Stomach Cancer Risk factors
Helicobacter pylori infection
- Helicobacter pylori (H pylori) is a bacterium that generally infects the stomach and the duodenum and causes inflammation in these organs.
- An increased incidence of stomach cancers has been observed in individuals with the H pylori.
- Induces phenotypic changes-mucosal atrophy, intestinal metaplasia & dyplasia.
- Gastritis /atrophy→ ↓acid production → bacterial overgrowth → reduction of nitrates-nitrites → along with amine/amide/urea → nitrosamines.
- Interferes with antioxidant function by ↓intragastric ascorbic acid concentration.
- Excess of cell proliferation → greater replication errors →mutation → neoplasia.
- DNA damage – free radical, oxidants & reactive nitrogen species all cause DNA damage → point mutations → either DNA repair / apoptosis.
Chronic atrophic gastritis
- It is a condition in which long-term inflammation of the stomach mucosa causes the loss of stomach mucosal cells and subsequent replacement with the intestinal and fibrous tissue.
- Various studies have shown that the patients with atrophic gastritis are at increased risk of developing stomach cancer.
- Smoked or salted foods,
- low intake of fruits and vegetables,
- improperly prepared/stored food,
- foods rich in nitrates, and
- foods contaminated with aﬂatoxin
- Regular exposure to heavy metals or harmful gases/fumes, especially those encountered in coal, metal, or rubber industry, has been found to increase the risk of stomach cancer.
Genetic Cancer Predisposition Syndromes
Some inherited cancer predisposition syndromes have been reported to be associated with a high incidence rate of stomach cancer.
Following are some examples:
- Hereditary diffuse stomach cancer
- germ line mutations of the E-cadherin gene(CDH1), involved in cellular adhesion, assoc with diffuse type gastric ca & lobular breast cancer.
- Poorly differentiated, infiltrative & signet cell type.
- Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC)
- generally caused by mutation in the MLH1 or MSH2 gene
- mismatch repair gene mutation results in micro satellite instability.
- most commonly associated with colorectal cancer and endometrial Cancer,
- 3.2 fold increase risk gastric cancer
- Familial adenomatous polyposis (FAP)
- caused by mutations in the APC gene
- Autosomal Dominant with high penetrance
- gastric polyps occur in 27-70% of affected individuals
- Li-Fraumeni syndrome (caused by mutation in the TP53 gene), and
- mutations in the breast cancer genes – BRCA1 or BRCA2.
- Hypermethylation may be observed in the early carcinogenesis of both intestinal & diffuse type gastric cancer.
- Hypermethylation may lead to development of the replication error phenotype, silencing of tumor suppressor genes & altered cellular adhesion because of silencing of E-cadherin.
- 31-39% of gastric patients associated with MSI (low & high), occur early in gastric carcinogenesis of RER phenotype, leading to inactivation of tumor suppressor genes.
- MSI is associated with intestinal type and distal gastric cancers.
Older age individuals especially men are at significantly higher risk of developing gastric cancer.
Smoking, heavy alcohol intake, obesity, low socioeconomic status, infection with Epstein-Barr virus (EBV), and some disorders like Menetrier disease, are other reported gastric cancer risk factors.
Risk Factors for Intestinal and Diffuse types of Stomach cancer
Stomach cancer may be broadly divided into two histopathological types, intestinal type and diffuse type.
First, we will compare the demographics or the population distribution of the two different variants of stomach cancer, that is, the intestinal and diffuse type. The intestinal variant is more common in the elderly, whereas, the diffuse type is more common in the young population. Intestinal variant is more commonly seen in the males, whereas, diffuse variant is more common in the females.
Intestinal variant is common in endemic regions of Japan and south-east Asia, whereas, diffuse variant is more common in the developed countries.
To understand the location of these tumors and pathophysiology, first we have to know the normal anatomy of the stomach.
The stomach lies in the upper part of the abdomen, called as epigastric region.
Gastroesophageal junction is the landmark where the esophagus joins the stomach.
The most upper part of stomach is known as cardia.
Below the cardia, lies the body of stomach.
The most distal part of the stomach, where it narrows down, is called as antrum.
And pylorus is the distance sphincter of the stomach, that controls the passage of gastic contents into the small intestine.
Now, after understanding the normal anatomy of the stomach, we will compare the distribution of the intestinal and the diffuse variant. The intestinal variant of stomach cancer is most commonly located either in the body or the pylorus.
Whereas, the diffuse variant maybe seen equally in any part of the stomach, that is, either cardia, body or pylorus.
Now we move on to the risk factors for different subtypes of stomach cancer.
H. pylori infection is the most common cancer risk factor for the intestinal variant.
Whereas, the diffuse variant of stomach cancer is not associated with H. pylori infection.
