Gastritis, Gastric Cancers, and Submucosal Tumors: Gastritis and Gastric Cancers: Acid and Atrophy

0:00Welcome to Board Pearls. This is episode one of two of the Gastritis, Gastric Cancers, and Submucosal Tumors chapter, in the Stomach and Small Bowel Disorders module. This episode covers the stomach lining before cancer and the stomach that makes too much or too little acid. A woman with autoimmune atrophic gastritis shows where the damage is, why her iron deficiency came years before B12 deficiency, how to biopsy so the pathologist can make the call, and what to replace and watch for. A man with intestinal metaplasia after H. pylori shows how infection becomes cancer, how the damage is staged, and who needs surveillance. A man with Zollinger-Ellison syndrome shows how a gastrinoma is proven and found, and how multiple endocrine neoplasia type one, MEN1, changes treatment. And a woman with Menetrier disease has giant folds with the opposite acid picture.

0:56Here's the first patient. A fifty-eight-year-old woman with Hashimoto thyroiditis on levothyroxine has had iron deficiency anemia on and off for six years, never explained. A colonoscopy was normal, and oral iron helped only partly. Now she has numbness and tingling in her feet and is unsteady in the dark. Her hemoglobin is ten point two, with a mean corpuscular volume of one hundred eight. The smear shows hypersegmented neutrophils. Her B12 is low, and methylmalonic acid and homocysteine are high.

1:26Iron deficiency for years, then B12 deficiency with nerve damage, in a woman with Hashimoto thyroiditis, points to autoimmune atrophic gastritis with pernicious anemia. One anatomic fact explains the entire disease. In autoimmune gastritis, the immune system destroys parietal cells, which live in the body and fundus of the stomach. The antrum is spared.

1:49Parietal cells make both acid and intrinsic factor, so losing them causes three things at once. There's no acid. There's no intrinsic factor, so B12 isn't absorbed. And iron absorption falls, because acid is needed to convert dietary ferric iron to the ferrous form the duodenum absorbs.

2:08The spared antrum explains the rest. The antral G cells still make gastrin. Normally acid switches them off through somatostatin, and with no acid that brake is gone, so gastrin rises and stays high. Chronically high gastrin stimulates the enterochromaffin-like cells in the body. Over years they become hyperplastic, and some form small type one gastric neuroendocrine tumors, NETs.

2:35The cancer risk is real but smaller than once thought. A smaller number of patients develop intestinal metaplasia and adenocarcinoma, though the cancer risk in pure autoimmune gastritis without H. pylori is lower than once thought. Her anemia, her high gastrin, and any tumor found are all consequences of the same lesion.

2:54That lesion also explains why her story unfolded in this order. The iron deficiency came first, years earlier, because poor iron absorption starts as soon as acid falls. Liver B12 stores last two to five years, so that deficiency appears only when they run out. That's why unexplained iron deficiency in an older patient without H. pylori is a typical first presentation of autoimmune gastritis. Nobody thought of her stomach, because a normal colonoscopy seemed to close the case.

3:24Now her B12 has run out, and it shows in her blood and her spinal cord. She has a megaloblastic anemia, with a high mean corpuscular volume, MCV, hypersegmented neutrophils, and high methylmalonic acid and homocysteine. She also has subacute combined degeneration of the spinal cord. The dorsal columns are damaged, so she loses vibration and position sense, which is why she's unsteady in the dark, when she can't use her eyes to compensate. The corticospinal tracts can be damaged too, causing brisk reflexes and an upgoing toe.

3:58Her Hashimoto thyroiditis is a clue as well, because autoimmune gastritis clusters with other organ-specific autoimmune diseases. They're thyroiditis, type one diabetes, vitiligo, and Addison disease. A thyroid history in a patient with macrocytic anemia suggests the diagnosis.

