Case Report5-ALA−Induced Fluorescence in Leptomeningeal Dissemination of Spinal Malignant Glioma
Introduction
5-Aminolevulinic acid (5-ALA)-fluorescence–guided resection of malignant glioma is well established in many neurooncology departments. 5-ALA is accumulated and converted to the fluorescent agent protoporphyrin IX in the mitochondria of malignant gliomas, allowing a selective visualization of tumor tissue after blue-light illumination. Subsequently, 5-ALA-fluorescence–guided surgeries of malignant glioma result in more complete resections and were shown to be associated with prolonged progression-free survival.1, 2, 3 Besides malignant glioma, positive 5-ALA staining of various cerebral and spinal pathologies, such as cerebral metastases or spinal tumors, has been reported.4, 5, 6, 7, 8, 9, 10 Here, we report on a patient with a leptomeningeal spread of a K27M-mutated anaplastic astrocytoma (World Health Organization° [WHO] III), which was detected by its faint 5-ALA−induced fluorescence.
A 26-year-old female patient was admitted to our neurosurgical department presenting with progressive paraplegia. An incomplete resection of a spinal astrocytoma (WHO° II) involving the thoracic levels Th1–Th3 was performed in an external neurosurgical department 4 years before. An adjuvant combined radiotherapy/chemotherapy with a total of 54 Gy was induced according to the Stupp protocol. One year thereafter, the patient suffered from a progression of the spinal astrocytoma leading to a loss of power in both legs. Chemotherapy with bevacizumab was started, leading to an improvement of the neurologic deficits and enabling the patient to walk. Presently, the patient suffered from a progressive paraplegia but also from an impairment of the cranial nerve function with an impairment of swallowing and a sensory loss in the left side of her face. Magnetic resonance imaging (MRI) of the central nervous system showed no progression of the spinal astrocytoma but distended cranial nerves and a distended, partially contrast-enhancing cauda equina (Figure 1, A–C). The cerebrospinal fluid (CSF) obtained by lumbar puncture showed increased protein (146 mg/dL) and lactate levels (7.9 mmol/L) and reduced glucose levels (15 mg/dL). However, recurrent cytopathologic examination of the CSF at 3 times failed to detect malignant cells. Due to further progressive dysfunction of the cranial nerves, we decided to obtain a histopathologic specimen from the cauda equina. 5-ALA was administered 3 hours before surgery in a dose of 20 mg per kilogram body weight as described previously.1, 6 An open biopsy with excision of the sensory nerve root from the cauda equina was performed with intraoperative neurophysiological monitoring (motor and somatosensory evoked potentials). A surgical microscope equipped with a 5-ALA tool (OPMI Pentero 800 microscope with the BLUE 400 tool; Carl Zeiss Meditec, Oberkochen, Germany) was used to visualize 5-ALA−induced fluorescence. Intraoperatively, the nerve roots showed a clearly discernible but light pink 5-ALA−induced fluorescence, which was slightly stronger outside the surgical situs following excision (Figure 1, D). Histopathologic examination confirmed a leptomeningeal spread of a K27M-mutated anaplastic astrocytoma (WHO° III) without R132H-IDH1 mutation (Figure 2). After surgery, the patient partially recovered but died due to neurologic deterioration 1 month thereafter.
The leptomeningeal spread of malignant glioma is not considered to be a rare condition of tumor recurrence and may occur in more than 20% of glioma patients.11, 12, 13 Usually, leptomeningeal spread of malignant glioma is confirmed by either MRI or CSF cytology obtained by lumbar puncture.11, 12, 14 Since CSF cytology could be false negative, as in the present case, a surgical biopsy for histopathologic examination could be indicated if a leptomeningeal spread is clinically assumed. As shown here and during surgery of patients with recurrent malignant glioma, previous application of 5-ALA might intraoperatively help to identify leptomeningeal spread. In the present case, 5-ALA−induced fluorescence intensity was much less pronounced than in solid malignant glioma. The thinner layer of malignant cells accumulating and converting 5-ALA might be a plausible explanation. Such a clearly discernible but lighter pink 5-ALA−induced fluorescence is well known from the infiltration zone of malignant glioma.15, 16 A case of a diffuse cerebral subpial spread of a glioblastoma was previously visualized by strong 5-ALA−induced fluorescence and confirmed by histopathologic analysis.17 Next to intraoperative detection of diffuse cerebral subpial spread, 5-ALA might reliably stain spinal malignant astrocytoma.9, 18
Therapy of leptomeningeal spread remains challenging, and different authors favor different first-line strategies. Examples are radiation therapy (brain: whole-brain radiation therapy with 30 Gy/focal radiation therapy, spine: intensity-modulated radiation with 40–50 Gy) and temozolomide and other adjuvant chemotherapy (temozolomide, lomustine, bevacizumab) and intrathecal chemotherapy (intrathecal methotrexate, liposomal cytarabine).12, 19 However, the prognosis of patients suffering from malignant glioma subpial spread remains limited.12, 19
In the future, spectrometrical detection of residual fluorescence—even in macroscopic nonfluorescent tissue—might give new insight into the relative amount of tumor cells and help to detect leptomeningeal spread and tumor infiltration.
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Conflict of interest statement: Professor Sabel is a consultant for Johnson & Johnson Company and Integra Company. All other authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.