PATHOLOGY CASE 2

PATHOLOGY CASE 2

INTRODUCTION

A 30-year-old male banker complains of midepigastric gnawing and boring pain for the last week. The pain is worse at night and is somewhat better immediately after he eats. He has not had any fever, nausea, or vomiting. He takes about one 500-mg acetaminophen tablet a week for headaches but does not take any other medications. Upper endoscopy reveals a 2-cm mucosal defect in the antrum of the stomach. There is mild edema in the adjacent mucosa, but there is no thickening of the edges of the ulcer.

· What is the most likely diagnosis?

· What are complications from this condition?

· What is the most likely mechanism of this disorder?

ANSWERS TO CASE 2: Peptic Ulcer Disease

Summary: A 30-year-old man has acute onset of midepigastric pain somewhat relieved by eating. Upper endoscopy reveals a 2-cm gastric ulcer.

· Most likely diagnosis: Peptic ulcer disease.

· Long-term complications: Erosion or perforation with bleeding; gastric carcinoma in patients with chronic gastritis.

· Most likely mechanism: Most often associated with Helicobacter pylori organisms that produce bacterial urease and protease, damaging the mucus layer and exposing the underlying epithelium to acid-peptic injury.

CLINICAL CORRELATION

Introduction

Ulcers are disruptions of the mucosa of the gastrointestinal tract that extend through the muscularis mucosa into the submucosa or deeper. Peptic ulcers occur most frequently in the stomach and duodenum. Peptic ulcers are often remitting, relapsing lesions that may be seen in young adults but more often occur in middle-aged to older adults. They are usually chronic, solitary lesions caused by the action of gastric acid and pepsin, both of which are thought to be required for the development of peptic ulcers. Helicobacter pylori infection of gastric mucosa is present in 90 to 100 percent of patients with a duodenal ulcer and 70 percent of those with a gastric ulcer. Damage to the protective mucus layer by bacterial urease and protease exposes the underlying epithelial cells to the influence of acid-peptic digestion and may lead to inflammation. The chronically inflamed mucosa is more susceptible to acid-peptic injury and thus more prone to ulceration.

Approach to Gastric Pathology

Definitions

Diaphragmatic hernia: Weakness or partial to total absence of a portion of the diaphragm, usually on the left, which may permit the abdominal contents to herniate into the thorax during in utero development. Diaphragmatic hernias differ from hiatal hernias in that the defect in the diaphragm does not involve the hiatal orifice.

Pyloric stenosis: Congenital hypertrophic pyloric stenosis is seen in infants usually during the second or third week of life. Hypertrophy of the muscularis propria of the pylorus results in a palpable mass and obstruction with associated regurgitation and persistent projectile vomiting. Male infants are affected 3 to 4 times more often than are females. Treatment consists of surgical splitting of the muscle. Pyloric stenosis may be acquired in adults with chronic antral gastritis or peptic ulcers near the pylorus. Other causes of acquired pyloric stenosis include gastric carcinomas, lymphomas, and adjacent carcinomas of the pancreas.

Gastritis: Inflammation of the gastric mucosa. The inflammation may be predominantly acute, with neutrophilic infiltration, or chronic, with a predominance of lymphocytes and plasma cells. The classification and pathogenesis of acute and chronic gastritis are discussed below.

Ulcer: A disruption of the mucosa extending through the muscularis mucosa into the submucosa or deeper. Ulcers may occur anywhere in the gastrointestinal tract but are seen most often in the stomach and duodenum, associated with peptic ulcer disease.

Peptic ulcer disease: Peptic ulcers are chronic, usually solitary lesions of the gastrointestinal mucosa caused by the action of acid-peptic juices. Both acid and pepsin are necessary for peptic ulcer disease to develop.

Hypertrophic gastropathy: A group of uncommon conditions characterized by enlargement of the rugal folds of the gastric mucosa caused by hyperplasia of the mucosal epithelial cells. The three variants are (1) Menetrier disease with marked hyperplasia of the surface mucous cells with atrophy of the gastric glands that may lead to severe loss of plasma proteins, (2) Zollinger-Ellison syndrome with gastric gland hyperplasia secondary to excessive gastrin secretion by a tumor (gastrinoma), and (3) hypertrophic-hypersecretory gastropathy with hyperplasia of the parietal and chief cells within the gastric glands. These three conditions may mimic gastric cancer on radiographic studies. The excessive amount of acid secretion in the second and third conditions predisposes patients to peptic ulceration.