Due to successful anti-H. pylori therapies available, the incidence of intestinal variant of stomach cancer is coming down. On the other hand, the incidence of diffuse variant is increasing.
Dietary factors such as high salt or nitrate containing foods increase the incidence of intestinal variant of stomach cancer. Also, increased intake of smoked or packaged or processed food increases the incidence of intestinal subtype.
Smoking is also a major risk factor for the intestinal subtype of stomach cancer, and the incidence increases with the intensity and duration of smoking. Any long-standing benign ulcers of the stomach may also increase the risk of developing intestinal subtype of stomach cancer.
On the other hand, the most important risk factor for diffuse variant of stomach cancer is genetical or familial, that is, it may be inherited from other family members.
Stomach cancer may also be classified based on their location, that is, whether it is proximally located or distally located in the stomach.
Proximally located means either in the gastroesophageal junction or cardia.
Whereas, distally located means either in the body or pylorus of the stomach.
The intestinal subtype of stomach cancer is less commonly seen in the GE junction and proximal part of stomach, and more commonly seen in the body and pylorus. And the diffuse variant is seen equally in the cardia, body and the pylorus of stomach.
There has been a gradual increase in the incident of GE junction and proximal stomach tumors and a gradual decrease in the tumors in the body and pylorus, Let’s understand why.
H pylori infection is very commonly seen all over the world. Long standing infection with H. pylori leads to damage to normal epithelium of stomach, which is called as atrophic gastritis, due to which there is a decrease in gastric acid production.
Due to chronic gastritis caused by H. pylori infection, there is a increased chance of cancers in the body and pylorus of the stomach. On the other hand, atrophic gastritis caused by chronic H. pylori infection decreases the acid production by the stomach.
It reduces the chances of GERD, thereby reducing the chances of cancer in the GE junction and the cardiac region of the stomach.
But nowadays, due to successful anti-H. pylori therapy available, the cancers in the body and the pylorus have decreased, whereas, those in the GE junction and cardia have increased.
Symptoms and Signs of Stomach Cancer
Signs and Symptoms of Localised/Locally Advanced Stomach Cancer
It may be one or more of the following-
- Abdominal discomfort
- Abdominal pain or bloating
- Early satiety or feeling full quickly on eating small meals
- Nausea and/or vomiting
- Black coloured stools due to bleeding
- Reflux of gastric contents causing heartburn
Signs and Symptoms of Advanced/ Metastatic Stomach Cancer
Symptoms of metastatic disease depend on the site of metastasis and the local extent. Most common site of metastasis are liver, peritoneum, lungs, bones, etc. So, in addition to the local symptoms as discussed above, one or more of the following may be seen depending on the distant spread of tumor.
- Asctis, or fluid collection in peritoneal cavity
- Yellowish discoloration of eyes and/or urine due to liver involvement
- Cough, breathlessness or chest pain due to spread to lungs or pleura
- Pain at bony sites, back pain
- Palpable supraclavicular (Virchow’s) lymph node
- Palpable periumbilical (Sister May Joseph’s) lymph node
- Peritoneal metastasis palpable by rectal examination (Blumer’s shelf)
- Palpable ovarian mass (Krukenberg’s tumor)
- Acanthosis nigricans & seborrheic keratosis
Signs and Symptoms dependent on location
- Proximal stomach tumor most commonly presents with dysphagia.
- Whereas, distal tumor presents with persistent vomiting.
- Most commonly, Diffuse stomach cancer causes early satiety.
Stomach Cancer Staging Investigations
In this test, a thick, viscous liquid containing barium (a heavy element that reflects x-rays) is first swallowed. Then, x-rays are obtained for the upper gastrointestinal system where any abnormal area is detected by the irregular barium coating. It is cost effective with 90% accuracy of detection. However, it can not distinguish benign from malignant gastric ulcers.
Upper GI endoscopy is the first and the most important test to be done, when we are suspecting a patient to have stomach cancer. It help us to take a biopsy from the mass. Flexible upper endoscopy helps take multiple biopsies (>7) around ulcer crater for histology. Accuracy is 98%, increases with direct-brush cytology.
And also to do a endoscopic ultrasound, to look for the depth of the infiltration of the tumor into the esophageal wall and the local structures, and to look for the involvement of regional lymph nodes. It aids in further staging of previously diagnosed tumors and may helpful in identifying early diffuse gastric cancer. With an added capability to evaluate gastric wall tumor invasion (define the T stage) and provide information morphology of LN status, it has an accuracy of up to 90% for ‘T’ & 75% for ‘N’ staging
Computed tomography (CT) scan
CT abdomen & pelvis is important part of the staging. It is useful for non-invasive assessment of perigastric lymph nodes, peritoneal disease & intra-abdominal visceral (liver) metastasis and degree of tumor penetration. With modern multiphase, multidetector spiral CT, there is increased accuracy in the assessment of extra gastric disease & mural penetration(≥T2).
