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Keywords:

  • Renal cell carcinoma;
  • prognosis;
  • thrombocytosis

Abstract

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

Objectives To better define the relationship between platelet count and survival using a retrospective analysis in patients with thrombocytosis and metastatic renal cell carcinoma (RCC), some of whom had a shorter life expectancy than those with a normal platelet count.

Patients and methods The records were reviewed of patients with stage IV RCC who had undergone a variety of adjuvant therapies after nephrectomy between 1972 and 1992. Entry criteria included a tissue diagnosis of RCC, at least one platelet count and a complete follow-up until the time of death. Of 350 patients available for review, 259 met the entry criteria. Patients were divided into two groups: group 1 included 112 patients whose platelet counts remained at < 4 × 105/µL between the time of nephrectomy and the time of death; group 2 included 147 patients with at least one platelet count of > 4 × 105/µL (mean age in each group 57 years).

Results The mean ( sd) survival for group 1 was 151 (34) months, compared with 92 (18) months for those in group 2. Using the log-rank chi-square test the difference in survival between the groups was significant (P = 0.005). Controlling for established prognostic indicators of pathological stage, nuclear grade and cell type, using Cox's regression technique, the difference in survival between the groups remained significant (P = 0.015).

Conclusions These results suggest that patients with metastatic RCC who receive adjuvant therapy and have a persistently normal platelet count have a 64% longer life expectancy than those with thrombocytosis. The difference is highly statistically significant when controlled for nuclear grade, cell type and pathological stage.


Introduction

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

RCC has a wide range of biological behaviour and in general patients have a poor prognosis; 12–25% of patients with a new diagnosis of RCC will have metastatic disease at presentation [1]. The mortality at 15 months is 50% and the 5-year survival rate is < 10% [2]. As surgical extirpation is the only means of cure, several adjuvant therapies are used for metastatic disease. However, adjuvant therapies are minimally successful, have toxic side-effects and are costly. Prognostic indicators that can accurately predict survival rates in patients with RCC can be used to select those patients most likely to benefit from adjuvant therapy, sparing poor candidates unnecessary morbidity. Numerous prognosticators have been evaluated; pathological stage, nuclear grade and cell type are the most important variables in predicting survival [3].

Secondary or reactive thrombocytosis occurs in several clinical conditions, including various malignancies [4]; it also occurs in patients with metastatic RCC [5]. We observed that some patients with thrombocytosis and metastatic RCC had a shorter life expectancy than those with a normal platelet count. The purpose of the present study was to determine if the platelet count correlates with survival in patients with metastatic RCC, in an effort to identify an additional prognostic indicator.

Patients and methods

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

The records of patients with stage IV RCC between 1972 and 1992 from Boston University (BU) and Emory University Hospital (EUH) were reviewed (the Cellcore Corporation provided data on the BU patients). Of 350 patients available for review, 259 (74%) met the entry criteria; 174 were from BU and 85 from EUH. Entry criteria included a tissue diagnosis of RCC, at least one platelet count, and follow-up until death. All patients had undergone one of several adjuvant treatments for metastatic RCC, including immunotherapy, chemotherapy and hormonal therapy.

The data abstracted included all of the platelet counts obtained from nephrectomy to the time of death, survival time, pathological stage (surgically staged according to Robson's classification [6]), nuclear grade (using the Fuhrman grading system [7]), histological pattern, and age at the time of nephrectomy. Nuclear grade and the histological pattern were not available for all patients. The patients were divided into two groups; group 1 included 112 patients who maintained a normal platelet count (leqslant R: less-than-or-eq, slant 4 × 105/µL) from the time of nephrectomy to the time of death and group 2 included 147 with at least one platelet count of > 4 × 105/µL from the time of nephrectomy to the time of death. The mean age was 57.1 years in group 1 and 57.3 years in group 2.

Results

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

The patients in group 1 had their platelets counted a mean of 6.2 times while those in group 2 were counted a mean of 5.5 times. The mean ( sd) survival for groups 1 and 2 were 151 (34) and 92 (18) months, respectively. Using the log-rank chi-square analysis [8], the difference in survival between the groups is significant (P = 0.005). The Kaplan–Meier survival plot ( Fig. 1) of the cumulative survival with time shows that there was a slower decline in survival in group 1. At ≈ 6.5 years the curves meet, indicating that after this time the difference in survival between the groups caused by the difference in platelet counts significantly diminished. Both curves continue to zero survival because follow-up through to death was an entry criteria for the study. The 5-year survival was thus analysed to eliminate deaths from causes other than RCC; this increased the significance (P < 0.001), indicating that thrombocytosis was more important for disease-specific survival.

image

Figure 1. The Kaplan–Meier survival plot of group 1 (green) and group 2 (red).

