Preoperative Butyrylcholinesterase Level as an Independent Predictor of Overall Survival in Clear Cell Renal Cell Carcinoma Patients Treated with Nephrectomy

The prognostic factors for the overall survival (OS) of clear cell renal cell carcinoma (ccRCC) patients treated with nephrectomy are not well defined. In the present study, we investigated the prognostic significance of preoperative butyrylcholinesterase (BChE) levels in 400 ccRCC patients undergoing radical or partial nephrectomy from 1992 to 2013 at our institution. Univariate and multivariate analyses were performed to determine the clinical factors associated with OS. Among the enrolled patients, 302 were diagnosed with organ-confined disease only (T1-2N0M0), 16 with lymph node metastases, and 56 with distant metastases. The median preoperative BChE level was 250 U/L (normal range, 168–470 U/L), and median follow-up period was 36 months. The 3-year OS rate in patients with preoperative BChE levels of ≥100 U/L was significantly higher than in those with levels of <100 U/L (89.3% versus 77.7%, P = 0.004). On univariate analysis, performance status; anemia; hypoalbuminemia; preoperative levels of BChE, corrected calcium, and C-reactive protein; and distant metastasis status were significantly associated with OS. Multivariate analysis revealed that preoperative BChE levels and distant metastasis status were significantly associated with OS. Our findings suggest a possible role of preoperative BChE levels as an independent predictor of OS after nephrectomy in ccRCC patients.


Introduction
Despite an increase in early diagnosis owing to improved imaging technologies, up to one-third of renal cell carcinoma (RCC) patients are diagnosed with the disease at metastatic stages [1]. Of the remaining two-thirds, approximately 20%-40% of those treated with nephrectomy develop metachronous metastases or local recurrence [2]. Therefore, it is essential to accurately stratify patients according to their overall survival (OS) or recurrence-free survival (RFS) after surgery. Several clinical, pathological, and molecular markers such as C-reactive protein (CRP), preoperative platelet count, and plasma fibrinogen level have enabled more accurate prognosis in RCC [3][4][5][6]. However, in general, prognostic factors for OS of RCC patients, particularly those with clear cell RCC (ccRCC), treated with nephrectomy remain poorly defined.
Systemic inflammation is a common host reaction to carcinogenesis or cancer progression [7]. Butyrylcholinesterase (BChE) is an alpha-glycoprotein present in many tissue types, including the central and peripheral nervous system, and in the liver. Low BChE serum levels have been reported in many clinical conditions such as liver damage, inflammation, injury, and malnutrition [8]. A decrease in pretreatment serum BChE level has also been suggested as a useful prognostic parameter in advanced cancer patients with or without hepatic involvement [9][10][11][12]. However, the predictive value of serum BChE level in kidney cancer patients is unknown. Thus, in the present study, we aimed to evaluate 2 The Scientific World Journal the prognostic significance of pretreatment BChE levels in patients with ccRCC undergoing nephrectomy.

Patients.
In the present study, we reviewed the clinical charts of 551 patients who underwent partial, radical, or cytoreductive nephrectomy between 1992 and 2013 at a single institution. Our analysis focused on 400 patients who were diagnosed with ccRCC postoperatively. Covariates including age; gender; Eastern Cooperative Oncology Group performance status (PS); preoperative laboratory data on serum levels of hemoglobin, albumin, BChE, corrected calcium (Ca), lactate dehydrogenase (LDH), CRP, and neutrophillymphocyte ratio (NLR); clinical T stage; and distant metastasis status were analyzed. All laboratory data were routinely collected before surgery in all patients. Tumor staging was performed according to the American Joint Committee on Cancer Staging Manual [13]. The study protocol and informed consent documents were reviewed and approved by the Hirosaki University institutional review board.

Follow-Up Schedule.
After nephrectomy, patients with T1 disease received annual followup, whereas those with T2/T3/T4 status were evaluated every 3 months for 2 years and 6 months thereafter. During the follow-up visits, patients underwent physical examination, ultrasonography, and computed tomography (CT).

