Gastric Cancer

By: Zeinab Helmy

Professor of Internal Medicine
Faculty of Medicine, Al- Azhar University
Contents:
• Anatomy, histology and physiology.
• Incidence.
• Mortality.
• Etiology and risk factors.
• Prevention, screening.
• Classification (TNM).
• Pathology, pathogenesis.
• Clinical features.
• Diagnosis and staging.
• Management of gastric cancer.
• Metastasis
• Survival
Anatomy and histology of the stomach:
The stomach is a large, muscular, and hollow organ located on the left side of
the upper abdomen.
It is anatomically divided into 4 main
parts:
1. Cardia.
2. Fundus.
3. Body.
4. Pylorus.
Histologically it divided into 3 parts:
cardia*, fundus* and pylorus*.
[fundus and body are histologically
identical). M S M S
1. Mucosa: It has three parts:
A. Epithelial tissue: simple columnar
B. Lamina propria: It is a layer of
connective tissue contains blood,
lymphocytic vessels & lymphoid
tissue (lymphocyte to produce
ABs, and macrophages to
phagocytize
foreign material that get through
the epithelium).
C. Muscularis mucosae: two smooth
muscle layers.
Simple columnar epithelial layer had
millions of holes called gastric pits.
Gastric pits connect to gastric glands
and thus allow the glandular
products to be delivered into the
stomach lumen.
2. Submucosa:
It is rich of blood and lymphatics. this layer also contains the submucosal
(Meissner’s) plexus.
Submucosal plexus carries parasympathetic innervation to the blood vessels
and smooth muscle of the stomach wall.
Parasympathetic stimulation is associated with ‘rest and digest’ functions and
therefore, stimulates digestion.
3. Muscularis externa:
It is formed of 3 layers of smooth muscles, outer longitudinal, inner circular, and
innermost oblique.
The myenteric (Auerbach's) plexus lies between the outer longitudinal layer and
inner circular layer, and carrying both sympathetic a and parasympathetic fibers
to the smooth muscle layers.
4. Serosa:
Gastric glands:
There are 3 types of gastric glands found in the stomach:
❖ Cardiac glands & Pyloric glands: predominantly produce mucous
secretions.
❖ Fundic (gastric) glands: present in the fundus/body, gland contain parietal
cells and chief cells, and producing digestive gastric juice.
Cells found in the gastric
glands include:
❖ Mucous neck cells
(foveolar cells).
❖ Chief cells (peptic cell).
❖ Parietal cells (oxyntifc
cells).
❖ G cells.
❖ Enterochromaffin-like
cells (ECLs).
The structure of gastric gland
from fundus or body,
Acid and pepsinogen producing
glands are referred to as
oxyntic glands.
Parietal cells referred as
oxyntic cells.
Chief cell referred as peptic
cell.
Incidence of gastric cancer:
The incidence of gastric cancer in male are two to three times more susceptible
than female.
The incidence is noted that more than 50% of new incidents come up in
developing countries.
Areas with the highest risk for gastric cancer include:
• Central and South America, Eastern Europe and East Asia (China and
Japan).
The low-risk regions include:
• Australia and New Zealand, Southern Asia, North and East Africa and
North America.

The five-year survival rate is mildly good only in Japan.