Discussion

Normal Stomach

The stomach is divided into four anatomic regions: the cardia, fundus, body or corpus, and antrum. The pyloric sphincter demarcates the antrum from the duodenum. Infoldings of mucosa and submucosa, or rugae, extend longitudinally and are most prominent in the proximal stomach. Several types of cells are found in the stomach: Parietal cells produce gastric hydrochloric acid and intrinsic factor involved in the absorption of vitamin B₁₂, chief cells secrete the proteolytic enzymes pepsinogen I and II, surface and mucous neck cells secrete mucus involved in the protection of the mucosa from gastric acid, and G cells found in the antral, pyloric, and duodenal mucosa produce gastrin.

The secretion of gastric acid is proportional to the total number of parietal cells in the glands of the body and fundus of the stomach. The secretory process may be divided into three phases: cephalic, gastric, and intestinal. Gastrin, which is released in response to vagal stimulation, is the most important mediator of gastric acid secretion. Histamine also stimulates acid secretion. Thus, surgical interruption of vagal stimulation and inhibition of histamine stimulation by blocking the H2 receptor on the parietal cell membrane are effective maneuvers for reducing gastric acid production. Several factors act together to protect the stomach from digestion by gastric acid. Mucus secretion, bicarbonate secretion, the epithelial barrier formed by tight intercellular junctions, a rich mucosal blood flow that removes back-diffused acid, and a reflex vasodilationdilation in response to toxins or acid breach of the epithelial layer all contribute to the mucosal barrier.

Gastritis

Inflammation of the gastric mucosa occurs in a variety of clinical situations and may be acute or chronic. Acute gastritis varies in severity; it may be asymptomatic, cause epigastric pain with nausea and vomiting, or present with massive hematemesis. Acute erosive gastritis (see Table 2-1) is an important cause of acute gastrointestinal bleeding. In chronic gastritis, there are chronic mucosal inflammatory changes, usually without erosions, that may lead to mucosal atrophy and dysplastic epithelium, predisposing the patient to the development of carcinoma (Table 2-2).

 

Table 2-1. SELECTED ETIOLOGIES OF ACUTE GASTRITIS

Heavy use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin

Excessive alcohol consumption

Heavy smoking

Uremia

Cancer chemotherapy

Severe stress: burns (Curling ulcer), trauma, or surgery with increased intracranial pressure leading to increased vagal tone (Cushing ulcer)

Ischemia and shock

Suicide attempts with acids and alkali

Mechanical trauma (nasogastric intubation)

After distal gastrectomy

Table 2-2. SELECTED ETIOLOGIES OF CHRONIC GASTRITIS

Chronic infection, such as Helicobacter pylori

Immunologic, associated with pernicious anemia

Toxic, such as alcohol and cigarette use

Postsurgical, especially after antrectomy

Obstruction, such as bezoars

Radiation

Granulomatous conditions, such as Crohn disease

Other conditions, such as graft-versus-host disease, amyloidosis, uremia

Most cases of chronic gastritis are thought to be associated with chronic Helicobacter pylori infection. Chronic gastritis that results from H. pylori infection most often involves the antrum and is not associated with pernicious anemia. Most patients improve with antibiotic treatment, and relapses of chronic gastritis are associated with a recurrence of infection. Patients are at risk for developing peptic ulcer disease and gastric cancer, including adenocarcinoma and lymphoma.

Patients with autoimmune gastritis (diffuse atrophic gastritis) may have nausea, vomiting, and upper abdominal pain. Patients usually have autoantibodies to gastric parietal cells or intrinsic factor. Destruction of gastric glands of the fundus leads to loss of acid production (achlorhydria) and hypergastrinemia. Loss of intrinsic factor leads to pernicious anemia. Patients may have other autoimmune disorders, such as Hashimoto thyroiditis or Addison disease.

