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Hemangioblastoma of the corpus callosum: A case report and review of the literature on its origin
Neurochirurgie 56 (2010) 382–385
Clinical case
Hemangioblastoma of the corpus callosum: A case report and review of the literature on its origin L’hémangioblastome du corps calleux : cas clinique et revue de la littérature sur son origine O. Sacko a,c,∗ , S. Bouillot-Eimer d , M. Sesay b , E. Uro-Coste e , F.-E. Roux c , H. Loiseau a a
Department of Neurosurgery, Pellegrin University Hospital, 33076 Bordeaux, France Department of Anesthesiology, Pellegrin University Hospital, 33076 Bordeaux, France c Department of Neurosurgery, Purpan University Hospital, 31059 Toulouse, France d Department of Neuropathology, Pellegrin University Hospital, Bordeaux, France e Department of Neuropathology, Rangueil University Hospital, Toulouse, France b
a r t i c l e
i n f o
Article history: Received 20 February 2009 Accepted 29 June 2009 Available online 31 December 2009 Keywords: Corpus callosum Histogenesis Supratentorial hemangioblastoma Stromal cells VHL gene
a b s t r a c t A third case of corpus callosum hemangioblastoma (HB) is presented. With no preoperative embolization, surgery was uneventful and the postoperative course was excellent. Based on the literature, we attempted to clarify the histogenesis of HB and to explain why they are exceptional in the supratentorial region in contrast to the posterior cranial fossa. The VHL gene is expressed particularly in Purkinje cells of the cerebellum, but this expression is also possible in supratentorial structures. Its mutation leads to developmental arrest of angioblasts that become potentially neoplastic cells. These CD133-positive pluripotent neoplastic angioblasts, similar to stem cells, may be immature HB in the brain. They also express VEGF, coexpress Epo/EpoR, and are capable of differentiation into primitive vascular structures. This coexpression may not only mediate developmental stagnation, but may also induce HB proliferation. Therefore, HB tumorigenesis may be initiated during embryogenesis and may originate from angiomesenchyma because of the expression of three cell types (stromal cells, pericytes, and endothelial cells) in vimentin. Their capacity for proliferation and differentiation in HB depends on the microenvironment. © 2009 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Corps calleux Histogenèse Hémangioblastome supratentoriel Cellules stromales Gène VHL
Les auteurs présentent le troisième cas d’hémangioblastome du corps calleux. L’exérèse chirurgicale, ainsi que les suites postopératoires se sont bien déroulées. Avec une revue de la littérature, les auteurs tentent d’expliquer pourquoi les hémangioblastomes sont rares au niveau supratentoriel par rapport à la fosse postérieure. Cette approche est la première dans la littérature. La mutation de la gêne VHL entraîne un arrêt de la différentiation des angioblastes qui deviennent potentiellement néoplasiques. Ce gène s’exprime particulièrement dans les cellules de Purkinje du cervelet, mais peut s’exprimer aussi dans les structures supratentorielles. Ces angioblastes néoplasiques sont pluripotents, CD133+ et expriment le VEGF. Ils sont suspectés d’être des hémangioblastomes immatures dans le système nerveux et leur genèse peut être initiée pendant l’embryogénèse. © 2009 Elsevier Masson SAS. Tous droits réservés.
1. Introduction Abbreviations: AVM, arteriovenous malformation; EMA, epithelial membrane antigen; Epo, erythropoietin; EpoR, erythropoietin receptor; HIF1, hypoxiainducible factor-1; HB, hemangioblastoma; ICD-O, International Classification of Diseases, Oncology; GFAP, glial fibrillary acid protein; NSE, neuron-specific enolase; SMA, smooth muscle actin; VEGF, vascular endothelial growth factor; VHL, Von Hippel Lindau. ∗ Corresponding author. Department of Neurosurgery, Purpan University Hospital, Place Baylac, 31059 Toulouse, France. Tel.: +33 6 65 47 63 03. E-mail address: [email protected] (O. Sacko). 0028-3770/$ – see front matter © 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.neuchi.2009.11.006
Hemangioblastomas (HB) constitute 1.3 to 2.5% of all intracranial space-occupying lesions, and 7 to 12% of posterior cranial fossa tumors. They are isolated lesions or included in Von HippelLindau’s (VHL) disease. We report a patient with an isolated cystic HB of the corpus callosum without systemic lesions. Supratentorial HB are exceptional. In the WHO classification (2000), HB are defined as tumors of uncertain histogenesis, when in the 2007 classification this tumor entity was classified as “other neoplasms related to the
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Fig. 1. MRI with contrast enhancement demonstrating a large cyst with a mural nodule that seemed to adhere to the splenium. L’IRM après l’injection de gadolinium objective des portions kystique et nodulaire en contact avec le splénium du corps calleux.
