Topics: Staging and treatment for pancreatic cancer. Staging systems for pancreatic cancer: Differences between the Japanese and UICC systems

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1 M. J Hep Kobari Bil Pancr and S. Surg Matsuno: (1998) Staging 5: system for pancreatic cancer 121 Topics: Staging and treatment for pancreatic cancer Staging systems for pancreatic cancer: Differences between the Japanese and UICC systems Masao Kobari and Seiki Matsuno First Department of Surgery, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai , Japan Abstract: Differences between the clinical staging system of the Japan Pancreas Society (JPS) and the Union Internationale Contre le Cancer (UICC) stage classification may account for reported differences in the prognosis of pancreatic carcinoma between Japan and the West. In the review, we compared the characteristics of the JPS and UICC staging in 1689 patients, registered with the JPS from 1981 to 1990, who underwent resection for carcinoma of the pancreatic head. The survival rates correlated well with the JPS stage classification. The UICC staging did not reflect differences in prognoses among the stages. The current JPS staging system, introduced in 1993, still differs from that of the UICC. To compare the results of treatment for patients with pancreatic cancer it is important to establish a more practical and universal staging system for carcinoma of the pancreas. Key words: staging, pancreatic cancer, UICC Introduction In Japan, the first edition of the General rules for surgical and pathological studies on cancer of pancreas was published 1980, 1 followed by two revisions the second edition in 1982, 2 and the third edition in The registration of pancreatic cancer with the Registration Committee of the Japan Pancreas Society (JPS) was started in 1981 and patients were registered in the 10 years to From evaluation of the results of treatment for these patients according to stage or histological classification, and with the understanding of new diseases such as mucin hypersecreting pancreatic tumor, a new edition of General rules for Surgical and pathological studies on cancer of pancreas (the fourth Offprint requests to: M. Kobari Received for publication on Sept 8, 1997; accepted on March 25, 1998 edition) was published in But there are still some differences between the JPS stage classification (JPS- SC) 5 and the Union Internationale Contre le Cancer stage classification (UICC-SC) 6 and these differences may account for differences in the prognosis of pancreatic carcinoma reported in Japan and Western countries. In this review, we compared the JPS-SC in the third edition of the General rules for surgical and pathological studies of cancer of pancreas 3 with the stage classification of the UICC 6 according to survival analyses in the Report of cases collected during a 10-years period, as above. 4 The features of the current stage classification of the JPS 5 are also discussed. Patients and methods Staging systems were compared between the third edition of the JPS stage classification and the UICC stage grouping. Differences between staging systems in the third 3 and fourth editions 5 of the JPS stage classification were also analyzed. The new stage groupings for pancreatic cancer published in 1997 by the UICC are also shown. Survival analysis The results of resective treatment were analyzed in 1689 patients with carcinoma of the head of the pancreas registered with the JPS from 1981 until The patients who underwent resection were individually classified according to the UICC stage grouping 6 and the JPS stage classification (third edition 3 ) at the same time by the attending surgeons according to operative explorations or investigation of resected specimens. Both the UICC and the JPS stages were recorded simultaneously on record cards and the cards were registered with the Registration Committee of the JPS. Survival rates were compared in JPS and UICC stages.

