Journal of Neuro-Oncology 14: 237-241, 1992. © 1992KluwerAcademic Publishers. Printedin the Netherlands. Clinical Study
Differentiation of a primitive neuroectodermal tumor into a benign ganglioglioma
J. Russel Geyer, 1 Deborah Schofield, 2 Mitchell Berger 3 and Jerrold Milstein 4 1Pediatrics, 2 Pathology, 3 Neurological Surgery, 4Neurology, Children's Hospital & Medical Center, University of Washington, Seattle, Washington, USA
Key words: cerebellar neuroblastoma, primitive neuroectodermal tumor (PNET), computerized tomography (CT), cell differentiation Abstract We describe a case of cerebellar neuroblastoma with histologic documentation of maturation into a ganglioglioma sixteen months later. Only chemotherapy was administered following the initial surgery and the child is well and disease-free three years following her final surgical procedure. The outcome of this patient supports previous hypotheses that the cerebellar neuroblastoma may be a less malignant tumor than its other primitive neuroectodermal posterior fossa counterparts. Furthermore, this case suggests a role for second-look surgery in the management of selected pediatric brain tumors.
Introduction Cerebellar neuroblastoma is a recently described entity classified by some authors as a primitive neuroctodermal tumor (PNET) with neuronal differentiation [1, 2]. We report a patient with the diagnosis of cerebellar neuroblastoma who received multiagent chemotherapy followed by resection of the residual tumor at the completion of therapy. The histopathology of this second-look reoperation procedure was consistent with ganglioglioma, suggesting differentation from the original tumor. This case provides further evidence that cerebellar neuroblastoma is an entity distinct from other primitive neuroectodermal tumors (PNETs) and which may share biologic features similar to peripheral neuroblastomas.
Case report A 16-month-old white female was initially evaluat-
ed for protracted emesis at an outside institution. A computed tomography (CT) scan demonstrated a left cerebellar tumor and associated obstructive hydrocephalus. A ventriculostomy was placed followed by a ventriculoperitoneal shunt, and the tumor was subsequently subtotally resected. In the postoperative period, the patient developed candidal fungemia and was tranferred to Children's Hospital and Medical Center, Seattle for further treatment. After a three week course of intravenous amphotericin, she underwent another suboccipital craniectomy with a near total resection of the remaining tumor. The ventriculoperitoneal shunt was also revised at this time because of inadequate function. A staging work-up was negative which included cerebrospinal fluid (CSF) cytology and a myelogram. Because of her young age, the child was treated according to a Childrens Cancer Study Group (CCSG) protocol utilizing vincristine, procarbazine, cisplatin, CCNU, hydroxyurea, prednisone, cyclophosphamide and cytosine arabin-
238
Fig. 1. Discreteislands of looselypacked cells within a loose neurofibrillary backgroundare surrounded by sheets of smaller densely
packed cells (H&E stain).
sode ('8 drugs in 1 day') [3]. No irradiation was administered. After completing ten cycles of chemotherapy over a period of one year, a residual area of tumor enhancement increased in size on CT scan. This prompted a third operation and gross total resection of the enhancing area, 18 months after the initial diagnosis. Subsequent to this final procedure, the child received no additional therapy. She remains neurologically intact and free of detectable disease by CT and magnetic resonance imaging (MRI) three years after the third operation (four and a half years after her original diagnosis).
Pathology All specimens were fixed in formalin and processed in paraffin. Sections for both hematoxylin and eosin (H&E) and immunoperoxidase staining were cut at 6 micron thickness. The specimen which was received from the second resection (one month after the first operation)
consisted of multiple fragments of soft, gray hemorrhagic tissue which measured 3 × 3 × 2 cm in aggregate. H & E stained sections showed sheets of neoplastic cells characterized by small round to slightly irregular nuclei with inconspicuous nucleoli and a thin rim of cytoplasm. In many regions, there were discrete islands of slightly larger cells with round nuclei, occasional nucleoli and a moderate amount of eosinophilic cytoplasm (Fig. 1). These areas were less cellular, associated with a loose neurofibrillary background and stained strongly with an antibody directed against synaptophysin (Fig. 2). Scattered GFAP (glial fibrillary acidic protein) positive cells were also noted. The specimen received at the time of the 'second-look', e.g. final operation, consisted of multiple fragments of pink-tan soft tissues which measured approximately 2 × 1 × 1 cm in aggregate. After formalin fixation and routine processing, H&E stained sections showed slightly immature ganglion cells scattered throughout a relatively dense fibrillary background (Fig. 3 ). Clusters of
239
Fig. 2. Synaptophysinstain of the same area as illustratedin Fig. 1, highlightingthe islandsof neuroblasts.
immature neuroblasts were not seen. The final diagnosis at this time was ganglioglioma.
