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Neuropathology 2015; 35, 184–191
doi:10.1111/neup.12178
Cas e Rep o r t
Primary central nervous system angiosarcoma: A case report and literature review Emanuele La Corte,1* Francesco Acerbi,1* Marco Schiariti,1 Morgan Broggi,1 Emanuela Maderna,2 Bianca Pollo,2 Raffaele Nunziata,2 Elio Maccagnano3 and Paolo Ferroli1 1
Department of Neurosurgery, 2Division of Neuropathology, and 3Department of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Angiosarcoma is a rare vascular malignant neoplasm that mainly occurs in skin and soft tissues. Intracranial localization is very rare and only a few cases have been reported. This report intends to present the clinical, radiological and pathological pictures of a primary central nervous system angiosarcoma along with a review of the literature. A 35-year-old woman presented at our institution with weakness and sensory disturbances of her right hand. Neuroimaging revealed a roughly round, hemorrhagic and moderately enhancing lesion in the left frontal posterior region. The tumor was totally removed under awake anesthesia and continuous monitoring of motor and language functions. Histopathology revealed an epithelioid angiosarcoma. Radical removal, followed by adjuvant radiotherapy and chemotherapy, is able to completely control the disease for a relatively long period. Key words: brain angiosarcoma, central nervous system tumor, neurosurgery, survival, treatment.
INTRODUCTION Angiosarcoma is a rare vascular malignancy (less than 1% of sarcomas) and mainly occurs in skin and soft tissues.1–3 Localization in the CNS is extremely rare and only a few cases of primary brain angiosarcomas have been reported so far in the literature4–22 (Table 1). It may occur in the CNS as a metastatic or a primary brain tumor. The prognosis for angiosarcoma is generally poor with a 5-year survival rate
Correspondence: Emanuele La Corte, MS, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 11, 20133 Milan, Italy. Email: [email protected] *Both co-authors equally contributed to the manuscript. Informed Consent: Obtained from the patient. Received 14 August 2014; revised and accepted 25 September 2014; published online 1 November 2014.
© 2014 Japanese Society of Neuropathology
of 12%.8 Angiosarcomas of the CNS are not easy to recognize on radiological imaging since MRI findings can resemble those of cavernous angiomas.30 We present a rare case of primary epithelioid angiosarcoma in a 35-year-old woman who was still disease-free 37 months after radical surgical resection, chemotherapy (CHT) and radiotherapy (RT). Our purpose is to review the literature on primary CNS angiosarcomas, elucidating their clinical, radiological and pathological features, and make recommendations for the optimal diagnosis and management of these patients.
SEARCH STRATEGY AND SELECTION CRITERIA The literature review was predominately based on articles published in the past 35 years and identified through multiple searches of PubMed using the following keywords: “primary brain angiosarcoma” AND “central nervous system angiosarcoma”. Only papers published in English and dealing with CNS primary angiosarcoma were reviewed. Some additional papers were selected from the reference lists of papers identified previously in PubMed. The final reference list was generated on the basis of originality and relevance to the broad scope of this review.
CLINICAL SUMMARY A 35-year-old woman started to complain of paraesthesia in her right hand and arm followed by distal motor impairment that appeared immediately after pregnancy and delivery. Her previous clinical history was negative. Her familiar history was positive for familiar glycosuria, spina bifida and epilepsy. Pre-operative brain imaging (MRI scans) showed a partially hemorrhagic, moderateenhancing lesion in the left frontal lobe with peripheral edema. Differential diagnosis included a bleeding cavernous angioma or any other vascular or bleeding tumor
39 41 37 27
18 73 4 weeks 16 56 68 9
M F F M M M M
M M M F F M M
M F
Paulus et al. (1991)19
© 2014 Japanese Society of Neuropathology
Fuse et al. (1995)9 Antoniadis et al. (1996)4 Lach and Benoit (2000)14 Merimsky et al. (2000)18
Suzuki et al. (2000)21 Kurian et al. (2006)13 Guode et al. (2008)10 Lach et al. (2008)15 Balamurali et al. (2009)5
Baldovini et al. (2013)6 This study 54 35
24 26 2 weeks
1 6 32 2 week-72 (mean 38)
Septum pellucidum L frontal
Occipitoparietal Cervical spine L frontotemporal R cerebellopontine angle Pineal R parietal L parietoccipital
R parietal L parietal R frontoparietal Parietal
Anterior cranial fossa Cervicomedullary region R occipital 6 cerebral parenchyma (parietal most frequent), 1 meninges, 1 not stated Temporal Frontal R temporal
R posterior parietal L posterior frontal Thoracic and lumbar spinal region L posterior parietooccipital
Location (lobe/region)
Parenchyma Parenchyma
Parenchyma Parenchyma Parenchyma Parenchyma Parenchyma Parenchyma Parenchyma
Parenchyma Parenchyma Parenchyma Parenchyma
Parenchyma Parenchyma Meninges
Meninges Meninges Parenchyma Parenchyma/ Meninges
Parenchyma
Parenchyma Parenchyma Meninges
Assumed CNS tissue origin
Unknown Unknown Congenital angiosarcoma Unknown Uterine fibromas Unknown Congenital deafness and occupational exposure to chemicals Unknown Unknown Cas Unknown Unknown Unknown Exposure to thorotrast-dioxide 62 yrs prior Unknown Unknown
Unknown Unknown Previous chordotomy Exposure to industrial solvents Unknown Unknown Unknown Unknown
Predisposing factor
F, female; M, male; L, left; R, right; S, surgical; GTR, gross total resection; RT, radiotherapy; CT, chemotherapy; PR, partial resection.