2 122 M. Kobari and S. Matsuno: Staging system for pancreatic cancer Fig. 1. Japan Pancreas Society (JPS) stage classification (third edition). 3 For all Figs., see text for explanations of abbreviations The survival rates of patients treated at the First Department of Surgery, Tohoku University School of Medicine in the past 10 years were also compared according to JPS stages in the third 3 and fourth edition 5 of the JPS stage classification. Survival curves were calculated by the Kaplan-Meier method. Differences between survival curves were analyzed by the generalized Wilcoxon method and the log-rank test. A probability value of less than 0.05 was considered to be significant difference. Results Stage classification of the JPS (third edition) 3 The staging classification for carcinoma of the pancreas as proposed by the JPS is shown in Fig This classification is based on macroscopic examination and each stage is judged by preoperative imaging diagnosis or surgical exploration, including macroscopic evaluation of surgical specimen, as in the UICC-SC. T indicates only the size of the tumor at its greatest dimension. T1 is a tumor with a diameter less than 2cm; T2 is a tumor with a diameter of 2 4cm; T3 is a tumor with a diameter of 4 6cm; T4 is a tumor with a diameter of more than 6 cm. N indicates lymph node metastasis. N0 indicates no lymph node involvement. N1 (group 1) is involvement of the primary group of lymph nodes situated close to the tumor; N2 (group 2) is involvement of the secondary group of lymph nodes between N1 and N3; N3 (group 3) is involvement of the tertiary group of lymph nodes considered as juxta-regional lymph nodes. S indicates direct anterior capsular invasion. Rp indicates retroperitoneal invasion (fat, connective tissue, nerves, or bile duct). PV designates direct tumor invasion of the portal venous systems. S, Rp, and PV are separated into four groups according to the extent of extrapancreatic tissue invasion. 0, absence of tumor invasion, for example S0, Rp0, PV0; 1, suspected invasion; 2, definite invasion; S3, Rp3, and PV3 indicate severe invasion extending directly to adjacent organs (stomach or colon), retroperitoneum (aorta, superior mesenteric artery, inferior vena cava, kidney, or adrenal gland), and portal vein, respectively. Fig. 2. Union Internationale Contre le Cancer (UICC) stage grouping (1983) 3 Stage I is T1, N0, S0, Rp0, PV0. If any of the staging factors T2, N1, S1, Rp1, PV1 are found, the stage is II. If any of the staging factors T3, N2, S2, Rp2, PV2 are found, the stage is III. The diagnosis is stage IV if any of the staging factors T4, N3, S3, Rp3, or PV3 are found. Distant metastasis, including hepatic metastasis and peritoneal dissemination, is also classified as stage IV. Criteria for UICC grouping (1987) 6 and comparison with JPS staging (third edition) 3 The criteria for UICC stage grouping are also shown in the JPS staging 3 (Fig. 2). 3 The staging factors employed in the UICC-SC are: primary tumor, T; lymph node metastasis, N; and distant metastasis, M. Assessment of each category is made by physical examination, imaging, and/or surgical exploration. In the UICC staging, T includes not only tumor size but also the extent of tumor invasion to tissues surrounding the pancreas. In the JPS staging, T means only tumor size, and the extent of tumor invasion is expressed by S, Rp, or PV. In UICC stage I, the tumor is limited to the pancreas (T1) or extends directly to the duodenum, bile duct, or peripancreatic tissues (T2) without lymph node metastasis (N0). In UICC stage II, the tumor extends directly to the stomach, spleen, colon, or adjacent large vessels (T3), but is without lymph node metastasis (N0). In UICC stage III, positive regional lymph node metastasis is included (N1). UICC stage IV contains distant metastasis, including extrapancreatic lymph node metastasis. In the JPS-SC, we attach as much importance to the extent of lymph node metastasis as to the size of the tumor and the extent of invasion to extrapancreatic tissues.

3 M. Kobari and S. Matsuno: Staging system for pancreatic cancer 123 Survival rate according to JPS stage classification (third edition) 3 The 3-year survival rates of resected pancreatic head cancer in the 1689 patients registered with the JPS from 1981 to 1990 were 66.2% in stage I (n 165), 37.2% in stage II (n 382), 25.4% in stage III (n 474), and 12.7% in stage IV (n 668). The 5-year survival rates were 48.1% in stage I, 27.7% in stage II, 22.3% in stage III, and 8.8% in stage IV. The prognosis was better in the early stages of pancreatic cancer and both the 3- and 5-year survivals showed significant differences between stages I and II and between stages III and IV. Survival rate according to UICC stage grouping (1987) 6 Of the 1521 patients with resected pancreatic head cancer for whom all UICC staging factors were accurately recorded, 320 patients (21.0%) were in stage I and 182 patients (12.0%) in stage II. Five hundred and eight-six patients (38.5%) were in stage III and 433 (28.5%) in stage IV. The number of patients in UICC stage I was more than two times and the number in UICC stage II was about half compared with the numbers of patients in stages I and II according to the JPS- SC. The 3-year survival rates were 44.3% in UICC stage I, 22.5% in UICC Stage II, 16.3% in UICC Stage III, and 9.6% in UICC Stage IV. The 5-year survival rates were 32.5% in UICC stage I, 11.5% in UICC stage II, 12.0% in UICC stage III, and 6.6% in UICC stage IV. Current staging classification of the JPS (fourth edition) 5 The current staging system was proposed by the JPS in 1993 (Fig. 3). 