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| Year : 2014 | Volume
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| Issue : 4 | Page : 542-548 |
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| Histomorphological spectrum and immunohistochemical characterization of hemangioblastomas: An entity of unclear histogenesis
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Sridhar Epari1, Rohini Bhatkar1, Aliasgar Moyaidi2, Prakash Shetty2, Tejpal Gupta3, Subhada Kane1, Rakesh Jalali3
1 Department of Pathology, Tata Memorial Hospital and ACTREC, Mumbai, Maharashtra, India
2 Department of Surgical Oncology, Tata Memorial Hospital and ACTREC, Mumbai, Maharashtra, India
3 Department of Radiation Oncology, Tata Memorial Hospital and ACTREC, Mumbai, Maharashtra, India
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| Date of Web Publication | 11-Oct-2014 |
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 Abstract | | |
Introduction: Hemangioblastomas (HBs) are rare WHO grade I neoplasms of uncertain histogenesis. Most are sporadic and association with von Hippel-Lindau disease (VHL) is uncommon. Materials and Methods: Histomorphological and immunohistochemical evaluation of 24 cases of HBs was done. Results: Age range was 15-68 yrs (median: 30 yrs) with male:Female of 1.2:1 (M-13; F-11). Cerebellum was commonest location (n = 20), one each was seen in brain stem, cervical spinal cord, fourth ventricle and frontal lobe, respectively. VHL association was noted in 5 cases. Four cases were recurrent in nature of which 3 were in association with vHL. Histologically, reticular variant was the predominant subtype (n = 15), 5 were of cellular variant and 4 were mixed. Nuclear pleomorphism, nuclear cytoplasmic inclusions, cytoplasmic vacuolation were noted in the stromal cells in varying proportions. Immunohistochemical evaluation was successful in only 11 cases and of which 8 showed stromal cell positivity for alpha-inhibin. CD56 (NCAM), Nestin and synaptophysin positivity was seen in 6, 7 and 4 cases, respectively. Nestin positivity was noted in stromal cells only and no reactivity with the endothelial cells seen. S-100 protein and NSE positivity was seen in 8 and 10 cases, respectively. Glial fibrillary acidic protein (GFAP) showed two distinct patterns of immunoreactivity - scattered stromal cell positivity (n:5) and pattern of reactive astrogliosis positivity (n:10). CD44 positivity was noted in 5 cases. VEGF and EGFR positivity was seen in 5 cases each. None of the cases showed positivity for epithelial membrane antigen and no stromal cells in any of the cases showed positivity for CD34 and CD31. Conclusion: HBs can occur in throughout the neuroaxis. Cerebellum is the commonest site of occurrence for HBs and uncommonly can occur in the supratentorial compartment and spinal cord. Its association with vHL is uncommon and no histological or immunohistochemical correlation was identified with the same. Keywords: Hemangioblastoma, immunohistochemistry, von Hippel-Lindau disease
How to cite this article:
Epari S, Bhatkar R, Moyaidi A, Shetty P, Gupta T, Kane S, Jalali R. Histomorphological spectrum and immunohistochemical characterization of hemangioblastomas: An entity of unclear histogenesis
. Indian J Pathol Microbiol 2014;57:542-8 |
How to cite this URL:
Epari S, Bhatkar R, Moyaidi A, Shetty P, Gupta T, Kane S, Jalali R. Histomorphological spectrum and immunohistochemical characterization of hemangioblastomas: An entity of unclear histogenesis
. Indian J Pathol Microbiol [serial online] 2014 [cited 2023 Nov 30];57:542-8. Available from: https://www.ijpmonline.org/text.asp?2014/57/4/542/142645 |
| Introduction | |  |
The term 'hemangioblastoma' (HB) was introduced by Cushing and Bailey in 1928, occurs in the central nervous system (CNS) and represents 1.5-2.5% of all the intracranial neoplasms. [1],[2] As per the current WHO CNS tumors classification, it is a grade I tumor. They are usually infratentorial; cerebellum around the fourth ventricle is the commonest site of occurrence and supratentorial location is lesser common. Other very rare extracerebellar sites of occurrence include spinal cord (more commonly medulla, spinal roots including cauda equina), brain stem, optic nerve, retina and craniospinal meninges. [3],[4],[5],[6],[7] HBs may be associated with von Hippel-Lindau (VHL) disease, which is an autosomal dominant disease.
