CiteSeerX — Lymph Node Count

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Lymph-node involvement is a crucial variable in gastric malignancy it being associated with an unfa- vorable outcome. The number of metastatic regional lymph nodes has been shown to be a significant prognostic factor after curative resection of gastric cancer and has been adopted by the UICC 1997 nodal stage classification of gastric cancer (1-3). The probability of identifying node-positive cancers increases with the number of lymph nodes resected and examined (4, 5).

Thus, the extent of lymphadenectomy is considered to be another critical factor for gastric cancer outcome.

However, much controversy exists concerning the optimal extent of lymph-node dissection. According to some authors, extended lymph node dissection, with complete removal of perigastric and extraperigastric nodes, results in improved survival rates (6, 7). Others

have demonstrated that the status of perigastric lymph nodes, which are always dissected irrespective of the type of lymph-node dissection performed, can provide adequate prognostic information (8, 9).

In the present investigation, an attempt is made to establish whether the number of metastatic regional nodes, irrespective of peri- or extraperigastric location, could be a prognostic indicator of curatively resected gastric cancers.

Patients and Methods

A retrospective analysis has been made on 154 patients who underwent curative resection of gastric carcinoma, at the Department of Surgery "Pietro Val-

Lymphadenectomy in Gastric Cancer: Influence on Prognosis of Lymph Node Count

A. Giuliani, A. Caporale, M. Corona, M. Di Bari, M. Demoro, T. Ricciardulli, P. Gozzo, G. Galati, A. Tocchi Dept. of Surgery "Pietro Valdoni", University "La Sapienza", Rome, Italy

To better understand the role of the number of lymph nodes retrieved on long-term outcome of gastric cancer treatment, 154 patients who had undergone curative resection, with dissection of >15 nodes were retrospectively studied. Dissection of perigastric and extraperigastric lymph nodes, defined as ‘extended’ (>26 nodes dissected) in 39 cases and ‘limited’ (≤26 nodes dissected) in 115 cases, was performed. A total of 3479 lymph nodes (mean 22.6 per specimen), were dissected and of these 721 showed metastases. A mean of 8.1 lymph node metastases, per metastatic case, was found. Regression analysis showed no independent factor associated with the extent of lymphadenectomy. Depth of wall invasion (p=0.000) and histological growth pattern (p=0.044) were indepen- dently associated with the number of lymph nodes involved (pN0, pN1 1-7, pN2 >7). The cumulative 5-year survival rate was 47% in patients without lymph node metastases; 29% in those with 1-7 nodes involved and 17%

in those with >8 nodes involved (p=0.002). Receiver operating characteristic (ROC) curve analysis, in 65 node- negative cancer cases, demonstrated an area under the curve for vital status (alive or dead) of 0.602 (95% CI:

0.473 - 0.721). All node-negative cases with a number equivalent to or exceeding the cutoff point of 23 nodes were alive. ROC analysis showed 11 to be the cutoff number of metastasized lymph nodes in correlation with vital status. Almost all those patients in whom the number of positive nodes was equivalent to, or exceeded the cutoff point had died (area under the ROC curve 0.633; 95% CI: 0.524 - 0.733). ROC analysis showed that the cutoff lymph node ratio, in relation to vital status, was 0.33. The majority of patients at or above this cutoff point had died (area under ROC curve 0.682; 95% CI: 0.574 - 0.776). Multivariate survival analysis showed that lymph node ratio was the only independent prognostic factor (p=0.001). The present findings suggest that, in lymphadenectomy with at least 15 nodes, the number and status of regional nodes dissected, irrespective of the location, provide reliable prognostic information on curatively resected gastric carcinomas.

Key Words: Gastric cancer, Lymphadenectomy, Lymph node count

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doni" Rome University "La Sapienza" between 1992 and 1998. "Curative" was used to define a resection in which the tumor was shown to be completely removed, at intraoperative and histopathological evaluation.

Cases showing macroscopic serosal involvement, those with tumors invading adjacent structures and those with <15 lymph nodes examined in resected specimens were excluded. Patients who had died, in the postoperative course, as well as those with incom- plete survival information were also excluded.

