Journal of Neuro-Oncology

, Volume 113, Issue 3, pp 485–493

Histopathological correlates with survival in reoperated glioblastomas

  • Graeme F. Woodworth
  • Tomas Garzon-Muvdi
  • Xiaobu Ye
  • Jaishri O. Blakeley
  • Jon D. Weingart
  • Peter C. Burger
Clinical Study


The addition of concomitant and adjuvant chemotherapy to radiation therapy after surgical resection has increased significantly the survival of patients with glioblastoma (GB). In conjunction, there has been an increasing fraction of patients who present with new enlarged areas of contrast enhancement and edema on post-treatment imaging that improve without further treatment. It remains to be established how this phenomenon, commonly termed pseudoprogression, can be distinguished from true tumor recurrence defined as the histological presence of active high-grade tumor, as well as its prognostic significance. Data for over 500 patients undergoing surgery for recurrent GB were reviewed. Pathological specimens were categorized as those that contained active high-grade glioma in any amount, and those that did not. Patient survival was compared between these two groups, and independent associations were assessed using Cox proportionate hazards regression analysis. 59 patients met the study criteria including complete pathological and follow-up data. Mean age was 53 ± 11 years. Median survival from suspected recurrence and initial diagnosis were 8 [5–14] and 20 [12–30] months. Seventeen patients (29 %) had no evidence of active high-grade tumor and 42 (71 %) had at least focal active high-grade glioma. Pathologic pseudoprogression at re-operation (p = 0.03) and gross total resection (p = 0.01) were independently associated with survival. The histopathological features defined here and used to assess the tumor at reoperation were independently associated with survival. These findings may be important in designing treatment strategies and clinical trial endpoints for patients with GB.


