Gastro-Esophageal Reflux Disease (GERD) Dr. Mamlook Elmagraby

Objectives of the lecture: Upon completion of this lecture, students should be able to: Describe the definition of reflux esophagitis Know the pathogenesis, pathology (gross and microscopic features), clinical features and complications of reflux esophagitis Describe the definition of Barrett esophagus know the pathogenesis, pathology (gross and microscopic features), clinical features and complications (dysplasia and adenocarcinoma)of Barrett esophagus Know the cause and features of squamous cell carcinoma

Esophagitis Causes of esophageal mucosa inflammation: Prolonged gastric intubation Uremia Ingestion of corrosive substances Radiation or chemotherapy Infection

Gastroesophageal reflux disease (GERD) Reflux of gastric contents into the lower esophagus is the most frequent cause of esophagitis The associated clinical condition is termed gastroesophageal reflux disease (GERD) In the United States, GERD is the most common gastrointestinal disorder with which patients present in the outpatient setting The stratified squamous epithelium of the esophagus is resistant to food trauma but is sensitive to acid

Gastroesophageal reflux disease (GERD) Lower esophageal sphincter tone protects against reflux of acidic gastric contents, which are under positive pressure The submucosal glands of the proximal and distal esophagus contribute to mucosal protection by secreting mucin and bicarbonate

Gastroesophageal reflux disease (GERD) Pathogenesis Reflux of gastric juices is central to the development of mucosal injury in GERD   In severe cases, duodenal bile reflux may aggravate the damage In many cases, no definitive cause is identified Conditions that decrease lower esophageal sphincter tone or increase abdominal pressure contribute to GERD

Gastroesophageal reflux disease (GERD) There are many contributing factors to GERD Central nervous system depressants Obesity Pregnancy Increased gastric volume Delayed gastric emptying Alcohol or tobacco exposure Hiatal hernia Hiatal hernia is characterized by separation of the diaphragmatic crura and protrusion of the stomach into the thorax through the resulting gap. Congenital hiatal hernias are recognized in infants and children, but many are acquired in later life. Hiatal hernia is symptomatic in fewer than 10% of adults; symptoms when present resemble GERD since hiatal hernia can cause LES incompetence Causes Age-related changes in your diaphragm Injury to the area, for example, after trauma or certain types of surgery Being born with an unusually large hiatus Persistent and intense pressure on the surrounding muscles, such as while coughing, vomiting, straining during a bowel movement, exercising or lifting heavy objects

Achalasia and hiatal hernias Achalasia and hiatal hernias. Comparison between sliding and paraesophageal (rolling) hiatal hernias.

Gastroesophageal reflux disease (GERD) Morphology Simple hyperemia (redness) may be the only alteration The mucosa in severe esophagitis shows erosions or ulceration In mild GERD the mucosal histology is often unremarkable With more significant disease, the histologic features of GERD include: Eosinophils and neutrophils in the epithelial layer Basal zone hyperplasia Elongation of lamina propria papillae

Reflux esophagitis with scattered intraepithelial eosinophils Esophagus, reflux esophagitis This image shows basal zone hyperplasia, characterized by a basal layer greater than 15%, and elongation of papillae that extend into the outer one third of the epithelium

Gastroesophageal reflux disease (GERD) Clinical Features GERD is most common in those over 40 years of age but also occurs in infants and children   The most frequently symptoms are: Heartburn dysphagia regurgitation of sour-tasting gastric contents Rarely, chronic GERD is presented by attacks of severe chest pain that may be mistaken for heart disease Treatment with proton pump inhibitors reduces gastric acidity and provides symptomatic relief .Regurgitation is the return of undigested food back up the esophagus to the mouth, without the force and displeasure associated with vomiting. Regurgitation which is the passive expulsion of ingested material out of the mouth