5 The surgical staging is shown in the General rules for surgical and pathological studies on cancer of the pancreas. 5 T categories are assigned according to the extent of tumor invasion, as follows: T1, Tumors which are S0, rp0, PV0, A0, DU0, and CH0,1 (see below for definitions) T1a, Tumors 2.0cm or less at the greatest dimension T1b, Tumors more than 2.0 cm at the greatest dimension T2, Tumors classified as one or more of the following: S1, rp1, PV1, A1, DU1,2,3, and CH2,3, regardless of size T3, Tumors classified as one or more of the following: S2,3, rp2,3, PV2,3, and A2,3, regardless of size The T category in this latest staging system no longer indicates only size. This point is very different from the previous JPS staging system. 3 The grading from 0 to 3 for category S, category RP, category PV, and category N is the same as the system in the third edition. 3 However in the fourth edition, 5 A denotes the arterial system, including common hepatic artery, superior mesenteric artery, splenic artery, celiac artery, and aorta. The grading from 0 to 3 for category A is: A0, no evidence of invasion; A1, invasion suspected; A2, definite invasion; and A3, marked invasion with stenosis or obstruction of the arterial system. DU denotes duodenal wall. The grading from 0 to 3 for category DU is: DU0, no evidence of invasion; DU1, invasion suspected; DU2, definite invasion, but limited to the duodenal wall; and DU3, marked invasion with tumor penetration into the duodenal lumen or stenosis of the duodenum. CH denotes distal bile duct. The grading from 0 to 3 for category CH is: CH0, no evidence of invasion; CH1, invasion suspected; CH2, definite invasion; and CH3, marked invasion with stenosis or obstruction of the bile duct. The category P denotes peritoneal metastasis. The grading from 0 to 3 for category P is: P0, no peritoneal metastasis; P1, metastasis to the peritoneum adjacent to the pancreas; P2, a few metastases to distant peritoneum; and P3, numerous metastases to distant peritoneum. Category H denotes liver metastasis. The grading from 0 to 3 for category H is: H0, no liver metastasis; H1, metastasis limited to one lobe; H2, a few metastases to both lobes; H3, numerous metastases to both lobes. Category M denotes distant metastasis other than those to peritoneum or liver. Comparison of survival rates for patients treated at our university hospital according to the third 3 and fourth editions 5 of the JPS stage classification For the third edition of the JPS stage classification, 3 survival curves according to JPS stages were well Fig. 3. Current JPS stage classification (fourth edition) 5

4 124 M. Kobari and S. Matsuno: Staging system for pancreatic cancer separated into three groups: stage I, stage II and III, and stage IV. In the fourth edition, 5 survival curves were also divided into three groups: stages I and II, stages III and IVa, and stage IVb. For both editions, each stage group reflected the prognosis well (Fig. 4). The survival curves according to category N in the fourth edition were well separated between N0 and N1 and also between N1 and N2 or N3 (Fig. 5). This difference in survival curves seems better than that in the third edition. Fig. 4. Survival rates according to the JPS stage classifications (third edition 3 vs fourth edition 5 ). *P 0.01 Fig. 5. Survival rates according to category N in the JPS stage classifications (third edition 3 vs fourth edition 5 ). *P 0.01

5 M. Kobari and S. Matsuno: Staging system for pancreatic cancer 125 The T category in the fourth edition significantly well reflected the prognosis of the patients (Fig. 6). New stage grouping proposed by the UICC (1997) 16 (Fig. 7) T categories. Tis, carcinoma in situ; T1, tumor limited to the pancreas, 2 cm or less at greatest dimension; T2, tumor limited to the pancreas, 2 cm or more at greatest dimension; T3, tumor extending directly to any of the following: duodenum, bile duct, peripancreatic tissue; T4, tumor extending directly to any of the following: stomach, spleen, colon, adjacent large vessels. N categories. N0, no regional lymph node metastasis; N1, regional lymph node metastasis; N1a, metastasis in a single regional lymph node; N1b, metastasis in multiple regional lymph nodes. M categories. M0, no distant metastasis; M1, distant metastasis. Fig. 6. Three- and 5-year survival rates according to category T in the JPS stage classification (fourth edition 5 ). *P 0.01 Discussion Despite advances made in tumor imaging diagnosis, the proportion of patients