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Journal of Advanced Pharmaceutical Research. 2012, 3(3), 49- 57. Review paper

Gastric Cancer: An Overview Trilochan Satapathy*, Prasanna kumar Panda University department of Pharmaceutical sciences, Utkal University, Vanivihar, Bhubaneswar, Odisha, India *

Corresponding author E-mail: [email protected]; Mob: +91-7898369287 Received: 17 May, 2012; Accepted: 03 Jun, 2012

ABSTRACT Despite marked decreases in incidence over the last century, particularly in developed countries, Gastric cancer (GC) is still the second leading cause of cancer death worldwide. It has complex pathogenetic mechanisms with multiple carcinogenic processes implicated, and is only moderately sensitive to chemotherapy and radiation. Accurate staging for gastric cancer is possible with the availability of sophisticated imaging studies, endoscopic ultrasound, and laparoscopy. Surgery remains the gold standard for the cure of loco regional disease. However, in most countries, the diagnosis is made at an advanced stage, and the 5-year survival for surgically resectable disease stays far below 50%. The efficacy of chemotherapy and/or radiation therapy in addition to surgery has been actively studied over the last 30 years. Postoperative chemo radiation is the standard of care in high-risk patients with resected primary disease. Chemotherapy has yielded better results than best supportive care for metastatic gastric cancer and also improves quality of life. The last decade has seen newer agents used alone or in combination, with promising results. Frequent consumption of fruits, vegetables, and whole grains has been associated with a reduced risk of stomach cancer in the majority of case-control studies of these factors; however, prospective studies have been less consistent. The purpose of this review is to address the disease characteristics, etiology and risk factors associated with gastric cancer. Keywords: Gastric cancer, H.Pylori, pathogenesis, diagnosis

INTRODUCTION

Underneath is the submucosa; then is the layer of muscle;

Gastric cancer (GC) is very common and is the second

next is the subserosa. The outer layer is the serosa.

leading cause of cancer deaths worldwide. Approximately

Gastric cancers are malignancies arising in any part of

65% of gastric cancer patients present with locally

stomach. Most gastric cancers arise in the antrum, the

advanced or metastatic disease, and the majority will

distal third of the stomach. The predominant site of

have systemic disease at some time during the course of

gastric cancer occurrence has changed over the last 30

their illness. The emergence of new chemotherapy agents

years (Gonzalez et al., 2002; Ladero et al., 2002; Yasui

and

increasing

et al., 2001; Yamasita et al., 2002; Alexandar et al.,

knowledge of biological pathways underlying GC and the

1993; Powell et al., 1990). A large number of tumors

ability to predict which patients or tumors will respond to

involving the proximal stomach and gastro-esophageal

which treatment, may lead to improved GC patient

junction have been found. The lesser curvature of the

outcomes. Targeted therapies have emerged as a new

stomach is more frequently involved than the greater

hope in cancer management during recent years. (Meza-

curvature. Several different types of cancer can occur in

Junco and Sawyer, 2012).

the stomach. Adenocarcinoma, which starts in the

The stomach wall is divided into three major areas:

glandular cells, is the most common cancer of the

fundus, corpus, or body, and antrum and it has five

digestive tract and histology accounts for 90-95% of all

layers: the inner lining (the mucosa) contains glands.

gastric malignancies. It can spread to nearby lymph nodes

targeted

therapies,

together

with

(LN) and other areas of the body, such as the liver,

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ISSN: 2229-3787

pancreas, colon, lung, and ovaries. Other types of

Atrophic gastritis (AG) is a histopathological entity that is

malignancy in the stomach are sarcoma arising from the

characterized by chronic inflammation of the gastric

cells of the muscle layer, and more common, lymphoma

mucosa with loss of gastric glandular cells and

arising in the B and T cells of the lamina propria. The

replacement by intestinal-type epithelium, pyloric-type

latter two types of malignancies have different prognosis

glands, and fibrous tissue. Atrophy of the gastric mucosa

and require different management than adenocarcinoma.

is the endpoint of chronic processes, such as chronic

In this review we will concentrate in types, etiology,

gastritis associated with Helicobacter pylori (H. pylori)

Pathophysiology, risk factors, Diagnosis, treatment for

infection, other unidentified environmental factors, and

gastric cancer.

autoimmunity directed against gastric glandular cells

Types of stomach cancer:

(Yashimura et al., 2000). There is evidence from animal

The cells that form the tumor determine the type of

model that nitrosamine plays a role in developing

stomach cancer. Cancers arising from the stomach can be

malignancy.Achlorhydria in atrophic gastritis allows

broadly classified into 4 types, each of which has vastly

bacterial colonization of the stomach, most extremely in

different treatment strategies and prognostic implications.

places where overgrowth may cause nitrate reduction and

These include:

transform the nitrate, which exist in many foods to

Cancers that begin in the epithelial surface of stomach

potentially develop carcinogenic N-nitroso compounds.

