tbl 2 stomach pathology readings

Question 1

Gastritis results from mucosal injury. When ________ are present, the lesion is referred to as acute gastritis . When cell injury and regeneration are present but inflammatory cells are rare or absent, the term _________ is applied. Agents that cause gastropathy include nonsteroidal anti-inflammatory drugs, alcohol, bile, and stress-induced injury. Acute mucosal erosion or hemorrhage, such as Curling ulcers or lesions following disruption of gastric blood flow, for example, in portal hypertension, can also cause gastropathy that typically progresses to gastritis. The term hypertrophic gastropathy is applied to a specific group of diseases exemplified by Ménétrier disease and Zollinger-Ellison syndrome (discussed later).

Both gastropathy and acute gastritis may be asymptomatic or cause variable degrees of epigastric pain, nausea, and vomiting. In more severe cases, there may be mucosal erosion, ulceration, hemorrhage, hematemesis, melena, or, rarely, massive blood loss.

Answer 1

neutrophils; gastropathy

Question 2

[Acute Gastritis: Pathogenesis]
The gastric lumen is strongly acidic, with a pH close to 1—more than 1 million times more acidic than the blood. This harsh environment contributes to digestion but also has the potential to damage the mucosa. Multiple mechanisms have evolved to protect the gastric mucosa. Mucin secreted by ________ forms a thin layer of mucus that prevents large food particles from directly touching the epithelium. The mucus layer also promotes formation of an “unstirred” layer of fluid over the epithelium that protects the mucosa; it has a neutral pH as a result of secretion of bicarbonate ions by __________. Finally, the rich blood supply of the gastric mucosa efficiently buffers and removes protons that back-diffuse into the lamina propria. Gastropathy, acute gastritis, and chronic gastritis can occur after disruption of any of these protective mechanisms. The main causes include:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX)-dependent synthesis of __________ and I2, which stimulate nearly all of the above defense mechanisms including mucus and bicarbonate secretion, mucosal blood flow, and epithelial restitution. Although COX-1 plays a larger role than COX-2, both isoenzymes contribute to mucosal protection. Thus, while the risk for development of NSAID-induced gastric injury is greatest with nonselective inhibitors, such as aspirin, ibuprofen, and naproxen, selective COX-2 inhibition, for example, by ________, can also result in gastropathy or gastritis.

Answer 2

surface foveolar cells; surface epithelial cells;

prostaglandins E2; celecoxib

Question 3

[Acute gastritis pathogenesis part 2]

• The gastric injury that occurs in uremic patients and those infected with urease-secreting H. pylori may be due to inhibition of gastric bicarbonate transporters by __________.
• Reduced ______ and bicarbonate secretion have been suggested as factors that explain the increased susceptibility of older adults to gastritis.
• Hypoxemia and decreased oxygen delivery may account for an increased incidence of gastropathy and acute gastritis at high altitudes.
• Ingestion of harsh chemicals, particularly acids or bases, either accidentally or in a suicide attempt, leads to severe gastric mucosal damage as a result of direct injury to epithelial and stromal cells. Direct cellular damage also contributes to gastritis induced by excessive alcohol consumption, NSAID use, and radiation therapy. Agents that inhibit DNA synthesis or the mitotic apparatus, including those used in cancer chemotherapy, may cause generalized mucosal damage due to ____________.

Answer 3

ammonium ions; mucin; insufficient epithelial renewal

Question 4

[Acute gastritis morphology]

Histologically, gastropathy and mild acute gastritis may be difficult to recognize, since the lamina propria shows only _________ and slight vascular congestion. The surface epithelium is intact, but hyperplasia of __________ is typically present. Neutrophils, lymphocytes, and plasma cells are not prominent.

The presence of neutrophils above the __________ in contact with epithelial cells is abnormal in all parts of the gastrointestinal tract and signifies active inflammation, or, at this site, gastritis (rather than gastropathy). The term active inflammation is preferred over acute inflammation throughout the luminal gastrointestinal tract, since active inflammation may be present in both acute and chronic disease states. With more severe mucosal damage, erosions and hemorrhage develop. Hemorrhage may manifest as dark punctae in an otherwise hyperemic mucosa. Concurrent presence of erosion and hemorrhage is termed ________________.

