Lhermitte-Duclos Disease (Dysplastic Gangliocytoma of the Cerebellum)
Lhermitte-Duclos disease (LDD) or dysplastic gangliocytoma of the cerebellum was first described in 1920 by Lhermitte and Duclos. It is a benign, usually unilateral cerebellar mass manifesting predominantly in young adults (mean age 34 years, with a broad range from neonatal to >70 years) and usually presents with symptoms of ataxia and increased intracranial pressure (1,2). MRI imaging shows broadening of the folia with a striated or laminated appearance on T2-weighted images. The uniqueness of these imaging characteristics makes a preoperative diagnosis on the base of MRI possible (2,4). Complete surgical resection is attempted in the majority of cases. The lack of a sharp border between tumor and normal cerebellar tissue, however, limits the accuracy of surgical excision. Outcome without surgical intervention is poor due to the mass effect of the enlarging mass (4).
Diagnostic microscopic features include replacement of the granular and Purkinje cell layers by large polygonal gangliocytic neurons and the abnormal presence of myelinated fibers in the outer molecular layer. Electron microscopy studies indicate that the large abnormal neurons represent hypertrophied granule cells. In some cases, the molecular layer also shows hypercellularity, composed of ectopic granule cells and dysplastic ganglion cells. In addition, abnormal subarachnoid vasculature, and microcalcifications in association with small vessels can be seen in LDD lesions. The transition from normal to pathological cerebellar cortex is gradual and accompanied by disappearance of Purkinje cells and vanishing of central white matter. Proliferation markers usually reveal undetectable or very low proliferative activity (1,2,4).
It is still unclear if LDD is a hamartoma or neoplasm. It has been hypothesized that LDD represents a defect in regulation of cell size superimposed upon aberrant migration of granule cell precursors. Despite their large ganglionic appearance, immunohistochemical studies show that the large cells express many granular neuron markers and few Purkinje neuron markers (2,7).
Although the lesion is histopathologically benign, recurrences following surgical resection are not uncommon. Regrowth of LDD lesions has been used as an argument in favor of a neoplastic process, while others argue that recurrences derive from partially resected or multifocal lesions. The orderly orientation of axons originating from the abnormal neurons, the absence of significant proliferative activity, as well as data from a mouse model support the concept that growth of tumor in LDD arises from hypertrophy of individual cells rather than hyperplasia (2,4,7,8). However, despite their normal perpendicular orientation, the axons from abnormal neurons in LDD differ from the normally non-myelinated granule cell axons by the presence of myelination. The reduction of Purkinje cells and white matter are supposed to be secondary changes (4).
An important consideration in the management of patients with LDD is its association with Cowden disease (CD) (1-3). Evidence for CD is found in almost half of the patients with LDD. It is an autosomal dominant inherited condition that causes a variety of hamartomas and neoplasms, affecting about 1 in 200 000 individuals. LDD is the major CNS manifestation. Additional cerebral manifestations include megalencephaly and mental retardation. Peripheral lesions include facial trichilemmomas, acral keratoses, oral mucosal papillomatosis, hamartomatous gastrointestinal polyps, benign and malignant thyroid neoplasms, endometrial carcinoma, breast cancer, other genito-urinary tumors, lipomas and fibromas (1,3). The lifetime risk for breast cancer in CD is 25-50%, for (follicular) thyroid cancer 10%.
CD and LDD are associated with germline mutations in the PTEN gene, which is located at chromosome 10q23. However, the precise relationships are less clear, as not all patients with LDD develop symptoms of CD, some patients with LDD lack germline mutations in PTEN, and not all patients with germline PTEN mutations manifest CD. In a subset of mutation negative CD cases, a mutation in the PTEN promotor region has been recently identified (5)
The product of the phosphatase and tensin homologue (PTEN) gene is a phosphatase that negatively regulates signal transduction in the phosphatidylinositol 3-kinase (PI3K) pathway. Inactivation of PTEN results in increased levels of phosphorylated AKT (p-AKT), promoting cell growth, proliferation and survival through multiple downstream effectors. Activation of the PI3K/AKT pathway could also account for the prominent vascular changes seen in LDD by promoting angiogenesis via upregulation of vascular endothelial growth factor (2).
Immunohistochemical studies in a series of LDD cases showed negative staining for PTEN and positive reactivity for p-AKT in a majority of cases. The most consistent finding, however, was positive immunostaining for p-S6, which is phosphorylated by mTOR (mammalian target of rapamycin), one of the downstream effectors of the PI3K/AKT pathway. Phosphorylated p-S6 was also detected in cases without PTEN germline mutation, suggesting an alternate pathway of mTOR activation in a subset of patients with LDD, in particular in individuals with childhood onset of disease (2).
Contributed by Julia Kofler, MD and Geoffrey Murdoch, MD, PhD