A rare WHO Grade I Lesion of the Posterior Fossa with Recurrence Biological Behavior - Dysplastic Gangliocytoma of the Cerebellum: Case Report

Abstract

Dysplastic gangliocytoma of the cerebellum (DGC) or Lhermitte-Duclos Disease is a rare lesion (World Health Organization [WHO] grade I) characterized by thickened folia and replacement of the internal granular layer by abnormal ganglion cells. More commonly, the compromised patients are young adults presenting ataxia, seizures, obstructive hydrocephalus, and increased intracranial pressure. Dysplastic gangliocytoma of the cerebellum is intimately associated with Cowden syndrome, a hereditary disorder caused by a germline mutation in the PTEN tumor suppressor gene on chromosome 10q23. Large neurons of DCG show vesicular nuclei with prominent nucleoli. Expansion of the internal granular layer determines vacuolization of the molecular layer and white matter, which can be related to the bright stripes identified on T2-weighted magnetic resonance imaging. Herein, the authors report a female patient who developed long- time recurrence of DGC and discuss pathological findings and differential diagnosis of this rare cerebellar lesion.

Resumo

O gangliocitoma displásico de cerebelo (GDC) ou a Doença de Lhermitte-Duclos é uma lesão rara (Organização Mundial de Saúde [OMS] grau I) caracterizada por folhas cerebelares espessadas e substituição da camada granular interna por células ganglionares anormais. Mais comumente, os pacientes comprometidos são adultos jovens que apresentam ataxia, convulsões, hidrocefalia obstrutiva e aumento da pressão intracraniana. O GDC está intimamente associado à síndrome de Cowden, um distúrbio hereditário causado por uma mutação da linha germinativa no gene supressor de tumor PTEN no cromossomo 10q23. Os neurônios grandes do GDC mostram núcleos vesiculares com nucléolos proeminentes. A expansão da camada granular interna determina a vacuolização da camada molecular e da substância branca, as quais podem ser relacionadas às faixas brilhantes identificadas na ressonância magnética ponderada em T2. Aqui, os autores relatam uma paciente do sexo feminino que desenvolveu recorrência em longo prazo de GDC e discutem os achados patológicos e o diagnóstico diferencial desta rara lesão cerebelar.

Keywords

dysplastic gangliocytoma of the cerebellum - lhermitte-duclos disease - central nervous system tumors - cowden syndrome - pathology

Palavras-chave

gangliocitoma displásico do cerebelo - doença de lhermitte-duclos - tumores do sistema nervoso central - síndrome de cowden - patologia

Introduction

Dysplastic gangliocytoma of the cerebellum (DGC) or Lhermitte-Duclos Disease is a rare lesion (World Health Organization [WHO] grade I) characterized by thickened folia and replacement of the internal granular layer by abnormal ganglion cells. More frequently, the compromised patients are young adults with signs and symptoms of increased intracranial pressure.[1] [2] [3] [4] Dysplastic gangliocytoma of the cerebellum is intimately associated with Cowden syndrome, a hereditary disorder caused by a germline mutation in the PTEN tumor suppressor gene on chromosome 10q23. Large neurons of DCG show vesicular nuclei with prominent nucleoli. Expansion of the internal granular layer determines vacuolization of the molecular layer and white matter, which can be related to the bright stripes identified on T2-weighted magnetic resonance imaging (MRI). The prognosis is good, but recurrence is found in ∼ 25% of the patients.[1] [2] [5] [6] [7] [8] The authors report a case of recurrent DGC and discuss fundamental pathologic findings of this rare lesion.

