is a gastric cancer of well-differentiated neuroendocrine cells associated with endocrine cell hyperplasia.
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An 80-year-old Korean man comes to the office because of abdominal pain, weight loss, and early satiety. He says that he has been experiencing some discomfort in the mid-epigastrium. The pain started approximately a year ago, but he thought it was acid indigestion so he took a proton pump-inhibitor which alleviated his pain. The pain has since worsened and he is now experiencing dysphagia. He has lost 9.1-kg (20-lb) over the past 6 months, is easily fatigued, and unable to perform daily tasks around the house. He has a history of coronary artery disease and hypertension. Physical examination shows tenderness to deep palpation in the mid-epigastrium as well as cachexia. Laboratory findings include anemia with a hemoglobin of 8.0 g/dL and hematocrit of 24% with a mean corpuscular volume of 70 fL. A fecal occult blood test is positive. Which of the following is the most likely diagnosis?
Gastric cancer is when malignant or cancerous cells arise in the stomach.
This cancer can appear in any part of the stomach and it’s classified into adenocarcinoma, lymphoma, carcinoid tumor, and leiomyosarcoma; depending on the type of cells it originates from.
Adeno- means gland; so, adenocarcinoma arises from columnar glandular epithelium.
Lymphoma arises from lymphocytes.
Carcinoid tumor is originated in the G-cells of the stomach.
And leiomyosarcoma arises from smooth muscle cells from the gastric wall.
Gastric cancer is generally considered a poor prognosis cancer, because it doesn't cause specific symptoms until later stages.
The stomach has four regions: the cardia, the fundus, the body, and the pyloric antrum.
There’s also a pyloric sphincter or valve at the end of the stomach, which closes while eating, keeping food inside for the stomach to digest.
Now, the gastric wall is made up of four layers: from the outside in, there’s the adventitia, or serosa; the muscular layer; the submucosa; and the mucosa.
The mucosa comes into direct contact with food, and it also has three layers of its own.
The innermost layer is the epithelial layer and it absorbs and secretes mucus and digestive enzymes.
The middle layer is the lamina propria and it has blood, lymph vessels, and mucosa associated lymphoid tissue, or MALT for short, which are nodules of immune cells called lymphocytes, in charge of eliminating pathogens that could pass through the epithelial layer.
The outermost layer of the mucosa is the muscularis mucosa, and it’s a layer of smooth muscle that contracts and helps with the break down food.
The epithelial layer dips down below the surface of the stomach lining to form gastric pits.
And these pits are contiguous with gastric glands below which contain various epithelial cell types, each secreting a variety of substances.
So for example, foveolar cells, or surface mucus cells, secrete mucus, which is a mix of water and glycoproteins that coats the stomach epithelial cells.
With all of these digestive enzymes and hydrochloric acid floating around, the stomach and duodenal mucosa would get digested if not for this mucus which coats and protects the epithelial cells.
Within the glands, particularly in the body and fundus of the stomach, are parietal cells, which secrete hydrochloric acid to help maintain an acidic pH in the stomach.
There are also chief cells that secrete pepsinogen to digest proteins.
And then there are G cells which secrete gastrin, which has a number of effects, including stimulation of parietal cells to secrete hydrochloric acid.
Now, adenocarcinoma is the most common type of gastric cancer, and it originates in the columnar glandular epithelium.
It is further divided into two subtypes: intestinal, or well-differentiated adenocarcinoma; and diffuse, or undifferentiated adenocarcinoma.
Intestinal type is the most common.
H. pylori releases some virulence factors, such as cagA, that go inside the epithelial cells and cause extensive damage.
When this happens, the normal epithelium of the stomach gets continuously damaged and repaired.
Over time, the stomach cells in the epithelium change and start to resemble intestinal epithelium.
This is called metaplasia, which is when one type of cells in the body changes to resemble cells in another part of the body.
Tumor suppressor genes, which normally code for proteins that stop the cell cycle or promote apoptosis, are the cell cycle’s very own brake pedal, while proto-oncogenes, which normally code for proteins that promote the cell cycle, are the cell cycle’s accelerator pedal.
Mutations can occur in both.
When this happens, metaplastic cells start dividing uncontrollably, and more mutations accumulate with each division.
So eventually, these mutations might make the cells malignant, meaning they gain the ability to invade neighboring tissues and spread to distant sites.
This type of adenocarcinoma typically appears on the lesser curvature of the antrum as a large, irregular ulcer, with heaped up edges.
Histologically, it’s a well differentiated cancer, meaning they resemble normal intestinal cells.
Alternatively, diffuse type of adenocarcinoma can appear in any part of the stomach, and it’s mostly related to genetic mutations in the CDH1 gene, a tumor suppressor gene that codes for a membrane adhesion molecule called E-cadherin.
Normally, E-cadherin helps epithelial cells stick to one another and it also transmits signals that control the progression of cell cycle.
But, when E-cadherin isn’t working properly, cells detach and starts dividing uncontrollably.
This type of adenocarcinoma has an increased ability to spread and invade adjacent structures, so it’s way more aggressive than the intestinal type.
It can appear in any part of the stomach, and it can cause gastric linitis or linitis plastica, where the stomach wall grow thick and hard, and look like a leather bottle.
This is the result of diffuse adenocarcinoma invading the connective tissue of the submucosa, causing it to become thicker and more rigid.
Histologically, there’s signet ring cells scattered throughout the connective tissue, that look, well, like a signet ring, because the cytoplasm has giant vacuoles that push the nucleus to the edge of the cell.
Now, there’s other less common types of gastric tumors like lymphomas, carcinoid tumors, and leiomyosarcomas.
Lymphomas arise mostly from lymphocytes found in MALT, or mucosa-associated lymphoid tissue.
Histologically, it usually appears as diffuse lymphocytes surrounding the normal lymphoid nodules and epithelial cells.
Carcinoid tumor arises in neuroendocrine cells such as the G-cells of the stomach.
It’s a well differentiated tumor, that usually appear as a protruding mass from the mucosa, called polyp.