Review Article - (2022) Volume 12, Issue 11
Received: 26-Apr-2022, Manuscript No. EJEBAU-22-13156; Editor assigned: 28-Apr-2022, Pre QC No. EJEBAU-22-13156(PQ); Reviewed: 12-May-2022, QC No. EJEBAU-22-13156; Revised: 10-Oct-2022, Manuscript No. EJEBAU-22-13156(R); Published: 17-Oct-2022, DOI: 10.36648/2248-9215.12.83
Gastric Cancer (GC), also known as gastric adenocarcinoma, or stomach cancer, is one of the most common types of malignant neoplastic cancer and it is a major concern on a global scale as it leads to a significantly higher mortality rate worldwide. It is the third related case of cancer related death. If metastasis occurs at a notable rate the survival rate might drop down to as low as 32%. The occurrence of gastric cancer increases gradually with age, but in most cases (approximately 10% cases) it is diagnosed at the age of either 45 years or younger. Cancer progression takes place in multiple stages. However, a decline in the rate of gastric cancer can be seen, and it can be attributed to the effect of following proper hygienic practices, intake of nutritious diet, eradication of Helicobacter pylori infection etc. These act as primitive measures of prevention. Patients who fall under the high risk category should be diagnosed at an early stage so that proper treatment could be provided. This review article gives brief information about the different classes of GC, symptoms and risk factors associated with the same, and also reflect on the importance of treatments including surgery and therapy.
Gastric cancer; Classification; H. pylori; Risk factors; Symptoms; Treatment; Surgery; Therapy
Gastric Cancer or Gastric Carcinoma (GC) is the fourth common disease in worldwide. It is the second cause of death among many other malignancies across the globe. The stomach is located in the digestive tract in between the esophagus and small intestine. The stomach secretes enzymes and some gastric acids that help in the digestion process. Some intrinsic factors that is required for the absorption of vitamin B12 is also secreted by the stomach. It is lined with epithelial cells that form a mucosal membrane. Sometimes these lining gets infected by causing inflammation known as gastritis which then causes gastric ulcers that eventually leads to gastric cancer. More than 50% of cases are rising in developing countries day by day. This causes a 15-20 fold variation of risk among the highest and lowest populations. countries like East Asia, Eastern Europe, Central and South America have high risk of gastric cancer because of their greater populations meanwhile countries like Southern Asia, North and East Africa, North America, Australia and New Zealand are less prone to the risk [1-5].
Gastric cancers are classified primarily based on their anatomic site as cardiac and non-cardiac. Cancers that develop in the gastric area joining the esophageal-gastric junction is cardiac gastric cancer. Non-cardiac cancer is also called as distal stomach cancer develops in the lower region of the gut. These two types diffuse together to form the intestinal type. Some of the risk factors for gastric cancer involve factors like diet that deals mainly with the consumption of salt, nutrition among fruits and vegetables.
Consumption of preserved and processed food like cans food and meat such as red meat also plays a vital role in increasing the risk of gastric cancer. Later, lifestyle habits have a great impact in stimulating the risk of disease. Habits like smoking and consumption of alcohol has great negative effect in lowering the risk of gastric cancer. Genetic factors have their contribution as well. Sometimes other factors like viral factors, exposure to radiations has also shown to increase the chance of gastric cancer. Infections with Helicobacter pylori have a major effect in causing gastric cancer. Although, this infection is most common among almost all people, it is found to be a greater cause. There are also many other relative factors like history of mucosa associated lymphoid tissue lymphoma, pernicious anemia and any surgeries related to stomach that has taken place previously. The chances increase when there is a first degree family member. Some factors that are found in hereditary gastric cancer (CDH1) where approximately 80% of patients develop gastric cancer. The majority vast of gastric cancers are the non-cardia intestinal type that happens through progression of Atrophic Gastritis (AG) to the intestinal metaplasia that leads to gastric cancer, which is also referred as H. pylori infection. Infection by H. pylori leads to the inflammation of the mucosal membrane of the gut, which results in a condition called atrophic gastritis. It is known as a chronic inflammatory stage which has the ability to develop to gastric cancer. Although this infection is shown to precipitate these cases, 1-3% of the infected people will subsequently grow gastric cancer. Some many other risk factors also involve age, male gender, genetic backgrounds, etc. Recently many markers have been used for detection of gastric cancer. This includes Carcino Embryonic Antigen (CEA), Carbohydrate Antigens (CA)-CA19-9, CA72-4, CA125, CA24-2, etc., pepsinogen and Alpha Feto Protein (AFP) is also used. The sensitivity and specificity of all these markers are quite less. This makes it challenging for early detection of gastric cancer where the patients also experience no symptoms until the disease reaches the advanced stage.
Gastric cancer is known to be a complex, heterogeneous disease that involves multiple genetic and epigenetic alterations. In case of the early gastric cancer, the most recommended treatment is radical surgery with or without perioperative chemotherapy. Some therapies that are targeting the biological molecules are reported to provide protection for patients with overall survival and AGC. Trastuzumab, is a monoclonal antibody for Human Epidermal growth factor Receptor 2 (HER2) is been discovered with chemotherapy as the first line treatment for HER2 positive gastric cancer patients. Ramucirumab, also an anti-Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) has shown as the second line treatment. Immunotherapy has also been proven to elicit an innovative treatment. This treatment is able to reverse tumor immune response escape associated with suppression of the immune checkpoint pathway.
Immunotherapy has been approved for last line treatment for patients with gastric cancer. It has its clinical importance and application with desired outcomes, limitations [6-8].
Classification of Gastric Cancer
Lauren system of classification: The system of classification which is used to classify gastric adenocarcinomas is the Lauren classification (Lauren). Till date it is the most frequently used Gastric Cancer (GC) classification. According to this system of classification, gastric adenocarcinomas are divided into two major classes called intestinal and diffuse.
