GERD, peptic ulcers, gastritis, and stomach cancer: Pathology review

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Case Study0:00–0:40

A 61-year-old man, named Shawn, comes to the emergency department because of substernal chest pain and heartburn. He mentions that his symptoms worsen typically after coffee, heavy meals or during times of stress.
He also feels the pain at night when he is lying in bed and has previously been woken from sleep by discomfort. He has not noticed any dyspnea, diaphoresis, or palpitations but is currently experiencing some nausea and a sour taste in his mouth.
Shawn also denies a history of previous cardiovascular conditions. His ECG is normal.
Shawn has gastroesophageal reflux disease, or GERD. GERD is a condition caused by a transient lower esophageal sphincter relaxation, which enables stomach contents and acid to re-enter esophagus and damage esophageal mucosa.

GERD0:40–3:08

As a result, people with GERD present with symptoms such as retrosternal chest pain, heartburn, regurgitation, and dysphagia.
It’s important to note that GERD symptoms tend to worsen after eating, when lying down, or bending over. Now, if stomach acid gets to the throat, it can cause laryngopharyngeal reflux, which has a different set of symptoms such as acidic taste in the mouth, sore throat, chronic cough, and hoarseness.
In the mouth, gastric acid can even damage tooth enamel. Finally, if inhaled, stomach acid can cause pneumonia and asthma.
GERD is commonly associated with conditions such as decreased esophageal motility, gastric outlet obstruction, and hiatal hernia.
Risk factors for GERD include lifestyle habits such as caffeine, alcohol, and smoking; use of some medications, such as antihistamines and calcium channel blockers; but also, obesity; pregnancy; and Zollinger-Ellison syndrome.
For your exam, it’s important to know that long-term complications of GERD include esophagitis, esophageal strictures, Barrett's esophagus, esophageal adenocarcinoma, and pulmonary fibrosis.
Now, a classic GERD presentation can be diagnosed based on clinical symptoms and history alone, but diagnostic methods such as endoscopy or x-ray with barium contrast can be useful in identifying GERD complications.
The treatment of gastroesophageal reflux disease is based on lifestyle changes, such as eating small servings and avoiding heavy food, coffee, alcohol, and smoking; and medical therapy, which includes the use of antacids, H2 receptor antagonists, and proton pump inhibitors.
Finally, surgical treatment can be an option in those individuals whose symptoms do not improve after medical therapy; or in individuals that have developed complications, such as esophageal strictures or Barrett's esophagus.Now Barrett’s esophagus is a premalignant condition that develops when there’s chronic exposure of the lower part of the esophagus to stomach acid.

Barrett’s Esophagus3:08–4:27

As mentioned, this is especially common in individuals with GERD. The acid irritates the mucosa of the esophagus causing inflammation and subsequent necrosis.
Eventually, this results in metaplasia where the normal nonkeratinized stratified squamous epithelium of the lower esophagus is replaced with nonciliated columnar epithelium and goblet cells; a type of cell that’s better adapted to withstand the acidity.
Now you have to know that the intestinal metaplasia is a normal, adaptive response of the esophageal mucosa. Like how you can get a tan when exposed to sunlight.
But if the irritation persists, metaplasia can progress to dysplasia and eventually esophageal adenocarcinoma. Individuals with Barrett’s esophagus are often asymptomatic, but in some cases, they can present with symptoms typical of GERD, such as heartburn, regurgitation, and dysphagia.
Finally, Barrett's esophagus is diagnosed by esophagogastroduodenoscopy with biopsy; and it’s treated by endoscopic ablation or surgical resection.
Moving on to esophageal cancer. The two main types of esophageal cancer are adenocarcinoma and squamous cell carcinoma.

