Patients with spinal metastasis from glioblastoma are diagnosed at a relatively young mean age of 44 years and survival of 17.8 months from the initial cranial diagnosis.Reference Shahideh, Fallah and Munoz 1 In the literature, the median time of glioblastoma to spinal metastasis is 10-13 months, with a median time of 3-4 months from spinal metastasis to death.Reference Saito, Kumabe and Jokura 2 Only one patient survived 20 months after treatment.Reference Lawton, Nagasawa and Yang 3 Although 6% patients with hemispheric glioblastomas have spinal seeding at autopsy, only 0.4-2% presented with symptoms while aliveReference Salazar and Rubin 4 because patients do not live long enough for small tumor implants to grow to a symptomatic size.Reference Vertosick and Selker 5
In the literature, there are only a few rare examples of delayed recurrence.Reference Maslehaty, Cordovi and Hefti 6 To our knowledge, the following patient has the longest duration of onset of spinal recurrence from glioblastoma: 62 months from initial presentation.
Case Report
A 48-year-old Caucasian man noted pressure on the right side of his head by the end of 2007. Then the headaches worsened with new onset of blurring of vision. By spring 2008, a computed tomography (CT) and magnetic resonance imaging (MRI) scans revealed a 6.3×5.4×4.6 cm3 mass in the genu of the corpus callosum. He underwent stereotactic biopsy. The pathology was astrocytoma grade III. There was no necrosis seen in the material submitted. Soon after that, he received a gross total resection and the pathology was grade IV per World Health Organization classification. The resected specimen showed extensive necrosis. The viable tumor had generally moderate but with focally high cellularity and was composed of a mixture of small cells with little cytoplasm and gemistocytic forms. Microvascular and endothelial proliferation was identified. The Ki67 labeling index was approximately 10%. Immunochemistry with MIB-1 antibody revealed a large number of immunopositive cells in the proliferative phase of the cell cycle. A neuropathologist reviewed the slides as well and concurred with the glioblastoma diagnosis. Tests at the Mayo Clinic detected mutation of isocitrate dehydrogenase 1, but not of promotor methylation of O6-methylguanine-methyltransferase in the resection specimen.
A shunt was put in on the sixth day postoperatively because of persistent high intracranial pressure. The patient then received adjuvant three-dimensional conformal radiation to 60 Gy in 30 fractions and chemotherapy (temozolomide at 75 mg/m2/day, given 7 days per week during the entire duration of radiotherapy). After a 4-week break, he received six cycles of adjuvant temozolomide according to the standard 5-day schedule every 28 days for 6 cycles, completed in early 2009. Regular follow-up MRI and positron emission tomography (PET)/CT scans did not show any tumor.
About 4 years after completion of all treatments, in the summer of 2013, the patient developed a low backache with paraparesis. Initial PET/CT did not show any abnormality in the spine, although intracranial recurrence was seen. Later, a 3-Tesla MRI of the lumbar spine revealed four intradural enhancing nodules between L1 and L3. The largest nodule was 0.7×0.7×0.6 cm3 at the L2 level (Figure 1). At the same time, the T2 MRI head scan showed a mass-like heterogeneous solid and cystic 1.7×1.2×1.3 cm3 hyperintensity of the right parasagittal frontal lobe, posterior and superior to the resection cavity. It demonstrated irregular peripheral and minimal central enhancement. Palliative high-dose radiation to the L-spine of 40 Gy in 20 fractions was completed in the fall of 2013 with concurrent temozolomide followed by nine cycles of maintenance doses.
MRI of the brain (T2 scan) and lumbar spine at recurrence in July 2014.
An MRI spine scan in early 2014 showed stability of drop metastases and a shrinkage of the recurrent primary tumor. By December 2014, the primary in the brain progressed (Figure 2). Since October 2014, the patient was on dexamethasone 4 mg once daily. In December 2014, chemotherapy was changed to bevacizumab. He could no longer walk and needed a total lift and wheelchair. His symptoms and quality of life were improved with bevacizumab in spring 2015. He was more alert, with improved memory and speech while the dexamethasone was tapered. He is still alive 22 months after treatment of spinal metastases and 84 months since the initial diagnosis of cranial glioblastoma. The latest MRI of the head and spine in April 2015 showed some tumor progression (Figure 3). The amount of edema around the brain primary was less than December 2014.
