This topic refers to gastric adenocarcinoma, the most common type of stomach neoplasm.
- Second most common cancer in the world (in 1990)
- Decreasing in frequency
- Marked geographical variation - rates are up to 20 times higher in Japan than in some Western countries
- Higher incidence in developing countries (60% of cases)
- Diffuse subtype more common in women
- Diet the most frequently quoted factor
- Fruits and vegetables are protective
- High salt foods are associated with higher risk
- H. pylori infection is thought to be an important causative agent
- H. pylori genes are associated with the development of carcinogenesis
- H. pylori increases cellular proliferation, and important driver of carcinogenesis
- H. pylori increases the activity of free radicals in the stomach, increasing the rate of mutation
- Chronic bile reflux is a rare cause
- Autoimmune gastritis can also increase the incidence of gastric carcinoma
- There are several genetic associations:
- Heterozygous mutations of the E-cadherin gene are associated with a higher risk of gastric cancer
- Hereditary non-polyposis colon cancer syndrome (HNPCC) patients have a higher incidence of gastric cancer due to microsatellite instability
- Other polyposis syndromes can cause carcinoma to develop in the stomach (eg. familial adenomatous polyposis)
- Patients with blood group A+ have an increased incidence of gastric carcinoma, possibly due to interaction of H. pylori with the antigen.
Atrophic gastritis and autoimmune gastritis are both associated with development of malignancy.
Intestinal metaplasia occurs when the epithelial cells of the stomach transform into a different structure resembling that of the stomach; this often occurs in response to atrophic gastritis.
Gastric intraepithelial neoplasia is a pre-malignant condition where neoplastic cells are limited to the epithelium. About 80% of these cases progress to invasive disease.
Modes of Spread
Local invasion most often occurs into the duodenum, but can also occurs to neighbouring organs such as the pancreas.
Lymphatic spread is common for all carcinomas and occurs to the coeliac nodes. Spread along lymphatics within the stomach can occur up to 5 cm from the macroscopic tumour.
Haematogenous spread is more common in the intestinal subgroup of carcinoma, usually involving the liver.
Transcoelaemic spread occurs with involvement of the peritoneal cavity, most frequently with diffuse type carcinomas.
A known presentation is with large bilateral ovarian metastases through haematogenous or transcoelaemic routes - this is known as a Krukenberg tumour.
Symptoms are uncommon until advanced disease has developed. A number of patients have non-specific dyspepsia. Pain that is worsened by eating, or that does not completely resolve, is associated with malignancy in some cases. Haematemesis and gastric outlet obstruction are uncommon but helpful symptoms. Weight loss and anorexia suggest metastatic disease.
A mass may be palpable in the upper abdomen. Important signs for advanced disease include hepatomegaly and supraclavicular lymphadenopathy (Virchow's node).
Bloods may show anaemia and iron deficiency; liver metastases may lead to abnormalities in liver function tests.
CT staging is essential to determine the extent of disease (liver or nodal involvement).
PET scanning allows detection of occult distant disease.
Gastric carcinoma has four macroscopic patterns:
- Polypoid, forming a exophytic lesion that extends into the stomach lumen
- Fungating, where a polypoid lesion has extensive central ulceration
- Ulcerating, where the appearance is an ulcer in the gastric wall.
- Diffuse, where tumour infiltrates the mucosa and submucosa of the stomach wall widely. This type is most commonly associated with signet ring adenocarcinoma variant.
Microscopy can be classified based on WHO or Lauren systems. Rare variants fall outside these categories.
WHO divides tumours into several types:
- Tubular adenocarcinoma, comprising tubular structures lined by cuboidal cells that may form acini
- Papillary adenocarcinoma, which is usually exophytic, and formed by finger like processes lined with cuboidal cells
- Mucinous adenocarcinoma, characterised by large mucin lakes
- Signet ring adenocarcinoma, characterised by a large population of signet ring cells (intracytoplasmic mucin, peripheral nucleus)
Rare variants include adenosquamous, squamous, and undifferentiated carcinoma.
The Lauren classification is simpler:
- Intestinal type tumours form discrete masses and the malignant cells form glandular structures. This tumour arises from intestinal metaplasia. These tumours are typically tubular, papillary or mucinous adenocarcinomas.
- Diffuse type tumours are poorly cohesive and infiltrate widely throughout the mucosa and submucosa. Cells are often located singly, and a desmoplastic stromal reaction is seen. This category includes most of the signet ring adenocarcinomas in the WHO classification.
- Mixed tumours exhibit both patterns
Gastric carcinoma has a variable staining pattern for CK7 and CK20, but trends towards CK7+/CK20- (although cases of CK7+/CK20+ and CK7-/CK20- exist). E-cadherin staining is negative for most signet ring/diffuse adenocarcinomas.
TP53 mutations are common in all cases. Germline mutation of CDH1, which codes for the E-cadherin protein, is associated with an elevated risk of diffuse gastric carcinoma. Sporadic cases of diffuse adenocarcinoma have deactivating mutations of CDH1 or expression is reduced by hypermethylation. In contrast, mutations in AFP (eg. familial adenomatous polyposis) are associated with intestinal type adenocarcinomas.
Gastric carcinomas are staged according to the TNM system.
T1: Confined to mucosa (T1a) or submucosa (T1b)
T2: Invasion into muscularis propria
T3: Invasion through muscularis propria
T4: Invasion through serosa (T4a) or into adjacent organs (T4b)
N1: 1-2 nodes
N2: 3-6 nodes
N3: 7+ nodes
M1: Distant metastases