Childs Nerv Syst (2015) 31:167–171 DOI 10.1007/s00381-014-2509-1
CASE REPORT
Pilocytic astrocytoma with anaplastic features presenting good long-term clinical course after surgery alone: a case report Katsuya Saito & Masahiro Toda & Kazunari Yoshida
Received: 28 June 2014 / Accepted: 22 July 2014 / Published online: 7 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Introduction
Abstract Purpose Pilocytic astrocytomas (PAs) are the most common brain tumor in children and typically have an excellent prognosis. However, some PAs show histologically anaplastic features. It is reported that PAs with anaplastic features often need the postoperative radiation and chemotherapy due to aggressiveness such as early local recurrence and dissemination. We describe an interesting case of primary anaplastic PA with good clinical course in the long-term. Methods A 10-year-old man presented with worsening headache and vomiting. Magnetic resonance imaging (MRI) showed a large cystic tumor with contrast-enhanced solid component in a right occipital lobe. Magnetic resonance spectroscopy (MRS) showed the decrease of N-acetylaspartate (NAA) and the increase of choline and lipids, which suggested the malignancy. Results The patient was operated with an occipital lobectomy. The tumor was incompletely resected due to the deep invasion to the inner wall of lateral ventricle. Pathological diagnosis was a pilocystic astrocytoma with anaplastic features. Although aggressive features were suspected from magnetic resonance spectroscopy and pathological findings, the remnant tumor showed no recurrence for 8 years without any postoperative treatments. Conclusion PAs could exhibit variable behavior, and careful managements including wait-and-scan should be considered, because adjuvant therapies may cause child’s growth disorder and malignant transformation.
Pilocytic astrocytoma (PA) is the most common brain tumor in children. PAs are classified by the World Health Organization (WHO) as grade I tumors, which typically have an excellent prognosis [15]. Proliferative activity is generally low with MIB-1 labeling index ranging from 0 to 3.9 % [10]. However, it was reported that some PAs show clinically aggressive features exceptionally [1, 3, 6, 9–11, 13, 18, 19]. Although the predictive factors for PAs with aggressive features remain controversial, most papers reported that histological anaplasia was one of the comparatively reliable findings [5, 10, 12, 13]. PAs with anaplastic features or anaplastic PAs were seen in 2 to 5 % of PA cases [18]. The clinical outcomes of anaplastic PAs were reported to be corresponding to WHO grade II or III gliomas [12, 13, 16, 18], and therefore, some articles suggested that anaplastic PAs needed the postoperative radiation and chemotherapy due to aggressiveness such as early local recurrence and dissemination [1, 16, 19]. Most of anaplastic PAs have been reported to occur as a secondary transformation from ordinary PAs with exposure to ionizing radiation [3, 9, 13, 16, 19]. The present case was, however, a primary case of anaplastic PA. The primary anaplastic PAs have ever been rarely reported [1, 10, 18]. Here, we report a rare and successful case of primary anaplastic PA with good long-term outcome despite of no adjuvant therapy.
Keywords Pilocystic astrocytoma . Anaplastic feature . Anaplastic pilocystic astrocytoma . Long-term outcome
Case report
K. Saito (*) : M. Toda : K. Yoshida Department of Neurosurgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan e-mail: [email protected]
A 10-year-old man presented with worsening headache and vomiting, and he was referred to our hospital. He did not have any past history and any family history associated with neurofibromatosis type 1 (NF1). Visual
168
test showed severe papilledema and left homonymous hemianopia. Magnetic resonance imaging (MRI) showed a large cystic tumor with contrast-enhanced solid component in a right occipital lobe (Fig. 1a–d). In addition, the tumor invasion into a right lateral ventricle was suspected (Fig. 1e). Magnetic resonance spectroscopy (MRS) showed the decrease of N-acetylaspartate (NAA) and the increase of choline and lipids, which suggested the malignancy (Fig. 1f–g). Angiography showed no tumor stain. The patient was operated with an occipital lobectomy. Intraoperative findings showed that the well-vascularized tumor deeply invaded the inner wall of the right lateral ventricle (Fig. 2a–b). Although the tumor was grossly resected, we left the only tumor component invading the ventricular wall due to invasive and easy-bleeding nature of the tumor. The postoperative course was uneventful. Postoperative MRI in 1 month showed no solid mass with contrast enhancement (Fig. 2c–e), although a small part of tumor was left during an operation. Wait-and-scan management every 6 months was performed for the residual tumor without any adjuvant therapies, because he was a child.