Glioblastoma Pathology Recurrence Treatment effect Pseudoprogression 


  1. 1.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996PubMedCrossRefGoogle Scholar
  2. 2.
    de Wit MC, de Bruin HG, Eijkenboom W, Sillevis Smitt PA, van den Bent MJ (2004) Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 63(3):535–537PubMedCrossRefGoogle Scholar
  3. 3.
    Chamberlain MC, Glantz MJ, Chalmers L, Van Horn A, Sloan AE (2007) Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. J Neurooncol 82(1):81–83PubMedCrossRefGoogle Scholar
  4. 4.
    Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9(5):453–461PubMedCrossRefGoogle Scholar
  5. 5.
    Chaskis C, Neyns B, Michotte A, De Ridder M, Everaert H (2009) Pseudoprogression after radiotherapy with concurrent temozolomide for high-grade glioma: clinical observations and working recommendations. Surg Neurol 72(4):423–428PubMedCrossRefGoogle Scholar
  6. 6.
    Pouleau HB, Sadeghi N, Baleriaux D, Melot C, De Witte O, Lefranc F (2012) High levels of cellular proliferation predict pseudoprogression in glioblastoma patients. Int J Oncol 40(4):923–928PubMedGoogle Scholar
  7. 7.
    Young RJ, Gupta A, Shah AD, Graber JJ, Zhang Z, Shi W et al (2011) Potential utility of conventional MRI signs in diagnosing pseudoprogression in glioblastoma. Neurology 76(22):1918–1924PubMedCrossRefGoogle Scholar
  8. 8.
    Hu X, Wong KK, Young GS, Guo L, Wong ST (2011) Support vector machine multiparametric MRI identification of pseudoprogression from tumor recurrence in patients with resected glioblastoma. J Magn Reson Imaging 33(2):296–305PubMedCrossRefGoogle Scholar
  9. 9.
    Gunjur A, Lau E, Taouk Y, Ryan G (2011) Early post-treatment pseudo-progression amongst glioblastoma multiforme patients treated with radiotherapy and temozolomide: a retrospective analysis. J Med Imaging Radiat Oncol 55(6):603–610PubMedCrossRefGoogle Scholar
  10. 10.
    Gahramanov S, Raslan AM, Muldoon LL, Hamilton BE, Rooney WD, Varallyay CG et al (2011) Potential for differentiation of pseudoprogression from true tumor progression with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging using ferumoxytol vs. gadoteridol: a pilot study. Int J Radiat Oncol Biol Phys 79(2):514–523PubMedCrossRefGoogle Scholar
  11. 11.
    Forsyth PA, Kelly PJ, Cascino TL, Scheithauer BW, Shaw EG, Dinapoli RP et al (1995) Radiation necrosis or glioma recurrence: is computer-assisted stereotactic biopsy useful? J Neurosurg 82(3):436–444PubMedCrossRefGoogle Scholar
  12. 12.
    Topkan E, Topuk S, Oymak E, Parlak C, Pehlivan B (2012) Pseudoprogression in patients with glioblastoma multiforme after concurrent radiotherapy and temozolomide. Am J Clin Oncol 35(3):284–289Google Scholar
  13. 13.
    Bland JM, Altman DG (1998) Survival probabilities (the Kaplan–Meier method). BMJ 317(7172):1572PubMedCrossRefGoogle Scholar
  14. 14.
    Stel VS, Dekker FW, Tripepi G, Zoccali C, Jager KJ (2011) Survival analysis I: the Kaplan–Meier method. Nephron Clin Pract 119(1):c83–c88PubMedCrossRefGoogle Scholar
  15. 15.
    Hart MG, Grant R, Garside R, Rogers G, Somerville M, Stein K (2008) Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev 16(3):CD007294Google Scholar
  16. 16.
    Perry J, Chambers A, Spithoff K, Laperriere N (2007) Gliadel wafers in the treatment of malignant glioma: a systematic review. Curr Oncol 14(5):189–194PubMedCrossRefGoogle Scholar
  17. 17.
    Taal W, Brandsma D, de Bruin HG, Bromberg JE, Swaak-Kragten AT, Smitt PA et al (2008) Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 113(2):405–410PubMedCrossRefGoogle Scholar
  18. 18.
    Chamberlain MC (2008) Pseudoprogression in glioblastoma. J Clin Oncol 26(26):4359 (author reply 4359–4360)Google Scholar
  19. 19.
    Sanghera P, Perry J, Sahgal A, Symons S, Aviv R, Morrison M et al (2010) Pseudoprogression following chemoradiotherapy for glioblastoma multiforme. Can J Neurol Sci 37(1):36–42PubMedGoogle Scholar
  20. 20.
    Yaman E, Buyukberber S, Benekli M, Oner Y, Coskun U, Akmansu M et al (2010) Radiation induced early necrosis in patients with malignant gliomas receiving temozolomide. Clin Neurol Neurosurg 112(8):662–667PubMedCrossRefGoogle Scholar
  21. 21.
    Yang I, Huh NG, Smith ZA, Han SJ, Parsa AT (2010) Distinguishing glioma recurrence from treatment effect after radiochemotherapy and immunotherapy. Neurosurg Clin N Am 21(1):181–186PubMedCrossRefGoogle Scholar
  22. 22.
