Journal of Neurosurgery: Pediatrics - = 107(2):137

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August 2007 Volume 107, Number = 2

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Anaplastic ganglioglioma arising from = a=20 Lhermitte=E2=80=93Duclos-like lesion

Case report

Hidehiro=20 Takei, M.D.^1,², Robert Dauser, = M.D.³, Jack Su, M.D.⁴, = Murali Chintagumpala,=20 M.D.⁴, Meenakshi B.=20 Bhattacharjee, M.D.¹, Jeremy Jones, = M.D.⁵, and=20 Adekunle M. Adesina, = M.D.,=20 Ph.D.¹

Abbreviations used in this = paper: CS=20 =3D Cowden syndrome; GFAP =3D glial fibrillary acidic = protein; ICP=20 =3D intracranial pressure; LDD =3D = Lhermitte=E2=80=93Duclos disease; MAP2=20 =3D microtubule-associated protein 2; MR =3D magnetic = resonance;=20 mTOR =3D mammalian target of rapamycin; PTEN =3D = phosphatase and=20 tensin homolog deleted from chromosome 10.

Address reprint requests to: = Hidehiro=20 Takei, M.D., Department of Pathology, The Methodist = Hospital,=20 6565 Fannin Street, Houston, Texas 77030. email: takei327@aol.com.

DOI: 10.3171/PED-07/08/137

Figures = and Tables=20

Abstract	IntroductionCase ReportDiscussionReferences

3D""=20 The=20 authors report the case of a 7-year-old boy with a = history of=20 developmental delay who presented with aggressive = behavior. A=20 magnetic resonance (MR) image showed a mass lesion = originating=20 from the cerebellar vermis with an atypical folial = pattern and=20 contrast enhancement. Histologically, the subtotally = resected=20 specimen consisted mostly of neuropil with nodular = foci of=20 ganglion cells. Lhermitte=E2=80=93Duclos disease (LDD) = was diagnosed=20 in the patient. A retrospective review of the tissue = sections=20 showed a nidus of associated astrocytic proliferation, = suggesting a diagnosis of ganglioglioma. Five years = later, the=20 patient experienced an altered mental state and a = facial=20 droop. An MR image revealed a cerebellar mass with = cystic=20 areas and an enhancing nodule. The resected tissue = specimen=20 consisted primarily of a mixed proliferation of glial = and=20 ganglion cells consistent with a ganglioglioma. Two = years=20 later, a third craniectomy was performed in the = patient for=20 worsening headache and ataxia. Histologically, the = tumor=20 showed progressive anaplasia and was most accurately=20 classified as an anaplastic ganglioglioma.=20 Immunohistochemically, most of the tumor cells were=20 immunoreactive for anti-phospho-mammalian target of = rapamycin=20 (mTOR) and phospho-S6 ribosomal protein antibodies. In = contrast, the subpopulation of neoplastic ganglion = cells in=20 the tissue, particularly from the first surgery, did = not=20 express phosphatase and tensin homolog deleted from = chromosome=20 10 (PTEN). This immunohistochemical pattern suggests = that the=20 large dysplastic ganglion cells (the gangliocytomatous = component) forming the greater part of the lesion were = associated with activation of the phosphatidylinositol = 3-kinase=E2=80=93PTEN/Akt/mTOR signaling pathway, a = feature previously=20 reported in LDD. This case represents the first report = of an=20 anaplastic ganglioglioma arising in an LDD-like=20 lesion.

KEYWORDS:anaplastic = ganglioglioma;=20 cerebellum; immunohistochemistry; = Lhermitte=E2=80=93Duclos disease;=20 pediatric neurosurgery.

Introduction	AbstractIntroduction = <<Case ReportDiscussionReferences

Lhermitte=E2=80=93Duclos disease, also known as = dysplastic=20 cerebellar gangliocytoma, is a rare, slowly enlarging, = mass=20 lesion of the cerebellum. More than 100 cases of LDD = have been=20 described in the literature since the first = description in=20 1920 by Lhermitte and Duclos.¹³ Clinical=20 manifestations of LDD frequently include a = longstanding=20 history of vague neurological symptoms and cerebellar = signs=20 related to a progressive posterior fossa mass. = Histologically,=20 the lesion of LDD is composed of dysplastic ganglion = cells=20 that are mostly confined to the internal granule cell = layer.=20 Although histopathological findings can confirm the = diagnosis=20 of LDD, MR imaging is often sufficient to demonstrate = its=20 characteristic features, which consist of a typically = striated=20 pattern of hyperintensity on T2-weighted images and=20 hypointensity on T1-weighted images, with no = enhancement=20 following gadolinium=E2=80=93diethylenetriamine = pentaacetic acid=20 administration. The pathogenesis of LDD remains = controversial,=20 and the debate as to whether it represents a = neoplastic,=20 malformative, or hamartomatous lesion is still = ongoing. It has=20 recently been reported that LDD is associated with the = autosomal-dominant, familial, multiple = hamartoma-neoplasia=20 syndrome (or CS)^6,12,20,23 and that=20 both conditions are associated with germline mutations = in=20 thePTEN gene, a tumor suppressor gene, on = chromosome=20 10q23.^{6,12,21,25,29} Although=20 several recurrent cases of LDD after subtotal = resection have=20 been reported,^10,14,24 to the=20 best of our knowledge, the occurrence of other = neoplasms=20 within an LDD lesion have not been recorded.

