Peritoneal Involvement in Stage II Colon Cancer

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1 Anatomic Pathology / PERITONEAL INVOLVEMENT IN STAGE II COLON CANCER Peritoneal Involvement in Stage II Colon Cancer A.M. Lennon, MB, MRCPI, H.E. Mulcahy, MD, MRCPI, J.M.P. Hyland, MCh, FRCS, FRCSI, C. Lowry, MB, A. White, RGN, RN, DipONC, D. Fennelly, MD, FRCPI, J.J. Murphy, FRCS, FRCSI, D.P. O Donoghue, MD, FRCPI, FRCP and K. Sheahan, MB, BSc, FRCPI, FCAP, FRCPath Key Words: Colorectal cancer; Peritoneum; Local peritoneal involvement; Prognosis; Clinicopathologic staging; Lymph node negative; Dukes B; Stage II; Survival; TNM, T4 Abstract A pathologist (K.S.) reviewed histologic slides for peritoneal involvement by tumor cells for 118 patients with stage II colon cancer. Patients were followed up for a median of 6 years. Tumor cells were found free in the peritoneal space in 16 cases (13.6%). The presence of cancer cells free in the peritoneal space was associated with lymphovascular invasion (P =.001) and neural invasion (P <.001). The overall 5-year survival was 80% in the patient population, but was 39% and 86% for those with and without tumor cells free in the peritoneal space, respectively (P <.0001). Multivariate analysis confirmed that free tumor cells within the peritoneal space (P <.0001) and lymphovascular invasion (P =.007) were related independently to outcome. Peritoneal involvement with tumor cells free in the peritoneal space in stage II colon cancer is a powerful indicator of outcome; patients have a survival similar to that for patients with stage III disease. Colorectal cancer is the third most common cancer and the second leading cause of death due to cancer in Western society. It is estimated that 130,000 people in the United States developed this disease in 2000 and that 56,000 died of their disease. 1 Stage II cancers, ie, cases in which the cancer has spread beyond the muscularis propria but has not involved the regional lymph nodes, 2 accounts for more than one third of all colorectal cancers. Despite advances in the treatment of cancer, 5-year survival rates range from 50% to 78%. 3,4 Even in groups undergoing curative surgery, there is considerable heterogeneity in treatment patterns. Several studies have shown a benefit for adjuvant therapy for patients with stage III colon cancer but not for patients with stage II disease. 5,6 This failure to demonstrate a benefit of adjuvant therapy for patients with stage II colon cancer may be due to our inability to distinguish a subset of patients with a poor prognosis. However, if we could identify factors within this group that are associated with a poor outcome, we could target such patients for adjuvant therapies while avoiding chemotherapy for patients without poor prognostic variables. Many studies have looked at pathologic prognostic markers One study by Shepherd et al 7 assessed a large number of pathologic variables in a prospective series of patients with colon cancer and identified peritoneal involvement as an important and independent prognostic factor, in both the overall population and the subgroup undergoing curative surgery. However, peritoneal involvement has not been studied in patients with stage II disease alone. Our aim was to assess peritoneal involvement in a large group of patients with stage II colon cancer to determine whether this pathologic feature can help distinguish a group of patients with a poor prognosis. 108 Am J Clin Pathol 2003;119: Downloaded 108 from

2 Anatomic Pathology / ORIGINAL ARTICLE Materials and Methods Patients In this retrospective study, we identified 137 consecutive patients (median age, 70 years; range, years; 58 women) with stage II colon cancer who underwent surgery in our hospital between 1992 and Patient details were identified from a prospectively maintained database. We excluded 7 stage II cases that had clinical or pathologic evidence of free tumor perforation and 5 cases in which tumors had invaded adjacent organs at the time of operation because these operative factors are already known to be associated with a poor prognosis independent of tumor stage. Another 7 cases were excluded because histologic assessment revealed no peritoneum present in the tumor blocks. Thus, 118 patients were available for assessment. Patients were followed up for a median of 6 years (range, 3-9 years) or until death. Slide Review All original H&E-stained slides were retrieved and reviewed by one pathologist (K.S.), who was unaware of clinical details and outcome. The median numbers of tumor and peritoneal blocks examined were 3 (range, 2-8 tumor blocks) and 3 (range, 1-7 peritoneal blocks), respectively. The mean number of lymph nodes examined was 1 (range, 1-29 nodes). All cases were confirmed as N0 M0, and slides were examined additionally for lymphovascular invasion, perineural invasion, and tumor differentiation. The Shepherd scheme of assessment of peritoneal involvement was used throughout the study. 