renal cell carcinoma ( rcc ) is the most common primary malignant neoplasm of the kidney and accounts for about 3% of all adult neoplasms .
the incidence of rcc has been increasing during the past two decades in all age groups .
the greatest increase has been in patients with localized tumors as a result of incidental detection , which is thought to be the result of more widespread use of abdominal ultrasound and computed tomography . however , about 30% of patients with rcc already have metastatic disease at the time of diagnosis , and 10% to 14% of patients experience local recurrence or distant metastasis after nephrectomy despite a finding of pathologically confined disease at the time of nephrectomy [ 3 - 5 ] .
well - known pathological and clinical variables have been identified and sometimes integrated into nomograms to better predict disease recurrence , but with only partial success . with a better understanding of the biology of rcc
, laboratory values and molecular markers are increasingly being investigated as potential predictive factors for rcc [ 6 - 8 ] .
disease progression appears to depend on a complex interaction between the tumor and host inflammatory responses .
it is estimated that underlying infection and inflammatory responses are linked to 15% to 20% of all deaths from cancer worldwide .
the serum level of c - reactive protein ( crp ) , a nonspecific inflammatory acute - phase protein , is frequently increased in patients with metastatic rcc and is a predictor of prognosis .
however , secondary thrombocytosis has been reported with many malignant diseases ; the survival of such patients has been reported to be significantly shorter . the prognostic value of the platelet count has been studied in patients with localized and metastatic rcc ; patients with thrombocytosis had a poorer survival than did patients with a normal platelet count . the purpose of this study was to investigate the association of preoperative crp elevation and thrombocytosis with the prognosis of patients with non - metastatic rcc .
the medical records of 177 patients with non - metastatic rcc who underwent a radical nephrectomy between march 2000 and may 2008 and for whom preoperative crp and platelet levels were available for analysis were retrospectively reviewed .
there were 130 men and 43 women , with a mean age of 53.5 years ( range , 28 - 83 years ) .
preoperatively , all patients were evaluated with a physical examination , routine hematology and biochemical analysis , and radiology studies , including abdominal computed tomography and chest x - ray .
the tumors were staged by using the 2002 tnm classification of the american joint committee on cancer ( ajcc )   and were graded according to fuhrman 's nuclear grading system .
all patients were evaluated postoperatively every 3 months for the first 2 years , every 6 months for the next 2 years , and yearly thereafter .
crp elevation was defined as a crp level 0.8 mg / dl , and thrombocytosis was defined as a platelet count 380,000/l in men and 370,000/l in women according to the normal reference range in our hospital .
disease recurrence was defined as local failure in the tumor bed or regional lymph nodes or distant metastasis .
the chi - square test or fisher 's exact test was used to analyze the correlation between preoperative crp elevation or thrombocytosis and the clinical and pathological variables , including age , gender , anemia , histology subtype , tumor size , t stage , nuclear grade , and metastasis during follow - up .
univariate and multivariate analyses were performed by using the log - rank test or the cox proportional hazards regression model . for all tests ,
the clinical and pathological characteristics of the 177 patients with non - metastatic rcc are summarized in table 1 .
the mean tumor size was 5.12 cm ( median , 4.50 ; range , 1 - 22 cm ) .
regional lymph node dissection was performed in 24 patients who showed suspicious lymph node metastasis on computed tomography . however , none had a pathological diagnosis of lymph node metastasis .
there were 38 patients ( 21.5% ) with crp elevations and 11 patients ( 6.2% ) with thrombocytosis . among patients with crp elevation ,
the mean follow - up period was 48.3 months ( median , 48.0 ; range , 13 - 111 months ) .
twenty - three patients ( 13.0% ) developed metastases and six patients died during the follow - up period .
preoperative crp elevation was significantly correlated with anemia ( p=0.001 ) , t stage ( p=0.004 ) , grade ( p=0.025 ) , and metastasis ( p<0.001 ) , but not with age , gender , tumor histology subtype , or tumor size ( table 2 ) .