Histologically, HBs are characterized by rich vascularity, typically consisting of capillary-sized blood vessels separated by intervascular stromal cells (SCs). These tumors are still regarded as 'neoplasms of uncertain histogenesis. Though the histological origin of the SCs is not yet fully characterized but has been shown to be the neoplastic cells. Moreover, it has been now shown that tumorigenesis of HBs depends on mutational inactivation of VHL tumor suppressor gene. [8] Few studies even suggested VHL gene regulation of tumor angiogenesis by negative regulation of vascular endothelial growth factor (VEGF) expression. [9],[10],[11]
In this study, we studied cases of HBs, in which an attempt to characterize SCs and to identify its differentiation was made by immunohistochemical evaluation for different markers of glial, neuroepithelial and neuronal differentiation. These cases were also analyzed for the expression of VEGF and EGFR as an exploration of possible tumorigenetic pathways. In addition, immunohistochemical expression of alpha-inhibin in HBs was also evaluated to substantiate its diagnostic efficacy, as reported earlier. [12]
| Materials and methods | | |
Cases
All the diagnosed cases were retrieved from the pathology departmental archival files of the years 2006 to 2012. They were reviewed and the cases where diagnosis was reconfirmed were included in the study sample. Clinicoradiological features of age, sex, location, association with vHL syndrome and radiological findings were noted.
Histology
A detailed evaluation of histological features was done on hematoxylin and eosin (HandE) stained sections and wherever possible, reticulin-stained sections were also included. The cases were subtyped into cellular, reticular and mixed histological types, based on the criteria described by Cushing and Bailey.
- Cellular: Predominant architecture of clustering of tumor cells, substantiated by poor reticulin.
- Reticular: No clustering or lobular architecture of the neoplastic stromal cells.
- Mixed: Predominant reticular architecture with presence of lesser (of any amount) areas of lobular architecture.
Immunohistochemical evaluation
Done on the sections from the whole paraffin blocks of HBs (n = 12). For antigen retrieval for different antibodies and their dilution folds used in the present study are listed in [Table 1]. Endogenous peroxidase activity was blocked by 3% hydrogen peroxidase followed by incubation with primary antibodies at 37 ° C for 1 hour. The sections were incubated with horseradish-peroxidase (HRP)-conjugated anti-mouse/rabbit IgG (MACH2 universal HRP polymer detection kit, Biocare) at 37 ° C for 30 minutes. The antigen-antibody complex was finally visualized using diaminobenzidine tetrahydrochloride (Sigma, St. Louis, MO, USA) and then counterstained with Meyer's hematoxylin. Rigorous washing three times with tris-buffered saline (TBS) supplemented with 0.01% Tween 20 accomplished between each step. | Table 1: Details of the antibodies used in this study and other corresponding technical details for immunohistochemistry procedure
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Clinical History (see [Table 2])
Immunohistological evaluation was done for alpha-inhibin, CD44, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) and to characterize the differentiation of stromal cells: Neuronal differentiation (neuron specific enolase, synaptophysin), neuroepithelial differentiation (S-100 protein, nestin, GFAP and CD56). Additionally, it has been done for cytokeratin, epithelial membrane antigen, CD31 and, CD34 was done to rule out the histological mimics. Immunoreactivity in more than 10% of tumor cells was considered as positive.
| Results | | |
Cases
A total of 24 reviewed and reconfirmed cases were included in the study. Four of which were in-house operated and the rest of them were referral. 12 cases had paraffin blocks, of which one did not reveal satisfactory immunohistochemical results. Clinico-radiological findings were available for 12 cases.