diagnosed with pancreatic cancer at an early stage has not increased. According to the Japanese report on collected cases in the 10 years to 1991, % of patients were classified as UICC stage I, 12.1% as stage II, 20.1% as stage III, and 56.1% as stage IV, and resection was performed for 33.1% of patients. In the 1994 report on 1133 collected cases, % of patients were UICC stage I; 10.4% stage II; 30.9% stage III, and 42.8% stage IV; the resection rate was 43.5%. In our analysis of the 1835 patients who underwent resection for carcinoma of the head of the pancreas until 1994, 6.1% of patients were classified as JPS stage I and 21.9% as JPS stage II; more than 70% of patients were classified as JPS stage III or IV. 7 These stage distributions were comparable to those in The National Cancer Data Base Report on Pancreatic Cancer. 8 In our survival analyses of the 1689 patients with resected pancreatic head cancer registered with the JPS from 1981 until 1990, the survival rate correlated well with the JPS-SC and survivals were longer in patients in stage I or II than in patients in stage III or IV (the 5-year survival rate for stage I was 48.1%, for stage II, 27.7%; for stage III, 22.3%; and for stage IV, 8.8%). In the UICC-SC, the survival rate was extremely high for stage I (32.5%) compared with survival rates in other stages (less than 10%) and there was no significant difference among survival rates at stages later than stage II. 9 The survival rate dropped between stage II and stage III. This pattern of survival rates was very similar to the difference in survival rates between N0 (high) and N1 (low). 9 The reason for the lack of difference in survival rates at stages later than stage II seems to be that N in UICC-SC is simply graded as absence of involvement (N0) or presence of involvement (N1). As stated above, in the JPS-SC, we attach as much importance to the extent of lymph node involvement as to the extent of Fig. 7. New UICC stage grouping (1997) 16

6 126 M. Kobari and S. Matsuno: Staging system for pancreatic cancer invasion to extrapancreatic tissues. The extent of macroscopic lymph node involvement assessed surgically was similar to the extent of histological lymph node involvement. 7 In the UICC-SC, stage I is distinguished from stage II by the presence or absence of invasion to peripancreatic organs (stomach, spleen, or colon) or large vessels (T1 or T2 vs T3) and when lymph node involvement is detected (N1) the stage is III. If distant metastasis is found (M1) the stage is IV. This staging system is simple, easy, and objective. In the JPS-SC, the extent of LN involvement (N) or the extent of peripancreatic tissue invasion (S, Rp, PV) is graded from 0 to 3 and the size of tumor (T) is included in the staging factors. One difference of the UICC staging system from the JPS-SC may be that patients are classified as UICC stage I even when anterior serosal invasion (S) or retroperitoneal invasion (RP) are found (UICC T2 3). Unlike the JPS-SC, the UICC-SC gives no clear description of S-, Rp-, and PV. And the definition of T2 in the UICC-SC is that a tumor shows limited direct extension to duodenum, bile duct, or peripancreatic tissues; this corresponds to S0 2, Rp0 2, and PV0 2, in the JPS-SC. Tsunoda et al. 10 reported that, with the UICC-SC, there are some underestimations of the stage, as follows. UICC T2 patients, i.e., patients with definite involvement of peripancreatic tissues corresponding to Rp2 in the JPS-SC, are allocated to UICC stage I. UICC T3 patients, who have invasions to the surrounding organs or adjacent large vessels, corresponding to Rp3 and PV2 3 in the JPS-SC, belong to UICC stage II. In the JPS-SC, the patients with these conditions (S3, Rp3, and/or PV3) belong to stage IV. This difference in description concerning extrapancreatic tissue invasion may account for the difference in survival curves between JPS-SC and UICC-SC, because the survival rates of patients with S0, patients with Rp0, patients with PV0, or patients with N0 were much higher than those of patients with S1 3, patients with R p 1 3, patients with PV1 3, or patients with N Tannapfel et al. 11 reported that lymph node involvement and direct extension of the tumor into peripancreatic tissue, as well as invasion into peripancreatic organs, significantly influenced survival. They found no relationship between survival and tumor size. Zerbi et al. 12 evaluated the prognostic value of the UICC-SC and JPS-SC in 74 patients undergoing resection for pancreatic carcinoma and classified according to both the UICC-SC and JPS- SC at the same time. According to the UICC-SC, there was a high proportion of patients in stage I (38%) and stage III (39%) and a low proportion in stage II (16%); most patients were in earlier stages compared with the distribution of patients according to the JPS-SC. On the other hand, the distribution of patients according to the JPS-SC increased as the stage progressed. Survival curves at each stage were separated well and the difference among the curves was significant for the JPS-SC. However, in