Esophageal Cancer4:27–6:29

Esophageal adenocarcinoma typically affects the lower third of the esophagus and it’s the most common type of esophageal cancer in the United States of America.
Risk factors for esophageal adenocarcinoma include obesity, smoking, achalasia, chronic GERD, and Barrett’s esophagus. Moreover, individuals with Barrett’s esophagus have 30-40 times increased risk of developing esophageal adenocarcinoma.
On the other hand, esophageal squamous cell carcinoma typically affects the upper two-thirds of the esophagus and it’s the most common type of esophageal cancer worldwide.
Risk factors for esophageal squamous cell carcinoma include smoking, alcohol, hot liquids, caustic strictures, and achalasia.
Another risk factor is food containing N-nitroso, like betel nuts, which is chewed like tobacco in Asian countries. Initially, individuals with esophageal cancer are asymptomatic; but as cancer obstructs the esophageal lumen it causes problems, such as dysphagia, initially for solids and then for liquids.
This can also lead to weight loss. Esophageal cancer has an aggressive course because there’s no serosa in the esophageal wall to serve as a barrier between the esophagus and surrounding structures.
Furthermore, individuals with esophageal cancer have a poor prognosis because they usually present late, in advanced stages of esophageal cancer.
Diagnosis is made by esophagogastroduodenoscopy, which is an imaging study that allows direct visualization and biopsy of esophageal cancer.
Finally, treatment options for this condition include endoscopic mucosal resection or mucosal ablation, esophagectomy, and chemoradiation.Okay, let’s move down to the stomach and look at gastritis, which is an inflammation of the gastric mucosa.

Acute gastritis6:29–9:04

There are two types of gastritis, acute and chronic gastritis. Remember that acute gastritis is characterized by neutrophil infiltration; whereas chronic gastritis is characterized by lymphocyte and plasma cell infiltration.
First, let’s start with acute gastritis, which is caused by an imbalance between mucosal defenses and the acidic environment of the stomach.
Acute gastritis starts with gastric erosions, which are mucosal lesions that are limited to the mucosal layer only. Gastric erosions should not be confused with gastric ulcers because ulcers can penetrate into the submucosa and or deeper.
Now, gastric erosions can be caused by excessive drinking of alcohol or long-term use of NSAIDs. NSAIDs work by blocking an enzyme called cyclooxygenase, thereby inhibiting the production of prostaglandin E2 that normally increase the production of gastric mucus and decrease the production of gastric acid.
In other words, decreased production of prostaglandins impairs mucosal defense, eventually causing gastric erosions. Also, acute gastric mucosal lesions can be caused by extreme physiological stress, such as sepsis, shock, and trauma.
These lessons can range from superficial erosions to full-thickness ulcers, which are called stress ulcers. Two important types of stress ulcers are Curling’s ulcers and Cushing’s ulcers.
Curling’s ulcers are typically seen in individuals with severe burns, who develop hypovolemia and subsequent ischemia of gastric mucosa.
On the other hand, Cushing’s ulcers are seen in individuals with brain injuries, when there’s an overstimulation of the vagus nerve, which results in an increased production of ACh and gastric acid.
Now, here’s an easy way to distinguish the two: think of curling iron for Curling’s ulcers and burns; and on the other hand, think of the brain and how it needs to be cushioned for Cushing’s ulcers.
Once the causative stressors are eliminated, stress ulcers spontaneously heal over the next few weeks. Individuals with acute gastritis typically present with epigastric pain, nausea, and vomiting; but in rare cases, they can present with life-threatening upper gastrointestinal bleeding that leads to melena.
On the other hand, in chronic gastritis, chronic inflammation leads to gastric atrophy, which is further followed by metaplasia.

