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 »  Abstract
 » Introduction
 » Case Report
 » Results
 » Discussion
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Table of Contents    
CASE REPORT
Year : 2011  |  Volume : 59  |  Issue : 4  |  Page : 612-615

Utility of intraoperative fluorescent diagnosis of residual hemangioblastoma using 5-aminolevulinic acid


Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan

Date of Submission20-Feb-2011
Date of Decision31-Mar-2011
Date of Acceptance10-Apr-2011
Date of Web Publication30-Aug-2011

Correspondence Address:
Satoshi Utsuki
Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara, Kanagawa 252-0473
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.84349

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 » Abstract 

Hemangioblastoma is a benign tumor of the cerebellum, and treatment involves surgical excision, both as the initial treatment and also in case of recurrence. Recurrence of hemangioblastoma can be local due to incomplete resection or can be distant and separate from the tumor resection region. Local recurrence can largely be avoided by verifying for any residual tumor intraoperatively before closure. In this study, we used intraoperative fluorescent diagnosis using 5-aminolevulinic acid (5-ALA) to verify the presence of a residual tumor during surgical resection. Nine patients with hemangioblastoma were given 1 g of 5-ALA orally before surgery, and a laser beam of 405 nm was focused on the tumor during resective surgery. Fluorescence of protoporphyrin IX (PPIX) was observed in the core of tumor in all the cases. Fluorescence of PPIX was observed in the peritumoral cyst wall in two patients after tumor resection, and in both of them fluorescent parts of PPIX were resected and histological examination showed tumor cells. Usually, there are no tumor cells in the peritumoral cyst of a hemangioblastoma, yet hemangioblastomas may sometimes recur from an unresected cyst wall. It is thus necessary to excise an infiltrating cyst of tumor cells to prevent recurrence. Intraoperative fluorescent diagnosis using 5-ALA is a useful method to discern whether tumor cells are present in the peritumoral cyst wall of a hemangioblastoma.


Keywords: 5-aminolevulinic acid, cyst wall, fluorescence diagnosis, hemangioblastoma, residual tumor


How to cite this article:
Utsuki S, Oka H, Kijima C, Miyajima Y, Hagiwara H, Fujii K. Utility of intraoperative fluorescent diagnosis of residual hemangioblastoma using 5-aminolevulinic acid. Neurol India 2011;59:612-5

How to cite this URL:
Utsuki S, Oka H, Kijima C, Miyajima Y, Hagiwara H, Fujii K. Utility of intraoperative fluorescent diagnosis of residual hemangioblastoma using 5-aminolevulinic acid. Neurol India [serial online] 2011 [cited 2019 Sep 15];59:612-5. Available from: http://www.neurologyindia.com/text.asp?2011/59/4/612/84349



 » Introduction Top


Hemangioblastoma, a benign tumor of the cerebellum, often occurs in adults and may recur. [1],[2] The recurrence may be from the site of tumor resection bed or distant from the initial tumor resection area. Recurrence in a region other than the area of primary resection may be due to non-visualization of tumor at that site preoperatively or may have been due to a diathesis of easy to occur tumors such as von Hippel-Lindau (VHL) disease. [2],[3] The tumor may also relapse and be part of a condition known as hemangioblastomatosis. [4] Local recurrence of tumor can be prevented if complete resection is performed during the initial surgery. Intraoperative photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) utilizes protoporphyrin IX (PPIX), which is a metabolite of 5-ALA that accumulates in tumor cells. Residual tumor can be detected macroscopically, since red fluorescence is observed when ultraviolet light irradiates PPIX. [5] This study investigated whether the residual tumor could be detected when PDD using 5-ALA is performed during surgical removal of hemangioblastomas.


