December 2002. Review Article.
In 1993, Wanebo et al. reported a 35% survival rate for pathologically confirmed completely resected (R0) gastric adenocarcinoma from a database of 18,365 patients. This finding was corroborated in more recent reports by Siewert et al.and Hansson et al. These and other large studies demonstrate that presence of lymph node metastases is the single most important prognostic finding in completely resected early and advanced gastric adenocarcinoma
( 1,
2,
3,
4 ) .
Kooby et al.( Memorial Sloan Kettering Cancer Center ) demonstrate that a significant proportion ( 40% ) of Western patients undergoing R0 resection will have node-negative disease. Survival for this group of patients is remarkably better (DSS = 79 2% at 10 years) than for their node-positive counterparts, irrespective of T stage. Some of these patients, however, will still go on to die of disease. Defining the biologic determinants of survival for patients with node-negative disease in a Western center was the primary objective of their study.
Proper staging of gastric cancer requires standard H&E histologic evaluation of at least 15 lymph nodes in the resected specimen to be considered N0, according to the fifth edition of the AJCC TNM classification. This criterion remains unchanged in the recently released sixth edition
( 1,
8 ).
Advanced T stage (or serosal involvement) was the most consistent negative predictor of survival in all reports.
The second most powerful indipendent predictor of poor outcome in this study was presence of vascular invasion. The incidence of VI was similar for T2-T4 tumors (20-22%) and slightly lower in T1 tumors (9%); thus, the progression of gastric wall invasion appeared to have little bearing on the presence of this finding. Furthermore, mean tumor size was equivalent (3.99 vs. 3.93 cm) whether VI was present or absent in this study, suggesting that in node-negative gastric cancer, VI identifies biologically more aggressive lesions independent of tumor size or depth of invasion
( 1 ).
Maheara et al. reviewed 730 records of patients with node-negative disease between 1965 to 1990. Similarly, they found VI present in 20% of specimens. Although the presence of VI was a significant finding on univariate analysis, it was not an independent predictor of survival on multivariate analysis. In this study, patients were not stratified by number of nodes evaluated, as it was performed before acceptance of this staging method, so it is likely that some node-positive patients were included in their analysis. In addition, VI was not routinely evaluated before 1970 and data collection was not complete with respect to this variable
( 1,
5 ).
More recently, Hyung et al. reported their experience with VI in node-negative disease in Korea. In this study only adequately staged patients with T2-T4 lesions were evaluated, and again, the incidence of VI was similar (20%). Their findings were similar to the observations of the Kooby analysis with respect to the poorer prognosis associated with advanced T stage and presence of VI.
A possible explanation of why patients with VI are more likely to die from disease is that they are more prone to develop metastatic disease
( 1,
6 ).
Maehara et al. affirm that gastric cancers with characteristics of vascular invasion have greater intratumoral angiogenesis and that VEGF and p53 overexpression is associated with intratumoral angiogenesis and metastases to distant organs
(12 ).
In the Chiung-Nien Chen et al. study, higher MVD was correlated with positive vascular invasion, depth of tumor invasion, positive lymph node metastasis, diffuse type cancer, and positive Helicobacter pylori infection. Vascular invasion
was the only factor that significantly correlated with MVD in multivariate analysis, and was also an independent prognostic factor. However, MVD was not an independent prognostic factor. Vascular invasion is a well-known factor for
hematogenous metastasis and is also an independently prognostic factor in gastric cancer.Local shedding of cancer cells into the tumor vascular stream that can commence at the onset of angiogenesis is quantitatively related to the
surface area of intratumoral vessels. The CDVI as a measure of global vascularity of the tumor might better reflect the surface area of intratumoral vessels. In the
present study, the patients with vascular invasion had significantly higher CDVI than those without. Poor prognosis of high CDVI patients may be related with hematogenous spreading for high frequency of vascular invasion. This may be the reason why high CDVI can predict early death in patients with stage III gastric cancer.
Thus, the preoperative CDVI in advanced gastric cancer patients may help to identify patients for appropriate pre-operative chemotherapy. Other than chemotherapy, different types of antiangiogenic compounds have been developed and shown to inhibit angiogenesis and the growth of some tumors in preclinical trials and a few compounds are further down the clinical road. Such agents may be
valuable in enhancing the efficacy of preoperative chemotherapy
of advanced gastric cancer patients with high CDVI tumors
( 16 ).
Yasuda et al indicate that micrometastasis of four or more lymph nodes or micrometastasis of extragastric (level 2) lymph nodes correlates with tumor
progression and with a poor 5-year survival rate among patients with histologically node-negative gastric cancer (T2 and T3). These additional parameters are useful
prognostic indicators of the risk for recurrence and may be helpful for deciding treatment strategies for adjuvant chemotherapy
( 17 ).
Neural invasion is known to be an indicator of poor outcome in cancers of the breast, biliary tract, colon and rectum, pancreas, prostate, skin, and others. It is thought that cancer cells breach the perineurium at sites of vascular ingrowth and that this offers another potential route of dissemination.
Kooby et al observed both a correlation between T stage and presence of NI, as well as a correlation between presence of NI and tumor size . Thus, they speculate that NI represents a marker of advanced tumor stage, in contrast to the biologically aggressive phenotype suggested by VI.
Duraker et al.confirm that although the incidence of PNI is high in gastric carcinoma and increases with the progression of disease, it does not provide any additional information to the classical prognostic parameters
( 1,
9 ).
Kooby et al found no association between age and survival in node-negative gastric cancer, but they observed an independent association between male gender and poor prognosis. The recent report by Hyung et al. suggested such an association, although it failed to reach statistical significance
( 1,
6 ).
Finally, Kooby et al. found that patients who underwent DSG had better survival than patients who underwent proximal subtotal, esophagogastric, or total gastrectomy. Interestingly, tumor site ( proximal vs. distal ) failed to demonstrate a significant association in this analysis. Perhaps this can be explained by the cohort of patients (n = 42) who required total gastrectomy for large distal tumors, and the "distal" designation was thus less relevant than the procedure performed
( 1 ).
The question of extent of lymphadenectomy in node-negative gastric cancer has been examined before. Memorial Sloan Kettering Surgery Department previously reported that extended lymphadenectomy ( > o/ = D2) benefitted the subset of patients with T3N0 disease but did not benefit the node-negative group as a whole. Their current report concurs with this finding in a larger number of patients and demonstrates an even greater survival advantage for adequately staged T3N0 patients (5-year survival 60% vs. 25%, P = .03, data not shown). A recent analysis performed by the German Gastric Cancer Group suggested that D2 lymphadenectomy may benefit the T2 and T3 node-negative subsets of patients by removing micrometastases.The value of this information, however, is clinically limited, as it remains impossible to determine nodal status preoperatively adenocarcinoma
( 1,
3,
7, 10, 11 ).
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