Kirk et al. (1992)11
Cookston et al. (1991)8 Mena et al. (1991)17
M F F M(5); F(3)
Russel and Rubinstein (1989)20
65
M
Charman et al. (1988)7
17 15 60
Age
M F M
Sex
Ziegler (1975)22 Mena and Garcia (1978)16 Kristoferitsch and Jeelinger (1986)12
Reference
Table 1 Cases of primary angiosarcoma of the CNS
S S + RT+CT
S S + RT+CT S S + RT S + RT S + RT S
S + RT S + CT+RT S RT
Unknown Unknown S
Unknown Unknown S + RT S(8) + RT(1)
S + RT
S + RT S Nothing
Treatment
GTR GTR
PR PR GTR PR GTR GTR PR
GTR GTR GTR Unknown
Unknown Unknown GTR
Unknown Unknown GTR Unknown
GTR
PR PR Unknown
Surgery
2 37+
5 20 11+ 6+ 48 6 11
29 41+ 18 2.5
Unknown Unknown 42+ 4 (4), 30, 39+, 102+, unknown Unknown Unknown 26+
13
2.5 2 1
Survival (months)
Primary CNS angiosarcoma 185
186
E La Corte et al.
Fig. 1 (A,B) Preoperative MRI show a roughly round lesion characterized on both axial T2-weighted and T1-weighted images by an heterogeneous signal with hypointense components on T2 and hyperintense components on T1 due to the presence of blood degradation products in different stages (subacute/chronic phases). (C) On axial T1-weighted with i.v. paramagnetic contrast administration, the lesion shows a moderate enhancement, mainly in its anterior portion.
(Fig. 1). From a radiologic point of view, it was not possible to exclude any other lesion. Her symptoms progressed and she was referred to our institution with the recommendation of surgical removal of the lesion. General physical examination was normal. She was awake, alert and well oriented, with a minimal impairment in her right hand movement. Any other neurological deficit was disclosed by neurological examination. Image-guided surgery was performed under awake anesthesia with brain mapping and continuous monitoring of motor and language performances. The tumor mass was brown and the surrounding arachnoid membrane was thickened. The tumor was highly vascular, firm but elastic and clearly demarcated from the surrounding brain parenchyma and it could be totally removed. The post-operative course was characterized by immediate improvement of her right hand movement and temporary dysarthria that completely recovered in 2 weeks. Post-operative CT and MRI ruled out complications and confirmed the completeness of the removal. Whole-body imaging (CT scan, positron emission tomography with 18fluorodeoxyglucose (FDG-PET)) ruled out the presence of a soft tissue primitive localization. On the ground of histopathological diagnosis, a course of cranial radiation therapy, consisting of 58 Gy fractionated conformational radiotherapy was administered (29 fractions; 2 Gy/day). Chemotherapy was also administered (six courses with two drugs: temozolomide 150 mg/m2 (days 1–5); gemcitabine 800 mg/m2 (days 1, 8, 15, 28).31 At 37 months of follow-up MRI ruled out recurrent disease (Fig. 2).
PATHOLOGICAL FINDINGS The specimen was fixed in Carnoy and paraffin embedded. Sections were processed for HE and immunohistochemical staining. Histopathological examination showed a tumor composed of irregular blood vessels loosing integrity, lined by neoplastic endothelial cells and large endothelial cells that formed sheets or nests. Vascular anastomotic channels of different shape and caliber were found and many tumor cells presented intracytoplasmatic vacuoles resembling primitive blood vessels. Neoplastic vascular cells showed large, hypercromatic, pleomorphic nuclei, prominent nucleoli and eosinophilic cytoplasms. Mitoses were frequent and areas of necrosis and hemorrhage could be seen. Immunohistochemical results showed strong expression of endothelial cell marker CD34 and faint expression of CD31. Immunostaining for vimentin suggested a mesenchymal origin. Cells were negative for GFAP, CK (AE1/AE3) and HMB45. Malignant features were supported by the MIB1/Ki67 index accounting for 20% (mean of five mitoses for 10 high power fields). These epithelial, vasoformative and highly malignant characteristics supported the diagnosis of epithelioid angiosarcoma (Fig. 3).
DISCUSSION Overview and epidemiology Soft tissue and bone sarcomas are rare tumors that constitute only 1% of all human malignancies. Angiosarcomas are malignant tumors originating from endothelial cells © 2014 Japanese Society of Neuropathology
Primary CNS angiosarcoma
187
Fig. 2 (A,B) Coronal (A) and axial (B) T1-weighted with i.v. paramagnetic contrast administration MRI show a small surgical cavity with clear margins, no contrast enhancement and no signs of recurrent disease 37 months after surgery. (C) Proton magnetic resonance spectroscopy (H1-MRS) has been also performed in order to evaluate the metabolic profile of the cerebral tissue next to the surgical cavity. There is no evidence of pathological metabolic profile.
that can occur in any region of the body, although they are most commonly located in the skin, breast, liver and deep tissues.3 Primary or secondary angiosarcoma of the CNS is rarely reported. The heart is the most common site of origin of metastatic CNS angiosarcomas. A review of the literature revealed 30 primary tumors originating from the cerebral parenchyma or meninges4–22 (Table 1). The diagnosis of primary angiosarcoma of the brain was done only after ruling out other localizations by whole body imaging. We have not included in our table two case reports, considered by the authors as primary CNS angiosarcoma, because of their clear extra-axial nature without any evidence of intradural extension.32 Angiosarcomas have been also described in peripheral nerves.33 Males (65%) were more frequently affected than females (35%). The age presentation ranged from 2 weeks to 73 years (mean 24 years). The most frequent site of origin was the CNS parenchyma (81%), with the parietal lobe being the most common location. The meninges (16%) represent a rare site of origin of primary CNS angiosarcomas. Only two cases were found in the posterior fossa, two cases occurred © 2014 Japanese Society of Neuropathology
in the spinal cord and one at the level of septum pellucidum.