 » Case Report Top


Nine patients (four males and five females, mean age 51 years, range 27-69 years) with hemangioblastoma were enrolled for this study between 1995 and 2010. In all the patients, tumor resection was done using intraoperative PDD with 5-ALA. All patients had detailed examination to exclude any phakomatosis, retinal angioma and abdominal mass lesions. Genetic studies for VHL disease done in two patients were negative. Of the nine patients, two had local recurrent lesion. Magnetic resonance imaging (MRI) showed one or more peritumoral cysts in all the patients. One of the nine hemangioblastomas with peritumoral cyst showed thin enhancement of the cyst (case 1) [Figure 1]. However, at this point of time, we could not study further the histological characters of this cyst as the patient refused to have surgery. During the subsequent 15 months of follow-up, the cyst increased in size, but contrast enhancement of the cyst wall disappeared except near the tumor attachment site; at this time, the patient agreed for surgery [Figure 2]. All patients received 1 g of orally administered 5-ALA, 2 hours prior to the introduction of an anesthetic. Tumor masses were excised under microscope, and the tumor bed was irradiated with 405 nm of excitation light using a semiconductor laser device (VLD-V1 version 2; M and M Co. Ltd., Tokyo, Japan). The presence of PPIX fluorescence was observed through a low-cut filter (cut 420 nm, M and M Co. Ltd.). The fluorescence of the PPIX waveform was confirmed by spectrometer and accessory software (BW-Spec V3.09; B and W TEK, Inc., Newark, DE, USA). This was necessary as all the visualized red fluorescent light may not have been the fluorescence of PPIX. The PPIX fluorescence spectrum has two peaks, a sharp peak at 636 nm and a slightly broader peak at 705 nm.
Figure 1: Contrast-enhanced axial T1-weighted MR image showing a recurrent hemangioblastoma in case 1. A homogeneous enhanced cyst was present adjacent to a homogeneous enhanced mass lesion at the left cerebellar hemisphere. Both the cyst and the mass lesion were in contact with a cavity formed by tumor resection

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Figure 2: Contrast-enhanced axial T1-weighted MR image showing a lesion 15 months after the image in Figure 1 was taken. The homogeneous enhanced mass lesion had become larger, and the cyst wall enhancement had disappeared

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 » Results Top


Fluorescence of PPIX was observed in the tumor mass in all the patients. After tumor resection with microscope, the region was observed under a laser beam of 405 nm. The fluorescence of PPIX was not observed at the point of attachment of the tumor mass in the brain. Of the nine tumors, fluorescence of PPIX was observed in two peritumoral cysts. One of the fluorescent peritumoral cysts was a recurrent tumor (case 1) [Figure 2] and [Figure 3]b [5] and the other was a first occurrence tumor (case 2) [Figure 4] and [Figure 5]b. The two fluorescent peritumoral cyst walls did not show any macroscopic abnormality [Figure 3]a and [Figure 5]a and histological examination of the resected fluorescent cyst walls confirmed the presence of tumor cells [Figure 6] and [Figure 7]. The part was the cystic wall with PPIX fluorescence of the macroscopy normality with the distance from tumor attachment. In these two cases after the cyst walls were resected, tumor cyst wall bed did not reflect the fluorescence of PPIX [Figure 5]c, which does not have a waveform that creates a sharp peak at 636 nm on spectrometer. No tumor cells were seen in the tissue [Figure 8]. The fluorescence of PPIX was not observed in the cyst wall of the other seven hemangioblastomas. A part of these cyst walls was also resected, but tumor cells were not seen histopathologically. Cyst walls with other cases are composed of collagen fiber, astrocytic gliosis and Rosenthal fibers and are devoid of tumor cells.
Figure 3: (a) Photogram showing peritumoral cyst wall after resection of an enhanced mass lesion under microscope with white light. Residual tumor cannot be identified. (b) Peritumoral cyst wall is observed through a cut filter in this equal magnification view. PPIX fluorescence is revealed when the excitation light, having a peak wavelength of 405 nm, is irradiated

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Figure 4: Contrast-enhanced axial T1-weighted MR image showing a homogeneous enhanced mass lesion with cyst at the right cerebellar hemisphere in case 2. The cyst wall shows no enhancement

