Prof. Yusuf Yıldırım

CAUSES & RISK FACTORS

Stomach (gastric) cancer occurs with the malignant transformation and uncontrolled proliferation of cells in the stomach. Stomach cancer can occur in any anatomical region of the stomach. The area where it develops the most is the lesser curvature, the antrum region. Most of the stomach cancers (about 90-95%) are of the adenocarcinoma type. Adeno cancers develop from gland cells in the innermost layer (mucosa) of the stomach. Unless a specific type of gastric cancer is mentioned, "stomach cancer" means "stomach adenocarcinoma". Stomach adenocarcinomas histological types can be “papillary”, “tubular”, “mucinous” and “signet ring cell”. Mucinous adenocarcinomas have abundant mucin in tumor areas. When mucin is found in large proportions intracellularly, this appearance is called “signet ring cell carcinoma”. Stomach cancer mostly affects the elderly and 65% of patients diagnosed are over 65 years old. The risk of developing stomach cancer in a lifetime is approximately 1% (1/96) in men and 0.7% (1/152) in women.

There are many known risk factors for stomach cancer, but it is not exactly clear how these factors affect the transformation of normal cells of the stomach into cancer cells. Risk factors known to increase the likelihood of stomach cancer include:

• Advanced age
• Male gender
• Certain geographic regions – Stomach cancer is more common in East Asia, Eastern Europe, as well as South and Central America compared to Africa and North America.
• Helicobacter pylori (H pylori) infection – Infection with the H pylori bacteria appears to be the prime cause of cancers, particularly in the lower (distal) part of the stomach. H pylori infection has also been linked to some types of lymphoma of the stomach. Despite this, most people who carry these bacteria in their stomach do not get cancer.
• Epstein-Barr virus (EBV) infection – Epstein-Barr virus (EBV) causes a disease known as infectious mononucleosis and most people get this infection, usually when they are children or teenagers. EBV appears to be associated with nasopharyngeal cancer and some forms of lymphoma. The virus is also found in cancer cells in about 5-10% of people with stomach cancer, but it is not yet clear whether the virus actually causes stomach cancer. Stomach cancers associated with EBV tend to grow and spread more slowly.
• Being overweight or obese
• Diet – People who consume large amounts of salted fish and foods preserved by salting, such as meat and pickled vegetables, have an increased risk of stomach cancer. Regularly eating processed, grilled or charcoal-cooked meats appears to increase the risk of noncardia stomach cancer. Low consumption of fruits and vegetables also likely increases the risk of stomach cancer. On the other hand, eating plenty of fresh fruit and raw vegetables (possibly because they contain various antioxidant substances that can block cell DNA-damaging substances) seems to reduce the risk of stomach cancer.
• Alcohol use
• Tobacco use – Smoking especially increases the risk factor for cardia region cancer.
• Previous stomach surgery – People who have part of their stomach removed to treat non-cancerous stomach conditions such as ulcers are more likely to develop stomach cancer. This could be related to the stomach making less acid, which allows more harmful bacteria to be present. Reflux of bile from the small intestine into the stomach after surgery may also contribute to an increased risk. These types of cancers typically develop years after surgery.
• Some stomach polyps – Unlike hyperplastic and inflammatory polyps, adenomatous polyps can sometimes develop into cancer.
• Pernicious anemia – Some cells in the stomach produce a substance called intrinsic factor (IF). IF is a necessary substance for the body to absorb vitamin B12 taken with food from the intestine. People who do not produce enough IF may experience a vitamin B12 deficiency, which affects the body's ability to make new red blood cells (erythrocytes) and can also cause other problems. This condition, called pernicious anemia, can result from stomach surgeries as well as some autoimmune conditions. People with pernicious anemia have an increased risk of stomach cancer along with anemia.
• Menetrier's disease (hypertrophic gastropathy) – In this rare disease, the overgrowth of the stomach lining causes large folds and layers in the stomach and leads to low stomach acid levels.
• Certain occupations – Workers in the coal, metal and rubber industries appear to be at higher risk of developing stomach cancer.
• Having type A blood – People with type A blood have a higher risk of developing stomach cancer. The reason for this is unknown.
• Common variable immunodeficiency (CVID) – Individuals with CVID are more likely to have stomach lymphoma and adenocarcinoma.
• Family history of stomach cancer
• Hereditary cancer syndromes – Some people inherit gene mutations from their parents that can increase their risk of stomach cancer. These inherited syndromes account for only a small percentage (2%) of stomach cancers. These are Hereditary diffuse gastric cancer (HDGC), Lynch syndrome (hereditary non-polyposis colorectal cancer or HNPCC), Familial adenomatous polyposis (FAP), Gastric adenoma and proximal polyposis of the stomach (GAPPS), Li-Fraumeni syndrome, Peutz-Jeghers syndrome (PJS).

