Purpose: The study aimed to investigate the expression of thymidine phosphorylase (TP) in renal cell carcinoma (RCC) and its correlation with clinicopathological features and thrombocytosis, and also to determine their prognostic significance. Patients and Methods: TP expression in 127 RCC specimens was evaluated with immunohistochemistry assays. Platelet (PLT) counts of patients before surgery were recorded. Correlations among TP expression, PLT and the clinicopathological features of the patients and their prognostic values were studied statistically. Results: Sixty-eight patients of high TP expression (54%) and 59 of low TP expression (46%) were detected. There were 25 patients with thrombocytosis (20%). High TP expression was significantly associated with tumor stage (p = 0.004), histological grade (p = 0.001) and thrombocytosis (p = 0.012). The 5-year overall survival rate was 88.1% in patients with low TP expression, whereas it was 61.8% in patients with high TP expression (p < 0.001). The 5-year survival rates for patients with and without thrombocytosis were 16.0% and 88.2%, respectively (p < 0.001). The multivariate analysis showed that high TP expression and thrombocytosis would play a role as independent prognostic factors in RCC patients. Conclusion: High TP expression and thrombocytosis can be regarded as independent prognostic factors of poor survival in patients with RCC.

Keywords:
Renal cell carcinoma, Thymidine phosphorylase, Thrombocytosis, Prognosis
1.
Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, Kiemeney LA: The epidemiology of renal cell carcinoma. Eur Urol 2011;60:615-621.
2.
Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, Kuczyk MA, Lam T, Marconi L, Merseburger AS, Mulders P, Powles T, Staehler M, Volpe A, Bex A: EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol 2015;67:913-924.
3.
Crispen PL, Breau RH, Allmer C, Lohse CM, Cheville JC, Leibovich BC, Blute ML: Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates. Eur Urol 2011;59:18-23.
4.
Motzer RJ, Mazumdar M, Bacik J, Russo P, Berg WJ, Metz EM: Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma. J Clin Oncol 2000;18:1928-1935.
5.
Meskawi M, Sun M, Trinh QD, Bianchi M, Hansen J, Tian Z, Rink M, Ismail S, Shariat SF, Montorsi F, Perrotte P, Karakiewicz PI: A review of integrated staging systems for renal cell carcinoma. Eur Urol 2012;62:303-314.
6.
Nativ O, Sabo E, Reiss A, Wald M, Madjar S, Moskovitz B: Clinical significance of tumor angiogenesis in patients with localized renal cell carcinoma. Urology 1998;51:693-696.
7.
Sumizawa T, Furukawa T, Haraguchi M, Yoshimura A, Takeyasu A, Ishizawa M, Yamada Y, Akiyama S: Thymidine phosphorylase activity associated with platelet-derived endothelial cell growth factor. J Biochem 1993;114:9-14.
8.
Ishikawa F, Miyazono K, Hellman U, Drexler H, Wernstedt C, Hagiwara K, Usuki K, Takaku F, Risau W, Heldin CH: Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature 1989;338:557-562.
9.
Akiyama S, Furukawa T, Sumizawa T, Takebayashi Y, Nakajima Y, Shimaoka S, Haraguchi M: The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression. Cancer Sci 2004;95:851-857.
10.
Ikeda M, Furukawa H, Imamura H, Shimizu J, Ishida H, Masutani S, Tatsuta M, Satomi T: Poor prognosis associated with thrombocytosis in patients with gastric cancer. Ann Surg Oncol 2002;9:287-291.
11.
Tomita M, Shimizu T, Hara M, Ayabe T, Onitsuka T: Preoperative leukocytosis, anemia and thrombocytosis are associated with poor survival in non-small cell lung cancer. Anticancer Res 2009;29:2687-2690.
12.
Gorelick C, Andikyan V, Mack M, Lee YC, Abulafia O: Prognostic significance of preoperative thrombocytosis in patients with endometrial carcinoma in an inner-city population. Int J Gynecol Cancer 2009;19:1384-1389.
13.