the UICC-SC, the survival curves overlapped at stages II and III. In an analysis of survival according to the UICC-SC in Norwegian patients, Bekkevold and Kambestad 13 tested a minor modification of UICC-SC and showed comparable prognoses for stages I and II and different prognoses for stages II and III, contrary to the present UICC-SC. 16 Balzano et al. 14 evaluated the following modified UICC-SC in their 228 patients who underwent resection for pancreatic cancer, and reported a better differentiation of stage II and III survival than for the standard UICC-SC: Stage I, T1N0M0; stage II, T1N1M0/T2N0M0; stage III, T2N1M0/T3 anynm0; stage IV, M1. However, the JPS-SC has a greater prognostic value than either the standard or the modified UICC-SC. In the current JPS stage classification in the new General rules for surgical and pathological studies on cancer of the pancreas (4th Edn), 5 tumor size was excluded from the T category, because the survival rates correlated well with stages even when the tumor size was omitted from the staging. 9 On graphs of survival, T is shown as the vertical axis, similar to T in the UICC system, but it is graded from 1 to 3 and this grading depends on the extent of peripancreatic tissue invasion, graded from 0 to 3. The Horizontal axis is N, graded from 0 to 3. This grading system is also very different from the UICC staging and is important as, in the analyses of survival rate among stages classified according to the JPS-SC, the extent of lymph node involvement and of extrapancreatic tissue invasion were the most important staging factors. 4,9 In our analyses of our small series of patients, N, T, and the stages of the current JPS stage classification (fourth edition) 5 reflected prognosis very well. Therefore, it is expected that when many cases are registered with the current JPS-SC, better differences in survival rates among the stages may be obtained. Last year, the JPS published the first English edition of Classification of pancreatic carcinoma, which is now in use in Japan. 15 The UICC also modified the stage classification of pancreatic cancer (Fig. 7) evaluated in this study and published a new edition last year. 16 There are still differences between the current JPS- SC and the new UICC-SC. To discuss the results of treatment for pancreatic cancer, it will be necessary to analyze the survival rates according to a common staging system. References 1. Japanese Pancreas Society (1980) General rules for surgical and pathological studies on cancer of pancreas (in Japanese). Kanehara Publishing, Tokyo

7 M. Kobari and S. Matsuno: Staging system for pancreatic cancer Japanese Pancreas Society (1982) General rules for surgical and pathological studies on cancer of pancreas (in Japanese). 2nd ed. Kanehara Publishing, Tokyo 3. Japanese Pancreas Society (1986) General rules for cancer of the pancreas (in Japanese). 3rd ed. Kanehara Publishing, Tokyo 4. Registration Committee of Pancreatic Cancer of Japan Pancreas Society (1991) Annual report of Registration Committee of Pancreatic Cancer Report of collected cases during 10 years (in Japanese). Registration Committee of Pancreatic Cancer, Kobe 5. Japanese Pancreas Society (1993) General rules for surgical and pathological studies on cancer of the pancreas (in Japanese). 4th ed. Kanehara Publishing, Tokyo 6. Pancreas (ICD-O ) (1987) UICC TNM Classification of malignant Tumors, 4th ed. In: Hermanek P, Sobin LH (eds) Springer, Berlin Heidelberg New York London Paris Tokyo, pp Registration Committee of Pancreatic Cancer of Japan Pancreas Society (1994) Annual report of Registration Committee of Pancreatic Cancer 1994 (in Japanese). J Jpn Pancr Soc 10: Niederhuber JE, Brennan M, Menck H (1995) The National Cancer Data Base Report on Pancreatic Cancer. Cancer 76: Kobari M, Sunamura M, Ohashi O, Saitoh Y, Yusa T, Matsuno S (1996) Usefulness of Japanese staging in the prognosis of patients treated operatively for adenocarcinoma of the head of the pancreas. J Am Coll Surg 182: Tsunoda T, Ura K, Eto T, Matsumoto T, Tsuchiya R (1991) UICC and Japanese stage classification for carcinoma of the pancreas. Int J Pancreatol 8: Tannapfel A, Wittekind C, Hünefeld G (1992) Ductal adenocarcinoma of the pancreas. Histological features and prognosis. Int J Pancreatol 12: Zerbi A, Balzano G, Bottura R, Di Carlo V (1994) Reliability of pancreatic cancer staging classifications. Int J Pancreatol 15: Bekkevold KE, Kambestad B (1995) Staging of carcinoma of the pancreas and ampulla of Vater. Tumor (T), lymph node (N), and distant metastasis (M) as prognostic factors. Int J Pancreatol 17: Balzano G, Bassi C, Zerbi A, Falconi M, Calori G, Butturini G, Leone BE, Pederzoli P, Di Carlo V (1997) Evaluation of UICC TNM classification for pancreatic cancer. Int J Pancreatol 21: Japan Pancreas Society (1996) Classification of pancreatic carcinoma: First English Edition. Kanehara Publishing, Tokyo 16. Pancreas (ICD-O C25.0 2,8) (1997) UICC TNM Classification of malignant tumors, 5th ed. In: Sobin LH, Wittekind C (eds) New York, John Wiley and Sons, pp 87 90