Gliomatosis cerebri = in young patients' report of three cases and review of the = literature

From: Subject: Gliomatosis cerebri in young patients' report of three cases and review of the literature Date: Sat, 26 Jun 2010 22:53:56 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CB1582.7569F080" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5931 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CB1582.7569F080 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/k3039143868tq022/fulltext.html Gliomatosis cerebri = in young patients' report of three cases and review of the = literature

Child's Nervous System

=A9 Springer-Verlag 2010

10.1007/s00381-010-1137-7

Review Paper

Gliomatosis cerebri = in young=20 patients' report of three cases and review of the literature

Alessandro Landi¹, Manolo Piccirilli¹,=20 Cristina Mancarella¹, = Felice Giangaspero³ and=20 Maurizio Salvati²

(1)	Department of Neurosurgical Sciences,=20 Neurosurgery, University of Rome =93Sapienza=94, Via Ostiense 121, = 00154 Rome, Italy

(2)	INM Neuromed Pozzilli, Isernia,=20 Italy

(3)	Department of Pathological Anatomy, = University=20 of Rome =93Sapienza=94, Rome, = Italy

Received:=20 11 March 2010 Accepted:=20 22 March 2010 Published online:=20 8 April 2010

Abstract

Gliomatosis cerebri (GC) is a rare disease, defined = as a=20 diffuse neoplastic glial cell infiltration of the brain. Diagnosis and=20 management of GC are difficult.

Method

The authors report a literature review and their = experience=20 based on three patients, two male, and one female, all younger than=20 10 years, who were treated for GC.

Results

Our series of three patients were combined for the = purposes of=20 survival assessment together with the 22 patients from the literature = review=20 yielding 25 evaluable patients with diagnosis of GC. We compared the = patients=20 treated (16) with chemo, RT, or both combined, with untreated patients = (7) to=20 evaluate the median survival. Even though, as expected, the number is = too small=20 to show a statistically significant increase of survival = (p =3D 0.08 log=20 rank test), we still demonstrated a slight increase in survival in the = group of=20 patients treated (26.6 vs 14.8 months). We also compared the = overall=20 survival according to treatment. The comparison between the group of = five=20 patients treated with radiotherapy only, ten treated with chemotherapy = with TMZ=20 and ten with chemo and RT combined, showed a slight increase in mean = survival,=20 although not statistically significant, in the second and third groups=20 (p =3D 0.6 log rank test).

Conclusion

The optimal treatment in children under = 10 years with GC=20 is still obscure and absolutely not clear because total surgical = resection is=20 impossible to perform for the diffuse nature of the disease; CHT with = TMZ seems=20 to be the best treatment for children because it demonstrates a little = reduction=20 of the extension tumoral mass, but the responsivity of this treatment is = extremely variable from case to case.

Keywords Gliomatosis=20 cerebri - Young=20 patients - Neurosurgery - Stereotaxic=20 biopsy - Chemotherapy - Radiotherapy

Introduction

Gliomatosis cerebri (GC) is a rare tumor of the = central nervous=20 system (CNS) characterized by diffuse neoplastic proliferation of glial = cells=20 and myelin sheath destruction. Only slight damage to neurons and axons = and=20 relative preservation of anatomical architecture have been observed. It = can be=20 difficult to diagnose clinically as it tends to present with = non-specific=20 progressive neurological symptoms [1]=20 or personality changes and often obscure, non-specific changes on = computerized=20 tomogram (CT). Magnetic resonance imaging (MRI), however, may suggest = the=20 diagnosis, especially on T2-weighted images [2=964],=20 where gliomatosis cerebri may be shown as areas of high signal change. = In spite=20 of advances in neuroimaging, GC still remains difficult to diagnose = during life.=20 According to the current World Health Organization (WHO) classification = of brain=20 tumors, the involvement of more than two lobes by an extensively = infiltrating=20 glioma is mandatory to establish the diagnosis of GC. It is a malignancy = that=20 has usually been found in adult patients, and the finding in children is = very=20 rare. In the literature, single cases or short series of GC have been = reported,=20 almost always with reference to adult patients. All age groups may be = affected,=20 but GC presents a peak of incidence in the second and fifth decades of = life,=20 without gender predominance; the cases reported in children are very few = [5=9613].=20 The authors report a literature review and their experience based on = three=20 patients, two male, and one female, all younger than 10 years, who = were=20 treated for GC.

