- Email: [email protected]
Cerebellar liponeurocytoma in two siblings suggests a possible familial predisposition
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Case Reports / Journal of Clinical Neuroscience 32 (2016) 154–156
[25] Niikawa S, Ito T, Murakawa T, et al. Recurrence of choroid plexus papilloma with malignant transformation. Neurol Med Chir (Tokyo) 1993;33:32–5. [26] Ortega-Martinez M, Cabezudo-Artero JM, Fernandez-Portales I, et al. Diffuse leptomeningeal seeding from benign choroid plexus papilloma. Acta Neurochir (Wien) 2007;149:1229–36 [discussion 1236–7]. [27] Peyre M, Bah A, Kalamarides M. Multifocal choroid plexus papillomas: case report. Acta Neurochir (Wien) 2012;154:295–9. [28] Valencak JB, Dietrich W, Raderer M, et al. Evidence of therapeutic efficacy of CCNU in recurrent choroid plexus papilloma. J Neurooncol 2000;49:263–8.
[29] Zachary G, George J, Jaishri B, et al. Management of disseminated choroid plexus papilloma: a case study. Pediatr Blood Cancer 2014;61:562–3. [30] Safaee M, Oh MC, Bloch O, et al. Choroid plexus papillomas: advances in molecular biology and understanding of tumorigenesis. Neuro Oncol 2013;15:255–67. [31] Tabori U, Shlien A, Baskin B, et al. TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors. J Clin Oncol 2010;28:1995–2001.
http://dx.doi.org/10.1016/j.jocn.2016.04.002
Cerebellar liponeurocytoma in two siblings suggests a possible familial predisposition Stylianos Pikis a, Yakov Fellig b, Emil Margolin c,⇑ a
Department of Neurosurgery, ‘‘Korgialenio Benakio” Red Cross Hospital of Athens, Athens 11526, Greece Department of Pathology, Hadassah–Hebrew University Medical Center, Jerusalem 91120, Israel c Department of Neurosurgery, Hadassah–Hebrew University Medical Center, Kiryat Hadassah, P.O. Box 12000, Jerusalem 91120, Israel b
a r t i c l e
i n f o
Article history: Received 8 April 2016 Accepted 12 April 2016
Keywords: Biology Cerebellar liponeurocytomas Familial Inheritance
a b s t r a c t There is limited data on the genetic origin and natural history of cerebellar liponeurocytoma. To the best of our knowledge there has been only one report of a familial presentation of this rare entity. We report a 72-year-old female with a posterior fossa tumor presenting with progressive cerebellar signs and symptoms. The patient underwent total tumor resection via an uncomplicated sub-occipital craniotomy. Histopathologic examination was diagnostic for cerebellar liponeurocytoma. Her sister was previously treated for a similar tumor. Our report provides further evidence for the possible existence of a hereditary abnormality predisposing afflicted families to cerebellar liponeurocytoma development. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Cerebellar liponeurocytoma is defined by the World Health Organization (WHO) as a rare, WHO grade II, cerebellar neoplasm of adults with consistent neuronal, variable astrocytic and focal lipomatous differentiation, and with a low proliferative potential [1]. The genetic origins of this rare entity are yet to be defined and to the best of our knowledge there has been only one report on cerebellar liponeurocytoma affecting different members of the same family [2]. We report a 72-year-old woman with cerebellar liponeurocytoma whose sister was treated in our department for a similar lesion and briefly review the available literature on the molecular biology and histopathologic abnormalities associated with cerebellar liponeurocytomas.
from the right cerebellar hemisphere and compressing the brainstem and fourth ventricle. The lesion was composed of a contrast enhancing superior component and an inferior component exhibiting fat signal (Fig. 1a). Her family history was significant for a sister who underwent partial resection of a cerebellar liponeurocytoma followed by postoperative radiosurgery due to residual tumor enlargement. Six years following operation this patient was asymptomatic without any evidence of tumor recurrence. The current patient underwent sub-occipital craniotomy and gross total resection of a soft, greyish, exophytic, easily dissected tumor. Mild improvement of her symptoms was noted postoperatively and she was discharged to a rehabilitation center. At the 3-year follow-up the patient was asymptomatic without evidence of tumor recurrence on brain MRI (Fig. 1b). 3. Histopathology report
2. Case report A 72-year-old woman was admitted to our clinic due to a posterior fossa space occupying lesion diagnosed by non-contrast head CT scan obtained during head trauma evaluation following a fall. She complained of a 5-month history of progressive headache, unsteadiness, and recurrent falls. Past medical history was significant for untreated hyperthyroidism which was managed pre-operatively. On neurological examination she had ataxia, a tendency to fall on the right, and bilateral dysdiadochokinesia, dysmetria, and intention tremor, worse on the right. Brain MRI revealed a 48 43 41 mm, intra-axial, exophytic lesion arising ⇑ Corresponding author. Tel.: +972 2 677 7092; fax: +972 2 643 1740. E-mail address: [email protected] (E. Margolin).
The neoplasm of the current patient (Fig. 2I–P) displayed typical morphological features of liponeurocytoma, that is, a highly cellular neoplasm, with extensive ‘‘lipomatous” differentiation, infiltrating the cerebellar parenchyma. Occasional rosettes and areas with a prominent vascular network were evident. Most neoplastic cells were relatively uniform, with round or oval nuclei, with finely dispersed chromatin, and clear or pale cytoplasm. There was no necrosis or microvascular proliferation and the MIB-1 proliferation index was 1–3%. In contrast, the neoplasm of her sister (Fig. 2A–H) displayed atypical morphological features, with only focal, minor ‘‘lipomatous” differentiation, focal papillary/pseudopapillary appearance, focal increased mitotic activity (up to six mitotic figures/10 high-power microscopic fields) and relatively high MIB-1 proliferation index (10–15%), as well as occasional
Case Reports / Journal of Clinical Neuroscience 32 (2016) 154–156
155
Fig. 1. Pre- and post-operative brain MRI. Sagittal T1-weighted gadolinium enhanced brain MRI demonstrating an enhancing cerebellar tumor compressing the brainstem and fourth ventricle (a) and gross total resection of the tumor (b).
Fig. 2. Histology of the surgical specimens. Neoplasms of the reported patient (I–P) and of her sister (A–H) were similar but not identical. While the neoplasm of the patient presented here showed typical morphological features of liponeurocytoma, including extensive ‘‘lipomatous” differentiation and low MIB-1 proliferation marker labeling index (1–3%), the neoplasm of her sister displayed atypical morphological features, with only focal, minor ‘‘lipomatous” differentiation, focal papillary/pseudopapillary appearance (B) and relatively increased MIB-1 proliferation marker labeling index (10–15%). Immunophenotype in both neoplasms was consistent with neurocytic/neuronal differentiation with variable immunopositivity for chromogranin, synaptophysin, MAP-2 and NeuN (M – weak and focal NeuN immunopositivity of neoplastic cells [⁄], relative to strong NeuN immunopositivity of internal granular cell layer neurons [⁄⁄]). There was focal immunopositivity for GFAP, more conspicuous in the neoplasm of the patient’s sister, possibly representing background gliosis. Both neoplasms were immunonegative for Olig-2. H&E = hematoxylin and eosin, NeuN = neuronal nuclear antigen, GFAP = glial fibrillary acidic protein, MAP-2 = microtubule-associated protein 2, Olig-2 = oligodendrocyte transcription factor 2.