Fig. 2. Selective internal carotid angiogram, profile, shows a blush on the distal aspect of the right pericallosal artery. L’artériographie sélective de la carotide interne montre un blush vasculaire en relation avec la péricalleuse droite.
meninges”. Therefore, based on the literature, we attempted to clarify the HB’s histogenesis and to explain why they are exceptional in the supratentorial region in contrast to the posterior cranial fossa.
feeding artery, the tumor was circumscribed. The mural nodule was completely excised along the gliotic margin away from the splenium. The cystic gliotic wall, nontumoral tissue, was not removed. There was no dural attachment.
2. Case report 2.1. Examination A 42-year-old woman was referred (January 2000) for recent memory impairment and a one-year history of headache. On admission, neurological examination showed fluctuating speech disorder and writing difficulties. Hemoglobin was normal. Head CT scan and MRI revealed a large loculated cystic mass occupying mainly the corpus callosal splenium, with a 1.8 cm homogeneous hyperdense wall nodule at its posterior side surrounded by edema (Fig. 1). Selective cerebral angiography demonstrated a vascular blush in the splenium, fed by distal aspect of the right pericallosal artery (Fig. 2). 2.2. Operation On January 31, 2000, a right parieto-occipital craniotomy without preoperative embolization was performed in the left-handed patient. The 5 cm tumor over the splenium appeared pinkish-grey in colour, highly vascular and surrounded by several enlarged cortical arteries. The draining veins were distended and contained red blood. With dissection under surgical microscope, a large cyst with xanthochromic fluid was evacuated. After carefully interrupting its
Fig. 3. Histopathological features of HB cells (HE × 25). Accumulation of lipid droplets in stromal cells without mitosis. The second component is composed of vascular channels of various sizes. Il existe une accumulation de gouttelettes lipidiques dans les cellules stromales sans mitose. L’autre composante est formée de réseau vasculaire de différentes tailles.
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2.3. Pathological findings The histopathological findings were consistent with HB, i.e., large vacuolated stromal cells and a rich capillary network (Fig. 3). Immunohistochemical studies showed that the stromal cells were strongly positive for vimentin, but negative for EMA, cytokeratins and GFAP. The endothelial component is highly positive for endothelial markers such as CD 34 and CD 31. A second and a third review by two other independents pathologists confirmed the diagnosis of HB. 2.4. The postoperative course The postoperative course was uneventful with the disappearance of the cyst and no enhancement of its wall on the control MRI at Day 3. CT-scan of the body, abdominal echography, fundoscopic examination, visual fields and spinal MRI were normal. There was no family history of VHL disease. The patient was discharged on Day 7 in excellent neurological condition. One month later, the patient returned to work. Contrast MRI (performed three months after surgery and then regularly) was normal 5.5 years after operation without neurological disorder. 3. Discussion HB of corpus callosum is exceptional. We report a third case following those of Zimmermann (1963) and Mariotti (1936). Nonhemispheric supratentorial HB have occurred in the optic nerve (Barrett et al., 2008; Higashida et al., 2007), cranial nerve (Roberti et al., 2007), sellar and suprasellar regions, basal ganglia and meninges (Russel and Rubinstein, 1977). The natural history of HB can be complex with some periods of tumor growth separated by periods of arrested growth, and many untreated HB may remain the same size for several years. The standard treatment is complete surgical removal, with or without preoperative embolization, whereas radiosurgery can be an alternative for multiple or deeply located small nodular HB. Microsurgery, which can cure solitary HB, is often complicated by significant vascularity, large tumor size, and excision difficulty in eloquent area. Total resection of HB should adhere to the principle of AVM dissection, i.e. coagulation-cutting of feeding arteries, followed by dissection of solid part and occlusion of the draining veins. It is important to find the feeding arteries and not to confuse them with red drainage veins. 3.1. Histology HB is characterized by a rich capillary network (Fig. 4) (endothelial cells and pericites) and large vacuolated stromal cells. The rich HB’s vascularity is due to overexpression of VEGFs (Hussein, 2007). Their most striking morphological feature is numerous lipidcontaining vacuoles, resulting in the typical ‘clear-cell’ morphology. These features can sometimes lead to differential diagnostic problems with metastatic renal carcinoma. Another histopathologic differential diagnosis of HB includes angiomatous meningiomas. The supratentorial location of the solid extraparenchymal hyperdense tumor with dural attachment is the most important feature in favour of meningiomas. 3.2. History of HB’s histogenesis In 1928, Cushing and Baley (1928) stated that HB originated from angiomesenchyme as a result of some dysgenetic abnormality, and introduced the term HB to emphasize its neoplastic origin from blood vessel. They excluded its occurrence in the cerebrum even though Russel and Rubinstein (1977) reported its rare occurrence in this location. In 1930, the synonym angioreticuloma was
Fig. 4. Histochemical staining with reticulin × 20 shows and emphasizes the reticulin pattern of the rich capillary network. La coloration par la réticuline souligne nettement le riche réseau capillaire.