Case Report

Female patient, 19 years old, with clinical complaint of headache and nausea, was referred to the neurosurgery service due a cerebellar lesion. No focal neurological deficits were found on the physical examination. Prior pathologic history included idiopathic pulmonary fibrosis and rheumatoid arthritis. A large process compromising the right cerebellar hemisphere, with mildly increased diffusivity, thickened folia and a “tiger-striping” pattern, was identified on MRI, compatible with DGC ([Figure 1]). The patient underwent gross totally surgical removal of the process. The specimen was composed by some irregular fragments of tissue, pale gray, elastic, weighing 18.0 g. The largest one measured 3.0 × 2.8 × 2.0 cm and was composed by cerebellar tissue exhibiting a prominent enlarged cortex. At microscopy, the internal granular cell layer was replaced by numerous moderate to large hypertrophic ganglion cells, which extended to the subpial zone of the molecular layer ([Figure 2]). The cortex was also expanded by small neurons, but there was relative preservation of the cerebellar architecture. Other histological findings include vacuolations of cerebellar white matter and abnormal myelination of the molecular layer by abnormal neurons ([Figure 3]). The diagnosis of DGC was then established. Recurrence of the process was identified 3 and 8 years after the initial procedure, and the patient underwent surgical resection at these moments. Actually, the patient is free of neurologic deficits and tumor recurrence on imaging screening.

Fig. 1 Dysplastic Gangliocytoma of the Cerebellum: Magnetic Resonance showing enlarged cerebellar folia.

Fig. 2 Dysplastic Gangliocytoma of the Cerebellum: Medium to large ganglion cells with mild cytologic abnormalities filling the internal granule cell layer, hematoxylin-eosin, 200X.

Fig. 3 Dysplastic Gangliocytoma of the Cerebellum: Large ganglion cells with small associated to small neurons and focus of calcification, hematoxylin-eosin, 200X.

Discussion

Dysplastic gangliocytoma of the cerebellum is a rare low-grade process frequently associated to ataxia, seizures, obstructive hydrocephalus, increased intracranial pressure and/or cerebellar injury. Uncommon clinical findings include orthostatic hypotension, acute subarachnoid hemorrhage, cranial nerve deficits, seizures, and mild intellectual disability.[1] [4] [8] [9] [10] Both the vermis and hemispheric cerebellar cortex may be affected. Compromised patients are usually in the 3^rd and 4^th decades of life, and there is no gender predilection. In some cases of DGC, the patients also exhibit neuronal heterotopias in the white matter, hydromelia, olivary nuclear hypertrophy, cervical syrinx, polydactyly, vascular malformations, macrocephaly/megalencephaly, and partial gigantism. Uncommon designations for DGC have been used, and include granule cell hypertrophy of the cerebellum, cerebellar hamartoma, neurocytic blastoma, neurocytoma myelinicum, cerebellar granule cell hypertrophy, gangliocytoma myelinicum diffusum, gangliomatosis of the cerebellum, and purkinjeoma.[3] [4] [7] [9] [11] [12]

The histogenesis of DGC is still undefined. The hypothesis suggesting a malformative/hamartomatous nature of DGC is defined as an incomplete development of the fetal external granular cell layer, which results in a reduced population of the internal granular cell layer, determining hypertrophy of the remaining neurons. It has been suggested that mass effect of DCG is associated to hypertrophy of individual ganglionic cells rather than pure neoplastic proliferation.[2] [3] [5] [8] [11] [13] [14] Presence of PTEN mutations or PTEN promoter alterations have been implicated in the neoplastic transformation of cerebellar tissue. The effects of PTEN are mediated through its actions on the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, abrogation of PTEN protein function resulting in increased intracellular levels of phosphorylated AKT, which promotes cellular enlargement and proliferation due different targets. PTEN loss determines downstream activation of S6 kinase, AKT and mTor, which can be demonstrated in ganglionic cell of the tumor. Dysplastic gangliocytoma of the cerebellum is recognized as a component of Cowden syndrome, an autosomal dominant phakomatosis linked to PTEN/MMAC-1 mutations. Pediatric patients do not harbor germline PTEN mutations.[2] [3] [5] [8] [11] [13] [14]