microvascular proliferation. Immunophenotype in both neoplasms was consistent with neurocytic/neuronal differentiation with variable immunopositivity for chromogranin, synaptophysin, microtubule-associated protein 2 (MAP-2) and neuronal nuclear
antigen (NeuN). There was focal immunopositivity for glial fibrillary acidic protein (GFAP), possibly representing background gliosis. Immunostains for oligodendrocyte transcription factor 2 (Olig-2), p53 and isocitrate dehydrogenase-1 (IDH-1) were
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Case Reports / Journal of Clinical Neuroscience 32 (2016) 154–156
negative. Fluorescence in-situ hybridization was negative for a deletion of chromosomes 1p/19q (Fig. 2). 4. Discussion Since its first description in 1978 by Bechtel et al. [3], there have been approximately 40 cases of cerebellar and 11 cases of supratentorial liponeurocytoma reported in the literature [4]. This tumor is composed of small neurocytic cells with round or oval nuclei and clear or pale staining cytoplasm, arranged in sheets or lobules. In the areas of lipidization, the nuclei of tumor cells are displaced to the periphery of the cell, resembling mature adipocytes. Necrosis and vascular proliferation occur rarely and have been associated with a more aggressive behavior of the tumor. On immunohistochemistry, the tumor cells typically express synaptophysin, neuron specific enolase, and MAP-2. Focal GFAP expression has been reported in most of the cases [1,5]. The MIB-1 proliferation index is usually low (1–3%). However, higher MIB-1 values have also been reported and have been associated with higher risk of recurrence and poor prognosis [6,7]. As described earlier in detail, the neoplasms presented here had similar immunophenotype consistent with neurocytic/neuronal differentiation, however with different morphological features. The genetic profile and cellular origin of cerebellar liponeurocytoma are yet to be defined. Anghileri et al. reported presence of the NEUROG1 transcript, absence of the ATOH1 transcript and overexpression of fatty acid-binding protein 4 in two cerebellar liponeurocytoma samples. According to the authors these findings suggest that cerebellar liponeurocytomas may occur as a result of transformation of cerebellar progenitor cells which are distinct from cerebellar granule progenitors and aberrant differentiation of these cells to adipose tumor cells [8]. In a genetic and expression profile study of 20 cerebellar liponeurocytoma patients Horstman et al. distinguished cerebellar liponeurocytoma from medulloblastomas by a different cDNA expression pattern, and absence of isochromosome 17q, PTCH, APC, or beta-catenin mutations in the former. Moreover, the presence of TP53 mutations in 20% of cerebellar liponeurocytomas, which are absent from central neurocytoma, suggested that their genetic pathways are different [4]. Wolf et al. provided evidence of an inheritable predisposition for cerebellar http://dx.doi.org/10.1016/j.jocn.2016.04.004
liponeurocytoma development. They reported on a young woman with cerebellar liponeurocytoma whose mother, maternal grandfather and uncle were previously diagnosed with similar tumors. The authors suggested the existence of a germline mutation predisposing only to liponeurocytoma formation [2]. The genetic defect predisposing to liponeurocytoma development in our patients is unknown. Unfortunately, even though planned, we were not able to perform genetic profile evaluation because one of the sisters did not consent to any further investigations offered. In conclusion, this is the second report describing cerebellar liponeurocytoma afflicting members of the same family, thus providing further evidence for a hereditary genetic predisposition to the development of this rare entity. Further studies to define the etiology and natural history, and to identify genetic abnormaloties unique to cerebellar liponeurocytoma, and subsequently guide genetic counseling and screening, are necessary.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
References [1] Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97–109. [2] Wolf A, Alghefari H, Krivosheya D, et al. Cerebellar liponeurocytoma: a rare intracranial tumor with possible familial predisposition. Case report. J Neurosurg 2015:1–5. [3] Bechtel JT, Patton JM, Takei Y. Mixed mesenchymal and neuroectodermal tumor of the cerebellum. Acta Neuropathol 1978;41:261–3. [4] Horstmann S, Perry A, Reifenberger G, et al. Genetic and expression profiles of cerebellar liponeurocytomas. Brain Pathol 2004;14:281–9. [5] Nishimoto T, Kaya B. Cerebellar liponeurocytoma. Arch Pathol Lab Med 2012;136:965–9. [6] Buccoliero AM, Caldarella A, Bacci S, et al. Cerebellar liponeurocytoma: morphological, immunohistochemical, and ultrastructural study of a relapsed case. Neuropathology 2005;25:77–83. [7] Karabagli P, Sav A, Pamir N. Case report does ‘‘cerebellar liponeurocytoma” always reflect an expected site? An unusual case with a review of the literature. Folia Neuropathol 2014;52:101–5. [8] Anghileri E, Eoli M, Paterra R, et al. FABP4 is a candidate marker of cerebellar liponeurocytomas. J Neurooncol 2012;108:513–9.