Further, a third type was also included in this list, known as the indeterminate type which included characterization of the adenocarcinoma which had infrequent histology. These classes differed not only in morphology but also in epidemiology, genetics and the pattern of progression of the disease. The intestinal type is the most common followed by the diffused type and indeterminate type. Intestinal type has an occurrence of 54% and it can be characterized by the formation of glands and there is cohesion between the tumor cells. It is observed more in males as compared to females and the frequency of occurrence is almost two times than that in females. It is more localized in the tantrum. In the intestinal type of gastric cancer, the tumor progression model is well established which thus allows a chance for secondary prevention and early detection. On the contrary, the diffused subtypes of gastric cancer do not show visible gland formation. They are diffusely present in the gastric walls and it infiltrates it. They also show very proper cohesion between cells. Signet ring cell carcinoma is a type included in diffuse subtype. It occurs in only 32% of cases and the occurrence is equal in both genders. Usually, people who suffer from diffuse GC are younger as compared to ones who suffer from intestinal GC. The difference between intestinal type and diffuse type also relies on the basis of the pattern they are caused. The intestinal type is exogenous, meaning that it is caused mainly by environmental factors. The diffuse type is endogenous, which means that it is majorly caused due to genetic and hereditary factors. However, there are evidences that suggest that intestinal subtype is also related with intestinal metaplasia, which is a condition where the cells forming the lines of stomach and intestine are replaced with other sets of cells which resemble the original cells, and it is a pre-cancerous condition. H. pylori infection also plays a private role.
Who system of classification: WHO system of classification was introduced in 2010, and till date it is the most detailed version of classification. It classifies not just gastric adenocarcinoma but all other types of gastric tumours as well.
If a comparison is made between the Lauren and WHO system of classification various subgroups of gastric adenocarcinoma were found, which are tubular, mucinous, papillary and mixed carcinoma. Tubular and papillary carcinoma fall within the intestinal type of stomach cancer and signet ring cell carcinoma and other poorly cohesive carcinoma fall under the Lauren diffuse type. The GC type which is most prevalent is tubular adenocarcinoma, followed by papillary and then comes mucinous type.
Goseki system of classification: The third system of classification is the Goseki system of classification which further divides GC based on the intracellular mucin production and the degree of tubular differentiation and forms four groups. Group 1 includes tubules which are well differentiated and the intracellular mucin is poor. Group 2 includes well differentiated tubules as well, with intracellular mucin rich. Group 3 includes poorly differentiated tubules and poor intracellular mucin. Group 4 includes poorly differentiated tubules with rich intracellular mucin. A prognostic independent value of this system is yet not confirmed and endoscopic or other surgical choices are still insufficient to provide precise treatment for individual patients.
Sub-Classification of Gastric Cancer
Intermittent gastric cancer: Intermittent gastric cancer is sporadic in nature and majorly affects population over the age of 45 years. Genetic factors do not have a major role in this type of GC however; environmental factors are very prevalent.
The patients are usually diagnosed around the age of 60 to 80 years and it affects males more as compared to females. The instances of intermittent GC are two times in males as compared to females, especially in high-risk countries. It encompasses approximately 80% of total GCs.
Early onset gastric cancer: Early onset gastric cancer also known as EOGC, occurs in individuals at 45 years of age or younger. It encompasses approximately 10% of total number of GCs. It acts as a good model to understand the genetic alterations which occur during the gastric carcinogenesis process. In EOGC H. pylori infection plays an important role, however, there is no statistical difference seen in IL1-β polymorphism between old and new patients. Epstein Barr virus causes infection which is seen to be decreased or absent in EOGC patient. These are often diffused, multifocal and majorly observed in females in higher frequency, which might be the cause of hormonal factors.
Gastric stump cancer: Gastric stump cancer or GSC is the cancer that occurs in the gastric remnant after partial gastric resection which is usually caused due to peptic ulcer disease or PUDs. It is observed that GSC occurs after five years of surgery. It represents approximately 1.1 to 8% of total cases of GCs. Gastrostomy acts as a well-established risk factor for GSC and the risk increases to 4 to 7 folds after 15 years of gastrostomy. GSCs seem to be more common in males as compared to females. Gastric remnants are more likely to get infected with EBV and it plays a major role in GSC. H pylori infection also acts as the main agent. The pathogenesis of GSC involves biliary pancreatic reflex, atrophic gastritis, where there is inflammation of gastric mucosa as the gastric cells get changed by fibrous cells or other intestinal sales. There is also chronic inflammation of the mucosa and intestinal metaplasia and dysplasia. Other causes can also include achlorhydria, where there is an absence of HCl production. Bacterial overgrowth also plays a major role. The diagnosis of these patients can be done with the help of endoscopy and biopsy. This disease is preceded by formation of a well-defined lesion and therefore multiple biopsies are recommended. But the benefit to cost ratio of these are yet to be considered.
Hereditary diffuse gastric cancer: It is the case of an autosomal male dominant susceptibility for diffuse GC and it encompasses over 1-3% of all GCs. The range of age for HDGC is around 14-69 years. A weekly differentiated adenocarcinoma penetrates into stomach wall which leads to thickening of the wall without forming a distinct mass. The major criteria seen for HDGC is inherited syndromes which majorly include germline mutation of the CDH1 gene which encodes for e- cadherin. The people who should be screened for HDGC might include two or more first on second degree relative who are diagnosed with diffuse GC before the age of 50, or 3 or more cases of diffuse GC in first or second degree relative irrespective of their age of onset. In HDGC family, patients who show no alterations in CDH1 gene, the clinical importance of other tumor suppressor genes like BRCA, CTNN1, STK11, and ATM etc. should be considered (Figure 1).
Figure 1: Pie chart representing percentage occurrence of different forms of GC.