Fig. 1 Preoperative MRI, showing a heterogeneously enhanced solid mass with cystic components in the right occipital lobe. Tumor size was 10×6× 6 cm. a Axial section on T2weighted image. b–d Axial, sagittal, and coronal sections on contrast-enhanced T1-weighted image. Tumor invasion to a right lateral ventricle was suspected (e). MRS, showing the malignant features. MRS showed the decrease of NAA (2 ppm) and the increase of choline (3.2 ppm) and lipids (0–2 ppm) in the tumor area (f), compared with the contralateral non-tumor area (g)
Childs Nerv Syst (2015) 31:167–171
Although 8 years have passed, follow-up MRI showed no recurrence (Fig. 2f–h).
Pathological findings In the present case, three neuropathologists (two pathologists of our institution and one pathologist of the external institution) were involved in the pathological diagnosis. As shown in Fig. 3a–h, histological examination of the resected specimen revealed proliferation of bipolar or multipolar astrocytic cells showing a biphasic pattern of compact (Fig. 3a) and loose (Fig. 3b) areas. Eosinophilic granular bodies (Fig. 3b) and Rosenthal fibers were present. In addition, atypical findings were observed: hypercellular areas with hyperchromatic, enlarged nuclei and multinuclear giant cells (Fig. 3c–d), mitotic figures (2 mitoses/10 high-power fields [HPF], Fig. 3e), high MIB-1 labeling index (8.5 %, Fig. 3f), necrosis with focal pseudopalisading (Fig. 3g), and endothelial proliferation (Fig. 3h). Necrosis was particularly prominent, and necrotic area occupied approximately 25 % of the
Childs Nerv Syst (2015) 31:167–171
169
Fig. 2 Intraoperative photographs and postoperative MRI findings. Intraoperative views, showing tumor invasion into the ventricular wall. While resecting the deep margin of tumor, a lateral ventricle got opened (a). At the intraventricular space, the vascularized tumor-like lesion invading the inner wall of lateral ventricle was observed (b). By the intraoperative pathology consultation, biopsy specimen of this lesion was identified to be the tumorous tissue. Axial (c), sagittal (d), and coronal (e) sections of contrast-enhanced T1-weighted MRI 1 month after the operation, showing no solid mass with contrast enhancement. Axial (f), sagittal (g), and coronal (h) sections of contrast-enhanced T1weighted MRI 8 years after the operation, showing no recurrence. Tu tumor, V ventricle, IW normalappearing inner wall of ventricle. Scale bar, 50 μm
tumor area. Immunohistochemically, the tumor cells were negative or weakly positive for p53. Although the number of mitotic figures was smaller than the inclusion criteria by Rodriguez et al. (4 mitoses/10 HPF) [13], the high MIB-1 index and presence of pseudopalisading necrosis are consistent with the diagnosis of PA with anaplastic features.
Discussion As long as we reviewed the literature, there were no firm histological criteria for a diagnosis of anaplastic PA or PA with anaplastic features. In most papers, histological features of anaplastic PAs were characterized by increased cellularity, multiple mitoses, pseudopalisading necrosis, and endothelial cell proliferation in addition to typical findings such as eosinophilic granular bodies and Rosenthal fibers [1, 9, 10, 13, 18, 19]. Genetic
alterations, such as BRAF, RAF1, and NF1 gene, which may be involved in the development of PAs have also been recently investigated by genomic studies [14]. Several oncogenic mechanisms of PAs that activate the Ras/ RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway have been demonstrated [14]. As a key player in activating this cascade in PA, tandem duplication of BRAF at 7q34 is the most common alteration (occurring in 53–73 % of PAs) and produces various KIAA1549-BRAF exon fusions [14]. However, there are conflicting reports about correlation of the KIAA1549-BRAF fusion with patient’s prognosis [14]. The BRAF rearrangement might not show as strong correlation as other prognostic markers for the clinical outcome of PAs. A lot of papers have reported that there are not still more reliable predictive factors for clinical aggressiveness of PAs than histological findings [4, 7, 8, 12, 14, 17]. In the present case, nuclear atypia, increased MIB-1 labeling index, marked necrosis with
170