invented by Roussy and Oberling (1930) because of the similarity between HB and reticuloendothelial cells, and they found evidence of hematopoiesis in HB. But the latter do not originate from reticuloendithelion because they not express CD68 and CD117. Von Hippel described retinal angiomatosis, and 27 years later, Lindau established the association between these angiomas and cysts of the cerebellum, pancreas, liver, kidney and adrenal gland (Lindau, 1931). According to Sabin’s work (1920), Lindau (1931) concluded that HB’s histological picture revealed an embryological type of the tumor cells and that HB originates from mesoblastic cells (destined to form choroid plexus of the fourth ventricle) included inside the neural tube when it closes in intrauterine life. This would explain its frequent localization in the rhomboencephalon and in the retina. In fact, during this period, vascularization occurs in the above structures before developing in the rest of the brain and spinal cord. In 1960, Stein et al. speculated an angiomesenchymal origin of HB, described embryonic blood and vessel formation in the HB tissue and suggested the presence of an arrest or defect in maturation of this tissue at a particular time in embryonic development. However, during the last decades, several histogenesis theories have been proposed for HB, including derivation from vasoformative elements (endothelium, pericytes or angiogenic cells), astrocytes, histiocytes, microglia, neuroepithelial or meningeal cells. Therefore, the histogenesis has been controversial, and in the WHO (2000) classification of the brain tumors, HB were classified in the category of “tumors of uncertain histogenesis”. Finally, the 2007 WHO classification of tumors of the central nervous system classified HB as “other neoplasms related to the meninges”. Recently, many immunohistochemical, cell culture and molecular studies (Chan et al., 2005; Ding et al., 2007; Higashida et al., 2007) confirm the original hypothesis of Cushing, Lindau and Stein and provide new insight into the histogenesis and pathogenetic progression of HB. In Vortmeyer et al. (2003) series, all HB with extramedullary hematopoiesis was associated with stromal cells and primitive vasoformation of striking morphological resemblance with embryonic blood island formation. Furthermore, in agreement with the hypothesis of angiomesenchymal histogenesis, Western blot and RT-PCR revealed the presence of EpoR and mRNA in all HB.
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Additionally, under specific microenvironments in the Park et al. series (2007), the angioblasts (neoplastic cells) were expanded and differentiated into red blood cells, granulocytic progenitors, and primitive vascular structures.
(Chan et al., 2005). Their capacities for proliferation and differentiation in HB depend on the microenvironment.
3.3. Immunohistochemistry
The current HB’s management includes surgery, endovascular embolization, radiosurgery and radiotherapy. Complete tumor removal of HB is curative and is associated with low morbidity and mortality (2%) (Hussein, 2007). Radiation therapy is indicated for recurrent HB, partial tumor resection or contraindication to the surgery.
