Progressive enlargement of a mass lesion in late cerebral radionecrosis

Case Reports / Journal of Clinical Neuroscience 18 (2011) 853–855

patient undergoing rituximab therapy at 18-month follow-up,4 surgery can rapidly improve pain relief and neurological morbidity of LYG for patients with spinal cord compression. However, the prognosis of patients with spinal LYG remains poor,3 due to systemic progression of disease, as shown by our patient. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jocn.2010.08.042. References

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2. Collins S, Helme RD. Lymphomatoid granulomatosis presenting as a progressive cervical cord lesion. Aust N Z J Med 1989;19:144–6. 3. Herderscheê D, Troost D, de Visser M, et al. Lymphomatoid granulomatosis: clinical and histopathological report of a patient presenting with spinal cord involvement. J Neurol 1988;235:432–4. 4. Ishiura H, Morikawa M, Hamada M, et al. Lymphomatoid granulomatosis involving central nervous system successfully treated with rituximab alone. Arch Neurol 2008;65:662–5. 5. Heslop HE. Biology and treatment of Epstein-Barr virus-associated non-Hodgkin lymphomas. Hematology Am Soc Hematol Educ Program 2005;1:260–6. 6. Lipford Jr EH, Margolick JB, Longo DL, et al. Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 1988;72:1674–81. 7. Liebow AA, Carrington CR, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol 1972;3:457–558.

1. Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 1979;43:360–73.

doi:10.1016/j.jocn.2010.08.041

Progressive enlargement of a mass lesion in late cerebral radionecrosis Yoshihiko Yoshii a,b,⇑, Koichi Sugimoto a,b, Kyoko Fujiwara b a b

Tsukuba Memorial Hospital, Tsukuba Brain and Spine Center, Tsukuba-city, Ibaraki, Japan Department of Neurosurgery, Faculty of Medicine, University of Ryukyu, 207 Nishihara, Uehara-Cho, Okinawa 903-0215, Japan

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Article history: Received 5 August 2010 Accepted 24 August 2010

Keywords: Immunohistochemistry Inflammation-related cytokines Late cerebral radionecrosis Necrotic factor Progressive enlargement

a b s t r a c t The progressive enlargement of a mass lesion in late cerebral radionecrosis (LCR) was studied using a surgical specimen from a woman’s irradiated brain. Using immunohistochemical (IHC) staining on paraffinembedded sections, expression of tumor necrosis factor-alpha (TNFa), interleukin (IL)6, Flk-1, and vascular endothelial growth factor (VEGF) was semi-quantitatively evaluated in the necrotic area and areas distant and adjacent to the necrotic area. High immunoreactivity for TNFa, IL6, and VEGF in regions distant to the necrotic core were strongly associated with inflammatory cell density, hyalinized vessels, and vascularization. Ghost cells stained with glial fibrillary acidic protein (GFAP), Ki-M1P, KP-1, ubiquitin-C-terminal hydrolase 1, and fibrinoid necrosis were observed in the necrotic area and adjacent regions. These results suggest that necrotic factors, inflammatory reaction, and angiogenetic factors act temporally and spatially through radiation-induced vascular endothelial cell damage to contribute to the progressive enlargement of an enhancing mass lesion in LCR. Ó 2010 Elsevier Ltd. All rights reserved.

1. Introduction Extensive coagulative necrosis and progressive enlargement of a mass lesion are clinicopathologic characteristics of late cerebral radionecrosis (LCR). Reports suggest involvement of cytokine pathways.1,2 Inflammatory reactions have been observed following exposure to radiation, and secretion of tumor necrosis factor (TNF)-alpha(a) and transforming growth factor (TGF)-beta(b) after irradiation of endothelial cells has been reported.3–5 Indeed, secretion of cytotoxic molecules induced by chronic activation of microglia may cause brain tissue damage.6 In the current report, a surgical specimen from a patient with progressive enlargement of a mass lesion in LCR was studied using immunohistochemistry (IHC).