Fig. 3 Histological findings of the resected tumor. Astrocytic bipolar or multipolar cells proliferate forming compact areas (a) and loose areas (b). Eosinophilic granular bodies are frequently observed (b, arrows). Hypercellular areas with hyperchromatic enlarged nuclei (c) and multinuclear giant cells (d, arrows) are seen. Mitotic figures (e, arrow) and increased MIB-1 labeling index (f) are observed. Tumor necrosis (asterisk) with focal pseudopalisading (arrows) is prominent (g). Endothelial proliferation with enlargement of endothelial cells is also seen (h). a–e, g, h Hematoxylin-eosin stain. f Immunostain for Ki-67 (MIB-1). a– d, f Magnification ×20. e Magnification ×40. g, h Magnification ×10
focal pseudopalisading, and endothelial proliferation were remarkably seen. The number of mitotic figures (2 mitoses/10 HPF) was smaller than the inclusion criteria by Rodriguez et al. (4 mitoses/10 HPF) [13]; however, some reports of anaplastic PA did not always meet the criteria [1, 18]. On the other hand, mitotic figures in the conventional PA were reported to be much rarer (1–2 mitoses/50 HPF) [15]. Taken together,
Childs Nerv Syst (2015) 31:167–171
these histological findings of the present case were not compatible with ordinary PA, suggesting that this tumor should be classified as an anaplastic PA. Regarding the outcome of anaplastic PAs, Rodriguez et al. demonstrated that median overall and progressionfree survivals in anaplastic PAs were 24 and 14 months, respectively [13]. Overall and progression-free survivals were shorter in the cases of prior radiation for a PA precursor, increasing mitotic activity, and presence of necrosis after adjusting for age and site. They also reported that the overall survival of anaplastic PAs without necrosis was close to grade II astrocytomas, and that of anaplastic PAs with necrosis was close to grade III astrocytomas. Bowers et al. reported that an MIB-1 index over 2.0 was associated with an increased frequency of tumor progression among children with PAs [2]. In many reported cases, adjuvant therapies were often applied as postoperative treatments for anaplastic PAs [3, 9, 13, 16]. Unlike our case, typical clinical features of anaplastic PAs are adult age (a median age of 26–35 years) and malignant transformation, according to previous reports [1, 18, 19]. Although it might be interesting to investigate the relationship between these factors (patient’s age and onset type) and the prognosis, further collection of case series is needed, because anaplastic PAs are very rare and poorly understood. The outcome of present case was assumed to be corresponding to a malignant glioma from the MRS findings and the aggressive pathological features. During an operation, the tumor component invading into the inner wall of a lateral ventricle was intentionally left. Although some papers recommended the adjuvant therapies for the aggressive histology, we experienced a successful long-term management without any adjuvant therapies in a rare case of primary anaplastic PA. This experience might highlight variable biological behavior of anaplastic PAs. We think that careful managements including wait-and-scan should be considered especially in a child-onset case of primary anaplastic PA, because adjuvant therapies may cause child’s growth disorder and malignant transformation including secondary anaplastic PAs.
Conclusion PAs could exhibit variable behavior. The predictive factors for aggressive PAs remain unclear. Even if the malignant biological features are suspected from MRS and histological findings, careful managements including wait-and-scan are recommended, because there are pediatric-specific problems in the postoperative management.
Childs Nerv Syst (2015) 31:167–171 Acknowledgments We are very grateful to Yoichi Nakazato of the Department of Human Pathology, Gunma University Graduate School of Medicine for his comment on the pathological findings. We also thank Tokuhiro Kimura and Eiji Ikeda of the Department of Pathology, Keio University School of Medicine (present institution; Department of Pathology, Yamaguchi University Graduate School of Medicine), for the pathological diagnosis.
171
9.
10.
Conflict of interest The authors declare no conflicts of interest. 11.
