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Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)

Author: Eman Abdelzaher, M.D., Ph.D.

Editorial Board Member: P.J. Cimino, M.D., Ph.D.

Deputy Editor-in-Chief: Chunyu Cai, M.D., Ph.D.

Last author update: 1 July 2024

Last staff update: 1 July 2024

Copyright: 2002-2024, PathologyOutlines.com, Inc.

PubMed Search: Dysplastic gangliocytoma of the cerebellum

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Table of Contents

Cite this page: Abdelzaher E. Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumordysplasticgangliocytoma.html. Accessed July 15th, 2024.

Definition / general

Dysplastic cerebellar gangliocytoma, also known as Lhermitte-Duclos disease (LDD), is a cerebellar lesion characterized by thickened cerebellar folia caused by dysplastic ganglion cells that conform to the existing cortical architecture (J Neuropathol Exp Neurol 2005;64:341)
CNS WHO grade 1

Essential features

Rare cerebellar lesion associated with Cowden syndrome (CS) and germline mutations in the PTEN gene (J Neuropathol Exp Neurol 2005;64:341, J Radiol Case Rep 2020;14:1)
First described by Lhermitte and Duclos in 1920 (J Neurosci Rural Pract 2023;14:127)
Typical imaging findings alone are usually sufficient for the diagnosis of LDD, especially the tiger stripe sign (Clin Radiol 2023;78:33)
Classical histological hallmarks include relative preservation of the cerebellar architecture with replacement of the granule cell layer by dysplastic ganglion cells, loss of Purkinje cells and expansion and hypermyelination of the molecular layer (J Neuropathol Exp Neurol 2005;64:341)

Terminology

Not recommended by WHO: cerebellar granule cell hypertrophy; diffuse hypertrophy of the cerebellar cortex; gangliomatosis of the cerebellum

ICD coding

ICD-O: 9493/0 - dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos)
ICD-11: 2A00.21 & XH6K00 - mixed neuronal - glial tumors & dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos)

Epidemiology

Rare (J Radiol Case Rep 2020;14:1, World Neurosurg 2017;104:398)
Wide age range; however, most cases are reported in adults (third and fourth decades) (J Neuropathol Exp Neurol 2005;64:341, World Neurosurg 2017;104:398)
No gender predilection (J Radiol Case Rep 2020;14:1)

Sites

Cerebellum, usually unilateral, rarely bilateral (Cerebellum 2013;12:127, World Neurosurg 2019;127:319, Pan Afr Med J 2019;33:118)

Pathophysiology

Its nature, hamartomatous versus neoplastic, remains unclear (Acta Neurol Scand 2002;105:137)
Suggested cell of origin is the cerebellar granule neuron (Acta Neuropathol 1992;84:570)
Pathogenesis of LDD, in most cases, is related to loss of the inhibitory influence of PTEN on the PI3K pathway with activation of the AKT / mTOR signaling pathway resulting in aberrant migration and hypertrophy of granule cells; murine transgenic models with localized PTEN loss support this hypothesis (J Neuropathol Exp Neurol 2005;64:341, Nat Genet 2001;29:404)

Etiology

PTEN mutations have been identified in virtually all cases of adult onset LDD but not in childhood onset cases (Am J Hum Genet 2003;73:1191)
Adult onset LDD is considered pathognomonic of Cowden syndrome; both are considered a single phakomatosis that now belongs to PTEN hamartoma tumor syndrome (PHTS) (World Neurosurg 2017;104:398, J Neurosci Rural Pract 2023;14:127)
Cowden syndrome is an autosomal dominant disorder characterized by multiple hamartomas involving tissues derived from all 3 germ cell layers and increased risk of breast, thyroid, endometrial, renal and colon cancers (Clin Cancer Res 2012;18:400)
The majority (85%) of patients with Cowden syndrome have a germline mutation in PTEN; recently, other Cowden syndrome predisposition genes have been identified including the SDH genes, PIK3CA, KLLN and WWP1 (Hum Mol Genet 2020;29:R150, World Neurosurg 2017;104:398, Am J Hum Genet 2008;83:261)
Although the associations between LDD, Cowden syndrome and germline PTEN mutations are well documented, the precise relationships among them are less clear, as not all patients with LDD develop the clinical manifestations of Cowden syndrome and some patients with LDD lack germline mutations in PTEN; furthermore, not all patients with germline PTEN mutations manifest Cowden syndrome (J Neuropathol Exp Neurol 2005;64:341)