(Carcinomas):

This occurs more often in antrum gastritis with intestinal

Majority of the carcinomas arising in the stomach are

metaplasia and non-typical proliferation. The course of

adenocarcinomas, contributing to nearly 90% of all

gastritis is rather long and gastric cancer is believed to

gastric malignancies. These tumors arise from the

develop slowly over many years (Stockbruegger, 1985).

glandular cells that line the inside of the stomach.

Gastric polyps

Cancer

that

begins

in

immune

system

cells

Classic studies and the majority of textbooks on gastro-

(lymphoma):

intestinal pathology indicate that although adenomatous

The walls of the stomach contain a small number of

polyps (Park and Lauwers, 2008) have a high malignant

immune system cells that can develop cancer. Lymphoma

potential and are frequently associated with synchronous

in the stomach is rare.

gastric

Cancer that begins in hormone-producing cells

transformation is very low for hyperplastic gastric polyps

(carcinoid tumours):

and is virtually absent in sporadic fundic-gland polyps

Hormone-producing cells can develop into gastric

(FGPs) (Ming, 1977) as a conse-quence, the diagnosis of

carcinoids. Carcinoids of the stomach are rare.

an adenomatous gastric polyp may trigger inclusion of the

Cancer that begins in nervous system tissues:

patient into an endoscopic surveillance program, whereas

A gastrointestinal stromal tumor (GIST) begins in

only limited follow-up is generally proposed for patients

specific nervous system cells found the stomach. GIST is

with diagnoses of hyper- plastic polyps, inflammatory

a rare form of stomach cancer.

malignant

Gastric polyps other than adenomatous polyps display molecular alterations that may lead to neoplastic

Six different pathological disorders have been described as increasing the risk for malignancy in the stomach. The have

of

studies contest this long-held management approach.

Precancerous lesions of stomach

processes

risk

polyps, or FGPs. (Stolte, 1995) However, molecular

(Mayoclinic.com)

Disease characteristics:

following

adenocarcinomas,

been

implicated

progression, and might carry unknown risks of malignant transformation.

as

precancerous lesions. Chronic atrophic gastritis

Gastric ulcer

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Some gastric cancers are considered to transform from

chronic atrophic gastritis than in normal controls. Bile

gastric ulcers, but with a low rate, 1-5% in China.

acid salt is known to be harmful to gastric mucosa and the

Cancerous degeneration of ulcer was small and the

damage becomes more severe with the increase of bile

epithelial regeneration at the ulcer’s edge and benign

acid salt concentration and prolongation of exposure.

fusion of the muscularis mucosa with the muscularis

Therefore, it can be suggest that the bile acid salt in the

propria were very common. The cancerous tissue

gastric juice is one of the carcinogenic factors (Xu, 1992).

extending to node metastasis was rare. Therefore, the

Pernicious anemia

cancerous tissue down to the submucosa was found at the

Because atrophic gastritis develops over a long period of

margin but not at the base of the ulcer. These patients

time, it is typically found later in life. Years of ongoing

should be thought seriously, especially if they are more

inflammation from the condition result in the gradual

than 45 years old, the symptoms of gastric ulcer are

wasting away (atrophy) of the stomach lining. In turn, the

persistent 1 month after treatment. These findings that

stomach produces less gastric acid. People with atrophic

conform well to Hauser’s criteria blood test are positive.

gastritis usually have no symptoms, although some may

These results suggest that multiple biopsies should be

experience stomach pain, nausea, vomiting or weight

taken from the edge of chronic ulcers. The most distinct

loss. In a few cases, patients may also develop pernicious

feature of malignant ulcer was the lack of cancerous

anemia, the inability to absorb vitamin B-12 from the

infiltration and muscular residue in the scar tissue of ulcer

gastrointestinal tract. This can lead to dementia and an

base. The existence of this type of ulcer clinically and

increased risk of stroke and other health problems in

patho morphologically supports the viewpoint that gastric

older patients if left untreated. There are few reports of

cancer ulcer can undergo malignant change (Zhao, 1992).