Chronic gastritis9:04–13:11

If the inflammation persists, metaplasia can progress to dysplasia and eventually gastric adenocarcinoma. Now, there are two types of chronic gastritis: chronic autoimmune gastritis and Helicobacter pylori-associated gastritis.
Chronic autoimmune gastritis, also known as type A gastritis, affects the body and fundus of the stomach; and it represents an example of a type IV hypersensitivity.
In chronic autoimmune gastritis, there are autoantibodies against H+/K+ ATPase on parietal cells and intrinsic factor. Autoantibodies against H+/K+ ATPase decrease gastric acid secretion, thereby causing hypochlorhydria, which is associated with impaired iron absorption and hyperplasia of gastrin cells or short G-cells.
As a result, there’s an increased secretion of gastrin, hypergastrinemia, which is a hormone that has a trophic effect on enterochromaffin-like cells, or ECL cells; therefore, these individuals are at risk for developing neuroendocrine tumors.
Autoantibodies against intrinsic factor lead to decreased absorption of vitamin B12, resulting in pernicious anemia. Finally, in chronic autoimmune gastritis chief cells are also lost and this results in decreased levels of serum pepsinogen.
Diagnosis of chronic autoimmune gastritis includes endoscopic biopsy, but also detection of anti-parietal cell antibodies, anti-IF antibodies; and levels of serum gastrin and pepsinogen.
On the other hand, Helicobacter pylori-associated chronic gastritis, also known as type B gastritis, is the most common type of gastritis.
Usually, it affects the antrum but it can spread to the body of the stomach. Moreover.
when the gastritis is mostly confined to the antrum, gastric acid levels are normal or elevated. Now, for your exam, it’s important to know that Helicobacter pylori inflammation decreases the number of somatostatin-secreting cells, also known as delta cells.
Delta cells produce hormone somatostatin, which inhibits gastrin. In type B gastritis, decreased somatostatin leads to high levels of gastrin, so there’s increased hydrogen ion secretion by parietal cells.
As a result, pH of the gastric fluid decreases, and the risk for developing duodenal ulcers and duodenal gastric metaplasia increases.
On the other hand, in extensive Helicobacter pylori-associated chronic gastritis, when inflammation spreads to the body of the stomach, level of gastric acid is typically low; therefore, there’s an increased risk of developing neuroendocrine tumors just like in chronic autoimmune gastritis.
Also, people with Helicobacter pylori-associated chronic gastritis have an increased risk of developing gastric MALT lymphoma.
Individuals with chronic gastritis can be asymptomatic, but in some cases, they can present with epigastric pain, nausea, and vomiting.
Diagnosis of Helicobacter pylori-associated chronic gastritis includes endoscopic biopsy, but also detection of Helicobacter pylori using serology, stool antigen test, and urease breath test.
Generally, chronic gastritis treatment is aimed at the underlying cause. It usually involves antacids or antibiotics, because eradication of Helicobacter pylori improves symptoms and decreases the risk of malignancy.
Next, we have Ménétrier disease which is also called giant hypertrophic gastritis. This is a form of gastritis which features hyperplasia of gastric mucosa and subsequent hypertrophy of gastric folds, also known as gastric rugae.

Ménétrier Disease13:11–14:10

Hypertrophic rugae look like brain gyri, giving the stomach mucosa brain-like appearance. In Ménétrier disease, there’s an excess production of mucus, which is further followed by protein loss and finally parietal cell atrophy.
As a result, there’s also decreased acid production. For your exam, it’s important to remember that Ménétrier disease is a precancerous condition.
These individuals typically present with weight loss, anorexia, vomiting, epigastric pain, and edema, due to protein loss.
You can remember the clinical presentation by the acronym WAVEE. Now let’s focus on Peptic ulcers which are chronic lesions in areas exposed to excess gastric acid and peptic juices.

