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2018, Volume 34, Number 1, Page(s) 092-099
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DOI: 10.5146/tjpath.2014.01283 |
Lhermitte-Duclos Disease: A Rare Lesion with Variable Presentations and Obscure Histopathology |
Evrim ÖNDER1, Ata Türker ARIKÖK1, Erhan TÜRKOĞLU2, Murat ALPER1 |
1Department of Pathology, Ankara Dışkapı Yıldırım Beyazıt Research and Training Hospital, ANKARA, TURKEY
2Department of Neurosurgery, Ankara Dışkapı Yıldırım Beyazıt Research and Training Hospital, ANKARA, TURKEY |
Keywords: Lhermitte-Duclos, Cerebellum, Histopathology |
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Since Lhermitte-Duclos is a quite rare disorder with both neoplastic
and hamartomatous features, clinical and pathological diagnosis
can sometimes be challenging. For the pathologist it is of extreme
importance to be aware of variable clinical and histopathological
presentations of such a rare lesion particularly to differentiate it from
the low-grade glial and neuronal tumors. We present four cases of
Lhermitte-Duclos in a histopathological perspective. Although
enlargement of the internal granular layer of the cerebellum is a
consistent finding in our cases, morphological severity was highly
variable and in some cases the enlargement was insignificant.
Frozen sections of one case did not reveal diagnostic findings. The
vacuolar change observed in the paraffin sections was obscure in the
frozen. Pathological diagnosis of Lhermitte-Duclos disease can be
extremely difficult in the absence of proper clinical information and
the pathologist should be watchful for any irregularity in the internal
granular layer in evaluating the cerebellar tissue which is otherwise
normal. |
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Lhermitte-Duclos disease (LDD), also known as dysplastic
cerebellar gangliocytoma, is a unique disorder of cerebellum
with the features of malformation, hamartoma and benign
neoplasm. Although it is categorized as a WHO grade I
tumor, its histology is more likely a hamartoma with enlarged
abnormally developed cerebellar folia containing dysplastic
rather than neoplastic cells 1,2. Combination of aberrant
migration and hypertrophy of the granular cells have been
shown to be responsible from its histogenesis 2. Since the
initial report by Lhermitte and Duclos in 1920, LDD was
reported to occur at any age but most cases are identified in
adults at 3rd or 4th decades 2,3. Accumulating evidences
indicate a strong association between LDD and Cowden
disease (CD), which is a multiple hamartoma syndrome with an increased risk of benign and malignant tumors 4,5. Germline mutations in the phosphatase and tensin
homologue (PTEN) gene on chromosome 10 was found
to be linked to both conditions and the loss of inhibitory
influence of PTEN on the PI3K pathway and activation of the
AKT/mTOR signaling was suggested to be the responsible
pathogenetic mechanism 5,6. Nevertheless, sporadic
cases are also well known, particularly if the onset is in the
childhood 6,7. Presentation of the disease may be variable
but most common symptoms are progressive mass effect in
posterior fossa with cerebellar dysfunction and increased
intracranial pressure. Magnetic resonance imaging (MRI)
is certainly the imaging modality of choice and it usually
displays a hyperintense lesion with a characteristic striated
pattern of exaggerated folia in T2-weighted images 8.
In particular for pathologist, making a diagnosis of LDD
can be extremely difficult in the absence of proper clinical
information. However recognition of the disease carries
critical importance not only for differentiating it from
other cerebellar tumors, but also making a prompt clinical
examination with respect to CD. Here we present four
cases of LDD in a histopathologic perspective. Clinical and
radiological background of each case was also provided.
Informed consents were obtained for all the cases prior to
this report. |
Top
Abstract
Introduction
Case Presentation
Disscussion
References
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Case 1: A 42-year-old male presented with headache, blurry
vision and seizure. His physical and systemic examinations
were normal. Bilateral papilledema was observed in neurological examination. Cranial MRI revealed a
well-defined lesion in the right cerebellar hemisphere,
hypointense to brain parenchyma on T1-weighted images.
The lesion was slightly hyperintense on T2 weighted images.
