Case Presentations: Gastric Polyps and The Company They Keep. Elizabeth Montgomery, MD Department of Pathology Johns Hopkins Hospital Baltimore MD

Transcription

1 Case Presentations: Gastric Polyps and The Company They Keep Elizabeth Montgomery, MD Department of Pathology Johns Hopkins Hospital Baltimore MD

2 Case 1 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.

3 Antrum 68 yo woman

4 Body Body

5 polyp

6 Diagnosis, Case 1 Autoimmune gastritis Hyperplastic polyp

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

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

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

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

11 A few Comments on Helicobacter pylori Gastritis

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

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

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

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

17 Duodenal and Pre-Pyloric Ulcers

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

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

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

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

22 Carcinoma in Environmental Metaplastic Atrophic Gastritis (EMAG)

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

24 Autoimmune gastritis

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

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

27 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

28 Autoimmune Metaplastic Atrophic Gastritis (AMAG) - Autopsy

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

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

31 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

32 Hyperplastic Polyps Hyperplastic polyps may arise anywhere in the stomach Slight preference for the antrum 20% multiple Considered to be non-neoplastic lesions (though many molecular alterations reported) It is unusual for hyperplastic polyps to arise in normal stomachs.

33 Hyperplastic Polyps - Associations Most strongly associated with atrophic gastritis of either autoimmune or environmental (e.g., Helicobacter pyloriassociated) types post-antrectomy state chemical/reactive gastropathy following therapy for gastric antral vascular ectasia ( watermelon stomach ).

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37 Hyperplastic Polyps and Autoimmune Gastritis Extensively documented association. Autoimmune gastritis is suggested histologically when biopsies show corpuspredominant gastritis, glandular atrophy, and intestinal metaplasia.

38 Antrum 68 yo woman

39 Gastrin stain

40 Hyperplastic polyp

41 Body Body

42 Gastrin stain

43 Chromogranin Stain

44 ECL Hyperplasia - Carcinoids

45 Multiple Gastric Carcinoids

46 Case 2 A partial gastrectomy was performed for a cancer in a 55 year old woman with a history of type 1 diabetes (so an autoimmune diathesis )

47 The background gastric body lacks parietal cells Type 1 carcinoid arising in gastric body of 50+ woman with history of type 1 diabetes

48 Type 1 carcinoid arising in gastric body of 50+ woman with history of type 1 diabetes

49 Intestinal metaplasia The flat oxyntic mucosa surrounding Type 1 carcinoid ECL cell hyperplasia (pseudo)pyloric metaplasia

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52 When Does It Stop Being ECL Cell Hyperplasia and Become Carcinoid? Extensive literature on hyperplasiadysplasia-neoplasia no practical value Some use a cut-off of 0.5 mm as carcinoid Our definition if the endoscopist sees a nodule it s a carcinoid It is pointless to measure minute lesions they never hurt the patients even as full fledged carcinoids

53 Some Issues Many pathologists don t know how to diagnose autoimmune gastritis/pernicious anemia pattern Many internal medicine/family practice colleagues have no idea that they need to give their patients vitamin B12 when the diagnostic line in the pathology report says autoimmune gastritis and think their patients have uncomplicated iron deficiency anemia -the high gastric ph does not allow for iron absorption Many surgery colleagues want to perform aggressive resections for such tumors

54 Another Type 1 carcinoid of the gastric body. There is no background oxyntic mucosa

55 Type 1 carcinoid, Chromogranin stain. Note the ECL cell hyperplasia in the background

56 Type 1 carcinoid -

57 We avoid doing ki-67 stains in Type 1 carcinoids since they are essentially always indolent and results such as this one don t mean anything - (metastases are rare for type 1 carcinoids and deaths are exceptional)

58 Time to Talk About Type 2 Carcinoid Slide A is from the duodenum and slide B is from the stomach. What syndrome can you dream up to explain these findings?

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61 B

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64 A, gastrin stain

65 B, gastrin stain

66 Diagnosis Zollinger-Ellison Syndrome with a duodenal gastrinoma and a gastric carcinoid tumor/wdnet of ECL cell type

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68 Zollinger-Ellison

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72 Type 3 Gastric NET No autoimmune backdrop, no Zollinger Ellison (no gastrinoma) In other words, no hypergastrinemia More aggressive than type 1 with about a third dying of disease and metastases in about 70% (metastases are rare for type 1 and deaths are exceptional) data poor on type 2 but they are indolent

73 Type 3 carcinoid note the intact background oxyntic mucosa

74 This lesion is easy to diagnose as type 3 NET/carcinoid because there is intact oxyntic mucosa

75 For this lesion, we need more information to subtype it if we know it s antral then it is type 3

76 Another Type 3 carcinoid in a patient with normal serum gastrin. The background is normal oxyntic mucosa. This lesion is spindly and reminiscent of a gastrointestinal stromal tumor.