    Brandes AA, Tosoni A, Spagnolli F, Frezza G, Leonardi M, Calbucci F et al (2008) Disease progression or pseudoprogression after concomitant radiochemotherapy treatment: pitfalls in neurooncology. Neuro Oncol 10(3):361–367PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou J, Blakeley JO, Hua J, Kim M, Laterra J, Pomper MG et al (2008) Practical data acquisition method for human brain tumor amide proton transfer (APT) imaging. Magn Reson Med 60(4):842–849PubMedCrossRefGoogle Scholar
  24. 24.
    Sanghera P, Perry J, Sahgal A, Symons S, Aviv R, Morrison M et al (2010) Pseudoprogression following chemoradiotherapy for glioblastoma multiforme. Can J Neurol Sci 37(1):36–42Google Scholar
  25. 25.
    Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G et al (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26(13):2192–2197PubMedCrossRefGoogle Scholar
  26. 26.
    Ozdemir N, Celkan T (2010) Pseudoprogression after radiotherapy with concurrent temozolomide in a child with anaplastic astrocytoma. Pediatr Hematol Oncol 27(4):317–319PubMedCrossRefGoogle Scholar
  27. 27.
    Pytel P, Lukas RV (2009) Update on diagnostic practice: tumors of the nervous system. Arch Pathol Lab Med 133(7):1062–1077PubMedGoogle Scholar
  28. 28.
    Roldan GB, Scott JN, McIntyre JB, Dharmawardene M, de Robles PA, Magliocco AM et al (2009) Population-based study of pseudoprogression after chemoradiotherapy in GBM. Can J Neurol Sci 36(5):617–622PubMedGoogle Scholar
  29. 29.
    Yang I, Aghi MK (2009) New advances that enable identification of glioblastoma recurrence. Nat Rev Clin Oncol 6(11):648–657PubMedCrossRefGoogle Scholar
  30. 30.
    Gahramanov S, Raslan AM, Muldoon LL, Hamilton BE, Rooney WD, Varallyay CG et al (2011) Potential for differentiation of pseudoprogression from true tumor progression with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging using ferumoxytol vs. gadoteridol: a pilot study. Int J Radiat Oncol Biol Phys 79(2):514–523Google Scholar
  31. 31.
    Brandsma D, van den Bent MJ (2009) Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol 22(6):633–638Google Scholar
  32. 32.
    Salhotra A, Lal B, Laterra J, Sun PZ, van Zijl PC, Zhou J (2008) Amide proton transfer imaging of 9L gliosarcoma and human glioblastoma xenografts. NMR Biomed 21(5):489–497PubMedCrossRefGoogle Scholar
  33. 33.
    Zhao X, Wen Z, Huang F, Lu S, Wang X, Hu S et al (2011) Saturation power dependence of amide proton transfer image contrasts in human brain tumors and strokes at 3 T. Magn Reson Med 66(4):1033–1041Google Scholar
  34. 34.
    Zhou J, Lal B, Wilson DA, Laterra J, van Zijl PC (2003) Amide proton transfer (APT) contrast for imaging of brain tumors. Magn Reson Med 50(6):1120–1126PubMedCrossRefGoogle Scholar
  35. 35.
    Barajas RF Jr, Chang JS, Segal MR, Parsa AT, McDermott MW, Berger MS et al (2009) Differentiation of recurrent glioblastoma multiforme from radiation necrosis after external beam radiation therapy with dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. Radiology 253(2):486–496PubMedCrossRefGoogle Scholar
  36. 36.
    Tsien C, Galban CJ, Chenevert TL, Johnson TD, Hamstra DA, Sundgren PC et al (2010) Parametric response map as an imaging biomarker to distinguish progression from pseudoprogression in high-grade glioma. J Clin Oncol 28(13):2293–2299PubMedCrossRefGoogle Scholar
  37. 37.
    Tihan T, Barletta J, Parney I, Lamborn K, Sneed PK, Chang S (2006) Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions? Hum Pathol 37(3):272–282PubMedCrossRefGoogle Scholar
  38. 38.
    Kim JH, Bae Kim Y, Han JH, Cho KG, Kim SH, Sheen SS et al (2012) Pathologic diagnosis of recurrent glioblastoma: morphologic, immunohistochemical, and molecular analysis of 20 paired cases. Am J Surg Pathol 36(4):620–628PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Graeme F. Woodworth
    • 1
  • Tomas Garzon-Muvdi
    • 4
  • Xiaobu Ye
    • 2
  • Jaishri O. Blakeley
    • 3
  • Jon D. Weingart
    • 4
  • Peter C. Burger
    • 5
  1. 1.Department of NeurosurgeryUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Division of BiostatisticsJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Division of Neuro-Oncology, Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Department of NeurosurgeryJohns Hopkins University School of MedicineBaltimoreUSA
  5. 5.Division of Neuropathology, Department of PathologyJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations