Asia Oceania Journal of Nuclear Medicine and Biology

Asia Oceania Journal of Nuclear Medicine and Biology

In vivo imaging of cellular proliferation in renal cell carcinoma using 18F-fluorothymidine PET

Document Type : Original Article

Authors
Peter K. Wong 1
Sze Ting Lee 2
Carmel Murone 3
John Eng 2
Nathan Lawrentschuk 1
Salvatore U. Berlangieri 2
Kunthi Pathmaraj 2
Graeme J. O'Keefe 2
John Sachinidis 2
Amanda J. Byrne 2
Damien M. Bolton 1
Ian D. Davis 4
Andrew M. Scott 2
1 Department of Surgery and Urology, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia
2 Centre for PET, Austin Hospital, Heidelberg, Victoria, Australia
3 Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Victoria, Australia
4 Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia
10.7508/aojnmb.2014.01.002
Abstract
Objective(s): The ability to measure cellular proliferation non-invasively in renal cell carcinoma may allow prediction of tumour aggressiveness and response to therapy. The aim of this study was to evaluate the uptake of 18Ffluorothymidine (FLT) PET in renal cell carcinoma (RCC), and to compare this to 18F-fluorodeoxyglucose (FDG), and to an immunohistochemical measure of cellular proliferation (Ki-67).
Methods: Twenty seven patients (16 male, 11 females; age 42-77) with newly diagnosed renal cell carcinoma suitable for resection were prospectively enrolled. All patients had preoperative FLT and FDG PET scans. Visual identification of tumour using FLT PET compared to normal kidney was facilitated by the use of a pre-operative contrast enhanced CT scan. After surgery tumour was taken for histologic analysis and immunohistochemical staining by Ki-67.
Results: The SUVmax (maximum standardized uptake value) mean±SD for FLT in tumour was 2.59±1.27, compared to normal kidney (2.47±0.34). The mean SUVmax for FDG in tumour was similar to FLT (2.60±1.08). There was a significant correlation between FLT uptake and the immunohistochemical marker Ki-67 (r=0.72, P<0.0001) in RCC. Ki-67 proliferative index was mean ± SD of 13.3%±9.2 (range 2.2% - 36.3%).
Conclusion: There is detectable uptake of FLT in primary renal cell carcinoma, which correlates with cellular proliferation as assessed by Ki-67 labelling index.
This finding has relevance to the use of FLT PET in molecular imaging studies of renal cell carcinoma biology.
Keywords
FDG PET
FLT PET
Renal cell carcinoma
  1. Buck AK, Herrmann K, Buschenfelde CM, Juweid ME, Bischoff M, Glatting G, et al. Imaging bone and soft tissue tumors with the proliferation marker [18F]fluorodeoxythymidine. Clin Cancer Res. 2008; 14: 2970-7.
  2. Cobben DC, Elsinga PH, Suurmeijer AJ, Vaalburg W, Maas B, Jager PL, et al. Detection and grading of soft tissue sarcomas of the extremities with 18F-3′-fluoro-3′-deoxy-l-thymidine. Clin Cancer Res. 2004; 10: 1685-90.
  3. Apisarnthanarax S, Alauddin MM, Mourtada F, Ariga H, Raju U, Mawlawi O, et al. Early detection of chemoradioresponse in esophageal carcinoma by 3'-deoxy-3'-3H-fluorothymidine using preclinical tumor models. Clin Cancer Res. 2006; 12: 4590-7.
  4. Atkinson DM, Clarke MJ, Mladek AC, Carlson BL, Trump DP, Jacobson MS, et al. Using fluorodeoxythymidine to monitor anti-EGFR inhibitor therapy in squamous cell carcinoma xenografts. Head Neck. 2008; 30: 790-9.
  5. Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q, et al. 3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res. 2003; 63: 3791-8.
  6. Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, et al. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol. 2007; 25: 4714-21.
  7. Pio BS, Park CK, Pietras R, Hsueh WA, Satyamurthy N, Pegram MD, et al. Usefulness of 3'-[F-18]fluoro-3'-deoxythymidine with positron emission tomography in predicting breast cancer response to therapy. Mol Imaging Biol. 2006; 8: 36-42.
  8. Buck AK, Bommer M, Stilgenbauer S, Juweid M, Glatting G, Schirrmeister H, et al. Molecular imaging of proliferation in malignant lymphoma. Cancer Res. 2006; 66: 11055-61.
  9. Buck AK, Halter G, Schirrmeister H, Kotzerke J, Wurziger I, Glatting G, et al. Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG. J Nucl Med. 2003; 44: 1426-31.
  10. Buck AK, Schirrmeister H, Hetzel M, Von Der Heide M, Halter G, Glatting G, et al. 3-deoxy-3-[(18)F]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules. Cancer Res. 2002; 62: 3331-4.
  11. Chen W, Cloughesy T, Kamdar N, Satyamurthy N, Bergsneider M, Liau L, et al. Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med. 2005; 46: 945-52.
  12. Choi SJ, Kim JS, Kim JH, Oh SJ, Lee JG, Kim CJ, et al. [18F]3'-deoxy-3'-fluorothymidine PET for the diagnosis and grading of brain tumors. Eur J Nucl Med Mol Imaging. 2005; 32: 653-9.
  13. Francis DL, Freeman A, Visvikis D, Costa DC, Luthra SK, Novelli M, et al. In vivo imaging of cellular proliferation in colorectal cancer using positron emission tomography. Gut. 2003; 52: 1602-6.
