Despite increasing awareness of dPLGGs, there is limited knowledge on their molecular profile and long-term response to adjuvant therapy. In this systematic review, we report the molecular alterations, treatment offered and the survival experience of 332 children with dPLGGs reported in the literature. Sixty-five percent of cases had primary disseminated disease and 25% had a secondary tumor dissemination at an average time of 21.9 months from solitary tumor diagnosis, with timing of dissemination unknown in 47%. Sixty-two percent of studies reviewed characterized some of the molecular alterations harbored by this subgroup of PLGG.
The most common molecular alterations in dPLGG cases identified in this review were whole arm chromosomal loss of 1p (64/85) and BRAF-KIAA1549 fusion (52/95). Alterations encountered less frequently were 19q deletion (19/87), 1p/19q co-deletion (18/87) and BRAF p.V600E (5/72). This suggests that 1p deletion may have a mechanistic role in glioma leptomeningeal or parenchymal dissemination. Seventy-four percent of cases reviewed were not interrogated for 1p deletion. Further research is needed to ascertain the possible role of 1p deletion in PLGG dissemination. While the frequency of BRAF-KIAA1549 fusion in non-disseminated PLGGs is high (34 – 73%), 1p deletion, either with or without 19q co-deletion, is uncommon (3 - 15%) and has mainly been described in oligodendrogliomas, occurring with IDH mutation.7,32,33,34,35 Frequency of BRAF p.V600E in PLGG differs by histology.36,37,38 A high rate of mutation is found in pleomorphic xanthoastrocytoma (50 – 78%) with moderate rates in gangliogliomas (13 – 49%) and lower rates in pilocytic astrocytoma and other glioma subtypes (0 – 14.3%).38,39,40 Fukuoka et al have identified a unique IDH wild-type oligodendroglioma-like tumors harboring BRAF p.V600E with no 1p/19q co-deletion in a small subset of adolescents and young adults.41 Other alterations including FGFR mutation or fusion and deletion of CDKN2A are encountered less frequently in PLGGs.7,36,37,38
The biologic features which permit PLGG to disseminate throughout the craniospinal axis remain unclear and the role of specific molecular alterations in this process is unknown. Previous studies have suggested tumor dissemination occurs via the CSF pathway with tumor cells penetrating ependymal lining and interstitial spaces and adhering to leptomeninges at near and distant sites.9,10,42 A study conducted by Tabori et al. identified an increased rate of epidermal growth factor receptor (EGFR) amplification in dPLGGs compared to non-disseminated PLGGs which seem to suggest the possible role of EGFR amplification in tumor dissemination.43 The increased EGFR amplification promoting tumor growth and the invasive potential of tumor cells may potentially promote tumor dissemination.44,45 In other CNS tumor types, some biomarkers have been identified to promote tumor metastasis. Overexpression of ERBB2 (also known as HER2) leading to activation of the PI3K/AKT signaling pathway and ERK1/2 pathway which results in the up-regulation of S100A4, a pro-metastatic gene have been found in metastatic medulloblastoma compared with localized medulloblastoma.46,47 S100A4 has also been found to be up-regulated more often in ependymoma and glioblastoma than in low grade astrocytoma.48,49 It is thus possible that ERBB2 may act in synergy with genetic alterations affecting the RAS/MAPK signaling pathway while also promoting PLGG dissemination via the PI3K/AKT and ERK1/2 pathways. Increased expression of PDGFR, a tyrosine kinase has also been found in low grade gliomas.50,51 PDGFR promotes glioma stem cell migration and invasion through increasing MMP-2 activity.52,53 PDGFR-induced MMP-2 activity in low grade gliomas may contribute to tumor dissemination. While understudied and largely speculative within PLGGs, the drivers of metastasis are known for other CNS tumors. Their possible connection with PLGG dissemination is an intriguing prospect that warrants attention.