Gangliogliomas may occur throughout = the central=20 nervous system, but the majority are supratentorial = and=20 involve the temporal lobe.²²=20 Gangliogliomas arising from the cerebellum are = uncommon,=20 however, and the anaplastic variant is much more rare = in this=20 location. We report a case of an an-aplastic = ganglioglioma=20 arising against a background of a benign cerebellar=20 gangliocytic tumor histologically similar to LDD (that = is, an=20 LDD-like lesion).

Case Report	AbstractIntroductionCase Report = <<DiscussionReferences

History and Examination=20

This 7-year-old boy with a history of developmental = delay=20 presented in 1998 with aggressive behavior during = school.=20 There were no signs of increased ICP or gait = disturbances. An=20 MR imaging study revealed a large nonhomogeneous mass = lesion=20 (low isointensity on T1-weighted images and high = intensity on=20 T2-weighted images) with patchy enhancement, = originating in=20 the vermis and measuring 6 cm at the largest dimension = (Fig. 1A=20 and B). The neuroradiological differential diagnoses = included=20 a primitive neuroectodermal tumor, an ependymoma, or = an=20 atypical pilocytic astrocytoma.

View=20 larger version = (126K)

Fig. 1. = Sagittal=20 T1-weighted MR images of the patient at=20 presentation showing a large = nonhomogeneous mass=20 lesion with low isointensity, originating = in the=20 cerebellar vermis and measuring 6 cm at = the=20 greatest dimension (A), and demonstrating = patchy=20 contrast enhancement (B).

Operations and Postoperative = Course=20

Subtotal resection of the lesion was performed. The = impression of the frozen section and the = intraoperative=20 consultation, as well as the final histological = diagnosis, was=20 LDD. Two months after the craniotomy, the patient = showed signs=20 of increased ICP, for which a ventriculoperitoneal = shunt was=20 placed, and the patient has remained dependent on a=20 ventriculoperitoneal shunt since that time.

In 2003, he experienced an altered mental state and = a=20 facial droop. An MR imaging study revealed a residual=20 cerebellar mass, measuring approximately 6 cm in = diameter,=20 with cystic areas and an enhancing nodule (Fig. 2A). = Sub-occipital craniotomy with resection of the = cerebellar=20 lesion was performed. The histological diagnosis of = the tumor=20 was a ganglioglioma.

In 2005, a third craniotomy was performed for = worsening=20 headache and ataxia. A preoperative MR image showed a = rapidly=20 enhancing mass involving the entire cerebellar vermis = as well=20 as the paramedian cerebellar hemispheres, measuring=20 approximately 8 =C3=97 7 =C3=97 6.7 cm (Fig. 2B). = The=20 cerebellar tonsils were also noted to be herniating = through=20 the foramen magnum. The histological diagnosis of the = lesion=20 was an anaplastic ganglioglioma. The patient received=20 radiation therapy but experienced further tumor = progression 5=20 months after completing the therapy. He is currently = receiving=20 an experimental treatment of a Phase 1 study protocol. = Clinical follow-up information revealed no signs or = symptoms=20 suggestive of CS.

View=20 larger version = (140K)

Fig. 2. A: = Axial=20 T1-weighted contrast-enhanced MR image = obtained at=20 the 5-year follow-up showing a residual = cerebellar=20 mass measuring approximately 6 cm in = diameter with=20 cystic areas and an enhancing nodule. B: = An MR=20 image obtained at the 7-year follow-up = revealing a=20 rapidly enhancing mass involving the whole = of the=20 cerebellar vermis and paramedian = cerebellar=20 hemispheres. The mass measures 8 =C3=97 7 = =C3=97 6.7=20 cm.