mal enhancement in the frontal lobe, as detected by MRI with gadolinium-diethylene-triaminepenta-acetic acid (Gd-MRI) (Fig. 1b). The patient had previously undergone resection of a malignant peripheral nerve sheath tumor by the Otolaryngology and Radiology Division of Ryukyu University Hospital and was irradiated after surgery to the ethmoid sinus and frontal base with 6 Mv Linac beams with 50 Gy in 1.5 Gy fractions (Fig. 1a). A small mass was observed in the frontal lobe 2 years after the patient underwent radiotherapy. She was admitted 10 months later for headaches and convulsions. Imaging revealed the enhancing mass had enlarged and was accompanied by significant oedema (Fig. 1b). The enhancing area was observed in the irradiated field within the 90% dose line (Fig. 1a). Total extirpation of the mass was performed presuming the diagnosis of recurrent and/or invasive tumor. The tissue diagnosis was radionecrosis.

2. Material and methods 2.1. Immunohistochemistry The surgical specimen was taken from a 55-year-old woman who presented with a frontal headache and had an area of abnor⇑ Corresponding author. Tel.: +81 29 864 1212; fax: +81 29 864 8135. E-mail address: [email protected] (Y. Yoshii).

The surgical specimen was fixed with buffered formalin and embedded in paraffin. Sections were subjected to microwave antigen retrieval and were incubated with antibodies for TNFa (Abcam, Cambridge, MA, USA), interleukin (IL) 6 (Abcam), and Flk-1 (Santa

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Case Reports / Journal of Clinical Neuroscience 18 (2011) 853–855

Fig. 1. (a) Sagittal CT reconstruction showing the region studied, which had received 90% to 100% of the total radiotherapy (RT) dose (50 Gy in 1.5 Gy fractions) to the ethmoid sinus and frontal base after surgery. (b) Sagittal gadolinium enhanced (GD)-MRI: pre-RT (left); 2 years after RT (middle) showing a small, enhancing area in the frontal lobe; and 2 years and 10 months after RT (right) showing that the area of enhancement and edema had enlarged markedly.

immunopositive for TNFa, IL6, and VEGF. Inflammatory cells were strongly immunopositive for vimentin, Ki-M1P, KP-1, and UCHL. The histopathological findings are summarized in Table 1.

Cruz Biotechnology, Santa Cruz, CA, USA). In additional studies, vascular endothelial growth factor (VEGF) (Santa Cruz Biotechnology), KP-1 (CD68, Dako Cytomation, Glostrup, Denmark), Ki-M1P (Seikagaku, Tokyo, Japan), ubiquitin-C-terminal hydrolase 1 (UCHL), L26, leucocyte common antigen (LCA), vimentin, and GFAP all from (Dako) were used. Negative controls were processed with adjacent sections. All sections were incubated with a biotinylated secondary antibody, horseradish peroxidase-labeled streptavidin, and diaminobenzidine.

3. Discussion Radiation-induced vascular endothelial cell damage has long been associated with microcirculation disorders and progressive loss of the blood brain barrier (BBB). The role of TNFa in BBB damage has been well established.3,7,8 The current pathological study revealed: that (i) vascular change and an inflammatory reaction occur distant to the necrotic core and (ii) the necrotic core is formed at the end of the inflammatory reaction, when tissue is beyond repair. Additionally, TNFa, IL6, and VEGF appear to contribute to tissue necrosis and neovascularization distant to the necrotic core. Our results also suggest that the overproduction of VEGF and Flk-1 may contribute to abnormal vessel structure, including telangiectasia and angiomatoid vessels. Finally, our results indicate that progressive enlargement of an enhancing mass in LCR is associated with vascular endothelial cell damage in the irradiated field. It is thought that ionizing radiation induces untargeted effects of genomic instability (so-called radiation-induced bystander effects or radiation-induced genomic instability).9,10 If immediate endothelial cell damage was extensive, the vessels would be dam-

