i ri

Fig. 3.28 E-cadherin expression in gastric adenocarcinoma. A Intestinal type of adenocarcinoma showing a normal pattern of membranous staining. B Diffuse type of adenocarcinoma with reduced E-cadherin expression. Normal expression can be seen in the non-neoplastic gastric epithelium overlying the tumour. C Undifferentiated gastric carcinoma with highly reduced membranous expression and dot-like cytoplasmic expression.

growth factor, and K-sam {1879}. Amplification of c-erbB-2, a transmembrane tyrosine kinase receptor oncogene, occurs in approximately 10% of lesions and overexpression associates with a poor prognosis {375}. Telomerase activity has been detected by a PCR-based assay frequently in the late stages of gastric tumours and observed to be associated with a poor prognosis {719}.

Prognosis and predictive factors

Early gastric cancer

In early gastric cancers, small mucosal (< 4 cm), superficial (> 4 cm) and Pen B lesions have a low incidence of vessel invasion and lymph node metastasis and a good prognosis after surgery (about 90% of patients survive 10 years). In contrast, penetrating lesions of the Pen A type are characterized by a relatively high incidence of vessel invasion and lymph node metastasis and a poor prognosis after surgery (64.8% 5-year survival).

Advanced gastric cancer Staging. The TNM staging system for gastric cancer is widely used and it provides important prognostic information. Lymphatic and vascular invasion carries a poor prognosis and is often seen in advanced cases. Lymph node status, which is part of the TNM system, is also an important prognostic indicator. The 5th edition of the UICC TNM Classification of Malignant Tumours {66} and the AJCC Manual for the Staging of Cancer {1} published in 1997, have a number-based classification scheme for reporting nodal involvement in gastric cancer. Roder et al recently published data supporting the value of this reporting system. These authors found that for patients who had nodal involvement in 1-6 lymph nodes (pN1), the 5-year sur-

Fig. 3.29 CGH analysis of a poorly differentiated gastric adenocarcinoma: copy number gains at chromosomes 3q21, 7p15, 8q, 10p12-15, 11q13, 12q24, 13q13-14, 15q23-25, 17q24, 20 and 21q21. Copy number losses at chromosomes 4q12-28 and 5.

ptm┬╗scp SKutno^a

Fig. 3.30 TP53mutations in gastric carcinoma. The mutations are shown by both single-strand conformation polymorphisms (SSCP)as well as direct sequencing. There is a G to A substitution indicated by the right hand panel.

vival rate was 44% compared with a 30% survival rate in patients with 7-15 lymph nodes involved with tumour (pN2). Patients with more than 15 lymph nodes involved by metastatic tumour (pN3) had an even worse 5-year survival of 11% {1602}. Gastric carcinoma with obvious invasion beyond the pyloric ring, those with invasion up to the pyloric ring, and those without evidence of duodenal invasion have 5-year survival rates of 8%, 22%, and 58%, respectively {671}. Patients with T1 cancers limited to the mucosa and submucosa have a 5-year survival of approximately 95%. Tumours that invade the muscularis propria have a 60-80% 5-year survival, whereas tumours invading the subserosa have a 50% 5-year survival {2181}. Unfortunately, most patients with advanced carcinoma already have lymph node metastases at the time of diagnosis. Histological features. The value of the his-tological type of tumour in predicting tumour prognosis is more controversial. This relates in part to the classification scheme that is used to diagnose the cancers. Using the Lauren classification, some believe that diffuse lesions generally carry a worse prognosis than intestinal carcinomas. The prognosis is particularly bad in children and young adults, in whom the diagnosis is often delayed {1986, 1554} and likely fit into the category of HDGC. However, others have not found the Lauren classification to predict prognosis {1788, 1177}. One study found that only the Goseki classification {610} added additional prognostic information to the TNM stage {610}. 5-year survival of patients with mucus rich (Goseki II and IV) T3 tumours was significantly worse than that of patients with mucus poor (Goseki I and III) T3 tumours (18% vs. 53% p<0.003) {1177}. A second study validated these findings {1788}. Another classification scheme for gastric carcinoma was proposed by Carneiro et al that may also have prognostic value {610}. The recognition of mixed carcinoma may be important since patients harbouring this type of carcinoma may also have a poor outcome {610}.