References 12. 1. Azad A, Deb S, Cher L (2009) Primary anaplastic pilocytic astrocytoma. J Clin Neurosci Off J Neurosurg Soc Australas 16(12): 1704–1706. doi:10.1016/j.jocn.2009.04.012 2. Bowers DC, Gargan L, Kapur P, Reisch JS, Mulne AF, Shapiro KN, Elterman RD, Winick NJ, Margraf LR (2003) Study of the MIB-1 labeling index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents. J Clin Oncol Off J Am Soc Clin Oncol 21(15):2968–2973. doi:10.1200/jco.2003.01.017 3. Ellis JA, Waziri A, Balmaceda C, Canoll P, Bruce JN, Sisti MB (2009) Rapid recurrence and malignant transformation of pilocytic astrocytoma in adult patients. J Neuro-Oncol 95(3):377–382. doi:10. 1007/s11060-009-9935-z 4. Hawkins C, Walker E, Mohamed N, Zhang C, Jacob K, Shirinian M, Alon N, Kahn D, Fried I, Scheinemann K, Tsangaris E, Dirks P, Tressler R, Bouffet E, Jabado N, Tabori U (2011) BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res Off J Am Assoc Cancer Res 17(14):4790– 4798. doi:10.1158/1078-0432.ccr-11-0034 5. Horbinski C, Hamilton RL, Nikiforov Y, Pollack IF (2010) Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol 119(5): 641–649. doi:10.1007/s00401-009-0634-9 6. Hsieh MS, Ho JT, Lin LW, Tu PH, Perry A, Huang AP (2012) Cerebellar anaplastic pilocytic astrocytoma in a patient of neurofibromatosis type-1: case report and review of the literature. Clin Neurol Neurosurg 114(7):1027–1029. doi:10.1016/j.clineuro.2012.01.034 7. Jeuken JW, Wesseling P (2010) MAPK pathway activation through BRAF gene fusion in pilocytic astrocytomas; a novel oncogenic fusion gene with diagnostic, prognostic, and therapeutic potential. J Pathol 222(4):324–328. doi:10.1002/path.2780 8. Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic
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astrocytomas. Cancer Res 68(21):8673–8677. doi:10.1158/00085472.can-08-2097 Krieger MD, Gonzalez-Gomez I, Levy ML, McComb JG (1997) Recurrence patterns and anaplastic change in a longterm study of pilocytic astrocytomas. Pediatr Neurosurg 27(1): 1–11 Otero-Rodriguez A, Sarabia-Herrero R, Garcia-Tejeiro M, ZamoraMartinez T (2010) Spontaneous malignant transformation of a supratentorial pilocytic astrocytoma. Neurocirugia (Asturias, Spain) 21(3):245–252 Peters KB, Cummings TJ, Gururangan S (2011) Transformation of juvenile pilocytic astrocytoma to anaplastic pilocytic astrocytoma in patients with neurofibromatosis type I. J Pediatr Hematol Oncol 33(5):e198–e201. doi:10.1097/MPH.0b013e318205e230 Rodriguez EF, Scheithauer BW, Giannini C, Rynearson A, Cen L, Hoesley B, Gilmer-Flynn H, Sarkaria JN, Jenkins S, Long J, Rodriguez FJ (2011) PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma. Acta Neuropathol 121(3):407–420. doi:10. 1007/s00401-010-0784-9 Rodriguez FJ, Scheithauer BW, Burger PC, Jenkins S, Giannini C (2010) Anaplasia in pilocytic astrocytoma predicts aggressive behavior. Am J Surg Pathol 34(2):147–160. doi:10.1097/PAS. 0b013e3181c75238 Sadighi Z, Slopis J (2013) Pilocytic astrocytoma: a disease with evolving molecular heterogeneity. J Child Neurol 28(5):625–632. doi:10.1177/0883073813476141 Scheithauer BW, Hawkins C, Tihan T, VandenBerg SR, Burger PC (2007) World Health Organization classification of tumours of the central nervous system, 4th edn. International Agency for Research on Cancer, Lyon Stuer C, Vilz B, Majores M, Becker A, Schramm J, Simon M (2007) Frequent recurrence and progression in pilocytic astrocytoma in adults. Cancer 110(12):2799–2808. doi:10.1002/cncr.23148 Tian Y, Rich BE, Vena N, Craig JM, Macconaill LE, Rajaram V, Goldman S, Taha H, Mahmoud M, Ozek M, Sav A, Longtine JA, Lindeman NI, Garraway LA, Ligon AH, Stiles CD, Santagata S, Chan JA, Kieran MW, Ligon KL (2011) Detection of KIAA1549BRAF fusion transcripts in formalin-fixed paraffin-embedded pediatric low-grade gliomas. J Mol Diagn JMD 13(6):669–677. doi:10. 1016/j.jmoldx.2011.07.002 Tsuda K, Ishikawa E, Saito A, Satomi K, Sakata A, Takano S, Morishita Y, Noguchi M, Matsumura A (2011) Primary cerebellar pilocytic astrocytoma with anaplastic features in a patient with neurofibromatosis type 1—case report. Neurol Med Chir 51(4):315–318 Yong EX, McKelvie P, Murphy M, Wang YY (2014) Anaplastic pilocytic astrocytoma. J Clin Neurosci Off J Neurosurg Soc Australas. doi:10.1016/j.jocn.2014.02.014
CASE REPORT
Pilocytic astrocytoma with anaplastic features presenting good long-term clinical course after surgery alone: a case report Katsuya Saito & Masahiro Toda & Kazunari Yoshida
Received: 28 June 2014 / Accepted: 22 July 2014 / Published online: 7 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Introduction