HB is mainly composed of three cell types: stromal, pericites and endothelial cells. The stromal cells express vimentin, VEGF and telomerase (Ding et al., 2007). These cells have ultrastructural and antigenic heterogeneity. They have showed a variable expression for neuroectodermal markers (S-100 protein, CD 56, CD99) and NSE, but this immunoreactivity is not specific and does not prove its neuronal origin (Perentes and Rubinstein, 1987). The endothelial cells express factor-VIII, vimentin, CD34 and Flt-1 (VEGF-receptor). The pericites express vimentin and SMA. In the Chan et al. (2005) study, the CD133 (stem cell marker) positive cells were diffusely within HB. These stem cells may represent potentially immature HB in the brain. 3.4. Cell culture In the Ding et al. (2007) series, the stromal cells grew rapidly after cell cultures, while the endothelial cells showed apoptosis. Furthermore telomerase, PCNA, Ki-67 are expressed in stromal cells, and in the molecular analysis, allelic losses and mutation of the VHL tumor suppressor gene (Catapano et al., 2005) have been found in these cells, suggesting that stromal cells represent the neoplastic component of HB. 3.5. Molecular analysis The association HB/VHL complex has been estimated at about 25% (Sakashita et al., 1999) and symptomatic HB can be found in 10 to 40% of VHL disease (Catapano et al., 2005). The genetic hallmark of HB is loss of function of the VHL tumor suppressor protein. This gene (3p25.26) is required for oxygen-dependent degradation of HIF-1 alpha, which is constitutively overexpressed leading to increased transcription of HIF-1-regulated gene, including VEGF (Zagzag et al., 2005). HB’s vascular network may be induced by VEGF autocrine/paracrine by stromal cells (Ding et al., 2007). Developmental arrest of angioblasts is primarily initiated by inactivation of VHL gene (Vortmeyer et al., 2003). This gene is expressed particularly in Purkinje cells of the cerebellum (Sakashita et al., 1999). HB are composed of developmentally arrested neoplastic angioblasts that are pluripotent, express stem cell markers, VEGF, coexpress Epo/EpoR and are capable of differenciation into primitive vascular structure (Ding et al., 2007, Park et al., 2007, Vortmeyer et al., 2003). This coexpression may not only mediate developmental stagnation but may also induce HB’s proliferation. Therefore, HB’s tumorigenesis may be initiated during embryogenesis, and may originate from angiomesenchyme because of the expression of the 3 cell types in vimentin. 3.6. Hypothesis about the supratentorial location of HB VHL gene is expressed particularly in Purkinje cells of the cerebellum, but this expression is also possible in supratentorial structures (Sakashita et al., 1999). Its mutation leads to developmental arrest of angioblasts that became potential neoplastic cells. These CD133 positive pluripotent neoplastic angioblast, similar to stem cells, may represent potentially immature HB in the brain
3.7. Treatment strategies
4. Conclusion Our case is one of the rare examples of supratentorial HB, which must be considered in the differential diagnosis of cystic tumors with mural nodule. Solitary HB can be surgically cured. HB may originate from the angiomesenchyme. They are composed of developmentally arrested stem cells including hemangioblast that coexpress Epo/EpoR because of VHL gene deficiency. The capacity of potential neoplastic immature HB for proliferation and differentiation depend on the microenvironment, which is more favorable in the cerebellum because of the high expression of the VHL gene. References Barrett, R., Meyer, D., Boulos, A., Eames, F., Torres-Mora, J., 2008. Optic nerve hemangioblastoma. Ophtalmology 115 (11), 2095. Catapano, D., Muscarella, L.A., Guarnieri, V., Zelante, L., D’Angelo, V.A., D’Agruma, L., 2005. Hemangioblastomas of CNS: molecular genetic analysis and clinical management. Neurosurgery 56 (6), 1215–1221. Chan, C.C., Chew, E.Y., Shen, D., Hacckett, J., Zhuang, Z., 2005. Expression of stem cells markers in ocular hemangioblastoma associated with von Hippel-Lindau (VHL) disease. Mol Vis 11, 697–704. Cushing, H., Baley, P., 1928. Tumors arising from the blood vessels of the brain: Angiomatous malformations and hemangioblastomas. Charles C Thomas, Springfield. Ding, X.H., Zhou, L.F., Tan, Y.Z., Zhao, Y., Zhu, J., 2007. Histologic and histogenetic investigations of intracranial hemangioblastomas. Surg Neurol 67, 239–245. Higashida, T., Sakata, K., Kanno, H., Kawazaki, T., Tanabe, Y., Yamamoto, I., 2007. Hemangioblastoma of the optic nerve. Neurol Med Chir (Tokyo) 47 (5), 215–218. Hussein, M.R., 2007. Central nervous system capillary haemangiolastoma: the pathologist’s viewpoint. Int J Exp Path 88, 311–324. Lindau, A., 1931. Discussion on vascular tumors of the brain and spinal cord. Proc Roy Soc Med 24, 363–370. Mariotti, D., 1936. Angioreticuloma del corpo calloso. Pathologica 28, 1–7. Park, D.M., Zhuang, Z., Chen, L., Szerlip, N., Maric, I., Li, J., Sohn, T., Kim, S.H., Lubensky, I.A., Vortmeyer, A.O., Rodgers, G.P., Oldfield, E.H., Lonser, R.R., 