Histological Features (see [Table 3])
The age range was 15-68 yrs (median: 30 yrs) with sex ratio of Male:Female of 1.2:1 (M-13; F-11). Most common location was posterior fossa with cerebellum (n = 20) being the commonest site. One case each was seen in brain stem, cervical spinal cord, fourth ventricle and frontal lobe of cerebral hemisphere. von Hippel-Lindau (vHL) disease association was noted in 5 cases and rest of them appeared to be of sporadic nature. The commonest presenting symptoms were headache, vomiting, ataxia and diplopia, probable due to the predominant number of cases in the posterior fossa. Radiological data was available in 12 cases and all (including those located in frontal lobe and spinal cord ones) showed similar features of predominant cystic with contrast enhancing nodule [Figure 1]. Four cases were recurrent in nature of which 3 were in association with vHL and one is sporadic (see [Table 2]). | Figure 1: Magnetic resonance imaging (MRI) spectrum of hemangioblastomas. A&B: Sagittal T1-weighted post-contrast (a) and axial T2-weighted (b) MRI images of patient no. 7, respectively; C&D: Axial (c) and sagittal (d) T1-weighted post-contrast MRI images of patient no. 11, respectively; E&F: Axial T1-weighted post-contrast (e) and sagittal T2-weighted (f) MRI images of patient no. 19 respectively; G&H: Sagittal spine T1-weighted post-contrast (g) and sagittal T2- weighted (h) MRI images of a cervical spinal cord hemangioblastoma patient no. 10, respectively
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Histological feature
All cases showed rich dense capillary network interspersed with occasional medium-sized feeder-like blood vessels and intervascular stromal cells. They were subtyped into cellular, reticular and mixed histological variants (as per the criteria described in the materials and methods). The reticular (R) variant [Figure 2] was the commonest and was seen in 15 cases (15/24; 62.5%), cellular (C) variant [Figure 3] and mixed (M) variants [Figure 4] were 5 and 4 cases, respectively. The stromal cells were heterogeneous in cytomorphology with admixture of different forms in each case. The stromal cells, which showed moderate to abundant cytoplasm with polygonal shape were designated as epithelioid and predominance of these cells was noted in 17 cases (17/24; 71%); the predominant stromal cells in the rest of the cases showed indistinct cytoplasm and were designated as non-epithelioid (7/24; 29%). Cytoplasmic micro- and macro-vacuolation (in respect to the sized of the nuclei) in the stromal cells [Figure 5] a and b was noted in most of the cases with epithelioid cytomorphology (n: 15/18; micro: 13; macro: 2). Non-vacuolated stromal cells showed either pale to clear or eosinophilic cytoplasm [Figure 5] c and d. Scattered bizarre large pleomorphic cells with smudgy degenerated chromatin [Figure 5] e and f] (n:4; R:7/15;M:3/4;C:4/5) and intranuclear inclusions (n:8; R:3/15;M:3/4;C:2/5) were also noted [Figure 5] h]. Singly scattered intralesional mast cells (as identified on Giemsa-stained sections and/or on immunohistochemistry for CD117) were noted commonly (n: 10/12). Interestingly, in two of the cases, intracytoplasmic inclusion-like eosinophilic bodies were seen in the stromal cells [Figure 5]g. The vascular spaces were predominantly of capillary size with occasional presence of feeder-like medium-sized blood vessels in few cases. Lymphangiectasia-like areas were also seen focally in 4 cases [Figure 6]a and b. Myointimal hyperplasia of these medium-sized blood vessels was noted in two cases [Figure 6]c. Extramedullary hematopoiesis was identified in only one case [Figure 6]d. | Figure 2: (a: HE stain ×50; b: HE stain ×100) Representative histophotomicrographs of reticular variant (n = 15), where the stromal cells are seen investing by thin-walled capillary-like vessels (at places dilated), mimicking a capillary hemangioma-like. Inset (c: reticulin stain ×200) is a photomicrograph of reticulin stain with pericellular
pattern of reticulin
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 | Figure 3: (a: HE ×50; b: HE ×100) Representative histophotomicrographs of cellular variant (n = 5), where the stromal cells are seen in lobules, separated by with thin-walled capillary-like vessels, exhibiting a nesting/organoid architecture. Inset (c: reticulin stain ×200) is a photomicrograph of reticulin stain with areas of poor reticulin network
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 | Figure 4: (a: HE ×50; b: HE ×100) Representative histophotomicrographs of mixed variant (n = 4), where areas of both reticular and cellular variants seen. The area marked with ¤ (area delineated by intact black lines) represents reticular variant and the areas represented by blue dotted lines are of cellular variant. Inset (c: reticulin stain ×200) is a photomicrograph of reticulin stain depicts retic poor and rich areas