In Europe, the ratio fluctuates between 10–30%.
The increased five-year survival rate is probably due to early
diagnosis.
The rate of proximal GC is higher in comparison to the distal one.
This trend might be explained by the increased standards of hygiene,
better food conservation, a high intake of fresh fruits and vegetables
and Helicobacter pylori eradication.
Etiology and Risk factors:
Gender: Stomach cancer is more common in men than in women.
Age: There is a sharp increase in stomach cancer rates in people over age 50.
Most people diagnosed with stomach cancer are between 60 & 80 years.
Geography: Stomach cancer is more common in Japan, China, South and East
Europe, and South and Central America.
But less common in North and West Africa, South Central Asia, and North
America.
Helicobacter pylori infection: It seems to be a major cause of stomach cancer,
especially cancers in the lower part of the stomach.
Even so, most people who carry this germ in their stomach never develop
cancer.
Stomach lymphoma: People who have had a mucosa-associated lymphoid tissue
(MALT) lymphoma have an increased risk of getting adenocarcinoma of
the stomach.
H pylori infection is also linked to MALT lymphoma of the stomach.
Diet: An increased risk of stomach cancer is seen in people with diets that have
large amounts of
• Smoked foods.
• Salted fish and meat.
• Pickled vegetables (‫)خضروات مخللة‬.
• Nitrates and nitrites are substances commonly found in cured meats
(‫)اللحوم المعالجة‬.
On the other hand, eating lots of fresh fruits and vegetables appears to lower
the risk of stomach cancer.
Smoking: particularly in the upper portion of the stomach near the esophagus.
The rate of stomach cancer is increased about doubled in smokers.
Obesity: Overweight or obese is a possible cause of cancers of the cardia.
Previous stomach surgery:
Stomach cancers are more likely to develop in people who have had part
of their stomach removed to treat non-cancerous diseases as ulcers.
This might be because:
• The stomach makes less acid, which allows more nitrite-producing
bacteria to be present.
• Bile Reflux from the small intestine into the stomach after surgery
might also add to the increased risk.
Pernicious anemia: People with this disease have an increased risk of stomach
cancer.
Hypertrophic gastropathy (menetrier disease):
In this condition, excess growth of the stomach lining causes large folds
in the lining and leads to low levels of stomach acid.
Type A blood: For unknown reasons, people with type A blood have a higher risk
of getting stomach cancer.
Inherited cancer syndromes: Some inherited conditions may raise a person’s risk
of stomach cancer.
Hereditary diffuse gastric cancer: This inherited syndrome greatly increases the
risk of developing stomach cancer. This condition is rare, but the lifetime
stomach cancer risk among affected people is about 70% to 80%.
Chronic atrophic gastritis.
Intestinal metaplasia: The normal lining of the stomach is replaced with cells
that closely resemble the cells that usually line the intestine.
Gene mutation: are called
Oncogenes: Genes that help cells grow and divide.
Tumor suppressor genes: Genes that help keep cell division under control or
cause cells to die at the right time.
Prevention:
There is no sure way to prevent stomach cancer, but there are things you can do
that could lower your risk.
• Staying at a healthy weight.
• Getting regular physical activity.
• Healthy eating pattern: which includes a variety of colorful fruits and
vegetables and whole grains.
• Avoiding smoking.
• Treating H pylori infection.
• Aspirin: Using aspirin or other non-steroidal anti-inflammatory drugs
(NSAIDs) seems to lower the risk of stomach cancer.

Screening and detection:

Screening means testing people for early stages of a disease before they have
any symptoms.
There are two main modalities for gastric cancer screening:
1. Upper endoscopy:
Upper endoscopy allows for direct visualization of the gastric mucosa
and for biopsies to be obtained.
2. Contrast radiography:
Double-contrast barium radiographs with radiography can identify
malignant gastric ulcers, infiltrating lesions, and some early gastric
cancers. But, about 50 % false-negative of cases with barium studies.
In early gastric cancer, the sensitivity of a barium study may be as
low as 14 %.
The barium study may be superior to upper endoscopy in patients
with linitis plastica. It is a type of adenocarcinoma. It spreads to the
muscles of the stomach wall and makes it thicker and more rigid. It
more obvious on the radiographic study, while the endoscopic
appearance may be relatively normal.
 • Classification:

There are several classification systems used for stomach cancer

around the world.
A. Histological classification:

• Adenocarcinomas:
It is developed in the epithelial mucosal cells of the stomach.
• Lymphoma:
It is a cancer of the lymphoid tissue in the stomach.
• Gastrointestinal stromal tumors (GISTs):
Arsis from a special cell found in the lining of the stomach called interstitial
cells of Cajal (ICCs). These tumors may develop through the digestive tract,
but about 60 to 70 % occur in the stomach.
• Leiomyosarcomas:
Tumors of smooth muscle of wall of stomach.
• Carcinoid tumors: Typically start in the hormone-producing cells of the
stomach. These tumors usually do not spread to different organs.
 B. Lauren’s classification:

This classification is based on how the gastric tissue looks and behaves when
examined under a microscope.

This system is most often used to describe how adenocarcinoma tumors (the
most common type of stomach cancer) look and behave.

Lauren’s classification divides adenocarcinoma of the stomach into 2 main types:

Intestinal type Diffuse type

• Environmental
• Not related to blood group
• Gastric atrophy, intestinal metaplasia
• Associated with H. pylori
• Mainly distal (body- antrum)
• Well differentiated tumor cells
• Gland formation.
• Grow slowly.
• Is metastasizing slower
• Hematogenous spread
• Male ˃ female.
• Occurs in old age group.
• Familial
• Blood group A
• Associated with GERD
• Not associated with H. pylori
• Mainly proximal (GEJ- cardia)
• Poorly differentiated tumor cells.
• Tend to scatter throughout the stomach.
• Aggressive.
• Is metastasizing rapidly
• Transmural and lymphatic spread
• Female = male
• Younger age group.
C. Macroscopic classification:
Stomach cancer Grading:
• Grading describes how the cancer cells look compared to normal, healthy cells.
• The grade of cancer is used to help predict how the cancer will grow and to plan
treatment and prognosis.
• Some types of cancer, the grade is used to stage a cancer.
• The pathologist gives stomach cancer a grade from 1 to 4 (The lower the
number, the lower the grade).
• The grade is a description of the differentiation of the cancer cells.
• Differentiation is how the cancer cells look and behave compared to normal cells.