Brookman-May S, May M, Ficarra V, Kainz MC, Kampel-Kettner K, Kohlschreiber S, Wenzl V, Schneider M, Burger M, Wieland WF, Otto W, Tilki D, Gilfrich C, Hohenfellner M, Pahernik S, Chromecki TF, Stief C, Zigeuner R; Members of the CORONA (Collaborative Research On Renal Neoplasms Association) Project: Does preoperative platelet count and thrombocytosis play a prognostic role in patients undergoing nephrectomy for renal cell carcinoma? Results of a comprehensive retrospective series. World J Urol 2013;31:1309-1316.
14.
Gu L, Li H, Gao Y, Ma X, Chen L, Li X, Zhang Y, Fan Y, Zhang X: The association of platelet count with clinicopathological significance and prognosis in renal cell carcinoma: a systematic review and meta-analysis. PLoS One 2015;10:e0125538.
15.
Novara G, Ficarra V, Antonelli A, Artibani W, Bertini R, Carini M, Cosciani Cunico S, Imbimbo C, Longo N, Martignoni G, Martorana G, Minervini A, Mirone V, Montorsi F, Schiavina R, Simeone C, Serni S, Simonato A, Siracusano S, Volpe A, Carmignani G; SATURN Project-LUNA Foundation: Validation of the 2009 TNM version in a large multi-institutional cohort of patients treated for renal cell carcinoma: are further improvements needed? Eur Urol 2010;58:588-595.
16.
Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6:655-663.
17.
Wang L, Huang X, Chen Y, Jin X, Li Q, Yi TN: Prognostic value of TP/PD-ECGF and thrombocytosis in gastric carcinoma. Eur J Surg Oncol 2012;38:568-573.
18.
Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 1992;3:65-71.
19.
Sengupta S, Sellers LA, Matheson HB, Fan TP: Thymidine phosphorylase induces angiogenesis in vivo and in vitro: an evaluation of possible mechanisms. Br J Pharmacol 2003;139:219-231.
20.
Okamoto E, Osaki M, Kase S, Adachi H, Kaibara N, Ito H: Thymidine phosphorylase expression causes both the increase of intratumoral microvessels and decrease of apoptosis in human esophageal carcinomas. Pathol Int 2001;51:158-164.
21.
Takebayashi Y, Yamada K, Miyadera K, Sumizawa T, Furukawa T, Kinoshita F, Aoki D, Okumura H, Yamada Y, Akiyama S, Aikou T: The activity and expression of thymidine phosphorylase in human solid tumours. Eur J Cancer 1996;32A:1227-1232.
22.
Takayama T, Mugiya S, Sugiyama T, Aoki T, Furuse H, Liu H, Hirano Y, Kai F, Ushiyama T, Ozono S: High levels of thymidine phosphorylase as an independent prognostic factor in renal cell carcinoma. Jpn J Clin Oncol 2006;36:564-569.
23.
O'Brien T, Cranston D, Fuggle S, Bicknell R, Harris AL: Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res 1995;55:510-513.
24.
Jones A, Fujiyama C, Turner K, Cranston D, Williams K, Stratford I, Bicknell R, Harris AL: Role of thymidine phosphorylase in an in vitro model of human bladder cancer invasion. J Urol 2002;167:1482-1486.
25.
Imazano Y, Takebayashi Y, Nishiyama K, Akiba S, Miyadera K, Yamada Y, Akiyama S, Ohi Y: Correlation between thymidine phosphorylase expression and prognosis in human renal cell carcinoma. J Clin Oncol 1997;15:2570-2578.
26.
Wada S, Yoshimura R, Naganuma T, Yoshida N, Narita K, Ikemoto S: Thymidine phosphorylase levels as a prognostic factor in renal cell carcinoma. BJU Int 2003;91:105-108.
27.
Padrik P, Saar H: Thymidine phosphorylase as a prognostic factor in renal cell carcinoma. Int Urol Nephrol 2010;42:295-298.
28.
Verheul HM, Jorna AS, Hoekman K, Broxterman HJ, Gebbink MF, Pinedo HM: Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood 2000;96:4216-4221.
29.
Karpatkin S, Pearlstein E: Role of platelets in tumor cell metastases. Ann Intern Med 1981;95:636-641.
30.
Bensalah K, Leray E, Fergelot P, Rioux-Leclercq N, Tostain J, Guille F, Patard JJ: Prognostic value of thrombocytosis in renal cell carcinoma. J Urol 2006;175(3 pt 1):859-863.
© 2016 S. Karger AG, Basel
2016
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.