Pathological = Findings=20

First Resection and Biopsy = Procedure=20

Histological examination of the tissue sample = resected in=20 1998 showed loss of the normal cerebellar architecture = with=20 thickened cerebellar folia, loss of Purkinje cells, = and poorly=20 defined white matter. For the most part, the tissue = consisted=20 of neuropil in which there were foci of dysplastic = ganglion=20 cells with abundant cytoplasm, large nuclei, prominent = nucleoli, and occasional multinucleation (Fig. 3A). = There=20 were also scattered vacuoles interspersed in the = neuropil. The=20 tissue appeared lobulated in some places. These = features were=20 histologically compatible with the diagnosis of LDD. = In=20 addition, there was a minor component with slightly = increased=20 cellularity consisting of a mixture of ganglion and = glial=20 cells (Fig. 3B). = A special=20 stain (Luxol fast blue) revealed isolated myelinated = fibers=20 and some bundles of myelinated fibers separating the = clusters=20 of ganglion cells. Axonal stains identified many axon = bundles=20 coursing throughout the tissue in a relatively = organized=20 pattern.

View=20 larger version = (194K)

Fig. 3.=20 Photomicrographs showing histological = features of=20 the tissue specimen from the first surgery = at=20 presentation.Upper: The LDD-like = area is=20 characterized by a small lobular = architecture=20 composed of vacuolated neuropil with = randomly=20 distributed dysplastic ganglion=20 cells.Lower: A focal area with a = mixture of=20 ganglion cells and glial cells is = demonstrated. H=20 & E, original magnification =C3=97=20 100(upper), =C3=97 = 200(lower), and =C3=97=20 400(inset).

Second Resection and Biopsy = Procedure=20

Histologically, the specimens resected in 2003 = consisted=20 predominantly of a proliferation of glial cells with=20 fibrillary cytoplasm, admixed with scattered ganglion = cells as=20 well as numerous eosinophilic granular bodies (Fig. 4). = Mitotic=20 figures were not seen. There were chronic inflammatory = cell=20 infiltrates in some places. These histological = features were=20 characteristic of a ganglioglioma. In addition, there = was a=20 minor component with residual LDD-like features.

View=20 larger version = (232K)

Fig. 4.=20 Photomicrograph showing histological = features of=20 the tissue specimen from the second = surgery at the=20 5-year follow-up. A proliferation of glial = cells=20 admixed with scattered ganglion cells is = seen as=20 are numerous eosinophilic granular=20 bodies(inset, arrows). H & E, = original=20 magnification =C3=97 100 and =C3=97=20 400(inset).

Third Resection and Biopsy = Procedure=20

Histologically, the tumor resected in 2005 showed=20 progressive anaplasia including cellular pleomorphism, = hypercellularity, and a few typical and rare atypical = mitotic=20 figures (Fig. 5). = Scattered=20 eosinophilic granular bodies were also noted. The = tumor was=20 most accurately classified as an anaplastic = ganglioglioma. In=20 addition, there was a minor component with residual = LDD-like=20 features.

View=20 larger version = (237K)

Fig. 5.=20 Photomicrograph showing histological = features of=20 the tissue specimen from the third surgery = at the=20 7-year follow-up. The tumor demonstrates=20 progressive anaplasia with cellular = pleomorphism=20 and hypercellularity.Upper left = inset shows=20 a mitotic figure;lower right inset = shows an=20 eosinophilic granular body(arrow). = H &=20 E, original magnification =C3=97 100 and = =C3=97=20 400(insets).

View=20 larger version = (250K)

Fig. 6.=20 Photomicrographs showing = immunohistochemical=20 findings. A: Tissue specimen showing the = glial=20 component in ganglioglioma expressing = GFAP. B:=20 Many neoplastic ganglion cells labeled = with=20 synaptophysin. C: Neoplastic ganglion = cells=20 highlighted with MAP2. D: Some ganglion = cells with=20 no immunoreactivity with PTEN=20 antibody(arrows). E and F: Many of = the=20 neoplastic ganglion cells were strongly=20 immunoreactive for anti-phospho-mTOR (E) = and=20 phospho-S6 ribosomal protein (F) = antibodies. H=20 & E, original magnification =C3=97 200 = (A=E2=80=93D) and =C3=97=20 400 (E, F, andinset).

