Original Study
Prognostic Significance of Preoperative Serum Lactate Dehydrogenase in Upper Urinary Tract Urothelial Carcinoma Xin-Ke Zhang,1,2 Zhi-Ling Zhang,1,3 Xu Lu,4 Ping Yang,1,2 Mu-Yan Cai,1,2 Wan-Ming Hu,1,2 Jing-Ping Yun,1,2 Fang-Jian Zhou,1,3 Chao-Nan Qian,1 Yun Cao1,2 Abstract Upper urinary tract urothelial carcinoma (UUTUC) is one of the uncommon malignancies. In this study, we retrospectively evaluated the prognostic implication of the preoperative lactate dehydrogenase in 100 UUTUC patients. We found that the preoperative lactate dehydrogenase was an independent prognostic factor for patients with UUTUC. This finding could be of help in clinical practice. Background: Upper urinary tract urothelial carcinoma (UUTUC) is one of the uncommon malignancies lacking of prognostic indicators. Lactate dehydrogenase (LDH) has been demonstrated to correlate with clinical outcomes in human cancers. In this study, we aimed to evaluate the prognostic implication of the preoperative LDH in UUTUC. Patients and Methods: A cohort of 100 UUTUC samples along with the preoperative LDH value was recruited from January 1990 to June 2011. The cutoff value was set at 245 u/L for the upper value of normal limitation. Univariate and multivariate analyses were conducted to determine the association of LDH with overall survival (OS) and disease-free survival (DFS). Results: Kaplan-Meier analysis revealed that high level of LDH (> 245 u/L) was significantly associated with poor OS (P < .001) and DFS (P ¼ .002). Multivariate Cox proportional analysis indicated LDH, controlled by vascular invasion, pathological stage, lymph node status, subsequent bladder tumor, tumor grade, tumor necrosis, architecture, and multifocality, was as an independent predictor of OS (hazard ratio, 3.181; 95% confidence interval, 1.223-8.276; P ¼ .018) and DFS (hazard ratio, 3.041; 95% confidence interval, 1.247-7.417; P ¼ .015). Stratified showed that elevated serum LDH was correlated with the worse OS in patients without lymph node metastasis (P ¼ .002) and those at advanced pathological stage (P < .001). Conclusion: The preoperative LDH was an independent prognostic factor for patients with UUTUC and could be used as a risk factor to predict the tumor aggressiveness. Clinical Genitourinary Cancer, Vol. -, No. -, 1-5 ª 2016 Elsevier Inc. All rights reserved. Keywords: Disease-free survival, Lactate dehydrogenase, Overall survival, Prognosis, Upper urinary tract urothelial carcinoma
Introduction Upper urinary tract urothelial carcinoma (UUTUC), including renal pelvic and ureteric cancers, represents approximately 5% of urothelial carcinomas.1 It is typically accompanied with multiple 1 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China 3 Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China 4 Department of Biology, University of Findlay, Findlay, OH
Submitted: Aug 7, 2015; Revised: Dec 28, 2015; Accepted: Jan 16, 2016 Address for correspondence: Yun Cao, MD, PhD, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou 510060, China E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2016.01.003
lesions at a site, high recurrence rates, and distant metastasis.2 Surgical resection is considered the predominant treatment for UUTUC.3 Traditional surgical procedure combined with chemotherapy could be helpful for a minority of patients. A multiinstitutional retrospective study indicated that high-risk UUTUC patients did not benefit with a significant overall survival or cancerspecific survival from adjuvant chemotherapy.4 As a result, personalized individual therapy should be a promising strategy to improve the prognosis of patients insensitive to conventional therapy.5,6 Novel biomarkers that are of better prognostic significance in the selection of patients for neo-adjuvant should be explored. Cancer cells appear to consume more lactate than the normal cells.7 Several studies have shown that high level of lactate
Clinical Genitourinary Cancer Month 2016
-1
Preoperative LDH in UUTUC dehydrogenase (LDH), an enzyme catalyzing lactate into pyruvate, serves as an unfavorable prognostic factor in lymphoma, prostate cancer, and testicular cancer.8-10 Serum LDH was also reported as a predictor for the survival benefit conferred by mammalian target of rapamycinecontaining complex 1inhibition in poor-risk renal cell carcinoma.11 Since the level of circulating blood LDH can be easily determined in clinic, it could be an indicator to reflect tumor burden and a useful biomarker that is practical in clinical management. In this study, the prognostic significance of serum LDH in UUTUC was determined in a cohort of 100 patients.
