Session Outline Gastric Epithelial Polyps

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]

Session Outline

• Gastric Epithelial Polyps, including Unusual Types

• An Update on the Classification and Staging of Gastric Carcinoma

• Ancillary Testing in Gastric Carcinoma

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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

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Fundic Gland Polyp in FAP Patient

6 6 Fundic Gland Polyp with Low‐Grade Dysplasia in FAP Patient

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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

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GAPPS: Proximal Fundic Gland Polyposis

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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

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Oxyntic Gland Polyp / Adenoma: Crowded Deep Glands

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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

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Gastric Hyperplastic Polyp with Low‐Grade Dysplasia

18 18 Gastric Hyperplastic Polyp with Low‐Grade Dysplasia

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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)

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.

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

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Gastric Adenoma, Intestinal Type, with Low‐Grade Dysplasia

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Gastric Adenoma, Foveolar Type, with Low‐Grade Dysplasia

30 30 Gastric Adenoma, Foveolar Type, with Low‐Grade Dysplasia: Note the characteristic apical mucin cap

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Gastric Adenoma, Foveolar Type, with High‐Grade Dysplasia

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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

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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 Gland Adenoma with Invasive Adenocarcinoma

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Pyloric Gland Adenoma with Invasive Adenocarcinoma

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Pyloric Gland Adenoma in Familial Adenomatous Polyposis 42 42 Pyloric Gland Adenoma in Familial Adenomatous Polyposis 43 43

Pyloric Gland Adenoma with HGD in FAP Patient 44 44

Pyloric Gland Adenoma: MUC5AC with surface positivity 45 45 Pyloric Gland Adenoma: diffuse MUC6 positivity 46 46

Gastric Cancer: 3rd commonest CA worldwide (603,419 new cases/year and 446,052 related deaths / year

Heterogeneous disease

• > 60/100k:Asia, East. Europe, Central / So. Am. ΔIncidence • < 15/100k:North Am., Northern Europe, Africa, South- East Asia.

• H Pylori (pathogenicity factors), Smoking, Bile Reflux, Etiologies Genetic predisposition (IL-1β;IL-1RN), Diet (poor in β carotene; vitamin A & C)

Increasing absolute • Worldwide, the absolute number of new cases/year number increasing because of aging population 47

Gastric Carcinoma: Textbook Classifications

Laurén Classification WHO (2010) Classification Intestinal type Tubular adenocarcinoma Papillary adenocarcinoma Mucinous adenocarcinoma Diffuse type Poorly cohesive carcinoma, signet ring cell carcinoma Poorly cohesive, other cell types Mucinous adenocarcinoma with signet ring cells Indeterminate type Mixed carcinomas Squamous cell carcinoma Undifferentiated carcinoma Gastric carcinoma with lymphoid stroma Hepatoid carcinoma (AFP‐producing) Choriocarcinoma (HCG‐producing) Neuroendocrine carcinoma, including MANEC Adenocarcinoma of fundic/oxyntic gland type

Conventional classification schemes are still useful in clinical practice. 48 48 Gastric Carcinoma: TCGA

TCGA Frequency Classification

EBV‐associated 5‐10%

MSI‐H 10‐20%

Chromosomal ~50% instability (CIN)

Genomically stable ~20% (GS)

Analysis of 295 primary gastric carcinomas as part of The Cancer Genome Atlas (TCGA) project. 49 The Cancer Genome Atlas. Nature 2014;513:202-209. 49

Gastric Carcinoma: TCGA using IHC

•EBER-ISH GC (n=146) •MMR proteins

•E-Cadherin REMAINING EBV GC •P53 GC (n=7) 5%

REMAINING MSI‐H GC 16% GC (n=24)

GC WITH ABERRANT E‐ REMAINING GC CADHERIN: Genomically Stable 21% (n=30)

7% Gp 5 (n=10) GC WITH ABERRANT P53: 51% GC WITH NORMAL P53 Chromosomal instability (n=75)

Setia N, et al. A protein and mRNA expression‐based classification of gastric cancer. Mod Pathol. 50

EBV-Associated Gastric Carcinoma: Key Points

Feature Characteristics Clinical Features • Accounts for 5‐10% of all gastric carcinomas. • Predominantly men (2:1); mean age 65 years. • Cardia / Fundus / Body >> Antrum • 35% of tumors in post‐surgical gastric stump/remnants are EBV positive.