Abstract Purpose Pilocytic astrocytomas (PAs) are the most common brain tumor in children and typically have an excellent prognosis. However, some PAs show histologically anaplastic features. It is reported that PAs with anaplastic features often need the postoperative radiation and chemotherapy due to aggressiveness such as early local recurrence and dissemination. We describe an interesting case of primary anaplastic PA with good clinical course in the long-term. Methods A 10-year-old man presented with worsening headache and vomiting. Magnetic resonance imaging (MRI) showed a large cystic tumor with contrast-enhanced solid component in a right occipital lobe. Magnetic resonance spectroscopy (MRS) showed the decrease of N-acetylaspartate (NAA) and the increase of choline and lipids, which suggested the malignancy. Results The patient was operated with an occipital lobectomy. The tumor was incompletely resected due to the deep invasion to the inner wall of lateral ventricle. Pathological diagnosis was a pilocystic astrocytoma with anaplastic features. Although aggressive features were suspected from magnetic resonance spectroscopy and pathological findings, the remnant tumor showed no recurrence for 8 years without any postoperative treatments. Conclusion PAs could exhibit variable behavior, and careful managements including wait-and-scan should be considered, because adjuvant therapies may cause child’s growth disorder and malignant transformation.
Pilocytic astrocytoma (PA) is the most common brain tumor in children. PAs are classified by the World Health Organization (WHO) as grade I tumors, which typically have an excellent prognosis [15]. Proliferative activity is generally low with MIB-1 labeling index ranging from 0 to 3.9 % [10]. However, it was reported that some PAs show clinically aggressive features exceptionally [1, 3, 6, 9–11, 13, 18, 19]. Although the predictive factors for PAs with aggressive features remain controversial, most papers reported that histological anaplasia was one of the comparatively reliable findings [5, 10, 12, 13]. PAs with anaplastic features or anaplastic PAs were seen in 2 to 5 % of PA cases [18]. The clinical outcomes of anaplastic PAs were reported to be corresponding to WHO grade II or III gliomas [12, 13, 16, 18], and therefore, some articles suggested that anaplastic PAs needed the postoperative radiation and chemotherapy due to aggressiveness such as early local recurrence and dissemination [1, 16, 19]. Most of anaplastic PAs have been reported to occur as a secondary transformation from ordinary PAs with exposure to ionizing radiation [3, 9, 13, 16, 19]. The present case was, however, a primary case of anaplastic PA. The primary anaplastic PAs have ever been rarely reported [1, 10, 18]. Here, we report a rare and successful case of primary anaplastic PA with good long-term outcome despite of no adjuvant therapy.
Keywords Pilocystic astrocytoma . Anaplastic feature . Anaplastic pilocystic astrocytoma . Long-term outcome
Case report
K. Saito (*) : M. Toda : K. Yoshida Department of Neurosurgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan e-mail: [email protected]
A 10-year-old man presented with worsening headache and vomiting, and he was referred to our hospital. He did not have any past history and any family history associated with neurofibromatosis type 1 (NF1). Visual
168
test showed severe papilledema and left homonymous hemianopia. Magnetic resonance imaging (MRI) showed a large cystic tumor with contrast-enhanced solid component in a right occipital lobe (Fig. 1a–d). In addition, the tumor invasion into a right lateral ventricle was suspected (Fig. 1e). Magnetic resonance spectroscopy (MRS) showed the decrease of N-acetylaspartate (NAA) and the increase of choline and lipids, which suggested the malignancy (Fig. 1f–g). Angiography showed no tumor stain. The patient was operated with an occipital lobectomy. Intraoperative findings showed that the well-vascularized tumor deeply invaded the inner wall of the right lateral ventricle (Fig. 2a–b). Although the tumor was grossly resected, we left the only tumor component invading the ventricular wall due to invasive and easy-bleeding nature of the tumor. The postoperative course was uneventful. Postoperative MRI in 1 month showed no solid mass with contrast enhancement (Fig. 2c–e), although a small part of tumor was left during an operation. Wait-and-scan management every 6 months was performed for the residual tumor without any adjuvant therapies, because he was a child.