Data concerning the age and sex of patients, site and size of the tumor, type of gastric resection and extent of lymph node dissection, histological type, grading, depth of wall invasion, number of lymph nodes examined, lymphatic and perineural microinvasion as well as stromal reaction were obtained from clinical and surgical records and from histopathologic reports. All surgeons taking part in this study were from the same surgical team and effected, to the best of their ability, standardised lymph node dissection. Thus, in patients undergoing subtotal gastrectomy, node dissection included the nodes along the lesser and greater curvatures, supra- and infrapyloric nodes and those along the left gastric and common hepatic arteries. In some subtotal gastrectomies, nodes at the splenic hilum and at the hepatoduodenal ligament were also removed. Node dissection including right and left car- dial nodes, those along the lesser and greater curvatures, those supra- and infrapyloric, those along the left gastric, common hepatic and celiac arteries and those at the splenic hilum had also been carried out, in total gastrectomized patients. In some total gastrectomies, nodes along the splenic artery and the hepatoduodenal ligament were also removed. Distal gastrectomy was performed when a safe proximal margin was feasible, otherwise total gastrectomy was carried out.

Distal pancreas and spleen were left in situ unless directly involved. Histopathological examinations were all performed by the same pathologist. All lymph nodes from resected specimens were retrieved using routine techniques (inspection, palpation and serial sections). Removal of >26 nodes was defined as complete or extended lymphadenectomy while removal of ≤26 nodes was defined as standard or limited node dissection (10-13).

The node-positive cancers were classified, according to the number of nodes involved, into: pN1= 1 to 7 positive nodes; pN2 >8 positive nodes.

Survival information was obtained by means of direct contact with the patient or family members.

At the time of this report, 71 patients (46%) had died, the death of 53 of them was related to gastric can-

cer (74%) and of 18 to other diseases or unknown caus- es (26%). Median overall survival was 32 months (range: 1-122). Median survival of the patients that died was 14 months (range: 1-93 months); median survival of the remaining patients was 46 months (range:

16-122).

Differences between the groups were analyzed for statistical significance using the chi-square test. Logis- tic regression analysis was performed to analyze independent variables associated with the number of lymph nodes. Receiver Operating Characteristic (ROC) curve analysis was performed to detect the cutoff number of lymph nodes predictive of survival or death and the discriminating values with 95% specificity. Cumula- tive survival rates were calculated using the Kaplan- Meier method and compared with the log rank test.

Cox technique was used for the multivariate survival analysis. Significance was established at p<0.05.

Results

A total of 3479 lymph nodes were removed and examined, with a mean number of 22.6 lymph nodes examined per gastrectomy specimen. Of the 154 resected specimens, 89 presented 721 metastatic lymph nodes; the mean number of involved nodes was 8.1 per specimen.

The clinicopathological characteristics of the patients, as far as the extent of lymphadenectomy and number of lymph nodes involved is concerned, are summarized in Tables I and II.

Regression analysis, including the parameters found to be significant in table I, revealed that the only independent factor associated with the extent of lymphadenectomy was the type of gastrectomy (p=0.021).

Regression analysis of the variables found to be significant in table II showed that depth of wall invasion (p=0.000) and the histological growth pattern (p=0.044) were independent factors associated with the number of lymph nodes involved (Table III).

There was no significant difference in cumulative survival between cases with >26 lymph nodes examined and those with ≤26 lymph nodes examined.

The cumulative survival curves showed a significant difference to the number of metastatic lymph nodes (Fig. 1).

ROC analysis demonstrated, in the 65 node-negative patients, an area under the ROC curve, for vital status (alive or dead), of 0.602 (95% CI: 0.473 - 0.721). The cutoff number of lymph nodes removed and examined, affecting survival, was 23. All the node-

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Table I - Clinicopathological characteristics of 154 gastric cancer patients in relation to the extent of lymph-node dissection

Dissection

Variable N. ≤26 N. >26 p value

Age (years)

<66 54 17

>65 61 22 NS

Sex

male 77 22

female 38 17 NS

Site

Distal third 82 21

Middle third 18 14

Upper third 15 4 0.027

Size

<26 mm 47 10

26-50 mm 42 13

>50 mm 26 16 0.023

Gastrectomy

distal 76 16

total 39 23 0.006

Depth of wall invasion

mucosa and submucosa 32 6

muscularis propria and subserosa 76 26

serosa 7 7 0.019

Grade

G1 9 1

G2 47 13

G3 59 25 NS

Histological growth pattern

expansive 51 17

infiltrative 68 28 NS

Lauren classification

intestinal 61 24

diffuse 53 16 NS

Lymphatic microinvasion

absent 94 27

present 21 12 NS

Perineural microinvasion

absent 102 29

present 13 10 0.030

Stromal reaction

present 58 16

absent 51 29 0.046

NS: not significant

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Table II - Clinicopathological characteristics of 154 gastric cancer patients in relation to status and number of lymph nodes involved