77 A spindled type 3 carcinoid

78 Type 3 carcinoid note the intact parietal cells

79 Type 3 carcinoid and others pitfall alert note weak AE1/3

80 Type 3 carcinoid Cam 5.2 saves the day.

81 Type 3 carcinoid Chromogranin stain No ECL cell hyperplasia in adjoining mucosa

82 True high grade gastric neuroendocrine lesions can also be very rarely encountered and are most often metastases from the lung; this was primary in the antrum

83 Mitoses in this small cell carcinoma are easy to find

84 This is a synaptophysin stain

85 What Do We Need to Assure? Be sure you know how to diagnose autoimmune gastritis!!!! Many pathologists do not know how. Clinicians do not know what it is we have begun to report autoimmune gastritis/pernicious anemia pattern We see autoimmune gastritis in about 2% of our gastric biopsies in house at Johns Hopkins if this diagnosis is never in your path reports you are not recognizing the pattern and the patient needs you to! Think of autoimmune gastritis when the biopsy of body looks like antrum with bottom-heavy inflammation.

86 Sample report Gastric body (biopsy): Autoimmune gastritis/pernicious anemia pattern Note; These patients are prone to both iron deficiency anemia and pernicious anemia (the high gastric ph interferes with iron absorption) as well as various epithelial neoplasms. Correlation with serum gastrin and studies of vitamin B12 levels may be of interest.

87 Follow-Up of Autoimmune Gastritis European societies have endorsed gastric surveillance every 1-3 years in autoimmue gastritis patients US Societies have yet to do so. The data supporting the European guidelines are weak

88 Case 3 Large gastric body polyp in a 72 year old woman with long history of autoimmune gastritis

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92 Pyloric Gland Adenoma Defining series, Vieth et al. - Virchows Arch Apr;442(4): % 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%). Some showed transition to adenocarcinoma Now known to have GNAS* mutations, both sporadic and syndromic examples (familial adenomatous polyposis), which they share with oxyntic gland adenoma/chief cell adenoma. *guanine nucleotide-binding protein (G protein), alpha subunit

93 Table 1 Location of pyloric gland adenoma (PGA) throughout the gastrointestinal tract based on a recent analysis of 373 patients with PGA in Bayreuth including 90 cases that were published elsewhere7 Duodenum2.7% Bulb 8.3% Antrum3.8% Corpus 54.1% Cardia17.4% Oesophagus (in Barrett s)2.4% Remaining stomach BII3.4% Rectum1.1% (4 cases) Papilla of Vater0.8% Pancreatic duct0.3% Bile duct1.4% Gall bladder4.3% BII, Billroth II.

94 Table 2 Distribution of pyloric gland adenoma cases in Baltimore at Johns Hopkins Hospital Duodenum14.8% Bulb10.0% Antrum2.6% Corpus 37.0% Cardia13.2% Oesophagus (in Barrett s)2.6% Papilla of Vater1.5% Pancreatic duct3.7% Gall bladder 15.3% Vieth M, Montgomery EA. Some observations on pyloric gland adenoma: an uncommon and long ignored entity! J Clin Pathol 2014

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98 Pyloric gland adenoma Ki-67

99 Pyloric gland adenoma MUC 6

100 Pyloric gland adenoma, MUC5AC

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104 CDX2

105 MUC2

106 MUC5

107 MUC6

108 Zone of intramucosal carcinoma (invasion of the lamina propria)

109 Syndromic Pyloric Gland Adenoma? In patients with familial adenomatous polyposis (normal background mucosa seen; US population); have GNAS mutations like those associated with autoimmune gastritis We have seen polyps that look like PGA in patients with McCune Albright syndrome (GNAS mutations) In patients with Lynch syndrome? (essentially all cases in this series had background of damaged gastric mucosa; Korean population)

110 Consequences of Autoimmune Gastritis Atrophy of oxyntic mucosa Pernicious anemia Gastric adenomas (either intestinal or pyloric type since these types of metaplasia are found) Type 1 carcinoid tumors (from ECL cell hyperplasia) Hyperplastic polyps Adenocarcinomas

111 Gastric Adenomas in a Western Intestinal type Population Gastric foveolar type Pyloric gland adenoma (has GNAS mutations) Oxyntic gland/chief cell adenoma evolving concept since very rare (has GNAS mutations)

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

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

114 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

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117 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 is worse!

