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Clinical relevance of imaging proliferative activity in lung nodules

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Recently, the thymidine analogue 3′-deoxy-3′[18F]fluorothymidine (FLT) has been introduced for imaging proliferation with positron emission tomography (PET). In this prospective study, we examined the accuracy of FLT for differentiation of benign from malignant lung lesions and for tumour staging.

Methods

A total of 47 patients with newly diagnosed pulmonary nodules on chest CT suspicious for malignancy were examined with FLT-PET in addition to routine staging procedures. A total of 43 patients also underwent 2-[18F]fluoro-2-deoxy-D-glucose (FDG) PET imaging. Within 2 weeks, patients underwent resective surgery or core biopsy of the pulmonary lesion.

Results

Histopathology revealed malignant lung tumours in 32 patients (20 non-small cell lung cancer, 1 small cell lung cancer, 1 pulmonary carcinoid, 1 non-Hodgkin’s lymphoma, nine metastases from extrapulmonary tumours) and benign lesions in 15 patients. Increased FLT uptake was exclusively related to malignant tumours. FLT-PET was false negative in two patients with non-small cell lung cancer, in the patient with a pulmonary carcinoid and in three patients with lung metastases. The sensitivity of FLT-PET for detection of lung cancer was 90%, the specificity 100% and the accuracy 94%. Fifteen out of 21 patients with lung cancer had mediastinal lymph node metastases. FLT-PET was true positive in 7/15 patients, resulting in a sensitivity of 53% for N-staging (specificity 100%, accuracy 67%). Clinical TNM stage was correctly identified in 67% (20/30) patients, compared to 85% (23/27) with FDG-PET.

Conclusion

FLT-PET has a high specificity for the detection of malignant lung tumours. Compared with FDG, FLT-PET is less accurate for N-staging in patients with lung cancer and for detection of lung metastases. FLT-PET therefore cannot be recommended for staging of lung cancer.

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References

  1. Hicks RJ, Kalff V, MacManus MP, Ware RE, Hogg A, McKenzie AF, et al. 18F-FDG PET provides high-impact and powerful prognostic stratification in staging newly diagnosed non-small cell lung cancer. J Nucl Med 2001;42:1596–1604.

    CAS  PubMed  Google Scholar 

  2. Kalff V, Hicks RJ, MacManus M, Binns DS, McKenzie AF, Ware RE, et al. Clinical impact of 18F fluorodeoxy-glucose positron emission tomography in patients with non-small-cell lung cancer: a prospective study. J Clin Oncol 2001;19:111–8.

    CAS  PubMed  Google Scholar 

  3. Gould MK, Maclean CC, Kuschner WG, Rydzak CE, Owens DK. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA 2001;285:914–24.

    Article  CAS  PubMed  Google Scholar 

  4. Kubota R, Kubota K, Yamada S, Tada M, Takahashi T, Iwata R. Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. J Nucl Med 1994;35:104–112.

    CAS  PubMed  Google Scholar 

  5. Shreve PD, Anzai Y, Wahl RL. Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants. Radiographics 1999;19:61–77.

    CAS  PubMed  Google Scholar 

  6. Buck AC, Schirrmeister HH, Guhlmann CA, Diederichs CG, Shen C, Buchmann I, et al. Ki-67 immunostaining in pancreatic cancer and chronic active pancreatitis: does in vivo FDG uptake correlate with proliferative activity? J Nucl Med 2001;42:721–5.

    PubMed  Google Scholar 

  7. Shields AF, Grierson JR, Kozawa SM, Zheng M. Development of labeled thymidine analogs for imaging tumor proliferation. Nucl Med Biol 1996;23:17–22.

    Article  CAS  PubMed  Google Scholar 

  8. Shields AF, Larson SM, Grunbaum Z, Graham MM. Short-term thymidine uptake in normal and neoplastic tissues: studies for PET. J Nucl Med 1984;25:759–64.

    CAS  PubMed  Google Scholar 

  9. Eary JF, Mankoff DA, Spence AM, Berger MS, Olshen A, Link JM, et al. 2-[C-11]thymidine imaging of malignant brain tumors. Cancer Res 1999;59:615–21.

    CAS  PubMed  Google Scholar 

  10. Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 1998;4:1334–6.

    Article  CAS  PubMed  Google Scholar 

  11. Machulla HJ, Blocher A, Kuntzsch M, Piert M, Wei R, Grierson JR. Simplified labeling approach for synthesizing 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT). J Radioanal Nucl Chem 2000;24:843–6.

    Article  Google Scholar 

  12. Visvikis D, Francis D, Mulligan R, Costa DC, Croasdale I, Luthra SK, et al. Comparison of methodologies for the in vivo assessment of 18FLT utilisation in colorectal cancer. Eur J Nucl Med Mol Imaging 2004;31:169–78.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Cobben DC, Elsinga PH, Suurmeijer AJ, Vaalburg W, Maas B, Jager PL, Hoekstra HJ. 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.

    CAS  PubMed  Google Scholar 

  15. Cobben DC, Jager PL, Elsinga PH, Maas B, Suurmeijer AJ, Hoekstra HJ. 3′-18F-fluoro-3′-deoxy-L-thymidine: a new tracer for staging metastatic melanoma? J Nucl Med 2003;44:1927–32.

    CAS  PubMed  Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. Buck AK, Schirrmeister H, Hetzel M, Von Der Heide M, Halter G, Glatting G, et al. 3-Deoxy-3-[18F]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules. Cancer Res 2002;62:3331–4.