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Figure 5: (a) Photogram of nodal lesion showing peritumoral cyst wall after resection under microscope with white light. Residual tumor cannot be identified. (b) Peritumoral cyst wall is observed through a cut filter in this equal view. PPIX fluorescence is revealed when the excitation light, having a peak wavelength of 405 nm, is irradiated. (c) Peritumoral cyst wall is observed through a cut filter in this equal view. PPIX fluorescence is missing and only a pale blue light of exposed excitation is observed

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Figure 6: Photomicrograph showing histological findings of the cyst wall where fluorescence was observed in case 1. The tumor cells form a thin line to border the cyst wall, and gliosis surrounds the circumference(hematoxylin and eosin staining, original magnification ×100)

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Figure 7: Photomicrograph showing histological findings of the cyst wall in case 2 where fluorescence was observed. The tumor cells form a thin line to border the cyst wall, and gliosis surrounds the circumference(hematoxylin and eosin staining, original magnification ×200)

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Figure 8: Photomicrograph showing histological findings of the cyst wall in case 2 where fluorescence was not observed. No tumor cells were seen (hematoxylin and eosin staining, original magnification ×100)

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 » Discussion Top


Hemangioblastoma is a benign tumor with a surrounding border clear of tumor. Recurrence of hemangioblastoma is unusual if the tumor resection is complete. The reported recurrence rates with long-term follow-up varied between 15% and 27%, [1],[2] even with the complete resection of the tumor. Risk factors for recurrence are: Young age at the time of diagnosis, VHL disease, and multicentric tumors. Recurrence of tumor in patients with incomplete resection can be treated by surgical resection with no further recurrences. Intraoperative PDD using 5-ALA is mainly performed while resecting malignant tumors such as malignant glioma, and outcomes are better as this allows better resection rates. [6],[7]

A small amount of residual benign tumor may be hard to detect. There are limited reports on the use of intraoperative PDD using 5-ALA in the detection of residual benign tumor. [8],[9] Jagannathan et al. [10] reported that recurrence of tumor can be minimized by checking all hemangioblastoma cyst walls, including peritumoral cysts, and further resecting the lesion like tumor after hemangioblastoma removal. We have used PDD using 5-ALA in hemangioblastoma surgery. Fluorescence of PPIX was found in two of nine peritumoral cyst walls after resection of the tumor, and a residual tumor was found in this study. Our results suggest that objectively, intraoperative PDD using 5-ALA is useful in finding residual tumor in hemangioblastoma surgery.

MRI studies suggest that cysts of hemangioblastoma are intratumoral cysts and peritumoral cysts in location. [11] The mechanisms of formation of intratumoral and peritumoral cysts are different. Intratumoral cysts are a result of tumor necrosis, while peritumoral cysts develop as a result of a tumor interstitial process that begins with the occurrence of edema. [12],[13] These peritumoral cysts are organized in gliosis and Rosenthal fibers without tumor cells and are located in the brain tissue adjacent to hemangioblastomas. [14] This observation does not warrant resection of the cyst walls of hemangioblastoma, and excision of the cyst wall may result in new neurologic deficits. However, there are cases of hemangioblastoma recurrence due to infiltration of tumor cells into brain parenchyma or cyst walls. [15] These peritumoral cysts might be intratumoral cysts in imitation of peritumoral cysts. The cyst wall of an intratumoral cyst might appear like that of a peritumoral cyst because the cyst wall becomes thin with an increase in size. [5],[15] As seen in one of our patients, there was an enhancement of the cyst wall with the initial recurrence of hemangioblastoma. At first, this cyst was judged to be an intratumoral cyst. In the follow-up, there was change in the morphology of the cyst and was like the peritumoral cyst as seen in hemangioblastoma, and the cyst wall did not enhance with contrast with increase in cyst size. This case illustrates that the peritumoral cysts of hemangioblastoma can have the imaging characteristics of intratumoral cysts. The other mechanism of recurrence is implantation of floating tumor cells consisting of gliosis and Rosenthal fibers in the cyst wall in the peritumoral cyst. Though rare, there is a report of a hemangioblastoma appearing similar to an arachnoid cyst without the mural nodule and enhancement effect of the cyst wall on MRI. [16] To prevent recurrence of hemangioblastomas such as these, it is necessary to resect the entire cyst wall, which tumor cells can infiltrate. PDD using 5-ALA contributes to thorough resection of hemangioblastomas.