Patient Characteristics.
The pretreatment characteristics of all patients are listed in Table 1. All diagnoses were conducted based on CT findings. Among the enrolled patients, 302 were diagnosed with organ-confined disease (T1-2N0 M0), whereas 56 had a distant metastasis (any T, any N, and M1). The most frequent metastasis sites were the lungs (36 patients, 64%) and the bone (9 patients, 16%).

Oncological
Outcomes. The OS was 88.6% for all 400 enrolled patients (Figure 1). By the end of the follow-up   Table 2. Kaplan-Meier curves for OS of all patients, stratified by different serum BChE levels, are shown in Figure 2.
The Scientific World Journal 3 Multivariate analysis using the Cox proportional hazard model revealed that metastasis status and serum BChE level were independent prognostic predictors for OS (Table 3). No significant relation was noted between the BChE level and distant metastasis status.

Discussion
Results from the present study validate the possible role of preoperative serum BChE levels as an independent prognostic factor for OS after surgery in ccRCC patients. To our knowledge, this retrospective analysis is the first report to evaluate the prognostic significance of pretreatment serum BChE levels in ccRCC patients.
Cholinesterases are a group of enzymes that hydrolyze acetylcholine and other choline esters. There are 2 main types of cholinesterases with different biochemical properties [14]. Acetylcholinesterase is present in all excitable tissues-such as the central and peripheral nerve systems and musclesand erythrocytes. The other cholinesterase, BChE, is also present in the nervous system as well as the liver. As BChE is synthesized in the liver, a hepatocellular impairment would 4 The Scientific World Journal  result in a decreased activity of the enzyme. In fact, reduction of BChE levels often occurs in acute and chronic liver damage, cirrhosis, and liver metastasis. Similarly, low BChE levels have been reported during stress and inflammation, as well as in cases of protein-energy malnutrition and other clinical conditions [8].
In geriatric patients, BChE levels have been suggested as a useful biomarker for malnutrition or a disease prognostic indicator [15]. Levels of CRP, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) have been reported to significantly increase in frail elderly patients, whereas BChE activity has been observed to significantly decrease ( < 0.005) [14]. In addition, BChE activity has been reported to negatively correlate with IL-6 and TNF-alpha levels [14].
Advanced cancer is a clinical condition involving mild to moderate inflammation. Systemic inflammation has been described to be associated with poor prognosis in a variety of malignancies [16]. Plasma BChE levels have been shown to decrease in advanced cancer patients with or without hepatic involvement, despite the other liver function tests yielding normal results [17]. One of the possible mechanisms for such BChE activity decrease in cancer patients could be secondary anorexia accompanying malignancy [18]. Santarpia et al. suggested that besides albumin levels and Karnofsky index, serum BChE levels were a survival predictive factor in terminal cancer patients with peritoneal carcinomatosis [9]. In another study involving patients with head and neck or uterine cervical cancer, BChE activity was demonstrated to be an effective prognostic marker [10].
The present study has limitations inherent to any retrospective analysis with a limited number of patients. Although 76% of the enrolled patients were diagnosed with organconfined disease, the other 24% had an advanced disease with metastases to the lymph nodes or other distant sites. BChE is a sensitive yet nonspecific serum biomarker. Therefore, a decreased BChE level might result from an inflammation or physical stress. In addition, the correlation between the decrease of serum BChE level and advanced disease or distant metastasis was obscure in this study. However, in ccRCC patients, low serum BChE levels could suggest other systemic disorders, including poor PS or secondary malnutrition. In addition, BChE levels seem to correlate with cancer activity and nutritional status in ccRCC patients.

Conclusion
Our results validate the possible role of preoperative serum BChE levels as an independent prognostic factor after surgery in ccRCC. BChE levels may correlate with cancer activity and nutritional status in ccRCC patients. Therefore, our findings suggest that serum BChE assessment be included in the routine clinical evaluation of patients with ccRCC.