Variable N 0 N+ 1-7 N+ >8 p value

Age (years)

<66 32 21 18

>65 33 33 17 NS

Sex

male 40 38 21

female 25 16 14 NS

Site

distal third 48 34 21

middle third 11 12 9

upper third 6 8 5 NS

Size

<26 mm 33 17 7

26-50 mm 17 24 14

>50 mm 15 13 14 0.016

Gastrectomy

distal 40 35 17

total 25 19 18 NS

Depth of wall invasion

mucosa and submucosa 31 7 0

muscularis propria and subserosa 31 44 27

serosa 3 3 8 0.000

Grade

G1 9 1 0

G2 29 24 7

G3 27 29 28 0.001

Histological growth pattern

expansive 39 23 6

infiltrative 27 36 33 0.000

Lauren classification

intestinal 43 30 12

diffuse 21 24 24 0.005

Lymphatic microinvasion

absent 57 42 22

present 8 12 13 0.004

Perineural microinvasion

absent 61 46 24

present 4 8 11 0.001

Stromal reaction

present 39 23 13

absent 19 35 26 0.001

NS: not significant

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Table III - Regression analysis of potential risk factors for number of lymph nodes involved

Variables * Coefficient Standard error Odds ratio p value

Histological growth pattern -0.032879 0.096740 -0.33988 NS

Lauren classification 0.195402 0.096245 2.03026 0.044158

Stromal reaction -0.105784 0.073628 -1.43674 NS

Grading 0.102790 0.095746 1.07357 NS

Depth of wall invasion 0.319659 0.083762 3.81626 0.000200

Lymphatic microinvasion 0.021260 0.102730 0.20695 NS

Perineural microinvasion 0.121223 0.103924 1.16646 NS

Size 0.039529 0.080158 0.49314 NS

* Significant factors in Table II included in regression analysis.

Fig. 1 - Cumulative survival curves according to number of lymph nodes involved. (pN0 = negative nodes; pN1 = 1 - 7 positive nodes;

pN2 = positive nodes > 8). p=0.0001 (log rank test).

Cumulative Percent Survival

Months after surgery

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negative cases, with a number of nodes equal to or above the cutoff point, are alive (sensitivity=100%;

specificity 32.7%; predictive value 100%). The cumulative survival curves for node-negative patients, according to the number of nodes examined, are shown in Figure 2.

In the 89 node-positive cases, 17 was found to be the cutoff number of removed lymph nodes that influenced the vital status. The node-positive patients with a number of nodes equal to or above the cutoff value had longer, albeit not statistically significant, survival (sensitivity=64.5%; specificity=46.6%; predictive value 71.1%). The area under the ROC curve was 0.551 (95% CI: 0.442 - 0.657).

The cutoff number of metastasized lymph nodes in relation to vital status was 11. All patients presenting a number of positive nodes, at or above the cutoff limit had died (sensitivity=87.1%; specificity=36.2%; predictive value 84.0%). The area under the ROC curve was 0.633 (95% CI: 0.524-0.733). Cumulative survival curves, according to number of lymph nodes involved, are shown in Figure 3.

The cutoff lymph node ratio (number of involved

nodes divided by number of removed nodes) in the 89 node-positive cases influencing the vital status was 0.33. Almost all the patients, at or above this cutoff ratio, have died (sensitivity 77.4; specificity 58.6; predictive value 82.9). The area under the ROC curve was 0.682 (95% CI: 0.574 - 0.776). Cumulative survival curves according to lymph node ratio are shown in Fig- ure 4.

A multivariate survival analysis, using Cox's pro- portional hazard model, which included the number of lymph nodes dissected, the extent of lymph node dissection, the number of positive nodes and the lymph node ratio, revealed that the lymph node ratio was the only independent predictor of prognosis (Table IV).

Multivariate analysis failed to reveal any independent predictor of prognosis in node-negative cancers.

Discussion

The most important factors for survival of gastric cancer patients are distant metastases and lymph node involvement. Lymph node status is, therefore, a critical

Fig. 2 - Cumulative survival curves in node-negative cases according to the number of lymph nodes dissected.

p=0.0001 (log rank test).