Helicobacter pylori infection: H. pylori cause gastric cancer by two major pathways, these are direct and indirect pathways. In the direct pathway the bacteria acts on epithelial cells of gastric system by gene mutation and induction of protein modulation. The indirect pathway includes indirect action on gastric epithelium by H. pylori which are caused by inflammation. Studies have shown the importance of gastritis in causing gastric cancer. It is also established that H. pylori directly regulates the function of epithelial cells by bacterial agents, like cagA. These pathways work together for the development of gastric cancer, but the relation between them is still not known (Figure 2).
Recent recollected and potential studies have demonstrated that patients suffering from H. pylori infection are at a greater risk for GC than the ones who are not infected by it (Figure 3).
Figure 2: Direct and indirect actions of Helicobacter pylori on gastric epithelial cells in gastric carcinogenesis.
Figure 3: Pathways of H. Pylori infection leading to gastric cancer.
Indirect action of H. pylori on gastric epithelial cells: Gastric cancer related with H. pylori infection is invariably associated with gastritis and it is found that the risk factor of a patient for gastric cancer is directly proportional to the degree of severity of gastritis, and mainly, chronic atrophic gastritis of the corpus. Few evidences have reflected the fact that Gastric Ulcers (GU) are related with the development of GC; however, the reverse of it is related with Duodenal Ulcer (DU). Patient suffering with DU generally have tantrum predominant gastritis in contrast to corpus predominant gastritis in case of GU. In DU there are instances of little mucosal atrophy which reaches various degrees in GU. Hence, all this data emphasis on the importance of corpus gastritis in the development of GC. Various cell types are involved in H. pylori induced chronic gastric mucosa, mainly, CD4T cells. These CD4T cells can be categorized as TH1 and TH2 types. Their basis of classification is dependent on the secretion of interferon IFN gamma (IFN-γ) by TH1 cells and interleukin-4 (IL-4) by TH2 cells. Due to antigenic stimulation involved in H.pylori infection infected gastric mucosa produces a large amount of IFN- γ and a considerably low level of IL-4. Corpus gastritis and mucosal atrophy cases are boosted due to TH-1 type immune response, and this in return leads to the formation of GU and GC. It was also found that deficiency of IFN-γ causes impairment of development of gastritis by H. pylori infection; however it is enhanced in the absence of IL-4. Hence, the development of gastritis is greatly determined by CD4T cells of TH-1 type and IFN- γ. Apart from T cell infiltration and mononuclear activation, a wide range of proinflammatory cytokines are produced in the gastric mucosa which is a characteristic of H. pylori induced gastritis; few of these cytokines have an important role in cancer development, the most common being IL- 1β. It links gastric inflammation with gastric cancer. The expression of IL-1β is enhanced by H. pylori infection. It serves dual role by acting as an inflammatory mediator by causing enhanced activation of nuclear factor kB (NF-kB) in inflammatory as well as epithelial cells. It also induces hepatocyte growth factor. Thus, in case of GC caused by H. pylori infection IL-1β has a significant role to play. The gastric mucosa has an enhanced production of not just IL-1β but also Tumor Necrosis Factor-α (TNF-α), IL-6, IL-7 and IL-8. IL-1β along with TNF-α plays an important role in enhancement of NF-KB activation. IL-6 and IL-11 quantities are also increased in H. pylori induced gastric mucosa. NF-kB has various roles, including enhanced cyclooxygenase-2 production. Increased production of NF-kB in epithelial, mesenchyme and inflammatory cells causes this effect, which in turn increases the danger of GC in gastric mucosa. When NF-kB acts on epithelial cells they may induce an anti-apoptotic action. Activation of NF-kB enhances production of various cytokines which causes inflammation of gastric cells.
Direct action of H. pylori on gastric epithelial cells: Various in vitro studies using gastric epithelial cells of humans have showed that action of H. pylori is directed on the gastric epithelial cells for modulation of a variety of cellular functions. They modulate and regulate functions like growth of cells, programmed cell death, or cell migration leading to induction of ‘hummingbird phenomenon’ which is characterized by an extremely elongated cell shape. Recent studies highlighted a type 4 based secretion apparatus of bacteria which is encoded by the cagPA1, which is cag pathogenicity island of H. pylori and mediates a lot of vital functions of H. pylori directed on epithelial cells by delivering bacterial agents in the cells and cagA protein uses this structure to enter the cells (Figure 4).
Figure 4: Helicobacter pylori induced intracellular signaling events that are involved in gastric cancer development. AID, activation-induced cytidine deaminase; cagPAI, cag Pathogenicity Island; NF-Kb, nuclear factor-kB; SHP2, Src homology 2 containing protein tyrosine phosphate.
Risk Factors
Evidence shows that stomach cancer is an outcome of a collection of many risk factors also protective factors like environmental, genetic, nutrition, chemical exposure, infections host pathogenic also some pathological conditions.
Dietary Factors
Diet and nutrition are one of the important factors in introducing gastric cancer.
Salt: Salt is been reported to be a risk factor for gastric cancer in 1950. It has influenced human existence since civilization. It has its importance in cultural, socioeconomic in history of mankind. Many control and cohort studies have confirmed the risk of salt consumption in gastric cancer. The higher the level of salt consumption, the higher the risk of cancer. A high salt concentration present in stomach is able to destroy the mucosal barrier which will lead to inflammation and causes damage like diffusing erosion and degeneration. The induced concentration can act by promoting the effect of food derived carcinogens. It is therefore proven that high intake of salt eventually increases the risk of gastric cancer. Those countries where diets are rich in salty and canned foods like Japan has been reported to have high risk of cancer. Preservation of food with salt is considered to be a human practice. The mechanism of salt to be a risk factor of gastric cancer may act synergistically with H. pylori infection associated with changes in viscosity of mucous, expression of cagA that induces inflammation in the epithelium of gut. A study was a total of 628 men with 40-50 years were tested for prevalence H. pylori 474 men were tested positive for IgG antibody against the bacterium. A synergistic effect of H. pylori infection and salt intake has been confirmed in case control studies in countries like Korea and Japan.
