Gastric Cancer

Gastric Adenocarcinoma

1. Epidemiology
• 50 years ago, gastric cancer accounted for 20% to 30% of all cancer deaths in the U.S.
• now it is a relatively rare disease in the United States (~ 27,500 new cases per year with ~ 11,000 deaths)
• the reason for this trend is unknown
• the decline has been in antral tumors of the intestinal type; cancers of the gastric cardia have been increasing in incidence
• worldwide, gastric cancer is the fourth most common cancer
• worldwide, there is considerable geographic variation in the incidence of gastric cancer: Japan has an incidence ten times higher than in the U.S.
• Chile, Iceland, Costa Rica have incidences of the disease much higher than in the U.S.
• 2:1 male to female ratio; higher incidence among blacks than whites in the U.S.
• peak incidence is in the sixth and seventh decades of life


2. Etiology
1. Diet
• gastric cancer appears to be correlated with foods containing high levels of salt, nitrates, and nitrites
• nitrates and nitrites can be converted to carcinogens, the n-nitrosamines
• ascorbic acid can prevent the conversion of nitrites to nitrosamines


2. Helicobacter Pylori
• parallels exist between regional rates of gastric cancer and H. pylori infection
• H. pylori is more associated with the intestinal type cancer than with the diffuse type
• chronic H. pylori infection leads to acute and chronic gastritis, which may progress to chronic atrophic gastritis with metaplasia, followed by dysplasia
• in addition, chronic atrophic gastritis leads to achlorhydria with consequent anaerobic bacterial overgrowth
• anaerobic organisms are capable of reducing nitrate to nitrite, which induces the synthesis of nitroso compounds that possess mutagenic potential
• H. pylori also causes production of growth regulatory peptides
• trials aimed at gastric cancer prevention by the treatment of H. pylori infection are currently under way



3. Polyps
• adenomatous gastric polyps are rare but carry a high risk for the development of cancer
• the risk is greatest for polyps > 2 cm
• fundic gland polyps are associated with PPI use, and do not appear to have malignant potential


4. Previous Gastric Surgery
• gastric surgery for benign conditions increases the risk of gastric cancer twofold to sixfold
• occurs 15 to 20 years following gastric resection and is most commonly associated with a Billroth II reconstruction
• vagotomy and antrectomy causes hypochlorhydria, leading to bacterial overgrowth
• bacterial overgrowth can lead to increased conversion of nitrites to nitroso compounds, which can cause metaplasia, dysplasia, and eventually cancer
• the continuous bathing of the gastric mucosa with alkaline secretions is likely another important factor


5. Hereditary Risk Factors
• hereditary diffuse gastric cancer results from a gene mutation in E-cadherin, a cell adhesion molecule
• Li-Fraumeni syndrome results from a mutation in p53
• hereditary nonpolyposis colon cancer (Lynch syndrome) is associated with gastric and ovarian cancers
• Peutz-Jegher’s syndrome


6. Other Risk Factors
• pernicious anemia results in achlorhydria
• PPIs, which result in achlorhydria and corpus gastritis, have not been shown to cause gastric cancer


3. Pathology
1. Gross Appearance
• gastric cancers are divided into 4 subtypes based on macroscopic appearance: polypoid, fungating, ulcerative, and scirrhous (linitis plastic)
• scirrhous tumors infiltrate the entire wall of the stomach and cover a very large surface area
• distribution of tumors: 40% distal, 30% middle, 30% proximal


2. Histologic Appearance
• 2 major histologic types: intestinal and diffuse
• additional histologic subtypes include papillary, tubular, mucinous, and signet-ring cell


1. Intestinal Type
• localized to the antrum
• arises in the setting of intestinal metaplasia
• tumors have a glandular structure resembling colon cancer
• predominates in high risk areas
• more closely associated with H. pylori than the diffuse type


2. Diffuse Type
• arises out of single-cell mutations within normal gastric glands
• not associated with intestinal metaplasia
• poorly differentiated
• associated with more proximal tumors
• seen more often in women and young patients
• stage for stage, has a worse prognosis than the intestinal type


3. Methods of Spread
• regional lymphatics
• direct extension into adjacent organs (liver, spleen, pancreas, transverse colon and mesentery)
• systemically via the portal vein
• transperitoneally (ovaries – Krukenberg’s tumor, pelvic cul-de-sac – Blumer’s shelf)


4. Early Gastric Cancer (EGC)
• histologically confined to the mucosa and submucosa
• may have lymph node involvement (3%, mucosal tumors; 20% submucosal tumors)
• comprises > 50% of all gastric cancers diagnosed in Japan, largely as a result of mass screening programs
• comprises < 10% of gastric cancers diagnosed in the U.S.
• cure rates are greater than 90% at 5 years


4. Pathologic Staging
1. Classification by Location
• tumors involving the G-E junction with the tumor epicenter no more than 2 cm into the proximal stomach are now classified as esophageal cancers
• G-E junction tumors with their epicenter located more than 2 cm into the proximal stomach are classified as stomach cancers


2. TNM Classification
1. T Category
• T1a: tumor does not invade the submucosa
• T1b: tumor invades the submucosa
• T2: tumor invades the muscularis propria
• T3: penetrates the subserosal connective tissue but not the serosa
• T4: penetrates the serosa or invades adjacent organs


2. N Category
• number of examined nodes affects the accuracy of staging and influences survival
• AJCC guidelines recommend that a minimum of 16 nodes be removed for pathologic evaluation, and that 30 or more is preferable