Immunohistochemical staining was performed on=20 formalin-fixed, paraffin-embedded tissue specimens = using the=20 avidin-biotin complex method. Antigen retrieval was = undertaken=20 using steam heat. Primary antibodies against the = following=20 antigens were used: synaptophysin (clone SY38, = dilution 1:30;=20 Dako); phosphorylated neurofilament protein (clone = 2F11,=20 dilution 1:25; Dako); GFAP (clones 4A11, 1B4, and 2E1, = dilution 1:500; BD Biosciences Pharmingen); Ki 67 = (clone=20 MIB-1, dilution 1:500; Dako); MAP2 (clone AP20, = dilution=20 1:1000; Roche Molecular); human PTEN (clone 6H2.1, = dilution=20 1:200; Cascade Bioscience); phos-pho-mTOR (clone 49F9, = dilution 1:30; Cell Signaling Technology); and = phospho-S6=20 ribosomal protein (clone 2F9, dilution 1:30; Cell = Signaling=20 Technology).

The glial component in the=20 ganglioglioma/anaplastic ganglioglioma was labeled = with=20 anti-GFAP antibody (Fig. 6A). = Some=20 neoplastic ganglion cells in these tumors were = highlighted=20 using antisynaptophysin (Fig. 6B), = phosphorylated neurofilament protein, and MAP2 = antibodies (Fig. 6C).=20 These cells did not express PTEN (Fig. 6D). = Most of=20 the neoplastic ganglion cells were immunoreactive for=20 anti-phospho-mTOR (Fig. 6E) = and=20 phospho-S6 ribosomal protein (Fig. 6F)=20 antibodies. In the anaplastic ganglioglioma the Ki 67 = labeling=20 index was approximately 5%, counted in the most = mitotically=20 active areas.

Discussion	AbstractIntroductionCase ReportDiscussion <<

This is a case in which a very small nidus of=20 gangliogliomatous component against a background of = dysplastic=20 cerebellar gangliocytoma progressively replaced a = large area=20 of the cerebellar tumor with increasing anaplasia over = an=20 8-year follow-up period. Gangliocytoma in the = cerebellum is=20 used synonymously for LDD, and it has not been = reported to=20 occur outside of this disease. The present case is = unique=20 because the astrocytic proliferation within the tumor = was so=20 limited in the specimen from the first surgery that = the=20 histological features closely mimicked those of a = dysplastic=20 cerebellar gangliocytoma, or LDD. The tumor also = showed an=20 atypical folial pattern on MR imaging.

It is well known that occasionally gangliogliomas = may=20 demonstrate areas almost entirely devoid of an obvious = gliomatous component, thereby resembling a=20 gangliocytoma.²⁶ Handa=20 and colleagues⁸ = reported a=20 very similar case of a cerebellar hemispheric = ganglioglioma=20 with a small astrocytic component in a 53-year-old = patient. In=20 their case, the disappearance of Purkinje cells or = hypertrophy=20 of the internal granular cell layer, which are = characteristics=20 of LDD, was not observed. These investigators noted = that=20 differentiation from LDD was possible based on these=20 histological findings. Our case was more complicated = because=20 the internal granular layer was almost totally effaced = by=20 gangliocytic proliferation with loss of the overlying = Purkinje=20 cells. It is generally believed that the typical MR = imaging=20 findings of LDD, such as a nonenhancing mass in the = cerebellar=20 hemisphere with an alternating striated pattern of=20 corresponding low signal intensity on T1-weighted = images and=20 high signal intensity on T2-weighted images, are so=20 distinctive²⁸ that it=20 is unlikely that LDD will be confused with other = diseases.=20 Chen and coworkers,⁵ = however,=20 reported a case of a medulloblastoma in which the MR = imaging=20 findings were indistinguishable from those of LDD with = the=20 exception of the laminated/folial pattern, which = showed=20 contrast enhancement. Our case demonstrated a = cerebellar tumor=20 with an atypical folial pattern that was highlighted = on=20 T1-weighted images with contrast enhancement, probably = reflecting a diffuse leptomeningeal infiltration of = tumor=20 cells. The absence of typical MR imaging features of = LDD may=20 have been the only clue to the correct initial = histological=20 diagnosis in our case.

Although gangliogliomas may occur at almost any = location of=20 the central nervous system, those arising from the = cerebellum=20 are uncommon and only approximately 35 cases have been = reported so far in the literature.^{4,7=E2=80=939,11,15,17,18}=20 Gangliogliomas occurring in the cerebellum and in = other more=20 common locations (such as the temporal lobes) tend to = be found=20 in pediatric and young adult populations at = presentation, with=20 the patient age ranging from 3 months to 53 years = (mean 16.2=20 years). The most common presenting symptoms in = patients are=20 those related to increased ICP and/or cerebellar = dysfunction,=20 in contrast to patients with supratentorial = gangliogliomas,=20 who commonly present with a long history of = seizures.²⁶=20 Neuroradiologically, it was reported that the majority = of=20 these lesions with well-described neuroimaging = findings were=20 contrast enhancing and that nearly half demonstrated = cyst=20 formation and the presence of calcification. The main=20 differential diagnoses include pilocytic astrocytoma = and=20 dysplastic cerebellar gangliocytoma/LDD. Malignant=20 transformation of cerebral ganglioglioma has been = reported to=20 be as high as 10% of cases;^16,27 however,=20 to our knowledge this is the first documented case of=20 cerebellar ganglioglioma with anaplastic = transformation.