Treatment approach for dPLGGs was observed to be similar to that of non-disseminated PLGGs for all treatment modalities. Neurosurgical intervention was largely influenced by the timing of dissemination and the location of primary lesion if identified. The majority (72%) of cases with primary disseminated tumors only had a biopsy done and the remaining 28% had either a gross total resection (GTR) or subtotal resection (STR) of a dominant lesion. As expected, the reverse was observed for cases with secondary disseminated tumors with the majority (65%) of cases having either a GTR or STR and 35% undergoing biopsy alone. A less invasive surgical approach is typically favored in patients with primary dissemination wherein the primary goal is to obtain diagnostic tissue rather than attempt curative excision of lesions. An exception is when a dominant lesion is causing symptoms related to mass effect, edema, or cortical irritation, and surgical resection or debulking facilitates symptom resolution and/or adjuvant therapy initiation. Identifying tumors with dissemination potential would help predict prognosis more accurately and allow improved counselling for patient.
Adjuvant therapy is indicated in almost all cases of dPLGG. The predominant chemotherapeutic agents for first line therapy were vincristine and carboplatin. This treatment combination has been shown to be effective in the management of PLGG.5,54,55,56 Second line treatment in cases of disease progression or adverse drug reactions was far more heterogeneous (Table 4). Few children (1.4%) received targeted therapies such as BRAF or MEK 1/2 inhibitors as a second line regimen based on reports from recent studies. Radiotherapy was utilized less frequently, as second or third line therapy for disease progression despite multimodal chemotherapy. The few cases who received radiation as first line therapy were all older children with ages ranging between 3 and 16 years.
The clinical course of dPLGGs tends to be protracted and may require multiple interventions including salvage therapy for disease progression. Compared to non-disseminated PLGG, dPLGG is associated with a worse outcome.5,10,11,21,57 Hukin et al reported a 5-year survival rate of 68% and 87% in a cohort of dPLGG and non-disseminated PLGG, respectively.11 Based on the available survival data, 73% of cases reviewed were alive at the last follow-up. Primary disseminated tumors were associated with similar survival rates as secondary disseminated tumors (72% vs. 70%). Survival is likely influenced by the biologic ramifications of molecular alterations specific to each tumor. Tumors expressing BRAF-KIAA1549 fusion have been observed to have a better survival than BRAF p.V600E (69% vs 52%).7,38 Survival for tumors with wild-type BRAF is better than tumors with BRAF p.V600E but not significantly different from tumors with BRAF-KIAA1549 fusion.33,38,58 CDKN2A homozygous deletion is also associated with a worse survival outcome especially when the tumor also harbors BRAF p.V600E .5,6,32,36,38 From these results, only primary disseminated tumors expressed BRAF- KIAA1549 fusion, which may play a role in the higher survival seen in this cohort. None of the secondary disseminated tumors interrogated for BRAF-KIAA1549 fusion were found to be positive, and two out of the 3 cases tested had BRAF p.V600E. None of the secondary disseminated tumors was interrogated for CDKN2A deletion. While broad generalizations might be gleaned from a review of the literature, the true relationship between molecular alterations and prognosis in dPLGG demands further study.
There are several limitations to be considered in the interpretation of results presented in this review. The clinical use of variable terminologies to describe this tumor type may have influenced our search results. Beyond including the most common descriptors, we address this by reviewing the reference lists of articles initially identified to find additional articles which may not have been captured by the original search terms. There was a lack of comprehensive reporting on the genomic profile of tumors to draw meaningful conclusions on the pattern of molecular alterations found in all dPLGGs. Finally, many of the included studies were case reports and small case series that carried a measurable risk of bias as determined by the ROBINS-I tool. Based on our GRADE assessment of quality of evidence, all studies reviewed either ranked low or moderate in quality with none ranking high. This underscores the need for clinical trials to specifically include and sub-analyze dPLGG cohorts to better understand the efficacy of PLGG regimen and targeted molecular therapies in the management of this disease.