The cerebellar folia were prominent with compression to 4th
ventricle and causing hydrocephalus (Figure 1A-C). The
patient underwent surgical removal with the suspicion of
LDD. Pathological evaluation of the H&E stained slides
revealed multiple fragments of cerebellar tissue without an
apparent change. Close examination demonstrated some
neuronal appearing cells forming two or three disorganized
rows in one of the fragments. The cells had large vesicular
nuclei and prominent nucleoli. The orientation was
haphazard and there were some smaller ganglionic cells
and a few Purkinje cells in between. Some nuclei were pleomorphic but mitosis was absent. A cystic degeneration
was observed in the neighbouring molecular layer (Figure
2A,B). An immunohistochemistry panel composed of
glial fibrillary acidic protein (GFAP), synaptophysin,
chromogranin, neurofilament, Ki67 and PTEN was applied. GFAP positivity was observed only in the fibrillary
background whereas synaptophysin, neurofilament and
chromogranin positivity demonstrated the neuronal
nature of these cells (Figure 3). PTEN expression was weak
and variable. Ki67 labelling was observed in one or two
isolated cells. The family history was negative for CD. No
hamartomatous lesion was found in physical examination.
The post-operative course was uneventful and patient is
doing well at 10 years follow-up.
Click Here to Zoom |
Figure 1: T2-weighted axial (A), coronal (B) and sagittal FLAIR (C) sections showing a well-defined and slightly hyperintense lesion in
the right cerebellar hemisphere. |
Click Here to Zoom |
Figure 2: Slightly enlarged internal granular layer (A) Dysplastic neuronal cells in the internal granular layer of cerebellum (B) (H&E;
x200, H&E; x400). |
Click Here to Zoom |
Figure 3: Synaptophysin positivity in neuronal elements
(Synaptophysin; x400). |
Case 2: A 26-year-old female complained of ataxic gate
and dizziness. Her physical, systemic and neurological
examinations were normal. Cranial MRI demonstrated
a well-defined lesion in the left cerebellar hemisphere
that was slightly hypointense on T1-weighted images and
hyperintense on T2 sections. The patient underwent surgery
and frozen section was performed with an initial diagnosis
of low-grade glioma. The post-operative MRI revealed a
residual mass lesion (Figure 4A-D). Re-evaluation of the
frozen sections demonstrated a subtle irregularity in the
internal granular layer. The usual fine fibrillarity was lost in the
adjacent white matter, eosinophilia was increased and white
matter somewhat appeared as an amorphous pink material requiring to be differentiated from the necrosis (Figure 5).
However, the subsequent routine follow-up slides clarified
that it was not the necrosis but the extensive vacuolation
of the white matter underlying the pink amorphous
appearance. In the squash preparations the background was
fibrillar and in focal area there were a few cells corresponding
to the dysplastic neurons (Figure 6). The post-operative
course was uneventful. The H&E stained slides of operation
material revealed cerebellar fragments with prominently
enlarged and disorganised internal granular layer. The cells
had large vesicular nuclei and demonstrated some degree
of pleomorphism. Mitosis was not observed. Orientation
was haphazard with some overlapping. Normal ganglionic cells were very few. Extensive vacuolation throughout the
molecular layer and white matter was a striking finding
(Figure 7). On immunohistochemical evaluation, GFAP
positivity was observed only in the fibrillary background
whereas synaptophysin, neurofilament and chromogranin
positivity demonstrated the neuronal nature of these cells.
PTEN expression was weak and variable (Figure 8). Ki67
labelling was observed in one or two isolated cells. The
family history was negative for CD. No hamartomatous
lesion was found in physical examination. The postoperative
course was uneventful with exception of the residual mass
appearance in MRI. The patient improved and was doing
well at 6 mounts of follow-up.
Click Here to Zoom |
Figure 4: Postoperative T1-weighted
axial MRI (A), T2 weighted axial (B),
coronal (C) and sagittal FLAIR (D)
images showing a well-defined residual
mass in the left cerebellar hemisphere,
slightly hyperintense on the T2
sequence. |
Click Here to Zoom |
Figure 5: A subtle irregularity in the internal granular layer.
Increased eosinophilia and loss of fibrillarity through the white
matter in frozen section (H&E; x200). |
Click Here to Zoom |
Figure 6: Small ganglionic cells and a few dyplastic neuros in a
fibrillary background of a cytologic preparation (H&E; x400). |
Click Here to Zoom |
Figure 7: Large vesicular nuclei and prominent nucleoli of the
dyplastic neurons of the internal granular layer (H&E; x400). |
Case 3: A 77-year-old female was admitted with severe
headache. Her physical, systemic and neurological
examinations were normal. MRI demonstrated a right
cerebellar lesion and a pontocerebellar arachnoid cyst with
mass effect on T1 and T2-weighted sections (Figure 9A-F).
Biopsies were taken due to the co-morbidity of the patient.
The initial diagnosis was LDD. Pathological evaluation
revealed fragments of distinctly vacuolated white matter.
Among these, a small cerebellar fragment with haphazardly
oriented and enlarged internal granular layer was observed.
