Keywords
leptomeningeal glioneuronal tumor - polyradiculopathy - hydrocephalus - oligodendroglial-like
leptomeningeal tumor of childhood - PCV chemotherapy
Palavras-chave
tumor glioneural leptomeníngeo difuso - polirradiculopatia - hidrocefalia - oligodendroglial-like
- PCV
Introduction
The diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare primary central nervous
system (CNS) neoplasm, which was recognized as a distinctive entity in 2016 by the
World Health Organization (WHO) classification of CNS tumors.[1] Usually, its diagnosis, based on clinical-epidemiological aspects, is difficult
and challenging because it has no pathognomonic signs, and its clinical presentation
and imaging findings may vary widely. Despite this, in most descriptions, it was more
prevalent at a young age, showed slow-growing rate, and imaging exams revealed communicating
hydrocephalus with intense leptomeningeal enhancement on T1-weigheted images, more
frequently in the basal cisterns. Nevertheless, its genetic and epigenetic changes
and its exact biological behavior are not yet fully known.[2]
[3] We described a late diagnosis of DLGNT in a patient that progressively developed
hydrocephalus and polyradiculopathy. Clinical manifestations, imaging and histological
characteristics are reported and discussed in the present paper to add evidence and
advance current knowledge about the DLGNT.
Case Report
A 17-year-old male patient sought medical attention at a hospital a few years ago
complaining of low back pain, motor incoordination, dizziness, gait disturbance, urinary
incontinence, blurred vision, headache, and episodic epileptic seizures, which all
had gotten worse progressively in the last months. On his brain computed tomography
(CT), a hydrocephalus was diagnosed, which required a ventriculoperitoneal shunt.
Due to relief of most of the symptoms, the patient abandoned the follow-up and investigation
workup, though the etiology of the hydrocephalus was not accomplished. The patient
sought medical attention in our service due to back pain, weakness, and muscle atrophy
in the lower limbs, urinary and fecal incontinence, paresthesia and hypoesthesia in
different regions of the body. The brain and spine magnetic resonance imaging (MRI)
showed a diffuse contrast enhancement on T1-weighted images in addition to multiple
infiltrative nodular and cystic lesions in the cranial and spinal subarachnoid space,
especially in the basal cisterns, brain ventricles, and in the cauda equina ([Fig. 1], [2]). A biopsy of a lesion in the cauda equina was performed, and the diagnosis of diffuse
leptomeningeal glioneuronal tumor was confirmed ([Figs. 3], [Table 1]). At this time, a palliative treatment was proposed, and, a month later, he started
to receive three-dimensional conformal radiotherapy to the craniospinal axis (36 Gy
in 20 fractions over 4 weeks) with a boost to the sacral tumor (18 Gy in 10 fractions
over 2 weeks), adding up to a total dose of 54 Gy. After that, he underwent 3 courses
of conventional procarbazine, lomustine, and vincristine (PCV) chemotherapy over 14
weeks, without any complications. Despite partial response to the treatment ([Fig. 4]), the patient had improvement in pain levels, function, and quality of life. Although
he is still incontinent and unable to walk without assistance, we consider that his
condition of total disability and full dependency (40% on KPS scale) has positively
changed to a functional status, in which he is able to care for most of his needs
(60% on KPS scale) and can be included in a rehabilitation program.
Table 1
Immunohistochemistry staining results
|
Stain
|
Results
|
Characteristics
|
|
S100
|
Positive
|
|
|
Neu-N
|
Positive
|
Weak
|
|
GFAP
|
Positive
|
Diffuse
|
|
Synaptophysin
|
Positive
|
|
|
EMA
|
Positive
|
Focal
|
|
CD68
|
Positive
|
Macrophages
|
|
BRAF
|
Positive
|
Focal
|
|
Ki67
|
Positive
|
< 5%
|
|
Mutant IDH1
|
Negative
|
|
Abbreviations: S100, S100 protein; BRAF, BRAF mutation test; CD68, GFAP, glial fibrillary acid protein; Ki67, Ki-67 labeing index.
Fig. 1 T1-weighted magnetic resonance imaging with gadolinium. Diffuse leptomeningeal enhancement
to the gadolinium injection in the (A) basal cisterns, 4th ventricle, and cervical spinal cord, (B) thoracic spinal cord, and (C) lumbar spinal cord, and cauda equina.
Fig. 2 T2-weighted and fluid attenuated inversion recovery magnetic resonance imaging. Hyperintense
subpial nodules and cysts in the (A) septum pelucidum, lateral ventricles, and 3rd ventricle, (B) thoracic spinal cord, and (C) lumbar spinal cord, and cauda equina.
