Nonneoplastic Gastric Pathology. Elizabeth Montgomery

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1 Nonneoplastic Gastric Pathology Elizabeth Montgomery

2 Disclosure Statement Dr. Montgomery reports no relevant financial relationships with commercial interests.

3 Stomach! We will begin with a whirwind tour of the things that we can encounter in gastric biopsies and then review some gastric lesions and their company

4 First, a few pitfalls

5 A Few Benign Pitfalls Crushed mucosa with sloughed mucous neck cells Erosive gastritis/gastropathy including iron pill gastritis Signet cell change Gastric Xanthoma

6 Pitfall erosive gastropathy note that the reparative glands respect the muscularis mucosae border.

7 Pitfall - Iron pill gatritis with reactive changes

8 Pitfall - Iron pill gatritis with reactive changes

9 Pitfall - Iron pill gatritis with reactive changes iron stain

10 Pitfall - signet cell change in ischemic columnar mucosa; cells lose their cohesion and slough into the lumen whilst rounding up

11 Pitfall - signet cell change in ischemic columnar mucosa; cells retain E-Cadherin expression

12 Pitfall crushed mucosa with prominent mucus neck cells note the the sloughed single cells are not within lamina propria but floating and seen in gland lumina

13 Pitfall crushed mucosa with prominent mucus neck cells note the the sloughed single cells are not within lamina propria but floating and seen in gland lumina

14 Pitfall crushed mucosa with prominent mucus neck cells note the the sloughed single cells are not within lamina propria but floating and seen in gland lumina

15 Pitfall crushed mucosa with prominent mucus neck cells note the sloughed single cells are seen in gland lumina oil immersion (bad idea)

16 The real thing signet cell carcinoma - the bad cells are firmly in the lamina propria so not seen in the lumina

17 Gastric xanthoma

18 Gastric xanthoma, PAS

19 And now a whirlwind of things we encounter on biopsies..

20 Mucosal calcinosis seen in patients with renal failure or other disorders of calcium metabolism such as parathyroid adenomas

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22 Calcium pill gastritis

23 Proto pump inhibitor effect

24 Sarcina ventriculi Patient with diabetes and slow gastric emptying note exudate and organisms at low power

25 Sarcina ventriculi

26 Sarcina ventriculi gastritis Gram positive, anaerobic, sugar-fermenting bacterium, S. ventriculi was first observed in the human stomach in 1842 by Goodsir. Readily found in soil and is known to cause a similar type of gastric injury in animals. Delayed gastric emptying and carbohydrate stasis in association with acidic gastric juices may provide an ideal culture medium

27 1: Lam-Himlin D, Tsiatis AC, Montgomery E, Pai RK, Brown JA, Razavi M, Lamps L, Eshleman JR, Bhagavan B, Anders RA. Sarcina organisms in the gastrointest 1: Lam-Himlin D, Tsiatis AC, Montgomery E, Pai RK, Brown JA, Razavi M, Lamps L, Eshleman JR, Bhagavan B, Anders RA. Sarcina organisms in the gastroint Sarcina Ventriculi gastritis Studied patients all had underlying delayed gastric emptying (one had a bezoar) from diabetic neuropathy, narcotic use, and pyloric stenosis secondary to malignancy The organism may simply colonize pre-existing lesions but there are too few cases to draw firm conclusions as to whether the organism is truly a pathogen. Packets of 4, 8 or more cells with characteristic flattening Lam-Himlin D, Tsiatis AC, Montgomery E, Pai RK, Brown JA, Razavi M, Lamps L, Eshleman JR, Bhagavan B, Anders RA. Sarcina organisms in the gastrointestinal tract: a clinicopathologic and molecular study. Am J Surg Pathol Nov;35(11):

28 Lymphocytic gastritis Most common association Celiac disease followed by H. Pylori

29 Lymphocytic gastritis Most common association Celiac disease followed by H. Pylori

30 Collagenous gastritis poorly understood and sometimes resolves by itself presents with watery diarrhea just like collagenous colitis

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32 Granulomatous gastritis pattern can be Crohn s disease but always requires correlation with clinical findings

33 Cytomegalovirus gastritis note that the EPITHELIAL cells are often affected in the stomach

34 Cytomegalovirus gastritis the monocyte-rich inflammation can mimic a lymphoma

35 Russell body gastritis usually a curious incidental findings and only sometimesassociated with plasma cell disorders

36 Russell body gastritis, PAS/AB stain

37 Case A 68 year old woman with dyspepsia underwent upper endoscopy and had some gastric biopsies. The endoscopist thought the mucosa was atrophic and also saw a polyp.