Case Reports / Journal of Clinical Neuroscience 32 (2016) 154–156
[25] Niikawa S, Ito T, Murakawa T, et al. Recurrence of choroid plexus papilloma with malignant transformation. Neurol Med Chir (Tokyo) 1993;33:32–5. [26] Ortega-Martinez M, Cabezudo-Artero JM, Fernandez-Portales I, et al. Diffuse leptomeningeal seeding from benign choroid plexus papilloma. Acta Neurochir (Wien) 2007;149:1229–36 [discussion 1236–7]. [27] Peyre M, Bah A, Kalamarides M. Multifocal choroid plexus papillomas: case report. Acta Neurochir (Wien) 2012;154:295–9. [28] Valencak JB, Dietrich W, Raderer M, et al. Evidence of therapeutic efficacy of CCNU in recurrent choroid plexus papilloma. J Neurooncol 2000;49:263–8.
[29] Zachary G, George J, Jaishri B, et al. Management of disseminated choroid plexus papilloma: a case study. Pediatr Blood Cancer 2014;61:562–3. [30] Safaee M, Oh MC, Bloch O, et al. Choroid plexus papillomas: advances in molecular biology and understanding of tumorigenesis. Neuro Oncol 2013;15:255–67. [31] Tabori U, Shlien A, Baskin B, et al. TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors. J Clin Oncol 2010;28:1995–2001.
http://dx.doi.org/10.1016/j.jocn.2016.04.002
Cerebellar liponeurocytoma in two siblings suggests a possible familial predisposition Stylianos Pikis a, Yakov Fellig b, Emil Margolin c,⇑ a
Department of Neurosurgery, ‘‘Korgialenio Benakio” Red Cross Hospital of Athens, Athens 11526, Greece Department of Pathology, Hadassah–Hebrew University Medical Center, Jerusalem 91120, Israel c Department of Neurosurgery, Hadassah–Hebrew University Medical Center, Kiryat Hadassah, P.O. Box 12000, Jerusalem 91120, Israel b
a r t i c l e
i n f o
Article history: Received 8 April 2016 Accepted 12 April 2016
Keywords: Biology Cerebellar liponeurocytomas Familial Inheritance
a b s t r a c t There is limited data on the genetic origin and natural history of cerebellar liponeurocytoma. To the best of our knowledge there has been only one report of a familial presentation of this rare entity. We report a 72-year-old female with a posterior fossa tumor presenting with progressive cerebellar signs and symptoms. The patient underwent total tumor resection via an uncomplicated sub-occipital craniotomy. Histopathologic examination was diagnostic for cerebellar liponeurocytoma. Her sister was previously treated for a similar tumor. Our report provides further evidence for the possible existence of a hereditary abnormality predisposing afflicted families to cerebellar liponeurocytoma development. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Cerebellar liponeurocytoma is defined by the World Health Organization (WHO) as a rare, WHO grade II, cerebellar neoplasm of adults with consistent neuronal, variable astrocytic and focal lipomatous differentiation, and with a low proliferative potential [1]. The genetic origins of this rare entity are yet to be defined and to the best of our knowledge there has been only one report on cerebellar liponeurocytoma affecting different members of the same family [2]. We report a 72-year-old woman with cerebellar liponeurocytoma whose sister was treated in our department for a similar lesion and briefly review the available literature on the molecular biology and histopathologic abnormalities associated with cerebellar liponeurocytomas.
