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Annals of Surgical Oncology 8:305-310 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Immunohistochemical Detection of the Anti-Apoptosis Protein, Survivin, Predicts Survival After Curative Resection of Stage II Colorectal Carcinomas

Abeezar I. Sarela, MD, Nigel Scott, MD, Jane Ramsdale, Alexander F. Markham, PhD and Pierre J Guillou, MD

From the Professorial Surgical Unit (AIS, PJG), Department of Histopathology (NS, JR), and Molecular Medicine Unit (AFM), University of Leeds, St James’s University Hospital, Leeds, England.

Correspondence: Correspondence to: Professor P. J. Guillou, MD FRCS, F Med Sci, Clinical Sciences Building, Level 8, St James’s University Hospital, Leeds LS9 7TF, England; Fax: 44-113-244-9618.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: This study examined the role of Survivin protein, a novel inhibitor of apoptosis, in determining prognosis after curative resection of stage II colorectal carcinomas.

Methods: Expression of Survivin, P53, and BCL-2 was evaluated immunohistochemically in stage II colorectal carcinomas from 49 patients who were followed for up to 9 years after operation. The Cox proportional hazards regression model was used to examine the predictive value of several covariates.

Results: The patients comprised 33 men and 16 women with a median age of 71 years. There were 32 colonic and 17 rectal cancers comprising 40 T3 and nine T4 primary tumors. Survivin was expressed in 30 (61.2%), P53 in 30 (61.2%), and BCL-2 in 21 (42.9%) tumors. Expression of Survivin was independent of P53 or BCL-2 expression and histopathological characteristics of the tumor. The 5-year survival rate of patients with Survivin-positive tumors was significantly lower than that of patients with Survivin-negative tumors (52.5% vs. 94.1%, respectively; P = .01). On multivariate analysis, expression of Survivin (Hazard Ratio [HR] = 9; P = .03), and rectal origin of cancer (HR = 3; P = .05) were the only factors which independently predicted an increased risk of death from recurrent cancer.

Conclusion: Survivin expression within the tumor can identify patients with stage II colorectal carcinoma who are at increased risk of death from recurrent disease and might particularly benefit from adjuvant therapy.

Key Words: BCL-2 • Colorectal neoplasia • P53 • Prognosis • Survival


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The need for informative molecular markers that provide prognostic information over and above that given by conventional pathological staging of colorectal carcinomas has been recently highlighted.1,2 Such molecular prognostic markers are likely to be of greatest benefit in the management of patients with stage II colorectal carcinoma, who display a typical 5-year survival of 70% to 80%.3 Unlike patients with stage III colonic carcinoma, adjuvant 5-fluorouracil and leucovorin therapy may not result in any significant improvement in the survival characteristics of patients with stage II disease, as a whole.4 However, there is clearly a subgroup of patients with stage II colorectal carcinoma who are at higher risk of suffering recurrence and may benefit from adjuvant chemotherapy. Although several molecular markers have been reported to yield prognostic information for patients with colorectal carcinomas, few of these are specific to stage II disease, and their clinical applicability is presently unclear.5 It is suggested that examination of molecular genetic markers that reflect a specific cellular process such as apoptosis, which is pathogenetically important for cancer progression and response to chemotherapy, will yield potentially important prognostic information.6,7

Survivin is a recently described member of the family of inhibitor of apoptosis (IAP) proteins.8,9 It has also been implicated in the control of cell cycle kinetics and cellular proliferation.10 Survivin is found during embryonic and fetal development but is completely down-regulated and undetectable in normal adult tissues and becomes prominently reexpressed in several human malignancies, including cancers of the colon, stomach, pancreas, lung, prostate, and breast.8 As a result of its selective expression in malignant cells but not in surrounding normal tissues, Survivin has generated much interest for its role in modulating apoptosis induced by chemotherapeutic agents,11 as a target for anti-cancer drugs12 and as a novel marker of prognosis in malignancies.13 Using reverse transcription-polymerase chain reaction (RT-PCR), the authors have recently reported that Survivin mRNA is expressed in 62.7% of a series of colorectal carcinomas at stages I–IV and that Survivin gene expression predicted a significantly increased risk of death with recurrent disease specifically in patients with stage II disease.14 Consequently, the aim of the present study was to examine expression of the Survivin protein, by immunohistochemistry, in stage II colorectal carcinomas and to correlate this with the expression of known modulators of apoptosis in colorectal carcinomas, such as BCL-2 and P53,15 and histopathological features of the primary tumor as well as patient survival characteristics.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study group comprised 49 consecutive patients who had undergone histopathologically confirmed curative resection (R0) of primary, sporadic stage II (T3 or T4, N0) colorectal carcinomas. All patients had single tumors and underwent elective operations in a single surgical unit between 1990 and 1994. During the study period, two patients died of postoperative complications, and these patients have been excluded from the study. Liver and lung metastases were excluded by preoperative spiral computerised tomography scanning of the abdomen and plain chest radiography, respectively, in all cases. Neither liver nor peritoneal deposits were detected at intraoperative evaluation, in any of the cases. Pre- or post-operative chemotherapy or radiotherapy was not administered to any of these patients. All tumors were collected and processed uniformly and pathological assessment was conducted according to the guidelines of the United Kingdom Coordinating Committee on Cancer Research16 by a consultant histopathologist with a special interest in gastrointestinal pathology. It was confirmed that the circumferential resection margins were uninvolved in all rectal cancers. To allocate the TNM stage, a median of 18 (range 6–33) lymph nodes were counted.