2.1.1. Histopathological results The IHC staining patterns were assessed in three areas: (i) at the necrotic core; (ii) adjacent to the necrotic core; and (iii) distant to the necrotic core. At the necrotic core of acidophilic amorphous tissue (Supplementary Fig. 1), many obstructed vessels and angionecrotic cells were observed. Some ghost cells were strongly immunopositive for TNFa, and some cell fragments also were immunoreactive for IL6 and VEGF. The IHC staining pattern adjacent to the necrotic core was similar to the pattern observed at the necrotic core, but lymphocytes were occasionally observed around vessels. Distal to the necrotic core (Supplementary Fig. 2), many vessels with intimal thickening, as well as highly dense cellular and vascular areas, were observed. Telangiectatic, angiomatoid and obstructed vessels also were observed. Many inflammatory cells and vascular endothelial cells were strongly

Table 1 Histopathology and immunohistochemistry in the necrotic core (NC) and surrounding areas Pathological area

Cell Density

Ghost Cells

Fragmented Cells

Fibrinoid Necrosis

Obstructed Vessels

Hyalinized Vessels

Vascularization

Necrotic core Adjacent to NC Distant to NC

None–few Few Moderate–many

Moderate Few–moderate None

Few–moderate Few None

Moderate Minimal None

Moderate–many Few None–few

Moderate–many Moderate Moderate–many

Few (ghost) Few Many

Necrotic core Adjacent to NC Distant to NC

GFAP

Vimentin

Ki-M1P

KP-1

UCHL

L26

LCA

TNF a

IL6

VEGF

FLK1

None–few (ghost) Few (ghost)

None

Few (ghost)

Few (ghost) Few

Moderate (ghost) Moderate

None–few (ghost) Moderate

Many

Few

Moderate (ghost) Moderate (ghost) Many

None

Moderate (ghost) Many

Non–few (ghost) Few (ghost)

None

Few (ghost) Many

Few–moderate (ghost) Moderate (ghost) Many

Many

Moderate

Few

Many

None

Few– moderate

None

Note the prominent cell density, hyalinized vessels, and vascularization in the region distant to the coagulative necrosis. Note the immunoreactivity of ghost cells in the necrotic region and viable cells in the distant region for glial fibrillary acidic protein (GFAP), Ki-M1P, KP-1. Note the immunoreactivity of viable vascular endothelial cells and extravascular viable inflammatory cells for tumor necrosis factor (TNF)-a, interleukin (IL)-6, vascular endothelial growth factor (VEGF), and Flk-1 in the distant region. UCHL = ubiquitin-C-terminal hydrolase 1, LCA = leucocyte common antigen. The frequency of positive cells was evaluated on 200 and/or 400 magnified microscopic fields of each region. The criterion for none–few classification was a region where less than one third of all cells were positive, and the criterion for many was a region where more than two thirds of all cells were positive. Cell fragments expressing positivity were not counted.

Case Reports / Journal of Clinical Neuroscience 18 (2011) 855–857

aged and the enhancing mass would be immediately apparent on imaging. However, with more subtle vascular damage, vessel changes would be apparent only after several cell cycles of the damaged endothelial cells, and the enhancing mass lesion would develop in a delayed fashion. Because the radiosensitivity of endothelial cells differs among the innumerable blood vessels in the irradiated field, the development of LCR varies temporally and spatially.

4. Conclusion We conclude that a combination of factors released in response to radiation-induced vascular endothelial cell damage, including angiogenetic factors and the inflammatory response, act temporally and spatially to produce a progressively enlarging enhancing mass in LCR.

Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jocn.2010.08.041.