Peptic Ulcers14:10–21:08

Based on their location, there are two types of peptic ulcers: gastric ulcers, which are most commonly located in the antrum and gastroesophageal junction; and duodenal ulcers, which are typically found in the proximal part of the duodenum, called duodenal bulb.
In 70% of cases, gastric ulcers are caused by Helicobacter pylori infection, the same ones that cause chronic gastritis.
Helicobacter pylori is a gram-negative, non-invasive bacteria. This bacteria is actually sensitive to the acidic environment of the stomach, but in the stomach, it attaches to gastric mucosa or hides deep in the mucus that overlies gastric mucosa which protects it.
It also depends on endogenous urease production. Urease is an enzyme that breaks down urea into carbon acid and ammonia.
The ammonia acts as a base and it raises the pH of the environment which allows the bacteria to survive. At the same time, Helicobacter pylori induces local inflammation, eventually damaging the gastric mucosa.
Another common cause of gastric ulcers is long term use of nonsteroidal anti-inflammatory drugs, or NSAIDs, such as ibuprofen and aspirin.
NSAIDs impair mucosal defenses by inhibiting the production of prostaglandins that normally increase the production of gastric mucus and decrease the production of gastric acid.
Impaired mucosal defense eventually leads to the formation of gastric ulcers. So, for your exam, it’s important to remember that gastric ulcers arise due to decreased mucosal protection against gastric acid.
Gastric ulcers are most commonly found on the lesser curvature of the stomach, and if not treated, they can erode into the left gastric artery and cause upper gastrointestinal bleeding.
Gastric ulcers can also be associated with malignancy and in that case we’re talking about malignant gastric ulcers. These typically arise from gastric MALT lymphoma or gastric adenocarcinoma.
Since they can be malignant, these individuals require a biopsy. For your exam, you have to know that individuals with gastric ulcers present with epigastric pain that typically worsens 30 minutes after eating a meal due to stimulation of acid secretion; therefore these individuals avoid meals and consequently lose weight.
Now, let’s look at duodenal ulcers. In 90% of cases, they are also caused by Helicobacter pylori, which usually colonizes the antrum of the stomach.
Normally, the antrum has fewer secretory parietal cells than the rest of the stomach, to reduce the effect of gastric acid in the duodenum.
But, in Helicobacter pylori infection, local inflammation decreases the number of somatostatin-secreting delta cells. As a result, the pH of the gastric fluid decreases, but at the same time, risk for developing duodenal gastric metaplasia and duodenal ulcers increases.
So, in contrast to gastric ulcers, duodenal ulcers arise due to decreased mucosal protection and increased gastric acid secretion.
A less common cause of duodenal ulcers can be Zollinger-Ellison syndrome and you should suspect this condition in individuals that present with a duodenal ulcer in the distal part of the duodenum or any other atypical place.
It’s important to note that, in contrast to gastric ulcers, duodenal ulcers are rarely malignant, but they can be associated with hyperplasia of Brunner’s glands.
Also, in contrast to gastric ulcers, the pain with duodenal ulcers typically improves with eating; therefore these individuals usually present with weight gain.
Helicobacter pylori infection can be diagnosed using invasive or non-invasive methods. Invasive methods include endoscopic biopsy, which is usually taken from the antrum of the stomach where the bacteria is highly concentrated.
With the biopsy we can directly show the presence of Helicobacter pylori using special stains, like Giemsa; or perform the biopsy urease test, which is where the biopsy specimen is placed in a medium that contains urea.
The urease of Helicobacter pylori breaks down the urea, thereby increasing the pH of the medium and changing the color of the indicator from yellow to pink.
Also, Helicobacter pylori infection can be diagnosed using serology, stool antigen test, or urease breath test. Another test that is commonly used is the fecal occult blood test, which detects the presence of blood that’s invisible in the stool.
Now, it’s very important to remember that the treatment for peptic ulcers caused by Helicobacter pylori is triple therapy: clarithromycin, amoxicillin, and a PPI like omeprazole for 14 days.
Eradication of Helicobacter pylori improves symptoms and decreases the risk of malignancy. Treatment of peptic ulcers caused by NSAIDs consists of stopping NSAIDs and initiating PPIs for at least 8 weeks.
Now, as far as complications go, peptic ulcers are associated with hemorrhage, obstruction, and perforation. Hemorrhage is the most common complication, and in gastric ulcers, it usually occurs when the ulcer located on the lesser curvature of the stomach erodes into the left gastric artery.
On the other hand, hemorrhage in duodenal ulcers is more common in ulcers that are located on the posterior wall of the duodenum, where they erode into the gastroduodenal artery.
A key concept that is frequently tested is that peptic ulcers are the most common cause of iron deficiency anemia in men less than 50 years old, while colorectal carcinoma is the most common for men over 50.
The next complication is obstruction, which usually occurs in the pyloric channel or the first portion of the duodenum, due to chronic inflammation and subsequent scarring and fibrosis.
Finally, there’s perforation which is more common in ulcers that are located on the anterior wall of the duodenum. Perforation of an anterior duodenal ulcer can lead to referred pain to the shoulder due to irritation of the phrenic nerve and pneumoperitoneum, which can be seen on an x-ray as free air under the diaphragm.While we’re on the topic of peptic ulcers, let’s look at Zollinger-Ellison syndrome, also known as gastrinoma syndrome, is a condition that features one or more gastrin-secreting tumors.

