Histopathological grading does not affect survival after R0 surgery for gastric cancer

Histopathological grading does not affect survival after R0 surgery for gastric cancer

EJSO 2002; 28: 633±636 doi:10.1053/ejso.2002.1310, available online at http://www.idealibrary.com on 1 Histopathological grading does not affect sur...

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EJSO 2002; 28: 633±636 doi:10.1053/ejso.2002.1310, available online at http://www.idealibrary.com on

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Histopathological grading does not affect survival after R0 surgery for gastric cancer K. Inoue, Y. Nakane, T. Michiura, K. Nakai, H. Iiyama, M. Sato, S. Okumura, K. Yamamichi and K. Hioki Second Department of Surgery, Kansai Medical University, Osaka, Japan

Aim: It is unclear whether Histopathological Grading (UICC, TNM Classification) affects survival after resection for gastric cancer. Methods: To investigate the prognostic significance of Histopathological Grading after gastrectomy, 1455 patients who underwent gastric resection for gastric adenocarcinoma were reviewed. Results: The R0 (UICC, R Classification) resection rate was inversely correlated with the grade (86.5% for Grade 1, 79.7% for Grade 2 and 69.2% for Grade 3) and the R1 and R2 resection rates increased with the grade. The Histopathological Grading did not influence survival in the 1119 patients who underwent R0 resection (71.0% for Grade 1, 65.7% for Grade 2 and 66.7% for Grade 3). When multivariate analysis was performed for the 1119 cases undergoing R0 resection, the Histopathological Grading was not a determinant prognostic factor. Conclusion: We conclude that the UICC Histopathological Grading affects R0 resection rates, but does not affect # 2002 Elsevier Science Ltd. All rights reserved. survival independently. Key words: stomach neoplasms; histology; pathology; prognosis; TNM classification.

INTRODUCTION The TNM Classification of malignant tumours of the UICC (International Union Against Cancer) includes the following: residual tumor (R) classification, TNM (clinical and pathological) classification and histopathological grading.1 Prognosis is primarily influenced by the RClassification, and the pTNM pathological classification is another independent prognostic factor after treatment.2 It is unclear whether Histopathological Grading affects survival after resection. The aim of this study was to investigate the prognostic significance of histopathological grading after gastrectomy.

PATIENTS AND METHODS One thousand four hundred and fifty-five patients underwent gastrectomy for gastric adenocarcinoma between 1975 and 1994 at Kansai Medical University Hospital. The histopathological findings of these 1455 patients were recorded prospectively by the Histopathological Classification of the Japanese Classification of Gastric Carcinoma ( JGCA).3 In the histopathological Correspondence to: Kentaro Inoue, Second Department of Surgery, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570-8507, Japan. E-mail: [email protected] 0748±7983/02/$35.00

grading of the UICC, the primary tumor is divided into Grade 1 (well differentiated), Grade 2 (moderately differentiated), Grade 3 (poorly differentiated) or Grade 4 (undifferentiated).1 In this study, we translated the Classification of JGCA into the Grading of UICC as follows: Grade 1, papillary adenocarcinoma (134 patients) and well-differentiated tubular adenocarcinoma (245 patients); Grade 2, moderately differentiated tubular adenocarcinoma (443 patients) and Grade 3, poorly differentiated adenocarcinoma (401 patients), signet-ring cell carcinoma (187 patients) and mucinous adenocarcinoma (45 patients). There were no patients with undifferentiated tumor (Grade 4). The absence or presence of residual tumor after surgical treatment was classified as R0 (no residual tumor), R1 (microscopic residual tumor) or R2 (macroscopic residual tumor) according to the Residual Tumor (R) Classification of the UICC.1 The series was also stratified according to the pTNM Pathological Classification proposed by the UICC.1 Tumor location was classified according to the Japanese Classification of Gastric Carcinoma.3 The final date for follow-up was 27 December 2000. Follow-up information for patients was obtained from the Osaka Cancer Registry, routine clinic appointments, or telephone contact with the patient, family, or local physicians. Five-year survival rates and 95% confidence intervals (CI) were calculated using the Kaplan±Meier method. Overall mortality represents death due to any #