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References 1. Daigle JL, Hong JH, Chiang CS, et al. The role of tumor necrosis factor signaling pathways in the response of murine brain to irradiation. Cancer Res 2001;61:8859–65. 2. Kureshi SA, Hofman FM, Schneider JH, et al. Cytokine expression in radiationinduced delayed cerebral injury. Neurosurgery 1994;35:822–30. 3. Yoshii Y. Pathological review of late cerebral radionecrosis. Brain Tumor Pathol 2008;25:51–8. 4. Yuan H, Gaber MW, Boyd K, et al. Effects of fractionated radiation on the brain vasculature in a murine model: blood–brain barrier permeability, astrocyte proliferation, and ultrastructural changes. Int J Radiat Oncol Biol Phys 2006;66:860–6. 5. Natarajan M, Gibbons CF, Mohan S, et al. Oxidative stress signaling: a potential mediator of tumour necrosis factor alpha-induced genomic instability in primary vascular endothelial cells. Br J Radiol 2007;80:S13–22. 6. Dheen ST, Kaur C, Ling EA. Microglial activation and its implications in the brain diseases. Curr Med Chem 2007;14:1189–97. 7. Ljubimova N, Hopewell JW. Experimental evidence to support the hypothesis that damage to vascular endothelium plays the primary role in the development of late radiation-induced CNS injury. Br J Radiol 2004;77:488–92. 8. Wilson CM, Gaber MW, Sabek OM, et al. Radiation-induced astrogliosis and blood-brain barrier damage can be abrogated using anti-TNF treatment. Int J Radiat Oncol Biol Phys 2009;74:934–41. 9. Gaugler MH, Neunlist M, Bonnaud S, et al. Intestinal epithelial cell dysfunction is mediated by an endothelial-specific radiation-induced bystander effect. Radiat Res 2007;167:185–93. 10. Wright EG, Coates PJ. Untargeted effects of ionizing radiation: implications for radiation pathology. Mutat Res 2006;597:119–32.

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Growing skull fracture in an adult nine years after blunt head trauma Gilberto Ka Kit Leung a,⇑, Koon Ho Chan b, Kwun Ngai Hung a a b

Division of Neurosurgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China Division of Neurology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

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Article history: Received 14 September 2010 Accepted 22 September 2010

Keywords: Cerebrospinal fluid Complications Encephalocele Epilepsy Growing fracture Head injury

a b s t r a c t Growing skull fracture (GSF) is an uncommon but well recognized complication of calvarial fracture in infancy and early childhood. The condition is rare in adults, and involvement of the skull base in this group of patients affects mostly the orbital roof. We present a patient with an unusual GSF involving the cribriform plate in a 37-year-old man who presented with late-onset epilepsy and recurrent meningitis 9 years after the initial trauma. Imaging studies revealed an associated intraethmoidal meningoencephalocele. The patient recovered well after a limited transcranial repair with preservation of olfactory function. A high index of suspicion should be exercised in the management of patients who present with these symptoms even many years after injury. Ó 2010 Elsevier Ltd. All rights reserved.

1. Introduction Growing skull fracture (GSF) is an uncommon but well-recognized complication of calvarial fracture in infancy and early childhood.1 The condition is rare in adults, and involvement of the skull base is even rarer.2 We present a patient with an unusual GSF involving the cribriform plate in an adult who presented 9 years after injury. 2. Case report A 37-year-old man presented with a 3-month history of intermittent fever, nasal discharge and tonic–clonic seizure. He ⇑ Corresponding author. Tel.: +852 2255 3368; fax: +852 2818 4350. E-mail address: [email protected] (G.K.K. Leung).

had sustained a left cribriform plate fracture from blunt head trauma 9 years prior (Fig. 1a) The injury was managed conservatively, and no meningoencephalocele was seen on follow-up. He did not complain of any neurological symptoms until this presentation. On examination, his olfactory function was intact. Cerebrospinal fluid (CSF) rhinorrhea was confirmed biochemically. Prophylactic antibiotics and antiepileptic medications were given. A CT scan revealed a defect in the left cribriform plate corresponding to the previous fracture site. The defect had increased significantly in size, suggestive of a GSF (Fig. 1b). MRI studies revealed an associated left intraethmoidal meningoencephalocele (Fig. 2). A transcranial repair was performed through a left frontal craniotomy. A meningoencephalocele was herniating through a 1.5-cm skull defect into the nasal cavity. The left olfactory bulb could not