A 50-year-old man developed severe headache with diplopia, right-sided hearing loss, and tinnitus. MRI of the brain revealed mild hydrocephalus and a cystic mass in the posterior third ventricle. He sought the opinion of 5 independent neurosurgeons, 4 of whom recommended resection or biopsy. The fifth surgeon recommended observation, and the patient opted to follow this recommendation. He continued to have brain MRI performed annually over the next 5 years.
After 5 years, a cystic mass was noted again with some enlargement, and the area of enhancement had decreased in size. Due to his daughter's diagnosis of neuroblastoma and subsequent treatments, he did not pursue further evaluation until 4 years later, when he developed severe right hip and lower back pain. The pain was refractory to standard treatments including chiropractic manipulation and narcotics. Six months later, brain and spinal MRI showed increased size of the pineal mass as well as a 1.5-cm mass located at L5–S1 along the lumbothoracic spine, radiologically consistent with leptomeningeal dissemination. He underwent a laminectomy of the right L5–S1 intradural leptomeningeal tumor. Histopathological diagnosis of the tumor at that time was felt to be consistent with PNET, likely pineoblastoma. Per our review of records from that time, cytological analysis of the cerebrospinal fluid (CSF) was not performed peri-operatively. He was subsequently treated with induction chemotherapy with cyclophosphamide, followed by autologous stem cell transplant. The reason for treating with cyclophosphamide as opposed to standard combination chemotherapy was patient preference in light of his underlying hearing loss. He was then treated with radiation to the entire craniospinal axis to a total radiation dose of 3,600 cGy administered over 24 fractions, followed by a boost to the lower spine (T11–S3).
Brain MRI repeated 3 months later showed evidence of radiologic improvement. However, after several more months the patient was noted to have weight loss, diminished appetite, and lethargy, which gradually improved. He was started on isotretinoin (Accutane) and continued this medication for 5 months. MRI revealed recurrence of the malignancy in the form of a small residual pineal mass, which was deemed unresectable by surgical consultants. This finding was best visualized on T1 coronal imaging with gadolinium contrast; enhancement was seen at the pineal gland mass abutting the tectum of the midbrain (fig. , white arrow). Lumbar spine MRI showed multiple areas of linear enhancement best noted on an axial T1 image with gadolinium contrast and fat saturation, with enhancement seen at the cauda equina (fig. , white arrow). These findings were consistent with progression of disease and new drop metastases. Of note, the patient was symptomatic with worsening lower back pain. There were nodules noted on the lumbar spine and cauda equina. By this time, nearly 11 years had elapsed from the time of initial diagnosis and approximately 5 years from his initial surgery. Additional staging showed no evidence of cancer systemically and CSF cytology was negative.
Fig. 1 MR images at the time of referral to the Duke Brain Tumor Center. a Brain MRI, coronal T1 image with gadolinium contrast, enhancement seen at the pineal gland mass abutting the tectum of the midbrain (white arrow). b MRI of the lumbar spine, axial T1 (more ...)
Recommendations at other institutions included temozolomide in combination with oral etoposide; cisplatinum, lomustine (CCNU), and vincristine; or procarbazine with lomustine and vincristine (PCV regimen). He sought further recommendations at our institution.
His medical history was only notable for right-sided hearing loss and tinnitus of undetermined etiology; he had presented with these symptoms shortly before initial diagnosis 11 years prior. Family history was significant for a daughter who died of neuroblastoma at age 9, as well as a sister diagnosed with melanoma at age 41; another sister with breast cancer had been diagnosed in her early forties. His neurologic and physical exams were unremarkable aside from his bilateral hearing loss, for which he required hearing aids.
Upon presentation to our institution, the initial tumor sample from the laminectomy 5 years prior was re-examined by our neuropathology team. Microscopic examination of the biopsy showed a solid proliferation of small, round, blue cells with scant cytoplasm. In light of findings possibly consistent with a rare intracranial form of Ewing's sarcoma rather than PNET, further analysis was performed to revisit the initial diagnosis. By immunohistochemistry there was strong and diffuse CD99 reactivity. Synaptophysin, neurofilament protein, and cytokeratin were also positive. BAF47 was retained in the tumor nuclei. CD20, GFAP, and PLAP were negative. The Mib-1 index was approximately 15%. Fluorescence in situ hybridization (FISH) testing confirmed rearrangement involving the EWSR1(22q12) gene region as detected by break-apart signals (fig. ). The diagnosis of a neuroectodermal neoplasm consistent with Ewing's sarcoma was made.
Immunofluorescent image of FISH analysis revealing EWS chromosomal rearrangement.
In consideration of the patient's pre-existing bilateral hearing loss and strong desire to avoid any debilitating peripheral neuropathy, we recommended a non-platinum-containing 28-day regimen consisting of the following drugs: etoposide (VP-16) at 100 mg oral for 21 days on/7 days off; vorinostat (Zolinza) 400 mg oral daily on a 7-days-on/7-days-off schedule; and bevacizumab 10 mg/kg IV every 2 weeks. Eight weeks after initiation of this regimen, brain MRI was performed and was consistent with significant radiographic response of his disease at the level of the pineal gland with no evidence of change in the spinal images. Notably, the patient experienced resolution of his lower back pain. MR images 1 year after initiation of treatment demonstrated continued improvement. T1 coronal MR images of the brain with gadolinium contrast demonstrated reduction in enhancement seen at the pineal gland mass abutting the tectum of the midbrain (fig. , white arrow). A sagittal T1 MR image of the lumbar spine with gadolinium contrast revealed no significant change in enhancement (fig. , white arrow). The patient continued this treatment regimen for a total of 16 months with no evidence of radiographic or clinical progression. During the treatment course, primary toxicities included diarrhea (grade 1) and fatigue (grade 1). Despite these toxicities, he was able to main an active work schedule and good quality of life. At 17 months into his current treatment regimen, the patient was found to have new disease at the right cranial nerves VII and VIII in the right internal acoustic canal along with new disease in the thoracic spinal cord and cauda equina. Salvage therapy was started consisting of metronomic temozolomide 50 mg/m2 with bevacizumab 10 mg/kg i.v.q. 2 weeks. Unfortunately, the patient developed clinical decline and MRI showed spread of leptomeningeal disease. The decision was made to transition to hospice.
Fig. 3 MRI images taken 1 year after the initiation of treatment regimen with etoposide, vorinostat, and bevacizumab. a Brain MRI, coronal T1 image with gadolinium contrast, reduction in enhancement seen at the pineal gland mass abutting the tectum of the midbrain (more ...)