4:15Proving it starts with biopsies taken the right way. At endoscopy, her gastric body looks pale and smooth, with loss of the rugal folds, while the antrum looks normal. Biopsies are taken separately from the antrum and the body and labeled separately, because the diagnosis depends on showing atrophy of the body with a spared antrum, and a single unlabeled jar can't show that. The standard Sydney protocol takes two from the antrum, two from the body, and one from the incisura.

4:42Her biopsies confirm the pattern. They show atrophy of the body, with the acid-producing glands replaced by metaplastic lining, plus lymphocytes and hyperplastic enterochromaffin-like cells. The antrum is normal.

4:58Blood tests support the biopsies. Anti-parietal cell antibodies target the alpha and beta subunits of the proton pump and are present in most patients, so they're the sensitive test. Anti-intrinsic factor antibodies bind intrinsic factor either at its B12 binding site, type one, or at its ileal receptor binding site, type two. They're present less often but are more specific.

5:24The other markers reflect the atrophy and the spared antrum. Fasting gastrin is very high. Pepsinogen one, made by the chief cells of the body, is low, and so is the ratio of pepsinogen one to two, both serologic signs of body atrophy. Hers show both antibodies positive, a very high gastrin, and a low pepsinogen one.

5:45One more test is essential and often forgotten. It's H. pylori, by breath test or stool antigen, because the long-term cancer risk in autoimmune gastritis is much higher when H. pylori has also been at work. Hers is negative.

6:00Her very high gastrin can suggest a gastrinoma, and the gastric pH settles it. In autoimmune gastritis the stomach makes no acid, so the gastric pH is high. In Zollinger-Ellison syndrome the stomach is flooded with acid, so the pH is low. It's the same gastrin with the opposite pH, and the third patient in this episode shows the other side.

6:22Treatment replaces what she's lost, because nothing reverses the atrophy. B12 can be replaced by injection, intramuscular cyanocobalamin one thousand micrograms weekly for one to two months, then monthly for life. It can also be given by mouth at high dose, one to two thousand micrograms daily. Oral B12 works without intrinsic factor because at that dose a small fraction is absorbed by mass action, bypassing the intrinsic factor pathway. She chooses injections.

6:53Her iron needs a different approach than usual. Iron is replaced by mouth, with ferrous sulfate, or intravenously, with iron sucrose or ferric carboxymaltose, when absorption is impaired or oral iron fails. Without acid, oral iron is poorly absorbed, which explains her six years of partial response. Thyroid function is checked at diagnosis. Her risk of autoimmune thyroid disease is raised, but her thyroid cancer risk isn't, and it's actually lower than in the general population.

7:20Over the years, the high gastrin and the atrophic lining set what to watch for. Endoscopic surveillance every three to five years looks for type one neuroendocrine tumors, and for intestinal metaplasia or dysplasia that would need closer follow-up, with shorter intervals once a tumor has been removed. Type one tumors over one centimeter are removed endoscopically, and smaller ones are watched. Gastrectomy for the tumor alone is never the answer, because it doesn't remove the gastrin drive.

7:49Her tumor type is the reassuring one. Type one tumors make up about eighty percent of gastric neuroendocrine tumors, and most are biologically silent. They're small, often multiple, sit in the body and fundus on a background of atrophy, and have a low risk of malignancy. They secrete histamine rather than serotonin, which the liver clears, so they don't cause carcinoid syndrome, and distant spread is uncommon.

8:11A different tumor would change the plan. A gastric neuroendocrine tumor with a normal gastrin is very different, aggressive, and treated like adenocarcinoma. And if her biopsies find intestinal metaplasia, it's staged the same way as after H. pylori gastritis, as the next patient shows.

8:30At her diagnostic endoscopy, a four-millimeter polyp in the body was a type one neuroendocrine tumor, so it's watched. Six months later, on monthly B12 injections and intravenous iron, her hemoglobin is normal. Her feet still tingle, but she's steadier.

8:47The second patient's atrophy comes from infection, and it's further along the road to cancer. A fifty-two-year-old man who emigrated from Guatemala twenty years ago has a year of dyspepsia. He has no alarm features, but because of where he grew up and because his father died of stomach cancer, he has an endoscopy. Sydney protocol biopsies show active H. pylori gastritis, with intestinal metaplasia in both the antrum and the body. The metaplasia is the incomplete, colonic type. He smokes, and his diet is heavy on salted and processed meat.

9:20He has H. pylori gastritis with intestinal metaplasia, a precancerous condition, and his management depends on where he sits on the path from infection to cancer. Intestinal-type gastric adenocarcinoma develops in steps. Chronic active gastritis comes first, then atrophic gastritis, where gastric glands are lost, then intestinal metaplasia, where gastric lining is replaced by intestinal-type cells, then dysplasia, then cancer. He's at intestinal metaplasia, past atrophy and not yet at dysplasia.

9:52Years of injury from the bacterium drive each step, and several factors set the pace. CagA strains cause more inflammation and carry higher risk. Host genes for inflammatory cytokines, such as interleukin one beta and tumor necrosis factor alpha, change how fast a person progresses. Smoking, a high-salt diet heavy in processed meat, and a diet low in fruit and vegetables add to it.

10:17Where the infection sits decides which path it takes. Infection confined mostly to the antrum raises gastrin and acid and causes duodenal ulcers. Infection that spreads across the body damages parietal cells, acid falls, and that pattern moves toward cancer. His metaplasia in both antrum and body is the second pattern.

10:38Diffuse-type adenocarcinoma, the signet ring type, doesn't follow these steps. It arises from stomach lining that isn't atrophic, through loss of the adhesion protein E-cadherin. That's why it's the type linked to inherited CDH1 mutations. A father with diffuse-type cancer at a young age would raise hereditary diffuse gastric cancer instead.

11:00His first treatment is eradication. The infection is treated at every step, because eradication removes the ongoing injury and slows progression. But once metaplasia exists, eradication lowers the cancer risk without bringing it back to that of someone never infected. In a large American cohort followed for ten years, treated patients had a lower gastric cancer rate than untreated ones, but still a clearly higher rate than people never infected. That gap is why surveillance is added for some patients.

11:27He takes optimized bismuth quadruple therapy for fourteen days, and a breath test six weeks later, with his proton pump inhibitor, PPI, held, confirms cure. A persistent infection would have kept driving the process.

11:41His diagnosis widens who else gets tested. His household members should be offered testing, and his siblings and children should be tested too, because first-degree relatives of someone with gastric cancer are on the testing list. The twenty twenty-four American College of Gastroenterology guideline also tests everyone with autoimmune gastritis and everyone with a premalignant gastric condition: atrophy, intestinal metaplasia, or dysplasia.

12:08Whether he also needs surveillance depends on how much of his stomach is affected, which is why the biopsies had to come from both antrum and body. The Operative Link on Gastritis Assessment, OLGA, stages atrophy. The Operative Link on Gastric Intestinal Metaplasia assessment, OLGIM, stages intestinal metaplasia. Each runs from zero to four, combining severity in the antrum, including the incisura, with severity in the body. OLGIM is increasingly preferred because pathologists agree on intestinal metaplasia more reliably than on atrophy. A patient with biopsies only from the antrum can't be staged at all.

12:50The stage decides surveillance. Stages zero and one are low risk and need no surveillance. Stage two is intermediate. Stages three and four mean extensive atrophy or metaplasia with a meaningfully higher cancer risk, and they need surveillance endoscopy about every three years.

13:07His biopsies also had to be read against a mimic that isn't on this path. Reactive, or chemical, gastropathy shows foveolar hyperplasia with a corkscrew look and very little inflammation, usually in the antrum, from bile reflux or nonsteroidal anti-inflammatory drugs, NSAIDs. It isn't a step toward cancer, and the treatment is to remove the exposure.

13:31Beyond the stage, risk modifiers can move a stage two patient into surveillance. They're Asian or Hispanic ethnicity, immigration from a country where gastric cancer is common, a family history of gastric cancer, incomplete rather than complete metaplasia, and metaplasia involving both antrum and body. Complete metaplasia looks like small-bowel lining, while incomplete metaplasia looks like colonic lining and carries higher risk.

13:58His metaplasia is moderate in both antrum and body, an OLGIM stage of three, which alone means surveillance, and he has nearly every modifier. He needs surveillance endoscopy every three years. Mild, complete metaplasia limited to the antrum with no modifiers would need no surveillance at all, and eradication and a test of cure would be the whole plan. The extent, type, and stage decide, not the word metaplasia.

14:26His surveillance exams have to be done well. Each is a careful examination of the whole stomach with high-definition white light and narrow-band imaging, and targeted biopsies of anything suspicious. The goal is to find dysplasia or early cancer while it can be removed endoscopically. About four in five early gastric cancers cause no symptoms or only ulcer-like dyspepsia, so surveillance can't wait for symptoms.

14:51What surveillance finds early can be removed through the scope. A differentiated, non-ulcerated early cancer under two centimeters, confined to the mucosa or submucosa, without lymphovascular invasion, can be removed by endoscopic mucosal resection or submucosal dissection in selected cases. His first surveillance exam, three years later, shows stable metaplasia and no dysplasia. One of his siblings is positive and treated.

15:20The third patient's stomach makes far too much acid, not too little. A forty-four-year-old man has had three duodenal ulcers in four years, despite H. pylori eradication confirmed by a negative breath test, and he takes no NSAIDs. His latest endoscopy shows an ulcer in the bulb, another in the third part of the duodenum, grade C esophagitis, and thickened gastric folds. He's had chronic watery diarrhea for a year, and it improves when his PPI dose is raised. His sister had kidney stones and a parathyroid operation.

15:53Recurrent ulcers after confirmed eradication, with no NSAIDs, raise suspicion of a gastrinoma. So do multiple ulcers, ulcers beyond the duodenal bulb, ulcers that recur despite standard treatment, ulcers with secretory diarrhea or severe esophagitis, and a personal or family history of MEN1. He has all of them.

16:17He has suspected Zollinger-Ellison syndrome, and its mechanism explains each finding. A gastrinoma, a neuroendocrine tumor in the duodenum or pancreas, secretes gastrin without feedback control. The constant gastrin enlarges the parietal cell mass and drives huge acid output, which overwhelms the defenses of the duodenum and jejunum, so ulcers appear far beyond the bulb, and it burns the esophagus. Gastrin's growth effect thickens the gastric folds.

16:46His diarrhea has two causes, both from the acid. Part comes from the sheer volume of acid entering the small bowel. Part is fat malabsorption, because acid inactivates pancreatic lipase and precipitates bile salts. That's why raising his PPI dose helped.

17:04Proving it starts with a test whose conditions matter. The first test is a fasting serum gastrin with a gastric pH, measured together and off PPI for at least seven days when safe, because PPIs raise gastrin two- to three-fold on their own. In a patient with a severe ulcer or recent bleed, stopping acid suppression is dangerous. Then the diagnosis is made with imaging and a measured high basal acid output instead.

17:30The two numbers are read together. A gastrin over one thousand picograms per milliliter with a gastric pH under two is diagnostic. A high gastrin with a pH over two means the stomach makes no acid, as in the first patient, and is not Zollinger-Ellison syndrome however high the gastrin. A gastrin between about one hundred ten and one thousand, with acid present, is inconclusive and needs a secretin test.

