Osteoblastic metastases from astrocytomas: A report of two cases

Medical and Pediatric Oncology 19:318-324 (1991)

Osteoblastic Metastases From Astrocytomas: A Report of Two Cases Darryl C. Longee, MD, Henry S. Friedman, MD, Peter C. Phillips, MD, Peter C. Burger, MD, W. Jerry Oakes, MD, Dan Heffez, MD, Moody Wharam, MD, Lewis Strauss, MD, Gregory N. Fuller, MD, PhD, and S. Clifford Schold, MD The spread of primary central nervous system (CNS) neoplasms beyond the confines of the neuraxis i s a relatively uncommon observation. Extraneural metastases involving bone are quite rare, and have been observed almost exclusively in cases of medu Iloblastoma, high-grade (III-IV) astrocytoma, and glioblastoma multiforme. To date there has been only one case reported

of bone metastasis from a ”well-differentiated” astrocytoma. We now report two cases of astrocytoma in children with diffuse osteoblastic metastases and a fulminant clinical course. These cases demonstrate that due to the potential morphologic heterogeneity of these neoplasms, an initial biopsy diagnosis of low-grade astrocytoma does not always imply a benign clinical course.

Key words: bone metastasis, computed tomography, magnetic resonance imaging

INTRODUCTION

Extraneural metastases from central nervous system (CNS) neoplasms, although uncommon, have been observed with increasing frequency since the 1950’s [ 1-51. This may reflect a greater recognition of this condition, improved diagnostic techniques, or the overall increased survival times in treated patients. Hoffman and Duffner reviewed the literature up to 1984 and found a total of 282 cases of extraneural metastases [6]. Medulloblastoma has historically been the most common tumor to metastasize outside the CNS axis, followed closely by high-grade astrocytomas. Lung and pleura (60%), lymph nodes (51%), bone (30%), and liver (22%) are the most common sites of extraneural metastases from the latter neoplasms [4]. Astrocytomas diagnosed as “low-grade” usually connote a relatively good prognosis. Although occurrences of neuraxis dissemination from low-grade gliomas have been reported [ 7 ] , it is much less common than in the high-grade astrocytic tumors [8]. Extraneural metastases are exceedingly rare in patients with low-grade tumors. There has been one case reported of diffuse bone metastases from a “well-differentiated’’ astrocytoma in a child, although portions of the original tumor demonstrated features suggesting a higher grade of malignancy [9]. We report two cases of ostensibly low-grade astrocytomas in children with diffuse osteoblastic metastases and a fulminant clinical course. These cases demonstrate 0 1991 Wiley-Liss, Inc.

that gliomas felt histologically to be “low-grade” tumors on initial biopsy do not always pursue a benign clinical course. CASE REPORTS Case 1

The patient was a 13-year-old white male who was well until April 1986 when he presented with intermittent headaches, nausea and vomiting, and intermittent diplopia. Papilledema was found and a CT scan of the head demonstrated a deep right hemisphere mass blocking the foramen of Monro, producing secondary ventricular dilation (Fig. 1). The child was begun on dexamethasone and improved symptomatically. He was referred to Duke Medical Center. An MRI scan confirmed a large right thalamic mass, and a right fronto-parietal craniotomy and open biopsy From the Departments of Pediatrics, Medicine, Neurosurgery and Pathology, Duke University Medical Center, Durham, North Carolina (D.C.L., H.S.F., P.C.B., W.J.O., G.N.F., S.C.S.); Departments of Neurology, Oncology, Neurosurgery and Radiation Oncology, Johns Hopkins University, School of Medicine, Baltimore (P.C.P., D.H., M.W., L.S.). Received April 17, 1990; accepted February 25, 1991. Address reprint requests to Darryl C . Longee, M.D., Arkansas Children’s Hospital, Division of Hematology-Oncology, 800 Marshall Street, Little Rock, AR 72202.

