Journal of Neuro-Oncology

, Volume 96, Issue 3, pp 375–384 | Cite as

The imaging and neuropathological effects of Bevacizumab (Avastin) in patients with leptomeningeal carcinomatosis

  • B. K. Kleinschmidt-DeMasters
  • Denise M. Damek
Clinical Study - Patient Study


Bevacizumab (Avastin, Genetech/Roche) is an anti-angiogenic drug approved for treating patients with malignant gliomas that reduces edema and mass effect, but has been suggested to promote multifocal tumor spread within the brain. Patients with systemic malignancies are also treated with bevacizumab, but there is limited information regarding effects of the drug on the neuroimaging or neuropathological features of metastatic CNS disease. We report 2 patients with non-small cell lung carcinomas who had received bevacizumab for their systemic cancers and then developed cognitive deficits consistent with white matter dementia. Diagnosis of leptomeningeal carcinomatosis (LC) was confounded and delayed by the finding of atypical neuroimaging features, including minimal to absent leptomeningeal enhancement and unusual perivascular and punctate hemorrhagic lesions and multifocal subgyral signal abnormalities suspicious for vasculitis or small vessel vasculopathy. Neuropathological assessment confirmed LC but, in the autopsy case also disclosed extraordinary perivascular spread of individual metastatic tumor cells to the depth of capillaries. The pattern was reminiscent of vascular “cooption” by tumor seen in experimental animals in preclinical trials of bevacizumab. Small infarctions were associated with perivascular tumor and vasculopathy, unusual features of LC in patients who do not receive bevacizumab. In the biopsied patient, multiple perivascular tumor nodules were identified in superficial cortex. In these two patients, bevacizumab appeared to alter neuroimaging characteristics of LC, confounded diagnosis and possibly also influenced the pattern of tumor spread of LC. More cases will need to be studied to confirm this latter finding.


Carcinomatous meningitis Vasculopathy Neuroimaging White matter Anti-angiogenic 



The authors thank Ms. Lisa Litzenberger for expert photographic assistance, Mrs. Diane Hutchinson for manuscript preparation, and Dr. Zachary Weber who performed the general autopsy. This study was supported, in part, by funding from the Plachy-Rubin Fund for Neuro-oncology.