Gastroesophageal reflux disease (GERD) Complications of reflux esophagitis include: Esophageal ulceration Hematemesis Melena Stricture development Barrett esophagus (a precursor lesion to esophageal carcinoma) Melena Passage of dark-colored, tarry stools Stricture an abnormal narrowing or contraction of a body passage or opening Precursor from which another is derived

Barrett Esophagus Barrett esophagus is a complication of chronic GERD that is characterized by intestinal metaplasia within the esophageal squamous mucosa   The incidence of Barrett esophagus is rising; it occur in as many as 10% of individuals with symptomatic GERD White males are affected most often and typically present between 40 and 60 years of age Barrett esophagus confers an increased risk for development of esophageal adenocarcinoma Most individuals with Barrett esophagus do not develop esophageal cancer

Barrett Esophagus Morphology It appears as a salmon pink, granular mucosa between the smooth, white esophageal squamous mucosa and the more light brown gastric mucosa It may exist as "tongues, as an irregular circumferential band or as isolated patches in the distal esophagus The squamous epithelium is replaced by metaplastic columnar epithelium Dysplastic changes can occur in the Barrett mucosa Complications of Barrett esophagus include ulceration, stricture, the development of adenocarcinoma

Barrett esophagus. A-B, Gross view of distal esophagus (top) and proximal stomach (bottom) showing normal gastroesophageal junction and the granular zone of Barrett esophagus (arrow). Esophagus, metaplastic columnar epithelium of Barrett esophagus This image shows the esophageal squamous epithelium replaced by an intestinal type of metaplastic columnar epithelium containing goblet cells

Barrett Esophagus Clinical Features Diagnosis of Barrett esophagus is usually brought about by GERD symptoms and requires endoscopy and biopsy   Most clinicians recommend periodic surveillance endoscopy with biopsy to screen for dysplasia High-grade dysplasia and intramucosal carcinoma, always require therapeutic intervention Available modalities include surgical resection; photodynamic therapy, radiofrequency ablation, endoscopic mucosectomy Screen To examine a group to separate certain individuals from it Surveillance close observation

Esophageal Carcinoma There are two types of cancer arise in the esophagus: Squamous cell carcinomas Adenocarcinomas Squamous cell carcinomas constitute 90% of esophageal cancers Adenocarcinoma arising in Barrett esophagus is more common in whites than in blacks Squamous cell carcinomas are more common in blacks The prognosis of these carcinomas are poor

Squamous Cell Carcinoma Esophageal squamous cell carcinoma occurs in adults older than 45 years of age and affects males more frequently than females It is more common in African Americans than in whites Esophageal squamous cell carcinoma is more common in rural and underdeveloped areas The countries with highest incidences are Iran, central China, Hong Kong, Argentina, Brazil, South Africa Underdeveloped Having a low level of economic productivity and technological sophistication, developing

Squamous Cell Carcinoma Pathogenesis. Risk factors include: Alcohol Tobacco use Poverty Caustic esophageal injury Achalasia Plummer-Vinson syndrome Frequent consumption of very hot beverages Previous radiation therapy to the mediastinum Plummer-Vinson syndrome iron deficiency anemia, dysphagia, esophageal stenosis, and atrophic glossitis (possibly autoimmune condition)

Squamous Cell Carcinoma A majority of esophageal squamous cell carcinomas in western countries are related to the use of alcohol and tobacco (synergy)   Esophageal squamous cell carcinoma also is common in some regions where alcohol and tobacco use are uncommon In areas where alcohol and tobacco use are uncommon , the risk factors may be: Nutritional deficiencies Exposure to polycyclic hydrocarbons, nitrosamines (mutagenic compounds) HPV infection also has been implicated in esophageal squamous cell carcinoma in high-risk regions Synergy corporation, that creates an enhanced combined effect

Squamous Cell Carcinoma Morphology In contrast to the distal location of most adenocarcinomas, half of squamous cell carcinomas occur in the middle third of the esophagus   Squamous cell carcinoma begins as an in situ lesion in the form of squamous dysplasia Early lesions appear as small, gray-white plaque-like thickenings Over months to years, they grow into tumor masses that may be polypoid and protrude into and obstruct the lumen Polypoid resembling a polyp Polyp tumor protruding from the mucous lining of a hollow organ, sometimes causing obstruction