Z-E Syndrome21:08–23:20

Two-thirds of these tumors are malignant and they are usually located in the pancreas, but they can be also found in the duodenum, stomach, or other organs.
High levels of gastrin increase acid secretion from parietal cells in the stomach. Ultimately, this results in the formation of treatment-resistant and recurrent peptic ulcers, which are typically located at the distal duodenum and jejunum.
Gastrin also has a trophic effect on parietal cells, so it induces parietal cell proliferation, thereby increasing the mass of fundic glands and enlarging mucosal folds of the fundus.
The most common symptoms of Zollinger-Ellison syndrome include abdominal pain, due to peptic ulcers, diarrhea, and malabsorption.
Diarrhea and malabsorption occur because excessive gastric acid inactivates pancreatic and intestinal enzymes and prevents normal digestion and absorption.
The majority of the cases of gastrinoma leading to Zollinger-Ellison syndrome are sporadic, but in 20-30% it can be associated with multiple endocrine neoplasia type 1, or short MEN1.
The best initial test for diagnosing Zollinger-Ellison syndrome is fasting serum gastrin level, which typically shows high levels of serum gastrin; while the best confirmatory test is the secretin stimulation test.
In Zollinger-Ellison syndrome, the secretin stimulation test is positive because gastrin levels remain high after administration of secretin, which normally inhibit gastrin release.
Finally, non-metastatic gastrinoma is best managed by surgical resection. Along with resection, patients with Zollinger-Ellison syndrome are treated with medical therapy that involves octreotide, a somatostatin analog that works by decreasing gastrin levels; and proton pump inhibitors, which work by decreasing production of gastric acid.Last but not least, gastric cancer!

Gastric Cancer23:20–27:51

The most common type of gastric cancer is gastric adenocarcinoma which can be further subdivided into intestinal, or well-differentiated adenocarcinoma; and diffuse, or undifferentiated adenocarcinoma.
Intestinal type is more common and it’s associated with Helicobacter pylori infection, tobacco smoking, achlorhydria, chronic gastritis, and dietary nitrosamines, such as smoked foods.
This type of adenocarcinoma typically appears on the lesser curvature of the antrum and it tends to grow as a nodular, polypoid, well-demarcated mass that projects into the stomach lumen.
If it becomes ulcerated, it looks like a large, irregular ulcer, with heaped-up edges that can cause upper gastrointestinal bleeding.
Histologically, well-differentiated cancer means that it resembles intestinal or columnar cells, which form glandular formations.
Alternatively, diffuse type of adenocarcinoma can appear in any part of the stomach, and it’s related to genetic mutations of the CDH1 gene, which is a tumor suppressor gene that codes for a membrane adhesion molecule called E-cadherin.
Normally, E-cadherin helps epithelial cells stick to one another, but it also controls the progression of the cell cycle.
When E-cadherin isn’t working properly, cells detach and start dividing uncontrollably, making it way more aggressive than the intestinal type.
For your exam, it’s important to remember that diffuse type of adenocarcinoma often infiltrates large areas of stomach wall; and that it can cause gastric linitis or linitis plastica, a condition where the stomach wall grow thick and hard, and looks like a leather bottle.
Histologically, there are signet ring cells that do not form glands. These signet ring cells are scattered throughout the connective tissue and the cytoplasm has giant mucin-filled vacuole that pushes the nucleus to the edge of the cell.
Now, early symptoms of gastric carcinoma include malaise, loss of appetite and dyspepsia, while later symptoms include epigastric pain, nausea, vomiting, and weight loss.
They could also have acanthosis nigricans, which is a rare feature of gastric carcinoma that involves darkening of the skin, typically at the axilla and other skin folds.
Another thing to look for is the Leser–Trélat sign, which is an abrupt appearance of multiple pigmented skin lesions, called seborrheic keratoses.
The most common site of metastasis of gastric carcinoma is the liver, but it can also spread to the peritoneum and lungs.
For your exam, it’s important to remember that complications of gastric cancer also include metastasis to lymph nodes, such as metastasis to the left supraclavicular node, also known as Virchow’s node.
Alternatively, metastasis to periumbilical region results in the formation of subcutaneous mass called the Sister Mary Joseph nodule.
In women, the bilateral metastases to the ovaries cause a particular tumor called Krukenberg tumor, which has abundant signet ring cells; while Blumer shelf tumor represents metastasis into the caudal portion of the peritoneal cavity, called the pouch of Douglas.
Factors that influence survival rate in individuals with gastric cancer include depth of invasion through the gastric wall and metastasis to regional lymph nodes.
Moreover, the prognosis for gastric adenocarcinoma that has extended beyond the submucosa is poor, less than 10% 5-year survival; while the prognosis for gastric adenocarcinoma that is confined to the mucosa and submucosa is good, more than 90% 5-year survival.
Other less common types of gastric tumors include lymphomas, carcinoid tumors, and leiomyosarcomas. Diagnosis is made by endoscopy and biopsy, while an X-ray with barium contrast and abdominopelvic CT are used for further evaluation.
Finally, the definitive treatment for stomach cancer is gastrectomy.All right, as a quick recap. GERD is a condition caused by a transient lower esophageal sphincter relaxation, which causes symptoms such as retrosternal chest pain, heartburn, regurgitation, and dysphagia.

