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

2. 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

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

4. 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

5. 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

6. 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

7. 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

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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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)

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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.

28. 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

29. 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

30. 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