2007. Von HippelLindau diseases-associated hemangioblastomas are derived from embryologic multipotent cells. PLOS Med 4 (2), 333–341, e60. Perentes, E., Rubinstein, L.J., 1987. Recent application of immunoperoxydase histochemistry in human neuro-oncology. Arch Pathol Lab Med 111, 796–812. Roberti, F., Jones, R.V., Wright, D.C., 2007. Cranial nerve hemangioblastomas. Report of the rare case and review of the literature. Surg Neurol 67 (6), 640–646. Roussy, G., Oberling, C., 1930. Angiomatous tumors of central nervous system. Press Med 38, 179–185. Russel, D.S., Rubinstein, L.J., 1977. Pathology of tumors of the nervous system. Williams & Wilkins, Baltimore. Sabin, F.R., 1920. Studies on the origin of blood vessels and of red blood corpuscles as seen in the living blastoderm of chicks during the second day of incubation. Contr Embryol 9, 213–262. Sakashita, N., Takeya, M., Kishida, T., 1999. Expression of von Hippel-Lindau protein in normal and pathological human tissues. Histochem J 31, 133–144. Stein, A.A., Schilp, A.O., Whitfield, R.D., 1960. The histogenesis of hemangioblastoma of the brain. J Neurosurg 17, 751–761. Vortmeyer, A.O., Frank, S., Jeong, S.-Y., Yuan, K., Ikejiri, B., Lee, Y.-S., Bhowmick, D., Lonser, R.R., Smith, R., Rodgers, G., Oldfield, E.H., Zhuang, Z., 2003. Developmental arrest of angioblastic lineage initiates tumorogenesis in von Hippel-Lindau disease. Cancer Res 63, 7051–7055. Zagzag, D., Krishnamachary, B., Yee, H., Okuyama, H., Chiriboga, L., Ali, M.A., Melamed, J., Semenza, G.L., 2005. Stromal cell-derived factor-1 alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res 65 (14), 6178–6188. Zimmermann, H., 1963. Vascular tumours of the brain. Clin Neurosurg 9, 264–274.
Clinical case
Hemangioblastoma of the corpus callosum: A case report and review of the literature on its origin L’hémangioblastome du corps calleux : cas clinique et revue de la littérature sur son origine O. Sacko a,c,∗ , S. Bouillot-Eimer d , M. Sesay b , E. Uro-Coste e , F.-E. Roux c , H. Loiseau a a
Department of Neurosurgery, Pellegrin University Hospital, 33076 Bordeaux, France Department of Anesthesiology, Pellegrin University Hospital, 33076 Bordeaux, France c Department of Neurosurgery, Purpan University Hospital, 31059 Toulouse, France d Department of Neuropathology, Pellegrin University Hospital, Bordeaux, France e Department of Neuropathology, Rangueil University Hospital, Toulouse, France b
a r t i c l e
i n f o
Article history: Received 20 February 2009 Accepted 29 June 2009 Available online 31 December 2009 Keywords: Corpus callosum Histogenesis Supratentorial hemangioblastoma Stromal cells VHL gene
a b s t r a c t A third case of corpus callosum hemangioblastoma (HB) is presented. With no preoperative embolization, surgery was uneventful and the postoperative course was excellent. Based on the literature, we attempted to clarify the histogenesis of HB and to explain why they are exceptional in the supratentorial region in contrast to the posterior cranial fossa. The VHL gene is expressed particularly in Purkinje cells of the cerebellum, but this expression is also possible in supratentorial structures. Its mutation leads to developmental arrest of angioblasts that become potentially neoplastic cells. These CD133-positive pluripotent neoplastic angioblasts, similar to stem cells, may be immature HB in the brain. They also express VEGF, coexpress Epo/EpoR, and are capable of differentiation into primitive vascular structures. This coexpression may not only mediate developmental stagnation, but may also induce HB proliferation. Therefore, HB tumorigenesis may be initiated during embryogenesis and may originate from angiomesenchyma because of the expression of three cell types (stromal cells, pericytes, and endothelial cells) in vimentin. Their capacity for proliferation and differentiation in HB depends on the microenvironment. © 2009 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Corps calleux Histogenèse Hémangioblastome supratentoriel Cellules stromales Gène VHL
Les auteurs présentent le troisième cas d’hémangioblastome du corps calleux. L’exérèse chirurgicale, ainsi que les suites postopératoires se sont bien déroulées. Avec une revue de la littérature, les auteurs tentent d’expliquer pourquoi les hémangioblastomes sont rares au niveau supratentoriel par rapport à la fosse postérieure. Cette approche est la première dans la littérature. La mutation de la gêne VHL entraîne un arrêt de la différentiation des angioblastes qui deviennent potentiellement néoplasiques. Ce gène s’exprime particulièrement dans les cellules de Purkinje du cervelet, mais peut s’exprimer aussi dans les structures supratentorielles. Ces angioblastes néoplasiques sont pluripotents, CD133+ et expriment le VEGF. Ils sont suspectés d’être des hémangioblastomes immatures dans le système nerveux et leur genèse peut être initiée pendant l’embryogénèse. © 2009 Elsevier Masson SAS. Tous droits réservés.