Patients and Methods Patients The data (for retrospective analysis) of 127 UUTUC patients who were performed radical nephroureterectomy with bladder cuff excision in Sun Yat-sen University Cancer Center (SYSUCC) from January 1990 to June 2011 was obtained. The use of tissues for this study has been approved by the Institute Research Medical Ethics Committee of SYSUCC. The entire clinicopathological data was collected in the same institution, including age at diagnosis, gender, vascular invasion, tumor grade, tumor site, subsequent bladder tumor, multifocality, and TNM classification of each patient. Laboratory data was retrieved from the routine blood tests of these patients 2 weeks before surgery. Patients with preoperative infection, fever, other tumors, with a history of invasive bladder cancer prior to treatment, or who received the treatment of neo-adjuvant or adjuvant chemotherapy or radiotherapy were excluded (see Supplemental Figure 1 in the online version), and eventually, 100 specimens of UUTUC were enrolled in this retrospective study. No informed consent (written or verbal) was obtained for the use of retrospective tissue samples from the patients (some of whom were deceased) because this was deemed unnecessary by the ethics committee. All samples were anonymous. The recruited patients were observed by cystoscopy, ureteroscopy, and other physical examinations if needed to investigate local recurrence and distant metastasis regularly.
Selection of Cutoff Value The cutoff value of LDH was determined by the serum normal range from Sun Yat-sen University Cancer Center. We took the upper limit of normal range as the cutoff value of the LDH,12 which was 245 u/L. Higher than the cutoff value was considered as a high level of LDH.
Statistical Analysis
2
-
Statistical analyses were performed using SPSS software, version 16.0 (SPSS, Chicago, IL). The relationship of the biomarker with other clinicopathologic characteristics was analyzed by chi-square tests. Univariate analysis was used to define the association of prognostic indicators with survival of patients by log-rank test. Multivariate analysis could find the independent prognostic biomarkers for survival of patients with Cox proportional hazards regression model. Survival curve was graphed between high and normal level of LDH by the Kaplan-Meier method. Hazard ratios were evaluated as the relative risk of these variables with corresponding 95% confidence intervals (CIs) from the Cox regression analysis.13 P < .05 was considered as a significantly statistical difference.
Clinical Genitourinary Cancer Month 2016
Table 1 Correlation Between LDH and Clinicopathological Features in UUTUC LDH (u/L) All Cases
£245
>245
Female
21
21 (23.3%)
0 (0.0%)
Male
79
69 (76.7%)
10 (100%)
Gender
P Value .086
Age at diagnosis, years
.548
3
65
57 (63.3%)
8 (80.0%)
Low
21
19 (21.1%)
2 (20.0%)
High
79
71 (78.9%)
8 (80.0%)
Pelvic
57
51 (56.7%)
6 (60.0%)
Ureteric
43
39 (43.3%)
4 (40.0%)
Tumor grade
.935
Tumor site
.637
Multifocality
.589
No
58
53 (58.9%)
5 (50.0%)
Yes
42
37 (41.1%)
5 (50.0%)
No
69
65 (72.2%)
4 (40.0%)
Yes
31
25 (27.8%)
6 (60.0%)
No
52
50 (55.6%)
2 (20.0%)
Yes
48
40 (44.4%)
8 (80.0%)
Vascular invasion
.037
Tumor necrosis
.033
Architecture
.069
Papillary
57
54 (60.0%)
3 (30.0%)
Non-papillary
43
36 (40.0%)
7 (70.0%)
The values in bold indicate statistical significance between two groups. Abbreviations: LDH ¼ lactate dehydrogenase; UUTUC ¼ upper urinary tract urothelial carcinoma.
Results Patients’ Characteristics The clinicopathological characteristics of patients with UUTUC are shown in Table 1. Seventy-nine (79.0%) cases were male, and 21 (21.0%) cases were female. The mean age was 60.3 years. The average follow-up interval was 45.8 months, with a range from 1 to
Xin-Ke Zhang et al 151 months. The 2-year and 5-year overall survival (OS) were 83% and 70%, respectively. The median OS was 37.0 months. The rates of disease-free survival (DFS) at the second and fifth year were 80% and 66%, respectively.