118 Pyloric Gland Adenoma Gastric Foveolar Adenoma

119 Rare Oxyntic Gland/Chief Cell Adenoma Same lesions have been termed gastric adencarcinoma of fundic type, despite benign follow-up in all cases reported to date. Have GNAS mutations Limited numbers of cases reported to date so they are either benign of very low-grade/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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122 Oxyntic gland adenoma, Ki-67 only stains the gastric mucosa proliferative compartment over the lesion

123 MUC6 stain

124 Super rare oxyntic gland adenocarcinoma/chief cell adenocarcinoma

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126 Ki-67

127 MUC6

128 Gastric Hyperplasia Oxyntic hyperplasia Zollinger Ellison syndrome Foveolar hyperplasia - Ménétrier's Disease

129 Ménétrier's Disease Marked foveolar hyperplasia with abundant mucus production glandular atrophy edematous but typically uninflamed lamina propria most commonly limited to the body and fundus. Knowledge of the endoscopic appearance of giant folds, hypoproteinemia and peripheral edema, and lack of intervening normal mucosa can help to distinguish Menetrier s disease from hyperplastic polyp

130 Menetrier s Disease

131 Ménétrier's Disease antrum is spared

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133 Ménétrier's Disease

134 Ménétrier's Disease Hypertrophic gastropathy Giant folds Hypoalbuminemia Foveolar hyperplasia Hypochlorohydria

135 Menetrier s Disease

136 Pathogenesis Overproduction of transforming growth factor alpha (TGF alpha) has been documented could account for decreased acid production, hyperplasia of surface mucous cells, oxyntic atrophy, and increased mucin production. Transgenic mice that overproduce TGF alpha have features of Ménétrier's disease, including foveolar hyperplasia, increased mucin content TGF alpha is one of six ligands that bind to the epidermal growth factor receptor, and increased production of any of these ligands may contribute to Ménétrier's disease.

137 Targeted Treatment Burdick JS, Chung E, Tanner G, Sun M, Paciga JE, Cheng JQ, Washington K, Goldenring JR, Coffey RJ.Treatment of Ménétrier's disease with a monoclonal antibody against the epidermal growth factor receptor. N Engl J Med Dec 7;343(23): Settle SH, Washington K, Lind C, Itzkowitz S, Fiske WH, Burdick JS, Jerome WG, Ray M, Weinstein W, Coffey RJ.Chronic treatment of Ménétrier's disease with Erbitux: clinical efficacy and insight into pathophysiology. Clin Gastroenterol Hepatol Jul;3(7):654-9.

138 Case A biopsy was performed of a gastric polyp and diagnosed as a hyperplastic polyp. The gastroenterologist called and pointed out that the diagnosis was wrong.

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141 Gastric Peutz-Jeghers polyp

142 Peutz-Jeghers Polyposis Autosomal-dominant condition - germline mutations in the LBK1/STK11 gene on chromosome 19p13.3, Polyposis and distinctive melanin pigmentation around the lips, buccal (cheek) mucosa, and sometimes eyelids and hands. Because the pigment may fade after puberty, the syndrome is not excluded even if pigment is absent in an adult presentation.

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144 Clinical Features of Peutz-Jeghers Syndrome Average age at diagnosis 23 to 26 years Benign complications predominate in early decades Intussusception and obstruction Torsion, infarction and bleeding Anal prolapse Malignancy more common after 4 th decade Average age at diagnosis of cancer 40 to 50 years 95% combined incidence of cancer after age 65 (GI and non GI primary breast, ovary, pancreas)

145 Pathologic Features of Peutz-Jeghers Syndrome Hamartomatous polyps located throughout the gastrointestinal tract Distribution of polyps: 78% small bowel (jejunum > ileum) 42% colon 38% stomach 28% rectum

146 Gastric Peutz-Jeghers Polyps Unlike the small bowel polyps which show prominent arborization of the muscularis mucosae, gastric Peutz-Jeghers polyps are composed mostly of dilated or branching mucus-filled pits and may have relatively inconspicuous smooth muscle. Occasional examples of gastric Peutz- Jeghers polyps have the classic arborizing architecture with strands of smooth muscle, but most have less specific features (but some degree of smooth muscle proliferation).