1. Introduction Abbreviations: AVM, arteriovenous malformation; EMA, epithelial membrane antigen; Epo, erythropoietin; EpoR, erythropoietin receptor; HIF1, hypoxiainducible factor-1; HB, hemangioblastoma; ICD-O, International Classification of Diseases, Oncology; GFAP, glial fibrillary acid protein; NSE, neuron-specific enolase; SMA, smooth muscle actin; VEGF, vascular endothelial growth factor; VHL, Von Hippel Lindau. ∗ Corresponding author. Department of Neurosurgery, Purpan University Hospital, Place Baylac, 31059 Toulouse, France. Tel.: +33 6 65 47 63 03. E-mail address: [email protected] (O. Sacko). 0028-3770/$ – see front matter © 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.neuchi.2009.11.006
Hemangioblastomas (HB) constitute 1.3 to 2.5% of all intracranial space-occupying lesions, and 7 to 12% of posterior cranial fossa tumors. They are isolated lesions or included in Von HippelLindau’s (VHL) disease. We report a patient with an isolated cystic HB of the corpus callosum without systemic lesions. Supratentorial HB are exceptional. In the WHO classification (2000), HB are defined as tumors of uncertain histogenesis, when in the 2007 classification this tumor entity was classified as “other neoplasms related to the
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Fig. 1. MRI with contrast enhancement demonstrating a large cyst with a mural nodule that seemed to adhere to the splenium. L’IRM après l’injection de gadolinium objective des portions kystique et nodulaire en contact avec le splénium du corps calleux.
Fig. 2. Selective internal carotid angiogram, profile, shows a blush on the distal aspect of the right pericallosal artery. L’artériographie sélective de la carotide interne montre un blush vasculaire en relation avec la péricalleuse droite.
meninges”. Therefore, based on the literature, we attempted to clarify the HB’s histogenesis and to explain why they are exceptional in the supratentorial region in contrast to the posterior cranial fossa.
feeding artery, the tumor was circumscribed. The mural nodule was completely excised along the gliotic margin away from the splenium. The cystic gliotic wall, nontumoral tissue, was not removed. There was no dural attachment.
2. Case report 2.1. Examination A 42-year-old woman was referred (January 2000) for recent memory impairment and a one-year history of headache. On admission, neurological examination showed fluctuating speech disorder and writing difficulties. Hemoglobin was normal. Head CT scan and MRI revealed a large loculated cystic mass occupying mainly the corpus callosal splenium, with a 1.8 cm homogeneous hyperdense wall nodule at its posterior side surrounded by edema (Fig. 1). Selective cerebral angiography demonstrated a vascular blush in the splenium, fed by distal aspect of the right pericallosal artery (Fig. 2). 2.2. Operation On January 31, 2000, a right parieto-occipital craniotomy without preoperative embolization was performed in the left-handed patient. The 5 cm tumor over the splenium appeared pinkish-grey in colour, highly vascular and surrounded by several enlarged cortical arteries. The draining veins were distended and contained red blood. With dissection under surgical microscope, a large cyst with xanthochromic fluid was evacuated. After carefully interrupting its
Fig. 3. Histopathological features of HB cells (HE × 25). Accumulation of lipid droplets in stromal cells without mitosis. The second component is composed of vascular channels of various sizes. Il existe une accumulation de gouttelettes lipidiques dans les cellules stromales sans mitose. L’autre composante est formée de réseau vasculaire de différentes tailles.