from the right cerebellar hemisphere and compressing the brainstem and fourth ventricle. The lesion was composed of a contrast enhancing superior component and an inferior component exhibiting fat signal (Fig. 1a). Her family history was significant for a sister who underwent partial resection of a cerebellar liponeurocytoma followed by postoperative radiosurgery due to residual tumor enlargement. Six years following operation this patient was asymptomatic without any evidence of tumor recurrence. The current patient underwent sub-occipital craniotomy and gross total resection of a soft, greyish, exophytic, easily dissected tumor. Mild improvement of her symptoms was noted postoperatively and she was discharged to a rehabilitation center. At the 3-year follow-up the patient was asymptomatic without evidence of tumor recurrence on brain MRI (Fig. 1b). 3. Histopathology report
2. Case report A 72-year-old woman was admitted to our clinic due to a posterior fossa space occupying lesion diagnosed by non-contrast head CT scan obtained during head trauma evaluation following a fall. She complained of a 5-month history of progressive headache, unsteadiness, and recurrent falls. Past medical history was significant for untreated hyperthyroidism which was managed pre-operatively. On neurological examination she had ataxia, a tendency to fall on the right, and bilateral dysdiadochokinesia, dysmetria, and intention tremor, worse on the right. Brain MRI revealed a 48 43 41 mm, intra-axial, exophytic lesion arising ⇑ Corresponding author. Tel.: +972 2 677 7092; fax: +972 2 643 1740. E-mail address: [email protected] (E. Margolin).
The neoplasm of the current patient (Fig. 2I–P) displayed typical morphological features of liponeurocytoma, that is, a highly cellular neoplasm, with extensive ‘‘lipomatous” differentiation, infiltrating the cerebellar parenchyma. Occasional rosettes and areas with a prominent vascular network were evident. Most neoplastic cells were relatively uniform, with round or oval nuclei, with finely dispersed chromatin, and clear or pale cytoplasm. There was no necrosis or microvascular proliferation and the MIB-1 proliferation index was 1–3%. In contrast, the neoplasm of her sister (Fig. 2A–H) displayed atypical morphological features, with only focal, minor ‘‘lipomatous” differentiation, focal papillary/pseudopapillary appearance, focal increased mitotic activity (up to six mitotic figures/10 high-power microscopic fields) and relatively high MIB-1 proliferation index (10–15%), as well as occasional
Case Reports / Journal of Clinical Neuroscience 32 (2016) 154–156
155
Fig. 1. Pre- and post-operative brain MRI. Sagittal T1-weighted gadolinium enhanced brain MRI demonstrating an enhancing cerebellar tumor compressing the brainstem and fourth ventricle (a) and gross total resection of the tumor (b).
Fig. 2. Histology of the surgical specimens. Neoplasms of the reported patient (I–P) and of her sister (A–H) were similar but not identical. While the neoplasm of the patient presented here showed typical morphological features of liponeurocytoma, including extensive ‘‘lipomatous” differentiation and low MIB-1 proliferation marker labeling index (1–3%), the neoplasm of her sister displayed atypical morphological features, with only focal, minor ‘‘lipomatous” differentiation, focal papillary/pseudopapillary appearance (B) and relatively increased MIB-1 proliferation marker labeling index (10–15%). Immunophenotype in both neoplasms was consistent with neurocytic/neuronal differentiation with variable immunopositivity for chromogranin, synaptophysin, MAP-2 and NeuN (M – weak and focal NeuN immunopositivity of neoplastic cells [⁄], relative to strong NeuN immunopositivity of internal granular cell layer neurons [⁄⁄]). There was focal immunopositivity for GFAP, more conspicuous in the neoplasm of the patient’s sister, possibly representing background gliosis. Both neoplasms were immunonegative for Olig-2. H&E = hematoxylin and eosin, NeuN = neuronal nuclear antigen, GFAP = glial fibrillary acidic protein, MAP-2 = microtubule-associated protein 2, Olig-2 = oligodendrocyte transcription factor 2.