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Survival according to the patients' pathological stage at nephrectomy is summarized in Table 1. The disproportionate number of patients with stage IV disease is a reflection of the patients from BU, who all had stage IV RCC at the time of nephrectomy. Nephrectomies were performed on stage IV patients as part of various clinical trials of adjuvant therapies for advanced disease. The survival of patients according to stage is also summarized in Table 1. When controlled for stage using Cox's regression technique [8] the difference in survival between the groups remained significant (P = 0. 022).

Table 1.  The survival of two groups of patients (group 1 normal platelet count, group 2 with thrombocytosis), with stage, grade and cell type
VariableGroup 1Group 2
Mean (95% CI) [n] survival, months Stage
 I210 (73–730) [13]436 (81–76) [4]
 II 91 (14–1040) [6]191 (41–431) [10]
 III190 (80–440) [4]81 (41–151) [19]
 IV34 (25–48) [89]19 (15–23) [114]
 Total ( sd) 151 (34) [112]92 (18) [147]
Mean survival, months
Nuclear grade
 Well40 [46]21 [46]
 Moderate49 [8]20 [14]
 Poor5 [6]11 [8]
Cell type
 Clear31 [57]21 [55]
 Granular39 [6]23 [9]
 Spindle – [0]9 [7]

Nuclear grade was available for 137 of 259 patients (53%) and survival based on nuclear grade is also shown in Table 1. When controlled for nuclear grade the difference in survival between the groups remained significant (P = 0.0048). The cell type of each tumour was available for 134 of 259 patients (52%); survival based on cell type is also shown in Table 1. When controlled for cell type the difference between the groups remained significant (P = 0.0014).

The patients in both groups were of similar age, stage distribution and number of platelet counts obtained. Whether or not one group of patients had more comorbidity than the other is unknown, and nor is it known which adjuvant therapy each patient underwent. Given the many patients in each group there is no reason to suspect that either concomitant illness or adjuvant therapies differed between the groups, although this was not formally confirmed. When controlled for all three prognostic indicators (pathological stage, nuclear grade and cell type), the difference between the groups remained significant (P = 0.015).

Discussion

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

In an effort to improve cure rates and prolong survival, the adjuvant therapies for RCC evaluated in clinical trials include immunotherapy, autolymphocyte therapy, chemotherapy and hormonal therapy; however, response rates have been low. Various immunotherapy protocols have reported the best response rates (0–50%), although most partial and complete response rates are < 25% [9,10]. Autolymphocyte therapy has a partial response rate of 18% [11]. Reports on chemotherapeutic agents such as vinblastine have shown response rates of < 10–25% [10,12]. The hormonal agents have given the lowest response rates (leqslant R: less-than-or-eq, slant 5%) [10,13]. In addition to limited response rates, these treatments can have side-effects, e.g. flu-like syndrome, fever, chills, malaise, myalgias, anorexia, nausea, vomiting, diarrhoea and abnormalities on liver function tests [10,14,15].

Several prognostic indicators have been examined as a means of predicting survival in patients with metastatic RCC; these indicators have a role in selecting patients for potentially toxic treatments. Fossa et al.[16] retrospectively reviewed patients with metastatic RCC who had been treated with chemotherapy or IFN-α (3-year survival 8% and 24%, respectively) and found the ESR, performance status and weight loss to be independent prognostic factors. Based on these prognosticators they were able to divide patients into a good- or poor-prognosis group. Among patients in the former group, the difference in the expected 3-year survival was 15% and 48% for chemotherapy and IFN-α, respectively. However, in the poor-prognosis group there was no survival difference. This study shows the ability to select a subset of patients most likely to benefit from an aggressive therapeutic intervention, while allowing those unlikely to benefit to be spared potential side-effects. Other prognostic factors which have been examined include tumour stage, nuclear grade, cell type, histological pattern, nuclear morphometry, DNA content (ploidy), tumour size, tumour multiplicity, time from diagnosis to metastases, number of metastatic sites, previous chemotherapy, serum IL-6 level, age, sex, race and presenting symptoms [3,17–19]. Most recently, Shimazui et al.[20] reported another prognostic factor, the nucleolar organizer regions of neoplastic nuclei.