<23 Dissected nodes

>23 Dissected nodes

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prognostic variable in potentially curable cases. Classi- fication of node involvement, based on the anatomical location of nodes (10, 14) with respect to the index tumor, has been criticized on account of the complexi- ty and unclear boundaries, at surgery as well as on resected specimens, between the adjacent located stations and thus, the possibility of unreliable or subjec- tive interpretation of lymph node status. The theory that the extent of lymphadenectomy was defined by the regional lymph node areas was, therefore, challenged.

Furthermore, the prognostic impact of the number of positive lymph nodes was more important as compared to their location and that the level of positive lymph nodes was reported to be a variable dependent upon their number (15). Node classification has, therefore, been redefined according to the number of metastatic (3) nodes rather than to their location. The advantages of this new classification are simplicity, reliability, reproducibility and a more accurate estima- tion of prognosis (16-18). The probability of identifying node-positive cancer is related to the number of dissected and examined nodes i.e., the extent of surgical node removal, and the optimization of pathologic

node retrieval, from the surgical specimen, determines the number of nodes to be attributed to the individual patient. Japanese authors, on the basis of studies of lymphatic flow, nodal spread of the cancer cell and of long term results, have recommended extensive lym- phadenectomies (6, 19-21). Western authors, on the other hand, in prospective randomised trials, compar- ing limited and extended node dissections, showed a significant increase in postoperative morbility and mortality rates in extended dissections and no significant improvement in survival (22-26). The optimal extent of node dissection is still controversial. The question to be asked is: How many nodes need to be dissected to curatively resect gastric cancer?

The aim of the present study was to establish whether, in gastric cancer patients, operated on with a curative intent, the number of resected lymph nodes, irrespective of their location, could be considered a prognostic indicator and if it might be possible to determine a cutoff number of dissected nodes from which to glean reliable prognostic information. The results of anatomical investigations, despite demon- strating a considerable variation both in the total num-

Fig. 3 - Cumulative survival curves according to the number of positive nodes.

P=0.00813 (log rank test).

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ber of nodes and in the number of nodes per station, showed that an average of 27 nodes might be expected to be found in a specimen when dissection of stations 1-11 of the JRSGC is performed (13). Furthermore, removal of >26 nodes was defined as extended lym-

phadenectomy while dissection of ≤26 nodes was defined as standard lymphadenectomy. However, it should also be taken into consideration that the number of lymph nodes examined per surgical specimen, depends not only on the surgeon's skill, but may also

Fig. 4 - Cumulative survival curves according to lymph node ratio (involved nodes/dissected nodes).

p=0.00506 (log rank test).

Table IV - Multivariate survival analysis for independent prognostic factors

Coefficient Standard error Odds ratio p value Overall number of lymph nodes dissected -0.002111 0.014366 -0.146973 NS Extent of lymphadenectomy (≤26; >26) -0.029509 0.219433 -0.134480 NS Number of positive nodes

(N 0; N+ 1-7; N+ >=7) 0.284506 0.338307 0.840971 NS

Lymph node ratio

(node-dissected/node-positive) 1.990053 0.656622 3.030743 0.001

NS: not significant

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be related to the histological retrieval technique employed and a meticolous search for the nodes by the pathologist. The mean number of nodes retrieved, in our patients, was far lower than the mean number of nodes reported by others (18, 27) even if it was suffi- cient to provide the prognostic information related to node status. We used the number of lymph nodes as a diagnostic test. The population of the node-negative cases, on the one hand, and the node-positive cases, on the other, although both submitted to curative surgery, included individuals with different prognosis.

In gastric cancer patients, a number of nodes with the sensitivity to detect successfully treated cases and, therefore, with a favorable longterm outcome and, on the other hand, incurable cases and, therefore, with a poor survival, could be feasible.

From a theoretical point of view, in node-negative cases, lymph node dissection could be omitted while in some node-positive cases, lymph node dissection, however extended, could be inadequate. Although the areas under the ROC curves were not large, in our study population, lymph-node dissection of >23 nodes in negative-node cancers led to optimal survival, while dissection of >11 or more positive-nodes did not lead to any prognostic benefit. It is difficult to explain the survival benefit in negative-node cancers following dissection of a larger number of uninvolved nodes with respect to that recommended by the 1997 UICC TNM classification (3). As observed also by others, negative nodes, at routine histological examination, were fre- quently found to contain isolated malignant cells at reverse transcriptase-polymerase chain reaction and immunohistochemical techniques with monoclonal antibodies (28, 29). Removal of a large number of apparently uninvolved nodes, possibly eliminating this malignant microinvolvement, resulted in improved prognosis. Some authors have suggested that these findings form the theoretical basis for the routine application of "prophylactic" extended lymphadenectomy (30). However, in our node-negative cases, multivariate analysis failed to reveal any independent predictor of survival.