microvascular proliferation. Immunophenotype in both neoplasms was consistent with neurocytic/neuronal differentiation with variable immunopositivity for chromogranin, synaptophysin, microtubule-associated protein 2 (MAP-2) and neuronal nuclear
antigen (NeuN). There was focal immunopositivity for glial fibrillary acidic protein (GFAP), possibly representing background gliosis. Immunostains for oligodendrocyte transcription factor 2 (Olig-2), p53 and isocitrate dehydrogenase-1 (IDH-1) were
156
Case Reports / Journal of Clinical Neuroscience 32 (2016) 154–156
negative. Fluorescence in-situ hybridization was negative for a deletion of chromosomes 1p/19q (Fig. 2). 4. Discussion Since its first description in 1978 by Bechtel et al. [3], there have been approximately 40 cases of cerebellar and 11 cases of supratentorial liponeurocytoma reported in the literature [4]. This tumor is composed of small neurocytic cells with round or oval nuclei and clear or pale staining cytoplasm, arranged in sheets or lobules. In the areas of lipidization, the nuclei of tumor cells are displaced to the periphery of the cell, resembling mature adipocytes. Necrosis and vascular proliferation occur rarely and have been associated with a more aggressive behavior of the tumor. On immunohistochemistry, the tumor cells typically express synaptophysin, neuron specific enolase, and MAP-2. Focal GFAP expression has been reported in most of the cases [1,5]. The MIB-1 proliferation index is usually low (1–3%). However, higher MIB-1 values have also been reported and have been associated with higher risk of recurrence and poor prognosis [6,7]. As described earlier in detail, the neoplasms presented here had similar immunophenotype consistent with neurocytic/neuronal differentiation, however with different morphological features. The genetic profile and cellular origin of cerebellar liponeurocytoma are yet to be defined. Anghileri et al. reported presence of the NEUROG1 transcript, absence of the ATOH1 transcript and overexpression of fatty acid-binding protein 4 in two cerebellar liponeurocytoma samples. According to the authors these findings suggest that cerebellar liponeurocytomas may occur as a result of transformation of cerebellar progenitor cells which are distinct from cerebellar granule progenitors and aberrant differentiation of these cells to adipose tumor cells [8]. In a genetic and expression profile study of 20 cerebellar liponeurocytoma patients Horstman et al. distinguished cerebellar liponeurocytoma from medulloblastomas by a different cDNA expression pattern, and absence of isochromosome 17q, PTCH, APC, or beta-catenin mutations in the former. Moreover, the presence of TP53 mutations in 20% of cerebellar liponeurocytomas, which are absent from central neurocytoma, suggested that their genetic pathways are different [4]. Wolf et al. provided evidence of an inheritable predisposition for cerebellar http://dx.doi.org/10.1016/j.jocn.2016.04.004
liponeurocytoma development. They reported on a young woman with cerebellar liponeurocytoma whose mother, maternal grandfather and uncle were previously diagnosed with similar tumors. The authors suggested the existence of a germline mutation predisposing only to liponeurocytoma formation [2]. The genetic defect predisposing to liponeurocytoma development in our patients is unknown. Unfortunately, even though planned, we were not able to perform genetic profile evaluation because one of the sisters did not consent to any further investigations offered. In conclusion, this is the second report describing cerebellar liponeurocytoma afflicting members of the same family, thus providing further evidence for a hereditary genetic predisposition to the development of this rare entity. Further studies to define the etiology and natural history, and to identify genetic abnormaloties unique to cerebellar liponeurocytoma, and subsequently guide genetic counseling and screening, are necessary.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
References [1] Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97–109. [2] Wolf A, Alghefari H, Krivosheya D, et al. Cerebellar liponeurocytoma: a rare intracranial tumor with possible familial predisposition. Case report. J Neurosurg 2015:1–5. [3] Bechtel JT, Patton JM, Takei Y. Mixed mesenchymal and neuroectodermal tumor of the cerebellum. Acta Neuropathol 1978;41:261–3. [4] Horstmann S, Perry A, Reifenberger G, et al. Genetic and expression profiles of cerebellar liponeurocytomas. Brain Pathol 2004;14:281–9. [5] Nishimoto T, Kaya B. Cerebellar liponeurocytoma. Arch Pathol Lab Med 2012;136:965–9. [6] Buccoliero AM, Caldarella A, Bacci S, et al. Cerebellar liponeurocytoma: morphological, immunohistochemical, and ultrastructural study of a relapsed case. Neuropathology 2005;25:77–83. [7] Karabagli P, Sav A, Pamir N. Case report does ‘‘cerebellar liponeurocytoma” always reflect an expected site? An unusual case with a review of the literature. Folia Neuropathol 2014;52:101–5. [8] Anghileri E, Eoli M, Paterra R, et al. FABP4 is a candidate marker of cerebellar liponeurocytomas. J Neurooncol 2012;108:513–9.