Materials and methods

Case=20 1 =20

An 8-year-old male child was admitted to our = hospital with a=20 3-year clinical history of generalized Jacksonian convulsion. MRI showed = a=20 diffuse progressive white matter changes involving = fronto-temporo-parietal left=20 lobes and fronto-temporal right lobes. On T2-weighted images, there was = a=20 diffuse hyperintensity. Then, the patient underwent brain stereotaxic = biopsy.=20 The examination of the histological specimen revealed a diffusely = infiltrating=20 grade II astrocytoma according to WHO. The neoplastic cells were = variably=20 differentiated. Immunohistochemically, tumor cells were positive for = glial=20 fibrillary acidic protein (GFAP). A diagnosis of gliomatosis cerebri was = made.=20 Therefore, we adopted a wait-and-see policy, performing a MRI every=20 3 months. After 2 years of neuroradiological and clinical = stability,=20 the patient presented in a new MRI, an enhancement of the left frontal = and=20 temporal part of the lesion, after gadolinium administration. This = patient was=20 treated by chemotherapy (CHT) with temozolomide (TMZ)=20 75 mg/m²/day for 21 days for 12 cycles of = 28 days. The=20 patient showed disease stabilization for 3 years. After this = period, the=20 patient presented a tumor regrowth pointed out by a MRI and = spectroscopy, which=20 revealed a new multifocal enhancement with deep structures involvement. = He was=20 treated with WBRT. The patient had an overall survival of 5 years = and=20 7 months. Karnofsky Performance Score (KPS) was over 70 until = 20 days=20 before exitus.

Case=20 2 =20

A 6-year-old male child was admitted to our = institute with an=20 8-month clinical history of seizures. MRI was performed and showed = typical=20 neuroradiological aspects of IV WHO glioblastoma, which involved = diffusely both=20 cerebral hemispheres. The patient underwent brain stereotaxic biopsy;=20 histological data confirmed the suspects of MRI and showed a grade IV = WHO=20 glioblastoma, allowing the diagnosis of gliomatosis cerebri. This = patient was=20 treated by chemotherapy with TMZ 75 mg/m²/day for = 21 days=20 for 12 cycles of 28 days. The patient showed absence of seizures = for almost=20 4 months until those begun again. He underwent MRI and = spectroscopy, which=20 showed a tumor regrowth. The patient underwent a stereotactic = radiotherapy on=20 the hyperintensive lesions at a dose of 16 Gy in two fractions. The = patient=20 died after 9 months from the beginning of radiotherapy. Karnofsky=20 Performance Score (KPS) was 80 until 15 days before exitus. The = patient's=20 overall survival was 13 months.

Case=20 3 =20

An 8-year-old female child was admitted to our = hospital with a=20 1-year clinical history of prolonged secondary generalized seizures. MRI = showed=20 typical aspects of diffuse gliomatosis cerebri involving the entire = right=20 hemisphere, fronto-temporal left lobe, with diffuse cerebellar = localization. The=20 patient underwent brain stereotaxic biopsy, and the histological = patterns showed=20 a grade III WHO astrocytoma. The patient underwent a chemotherapy = treatment with=20 TMZ 75 mg/m²/day for 21 days for 12 cycles of = 28 days.=20 The patient showed disease stabilization for 6 months. After this = period,=20 the patient showed seizures again and underwent MRI and spectroscopy, = which=20 showed a little reduction of the tumor's volume. She was treated with a=20 stereotactic radiotherapy on the hyperintensive lesions at a dose of = 16 Gy=20 in two fractions. The patient died after 11 months. Kamofsky = Performance=20 Score (KPS) was 70 until 25 days before exitus. Her overall = survival was=20 17 months.