Answer 4

moderate edema; foveolar mucus cells

basement membrane; acute erosive hemorrhagic gastritis

Question 5

Stress-related gastric injury occurs in patients with severe trauma, extensive burns, intracranial disease, major surgery, serious medical disease, and other forms of severe physiologic stress. More than 75% of critically ill patients develop endoscopically visible gastric lesions during the first 3 days of their illness. In some cases, the associated ulcers are given specific names based on location and clinical associations.

Examples are as follows:
- Stress ulcers affecting critically ill patients with shock, sepsis, or severe trauma.

• Curling ulcers occur in the __________ and are associated with severe burns or trauma.
• Cushing ulcers arise in the stomach, duodenum, or esophagus of those with ________ and have a high incidence of perforation.

Answer 5

proximal duodenum; intracranial disease

Question 6

[Stress related mucosal disease- pathogenesis]
The pathogenesis of stress-related gastric mucosal injury is most often due to _______. This may be caused by systemic hypotension or reduced blood flow resulting from stress-induced _____ vasoconstriction. Upregulation and increased release of the vasoconstrictor ____________ also contributes to ischemic gastric mucosal injury, while increased _______ expression appears to be protective. Cushing ulcers are thought to be caused by direct stimulation of vagal nuclei resulting acid hypersecretion. Systemic acidosis may also contribute to mucosal injury by lowering the intracellular pH of mucosal cells.

Answer 6

local ischemia; splanchnic; endothelin-1; COX-2

Question 7

[stress related mucosal injury: morphology]
Stress-related gastric mucosal injury ranges from shallow erosions caused by superficial epithelial damage to deeper lesions that penetrate the depth of the mucosa. Acute ulcers are rounded and typically less than ____ in diameter. The ulcer base frequently is stained brown to black by acid-digested extravasated red cells. Unlike peptic ulcers, which arise in the setting of chronic injury, acute stress ulcers are found anywhere in the stomach and are often ______. They are sharply demarcated, with essentially normal adjacent mucosa, although there may be suffusion of blood into the mucosa and submucosa and some inflammatory reaction. The scarring and _________ of blood vessels that characterize chronic peptic ulcers are absent. Healing with complete reepithelialization occurs days or weeks after the injurious factors are removed.

Answer 7

1 cm; multiple; thickening

Question 8

[stress related mucosal injury: clinical features]
Most critically ill patients admitted to hospital intensive care units have histologic evidence of gastric mucosal damage. Ulcers are associated with nausea, vomiting, melena, and _______________. Bleeding from superficial gastric erosions or ulcers that may require transfusion develop in 1% to 4% of these patients. Other complications, including perforation, also may occur. Prophylaxis with __________ may blunt the impact of stress ulceration, but the most important determinant of outcome is the severity of the underlying condition.

Answer 8

coffee-ground hematemesis; proton pump inhibitors

Question 9

Helicobacter pylori Gastritis
The discovery of the association of H. pylori with peptic ulcer disease revolutionized the understanding of chronic gastritis. These spiral-shaped or curved bacilli are present in gastric biopsy specimens from almost all patients with duodenal ulcers and a majority of those with gastric ulcers or chronic gastritis. Acute H. pylori infection is subclinical in most cases; rather, it is the chronic gastritis that ultimately brings the afflicted person to medical attention. H. pylori infection most often presents as an _________ with increased acid production. The increased acid production may give rise to peptic ulcer disease of the duodenum or stomach.

While in most cases H. pylori gastritis is limited to the antrum, in some individuals it progresses to involve the gastric body and fundus, resulting in reduced ____________ and acid secretion. Reduced acid output results in ____________, as in autoimmune atrophic gastritis. In addition, extension of the gastritis to the gastric body and fundus results in intestinal metaplasia and increased risk of gastric cancer.

