|Year : 2015 | Volume
| Issue : 1 | Page : 42-46
Is thrombocytosis a useful prognostic marker in renal cell carcinoma? Results of a single-center retrospective analysis
Vivek Venkatramani, Arabind Panda, Nitin S Kekre
Department of Urology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Web Publication||1-Jan-2015|
Prof Nitin S Kekre
Department of Urology, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Our aim was to determine the correlation of platelet count with stage and grade of renal cell carcinoma (RCC) and to determine whether progression of disease was more likely in those with thrombocytosis.
Materials and Methods: A retrospective review of patients with RCC from January 2004 to December 2011 was undertaken. Patients with no preoperative platelet count and those with multiple tumors were excluded. Disease progression was defined as appearance of local recurrence or distant metastasis on follow-up. Thrombocytosis was defined as a platelet count of >400,000/cumm. Standard tests of significance and multivariate analysis using logistic regression were performed.
Results: A total of 322 cases were identified. The median follow-up was 7 months (range, 2-84 months). The platelet count correlated significantly with higher Fuhrmann grade, as well as increasing TNM stage at diagnosis. Patients with a platelet count of >400,000/cumm (n = 35) had a significantly higher mean tumor size and worse grade at diagnosis than those with a normal platelet count (n = 287). Patients with thrombocytosis also had a significantly worse stage at presentation. Progression of disease was seen more often in patients with thrombocytosis (28.6% vs 11.9%, P = 0.07). The median time to progression was significantly faster in patients with thrombocytosis (9 vs 18 months, P = 0.018). However, on multivariate analysis TNM stage was the only significant predictor of time to progression.
Conclusion: Rising platelet count correlated significantly with advancing stage and grade of disease. Patients with thrombocytosis were significantly more likely to have advanced tumors at presentation, poorer histological features, and rapid disease progression.
Keywords: Prognostication, renal cell carcinoma, thrombocytosis
|How to cite this article:|
Venkatramani V, Panda A, Kekre NS. Is thrombocytosis a useful prognostic marker in renal cell carcinoma? Results of a single-center retrospective analysis. Indian J Urol 2015;31:42-6
|How to cite this URL:|
Venkatramani V, Panda A, Kekre NS. Is thrombocytosis a useful prognostic marker in renal cell carcinoma? Results of a single-center retrospective analysis. Indian J Urol [serial online] 2015 [cited 2020 Oct 21];31:42-6. Available from: https://www.indianjurol.com/text.asp?2015/31/1/42/145292
| Introduction|| |
Renal cell carcinoma (RCC) is referred to as the 'internists' tumor' due to its varied presentation and often unpredictable course. Every urologist has known patients with small renal masses but distant metastases, and at the other end of the spectrum, those who survive years with extensive disease. Some may even have seen spontaneous regression of metastatic RCC.
Prognostication of these cases has remained difficult, and a bewildering number of markers and prognostic systems have been used to better characterize prognosis in RCC.  The need for accurate prognostication became even more acute with the advent of targeted therapy for advanced RCC, and here too, new systems were devised.  Of these, the International Metastatic RCC Database Consortium prognostic model has proven accurate and has recently been externally validated. , There is now a growing body of the literature, suggesting that thrombocytosis could prove a simple, accurate and inexpensive prognostic marker in many malignancies, including RCC.  We, therefore, decided to review our experience to determine the prognostic significance of the platelet count in all stages of RCC.
| Materials and Methods|| |
Ours is tertiary medical center in southern India with a large uro-oncology practice. We undertook a retrospective review of our electronic medical record database. All patients with biopsy or histopathologically proven RCC from January 2004 to June 2011 were eligible for inclusion. Patients undergoing either partial or radical nephrectomy were included. Patients with no record of a preoperative platelet count were excluded. Those with bilateral or multiple tumors [including von Hippel Lindau (vHL) disease] were also excluded from the study.
TNM staging was reviewed according to the American Joint Committee for Cancer 2009 revision of the International TNM classification. Tumor and nodal status were based on histopathology of the surgical specimen with radiological input. Metastases status was assessed using imaging studies, namely contrast-enhanced computed tomography (CECT) of the abdomen and chest X-ray, with CT chest in selected cases. Baseline data collected on all patients included demographic variables, laboratory parameters, TNM stage, pathological features, and available follow-up and survival data. The Fuhrmann system was used to assess tumor grade. Disease progression was defined as the new appearance of local recurrence or distant metastasis on a follow-up visit. Thrombocytosis was defined as a platelet count above 400,000/cubic milliliter (cuml).