147 A perfect Peutz-Jeghers gastric polyp but what if they biopsied in the circle

148 A perfect Peutz-Jeghers gastric polyp

149 Another perfect gastric Peutz-Jeghers polyp normal site specific mucosa in a dirorganized arrangement

150 Real Life - Polyp from a patient with Peutz-Jeghers syndrome

151 Real life - Polyp from a PJ patient

152 Peutz-Jeghers polyps in small intestine note that the background flat mucosa is normal

153 A perfect small bowel Peutz- Jeghers polyp our data showed that even a single small bowel Peutz-Jeghers polyps probably means the patient has the syndrome Burkart AL, Sheridan T, Lewin M, Fenton H, Ali NJ, Montgomery E. Do sporadic Peutz-Jeghers polyps exist? Experience of a large teaching hospital. Am J Surg Pathol Aug;31(8):

154 A perfect small bowel Peutz- Jeghers polyp

155 Small bowel Peutz-Jeghers polyp

156 Dysplasia in Peutz- Jeghers polyps is uncommon

157 Gastric Hamartomatous Lesions Peutz-Jeghers Juvenile polyposis/cowden s disease (Cronkhite-Canada)

158 Juvenile Polyposis Genetically heterogeneous condition in which some families have autosomal dominant germline mutations in the DPC4 gene on chromosome 18q21. Polyps in juvenile polyposis can be limited to the colon or can be generalized, involving the colon, small bowel, and stomach. Some patients appear to have juvenile polyposis predominantly confined to the stomach.

159 Gastric juvenile polyposis note that the flat mucosa appears normal

160 Gastric juvenile polyposis note that the flat mucosa appears normal

161 Syndromic gastric juvenile polyposis

162 Syndromic gastric juvenile polyposis in Italian patient

163 Juvenile Polyp nice flat mucosal surface

164 Real life - polyp from a patient with known juvenile polyposis it cannot be separated from a hyperplastic polyp

165 Distinction between Gastric HP and Syndromic Polyps 1) The patient may have a previously characterized polyposis syndrome Best Discriminator!!!!!! 2) There may be biopsies of the non-polypoid gastric mucosa showing an atrophic or inflammatory gastropathy of the type associated with the development of hyperplastic polyps 3) Hyperplastic polyps frequently show a more lobulated or villiform surface as compared to the often rounded surface of juvenile polyps

166 Peutz-Jeghers Polyp Juvenile Polyp Hyperplastic Polyp Epithelium Unremarkable Eroded or Normal Damaged with reactive or regenerative changes; chemical gastropathy changes. Pit and Gland Architecture Pits and glands are grouped or packeted with intervening septations of smooth muscle strands Disorganized with varying sizes and shapes. Sometimes forms edematous club-shaped or irregular villiform structures Surface of pits connect to deeper portions of glands in a linear trajectory. Glands and pits are generally small, regular and orderly although surface glands can appear disorganized and eroded. Lamina Propria Unremarkable Edematous Granulation tissue common Unremarkable or inflamed Smooth Muscle Short wispy or chunky bundles not connected to muscularis mucosae Unremarkable Long sweeping bundles; Connects with muscularis mucosae

167 From Lam-Himlin et al

168 Cronhkite-Canada Polyposis Diffuse polyposis occurring in patients with unusual ectodermal abnormalities, including alopecia, onychodystrophy (this means fingernails that are falling apart) and skin hyperpigmentation. Europeans and Asians -mean age at onset of 59 years. Male to to female ratio is 3:2. Neither a familial association nor a genetic defect are known. Affects whole GI tract except esophagus

169 Cronkhite-Canada Polyposis The most common presenting symptoms include diarrhea, weight loss, nausea, vomiting, hypogeusia and anorexia. Mucoid diarrhea results in the depletion of the patients protein reserves such that the patient loses his (usually) hair and nails. Potentially fatal complications, such as malnutrition, gastrointestinal bleeding and infection, often occur, and the mortality rate has been reported to be as high as 60%.

170 Cronkhite-Canada Polyposis the flat mucosa is ABNORMAL

171 Cronkhite-Canada polyposis

172 Cronkhite-Canada polyposis

173 TYPE OF GASTRIC POLYP LIKELY APPEARANCE OF BACKGROUND GASTRIC MUCOSA Hyperplastic polyp Gastritis (autoimmune or environmental) Syndromic/Hamartomatous polyp (juvenile or Peutz-Jeghers type) Menetrier s disease Cronkhite-Canada syndrome Fundic gland polyp/polyposis Gastric adenoma, intestinal type Normal Abnormal, involving the entire gastric body but sparing the antrum Abnormal, involving entire stomach Normal Gastritis (autoimmune or environmental) Gastric adenoma, gastric foveolar type Normal Gastric adenoma, pyloric gland type Abnormal (autoimmune gastritis) Gastric adenoma, oxyntic gland type Normal

174 Thank you