Risk factors and etiology Etiology and oncogenetic pathways of angiosarcoma development are still unknown. Genetic factors may play a key role, along with environmental factors. Angiosarcoma has been associated with both chromosomal abnormalities and inheritable genetic diseases. Frequent chromosome abnormalities are gains in the normal number of two of each chromosome 5, 20 and 8 and losses of chromosomes 7, 22 and the male Y chromosome.34 There are case reports of angiosarcoma in patients with Klippel Trenaunay syndrome, Von Hippel Lindau disease and Von Recklinghausen neurofibromatosis.3,24,35 Non-CNS angiosarcomas have also been associated with environmental factors such as chronic lymphedema, trauma and previous irradiation exposure, some cancerous materials such as vinyl chloride, chemotherapy, arsenic and thorium dioxide as a contrast dye for angiography and foreign
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Fig. 3 (A,B) Photomicrograph showing the tumor composed of irregularly arranged fascicles of epithelioid tumor cells, with several tumor cells containing intracytoplasmic vacuoles, which resemble primitive blood vessels. Mitoses were common. HE stain, 10× and 20×. Insert: high-magnification histological picture. HE stain, 40×. (C) Photomicrographs showing immunohistochemical reaction to CD34, CD31 (D) and anti-vimentin (VIM) antibodies (E), 20×. (F) Photomicrographs showing immunohistochemical staining for proliferating index Ki67/MIB1, 20×.
materials (Dacron and other surgical materials).5,7,11,18, 25–28,36,37 There have also been a few isolated reports of angiosarcomas among primary relatives without obvious cause.38,39 This suggests a rare inheritable variant of angiosarcoma or possible unknown exposure to an angiosarcoma-causing agent among family members. Our review of the literature regarding primary CNS angiosarcoma revealed two patients presenting with congenital tumors,11,21 one with a previous history of spine surgery (chordotomy),12 one who underwent hysterectomy for uterine fibroma,4 two with a history of occupational
exposure to industrial solvents and chemicals7,18 and one with a history of exposure of thorotrast-dioxide as a radiologic contrast medium.5
Histopathology Angiosarcoma is characterized by strands of spindle cells and nests of epithelioid cells, vasoformative areas with arborized vascular channels lined by neoplastic endothelial cells. Tumor endothelial cells are large, hyperchromatic, with pleomorphic nuclei, prominent nucleoli and abundant © 2014 Japanese Society of Neuropathology
Primary CNS angiosarcoma eosinophilic cytoplasm. Mitoses are frequent and necrosis is occasionally observed. Based on the large number of mitotic cells, our case was diagnosed as an epithelioid angiosarcoma, rather than an epithelioid hemangioendothelioma or an epithelioid sarcoma. Epithelioid hemangioendothelioma is a low-grade vascular malignancy formed by loosed aggregates of spindle cells in a focal cord-like arrangement supported by a myxoid stroma. Conversely, epithelioid sarcoma consists of cellular nodules of epithelioid cells with central necrosis, but mitotic activity is usually low. Epithelioid angiosarcoma is a rare variant of high-grade malignancy characterized by alternating foci of spindle and epithelioid cells and vasoformative areas of dilated vascular channels. Immunohistochemical investigation was a useful diagnostic tool in the differential diagnosis of angiosarcoma from other neoplasms. Epithelioid vascular tumor cells expressed sensitive markers for endothelial cells CD34 and CD31. Although it has been accepted that CD31 is a specific and sensitive endothelial marker, some vascular lesions are negative for CD31 and positive for other vascular markers, such as CD34 and factor VIII. The present case supports such hypothesis, that malignant endothelial lesions may demonstrate heterogeneity of expression of vascular antigens.40 The expression of vimentin has also been shown, suggesting a mesenchymal origin. Differential diagnosis includes other vascular/bleeding tumors of the CNS such as metastases (carcinoma, melanoma), epithelioid sarcoma, hemangioblastoma, solitary fibrous tumor, hemangioendothelioma and cavernous angioma.29,41,42 The application of immunohistochemical techniques has become a useful diagnostic tool, the immunopositivity or negativity of endothelial markers, cytokeratins, S100, HMB45 and MIB1/Ki67 are useful in the differential diagnosis of angiosarcoma from epithelioid sarcoma, metastatic carcinoma, malignant melanoma and hemangioblastoma.
Clinical presentation The clinical manifestations of these tumors are related to their anatomical sites in the CNS and frequently act like a space-occupying lesion, producing focal symptoms when in eloquent areas along with raised intracranial pressure syndrome. The clinical course of brain angiosarcoma may be characterized by the rapid onset or abrupt aggravation of symptoms due to intra-lesional and extra-lesional hemorrhage (18 out of 31 cases).6,7,10–13,15–17,21,30
Diagnostic evaluation The radiological appearance of cerebral angiosarcomas is not typical and differential diagnosis includes most common brain lesions such as bleeding metastases, gliomas and cavernomas. Our case represents one of the most © 2014 Japanese Society of Neuropathology
189 common radiological features of the lesion found in the literature.4,7,8,30 Brain MRI disclosed a heterogeneous mixed signal intensity lesion on T1-weighted images with moderate enhancement in some areas after contrast injection. The lesion showed intra-lesional mixed signal intensity on both T1 and T2-weighted images with blood degradation products in different stages. These characteristics might wrongly direct the MRI radiological diagnosis toward a cavernous angioma as already observed by Matsumoto et al.30 Due to the absence of flow-void on MRI, which is suggestive for high-flow vascular structures, a digital subtraction angiography (DSA) has not been performed. However, cerebral DSA has been found to be non-diagnostic of primary CNS angiosarcomas, since these lesions very often do not display any hypervascularization or pathological circulation.8,9,13,16,32 DSA appeared normal in most of the cases, while one case in the literature showed a blush in the neoplastic area.17 Probably, a CT scan would be used to disclose calcifications and/or the presence of fresh blood. Ultrasound has been rarely used in congenital cases in infants.11
Outcomes Since primary malignant vascular tumors of the CNS are rare and differ considerably, treatment and survival are variable (Table 1). The reported prognosis of angiosarcomas is generally poor, with some surprising exceptions, such as our 35-year-old woman that is still disease-free 37 months after radical surgical resection, chemotherapy and radiotherapy. Median survival rate is 8 months.8 Death in these patients is generally due to metastatic disease, most commonly in the lung followed by bone and soft tissues.13,18,30
Management Due to the rarity of the disease it is impossible to provide robust data to support different forms of treatments and we obviously lack Level 2 or 3 treatment recommendations. Strategies of treatment are variable and specifically focused on the single patient on the ground of “expert opinions” and literature reviews. As for most brain tumors, surgical resection seems to be the first-line treatment option in order to obtain histopathological diagnosis and mass effect relief. Due to the high rate of recurrence and metastases, resection should be as radical as possible.8,10,21,32 The role of adjuvant treatment in the survival of patients with brain angiosarcoma remains to be elucidated, even though the analysis of these 31 patients seems to support radiotherapy as an important tool to improve disease control.4,7–10,13,15,17,18,22 Reported treatment plans and doses are extremely variable (whole brain, focal, whole brain plus focal boost, cranio-spinal irradiation with doses from
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30 to 60 Gy). Even more confusing are the data regarding chemotherapy and the several drugs that have been used.4,18,32 At any rate, given the malignant features of the disease, there are data and rationale enough to support the use of all the three weapons against the tumor in a synergic way.4 Most long-survivors received, in fact, all these treatments. Further studies are required to clarify the role of the association of anti-angiogenesis drugs with temozolomide and their synergistic effect, as proposed in two case reports of extra-axial retro-orbital angiosarcomas by Hackney et al.32 Furthermore, an ongoing phase II trial is studying the role of bevacizumab in treating patients with unresectable soft tissue angiosarcoma (NCT00288015). Park et al.23 reported the preliminary results and showed a median progression-free survival of 12 weeks. However,we should highlight that one of the exclusion criteria of the trial was the involvement of the CNS.
