GASTRIC CANCER: A GLOBAL VIEW

By Dr. Linda Girgis

Gastric cancer, also known as stomach cancer, remains an aggressive cancer around the globe. Over the past several decades, there has been a slight decrease in incidence, yet it remains the fourth most common cancer and the second deadliest across the world.  Some factors that are thought to be responsible for the declining incidence include better nutrition, food preservation, improved prevention and earlier diagnosis and treatment. However, it still carries a poor prognosis and is often diagnosed at advanced stages of disease.

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The incidence of gastric cancer varies throughout the world, with clear differences in rates across ethnicities. Across the world, there are 989,600 new cases of gastric cancer every year with an annual death rate of 738,000. Disease is usually diagnosed after it has invaded the muscularis propriam, when patients begin exhibiting symptoms. Symptoms at this stage are vague, but in advanced stages patients often develop the classic triad of symptoms: anemia, weight loss, and refusal to eat meat.

The peak incidence of gastric cancer is between 60-80 years of age. In India, it is seen at much earlier ages: 25-55 years. In all countries, the incidence is higher in males. In developing countries and lower social economic groups, distal gastric cancers are most common. H. pylori infection and dietary factors appear to play a role in distant tumors.

Proximal gastric cancers are most often seen in patients with GERD and/or obesity and are the more common type in developed countries and in higher socio-economic groups. In Japan, distal tumors are the most common whereas proximal tumors are more common in the rest of the world.

The highest incidence of gastric cancer occurs in Eastern Asia, South America, and Eastern Europe. The lowest incidence is observed in North America and Africa. Significant variations of incidence have been observed in ethnic groups living in the same area. In the US, for example, African Americans, Hispanics, and Native Americans have the highest incidence. However, ethnicity does not seem to be a lone factor as natives of Japan and China have a higher incidence if they live in Singapore as compared to those living in Hawaii.

RISK FACTORS of Gastric Cancer

  • Cigarette smoking
  • Male gender
  • Diet
  • pylori infection
  • Atrophic gastritis
  • Partial Gastrectomy
  • Menetrier’s Disease
  • Genetic factors (hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, hereditary diffuse gastric cancer, Peutz- Jegher’s Syndrome).
  • Family history
  • Obesity

Screening for gastric cancer is common in Japan and Korea, where the incidence is much higher.  In Japan, since 1985, over five million have been screened and over 6,000 cases of gastric cancer were detected. Approximately 50% of these detected cancers were in the early stages. According to the studies conducted in Miyagi Prefecture, Japan, screening by the indirect x-ray method resulted in a positive predictive of 1.78%. Of note, the rate of gastric cancer deaths has been declining in Japan and these studies seem to suggest screening is effective. In the US, the National Cancer Institute found inadequate evidence to advise screening.

SYMPTOMS of Gastric Cancer

Gastric cancer is often not found in the early stages because symptoms do not develop until it becomes invasive. Often, the symptoms may be vague. Patients may experience heartburn, abdominal pain or discomfort, nausea, vomiting, diarrhea, constipation, bloating, anorexia, and sensation of food getting stuck in the throat while eating. More severe symptoms include weakness, fatigue, vomiting blood, blood in the stool, and unexplained weight loss.

The initial diagnosis is commonly delayed because approximately 80% of patients are asymptomatic in early stages of gastric cancer. In the US, most cases are diagnosed after local invasion has advanced. The gold standard of diagnosis of gastric cancer is the EGD, which is highly sensitive and specific. This is especially true when it is combined with endoscopic biopsy. Once the initial diagnosis is made, CT scanning should be done to access the tumor spread. Endoscopic ultrasonography (EUS) is a very important tool for staging because it helps determine depth of tumor invasion and lymph node involvement, both important prognostic factors.

Classifications of Gastric Cancers

Classification of these cancers is clinically based on early and advanced stages of disease in order to determine the best treatment. Early gastric carcinoma is defined as tumor confined to the mucosa and/or submucosa either with or without lymph node involvement despite tumor size. Most of these are small, approximately 2- 5 cm in size and located at the lesser curvature around the angularis. When this carcinoma is multifocal it tends to carry a worse prognosis. Early carcinomas are further broken in types depending on the growth pattern. The five year survival for early cancers is excellent with a survival rate above 90 %. Advanced carcinomas, in contrast, are more invasive with a worse prognosis and a five year survival less than 60%. Advanced cancers are further divided into types based on whether they are exophytic, ulcerated, infiltrative or combined.

HISTOLOGIC SUBTYPES (2010 WHO CLASSIFICATION)

  1. TUBULAR ADENOCARCINOMA

This is the most common histiologic type of gastric cancer.  Grossly, it tends to form polypoid or fungating tumors. On histiologic exam, irregular, distended, fused, or branching tubules are observed. These tubules have varying sizes.