2002 Elsevier Science Ltd. All rights reserved.

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K. INOUE ET AL.

cause during follow up. The lost cases were treated as censored data for the analysis of survival rates. Differences in survival were evaluated using the log-rank test. Differences in the distribution of variables were analyzed statistically using the Chi-square method. Multivariate analysis was performed using Cox's proportional-hazards regression model. StatView±J for Macintosh Version 5.0 (SAS Inc.) was used to generate these analyses.

RESULTS The distribution of the histopathological grades by sex and age of the 1455 patients are shown in Table 1. Table 2 shows the distribution of the histopathological grades of all cases by primary tumor site, stratified according to the depth of tumor. Of the 1455 patients entering the study, 1119 (76.9%) R0 resections were performed. The R-Classification

distribution by Histopathological Grading is shown in Table 3, and there was a correlation between the Histopathological Grading and the R-Classification. The R0 resection rate was inversely correlated with the grade and the R1 and R2 resection rates increased with the grade. One hundred and two (7.0%) of the 1455 patients were lost to follow-up and 1353 were followed up for a minimum of five years or until death. The 5-year survival rate of 1455 patients by Histopathological Grading was Table 3 R-Classification distribution by the Histopathological Grading Histopathological Grading Grade 1 Grade 2 Grade 3

R-Classification R0

R1

R2

328 (86.5) 353 (79.7) 438 (69.2)

4 (1.1) 15 (3.4) 38 (6.0)

47 (12.4) 75 (16.9) 157 (24.8)

P , 0.0001. Table 1 Distributions of the histopathological grades by sex and age of the 1455 patients who underwent gastrectomy at the Kasai Medical University Hospital between 1975 and 1994 Age 20±49

50±69

70

Male Grade 1 Grade 2 Grade 3

16 (10.7) 39 (26.0) 95 (63.3)

172 (32.7) 180 (34.2) 174 (33.1)

79 (34.6) 94 (41.2) 55 (24.1)

Female Grade 1 Grade 2 Grade 3

15 (9.6) 29 (18.5) 113 (72.0)

56 (21.4) 61 (23.3) 145 (55.3)

41 (31.1) 40 (30.3) 51 (38.6) Figure 1 Overall survival curves of 1455 patients after gastrectomy by the Histopathological Grading.

P , 0.0001

Table 2 Distributions of the histopathological grades by tumor depth and site of the 1455 patients who underwent gastrectomy Tumor location Upper

Middle

Lower

Early gastric cancer Grade 1 27 (58.7) Grade 2 10 (21.7) Grade 3 9 (19.6)

79 (30.7) 73 (28.4) 105 (40.9)

91 (44.8) 58 (28.6) 54 (26.6)

Advanced gastric cancer Grade 1 52 (24.4) Grade 2 69 (32.4) Grade 3 92 (43.2)

46 (13.6) 81 (24.0) 210 (62.3)

83 (21.2) 149 (38.1) 159 (40.7)

P , 0.0001.

Figure 2 Overall survival curves of 1119 patients who underwent R0 resection by the Histopathological Grading.