CONCLUSIONS In the presented case the preoperative misdiagnoses of frontal cavernous angioma was done on the grounds of MRI. Histopathological and immunohistochemical investigation revealed a primary epithelioid angiosarcoma; no other primary neoplasm could be detected. Radical removal under awake anesthesia due to the eloquent tumor location, followed by adjuvant radiotherapy and chemotherapy was able to completely control the disease in the following 37 months. This case report highlights the importance for neurosurgeons and pathologists to recognize primary cerebral angiosarcomas in the setting of hemorrhagic lesions of the CNS.
ACKNOWLEDGMENTS We wish to thank Professor Juan Rosai, for his invaluable help in histopathological analysis. We are in debt to Professor Allen Fertziger for his long-lasting commitment in transforming our Italian-English into a correct and understandable English with just some Latin flavor.
DISCLOSURE The authors have no personal, financial or institutional interest in any of the drugs, materials or devices described in this article.
REFERENCES 1. Bardwil JM, Mocega EE, Butler JJ, Russin DJ. Angiosarcomas of the head and neck region. Am J Surg 1968; 116: 548–553.
2. Enziger FM, Weiss SW. Soft Tissue Tumors. St. Louis, MO: CV Mosby, 1988; 545–556. 3. Meis-Kindblom JM, Kindblom LG. Angiosarcoma of soft tissue: a study of 80 cases. Am J Surg Pathol 1988; 22 (6): 683–697. 4. Antoniadis C, Selviaridis P, Zaramboukas T, Fountzilas G. Primary angiosarcoma of the brain: case report. Neurosurgery 1996; 38: 583–585. 5. Balamurali G, du Plessis DG, Wengoy M, Bryan N, Herwadkar A, Richardson PL. Thorotrast-induced primary cerebral angiosarcoma. Neurosurgery 2009; 65 (1): E210–E211. 6. Baldovini C, Martinoni M, Marucci G. Epithelioid angiosarcoma of the septum pellucidum. Case Rep Pathol 2013. doi: 10.1155/2013/603671. 7. Charman HP, Lowenstein DH, Cho KG, DeArmond SJ, Wilson CB. Primary cerebral angiosarcoma. Case Report. J Neurosurg 1988; 68: 806–810. 8. Cookston M, Cotter GW, Schlitt M, Bastian FO. Primary angiosarcoma of the brain. South Med J 1991; 84 (4): 517–520. 9. Fuse T, Takagi T, Hirose M. Primary intracranial epithelioid angiosarcoma. Neurol Med Chir 1995; 35: 364–368. 10. Guode Z, Qi P, Hua G, Shangchen X, Hanbin W. Primary cerebellopontine angle angiosarcoma. J Clin Neurosci 2008; 15: 942–946. 11. Kirk IR, Dominguez R, Castillo M. Congenital primary cerebral angiosarcoma: CT, US and MR findings. Pediatr Radiol 1992; 22: 134–135. 12. Kristoferitsch W, Jeelinger K. Multifocal spinal angiosarcoma after chordotomy. Acta Neurochir 1986; 79: 145–153. 13. Kurian KM, Tagkalakis P, Erridge SC, Ironside JW, Whittle IR. Primary intracranial angiosarcoma of the pineal gland. Neuropathol Appl Neurobiol 2006; 32 (5): 557–561. 14. Lach B, Benoit BG. Primary composite angiogenic leiomyosarcoma-epithelioid angiosarcoma of the brain. Ultrastruct Pathol 2000; 24 (5): 339–346. 15. Lach B, Hassounah M, Khafaga Y. Primary angiosarcoma of the brain in a child. Fetal Pediatr Pathol 2008; 27 (3): 175–183. 16. Mena H, Garcia JH. Primary brain sarcomas: light and electron microscopy features. Cancer 1978; 42: 1298– 1307. 17. Mena H, Ribas JL, Enzinger FM, Parisi JE. Primary angiosarcoma of the central nervous system. J Neurosurg 1991; 75: 73–76. 18. Merimsky O, Lepechoux C, Terrier P, Vanel D, Delord JP, LeCesne A. Primary sarcomas of the central nervous system. Oncology 2000; 58 (3): 210– 214. © 2014 Japanese Society of Neuropathology
Primary CNS angiosarcoma 19. Paulus W, Slowik F, Jellinger K. Primary intracranial sarcomas: histopathological features of 19 cases. Histopathology 1991; 18: 395–402. 20. Russell DS, Rubinstein LJ. Pathology of Tumors of the Nervous System. Baltimore, MD: Williams and Wilkins, 1989; 657–658. 21. Suzuki Y, Yoshida YK, Shirane R, Yoshimoto T, Watanabe M, Moriya T. Congenital primary cerebral angiosarcoma. Case report. J Neurosurg 2000; 92 (3): 466–468. 22. Ziegler JW. Primary angiosarcoma of the brain: report of a case. J Am Osteopath Assoc 1975; 74: 957–960. 23. Park MS, Ravi V, Araujo DM. Inhibiting the VEGFVEGFR pathway in angiosarcoma, epithelioid hemangioendothelioma, and hemangiopericytoma/ solitary fibrous tumor. Curr Opin Oncol 2010; 22 (4): 351–355. 24. Martz CH. Von Hippel-Lindau disease: a genetically transmitted multisystem neoplastic disorder. Semin Oncol Nurs 1992; 8 (4): 281–287. 25. Nanus DM, Kelsen D, Clark DG. Radiation-induced angiosarcoma. Cancer 1987; 60 (4): 774–779. 26. Creech JL, Johnson MN. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med 1974; 16 (3): 150–151. 27. McIntosh BC, Narayan D. Head and neck angiosarcomas. J Craniofac Surg 2005; 16 (4): 699–703. 28. Falk H, Thomas LB, Popper H, Ishak KG. Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet 1979; 24 (2): 1120–1123. 29. Kepes JJ, Rubinstein LJ, Maw G, Burdick B. Epithelioid hemangiomas (hemangioendotheliomas) of the central nervous system and its coverings: a report of three cases. J Neuropathol Exp Neurol 1986; 45: 319. 30. Matsuno A, Nagashima T, Tajima Y, Sugano I. A diagnostic pitfall: angiosarcoma of the brain mimicking cavernous angioma. J Clin Neurosci 2005; 12 (6): 688– 691. 31. Stacchiotti S, Palassini E, Sanfilippo R et al. Gemcitabine in advanced angiosarcoma: a retrospective case series analysis from the Italian Rare Cancer Network. Ann Oncol 2012; 23 (2): 501–508.