7 The scheme was as follows: type 1, tumor well clear of the closest peritoneal surface; type 2, mesothelial inflammatory reaction with tumor near but not at the peritoneal surface; type 3, tumor at the peritoneal surface with inflammatory reaction, mesothelial hyperplasia, and/or ulceration; and type 4, tumor cells free in the peritoneum Image 1, which we subsequently defined as true peritoneal involvement. Statistical Analysis The chi-square test was used to compare categorical variables. For survival analyses, Kaplan-Meier curves were constructed, and differences in survival between groups were assessed by using the log-rank test. Multivariate survival analyses were performed with the Cox proportional hazards model using the Statistical Package for the Social Sciences (SPSS, Chicago, IL). Two-sided P values less than.05 were considered significant in all analyses. Results Image 1 shows examples of the different peritoneal involvement types. The majority of patients (69.5%) had no evidence of tumor at the peritoneal surface (type 1 or type 2), while 16.9% had tumor at the surface (type 3). The remaining 13.6% of cases had tumor cells free within the peritoneal cavity (type 4). Table 1 shows the relationship between peritoneal involvement (type 4) and clinicopathologic features. Peritoneal involvement was unrelated to tumor site or differentiation. However, there was a close association between the presence of lymphovascular or perineural invasion and peritoneal involvement. Both lymphovascular invasion and neural invasion were found relatively rarely in patients with involvement assessed as types 1 through 3, but they were found frequently in cases with true peritoneal involvement. Table 1 Relationship Between Peritoneal Involvement and Clinical and Pathologic Variables in 118 Patients With Stage II Colon Cancer * Type of Peritoneal Involvement Variable 1 (n = 53) 2 (n = 29) 3 (n = 20) 4 (n = 16) P Tumor site.11 Left 19 (36) 15 (52) 8 (40) 10 (62) Right 34 (64) 14 (48) 12 (60) 6 (38) Differentiation.43 Well 4 (8) 2 (7) 4 (20) 0 (0) Moderate 41 (77) 26 (90) 14 (70) 15 (94) Poor 8 (15) 1 (3) 2 (10) 1 (6) Lymphovascular invasion.001 Absent 42 (79) 23 (79) 14 (70) 5 (31) Present 11 (21) 6 (21) 6 (30) 11 (69) Neural invasion <.001 Absent 50 (94) 28 (97) 18 (90) 9 (56) Present 3 (6) 1 (3) 2 (10) 7 (44) * Data are given as number (percentage). For a description of the types of peritoneal involvement, see the text. Chi-square test for trend. Downloaded from Am J Clin Pathol 2003;119:

3 Lennon et al / PERITONEAL INVOLVEMENT IN STAGE II COLON CANCER A B C D Image 1 Examples of peritoneal involvement, types 1 to 4. A, Type 1. Tumor well clear of peritoneum (original magnification 40). B, Type 2. Tumor near but clear of the peritoneum (original magnification 100). C, Type 3. Tumor at peritoneal surface with associated inflammatory or fibrotic reaction (original magnification 200). D, Type 4. Tumor cells free in the peritoneum (original magnification 400). The number of slides that included peritoneum ranged from 1 to 7 per case. No significant association was seen between the presence of free tumor cells in the peritoneum (type 4) and the number of peritoneal blocks (type 4, median, 3 blocks; range, 2-5 blocks; type 3, median, 3 blocks; range, 1-7 blocks; P =.06). However, for 15 patients, only 1 peritoneal block was available for analysis, and none of these were graded as type 4. The mean number of lymph nodes examined was 1 (range, 1-29). There was no association between the number of lymph nodes and survival when entered into a proportional hazards model or when dichotomized around the median. In addition, the number of lymph nodes was not significant when entered as a covariate into a multivariate model. There were 44 deaths in the patient population during the follow-up period; 26 of these were related to cancer. Figure 1 and Table 2 show the association between clinicopathologic variables and cancer-related survival in the patient population. Vascular and neural invasion both were related closely to long-term outcome. Survival was similar in patients with types 1, 2, or 3 involvement. In contrast, more than 60% of patients with type 4 involvement died of cancer within 3 years of surgery. Multivariate analyses were performed to identify features significantly and independently related to outcome, 110 Am J Clin Pathol 2003;119: Downloaded 110 from