Discussion
The relationship of cerebellar neuroblastoma to PNETs (with neuronal or ganglion cell differentiation) and the overlap between neuroblastoma and desmoplastic medulloblastoma have not been well defined by neuropathologists. There is, however, increasing evidence which supports the view that the cerebellar neuroblastoma should be separated from the PNET/medulloblastoma group as its biologic behavior may be more benign [1, 4, 5]. A unique feature of the peripheral neuroblastoma is the observation that this tumor may mature into a ganglioneuroma. Although a well-recognized and frequently spontaneous biologic phenomenon in some groups of peripheral neuroblastomas, cerebellar differentiation has been well documented in only two previous cases of the cerebellar lesion (Table 1) [6, 7]. In both cases, the patients were less than three years of age and the
tumor arose in the cerebellar vermis. Documented differentiation followed neuraxis radiation in combination with chemotherapy in one child and neutaxis radiation alone in another. In our case, differentiation was documented following treatment with chemotherapy alone. Differentiation into ganglioglioma may therefore be either a spontaneous process or non-specifically induced by radiation or chemotherapy. This case also illustrates the potential value of second-look surgery when residual enhancement persists. Documentation of differentiation to ganglioglioma obviated the need for further therapy, i.e. cranial irradiation, which would otherwise have been undertaken. In summary, we present a case of cerebellar neuroblastoma with apparent histologic differentiation to ganglioglioma in association with administration of only chemotherapy. This report also illustrates the potential value of second-look surgery when residual enhancement persists following the completion of chemotherapy in young children with cerebellar neuroblastoma.
240
Fig. 3. H&E stained sections of tissue removed at the time of the second-look operation were characterized by slightly immature ganglion cells lacking Nissl substance. The cells are randomly scattered throughout a dense fibrillary stroma.
Geyer, M.D. and NIH K08 NS01253-03 under Mitchel Berger, M.D.
Acknowledgements This research was supported in part by CIA NIH Grant Award K08 CA01451-03 under J. Russell
Table 1. Age
Original diagnosis
Location
Therapy
Recurrent diagnosis
Intraoperative interval
Patient 1
15 mo
Cerebellar Neuroblastoma
V
Ganglioglioma
67 mo
Patient 2
2.5yr
Cerebellar Neuroblastoma
V
3000 tad (CO-60) CY-P VCR CS-rad (dosage NA)
Patient 3 (current patient)
15 mo Neuroblastoma
Cerebellar
LH Chemotherapy
V LH CY-P VCR CS-rad
= = = = =
cerebellar vermis. left cerebellar hemisphere. cyclophosphamide. vincristine. craniospinal irradiation.
'8-in-l'
Ganglioneuroma 4yr with melanosis Ganglioglioma 16mo
241
References 1. Pearl GS, Takei Y: Cerebellar 'neuroblastoma': nosology as it relates to medulloblastoma. Cancer 47: 772-779, 1981 2. Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42: 1-15, 1983 3. Pendergrass TW, Milstein JM, Geyer JR, Mulne AF, Kosnik EJ, Morris JD, Heideman RL, Ruyrnann FB, Stuntz JT, Bleyer WA: Eight drugs in one day chemotherapy for brain tumors: experience in 107 children and rationale for preradiation chemotherapy. J Clin Oncol 5(8): 1221-1281, 1987
4. Yagishita S, Itoh Y, Chiba Y, Kuwana N: Morphological investigations on cerebellar 'neuroblastoma' group. ACTA Neuropathol (Berlin) 56(1): 22-28, 1982 5. Schofield D, Yunis EJ, Geyer JR, Albright AL, Berger MS, Taylor SR: DNA content and other prognostic features in childhood medulloblastoma: proposal of a scoring system. Cancer (In press). 6. Warzok R, Jaenisch W, Lang G: Morphology and bioogy of cerebellar neuroblastomas. J Neuro-Oncol 1: 373-379, 1983 7. De Chadarevian JP Montes JL, O'Gorman AM, Freeman CR: Maturation of cerebellar neuroblastoma into ganglioneuroma with melanosis. Cancer 59: 69-76, 1987
Address for offprints: J.R. Geyer, Hematology/Oncology, Children's Hospital, 4800 Sand Point Way NE, Seattle, WA 98105, USA
Differentiation of a primitive neuroectodermal tumor into a benign ganglioglioma
J. Russel Geyer, 1 Deborah Schofield, 2 Mitchell Berger 3 and Jerrold Milstein 4 1Pediatrics, 2 Pathology, 3 Neurological Surgery, 4Neurology, Children's Hospital & Medical Center, University of Washington, Seattle, Washington, USA
Key words: cerebellar neuroblastoma, primitive neuroectodermal tumor (PNET), computerized tomography (CT), cell differentiation Abstract We describe a case of cerebellar neuroblastoma with histologic documentation of maturation into a ganglioglioma sixteen months later. Only chemotherapy was administered following the initial surgery and the child is well and disease-free three years following her final surgical procedure. The outcome of this patient supports previous hypotheses that the cerebellar neuroblastoma may be a less malignant tumor than its other primitive neuroectodermal posterior fossa counterparts. Furthermore, this case suggests a role for second-look surgery in the management of selected pediatric brain tumors.
