Development of Stereotactic Mass Spectrometry for Brain Tumor Surgery

Malignant brain tumors present a major challenge in neurosurgery not only for their biological behavior but also because of their infiltration in the functioning brain. Currently preferred diagnostic imaging techniques, namely magnetic resonance imaging (MRI),1 have limited sensitivity and specificity to detect the full extent of malignant brain tumors, making it especially difficult to distinguish tumor from peritumoral edema and to recognize low density of tumor cells within otherwise normal brain tissue. Diagnosis, grading of tumors, and treatment rely primarily on neuro-pathological documentation of tissue, including cellular and nuclear morphology, proliferation, necrosis, vascu-larization, and characteristic cytogenetic aberrations.2 Moreover, when single biopsies or sparse surgical samples are used, there may be considerable heterogeneity, leading to sampling error. Surgical pathology-based approaches need to be complemented by improved intraoperative definition of tumors and their margins. This definition will help us obtain samples from appropriate histopathological areas and may provide additional molecular tissue characterization of the tumor. This improved tumor definition will help intraoperative decision making and maximize the extent of tumor resection.3 Surgery remains the first line of treatment for most brain tumor patients, and prognosis for many brain tumors depends significantly on the extent of surgical resection,4–7 but this must be balanced against preservation of functioning cortex and white matter.8–10 In recent years, there has been significant progress in developing imaging and image-guidance platforms for localizing and targeting brain tumors and revealing the full extent of infiltrating tumor with the anatomic and functional definition of involved brain areas.11–13 Frameless stereotaxy and neuro-navigation is key for aiding the neurosurgeon in the coregistration of the individual patient’s anatomy and images. Mass spectrometry is a well-established, sensitive analytical technique used to identify and characterize molecules based on their mass and fragmentation pattern, respectively. The recent adaptation of mass spectrometers and their respective computer applications to accommodate tissue analysis provides simultaneous molecular profiling of hundreds of molecules without the need for radioactive or fluorescent tag.14 An increasing number of studies support the concept of mass spectrometry as an efficient tool to recognize and delineate pathology directly from tissue specimens.15–17 In 2004, desorption electrospray ionization (DESI) was introduced as an ambient desorption/ionization method for mass spectrometry18 and subsequently proven to be applicable to tissue imaging.19,20 The DESI technique is well suited for clinical deployment because it is a soft ionization method that allows the analysis of intact biomolecules and provides direct sampling of the tissue in the ambient environment without specialized sample preparation.21 The present study introduces the integration of DESI mass spectrometry into surgery for in vivo molecular tissue characterization and intraoperative definition of tumor boundaries, without systemic injection of contrast agents. This novel approach will provide complex molecular information during the surgery, complementing preoperative and intraoperative MRI and positron emission tomography (PET) with a potentially more sensitive and specific assessment of tumor boundaries in vivo.