Review27:51–30:11

Barrett’s esophagus is a premalignant condition which develops when there’s a chronic exposure of the lower part of the esophagus to acidic stomach content, which is especially common in individuals with GERD.
Next, there are two types of esophageal cancer: adenocarcinoma, which typically affects the lower third of the esophagus, and squamous cell carcinoma, which typically affects the upper two-thirds of the esophagus.
Next, there are two types of gastritis. Acute gastritis, which is common in individuals who drink alcohol or take daily NSAIDs, is caused by an imbalance between mucosal defenses and the acidic environment of the stomach.
Chronic gastritis, on the other hand, can be autoimmune, which affects the body and fundus of the stomach; and it’s characterized autoantibodies against H+/K+ ATPase on parietal cells and intrinsic factor.
The more common cause is Helicobacter pylori-associated chronic gastritis and it usually affects the antrum of the stomach.
Next, we have Ménétrier disease, which is a type of gastritis that features hyperplasia of gastric mucosa and subsequent hypertrophy of gastric folds, also known as gastric rugae.
Peptic ulcers refer to chronic lesions in areas exposed to gastric acid and peptic juices and they are typically caused by Helicobacter pylori infection.
Next, there’s Zollinger-Ellison syndrome, which is a condition that features one or more gastrin-secreting tumors that ultimately lead to the formation of treatment-resistant and recurrent peptic ulcers, which are typically located at the distal duodenum and jejunum.
Finally, the most common type of gastric cancer is adenocarcinoma. There are two types of gastric adenocarcinoma: intestinal, or well-differentiated adenocarcinoma which is usually located on the lesser curvature of the antrum; and diffuse, or undifferentiated adenocarcinoma, which can appear in any part of the stomach and cause linitis plastica.
Now back to our case. Shawn complained about substernal chest pain and heartburn that are aggravated typically after coffee, heavy meals or during times of stress.

Summary30:11–31:03

Also, he mentions a sour taste in his mouth and pain at night when he is lying in bed. So, based on his clinical symptoms and history, we can say that Shawn has a classic GERD presentation, so we don’t need further diagnostic testing, such as endoscopy or x-ray with barium contrast.
We could order additional diagnostics if we suspect GERD complications like Barret’s esophagus or esophageal adenocarcinoma.
As far as treatment goes, lifestyle changes, such as eating small servings and avoiding heavy food, coffee, alcohol, and smoking should be recommended.
It’s also important to start medical therapy too, which consists of antacids, H2 receptor antagonists,