pernicious anemia in Chinese patients and does not play a

Remnant Gastric Cancer

significant role as a predisposing cause of gastric cancer

Remnant gastric cancer is generally defined as cancer that

in China (Au et al., 1998; Zuidema, 1996).

has developed in the remnant stomach 5 years after

Epidemiology:

gastrectomy. However, in many recent reports, remnant

Stomach cancer incidence is known to increase with age

gastric cancer has been defined as cancer that has

with the peak incidence occurring at 60-80 years. Cases

developed

partial

in patients younger than 30 years are very rare (Theuer et

gastrectomy regardless of the disease or the operative

al., 1996, Nakmura et al., 1999). In India, the age range

methods used for gastrectomy. With the development of

for stomach cancer is 35-55 years in the South and 45-55

the

partial

years in the North. The disease shows a male

gastrectomy for benign disease is on the decrease, and so

preponderance in almost all countries, with rates two to

remnant gastric carcinoma that develops after surgery for

four times higher among males than females (Jemal et al.,

benign diseases is also on the decrease. Nonetheless, on

2011, Yeole, 2008).Gastric cancer can develop both in

account of performing regular endoscopic examination,

the proximal and the distal region. Distal gastric cancers

the rate of detecting early gastric cancer has recently

predominate in developing countries, among blacks, and

increased, and so the long-term survival after surgery has

in the lower socio-economic groups. Dietary factors and

increased.

As a consequence, remnant gastric cancer

Helicobacter pylori (H. pylori) infection are major risk

after partial gastrectomy for malignant diseases is on the

factors for the development of distal tumors. Proximal

increase. (Ohashi et al., 2007).

tumors are more common in developed countries, among

Cholecystitis

whites, and in higher socio-economic classes. The major

It was found that both the content of various kinds of

risk factors for proximal cancers are gastro esophageal

biliary acid salt and pH value of gastric juice were much

reflux disease and obesity. Distal tumors continue to

in

the

medication for

remnant

stomach

treating gastric

after

ulcer,

higher in patients with gastric cancer, gastric ulcer, and

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ISSN: 2229-3787

predominate in Japan in contrast to the increasing

Etiology:

prevalence of proximal tumors in the rest of the world

Gastric cancer, of all cancers, is the end result of the

(Crew and Neugut, 2006)

interplay of many risk factors as well as protective

Geographic distribution

factors. Genetic and environmental factors are likely to

The steady decline in the incidence and mortality of

play a role in the etiology of the disease. Several factors

stomach cancer in most affluent countries has been

are suspected to play a role in gastric carcinogenesis,

attributed to changes in dietary pattern, food storage, and

including the effects of diet, exogenous chemicals,

control of H. pylori infection. The incidence of gastric

intragastric synthesis of carcinogens, genetic factors,

cancer varies in different parts of the world with highest

infectious agents, and pathological conditions in the

incidence rates documented in Eastern Asia, Eastern

stomach (such as gastritis). According to Correa, there is

Europe, and South America, while North America and

evidence from pathology and epidemiology studies that

Africa show the lowest recorded rates (Jemal et al, 2011;

gastric carcinogenesis develops with the following

Jemal et al 2007; Goldstein et al., 2004). Stomach cancer

sequential stages: chronic gastritis; atrophy; intestinal

is the fifth most common cancer in Europe with 159 900

metaplasia; and dysplasia. The initial stages of gastritis

new cases and 118 200 deaths reported in 2006 (Jackson

and atrophy have been linked to excessive salt intake and

et al., 2009). The population of Linxian, China is known

infection with H pylori (Correa, 1992).

to have one of

Environmental and other factors involved in

the highest rates of oesophageal/gastric

cardia cancer in the world (Qiao et al., 2009). In India, the incidence of gastric carcinoma is higher in the southern and north-eastern states with Mizoram recording an age-adjusted rate of 50.6 and 23.3 for men and women respectively

(Dikshit

et

al.,

2011,

Sharma

and

Radhakrishnan, 2011). A recent assessment of 556 400 deaths due to cancer in India in 2010 based on a nationally representative survey found that stomach cancer with a mortality rate of 12.6% is the second most common fatal cancer (Dikshit et al., 2012). Significant variations in the incidence of gastric cancer have been observed between different ethnic groups living in the same region; African-Americans, Hispanics and Native Americans are affected more than Caucasians in the United States. High frequency of gastric cancer has been documented in Maoris of New Zealand (Parkin, 2004). However, the geographical distribution of gastric cancer cannot be ascribed to racial differences alone. For example, natives of Japan and China living in Singapore have higher rates than their counterparts in Hawaii. Furthermore, people who migrate from high incidence areas such as Japan to low-incidence regions such as the United States were found to have reduced gastric cancer

the susceptibility of gastric cancer: Several

epidemiological

evidences

indicate

that

environmental factors play an important role in gastric carcinogenesis.