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enhancement of both frontal horns and the third ventricle suggestive of tumor seeding. Plain radiographs showed multiple osteoblastic lesions of the vertebrae, ribs, and pelvis (Fig. 3). A bone scan revealed widespread multifocal uptake in both the axial and appendicular skeleton. Bone marrow aspirate and biopsy from the right anterior iliac crest showed no evidence of malignancy. Thin needle aspirate of the left femur revealed malignant tumor cells. Immunohistochemical analysis demonstrated that the cells were positive for UJ13A (panneuroectodermal antibody) and GFAP, consistent with a metastasis from an astrocytic neoplasm. The parents declined further therapeutic intervention and the patient died at home in February 1987, 8 months

Fig. 1. Cranial CT scan from case 1 demonstrating an enhancing mass in the region of the right thalamus and basal ganglia, producing obstruction of the right lateral ventricle at the level of the foramen of Monro.

were performed in June 1986. The tumor was a moderately cellular mass which, from the small fragments available for study, showed a generally discrete margin with the surrounding brain. The cells were elongated and terminated On the via tapered, fibrillq acidic protein (GFAP)-positive processes (Fig. 2). The nuclei were oval to fusiform in shape and had a moderate chromatin density. Scattered mitoses were observed. No microcysts, Rosenthal fibers, or vascular proliferation was seen. The diagnosis of pilocytic astrocytoma was rendered. Following ventriculo-peritonea1shunting 1 week later, the patient was referred for intervention with radiotherapy. The child was treated with 5,400 cGy to the tumor in 180 cGy daily fractions over a 6 week period in July and August 1986. He did well until September 1986 when he developed back pain leading to a rapidly progressive quadriparesis. Metrizamide myelography revealed evidence of subarachnoid metastases throughout the entire spinal cord. The patient was treated with spinal axis irradiation (cervical-lumbosacra1 spine), receiving 3,520 cGy (in 160 cGy daily fractions) in September and October. The patient had ‘linical improvement and in January 1987 he was readmitted with multiple cranial nerve palsies. CT scanning demonstrated periependymal

Fig. 2. Tumor biopsy specimen from caSe 1. Note the prominent, elongated cytoplasmic processes charactenstic of pilocytic astrocytoma. H&E. x400.

Fig. 3. Plain radiograph of pelvis from case 1 , 7 months after diagnosis, demonstrates multiple osteoblastic lesions involving right acetabulum and both femora.

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after diagnosis. At autopsy, the neoplasm was extensively distributed in the intracranial-intraspinal subarachnoid spaces. The medulla and upper cervical cord were encased by a thick rim of tumor and a 2.5 cm mass was present over the cerebellum. Microscopically, the neoplasm was generally similar to that seen in the biopsy (Fig. 4A) although large areas were markedly cellular, without process formation, and associated with abundant mitotic activity and vascular proliferation (Fig. 4B). Elsewhere the lesion was highly fibrillar with large anuclear zones composed of delicate cytoplasmic processes. Microcysts were present in these areas. The cells in these highly fibrillar areas were strongly positive for GFAP.

Fig. 4. Autopsy brain specimen from case 1. Panel A: A representative area of the tumor with morphologic features similar to those of the initial biopsy, including pronounced fibrillarity with large anuclear zones composed of delicate cytoplasmic processes. H&E. x400. Panel B: A representative portion of the tumor which exhibits features suggestive of a more aggressive neoplasm, including marked cellularity, very little process formation, and vascular proliferation. H&E. x250.

Case 2

A 9-year-old black female presented in October 1988 with a 2-month history of intermittent nausea and vomiting, diplopia, and progressive gait ataxia. Physical examination revealed bilateral papilledema. Cranial MRI scan demonstrated ventriculomegaly with an intrinsic brainstem mass at the level of the superior colliculus on the right with extension into the inferior midbrain and pons (Fig. 5). The child was begun on dexamethasone and referred to Johns Hopkins Hospital where an open biopsy was performed in October 1988. The surgical specimen consisted of multiple small fragments of white matter. The tissue was hypercellular due to the presence of an infiltrating neoplasm (Fig. 6). The latter consisted of astrocytes with oval nuclei of low chromatin density. No mitoses, vascular proliferation, or necrosis was seen. There were no microcysts or Rosenthal fibers. The diagnosis of a well-differentiated astrocytoma was rendered. Persistent hydrocephalus necessitated the placement of a ventriculo-peritoneal shunt in November 1988. Plain radiographs of the abdomen 1 week later revealed multiple osteoblastic lesions of the pelvis (Fig. 7). A skeletal survey and bone scan demonstrated similar lesions involving the humeri, femora, and tibiae bilaterally, thoracic and lumbar verkbrae, ribs and skull. A