Some patients with medullary carcinomas with circumscribed, pushing growth margins and a marked stromal inflammatory reaction exhibit a better prognosis than those with other histological tumour types {430}. Some of these patients are in HNPCC kindreds who have MSI-H, a feature associated with better survival. However, not all studies agree that stro-mal response and pushing margins predict a better prognosis {1788, 1177}. In summary, gastric carcinoma is a heterogeneous disease biologically and genetically, and a clear working model of gastric tumourigenesis has yet to be formulated. More tumours appear to be related to environmental than to genetic causes, although both may play a role in individual cases. Characterization of the various pathways should afford multiple opportunities to design more specific and therefore more effective therapies.

Endocrine tumours of the stomach CiPf

L.H. Sobin R. Arnold


Most endocrine tumours of the stomach are well differentiated, nonfunctioning enterochromaffin-like (ECL) cell carcinoids arising from oxyntic mucosa in the corpus or fundus. Three distinct types have are recognized: (1) Type I, associated with autoimmune chronic atrophic gastritis (A-CAG); (2) type II, associated with muliple endocrine neoplasia type 1 (MEN-1) and Zollinger-Ellison syndrome (ZES); type III, sporadic, i.e. not associated with hypergastrinaemia or A-CAG.

ICD-O Code


Small cell carcinoma

8240/3 8041/3


In the past, carcinoid tumours of the stomach have been reported to occur with an incidence of 0.002-0.1 per 100,000 population per year and to account for 2-3 % of all gastrointestinal carcinoids {587} and 0.3 percent of gastric neoplasms {1132}. More recent studies, however, based on endoscopic techniques and increased awareness of such lesions, have shown a much higher incidence of gastric carcinoids, which may now account for 11-41% of all gastrointestinal carcinoids {1588, 1764, 1782}. The incidence of gastric carcinoids is higher in Japan, where they re-present 30% of all gastrointestinal carcinoids, which may be due to the high incidence of chronic atrophic gastritis in this country {1277}.

Age and sex distribution

Type I gastric ECL-cell carcinoids have been reported to represent 74% of gastric endocrine tumours and to occur most often in females (M:F ratio, 1:2.5). The mean age at biopsy is 63 years (range 15-88 years). Type II ECL-cell carcinoids represent 6% of all gastric endocrine tumours and show no gender predilection (M:F ratio, 1:1) at a mean age of 50 years (range 28-67 years) {1590}. Type III ECL-cell carcinoids constitute 13% of all gastric endocrine tumours and are observed mainly in male patients (M:F ratio, 2.8:1) at a mean age of 55 years (range 21-38 years) {1590}. Small cell carcinoma (poorly differentiated endocrine carcinoma) accounts for 6% of gastric endocrine tumours and prevails in men (M:F ratio, 2:1) at a mean age of 63 years (range 41-61 years) {1590}. Gastrin cell tumours represent less than 1% of gastric endocrine tumours {1590} and are reported in adults (age range 55-77).


Gastrin has a trophic effect on ECL-cells both in humans and experimental animals {172, 652}. Hypergastrinaemic states, resulting either from unregulated hormone release by a gastrinoma or from a secondary response of antral G cells to achlorhydria, are consistently associated with ECL-cell hyperplasia {172}.

Autoimmune chronic atrophic gastritis (A-CAG)

This disease is caused by antibodies to parietal cells of the oxyntic mucosa. It leads to chronic atrophic gastritis (with or without pernicious anaemia) which leads to an increase in gastrin production.

Zolinger-Elison syndrome

This disease results from hypergastrinaemia due to gastrin-producing neoplasms that are preferentially located in the small intestine and pancreas. ECL-cell proliferation is usually limited to hyperplastic lesions of the simple linear type {1042, 1777}.

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