Delayed Radiation Necrosis 7 Years After Gamma

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cent to eloquent brain areas.4,8) The primary goal of GKS in the treatment of ... years after gamma knife surgery showing a heterogeneously en- hanced mass ...
Neurol Med Chir (Tokyo) 50, 62¿66, 2010

Delayed Radiation Necrosis 7 Years After Gamma Knife Surgery for Arteriovenous Malformation —Two Case Reports— Tatsuki OYOSHI, Kazuho HIRAHARA*, Koichi UETSUHARA*, Kazutaka YATSUSHIRO, and Kazunori ARITA Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima; *Department of Neurosurgery, Kagoshima City Hospital, Kagoshima

Abstract A 44-year-old woman and a 55-year-old woman were treated with gamma knife surgery (GKS) for occipital arteriovenous malformation (AVM). Angiography confirmed complete nidus obliterations 2 years after GKS. However, both patients complained of chronic headache and visual symptoms from around 7 years after GKS. Magnetic resonance imaging showed round masses with or without cystic change surrounded by large areas of brain edema. Angiography also showed complete obliteration of AVM at this time. Extended corticosteroid treatment failed to control the edema. Both patients underwent total surgical removal of the mass. Visual disturbance and chronic headache improved postoperatively and the brain edema rapidly subsided. The histological diagnosis was radiation necrosis in both cases, attributed to the low conformity index and large 12-Gy volume due to usage of a large collimator for GKS. These cases of delayed radiation necrosis after GKS suggest that surgical removal of necrotic lesions is necessary for radiation necrosis intractable to medical treatment. Key words: delayed radiation necrosis, 12-Gy volume, conformity

arteriovenous malformation,

Introduction

gamma knife surgery,

giography demonstrated that the AVM was supplied by branches of both the right middle cerebral artery (MCA) and the posterior cerebral artery (PCA), and drained into the right transverse sinus. As the patient was reluctant to undergo surgical removal, GKS was performed in November 1999. The nidus (5.9 cm3) was covered with a 50% isodose volume, with a maximal dose of 42 Gy to obtain the prescription dose of 21 Gy, using a combination of both 8and 14-mm collimator helmets. Complete obliteration of the AVM was confirmed by angiography 2 years after GKS. However, MR imaging at 4 years after GKS showed a small area of brain edema in the right occipital lobe (Fig. 1B). The patient again experienced severe migraine-like headache and transient visual abnormality on the left side in November 2006. MR imaging showed a heterogeneously enhanced mass with a cyst in the treated area associated with surrounding brain edema (Fig. 1C, D), but angiography revealed no vascular abnormalities. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed the mass was hypometabolic. The patient was treated with corticosteroids for the next 6 months, but the symptoms did not improve. The mass was surgically removed in July 2007 and the histological diagnosis was

Gamma knife surgery (GKS) is a widely accepted treatment modality for cerebral arteriovenous malformation (AVM), particularly for deep seated lesions or lesions adjacent to eloquent brain areas.4,8) The primary goal of GKS in the treatment of cerebral AVM is the complete angiographic obliteration of the nidus and normalization of the hemodynamics.11,23,25) However, delayed radiation-induced complications remain a significant problem in some patients treated with radiosurgery. The majority of these adverse events occur within 3 years of radiosurgical treatment.21) Here we describe 2 cases of histologically proven delayed radiation necrosis that became symptomatic 7 years after GKS for AVM and were successfully treated by surgical removal.

Case Reports Case 1: A 44-year-old woman presented to our hospital for evaluation of migraine-like headache and transient visual defect in October 1999. Magnetic resonance (MR) imaging revealed a right occipital lobe AVM (Fig. 1A), and an-

Received October 9, 2008; Accepted February 2, 2009 Author's present address: T. Oyoshi, M.D., Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.

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Delayed Radiation Necrosis 7 Years After Radiosurgery

Fig. 1 Case 1. A: T2-weighted magnetic resonance (MR) image showing an arteriovenous malformation in the right occipital lobe. B: T2-weighted MR image at 4 years after gamma knife surgery showing a small area of brain edema in the right occipital lobe. C: T1-weighted MR image with gadolinium at 7 years after gamma knife surgery showing a heterogeneously enhanced mass with cyst in the right occipital lobe. D: T 2weighted MR image showing the cyst was hyperintense, associated with marked perifocal edema.