Positron emission tomography (PET) scan
PET is very useful for evaluation for GIT malignancies. In one study, only 2/3 of primary tumors were found to be FDG avid. It did not identify occult peritoneal disease but did identify extraperineal M1 disease (bone, liver,retroperoneal LN).
Laboratory Tests for Biopsy Samples
Vast majority of stomach cancers are adenocarcinoma. They arise on background of chronic gastritis, intestinal metaplasia, dysplasia. It may be polypoid, ulcerative or infiltrative (extreme is linitis plastica – “leather bottle stomach). On microscopy, it may of two types-
- Intestinal type (forms glands – like cancers of colon and oesophagus)
- Diffuse type – dissociated tumour cells often containing a mucinous “blob” – signet ring cells
Sometimes, the tumor spread to peritoneum or abdominal structures may not be diagnosed accurately on imaging. So laparoscopic exploration of the abdomen and collection of peritoneal fluid for cytology may be required.
In this technique, incisions are made at appropriate places and a hollow flexible device equipped with a camera and a light source is inserted through the incision. This technique can be utilized to collect biopsy samples from the affected areas, and are very useful in the diagnosis of radiographically occult disease and in determining the extent of disease spread to the liver or peritoneum.
Stages of Stomach Cancer
The stomach is a J-shaped sac-like organ that connects the esophagus to the duodenum (the first part of the small intestine). It serves as a mixing chamber and holding reservoir for ingested food.
It mainly consists of 5 parts – Cardia, Fundus, Body, Antrum, and Pylorus; and 5 layers – Mucosa, Submucosa, Muscularis Propria, Subserosa, and Serosa.
Adenocarcinoma (affecting mucosal cells that lines the innermost lining of the stomach) is the most common type of stomach cancer.
Now, after discussing the different layers of the stomach wall, let’s discuss the T-staging of the stomach cancer.
First is the Tis or carcinoma in situ. This is not considered as malignant and is localized to the epithelium.
Infiltration of lamina propria or muscularis mucosa is called as T1a disease.
Infiltration into the submucosa is called as T1b.
Muscularis propria infiltration is called as T2.
Infiltration of subserosa is called as T3. And infiltration of the tumor into the serosa is called as T4a disease.
When the tumor extends through the stomach walls to involve the adjacent structures it is called as T4b.
In this figure, the tumor extends to involve the colon.
And here it infiltrates the pancreas.
And here the tumor infiltrates into the spleen.
And here it invades the kidney.
It may also infiltrate into the liver or the diaphragm.
Now next comes the N staging or the nodal staging.
The regional nodes which drain the stomach are different in different part of the stomach.
These nodes drain the lesser curvature of the stomach.
And these drain the upper part of the greater curvature of the stomach.
And these the lower part.
These nodes drain the pyloric antrum.
All the nodes draining the different part of the stomach, ultimately drain into these nodes which are called the coeliac nodes.
Depending on the number of regional lymph nodes involved, it can be divided into different N stages.
N0 – No regional lymph node involved by tumor.
N1 – Cancer has spread to 1 or 2 regional lymph nodes.
N2 – Cancer has spread to 3 to 6 regional lymph nodes.
N3a – Cancer has spread to 3 to 6 regional lymph nodes.
N3b – Cancer spread to >/=6 regional lymph nodes.
M0 – Cancer has not spread to non-regional lymphj nodes and/or distant organs.
M1 – Cancer that has spread to the distant important organs such as lungs, bones, and brain
Distant metastasis may be seen to the liver.
The peritoneum in form of multiple peritoneal deposits.
To the lungs in form of multiple nodular deposits.
Rarely, it may spread to the left supraclavicular lymph node which presents as nodular deposits in the left side of the neck.
Or a nodular deposit in the periumbilical region called as sister Mary Joseph Nodule.
It may also present as pelvic deposits in the rectovesical pouch or pouch of Douglas.
Or as nodular deposits in one or both the ovaries, called as Krukenberg’s tumor.
Very rarely, it may also spread to brain or bones.
The stomach cancer treatment mainly depends on the stage, location of the tumor, performance status of the patient, the presence of certain genetic abnormalities, along with other factors.
Treatment of Stomach Cancer
The stomach cancer treatment mainly depends on the stage, location of the tumor, performance status of the patient, the presence of certain genetic abnormalities, along with other factors.
First we will discuss the treatment for localized disease. Earlier stages of the stomach cancer include the Tis and T1a disease, that is, the disease extending up to muscular mucosa.Endoscopic mucosal resection is the technique used for the treatment of Tis and T1a disease.This procedure is performed through an endoscope, in which first a fluid is injected below the lesion, and then the lesion is removed from the sorrounding structures.
