foveolar adenoma). – Diffuse MUC6 positivity with MUC5AC positivity seen on surface. 1. Chen Z et al. Am J Surg Pathol 2009;33:186-193. 2. Vieth M et al. Virchows Arch 2003;442:317-321. 3. Wood LD et al. Am J Surg Pathol 2014;38:389-393. 4. Hackeng W et al. Histopathology 2016;70:549-557. 5. Lee S et al. Am J Surg Pathol 2014;38:784-792. 33 6. Choi WT et al Histopathology. 2018 May;72(6):1007‐1014. 33 Pyloric Gland Adenoma 34 34 Pyloric Gland Adenoma Pyloric Gland Adenoma: “Ground Glass” eosinophilic cytoplasm with no apical mucin cap 35 35 Pyloric Gland Adenoma: “Ground Glass” eosinophilic cytoplasm with no apical mucin cap 36 36 Pyloric Gland Adenoma • Clinical Associations: – 60% are associated with a background of intestinal metaplasia. – 40% are associated with autoimmune atrophic gastritis – increased risk of HGD in this setting – Seen in patients with familial adenomatous polyposis (FAP). – Rarely seen in patients with Lynch syndrome. • ~50% have high‐grade dysplasia and ~10% can progress to invasive adenocarcinoma. 1. Chen Z et al. Am J Surg Pathol 2009;33:186-193. 2. Vieth M et al. Virchows Arch 2003;442:317-321. 3. Wood LD et al. Am J Surg Pathol 2014;38:389-393. 4. Hackeng W et al. Histopathology 2016;70:549-557. 5. Lee S et al. Am J Surg Pathol 2014;38:784-792. 37 6. Choi WT et al. Histopathology. 2018 May;72(6):1007‐1014. 37 Pyloric Gland Adenoma Feature Low‐Grade Dysplasia High‐Grade Dysplasia Cytology • Preserved nuclear polarity • Loss of nuclear polarity • Inconspicuous nucleoli or • Prominent, enlarged nucleoli only occasional enlarged • Nuclear size variation nucleoli • Uniform nuclear size Architecture • Closely packed tubular glands • Complex glandular architecture including cribriform glands and intraluminal papillary tufts 38 1. Chen Z et al. Am J Surg Pathol 2009;33:186-193. 38 Pyloric Gland Adenoma with High‐Grade Dysplasia (cribriform architecture, nuclear enlargement, prominent nucleoli, increased mitotic activity) 39 39 Pyloric