Introduction Cerebellar neuroblastoma is a recently described entity classified by some authors as a primitive neuroctodermal tumor (PNET) with neuronal differentiation [1, 2]. We report a patient with the diagnosis of cerebellar neuroblastoma who received multiagent chemotherapy followed by resection of the residual tumor at the completion of therapy. The histopathology of this second-look reoperation procedure was consistent with ganglioglioma, suggesting differentation from the original tumor. This case provides further evidence that cerebellar neuroblastoma is an entity distinct from other primitive neuroectodermal tumors (PNETs) and which may share biologic features similar to peripheral neuroblastomas.
Case report A 16-month-old white female was initially evaluat-
ed for protracted emesis at an outside institution. A computed tomography (CT) scan demonstrated a left cerebellar tumor and associated obstructive hydrocephalus. A ventriculostomy was placed followed by a ventriculoperitoneal shunt, and the tumor was subsequently subtotally resected. In the postoperative period, the patient developed candidal fungemia and was tranferred to Children's Hospital and Medical Center, Seattle for further treatment. After a three week course of intravenous amphotericin, she underwent another suboccipital craniectomy with a near total resection of the remaining tumor. The ventriculoperitoneal shunt was also revised at this time because of inadequate function. A staging work-up was negative which included cerebrospinal fluid (CSF) cytology and a myelogram. Because of her young age, the child was treated according to a Childrens Cancer Study Group (CCSG) protocol utilizing vincristine, procarbazine, cisplatin, CCNU, hydroxyurea, prednisone, cyclophosphamide and cytosine arabin-
238
Fig. 1. Discreteislands of looselypacked cells within a loose neurofibrillary backgroundare surrounded by sheets of smaller densely
packed cells (H&E stain).
sode ('8 drugs in 1 day') [3]. No irradiation was administered. After completing ten cycles of chemotherapy over a period of one year, a residual area of tumor enhancement increased in size on CT scan. This prompted a third operation and gross total resection of the enhancing area, 18 months after the initial diagnosis. Subsequent to this final procedure, the child received no additional therapy. She remains neurologically intact and free of detectable disease by CT and magnetic resonance imaging (MRI) three years after the third operation (four and a half years after her original diagnosis).
Pathology All specimens were fixed in formalin and processed in paraffin. Sections for both hematoxylin and eosin (H&E) and immunoperoxidase staining were cut at 6 micron thickness. The specimen which was received from the second resection (one month after the first operation)
consisted of multiple fragments of soft, gray hemorrhagic tissue which measured 3 × 3 × 2 cm in aggregate. H & E stained sections showed sheets of neoplastic cells characterized by small round to slightly irregular nuclei with inconspicuous nucleoli and a thin rim of cytoplasm. In many regions, there were discrete islands of slightly larger cells with round nuclei, occasional nucleoli and a moderate amount of eosinophilic cytoplasm (Fig. 1). These areas were less cellular, associated with a loose neurofibrillary background and stained strongly with an antibody directed against synaptophysin (Fig. 2). Scattered GFAP (glial fibrillary acidic protein) positive cells were also noted. The specimen received at the time of the 'second-look', e.g. final operation, consisted of multiple fragments of pink-tan soft tissues which measured approximately 2 × 1 × 1 cm in aggregate. After formalin fixation and routine processing, H&E stained sections showed slightly immature ganglion cells scattered throughout a relatively dense fibrillary background (Fig. 3 ). Clusters of
239
Fig. 2. Synaptophysinstain of the same area as illustratedin Fig. 1, highlightingthe islandsof neuroblasts.
immature neuroblasts were not seen. The final diagnosis at this time was ganglioglioma.