preoperative thrombocytosis was significantly correlated with anemia ( p=0.003 ) , t stage ( p=0.002 ) , and metastasis ( p=0.001 ) , but not with age , gender , tumor histology subtype , tumor size , or grade ( table 3 ) .
no significant correlation was found between preoperative crp levels and platelet counts when analyzed by using pearson 's correlation coefficient ( r=0.132 , p=0.079 ) .
kaplan - meier recurrence - free survival curves according to crp level showed that the survival rate of patients with crp elevation ( crp0.8 mg / dl ) was significantly lower than that of patients with normal crp levels ( p<0.001 ) ( fig .
the univariate analysis identified anemia , crp elevation , thrombocytosis , tumor histology subtype , tumor size , t stage , and grade as significant prognostic factors for recurrence - free survival , whereas the multivariate analysis showed that crp elevation ( p=0.033 ) and tumor size ( p=0.007 ) were independent prognostic factors ( table 4 ) .
crp is an acute phase reactant that is produced exclusively by hepatocytes in response to cytokines such as interleukin ( il)-6 , which are known mediators of ongoing inflammatory processes .
an elevation of the serum concentration of this protein indicates the presence of acute inflammation , which is observed 8 to 12 hours after the onset of infection . the relationship between cancer and crp elevation
hepatic production of crp is induced by cytokines such as il-1 , tumor necrosis factor ( tnf ) , and primarily il-6 , which is frequently overproduced by the tumor cells themselves .
experimental studies on rcc cell lines and expression studies of renal surgical specimens have shown that at least some renal tumors produce il-6 , which functions as an autocrine growth factor of the rcc .
therefore , the presence of a systemic inflammatory response might be associated with aggressive rcc behavior .
the prognostic value of crp levels has been reported in many recent studies of cancers , including those of the esophagus , ovaries , and colon [ 21 - 23 ] .
however , the mechanism by which a systemic inflammatory response affects cancer - specific survival in patients with rcc is unclear .
hwang et al studied the relationship between crp and survival in patients with rcc who underwent a radical nephrectomy .
they reported a statistically insignificant difference in the survival rates of patients with and without crp elevation and concluded that crp was not a significant prognostic factor for rcc when compared with tumor stage , grade , tumor size , and cell type .
however , komai et al demonstrated that the 5-year and 10-year disease - specific survival rates ( 75% and 30% , respectively ) in patients with high crp levels were significantly worse than the rates in patients with normal crp levels ( both 93% , p<0.001 ) and suggested that the preoperative crp level is associated with poor survival in patients with localized rcc .
in addition , they reported that the crp level is a useful preoperative screening tool in patients with localized rcc .
blay et al reported that pretreatment il-6 and crp were significantly associated with the effects of cytokine therapy and high il-6 and that the crp level indicated a poor response to cytokine therapy . in the present study ,
preoperative crp elevation was associated with a poorer prognosis and a higher recurrence rate in patients with non - metastatic rcc .
this result confirms the importance of the preoperative crp level as an independent prognostic factor for tumor recurrence and is consistent with the findings of earlier reports showing that a high crp level is associated with poor survival in localized rcc .
secondary or reactive thrombocytosis has been associated with tumor metastasis and poor survival in cancer patients .
the pathophysiologic mechanism of reactive thrombocytosis may be tumor - associated elevation of circulating platelets by tumor - derived humoral factors such as il-6 and macrophage colony - stimulating factor ( m - csf ) that may be responsible for the development of cancer - related thrombocytosis .
il-6 is a potent stimulator of megakaryocytopoiesis , and tumor cells have been shown to release il-6 both in vitro and in vivo .
these observations suggest that il-6 plays a role in the development of tumor - associated thrombocytosis .
karakiewicz et al analyzed 1828 patients with rcc by univariable , multivariable , and predictive accuracy analyses with regard to rcc - specific mortality .
in that study , they showed that the addition of thrombocytosis to the base model ( age , tumor size , tnm stage , ecog - performance status , fuhrman grade , and histology subtype ) increased the predictive accuracy by only 0.3% ( from 85.3% to 85.6% ) ; these changes in predictive accuracy were not statistically significant .
consequently , they concluded that patients who presented with thrombocytosis did not have poorer prognosis than did their counterparts who did not exhibit these apparently unfavorable characteristics , as long as the effects of the tnm stage , histology , tumor grade , and ecog - performance status were considered .
however , many investigators have reported that thrombocytosis is related to a poor prognosis in patients with rcc .
, they showed that patients with thrombocytosis had a mean survival of 45.2 months compared with 76.6 months in patients without thrombocytosis ( p=0.0002 ) and concluded that preoperative thrombocytosis is associated with a poorer survival than is a normal platelet count . in the present study
, we showed that preoperative thrombocytosis was significantly correlated with anemia , t stage , and metastasis .
in addition , thrombocytosis was a significant prognostic factor associated with recurrence - free survival in the univariate analysis .
therefore , thrombocytosis was associated with a poorer prognosis and a higher recurrence rate in patients with non - metastatic rcc ; these findings are consistent with those of previous studies .
ito et al showed that preoperative crp levels and platelet counts had a significant correlation and suggested that this was because the reactive thrombocytosis and crp elevation in rcc were both caused by the production of inflammatory cytokines such as il-6 .
as in the study by ito et al , we analyzed the relationship between preoperative crp and platelet count .
however , we did not find a statistically significant association between preoperative crp and platelet count ( r=0.132 , p=0.079 ) .
therefore , the exact relationship between preoperative crp and platelet count remains to be determined .
a limitation of this study is that several variables could not be considered in the current analysis .
nonetheless , all available variables were included , and our findings indicate that several known prognostic factors were valuable as prognostic factors
the reason for this result was , to some extent , too many patients in stage t1 rather than other t stages and a small number of patients with grade 4 compared with other grades according to the early detection of rcc nowadays .
preoperative crp elevation and thrombocytosis were associated with a poorer prognosis and a higher recurrence rate in patients with non - metastatic rcc . moreover ,
however , preoperative thrombocytosis was not an independent prognostic factor for tumor recurrence and prognosis .
 purposethe aim of this study was to investigate the association of preoperative c - reactive protein ( crp ) elevation and thrombocytosis with the prognosis of patients with non - metastatic renal cell carcinoma ( rcc).materials and methodsthis was a retrospective review of the medical records of 177 patients ( 130 men and 47 women ) with non - metastatic rcc who underwent a radical nephrectomy between march 2000 and may 2008 and for whom preoperative crp and platelet data were available for analysis . 
 preoperative crp elevation and thrombocytosis were compared with clinical and pathological variables.resultsthere were 38 patients with crp elevation and 11 patients with thrombocytosis . 
 the mean follow - up time was 48.3 months ( median , 48.0 ; range , 13 - 111 months ) . 
 twenty - three patients ( 13.0% ) developed metastases and six patients died during the follow - up period . 
 crp elevation was significantly correlated with anemia ( p=0.001 ) , t stage ( p=0.004 ) , grade ( p=0.025 ) , and metastasis ( p<0.001 ) . 
 thrombocytosis was significantly correlated with anemia ( p=0.003 ) , t stage ( p=0.002 ) , and metastasis ( p=0.001 ) . 
 the univariate analysis identified anemia , crp elevation , thrombocytosis , tumor histology subtype , tumor size , t stage , and grade as significant prognostic factors associated with recurrence - free survival , whereas the multivariate analyses showed that crp elevation ( p=0.033 ) and tumor size ( p=0.007 ) were independent prognostic factors.conclusionspreoperative crp elevation and thrombocytosis were associated with a poorer prognosis and a higher recurrence rate in patients with non - metastatic rcc . 
 moreover , preoperative crp elevation appeared to be an independent predictor of tumor recurrence and prognosis . 
 preoperative thrombocytosis , however , was not an independent prognostic factor for tumor recurrence and prognosis . 