    CAS  PubMed  Google Scholar 

  18. Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P, et al. In vivo validation of 3′deoxy-3′-[18F]fluorothymidine ([18F]FLT) as a proliferation imaging tracer in humans: correlation of [18F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res 2002;8:3315–23.

    CAS  PubMed  Google Scholar 

  19. Buck AK, Halter G, Schirrmeister H, Glatting G, Mattfeldt T, Neumaier B et al. Functional imaging of pulmonary nodules with FDG and FLT-PET. J Nucl Med 2003;44(9):1426–31.

    CAS  PubMed  Google Scholar 

  20. Schmidlin P. Improved iterative image reconstruction using variable projection binning and abbreviated convolution. Eur J Nucl Med 1994;21:930–6.

    Article  CAS  PubMed  Google Scholar 

  21. Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med 2002;43:1210–7.

    CAS  PubMed  Google Scholar 

  22. Dittmann H, Dohmen BM, Kehlbach R, Bartusek G, Pritzkow M, Sarbia M, Bares R. Early changes in [18F]FLT uptake after chemotherapy: an experimental study. Eur J Nucl Med Mol Imaging 2002;29:1462–9.

    Article  CAS  PubMed  Google Scholar 

  23. Seitz U, Wagner M, Neumaier B, Wawra E, Glatting G, Leder G, et al. Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) in pancreatic cancer cell lines. Eur J Nucl Med Mol Imaging 2002;29:1174–81.

    Article  CAS  PubMed  Google Scholar 

  24. Mier W, Haberkorn U, Eisenhut M. [18F]FLT; portrait of a proliferation marker. Eur J Nucl Med Mol Imaging 2002;29:165–9.

    Article  CAS  PubMed  Google Scholar 

  25. Shields AF. PET imaging with 18F-FLT and thymidine analogs: promise and pitfalls. J Nucl Med 2003;44:1432–34.

    CAS  PubMed  Google Scholar 

  26. Kong XB, Zhu QY, Vidal PM, Watanabe KA, Polsky B, Armstrong D, et al. Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3′-fluoro-3′-deoxythymidine and 3′-azido-3′-deoxythymidine. Antimicrob Agents Chemother 1992;36:808–18.

    CAS  PubMed  Google Scholar 

  27. Lu L, Samuelsson L, Bergstrom M, Sato K, Fasth KJ, Langstrom B. Rat studies comparing 11C-FMAU, 18F-FLT, and 76Br-BFU as proliferation markers. J Nucl Med 2002;43:1688–98.

    CAS  PubMed  Google Scholar 

  28. Hellwig D, Ukena D, Paulsen F, Bamberg M, Kirsch CM. Onko-PET der Deutschen Gesellschaft fur Nuklearmedizin. [Meta-analysis of the efficacy of positron emission tomography with F-18-fluorodeoxyglucose in lung tumors. Basis for discussion of the German Consensus Conference on PET in Oncology 2000]. Pneumologie 2001;55:367–77.

    CAS  PubMed  Google Scholar 

  29. 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.

    CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. Dosaka-Akita H, Hommura F, Mishina T, Ogura S, Shimizu M, Katoh H, Kawakami Y. A risk-stratification model of non-small cell lung cancers using cyclin E, Ki-67, and ras p21: different roles of G1 cyclins in cell proliferation and prognosis. Cancer Res 2001;61:2500–4.

    CAS  PubMed  Google Scholar 

  32. Vansteenkiste JF, Stroobants SG, Dupont PJ, De Leyn PR, Verbeken EK, Deneffe GJ, et al. Prognostic importance of the standardized uptake value on 18F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: an analysis of 125 cases. Leuven Lung Cancer Group. J Clin Oncol 1999;17:3201–6.

    CAS  PubMed  Google Scholar 

  33. 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.

    CAS  PubMed  Google Scholar 

  34. Oyama N, Ponde DE, Dence C, Kim J, Tai YC, Welch MJ. Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation. J Nucl Med 2004;45:519–25.

    PubMed  Google Scholar 

  35. Sugiyama M, Sakahara H, Sato K, Harada N, Fukumoto D, Kakiuchi T, et al. Evaluation of 3′-deoxy-3′-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice. J Nucl Med 2004;45:1754–8.

    CAS  PubMed  Google Scholar 

  36. Francis DL, Visvikis D, Costa DC, Croasdale I, Arulampalam TH, Luthra SK, et al. Assessment of recurrent colorectal cancer following 5-fluorouracil chemotherapy using both 18FDG and 18FLT PET. Eur J Nucl Med Mol Imaging 2004;31:928.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Nuclear Medicine, University of Ulm, Robert-Koch-Strasse 8, 89081, Ulm, Germany

    Andreas K. Buck, Holger Schirrmeister, Clemens Kratochwil, Andreas Wahl, Gerhard Glatting, Felix M. Mottaghy, Bernd Neumaier & Sven N. Reske

  2. Department of Internal Medicine II—Pulmonary Medicine, University of Ulm, Ulm, Germany

    Martin Hetzel

  3. Department of Thoracic Surgery, University of Ulm, Ulm, Germany

    Gisela Halter

  4. Department of Pathology, University of Ulm, Ulm, Germany

    Peter Möller & Torsten Mattfeldt

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  1. Andreas K. Buck
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  2. Martin Hetzel
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  3. Holger Schirrmeister
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Correspondence to Andreas K. Buck.

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Buck, A.K., Hetzel, M., Schirrmeister, H. et al. Clinical relevance of imaging proliferative activity in lung nodules. Eur J Nucl Med Mol Imaging 32, 525–533 (2005). https://doi.org/10.1007/s00259-004-1706-7

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  • DOI: https://doi.org/10.1007/s00259-004-1706-7

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