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Keywords:

  • prognosis;
  • renal cell carcinoma;
  • thrombocytosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Background: Thrombocytosis has been reported in many types of malignancies and has been studied as a prognostic factor. In the present study, we examined the incidence of thrombocytosis in patients with renal cell carcinoma (RCC) in order to evaluate the prognostic value of thrombocytosis.

Methods: One hundred and ninety-six patients treated by radical nephrectomy for RCC were enrolled in this study. We divided the patients into a normal platelet count group and a thrombocytosis group according to the presurgical platelet count. The two groups were compared pathologically and clinically, including prognosis.

Results: Thrombocytosis was present in 16 patients (8.2%). Platelet counts had normalized after nephrectomy in all patients with thrombocytosis. There was no correlation between histological type or grade and thrombocytosis. However, there were correlations between thrombocytosis and tumor size and tumor stage. Patients with thrombocytosis had a worse prognosis than patients without thrombocytosis (P = 0.0028). When adjusted for stage or tumor size, the correlation was limited to low stage (stage 1 + 2: P = 0.0041, stage 3 + 4: P = 0.2983) or small tumors (tumor size: ≤4 cm, P = 0.0021; 4–7 cm, P = 0.0142; >7 cm, P = 0.8158).

Conclusion: Thrombocytosis is an inexpensive and easy tool with which to evaluate the prognosis of RCC patients in daily medical practice.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

The association between malignancy and a raised platelet count has been recognized for almost a century.1 Recently, thrombocytosis has been reported in many kinds of malignancy and has been studied as a prognostic factor.2–7 In the present study, we examined the incidence of thrombocytosis in patients with renal cell carcinoma (RCC) and attempted to evaluate the prognostic value of thrombocytosis.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

One hundred and ninety-six patients treated by radical nephrectomy for RCC from January 1982 to December 2001 at Showa University Hospital, Tokyo, Japan, were enrolled in the study. Their records were reviewed retrospectively. Patients were divided into a normal platelet count group and a thrombocytosis group according to their platelet counts before nephrectomy. Thrombocytosis was defined as a platelet count over 40 × 104/µL, while a normal platelet count was defined as being below 40 × 104/µL. We compared these two groups pathologically and clinically, including prognosis. All values are presented as the mean ± SD.

Tumor stage was classified according to the TMN classification of Union Internationale Contre le Cancer.8 T and N stages were determined by histopathological analyses of surgical specimens. Computed tomography and/or magnetic resonance imaging of the lungs and abdomen were used to diagnose metastasis. Nuclear grade was determined according to the Japanese grading system.9 Mean follow up was 43.3 (range 5–140) and 64.3 months (range 1–202) in patients with thrombocytosis and a normal platelet count, respectively. The χ2 or Mann–Whitney U-test was used when appropriate to compare the two groups. Cause-specific survival curves were determined by the Kaplan-Meier method. Differences in the survival curves were assessed by a log-rank test.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

The platelet count of the patients before nephrectomy was 24.5 ± 9.5 × 104/µL. Thrombocytosis was present in 16 patients (8.2%). Platelet count had normalized after nephrectomy in all thrombocytosis patients (within 1 month in 13 patients and within 3 months in three patients). The platelet counts with and without thrombocytosis were 48.3 ± 9.1 (40.1–81.7) × 104/µL and 22.4 ± 6.0 (10.6–38.1) × 104/µL, respectively. The ages of the patients with and without thrombocytosis were 60.4 ± 12.4 and 59.8 ± 11.9, respectively. Thrombocytosis was present in five of 52 female patients (9.6%) and 11 of 144 male patients (7.6%). There were no significant differences in age or sex. The hemoglobin value in patients with thrombocytosis was 10.4 ± 1.5 g/dL, which was significantly (P < 0.0001) lower than that of patients with normal platelet counts (13.6 ± 1.9 g/dL). The white blood cell count of patients with thrombocytosis was 8.7 ± 4.0 × 103/µL, which was significantly (P = 0.0023) higher than that of patients with normal platelet counts (6.4 ± 2.0 × 103/µL).

The pathological findings are shown in the Table 1. No correlation existed between histological type or grade and thrombocytosis. However, there were correlations between tumor size and tumor stage and thrombocytosis. Large tumors or tumors with metastasis had a higher frequency of thrombocytosis. Perirenal fat invasion or renal vein invasion did not have an effect on frequency.

Table 1.   Pathological findings and relation to thrombocytosis
 Normal plateletsThrombocytosisP-value
  • *

    ≤4 cm vs >4 cm, NS; ≤7 cm vs >7 cm, P = 0.0023.

  • **

    stage 1 vs stage 2, P = 0.0002; stage 2 vs stage 3, NS; stage 3 vs stage 4: P = 0.0477; stage 1 vs stage 4, P < 0.0001; stage 1 vs stage 3, NS; stage 2 vs stage 4, NS.

  • ***

    T1 vs T2, P = 0.0031; T2 vs T3, NS; T1 vs T3: P = 0.0022. RCC, renal cell carcinoma.

