Chapter 17 part 4--stomach part 2 Flashcards
Complications of chronic gastritis–list
- Peptic ulcer disease
- Mucosal atrophy and Intestinal metaplasia
- Dysplasia
- Gastric Cystica
Peptic Ulcer Disease (PUD)
- chronic mucosal ulceration affecting duodenum or stomach
- most common form occurs in gastric antrum or duodenum associated with H. pylori infection
PUD in the gastric fundus or body is accompanied by what?
-MUCOSAL ATROPHY (due to H. pylori or autoimmune gastritis)
Epidemiology of Peptic Ulcer Disease–associated with what??
- All peptic ulcers are associated with H. pylori infection, NSAIDs (including low-dose aspirin for cardiovascular benefits) or cigarette smoke
- NSAID risk is increased by concurrent H. pylori infection
Other risk factors for PUD include
- COPD
- illicit drugs (that reduce mucosal blood flow)
- alcoholic cirrhosis
- psychological stress
- Zollinger-Ellison syndrome
- certain viral infections–CMV an HSV!!
Pathogenesis of PUD
- imbalances in mucosal damage and defenses
- Hyperacididty due infection, parietal cell hyperplasia, excessive secretory response, or increased gastrin production (secondary to hypercalcemia or produced by a tumor)
- NSAIDS and steroids–block normal prostaglandin cytoprotective effects
- cigarette smoking (and CV disease) impairs mucosal blood flow and healing
Gross Morphology of PUD
- Most ulcers are solitary
- gross: sharply punched out defect with overcharging mucosal borders and smooth, clean ulcer bases
Microscopic morphology of UPD
- thin layers of fibrinoid debris with underlying inflammation merging into granulation tissue and deep scarring
- surrounding mucosa exhibits chronic gastritis
Clinical features of PUD
- S/S: epigastric gnawing, burning, or aching pain, worse at night and 1-3 hours after meals
- nausea, vomiting, bloating, belching and weight loss can also occur
Complications of PUD
- anemia
- hemorrhage
- perforation
- obstruction
- Malignant transformation is rare and is related to underlying gastritis
Treatment of PUD
-focused on H. Pylori eradication, removal of offending agents (NSAIDS) and neutralization or reduced production of gastric acid
Mucosal atrophy and intestinal metaplasia
–Long standing chronic gastritis leads to parietal cell loss, associated with intestinal metaplasia and an increased risk of gastric adenocarcinoma
Mucosal atrophy and intestinal metaplasia–risk of malignancy is greatest in what kind of gastritis?
-autoimmune gastritis
Mucosal atrophy and intestinal metaplasia–Achlorydia
-Achlorydia due to parietal cell deficiency may predispose to cancer by allowing bacterial overgrowth with production of carcinogenic nitrosamines
Dysplasia
- Long standing chronic gastritis exposes epithelium to inflammation-related free radical damage and proliferative stimuli
- overtime, combo can lead to accumulation of genetic alterations resulting in carcinoma; pre invasive, in situ lesions can be recognized histologically as dysplasia
Gastritic cystica
- Exuberant reactive epithelial proliferation with entrapped epithelium-lined cysts that can exhibit changes that mimic invasive adenocarcinoma
- associated with chronic gastritis and partial gastrectomy
Hypertrophic Gastropathies–what are they?
- uncommon
- features giant enlargement of gastric rural folds due to epithelial hyperplasia; linked to excessive growth factor production
Hypertrophic Gastropathies–includes what diseases?
- Menetrier Disease
- Zollinger Ellison syndrome
Zollinger-Ellison Syndrome–cause
-caused by gastrin-secreting tumors (gastrinomas) typically in the small bowel or pancreas
Zollinger-Ellison Syndrome–presentation
-multiple duodenal ulcers and/or chronic diarrhea
Zollinger-Ellison Syndrome–pathogenesis
-Elevated gastrin levels induce a marked (unto 5x) increase in gastric parietal cells and more modest increases in mucous neck cells and gastric endocrine cells
Zollinger-Ellison Syndrome–how do they arise and what are they associated with?
- gastronomes are sporadic in 75% of pts
- in remainder, they are associated with multiple endocrine neoplasia, type I (MEN-I)
- 60-90% of gastronomes are malignant!!
Gastric polyp
- nodules or masses that project above level of surrounding mucosa
- can result from epithelial or stromal hyperplasia, inflammation, ectopic or neoplasia
Inflammatory and Hyperplastic polyps
- constitute 75% of gastric polyps
- incidence depends on local prevalence of H. Pylori infections
- most common bw age 50 and 60 and arise in association with chronic gastritis
Inflammatory and Hyperplastic polyps morphology
- majority <1 cm and frequently multiple
- typically have smooth surface, occasionally with superficial erosions
- histo: show irregular, mystically dilated and elongated glands with variable amounts of acute and chronic inflammation
Inflammatory and Hyperplastic polyps–risk of dysplasia–when?
-risk of dysplasia increases with size; polyps>1.5 cm should be resected!
Fundic gland polyps
- occur sporadically
- women over 50 or in setting of familial adenomatous polyposis (FAP)
- incidence also increased by proton pump inhibitors and consequent gastrin secretion
- single or multiple, smooth, well-circumscribed lesions composed of irregular, mystically dilated glands with minimal inflammation
Gastric adenoma
- comprise 10% of gastric polyps
- almost always occur with FAP or chronic gastritis with atrophy and intestinal metaplasia
- male:female=3:1 and incidence increases with age
- usually solitary and <2cm but all exhibit some dysplasia
- 30% harbor carcinoma and lesions >2cm are concerning
Gastric adenocarcinoma–2 types
- More than 90% of gastric malignancies are adenocarcinomas
- divided into intestinal and diffuse–have different risk factors, genetic perturbations and clinical and pathologic presentations
Epidemiology of gastric adenocarcinoma–incidence
- distribution widely variable
- Japan, Chile, Costa Rica, and Eastern Europe=20x more than North America and N. Europe
- The U.S. incidence decreased 85% in the 20th century bc of decreases in the intestinal form that is associated with atrophic gastritis
- responsible for <2.5% of all cancer deaths in US
Environmental factors that play a role in gastric adenocarcinoma
- H. pylori infections
- Diet also influences risk
- dereased consumption of carcinogens (N-nitroso compounds and bento [a] pyrene, associated with some forms of food preservation and increased intake of antioxidants in green leafy vegetables and fruits reduce gastric cancer incidence
role of partial gastrectomy (e.g. for PUD) in gastric adenocarcinoma
-increases risk for adenocarcinoma by permitting bile reflux and the development of chronic gastritis
Pathogenesis of gastric adenocarcinoma
- Loss of intercellular adhesion is a key step in oncogenesis, particularly of DIFFUSE gastric cancer
- germline mutations in the CDH1 gene encoding E-cadherin are associated with familial gastric carcinomas and also occur in 50% of sporadic lesions
INTESTINAL-TYPE gastric cancers pathogenesis
-associated with FAP, mutations in proteins that associate with E-cadherin (e.g., B-catenin), TGFBRII, BAX, IGFRII, and p16/INK4a
In both types of gastric cancer associated with H. pylori infections (diffuse and intestinal-type), what influences risk for development of cancer?
- immune response gene polymorphisms
- p53 mutations are also present in the majority of sporadic cancers of both types
What part of the digestive tract/stomach is more commonly involved in gastric cancers? order of involvement?
-Antrum>lesser curvature>greater curvature
Tumors with INTESTINAL morphology
-form bulky exophytic tumors composed of glandular structures; these develop from precursor lesions, including flat dysplasia and adenomas
Tumors with DIFFUSE INFILTRATIVE pattern of growth tend to be
-composed of SIGNET-RING CELLS (intracellular mucin vacuoles push the nucleus to the periphery) that are discohesive and do not form glands–also tend to induce a fibrous desmoplastic response
precursor lesions for gastric adenocarcinomas
- no identified precursor lesions
- gros correlate to these tumors is a rigid thickened gastric wall termed linitus plastica (“leather bottle”)
Clinical features of gastric carcinoma
- insidious disease
- early symptoms: resemble those for chronic gastritis—dysphagia, dyspepsia, and nausea
- Advanced stages=weight loss, anorexia, altered bowel habits, anemia, and hemorrhage
Prognosis of gastric carcinoma
- depends on DEPTH OF INVASION and the EXTENT OF NODAL OR DISTANT METASTASES
- 5yr survival of early gastric cancer after resection is >90% even with nodal spread
- advanced gastric cancer 5yr survival <20%
- overall 5 yr survival in US is 30%
Lymphoma–extranodal lymphomas arise where?
-can arise in any tissue but do so most commonly in GI tract and especially in stomach
Lymphoma presentations
-dsypepsia and epigastric pain; hematemesis, melon or weight loss can also occur
GI lymphomas
- aka mucosa-associated lymphoid tissue or MALTOMAS
- make up 5% of gastric malignancies
- most are marginal zone B-cell lymphomas
- smaller fraction of primary GI lymphomas are large B-cell lymphomas
Pathogenesis of Extranodal marginal B-cell lymphomas
- arise at sites of chronic inflammation
- in stomach, associated with chronic H. pylori infection
- antibiotic treatment and H. pylori eradication can induce durable tumor regression
Antibiotic resistant tumors harbor what kind of genetics??
- t (11;18) translocation!!!
- t (1;14) and t(14;18) translocations are less common but are predictive for response failure!
t(11;18) translocation–what does it do?
-links the apoptosis inhibitor 2 gene (API2 on chromosome 11) with the “mutated in MALT lymphoma gene” (MLT on chromosome 18)
What does the t(14;18) translocation do?
-increases MLT!!
What does the t(1:14) translocation do?