Fig. 5. Brain MRI of case 2 at diagnosis. TI-weighted image reveals low signal-intensity tumor (arrows) infiltrating midbrain and deforming the fourth ventricle.

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no evidence of tumor. An MRI scan of the spine with gadolinium-diethylenetriaminepenta-acetic acid (GdDTPA) showed no evidence of subarachnoid spread. The child was entered on the Pediatric Oncology Group Study #8833 and received four courses of cisplatin and cyclophosphamide at 4 week intervals beginning in October 1988. A bone scan in January 1989 revealed decreased tracer uptake in the thoracic and lumbar vertebrae and ribs; however, new activity was noted in the C2 vertebral body. An MRI scan of the head with Gd-DTPA demonstrated enhancement in the subarachnoid space along the cerebral convexities consistent with leptomeningeal dissemination. In March 1989 the patient developed bowel and bladder incontinence, weakness and hyporeflexia in the lower extremities, and decreased sensory perception. Fig. 6. Tumor biopsy specimen from case 2, showing an infiltrating low-grade neoplasm. No mitotic figures, vascular proliferation, or MRI scanning of the head demonstrated progressive leptomeningeal and subependymal enhancement of the necrosis is seen. H&E. x400. left frontal and occipital horns, right basal ganglia, and both thalami. MRI examination of the spine revealed diffuse leptomeningeal enhancement from the cervical to lumbar spine. The child died 1 week later, 5 months after diagnosis. Permission for autopsy was denied. DISCUSSION

Fig. 7. Plain radiograph of pelvis from case 2, 2 weeks after diagnosis, revealing multiple osteoblastic metastatic lesions involving iliac wings, acetabuli, ischii, and femora.

bone biopsy of the right ilium revealed numerous cells with conspicuous glassy pink cytoplasm and radiating processes (Fig. 8A). Moderate nuclear pleomorphism was present. Mitotic figures were not seen. The cells were positive for GFAP and S-100 protein (Fig. 8B). Bone marrow aspirate and biopsy were negative for malignancy. CT scan of the chest and abdomen showed

As of this writing there have been 32 reported cases of bone metastases from astrocytic tumors [5,9-321. All but one of the cases [9] occurred with high-grade astrocytomas; glioblastomas accounted for 20 of these cases (61%), while anaplastic astrocytomas were responsible for 11. The most common site of bone metastasis was the vertebrae (73%), followed by ribs, pelvis, and appendicular skeleton. Of the 19 cases in which an autopsy was performed, skeletal metastases alone were found in eight cases. Hematogenous and lymphatic dissemination are the most frequently implicated mechanisms of extraneural metastases from CNS neoplasms. Liwnicz and Rubenstein emphasized that surgical procedures play a significant role in distant disseminationby enabling tumor cells access to extrameningeal blood and lymph vessels [22]. Indeed, 27 of the 31 patients with bone metastases from astrocytic tumors had undergone at least one surgical procedure. However, extraneural metastases occurred in the absence of surgery in five cases [14,16,29,30,32]. Kung observed vascular invasion by glioma cells at the ultrastructural level in one study [33]. Vascular invasion of the dural or meningeal vessels was documented in five cases of bone metastases, including two of the five nonsurgical patients [14,16,22,24]. Kingston reported the first case of widespread osteoblastic metastases from a "well-differentiated" (Kernohan grade 2) astrocytoma, although portions of the

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Fig. 8. Bone biopsy of right iliac crest from case 2, 2 weeks after diagnosis. Panel A: An H&E stained section which reveals clusters of stellate and spindle-shaped cells with eosinophilic cytoplasm and prominent cytoplasmic processes. X 320. Panel B: The intense positivity of the cell clusters following immunostaining for GFAP. X 320.