Low grade:

• Means that the cancer cells are well differentiated.

• They look and act much like normal cells.
• Lower grade cancer cells tend to be slow growing and are less likely to
spread.

High grade:

• Means that the cancer cells are poorly differentiated, or undifferentiated.

• They look and act less normal, or more abnormal.
• Higher grade cancer cells tend to grow more quickly and are more likely to
spread.

Important of grading:

• Knowing the grade gives the healthcare team an idea of how quickly the
cancer may be growing and how likely it is to spread.
• This helps them plan the treatment.
• The grade can also help the healthcare team predict how you might respond
to treatment.
Staging of gastric cancer (often called the extent of cancer):
• The stomach is made up of different layers of tissues. The stage often
depends on which layer the tumor has grown into.

Staging describes or classifies a cancer based on:

1. when first diagnosed.

2. which parts of the organ have cancer.
3. whether the cancer has metastasized.
4. where it has spread.
Why are cancers staged?
The stage of cancer is used to:
• Help plan treatment.
• Predict a prognosis.

TNM staging system:

T: is usually given as a number from 1 to 4.

• It describes the size of the primary tumor.
• It also describes if the tumor has grown into other parts of the organ with
cancer or tissues around the organ.
• A higher number means that the tumor is larger.
• It may also mean that the tumor has grown deeper into the organ or into
nearby tissues.
N:
• It describes whether cancer has spread to lymph nodes around the organ.
• N0 means the cancer hasn’t spread to any nearby lymph nodes.
• N1, N2 or N3 means cancer has spread to lymph nodes.
M:
• It describes whether the cancer has spread to other parts of the body
through the blood or lymphatic system.
• M0 means that cancer has not spread to other parts of the body.
• M1 means that it has spread to other parts of the body.
T1a= Mucosa

T1b= Submucosa

T2= Muscularis propria

T3= Serosa

T4= infiltration

Types of TNM staging:

Solid tumor cancers may be given both a clinical and pathologic stage.

Clinical stage (It is given before treatment):

• Based on the results of exams and tests (imaging) done at the time of diagnosis.
• Doctors often choose a treatment based on the clinical stage.
• The clinical stage is shown by a lowercase “c” before the letters TNM.

Pathologic stage:

• It is based on the results of tests and exams done when the cancer is found and
what is learned about the cancer during surgery and when looking at the tissue
after it is removed by surgery.
• It gives more information about the cancer than the clinical stage.
• The pathologic stage is shown by a lowercase “p” before the letters TNM on a
pathology report.
 The stage of cancer doesn’t change:
• Once a person is told what stage the cancer is, the stage of cancer doesn’t change.
• If a stage 2 cancer comes back (recurs) after it is treated, it is still stage 2 cancer
that has recurred.
• And if the cancer has spread to a distant part of the body after it is treated, it is
still stage 2 cancer but it is metastatic.
• This is important because the stage at diagnosis is used to study survival
statistics and treatments for specific stages of cancer.

Restaging:
• Restaging helps doctors plan further treatment when cancer comes back or
gets worse after the initial treatment.
• Restaging doesn’t mean that a stage 2 cancer changes to a stage 3 cancer.
The stage of a cancer doesn’t change.
• But a tumor initially staged as a T2 may be described as a T3 or T4 if the
cancer has grown larger or grown into nearby tissues.
• This may be found with further tests after treatment. When restaging is done,
it is shown with a lowercase “r” before the letters TNM on a medical report.

• stage 0: carcinoma in situ, a precancerous change.

• stage 1: the tumor is usually small and hasn’t grown outside the organ.
• stages 2 and 3: the tumor is larger or has grown outside of the organ it
started in to nearby tissue.
• stage 4: the cancer has spread through the blood or lymphatic system to a
distant site in the body (metastatic spread).
Clinical Features:

• The symptoms of gastric cancer are frequently vague and non-specific.

• The patients often presenting at an advanced stage.
• The common presenting symptoms include dyspepsia (particularly if new
onset or not responsive to simple PPI treatment),
• Dysphagia, early satiety, vomiting, or melena.
• Intolerance of meat.
• Non-specific cancer symptoms (anorexia, weight loss, or anemia).