The cells of the internal granular layer had large, vesicular
nuclei. Scattered cells with nuclear pleomorphism were
detected. Mitosis was not present and a few ectatic vessels
were observed in the lesion. Immunohistochemistry
demonstrated immunoreactivity with synaptophysin,
neurofilament and chromogranin (Figure 10A-C). The
dysplastic cells were totally negative with GFAP and PTEN
(Figure 11). No nuclear staining was detected with Ki67.
The family history was negative for CD. No hamartomatous
lesion was found in physical examination. The patient died
in two mounts after biopsy.
Click Here to Zoom |
Figure 9: T2-weighted axial (A), T1-weighted axial (B), DWI (C), T2-weighted axial FLAIR (D), T2-weighted coronal (E) and T2-
weighted sagittal FLAIR (F) images showing right pontocerebellar arachnoid cyst and thickening of cerebellar folia with striations and
abnormal signal. The lesion is bright on diffusion-weighted images as well as on the ADC map. |
Click Here to Zoom |
Figure 10: Extensive vacuolation and dilated vessels in the white
matter (A) Nuclear pleomorphism in dysplastic neurons (B)
Chromogranin positivity in the neurons infiltrating the white
matter (C) (H&E; x400, H&E; x400, Chromogranin; x400). |
Case 4: A 19-year-old female presented with headache
and dizziness. Her complaints started three months ago.
Her physical and systemic examinations and neurological
examinations were normal. MRI demonstrated a right
cerebellar hyperintense lesion compressing the fourth
ventricle in T2 images. The lesion was slightly hypointense
on T1 sequence. Surgical removal was performed with an
initial diagnosis of low-grade glioma. The post-operative
course was uneventful. Pathological evaluation revealed
small fragments of cerebellar tissue without any apparent
neoplastic infiltration. Cystic vacuolation was not so
prominent. Careful examination demonstrated some
large vesicular nuclei in the internal granular layer with
a disordered arrangement. A slight pleomorphism was
observed and some identical cells also appeared to infiltrate
the white matter (Figure 12A,B). Immunohistochemistry
demonstrated immunoreactivity with synaptophysin,
neurofilament and chromogranin (Figure 13). The
dysplastic cells were totally negative with GFAP. PTEN
expression was weak and variable. No nuclear staining
was detected with Ki67. The family history was negative for CD. No hamartomatous lesion was found in physical
examination. The patient improved and was doing well at
2 years of follow-up.
Click Here to Zoom |
Figure 12: Partial replacement of the internal granular layer by
the dysplastic neurons (A), some neurons infiltrate the white
matter (B) (H&E; x400). |
Click Here to Zoom |
Figure 13: Neurofilament positivity in neuronal cytoplasms
(Neurofilament; x200). |
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Top
Abstract
Introduction
Case Presentation
Disscussion
References
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Lhermitte-Duclos disease (LDD) is a unique disorder
of cerebellum and its pathologic bases have long been
debated. It had been suggested to be a neurocytic blastoma,
hamartoma or hyperplasia. Currently it is known to be
associated with CD and both conditions are linked to germ
line mutations on PTEN gene. There are also sporadic cases
that lack a PTEN mutation and CD phenotype, especially
if the onset is in the childhood 5,6. Since it is a quite
rare disorder with both neoplastic and hamartomatous
features, the clinical and pathological diagnosis of LDD can
sometimes be challenging. Although MRI is particularly
sensitive in depicting the enlarged folia, vague radiographic
findings and variable presentation may sometimes further
complicate the diagnosis 9,10. In addition, some other
cerebellar lesions and especially medulloblastoma have
also been reported to demonstrate radiological features
mimicking LDD 11,12. Likewise the pre-operative
diagnoses were low-grade glioma in two of our four cases.
So with respect to pathological diagnosis, especially in the
absence of suggestive clinical data, awareness of this rare
lesion is of extreme importance.
The relative preservation of the cerebellar architecture seems
to be the most important challenge for pathologist. Although
the most prominent histopathological abnormality in LDD
is the massive replacement and expansion of the internal
granular layer by large neurons with vesicular nuclei, this replacement is not uniform and morphological severity
varies between patients and within the individual lesion2. This variation was a pronounced feature of our cases.
Although the enlargement and crowdedness of internal
granular layer was a consistent finding, in two cases (case 1
and case 4) the enlargement was somewhat inconspicuous
requiring a careful examination. In these cases there were
also some scattered cells in the molecular layer that needed
to be differentiated from other infiltrations such as glioma.
The other two cases demonstrated an apparent enlargement
with varying thicknesses. The frozen sections, on the other
hand, demonstrated only some subtle changes and did
not yield a diagnostic frozen report. In all of our cases the
cellular arrangement was haphazard. The cells populating
the internal granular layer had vesicular nuclei larger than
that of the normal inhabitants. Nucleoli were prominent and
our three cases (case 1, case 2 and case 3) demonstrated some
degree of pleomorphism appearing as marked variation
in nuclear size and shape. None of our cases had mitosis.