  1. PAPILLARY ADENOCARCINOMA

This is also a common type of early gastric cancer which often occurs in older people. It frequently occurs in the proximal stomach and often associated with liver metastasis and involvement of the lymph nodes. On histiologic exam, there is a central core of fibrovascular material scaffolding epithelial projections.

  1. MUCINOUS ADENOCARCINOMA

This type accounts for 10 % of all gastric cancers.  Histiologically, extracellular mucinous pools comprising at least 50% of the tumor volume are seen. The cells of the mass can form glandular architecture with irregular clusters of cells. Additionally, scattered signet ring cells can be observed floating in the mucinous pools. 

  1. SIGNET RING CELL CARCINOMA/POORLY COHESIVE CARCINOMAS

These tumors are often formed by a combination of signet ring cells and non-signet ring cells. Poorly cohesive non-signet ring cells are those that appear like histiocytes, plasma cells, and lymphocytes. These cells can form irregular microtrebaculae, often with severe desmoplasia in the gastric wall. Grossly, it can have a depressed or ulcerated surface.

Micropapillary gastric cancer is a newer discovered subtype. Histoilogically, small chains of papillary clusters of tumor cells are observed. These do not possess a distinct fibrovascular core.

Genetic factors appear to play a role in gastric cancer, and the number of genes and molecules implicated is huge. It is suggested that gastric carcinogenesis is a multi-step operation, where general and specific genetic alterations result in the transformation of normal cells into cancerous ones.  The familial form of gastric cancer has been known since the 1800’s, when it was noted in Napolean Bonapart’s family. These account for 1-3% of all gastric cancers and have now been determined to arise from a mutation in the CDH1 gene. Also observed in the hereditary form of gastric cancer are TP53 suppressor gene mutations. BRCA2 gene mutations have been observed in familial clusters of gastric cancer, as well as other cancers. Genetic instability at the microsatellite instability (MSI) level has received significant attention in gastric cancer and it has been suggested that it is present in 10-15% of gastric cancers. Gene polymorphism has also been studied extensively in gastric carcinogenesis and polymorphism in genes from diverse pathways is strongly associated with gastric cancer. For example, the IL1B gene has been shown to play an important role in a person’s inflammatory response to H. pylori infection.

The treatment depends on the location of the tumor and how far it is spread. It is therefore imperative to determine the exact stage of the disease.

TREATMENT of Gastric Cancer

Stage 0:  These cancers are limited to the inner lining layer of the stomach. Because there has been no spread or invasion, they can be treated by surgery alone. No chemotherapy or radiation is needed. In Japan where it is much more common, the tumor is often resected endoscopically. It is extremely rare to find it so early in the US.

Stage I

     1A: Typically, a total or subtotal gastrectomy with lymph node excision is performed. No other treatment is needed.

      1B: Total or subtotal gastrectomy is performed. Sometimes, chemotherapy is given prior to the surgery to shrink the tumor size. If the lymph nodes were free of disease, no further treatment than observation is offered. However, many doctors prefer treatment with chemoradiation or chemotherapy following surgery. If cancer is detected in the lymph nodes at the time of surgery, chemoradiation, chemo alone, or a combination of the two is done. If the patient is too sick for surgery, they may be treated with chemoradiation.

STAGE II: Surgery is done to remove all or part of the stomach, the omentum, and local lymph nodes. Chemoradiation is often done prior to surgery to shrink the tumor size. Following surgery, chemoradiation or chemo alone is performed.

STAGE III: Surgery is again the mainstay of treatment in this stage. However, in this stage it may not be possible to excise al of the tumor. Chemoradiation or chemo alone is often used before surgery and again after. For those with some tumor left behind, chemoradiation is done.

STAGE IV:  In this stage, cancer has spread to distant organs. Treatment is more aimed at keeping the cancer under control and alleviating symptoms.  This may include surgery, chemoradiation or chemo alone. In some cases, a laser beam can be directed through an endoscope to destroy most of the tumor. Targeted therapy is helpful in advanced stages of cancer.  Herceptin can be added for those whose tumors are HER2 +. For some, Ramucirumab may provide some benefit, either alone or combined with other chemo.

RECURRENT CANCER: The same treatment as for stage IV.

Despite the advances in treatment of gastric cancer, the prognosis remains dismal. In the US, the overall 5 year survival rate remains 29%. In contrast, the rate in China is 57.6 % where disease is often detected at an early stage. Clearly, we need more research. 

Linda Girgis MD, FAAFP is a family physician practicing in South River, New Jersey. She was voted one of the top 5 healthcare bloggers in 2016. Follow her on twitter @DrLindaMD.


 

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