Fluorescence Guided Brain Tumor Surgery: Case Report
Salvador
Manrique-Guzman, Lucino Castillo-Rueda, Stefan Wolfsberger, Tenoch Herrada-Pineda, Francisco
Revilla-Pacheco, Jaime Torres-Corzo, Mauro Loyo-Varela, Walter Stummer
Salvador
Manrique-Guzman, Tenoch Herrada Pineda, Francisco Revilla Pacheco, Mauro
Loyo-Varela, Department of Neurosurgery, ABC Medical Center, Mexico City, Mexico
Lucino
Castillo-Rueda, Jaime Torres-Corzo,
Department of
Neurosurgery, Hospital Central Dr. Ignacio Morones Prieto S.S.A., San Luis
Potos¨ª, S.L.P. Mexico
Stefan
Wolfsberger, Department of Neurosurgery, Medical
University, Vienna, Austria
Walter Stummer,
Department of
Neurosurgery. Heinrich-Heine-Universität, D¨¹sseldorf, Germany
Correspondence to: Salvador Manrique-Guzman, MD, MSc, Department Of
Neurosurgery, ABC Medical Center. Mexico City. Mexico.
Email: manriquemd@yahoo.com
Telephone: +52-55-55161226
Received: March 13,
2015
Revised: April 18, 2015
Accepted: April 21, 2015
Published online: May 13, 2015
ABSTRACT
Glioblastoma
in the most common malignant glioma in adults with 22,500 new cases diagnosed
each year. Median survival is less than one year with high rates of
neurological disabilities. The current treatment approach includes surgery,
chemotherapy and radiotherapy. Tumor resection has prognostic value and
maximizing tumor resection should be always attempted. Fluorescence guided
surgery for brain tumors have improved tumor resection with specificity up to
98%. Limitations for this technology includes lack of modified surgical
microscopes in neurosurgical centers worldwide. We present the first two cases
done in Mexico with no surgical complications using fluorescent technique. This
paper supports the safety and advantages of using fluorescence guided surgery
for malignant gliomas.
© 2015 ACT. All
rights reserved.
Key words: Glioblastoma; 5-aminolevulinic acid; Extent of
resection; Protoporphyrin IX; Meningioma
Manrique-Guzman S,
Castillo-Rueda L, Wolfsberger S, Pineda TH, Pacheco FR, Loyo-Varela M, Stummer
W. Fluorescence Guided Brain Tumor Surgery: Case Report. International Journal of Neurology Research 2015; 1(2): 88-92 Available from: URL:
http://www.ghrnet.org/index.php/ijnr/article/view/1112
INTRODUCTION
Glioblastoma is the most common primary CNS tumor, the incidence of
malignant glioma is around 5/100,000, approximately 22,500 new cases each year.
Malignant glioma may develop at all ages, the peak incidence being in the fifth
and sixth decade of life[1,2]. Median survival is generally less
than one year from time of diagnosis, most patient die within two years[3].
Malignant glioma comprises glioblastoma (World Health Organization Grade IV),
anaplasic astrocytoma (WHO grade III), mixed anaplasic oligoastrocytoma (WHO
grade III) and anaplasic oligodendroglioma (WHO grade III). Glioblastoma has
the worst prognosis[4]. Malignant gliomas are 40% more common in men
and twice as common in whites as in blacks. The median age of diagnosis is 64
years in GBM and 45 in case of anaplastic gliomas[1,5].
A
multidisciplinary team should evaluate the patient. Rapid symptom relief should
be prompted with high doses of corticosteroids with quick tapering according to
individual needs. There is no need for prolonged steroid therapy after tumor
resection or prophylaxis during radiotherapy. Antiepileptic therapy is
indicated in patients presenting with initial seizure[4].
For newly
diagnosed patients surgery is the gold standard as the initial therapeutic
approach for tumor debulking and obtaining tissue for diagnosis. Tumor
resection has prognostic value, maximizing tumor resection should be attempted
considering neurological function and preserving quality of life (QoL). Once
the diagnosis for malignant glioma is established, fractionates focal
radiotherapy (60 Gy) and chemotherapy is continue. The first-line choice for
chemotherapy is Temozolamide (TMZ 75 mg/m2), administered daily (7
day/week) around 1 or 1.5 hour before radiotherapy during the initial phase.
For the maintenance phase the doses rises to 150-200 mg/m2 on a
daily x5 schedule every 28 days with blood count checked on days 21 and 28.
Concomitant and adjuvant TMZ chemotherapy improved survival from 2 to 5 year in
large randomized trial[3,4].