 
 » References Top

1.de la Monte SM, Horowitz SA. Hemangioblastomas: Clinical and histopathological factors correlated with recurrence. Neurosurgery 1989;25:695-8.  Back to cited text no. 1
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2.Niemela M, Lemeta S, Summanen P, Bohling T, Sainio M, Kere J, et al. Long-term prognosis of haemangioblastoma of the CNS: Impact of von Hippel-Lindau disease. Acta Neurochir (Wien) 1999;141:1147-56.  Back to cited text no. 2
    
3.Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg 2003;98:82-94.  Back to cited text no. 3
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4.Weil RJ, Vortmeyer AO, Zhuang Z, Pack SD, Theodore N, Erickson RK, et al. Clinical and molecular analysis of disseminated hemangioblastomatosis of the central nervous system in patients without von Hippel- Lindau disease. J Neurosurg 2002;96:775-87.  Back to cited text no. 4
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5.Utsuki S, Oka H, Sato K, Shimizu S, Suzuki S, Fujii K. Fluorescence diagnosis of tumor cells in hemangioblastoma cysts with 5-aminolevulinic acid. J Neurosurg 2010;112:130-2.  Back to cited text no. 5
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6.Pichlmeier U, Bink A, Schackert G, Stummer W. Resection and survival in glioblastoma multiforme: An RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol 2008;10:1025-34.  Back to cited text no. 6
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7.Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: A randomised controlled multicentre phase III trial. Lancet Oncol 2006;7:392-401.  Back to cited text no. 7
    
8.Kajimoto Y, Kuroiwa T, Miyatake S, Ichioka T, Miyashita M, Tanaka H, et al. Use of 5-aminolevulinic acid in fluorescence-guided resection of meningioma with high risk of recurrence. Case report. J Neurosurg 2007;106:1070-4.  Back to cited text no. 8
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9.Shimizu S, Utsuki S, Sato K, Oka H, Fujii K, Mii K. Photodynamic diagnosis in surgery for spinal ependymoma. Case illustration. J Neurosurg Spine 2006;5:380.  Back to cited text no. 9
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10.Jagannathan J, Lonser RR, Smith R, DeVroom HL, Oldfield EH. Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg 2008;108:210-22.  Back to cited text no. 10
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11.Richard S, Campello C, Taillandier L, Parker F, Resche F. Haemangioblastoma of the central nervous system in von Hippel-Lindau disease. French VHL Study Group. J Intern Med 1998;243:547-53.  Back to cited text no. 11
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12.Lohle PN, Wurzer HA, Seelen PJ, Kingma LM, Go KG. The pathogenesis of cysts accompanying intra-axial primary and metastatic tumors of the central nervous system. J Neurooncol 1998;40:277-85.  Back to cited text no. 12
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13.Lonser RR, Vortmeyer AO, Butman JA, Glasker S, Finn MA, Ammerman JM, et al. Edema is a precursor to central nervous system peritumoral cyst formation. Ann Neurol 2005;58:392-9.  Back to cited text no. 13
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14.Hussein MR. Central nervous system capillary haemangioblastoma: The pathologist's viewpoint. Int J Exp Pathol 2007;88:311-24.  Back to cited text no. 14
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15.Bishop FS, Liu JK, Chin SS, Fults DW. Recurrent cerebellar hemangioblastoma with enhancing tumor in the cyst wall: Case report. Neurosurgery 2008;62:E1378-9.  Back to cited text no. 15
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16.Vatsal DK, Husain M, Husain N, Chawla S, Roy R, Gupta RK. Cerebellar hemangioblastoma simulating arachnoid cyst on imaging and surgery. Neurosurg Rev 2002;25:107-9.  Back to cited text no. 16
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

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