Selection of the Cutoff Value for LDH The patients with UUTUC were separated into 2 groups; the normal level of LDH ( 245 u/L) and a high level of LDH (> 245 u/L). No differences were observed between these 2 groups with respect to gender, age at diagnosis, tumor diameter, tumor grade, tumor site, architecture, pathological stage, lymph node status, and multifocality (Table 1).
The Relationship With LDH on UUTUC Patients’ Survival Univariate analyses revealed that LDH, as well as vascular invasion, pathological stage, lymph node status, subsequent bladder tumor, tumor grade, tumor necrosis, architecture, and multifocality, were significantly associated with the outcome of patients with UUTUC (P < .05; see Supplemental Table 1 in the online version). A high level of LDH was strongly linked to worse OS (P < .001; Figure 1A) and DFS (P ¼ .001; Figure 1B). Multivariate analyses suggested that a high level of LDH was independently correlated with poor OS (P ¼ .018; see Supplemental Table 1 in the online version) and DFS (P ¼ .015; see Supplemental Table 2 in the online version).
Stratified Analysis for OS and DFS Stratified survival analyses showed that a high level of LDH was closely correlated with poor prognosis for OS (P ¼ .002, P < .001) and DFS (P ¼ .128; P < .001) in the subgroups of patients with N0 classification and at T2-T4 stage (Figures 2 and 3).
Discussion Previous studies have demonstrated that elevated serum LDH level was significantly correlated with unfavorable prognosis in malignancies, including squamous cell cancer, ovarian cancer, gastric cancer, and nasopharyngeal carcinoma.14-17 In our study, a high LDH level was associated with the advanced pathological stage, lymph node metastasis, subsequent bladder tumor, vascular invasion, and tumor necrosis. These findings were partially in agreement with that of published literature showing that the high serum LDH level might reflect heavier tumor burden in gastric cancer.18 The acidic microenvironment generated by active metabolism of tumor cells could easily prompt the proliferation and metastasis of tumor cells, and the aggressive angiogenesis might be associated with the metastasis of tumor cells due to the vascular endothelial growth factor stimulated by overexpression of hypoxia inducible factor because of elevated LDH.19 Therefore, the tumor burden and angiogenesis due to the elevated LDH could have an impact on the survival of patients with UUTUC. High serum LDH may be helpful for the UUTUC patients in selection of a suitable postoperative therapy and might provide useful information to predict and monitor bladder recurrence of UUTUC patients. Our data that elevated serum LDH level was significantly related to poor OS and DFS in patients with UUTUC was also in line with previous studies showing that patients with elevated serum LDH level had shorter survival than those with normal serum LDH level in metastatic renal cell carcinoma,11 germ cell tumors,20 and hepatocellular carcinoma.21 However, Kluth et al reported that high level of serum LDH was not a significant predictor,22 which was not consistent with the results found in our study. The threshold in the Kluth et al study was set at 1000 u/L, much higher than that in our study (245 u/L). We believe that the different cutoff values of LDH could lead to the opposite conclusions between Kluth’s and our
Figure 1 The Association of LDH With the Survival of UUTUC Patients; Overall Survival (A) and Disease-Free Survival (B)
Abbreviations: DFS ¼ disease-free survival; LDH ¼ lactate dehydrogenase; OS ¼ overall survival; UUTUC ¼ upper urinary tract urothelial carcinoma.
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Preoperative LDH in UUTUC Figure 2 Survival Curves of High and Normal Levels of LDH in UUTUC Patients Without Lymph Node Metastasis; Overall Survival (A) and Disease-Free Survival (B)
Abbreviations: DFS ¼ disease-free survival; LDH ¼ lactate dehydrogenase; OS ¼ overall survival; UUTUC ¼ upper urinary tract urothelial carcinoma.
studies. Taken together, our data revealed that high level serum LDH was very useful to predict the adverse prognosis in the UUTUC patients. In the present study, a high level of LDH was an unoptimistic prognostic factor in patients without lymph node metastasis or at advanced pathological stage. This may therefore offer help to distinguish which patients should be timely monitored for tumor aggressiveness. On the other hand, a high level of LDH was more
frequently found in patients at an advanced stage, and UUTUC patients with high serum LDH had shorter survival, indicating that the elevated LDH level might be correlated with a more aggressive pathological phenotype. This might be explained by the fact that more LDH was released by the smooth muscle cells or renal cells due to the invasion of smooth muscle tissues or renal parenchyma in UUTUC patients of advanced stage.