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191 32. Hackney JR, Palmer CA, Riley KO, Cure JK, Fathallah-Shaykh HM, Nabors LB. Primary central nervous system angiosarcoma: two case reports. J Med Case Rep 2012; 6 (1): 251–255. 33. Bricklin AS, Rushton HW. Angiosarcoma of venous origin arising in radial nerve. Cancer 1977; 39 (4): 1556– 1558. 34. Schuborg C, Mertens F, Rydholm A et al. Cytogenetic analysis of four angiosarcomas from deep and superficial soft tissue. Cancer Genet Cytogenet 1998; 100 (1): 52–56. 35. Lederman SM, Martin EC, Laffey KT, Lefkowitch JH. Hepatic neurofibromatosis, malignant schwannoma, and angiosarcoma in von Recklinghause’s disease. Gastroenterology 1987; 92 (1): 234–239. 36. Heath CW, Key MM. Letter: nationwide surveillance of angiosarcoma of the liver in the United States. Arch Pathol 1974; 98 (1): 66–67. 37. Kojiro M, Nakashima T, Ito Y, Ikezaki H, Mori T, Kido C. Thorium dioxide-related angiosarcoma of the liver. Pathomorphologic study of 29 autopsy cases. Arch Pathol Lab Med 1985; 109 (9): 853–857. 38. Khan MI, Medhat O, Bonnet G. Angiosarcoma in father and son: a case report and literature review. N Z Med J 2004; 117 (1203): U1103. 39. Taratuto AL, Sevlever ZG, Saccoliti SM. Epithelioid hemangioendothelioma of the central nervous system. Immunohistochemical and ultrastructural observations of a pediatric case. Pediatr Neurosci 1988; 14: 11–14. 40. Miettinen M, Lindenmayer E, Chaubal A. Endothelial cell markers CD31, CD34, and BHN9 antibody to Hand Y- antigens-evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. Mod Pathol 1994; 7: 82–90. 41. Shintaku M, Miyaji K, Adachi Y. Gliosarcoma with angiosarcomatous features: a case report. Brain Tumor Pathol 1998; 15: 101–105. 42. Weiss SW, Ishak KG, Dail DH, Sweet DE, Enzinger FM. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 1986; 3: 259– 287.
Neuropathology 2015; 35, 184–191
doi:10.1111/neup.12178
Cas e Rep o r t
Primary central nervous system angiosarcoma: A case report and literature review Emanuele La Corte,1* Francesco Acerbi,1* Marco Schiariti,1 Morgan Broggi,1 Emanuela Maderna,2 Bianca Pollo,2 Raffaele Nunziata,2 Elio Maccagnano3 and Paolo Ferroli1 1
Department of Neurosurgery, 2Division of Neuropathology, and 3Department of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Angiosarcoma is a rare vascular malignant neoplasm that mainly occurs in skin and soft tissues. Intracranial localization is very rare and only a few cases have been reported. This report intends to present the clinical, radiological and pathological pictures of a primary central nervous system angiosarcoma along with a review of the literature. A 35-year-old woman presented at our institution with weakness and sensory disturbances of her right hand. Neuroimaging revealed a roughly round, hemorrhagic and moderately enhancing lesion in the left frontal posterior region. The tumor was totally removed under awake anesthesia and continuous monitoring of motor and language functions. Histopathology revealed an epithelioid angiosarcoma. Radical removal, followed by adjuvant radiotherapy and chemotherapy, is able to completely control the disease for a relatively long period. Key words: brain angiosarcoma, central nervous system tumor, neurosurgery, survival, treatment.
INTRODUCTION Angiosarcoma is a rare vascular malignancy (less than 1% of sarcomas) and mainly occurs in skin and soft tissues.1–3 Localization in the CNS is extremely rare and only a few cases of primary brain angiosarcomas have been reported so far in the literature4–22 (Table 1). It may occur in the CNS as a metastatic or a primary brain tumor. The prognosis for angiosarcoma is generally poor with a 5-year survival rate
Correspondence: Emanuele La Corte, MS, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 11, 20133 Milan, Italy. Email: [email protected] *Both co-authors equally contributed to the manuscript. Informed Consent: Obtained from the patient. Received 14 August 2014; revised and accepted 25 September 2014; published online 1 November 2014.