A review of the literature was conducted using = PubMed, an=20 internet medical literature search engine. The search was undertaken = using the=20 terms =93gliomatosis cerebri=94, =93child=94. These terms were linked = using the=20 combinations of =93gliomatosis cerebri=94 plus =93child=94 or =93young = patients=94.=20 References from the retrieved reports were checked to identify other = possible=20 reports. We selected manuscripts reporting young patient from the age of = 0 to=20 10 years affected by gliomatosis cerebri. Data extracted included, = number=20 of patients, male/female ratio, age distribution, location of the = lesions,=20 treatment, mortality, and for some of them histochemical and=20 immuno-histochemical stainings (Table 1).=20 Twenty-two cases of young patients that were found in literature all had = histologic confirmation by either biopsy (13) or autopsy (5). Details of = therapeutic intervention were available for 16 patients. Radiation = therapy was=20 done in ten patients with doses ranged from 2700 cGy to = 7265 cGy and=20 in conjunction with chemotherapy in seven patients. Chemotherapy alone = was used=20 in three cases, and three patients received symptomatic medical care = only.

Table 1 Historic=20 cohort: treatment, localization and survival

Alessandro Landi
Email:=20 link55@libero.it

Reference	Age (year)	Diagnosis	Localization	Treatment	LOS, months	Alive
Armstrong et al. 2006 [5]=20	8	Biopsy	B. thalamus, upper brain stem	5,700 (IF)cGy	17.5	No
Armstrong et al. 2006 [5]=20	4	Biopsy	B.T., B. thalamus, corpus callosum, = pons	2,700 (WB)cGy, VCR	6.5	No
Armstrong et al. 2006 [5]=20	9	Biopsy	B.F., R.T.	2,500 (WB), 2,800 (IF),TMZ	20	No
Armstrong et al. 2006 [5]=20	1.6	Biopsy	L.P., L.T., L. occipital	PCV	22	Yes
Armstrong et al. 2006 [5]=20	8	Biopsy	R.P., R.T., B. thalamus, basal ganglia	5,800 (IF), TMZ	16	Yes
Barth et al. 1988 [6]=20	0	Autopsy	B. hemispheres, brainstem, cerebellum	None	0,25	No
Caroli et al. 2005 [7]=20	8	Biopsy	L.F., corpus callosum, L.P., L. = occipital	None	11	No
Cummings et al. 1999 [31]=20	7	Autopsy	B. hemispheres, brainstem, cerebellum, = leptomeninges,=20 spinal cord	7,265 cGy	5	No
Filho et al, 2008 [12]=20	3	Biopsy	Subarachnoid space,FCP	VCR, Carboplatin, TMZ	82	Yes
Geremia et al. 1988 [32]=20	9	Autopsy	B.F.	Corticotropi, imuran	156	No
Jayawant et al. 2001 [8]=20	10	Autopsy	Brain and spinal cord	None	3	No
Jennings et al. 1995 [9]=20	0	Biopsy	L.F.	Corticotropin	13	No
Jennings et al. 1995 [9]=20	0.66	Biopsy	L.F. white matter, cortex, = leptomeninges	Corticotropin	15	Yes
Jennings et al. 1995 [9]=20	6	Biopsy	R.F.	None	10	Yes
Maton et al., 2007	0	Biopsy	R. hemisphere	None	48	Yes
Maton et al., 2007	1	Biopsy	R.T., basal ganglia, insula, thalamus	Chemo, RT	48	Yes
Maton et al., 2007	8	Biopsy	L.F.T.P., basal ganglia, thalamus, = midbrain	VCR, carbaplatin, RT	48	Yes
Ross et al. 1991 [33]=20	7	Autopsy		None	276	No
Shahar et al. 2002 [11]=20	5	Biopsy	R.F.	RT	18	Yes
Shahar et al. 2002 [11]=20	10	Biopsy	R.T.	Chemo	24	No
Vates et al. 2003 [13]=20	6	Biopsy		3,000 cGy, TMZ, thalidomide	9	No
Yip et al. 2004 [34]=20	7	Autopsy	Brainstem, cerebellum, cerebral = hemispheres	4,500 cGy, carboplatin	13	No

LOS indicates length of survival, B = bilateral,=20 R right, L left, F frontal, T temporal, = P=20 parietal, RT radiation therapy, cGY centigrays, TMZ = temozolomide, PCV procarbazione, lomustine, and vincristine, = VCR=20 vincristina