After discharge from the hospital, patients attended follow-up clinics at 3–6 monthly intervals. A detailed clinical examination and measurement of carcinoembryonic antigen serum levels were performed at each visit. Colonoscopic surveillance was conducted at regular intervals, and computerized tomography scans of the abdomen and chest radiographs were ordered when clinically indicated. Survival was measured from the date of operation to date of the latest follow-up visit or death due to recurrent cancer. The clinical ethics committee for St James’s University Hospital approved these studies.

Immunohistochemical Staining for Survivin and the Scoring Method for Its Expression
Briefly, 3-µm sections were cut from archived paraffin blocks of these colorectal carcinomas and stained with H&E for histopathological assessment. For Survivin antigen retrieval, deparaffinized and rehydrated sections were immersed in 10-3 m sodium citrate buffer (pH 6.0), boiled for 1 minute in a pressure cooker, and then cooled and washed in tap water. After the sections had been quenched with hydrogen peroxide and methanol, and blocked, the primary anti-Survivin monoclonal antibody (mAb 8E2 kindly provided by Dr Dario Altieri of Yale University), which has been previously characterized,17 was applied at a dilution of 1:5 and incubated overnight at room temperature. After washing, biotinylated rabbit anti-mouse immunoglobulin (Dako; 1:200 dilution) followed by streptavidin-biotin complex conjugated to horse-radish peroxidase (Dako) were applied at room temperature. Finally, 3,3'-diaminobenzidine (Sigma) was used for color development and hematoxylin for counterstaining. Negative control slides that excluded the primary antibody were prepared for each section. A colon carcinoma which strongly expressed Survivin mRNA by RT-PCR14 was used as a positive control. As previously described,17 the mean percentage of positive tumor cells in at least five areas at x400 magnification was determined and assigned to one of five categories: (1) 0, <5%; (2) 1, 5% to 25%; (3) 2, 25% to 50%; (4) 3, 50% to 75%; and (5) 4, >75%. The intensity of Survivin immunostaining was scored as (1) weak, 1+; (2) moderate, 2+; and (3) intense, 3+. The percentage of positive tumor cells and staining intensity were multiplied to produce a weighted score for each case. In tumors displaying heterogeneous staining, the predominant pattern was considered for scoring. Cases with weighted scores < 1 were defined as negative; all others were defined as positive.

Immunohistochemical Staining for BCL-2 and P53
Deparaffinized and rehydrated sections were immunostained for P53 and BCL-2 by using the avidin-biotin-peroxidase complex technique, as described previously by one of the authors (NS).18 Briefly, the BCL-2 antigen retrieval technique was the same as that for Survivin. For P53 antigen retrieval, the sections were immersed in 10-3 m sodium citrate buffer (pH 6.0) and heated in a microwave at 100°C twice for 5 minutes. The primary monoclonal antibodies for P53 (clone DO-7, Dako; dilution 1:100) and BCL-2 (clone 124, Dako; dilution 1:40) were applied at room temperature for 60 minutes. Scoring criteria for BCL-2 were as described previously.18 For P53 expression, sections with >10% tumor cells demonstrating nuclear staining were labeled positive.