4 Anatomic Pathology / ORIGINAL ARTICLE A B Type 1 (n = 53) Type 2 (n = 29) Type 3 (n = 20) Type 4 (n = 16) Well (n = 10) Moderate (n = 96) Poor (n = 12) C D No vascular invasion (n = 84) Vascular invasion (n = 34) No neural invasion (n = 105) Neural invasion (n = 13) Figure 1 Survival of 118 patients with stage II colorectal cancer stratified by local peritoneal involvement (A), tumor differentiation (B), vascular invasion (C), and neural invasion (D). and both forward and backward regression provided the same final model Table 3. This included type 4 involvement and lymphovascular invasion, but neural invasion was excluded owing to its close relationship to peritoneal involvement and lymphovascular invasion. A secondary survival analysis with all-cause mortality was done to correct for any potential bias in the reporting of deaths. Type 4 involvement again emerged as the most powerful prognostic indicator in the final multivariate model (data not shown). Discussion Stage II colon cancers clearly possess the necessary biologic attributes that permit them to break down direct barriers to tumor spread, to invade tissues, and to extend beyond the bowel wall. However, by definition, they have not metastasized to lymph nodes or to distant organs, so that careful surgery, which includes an adequate resection margin, should result in cure, at least according to conventional Downloaded from Am J Clin Pathol 2003;119:

5 Lennon et al / PERITONEAL INVOLVEMENT IN STAGE II COLON CANCER paradigms. However, approximately one third of stage II cancers recur, presumably either because of the presence of undetected metastases at the time of surgery or because of direct spread into the peritoneal cavity. For the purposes of the present study, as in previous studies, 7 we excluded patients with stage II cancer with clinical or pathologic evidence of free perforation or involvement of adjacent organs at the time of operation because these factors are known to be associated with a poor prognosis. Their inclusion might have led to a spurious association between free tumor cells in the peritoneal cavity and other poor prognostic variables and outcome. When we assessed these patients, independent of the study, they had a uniformly poor prognosis, justifying their exclusion. Our results show that tumor cells were detectable in the peritoneal space (type 4) in 13.6% of cases. In addition, we found that type 1, 2, and 3 cancers shared similar clinicopathologic characteristics and had a uniformly good long-term prognosis. In contrast, when compared with patients with type 1, 2, or 3 involvement, patients with type 4 involvement had extremely high rates of lymphovascular invasion (69% [11/16] vs 22.5% [23/102]) and neural invasion (44% [7/16] vs 5.9% [6/102]). Furthermore, more than 60% of patients with type 4 involvement died of recurrent or metastatic disease within 3 years of the initial surgery. Indeed, the long-term outcome for this group was as poor as that for patients who underwent surgery in our institution for stage III disease during the same period (data not shown). Data are available from 4 previous studies 7-10 on microscopically detectable tumor cells involving the peritoneum. Newland et al 8,9 examined patients with stage I, II, 8 and III 9 colorectal cancer. Shepherd et al 7,10 also studied patients with a range of tumor stages but dealt separately with rectal 10 and colon cancer. 7 We specifically focused on patients with potentially curative stage II colon cancer because we wanted to minimize any survival bias caused by variable anatomic staging of peritoneal tumor cell positive and peritoneal tumor cell negative cases. In addition, we wanted to determine what proportion of apparently localized cancers were capable of penetrating through the peritoneal lining and whether this was associated with other clinicopathologic variables and long-term outcome. Shepherd et al 7,10 and Newland et al 8,9 found that Table 2 Survival Data for 118 Patients With Stage II Colon Cancer Stratified by Anatomic and Pathologic Features 5-Year No. of Cases Survival (%) Tumor site.43 * Left Right Differentiation.29 Well Moderate Poor Lymphovascular invasion.0006 * Absent Present Neural invasion <.0001 * Absent Present Type of peritoneal involvement < * Log-rank test. Log-rank test for trend. tumor cells at or free in the peritoneum were independent prognostic indicators and were associated with a significantly worse prognosis. Shepherd et al 7 classified types 3 and 4 together as T4, while our data suggest that type 4 alone is a stronger predictor of survival in patients with stage II disease. This discrepancy may be because Shepherd et al 7,10 looked at all stages, while we specifically focused on patients with stage II disease. In a study by Newland et al, 9 relatively few cases had evidence of free peritoneal surface involvement (B2 = 5%). However, it is unclear from a previous article by Davis and Newland 11 whether peritoneal invasion corresponds to type 3 or 4 peritoneal involvement. This low prevalence of peritoneal involvement contrasts with our results and with those of Shepherd et al, 7,10 who found that 20% of patients with stage II disease had type 4 involvement. Previous articles indicate that documentation of peritoneal involvement by tumor requires extensive sampling and serial sectioning and can be missed during routine histopathologic examination. 