Results

Our series of three patients were combined for the = purposes of=20 survival assessment together with the 22 patients from the literature = review=20 yielding 25 evaluable patients with diagnosis of GC. From this cohort = study, we=20 excluded two patients because their prolonged survival (greater than=20 150 months) could be related to an erroneous initial diagnosis of = GC. We=20 compared the patients treated (16) with chemo, RT, or both combined, = with=20 untreated patients (7) to evaluate the median survival (Fig. 1).=20 Even though, as expected, the number is too small to show a = statistically=20 significant increase of survival (p =3D 0.08 log rank = test) we still=20 demonstrated a slight increase in survival in the group of patients = treated=20 (26.6 vs 14.8 months). We also compared the overall survival = according to=20 treatment. The comparison between the group of five patients treated = with=20 radiotherapy only, ten treated with chemotherapy with TMZ, and ten with = chemo=20 and RT combined, showed a slight increase in mean survival, although not = statistically significant (p =3D 0.6 log rank test), = in the second and=20 third groups (Fig. 2).=20

Fig. 1 Kaplan=96Meier=20 curves. Comparison between a group of patients treated with chemo, RT, = or both=20 combined and untreated patients. We can see a slight increase in = survival in the=20 treated patients (26.6 vs 14.8 months)

Fig. 2 Kaplan=96Meier=20 curves. Comparison between a group of five patients treated with RT = only, ten=20 treated with TMZ, and ten with both combined. The curve show a slight = increase=20 in mean survival although not statistically significant = (p =3D 0.6 log rank=20 test) in the second and third groups

Discussion

Gliomatosis cerebri is a rare primary brain = malignancy,=20 initially described by Nevin [14]=20 in 1938 and then by Scheinker and Evans in 1943 on the basis of = pathological=20 criteria during autopsy. They defined GC as =93diffuse enlargements of = the=20 affected regions, with intactness of their general configuration; = widespread=20 extension of the process; absence of demarcation between normal and = affected=20 areas corresponding to a glial proliferation associated to myelinolysis = with=20 only slight involvement of the axis cylinders and nerve cells=94 = [4].=20 Nowadays, diagnosis of GC in children can be established using improved=20 neuroimaging (MRI and TC techniques), and it is histologically defined = by=20 stereotaxic brain biopsy [15].=20 Actually, GC is defined as a diffuse glial tumor infiltrating the brain=20 extensively, involving more than two lobes, frequently bilaterally and = often=20 extending to infratentorial structures and even to the spinal cord. It = is=20 usually considered to be a malignant lesion usually corresponding to a = WHO grade=20 III [4,=20 16].=20 A congenital predisposition has been also proposed for the association = with von=20 Recklinghausens disease [17],=20 but the fact that GC affects all age groups suggests that this pathology = arises=20 as a de novo tumor. MRI data are an important help for a correct = diagnosis. The=20 characteristic hallmarks of the lesion on MRI are hypointensity in = T1-weighted=20 sequences and hyperintensity in T2-weighted sequences and Flair. = T2-weighted=20 images are now considered the gold standard imaging technique for the = diagnosis=20 of GC [2=964,=20 18,=20 19].=20 A typical finding in MRI is diffuse infiltration of the cortex with an=20 enlargement of the cortical sulci and poor demarcation of the gray and = white=20 matter. MRI with fluid attenuated inversion recovery images (FLAIR) has = a better=20 definition of lesion extent and delineation of callosal infiltration and = cortical spread. The diffuse extensive contiguous involvement, mainly = central,=20 with preservation of overall cerebral structures, represents the key to = the=20 diagnosis of GC. Neurosurgical stereotaxic biopsy is necessarily for=20 histological data, to establish a correct stadiation of the disease. =

Response to the treatment, outcome, and survival time = reported=20 by different authors are extremely variable.

Although radiation therapy and different chemotherapy = regimens=20 have been attempted, the prognosis of GC is still poor. In our study, = one=20 patient died after 13 months, one had an overall survival of = 5 years=20 and 7 months and after 3 years showed a regrowth of the = disease, and=20 one had a little reduction of the neuroradiological aspects. The = duration of=20 survival from the beginning of the symptoms to death is quite variable, = ranging=20 from weeks to years. This phenomenon is explained by the fact that = low-grade=20 glioma may be misdiagnosed as GC [20].=20

Because almost all the cases have been diagnosed = postmortem,=20 there is little evidence regarding the best treatment option. It is = impossible=20 to perform a surgical resection for the diffuse infiltrative nature of = GC. At=20 the moment, stereotaxic biopsy is the treatment of choice for a = diagnosis.