radiation necrosis (Fig. 2 upper). Brain edema subsided rapidly and she was discharged without headache. Case 2: A 55-year-old woman presented with headache in November 1999. The patient showed no neurological deficits. MR imaging revealed a left occipital lobe AVM (Fig. 3A). Angiography demonstrated that the AVM was supplied by branches of both the left MCA and the PCA, and drained into the left transverse sinus. GKS was performed in December 1999. The nidus (7 cm3) was covered with a 45% isodose volume, with a maximal dose of 44.4 Gy, to obtain the prescription dose of 20 Gy, using a 14-mm collimator helmet. Postradiosurgical MR imaging at 20 months revealed neither enhancement of the nidus nor flow void signal abnormalities. Complete obliteration of the AVM was confirmed angiographically at 24 months after GKS. The patient remained free of neurological symptoms for 7 years after GKS. However, MR imaging at 5 years after GKS showed a large area of brain edema in the left occipital lobe. The patient complained of headaches and presented with right homonymous hemianopsia in June 2006. MR imaging identified a heterogeneous hemorrhagic mass in the treated area, surrounded by severe brain swelling (Fig. 3B, C). Angiography revealed no vas-

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Fig. 2 Upper: Case 1. Photomicrograph of radiation necrosis demonstrating thickening of vessel walls, hyalinization (arrowheads), and some necrotic areas (arrows). Hematoxylin and eosin stain, original magnification ×30. Lower: Case 2. Photomicrograph showing extensive necrosis (arrowheads) adjacent to gliotic edematous brain tissue and numerous hemosiderin-laden macrophages (arrows). Hematoxylin and eosin stain, original magnification ×50.

cular abnormalities and FDG-PET showed the mass was hypometabolic. The patient was medically treated with corticosteroids for 11 months, but brain edema remained undiminished and symptoms continued. The mass was surgically removed in July 2007. MR imaging performed 10 days later showed the brain swelling was dramatically diminished. Follow-up MR imaging at 7 months after surgical removal showed complete disappearance of brain edema (Fig. 3D). The histological diagnosis was radiation necrosis (Fig. 2 lower). The patient was discharged without headache or neurological deficits other than the pre-existing right homonymous hemianopsia.

Discussion The long-term complications of radiation therapy, including radiation necrosis, cyst formation, hemorrhage, increased seizure frequency, and arterial stenosis,7) occur in 3.2–19.8% of patients who undergo radiation therapy for AVM.31) Among 144 patients who underwent AVM radiosurgery, symptomatic cyst formation occurred in 5 patients (4%) at a median of 65 months after radiosurgery.20) Delayed hemorrhage rarely occurs in the treated area after angiographic obliteration of the AVM by GKS. Only 10 cases of delayed hemorrhage, including the present cases, have been reported after angiographic ob-

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Fig. 3 Case 2. A: T2-weighted magnetic resonance (MR) image showing an arteriovenous malformation in the left occipital lobe. B: T1-weighted MR image at 7 years after gamma knife surgery showing a mass with hemorrhages in the left occipital lobe with center hyperintense to the brain. C: T2-weighted MR image showing the mass with heterogeneously intense center, and a large area of surrounding brain edema. D: Follow-up T2weighted MR image at 7 months after surgical removal showing complete disappearance of brain edema in the left occipital lobe.

literation of AVM after GKS.12,22,32) Repeated angiography revealed no recanalization of the original malformations in 7 of these 10 patients.12,22,32) Radiation necrosis was histologically evident in up to 33% of patients who underwent radiosurgery,2) but became symptomatic in only 1.7–7.6%.7) The majority of reported cases of radiation necrosis were detected within 3 years of radiosurgical intervention.8,21,24,26) However, radiation necrosis may occur more than 5 years after GKS, as in our cases (Table 1).3,30,32) The mechanism for such late radiation necrosis after radiosurgery remains unclear. The most widely accepted theory attributes delayed radiation necrosis to endothelial cell damage. In the early stages, fibrinoid necrosis of blood vessel walls occurs, followed by vessel wall thickening, hyalinization, and telangiectasia.27) Such sclerotic damage to the capillary walls results in porosity associated with progressive destruction of the blood-brain barrier.1) An influx of leukocytes to damaged areas leads to over-production of various cytokines, inducing oligodendrocyte apoptosis. Serum leakage into the brain parenchyma through the abnormal capillaries causes glial injury and extensive fibrinoid coagulative degeneration, predominantly of the white matter.1,13,15,18) This process eventually forms a hard mass with ill-defined contours.1,13,15) In our two cases, the masses removed by surgery were elastic and hard, and the presence of these pathological changes was also confirmed. The total volume of tissue irradiated with Æ12 Gy, or the 12-Gy volume, is correlated with the risk of developing symptomatic radiation necrosis.6) In the present cases, the 12-Gy volume was larger than the total target volume and conformity indices were as low as 0.61 and 0.57 in Cases 1 and 2, respectively, thus representing the possible cause of radiation necrosis. The large 12-Gy volumes and low conformity indices were caused by the large size of the collimator (14 mm) with very few shots used in GKS for these two cases. Use of a large collimator helmet was not uncommon for GKS for moderate- or large AVMs nearly a de-

Table 1 Summary of reported cases of delayed radiation necrosis more than 5 years after stereotactic radiosurgery for arteriovenous malformation

Author (Year)

Age at GKS (yrs)/ Sex

Yamamoto et al. (1996)32)

