Optic Pathway Gliomas are commonly complicated by hydrocephalus, which may require CSF diversion. Because of the large size and location of these tumors, third ventriculostomy is usually not feasible and insertion of a ventricular-peritoneal shunt is the common management option for optic/hypothalamic LGG-associated hydrocephalus.
CSF ascites is a rare complication of ventriculo-peritoneal shunts and has been anecdotally reported in children with optic gliomas. [6–11, 16–19]. Although the existing literature describes the event to affect to a young population, patients in our series were diagnosed with a LGG at a younger median age than the previously reported cases (14 vs 21 months); with most of our patients being infants younger than twenty four months of age at diagnosis. Young age itself represents a known contributing factor of adverse prognosis for pediatric gliomas [21]; based on our observations, infant gliomas could be considered as a risk factor to develop ascites. Z.Gil et al [7] reported on 22 children diagnosed with chiasmatic-hypothalamic LGG, 12 underwent shunt placement and 4 developed VPS-associated ascites, all of them were affected by a tumor located in the chiasm or the visual pathway. By contrast, they did not find any cases of ascites as a result of VPS placement among the five children suffering from hypothalamic glioma. In our case series of 19 patients, 16 had a OPG, while 2 had a thalamic lesion and one an hemispheric LGG.
Existing literature suggests ascites as an early event and our cohort confirms these findings with a median time of five months between VPS insertion and onset of ascites. Seven patients developed ascites one year or later after VPS insertion, demonstrating that ascites may also present as a late complication in the course of this disease.
The etiology of ascites in this context is multifactorial and complex and several possible mechanisms have been proposed [6–9]. It is thought to be the result of an imbalance between CSF production and absorption in presence of a patent VP shunt. West et al [10] described three children with OPG who developed ascites following VPS; they suggested that because the tumor is widely exposed to the cerebral spinal fluid, protein exuded by the tumor into the subarachnoid space would cause an elevated CSF protein concentration. We observed high protein level in both CSF and ascites fluid when performed. In our retrospective series, no differential analysis of protein was performed in the CSF and/or ascites hence we could not evaluate the respective characteristics of each fluid. However, this suggests that the high protein level in the CSF is a common factor among patients presenting this complication.
The management of ascites was successful in all cases, but the specific role of chemotherapy, radiotherapy or targeted therapy in the outcome is biased by the surgical interventions performed, since eighteen patients underwent shunt diversion and/or paracentesis and only one patient was exclusively managed medically; this patient had an excellent tumor control with dabrafenib only.
We chronologically analyzed the treatment approaches in our cohort in order to explore a potential correlation between clinical and radiological tumor course and the development of ascites. Eighteen patients received at least one modality of treatment prior to the complication including two patients who were irradiated. Overall our cohort was heavily treated prior and after ascites, demonstrating an aggressive course of the disease with high mortality rate.
The fact that ascites was detected at a median of three months following initiation of treatment and in six patients earlier than two months, could also suggests ascites as a result of tumor burden. This hypothesis would also be supported by the large tumor volume in the MRI scan performed at the time of the complication, in keeping with existing data of tumor measurement in surgically unresectable pLGG in functionally crucial locations [20, 21].
The onset of ascites was subsequently followed by a change in treatment in the majority of our patients at median of three months, supporting the hypothesis that ascites occurs as a consequence of tumor regrowth, thus reflecting the need for change or initiation of therapy. However, our data are limited to statistically confirm these premises and a larger cohort would be needed to better establish the role of ascites as a negative prognostic risk factor in pLGG.
KIAA1549-BRAF is known to be the most frequent molecular alteration in non-NF1 pLGG (60%), followed by BRAF V600E mutation (25%) [2–4]; Our cohort does not reproduce this proportion, with 8/19 tumors harboring BRAF V600E mutation; amongst twenty-one cases of ascites in patients with low grade glioma reported in the literature, only two had documented analysis of the RAS/MAPK pathway, both harboring BRAF V600E mutation. Of note, six BRAF mutated LGG in our series are Pilocytic Astrocytomas in contrast with known data that BRAF fusion is significantly enriched in this histology. Interestingly there were no patients with NF1 in our cohort neither in the existing literature. This support the known fact that gliomas related to NF1 are less likely to behave aggressively and ascites might also represent a complication exclusively related to sporadic hypothalamic gliomas.
Our data support that ascites is an unfavorable event in the course of a LGG, irrespective of alterations in the RAS/MEK pathway. The high mortality rate of 8/19 in our cohort may reflects the seriousness of the ascites as a complication in the course of pLGG and therefore ascites should be considered as an additional adverse prognostic risk factor to the previously identified diencephalic syndrome and disseminated disease [22–24]. Of note, none of our patients had disseminated disease, and diencephalic syndrome was specifically reported only in two patients. This mortality rate is higher than other case series on ascites complicating VPS in LGG, with only 2/21 deaths. However, the follow-up in these reports was shorter with a median follow-up time of only 27 months while we here report a longer follow-up with a median overall follow-up time of 69 months.
Eight patients in our cohort received targeted therapy as part of their treatment strategy (4 dabrafenib/4 trametinib), following different lines of chemotherapy and/or radiation. One patient with poor performance status was treated with dabrafenib and succumbed due to disease progression soon after diagnosis. All other patients treated with targeted therapy alone or as part of the treatment survived. This may suggest a role for targeted therapies in the management of this serious complication.
Limitations to our study are represented by its retrospective nature, the lack of uniform criteria for the management of both tumor and complications among different participating institutions and the long time period of collection, which has a reflection in the treatment modality delivered, with targeted therapies being only available in recent years and not uniformly across institutions. Moreover, only limited molecular analysis could be performed in the tumor samples with lack of data regarding further molecular alterations that could worsen the prognosis of these tumors such as CDKNA2 deletion [25].
In summary, we here report a case series of nineteen molecularly-characterized pLGG enriched in BRAF mutation that presented with ascites as an unusual but serious complication with a high mortality rate. Consequently, we suggest to consider ascites as an additional adverse prognostic risk factor in pLGG. The potential role of targeted therapy in the course of this complication as well as the understanding of the pathogenesis of ascites requires further prospective studies, including molecular characterization of tumor tissue and ascites fluid.