SYMPTOMS, DIAGNOSIS & STAGES

Stomach cancer at a very early stage rarely causes symptoms. Therefore, in countries where stomach cancer screening is not routine, most stomach cancers are identified after they have grown to large sizes or have spread outside the stomach and started to cause symptoms. While cancers that start in different parts of the stomach can generate different symptoms, in general, stomach cancer signs and symptoms (if the cancer has become symptomatic) include:

• Anorexia
• Involuntary weight loss
• Abdominal pain or discomfort
• Quick satiety (feeling full after eating a small meal)
• Heartburn (reflux) or indigestion
• Nausea and/or vomiting (with or without blood)
• Swelling or fluid accumulation in the abdomen
• Blood in stool
• Fatigue, weakness (due to anemia)
• Jaundice (if the cancer has spread to the liver)

If stomach cancer is suspected, examination and various tests will be needed for a definitive diagnosis. When cancer is detected, additional tests can be applied to obtain information about the extent of the disease.

• Physical examination
• Endoscopy (Gastroscopy)
• Biopsy – If an abnormal area is seen on the endoscopy, biopsy is the only way to find out if it is cancer or not. Some stomach cancers can start deep in the stomach wall, making it difficult to do biopsy with standard endoscopy. If there is such a doubt, a needle biopsy can be utilized to take sample from the deeper layers under the guidance of Endoscopic Ultrasound (EUS). If stomach cancer is found by microscopic examination of the biopsy samples, additional laboratory tests may be performed on the biopsy samples to guide treatment. These tests are HER2 test, PD-L1 test, MSI or MMR testing, Tumor Mutation Burden (TMB), NTRK gene fusion.
• Imaging methods – Barium X-ray, Computed tomography (CT), PET/CT scan, Chest (lung) X-ray, Magnetic resonance imaging (MRI), Endoscopic ultrasound (EUS)
• Laparoscopy (LS) – Even if the PET/CT scan performed following biopsy diagnosis does not show evidence of distant spread, LS may be performed to confirm whether the cancer is still confined to the stomach (and thus to ensure the utilization of surgical option to remove the tumor) before undertaking extensive surgery.
• Other Tests – Stool test to investigate the cause of existing anemia, liver function tests to investigate if there is jaundice and various tests (kidney function tests, bleeding-coagulation tests, ECG, etc.) can be done to prepare for the comprehensive operation.

When planning stomach cancer treatment, based on clinical staging (cTNM) data, we classify the disease in 4 groups. These are:

• Early stomach cancer (T1, N0-N3)
• Potentially resectable local or regional stomach cancer (T2-T4b, N0-N3)
• Unresectable local or regional stomach cancer (unsuitable for resection T2-T4b, N0-N3)
• Metastatic stomach cancer (M1)

These categories may seem complicated to you. You can talk to your doctor for more clear information about the stage of your disease.

TREATMENT & PROGNOSIS

Treatment in Early Stomach Cancer

Regardless of lymph node status, cancer is only in the inner layers of the stomach (in the mucosa or submucosa) and has not grown into the deeper layers of the stomach wall (cancer has not penetrated the muscularis propria, if penetrated it would be defined as advanced cancer). These tumors are usually located in the distal 1/3 of the stomach and the lesser curvature. Macroscopically, it can have 5 different appearances as polypoid, high, smooth, flat and pitted. About one-third of stomach cancers in Japan are early stomach cancers. On the other hand, the detection rate of the disease at this stage in America and Europe does not exceed 10%.

Early stomach cancer can typically be treated with gastrectomy and removal of the lymph nodes. If surgical results show the entire cancer removed and no lymph node involvement detected, the patient can usually be under close follow- up without further treatment. If it is not clear whether the entire cancer has been removed or have high risk factors for recurrence chemotherapy and radiation will likely be recommended. The 5- and 10-year survival rates following treatment are reported to be approximately 95% and 75% respectively.

Some Stage 0 cancers (Tis) can be treated with endoscopic resection. In this procedure, cancer and some layers of the stomach wall are removed via an endoscope inserted through the throat. This procedure is more often done in countries like Japan, where stomach cancer is often detected early during screening. It is rare to find stomach cancer this early in Western societies and Turkey thus, this treatment is not used that often.

Treatment of “Potentially Resectable” Local or Regional Stomach Cancer

These cancers have grown deeper into the stomach wall and may have involved nearby organs and structures (T2-T4b, N0-N3) but if no sign of spreading to other parts of the body, surgical removal can be an option. Cases up to clinical Stage 2A have the chance for curative surgery. Resections performed in Clinical Stage 2B-4A cases will most likely serve the purpose of palliative resection.

It is very important that all the necessary tests for the staging of these cancers are performed correctly before the surgery so that the doctors know the accurate extent of the cancer in the body. If the cancer has spread too far, trying to remove it probably won't help and the potential benefits of surgery won't outweigh the disadvantages. Besides CT and PET imaging test scans, other tests like endoscopic ultrasound (EUS) or staging laparoscopy can be helpful when making the decision to operation. After doing these testes if the disease is determined to be operable (resectable), some patients may be treated with subtotal gastrectomy (removal of part of the stomach) or total gastrectomy (removal of the entire stomach) as the initial treatment. Nearby (regional) lymph nodes (and possibly parts of nearby organs) are also removed. Some patients may first receive chemotherapy or chemoradiation therapy to shrink the cancer and facilitate surgery (neoadjuvant). In summary, depending on the situation treatment for this group of patients can start with "primary surgery" or "surgery following neoadjuvant chemotherapy". After surgery (as adjuvant therapy), chemo (or chemoradiation, if it had not been used prior to surgery) could be given in an attempt to kill any remaining cancer cells.