384
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2.3. Pathological findings The histopathological findings were consistent with HB, i.e., large vacuolated stromal cells and a rich capillary network (Fig. 3). Immunohistochemical studies showed that the stromal cells were strongly positive for vimentin, but negative for EMA, cytokeratins and GFAP. The endothelial component is highly positive for endothelial markers such as CD 34 and CD 31. A second and a third review by two other independents pathologists confirmed the diagnosis of HB. 2.4. The postoperative course The postoperative course was uneventful with the disappearance of the cyst and no enhancement of its wall on the control MRI at Day 3. CT-scan of the body, abdominal echography, fundoscopic examination, visual fields and spinal MRI were normal. There was no family history of VHL disease. The patient was discharged on Day 7 in excellent neurological condition. One month later, the patient returned to work. Contrast MRI (performed three months after surgery and then regularly) was normal 5.5 years after operation without neurological disorder. 3. Discussion HB of corpus callosum is exceptional. We report a third case following those of Zimmermann (1963) and Mariotti (1936). Nonhemispheric supratentorial HB have occurred in the optic nerve (Barrett et al., 2008; Higashida et al., 2007), cranial nerve (Roberti et al., 2007), sellar and suprasellar regions, basal ganglia and meninges (Russel and Rubinstein, 1977). The natural history of HB can be complex with some periods of tumor growth separated by periods of arrested growth, and many untreated HB may remain the same size for several years. The standard treatment is complete surgical removal, with or without preoperative embolization, whereas radiosurgery can be an alternative for multiple or deeply located small nodular HB. Microsurgery, which can cure solitary HB, is often complicated by significant vascularity, large tumor size, and excision difficulty in eloquent area. Total resection of HB should adhere to the principle of AVM dissection, i.e. coagulation-cutting of feeding arteries, followed by dissection of solid part and occlusion of the draining veins. It is important to find the feeding arteries and not to confuse them with red drainage veins. 3.1. Histology HB is characterized by a rich capillary network (Fig. 4) (endothelial cells and pericites) and large vacuolated stromal cells. The rich HB’s vascularity is due to overexpression of VEGFs (Hussein, 2007). Their most striking morphological feature is numerous lipidcontaining vacuoles, resulting in the typical ‘clear-cell’ morphology. These features can sometimes lead to differential diagnostic problems with metastatic renal carcinoma. Another histopathologic differential diagnosis of HB includes angiomatous meningiomas. The supratentorial location of the solid extraparenchymal hyperdense tumor with dural attachment is the most important feature in favour of meningiomas. 3.2. History of HB’s histogenesis In 1928, Cushing and Baley (1928) stated that HB originated from angiomesenchyme as a result of some dysgenetic abnormality, and introduced the term HB to emphasize its neoplastic origin from blood vessel. They excluded its occurrence in the cerebrum even though Russel and Rubinstein (1977) reported its rare occurrence in this location. In 1930, the synonym angioreticuloma was
Fig. 4. Histochemical staining with reticulin × 20 shows and emphasizes the reticulin pattern of the rich capillary network. La coloration par la réticuline souligne nettement le riche réseau capillaire.
invented by Roussy and Oberling (1930) because of the similarity between HB and reticuloendothelial cells, and they found evidence of hematopoiesis in HB. But the latter do not originate from reticuloendithelion because they not express CD68 and CD117. Von Hippel described retinal angiomatosis, and 27 years later, Lindau established the association between these angiomas and cysts of the cerebellum, pancreas, liver, kidney and adrenal gland (Lindau, 1931). According to Sabin’s work (1920), Lindau (1931) concluded that HB’s histological picture revealed an embryological type of the tumor cells and that HB originates from mesoblastic cells (destined to form choroid plexus of the fourth ventricle) included inside the neural tube when it closes in intrauterine life. This would explain its frequent localization in the rhomboencephalon and in the retina. In fact, during this period, vascularization occurs in the above structures before developing in the rest of the brain and spinal cord. In 1960, Stein et al. speculated an angiomesenchymal origin of HB, described embryonic blood and vessel formation in the HB tissue and suggested the presence of an arrest or defect in maturation of this tissue at a particular time in embryonic development. However, during the last decades, several histogenesis theories have been proposed for HB, including derivation from vasoformative elements (endothelium, pericytes or angiogenic cells), astrocytes, histiocytes, microglia, neuroepithelial or meningeal cells. Therefore, the histogenesis has been controversial, and in the WHO (2000) classification of the brain tumors, HB were classified in the category of “tumors of uncertain histogenesis”. Finally, the 2007 WHO classification of tumors of the central nervous system classified HB as “other neoplasms related to the meninges”. Recently, many immunohistochemical, cell culture and molecular studies (Chan et al., 2005; Ding et al., 2007; Higashida et al., 2007) confirm the original hypothesis of Cushing, Lindau and Stein and provide new insight into the histogenesis and pathogenetic progression of HB. In Vortmeyer et al. (2003) series, all HB with extramedullary hematopoiesis was associated with stromal cells and primitive vasoformation of striking morphological resemblance with embryonic blood island formation. Furthermore, in agreement with the hypothesis of angiomesenchymal histogenesis, Western blot and RT-PCR revealed the presence of EpoR and mRNA in all HB.