Initially, the correlation between baseline patient and tumor characteristics with the platelet count was studied. Patients were then classified into two arms: Those with and without thrombocytosis. These groups were then compared with respect to gross and microscopic tumor characteristics, TNM stage, and disease progression (as defined above). Standard statistical tests of significance were applied. Furthermore, multivariate analysis by logistic regression was performed using thrombocytosis, TNM stage, and tumor size as variables. A P < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 16.
| Results|| |
[Figure 1] describes the derivation of the study group after applying the exclusion criteria. A total of 649 patients with RCC were identified during the study period. There was no record of a platelet count in 308. Of the remaining 341 patients, 11 were diagnosed cases of vHL disease, and a further 8 had bilateral tumors, leaving 322 in the study group.
Baseline demographic and tumor variables of the study population are represented in [Table 1]. The association of clinical and staging variables with the platelet count is represented in [Table 2]. We discovered that the platelet count was significantly higher in females and those with Fuhrmann grade 3-4 tumors. The platelet count also showed a significant progressive increase with TNM stage.
|Table 2: Association of clinical and staging variables with the platelet count|
Click here to view
Patients were subsequently classified into those with thrombocytosis (n = 35) and compared with those with a normal platelet count (n = 287) [Table 3]. Both groups were similar with respect to age and gender. Patients with thrombocytosis had significantly larger tumors. Their tumors were also significantly more likely to have sarcomatoid and rhabdoid features, lymphovascular invasion, and capsular invasion at diagnosis. Patients with thrombocytosis had a significantly higher tumor stage; a significantly lower hematocrit and higher total leucocyte count than those with a normal platelet count. The rate of progression was higher in those with thrombocytosis with a significantly quicker median time to progression in this group.
Multivariate analysis of time to progression revealed TNM stage as the only significant predictor [Table 4]. The possible reason for this is the relatively short follow-up in our study.
| Discussion|| |
Thrombocytosis has been implicated as an adverse prognostic factor in a number of malignancies including RCC.  In these situations, the exact cause of the secondary thrombocytosis is unclear, but it appears that circulating cytokines and growth factors play an important role.  Of these, interleukin (IL)-6 appears to be the most potent stimulator of megakaryocyte progenitors, and a raised level has been demonstrated in the majority of patients with malignancy-associated thrombocytosis.  Other cytokines that have been implicated include macrophage-colony stimulating factor, thrombopoietin, and IL-11.  Platelets have also been implicated in tumor growth as they can secrete large concentrations of vascular endothelial growth factor (VEGF) that is crucial for tumor angiogenesis, while also stimulating megakaryocyte maturation at the bone marrow level. , Activated platelets also secrete thrombopoietin, which reinforces platelet formation in the bone marrow.  Platelets and their secretory product thrombospondin have also been implicated in tumor metastasis. The purported mechanisms include allowing adhesion of tumor cells to the vascular endothelium, penetration through the endothelial barrier, and preventing malignant cells from being cleared from the circulation. 
Over the past decade, a few studies have studied the prognostic significance of thrombocytosis in RCC. In the largest study so far Bensalah et al. reported that a platelet count > 450,000/cuml positively correlated with worsening T stage, Fuhrman grade, tumor size, lymph node status, and distant metastasis in 804 patients with RCC.  Patients with thrombocytosis also had a significantly worse 5-year survival on both univariate and multivariate analyses.  This impact on prognosis was seen for both localized and metastatic disease.  Inoue et al. also showed a positive correlation between thrombocytosis and tumor size and stage.  In their study, thrombocytosis was associated with a worse prognosis, but when adjusted for stage or tumor size, this was limited to pT1-2 tumors.  In the study by Cho et al., thrombocytosis significantly correlated with tumor size and metastasis.  It was a predictor of recurrence-free survival on univariate but not multivariate analysis.  Patel et al. reported a retrospective study on 237 patients who underwent radical nephrectomy for clinically localized disease.  They concluded that an increase in platelet count of >20% following radical nephrectomy could reliably predict recurrence and cancer-free survival. 