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 | Figure 5: (HE ×400). Histological spectrum of changes noted within the stromal cells; micro (a) and acrovacuolation (d), abundant pale (c) and eosinophilic cytoplasm (d), nuclear pleomorphism with smudgy chromatin (e, including the inset ei), binucleation (f), cytoplasmic eosinophilic inclusions (g) and nuclear cytoplasmic inclusions (hi-iv)
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 | Figure 6: a & b (HE ×50) Histophotomicrographs showing focal lymphectasia-like areas (n = 4). c (HE ×200) showing myointimal hyperplasia of occasional intralesional medium-sized blood vessel (n = 2) and d (HE ×400) showing an occasional foci of extramedullary hematopoiesis composed of nucleated RBCs in one of the case
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Immunohistochemical Findings (see [Table 4])
Immunohistochemical evaluation was done in 12 cases and it was unsatisfactory in one (possibly due to poor preservation of tissue) and thus results could be achieved in 11 cases only. 8 cases showed diffuse cytoplasmic positivity for alpha-inhibin (R:4/6;M:2/3;C:2/2) [Figure 7]a and no predilection for any particular histological subtype noted. CD56 (NCAM), Nestin and synaptophysin positivity was seen in 6 (R:3/6;M:2/3;C:1/2), 7 (R:3/6;M:2/3;C:2/2) and 4 (R:2/6;M:1/3;C:1/2) cases, respectively [Figure 7]b-d. Nestin positivity was noted in stroma cells only and no reactivity with the endothelial cells seen. S-100 protein and NSE positivity was seen in 8 (R:4/6;M:3/3;C:2/2) and 10 cases (R:5/6;M:3/3;C:2/2), respectively [Figure 7]e,f. Glial fibrillary acidic protein (GFAP) showed two distinct patterns of immunoreactivity - scattered stromal cell positivity [Figure 7]i (n:5; R:1/6;M:2/3;C:2/2) and pattern of reactive astrogliosis positivity [Figure 7] J, Ji, Jii] (n:10; R:5/6;M:3/3;C:2/2) cases. VEGF and EGFR positivity was seen in 5 cases each ([Figure 7] g and k, respectively). CD44 positivity was noted in 5 cases (R:2/6; M:1/3; C:2/2) [Figure 7]l. No stromal cells in any of the cases showed positivity for epithelial membrane antigen (EMA), CD34 and CD31 (however the endothelial cells were highlighted by CD34 [Figure 7] h] and CD31). | Figure 7: (IHC-stromal cells). Positivity for alpha-inhibin (a ×400; Ai-focal positivity), CD56 (b ×400), nestin (c ×400), synaptophysin (d ×400), S-100 protein (e ×400), NSE (f ×200), VEGF (g ×400) and GFAP (i ×400). CD34 highlights the endothelial cells while stromal cells were negative (h ×200). Reactive astrogliosis pattern of positivity for GFAP (j ×100, ji ×100 & jii ×400). Positivity for EGFR (k ×200; inset [ki] represents cytoplasmic granular pattern with membrane accentuation seen in one of the case) and CD44 (L ×200)
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| Discussion | | |
HBs are WHO grade I CNS tumors with rich capillary network and vacuolated stromal cells. In the present study, it was seen throughout the neuroaxis, with cerebellum (82%) being the commonest site; other sites were fourth ventricle (4%), spinal cord (4%), brain stem (4%) and frontal lobe (4%). The distribution of the location and their percentage is in congruence with the review reported by Acikalin et al. [4] In the present series of 24 cases, only 5 had been shown to be associated with vHL, and the sporadic occurrence was more frequent than the syndromic association. 4 cases had recurrence and were more frequently seen in cases associated with vHL than the sporadic ones (though the number of cases are too small to make a conclusion).
Based on the proportion of the clustering of SCs, HBs were classified into three subtypes - reticular (no clustering of SCs), cellular (predominant areas of clustering) and mixed (focal clustering of SCs) and was studied for any clinicopathological correlation. The commonest subtype identified in the study was reticular variant and the histological subtyping did not show any significant correlation with clinical findings of age, sex, location and association with vHL disease. However, the cases with clustering of SCs (cellular and mixed) appear to show more frequency of neuroepithelial and glial differentiation than those which lack the SCs clustering (reticular variants). Though the number of cases are less, but the combined group of cellular and mixed group showed higher incidence of neuroepithelial and glial differentiation (S100 protein positivity: 100% in C and M vs. 50% in R; CD56 (NCAM) positivity: 60% in C and M vs 50% in R; GFAP positivity: 80% in C and M vs. 17% in R; nestin positivity: 80% in C and M vs. 50% in R). These findings were similar to those reported by Hasselblatt et al. [13] No correlation with immunohistochemical expression of alpha-inhibin was identified with any of the subtypes.