We are aware that the number of nodes is a contin- uous variable and that cutoff points vary in relation to the characteristics of the cases examined. Our cutoff values are not, therefore, universally acceptable. How- ever, the results of the present study lead us to believe that the extent of lymphadenectomy, as performed in our surgical Unit, which is similar to the one carried out in the majority of Western countries, is therapeuti- cally adequate in gastric cancer patients submitted to curative resection. It is not certain that more extended

lymph node dissection is more accurate as far as the stage is concerned but would probably not improve long-term survival.

In the present study, the multivariate analysis identified the ratio of involved to dissected lymph nodes as the strongest prognostic node-related factor for survival. Other authors have identified this factor as a powerful prognostic factor in gastric cancer (31). How- ever, it would appear that the lymph node ratio, which is influenced more by the extent of node resection than by other node-related factors, requires at least 15 lymph nodes to be dissected and histologically studied, in order to provide reliable data.

In conclusion, data emerging from this study suggest that:

- lymph node classification, taking into account the number and status of dissected regional nodes, irrespective of the location, is effective in providing reliable prognostic information in gastric carcinomas submitted to curative resection;

- extended lymph node dissection (> 26 nodes) does not appear to improve the survival rate;

- a cutoff number of nodes to be dissected can be defined in node-negative, as well as in the node-positive cancers which would be useful in providing reliable survival information;

- there is a cutoff number of involved nodes above which no survival benefit can be guaranteed;

- there is a cutoff lymph node ratio able to provide useful prognostic information.

References

1. Maruyama K.: The most important prognostic factors for gastric cancer patients: a study using univariate and multivariate analyses. Scand. J. Gastroenterol. suppl. 22: 63-68, 1987.

2. Soreide J.A., Van Heerden J.A., Burgart L.J. et al.: Surgical as- pects of patients with adenocarcinoma of the stomach operated on for cure. Arch. Surg. 131: 481-486, 1996.

3. Sobin L.H., Wittekind C.: TNM classification of malignant tumors, International Union Against Cancer (UICC), 5th edn.

New York, Wiley and Sons, pp 59-62, 1997.

4. Lee H.K., Yang H.K., Kim W.H. et al.: Influence of the number of lymph nodes examined on staging of gastric cancer.

Br. R. J. Surg. 88: 1408-1412, 2001.

5. Bunt A.M., Hermans J., Van de Velde C.J. et al.: Lymph node retrieval in randomized trial on Western-type versus Japanese- type surgery in gastric cancer. J. Clin. Oncol. 14: 2289-2294, 1996.

6. Maruyama K., Okabayashi K., Kinoshita T.: Progress in gastric cancer surgery in Japan and its limits of radicality. World J. Surg. 11: 418-425, 1987.

7. Soga J., Ohyama S., Miyashita K. et al.: A statistical evalua-

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tion of advancement in gastric cancer surgery with special references to the significance of lymphadenectomy for cure.

World J. Surg. 12: 398-405, 1988.

8. De Liaño A.D., Ciga M.A., Ofeiza F. et al.: The value of D1 lymphadenectomy as prognostic marker in gastric cancer. He- patogastroenterology 48: 895-898, 2001.

9. Kim T.H., Han S.U., Cho Y.K., Kim M.W.: Perigastric lymph node status can be a simple prognostic parameter in patients with gastric cancer. Hepatogastroenterology 47:1475-1478, 2000.

10. Kajitani T.: Japanese Research Society for Gastric Cancer. The general rules for the gastric cancer study in surgery and pathol- ogy. Jpn. J. Surg. 11: 127-139, 1981.

11. Oñate-Ocaña L.F., Aiello-Crocifoglio V., Mondragon-Sanchez R., Ruiz-Molina J.M.: Survival benefit of D2 lymphadenectomy in patients with gastric adenocarcinoma. Ann. Surg. Oncol.

7: 210-217, 2000.