Answer 9

antral gastritis;

parietal cell mass; hypergastrinemia

Question 10

[Pathogenesis: H. Pylori]
H. pylori organisms have adapted to the ecologic niche provided by gastric mucus. Although H. pylori may invade the gastric mucosa, the contribution of invasion to disease pathogenesis is not known. Four features are linked to H. pylori virulence:
- ________, which allow the bacteria to be motile in viscous mucus
- ____, which generates ammonia from endogenous urea, thereby elevating local gastric pH around the organisms and protecting the bacteria from the acidic pH of the stomach
- ______, which enhance bacterial adherence to surface foveolar cells
- Toxins, such as that encoded by __________, that may be involved in ulcer or cancer development

These factors allow H. pylori to create an imbalance between gastroduodenal mucosal defenses and damaging forces that overcome those defenses.

Answer 10

Flagella; urease; Adhesins; cytotoxin-associated gene A (CagA)

Question 11

[Morphology: H. Pylori]
Gastric biopsy specimens generally demonstrate H. pylori in infected individuals. The organism is concentrated within mucus overlying ________ in the surface and neck regions. The inflammatory reaction includes a variable number of neutrophils within the _________, including some that cross the basement membrane to assume an intraepithelial location and accumulate in the lumen of __________ to create pit abscesses. The superficial lamina propria includes large numbers of plasma cells, often in clusters or sheets, as well as increased numbers of lymphocytes and macrophages. When intense, inflammatory infiltrates may create thickened _______, mimicking infiltrative lesions. Lymphoid aggregates, some with germinal centers, are frequently present and represent an induced form of ___________ that has the potential to transform into lymphoma. Intestinal metaplasia, characterized by the presence of goblet cells and ____________, also may be present and is associated with increased risk of gastric adenocarcinoma. H. pylori shows tropism for gastric foveolar epithelium and generally is not found in areas of intestinal metaplasia, acid-producing mucosa of the gastric body, or duodenal epithelium. Antral biopsies are therefore preferred for evaluation of H. pylori gastritis.

Answer 11

epithelial cells; lamina propria; gastric pits; rugal folds; mucosa-associated lymphoid tissue (MALT); columnar absorptive cells; columnar absorptive cells

Question 12

[Clinical features: H. Pylori]
In addition to histologic identification of the organism, several diagnostic tests have been developed including a noninvasive serologic test for anti– H. pylori antibodies, a stool test for the organism, and the urea breath test, based on the generation of ammonia by bacterial urease. Gastric biopsy specimens also can be analyzed by the ___________, bacterial culture, or polymerase chain reaction (PCR) assay for bacterial DNA. Effective treatments include combinations of _______ and proton pump inhibitors. Patients with H. pylori gastritis usually improve after treatment, although relapses can follow incomplete eradication or reinfection.

Answer 12

rapid urease test; antibiotics

Question 13

Autoimmune gastritis accounts for less than 10% of cases of chronic gastritis. In contrast H. pylori -associated gastritis, autoimmune gastritis typically spares the antrum and induces marked hypergastrinemia.
Autoimmune gastritis is characterized by the following:

• Antibodies to parietal cells and intrinsic factor that can be detected in serum and gastric = secretions
• Reduced ______ levels
• Antral endocrine cell hyperplasia
• Vitamin B 12 deficiency leading to _________ and neurologic changes
• Impaired gastric acid secretion (_______)

Answer 13

serum pepsinogen I; pernicious anemia;

achlorhydria

Question 14

[Autoimmune gastritis Morphology]
Autoimmune gastritis is characterized by diffuse damage of the _______ (acid-producing) mucosa within the body and fundus. Damage to the ____________ typically is absent or mild. With diffuse atrophy, the oxyntic mucosa of the body and fundus appears markedly thinned, and rugal folds are lost. Neutrophils may be present, but the inflammatory infiltrate more commonly is composed of _____, ____, _______; in contrast with H. pylori gastritis, the inflammatory reaction most often is deep and centered on the gastric glands. Parietal and chief cell loss can be extensive, and intestinal metaplasia may develop.

Answer 14

oxyntic; antrum and cardia;

lymphocytes, macrophages, and plasma cells

Question 15

Peptic ulcer disease (PUD) most often is associated with H. pylori infection or NSAID use. The imbalances of mucosal defenses and damaging forces that cause chronic gastritis are also responsible for PUD. In the United States, NSAID use is becoming the most common cause of gastric ulcers as H. pylori infection rates are falling and low-dose aspirin use in the aging population is increasing. PUD may occur in any portion of the gastrointestinal tract exposed to acidic gastric juices but is most common in the ____________. Peptic (acid-induced) injury may occur in the esophagus as a result of acid reflux (GERD) or acid secretion by ectopic gastric mucosa. Peptic injury in the small intestine may also be associated with gastric heterotopia, including that within a Meckel diverticulum.