The optimal treatment for GC is unclear: surgery is an = important=20 point of treatment only in adults; in children, surgery is only an = important=20 point for the histological diagnosis, which was obtained through a brain = biopsy,=20 performed in all of them by a frameless stereotactic way with the = neuronavigator=20 (Stealth Mach 3-Sofamor Danek). When the biopsy shows a high grade of=20 malignancy, the radiological examinations as MRI in T1-weighted = sequences and in=20 T2-weighted sequences, spectroscopy [21=9623],=20 diffusion, and perfusion help us to understand the glial nature of the = lesion.=20

The value of radiotherapy is difficult to establish = because the=20 beneficial effects are still anecdotal: WBRT is dangerous because the = disease is=20 widespread; and therefore, it involves a dangerous brain exposition to=20 radiations. So, we believe that the first line treatment is chemotherapy = with=20 TMZ [24=9626].=20 Temozolomide is an alkalising imidazotetrazine, which undergoes = spontaneous=20 conversion to the active alkylating agent and penetrates the blood-brain = barrier=20 that remains stable even under the acid conditions peculiar to the human = stomach, meaning that it can be administered orally in capsules, without = the=20 need for a hospital regimen. Moreover, among all the chemotherapic = drugs,=20 temozolomide has the most favorable toxicity profile, and its = bio-availability=20 after oral administration is about 100% [27].=20 It has been used in the treatment of primary malignant brain tumors = including=20 glioblastoma multiforme, anaplastic astrocytoma, and oligodendroglioma = [25].=20 In these malignant brain tumors, therapy with TMZ has demonstrated a = little=20 evidence of radiologic tumor regression associated with a little = improved=20 quality of life and survival. In our study, chemotherapy with TMZ=20 75 mg/m²/day for 21 days for 12 cycles of = 28 days=20 demonstrates a little reduction of the disease only in one case.

We also used WBRT and stereotactic RT as a second line = therapy=20 with the hope to succeed in stopping the evolution of the pathology = [28].=20 Because of the large volume that requires treatment, our dose = recommendation=20 reflects a balance between the clinical benefit and the possible = toxicity. In=20 our study, we show that clinical aspects in children with gliomatosis = cerebri=20 were a little similar: all of them presented epilepsy, with different = types of=20 crises, but anyone presented headache, weakness, behavioral changes, and = hemiparesis, typical aspects of gliomatosis cerebri in adults and = elderly=20 [29,=20 30].=20

We adopted a protocol treatment (Fig. 3)=20 that considered chemotherapy (TMZ 75 mg/m²/day for = 21 days=20 for 12 cycles of 28 days) as a gold standard after brain = stereotaxic biopsy=20 for diagnosis of GC. As a second line treatment, we used RT if the = patients had=20 a progressive symptoms seen at the follow-up (MRI every = 2=963 months) or RT=20 on the hyperintensive lesions seen on the spectroscopy images using a = different=20 dose tailored for each patient. WBRT is used as the last line treatment = when=20 there is a worsening of the symptoms (Table 2).=20

Fig. 3 A protocol=20 treatment that we used to treat our patients

Table 2 Patient=20 characteristics, treatments, and length of survival for the study = population=20

Patient	Age at diagnosis, years	Gender	Diagnosis	Treatment	LOS, months	Alive
1	8	M	Biopsy	TMZ, WBRT	67	No
2	6	M	Biopsy	TMZ, RT	13	No
3	8	F	Biopsy	TMZ, RT	17	No

TMZ temozolomide, RT radiotherapy=20

Conclusions

In conclusion, we think that the optimal treatment in = children=20 under 10 years with GC is still obscure and absolutely not clear = because=20 total surgical resection is impossible to perform for the diffuse nature = of the=20 disease; WBRT is dangerous for the extensive brain exposition from the=20 radiations; CHT with TMZ seems to be the best treatment for children = because it=20 demonstrates a little reduction of the extension tumoral mass, but the=20 responsivity of this treatment is extremely variable from case to case.=20

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