Histologic Associations • 80% of “gastric carcinomas with lymphoid stroma” are EBV positive. Molecular Alterations • High levels of DNA methylation. • Recurrent PIK3CA mutations. • Amplification of PD‐L1 and PD‐L1 overexpression by IHC in a subset of cases. Prognostic Implications • Improved prognosis. • Potential role for PD‐1/PD‐L1 immunotherapy.

The Cancer Genome Atlas. Nature 2014;513:202-209 51 Murphy et al. Gastroenterology 2009;137:824-833. 51 EBV‐Associated Gastric Carcinoma with Lymphoid Stroma

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EBV‐Associated Gastric Carcinoma with Lymphoid Stroma

53 These tumors are also known as medullary carcinoma or lymphoepithelioma‐like carcinoma 53

EBV‐Associated Gastric Carcinoma with Lymphoid Stroma

54 54 EBV‐Associated Gastric Carcinoma with Lymphoid Stroma

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EBER (EBV‐Associated Gastric Carcinoma)

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EBV‐Associated Gastric Carcinoma with signet ring cells

57 57 EBV‐Associated Gastric Carcinoma with signet ring cells

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EBER (EBV‐Associated Gastric Carcinoma w/ signet ring cells)

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MSI-H Gastric Carcinoma: Key Points

Feature Characteristics Clinical Features • Accounts for 10‐20% of all gastric carcinomas. • Women > men; older age (median 72 years). • Antrum >>> Body/Fundus or Cardia.

Histologic Associations • Intestinal type (tubular, mucinous, or papillary) histology. • Gastric carcinoma with lymphoid stroma (subset of cases). • May be associated with Helicobacter infection.

Molecular Alterations • Vast majority are sporadic due to loss of MLH1/PMS2 from MLH1 promoter hypermethylation. • Rarely Lynch syndrome associated.

Prognostic Implications • Likely improved prognosis (most studies). • Potential role for PD‐1/PD‐L1 immunotherapy.

The Cancer Genome Atlas. Nature 2014;513:202-209 60 Murphy et al. Gastroenterology 2009;137:824-833. 60 MSI‐H gastric carcinoma (intestinal type) arising in Helicobacter gastritis 61 61

MSI‐H gastric carcinoma (intestinal type) arising in Helicobacter gastritis

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MSI‐H gastric carcinoma (intestinal type) arising in Helicobacter gastritis

63 63 Loss of MLH1 and PMS2 expression with concurrent MLH1 promoter hypermethylation in MSI‐H gastric carcinoma

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MSI‐H Gastric Carcinoma with Lymphoid Stroma

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MSI‐H Gastric Carcinoma with Lymphoid Stroma

66 66 MSI‐H Gastric Carcinoma with Lymphoid Stroma

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MSI‐H Gastric Carcinoma: Loss of MLH1 and PMS2 Expression by Immunohistochemistry

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Mucinous Adenocarcinoma (40% were MSI‐H in TCGA study)

69 69 Mucinous Adenocarcinoma

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Papillary Adenocarcinoma (20% were MSI‐H in TCGA study)

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Papillary Adenocarcinoma

72 72 Papillary Adenocarcinoma

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Genomically Stable (GS) Gastric Carcinoma

Feature Characteristics Clinical Features • Accounts for ~20% of all gastric carcinomas. • Diagnosed at an earlier age than other types (median age 59 years). • Relatively equal M:F. • Occurs in all sites of the stomach. Histologic Associations • Poorly cohesive (diffuse type) gastric carcinoma, including those with signet ring cell differentiation.

Molecular Alterations • CDH1 (E‐cadherin) mutation, including patients with hereditary diffuse gastric cancer (HDGC). • RHOA mutations. • CLDN18‐ARHGAP fusion. Prognostic Implications • Poor prognosis with limited response to chemotherapy compared to other subtypes.

74 The Cancer Genome Atlas. Nature 2014;513:202-209 74

Poorly Cohesive (Diffuse Type) Adenocarcinoma

75 Poorly Cohesive (Diffuse Type) Adenocarcinoma

Poorly Cohesive (Diffuse Type) Signet Ring Cell Carcinoma

73 year old man with enlarged gastric folds (NOT Menetrier’s disease)

78 78 Diffuse‐Type (Poorly Cohesive) Gastric Carcinoma, Eosinophilic Variant

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Diffuse‐Type (Poorly Cohesive) Gastric Carcinoma, Eosinophilic Variant

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Diffuse‐Type (Poorly Cohesive) Gastric Carcinoma, Eosinophilic Variant

81 81 72 year old woman w/ nodular mucosa in the gastric antrum 82 82

72 year old woman w/ nodular mucosa in the gastric antrum

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Estrogen Receptor GATA3

Must evaluate for possibility of metastatic breast carcinoma in gastric biopsies from women GCDFP‐15 with poorly cohesive carcinoma. Mammaglobin

84 84 Gastric Carcinoma in Young Patients

• Between 2% and 10% of all gastric carcinomas are diagnosed in patients younger than 40 years of age. • Most case are poorly cohesive (diffuse type) histology.