Lhermitte=E2=80=93Duclos disease was recently = recognized as a=20 phenotypic variant of CS, and over 80% of patients = with CS=20 reportedly carry germline mutations = inPTEN.²⁹ Zhou et=20 al.²⁹ reported=20 that aPTEN mutation was detected in all tissue = samples=20 (15 cases) from patients with adult-onset LDD. In = contrast,=20 three tissue samples from patients with = childhood-onset LDD=20 were all found to be without mutations. ThePTEN = gene is=20 a tumor suppressor gene that codes for a phosphatase = that=20 negatively regulates the phosphatidylinositol=20 3-kinase=E2=80=93/Akt/mTOR pathway, thereby inducing = cell cycle arrest=20 and/or apoptosis.³ = The mTOR=20 kinase phosphorylates ribosomal S6 kinase, which leads = to=20 increased levels of phospho-S6. A novel function for = PTEN in=20 the control of cell size has recently been = discovered,² = and=20 several recent in vivo studies indicate that S6 kinase = plays=20 an essential role in the regulation of cell size using = this=20 signaling pathway.¹⁹ Abel et=20 al.¹ = studied 11=20 cases of LDD using immunohisto-chemistry and reported = that=20 most of the lesions were negative for PTEN and that = high=20 levels of immunoreactivity against phospho-Akt and = phospho-S6=20 were observed in the large ganglion cells forming the = lesions,=20 indicating activation of the PTEN/Akt/mTOR signaling = pathway.=20 The absence of PTEN immunoreactivity is presumed to = reflect=20 the loss of the inhibitory influence of this protein = on this=20 pathway, which may or may not be due to mutation of=20 thePTEN gene. It has also been suggested that = mTOR may=20 play a central role in the pathogenesis of LDD.¹ = The=20 results of the immunohistochemical analysis of our = case=20 showing loss of PTEN immunoreactivity, in the presence = of=20 phospho-S6 and phospho-mTOR positivity in the large = ganglion=20 cells, suggest that the large dysplastic ganglion = cells (the=20 gangliocytomatous component) forming the greater part = of the=20 lesion in the first surgical specimen have activated = mTOR and=20 S6 kinase, probably as a result of the loss of the = PTEN=20 inhibitory effect on the PTEN/Akt/mTOR signaling = pathway.

The pathogenesis of LDD remains an enigma and the=20 controversy as to whether it represents a malformation = (such=20 as hypertrophy of granule cells), hamartoma, or = neoplasm is=20 still ongoing. Although tumor regrowth is rare after=20 appropriate initial treatment, several cases of = recurrent LDD=20 have been reported.^10,14,24 The=20 close similarity of the histological features and=20 immunoprofile of the lesion we are describing to those = of=20 classic gangliocytoma/LDD raises the intriguing = possibility=20 that it may represent a case of a ganglioglioma = arising from a=20 true LDD; that is, the nidus of ganglioglioma was = already=20 present in the LDD at the time of the first = presentation and=20 surgery. The results of the immunohistochemical study = of our=20 case support this possibility.²⁹ Because=20 the diagnosis of LDD is, in general, confirmed by = histology,=20 it is extremely difficult or impossible to prove this=20 possibility retrospectively.

In summary, we presented a case of a = cerebellar=20 ganglioglioma in which the gliomatous component = (astrocytic=20 proliferation) was so limited that the histological = features=20 closely mimicked those of LDD, and this component = showed=20 increasing anaplasia over an 8-year follow-up period. = This=20 tumor demonstrated an atypical folial pattern on MR = imaging=20 with contrast enhancement. This enhancing folial = pattern is=20 unusual for classic LDD and may be of help in = differentiating=20 classic LDD and mimics (LDD-like lesions). This=20 immunohistochemical pattern (PTEN negative, phospho-S6 = positive, and phospho-mTOR positive) of = immunoreactivity in=20 large ganglion cells suggests that the large = dysplastic=20 ganglion cells (gangliocytomatous component) forming = most of=20 the lesion demonstrate activation of the PTEN/Akt/mTOR = signaling pathway.

References	AbstractIntroductionCase ReportDiscussionReferences = <<

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