30/F

pons

25/F

parietal

32/F

midbrain

Yamamoto et al. (1997)30) Chen et al. (2006)3) Present Case 1

28/M

parietal

24.1

68/M

11.4

44/F

temporal and thalamus occipital

Present Case 2

55/F

occipital

Location

Nidus volume (cm3)

SRS treatment dose (Gy)

Collimator size

0.68

GKS 21.6 (marginal) GKS 50 (central) GKS 17.5 (marginal) GKS 21 (marginal) LINAC 19 (marginal) GKS 21 (marginal) GKS 20 (marginal)

one target point with 14-mm collimator two target points with 18-mm collimator two target points with 4-mm collimator two target points with 18-mm collimator two target points with 20and 35-mm collimators eight target points with 14and 8-mm collimators six target points with 14-mm collimator

13.4 0.78

5.9 7.0

12-Gy volume (cm3)

Time from SRS to post-SRS symptom onset (yrs)

ND

7

ND

7

ND

7

ND

7

ND

13

25.2

7

26.8

7

GKS: gamma knife surgery, LINAC: linear accelerator, ND: not described, SRS: stereotactic radiosurgery.

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Delayed Radiation Necrosis 7 Years After Radiosurgery

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Table 2 Summary of reported cases of surgically removed radiation necrosis after stereotactic radiosurgery for arteriovenous malformation

Massengale et al. (2006)17) Author (Year) Age (yrs)/Sex Size (cm)/grade* Location SRS volume (cm3) SRS dose (Gy) Time from SRS to recurrent symptom onset (yrs) Time from onset of symptoms to surgery (mos) Time to symptom improvement *Grade: Spetzler-Martin grade.

1

2

3

4

5

6

7

Present Case 1

Present Case 2

23/F 4/III FP 23.7 27.5

31/F 2/II thalamus 4 25

40/M 4/IV BG 20 35

58/F 2/II FP 13 25

45/F 4/IV frontal 31.4 25

35/F 4/IV thalamus 30 18

47/F 4/IV thalamus 14.6 25

44/F 2/II occipital 5.9 21

55/F 3/III occipital 7 20

2

4

4

7

1

3

1.5

7

7

6

1

6

24

8

2

4

8

13

1 wk

2 mos

9 mos

unchanged

24 mos

24 mos

1 mo

1 mo

1 wk

BG: basal ganglia, FP: frontoparietal, SRS: stereotactic radiosurgery.

cade ago. Recently, high conformity of the prescription isodose has been considered as important for the safety of GKS.14) We now perform high-conformity planning with multiple (i.e., 8–15) shots using a small collimator helmet to avoid radiation necrosis. Regular follow up is thus mandatory for AVM patients who have undergone GKS with a large 12-Gy volume. Other precipitating factors for radiation necrosis include a large target area, repeated radiosurgery for the same lesion and inclusion of healthy brain tissue within the treatment volume, and patients displaying such factors should also receive regular follow-up examinations.4,6) The present cases illustrate that the differentiation of radiation necrosis from radiation-induced tumor based on MR imaging is not easy. Cases with neuro-imaging findings mimicking malignant gliomas have been reported.10,19,28) These lesions show various enhancement patterns, as expected given the breakdown of the blood-brain barrier. Swiss-cheese and soap-bubble patterns have been ascribed to radiation necrosis,9) but these appearances are not sufficiently specific for definitive diagnosis. In the present cases, lesions were depicted as a cold signal area on FDG-PET, which may support a diagnosis of radiation necrosis. Corticosteroids have become the first choice of non-surgical methods to treat radiation necrosis. Prolonged administration of corticosteroids usually provides dramatic improvements and good control.5,16) However, brain edema is not controlled by corticosteroids in some cases of severe radiation necrosis. In addition, medical treatment often causes weight gain, disfigurement, and life-threatening complications that affect the quality of life in longterm survivors.29) Six of seven patients improved after surgical resection for symptomatic radiation necrosis after GKS for cerebral AVM.17) Including the present cases, outcomes were not consistently associated with AVM size or location, or stereotactic radiosurgery treatment volume or dose (Table 2). Resection should be considered in such patients if no response is obtained to a course of steroids for several months, and before fixed deficit is sustained for a prolonged period (more than one year). In the present cases, large areas of brain edema quickly

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disappeared after resection, presumably due to deletion of the sources of leukocytes and cytokines to the brain. Histological examination of the surgical specimens also provided definitive diagnosis of radiation necrosis, which had not been fully established by the preoperative imaging diagnosis. Surgical resection of symptomatic necrotic cores is probably necessary for patients with medically intractable radiation necrosis.

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Address reprint requests to: Tatsuki Oyoshi, M.D., Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8–35–1 Sakuragaoka, Kagoshima 890–8520, Japan. e-mail: tatsuki@m2.kufm.kagoshima-u.ac.jp

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