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Recurrence following curative resection for GC: updating.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

November 2002.     Review Article.    To the previous article

Recurrence after curative resection for gastric cancer remains high. Chew-Wun Wu et al examined its incidence and factors related to recurrence pattern, while trying to avoid the interaction of various factors. A total of 611 gastric cancer patients after resection for curative intent (1988-1995) were analyzed.The result showed that 245 patients had recurrence (40.1).
None of the patients received chemotherapy in conjunction with their surgery. The recurrence in these patients reflects mainly the effects of surgical treatment alone.

Current study showed that most (73.5%) recurrences took place within the first 18 months after surgery, with continued but markedly decreased attribution in the third year. Nearly 90% of the recurrences occurred within 3 years, and only 7.3% occurred between the third and fifth years. These data suggest that a close follow-up schedule may be needed in the initial 3 years after surgery.
Their findings appear to be in agreement with the concepts that hematogenous or lymphatic spreads without intra-abdominal metastases occur rarely. Current results revealed that 8.9% of patients had distant lymphatic recurrence alone and 26.8% of patients had hematogenous recurrence alone. Nevertheless, 44.9% of patients had locoregional recurrence, and 49.8% of patients had both locoregional and distant recurrences (single and multiple recurrence together). The authors found a 44.9% local recurrence rate, with the most common site of recurrence the hepatoduodenal ligament, followed by the gastric bed. Male gender and medullary-type stromal reaction were two independent factors negatively affecting locoregional recurrence.
From these observations it may be postulated that gastric cancer prefers to spread intra-abdominally, and that locoregional control is therefore an important issue in treatment strategy.
Peritoneal dissemination is a major pattern of therapeutic failure and its recurrence rate was 53.5% in this study. The authors found that serosal invasion, scirrhous-type stromal reaction, and female gender were three independent factors associated with peritoneal dissemination. Peritoneal recurrence appeared once the initial cancer cells had serosal involvement, and the concept that once the tumor has spread through the gastric wall, complete surgical removal of all subclinical deposits is difficult.
Chew-Wun Wu et al found, as have others that liver, and lung, and bone are the most frequently hematogenous metastatic organs. Liver metastases show a tendency to occur earlier, whereas lung and bone metastases occur later. The liver is the first filter of cancer cells through the portal venous blood flow of the stomach; the lung functions as a secondary filter. Their observation of alpha-type growth tumor preferential hematogenous recurrence was in accord with that previously described by Nihei et al., that hematogenous metastases are common in cases with differentiated type. Alpha-type growth tumor expands with a distinct border, in contrast with the gamma type, which has an indistinct border. Similar to the observation of Sano et al., the authors noted that hematogenous recurrence also occurred in the patients with early gastric carcinoma. These data suggest that hematogenous metastasis may occur either in early or late stages of cancer invasion. It is conceivable that chest roentgenograms and abdominal ultrasonography may be warranted in the follow-up period, in particular within the first 3 years after operation.
In gastric cancer patients, lymph node metastasis is frequently observed in the specimens resected at the time of the operation. It is difficult, however, to differentiate lymph node recurrence from local recurrence in the hepatoduodenal ligament and peripancreatic areas, either through image studies or exploratory laparotomy. They noticed that those patients who had lymph node metastasis after systemic lymphadenectomy were still at high risk of developing remote lymphatic metastasis.
It is conceivable that the patterns of recurrence and the times to recurrence provide a biological basis for clinical monitoring of patients with the aim of modifying therapeutic modalities ( 1, 2, 3 ).

Marrelli et al affirm that the possibility of predicting the risk and type of recurrence in patients with resectable gastric cancer could have important implications for therapy, both in the choice of surgical approach (extent of lymphadenectomy, partial or total resection) and in appropriately planning potential complementary therapies (systemic or locoregional adjuvant chemotherapy).
Their study revealed considerable differences in the patterns of recurrence after radical surgery between intestinal-type and diffuse-type gastric carcinomas. The main difference was found in the onset of peritoneal recurrence; this was observed in 34% of diffuse-type cases compared to 9% of intestinal-type cases, and was the main pathway of spread in the former. Compared to intestinal-type cells, the diffuse type showed a greater predisposition to proliferate in the peritoneum, considering that 50% of the cases with infiltration of the serosa led to peritoneal carcinomatosis, which was observed in only 16% of T3 and T4 intestinal-type cases. On the contrary, recurrences of intestinal-type tumors were mainly locoregional or hematogenous.

In light of the high risk of peritoneal recurrence, normothermic or hyperthermic intraperitoneal adjuvant chemotherapy may be indicated in diffuse-type cases subjected to radical surgery. Recent studies reported considerable improvement in long-term survival in cases treated with these techniques. However, these procedures are associated with an increased risk of complications and operative mortality; for this reason, careful selection of eligible patients is necessary. Given the results of their study, in diffuse-type tumors with a diameter over 4 cm such therapies may be indicated; these two parameters are easily obtainable either preoperatively or intraoperatively. In contrast, the risk of peritoneal recurrence was rather low (9%) in cases with a diameter of less than 4 cm, even in the diffuse type. Recent diagnostic techniques, such as endoscopic ultrasonography, and peritoneal cytology may be helpful for better defining patients at a high risk of peritoneal carcinomatosis.

The incidence of hematogenous recurrence did not show significant differences between the intestinal and the diffuse types; in both groups of patients, they observed a higher frequency of this recurrence in lymph node-positive cases, a finding in accord with other reports ( Yoo Ch et al. BJS 2000) . However, the degree of involvement in the various organs was different, because the intestinal type metastasized primarily to the liver, whereas in the diffuse type the liver was involved in only half of the cases; in the other cases, hematogenous metastases involved distant organs. This behavior is indicative of the greater capacity of diffuse-type cells to pass through the hepatic filter. The involvement of distant organs could also explain the tendency toward a longer median time of onset observed in hematogenous metastases in the diffuse type compared to the intestinal type The median time of onset in peritoneal or locoregional recurrences showed overlap between the two histotypes.