17:55The secretin test works because gastrinoma cells respond backward. Secretin normally suppresses gastrin release from ordinary G cells, but gastrinoma cells respond paradoxically, and gastrin goes up. After two units per kilogram of intravenous secretin, a rise of more than one hundred twenty picograms per milliliter within ten to fifteen minutes diagnoses a gastrinoma. Milder high gastrin from a PPI, from H. pylori with G-cell hyperplasia, or from partial atrophy shows a flat or falling response.

18:26He has no recent bleed, so his PPI is held for a week. His fasting gastrin is four hundred fifty, with a gastric pH of one point five. After secretin, his gastrin rises by more than three hundred. He has Zollinger-Ellison syndrome.

18:42Next the tumor has to be found, and most hide in one region. Most gastrinomas lie in the gastrinoma triangle. It's bounded above by the junction of the cystic and common bile ducts, on the outside by the second and third parts of the duodenum, and on the inside by the neck and body of the pancreas. About seventy percent are in the duodenum, usually small and often multiple, and the rest are in the pancreas, usually single and larger.

19:08Each imaging test finds a different kind of tumor. Computed tomography, CT, or magnetic resonance imaging, MRI, finds larger pancreatic tumors and liver metastases. Gallium sixty-eight DOTATATE positron emission tomography with CT, PET-CT, a somatostatin receptor scan, is the preferred functional imaging. It has replaced the older octreotide scan and is better at seeing small duodenal-wall tumors. Endoscopic ultrasound is the most sensitive test for tumors inside the pancreas. Venous sampling after secretin is kept for tumors that hide from everything else.

19:47His sister's history matters before treatment, because about a quarter of gastrinomas occur in MEN1. MEN1 is autosomal dominant and involves parathyroid hyperplasia causing hyperparathyroidism, pituitary adenomas, often prolactinomas, and pancreatic or duodenal neuroendocrine tumors. It's checked with calcium, parathyroid hormone, and pituitary imaging. His calcium and parathyroid hormone are both high. His DOTATATE scan shows several small duodenal nodules and no liver disease. He has MEN1.

20:20His treatment has two goals in parallel, and acid control comes first, because the acid is what injures him. It's a high-dose PPI, often two to three times the usual reflux dose. It's titrated to a basal acid output under ten milliequivalents per hour with an intact stomach, under five after gastric surgery, and under one with severe reflux esophagitis, as he has.

20:42Tumor treatment depends on whether the disease is sporadic or part of MEN1. A sporadic, localized gastrinoma is explored surgically for cure. The surgeon opens the duodenum and feels its wall, because small duodenal tumors are often missed on imaging. Resectable tumors are found in up to seventy percent of sporadic cases, and about thirty percent achieve long-term cure.

21:07His MEN1 changes the surgical plan. In MEN1 the duodenal tumors are essentially always multiple and surgery rarely cures them, so treatment is mainly acid suppression, with surgery for tumors over about two to two and a half centimeters, which carry a higher risk of spread. And in MEN1 the parathyroids are fixed first, because high calcium itself stimulates gastrin release. Normalizing calcium lowers gastrin and acid output, often substantially.

21:40He has a parathyroidectomy, stays on a high-dose PPI, and his duodenal tumors are followed with imaging. Metastatic disease would be treated with somatostatin analogs such as octreotide or lanreotide, lutetium one seventy-seven DOTATATE radionuclide therapy, and everolimus, sunitinib, or chemotherapy for progression.

22:02The last patient has thick gastric folds too, but with low acid. A fifty-year-old woman has giant folds in the body of her stomach, sparing the antrum, plus leg swelling, weight loss, and a serum albumin of two point one. Her acid output is low. That's Menetrier disease. The cause is overproduction of transforming growth factor alpha, which acts on the epidermal growth factor receptor of the surface mucus cells.

22:28That signal explains all her findings. The surface mucus cells multiply into giant folds while the acid-producing glands shrink, so acid falls. The overgrown cells pour protein-rich mucus into the stomach, and that protein-losing gastropathy explains her low albumin, edema, and weight loss. Diarrhea, dyspepsia, and occult bleeding can also occur. The gastrinoma patient's folds come with high acid, while hers come with low acid and protein loss.