Dysplastic gangliocytoma of the cerebellum is typically a non-enhancing, unilateral lesion that is hypointense on T1-weighted MRI and hyperintense on T2 images. Magnetic resonance imaging frequently shows mildly increased diffusivity. Presence of superficial parallel linear striations is pathognomonic of DGC (“tiger-striping”), and represents thickened cerebellar folia.[1] [3] [11] [12] [13] [14] [15]

Gross, regional, pale enlarged folia which blend into the normal cerebellar cortex is a hallmark of DGC. Some cases exhibit discrete calcifications and/or white matter cavitation.[1] [2] [3] [4] [9] [16] At microscopy, variable replacement of the internal granular cell layer by moderate to large hypertrophic ganglion cells is a diagnostic feature of DGC. In more prominent lesions, the molecular layer can also be affected. Eventually, ganglionic cells of the lesion are found in the subpial zone of the molecular layer. An important diagnostic feature is the relative preservation of the cerebellar architecture. Other significant histological findings include large bizarre neurons, abnormal myelination of the molecular layer by abnormal neurons that run in parallel stacks within the deeper layers and in perpendicular array more superficially, dense capillary networks, reduction in the number of Purkinje cells, and vacuolations of cerebellar white matter.[1] [3] [4] [9] [10] [12] [16] [17] Dysplastic gangliocytoma of the cerebellum is constituted by large and small ganglionic cells of granule cell type. Large neurons contain prominent nucleoli, numerous mitochondria, moderately developed Golgi complexes, a relative paucity of ribosomes, inconspicuous Nissl substance, and cytoplasmic process filled with densely packed intermediate filaments and microtubules. Small neurons contain few mitochondria, abundant free ribosomes, and are multipolar. Dysplastic gangliocytoma of the cerebellum can show positive immunoexpression for synaptophysin, NeuN, chromogranin A, neurofilament protein, Leu-4 epitope, calbindin, and synaptic vesicle glycoprotein SV2. Presence of mitosis and necrosis are very rare findings. In DGC, the three neurofilament subtypes (NF-L, NF-M, NF-H) are strongly expressed by large neurons and granule cells demonstrating modest karyomegaly and cytoplasmic expansion. Neuronal cytomegaly of DGC appear to reflect an abnormality of cytoskeletal protein expression. GFAP expression is restricted to reactive astrocytes that may occupy the involved cortex and white matter.[1] [5] [6] [7] [13] [16] [18] [19] [20]

Differential diagnosis includes gangliocytoma, which determines a nodular tumoral mass, ganglioma, which exhibits a complex architecture and a solid / cystic lesion, and an infiltrating glioma with trapped Purkinje cells that is composed by atypical glia and presence of mitoses. Surgical resection is usually curative, but recurrence is not uncommon in long-term follow-up.[1] [7] [9] [12] [14] [16] [18] [20] [21] [22]

Conflict of Interests

The authors declare that there are no conflict of interests.