Discussion
The relationship of cerebellar neuroblastoma to PNETs (with neuronal or ganglion cell differentiation) and the overlap between neuroblastoma and desmoplastic medulloblastoma have not been well defined by neuropathologists. There is, however, increasing evidence which supports the view that the cerebellar neuroblastoma should be separated from the PNET/medulloblastoma group as its biologic behavior may be more benign [1, 4, 5]. A unique feature of the peripheral neuroblastoma is the observation that this tumor may mature into a ganglioneuroma. Although a well-recognized and frequently spontaneous biologic phenomenon in some groups of peripheral neuroblastomas, cerebellar differentiation has been well documented in only two previous cases of the cerebellar lesion (Table 1) [6, 7]. In both cases, the patients were less than three years of age and the
tumor arose in the cerebellar vermis. Documented differentiation followed neuraxis radiation in combination with chemotherapy in one child and neutaxis radiation alone in another. In our case, differentiation was documented following treatment with chemotherapy alone. Differentiation into ganglioglioma may therefore be either a spontaneous process or non-specifically induced by radiation or chemotherapy. This case also illustrates the potential value of second-look surgery when residual enhancement persists. Documentation of differentiation to ganglioglioma obviated the need for further therapy, i.e. cranial irradiation, which would otherwise have been undertaken. In summary, we present a case of cerebellar neuroblastoma with apparent histologic differentiation to ganglioglioma in association with administration of only chemotherapy. This report also illustrates the potential value of second-look surgery when residual enhancement persists following the completion of chemotherapy in young children with cerebellar neuroblastoma.
240
Fig. 3. H&E stained sections of tissue removed at the time of the second-look operation were characterized by slightly immature ganglion cells lacking Nissl substance. The cells are randomly scattered throughout a dense fibrillary stroma.
Geyer, M.D. and NIH K08 NS01253-03 under Mitchel Berger, M.D.
Acknowledgements This research was supported in part by CIA NIH Grant Award K08 CA01451-03 under J. Russell
Table 1. Age
Original diagnosis
Location
Therapy
Recurrent diagnosis
Intraoperative interval
Patient 1
15 mo
Cerebellar Neuroblastoma
V
Ganglioglioma
67 mo
Patient 2
2.5yr
Cerebellar Neuroblastoma
V
3000 tad (CO-60) CY-P VCR CS-rad (dosage NA)
Patient 3 (current patient)
15 mo Neuroblastoma
Cerebellar
LH Chemotherapy
V LH CY-P VCR CS-rad
= = = = =
cerebellar vermis. left cerebellar hemisphere. cyclophosphamide. vincristine. craniospinal irradiation.
'8-in-l'
Ganglioneuroma 4yr with melanosis Ganglioglioma 16mo
241
References 1. Pearl GS, Takei Y: Cerebellar 'neuroblastoma': nosology as it relates to medulloblastoma. Cancer 47: 772-779, 1981 2. Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42: 1-15, 1983 3. Pendergrass TW, Milstein JM, Geyer JR, Mulne AF, Kosnik EJ, Morris JD, Heideman RL, Ruyrnann FB, Stuntz JT, Bleyer WA: Eight drugs in one day chemotherapy for brain tumors: experience in 107 children and rationale for preradiation chemotherapy. J Clin Oncol 5(8): 1221-1281, 1987
4. Yagishita S, Itoh Y, Chiba Y, Kuwana N: Morphological investigations on cerebellar 'neuroblastoma' group. ACTA Neuropathol (Berlin) 56(1): 22-28, 1982 5. Schofield D, Yunis EJ, Geyer JR, Albright AL, Berger MS, Taylor SR: DNA content and other prognostic features in childhood medulloblastoma: proposal of a scoring system. Cancer (In press). 6. Warzok R, Jaenisch W, Lang G: Morphology and bioogy of cerebellar neuroblastomas. J Neuro-Oncol 1: 373-379, 1983 7. De Chadarevian JP Montes JL, O'Gorman AM, Freeman CR: Maturation of cerebellar neuroblastoma into ganglioneuroma with melanosis. Cancer 59: 69-76, 1987
Address for offprints: J.R. Geyer, Hematology/Oncology, Children's Hospital, 4800 Sand Point Way NE, Seattle, WA 98105, USA