PROGNOSTIC FACTORS OF GASTRIC CANCER

635

Table 4 Five-year survival rates and 95% confidence intervals in patients who underwent R0 resection by the Histopathological Grading when they are stratified by the pT Classification and pN Status Characteristics

Histopathological Grading Grade 1

Grade 2

Grade 3

pT Classification pT1 pT2 pT3

84.5 (79.2±89.8) 55.3 (45.8±64.8) 44.4 (19.6±69.1)

83.9 (77.6±90.2) 61.8 (54.2±69.4) 30.3 (17.0±43.7)

93.8 (90.1±97.5) 57.5 (50.2±64.8) 38.1 (26.9±49.2)

pN Status Negative Positive

85.3 (80.5±90.1) 39.5 (29.7±49.2)

81.5 (75.6±87.3) 49.9 (42.3±57.5)

90.6 (86.6±94.5) 42.5 (35.8±49.3)

Table 5 Multivariate analysis in 5-year survival of the 1455 patients who underwent gastric resection Hazard ratio for death Age 20±49 yr 50±69 yr . 70 yr

0.56 (0.43±0.72) 0.77 (0.64±0.93) 1

Location Upper third Middle third Lower third

1 0.74 (0.60±0.92) 0.78 (0.63±0.96)

Local spread pT1 pT2 pT3 pT4

0.29 (0.19±0.45) 0.62 (0.45±0.84) 0.79 (0.58±1.08) 1

Lymphatic spread Negative Positive Grading Grade 1 Grade 2 Grade 3 R-Classification R0 R1 R2

0.32 (0.24±0.42) 1 0.86 (0.69±1.07) 0.78 (0.64±0.95) 1 0.30 (0.25±0.36) 0.55 (0.38±0.79) 1

Table 6 Multivariate analysis in 5-year survival of the 1119 patients who underwent R0 resection

P value ,0.0001

0.017

,0.0001

,0.0001 0.037

,0.0001

62.6% (57.6±67.6) for Grade 1, 56.0% (51.2±60.7 ) for Grade 2 and 48.3% (44.3±52.3) for Grade 3, with significant difference (Fig. 1). However, Histopathological Grading did not influence survival in the 1119 patients who underwent R0 resection (Fig. 2). The 5-year survival rate of patients who underwent R0 resection by Histopathological Grading was 71.0% (65.9±76.1) for Grade 1, 65.7% (60.7±70.8) for Grade 2 and 66.7% (62.2±71.2) for Grade 3. When patients who underwent R0 resection were stratified by pT and pN categories, comparisons of survival by Histopathological Grading showed were homogenous (Table 4). Due to the small

Hazard ratio for death Age 20±49 yr 50±69 yr . 70 yr

0.54 (0.38±0.76) 0.72 (p.56±0.91) 1

Location Upper third Middle third Lower third

1 0.71 (0.53±0.96) 0.75 (0.57±0.99)

Local spread pT1 pT2 pT3 pT4

0.21 (0.12±0.38) 0.43 (0.26±0.70) 0.66 (0.39±1.10) 1

Lymphatic spread Negative Positive

0.31 (0.23±0.42) 1

Grading Grade 1 Grade 2 Grade 3

1.10 (0.82±1.46) 0.93 (0.72±1.20) 1

P value 0.001

0.058

,0.0001

,0.0001

0.532

number of patients (23 cases), survival among patients with pT4 tumors was not comparable. When multivariate analysis was performed for the 1455 cases undergoing gastrectomy, Histopathological Grading was found to be an independent predictor of survival (Table 5). However, in patients who underwent R0 resection, Histopathologic Grading was not a determinant factor by multivariate analysis (Table 6).

DISCUSSION Many subdivisions of gastric adenocarcinoma have been made on the basis of microscopic structure.4±8 Each type is different with regard to epidemiology, etiology, pathogenesis and behavior,9 and our clinical records support this. However, numerous studies investigating