Fruits and vegetables: Fruits and vegetables are known to be the rich sources of vitamins, minerals, phytochemicals, carotenoids, etc. they have a protective role against gastric cancer. It is the modulation of xenobiotic metabolizing enzymes especially phases II enzymes. They contribute to the preventive mechanism and antioxidant activity. Sometimes lack of intake of fresh vegetables and fruits has been proven to be a risk factor for gastric cancer. In contrast, increased intake of fruits and vegetables can decrease the risk of gastric cancer. Vegetables and fruits that are rich in carotenoids, vitamin specifically vitamin C, phytochemicals help modulate the xenobiotic enzymes during the process of distribution. These also have many antioxidants that can give prevention against metabolic damage. Vitamin C, referred as Ascorbic acid is a known powerful antioxidant which is found in higher concentrations among all the citrus foods. Some studies have proven that high intake of vegetables and fruits are associated with 37% lower risk of gastric cancer.
Meat: Red meat when taken with grain is rich in saturated fats and have protective fats like Omega-3 that contributes to inflammatory processes that results in increasing the risk of gastric cancer. Excessive consumption of this red meat, smoked meat, salty met and processed meat will eventually stimulate gastric cancer. All meats that are preserved are very rich in N-nitroso compounds. These substances can elicit the same effect as the red meat. Mechanisms carried out on the account of meat consumption increases the production of Nnitro so compounds, heterocyclic amines, polycyclic aromatic hydrocarbons that may increase the risk of gastric cancer.
Coffee and tea: They are the two most consumed beverages but hold bigger risk for gastric cancer. Caffeine, kahweol and cafetal present in the coffee sometimes give a protection.
Lifestyle Factors
Some of the lifestyle factors including attitudes, behaviors, and characteristics says much about their health conditions.
Smoking: Tobacco has proven to increase the risk of gastric cancer; it is indicated as the recent rise of gastric cancer in many developed nations. It has been calculated that 11% of global gastric cancers are caused by smoking. An analysis of 42 studies estimated that smokers have increased risk of gastric cancer 1.5 times higher than non-smokers. Hookah and opium use are also found to be risky for gastric cancer in recent studies. The effect of smoking is dose dependent and is increased in presence of alcohol. Exact mechanisms are unclear but it is found that formation of oxygen radicals and increased apoptosis is associated with smoking progressing gastric cancer.
Alcohol: Alcohol has been proven to increase the risk of gastric cancer, but the effect of amount of consumption is still controversial. The mechanism of alcohol stimulated gastric cancer involves a chronic inflammatory response from some direct effects of toxic metabolites of ethanol and cytokines which impairs the mucosal barriers which increases the absorption of nitrosamines. Some toxins like acetaldehyde, acetate arises from the metabolism of ethanol through enzyme alcohol dehydrogenase and aldehyde dehydrogenase. These can prone to genetic variants that increase level of toxins.
Obesity and physical activity: A study shows that an increase in relative risk of gastric cancer is associated with physical activity. A rising trend in obesity has increased concerns that contribute to cancer. A meta analysis study has proved that 55% increase in gastric cancer is among overweight and obese people.
Radiation
It is one of the unseen risk factors that contribute the gastric cancer. Exposures to radiation especially among uranium miners have a positive effect in increasing gastric cancer. A study from China shows the genetic instability as a result of gamma radiation has induced a chromatid break which has increased the risk of gastric cancer.
Genetic Factors
Mutations of certain inherited genes like GSTM1-null phenotype or CDH1 gene are found to increase gastric cancer. HDGC and loss of CDH1 are also associated with breast cancer, colorectal cancer. Familial Adenomatous Polyposis (FAP) one of the common forms of gastric cancer is an inherited condition caused by germline mutation in the APC gene.
Some 10% of stomach cancer cases are familial in origin.
Genetic factors involved in gastric cancer remain poorly understood, though specific mutations have been identified in a subset of gastric cancer patients. Familial aggregation of gastric cancer is known to occur in approximately 10% of the patients. Epidemiologic studies have shown that in the general population the risk of gastric cancer in first degree relatives with any type of gastric cancer are increased 2–3 fold. As yet, however, in the vast majority of these patients the underlying genetic cause remains unknown
Chromosomal Instability (CIN)
Chromosomal Instability (CIN) is the most common type of genomic instability observed in solid tumors. CIN is characterized by gross chromosomal abnormalities, such as gain or loss of whole chromosomes (aneuploidy) and/or fractions of chromosomes (Loss of Heterozygosis (LOH), amplifications, and translocations. These alterations could also affect the expression of oncogenes, tumor suppressor genes, and other genes, such as genes implicated in digestion, DNA repair genes (genome stability genes), growth regulators, and cell cycle checkpoint control genes, and so CIN has been detected as the most common feature of sporadic gastric cancers and has been reported in up to 84% of gastrointestinal tumors. Numerous DNA copy number variations have been reported, and subgroups with different patterns of DNA copy number alterations have been recognized, which have been associated with age, prognosis, lymph node status, and metastasis. Explored Comparative Genomic Hybridization (CGH) profiles of gastric adenocarcinomas in young and old patients. Familial aggregation of gastric cancer is known to occur in approximately 10% of the patients. Epidemiologic studies have shown that in the general population the risk of gastric cancer in first degree relatives with any type of gastric cancer are increased 2–3 fold. As yet, however, in the vast majority of these patients the underlying genetic cause remains unknown. The most important GC susceptibility gene is CDH1, which accounts for 1-3% of gastric cancers. Predisposing CDH1 mutations have been encountered in about 30% of strictly selected Hereditary Diffuse Gastric Cancer (HDGC) families. Moreover, CDH1 germline mutations may also occur in approximately 7% of patients diagnosed before 50 years of age with tumors exhibiting either a diffuse or a mixed histology. The recognition, surveillance and treatment of CDH1 mutation carriers are extensively described below.