Diagrams / tables

Images hosted on other servers:

Schematic diagram of Lhermitte-Duclos disease

Histological changes

Pathology

Clinical features

Most common: cerebellar signs as dysmetria, manifestations of obstructive hydrocephalus and increased intracranial pressure (J Neurosci Rural Pract 2023;14:127, J Neuropathol Exp Neurol 2005;64:341, J Radiol Case Rep 2020;14:1)
Often present: cranial nerve deficits, macrocephaly and seizures (Ann Neurol 1991;29:517)
Patients with isolated LDD may be asymptomatic for years (J Radiol Case Rep 2020;14:1)

Diagnosis

Neuroimaging is highly suggestive of diagnosis (J Radiol Case Rep 2020;14:1)
Biopsy
WHO diagnostic criteria
- WHO essential diagnostic criteria
  - Gangliocytic lesion that enlarges cerebellar folia
  - Densely packed ganglionic cells of various sizes
  - Matrix resembling normal neuropil, sometimes more coarsely fibrillar or vacuolated
- WHO desirable diagnostic criteria
  - PTEN mutation / deletion or loss of expression
  - Abnormal myelination and vacuolization in the outer molecular layer
  - Calcification and ectatic vessels

Radiology description

Magnetic resonance imaging (MRI)
- MRI is sensitive and is usually sufficient for diagnosis (J Radiol Case Rep 2020;14:1)
- Enlarged cerebellar folia
- T1: hypointense signal (J Radiol Case Rep 2020;14:1)
- T2: typical tiger stripe pattern (tigroid appearance) of alternating low and high signal (J Radiol Case Rep 2020;14:1)
- Typically, does not enhance (World Neurosurg 2017;104:398)
- No peritumoral edema (Clin Radiol 2023;78:33)
- Evidence of mass effect and hydrocephalus is common (J Neuropathol Exp Neurol 2005;64:341)
- Cystic changes in some cases (Clin Radiol 2023;78:33)
- Atypical cerebellar imaging findings may be encountered including vascular abnormalities, intratumoral calcification, intratumoral hemorrhage, heterogeneous enhancement and peritumoral edema (Clin Radiol 2023;78:33)
- Because of the strong association between LDD and Cowden syndrome, imaging of other organ systems such as the breast and colon should be considered in patients with LDD to rule out occult neoplasms in other organ systems (J Radiol Case Rep 2020;14:1)
Computed tomography (CT)
- Hypodense to isodense (World Neurosurg 2017;104:398)
- Calcification is uncommon (5%) (J Neuropathol Exp Neurol 2005;64:341)

Radiology images

Contributed by Eman Abdelzaher, M.D., Ph.D.

MRI, coronal T1 with contrast

MRI, axial T2

Images hosted on other servers:

Tiger stripe sign

Characteristic
alternating iso
and hyperintense
bands

T2 hyperintense right cerebellar lesion

FLAIR hyperintense right cerebellar lesion

Bilateral cerebellar lesions

Prognostic factors

Prognosis is generally favorable (J Radiol Case Rep 2020;14:1)
Although the lesion is histopathologically benign, recurrences following surgical resection are not uncommon (31%) (J Neuropathol Exp Neurol 2005;64:341)
Recognition of the disease is of particular importance because of the frequent association with Cowden syndrome; therefore, patients with LDD should be genetically tested and screened for Cowden syndrome and monitored for the development of additional malignant and benign tumors, including breast and thyroid cancers (Acta Neurol Scand 2002;105:137, J Neuropathol Exp Neurol 2005;64:341, World Neurosurg 2017;104:398, Am J Hum Genet 2003;73:1191)