As you can see in the figure, only the superficial cancerous portion is removed, while the remaining tissue remains unaffected.
Removal of the stomach is all an option for early stage disease, but is practiced less commonly.
Then comes the T1b disease which infiltrates upto the submucosa.
Gastrectomy is the preferred treatment for T1b disease.
Then comes the T2 disease which extends up to the muscularis propria.
And T3, which infiltrates the subserosal tissue.
And lastly, T4a which infiltrates the serosa.
Form T2a and T4a, surgery may not be sufficient and may not be possible in many cases, so a combination of chemotherapy, radiation therapy, and/or surgery may be required.
The combination of modalities to be used is decided by the oncologist on an individual patient basis, depending upon the exact stage of disease, performance status and comorbidities of the patient.
Now lets come to the treatment of the T4b disease, in which the tumor extends through the wall of the stomach to involve adjacent structures.
Surgery may not be possible in all cases of T4b disease, so in such cases, chemotherapy with or without radiation therapy may be used.
Whereas, if the tumor is surgically resectable, multimodality treatment with surgery, with or without chemotherapy or radiation therapy is used.
In T4b disease also, the decision to move ahead with surgery, or treat the disease with chemotherapy or radiation therapy is taken by the oncologist on an individual patient basis, depending upon the exact stage of the disease, performance status and the comorbidities of the patient. That is the treatment for non-metastatic stomach cancer.
Now we come to the treatment of metastatic disease. In all cases of metastatic disease, chemotherapy and/or targeted therapy is the mainstay of treatment. But other modalities like surgery, radiation therapy or bone-directed therapy may be used for palliation or relief of symptoms.
Chemotherapy for Stomach Cancer
Chemotherapy may be given for stomach cancer as neoadjuvant (before surgery), concurrent chemoradiation (along with radiation therapy), adjuvant (after surgical resection) or palliative (for metastatic disease) chemotherapy.
Systemic therapy agents that are effective in Stomach Cancer Treatment are-
Endoscopic Treatments for Early Stage Disease
Several types of endoscopic treatment can be employed for very early stage stomach cancers. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) is alternative to surgery with similar efficacy and safety for early-stage gastric cancer confined to gastric mucosa.
Other treatments like endoscopic tumor ablation and endoscopic stent placement aim mainly to relieve symptoms of more advanced staged gastric cancers.
Surgery for Stomach Cancer
Surgery is the treatment of choice for some earlier stage cancers that can be completely removed. Surgery can also be employed for higher stage disease that have not spread to distant parts and if the patient is medically fit.
Sometimes, surgery is combined with other treatments such as chemotherapy and/or radiation therapy as per physician discretion and patient’s condition. Surgery for stomach cancer may be partial or total gastrectomy. It may be a D1 resection or D2 resection depending upon number and stations of lymph nodes removed.
Role of Targeted Therapy
Targeted drugs are designed to target a specific gene or protein characteristic of the stomach cancer cells. With the advancement in diagnostic techniques, genetic abnormalities for gastric cancer have been identified that can be targeted with the help of targeted drugs. Molecular testing to confirm the genetic abnormality is the pre-requisite for starting a targeted therapy.
For example, Trastuzumab targets the HER2 protein and Ramucirumab targets receptor for VEGF. They are generally used alone or in combination with chemotherapy for the treatment of higher stage disease.
Role of Immunotherapy
Immunotherapeutic agents activate the immune system to recognize and kill cancer cells. Immune checkpoint inhibitors target PD-1, a protein on T-cells that normally helps keep these cells from attacking cancer cells. This activates the immune system to kill the PD-L1 expressing cancer cells.
Pembrolizumab may be used as the second-line or subsequent line therapy for MSI-H or dMMR positive unresectable/metastatic gastric tumors that have progressed on prior treatment and for which no satisfactory alternative treatment option is available.
Best Stomach (Gastric) Cancer Specialist in Delhi
Dr Sunny Garg is a renowned Medical Oncologist in New Delhi with an experience of around 10 years of treating stomach cancer patients. He has treated gastric cancer patients with Chemotherapy, Targeted Therapy, Immunotherapy and Personalized Cancer Treatment. He is currently practicing at Manipal Hospital, Dwarka.
Diagnostic modalities available at our hospital include Endoscopic Biopsy, Endoscopic Ultrasound, Barium Swallow, Whole Body PET CT, etc. Other treatment facilities for Stomach Cancer available are Partial Gastrectomy, Total Gastrectomy, Sleeve Gastrectomy, Billroth I Procedure, Billroth II Procedure, Radiation Therapy, etc.
Call +91 9686813020 for appointment.