© 2014 Japanese Society of Neuropathology
of 12%.8 Angiosarcomas of the CNS are not easy to recognize on radiological imaging since MRI findings can resemble those of cavernous angiomas.30 We present a rare case of primary epithelioid angiosarcoma in a 35-year-old woman who was still disease-free 37 months after radical surgical resection, chemotherapy (CHT) and radiotherapy (RT). Our purpose is to review the literature on primary CNS angiosarcomas, elucidating their clinical, radiological and pathological features, and make recommendations for the optimal diagnosis and management of these patients.
SEARCH STRATEGY AND SELECTION CRITERIA The literature review was predominately based on articles published in the past 35 years and identified through multiple searches of PubMed using the following keywords: “primary brain angiosarcoma” AND “central nervous system angiosarcoma”. Only papers published in English and dealing with CNS primary angiosarcoma were reviewed. Some additional papers were selected from the reference lists of papers identified previously in PubMed. The final reference list was generated on the basis of originality and relevance to the broad scope of this review.
CLINICAL SUMMARY A 35-year-old woman started to complain of paraesthesia in her right hand and arm followed by distal motor impairment that appeared immediately after pregnancy and delivery. Her previous clinical history was negative. Her familiar history was positive for familiar glycosuria, spina bifida and epilepsy. Pre-operative brain imaging (MRI scans) showed a partially hemorrhagic, moderateenhancing lesion in the left frontal lobe with peripheral edema. Differential diagnosis included a bleeding cavernous angioma or any other vascular or bleeding tumor
39 41 37 27
18 73 4 weeks 16 56 68 9
M F F M M M M
M M M F F M M
M F
Paulus et al. (1991)19
© 2014 Japanese Society of Neuropathology
Fuse et al. (1995)9 Antoniadis et al. (1996)4 Lach and Benoit (2000)14 Merimsky et al. (2000)18
Suzuki et al. (2000)21 Kurian et al. (2006)13 Guode et al. (2008)10 Lach et al. (2008)15 Balamurali et al. (2009)5
Baldovini et al. (2013)6 This study 54 35
24 26 2 weeks
1 6 32 2 week-72 (mean 38)
Septum pellucidum L frontal
Occipitoparietal Cervical spine L frontotemporal R cerebellopontine angle Pineal R parietal L parietoccipital
R parietal L parietal R frontoparietal Parietal
Anterior cranial fossa Cervicomedullary region R occipital 6 cerebral parenchyma (parietal most frequent), 1 meninges, 1 not stated Temporal Frontal R temporal
R posterior parietal L posterior frontal Thoracic and lumbar spinal region L posterior parietooccipital
Location (lobe/region)
Parenchyma Parenchyma
Parenchyma Parenchyma Parenchyma Parenchyma Parenchyma Parenchyma Parenchyma
Parenchyma Parenchyma Parenchyma Parenchyma
Parenchyma Parenchyma Meninges
Meninges Meninges Parenchyma Parenchyma/ Meninges
Parenchyma
Parenchyma Parenchyma Meninges
Assumed CNS tissue origin
Unknown Unknown Congenital angiosarcoma Unknown Uterine fibromas Unknown Congenital deafness and occupational exposure to chemicals Unknown Unknown Cas Unknown Unknown Unknown Exposure to thorotrast-dioxide 62 yrs prior Unknown Unknown
Unknown Unknown Previous chordotomy Exposure to industrial solvents Unknown Unknown Unknown Unknown
Predisposing factor
F, female; M, male; L, left; R, right; S, surgical; GTR, gross total resection; RT, radiotherapy; CT, chemotherapy; PR, partial resection.
Kirk et al. (1992)11
Cookston et al. (1991)8 Mena et al. (1991)17
M F F M(5); F(3)
Russel and Rubinstein (1989)20
65
M
Charman et al. (1988)7
17 15 60
Age
M F M
Sex
Ziegler (1975)22 Mena and Garcia (1978)16 Kristoferitsch and Jeelinger (1986)12
Reference
Table 1 Cases of primary angiosarcoma of the CNS
S S + RT+CT
S S + RT+CT S S + RT S + RT S + RT S
S + RT S + CT+RT S RT
Unknown Unknown S
Unknown Unknown S + RT S(8) + RT(1)
S + RT
S + RT S Nothing
Treatment
GTR GTR
PR PR GTR PR GTR GTR PR
GTR GTR GTR Unknown
Unknown Unknown GTR
Unknown Unknown GTR Unknown
GTR
PR PR Unknown
Surgery
2 37+
5 20 11+ 6+ 48 6 11
29 41+ 18 2.5
Unknown Unknown 42+ 4 (4), 30, 39+, 102+, unknown Unknown Unknown 26+
13
2.5 2 1
Survival (months)
Primary CNS angiosarcoma 185
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Fig. 1 (A,B) Preoperative MRI show a roughly round lesion characterized on both axial T2-weighted and T1-weighted images by an heterogeneous signal with hypointense components on T2 and hyperintense components on T1 due to the presence of blood degradation products in different stages (subacute/chronic phases). (C) On axial T1-weighted with i.v. paramagnetic contrast administration, the lesion shows a moderate enhancement, mainly in its anterior portion.
(Fig. 1). From a radiologic point of view, it was not possible to exclude any other lesion. Her symptoms progressed and she was referred to our institution with the recommendation of surgical removal of the lesion. General physical examination was normal. She was awake, alert and well oriented, with a minimal impairment in her right hand movement. Any other neurological deficit was disclosed by neurological examination. Image-guided surgery was performed under awake anesthesia with brain mapping and continuous monitoring of motor and language performances. The tumor mass was brown and the surrounding arachnoid membrane was thickened. The tumor was highly vascular, firm but elastic and clearly demarcated from the surrounding brain parenchyma and it could be totally removed. The post-operative course was characterized by immediate improvement of her right hand movement and temporary dysarthria that completely recovered in 2 weeks. Post-operative CT and MRI ruled out complications and confirmed the completeness of the removal. Whole-body imaging (CT scan, positron emission tomography with 18fluorodeoxyglucose (FDG-PET)) ruled out the presence of a soft tissue primitive localization. On the ground of histopathological diagnosis, a course of cranial radiation therapy, consisting of 58 Gy fractionated conformational radiotherapy was administered (29 fractions; 2 Gy/day). Chemotherapy was also administered (six courses with two drugs: temozolomide 150 mg/m2 (days 1–5); gemcitabine 800 mg/m2 (days 1, 8, 15, 28).31 At 37 months of follow-up MRI ruled out recurrent disease (Fig. 2).