Figure 3 Survival Curves of High and Normal Levels of LDH in UUTUC Patients With Advanced Pathological Stage (T3 and T4), Overall Survival (A) and Disease-Free Survival (B)
4
-
Abbreviations: DFS ¼ disease-free survival; LDH ¼ lactate dehydrogenase; OS ¼ overall survival; UUTUC ¼ upper urinary tract urothelial carcinoma.
Clinical Genitourinary Cancer Month 2016
Xin-Ke Zhang et al There are several limitations of this study. First, the sample size of this study is not large enough. Our conclusion needs to be verified in future by a multi-institution investigation. Second, the lack of other confounder biomarkers in this study might weaken the significance of our conclusion. Third, retrospective data requires validation by prospective multi-institution study. However, our data show that elevated level of LDH was significantly associated with clinical outcomes of UUTUC patients, and we therefore suggest LDH as a high risk factor for the development of the patients with UUTUC.
Conclusions Our analysis has showed the preoperative LDH was an independent prognostic factor for patients with UUTUC and could be used as a risk factor to predict the tumor aggressiveness.
Clinical Practice Points
2. 3. 4.
5. 6. 7. 8. 9. 10.
Our study showed that preoperative levels of LDH might be an
independent predictive biomarker for OS and DFS in patients with UUTUC. The new findings could be of help in clinical practice.
Acknowledgments The authors thank Dr. Chris Zhi-Yi Zhang (Department of Pathology, Sun Yat-sen University Cancer Center) for critical reading of this manuscript.
Disclosure This work was supported by grants from the National Natural Science Foundation of China (No. 81472380, No. 81472386) and from the National High Technology Research and Development Program of China (863 Program) (No. 2012AA02A501). The authors have stated that they have no conflicts of interest.
11.
12. 13. 14. 15.
16.
17.
18.
Supplemental Data
19.
Supplemental figure and tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.clgc. 2016.01.003.
20. 21.
References 1. Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell
22.
carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology 1998; 52:594-601. Genega EM, Porter CR. Urothelial neoplasms of the kidney and ureter. An epidemiologic, pathologic, and clinical review. Am J Clin Pathol 2002; 117(Suppl): S36-48. Zigeuner R, Pummer K. Urothelial carcinoma of the upper urinary tract: surgical approach and prognostic factors. Eur Urol 2008; 53:720-31. Vassilakopoulou M, de la Motte Rouge T, Colin P, et al. Outcomes after adjuvant chemotherapy in the treatment of high-risk urothelial carcinoma of the upper urinary tract (UUT-UC): results from a large multicenter collaborative study. Cancer 2011; 117:5500-8. Leung TW, Tung SY, Sze WK, et al. Treatment results of 1070 patients with nasopharyngeal carcinoma: an analysis of survival and failure patterns. Head Neck 2005; 27:555-65. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35:1164-71. Warburg O. On the origin of cancer cells. Science 1956; 123:309-14. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987-94. Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 2003; 21: 1232-7. von Eyben FE, Madsen EL, Liu F, Amato R, Fritsche H. Serum lactate dehydrogenase isoenzyme 1 as a prognostic predictor for metastatic testicular germ cell tumours. Br J Cancer 2000; 83:1256-9. Armstrong AJ, George DJ, Halabi S. Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin. J Clin Oncol 2012; 30: 3402-7. Yin C, Jiang C, Liao F, et al. Initial LDH level can predict the survival benefit from bevacizumab in the first-line setting in Chinese patients with metastatic colorectal cancer. Onco Targets Ther 2014; 7:1415-22. Roden AC, Garcia JJ, Wehrs RN, et al. Histopathologic, immunophenotypic and cytogenetic features of pulmonary mucoepidermoid carcinoma. Mod Pathol 2014; 27:1479-88. Yuce K, Baykal C, Genc C, Al A, Ayhan A. Diagnostic and prognostic value of serum and peritoneal fluid lactate dehydrogenase in epithelial ovarian cancer. Eur J Gynaecol Oncol 2001; 22:228-32. Ross CD, Gomaa MA, Gillies E, Juengel R, Medina JE. Tumor grade, microvessel density, and activities of malate dehydrogenase, lactate dehydrogenase, and hexokinase in squamous cell carcinoma. Otolaryngol Head Neck Surg 2000; 122: 195-200. Kolev Y, Uetake H, Takagi Y, Sugihara K. Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Ann Surg Oncol 2008; 15:2336-44. Cheng SH, Jian JJ, Tsai SY, et al. Prognostic features and treatment outcome in locoregionally advanced nasopharyngeal carcinoma following concurrent chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 1998; 41:755-62. Zhao Z, Han F, Yang S, Hua L, Wu J, Zhan W. The clinicopathologic importance of serum lactic dehydrogenase in patients with gastric cancer. Dis Markers 2014; 2014:140913. Lu H, Forbes RA, Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 2002; 277: 23111-5. Milose JC, Filson CP, Weizer AZ, Hafez KS, Montgomery JS. Role of biochemical markers in testicular cancer: diagnosis, staging, and surveillance. Open Access J Urol 2011; 4:1-8. Scartozzi M, Faloppi L, Bianconi M, et al. The role of LDH serum levels in predicting global outcome in HCC patients undergoing TACE: implications for clinical management. PloS One 2012; 7:e32653. Kluth LA, Xylinas E, Kent M, et al. Predictors of survival in patients with disease recurrence after radical nephroureterectomy. BJU Int 2014; 113:911-7.
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Preoperative LDH in UUTUC Supplemental Figure 1 A CONSORT Diagram Showing the Procedure of Patients Exclusion
Abbreviation: UUTUC ¼ upper urinary tract urothelial carcinoma.
5.e1
-
Clinical Genitourinary Cancer Month 2016
Xin-Ke Zhang et al Supplemental Table 1 Univariate and Multivariate Analyses of Overall Survival in UUTUC Univariate Analysis Variable
All Cases
HR (95% CI)
Gender
P Value
HR (95% CI)
P Value
Prognostic Significance of Preoperative Serum Lactate Dehydrogenase in Upper Urinary Tract Urothelial Carcinoma Xin-Ke Zhang,1,2 Zhi-Ling Zhang,1,3 Xu Lu,4 Ping Yang,1,2 Mu-Yan Cai,1,2 Wan-Ming Hu,1,2 Jing-Ping Yun,1,2 Fang-Jian Zhou,1,3 Chao-Nan Qian,1 Yun Cao1,2 Abstract Upper urinary tract urothelial carcinoma (UUTUC) is one of the uncommon malignancies. In this study, we retrospectively evaluated the prognostic implication of the preoperative lactate dehydrogenase in 100 UUTUC patients. We found that the preoperative lactate dehydrogenase was an independent prognostic factor for patients with UUTUC. This finding could be of help in clinical practice. Background: Upper urinary tract urothelial carcinoma (UUTUC) is one of the uncommon malignancies lacking of prognostic indicators. Lactate dehydrogenase (LDH) has been demonstrated to correlate with clinical outcomes in human cancers. In this study, we aimed to evaluate the prognostic implication of the preoperative LDH in UUTUC. Patients and Methods: A cohort of 100 UUTUC samples along with the preoperative LDH value was recruited from January 1990 to June 2011. The cutoff value was set at 245 u/L for the upper value of normal limitation. Univariate and multivariate analyses were conducted to determine the association of LDH with overall survival (OS) and disease-free survival (DFS). Results: Kaplan-Meier analysis revealed that high level of LDH (> 245 u/L) was significantly associated with poor OS (P < .001) and DFS (P ¼ .002). Multivariate Cox proportional analysis indicated LDH, controlled by vascular invasion, pathological stage, lymph node status, subsequent bladder tumor, tumor grade, tumor necrosis, architecture, and multifocality, was as an independent predictor of OS (hazard ratio, 3.181; 95% confidence interval, 1.223-8.276; P ¼ .018) and DFS (hazard ratio, 3.041; 95% confidence interval, 1.247-7.417; P ¼ .015). Stratified showed that elevated serum LDH was correlated with the worse OS in patients without lymph node metastasis (P ¼ .002) and those at advanced pathological stage (P < .001). Conclusion: The preoperative LDH was an independent prognostic factor for patients with UUTUC and could be used as a risk factor to predict the tumor aggressiveness. Clinical Genitourinary Cancer, Vol. -, No. -, 1-5 ª 2016 Elsevier Inc. All rights reserved. Keywords: Disease-free survival, Lactate dehydrogenase, Overall survival, Prognosis, Upper urinary tract urothelial carcinoma
Introduction Upper urinary tract urothelial carcinoma (UUTUC), including renal pelvic and ureteric cancers, represents approximately 5% of urothelial carcinomas.1 It is typically accompanied with multiple 1 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China 3 Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China 4 Department of Biology, University of Findlay, Findlay, OH