Statistical Analysis
The statistical software package SPSS 6.0 was used. Clinicopathological variables associated with Survivin expression as well as the correlation between Survivin and P53 or BCL-2 expression were analyzed by either the {chi}2 test or Fisher’s exact test. Survival analyses were conducted accorded to the Kaplan-Meier method and survival characteristics were compared using the log rank test. The Cox proportional hazards regression model was used to compare relative influences of different prognostic factors. A P value < .05 was considered to indicate statistical significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of Survivin in Colorectal Carcinomas
The anti-Survivin mAb 8E2 demonstrated a granular staining pattern in the cytoplasm of colorectal carcinoma cells (Fig. 1B). No expression of Survivin was detected in either the stromal cells of the carcinomas or in adjacent histologically normal colorectal epithelium. Based on weighted scores, 30 (61.2%) colorectal carcinomas were designated as Survivin-positive.



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  		FIG. 1. (A) A stage II colorectal carcinoma displaying negative immunohistochemical staining for Survivin (x100). (B) A stage II colorectal carcinoma displaying strongly positive immunohistochemical staining for Survivin. Survivin expression is limited to the cytoplasm of malignant cells (x400).

 
Correlation between Expression of Survivin and Clinicopathological Characteristics
This series comprised 33 men and 16 women with a median age of 72 (interquartile [IQ] range = 63–80) years. There were 32 colonic and 17 rectal cancers, which included 42 T3 and 7 T4 primary tumors. The median age of patients with Survivin-positive and Survivin-negative tumors was similar (71 years vs. 74 years; P = .13). As shown in Table 1, expression of Survivin was independent of gender, site of origin, and T category as well as histopathological characteristics, such as degree of differentiation, lymphocytic infiltration, extramural venous invasion, and type of invading margin, of the primary tumor.


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  		TABLE 1. Correlation between expression of Survivin and clinicopathological characteristics of patients with Stage II colorectal carcinoma
 
Correlation of Expression between Survivin and P53 or BCL-2
Cytoplasmic immunoreactivity for BCL-2 was found in 21 (42.9%) cases, and nuclear accumulation of P53 was detected in 30 (61.2%) cases. As shown in Table 1, there was no correlation of expression between Survivin and either P53 or BCL-2.

Survival Characteristics
The disease-specific 5-year survival rate of this cohort of patients was 65.3% (Fig. 2). The median follow-up period for this cohort of patients was 5 years. During this follow-up period, 12 patients died with recurrent disease. Ten patients died with recurrent liver disease; of these, two patients with rectal cancer also suffered pelvic recurrences, and two patients with colon cancer also had lung recurrences. Two patients with colon cancer died with lung recurrences only. Eleven (91.7%) deaths occurred in patients with Survivin-positive primary cancers in comparison with only one (8.3%) death in patients with Survivin-negative cancers (P < .02). When the patient cohort was stratified according to tumor expression of Survivin, the disease-specific 5-year survival rate of patients with Survivin-positive tumors was significantly worse than the survival of patients with Survivin-negative tumors (52.1% vs. 94.1%, respectively; P = .01; Figure 3). On univariate analyses, the expression of Survivin, an infiltrative tumor margin, a rectal site of the primary tumor, and a T4 category predicted a significantly increased risk of death with recurrent colorectal cancer (Table 2). On multivariate analysis of these predictive variables identified by univariate analysis, only the expression of Survivin and a rectal site of the primary tumor retained an independent value in predicting an significantly increased risk of death (Table 2).



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  		FIG. 2. Kaplan-Meier survival plot for patients with stage II colorectal carcinoma displaying a typical 5-year survival rate of 65.3%.

 


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  		FIG. 3. Kaplan-Meier survival plot of patients with curatively resected stage II colorectal carcinoma stratified according to tumor expression of Survivin. The 5-year survival rate of patients with Survivin-positive tumors was 52.1% as compared with that of 94.1% for patients with Survivin-negative tumors (P = .01).

 

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  		TABLE 2. Univariate and multivariate analysis of variables predicting the risk of death with recurrent colorectal carcinoma
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Immunohistochemically, expression of the Survivin protein by malignant cells was observed in 61.2% of stage II colorectal carcinomas. These results are entirely consistent with the detection of Survivin mRNA transcripts in 62.7% of colorectal cancers from the same cohort of patients, recently reported by the authors.14 A 95% concordance between Survivin mRNA expression by RT-PCR and Survivin protein expression by immunohistochemistry was noted in the 49 tumors included in the present study. When using the same monoclonal anti-Survivin antibody and immunohistochemical scoring system, Survivin expression was detected in 53.3% of a separate series of colorectal cancers at stages I–IV.19 The authors14 and others19 have previously confirmed that expression of Survivin is independent of the pathological stage of colorectal carcinomas. Interestingly, immunohistochemical detection of Survivin protein varies substantially in different human malignancies with only 34% of gastric carcinomas reported to be Survivin-positive,17 as compared with 78% of transitional cell carcinomas of the bladder20 and 93% of melanomas.21 Nonetheless, the available data support the original notion that Survivin a plays ubiquitous role in inhibiting apoptosis in common human malignancies8; the mechanisms underlying the organ-dependent differential expression of this protein presently remain unclear.