Continued refinement
in microsurgical techniques and the use of adjunctive technologies have reduced
major neurological morbidity to 8.5% and mortality of 1.7% for patients
undergoing craniotomy[6]. Radical resection of malignant gliomas
carries the risk of injuring the adjacent neural and vascular structures in the
brain, especially because of the infiltrative nature of the neoplasm, more
evident in eloquent brain areas (Table 1)[7]. Evidence shows the
presence of tumor cells centimeters beyond the presumed tumor margin[8].
Several factors can influence the survival of patient with GBM, which are age,
preoperative performance status according to the KPS, tumor location,
preoperative imaging characteristics, extent of tumor excision and
postoperative treatment (TMZ & RT)[6,9].
Neurosurgeons
have a central role in determining patient outcome by maximizing resection,
always with arbitrary decision[10]. Multiple resections for
carefully selected patients with recurrent disease have demonstrated ability of
increasing efficiency of adjuvant therapies. Repeated resections can be
achieved with no significant increase in postoperative deficits or wound
infections[11].
The treatment
of patients with high-grade glioma remains a challenge for modern therapy.
Cytoreductive surgery for malignant gliomas has been performed for decades,
from lobectomies to hemispherectomies[12,13]. The optimal extent of
resection depends on tumor size and location, the patient´s general and
neurological status and the surgeon experience. Survival advantage can be
achieved when the extent of resection reaches more than 89%. Aggressive
resection of 98% or more of the tumor volume was a significant independent
predictor of patient survival (adjusted rate ratio 1.6, 95% CI 1.3-2, p<0.0001)[14-17].
In recent
years, surgery has drawn efforts to improve outcome, using cut of the edge
technology like fluorescence visualization of the tumor by 5-aminolevulinic
acid, navigation-guided fence-post-procedure, intraoperative neurophysiological
monitoring and intraoperative magnetic resonance imaging[18-24].
Fluorescence
guided surgery has been recently added to the neurosurgeon arsenal to improve
tumor resection. 5-aminolevulinic acid (5-ALA) is a tool for identifying
residual tumor and extending resection margin of malignant glioma. This
technique was tested in a randomized Phase III study in Europe[25].
The exogenous administration (orally) of 5-ALA is formed within the
mitochondria from succinyle-choline acetate and glycine by 5-ALA-synthetasa,
located at the mitochondrial membrane. 5-ALA is the released and dehydrogenated
in the cytoplasm producing porphobilinogen then coproporphyrinogen III and
finally returns into the mitochondria as protoporphyrin IX (PpIX), a natural
precursor of heme, in the target tissue. It causes a negative feedback control
exerted by heme on the enzymatic step in ALA synthesis[26] (Figure
1).
PpIX is
present in nearly every nucleated cell; preferential formation and accumulation
of this photosensitizer have been demonstrated in tissues known to have a high
cellular turnover. The selective accumulation of PpIX is still poorly
understood, with a high specificity of 98%. Quantitative data demonstrate PpIX
concentration yielded the best classification efficiency (87%) as a diagnostic
variable. The probability of classifying tissue as normal given that it is
normal 92% with sensitivity (probability of classifying tissue, as abnormal
tumor given that it is abnormal is 84%. The positive predictive value (PPV) is
95% and the Negative Predictive Value (NPV) is 77%[27]. One theory
relies in a reduced ferrochelatase activity[28,29].
Using a
modified neurosurgical microscope, porphyrin can be intra-operatively
visualized (fluorescence) to identify residual malignant tumor. Due to the
intra-tumoral synthesis, 5-ALA differ from other fluorescing agents that have
been investigated for tumor discrimination such as fluorescein, which enter the
malignant gliomas via the defective blood-brain barrier[30].
Absorptions of blue light elevated the PpIX molecules from a electronic ground
state to a higher excited state, especially to a blue spectrum (around 400-440
nm). Under excitation of light, the intensity of PpIX fluorescence emitted by
tumors decreases continuously due to a photochemical decomposition of PpIX
called photo-bleaching[26].
5-ALA is
orally given on an empty stomach 3 to 4 hour prior to the anesthesia induction.
It is preferentially then, taken up by the liver, kidney, endothelium and skin.
The maximum PpIX plasma level is reached in 4 h after oral administration of
5-ALA with the recommend dose (20 mg/kg). The plasma levels rapidly decline
during the subsequent 20 h and becomes undetectable after 48 h. It has a
half-life of 1-3 h. Approximately 30% of the orally administrated 5-ALA is
excrete unchanged in urine within 12h. It has shown to be safe in a number of
studies, mild elevation of liver enzymes with no other signs of hepatic
disorders were reported (GTP 85%, GOT 81% & GGT 96%) on day 7 after
administration of 5-ALA. Skin photosensitivity occurred in <1% of patients[26].