Histologically, metastatic renal cell carcinomas (RCCs) are the closest differential and especially in elderly population it sometimes might become difficult to distinguish. Other close differentials (especially in children) are hemangiomas (with reticular variants of HBs) and pilocytic astrocytomas. Few recent studies demonstrated the presence of alpha-inhibin positivity in SCs and reported a good diagnostic immunohistochemical marker to identify HBs, especially when used in a panel of epithelial and glial markers. [12],[14],[15] Thus, immunohistochemistry for alpha-inhibin was studied in this study to see the expression of the same and positivity was noted in 72% (8/11) of the cases with no correlation with any histological subtyping. The frequency of alpha-inhibin positivity in the present study is lesser than that earlier reported frequencies of 100% and 91% by Hoang et al., and Jung et al., respectively. [14],[15]
Nestin is a type VI intermediate filament (IF) protein expressed in dividing cells during the early stages of development in the central nervous system (CNS), peripheral nervous system (PNS) and in myogenic and other tissues. Nestin gets downregulated on differentiation and replaced by tissue-specific intermediate filament proteins. During neurono and gliogenesis, nestin is replaced by cell type-specific intermediate filaments, e.g. neurofilaments and GFAP. Thus, its expression is usually transient and does not persist into adulthood. In normal adults, nestin expression is seen only in neural precursor cells of subgranular zone of hippocampus and subventricular zones. However, reinduction of nestin can occur in pathological states of regeneration or in cases of proliferative tumors. Eichmann et al. additionally demonstrated presence of nestin positivity in proliferating endothelial cells of endometrium and lack of reactivity in normal endothelial cells. [16] Subsequently, nestin immunoreactivity was shown in the proliferating endothelial cells in glial tumors also. [17] Interestingly, the endothelial cells of all HB cases were negative for nestin, suggesting non-proliferating; while the SC positivity suggest a possible precursor neuroepithelial differentiation. [16]
CD44 is an adhesion molecule and its proteins function as molecular switch between cell growth and inhibition of proliferation by interacting with ezrin/radixin/moesin (ERM) and the related merlin proteins. It also plays a role in cell adhesion and motility by interacting with cytoskeleton mediating through ankyrin. In this study, the positivity of stromal cells for CD44 was seen in 45% of the cases, suggesting a distinct signal transduction pathway from the other primary CNS glial and neuronal tumors. Expression two adhesion proteins (CD44 and CD56) coupled with immunoreactivity for GFAP, nestin and S-100 protein demonstrates the complexity of the SCs and possibly suggests an intermediate form between mesenchymal and epithelial cells.
In view of occurrence of HBs in vHL, possible role of VEGF explored in its causation was explored, as few studies had shown negative regulation of VEGF expression by VHL gene. Loss of VHL gene function will cause expression of VEGF, which in turn induces tumor angiogenesis. [18],[19],[20] In this study, expression of VEGF was studied by immunohistochemistry and was seen in approximately 45.4% (5/11), as was noted in few of the earlier studies. [15],[16],[17] Thus, suggesting a possibility of VEGF being, if not the only one, one of the mediators for tumoral angiogenesis and tumorigenesis. Chen et al. suggested involvement of EGFR of receptor tyrosine kinase (RTK) upregulation and signaling pathway in HBs. [21] In the present study, immunohistochemical expression of EGFR was analyzed and seen in 54.5% without any correlation with the histological subtype. EGFR expression in HBs, raises a possibility of tyrosine kinase receptor mediator signal transduction mechanism. Expression of VEGF and EGFR do reemphasize the suggestion by other earlier studies of involvement of these receptors in the pathogenesis of these tumors.
HBs can occur in throughout the neuroaxis. Cerebellum is the commonest site of occurrence for HBs and uncommonly can occur in the supratentorial compartment and spinal cord. Its association with vHL is uncommon and no histological or immunohistochemical correlation was noted. Reticular variant is commonest histological subtype. The present series also highlighted the uncommon occurrence of intracytoplasmic eosinophilic inclusion-like bodies and myointimal hyperplasia, which were never described in these tumors. VEGF is a possible mediator of tumoral angiogenesis and tumorigenesis and expression of EGFR suggests a possibility of receptor tyrosine kinase activity as the signal transduction initiator. Lastly, HBs do have the potential to recur and is more frequent in association with VHL gene than the sporadic cases.