tumor demonstrated marked cellular pleomorphism and foci of pallisading necrosis which would appear to indicate a glioblastoma [9]. In that case, a 13-year-old boy developed bone metastases 1 year after subtotal resection and radiotherapy, and I month after placement of a VP shunt. At autopsy, neuraxis dissemination of tumor was discovered. However, there were no visceral or intraperitoneal tumor deposits. Given the absence of tumor in the peritoneal cavity and the short interval between shunt placement and the development of bone metastases, the authors felt it unlikely that the shunt played a role in dissemination of the tumor.

Neuraxis dissemination and extraneural osteoblastic metastases occurred in our two cases as well. In case I , neuraxis dissemination developed within 4 months of craniotomy and VP shunt placement, with overt bony metastases subsequently detected 3 months later. Therefore, the shunt could have provided a channel for extraneural tumor dissemination. In case 2, however, widespread osteoblastic metastases were discovered only 1 week after VP shunt placement (and 2 weeks after open biopsy). It is unlikely that either the craniotomy or shunting procedure was involved in the development of extraneural metastases in this case. This scenario, as in

Bone Metastases in Astrocytomas Kingston’s case [9], is most compatible with hematogenous dissemination outside the neuraxis. Immunohistochemical staining with anti-GFAP antibodies confirmed that the bone lesions in both Kingston’s and our cases were glial tumors, although intermediate filament proteins, such as GFAP, cannot in general be considered “specific” for a certain cell type [25,34,35]. Given the aggressiveness of the neoplasms, it is important to ask whether the neoplasms were really well-differentiated or “benign.” In case 2, review of the histologic sections disclosed an unequivocally welldifferentiated fibrillary or “diffuse” astrocytoma (World Health Organization grade 11) tumor. The microscopic appearance gave no intimation about the subsequent course, although the original variation in histological malignancy in the fibrillary, “diffuse,” astrocytic neoplasms is well recognized. Case 1 is not so clearly resolved. Review of the surgical specimen revealed polar cells with long processes consistent with the typical well-differentiated (World Health Organization grade I) pilocytic astrocytoma. However, the cells were more crowded than is typical, the nuclei somewhat more hyperchromatic, and mitoses were seen. In addition, Rosenthal fibers were absent. Autopsy examination of the central nervous system confirmed the presence of large areas of the tumor which exhibited morphologic features characteristic of a more aggressive neoplasm. Thus, although the original lesion fit the general description of a pilocytic astrocytoma, there were atypical features. This case suggests that caution must be taken in assuming that all “pilocytic” neoplasms in the hypothalamus of children are “benign” in their clinical expression. Both patients described in this report with osteoblastic bone metastases from astrocytomas demonstrated fulminant clinical courses with widespread tumor dissemination and early death. It is thus evident that an ostensibly “benign” astrocytoma does not always pursue a “benign” clinical course. Indeed, Auer et al. have reported a patient with an apparent low-grade cerebellar astrocytoma who demonstrated a malignant clinical course [36]. However, the known histologic heterogeneity of gliomas may provide an explanation for this apparent paradox, with the poor clinical outcomes reflecting growth (and dissemination) of initially microscopic areas of highgrade tumor. Clinicians providing care for patients with apparent low-grade astrocytomas should be aware that a histologically low-grade tumor does not always imply a benign clinical course, and that metastatic disease may extend beyond the central nervous system. ACKNOWLEDGMENTS

This work was supported in part by the National Institute of Health grants NS-20023, CA-44640, CA-

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15525, and T32-NS07304, and by American Cancer Society Award CH-403. Dr. Friedman is the recipient of NINCDS Teacher Investigator Development Award 1K07-NS-00958. Dr. Schold is the recipient of a Jacob Javits Investigator Award from NINCDS NS-2058 1. The authors wish to thank Martha Timmons and Lisa Jones for their expert secretarial assistance in preparing this manuscript. REFERENCES 1. Campbell AN, Chan HSL, Becker LE, Daneman A, Park TS,

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