  14. Kenny LM, Vigushin DM, Al-Nahhas A, Osman S, Luthra SK, Shousha S, et al. Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [18F]fluorothymidine-positron emission tomography imaging: evaluation of analytical methods. Cancer Res. 2005; 65: 10104-12.
  15. Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P, et al. In vivo validation of 3'deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res. 2002; 8: 3315-23.
  16. Wagner M, Seitz U, Buck A, Neumaier B, Schultheiss S, Bangerter M, et al. 3'-[18F]fluoro-3'-deoxythymidine ([18F]-FLT) as positron emission tomography tracer for imaging proliferation in a murine B-Cell lymphoma model and in the human disease. Cancer Res. 2003; 63: 2681-7.
  17. Yap CS, Czernin J, Fishbein MC, Cameron RB, Schiepers C, Phelps ME, et al. Evaluation of thoracic tumors with 18F-fluorothymidine and 18F-fluorodeoxyglucose-positron emission tomography. Chest. 2006; 129: 393-401.
  18. Bouchelouche K, Oehr P. Positron emission tomography and positron emission tomography/computerized tomography of urological malignancies: an update review. J Urol. 2008; 179: 34-45.
  19. Liu G, Jeraj R, Vanderhoek M, Perlman S, Kolesar J, Harrison M, et al. Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate. Clin Cancer Res. 2011; 17: 7634-44.
  20. Been LB, Suurmeijer AJ, Cobben DC, Jager PL, Hoekstra HJ, Elsinga PH. [18F]FLT-PET in oncology: current status and opportunities. Eur J Nucl Med Mol Imaging. 2004; 31: 1659-72.
  21. Francis DL, Visvikis D, Costa DC, Arulampalam TH, Townsend C, Luthra SK, et al. Potential impact of [18F]3'-deoxy-3'-fluorothymidine versus [18F]fluoro-2-deoxy-D-glucose in positron emission tomography for colorectal cancer. Eur J Nucl Med Mol Imaging. 2003; 30: 988-94.
  22. van Waarde A, Cobben DC, Suurmeijer AJ, Maas B, Vaalburg W, de Vries EF, et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J Nucl Med. 2004; 45: 695-700.
  23. Wei LH, Su H, Hildebrandt IJ, Phelps ME, Czernin J, Weber WA. Changes in tumor metabolism as readout for Mammalian target of rapamycin kinase inhibition by rapamycin in glioblastoma. Clin Cancer Res. 2008; 14: 3416-26.
  24. Cher LM, Murone C, Lawrentschuk N, Ramdave S, Papenfuss A, Hannah A, et al. Correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in gliomas using 18F-fluoromisonidazole, 18F-FDG PET, and immunohistochemical studies. J Nucl Med. 2006; 47: 410-8.
  25. Cherk MH, Foo SS, Poon AM, Knight SR, Murone C, Papenfuss AT, et al. Lack of correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in non-small cell lung cancer assessed by 18F-Fluoromisonidazole and 18F-FDG PET. J Nucl Med. 2006; 47: 1921-6.
  26. Muzi M, Vesselle H, Grierson JR, Mankoff DA, Schmidt RA, Peterson L, et al. Kinetic analysis of 3'-deoxy-3'-fluorothymidine PET studies: validation studies in patients with lung cancer. J Nucl Med. 2005; 46: 274-82.
  27. Dittmann H, Dohmen BM, Paulsen F, Eichhorn K, Eschmann SM, Horger M, et al. [18F]FLT PET for diagnosis and staging of thoracic tumours. Eur J Nucl Med Mol Imaging. 2003; 30: 1407-12.
  28. Smyczek-Gargya B, Fersis N, Dittmann H, Vogel U, Reischl G, Machulla HJ, et al. PET with [18F]fluorothymidine for imaging of primary breast cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2004; 31: 720-4.
  29. van Westreenen HL, Cobben DC, Jager PL, van Dullemen HM, Wesseling J, Elsinga PH, et al. Comparison of 18F-FLT PET and 18F-FDG PET in esophageal cancer. J Nucl Med. 2005; 46: 400-4.
  30. de Riese WT, Crabtree WN, Allhoff EP, Werner M, Liedke S, Lenis G, et al. Prognostic significance of Ki-67 immunostaining in nonmetastatic renal cell carcinoma. J Clin Oncol. 1993; 11: 1804-8.
  31. Rioux-Leclercq N, Turlin B, Bansard J, Patard J, Manunta A, Moulinoux JP, et al. Value of immunohistochemical Ki-67 and p53 determinations as predictive factors of outcome in renal cell carcinoma. Urology. 2000; 55: 501-5.
  32. Visapaa H, Bui M, Huang Y, Seligson D, Tsai H, Pantuck A, et al. Correlation of Ki-67 and gelsolin expression to clinical outcome in renal clear cell carcinoma. Urology. 2003; 61: 845-50.
  33. Ak I, Can C. F-18 FDG PET in detecting renal cell carcinoma. Acta Radiol. 2005; 46: 895-9.
  34. Bachor R, Kotzerke J, Gottfried HW, Brandle E, Reske SN, Hautmann R. [Positron emission tomography in diagnosis of renal cell carcinoma]. Urologe A. 1996; 35: 146-50.
  35. Miyakita H, Tokunaga M, Onda H, Usui Y, Kinoshita H, Kawamura N, et al. Significance of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for detection of renal cell carcinoma and immunohistochemical glucose transporter 1 (GLUT-1) expression in the cancer. Int J Urol. 2002; 9: 15-8.
  36. Ramdave S, Thomas GW, Berlangieri SU, Bolton DM, Davis I, Danguy HT, et al. Clinical role of F-18 fluorodeoxyglucose positron emission tomography for detection and management of renal cell carcinoma. J Urol. 2001; 166: 825-30.
  37. Tehrani OS, Shields AF. PET imaging of proliferation with pyrimidines. J Nucl Med. 2013; 54: 903-12.