636 the prognostic significance of histopathologic types or grades have shown conflicting results.4,5,10±19 Our findings confirmed that the overall survival of the patients who underwent gastrectomy was associated with Histopathological Grading. However, no correlation between survival and Histopathological Grading was noted in the 1119 patients who underwent R0 resection (Table 5). Some studies have shown histopathological typing or grading to be an important factor in survival analyses.4,5,10±15,17,18 However, many of these studies have methodology problems. The prognostic significance of histopathological typing has been demonstrated using multivariate techniques,10,14,15,17,18 although some of these investigators did not stratify their series by R-Classification.10,15,18 The prognosis of solid tumors is primarily influenced by the R-Classification and the prognosis of R1 and R2 is very unfavorable and shows only minor variations. The Goseki histological classification has been demonstrated to be an independent prognostic factor by appropriate statistical analysis,14,17 but its value is uncertain and it has yet to be validated by clinical investigation.16,19 There is still no consensus regarding the relationships between histopathological classification and prognosis in gastric cancer. We conclude that the UICC Histopathological Grading correlates with R0 resection rates, but does not affect survival independently.

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K. INOUE ET AL. 6. Watanabe H, Jass JR, Sobin LH. Histological Typing of Oesophageal and Gastric Tumors, 2nd edn. Berlin: Springer-Verlag, 1990. 7. Goseki N, Takizawa T, Koike M. Differences in the mode of the extension of gastric cancer classified by histological type: new histological classification of gastric carcinoma. Gut 1992; 33: 606±12. 8. Hermanek P, Henson DE, Hutter RVP, Sobin L. TNM Supplement 1993 a Commentary on Uniform Use. Berlin: Springer-Verlag, 1993. 9. Stadtlander CT, Waterbor JW. Molecular epidemiology, pathogenesis and prevention of gastric cancer. Carcinogenesis 1999; 20: 2195±208. 10. Davessar K, Pezzullo JC, Kessimian N, Hale JH, Jauregui HO. Gastric adenocarcinoma: prognostic significance of several pathologic parameters and histologic classifications. Hum Pathol 1990; 21: 325±32. 11. Nakamura K, Ueyama T, Yao T, Xuan ZX, Ambe K, Adachi Y et al. Pathology and prognosis of gastric carcinoma. Findings in 10 000 patients who underwent primary gastrectomy. Cancer 1992; 70: 1030±7. 12. Iriyama K, Miki C, Ilunga K, Osawa T, Tsuchibashi T, Suzuki H. Prognostic significance of histological type in gastric carcinoma with invasion confined to the stomach wall. Br J Surg 1993; 80: 890±2. 13. Cimerman M, Repse S, Jelenc F, Omejc M, Bitenc M, Lamovec J. Comparison of Lauren's, Ming's and WHO histological classifications of gastric cancer as a prognostic factor for operated patients. Int Surg 1994; 79: 27±32. 14. Martin IG, Dixon MF, Sue-Ling H, Axon AT, Johnston D. Goseki histological grading of gastric cancer is an important predictor of outcome. Gut 1994; 35: 758±63. 15. Yu CC, Levison DA, Dunn JA, Ward LC, Demonakou M, Allum WH et al. Pathological prognostic factors in the second British Stomach Cancer Group trial of adjuvant therapy in resectable gastric cancer. Br J Cancer 1995; 71: 1106±10. 16. Roy P, Piard F, Dusserre-Guion L, Martin L, Michiels-Marzais D, Faivre J. Prognostic comparison of the pathological classifications of gastric cancer: a population-based study. Histopathology 1998; 33: 304±10. 17. Songun I, van de Velde CJ, Arends JW, Blok P, Grond AJ, Offerhaus GJ et al. Classification of gastric carcinoma using the Goseki system provides prognostic information additional to TNM staging. Cancer 1999; 85: 2114±18. 18. Adachi Y, Yasuda K, Inomata M, Sato K, Shiraishi N, Kitano S. Pathology and prognosis of gastric carcinoma: well versus poorly differentiated type. Cancer 2000; 89: 1418±24. 19. Monig S, Baldus SE, Collet PH, Zirbes TK, Bollschweiler E, Thiele J et al. Histological grading in gastric cancer by Goseki classification: correlation with histopathological subtypes and prognosis. Anticancer Res 2001; 21: 617±20.

Accepted for publication 3 May 2002