-increases BCL-10 expression!
Each of the translocations (11;18), (1:14); (14:18) leads to what?
-constitutive NF-kB transcription factor activation, promoting B-cell growth and survival
With time, these MALTomas can transform into
-the more aggressive diffuse large B cell lymphomas, often associated with inactivation of p53 and/or p16 tumor suppressor gene
Morphology of B-cell lymphomas (MALTomas)–microscopic
- dense infiltrate of atypical lymphocytes in the lamina propria
- focal invasion of the mucosal epithelium forms diagnostic lymphoepithelial lesions
- Markers are the same as for other mature B-cell tumors
Carcinoid tumor
- carcinoma like
- arises from diffusely distributed endocrine cells
- referred to as well-differentiated neuroendocrine tumors
- Most arise in the gut (lungs are second in frequency)
- 40% occur in small intestine
- cells of origin in the GI tract are responsible for hormone secretion that coordinate gut function
Gastric carcinoid tumors are associated with
-endocrine cell hyperplasia, autoimmune chronic atrophic gastritis, MEN-I, and Zollinger-Ellison synrome
Endocrine cell hyperplasia is linked to?
-proton pump inhibitor therapy
Carcinoid tumor vs. carcinoma course
-carcinoid tumors follow a more indolent course than most carcinomas
Gross morphology of carcinoid tumors
- yellow-tan intramural or submucosal masses forming small polypoid lesions
- An intense desmoplastic response makes them firm and can cause bowel obstruction
Microscopic morphology of carcinoid tumos
- tumors range from islands to sheets of uniform cohesive cells with scant granular cytoplasm and oval, stippled nuclei
- cells are typically positive for neuroendocrine markers like chromogranin A and synaptophysin
Clinical features of Carcinoid tumors
- peak incidence=6th decade
- usually indolent, slow growing malignancies
- symptoms are a fnx of hormones produced
Ileal carcinoid tumors secrete
-vasoactive products that manifest with cutaneous flushing, bronchospasm, increased bowel motility, and right sided cardiac valve thickening—carcinoid syndrome!!
Incidence of carcinoid syndrome
- occurs in less than 10% of patients with GI carcinoid due to hepatic metabolism of secreted products
- presence of syndrome is usually associated with bulky hepatic metastatic disease
The most important prognostic factor for GI carcinoid tumors is what??
-the primary site of the tumor!
Prognosis of FOREGUT carcinoid tumors
- esophagus, stomach and duodenum
- RARELY metastasize and are are cured by resection
Midgut carcinoids
- jejunum and ileum
- usually multiple and aggressive!!
Hindgut tumors
- only found incidentally
- includes appendiceal carcinoids, colonic carcinoids and rectal carcinoids
Appendiceal carcinoid tumor
- usually found at the tip
- less than 2 cm and usually benign
Colonic carcinoids
-can be large and metastasize
Recta carcinoids
-can secrete polypeptide hormones and/or cause pain but usually do NOT metastasize!!
Gastrointestinal stromal tumor
- aka GIST
- most common GI mesenchymal tumor
- more than half are in the stomach
Epidemiology of GIST
- peak age of Dx=6th decade
- incidence is increased in patients with NF type 1 and in children (usually females) with Carney triad!!!
Carney triad
-non hereditary syndrome with GIST, paragangliomas and pulmonary chondromas
Pathogenesis of GIST
- arises from interstitial cells of Cajal (pacemakers for gut peristalsis) in muscular propria
- 75-80% of all GISTs contain oncogenic GoF mutations in the gene coding for tyrosine kinase c-KIT (stem cell factor receptor)
- 8% have activating platelet-derived growth factor receptor-a (PDGFRA) mutations
- Constitutive tyrosine kinase activity leads to downstream activation of RAS and PI3K/AKT pathways promoting tumor cell proliferation and survival
GIST WITHOUT mutated mutated c-KIT or PDGFRA
- can have mutations in other genes that function in these pathways (NF1, BRAF, HRAS, or NRAS)
- more common =mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) complex proteins–may cause accumulation of succinate that dysregulates hypoxia inducible factor 1a (HIF-1a), increasing the transcription of vascular endothelial growth factor VEGF and insulin-like growth factor-1 (IGF1R) genes
Gross morphology of GIST
- usually solitary
- well-circumscribed fleshy masses
- can grow as large as 30cm
Microscopic morphology of GIST
- classified as either epithelioid (plump and cohesive cells) or spindle cell type
- c-KIT expression is the most useful diagnostic marker
Clinical features of GIST
- symptoms are related to mass effects or blood loss
- surgical resection is primary Tx for localized gastric GIST
- Metastases are rare when tumors are <5cm but common when >10cm–usually take the form of peritoneal serial nodules or liver implants
- spread outside abdomen is uncommon
GIST tumors not amenable to resection can be treated with?
-imantinib–a tyrosine kinase inhibitor that inhibits c-KIT and PDGFRA