Peptic Ulcer Disease

Peptic ulcers are usually solitary, arising from exposure of the mucosal epithelium to acid-peptic secretions. Peptic ulcer disease (PUD) occurs most often in middle-aged to older adults. The most common anatomic sites are the duodenum and the stomach, in a ratio of 4:1. H. pylori infection is present in virtually all patients with duodenal ulcers and 70 percent of patients with PUD involving the stomach. H. pylori can cause damage by (1) secreting urease, protease, and phospholipases, (2) attracting neutrophils that release myeloperoxidase, and (3) promoting thrombotic occlusion of capillaries, leading to ischemic damage of the epithelium. Complications of PUD include anemia, hemorrhage, perforation, and obstruction. Malignant transformation is rare and is related to underlying chronic gastritis.

Gastric Cancer

Most (90 to 95 percent) gastric malignancies are adenocarcinomas, with a smaller number of lymphomas, carcinoids, and spindle cell tumors. Although the incidence of gastric carcinoma has been decreasing in Western countries over the last 50 years, the prognosis is still poor, with a 20 percent 5-year survival. Risk factors for gastric carcinoma include nitrates; smoked, salted, or pickled foods; lack of fresh fruits and vegetables; chronic atrophic gastritis; H. pylori infection; partial gastrectomy; gastric adenomas; blood group A; and close relatives with gastric cancer. Two types of gastric carcinoma are recognized: the intestinal type and the diffuse type (Table 2-3).

 

Table 2-3. GASTRIC CARCINOMA SUBTYPES
	INTESTINAL TYPE	DIFFUSE TYPE
Incidence	Decreasing	No change
Average age	55 years	48 years
Male:female ratio	2:1	1:1
Chronic gastritis	Frequently associated	No particular association
Macroscopic growth pattern	Exophytic, polypoid, fungating	Ulcerative and/or diffusely infiltrative resulting in a rigid thickened wall, linitis plastica
Microscopic growth pattern	Gland-forming columnar epithelium; associated with intestinal metaplasia; usually mucin-producing	Infiltrative growth; noncohesive; poorly differentiated, often signet ring cells; mucin-producing

These may represent two distinct forms of gastric carcinoma. Dissemination of gastric carcinoma, as well as other primary abdominal adenocarcinomas, to the ovaries is known as Krukenberg tumors. The hallmark is the "signet ring cell" on microscopy, which is indicative of large cells with mucin, that push the nuclei to the periphery of the cell.

COMPREHENSION QUESTIONS

[2.1] A 59-year-old woman presents with occasional nausea and vague upper abdominal discomfort. Upper endoscopy reveals chronic gastritis of the fundus with flattened gastric mucosa but no acute ulceration. Which of the following is most likely to be associated with this finding?

A. Autoantibodies to parietal cells

B. Diet high in nitrites

C. Hyperchlorohydria

D. Hypoparathyroidism

E. Menetrier disease

[2.2] A 40-year-old man has burning epigastric pain starting 1 to 3 hours after eating, sometimes awakening him at night. Endoscopic biopsy demonstrates an acute ulcer in the prepyloric region of the stomach. Which of the following is most likely to be associated with this finding?

A. Blood group A

B. Congenital pyloric stenosis

C. Esophageal varices

D. Gastric carcinoma

E. Helicobacter pylori infection

[2.3] A 55-year-old woman seeks medical attention for fatigue and malaise that have been worsening over the last 2 months. She also has noticed loss of appetite and early satiety. Evaluation reveals an ulcerative mass located along the lesser curvature, and a biopsy shows an infiltrating adenocarcinoma. Further evaluation by abdominal CT imaging shows bilateral ovarian masses. Which of the following is this patient most likely to have?

A. Barrett mucosa

B. Krukenberg tumor

C. Primary ovarian neoplasm

D. Uterine cancer

ANSWERS

[2.1] A. Chronic atropic gastritis often is associated with autoantibodies to parietal cells. Loss of these cells leads to decreased gastric acid (hypochlorohydria) and decreased intrinsic factor. Lack of intrinsic factor results in deceased or absent vitamin B₁₂ absorption (pernicious anemia).

[2.2] E. Helicobacter pylori infection is closely associated with peptic ulcer disease as well as gastric carcinoma and lymphoma.

[2.3] B. The findings suggest that the patient's gastric cancer has metastasized to the ovaries; this is known as a Krukenberg tumor. Histology typically shows "signet ring" cells.

REFERENCES

Del Valle J. Peptic ulcer disease and related disorders. In: Kasper DL, Fauci AS, Longo DL, et al., eds. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:1746-1762.

Liu C, Crawford JM. The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:804-809, 816-827.