Answer 15

gastric antrum and first portion of the duodenum

Question 16

[Peptic Ulcer Disease Pathogenesis]
H. pylori infection and NSAID use are the primary underlying causes of PUD. More than 70% of PUD cases are associated with H. pylori infection and in these individuals PUD generally develops on a background of chronic gastritis. Because only 5% to 10% of H. pylori –infected individuals develop ulcers, it is probable that host factors as well as variation among H. pylori strains also contribute to the pathogenesis.

Gastric acid is fundamental to the pathogenesis of PUD. Hyperacidity may be caused by H. pylori infection, parietal cell hyperplasia, and excessive secretory responses. Insufficient inhibition of stimulatory mechanisms such as gastrin release may also contribute. For example, ___________, characterized by multiple peptic ulcerations in the stomach, duodenum, and even jejunum, is caused by uncontrolled release of gastrin by a tumor and the resulting massive acid production. Cofactors in peptic ulcerogenesis include chronic NSAID use, as noted; cigarette smoking, which impairs mucosal blood flow and healing; and high-dose corticosteroids, which suppress __________synthesis and impair healing. Peptic ulcers are more frequent in individuals with alcoholic cirrhosis, chronic obstructive pulmonary disease, chronic renal failure, and hyperparathyroid secretion.

Answer 16

Zollinger-Ellison syndrome; prostaglandin

Question 17

[Peptic Ulcers Disease: Morphology]
Peptic ulcers are four times more common in the __________ than in the stomach. Duodenal ulcers usually occur within a few centimeters of the pyloric valve and involve the anterior duodenal wall. Gastric peptic ulcers are predominantly located near the interface of the body and antrum.

Peptic ulcers are solitary in more than 80% of patients. Lesions less than 0.3 cm in diameter tend to be shallow, whereas those over 0.6 cm are likely to be deeper. The classic peptic ulcer is a round to oval, sharply punched-out defect. The base of peptic ulcers is smooth and clean as a result of peptic digestion of exudate and on histologic examination is composed of _________. Ongoing bleeding within the ulcer base may cause life-threatening hemorrhage. Perforation is a complication that demands emergent surgical intervention.

Answer 17

proximal duodenum ; richly vascular granulation tissue

Question 18

[Peptic Ulcers- Clinical Features]
Peptic ulcers are chronic, recurring lesions that occur most often in middle-aged to older adults without obvious precipitating conditions, other than chronic gastritis. A majority of peptic ulcers come to clinical attention after patient complaints of _______ or aching pain, although a significant fraction manifest with complications such as iron deficiency anemia, frank hemorrhage, or perforation. The pain tends to occur _________ during the day, is worse at night, and is relieved by alkali or food. Nausea, vomiting, bloating, and belching may be present. Healing may occur with or without therapy, but the tendency to develop subsequent ulcers remains.

PUD causes much more morbidity than mortality. A variety of surgical approaches were formerly used to treat PUD, but current therapies are aimed at H. pylori eradication with antibiotics and neutralization of gastric acid, usually through use of proton pump inhibitors. These efforts have markedly reduced the need for surgical management, which is reserved primarily for treatment of ulcers with uncontrollable bleeding or perforation.

Answer 18

epigastric burning; 1 to 3 hours after meals

Question 19

Dysplasia
Chronic gastritis exposes the epithelium to inflammation-related free radical damage and proliferative stimuli. Over time, this can lead to the accumulation of genetic alterations that result in carcinoma. Preinvasive in situ lesions can be recognized histologically as dysplasia, which is marked by variations in epithelial size, shape, and orientation along with ______ chromatin texture, ________ and nuclear enlargement. These overlap with and are sometimes difficult to distinguish from injury-associated regenerative changes

Answer 19

coarse; hyperchromasia,

Question 20

Inflammatory and Hyperplastic Polyps

Up to 75% of all gastric polyps are inflammatory or hyperplastic polyps. In the stomach, inflammatory and hyperplastic polyps represent opposite ends of the morphologic spectrum of a single entity; the distinction is based solely on the _______________. They most commonly affect individuals between 50 and 60 years of age, usually arising in a background of chronic gastritis that initiates the injury and reactive hyperplasia that cause polyp growth. If associated with H. pylori gastritis, polyps may regress after bacterial eradication.