MRI of the brain (T2 scan) in December 2014. The patient was started on bevacizumab after this.
MRI of the brain (T2 scan) and spine in April 2015. The brain primary had grown and there were a few more small spinal metastases.
Discussion
The mechanisms of tumor spread along cerebrospinal fluid pathways include perivascular growth, invasion of choroid plexus, or cortical surface and subpial spread. The incidence of spinal drop metastases was 0.4-2.0% in the literature.Reference Tinchon, Oberndorfer and Marosi 7 Clinical symptoms are due to the compression of the spinal cord, conus medullaris, or cauda equina, especially if left untreated. Diagnosis used to be made with myelogram and is now made with enhanced MRI of the spine, cerebrospinal fluid cytology, and/or PET scan.Reference Woesler, Kuwert and Probst-Cousin 8 Perhaps because of the limitation of resolution of PET scan as in this case, it has a low sensitivity for leptomeningeal or drop metastases. Not all cases have positive cerebrospinal fluid cytology.Reference Nakano, Yabe and Tsuji-Akimoto 9 The location of symptomatic spinal metastases is more frequently leptomeningeal (14%) than intramedullary (1.1%).Reference Stark, Nabavi and Mehdorn 10 There were only 3/42 (7%) lesions involving the cauda equina/conus medullaris in a previously reported series.Reference Lawton, Nagasawa and Yang 3
Multifocal spread of glioblastoma within the central nervous system can occur at initial presentation, but delayed symptomatic spinal drop metastasis is uncommon in the literature because most patients die early from the intracranial primary. Our patient corroborates the literature with symptomatic spinal metastases more commonly occurring in younger patients, as in Table 1.Reference Onda, Tanaka and Takeda 11 - Reference Birbilis, Matis and Eleftheriadis 14
Examples of spinal metastasis from cranial glioblastoma, modified from Lawton et alReference Lawton, Nagasawa and Yang 3
C=cervical; CRT=chemoradiation therapy; F=female; Fr=fraction; L=lumbar; M=male; NS=not specified; RT=radiotherapy; S=surgery; T=thoracic.
As for treatment of spinal drop metastases, different options include resection if the lesions can be localized. Steroids and focal radiotherapy have been used, with little clinical benefit.Reference Tinchon, Oberndorfer and Marosi 7 No treatment strategy has offered a therapeutic advantage because patients deteriorated rapidly regardless of intervention.Reference Chamberlain 15 Modern treatment with chemotherapy and targeted therapy is available and accounts for the long survival of our patient. Irinotecan had been reported by St. Jude Children’s Hospital for pediatric glioblastomaReference Broniscer, Chintagumpala and Fouladi 16 ; this may be tried in the future as second- or third-line therapies.
Routine prophylactic craniospinal axis irradiation as part of initial therapy is not indicated for infratentorial glioblastoma because of the rarity of spinal metastasis and its overall poor prognosis (8% 3-year survival), and with almost all recurrences being local in the cranium.Reference Kopelson and Linggood 17 However, the pattern of recurrence may be changing to out-of-radiation fields with concurrent temozolomide and bevacizumab.Reference Shields, Kadner, Vitaz and Spalding 18 As for the best management in gliosarcoma to prevent spinal metastases, further investigations are needed.Reference Koul, Tai and Dubey 19 , Reference Schindler, Capper, Korshunov, Schmieder and Brenke 20
In conclusion, the slow progression of our case is unique. Despite the rarity of spinal metastases in glioblastoma, it should be included in the differential diagnoses of causes for symptoms in the back and lower limbs. MRI is the diagnostic imaging of choice. PET scan has a lower sensitivity for leptomeningeal metastases as in this case. Local palliative radiotherapy and systemic treatment with chemotherapy and targeted therapy may improve patient survival. Temozolomide and bevacizumab were used in this case. Bevacizumab is a useful second-line systemic therapy, and our case is the first report of its use in spinal metastases of glioblastoma.
Disclosures
There are unlabeled/unapproved/experimental and/or investigational (non–Food and Drug Administration approved) use of drugs or products in the presentation. The authors declare no other disclosures.