38 Antrum 68 yo woman

39 Body Body

40 polyp

41 Diagnosis Autoimmune gastritis Hyperplastic polyp

42 Esophagus, Stomach, and Duodenum: Normal Anatomic Outlines and Relationships

43 Normal Antral Mucosa with Gastric Lumen (LUM), Foveolae (FOV), and Antral Glands (AG) Indicated H&E Mucus (PAS)

44 Normal Oxyntic Mucosa with Foveolae (FOV), Parietal Cells (PC), and Chief Cells (CC) Indicated H&E Stain Mucus Stain (PAS)

45 Major Endocrine Cell Types of the Stomach and Their Products - Immunostain Demonstrations

46 A few Comments on Helicobacter pylori Gastritis

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48 Two Australians win Nobel Prize in Medicine Awarded for work on peptic ulcer disease R. Warren Pathology B. Marshall GI Medicine & Microbiology

49 Helicobacter pylori: Curved Organisms (HP) with Flagellae Over Gastric Epithelium Light Microscopy Electron Microscopy

50 Helicobacter pylori: Routine Stains for Detecting and Verifying Bacillary and Coccoid Forms Giemsa (Diff-Quick) Coccoids: inset Immunostain Coccoids: arrows 52

51 Variant form Helicobacter heilmannii Reacts with H. pylri immunostain Similar clinical profile to H pylori Pediatric cases possible overrepresented

52 Prevalence of Helicobacter pylori Infection in Developing vs. Developed Countries Aliment Pharmacol Ther 1995;9(Supp2):33

53 Consequences of H. pylori infection Many are asymptomatic dyspepsia Peptic ucler Atrophy and intestinal metaplasia of mucosa Increased risk for intestinal type adenocarcinoma MALT lymphoma?? Link to autoimmune gastritis

54 Chronic Active H. pylori Gastritis with Neutrophilis (PMN s) in Gland

55 Duodenal and Pre-Pyloric Ulcers

56 Duodenal Ulcer with Brunner Gland (BG) Hyperplasia, Pancreatic Penetration and Exposed Artery

57 Eradication of H. Pylori in Recurrent Duodenal Ulcer NEJM 328 : , 1993

58 Benign Gastric Ulcer - Lesser Curve, Transitional Zone Antrectomy Specimen

59 Environmental Metaplastic Atrophic Gastritis Suspected causative factors: - H. pylori infection - Dietary: High salt; smoked foods; nitrates; poor fruit and vegetable intake - Others: Smoking

60 H. Pylori associated Metaplastic Atrophic Gastritis (Stemmermann s Technique; stained for alkaline phosphatase ) Advanced Early Red areas = intestinalization

61 H. Pylori Organisms Have Specific Affinity for Gastric Mucous Cells But Not Intestinal Absorptive Cells

62 Carcinoma in Environmental Metaplastic Atrophic Gastritis (EMAG)

63 Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, Terao S, Amagai K, Hayashi S, Asaka M; Japan Gast Study Group. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet Aug 2;372(9636):392-7.

64 Autoimmune gastritis

65 Metaplastic Atrophic Gastritis (MAG) Autoimmune vs. H.pylori Types Autoimmune H. pylori

66 Autoimmune vs. Environmental Metaplastic Atrophic Gastritis Autoimmune Red areas = intestinalization H. Pylori

67 Autoimmune MAG (AMAG) Etiology/ Pathogenesis: - Inherited predisposition - Autoimmune-induced damage Parietal cell antibodies Intrinsic factor antibody - H. pylori organisms usually absent Pathology: - Body (ONLY!) DIFFUSE METAPLASIA; mucosa thin Loss of oxyntic glands ( atrophy ) - Antrum - NO METAPLASIA; hyperplasia - Endocrine G-cell hyperplasia ECL cell hyperplasia

68 Autoimmune Metaplastic Atrophic Gastritis (AMAG) - Autopsy

69 Autoimmune Metaplastic Atrophic Gastritis (AMAG) vs. Normal Mucosa AMAG Normal Oxyntic Mucosa

70 Oxyntic Mucosa: Autoimmune Metaplastic Atrophic Gastritis (AMAG) -Intestinal and Pyloric Metaplasia H&E (PAS/Alcian Blue)

71 Autoimmune MAG (AMAG) Clinical Correlations Achlorhydria or marked hypochlorhydria B-12 malabsorption Serum gastrin - high levels Gastric cancer:?? risk increased Gastric ulcer: not a problem (no acid!) We used to think this was a Northern European disease but it is equal opportunity Female prevalence holds regardless of race

72 Case. A gastric body polyp from a 66 year old woman.

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78 Pyloric Gland Adenoma (PGA) Elster 1976 Described adenoma-like hyperplasia of mucoid glands Borchard et al and Watanabe et al 1990 Separately described similar lesions Term pyloric gland adenoma mentioned in 1990 WHO classification of gastric tumors Case reports of similar lesions in: Gallbladder Main pancreatic duct Duodenum Cervix uteri

79 Pyloric Gland Adenoma Largest study Vieth et al 90 patients with lesions in stomach (77 patients), duodenal bulb (7 patients), duodenum (1 patient), bile duct (3 patients) or gallbladder (2 patients). Veith et al. 2.7% of all gastric polyps Adults (73+/-12.8 years), Women (75%). In stomach, mostly in body (64%),often found in patients with autoimmune gastritis (36%) /-9.1 mm. transition to well-differentiated adenocarcinoma reported in 30%.

80 Clinical Features of JHU PGAs Gender distribution No. (%) Female 21 (64%) Male 12 (36%) Mean Age (range) 71.2 (47-85) Adenoma location Stomach 17 (46%) (13F, 2M) Duodenum 18 (48%) (9F, 7M) GE junction 2 (5%) Pancreas 1 (1%)

81 Background Mucosal Changes and in Gastric PGA 9 cases with surrounding mucosa available for assessment: 3 with autoimmune metaplastic and atrophic gastritis (AMAG) 5 with intestinal metaplasia

82 Pyloric gland adenoma in duodenum

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85 Pyloric gland adenoma Ki-67

86 Pyloric gland adenoma MUC 6

87 Pyloric gland adenoma, MUC5AC

88 Adenomas If lesion produces a polyp, it is referred to as an adenoma and the dysplasia graded whereas flat lesions are termed dysplasia. Background pathology is important just as for hyperplastic polyps.

89 Gastric Adenomas Intestinal type Gastric foveolar type Pyloric gland adenoma Oxyntic gland adenoma evolving concept since very rare

90 Gastric adenoma, intestinal type has intestinal metaplasia and arises in abnormal mucosa with intestinal metaplasia!

91 Gastric adenoma, gastric foveolar type pristine background mucosa, NO intestinal metaplasia anywhere. The cells have apical neutral mucin In Many ways equivalent to colorectal adenomas

92 Pyloric gland adenoma - cells lack apical mucin caps and these arise in stomachs with pyloric metaplasia of the body mucosa

93 Oxyntic gland adenoma stay tuned

94 Gastric Adenomas Abraham et al: defined them as intestinal or gastric type. Intestinal-type (containing at least focal goblet cells and/or Paneth cells), gastric-type (lined entirely by gastric mucin cells on PAS/alcian blue stain), or indeterminate. Abraham SC, Montgomery EA, Singh VK, Yardley JH, Wu TT. Gastric adenomas: intestinal-type and gastric-type adenomas differ in the risk of adenocarcinoma and presence of background mucosal pathology. Am J Surg Pathol Oct;26(10):

95 Adenomas, Abraham View Intestinal-type adenomas were significantly more likely than gastric-type adenomas to show highgrade dysplasia (p <0.0001), adenocarcinoma within the polyp (p = 0.016), intestinal metaplasia in the surrounding stomach (p < ), and gastritis (p = 0.002). Patients with intestinal-type adenomas more likely to have separate adenocarcinomas

96 Gastric Adenoma, Intestinal Type

97 Gastric Adenoma

98 Intestinal type adenoma the lesion arises in damaged background mucosa ( field effect ) whole stomach at risk

99 Gastric Adenoma, Gastric Foveolar Type Background stomach not at risk

100 Gastric Foveolar Type Adenoma

101 PAS/Alcian Blue

102 Muc5AC Muc6

103 Gastric Adenoma, Intestinal Type

104 Gastric Adenoma, Intestinal Type

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106 Carcinoma in gastric hyperplastic polyp

107 Literature Confusion Park do Y, Srivastava A, Kim GH, Mino-Kenudson M, Deshpande V, Zukerberg LR, Song GA, Lauwers GY. Adenomatous and foveolar gastric dysplasia: distinct patterns of mucin expression and background intestinal metaplasia. Am J Surg Pathol Apr;32(4): These authors claim that having foveolar differentiation (MUC5AC) was bad Difference between that and the scheme just noted is that these patients ALL had background intestinal metaplasia in their stomachs so essentially the authors are saying if the background IM is of the incomplete type this is worse! No need to waste your time doing silly MUC profiles on gastric dysplasia/neoplasia!

108 1: Ueyama H, Yao T, Nakashima Y, Hirakawa K, Oshiro Y, Hirahashi M, Iwashita A, Watanabe S. Gastric adenocarcinoma of fundic gland type (chief cell predomin 1: Ueyama H, Yao T, Nakashima Y, Hirakawa K, Oshiro Y, Hirahashi M, Iwashita A, Watanabe S. Gastric adenocarcinoma of fundic gland type (chief cell predo Oxyntic gland adenoma Rare Same lesions have been termed gastric adencarcinoma of fundic type, despite benign follow-up in the initial series. Our follow-up was also benign. Limited numbers of cases reported to date so they are either benign of very lowgrade/unlikely to kill patients Ueyama H, Yao T, Nakashima Y, Hirakawa K, Oshiro Y, Hirahashi M, Iwashita A, Watanabe S. Gastric adenocarcinoma of fundic gland type (chief cell predominant type): proposal for a new entity of gastric adenocarcinoma. Am J Surg Pathol May;34(5): Singhi AD, Lazenby AJ, Montgomery EA. Gastric adenocarcinoma with chief cell differentiation: a proposal for reclassification as oxyntic gland polyp/adenoma. Am J Surg Pathol Jul;36(7):

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111 Oxyntic gland adenoma, Ki-67 only stains the gastric mucosa proliferative compartment over the lesion

112 Fundic Gland Polyps Most common stomach polyp 2 distinct forms: sporadic and FAP-associated. originally described in patients with FAP and believed to be a manifestation of that syndrome, now recognized to be the most common gastric polyps in individuals without FAP. Sporadic - 1-2% of routine upper endoscopic examinations, most common in middle-aged females. small (a few millimeters and only rarely more than 1 cm), sessile, and dome-shaped. Not associated with inflammatory or atrophic background Asymptomatic.

113 Fundic Gland Polpys Sporadic may be single but are commonly multiple (usually a few polyps). Rarely patients without FAP will have carpeting of the body and fundus by numerous FGPs in a manner that resembles a polyposis syndrome.? use of proton pump inhibitors and the development of FGPs.

114 Fundic Gland Polpys FAP Associated v Sporadic FAP-associated FGPs occur in a majority of patients with FAP (reported frequencies range from 12.5% to 100% of FAP patients, depending on the age at endoscopy) Equal gender distribution. Younger ages, including children More numerous than sporadic FGPs, and hence patients with FAP are more likely to have fundic gland polyposis Approximately 25% of FAP-associated FGPs demonstrate low-grade epithelial dysplasia. Dysplasia in sporadic FGPs can occur but is distinctly unusual AND HAS NO RISK OF PROGRESSION TO CANCER!!!!!!

115 Fundic gland polyposis FAP patient Fundic Gland Polyps

116 Fundic Gland Polyps

117 Fundic Gland Polyps

118 Dysplasia in fundic gland polyp

119 Dysplasia in fundic gland polyp of the foveolar (low-risk) type

120 Dysplasia in fundic gland polyp of the foveolar (low-risk) type

121 Adenomas In general, gastric adenomas are rarely truly "sporadic" lesions. Most arise in dirty soil (intestinal or pyloric metaplasia after damage) Gastric foveolar types and oxyntic gland adenomas are both very rare In any individual patient complete removal of the adenoma should be performed, and biopsy of the surrounding gastric mucosa is useful to understand the clinicopathologic context of the adenoma.

122 Gastric Polyps Any projection above the adjacent mucosal surface. reactive/inflammatory, hamartomatous, or neoplastic in nature. The classification of gastric epithelial polyps can be challenging histologically, but can have important consequences both for the clinical management of the polyp itself as well as implications about the remainder of the patient s gastric mucosa.

123 Gastric Polyps Why the Fuss Dysplastic (pathologically equivalent to neoplastic) or nonneoplastic. Implications of various types of polyps for the remainder of the patient s gastric mucosa. Unlike colonic polyps (most of which are isolated findings in an otherwise normal background mucosa) many gastric polyps arise in association with either inflammatory/atrophic gastritities or in association with inherited polyposis syndromes. Correct classification of gastric polyps, even innocuousappearing polyps, may sometimes provide important clues as to abnormalities in the surrounding stomach.

124 Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, openlabel, randomised controlled trial. Lancet Aug 28;376(9742):

125 The Famous ToGA Trial Median overall survival was 13.8 months in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone TWO THREE MORE MONTHS IN EXCHANGE FOR A LARGE VERY EXPENSIVE TESTING INDUSTRY

126 HER2 Testing in Gastric Carcinoma HER2 overexpression found in just over 20% of gastric cancers and most of these are of the intestinal type. Approximately 7% of diffuse-type carcinomas show HER2 overexpression

127 HER2 Testing in Gastric Carcinoma Correlation between HER2 amplification by fluorescence in situ hybridization (FISH) and immunohistochemistry is less rigorous than for breast carcinoma as >20% of cases may carry low-level HER2 amplification by FISH without immunohistochemical reactivity. These patients do not benefit from treatment with Trastuzumab As a result, HER2 immunohistochemistry is the first line of evaluation for HER2 overexpression. Fluorescence in situ hybridization should be performed in equivocal (2+) cases.

128 HER2 Testing Biopsy specimen staining Resection staining pattern HER2 overexpression pattern No reactivity or no membranous reactivity in any tumor cell assessment No reactivity or membranous reactivity in <10% of tumor cells Negative (0) Tumor cell cluster with a faint or barely perceptible membranous reactivity irrespective of percentage of tumor cells stained Tumor cell cluster with a weak to moderate complete, basolateral or lateral membranous reactivity irrespective of percentage of tumor cells stained Tumor cell cluster with a strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumor cells stained Tumor cell cluster with a faint or barely perceptible membranous reactivity irrespective of percentage of tumor cells stained Tumor cell cluster with a weak to moderate complete, basolateral or lateral membranous reactivity irrespective of percentage of tumor cells stained Tumor cell cluster with a strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumor cells stained Negative (1+) Equivocal (2+) Positive (3+)

129 HER2 Testing , basal Hechtman JF, Polydorides AD. HER2/neu gene amplification and protein overexpression in gastric and gastroesophageal junction adenocarcinoma: a review of histopathology, diagnostic testing, and clinical implications. Arch Pathol Lab Med Jun;136(6): Artifact FISH