The molecular layer also enlarges and usually appears
as vacuolated in LDD2. In all of our cases there were
fragments of molecular layer or white matter demonstrating
some vacuolation. In case 1 and case 2, this appearance
required differentiation from a glioma but in case 4 the
vacuolation was not so prominent. Although calcification
is another finding reported in LDD, we did not observe
such foci2,6. In one of our cases (case 3) ectatic vessels
was prominent as another known finding of LDD. None of
our cases had proliferated vascular structures resembling to
those of high-grade glial tumors. LDD is known as a lesion
with a very low or undetectable proliferative activity6.
Accordingly, in our cases proliferative activities estimated
by Ki67 were lower than 1%.
In the medical histories of our patients there were no other
primary or secondary tumors. Further evaluation with
respect to hamartomatous lesions and family history did
not reveal any possible association with CD however our
cases were not genetically screened for PTEN mutation.
Although all of our patients are adults, the ages were
distributed in a wide range. Still it is important to keep in
mind that pediatric cases exist in the literatüre13.
Since Lhermitte-Duclos is a quite rare disorder, there
have been only a few systematic studies and literature
data is largely from single case reports. Most of these
reports focuses on the radiological features. However it
is extremely important for the pathologist to be aware of
the variable clinical and histopathological presentations of
such a rare lesion particularly to differentiate it from the low-grade glial and neuronal tumors. In frozen sections the
changes can be further subtle and even a normal appearing
cerebellar tissue should be closely evaluated with respect to
any derangement in the internal granular layer. |
Top
Abstract
Introduction
Case Presentation
Discussion
References
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1) WHO Classification of Tumours of the Central Nervous System.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. 4th ed.
Lyon: IARC; 2007.
2) N owak DA, Trost HA. Lhermitte-Duclos disease (dysplastic
cerebellar gangliocytoma): A malformation, hamartoma or
neoplasm? Acta Neurol Scand. 2002;105:137-45.
3) Lhermitte J, Duclos P. Sur un ganglioneurome diffus du cortex du
cervelet. Bull Assoc Fr Etud Cancer. 1920;9:99-107.
4) R obinson S, Cohen AR. Cowden disease and Lhermitte-Duclos
disease: An update. Case report and review of the literature.
Neurosurg Focus. 2006;20(1):E6.
5) Zhou XP, Marsh DJ, Morrison CD, Chaudhury AR, Maxwell
M, Reifenberger G, Eng C. 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;73:1191-8.
6) Abel TW, Baker SJ, Fraser MM, Tihan T, Nelson JS, Yachnis AT,
Bouffard JP, Mena H, Burger PC, Eberhart CG. Lhermitte-Duclos
disease: A report of 31 cases with immunohistochemical analysis
of the PTEN/AKT/mTOR Pathway. J Neuropathol Exp Neurol.
2005;64:341-9.
7) N owak DA, Trost HA, Porr A, Stölzle A, Lumenta CB. Lhermitte-
Duclos disease (Dysplastic gangliocytoma of the cerebellum).
Clin Neurol Neurosurg. 2001;103:105-10.
8) Wei G, Zhang W, Li Q, Kang X, Zhao H, Liu X, Tang X, Wu
Y, Han J, Yin H. Magnetic resonance characteristics of adultonset
Lhermitte-Duclos disease: An indicator for active cancer
surveillance? Mol Clin Oncol. 2012; 2: 415-20.
9) Thomas B, Krishnamoorthy T, Radhakrishnan VV, Kesavadas
C. Advanced MR imaging in Lhermitte-Duclos disease: Moving
closer to pathology and pathophysiology. Neuroradiology.
2007;49:733-8.
10) Bozbuga M, Gulec I, Suslu HT, Bayindir C. Bilateral Lhermitte-
Duclos Disease. Neurol India. 2010;58:309-11.
11) Douglas-Akinwande AC, Payner TD, Hattab EM. Medulloblastoma
mimicking Lhermitte-Duclos disease on MRI and CT.
Clin Neurol Neurosurg. 2009;111:536-9.
12) Savardekar A, Salunke P, Ahuja CK, Rane S, Singla N. Unusual
presentation in adult medulloblastomas: Imaging features
mimicking cerebellar dysplastic gangliocytoma (Lhermitte-
Duclos disease). Neurol India. 2012;60:555-7.
13) 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;34:30-5. |
Top
Abstract
Introduction
Case Presentation
Discussion
References
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