Pathological stage, nuclear grade and cell type have the strongest prognostic value [3]; once data examining other prognostic variables are controlled for stage, grade and cell type, in most studies the influence of these other variables becomes less significant. The present results show that the mean difference in survival of 59 months between group 1 and 2 remained significant even when controlled for tumour stage, nuclear grade and cell type. This represents a 64% increase in survival time for patients who maintain a normal platelet count after a diagnosis of metastatic RCC. To date there are few other prognostic factors that have shown independent significance. Further investigation is needed to understand more about both biological and molecular tumour markers that have prognostic value [21].

The mechanism by which thrombocytosis occurs or why it correlates with survival is unclear. Reactive or secondary thrombocytosis occurs in various malignancies [22]. In 1964, Levin and Conley [4] examined the platelet count of 14 000 patients admitted to the Johns Hopkins Hospital; 82 patients had thrombocytosis, of whom 38% harboured a malignancy. Silvis et al.[23] in 1970 found that 60% of 190 patients with lung cancer had thrombocytosis and in 1991, Hernandez et al.[24] noted thrombocytosis in 17.7% of patients with invasive cervical cancer previously treated with radiation. They noted a 65% 5-year survival rate in patients with a normal platelet count, whereas those patients with thrombocytosis had a 5-year survival rate of only 25%. Only recently have Blay et al.[5] noted thrombocytosis associated with metastatic RCC in their studies of IL-6.

A plausible mechanism for this haematological change in patients with metastatic RCC may be an overproduction of thrombocytopoietic hormone(s) acting on megakaryocytes and their precursors. Several haemopoietic growth factors have been shown to have the capacity to promote megakaryocytopoiesis. In vitro experimental studies have shown that three growth factors, including IL-6, IL-1 and leukaemia inhibitory factor, are capable of causing thrombocytosis [25–28]. Serum IL-6 has been shown to be elevated in most patients with reactive thrombocytosis [29]. Fresh renal carcinoma cells and cell lines express IL-6 mRNA and produce IL-6 in the supernatant [30–32]. Increased IL-6 serum levels have been detected in significant numbers of patients with RCC [17], and in these patients the prognosis is worse than in those with normal IL-6 levels.

The present Kaplan–Meier curve ( Fig. 1) shows clear significant differences in survival between group 1 and 2 throughout the first 6 years of follow-up. After 7 years the curves are not significantly different (and overlap). While the individual causes of death are unknown, we suggest that this reflects deaths from causes other than cancer after 7 years of follow-up. There were no patients with a platelet count of > 4.25 × 105/µL who survived for > 6 years. Taken together, these results support the hypothesis that thrombocytosis is a manifestation of aggressive tumours, that patients with thrombocytosis have a poorer survival than patients with normal platelet counts, and that tumours which cause a marked increase in platelet count are the most aggressive, with no long-term survivors.

Thrombocytosis may adversely affect patient survival because of the interactions between cancer cells and platelets [24] in patients with RCC. Thrombospondin, a platelet-secreted protein, is increased in patients with metastatic disease [33]. It was proposed that this protein in the presence of a normal clotting system promotes adhesion of tumour cells to the vascular endothelium and potentiates experimental tumour cell metastasis [34]. Also, it was suggested that the platelets have a role in the sequestration, adherence and penetration of tumour cells through the vascular endothelial barrier, and that they prevent the clearance of malignant cells from the circulation [35]. Experimental studies also have shown that reducing platelet numbers prevents metastasis [36].

In conclusion, the present study shows a clear association of thrombocytosis with decreased survival in patients with RCC. While it is difficult to determine the precise reason for this association, it is possible that the thrombocytosis is causally linked to increased tumour cell survival or enhanced metastatic capability. Even when tumour stage, grade and cell type are controlled for, thrombocytosis remains an important independent prognosticator. The clinical utility of this powerful independent prognosticator is in the counselling of individual patients, and in selecting patients for experimental or adjuvant therapies. The analysis of new therapies must take platelet counts into consideration, as those patients with thrombocytosis will have a poorer survival independent of the treatment that is being evaluated.

References

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

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

N.P. Symbas, MD, Urology Resident.

M.F. Townsend, MD, Urology Associates, Private Practice.

R. El-Galley, FRCS(Ed), Chief Resident.

T.E. Keane, MB, FRCSI, FACS, Assistant Professor.

S.D. Graham Jr, MD, Professor.

J.A. Petros, MD, Associate Professor.

J.A. Petros, M.D., Department of Urology, Emory University School Medicine, Emory Central Clinic – Department of Urology, 1365 Clifton Road NE, Atlanta, Georgia 30322, USA. e-mail: jpetros@emory.edu