The

fact

that

immigrants

exhibit

incidence rates similar to those of their country of origin has led researchers to accept exogenous influences such as environment and diet. The investigation from China showed that the risk factors of gastric cancer were living in high incidence area for a long period, low economic income, low consumption of fresh vegetables and fruits and animal protein, high intake of sweet potato and ink fish and salted meat, eating and drinking too much at one meal and mental injury, and a family history of gastric cancer. High intake of grains and low intake of animal fat and proteins appear to be associated with a decreased risk. Diets rich in vitamins A and C are associated with low risk for gastric cancer. Controversy exists over the role of nitrates found in soil-grown foods, drinking water, and prepared foods. Because refrigeration and a high intake of ascorbic acid inhibit the formation of nitrates, it is postulated that the presence of these factors may account for decreasing gastric cancer. Neither smoking tobacco nor drinking alcohol has been demonstrated to

risk (Howe et al., 2006, Parkin, 2004).

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ISSN: 2229-3787

increase the risk of gastric carcinoma (Huang, 2003; El-

An analysis of participants in a large European cohort

Omar et al., 2001).

study showed a significant association between gastric

Helicobacter pylori

cancer and meat consumption, principally in men and

H. pylori represent one of the most common human

women infected with the bacteria H. pylori, according to

infections, although its prevalence varies widely across

the March 1, 2006, issue of the Journal of the National

different countries. A progressive decrease has been

Cancer Institute. The risk of gastric cancer is greater

reported, at least in high socio-economic regions (Malaty,

among lower socioeconomic classes. Migrants from high-

2007). Since its discovery in 1984, H. pylori has been

to low-incidence nations maintain their susceptibility to

recognized

upper

gastric cancer, while the risk for their offspring

gastrointestinal diseases, such as peptic ulcer disease,

approximates that of the new homeland. These findings

gastric adenocarcinoma and primary gastric B-cell

suggest that an environmental exposure, probably

lymphoma (Suerbaum and Michetti, 2002). H. pylori

beginning early in life, is related to the development of

infection is a strong and well-established risk factor for

gastric cancer, with dietary carcinogens considered the

gastric cancer and has been classified as a group of

most likely factors (Sathian, 2012). A healthy lifestyle

carcinogen by the International Agency for Research on

(not smoking, not consuming excess alcohol, avoiding

Cancer (Fuccio et al., 2010). Several pathogenic

obesity and maintaining a good dietary intake of fiber,

pathways suggesting how the infection could increase the

fruit and vegetables) is associated with reduced risk of

risk of gastric cancer have been proposed, but it is

esophageal and gastric cancer and should be encouraged.

thought that long-term chronic inflammation represents

Tobacco

the primary mechanism (Naumann and Crabtree, 2004).

Tobacco smoking increases the risk of squamous cancer

H. pylori is specifically adapted to survive in the hostile

of the esophagus approximately nine fold compared with

acidic gastric environment and the colonization of the

age and sex matched controls. It also increases the risks

stomach by H. pylori results in the development of

for esophagogastric junction cancer and gastric cancer,

gastritis in virtually all infected subjects. The attachment

though to a lesser extent. It is not clear whether smoking

of the bacteria to the epithelial cells induces an

is

inflammatory response resulting in the recruitment of

(Lagergren et al., 2000, Engel et al., 2003).

neutrophils

Alcohol

as

a

major

followed

by

cause

B

of

and

several

T

lymphocytes,

a

risk

factor

for

esophageal

adenocarcinoma

macrophages and plasma cells, most of which generate

Squamous cancer of the esophagus and gastric cancer are

large amounts of reactive oxygen or nitrogen species

associated

(Zhang et al., 1996), implicated in epithelial cell damage

consumption does not appear to be a risk factor for

and carcinogenesis (Wang et al., 2005).

adenocarcinoma of the esophagus or for cancer at the

Dietary habits:

esophagogastric junction. (Lagergren et al., 2000,

Dietary habits have been implicated in the development

Bagnardi et al., 2001).

of

Inheritance

gastric

cancer.

Long-term

ingestion

of

high

with

alcohol

consumption.

Alcohol

concentrations of nitrates in dried, smoked, and salted

Gastric cancer shows familial clustering, indicating that

foods appears to be associated with a higher risk. The

family history is a risk factor. Environmental factors

nitrates are thought to be converted to carcinogenic

shared by family members may explain much of this

nitrites by bacteria. Other theories explain how certain

clustering effect in gastric cancer and may also contribute

chemicals are formed in meat that is cooked using high-

to the familial risk of esophageal cancers. Inheritance

temperature methods, such as pan frying or grilling, and

almost certainly has a role in the risk of developing both

describe the results of research on the relationship

squamous and adenocarcinoma of the esophagus.

between consumption of these chemicals and cancer risk.

Familial gastric cancer, for example due to E-cadherin

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ISSN: 2229-3787

gene mutation, is also recognised but overall, heredity

modifications (i.e. scoring and staining), allow reliable

makes only a very small contribution to the occurrence of

identification of patients who can derive life-prolonging

gastric and esophageal cancer (Hemminki and Jiang,

benefits

2002- Dhillon et al., 2001).

methodologies used for determining HER2 status:

Diagnosis of stomach cancer:

1. Immunohistochemistry (IHC) can show how much of

Several types of tests are used in the diagnosis of stomach

the HER2 protein is present in the tumour sample.

cancer. The main methods are:

2. In-situ hybridization methods (FISH, CISH, SISH)

Endoscopy – this is where a long tube with a tiny light

measures the amount of the HER2 gene in tumour cells

and camera is swallowed so that it can enter the stomach

IHC should be used as primary testing modality. Cases

and small bowel to allow the clinician to investigate any

with very high levels of HER2-overexpression (IHC 3+

abnormalities.

or IHC2+/FISH+) are eligible for Herceptin treatment.

Barium swallow or barium meal – this is where a white

All other cases with lower HER2-overexpression levels

liquid (barium meal) is given to the patient to be

should be re-tested with ISH (preferably SISH or CISH).

swallowed. This liquid shows up on X-ray, so once

Patients with ISH positive results are eligible for

swallowed, the doctor can watch the barium on the X-ray

Herceptin therapy (Hofmann, 2008, Vancutsem, 2009).

screen as it passes through the stomach.

CONCLUSION

Management of stomach cancer

H. pylori infection continues to play a key role in acid-

Treatment of stomach cancer depends on several factors

related disorders,

including the size, location and extent of the tumour, the

colonization with the bacterium invariably results in the

stage of disease, the patient’s age and overall health.

outcome of chronic gastritis. Subsets of patients have a

Current

4/5

progression of the chronic gastritis to either ulcer or

chemotherapy and palliative care. Surgery is the only

cancer. India has a high prevalence of H. pylori infection.

curative therapy for stomach cancer. In advanced stages,

There are limited studies from India to explain the

chemotherapy is, in most cases, the only treatment option

etiology of gastric cancer. Given the high prevalence

associated with a poor average survival of around 7-10

of H. pylori, trials are required to judge the potential

months.

benefit for its eradication to reduce gastric cancer.

HER2-positive stomach cancer

Providing medication for H. pylori eradication has to be

Human epidermal growth receptor 2 (HER2) is a protein

further evaluated. More research is required not only to

found on the surface of a cell which, when present in

develop suitable screening test, but also to demarcate

more than the usual amounts (called HER2 over

high-risk population and the effect of primary prevention

expression) triggers aggressive and abnormal tumour

programs. There is a need to clearly understand the risk

growth, as well as rapid development of metastases.

associated with diet for any kind of prevention. Properly

Studies have found that 16-22% of stomach tumours

designed

show high levels of HER2 (termed HER2-positive

interaction with H. pylori, diet and tobacco use are

stomach cancer). (Hofmann, 2008; Park et al., 2006).

required to understand etiology of gastric cancer. As

HER2 testing in stomach cancer

stomach cancer is one of the common cancers in India,

HER2 testing at first diagnosis is crucial to ensure

studies are required to understand the etiology and

appropriate stomach cancer treatment. Validated methods

prevention of gastric cancer. This may help in

and scoring systems to ascertain HER2 status in breast

responsiveness

cancer are well established and recent evidence has

helicobacter regimens.

shown that these same techniques, with some minor

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