22:58Her diagnosis needs a deep biopsy, because the lesion is in the foveolar layer and ordinary forceps biopsies often don't reach. Endoscopic ultrasound shows a thick mucosa with cystic glands and helps exclude cancer. The biopsy shows foveolar hyperplasia with cystic dilation, atrophy of the acid and chief cell glands, and little inflammation.

23:20Other causes of giant folds are excluded before the label. They're Zollinger-Ellison syndrome, lymphoma, linitis plastica, lymphocytic gastritis, and amyloid, and gastric varices can be mistaken for folds. H. pylori is tested, because it can cause a Menetrier-like picture that resolves with eradication. In children, cytomegalovirus causes a self-limited version.

23:45Her treatment blocks the signal that drives the disease. Cetuximab, an antibody against the epidermal growth factor receptor, reduces the hyperplasia and protein loss and is the preferred medical treatment, with albumin and a high-protein diet for support. A PPI helps symptoms but not the disease. Gastrectomy is for refractory protein loss, severe symptoms, or high-grade dysplasia, because Menetrier disease raises the risk of gastric cancer.

24:13Here are the traps the boards set in these patients. Autoimmune gastritis is missed in an older patient with unexplained iron deficiency. Unlabeled gastric biopsies can't show antral sparing. H. pylori isn't left unexcluded. Oral B12 can work without intrinsic factor. A high gastrin isn't a gastrinoma when the stomach makes no acid. And a small type one tumor doesn't go to gastrectomy.

24:38The metaplasia traps follow. Antrum-only biopsies can't stage metaplasia. Eradication doesn't erase cancer risk, and the test of cure isn't forgotten. Stage three or four isn't left without surveillance, and stage one without modifiers isn't surveyed. And first-degree relatives of a gastric cancer patient are tested.

24:58The gastrinoma and fold traps close the list. Gastrin isn't measured on a PPI, and the PPI isn't stopped after a recent bleed. The secretin test isn't skipped for intermediate values. Multiple MEN1 duodenal tumors aren't operated on for cure, and the gastrinoma isn't treated before the hyperparathyroidism. And Menetrier disease isn't confused with the high-acid folds of a gastrinoma.

25:24So, start to finish. Autoimmune gastritis destroys body parietal cells and spares the antrum: no acid, no intrinsic factor, poor iron and B12 absorption, and high gastrin that drives type one neuroendocrine tumors. Iron deficiency usually comes years before B12 deficiency.

25:42Diagnose it with separately labeled antral and body biopsies, antibodies, high gastrin, and low pepsinogen one, and exclude H. pylori. Replace B12 and iron, screen the thyroid, and survey every three to five years.

25:59Intestinal-type gastric cancer develops through gastritis, atrophy, metaplasia, and dysplasia, while diffuse type arises through E-cadherin loss. Eradicate H. pylori and confirm cure. Stage with antral and body biopsies using OLGIM, and survey stage three or four, or a lower stage with risk modifiers, about every three years with high-definition imaging.

26:23Suspect Zollinger-Ellison syndrome with multiple or post-bulbar ulcers, recurrence, diarrhea, severe esophagitis, or MEN1. Gastrin over one thousand with pH under two is diagnostic, and intermediate values need secretin. Localize with DOTATATE PET and endoscopic ultrasound, control acid with a high-dose PPI, resect sporadic tumors, and in MEN1 treat the parathyroids first.

26:52Giant body folds with low acid and protein loss are Menetrier disease, treated with cetuximab or gastrectomy.

27:00Episode two is the tumors of the stomach: gastric adenocarcinoma, lymphoma, neuroendocrine tumors, and gastrointestinal stromal tumors, GIST.

27:12For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode one of two of chapter seven, and I'll see you in the next one.