Case
presentation
We present two clinical scenarios of the first two cases performed in
Mexico using 5-ALA. The first case is of a 44 year-old male with prior history
of brain tumor resection in another hospital with pathological result
compatible with Grade III malignant glioma according the WHO classification and
adjuvant TMZ and fractionated radiotherapy (55 Gy) in 2001. He was then brought
back to the operating room for tumor recurrence in another hospital and finally
brought to us with frontal lobe syndrome. He was surgically intervened in the
Centro Medico Nacional 20 de Noviembre, ISSSTE, Mexico City, in December 2010.
Consent form was sign for 5-ALA (20 mg/kg. Gliolan®, Medac HmbH
Wedel, Germany) and a modified neurosurgical microscope was used (OPMI Pentero
900®, Carl Zeiss GmbH, Oberkochen, Germany). There were no complications during
the surgical procedure and the patient was discharged 4 days after. The
pathology report was consistent with the same grade III malignant glioma.
During the patient follow-up MR no tumor recurrence is seen (Figures 2 and 3).
The second
case is from a 37 year-old female with no relevant past-medical history
presenting in to the office complaining of headaches, nausea, amaurosis fugax,
left-eye ptosis and facial asymmetry. The head MR showed a left frontal
extra-axial lesion with important perilesional edema. This case was performed
in the Department of Neurosurgery, Hospital Central Dr. Ignacio Morones Prieto S.S.A.,
San Luis Potos¨ª, S.L.P. Mexico. After signing the consent form the patient was
taken to the operating room with previous administration of 5-ALA (20 mg/kg.
Gliolan®, Medac HmbH Wedel, Germany). We also used a modified
microscope (OPMI Pentero 900®, Carl Zeiss GmbH, Oberkochen, Germany)
using standard surgical techniques and Neuronavigation system (AxiEM Medtronic,
Inc.®) achieving gross total resection. No complications were
registered during surgery or after, and the patient was discharged from the hospital
3 days after the surgery. The final pathology report was compatible with Grade
I Meningioma. During the patient follow-up MR no tumor recurrence is seen
(Figures 4 and 5)
Discussion
Florescence guided surgery for malignant gliomas using 5-ALA has proven
to be a safe and useful tool for identifying residual tumor and optimizing the
extend of resection. As describe by Kamp and cols., we also found it useful
identifying normal brain tissue or changes like gliosis, necrosis, vascular
hyalization and scar formation in our patient with prior history of TMZ and
radiotherapy[31].
Infiltration
of eloquent areas is based with preop imaging (MR). Complete resection carries
a higher risk of postoperative neurological deficit, but incomplete resection
decreases survival. 5-ALA is not only a diagnostic drug; it has the value and
risk of extended cytoreduction in surgery for malignant gliomas.
There is
limited worldwide experience using the 5-ALA in extra-axial lesion such as
meningiomas. Valdes and cols., demonstrated in a pool of 15 patients
improvement in completing surgical resections and identifying tumor cells that
spread beyond the arachnoid layer. For meningiomas, PpIX has a sensibility of
83% and specificity of 100%[32]. With our patient we were able to
complete tumor removal and also were able to identify any tumor cell population
in the tumor margin.
Preserving the
balance between surgical resection and function preservations is major
challenge to all neurosurgeons. New technologies reduce the risk of temporal or
permanent neurological deficit and increase the patient opportunity for an
increase survival. The use of ALA for diagnosis and treatment has evolved. The
side-effect profile is minimal. It is important to point out that this technology
is also available in countries with an emerging economy such as in Mexico.
Conclusions
Fluorescence guided surgery to improve surgical resection using 5-ALA
and a modified microscope has proven to be a safe tool to achieve a more
aggressive tumor removal and improving survival. 5-ALA is useful to
discriminate neoplastic tissue from adjacent normal brain. One major limitation
include that 5-ALA is still not available worldwide and is non-FDA-approved.
The second major limitation is that not all neurosurgical centers have a
modified microscope with blue spectrum light source to provoke PpIX excitation.
Conjunct efforts must be address to provide this useful technology to all
surgical centers to improve patient¡¯s survival.
CONFLICT OF INTERESTS
The Author has no conflicts of interest to declare.
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Peer reviewers: Masashi Kameyama,
Division of Nuclear Medicine, Department of Radiology, School of Medicine, Keio
University, 35 Shinanomachi Shinjuku-ku, Tokyo, 160-8582, Japan; David Hung-Chi
Pan, M.D., Department of Neurosurgery, Taipei Veterans General Hospital, 201
Shih-Pai Road, Sec 2, Taipei, Taiwan.
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