The frequency with which dysplasia, a precancerous in situ lesion, develops in these polyps correlates with size; there is a significant increase in risk with polyps larger than _____.

Answer 20

degree of inflammation; 1.5 cm

Question 21

Fundic Gland Polyps
Fundic gland polyps occur sporadically and in individuals with _____________ (but not sporadic) may show dysplasia, but they almost never progress to become malignant. The incidence of sporadic lesions has increased markedly as a result of the widespread use of proton pump inhibitors. This likely results from increased gastrin secretion, in response to reduced acidity, and glandular hyperplasia driven by gastrin. Fundic gland polyps are nearly always asymptomatic, and are usually an incidental finding. These well-circumscribed polyps occur in the gastric body and fundus, often are multiple, and are composed of cystically dilated, irregular glands lined by flattened parietal and chief cells.

Answer 21

Familial adenomatous polyposis (FAP) Polyps associated with FAP

Question 22

Gastric Adenocarcinoma Pathogenesis

Gastric cancers are genetically heterogeneous, but certain molecular alterations are common. We will consider these first to be followed by the role of H. pylori– induced chronic inflammation and the association of a subset of gastric cancers with EBV infection.

• Mutations. While the majority of gastric cancers are not hereditary, mutations identified in familial gastric cancer have provided important insights into the mechanisms of carcinogenesis in sporadic cases. Germ line mutations in CDH1, which encodes _______, a protein that contributes to epithelial intercellular adhesion, are associated with familial gastric cancers, usually of the diffuse type. By comparison, mutations in CDH1 are present in about 50% of sporadic diffuse gastric tumors, while E-cadherin expression is drastically decreased in the rest, often by ________ of the CDH1 promoter. Thus, the loss of E-cadherin function seems to be a key step in the development of diffuse gastric cancer. In contrast to CDH1, patients with FAP who have germ line mutations in adenomatous polyposis coli (APC) genes have an increased risk for development of intestinal-type gastric cancer. Sporadic intestinal-type gastric cancer is associated with several genetic abnormalities including acquired mutations of β-catenin, a protein that binds to both E-cadherin and APC protein; microsatellite instability; and hypermethylation of genes including TGFβRII, BAX, IGFRII, and p16/INK4a. TP53 mutations are present in a majority of sporadic gastric cancers of both histologic types.

Answer 22

E-cadherin; methylation

Question 23

Gastric Adenocarcinoma Pathogenesis Part 2
• H. pylori. Chronic gastritis, most commonly due to H. pylori infection, promotes the development and progression of cancers that may be induced by diverse genetic alterations . As is the case with many forms of chronic inflammation, H. pylori– induced chronic gastritis is associated with increased production of proinflammatory proteins, such as ______ and _______. It is therefore not surprising that polymorphisms of genes that encode such factors and enhance production of these cytokines confer increased risk for development of chronic gastritis-associated gastric cancer in those with coexisting H. pylori infection.

Answer 23

interleukin-1β (IL-1β); tumor necrosis factor (TNF)

Question 24

Gastric Adenocarcinoma Pathogenesis Part 3

• Epstein-Barr virus (EBV). While H. pylori is most commonly associated with gastric cancer, approximately 10% of gastric adenocarcinomas are associated with Epstein-Barr virus (EBV) infection. Although the precise role of EBV in the development of gastric adenocarcinomas remains to be defined, it is notable that EBV episomes in these tumors frequently are clonal, suggesting that infection preceded neoplastic transformation. Further, TP53 mutations are uncommon in EBV-positive gastric tumors, suggesting that the molecular pathogenesis of these cancers is distinct from that of other gastric adenocarcinomas. Morphologically, EBV-positive tumors tend to occur in the proximal stomach and most commonly have a diffuse morphology with a _____________