Submitted: Aug 7, 2015; Revised: Dec 28, 2015; Accepted: Jan 16, 2016 Address for correspondence: Yun Cao, MD, PhD, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou 510060, China E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2016.01.003
lesions at a site, high recurrence rates, and distant metastasis.2 Surgical resection is considered the predominant treatment for UUTUC.3 Traditional surgical procedure combined with chemotherapy could be helpful for a minority of patients. A multiinstitutional retrospective study indicated that high-risk UUTUC patients did not benefit with a significant overall survival or cancerspecific survival from adjuvant chemotherapy.4 As a result, personalized individual therapy should be a promising strategy to improve the prognosis of patients insensitive to conventional therapy.5,6 Novel biomarkers that are of better prognostic significance in the selection of patients for neo-adjuvant should be explored. Cancer cells appear to consume more lactate than the normal cells.7 Several studies have shown that high level of lactate
Clinical Genitourinary Cancer Month 2016
-1
Preoperative LDH in UUTUC dehydrogenase (LDH), an enzyme catalyzing lactate into pyruvate, serves as an unfavorable prognostic factor in lymphoma, prostate cancer, and testicular cancer.8-10 Serum LDH was also reported as a predictor for the survival benefit conferred by mammalian target of rapamycinecontaining complex 1inhibition in poor-risk renal cell carcinoma.11 Since the level of circulating blood LDH can be easily determined in clinic, it could be an indicator to reflect tumor burden and a useful biomarker that is practical in clinical management. In this study, the prognostic significance of serum LDH in UUTUC was determined in a cohort of 100 patients.
Patients and Methods Patients The data (for retrospective analysis) of 127 UUTUC patients who were performed radical nephroureterectomy with bladder cuff excision in Sun Yat-sen University Cancer Center (SYSUCC) from January 1990 to June 2011 was obtained. The use of tissues for this study has been approved by the Institute Research Medical Ethics Committee of SYSUCC. The entire clinicopathological data was collected in the same institution, including age at diagnosis, gender, vascular invasion, tumor grade, tumor site, subsequent bladder tumor, multifocality, and TNM classification of each patient. Laboratory data was retrieved from the routine blood tests of these patients 2 weeks before surgery. Patients with preoperative infection, fever, other tumors, with a history of invasive bladder cancer prior to treatment, or who received the treatment of neo-adjuvant or adjuvant chemotherapy or radiotherapy were excluded (see Supplemental Figure 1 in the online version), and eventually, 100 specimens of UUTUC were enrolled in this retrospective study. No informed consent (written or verbal) was obtained for the use of retrospective tissue samples from the patients (some of whom were deceased) because this was deemed unnecessary by the ethics committee. All samples were anonymous. The recruited patients were observed by cystoscopy, ureteroscopy, and other physical examinations if needed to investigate local recurrence and distant metastasis regularly.
Selection of Cutoff Value The cutoff value of LDH was determined by the serum normal range from Sun Yat-sen University Cancer Center. We took the upper limit of normal range as the cutoff value of the LDH,12 which was 245 u/L. Higher than the cutoff value was considered as a high level of LDH.
Statistical Analysis
2
-
Statistical analyses were performed using SPSS software, version 16.0 (SPSS, Chicago, IL). The relationship of the biomarker with other clinicopathologic characteristics was analyzed by chi-square tests. Univariate analysis was used to define the association of prognostic indicators with survival of patients by log-rank test. Multivariate analysis could find the independent prognostic biomarkers for survival of patients with Cox proportional hazards regression model. Survival curve was graphed between high and normal level of LDH by the Kaplan-Meier method. Hazard ratios were evaluated as the relative risk of these variables with corresponding 95% confidence intervals (CIs) from the Cox regression analysis.13 P < .05 was considered as a significantly statistical difference.