Fig. 1 Preoperative MRI, showing a heterogeneously enhanced solid mass with cystic components in the right occipital lobe. Tumor size was 10×6× 6 cm. a Axial section on T2weighted image. b–d Axial, sagittal, and coronal sections on contrast-enhanced T1-weighted image. Tumor invasion to a right lateral ventricle was suspected (e). MRS, showing the malignant features. MRS showed the decrease of NAA (2 ppm) and the increase of choline (3.2 ppm) and lipids (0–2 ppm) in the tumor area (f), compared with the contralateral non-tumor area (g)
Childs Nerv Syst (2015) 31:167–171
Although 8 years have passed, follow-up MRI showed no recurrence (Fig. 2f–h).
Pathological findings In the present case, three neuropathologists (two pathologists of our institution and one pathologist of the external institution) were involved in the pathological diagnosis. As shown in Fig. 3a–h, histological examination of the resected specimen revealed proliferation of bipolar or multipolar astrocytic cells showing a biphasic pattern of compact (Fig. 3a) and loose (Fig. 3b) areas. Eosinophilic granular bodies (Fig. 3b) and Rosenthal fibers were present. In addition, atypical findings were observed: hypercellular areas with hyperchromatic, enlarged nuclei and multinuclear giant cells (Fig. 3c–d), mitotic figures (2 mitoses/10 high-power fields [HPF], Fig. 3e), high MIB-1 labeling index (8.5 %, Fig. 3f), necrosis with focal pseudopalisading (Fig. 3g), and endothelial proliferation (Fig. 3h). Necrosis was particularly prominent, and necrotic area occupied approximately 25 % of the
Childs Nerv Syst (2015) 31:167–171
169
Fig. 2 Intraoperative photographs and postoperative MRI findings. Intraoperative views, showing tumor invasion into the ventricular wall. While resecting the deep margin of tumor, a lateral ventricle got opened (a). At the intraventricular space, the vascularized tumor-like lesion invading the inner wall of lateral ventricle was observed (b). By the intraoperative pathology consultation, biopsy specimen of this lesion was identified to be the tumorous tissue. Axial (c), sagittal (d), and coronal (e) sections of contrast-enhanced T1-weighted MRI 1 month after the operation, showing no solid mass with contrast enhancement. Axial (f), sagittal (g), and coronal (h) sections of contrast-enhanced T1weighted MRI 8 years after the operation, showing no recurrence. Tu tumor, V ventricle, IW normalappearing inner wall of ventricle. Scale bar, 50 μm
tumor area. Immunohistochemically, the tumor cells were negative or weakly positive for p53. Although the number of mitotic figures was smaller than the inclusion criteria by Rodriguez et al. (4 mitoses/10 HPF) [13], the high MIB-1 index and presence of pseudopalisading necrosis are consistent with the diagnosis of PA with anaplastic features.