On examination:

• Clinical signs are usually absent, especially in the early stages, however
an epigastric mass may be felt in late-stage disease.
• Troisier sign is the presence of a palpable left supraclavicular node (Virchow
node) and is considered a sign of metastatic abdominal malignancy (typically
gastric).
• Other signs of metastatic disease include hepatomegaly, ascites, jaundice,
or acanthosis nigricans.
Investigations:
A. Laboratory Tests:
• Full blood count and liver function tests.
• Serological markers:

B. Imaging:
• Urgent upper GI endoscopy, allowing for the direct visualization of any
malignancy present and subsequent multiple biopsies (up to 7) taken.

NICE guidelines recommend referring for an urgent upper GI endoscopy, for any
patients presenting with new-onset dysphagia or aged > 55 years presenting
with weight loss and either upper abdominal pain, reflux, or dyspepsia.

• Abdominal CT.
• Endoscopic ultrasound.
Biopsies from suspected gastric malignancies should be sent for:
• Histology – for classification and grading of any neoplasia present
• CLO test – for the presence of H. Pylori
• HER2/neu protein expression – this will allow for targeted monoclonal
therapies if present.
Treatment:

1. Nutritional support, both pre- or post-treatment, via a NG (nasogastric) or RIG

(radiologically-inserted gastrostomy) tube.
2. The curative treatment:

A. Surgery.
The aim of surgery is to achieve loco-regional control by removing the tumor and
its local lymph nodes. The type of operation performed depends on the region of
the malignancy:
• Proximal gastric cancers – total gastrectomy
• Distal gastric cancers (antrum or pylorus) – subtotal gastrectomy
• Patients with early T1a tumors (tumors confined to the muscularis
mucosa) may be offered an Endoscopic Mucosal Resection (EMR).
B. Peri-operative chemotherapy.
3. Palliative Management:

This may include:

✓ Chemotherapy:
It is a systemic treatment, meaning it can treat tumors throughout his body.
Chemotherapy drugs can help shrink tumors, relieve symptoms, and prolong
life.
✓ Radiation therapy:
It is a targeted treatment, meaning it can be directed at specific tumors. It
can help shrink the tumors, stop bleeding, and relieve pain.
✓ Supportive care.
✓ Stenting (for patients who have gastric outlet obstruction secondary to an
obstructing cancer).
✓ Palliative surgery (usually distal gastrectomy or bypass surgery (a gasro-
jejunostomy) can be used when stenting fails or is not available.
✓ Targeted drug therapy or immunotherapy:
Targeted drug therapy can be used to treat advanced stomach cancer. These
drugs attack specific characteristics of the cancer. Some of these are:
• Imatinib (Gleevec), for stromal tumors
• Ramucirumab (Cyramza), for advanced stomach cancer when other
treatments aren’t effective
• Regorafenib (Stivarga), for stromal tumors
• Sunitinib (Sutent), for stromal tumors
• trastuzumab (Herceptin), for HER2-positive tumors
• Pembrolizumab (Keytruda) is an immunotherapy drug used to treat
stomach cancer that has returned or spread in people who have tried
but didn’t respond to or stopped responding to two or more types of
chemotherapy.
Complications:
Gastric outlet obstruction, iron-deficiency anemia, perforation, and
malnutrition.

Surgery:

✓ A subtotal gastrectomy is a procedure in which the surgeon removes the

part of the stomach that has tumors. This can help ease bleeding and
pain.
✓ If tumors in the lower part of the stomach are preventing food from
passing, gastric bypass surgery may be an option.
✓ In this procedure, part of the small intestine is attached to the upper
part of the stomach, bypassing the tumors, and allowing food to flow out
of the stomach.
 ✓ Sometimes, stomach cancer makes it difficult to eat. If that happens,
a feeding tube can be surgically inserted through the skin into the
stomach so you can get the nutrients you need.

Q. 1

Which of the following vitamin deficiency is found in patients with gastric cancer?

A Vitamin C

B Vitamin B 12

C Vitamin A

D Vitamin D
Definitions:

Achlorhydria refers to absence of HCl production in the stomach .

Defaecation is a reflex act involving colon, rectum, anal sphincters and

many striated muscles (diaphragm, abdominal and pelvic muscles).
The motor pathway is the pelvic nerves. Defaecation implies a
temporal release of anal continence brought about by a r eflex. The
coordinating centre is in the sacral spinal cord.

Enterogastrones are enterogastric inhibitory hormones liberated from

the duodenal mucosa by acid chyme (ie, cholecystokinin: CCK,
gastric inhibitory peptide: GIP, secretin, somatostatin, neuroten sin
and vasoactive intestinal peptide: VIP).