• Hereditary Diffuse Gastric Cancer (HDGC) – Autosomal dominant condition associated with poorly cohesive (diffuse type) gastric carcinoma and lobular breast carcinoma. – Germline mutation of the E‐cadherin (CDH1) gene. – Estimated lifetime risk of gastric carcinoma is ~80%. – Often treated with risk‐reducing total gastrectomy in at risk patients. • Histologic clues to HDGC. • Early stage disease is characterized by microscopic (1‐2 mm) and multiple foci of intramucosal carcinoma composed entirely of signet ring cells within the superficial gastric mucosa • Tumor cells larger near surface and smaller at the neck of the gastric glands

The Cancer Genome Atlas. Nature 2014;513:202-209 85

Intramucosal Signet Ring Cell Carcinoma

Hereditary Diffuse Gastric Carcinoma (HDGC) CDH1 germline mutation 86 86

Intramucosal Signet Ring Cell Carcinoma

Hereditary Diffuse Gastric Carcinoma (HDGC) CDH1 germline mutation 87 E-Cadherin IHC positive in tumor cells despite germline CDH1 mutation (This patient had a Q511X point mutation as opposed to a truncating mutation)

Hereditary Diffuse Gastric Carcinoma (HDGC) CDH1 germline mutation 88

Hereditary Diffuse Gastric Carcinoma (HDGC) CDH1 germline mutation hiding in Helicobacter gastritis 89 89

Chromosomal Instability (CIN) Gastric Carcinoma

Feature Characteristics Clinical Features • Accounts for ~50% of all gastric carcinomas. • Slightly more common in men than women. • Gastric cardia / GEJ > body > antrum.

Histologic Associations • Intestinal‐type morphology (tubular, papillary, and mucinous). • Subset of poorly cohesive (diffuse type) carcinoma.

Molecular Alterations • Aneuploidy. • TP53 mutation. • RTK‐RAS activation. Prognostic Implications • Variable prognosis. • Role for HER2 targeted therapy.

The Cancer Genome Atlas. Nature 2014;513:202-209 90 Murphy et al. Gastroenterology 2009;137:824-833. 90 Intestinal (Tubular Type) Gastric Carcinoma, NOS

91 91

Bartley A et al. Arch Pathol Lab Med 2016;140:1345-1363.

Summary of Selected CAP/ASCP/ASCO Statements Strength of Recommendation In patients with advanced gastroesophageal adenocarcinoma who are candidates for HER2‐targeted Strong therapy, the treating clinician should request HER2 testing. HER2 testing on biopsies or resections should be requested prior to initiation of trastuzumab therapy. Moderate HER2 testing on FNA cell blocks is acceptable. Laboratories should perform IHC testing first, followed by ISH only when the IHC result is 2+ (equivocal). Strong

Pathologists should use the Ruschoff/Hoffman scoring method.Strong Pathologists should select the tissue block with the areas of lowest grade tumor morphology for testing. Strong More than one tissue block may be tested if different morphologic patterns are present.

Bartley A et al. Arch Pathol Lab Med 2016;140:1345-1363.

Pathologists should mark areas of invasive carcinoma with strongest intensity of HER2 expression by IHC Strong for subsequent ISH scoring when required. Laboratories must specify the antibodies and probes used for the test and ensure that assays are Strong appropriately validated. Laboratories must incorporate HER2 testing into their QI program. In particular, laboratories should Strong participate in a formal proficiency testing program. 93 Ruschoff/Hoffman HER2 Scoring Magnification HER2 IHC Scoring Criteria for Surgical Scoring Criteria for Biopsy Guideline for Assessment Resection1 Specimen1 Intensity2 Negative (0) No reactivity or membranous reactivity in No reactivity or membranous reactivity Not applicable <10% of tumor cells in any tumor cells. Negative (1+) Faint/barely perceptible membranous Tumor cell cluster with a Faint/barely Membranous staining reactivity in ≥10% of tumor cells; cell are perceptible membranous reactivity visible only with high‐ reactive in only part their membrane. irrespective of % of tumor cells stained. power (e.g. 40x) objective.