Clinical Genitourinary Cancer Month 2016
Table 1 Correlation Between LDH and Clinicopathological Features in UUTUC LDH (u/L) All Cases
£245
>245
Female
21
21 (23.3%)
0 (0.0%)
Male
79
69 (76.7%)
10 (100%)
Gender
P Value .086
Age at diagnosis, years
.548
3
65
57 (63.3%)
8 (80.0%)
Low
21
19 (21.1%)
2 (20.0%)
High
79
71 (78.9%)
8 (80.0%)
Pelvic
57
51 (56.7%)
6 (60.0%)
Ureteric
43
39 (43.3%)
4 (40.0%)
Tumor grade
.935
Tumor site
.637
Multifocality
.589
No
58
53 (58.9%)
5 (50.0%)
Yes
42
37 (41.1%)
5 (50.0%)
No
69
65 (72.2%)
4 (40.0%)
Yes
31
25 (27.8%)
6 (60.0%)
No
52
50 (55.6%)
2 (20.0%)
Yes
48
40 (44.4%)
8 (80.0%)
Vascular invasion
.037
Tumor necrosis
.033
Architecture
.069
Papillary
57
54 (60.0%)
3 (30.0%)
Non-papillary
43
36 (40.0%)
7 (70.0%)
The values in bold indicate statistical significance between two groups. Abbreviations: LDH ¼ lactate dehydrogenase; UUTUC ¼ upper urinary tract urothelial carcinoma.
Results Patients’ Characteristics The clinicopathological characteristics of patients with UUTUC are shown in Table 1. Seventy-nine (79.0%) cases were male, and 21 (21.0%) cases were female. The mean age was 60.3 years. The average follow-up interval was 45.8 months, with a range from 1 to
Xin-Ke Zhang et al 151 months. The 2-year and 5-year overall survival (OS) were 83% and 70%, respectively. The median OS was 37.0 months. The rates of disease-free survival (DFS) at the second and fifth year were 80% and 66%, respectively.
Selection of the Cutoff Value for LDH The patients with UUTUC were separated into 2 groups; the normal level of LDH ( 245 u/L) and a high level of LDH (> 245 u/L). No differences were observed between these 2 groups with respect to gender, age at diagnosis, tumor diameter, tumor grade, tumor site, architecture, pathological stage, lymph node status, and multifocality (Table 1).
The Relationship With LDH on UUTUC Patients’ Survival Univariate analyses revealed that LDH, as well as vascular invasion, pathological stage, lymph node status, subsequent bladder tumor, tumor grade, tumor necrosis, architecture, and multifocality, were significantly associated with the outcome of patients with UUTUC (P < .05; see Supplemental Table 1 in the online version). A high level of LDH was strongly linked to worse OS (P < .001; Figure 1A) and DFS (P ¼ .001; Figure 1B). Multivariate analyses suggested that a high level of LDH was independently correlated with poor OS (P ¼ .018; see Supplemental Table 1 in the online version) and DFS (P ¼ .015; see Supplemental Table 2 in the online version).
Stratified Analysis for OS and DFS Stratified survival analyses showed that a high level of LDH was closely correlated with poor prognosis for OS (P ¼ .002, P < .001) and DFS (P ¼ .128; P < .001) in the subgroups of patients with N0 classification and at T2-T4 stage (Figures 2 and 3).
Discussion Previous studies have demonstrated that elevated serum LDH level was significantly correlated with unfavorable prognosis in malignancies, including squamous cell cancer, ovarian cancer, gastric cancer, and nasopharyngeal carcinoma.14-17 In our study, a high LDH level was associated with the advanced pathological stage, lymph node metastasis, subsequent bladder tumor, vascular invasion, and tumor necrosis. These findings were partially in agreement with that of published literature showing that the high serum LDH level might reflect heavier tumor burden in gastric cancer.18 The acidic microenvironment generated by active metabolism of tumor cells could easily prompt the proliferation and metastasis of tumor cells, and the aggressive angiogenesis might be associated with the metastasis of tumor cells due to the vascular endothelial growth factor stimulated by overexpression of hypoxia inducible factor because of elevated LDH.19 Therefore, the tumor burden and angiogenesis due to the elevated LDH could have an impact on the survival of patients with UUTUC. High serum LDH may be helpful for the UUTUC patients in selection of a suitable postoperative therapy and might provide useful information to predict and monitor bladder recurrence of UUTUC patients. Our data that elevated serum LDH level was significantly related to poor OS and DFS in patients with UUTUC was also in line with previous studies showing that patients with elevated serum LDH level had shorter survival than those with normal serum LDH level in metastatic renal cell carcinoma,11 germ cell tumors,20 and hepatocellular carcinoma.21 However, Kluth et al reported that high level of serum LDH was not a significant predictor,22 which was not consistent with the results found in our study. The threshold in the Kluth et al study was set at 1000 u/L, much higher than that in our study (245 u/L). We believe that the different cutoff values of LDH could lead to the opposite conclusions between Kluth’s and our
Figure 1 The Association of LDH With the Survival of UUTUC Patients; Overall Survival (A) and Disease-Free Survival (B)
Abbreviations: DFS ¼ disease-free survival; LDH ¼ lactate dehydrogenase; OS ¼ overall survival; UUTUC ¼ upper urinary tract urothelial carcinoma.
