Background
Colorectal cancer (CRC) is the third most common malignancy all round the world [
1]. At least 50% of CRC patients will develop a metastatic disease and about 5–25% of them are located in the lung [
2]. Due to the development of new chemotherapeutic drugs and minimal invasive video-assisted thoracoscopy and the fact that liver metastasectomy contributes to survival improvement, pulmonary metastasectomy has emerged as a potentially curative option in the multimodal management of metastatic CRC [
2,
3]. When compared with 5% for patients without pulmonary metastasis local treatment, the reported 5-year survival of CRC can be elevated up to 62% after pulmonary metastasectomy [
4]. Since the 1990s, a large number of retrospective studies have shown that multiple clinical features may be probable prognostic survival factors for patients after metastasectomy, such as the number of metastases, preoperative carcinoembryonic antigen serum (CEA) level, thoracic lymph node involvement, and surgical procedures [
4‐
8]. However, reliable and objective prognostic variables are still in urgent need of distinguishing patients who benefit from a surgical approach [
2,
4]. As a common tumor suppressor,
p53 overexpression is thought to be a probable prognostic factor and response to therapy. Nevertheless, the prognostic value of
p53 overexpression in CRC patients after pulmonary metastasectomy was investigated in few studies. Therefore, the objective of this retrospective study was to describe our experience in pulmonary metastasectomy for metastatic CRC and explore whether
p53 overexpression has prognostic value in pulmonary metastasectomy of CRC.
Methods
Between July 2002 and December 2013, 88 patients underwent resection of pulmonary metastases from colorectal cancer. Each patient had a proven tissue diagnosis of metastatic colorectal adenocarcinoma. The criteria for resection of pulmonary metastases included unilateral or bilateral resectable lung lesions, no local recurrence of primary lesions, and adequate cardiorespiratory function for complete resection of all pulmonary lesions. Extrapulmonary metastases of light tumor burden were included. Clinical, biochemical and imaging, and operative data were collected from computerized records. Immunohistochemical (IHC) staining for p53 was performed on paraffin-embedded 5-μm sections using mouse anti-human tumor protein p53 monoclonal antibody (DO-7, Dako, Denmark). Samples were considered positive when at least 20% of the cancer cells were positive for p53 staining. Follow-up data were obtained from the patients’ records and by contacting the patients’ respective general practitioners. The data were analyzed by SPSS 13.0 version. The prognostic effect of each variable on survival was evaluated using the Kaplan-Meier method and log-rank test. For the multivariate analysis of prognostic factors, the Cox regression model was used. P value of less than 0.05 was considered statistically significant.
Discussion
Even though there is no randomized trial evidence, resection of pulmonary metastases is considered to be an effective measure to improve the survival of the appropriately selected CRC patients with lung metastases. Multiple studies have evaluated a number of possible clinical or pathological prognostic indicators. However, the relationship between molecular abnormalities and survival is unclear [
5,
9‐
12].
As a tumor suppressor gene,
p53 is a common target of genetic alteration in human cancer [
13,
14], which exerts the function of controlling the induction of growth arrest and apoptosis by eliminating damaged cells [
15,
16]. Alteration of this gene is associated with postoperative outcome and poor prognosis [
17]. Technically,
p53 protein expression can be assessed by IHC and
p53 genomic status can be analyzed using direct gene sequencing [
18]. In consideration of its technical reproducibility and high concordance with that of genomic analysis, IHC still holds considerable promise as a convenient and inexpensive means [
18]. Therefore, IHC was adopted as a method to assess the
p53 expression in this study.
Previous studies have revealed
p53 protein expression with the help of IHC in 42–69% of CRCs [
15,
16,
18]. Multiple tumors with increased
p53 expression were associated with lymph node metastasis, extrathyroidal invasion, pleural infiltration, and tumor location [
19,
20]. Literature review showed that
p53 overexpression could be an adverse independent predictor of survival [
21,
22]. In addition,
p53 expression was found to be related to liver metastases of colorectal tumors in some studies [
23‐
25]. However, some investigations failed to document a significant inverse correlation of
p53 overexpression with CRC patients’ survival after pulmonary metastasectomy. One possible reason was that there were so many variables related to staining protocols and scoring systems that contrasting results were provided [
26]. More importantly, the relationship between
p53 overexpression and gene alteration was actually complicated [
27]. Protein overexpression is seen in gene mutation type and cases with wild type [
26,
28]. Generally, different kinds of antibodies mainly recognize certain mutants or wild type of genes, which cannot fully reflect protein expression to some extent.
In this study, p53 overexpression was shown in 42 (47.7%) cases with a significantly shorter survival (median OS 62.6 vs 42.1 months, p = 0.046), which suggested a potential candidate for modulating the risk of colorectal lung metastases of p53. However, a single-center retrospective design and highly selected patient population could have introduced biased information. Additionally, the small size of the population and the co-linear relation between the parameters may give rise to meaningless results of multivariate analysis. Therefore, a larger trial is needed to confirm the value of p53 overexpression or mutation.
Conclusions
In conclusion, surgical resection of pulmonary metastases may extend the survival of CRC patients even if there are extrapulmonary metastases. Besides, p53 overexpression may help judge the prognosis of patients who undergo pulmonary metastasectomy.
Acknowledgements
Thanks are due to Zhang Yigong from the Second Affiliated Hospital of Zhejiang University School of Medicine for the statistical analysis.
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