Treatment in “Unresectable” Local or Regional Stomach Cancer

These cancers have not spread to distant parts of the body (M0) but are still unable to be completely surgically removed (unresectable). Except in cases where there is obvious distant metastasis (e.g., diffuse liver metastasis, metastasis in extra-abdominal organs, Virchow's nodule, etc.), although inoperability criteria are controversial, cases with significant abdominal ascites, extensive peritoneal metastases, umbilical infiltration, Blummer's shelf sign, diffuse abdominal adenopathy and paraaortic lymph node involvement are considered inoperable.

First-line treatment options may include “chemotherapy alone”, “chemotherapy + immunotherapy”, “chemotherapy + immunotherapy + targeted drug trastuzumab (if cancer is HER2-positive)” or “chemotherapy + radiation therapy (chemoradiation)”. After treatment, the cancer stage (extension) is reassessed. At this point, CT and PET imaging test scans can be used along with other tests like endoscopic ultrasound (EUS) or staging laparoscopy.

If the cancer has shrunk enough with the initial (neoadjuvant) treatment, surgical removal of the cancer may be an option at this point. This may be in the form of subtotal or total gastrectomy. Nearby lymph nodes (and possibly some nearby organs or parts of organs) are also removed. If the cancer is still unresectable after neoadjuvant therapy, further therapy aims to control the growth of the cancer for as long as possible and to prevent or correct the problems it causes, which is similar to the treatment of metastatic disease. At times, even if the cancer is potentially resectable, the patient may not be healthy enough for major surgery or may not want to have surgery. In this case, the treatment aims to control cancer growth for as long as possible and to prevent or alleviate the problems it causes, similar to the treatment approach of metastatic cancer.

Treatment in Metastatic Stomach Cancer

These cancers have spread to distant parts of the body and are very difficult to treat. However, treatment can help keep the cancer under control and prevent or alleviate the problems it can cause. Treatment aimed at controlling the growth of the cancer are "chemotherapy alone", "chemotherapy + immunotherapy" or, if the individual is healthy enough, "chemoradiation combined with radiation therapy". For those people with “HER2-positive” cancer, the target therapy drug trastuzumab can be added to chemo (chemotherapy + trastuzumab), which can assist the chemotherapy to work better. Another option for patients with metastatic HER2-positive stomach cancer is to give "chemo + trastuzumab + immunotherapy (pembrolizumab)" as initial therapy.

If one type of medication does not work, another type of medication can be tried. Moreover, the patient can be included in clinical research of new treatments tested in clinical trials as it might be beneficial.

Palliative Surgical and Endoscopic Procedures

Patients with unresectable local or regional disease or metastatic disease, palliative types of surgery like gastric bypass (or less commonly subtotal gastrectomy) in some cases could be helpful to prevent obstruction of the stomach and/or intestines or to control bleeding. Even if these treatments do not destroy or shrink the cancer, they are often helpful in relieving pain, eating difficulties and other symptoms. Stomach cancer (and its treatment) can often cause problems with eating, and some people may need a feeding tube placement for adequate nutrition. A thin tube can be passed through the nose and throat into the stomach or intestines for a short period of nutritional need. On the other hand, a minor surgical procedure can be done to insert a gastrostomy tube (G tube) or jejunostomy tube (J tube) if a longer feeding tube is needed, this way liquid nutrition can directly be poured into the tube. 

Treatment Success and Prognosis (outlook)

The most important prognostic factor in stomach cancer is the TNM stage of the disease. When all the stages are included, the overall 5-year survival rate is around 33%. This is around 70% in localized (limited to the stomach) disease, 32% in regional disease (involvement of adjacent organs or lymph nodes) and 6% in metastatic disease. As T stage, N stage and M stage increase, survival rates decrease. Other prognostic factors are:

• Histological type (Lauren classification) and grade
• Tumor diameter and growth pattern
• Depth of invasion (in early gastric cancer)
• LVSI (in early gastric cancer)
• Genomics (various mutations and molecular markers)
• Tumor location
• Surgical margins (at least 2 cm negative surgical margin should be secured in early gastric cancer and at least 5 cm in late cancers)
• The extent of the lymph dissection
• Metastatic lymph node ratio (PNR: positive node ratio) (using PNR instead of “N stage”, especially in patients with D1 dissection, may prevent stage migration)
• Peritoneal cytology
• Experience of the health center and the operating surgeon
• Nutritional status (factors such as cachexia, loss of appetite and >10 kg loss may be associated with poor prognosis)
• Controversial factors: Serum tumor marker (Ca19.9, CEA and Ca125) levels, age, gender, race and geographic region (Women have a better prognosis. Although this difference is not significant in black race).

 You can visit our current website “oncosurgery.com.tr” for further information about stomach (gastric) cancer and its surgery.