Case reports

40 year old man with LDD diagnosed following traumatic brain injury (J Ayub Med Coll Abbottabad 2022;34:S733)
50 year old man with bilateral cerebellar cortex LDD (Pan Afr Med J 2019;33:118)
56 year old woman with dual diagnosis of Cowden syndrome and LDD (J Radiol Case Rep 2020;14:1)
59 year old woman with LDD manifesting with intratumoral hemorrhage (World Neurosurg 2018;114:326)

Treatment

Observation, unless symptomatic
Complete surgical resection is curative; however, the main technical problem during surgery is determining the actual margins of the lesion
- Intraoperative MRI and high definition fiber tractography have been proposed as guidance tools to increase the accuracy of resection (J Radiol Case Rep 2020;14:1, World Neurosurg 2017;104:398, World Neurosurg 2016:92:587.e9)
Novel molecular targeted therapy through pharmacologic inhibition of mTOR is promising; rapamycin was recently used successfully to treat bilateral infantile LDD and other PTEN mutation diseases (J Neuropathol Exp Neurol 2005;64:341, World Neurosurg 2017;104:398
Long term close follow up of patients with LDD is needed (World Neurosurg 2018;114:326)

Clinical images

Images hosted on other servers:

Distorted and enlarged cerebellar hemisphere

Gross description

Focal, well circumscribed lesion, usually restricted to one of the cerebellar hemispheres with folia hypertrophy and a coarse gyral pattern that extends into deeper layers (J Radiol Case Rep 2020;14:1, J Neurosurg Case Lessons 2021;2:CASE21451)

Gross images

Images hosted on other servers:

Enlarged cerebellar folia

Microscopic (histologic) description

Relative preservation of the cerebellar architecture: the folia are enlarged and distorted but not obliterated
Thickened cerebellar folia: the internal granular and molecular layers show diffuse enlargement and are replaced by variable sized dysplastic ganglionic cells with vesicular nuclei and prominent nucleoli; matrix resembles normal neuropil but is sometimes more coarsely fibrillar or vacuolated (J Neurosci Rural Pract 2023;14:127, J Neuropathol Exp Neurol 2005;64:341, J Radiol Case Rep 2020;14:1)
Abnormal molecular layer myelination: abnormally myelinated axons extending through molecular layer to pial surface (J Neuropathol Exp Neurol 2005;64:341)
Attenuated or absent Purkinje cell layer (J Neuropathol Exp Neurol 2005;64:341, J Radiol Case Rep 2020;14:1)
Vacuolization of the white matter and molecular layer (J Neuropathol Exp Neurol 2005;64:341, J Neurosci Rural Pract 2023;14:127)
Thinning of white matter (J Radiol Case Rep 2020;14:1)
Ectopic granule neurons are sometimes found under the pia or in the molecular layer; the resulting structure of these dysmorphic cerebellar folia has been referred to as inverted cerebellar cortex
Many of the lesions are highly vascular, with dense capillary networks or ectatic, thin walled blood vessels (J Neuropathol Exp Neurol 2005;64:341)
Microscopic calcification is common (J Neurosci Rural Pract 2023;14:127)
No mitosis (World Neurosurg 2017;104:398)

Microscopic (histologic) images

Contributed by Eman Abdelzaher, M.D., Ph.D.

Relative preservation of cerebellar architecture

Replaced internal granular layer

Dysplastic ganglion cells

Variable sized ganglion cells

Dysplastic ganglion cells with large nuclei and prominent nucleoli

Vacuolization of the white matter

Vacuolated neuropil matrix

Synaptophysin

Cytology description

Squash smears show scattered, enlarged cells with vesicular nuclei and prominent nucleoli, thickened axons and many capillary sized vessels against a fibrillary background (J Neurosci Rural Pract 2023;14:127)

Cytology images

Images hosted on other servers:

Enlarged cells with vesicular nuclei and prominent nucleoli

Enlarged cells / thickened axons and capillary sized vessels

Positive stains

Phosphorylated AKT (90%) and S6 (100%): increased expression in the large ganglionic cells reflecting AKT / mTOR pathway activation that results in increased cell size and lack of apoptosis (J Neuropathol Exp Neurol 2005;64:341, Am J Hum Genet 2003;73:1191)
Synaptophysin: positive in dysplastic ganglion cells (Medicine (Baltimore) 2022;101:e28667)
NeuN: variably positive in dysplastic ganglion cells
Neurofilament protein: positive in neuronal processes

Negative stains

PTEN: complete or partial loss of PTEN protein expression in most (75%) dysplastic ganglion cells (Am J Hum Genet 2003;73:1191)
GFAP (J Neuropathol Exp Neurol 2005;64:341)
Ki67: undetectable or very low (1 - 2%) proliferative activity; negative in ganglion cells (J Neuropathol Exp Neurol 2005;64:341, Acta Neuropathol 1992;84:570, Medicine (Baltimore) 2022;101:e28667)
Antibodies specific to the Purkinje cell antigens (CD3 [LEU4], PCP2, PCP4 and calbindin): may label a minor subpopulation of the large dysplastic ganglion cells (Acta Neuropathol 1992;84:570)

Electron microscopy description

Ganglion cells with neuronal features, including microtubules, synapses and clear vesicles

Molecular / cytogenetics description

Germline PTEN mutations in most but not all cases
Activation of mTOR pathway (J Neuropathol Exp Neurol 2005;64:341)

Molecular / cytogenetics images

Images hosted on other servers:

PI3K / PTEN / AKT signaling pathway

Pathogenic heterozygous PTEN mutation

Videos

Lhermitte-Duclos disease

Sample pathology report

Right cerebellar hemisphere mass lesion, gross total resection:
- Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), CNS WHO grade 1
- Molecular genetics: PTEN mutation / deletion or loss of expression

Differential diagnosis

Ganglioglioma:
- No preservation of cerebellar architecture
- Neoplastic ganglion cells do not form broad bands that replace the internal granular cell layer
- GFAP+ neoplastic glial component
- Eosinophilic granular bodies
- Perivascular chronic inflammation
- BRAF p.V600E mutation in a subset of gangliogliomas (Acta Neuropathol 2013;125:891)
Infiltrating glioma with entrapped Purkinje cells:
- GFAP+ neoplastic glial cells
- Hypercellularity in both cerebellar cortex and white matter
- Single cell layer of overrun ganglion cells (Purkinje cell layer)

Additional references

WHO Classification of Tumours Editorial Board: Central Nervous System Tumours, 5th Edition, 2022, Kleinschmidt-DeMasters: Diagnostic Pathology, 3rd Edition, 2022

Board review style question #1

A 35 year old man presented with a headache and ataxia. Magnetic resonance imaging (MRI) showed a left cerebellar hemisphere mass lesion with T2 hyperintensity and a tigroid pattern. A gross total resection of the mass was done and the histopathological features of the lesion are shown in the figure above. Which of the following genetic abnormalities is the hallmark of this tumor?

BRAF mutation
IDH mutation
PRKCA gene fusion
PTEN mutation

Board review style answer #1

D. PTEN mutation. Germline PTEN mutations are detected in most but not all cases of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease). Answers A, B and C are incorrect because BRAF mutations, IDH mutations and PRKCA gene fusion are associated with other neuroepithelial tumors such as gangliogliomas, IDH mutant adult type diffuse gliomas and papillary glioneuronal tumor, respectively.

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Reference: Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)

Board review style question #2

Lhermitte-Duclos disease (LDD) is closely associated with which of the following syndromes?

Cowden syndrome
Familial adenomatous polyposis
Lynch syndrome
Peutz-Jeghers syndrome

Board review style answer #2

A. Cowden syndrome. Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) is a component of Cowden syndrome. Answers B, C and D are incorrect because these syndromes are unrelated to LDD.

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Reference: Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)

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