7,12 One of the aims of our study was to determine whether routine treatment of colon cancer cases was adequate to assess peritoneal involvement. P Table 3 Final Regression Analysis Model of Factors Associated With Outcome in 118 Patients With Stage II Colon Cancer Relative Risk (95% beta SE beta Confidence Interval) P Type 4 peritoneal involvement ( ) <.0001 Lymphovascular invasion ( ) Am J Clin Pathol 2003;119: Downloaded 112 from

6 Anatomic Pathology / ORIGINAL ARTICLE In this retrospective study, we were able to assess peritoneal involvement in 94.4% of patients with stage II cancer who underwent surgery in our hospital. Overall, we examined a median of 3 peritoneal tissue blocks per patient. It is possible that had we sampled more peritoneal blocks per case as the tumors were being processed, we might have identified more patients with type 4 involvement. However, interestingly, our rate of type 4 involvement was similar to that found by Shepherd et al. 7 Recent studies have suggested that the number of lymph nodes retrieved may be directly proportional to outcome. 13 The mean number of lymph nodes in our study was 1 (range, 1-29 nodes). Although the number of lymph nodes retrieved in the present study was lower than the number retrieved in the study by Shepherd et al, 7 the percentage of patients with type 4 involvement (13.6% vs 20%) and their survival rates were similar. To ensure that the number of lymph nodes retrieved had not resulted in understaging type 4 involvement, we looked at whether there was an association between the number of lymph nodes and survival. There was no association between the number of lymph nodes and survival when entered into a proportional hazards model, dichotomized around the median, or entered as a covariate into a multivariate model. The American Joint Committee on Cancer Prognostic Factors Group recently recommended that the TNM staging system be modified with respect to T4. 12 The group subdivided T4 into T4a, tumor invading adjacent structures or organs, and T4b, in which tumor involves the visceral peritoneum. The definition used for tumor involving the visceral peritoneum included the following: (1) tumor near but not at the peritoneal surface with mesothelial inflammation or hyperplastic reaction; (2) tumor at the peritoneal surface with inflammatory reaction, mesothelial hyperplasia, and/or erosion/ulceration; (3) free tumor cells on the peritoneal surface with underlying ulceration of the visceral peritoneum. These correspond to types 2, 3, and 4 as defined by Shepherd et al 7 and as applied in the present study. Our study findings suggest that it is solely type 4 that confers a poor prognosis in stage II colon cancer. Peritoneal involvement with tumor cells free in the peritoneum in stage II colon cancer is a powerful indicator of outcome, such that these patients have a survival similar to that for patients with stage III disease. These results suggest that only stage II cancer with free tumor cells in the peritoneal cavity should be considered as pt4b. Assessment of peritoneal involvement may be of clinical value when attempting to identify patients at increased risk of tumor recurrence and death. From the Center for Colorectal Disease, St Vincent s University Hospital, Dublin, Ireland. Address reprint requests to Dr Sheahan: Pathology Dept, St Vincent s University Hospital, Elm Park, Dublin 4, Ireland. Acknowledgment: We thank the staff of the Histopathology Department for assistance in this project. References 1. Greenlee RT, Murray T, Bolden S, et al. Cancer statistics, CA Cancer J Clin. 2000;50: Sobin LH, Wittekind C (International Union Against Cancer [UICC]), eds. TNM Classification of Malignant Tumours. 5th ed. Baltimore, MD: Wiley-Liss; Tominaga T, Sakabe T, Koyama Y, et al. Prognostic factors for patients with colon or rectal carcinoma treated with resection only: five-year follow-up report. Cancer. 1996;78: Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer: results of a prospectively randomized trial. 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