  1. 1.
    Yan L, Hsu K, Beckman RA (2008) Antibody-based therapy for solid tumors. Cancer J 14:178–183CrossRefPubMedGoogle Scholar
  2. 2.
    Lynch SS, Cheng CM (2007) Bevacizumab for neovascular ocular diseases. Ann Pharmacother 41:614–625CrossRefPubMedGoogle Scholar
  3. 3.
    Simonds J, Miller F, Mandel J, Davidson TM (2009) The effect of bevacizumab (Avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope 119:988–992CrossRefPubMedGoogle Scholar
  4. 4.
    Torcuator R, Zuniga R, Mohan Y, Rock J, Doyle T, Anderson J, Gutierrez J, Ryu S, Jain R, Rosenblum M, Mikkelsen T (2009) Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis. J Neurooncol. doi:  10.1007/s11060-009-9801-z
  5. 5.
    Norden AD, Drappatz J, Wen PY (2008) Novel anti-angiogenic therapies for malignant gliomas. Lancet Neurol 7:1152–1160CrossRefPubMedGoogle Scholar
  6. 6.
    Dietrich J, Norden AD, Wen PY (2008) Emerging antiangiogenic treatments for gliomas—efficacy and safety issues. Curr Opin Neurol 21:736–744CrossRefPubMedGoogle Scholar
  7. 7.
    Gutin PH, Iwamoto FM, Beal K, Mohile NA, Karimi S, Hou BL, Lymberis S, Yamada Y, Chang J, Abrey LE (2008) Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. doi:  10.1016/j.ijrobp.2008.10.043
  8. 8.
    Chamberlain MC, Johnston S (2009) Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer 115:1734–1743CrossRefPubMedGoogle Scholar
  9. 9.
    Nghiemphu PL, Liu W, Lee Y, Than T, Graham C, Lai A, Green RM, Pope WB, Liau LM, Mischel PS, Nelson SF, Elashoff R, Cloughesy TF (2009) Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 72:1217–1222CrossRefPubMedGoogle Scholar
  10. 10.
    Vredenburgh JJ, Desjardins A, Herndon JE, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729CrossRefPubMedGoogle Scholar
  11. 11.
    Rubenstein JL, Kim J, Ozawa T, Zhang M, Westphal M, Deen DF, Shuman MA (2000) Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2:306–314CrossRefPubMedGoogle Scholar
  12. 12.
    Kokmen E, Naessens JM, Offord KP (1987) A short test of mental status: description and preliminary results. Mayo Clin Proc 62:281–288PubMedGoogle Scholar
  13. 13.
    Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198CrossRefPubMedGoogle Scholar
  14. 14.
    Dubois R, Scacheysky A, Lityan I, Pillon B (2000) The FAB: A fronal assessment battery at bedside. Neurology 55:1621–1628PubMedGoogle Scholar
  15. 15.
    Fischer I, Cunliffe CH, Bollo RJ, Raza S, Monoky D, Chiriboga L, Parker EC, Golfinos JG, Kelly PJ, Knopp EA, Gruber ML, Zagzag D, Narayana A (2008) High-grade glioma before and after treatment with radiation and Avastin: initial observations. Neuro Oncol 10:700–708CrossRefPubMedGoogle Scholar
  16. 16.
    Mathews MS, Linskey ME, Hasso AN, Fruehauf JP (2008) The effect of bevacizumab (Avastin) on neuroimaging of brain metastases. Surg Neurol 70:649–652CrossRefPubMedGoogle Scholar
  17. 17.
    Yachnis AT (2005) Vascular disease. In: Prayson RA (ed) Neuropathology. Elsevier Churchill Livingstone, Philadelphia, PA, pp 46–49 2005Google Scholar
  18. 18.
    Olson ME, Chernik NL, Posner JB (1974) Infiltration of the leptomeninges by systemic cancer. A clinical and pathologic study. Arch Neurol 30:122–137PubMedGoogle Scholar
  19. 19.
    Wasserstrom WR, Glass JP, Posner JB (1982) Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 49:759–772CrossRefPubMedGoogle Scholar
  20. 20.
    Kastenbauer S, Wiesmann M, Pfister H-W (2000) Cerebral vasculopathy and multiple infarctions in a woman with carcinomatous meningitis while on treatment with intrathecal methotrexate. J Neurooncol 48:41–45CrossRefPubMedGoogle Scholar
  21. 21.
    Guttman DH, Cantor CR, Piacente GJ, McCluskey LF (1990) Cerebral vasculopathy and infarction in a woman with carcinomatous meningitis. J Neurooncol 9:183–185CrossRefGoogle Scholar
  22. 22.
    Klein P, Haley EC, Wooten GF, VandenBerg SR (1989) Focal cerebral infarctions associated with perivascular tumor infiltrates in carcinomatous leptomeningeal metastases. Arch Neurol 46:1149–1152PubMedGoogle Scholar
  23. 23.
    Solans-Laque R, Bosch-Gil JA, Perez-Bocanegra C, Selva-O’Callaghan A, Simeon-Aznar CP, Vilardell-Tarres M (2008) Paraneoplastic vasculitis in patients with solid tumors: report of 15 cases. J Rheumatol 35:294–304PubMedGoogle Scholar
  24. 24.
    Taccone FS, Salmon I, Marechal R, Blecic SA (2007) Paraneoplastic vasculitis of central nervous system presenting as recurrent cryptogenic stroke. Int J Clin Oncol 12:155–159CrossRefPubMedGoogle Scholar
  25. 25.
    Geisler JP, Schraith DF, Manahan KJ, Sorosky JI (2004) Gemcitabine associated vasculitis leading to necrotizing enterocolitis and death in women undergoing primary treatment for epithelial ovarian/peritoneal cancer. Gynecol Oncol 92:705–707CrossRefPubMedGoogle Scholar
  26. 26.
    Niho S, Kubota K, Goto K, Ohmatsu H, Matsumoto T, Kakinuma R, Nishiwaki Y (2002) Triplet chemotherapy with vinorelbine, gemcitabine, and cisplatin for advanced non-small cell lung cancer: a phase II study. Br J Cancer 87:1360–1364CrossRefPubMedGoogle Scholar
  27. 27.
    Birlik M, Akar S, Tuzel E, Onen F, Ozer E, Manisali M, Kirkali Z, Akkoc N (2004) Gemcitabine-induced vasculitis in advanced transitional cell carcinoma of the bladder. J Cancer Res Clin Oncol 130:122–125CrossRefPubMedGoogle Scholar
  28. 28.
    Voorburg AM, van Beek FT, Slee PH, Seldenrijk CA, Schramel FM (2002) Vasculitis due to gemcitabine. Lung Cancer 36:203–205CrossRefPubMedGoogle Scholar
  29. 29.
    Ozcan C, Wong SJ, Hari P (2006) Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 354:980–982CrossRefPubMedGoogle Scholar
  30. 30.
    Levy CF, Oo KZ, Fireman F, Pierre L, Bania MA, Sadanandan S, Yamashiro DJ, Bender JL (2008) Reversible posterior leukoencephalopathy syndrome in a child treated with bevacizumab. Pediatr Blood Cancer 52:669–671 2009CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • B. K. Kleinschmidt-DeMasters
    • 1
    • 2
    • 3
  • Denise M. Damek
    • 2
    • 3
  1. 1.Department of Surgical PathologyUniversity of Colorado DenverAuroraUSA
  2. 2.Department of NeurologyUniversity of Colorado DenverAuroraUSA
  3. 3.Department of NeurosurgeryUniversity of Colorado DenverAuroraUSA

Personalised recommendations