Genetic Counselling and Criteria for CDH1 Mutation Testing
Genetic counseling is an essential component of the management of HDGC. It includes the analysis of the family history of at least three generations and histopathological confirmation of gastric (pre) malignancies. The revised international criteria as established by the International Gastric Cancer Linkage Consortium (IGCLC) to select patients with an increased risk of familial gastric cancer for CDH1 mutation testing are shown. Genetic testing is preferably initiated in an affected relative. In most countries the youngest age at which relatives at risk should be offered testing is set at age 18. Rare cases of gastric cancer before age 18 has been reported, but the overall risk of DGC before the age of 20 is very low.
Helicobacter pylori: It is a gram negative motile, spiral shape bacterium. Our gut is the natural reservoir of H.pylori. Its infection usually occurs in the onset of childhood and the bacterium remains in the host system without any microbial treatment. It gets transmitted from person to person by oral. It is calculated that half the world’s population is colonized with H. pylori and 15% develop gastric cancers. H. pylori is a very genetically diverse bacterium and genotypes associated with the virulence like vacAs 1, vcAm1, cagA. This causes changes in pathology that contributes to development of gastric cancer. Especially cagA positive strains of H. pylori are found more virulent it causes greater levels of inflammation of mucosa layer of the stomach. H. pylori is also shown to reduce acid secretion in stomach and reduces the risk of inflammation in the stomach. A study in Hong Kong has proven that long term use of PPIs (Proton Pump Inhibitors) can increase 2.4 times the risk of cancer that people received eradication therapy. The risk increases is in dose and duration dependent with PPIs (Figure 5).
Figure 5: Pie chart representation of the percentage of the risk factors.
Symptoms of Gastric Cancer
Gastric cancer is mostly asymptomatic that is they do not produce any noticeable symptoms or it may cause only nonspecific symptoms which are specific to only stomach. By the time the symptoms occur, the cancer would probably reach the advanced stage and would have undergone metalized that is spread to other parts of body which is also one of the reasons for poor relative progress.
The symptoms of gastric cancer are divided in two distinctive sections:
• Early stages stomach cancer symptoms.
• Advanced stomach cancer symptoms.
Early Stage Symptoms
It is most common for people to experience no symptoms at an early stage. As the gastric cancer grows and spreads it surely exhibits visible signs and symptoms even in early stages, the symptoms may include:
• Sudden weight loss without context.
• Severe pain in the abdomen or above the belly button area.
• Feeling nauseous along with vomiting.
• Decrease or loss of appetite.
• Severe indigestion and heartburn.
• Feeling very weak and fatigue.
• A feeling of fullness even after consuming small meals.
• Sometimes stool and vomit accompanied with blood.
In countries like United States, most of gastric cancers are not found until they have grown extremely large or the chance of spread to other parts of the body.
Advanced Gastric Cancer Symptoms
All symptoms of the advanced gastric cancer are far more complicated and serious than the early stage symptoms. In the advanced stage, the cancer would have grown and spread it begins to affect the surrounding organs such as liver and large intestine. If the cancer has grown into creating a blockage within the stomach the symptoms maybe,
• Loss of appetite
• Loss of weight significantly
• Vomiting without controls
If the cancer has spread to the liver it leads to Jaundice (yellowing of skin and eyes) and ascites (enlargement of stomach from fluid). The alarm symptoms like these have a diagnostic role in indicating the possible presence but gastric cancer but when referred to a diagnosis, it may suggest the stage and aggressiveness of the cancer and indicate spoor prognosis. The relationship between symptoms and the stage of cancer is always conceivable but when considered the profile of the symptoms in early gastric cancer that are unlike of benign cancer than the advanced gastric cancer. If there is weight loss in less than 40% of patients with early gastric cancer, it is considered as a common feature of the advanced cancer. By a number of 13 studies, weight loss is considered as the prognostic potential symptom of the gastric cancer. Out of these, 10 resulted significantly to the fatal outcome. Weight loss does not provocatively increase the post-operative complications but it reduces the responses and also increases the toxicity towards chemotherapy. The symptom of feeling nauseous and vomiting is controversial. 2 out of group of 4 studies has shown that the prognostic significance of vomiting as symptom and evaluated that it is correlated with survival.
Gastro intestinal bleeding has been considered as the most prognostic factor. It is been argued that this cause results in gastric cancer which in case would belong to the advanced stage of the gastric cancer.
Treatment
Gastrostomy for gastric cancer: Gastrostomy along with adequate lymph adenectomy is one of the main procedures used to treat gastric cancer. Many numbers of trials and metaanalysis of phase III studies with evidences have proven that gastrostomy is technically safe and it in fact provides better short term outcomes that other treatment. In some countries Japan, South Korea, use of these treatment techniques is still controversial due to the existing concerns about adequacy of oncology and capacity to carry out these. Due to these limitations, the spread of gastrostomy as a treatment for gastric cancer has become challenging.
Laparoscopic Gastrostomy
Laparoscopic surgery has been employed for treating gastric cancer since 1990, it is performed with patients with relatively low risk of lymph node metasis has reported the first case of effective laparoscopic surgery in 1991.
Hand Assisted Laparoscopic Surgery (HALS)
Laparoscopic gastrectomy has its own difficulties of limited mobility of instruments. In HALS, the surgeon’s let hand is allowed to go into the abdominal cavity via a pressurized sleeve which is about 6-7 cm long. HALS is a combination of advances in laparoscopic surgery and laparotomy. However, it has its own demerits as well as to a hand can encroach into intra-abdominal space also the procedure is very expensive. HALS is not generally much favorable to surgeons.
Laparoscopy Assisted Gastrectomy (LAG)
In this technique, after mobilization of stomach by laparoscopy, the stomach is resections and anastomosis is carried out for acutely locating the tumor by the use of endoscopic clips and laparoscopic ultrasonography. The use of three Dimensional (3D) Computed Tomographic (CT) during LAG is proven to be emphasized. Laparoscopy Assisted Total Gastrectomy (LATG) used for treating gastric cancer has not been generalized yet.
Total Laparoscopic Gastrectomy
The surgical process through minilaparotomy is sometimes quite difficult with patients who are obese. Total Laparoscopic Distal Gastrectomy (TLDG) has been carried out with minimal invasiveness. Recently, total laparoscopy is performed for almost many advanced cancer cases.
Delta Anastomosis
It is one of the gastroduodenostomy methods that require precise and careful laparoscopic skills. The duodenal bulb is transacted using a linear stapler and divided. Small entry holes are created along the edge of the stomach. Then the posterior walls of stomach are approximated using a linear stapler and the staple line is checked for any defects like color of anastomosis and the common hole is closed. The very concerning problem is to check for leakage of anastomosis.
Poor blood supply and increased pressure may lead to leakage of anastomosis.
Robotic Laparoscopic Treatment
Robotics technology has been employed in the treatment of cancers since 1994. The robotically surgical system has overcome many limitations and drawbacks of laparoscopy techniques. The main disadvantage of conventional laparoscopy is the unstable positioning of the 2D camera. This increases risk in surgeon’s hand and discomfort as “fulcrum effect”. It is the need of the surgeon to move their hand in the direction that is opposite to the tip of the instrument. While robotic surgery is mainly used for dissecting using multiple quadrants and also heavy organs like in gastric cancer, there are much need superior laparoscopic skills. Advantage of robotic surgery is that it facilitates the technical limitation of all the traditional laparoscopic techniques that is used to perform digestive restoration after performing total gastrectomy. An alternative to this is a way to perform a full hand sewn esopagojejunal anastomosis. Although the laparoscopic surgery can affect robotic gastrectomy, this is seen to provide easier adaptation and has a steep learning curve.
Advantages of Robotic Over Laparoscopic Gastrectomy
There are clearly various benefits of robotic gastrectomy than laparoscopic gastrectomy contributing to the invasiveness. In robotic gastrectomy, there is availability of articulated devices. This makes each surgical technique more precise and meticulous. It has a tremor suppression function, which helps to maintain a stable surgical field and is shown to be effective in reducing organ injuries and with a three dimensional image it is much clearer (Figure 6).
Figure 6: Diagrammatic representation of laparoscopy and robotic surgery.
Targeted Therapy
Targeted therapy being employed for solid tumors represents a new therapeutic onset. Many molecular targeted agents have exhibits significant anti-tumor activity through variety of types of tumor like colorectal cancer, renal cancer, breast cancer and gastric cancer. These therapeutic strategies include Epidermal Growth Factor receptor (EGFR) inhibitors, cell-cycle inhibitors and Matrix Metallo Proteinase (MMP) inhibitors.
HER-2 Therapy
It is an emerging type of therapy among various therapies for treating cancers. It drives through tumor genesis of spontaneous receptors homodynes and heterodimers. These results in breakdown of oncogenic cell signaling like PI3/ mTOR and MAPK. This leads to HER2-HER3 to transduce PI3K signaling through direct binding, this causes amplification of HER2 gene. HER2 is a 185-kDa protein molecule which is encoded by a gene that is located on chromosome number 17q21. 6-23% of gastric cancer cases have been reported on the account of the overexpression of HER2. It is a promising target used for targeted therapy because of its association with clinicopathological features. Expression of HER2 in gastric cancer is primarily determined by the use of immunohistochemistry or by detecting HER2 gene amplification by in suit hybridization.
Trastuzumab
It is the first molecular targeted agent that is approved to be one of the standard treatments for gastric cancer. This molecule inhibits the HER2 mediated signals, induces antibody dependent cellular cytotoxicity, and prevents breaking of extracellular domain of HER2. The trial proved that addition of trastuzumab to cytotoxic chemotherapy showed a clinical benefit when in comparison with normal chemotherapies. An antibody targeting HER2 known as Trastuzumab-Emtansine (TDM-1) is found significantly effective for breast cancer. However, for HER2 positive gastric cancer patients was not able to prolong during second-line treatment. This is because of the heterogeneity of HER2 expression or the change of pattern by first-line chemotherapy. Patients receiving chemotherapy along with trastuzumab showed more benefit. As a result, the European Medicine Agency (EMA) restricted the approval of trastuzumab for patients with gastric cancer. Besides these restrictions the Food and Drug Administration (FDA) ratified the therapy with trastuzumab for patients with HER2 overexpression. To overcome all these insufficiencies, Japan started multicenter phase II study HERBIS-1 for HER2 positive gastric cancer patients. They received cisplatin on 1st day and trastuzumab on day one of 21 days cycle. The response from RECIST trial was 68% and disease control was around 94%.
Pertuzumab
It is one of the HER2 targeted monoclonal antibody which is distinct and complementary to trasuzumab. It binds to the 2nd domain of HER2 receptor and activates antibody dependent cellular cytotoxicity that leads to death of cancer cells. Phase II study of first line pertuzumab with trasuzumab in patients with HER2 positive gastric cancer showed partial responses by 86% of patients.
Lapatinib
It is a small tyrosine kinase inhibitor of EGFR and HER2 which induces activation by binding to the intracellular ATP binding site of these kinases. This inhibits HER2 and EGFR dependent activation of PI3K and Ras pathways which leads to the down regulation of kinase phosphorylation in tumor cells. Lapatinib Optimization study among HER2 positive patients is a phase III trial of oxaliplatin with or without lapatinib in the first line advanced HER2 positive gastric cancers.
Afatinib
It is an inhibitor of EGFR, HER2 and HER4 and is found effective in eliminating HER2 gene mutations.
mTOR Inhibitors
It is an important mechanism of trasuzumab resistance is deregulation of HER2 downstream signal substrate. This includes the PIK3K or mTOR pathway. It is proven that PIL3CA mutations and Phosphate and Tension Homolog (PTEN) inactivation. This results in constitutive activation of all the downstream signals. Inhibiting the mTOR signal by an inhibitor enhances the amplification HER2 gastric cancer.
Therefore, it is proven that concomitant therapy between HER2 targeted agents and mTOR inhibitors provide effective benefit for gastric cancer.
EGFR Targeted Therapy
EGFR is a multifunctional receptor tran’s membrane glycoprotein molecule. It is a member of tyrosine kinase family of growth factor receptors. Epidermal Growth Factor (EGF) is a specific ligand that belongs to EGFR. It activates the receptor by binding and phosphorylating the tyrosine kinase receptor. This activation in turn induces many intracellular signal transduction pathways and promotes division of cell and angiogenesis. So, the signal transduction is mainly targeted to inhibit the tumor multiplication during the molecular targeted treatment of gastric cancer. The important EGFR therapeutic agents are anti-EGFR monoclonal antibodies and EGFR tyrosine kinase inhibitors. This in combination with cetuximab has been shown 44% remission rate in advanced gastric cancer patients.
Vascular Endothelial Growth Factor Targeted Therapy
In most of tumors, angiogenesis, metastasis and vascular formation are associated with vascular endothelial growth factor pathway. Bevacizumab is a recombinant humanized monoclonal antibody inhibits VEGF. It combines with VEGF and blocks the activation of VEGFR, this leads to inhibition of tumor angiogenesis. It is found to be very effective when combined with cisplatin and irinotecan for treatment of gastric cancer. A study of 47 cases was taken with implementation of this therapy and the effector rate was observed as 65% and survival time was about 12 months. The final remission rate was 75% (Figure 7).
Figure 7: Diagrammatic representation of vascular endothelial growth factor started therapy.
Immunotherapy
Immunotherapy is a branch of biological therapy for cancer as it uses living substances to treat the disease. Immunotherapy enables the body to fight against cancer as the immune system of the body is composed of WBCs, tissues and organs of lymph systems and fights infections and other diseases.
Normally the immune system fights abnormal cell growth and hence prevents or reduces the growth of several forms of cancer. The presence of tumor infiltrating lymphocytes, also called as TILs denote the presence of tumors in the body and that the immune system is responding to it. Its presence is better in the case of occurrence of tumors. Although the immune system can fight against cancer and slow down its growth but the cancer cells might escape this mechanism, either by undergoing genetic changes and not getting identified by the immune cells, or by possessing certain proteins that act by switching off the immune system, or by changing the surrounding normal cells so that the response of immune system is interfered. Thus, this is when immunotherapy shows proper action. Immunotherapy has shown better results in the treatment of cancer when the tumor cells are small. It can show enhanced outcome when the disease burden is limited. An investigation of KEYNOTE-001 trials where patients suffering from stage 4 Melanoma were treated with pembrolizumab showed that the baseline sum of lesion (s) size which was below the median was in self-alliance of the Overall Survival (OS) and better responses were seen in cases where the tumors were smaller. When patients were treated with immunotherapy in the complementary setting of malignant tumor cells which were at high metastatic propensity, high grade clinical benefits were observed. In several studies patients with stage 3 or 4 absolutely resected melanoma were treated with immunotherapy using anti PD1 molecule and it resulted in the increase in survival rate and there was no recurrence of the disease. Similarly, a group of patients suffering from advanced stage of NSCLS were given conclusive treatment of chemo radiation along with complimentary durvalumab versus placebo, and it resulted in a notable improvement of Progression Free Survival (PFS) and OS in the PACIFIC trial.
Another study reflected on a trial where patients suffering from metastatic cancer of the prostate gland were treated with or without comprehensive ipilimumab, the results indicated a positive and greater response do the addition of ipilimumab in case of one bone metastasis instead of 2 or more.
Modification of Radio Immunotherapy
Several studies involving clinical study and preclinical research have shown that the interconnection between the intra temporal T cells, the micro environment of tumor along with IR can help in formation of more effective radio immunotherapy. These along with several other substantiated information led to the understanding that potency of radiotherapy and immunotherapy can be greatly increased by treating all sites or most of them with metastatic disease. The same has been proposed by other studies which reflected on use of high dosage of IR provided with increased precision and less toxicity. This is also substantiated by clinical studies, using pembrolizumab along with SBRT, it showed that tumors that underwent partial irradiation had a similar effect to those that were completely irradiated. This proves that in case where irradiation of all lesions total is not possible partial irradiation will do the job in the same way. Moreover, these trials also showed that great control of large partial irradiation of tumors caused by immunotherapy can lead to improved local control by radiotherapy. The only controversy can arise by T cells being sensitive to radio waves, and radiotherapy in this relation might become immunosuppressive [9-11].