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Preoperative LDH in UUTUC Figure 2 Survival Curves of High and Normal Levels of LDH in UUTUC Patients Without Lymph Node Metastasis; Overall Survival (A) and Disease-Free Survival (B)
Abbreviations: DFS ¼ disease-free survival; LDH ¼ lactate dehydrogenase; OS ¼ overall survival; UUTUC ¼ upper urinary tract urothelial carcinoma.
studies. Taken together, our data revealed that high level serum LDH was very useful to predict the adverse prognosis in the UUTUC patients. In the present study, a high level of LDH was an unoptimistic prognostic factor in patients without lymph node metastasis or at advanced pathological stage. This may therefore offer help to distinguish which patients should be timely monitored for tumor aggressiveness. On the other hand, a high level of LDH was more
frequently found in patients at an advanced stage, and UUTUC patients with high serum LDH had shorter survival, indicating that the elevated LDH level might be correlated with a more aggressive pathological phenotype. This might be explained by the fact that more LDH was released by the smooth muscle cells or renal cells due to the invasion of smooth muscle tissues or renal parenchyma in UUTUC patients of advanced stage.
Figure 3 Survival Curves of High and Normal Levels of LDH in UUTUC Patients With Advanced Pathological Stage (T3 and T4), Overall Survival (A) and Disease-Free Survival (B)
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Abbreviations: DFS ¼ disease-free survival; LDH ¼ lactate dehydrogenase; OS ¼ overall survival; UUTUC ¼ upper urinary tract urothelial carcinoma.
Clinical Genitourinary Cancer Month 2016
Xin-Ke Zhang et al There are several limitations of this study. First, the sample size of this study is not large enough. Our conclusion needs to be verified in future by a multi-institution investigation. Second, the lack of other confounder biomarkers in this study might weaken the significance of our conclusion. Third, retrospective data requires validation by prospective multi-institution study. However, our data show that elevated level of LDH was significantly associated with clinical outcomes of UUTUC patients, and we therefore suggest LDH as a high risk factor for the development of the patients with UUTUC.
Conclusions Our analysis has showed the preoperative LDH was an independent prognostic factor for patients with UUTUC and could be used as a risk factor to predict the tumor aggressiveness.
Clinical Practice Points
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Our study showed that preoperative levels of LDH might be an
independent predictive biomarker for OS and DFS in patients with UUTUC. The new findings could be of help in clinical practice.
Acknowledgments The authors thank Dr. Chris Zhi-Yi Zhang (Department of Pathology, Sun Yat-sen University Cancer Center) for critical reading of this manuscript.
Disclosure This work was supported by grants from the National Natural Science Foundation of China (No. 81472380, No. 81472386) and from the National High Technology Research and Development Program of China (863 Program) (No. 2012AA02A501). The authors have stated that they have no conflicts of interest.
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Supplemental Data
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Supplemental figure and tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.clgc. 2016.01.003.
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Preoperative LDH in UUTUC Supplemental Figure 1 A CONSORT Diagram Showing the Procedure of Patients Exclusion
Abbreviation: UUTUC ¼ upper urinary tract urothelial carcinoma.
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Xin-Ke Zhang et al Supplemental Table 1 Univariate and Multivariate Analyses of Overall Survival in UUTUC Univariate Analysis Variable
All Cases
HR (95% CI)
Gender
P Value
HR (95% CI)
P Value