Squamous Cell Carcinoma Other tumors are either ulcerated or diffusely infiltrative lesions that spread within the esophageal wall Most squamous cell carcinomas are moderately to well differentiated Symptomatic tumors have often invaded the esophageal wall at time of diagnosis   The rich submucosal lymphatic network promotes circumferential and longitudinal spread

Squamous Cell Carcinoma These cancers may invade surrounding structures including: The respiratory tree, causing pneumonia The aorta, causing catastrophic extensive hemorrhage The mediastinum The pericardium   The sites of lymph node metastases vary with tumor location: Cancers in the upper third of the esophagus favor cervical lymph nodes Those in the middle third favor mediastinal, paratracheal, and tracheobronchial nodes Those in the lower third spread to gastric and celiac nodes

Esophagus, squamous cell carcinoma - Gross, mucosal surface The middle portion of the esophagus shows a large necrotic ulcer Esophagus, squamous cell carcinoma Nests (A group of similar objects) of squamous epithelial cells with lighter-staining keratin in their centers

Squamous Cell Carcinoma Clinical Features. Clinical manifestations begin insidiously and include dysphagia, painful swallowing, obstruction   Patients may unconsciously adjust to the increasing obstruction by altering their diet from solid to liquid foods Extreme weight loss and debilitation may occur as consequences of both impaired nutrition and tumor-associated cachexia As with adenocarcinoma, hemorrhage and sepsis may accompany tumor ulceration 5-year survival rates are 75% for patients with superficial esophageal carcinoma. The overall 5-year survival rate remains 9% Debilitation The depletion of strength or energy Cachexia progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia

Adenocarcinoma Esophageal adenocarcinoma typically arises in a background of Barrett esophagus and long-standing GERD   Risk for development of adenocarcinoma is greater: In patients with documented dysplasia In those who use tobacco In obese In patients having previous radiation therapy In the United States, esophageal adenocarcinoma occurs most frequently in white male The incidence is highest in Western countries (half of all esophageal cancers) and lowest in Korea, Thailand, Japan

The progression of Barrett esophagus to adenocarcinoma occurs over an extended period through the stepwise acquisition of genetic and epigenetic changes.   Chromosomal abnormalities and TP53 mutation are often present in the early stages of esophageal adenocarcinoma. Additional genetic changes and inflammation are thought to contribute to tumor progression.

Adenocarcinoma Morphology Esophageal adenocarcinoma usually occurs in the distal third of the esophagus and may invade the adjacent gastric cardia Early lesions may appear as flat or raised patches Later tumors may form large exophytic masses, infiltrate diffusely, or ulcerate and invade deeply On microscopic examination: Barrett esophagus frequently is present adjacent to the tumor Tumors typically produce mucin and form glands

Esophagus, advanced adenocarcinoma in Barrett esophagus - Gross, mucosal surface This esophagogastrectomy specimen shows a large, irregular, ulcerating tumor with heaped-up margins at the gastroesophageal junction. Note the pink metaplastic columnar epithelium and the adjacent white squamous mucosa Esophagus, adenocarcinoma in Barrett esophagus This image shows a glandular tumor composed of irregular back-to-back glands. Most tumors arising in Barrett esophagus are mucin-producing. Note the presence of squamous epithelium adjacent to the adenocarcinoma

Adenocarcinoma Clinical Features Patients most commonly present with pain or difficulty in swallowing, progressive weight loss, chest pain, or vomiting By the time signs and symptoms appear, the tumor usually has invaded submucosal lymphatic vessels As a result of the advanced stage at diagnosis, the overall 5- year survival rate is less than 25% By contrast, 5-year survival rate is 80% in the few patients with adenocarcinoma limited to the mucosa or submucosa