• References

• 1 Uchida D, Nakatogawa H, Inenaga C, Tanaka T. An Unusual Case of Lhermitte-Duclos Disease Manifesting with Intratumoral Hemorrhage. World Neurosurg 2018; 114: 326-329
• 2 Riegert-Johnson DL, Gleeson FC, Roberts M. , et al. Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pract 2010; 8 (01) 6
• 3 Thomas B, Krishnamoorthy T, Radhakrishnan VV, Kesavadas C. Advanced MR imaging in Lhermitte-Duclos disease: moving closer to pathology and pathophysiology. Neuroradiology 2007; 49 (09) 733-738
• 4 Stapleton SR, Wilkins PR, Bell BA. Recurrent dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) presenting with subarachnoid haemorrhage. Br J Neurosurg 1992; 6 (02) 153-156
• 5 Zhou XP, Marsh DJ, Morrison CD. , et al. Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. Am J Hum Genet 2003; 73 (05) 1191-1198
• 6 Yachnis AT, Trojanowski JQ, Memmo M, Schlaepfer WW. Expression of neurofilament proteins in the hypertrophic granule cells of Lhermitte-Duclos disease: an explanation for the mass effect and the myelination of parallel fibers in the disease state. J Neuropathol Exp Neurol 1988; 47 (03) 206-216
• 7 Abel TW, Baker SJ, Fraser MM. , et al. Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway. J Neuropathol Exp Neurol 2005; 64 (04) 341-349
• 8 Backman SA, Stambolic V, Suzuki A. , et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet 2001; 29 (04) 396-403
• 9 Capone Mori A, Hoeltzenbein M, Poetsch M, Schneider JF, Brandner S, Boltshauser E. Lhermitte-Duclos disease in 3 children: a clinical long-term observation. Neuropediatrics 2003; 34 (01) 30-35
• 10 Lhermitte J, Duclos P. Sur un ganglioneurome diffus du coertex du cervelet. Bull Assoc Fr Etud Cancer 1920; 9: 99-107
• 11 Pérez-Núñez A, Lagares A, Benítez J. , et al. Lhermitte-Duclos disease and Cowden disease: clinical and genetic study in five patients with Lhermitte-Duclos disease and literature review. Acta Neurochir (Wien) 2004; 146 (07) 679-690
• 12 Goto Y, Hashimoto N, Okita Y. , et al. A surgically treated case of Lhermitte-Duclos disease with a precise natural history and high uptake of FDG on PET. J Neurooncol 2010; 97 (03) 445-450
• 13 Kimura F, Ueda A, Sato E. , et al. Hereditary breast cancer associated with Cowden syndrome-related PTEN mutation with Lhermitte-Duclos disease. Surg Case Rep 2017; 3 (01) 83
• 14 Jiang T, Wang J, Du J. , et al. Lhermitte-Duclos Disease (Dysplastic Gangliocytoma of the Cerebellum) and Cowden Syndrome: Clinical Experience From a Single Institution with Long-Term Follow-Up. World Neurosurg 2017; 104: 398-406
• 15 Williams LG, Brimage P, Lechner C, Taylor RL, Masters L, Welgampola MS. Lhermitte-Duclos disease presenting with atypical positional nystagmus. J Clin Neurosci 2014; 21 (09) 1647-1649
• 16 Abi Lahoud G, Chalouhi N, Zanaty M, Rizk T, Jabbour P. Association of Lhermitte-Duclos disease and split cord malformation in a child. J Clin Neurosci 2014; 21 (11) 1999-2002
• 17 Giorgianni A, Pellegrino C, De Benedictis A. , et al. Lhermitte-Duclos disease. A case report. Neuroradiol J 2013; 26 (06) 655-660
• 18 Nowak DA, Trost HA. Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma): a malformation, hamartoma or neoplasm?. Acta Neurol Scand 2002; 105 (03) 137-145
• 19 Murray C, Shipman P, Khangure M. , et al. Lhermitte-Duclos disease associated with Cowden's syndrome: case report and literature review. Australas Radiol 2001; 45 (03) 343-346
• 20 Buhl R, Barth H, Hugo HH, Straube T, Mehdorn HM. Dysplastic gangliocytoma of the cerebellum: rare differential diagnosis in space occupying lesions of the posterior fossa. Acta Neurochir (Wien) 2003; 145 (06) 509-512 , discussion 512
• 21 Chen XY, Lu F, Wang YM. , et al. PTEN inactivation by germline/somatic c.950_953delTACT mutation in patients with Lhermitte-Duclos disease manifesting progressive phenotypes. Clin Genet 2014; 86 (04) 349-354
• 22 Moonis G, Ibrahim M, Melhem ER. Diffusion-weighted MRI in Lhermitte-Duclos disease: report of two cases. Neuroradiology 2004; 46 (05) 351-354