12. Siewert J.R., Bottcher K., Roder J.D. et al.: Prognostic rele- vance of systematic lymph node dissection in gastric carcinoma. German Gastric Carcinoma Study Group. Br. J. Surg. 80:

1015-1018, 1993.

13. Wagner P.K., Ramaswamy A., Ruschoff J., Schmitz-Moor- mann P., Rothmund M.: Lymph node counts with upper ab- domen: anatomical basis for lymphadenectomy in gastric cancer. Br. J. Surg. 78: 825-827, 1991.

14. Hermanek P., Sobin L.H.: TNM classification of malignant tumors, 4th edition. Berlin: Springer, 1992

15. Adachi Y., Kamakura T., Mori M. et al.: Prognostic significance of the number of positive lymph nodes in gastric carcinoma. Br. J. Surg. 81: 414-416, 1994.

16. Ichikura T., Tomimatsu S., Okusa Y., Usefuji K., Tamakuma S.: Comparison of the prognostic significance between the number of the metastatic lymph nodes and nodal stage based on their location in patients with gastric cancer. J. Clin. Oncol.

11: 1894-1900, 1993.

17. Kim J.P., Jung S.E.: Patients with gastric cancer and their prognosis in accordance with number of lymph node metastasis. Scand. J. Gastroenterol. 22 (s133): 33-35, 1987.

18. Noguchi Y., Imada T., Matsumoto A., Coit D.G., Brennan M.F.: Radical surgery for gastric cancer: a review of the Japan- ese experience. Cancer 64: 2053-2062, 1989.

19. Baba H., Ohshiro T., Yamamoto M. et al.: Clinicopathological characteristics of stage I gastric cancer: comparison of macroscopic and microscopic findings. Hepatogastroenterology 44:

554-558, 1997.

20. Bonenkamp J.J., van de Velde C.J.H., Kampschoer G.H.M. et al.: A comparison of factors influencing the prognosis of Japanese and Western gastric cancer patients. World J. Surg.

17: 410-415, 1993.

21. Yokota T., Saito T., Teshima S. et al.: Lymph node metastasis in early gastric cancer: how can surgeons perform limited surgery? Int. Surg. 83: 287-290, 1998.

22. Bonenkamp J.J., Songun I., Hermans J. et al.: Randomized comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 345: 745-748, 1995.

23. Dent D.M., Madden M.V., Price S.K.: Randomised comparison of R1 and R2 gastrectomy for gastric cancer. Br. J. Surg.

75: 110-112, 1988.

24. Bonenkamp J.J., Hermans J., Sasako M., van de Velde C.J.H.:

Extended lymph-node dissection for gastric cancer. N. Engl. J.

Med. 340: 908-914, 1999.

25. Cuschieri A., Weeden S., Fielding J. et al.: Patients survival after D1 and D2 resections for gastric cancer: a long-term results of the MRC randomized surgical trial. Br. J. Cancer 79:1522- 1530, 1999.

26. Sasako M.: Risk factors for surgical treatment in Dutch gastric cancer trial. Br. J. Surg. 84: 567-571, 1997.

27. Gunther K., Horbach T., Merkel S. et al.: D3 lymph node dissection in gastric cancer: evaluation of postoperative mortality and complications. Surg. Today 30: 700-705, 2000.

28. Noguchi S., Hiratsuka M., Furukawa H. et al.: Detection of gastric cancer micrometastasis in lymph nodes by amplifica- tion of keratin 19 mRNA with reverse transcriptase-polymerase chain reaction. Jpn. J. Cancer Res. 87: 650-654, 1996.

29. Cai J., Ikeguchi M., Maeta M., Kaibara N.: Micrometastasis in lymph node and microinvasion of the muscolaris propria in primary lesion of submucosal gastric cancer. Surgery 126: 32- 39, 1999.

30. Kodera Y., Schwarz R.E., Nakao A.: Extended lymph node dissection in gastric carcinoma: where do we stand after the Dutch and British randomized trials? J. Am. Coll. Surg. 195:

855-864, 2002.

31. Kwon S.J., Kim G.S.: Prognostic significance of lymph node metastasis in advanced carcinoma of the stomach. Br. J. Surg.

83: 1600-1603, 1996.

Received: July 3, 2003

Accepted in revised form: October 1, 2003 Dr. Andrea Giuliani

Via Parenzo n. 2 00198 Rome, Italy Fax: +39-068411588

E-mail: [email protected]