PATHOLOGICAL FINDINGS The specimen was fixed in Carnoy and paraffin embedded. Sections were processed for HE and immunohistochemical staining. Histopathological examination showed a tumor composed of irregular blood vessels loosing integrity, lined by neoplastic endothelial cells and large endothelial cells that formed sheets or nests. Vascular anastomotic channels of different shape and caliber were found and many tumor cells presented intracytoplasmatic vacuoles resembling primitive blood vessels. Neoplastic vascular cells showed large, hypercromatic, pleomorphic nuclei, prominent nucleoli and eosinophilic cytoplasms. Mitoses were frequent and areas of necrosis and hemorrhage could be seen. Immunohistochemical results showed strong expression of endothelial cell marker CD34 and faint expression of CD31. Immunostaining for vimentin suggested a mesenchymal origin. Cells were negative for GFAP, CK (AE1/AE3) and HMB45. Malignant features were supported by the MIB1/Ki67 index accounting for 20% (mean of five mitoses for 10 high power fields). These epithelial, vasoformative and highly malignant characteristics supported the diagnosis of epithelioid angiosarcoma (Fig. 3).
DISCUSSION Overview and epidemiology Soft tissue and bone sarcomas are rare tumors that constitute only 1% of all human malignancies. Angiosarcomas are malignant tumors originating from endothelial cells © 2014 Japanese Society of Neuropathology
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Fig. 2 (A,B) Coronal (A) and axial (B) T1-weighted with i.v. paramagnetic contrast administration MRI show a small surgical cavity with clear margins, no contrast enhancement and no signs of recurrent disease 37 months after surgery. (C) Proton magnetic resonance spectroscopy (H1-MRS) has been also performed in order to evaluate the metabolic profile of the cerebral tissue next to the surgical cavity. There is no evidence of pathological metabolic profile.
that can occur in any region of the body, although they are most commonly located in the skin, breast, liver and deep tissues.3 Primary or secondary angiosarcoma of the CNS is rarely reported. The heart is the most common site of origin of metastatic CNS angiosarcomas. A review of the literature revealed 30 primary tumors originating from the cerebral parenchyma or meninges4–22 (Table 1). The diagnosis of primary angiosarcoma of the brain was done only after ruling out other localizations by whole body imaging. We have not included in our table two case reports, considered by the authors as primary CNS angiosarcoma, because of their clear extra-axial nature without any evidence of intradural extension.32 Angiosarcomas have been also described in peripheral nerves.33 Males (65%) were more frequently affected than females (35%). The age presentation ranged from 2 weeks to 73 years (mean 24 years). The most frequent site of origin was the CNS parenchyma (81%), with the parietal lobe being the most common location. The meninges (16%) represent a rare site of origin of primary CNS angiosarcomas. Only two cases were found in the posterior fossa, two cases occurred © 2014 Japanese Society of Neuropathology
in the spinal cord and one at the level of septum pellucidum.
Risk factors and etiology Etiology and oncogenetic pathways of angiosarcoma development are still unknown. Genetic factors may play a key role, along with environmental factors. Angiosarcoma has been associated with both chromosomal abnormalities and inheritable genetic diseases. Frequent chromosome abnormalities are gains in the normal number of two of each chromosome 5, 20 and 8 and losses of chromosomes 7, 22 and the male Y chromosome.34 There are case reports of angiosarcoma in patients with Klippel Trenaunay syndrome, Von Hippel Lindau disease and Von Recklinghausen neurofibromatosis.3,24,35 Non-CNS angiosarcomas have also been associated with environmental factors such as chronic lymphedema, trauma and previous irradiation exposure, some cancerous materials such as vinyl chloride, chemotherapy, arsenic and thorium dioxide as a contrast dye for angiography and foreign
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Fig. 3 (A,B) Photomicrograph showing the tumor composed of irregularly arranged fascicles of epithelioid tumor cells, with several tumor cells containing intracytoplasmic vacuoles, which resemble primitive blood vessels. Mitoses were common. HE stain, 10× and 20×. Insert: high-magnification histological picture. HE stain, 40×. (C) Photomicrographs showing immunohistochemical reaction to CD34, CD31 (D) and anti-vimentin (VIM) antibodies (E), 20×. (F) Photomicrographs showing immunohistochemical staining for proliferating index Ki67/MIB1, 20×.
materials (Dacron and other surgical materials).5,7,11,18, 25–28,36,37 There have also been a few isolated reports of angiosarcomas among primary relatives without obvious cause.38,39 This suggests a rare inheritable variant of angiosarcoma or possible unknown exposure to an angiosarcoma-causing agent among family members. Our review of the literature regarding primary CNS angiosarcoma revealed two patients presenting with congenital tumors,11,21 one with a previous history of spine surgery (chordotomy),12 one who underwent hysterectomy for uterine fibroma,4 two with a history of occupational
exposure to industrial solvents and chemicals7,18 and one with a history of exposure of thorotrast-dioxide as a radiologic contrast medium.5
Histopathology Angiosarcoma is characterized by strands of spindle cells and nests of epithelioid cells, vasoformative areas with arborized vascular channels lined by neoplastic endothelial cells. Tumor endothelial cells are large, hyperchromatic, with pleomorphic nuclei, prominent nucleoli and abundant © 2014 Japanese Society of Neuropathology
Primary CNS angiosarcoma eosinophilic cytoplasm. Mitoses are frequent and necrosis is occasionally observed. Based on the large number of mitotic cells, our case was diagnosed as an epithelioid angiosarcoma, rather than an epithelioid hemangioendothelioma or an epithelioid sarcoma. Epithelioid hemangioendothelioma is a low-grade vascular malignancy formed by loosed aggregates of spindle cells in a focal cord-like arrangement supported by a myxoid stroma. Conversely, epithelioid sarcoma consists of cellular nodules of epithelioid cells with central necrosis, but mitotic activity is usually low. Epithelioid angiosarcoma is a rare variant of high-grade malignancy characterized by alternating foci of spindle and epithelioid cells and vasoformative areas of dilated vascular channels. Immunohistochemical investigation was a useful diagnostic tool in the differential diagnosis of angiosarcoma from other neoplasms. Epithelioid vascular tumor cells expressed sensitive markers for endothelial cells CD34 and CD31. Although it has been accepted that CD31 is a specific and sensitive endothelial marker, some vascular lesions are negative for CD31 and positive for other vascular markers, such as CD34 and factor VIII. The present case supports such hypothesis, that malignant endothelial lesions may demonstrate heterogeneity of expression of vascular antigens.40 The expression of vimentin has also been shown, suggesting a mesenchymal origin. Differential diagnosis includes other vascular/bleeding tumors of the CNS such as metastases (carcinoma, melanoma), epithelioid sarcoma, hemangioblastoma, solitary fibrous tumor, hemangioendothelioma and cavernous angioma.29,41,42 The application of immunohistochemical techniques has become a useful diagnostic tool, the immunopositivity or negativity of endothelial markers, cytokeratins, S100, HMB45 and MIB1/Ki67 are useful in the differential diagnosis of angiosarcoma from epithelioid sarcoma, metastatic carcinoma, malignant melanoma and hemangioblastoma.