Answer 24

marked lymphocytic infiltrate

Question 25

Gastric Adenocarcinomas Morphology

Gastric adenocarcinomas are classified according to their location in the stomach as well as gross and histologic morphology. The __________ that separates gastric cancers into intestinal and diffuse types correlates with distinct patterns of molecular alterations, as discussed earlier. Intestinal-type cancers tend to be bulky and are composed of glandular structures similar to esophageal and colonic adenocarcinoma.
Intestinal-type adenocarcinomas typically grow along broad cohesive fronts to form either an ________ or an ulcerated tumor. The neoplastic cells often contain ____________, and abundant mucin may be present in gland lumina.

Diffuse gastric cancers display an infiltrative growth pattern and are composed of ____________ that expand the cytoplasm and push the nucleus to the periphery, creating a signet ring cell morphology. These cells permeate the mucosa and stomach wall individually or in small clusters. A mass may be difficult to appreciate in diffuse gastric cancer, but these infiltrative tumors often evoke a desmoplastic reaction that stiffens the gastric wall and may cause diffuse rugal flattening and a rigid, thickened wall that imparts a “leather bottle” appearance termed ____________.

Answer 25

Lauren classification; exophytic mass; apical mucin vacuoles

discohesive cells with large mucin vacuoles; linitis plastica

Question 26

Neuroendocrine tumors, also referred to as __________, arise from neuroendocrine organs (e.g., the endocrine pancreas) and neuroendocrine-differentiated gastrointestinal epithelia (e.g., G cells). A majority of these tumors are found in the gastrointestinal tract, and more than 40% occur in the small intestine. The ___________ are the next most commonly involved sites. Gastric neuroendocrine tumors may be associated with endocrine cell hyperplasia, chronic atrophic gastritis, and Zollinger-Ellison syndrome. These tumors were called “carcinoid” because they are slower growing than carcinomas. The most current WHO classification describes these as low- or intermediate-grade neuroendocrine tumors. High-grade neuroendocrine tumors, termed neuroendocrine carcinoma, resemble small cell carcinoma of the lung ( Chapter 13 ) and, in the gastrointestinal tract, are most common in the _________.

Answer 26

carcinoid tumors’ tracheobronchial tree and lungs; jejunum

Question 27

Neuroendocrine cells morphology
Neuroendocrine tumors are intramural or submucosal masses that create _________. The tumors are yellow or tan in appearance and elicit an intense desmoplastic reaction that may cause kinking of the bowel and obstruction. On histologic examination, neuroendocrine tumors are composed of islands, trabeculae, strands, glands, or sheets of uniform cells with scant, pink granular cytoplasm and a round-to-oval stippled nucleus

Answer 27

small polypoid lesions

Question 28

The peak incidence of neuroendocrine tumors is in the sixth decade, but they may appear at any age. Symptoms are determined by the hormones produced. For example, the carcinoid syndrome is caused by vasoactive substances secreted by the tumor that cause cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea, and right-sided cardiac valvular fibrosis. When tumors are confined to the intestine, the vasoactive substances released are metabolized to inactive forms by the liver—a “first-pass” effect similar to that seen with oral drugs. Thus, carcinoid syndrome occurs in less than 10% of patients and is strongly associated with metastatic disease.

The most important prognostic factor for gastrointestinal neuroendocrine tumors is location:

• Foregut neuroendocrine (carcinoid) tumors found within the stomach, duodenum proximal to the ____________, and esophagus, rarely metastasize and are generally cured by resection. Rare duodenal gastrin-producing neuroendocrine tumors, also termed gastrinomas, may present with symptoms related to increased acid production, including pain and/or bleeding from gastroduodenal ulcers, refractory gastroesophageal reflux, and diarrhea due to inactivation of pancreatic enzymes by excessive gastric acid.
• Midgut neuroendocrine (carcinoid) tumors arise in the jejunum and ileum, are often multiple and tend to be aggressive. In these tumors, depth of local invasion, size, and the presence of ____________ are associated with poor outcome.
• Hindgut neuroendocrine (carcinoid) tumors arising in the appendix and colorectum are typically discovered incidentally. Those in the appendix occur at any age and are almost uniformly pursue a benign course. Rectal tumors tend to produce polypeptide hormones and may manifest with abdominal pain and weight loss. Because they are usually discovered when small, metastasis of rectal neuroendocrine tumors is uncommon.