Equivocal (2+) Weak to moderate, complete, basolateral, Tumor cell cluster with a weak to Membranous staining or lateral membranous reactivity in ≥10% moderate, complete, basolateral, or visible only with of tumor cells. lateral membranous reactivity intermediate (e.g. 10‐20x) irrespective of % of tumor cells stained. objective.

Positive (3+) Strong complete, basolateral, or lateral Tumor cell cluster with a strong Membranous staining membranous reactivity in ≥10% of complete, basolateral, or lateral visible with low power tumors. membranous reactivity irrespective of % (e.g. 2‐4x) objective. of tumor cells stained

1. Hofmann M, et al. Histopathology 2008;52:797-805. 2. Ruschoff J et al. Mod Pathol 2012;25:637-650. Tumor cell cluster defined ≥5 tumor cells. 94

HER2 IHC 3+ w/ Basolateral & Lateral Membranous Staining 95 95

HER2 FISH (Positive HER2/CEP17 >>2.0)

96 96 HER2 IHC 3+ (Positive) (Strong membranous staining easily visible with 2x objective magnification)

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HER2 IHC 2+ (Equivocal, Reflex to HER2 ISH) (Membranous staining only visible with 10‐20x objective magnification)

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HER2 IHC 1+ (Negative) (Faint membranous staining only visible with 40x objective magnification)

99 99 Biopsy: HER2 IHC 3+ (Positive) in Tumor Cell Clusters HER2 IHC 3+ (Positive) with Heterogeneity

HER2 IHC 3+ (Positive) with Heterogeneity Solid carcinoma without staining, Lower grade intestinal‐type carcinoma with 3+ staining.

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HER2 IHC: Antibody Selection, Pre‐Analytic Considerations & Reporting • FDA approved HER2 IHC tests – Dako HercepTest (used in the ToGA trial). – Ventana Pathway clone 4B5 (Tuscson, AZ) (used in my lab). – Thermo Fisher Scientific clone CB11 (St. Louis, MO) – CAP/ASCP/ASCO did not recommend use of a specific antibody. Some studies have found the Ventana 4B5 clone to have stronger staining.

• Pre‐analytic Considerations – A minimum of 5 biopsy fragments (preferably 6 to 8) should be obtained to account for intratumoral heterogeneity. – Tissue should be placed in formalin within 1 hour (cold ischemic time). – Tissue should be fixed in 10% neutral buffered formalin for 6 to 72 hours.

• Reporting – Recommended benchmark of 90% of HER2 reports available within 10 working days. – If send out to reference laboratory, recommended benchmark of 90% of specimens sent to the reference lab within 3 working days.

1. Bang Y et al. Lancet 2010;376:687-97. 2. Radu OM et al. Am J Clin Pathol 2012;137:583-594. 101

AJCC 8th Edition Staging Update

Gastric Primary Esophageal/Esophagogastric • Tumor with an epicenter >2 cm from • Tumor with an epicenter located EG junction. within 2 cm of the EG junction • Tumor with an epicenter within 2 cm and of EG junction but does not involve • Involves the EG junction. the EG junction.

102 AJCC 8th Edition Staging Update

• Assessment of at least 16 regional lymph nodes is recommended (improved survival in patients without advanced stage tumors, i.e. stage IA‐IIIA).

• Depends of the extent of the lymphadenectomy performed by the surgeon. – D1 lymphadenectomy: perigastric lymph nodes within 3 cm from the primary tumor. – D2 lymphadenectomy: extended dissection to include lymph nodes around the hepatic and splenic arteries.

Gholami S et al. J Am Coll Surg 2015;221:291-299. 103

Take Home Points

• Gastric Epithelial Polyps, including Unusual Types – Oxyntic gland adenoma/polyp – rare gastric polyp composed of chief cells. – Pyloric gland adenoma – important as it can progress to carcinoma. – Some patients with juvenile polyposis present initially with gastric polyposis with polyps resembling “hyperplastic” polyps. • An Update on the Classification of Gastric Carcinoma – EBV‐associated carcinoma is characterized by prominent lymphocytes and has a good prognosis. – MMR deficient (MSI‐H) gastric carcinoma account for 10‐20% of gastric carcinoma & can have an intestinal‐type histology and/or prominent tumor infiltrating lymphocytes. – Exclude breast carcinoma in any poorly cohesive carcinoma involving the stomach in women. • Ancillary Testing in Gastric Carcinoma – CAP/ASCO/ASCP Guidelines for HER2 testing – MMR protein immunohistochemistry and EBV in‐situ studies

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