Fig. 3 Histopathological and immunohistochemical study. (A) low power examination reveals a diffuse leptomeningeal proliferation of tumor cells
with clear cytoplasm; (B) at higher magnification, the nuclei are round and bland. No mitotic figures were
seen; (C, D) tumor cells were diffusely positive for S100 and glial fibrillary acidic protein
(GFAP).
Fig. 4 T1-weighted magnetic resonance imaging with gadolinium pre and posttreatment. Partial
remission of the tumor in response to radiotherapy plus procarbazine, lomustine, and
vincristine (PCV) chemotherapy. The nodular and thick gadolinium enhancement observed
on pretreatment T1-weighted magnetic resonance imaging (A, C and E) became thinner and less intense 3 months after the treatment (B, D and F).
Discussion
The DLGNT, also known as disseminated oligodendroglial-like leptomeningeal tumor of
childhood, is a primary CNS tumor characterized by diffuse leptomeningeal dissemination
of neoplastic glioneuronal cells. Despite its indolent progression, it can rarely
present itself as an isolated parenchymal lesion, and the morbidity and mortality
rates are frequently high.[4]
[5] Sometimes, its behavior can be more aggressive, especially in adults or elderly
people.[2] The clinical manifestations are directly related to the development of hydrocephalus
and infiltration of spinal and cranial nerves.
On MRI, the DLGNT is characteristically described as thick, nodular leptomeningeal
enhancement particularly around the basal cisterns, which may extend over the surface
of the brain and spinal cord. Further findings are the presence of small subpial cysts
or nodular T2 hyperintense lesions. Usually, it is isointense on T1-weighted images
and exhibits remarkable contrast enhancement, typically located in the posterior fossa,
brainstem, spinal cord, and cauda equine.[3]
[4]
[6] One of the most important characteristics of the DLGNT is that, often, there is
no definitely dominant primary parenchymal mass, even though, in the descriptions
of some cases, intraparenchymal lesions were detected, more frequently in the spinal
cords.[3]
[4] In the initial stages, the radiographic diagnosis might be challenging, since an
idiopathic communicating hydrocephalus and an unspecific diffuse leptomeningeal contrast
enhancement of the basal cisterns and spinal cord might represent several diseases.
The main differential diagnoses to DLGNT are tuberculous meningitis, meningeal carcinomatosis
from primary or secondary neoplasms, and fungal meningitis.[5]
The histogenesis of DLGNT is unknown, but it is postulated that they originate from
multipotent cells, positive for glial and neuronal markers, which are capable of divergent
differentiation.[4] In the histological aspect, these tumors have a low to moderate cellularity with
a biphasic astrocytic population (positive for glial fibrillary acidic protein [GFAP])
and neurocytes (positive for synaptophysin). The monomorphic aspect is predominant
and consists of oligodendroglial-like cells with clear cytoplasm and rounded nuclei.
The DLGNT usually has low mitotic rate. The presence of anaplasia or Ki67 > 4% might
predict a worse prognosis. The main immunohistochemical findings are: high reactivity
to oligodendrocyte transcription factor 2 (OLG-2), microtubule-associated protein
2 (MAP-2) and S-100. Typically, the NeuN, EMA, and mutant IDH1 (R132H) are negative.[4]
All DLGNT carry chromosomal arm 1p deletion, as others genetic and epigenetics aberrations
that are believed to activate the mitogen-activated protein kinase/ extracellular-signal-regulated
kinase (MAPK/ERK) pathway, mostly because of the KIAA1549: BRAF fusion. Such changes
have been proposed as tumors biomarkers and therapeutic targets, but there is currently
a lack of evidence that mitogen-activated protein kinase (MEK) inhibitors may improve
the clinical outcome of patients with DLGNT.[3]
Diffuse leptomeningeal glioneuronal tumor can be subdivided in two molecular classes,
based on DNA methylation profiling, namely, DLGNT-MC-1 and DLGNT-MC-2.[3] It is supposed that codeletion 1p19q is much more frequent in the DLGNT-MC-1 group,
which is associated to a lower age of diagnosis (median 5 vs 14 years) and a less aggressive clinical course. Furthermore, all patients in the
DLGNT-MC-2 group display a gain of chromosome 1p arm.
There is no guideline to treat DLGNT, and the current approaches are based on low-grade
glioma's treatment of children and young adults. It is not clear if different combinations
of surgery, radiotherapy, and chemotherapy can improve the clinical outcomes and survival;
therefore, a conservative or palliative approach must not be ruled out. Promising
outcomes have been described with temozolomide, bevacizumab, and vincristine associated
with carboplatin, and the E-HIT 2000–4 and SIOP-LGG 2004 chemotherapy protocols.[4]
[5]
In conclusion, our case report suggests that radiotherapy plus PCV chemotherapy can
have positive effects on DLGNT treatment and should be considered as a good approach
to treat this particular tumor.