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Additionally, under specific microenvironments in the Park et al. series (2007), the angioblasts (neoplastic cells) were expanded and differentiated into red blood cells, granulocytic progenitors, and primitive vascular structures.
(Chan et al., 2005). Their capacities for proliferation and differentiation in HB depend on the microenvironment.
3.3. Immunohistochemistry
The current HB’s management includes surgery, endovascular embolization, radiosurgery and radiotherapy. Complete tumor removal of HB is curative and is associated with low morbidity and mortality (2%) (Hussein, 2007). Radiation therapy is indicated for recurrent HB, partial tumor resection or contraindication to the surgery.
HB is mainly composed of three cell types: stromal, pericites and endothelial cells. The stromal cells express vimentin, VEGF and telomerase (Ding et al., 2007). These cells have ultrastructural and antigenic heterogeneity. They have showed a variable expression for neuroectodermal markers (S-100 protein, CD 56, CD99) and NSE, but this immunoreactivity is not specific and does not prove its neuronal origin (Perentes and Rubinstein, 1987). The endothelial cells express factor-VIII, vimentin, CD34 and Flt-1 (VEGF-receptor). The pericites express vimentin and SMA. In the Chan et al. (2005) study, the CD133 (stem cell marker) positive cells were diffusely within HB. These stem cells may represent potentially immature HB in the brain. 3.4. Cell culture In the Ding et al. (2007) series, the stromal cells grew rapidly after cell cultures, while the endothelial cells showed apoptosis. Furthermore telomerase, PCNA, Ki-67 are expressed in stromal cells, and in the molecular analysis, allelic losses and mutation of the VHL tumor suppressor gene (Catapano et al., 2005) have been found in these cells, suggesting that stromal cells represent the neoplastic component of HB. 3.5. Molecular analysis The association HB/VHL complex has been estimated at about 25% (Sakashita et al., 1999) and symptomatic HB can be found in 10 to 40% of VHL disease (Catapano et al., 2005). The genetic hallmark of HB is loss of function of the VHL tumor suppressor protein. This gene (3p25.26) is required for oxygen-dependent degradation of HIF-1 alpha, which is constitutively overexpressed leading to increased transcription of HIF-1-regulated gene, including VEGF (Zagzag et al., 2005). HB’s vascular network may be induced by VEGF autocrine/paracrine by stromal cells (Ding et al., 2007). Developmental arrest of angioblasts is primarily initiated by inactivation of VHL gene (Vortmeyer et al., 2003). This gene is expressed particularly in Purkinje cells of the cerebellum (Sakashita et al., 1999). HB are composed of developmentally arrested neoplastic angioblasts that are pluripotent, express stem cell markers, VEGF, coexpress Epo/EpoR and are capable of differenciation into primitive vascular structure (Ding et al., 2007, Park et al., 2007, Vortmeyer et al., 2003). This coexpression may not only mediate developmental stagnation but may also induce HB’s proliferation. Therefore, HB’s tumorigenesis may be initiated during embryogenesis, and may originate from angiomesenchyme because of the expression of the 3 cell types in vimentin. 3.6. Hypothesis about the supratentorial location of HB VHL gene is expressed particularly in Purkinje cells of the cerebellum, but this expression is also possible in supratentorial structures (Sakashita et al., 1999). Its mutation leads to developmental arrest of angioblasts that became potential neoplastic cells. These CD133 positive pluripotent neoplastic angioblast, similar to stem cells, may represent potentially immature HB in the brain
3.7. Treatment strategies
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