Discussion As long as we reviewed the literature, there were no firm histological criteria for a diagnosis of anaplastic PA or PA with anaplastic features. In most papers, histological features of anaplastic PAs were characterized by increased cellularity, multiple mitoses, pseudopalisading necrosis, and endothelial cell proliferation in addition to typical findings such as eosinophilic granular bodies and Rosenthal fibers [1, 9, 10, 13, 18, 19]. Genetic
alterations, such as BRAF, RAF1, and NF1 gene, which may be involved in the development of PAs have also been recently investigated by genomic studies [14]. Several oncogenic mechanisms of PAs that activate the Ras/ RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway have been demonstrated [14]. As a key player in activating this cascade in PA, tandem duplication of BRAF at 7q34 is the most common alteration (occurring in 53–73 % of PAs) and produces various KIAA1549-BRAF exon fusions [14]. However, there are conflicting reports about correlation of the KIAA1549-BRAF fusion with patient’s prognosis [14]. The BRAF rearrangement might not show as strong correlation as other prognostic markers for the clinical outcome of PAs. A lot of papers have reported that there are not still more reliable predictive factors for clinical aggressiveness of PAs than histological findings [4, 7, 8, 12, 14, 17]. In the present case, nuclear atypia, increased MIB-1 labeling index, marked necrosis with
170
Fig. 3 Histological findings of the resected tumor. Astrocytic bipolar or multipolar cells proliferate forming compact areas (a) and loose areas (b). Eosinophilic granular bodies are frequently observed (b, arrows). Hypercellular areas with hyperchromatic enlarged nuclei (c) and multinuclear giant cells (d, arrows) are seen. Mitotic figures (e, arrow) and increased MIB-1 labeling index (f) are observed. Tumor necrosis (asterisk) with focal pseudopalisading (arrows) is prominent (g). Endothelial proliferation with enlargement of endothelial cells is also seen (h). a–e, g, h Hematoxylin-eosin stain. f Immunostain for Ki-67 (MIB-1). a– d, f Magnification ×20. e Magnification ×40. g, h Magnification ×10
focal pseudopalisading, and endothelial proliferation were remarkably seen. The number of mitotic figures (2 mitoses/10 HPF) was smaller than the inclusion criteria by Rodriguez et al. (4 mitoses/10 HPF) [13]; however, some reports of anaplastic PA did not always meet the criteria [1, 18]. On the other hand, mitotic figures in the conventional PA were reported to be much rarer (1–2 mitoses/50 HPF) [15]. Taken together,
Childs Nerv Syst (2015) 31:167–171
these histological findings of the present case were not compatible with ordinary PA, suggesting that this tumor should be classified as an anaplastic PA. Regarding the outcome of anaplastic PAs, Rodriguez et al. demonstrated that median overall and progressionfree survivals in anaplastic PAs were 24 and 14 months, respectively [13]. Overall and progression-free survivals were shorter in the cases of prior radiation for a PA precursor, increasing mitotic activity, and presence of necrosis after adjusting for age and site. They also reported that the overall survival of anaplastic PAs without necrosis was close to grade II astrocytomas, and that of anaplastic PAs with necrosis was close to grade III astrocytomas. Bowers et al. reported that an MIB-1 index over 2.0 was associated with an increased frequency of tumor progression among children with PAs [2]. In many reported cases, adjuvant therapies were often applied as postoperative treatments for anaplastic PAs [3, 9, 13, 16]. Unlike our case, typical clinical features of anaplastic PAs are adult age (a median age of 26–35 years) and malignant transformation, according to previous reports [1, 18, 19]. Although it might be interesting to investigate the relationship between these factors (patient’s age and onset type) and the prognosis, further collection of case series is needed, because anaplastic PAs are very rare and poorly understood. The outcome of present case was assumed to be corresponding to a malignant glioma from the MRS findings and the aggressive pathological features. During an operation, the tumor component invading into the inner wall of a lateral ventricle was intentionally left. Although some papers recommended the adjuvant therapies for the aggressive histology, we experienced a successful long-term management without any adjuvant therapies in a rare case of primary anaplastic PA. This experience might highlight variable biological behavior of anaplastic PAs. We think that careful managements including wait-and-scan should be considered especially in a child-onset case of primary anaplastic PA, because adjuvant therapies may cause child’s growth disorder and malignant transformation including secondary anaplastic PAs.
Conclusion PAs could exhibit variable behavior. The predictive factors for aggressive PAs remain unclear. Even if the malignant biological features are suspected from MRS and histological findings, careful managements including wait-and-scan are recommended, because there are pediatric-specific problems in the postoperative management.
Childs Nerv Syst (2015) 31:167–171 Acknowledgments We are very grateful to Yoichi Nakazato of the Department of Human Pathology, Gunma University Graduate School of Medicine for his comment on the pathological findings. We also thank Tokuhiro Kimura and Eiji Ikeda of the Department of Pathology, Keio University School of Medicine (present institution; Department of Pathology, Yamaguchi University Graduate School of Medicine), for the pathological diagnosis.
171
9.
10.
Conflict of interest The authors declare no conflicts of interest. 11.
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