The need for prognostication in metastatic RCC has gained immense significance with the birth of targeted therapy, with accurate prognostication allowing individualization of therapy. In an early study, Symbas et al. studied 259 patients with metastatic RCC who received a variety of adjuvant therapies.  They discovered that those whose platelet count remained persistently normal had a 64% longer survival than those with thrombocytosis, even on multivariate analysis.  Perhaps the most important system for prognostication, the International Metastatic RCC Database Consortium prognostic model includes platelet count and neutrophil count above the upper limit of normal, as independent adverse factors.  The other components of this system are similar to those of the Memorial Sloan Kettering Cancer Centre (MSKCC) model and include hemoglobin less than the lower limit of normal, corrected calcium greater than the upper limit of normal, Karnofsky performance status <80%, and time from diagnosis to treatment of <1 year.  This model has recently been externally validated and has shown a concordance index of 0.68-0.73, which was better than other similar systems.  Other prognostic systems for metastatic RCC, including a revised model from the MSKCC (for patients treated with sunitinib), and one from the Cleveland Clinic also include the platelet count as one of the parameters.  While there is no doubt that a combination of factors will be most reliable in prognostication, the platelet count alone is a simple investigation that can give the clinician an indicator of the gravity of disease, and we believe that further prospective studies could help better establish its exact role.
The success of targeted therapy has also opened up the possibilities of neoadjuvant and adjuvant therapy for locally advanced RCC. Research in this area is underway and three randomized trials are ongoing to determine the efficacy of these drugs in the adjuvant setting.  The fact that thrombocytosis correlates well with adverse prognosis, even in patients with clinically nonmetastatic disease, may possibly be used to select patients who would benefit from further treatment.
Our study is limited by its retrospective nature and the relatively short follow-up of patients (median of 7 months). Only 18% (n = 58) of our patients had more than 3 years follow-up, and only 6.8% (n = 22) had more than 5 years follow-up. This could be the reason that platelet count was not deemed significant on multivariate analysis of time to progression. However, platelet count correlated well with other adverse clinicopathological factors and was associated with a significantly shorter time to progression. Our study remains the first such study from the Indian subcontinent and has the second largest sample size from similar papers.
| Conclusion|| |
Rising platelet count correlated significantly with advancing stage and grade of disease in RCC. Patients with thrombocytosis were significantly more likely to have advanced tumors at presentation, poorer histological features, and more rapid disease progression. Multivariate analysis shows TNM stage to be the only reliable predictor of time to progression and further prospective studies are needed to establish the utility of the platelet count in this setting, and in potentially predicting the need for adjuvant therapy.
| References|| |
Campbell S, Lane B. Malignant renal tumours. Campbell-Walsh Urol. 10 th
ed. Philadelphia: Elsevier Saunders; 2012. p. 1413-74.
Srinivasan R, Linehan W. Treatment of advanced renal cell carcinoma. Campbell-Walsh Urol. 10 th
ed. Philadelphia: Elsevier Saunders; 2012. p. 1475-91.
Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al
. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. J Clin Oncol Off J Am Soc Clin Oncol 2009;27:5794-9.
Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et al
. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: A population-based study. Lancet Oncol 2013;14:141-8.
Patel A, Bhavan R, Somani B, Nabi G. Correlation of percentage changes in platelet counts with recurrence rate following radical nephrectomy. Indian J Urol 2010;26:183-7.
Symbas NP, Townsend MF, El-Galley R, Keane TE, Graham SD, Petros JA. Poor prognosis associated with thrombocytosis in patients with renal cell carcinoma. BJU Int 2000;86:203-7.
Inoue K, Kohashikawa K, Suzuki S, Shimada M, Yoshida H. Prognostic significance of thrombocytosis in renal cell carcinoma patients. Int J Urol 2004;11:364-7.
Bensalah K, Leray E, Fergelot P, Rioux-Leclercq N, Tostain J, Guillé F, et al
. Prognostic value of thrombocytosis in renal cell carcinoma. J Urol 2006;175:859-63.
Cho D, Kim S, Lee S, Ahn H, Kim Y, Kim S. Prognostic Significance of Preoperative C-Reactive Protein Elevation and Thrombocytosis in Patients with Non-Metastatic Renal Cell Carcinoma. Korean J Urol 2011;52:104-9.
Sun M, Shariat SF, Cheng C, Ficarra V, Murai M, Oudard S, et al
. Prognostic factors and predictive models in renal cell carcinoma: A contemporary review. Eur Urol 2011;60:644-61.
Sciarra A, Cattarino S, Salciccia S, Alfarone A, Gentilucci A, Parente U, et al
. The emerging role of targeted therapy in renal cell carcinoma (RCC): Is it time for a neoadjuvant or an adjuvant approach? Crit Rev Oncol Hematol 2012;81:151-62.
[Table 1], [Table 2], [Table 3], [Table 4]