Clinical presentation The clinical manifestations of these tumors are related to their anatomical sites in the CNS and frequently act like a space-occupying lesion, producing focal symptoms when in eloquent areas along with raised intracranial pressure syndrome. The clinical course of brain angiosarcoma may be characterized by the rapid onset or abrupt aggravation of symptoms due to intra-lesional and extra-lesional hemorrhage (18 out of 31 cases).6,7,10–13,15–17,21,30
Diagnostic evaluation The radiological appearance of cerebral angiosarcomas is not typical and differential diagnosis includes most common brain lesions such as bleeding metastases, gliomas and cavernomas. Our case represents one of the most © 2014 Japanese Society of Neuropathology
189 common radiological features of the lesion found in the literature.4,7,8,30 Brain MRI disclosed a heterogeneous mixed signal intensity lesion on T1-weighted images with moderate enhancement in some areas after contrast injection. The lesion showed intra-lesional mixed signal intensity on both T1 and T2-weighted images with blood degradation products in different stages. These characteristics might wrongly direct the MRI radiological diagnosis toward a cavernous angioma as already observed by Matsumoto et al.30 Due to the absence of flow-void on MRI, which is suggestive for high-flow vascular structures, a digital subtraction angiography (DSA) has not been performed. However, cerebral DSA has been found to be non-diagnostic of primary CNS angiosarcomas, since these lesions very often do not display any hypervascularization or pathological circulation.8,9,13,16,32 DSA appeared normal in most of the cases, while one case in the literature showed a blush in the neoplastic area.17 Probably, a CT scan would be used to disclose calcifications and/or the presence of fresh blood. Ultrasound has been rarely used in congenital cases in infants.11
Outcomes Since primary malignant vascular tumors of the CNS are rare and differ considerably, treatment and survival are variable (Table 1). The reported prognosis of angiosarcomas is generally poor, with some surprising exceptions, such as our 35-year-old woman that is still disease-free 37 months after radical surgical resection, chemotherapy and radiotherapy. Median survival rate is 8 months.8 Death in these patients is generally due to metastatic disease, most commonly in the lung followed by bone and soft tissues.13,18,30
Management Due to the rarity of the disease it is impossible to provide robust data to support different forms of treatments and we obviously lack Level 2 or 3 treatment recommendations. Strategies of treatment are variable and specifically focused on the single patient on the ground of “expert opinions” and literature reviews. As for most brain tumors, surgical resection seems to be the first-line treatment option in order to obtain histopathological diagnosis and mass effect relief. Due to the high rate of recurrence and metastases, resection should be as radical as possible.8,10,21,32 The role of adjuvant treatment in the survival of patients with brain angiosarcoma remains to be elucidated, even though the analysis of these 31 patients seems to support radiotherapy as an important tool to improve disease control.4,7–10,13,15,17,18,22 Reported treatment plans and doses are extremely variable (whole brain, focal, whole brain plus focal boost, cranio-spinal irradiation with doses from
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30 to 60 Gy). Even more confusing are the data regarding chemotherapy and the several drugs that have been used.4,18,32 At any rate, given the malignant features of the disease, there are data and rationale enough to support the use of all the three weapons against the tumor in a synergic way.4 Most long-survivors received, in fact, all these treatments. Further studies are required to clarify the role of the association of anti-angiogenesis drugs with temozolomide and their synergistic effect, as proposed in two case reports of extra-axial retro-orbital angiosarcomas by Hackney et al.32 Furthermore, an ongoing phase II trial is studying the role of bevacizumab in treating patients with unresectable soft tissue angiosarcoma (NCT00288015). Park et al.23 reported the preliminary results and showed a median progression-free survival of 12 weeks. However,we should highlight that one of the exclusion criteria of the trial was the involvement of the CNS.
CONCLUSIONS In the presented case the preoperative misdiagnoses of frontal cavernous angioma was done on the grounds of MRI. Histopathological and immunohistochemical investigation revealed a primary epithelioid angiosarcoma; no other primary neoplasm could be detected. Radical removal under awake anesthesia due to the eloquent tumor location, followed by adjuvant radiotherapy and chemotherapy was able to completely control the disease in the following 37 months. This case report highlights the importance for neurosurgeons and pathologists to recognize primary cerebral angiosarcomas in the setting of hemorrhagic lesions of the CNS.
ACKNOWLEDGMENTS We wish to thank Professor Juan Rosai, for his invaluable help in histopathological analysis. We are in debt to Professor Allen Fertziger for his long-lasting commitment in transforming our Italian-English into a correct and understandable English with just some Latin flavor.
DISCLOSURE The authors have no personal, financial or institutional interest in any of the drugs, materials or devices described in this article.
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