For locoregional recurrence, their study confirms the validity of subtotal gastrectomy in the treatment of distal diffuse-type neoplasms when an adequate margin of distance from the tumor is obtained and microscopic examination does not show infiltration of the resection margins; statistical analysis did not demonstrate the type of exeresis to be a prognostic variable in either group of patients. An intraoperative frozen section of the resection margin is advisable in questionable cases.
In their experience, the extent of lymphadenectomy was associated with a reduction in the risk of recurrence in the intestinal and diffuse types of gastric carcinoma. The author's data also suggest that in the diffuse type, but not in the intestinal type, superextended lymphadenectomy may play a more important role in reducing the risk of recurrence. As reported by others, the diffuse type shows a greater propensity than the intestinal type to metastasize to third- and fourth-level lymph nodes. However, because of the low number of cases treated by superextended lymphadenectomy and to the nonrandomized design of this study, further investigations are necessary.

Certain biological-molecular characteristics might strongly influence the different patterns of recurrence in the two histotypes. Indeed, the adhesion of neoplastic cells to the mesothelium is favored by the presence of surface molecules such as CD44, of which the expression is greater in poorly differentiated tumors. Poorly differentiated, scirrhous-type tumors frequently present an altered immunohistochemical expression of E-cadherin; the reduced expression of this molecule is strongly associated with the onset of peritoneal carcinomatosis, whereas tumors metastasizing to the liver generally present a normal expression of this molecule. A recent study reported that, in the intestinal type of gastric cancer, proliferative activity is greater in superficial layers than in deeper ones, whereas in the diffuse type it is increased in deeper layers and in tumors infiltrating the serosa, thereby resulting in a greater propensity for endoperitoneal spread. More in-depth studies might help to clarify the biological differences between the two histotypes that represent the basis for their different clinical behaviors ( 4, 5 ).

Satoshi Ohno et al affirm that advanced age, tumor invasion into subserosa, intestinal and mixed type of histology, Borrmann type 0 to 2, tumor diameter (<6.5 cm), and tumor marker (carcinoembryonic antigen and alpha-fetoprotein) elevation were related to liver recurrence. By logistic regression analysis, independent risk factors for liver recurrence included Borrmann's classification, histology, and tumor marker elevation. The median time from the primary operation to liver recurrence was shortest in the tumor marker elevation group when compared with other independent predictors ( 6 ).

Marrelli et al confirm that preoperative positivity for CEA, CA 19-9 and CA 72-4 is an indipendent risk factor for hematogenous recurrence of gastric carcinoma; this aspect should be considered in the option of using adjuvant chemotherapy after surgery for gastric cancer.
The effect of tumor marker positivity was indipendent of the presence of lymph node involvement.
Since recurrences of early stages of gastric cancer are usually hematogenous rather than locoregional or peritoneal, the results of the present study help to explain the prevalent prognostic value of tumor markers in the early stages of gastric carcinoma ( 7 ).
In a previuos study Marrelli et al. observed that preoperative positivity of tumor markers has an adverse effect on the prognosis of patients who have undegone surgery for gastric cancer, especially in stages I and II of the disease, similar to the observations of other authors as well ( 8 ).


1) Chew-Wun Wu et al. Incidence and Factors Associated with Recurrence Patterns after Intended Curative Surgery for Gastric Cancer. World J. Surg. 27, 153-158, 2003. Pub Med

2) Nihei Z, Hirayama R, Sakamoto M, et al. Histologic features of gastric cancer in relation to patterns of spread. Acta Chir. Scand. 1989;155:43-46. Pub Med

3) Sano T, Sasako M, Kinoshita T, et al. Recurrence of early gastric cancer. Cancer 1993;72:3174-3178. . Pub Med

4) Daniele Marrelli et al. Different Patterns of Recurrence in Gastric Cancer Depending on Lauren's Histological Type: Longitudinal Study. Volume 26, Issue 9, pp 1160-1165, 2002; World Journal of Surgery. Pub Med

5) F Roviello, D Marrelli et al. A prospective study of peritoneal recurrence after curative surgery for gastric cancer. British Journal Surgery ( In Press ).

6) Satoshi Ohno, Toshiyuki Fujii, Shuhei Ueda,Takeru Nakamoto, Shoichi Kinugasa, Hiroshi Yoshimura, Mitsuo Tachibana, Hirofumi Kubota, Dipok Kumar Dhar, Naofumi Nagasue. Predictive factors and timing for liver recurrence after curative resection of gastric carcinoma. The American Journal of Surgery 185 (2003) 258-263. Pub Med

7) D Marrelli, E Pinto, A De Stefano, G De Manzoni, M Farnetani, L Garosi, and F Roviello. Preoperative positivitÓ of serum tumor markers is a strong predictor of hematogenous recurrence of gastric cancer. Journ Surg Oncol 2001; 78: 253-258. Pub Med

8) Marrelli D, Roviello F, et al. Prognostic significance of CEA, CA 19-9, and CA 72-4 preoperative serum levels in gastric carcinoma. Oncology 1999; 57: 55-62. Pub Med

9) Ikeda Y, Mori M, Kajiyama K, et al. Indicative value of carcinoembryonic antigen (CEA) for liver recurrence following curative resection of stage II and III gastric cancer. Hepato-gastroenterology 1996; 43:1281-7. Pub Med

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