| References | | |
| 1. | Cushing H, Bailey P. Tumours arising from the blood vessels of the brain. Angiomatous malformations and Haemangioblastomas. London: Bailliere. Tindall and Cox; 1928.  |
| 2. | Aldape KD, Plate KH, Vortmeyer AO, Zagzag D, Neumann HPH. Haemangioblastoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of tumours of the Central Nervous System. 4 th Ed. Lyon, France: IARC; 2007. p.184-6. |
| 3. | Kepes JJ, Slowik F. Arvid Lindau's cerebellar hemangioblastoma 70 years later. Some pediatric aspects. Ann N Y Acad Sci 1997;824:112-3. |
| 4. | Aickalin MF, Oner U, Tel N. Supratentorial haemangioblastoma: A case report and review of the literature. Arch Pathol Lab Med 2003;12:e382-4. |
| 5. | Neumann HP, Eggert HR, Weigel K, Friedburg H, Wiestler OD, Schollmeyer P. Hemangioblastomas of the central nervous system. A 10-year study with special reference to von Hippel-Lindau syndrome. J Neurosurg 1989;70:24-30. |
| 6. | Richmond BK, Schmidt JH. Congenital cystic supratentorial hemangioblastoma. Case report. J Neurosurg 1995;82:113-5. |
| 7. | Rubio A, Meyers SP, Powers JM, Nelson CN, de Papp EW. Hemangioblastoma of the optic nerve. Hum Pathol 1994;25:1249-51. |
| 8. | Vortmeyer AO, Gnarra JR, Emmert-Buck MR, Katz D, Linehan WM, Oldfield EH, et al. von Hippel-Lindau gene deletion detected in the stromal cell component of a cerebellar haemangioblastoma associated with von Hippel-Lindau disease. Hum Pathol 1997;28:540-3. |
| 9. | Hussein MR. Central nervous system capillary haemangioblastoma: The pathologist's viewpoint. Int J Exp Pathol 2007;88:311-24. [ PUBMED] |
| 10. | Wykoff CC, Pugh CW, Harris AL, Maxwell PH, Ratcliffe PJ. The HIF pathway: Implications for patterns of gene expression in cancer. Novatis Found Symp 2001;240:212-25. |
| 11. | Hatva E, Böhling T, Jääskeläinen J, Persico MG, Haltia M, Alitalo K. Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol 1996;148:763-75. |
| 12. | Takei H, Bhattacharjee MB, Rivera A, Dancer Y, Powell SZ. New immunohistochemical markers in the evaluation of central nervous system. A review of 7 selected adult and pediatric brain tumours. Arch Pathol Lab Med 2007;131:234-41. |
| 13. | Hasselblatt M, Jeibmann A, Gerss J, Behrens C, Rama B, Wassmann H, et al. Cellular and reticular variants of haemangioblastoma revisited: A clinicopathological study of 88 cases. Neuropathol Appl Neurobiol 2005;31:618-22. |
| 14. | Hoang MP, Amirkhan RH. Inhibin alpha distinguishes hemangioblastoma from clear cell hemangioblastoma from clear cell carcinoma. Am J Surg Pathol 2003;27:1152-6. |
| 15. | Jung SM, Kuo TT. Immunoreactivity for CD10 and Inhibin alpha in differentiating hemangioblastoma of central nervous system from metastatic clear renal cell carcinoma. Mod Pathol 2005;18:788-94. |
| 16. | Eichmann A, Corbel C, Nataf V, Vaigot P, Bréant C, Le Douarin NM. Ligand-dependent development of the endothelial and hemopoietic lineages from embryonic mesodermal cells expressing vascular endothelial growth factor receptor 2. Proc Natl Acad Sci USA 1997;94:5141-6. |
| 17. | Sugawara K, Kurihara H, Negishi M, Saito N, Nakazato Y, Sasaki T, et al. Nestin as a marker for proliferative endothelium in gliomas. Lab Invest 2002;82:345-51. |
| 18. | Stratmann R, Krieg M, Haas R, Plate KH. Putative control of angiogenesis in haemangioblastomas by von Hippel-Lindau tumour supressor gene. J Neuropathol Exp Neurol 1997; 56:1242-52. |
| 19. | Gnarra JR, Zhou S, Merrill MJ, Wagner JR, Krumm A, Papavassiliou E, et al. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumour supressor gene. Proc Natl Acad Sci 1996;93:10589-94. |
| 20. | Krieg M, Marti HH, Plate KH. Coexpression of Erythropoietin and Vascular Endothelial Growth Factor in Nervous system tumours associated with von Hippel- Lindau Tumour suppressor gene loss of function. Blood 1998;92:3388-93. |
| 21. | Chen GJ, Karajannis MA, Newcomb EW, Zagzag D. Overexpression and activation of epidermal growth factor receptor in hemangioblastomas. J Neurooncol 2010;99:195-200. |
Correspondence Address:
Sridhar Epari
Associate Professor and Asst Pathologist, Department of Pathology, ACTREC and Tata Memorial Hospital, Tata Memorial Centre, Mumbai
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0377-4929.142645
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4] |
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