Answer 28

ligament of Treitz; necrosis and mitoses

Question 29

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the abdomen, and more than half of these tumors occur in the stomach. A wide variety of other mesenchymal neoplasms may arise in the stomach. Many are named according to the cell type they most resemble; for example, smooth muscle tumors are called _____________, nerve sheath tumors are termed __________, and those resembling glomus bodies in the nail beds and at other sites are termed glomus tumors. These tumors are all rare and are not discussed here.

Answer 29

leiomyomas or leiomyosarcomas; schwannomas

Question 30

GISTs pathogenesis
The most common genetic change underlying the pathogenesis of GISTs is gain-of-function mutations of the gene encoding the ___________, the receptor for stem cell factor. These are present in 75% to 85% of all GISTs. An additional 8% of GISTs have mutations that activate a related tyrosine kinase, _____________. The term stromal reflects historical confusion about the origin of this tumor, which is now recognized to arise from the ______________ or pacemaker cells, of the gastrointestinal muscularis propria. For unknown reasons, GISTs bearing PDGFRA mutations are overrepresented in the stomach. KIT and PDGFRA gene mutations are mutually exclusive, reflecting their activities within the same signal transduction pathway. Germ line mutations in these same genes are present in rare familial GISTs, in which patients develop multiple GISTs and may also have diffuse hyperplasia of Cajal cells.

Both sporadic and germ line mutations result in constitutively active KIT or PDGFRA receptor tyrosine kinases and produce intracellular signals that promote tumor cell proliferation and survival ( Chapter 6 ). In GISTs without KIT or PDGFRA mutations, genes encoding components of the _______________ are most commonly affected. These mutations result in loss of SDH function and confer increased risk for both GIST and paraganglioma. One mutant allele is often inherited, with the second copy of the gene being either mutated or otherwise lost in the tumor. The loss of SDH causes a number of metabolic changes, including increased production of reactive oxygen species, activation of hypoxia induced factor (HIF), and increased dependency on glycolysis for ATP production, but how these alterations lead to transformation is uncertain.

Answer 30

tyrosine kinase KIT; platelet-derived growth factor receptor A (PDGFRA); interstitial cells of Cajal; mitochondrial succinate dehydrogenase (SDH) complex

Question 31

GISTs Morphology
Primary gastric GISTs usually form a solitary, well-circumscribed, fleshy, submucosal mass. Metastases may form multiple small serosal nodules or fewer large nodules in the liver; spread outside of the abdomen is uncommon. GISTs can be composed of thin, ___________ or plumper epithelioid cells. The most useful diagnostic marker is KIT, which is immunohistochemically detectable in 95% of these tumors.

Answer 31

elongated spindle cells

Question 32

GISTs clinical features
The peak incidence of gastric GIST is around 60 years of age, with less than 10% occurring in individuals younger than 40 years of age. Overall, GISTs are slightly more common in males. Small GISTs may come to clinical attention incidentally during work-up of other GI symptoms, which are common. Larger GISTs may present with symptoms related to mass effects or mucosal ulceration, such as intestinal obstruction or gastrointestinal bleeding. ____________ is the primary treatment for localized gastric GIST. The prognosis correlates with tumor size, mitotic index, and location, with gastric GISTs being somewhat less aggressive than those arising in the small intestine. Recurrence or metastasis is rare for gastric GISTs less than 5 cm in diameter but common for mitotically active tumors larger than 10 cm. Tumors that are unresectable or metastatic often respond, sometimes for years, to tyrosine kinase inhibitors that are active against KIT and PDGFRA, such as imatinib. Unfortunately, as in chronic myeloid leukemia ( Chapter 12 ), resistance to imatinib eventually arises due to outgrowth of subclones with additional mutations in KIT or PDGFRA. In some instances, these tumors respond to other tyrosine kinase inhibitors that retain activity against KIT and PDGFRA.

Answer 32

Complete surgical resection