Bariatric Surgery A Debatable Prevention Strategy
As discussed above, there is a relationship between increased BMI or obesity and Gastric Cancer, GC, but the validity of the same is not established yet. Several cohort studies worked on evaluation of the association between obesity and increased risk of GC. The results of the Meta-analysis indicated that there is a significant association between high BMI or obesity and higher risk of GC. This relationship becomes stronger with increasing value of BMI. Bariatric surgery is also known as weight loss surgery or gastric bypass and it consists of a wide range of procedures that are performed on patients suffering from obesity. Long term weight loss effect is observed by following Standard Operating Procedures (SOPs) like Roux en- Y surgery, sleeve gastrectomy. They function by altering the levels of gut hormones responsible for hunger leading to a new set point for managing appetite. Bariatric Surgery is a form of hormonal surgery and alteration in hormone is a result of malabsorption and restriction of the procedure. Long term studies showed that this procedure causes weight loss on a perpetual level along with added benefits like improvement from diabetes, advancement in prevention of Cardiovascular Disease, CVD, and a reduction in mortality rate from 40% to 23% (MK). Several studies indicated a decrease in cancer occurrence as compared to control, whereas others reported the opposite. The controversy results due to the difficulties that arise from extended period of studies for probable prevention of cancer. In contrast to this, it shows significant result in terms of weight loss, and metabolic benefits along with CVD disease improvement. An SOS trial was performed with a group of individuals in the age group of 37-60 years and BMI for men was ≥ 34 kg/m2 and for women it was ≥ 38 kg/m2. This study was followed for approximately 11 years. The women participants who underwent surgery showed the relatively less incidence of development of new cancers in comparison to control. Moreover, there was a significant difference for malignant and hematological malignancies. In women, who had bariatric surgery a 42% reduction in cancer risk was observed, however, there wasn’t any change in BMI. But, in men no such reduction took place.
McGill University, Canada which compared between 1035 morbidly obese patients who went through bariatric surgery, to 5476 patients matched for age, sex, morbid obesity. Over a 5 years follow up period there was 2% cancer development in the ones that underwent surgery as compared to 8.45% in controls for relative risks, RR, of 0.2. The procedure that was commonly used was Roux-en-Y gastric bypass and it was followed by vertical banded gastroplasty. But there were no results that indicated the connection between weight loss and the procedure used. However, the males covered a total of 34.1% and 36% in surgery and control groups respectively.
There was no incidence of reduction in the rate of cancer occurrence related to sex similarity; no relevance was shown with respect to ethnic background. A Meta evaluation was done using six bariatric surgical procedure studies with intervention and contrast manipulative groups, the use of each restrictive and malabsorptive technique, the greatest number of cancer mortality for a period of 5 to 16 years.
Comparison of most cancer incidence, analysis or mortality amongst 21058 patients who underwent surgery in contrast to 30682 controls confirmed the advantage of surgery. The overall cancel RR for the ones who went through surgery was 0.53. The RR value showed that bariatric surgery was a protection measure for women as RR was 0.68, but it was not the same for men (RR 0.99). Specific reduction in any cancer subtypes was not statistically proven. A comparison was made between the above stated meta analysis study and a register based retrospective nationwide population of Sweden from 1980 to 2006. The results reflected that there was no decrease in Standardized Incidence Ratios (SIRs) of development of cancer in association with bariatric surgery.
But the authors indicated that there was an increase in occurrence of Colo Rectal Cancer (CRC) SIRs which was associated with bariatric surgery follow up. A detailed report was prepared using more elaborate data from 1982-2009 and 70 cases of CRC were found in 15095 patients who went through bariatric surgery, and 373 CRC cases were found in 62016 obese control patients. These data were adjusted to SIR where a comparison was made between the expected number of cases to the expressed relative number of cases and a total of 1.6 CRC SIR was reported for bariatric surgery cohort, in comparison to 1.264 non-surgical cohort. Hence, it was inferred that there was a higher risk for CRC related with post bariatric operation and the risk was same for both the genders and it was statistically high in the two procedures that are widely used, namely vertical banded gastrectomy and adjustable gastric banding. Another study was made using hospital episode statistics database between 8794 patients who underwent bariatric surgery against equal number of propensity matched controls with an average follow up of 55.5 months. The time frame was in contrast to the period from diagnosis of obesity instead of that from surgery [12-14].
The authors mentioned that obese patients who opted for bariatric surgery showed a decreased incidence of breast cancer, prostate cancer and endometrial cancer. Gastric bypass showed effective results in controlling these cancers that are related with an individual’s hormone. Sleeve gastrectomy and gastric binding also showed promising results. However, weight loss surgery showed an increased incidence rate of CRC in both genders who opted for gastric bypass but not for gastric binding. These patients showed an increase in the rate of CRC occurrence which was directly related to the progression in time that followed the surgery.
Cancer progression due to obesity can be explained by two pathways direct and indirect. The direct pathway consists of adipokines and cytokines which are derived from adipose tissue and promote tumour growth. The indirect pathway focuses on the impact of metabolic factors like T2DM which is followed by higher levels of tumour promoters like insulin and IGF-1. Bariatric surgery has proven effective to disrupt both these pathways, and it also prevents some other probable mechanisms like change in the normal micro biota as well as epigenetic changes. Weight loss surgery is followed by decreased levels of T2DM and insulin levels which in turn act as a protective agent that rapidly reduces cancer incidence.
All these points along with potential benefits of bariatric surgery on patients suffering from obesity with a follow up of diagnosis and or including cancer treatment has been considered previously. But for patients who had a case of recent onset of cancer, bariatric surgery is supposed to be prophylactic as it has not achieved systemic evaluation [15-17].
This review article described the various classes of GC reflecting on the basis of the classification system; including Lawrence, WHO classification and Goseki classification, along with the various symptoms and risk factors associated with the disease. It also emphasized on the age, gender, family history, alcohol consumption and their relation with increased occurrence of the disease. It also focused on the primary treatment of the disease including better diet and proper lifestyle changes and gradually demonstrated the importance of various treatments like surgery and therapy. Gastric cancer is one of the leading causes of death worldwide and for some un known reason it affects more men than women. The disease is diagnosed at a later stage and hence the survival rate is very low. This disease can be potentially controlled by changing dietary habits and eradicating H. pylori infection.
However, since the disease is widespread and there is only limited information about the adverse consequences various effects have not been implemented. Secondary prevention including early detection and immediate treatment of precursor lesion or early cancer can help in reducing the burden of the disease.
Citation: Jeyabaskaran A, Bose A, Subashree K (2022) An Overview of Gastric Cancer: Classification, Risk Factors, Symptoms and Treatment. Eur Exp Bio. 12:83.
Copyright: © 2022 Jeyabaskaran A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
