Gastric cancer – causes, symptoms, diagnosis, treatment, pathology

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Try it free today! 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. In most
cases, it’s caused by the bacteria Helicobacter pylori, or H. pylori for short. H. pylori
releases some virulence factors, such as cagA, that go inside the epithelial cells and cause
extensive damage. The immune system detects this damage and cause an inflammatory response
within the gastric lining, causing gastritis. As long as H. pylori remains in the stomach,
it continues to damage the mucosa, and local inflammation persists, leading to chronic
gastritis. 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. Over time,
these metaplastic cells might accumulate mutations in the genes that are in charge of the cell
cycle and cell division. 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. These cells, more specifically
B-lymphocytes or B-cells, are in charge of recognizing and responding to any pathogen
that crossed pass the epithelial layer. So, a chronic H. pylori infection, for example,
can cause excessive B-cell proliferation, which makes these cells more prone to have
mutations and develop lymphoma. 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. Although
it mainly appears in the stomach, it can also arise in other parts of the digestive tract
like the intestine or the pancreas, which also have G-cells. Finally, leiomyosarcoma
arises from smooth muscle cells from the gastric wall and it’s extremely rare. Under the
microscope, cancerous cells can look like spindle, epithelial, or undifferentiated cells. Complications for gastric adenocarcinoma include
metastasis to the peritoneum; to lymph nodes, like the ones around the umbilicus and the
left supraclavicular node or Virchow’s node; or to distant organs, most frequently the
liver. The bilateral metastases of diffuse adenocarcinoma to the ovaries cause a particular
tumor called the Krukenberg tumor, which has abundant signet ring cells. Other complications are paraneoplastic syndromes,
which are problems caused by the primary tumor on other organs without necessarily being
metastasis. Paraneoplastic syndromes include the Leser-Trélat sign which is seborrheic
keratosis, or brownish spots all over the skin. It results from the stimulation of keratinocytes
by growth factors produced by the gastric cancer cells. Polyarteritis nodosa refers
to inflammation and necrosis of multiple medium-sized arteries, including those that supply the
kidneys and the heart; so they can eventually lead to kidney failure or myocardial infarction.
Now, cancer cells stimulate vascular and inflammatory cells to release tissue factor, which then
activates the coagulation cascade; therefore, there’s an increase in blood coagulability
that leads to thrombosis, or generation of blood clots. Trousseau syndrome consists of
the appearance of migratory thrombosis, in the veins. Finally, if gastric cancer grows
near the gastroesophageal junction, it can cause a stricture that makes it difficult
for food and liquids to pass through from the esophagus into the stomach, which is called
pseudoachalasia syndrome. Generally speaking, risk factors for gastric
cancer include a family history of gastric cancer, smoking, alcohol consumption, and
being obese. Also, the risk for gastric cancer increases with age. Specific risk factors
for the intestinal type of adenocarcinoma include being male, H. pylori infection, having
blood type A, a diet rich in nitrates, nitrosamines, highly-salted foods, pickled or smoked foods,
and conditions such as autoimmune gastritis, and pernicious anemia, and achlorhydria. Autoimmune
gastritis is when the self immune system attacks the parietal cells, causing inflammation.
Pernicious anemia is a condition where there’s decreased production of red blood cells due
to a deficiency of vitamin b12. And achlorhydria means decreased or lack of gastric acid production.
On the other side, there’s protective factors to prevent gastric cancer, and these include
a high intake of fruits, vegetables, fiber, and folate. Initially, gastric cancer can be asymptomatic.
If there are symptoms, they are usually vague like malaise, loss of appetite, and dyspepsia,
which is a burning sensation in the upper part of the abdomen. Once the disease progresses,
the main symptoms include epigastric pain, nausea, vomiting, and weight loss. In addition,
gastric cancer can ulcerate and bleed. If there’s significant blood loss, this can
cause anemia. Also, the accumulation of blood in the stomach can cause hematemesis, or vomiting
of blood. This can be bright red blood, or have a dark color like coffee grounds when
the red blood cells has been broken down by gastric acid. Finally, there could be melena
where the discolored blood can also appear in the stool, making it black. Other signs and symptoms include those of
paraneoplastic syndromes: Leser-Trélat sign, polyarteritis nodosa, and Trousseau syndrome.
Acanthosis nigricans is another sign that could be present, and involves darkening of
the skin at the axilla and other skin folds. Sister Mary Joseph sign is a mass around the
belly button caused by metastasis and enlargement of the lymph nodes in that area. Troisier’s
sign refers to an enlarged, hard Virchow’s node, also caused by metastasis. Finally,
if gastric cancer grows near the gastroesophageal junction, there might be dysphagia, or difficulty
swallowing. Diagnosis of gastric cancer is essentially
made with endoscopy, which is when a tube with a camera at the end is placed into the
stomach to directly visualize the tumor and take a biopsy. X-rays with barium contrast
of the upper GI tract can be useful to identify complications like ulcers. And finally, abdominopelvic
CT can be used to evaluate if the cancer has spread to nearby organs or lymph nodes in
order to determine the stage of the tumor. Treatment depends on the stage. For initial
stages, surgery can be performed to treat the cancer. For advanced stages, surgery can
only relieve the pain, called palliative surgery. Chemoradiotherapy after surgery is used to
increase the chance of survival. Unfortunately, the overall survival rate is very low because
gastric cancer is usually diagnosed at very advanced stages. All right, as a quick recap… Gastric cancer
is when malignant or cancerous cells arise in the stomach. It’s classified into adenocarcinoma,
lymphoma, carcinoid tumor, and leiomyosarcoma; although the first one accounts for the majority
of cases. Complications include metastasis and paraneoplastic syndromes like Leser-Trélat
sign, polyarteritis nodosa, and Trousseau syndrome. Risk factors include family history
of gastric cancer, smoking, alcohol consumption, and being obese. H. pylori infection is the
most important risk factor for the intestinal type of adenocarcinoma. Protective factors
include a high intake of fruits, vegetables, fiber, and folate. Early symptoms include
malaise, loss of appetite and dyspepsia. Epigastric pain, nausea, vomiting, and weight loss are
later symptoms. Diagnosis is made with endoscopy and biopsy. X-rays with barium contrast of
the upper GI and abdominopelvic CT are used for further evaluation. The treatment depends
on the stage. For initial stages, surgery can be sufficient. For advanced stages, there’s
palliative surgery combined with chemoradiotherapy.


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