5. Clinical Manifestations
1. Early Gastric Cancer (T1)
• symptoms of early gastric cancer are vague and nonspecific
• may mimic symptoms of gastric ulcer disease
• In the U.S, they are usually found incidentally on EGD for GERD or peptic ulcer disease


2. Locally Advanced Gastric Cancer
• weight loss, abdominal pain, and anorexia are the most common symptoms
• nausea and vomiting may occur if distal lesions obstruct the pylorus
• dysphagia is a dominant symptom for cancer of the cardia
• hematemesis is unusual, but anemia and occult blood in the stool are common
• 10% of patients present with evidence of widespread disease, including hepatomegaly, ascites, supraclavicular adenopathy (Virchow’s node), ovarian metastases (Krukenberg’s tumor), Blumer’s shelf, umbilical nodule (Sister Mary Joseph’s nodule)



6. Diagnosis and Clinical Staging
• upper endoscopy with biopsy is the most accurate diagnostic tool
• double-contrast barium UGI is a complementary study but it is difficult to distinguish benign from malignant ulcers by this study
• abdominal/pelvic CT scanning should be done for preoperative staging
• endoscopic ultrasound (EUS) provides accurate data about the depth of tumor penetration through the stomach wall and showing enlarged perigastric nodes
• EUS is most valuable in distinguishing early gastric cancers from more advanced tumors
• PET-CT is useful for evaluating for distant metastases
• laparoscopy may be used as a staging tool to determine the presence of small liver or intraperitoneal metastases not seen on CT scan


7. Treatment
1. Palliation
• unfortunately, many patients with gastric cancer present with advanced disease (distant metastases or invasion of a major vessel)
• patients with advanced disease who are not bleeding or obstructed should not be explored
• if the patient is bleeding or obstructed, then a palliative resection can be offered to improve the patient’s quality of life
• it is controversial whether a total gastrectomy is an appropriate palliative intervention
• if, at exploration, an obstructing lesion is not resectable, then a gastrojejunostomy can be performed
• for patients with metastatic obstructing proximal gastric tumors, palliation is best achieved with stents or endoscopic laser therapy
• radiation and chemotherapy offer little in the way of palliation


2. Curative Resection
• surgery is the only potentially curable therapy (R0 resection)
• much controversy exists regarding the extent of gastric resection and the completeness of the lymphadenectomy
• location of the primary tumor is defined as distal third, middle third, upper third, and cardia
• an adequate proximal and distal margin should be 4 to 6 cm from the tumor and should be confirmed with intraoperative frozen section


3. Tumors of the Distal Third
• best managed with subtotal gastrectomy (75%), to include 2 to 3 cm of duodenum
• left and right gastric vessels, left and right gastroepiploic vessels are ligated at their origin
• greater and lesser omentum are also removed
• resection includes the suprapyloric and infrapyloric nodes, as well as the nodes along the greater and lesser curves
• 16 or more nodes should be removed
• splenectomy is usually not part of the procedure
• reconstruction is by Roux-en-Y or Billroth II gastrojejunostomy
• Billroth I reconstruction is contraindicated because of the risk of local recurrence and resulting obstruction


4. Tumors of the Middle Third
• usually require a total gastrectomy
• if the tumor is small and well-differentiated, it may be possible to preserve a small cuff of the upper stomach
• splenectomy and/or distal pancreatectomy for greater curve tumors may be required
• reconstruction is by a Roux-en-Y esophagojejunostomy, with or without the creation of a pouch



5. Tumors of the Upper Third
• most surgeons prefer total gastrectomy
• another option is a proximal subtotal gastrectomy, but this operation may leave behind nodes along the lesser curve
• need a generous esophageal margin with frozen section control
• another option is an esophagogastrectomy through a combined laparotomy-thoracotomy approach


6. Tumors of the Cardia and Gastroesophageal Junction
• management is controversial
• surgical options include total gastrectomy and esophagogastrectomy with anastomosis in the chest or neck
• an anastomosis in the chest is prone to reflux and life-threatening leaks
• an anastomosis in the neck can be performed using 3 different incisions: (1) right thoracotomy, (2) midline laparotomy, (3) left cervical
• alternatively, the thoracic dissection can be performed using the transhiatal approach, obviating a thoracotomy
• intestinal continuity is reestablished with a left (preferable) or right colon interposition


7. Extent of Lymphadenectomy
• remains an area of great controversy
• D1: perigastric nodes; has been the standard procedure in the US
• D2: D1 + removal of nodes along the left gastric, hepatic, celiac, and splenic arteries, as well as splenic hilar nodes
• D3: D1 + D2 + removal of periaortic and porta hepatis nodes
• multiple randomized trials have not shown a survival benefit with D2 versus D1 lymphadenectomy, or with D3 versus D2 lymphadenectomy
• more recent analysis suggests that a D2 lymphadenectomy may be beneficial if it can be done without the increased morbidity/mortality of a splenectomy and distal pancreatectomy



8. Chemotherapy and Radiation
1. Neoadjuvant Chemotherapy
• several recent studies from Europe have shown improved 5-year survival rates over surgery first for stage II and III disease
• one advantage of preoperative chemotherapy is that adequate postoperative chemotherapy is often limited by postoperative complications and slow recovery


2. Adjuvant Chemotherapy and Radiation
• postoperative chemotherapy alone is indicated for patients who have had a D2 lymphadenectomy
• for patients who have had less than a D2 lymphadenectomy, postoperative chemoradiation is indicated