Haematemesis is defined as vomiting of whole blood or blood clots.

Incretins are hormones, which increase insulin secretion from the b-

cells of the pancreatic islets much earlier and to a greater extent, than
when the blood glucose concentration is elevated by intravenous
infusion (GIP, glicentin, glucagon-like peptides-1 and -2).

Intrinsic, enteric nervous system refers to the large number of

neuronal connections in the gut wall, in particular the submucosal
Meissner plexus, which regulates the digestive glands, and
the myenteric Auerbach plexus, primarily connected with gut motility.

Malabsorption describes the condition resulting from inefficient

absorption of nutrients by the gastrointestinal tra ct.

Melaena is defined as passage of dark tarry stools (coal -black, shiny,

sticky, and foul smelling).

Migrating motor complex refers to a gastric sequence of events, where

contractions occur each 90 min during fasting. There is a quiet period
(I) followed by a period of irregular contraction (II), and culminated
with a peristaltic rush (III) accompanied by increased gastric,
pancreatic and biliary secretion.
NANC neurons are non-adrenergic, non-cholinergic postganglionic
neurons, which liberate gastrin-releasing peptide (GRP) to the gastrin
producing G-cells.

Nitric oxide (NO) is a possible neurotransmitter between the

preganglionic and the NANC postganglionic neurons.

Paracrine secretion is the release of signal molecules to neighbour

cells.

Peptide hormone families are groups of hormones that

exhibit sequence homology: They possess a common amino acid
sequence, such as the gastrin family, which has sequence homology in
their terminal penta-peptide. Peptide
hormones have autocrine and paracrine functions in the
gastrointestinal tract.

Peristalsis is a propagating contraction of successive sections of

circular smooth muscle preceded by a dilatation. The dilatated
intestinal wall is drawn over its content in this reflex mechanism,
which transports the content aborally and is called the law of the gut.

Segmentation divides the small intestine into many segments by

localised circular smooth muscle contractions. Segmentation mixes
the intestinal content and propagate it at a slow rate, which allows
sufficient time for digestion and absorption.

· Slow waves (basic electrical rhythm) are slow gastrointestinal

depolarisation’s occurring at a frequency of 3 -18 per min. The slow
waves change the resting membrane potential of smooth muscles from
-50 to -40 mV.

· Spike potentials are periodic fast waves of depolarisation that

most often follow a slow wave, and then always initiate gastric
contractions (elicited by a rise in cytosolic [Ca 2+ ]).

· Vaso-active intestinal peptide (VIP) is a vasodilatator in line with

adenosine, ATP, NO. The increased bloodflow increases intestinal
secretion.
Stomach Conditions
• Gastroesophageal reflux: Stomach contents, including acid, can travel
backward up the esophagus. There may be no symptoms, or reflux may
cause heartburn or coughing.
• Gastroesophageal reflux disease (GERD): When symptoms of reflux
become bothersome or occur frequently, they’re called GERD. Infrequently,
GERD can cause serious problems of the esophagus.
• Dyspepsia: Another name for stomach upset or indigestion. Dyspepsia may
be caused by almost any benign or serious condition that affects the
stomach.
• Gastric ulcer (stomach ulcer): An erosion in the lining of the stomach, often
causing pain and/or bleeding. Gastric ulcers are most often caused by
NSAIDs or H. pylori infection.
• Peptic ulcer disease: Doctors consider ulcers in either the stomach or the
duodenum (the first part of the small intestine) peptic ulcer disease.
• Gastritis: Inflammation of the stomach, often causing nausea and/or pain.
Gastritis can be caused by alcohol, certain medications, H. pylori infection,
or other factors.
• Stomach cancer: Gastric cancer is an uncommon form of cancer in the U.S.
Adenocarcinoma and lymphoma make up most of the cases of stomach
cancer.
• Zollinger-Ellison syndrome (ZES): One or more tumors that secrete
hormones that lead to increased acid production. Severe GERD and peptic
ulcer disease result from this rare disorder.
• Gastric varices: In people with severe liver disease, veins in the stomach
may swell and bulge under increased pressure. Called varices, these veins
are at high risk for bleeding, although less so than esophageal varices are.
• Stomach bleeding: Gastritis, ulcers, or gastric cancers may bleed. Seeing
blood or black material in vomit or stool is usually a medical emergency.
• Gastroparesis (delayed gastric emptying): Nerve damage from diabetes or
other conditions may impair the stomach’s muscle contractions. Nausea and
vomiting are the usual symptoms.