Survivin expression was independent of the histopathological characteristics of stage II colorectal carcinomas, and this observation is supported by the only other report of Survivin protein expression in colorectal carcinomas.19 In contrast, Survivin expression is reported to be associated with an histologically more aggressive phenotype of neuroblastomas22 and transitional cell carcinomas of the bladder.20 Furthermore, in the present series, no statistically significant association between expression of Survivin and either P53 or BCL-2 was detected. The percentage of P53-positive tumors is similar to that in other series.23,24 Although Survivin and P53 are both critical modulators of the opposing cellular processes of proliferation and apoptosis, there is currently no evidence of interaction between mechanisms regulating the expression of each of these proteins.25 Indeed, apart from gastric carcinomas, which show a strong positive correlation between Survivin and P53 expression,17 these proteins appear to expressed independently in human malignancies,20,22 including colorectal cancers.19 Immunoreactivity for BCL-2 in the present series appears lower than that reported in a previous study of Survivin expression in colorectal carcinomas,19 and this might explain the absence herein of a positive correlation between Survivin and BCL-2 that has been observed in other studies.17,19,20,22

The present cohort of patients with stage II colorectal carcinomas displayed survival characteristics that are typical for this stage of the disease.3 In the authors’ series of colorectal cancers at stages I–IV, the pathological stage of disease at presentation is the most important variable affecting long-term outcome,14,26 and expression of Survivin mRNA predicts a significantly increased risk of death with recurrent cancer specifically in stage II disease but not in stage III disease.14 In the present study, patients with Survivin protein-positive stage II colorectal carcinomas exhibited a 5-year survival rate of 52%, which is very similar to that of patients with stage III colorectal carcinomas. In contrast, patients with Survivin-negative stage II colorectal carcinomas displayed a 5-year survival rate of 94%, not unlike that of patients with stage I disease.14,26 In a previous study, expression of Survivin protein did not independently predict a significantly worse outcome for the entire cohort of patients with stages I–IV colorectal carcinoma; however, stage-wise survival analysis was not reported.19 Survivin-positive cancers did, however, display substantially lower apoptotic indices that correlated with a significantly shorter 5-year survival rate.19 Survivin protein expression has also been reported to correlate with inhibition of apoptosis and shorter survival in gastric carcinomas.17 Impaired apoptosis is recognized to enhance tumor progression and to promote metastasis by enabling tumor cells to survive transit in the bloodstream and to grow in ectopic tissue sites lacking the otherwise essential survival factors.27 Impaired apoptosis is recognized to enhance tumor progression and promote metastasis by enabling tumor cells to survive transit in the bloodstream and to grow in ectopic tissue sites lacking the otherwise essential survival factors.27 Inhibition of tumor cell apoptosis due to expression of Survivin may contribute to increased aggressiveness of such tumors, resulting in a poor prognosis.

The present study confirms that study of Survivin expression might aid in the stratification of patients with stage II colorectal cancer into two separate groups whose prognosis and, by extension, indications for chemotherapy are significantly different. Few molecular events in colorectal carcinomas, such as allelic deletion on chromosome 18q,28 loss of expression of the deleted in colon cancer protein,29 Ki-RAS mutations,23 and expression of the REG gene26 are of prognostic value specifically in stage II disease. Furthermore, conflicting results from similar studies has led to much confusion in the literature. For example, one recent report demonstrates that allelic deletion on chromosome 18q is associated with poor survival of patients with stage II CRC,30 whereas another study concludes that this phenomenon does not provide any prognostic information.31 Consequently, it has been suggested that construction of composite genetic profiles of tumor tissues, with inclusion of several prognostic markers, may be a way forward.1 The present data provide a compelling case for inclusion of measures of Survivin expression in any such prognostic panel used for the purpose of selecting patients with stage II colorectal carcinoma for administration of adjuvant chemotherapy in future clinical trials.


   Acknowledgments
 
The authors are grateful to Yorkshire Cancer Research for funding which supported this research and to Ms. V. Allgar, consultant biostatistician, for advice.

Received for publication March 17, 2000. Accepted for publication October 2, 2000.


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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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