No of patients18016NS
Average age 60.459.8NS
Male/female133/4711/5NS
Histological type
 clear cell11512 
 granular cell  8 2 
 papillary RCC  3 1NS
Grade
 1 45 7 
 2 74 5 
 3  7 3NS
Tumor size
 <4 cm 49 2 
 4–7 cm 39 3 
 >7 cm 3810*
Stage
 1 64 1 
 2 15 5 
 3 34 2 
 4 13 7**
TNM
 T1 71 2 
 T2 19 5 
 T3 36 8 
 T4  0 0***
 N −12414 
 N +  2 1NS
 M −113 9 
 M + 13 6P < 0.01

The number of cancer deaths in patients with and without thrombocytosis was 7 (43.8%) and 34 (18.9%), respectively, and the mean number of months until death due to cancer was 13.9 and 36.1, respectively. The cause specific survival curve for the RCC patients divided by platelet count is illustrated in Fig. 1. Patients with thrombocytosis had a worse prognosis than patients without thrombocytosis (P = 0.0028). When adjusted for stage or tumor size, this correlation was limited to low stage (stage 1 + 2: P = 0.0041, stage 3 + 4: P = 0.2983) or small tumors (tumor size: ≤4 cm, P = 0.0021; 4–7 cm, P = 0.0142; >7 cm, P = 0.8158). There was no prognostic difference in the time of normalization from raised platelet counts.

image

Figure 1.  Cause specific survival curve of renal cell carcinoma patients divided by platelet count (P = 0.0028). ▴, normal platelet count (n = 180); •, thrombocytosis (n = 16).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Platelet count can increase in a variety of conditions, such as anemia, reduced iron stores, inflammation, the absence of a spleen, and primary proliferative disorders. Of all these conditions, malignant neoplasms are one of the most frequent causes of thrombocytosis. In a study of 14 000 adult out-patients at Johns Hopkins Hospital, Baltimore, USA, 82 patients (0.6%) had thrombocytosis. In this series, a malignant neoplasm was present in 31 of 82 patients (38%) with thrombocytosis and was the leading cause of thrombocytosis. The malignant neoplasms included seven stomach cancers, six colon cancers, five lung cancers, and 13 other neoplasms. The second leading cause was connective tissue disease in 18 patients (22%).10

Recently, thrombocytosis was studied as a prognostic factor in various kinds of malignancies.2–7 In general, malignancy-associated thrombocytosis tends to present in high stage cancer patients and is related to a poor prognosis. Although there are reports that indicate thrombocytosis is an independent prognostic factor in malignant tumors,2–5 the prognostic value of thrombocytosis remains controversial. Some reports have stated that thrombocytosis depends on tumor stage or tumor size, and therefore thrombocytosis does not specifically reflect malignant tumor conditions.6,7 To our knowledge, there are two studies concerning the prognosis of RCC patients with thrombocytosis. The first deals with metastatic tumors. In 259 metastatic RCC patients, thrombocytosis was present in 147 patients between the time of nephrectomy and the time of death. Patients with thrombocytosis showed significantly shorter survival rates than patients without thrombocytosis.2 The second study was conducted in patients after nephrectomy. In 204 patients with RCC who underwent nephrectomy, thrombocytosis was present in 26 patients between the time of nephrectomy and the time of death. The cancer specific death rate is five-fold greater in patients with a persistently normal platelet count after nephrectomy. In their study, the authors show that thrombocytosis is a prognostic factor that is independent of tumor stage and tumor grade.3 In the present study, our definition of thrombocytosis was limited to thrombocytosis before operation. Therefore, we can say that thrombocytosis is a good marker with which to evaluate a prognosis before nephrectomy.

Malignancy-associated thrombocytosis is caused by hormonal factors that are produced in tumor cells. Many types of cytokines have megakaryocyte potentiating activities and/or megakaryocyte colony-stimulating factor activities such as stem cell factor, thrombopoietin, granulocyte-macrophage colony-stimulating factor, interleukin-11 or interleukin-6 (IL-6), and are assumed to contribute to thrombocytosis to some extent.11 Recent studies have shown that thrombocytosis is mainly caused by IL-6,12–15 which potently promotes megakaryocyte maturation and induces platelet production.12 Serum IL-6 levels have been shown to be raised in most patients with malignancy-associated thrombocytosis.13–15

A recent study has described the important role of platelets in tumor growth. Tumor growth is dependent on the formation of new blood vessels from pre-existing capillaries, which is called angiogenesis.16 Tumor angiogenesis is dependent not only on endothelial cells and tumor cells, but also on platelet–endothelium interactions. Platelets adhere to tumor-related endothelium and release high concentrations of vascular endothelial growth factor (VEGF), which is a potent stimulator of angiogenesis. Vascular endothelial growth factor increases angiogenesis and further enhances vascular permeability. Platelets transport and synthesize VEGF.17,18 A strong positive correlation was found between serum VEGF values and platelets counts.19 Additionally, a positive correlation was found between serum VEGF values and disease progression in patients with cancer.18

In the present study, 16 of 196 patients (8.2%) with RCC before treatment exhibited thrombocytosis. Thrombocytosis correlated to metastasis and large tumors. The prognosis of the patients with thrombocytosis was worse than for the patients with normal platelet counts in small or low stage tumors. The reason for this finding is unclear. However, it is conceivable that thrombocytosis might indicate the malignant potential of small tumors. Thrombocytosis can be an inexpensive and easy tool with which to evaluate the prognosis of renal cell cancer patients in daily medical practice, however, further clinical study is needed.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References