Discussion
Historically, all embryonal tumours originating in the CNS were grouped under the umbrella term- PNET, irrespective of the site of tumour. They had similar appearance under microscope, consisting of small round blue, undifferentiated neuroepithelial cells, usually with high mitotic rate and had neuroectodermal origin. Even some tumours outside CNS, originating from the neural crest, were included and called pPNET, which resembled histomorphologically with Ewing sarcoma (ES) of bones and extra-osseous ES. Also, a reciprocal translocation t(11;22)(q24;q12) was found in more than 95% cases of both pPNETs and ESs, using cytogenetic analysis, so both were grouped together under Ewing sarcoma family of tumours (ESFT)(3). Intracranial ES/pPNET usually arise from meninges, while cPNETs have neuroparenchymal origin. While both cPNET and ES/pPNET have aggressive courses, the former rarely metastasises outside the CNS and the latter has higher metastatic potential, usually to bones and lungs. Treatment protocols also differ between the two types of PNET; CSI with focal boost RT and chemotherapy are needed for cPNET after its surgical debulking and for ES/pPNET, post-operative chemotherapy on the lines of ES followed by adjuvant local RT is sufficient. Hence, differentiation between the two entities is of utmost importance, especially in case of overlapping areas of CNS and peripheral nervous system (PNS) like meninges and spinal canal. The survival rates, though, are similar if treated as per the standard protocols, ranging from 50-70% for localized diseases(4).
The differentiation, not feasible by morphology, is done using CD99 (MIC2 glycoprotein) IHC and FISH for EWSR1 gene rearrangement. The membranous expression of CD99 serves as a highly reliable and sensitive diagnostic indicator for primary intracranial ES/pPNETs, positive in almost all cases and negative in cPNET(5,6). It is not advised as a specific IHC marker for diagnosing ES/pPNETs due to its positivity in other small, blue round cell tumours like lymphoblastic lymphomas, ependymomas, and rhabdomyosarcomas, even though the staining pattern in these tumours often appears cytoplasmic rather than the characteristic membranous staining seen in ES/pPNETs. The membrane protein FLI-1 is typically present in ES/pPNETs and employing both CD99 and FLI-1 IHC proves beneficial in the diagnosis(7). The gold standard to diagnose ES/pPNET and rule out cPNET, however is molecular testing to depict EWSR1 gene rearrangement. ES/pPNET has a characteristic translocation between EWSR1 gene on chromosome 22 and one of the ETS family of genes, most commonly FLI1 (chromosome 11), i.e., t(11;22)(q24;q12), and also ETV1 on chromosome 7 and ERG on chromosome 21. FISH assays using EWS break-apart probes are around 91-100% sensitive and specific; RT-PCR is used particularly to identify the partner gene for EWSR1, with a 67% concordance with FISH assays(8,9). The bottom line is that all morphologically diagnosed intracranial (and spinal canal) ES/PNET must be subjected to CD99 IHC and EWSR1 gene rearrangement using FISH to get a clear picture of the diagnosis and accordingly, plan for the treatment.
The initial theories considered CNS PNETs and MBs to be the same disease, arising in different locations, former arising supratentorial and the latter, infratentorial(10). Slowly, both were accepted to be different biologically(11). The 2007 WHO classification of CNS tumors included CNS-PNET not otherwise specified (NOS) and four morphologically distinct CNS-PNET variants - Medulloepithelioma (ME), CNS ganglioneuroblastoma, CNS neuroblastoma, and ependymoblastoma (EB). CNS PNETs were then recognized as a molecularly heterogeneous group, with the need for better classification. Based on the expression of cell lineage markers, LIN28 and OLIG2, 3 molecular subgroups were identified - primitive neural, oligo-neural and mesenchymal(1). DNA methylation profiling identified four molecular entities under CNS-PNET-CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC), CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1), and CNS HGNET with BCOR alteration (CNS HGNET-BCOR)(12). Top of Form
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The term PNET has been scrapped by WHO ever since WHO classification of CNS tumours 2016 due to the advent of molecular classification(13). As per the latest WHO classification of CNS tumours 2021, these tumours are under the classification of embryonal tumours, which are broadly divided into MBs and other CNS embryonal tumours. The latter include a host of tumours with different molecular and histological hallmarks, and a subgroup called CNS embryonal tumour, which was devoid of any such hallmark, i.e., not otherwise specified (NOS) and not elsewhere classified (NEC)(14). So, the erstwhile intracranial central PNET (cPNET) would now come under CNS embryonal tumour. cPNET account for 3-5% of paediatric CNS tumours and are at least five times less common than MBs. cPNET occur mainly in the cerebral hemispheres, the most common region being frontoparietal(15). Though biologically different, pinealoblastomas (PB) are sometimes included under cPNET and account for 20% of cPNET(16). cPNETs are usually diagnosed in young children, mainly less than 5 years old(17,18). Staging investigations are usually the same as those for MBs, although the clinical significance and correlation with long term disease control, especially that of the extent of resection, is less clear than for MB(17,18). The survival is even poorer compared to MB. For average-risk, the five-year progression-free survival (PFS) is 50% and >80% respectively and for high-risk, <20% and 50-60% respectively(19). Despite differences in outcome, treatment is still done on the lines of high-risk MBs in children as well as adult patients, due to the rarity of these tumors(20,21).
Given the fact that up to 33-35% of cPNETs have CSF spread at diagnosis, lumbar puncture and CSF cytology is a very crucial step in staging and evaluation of CNS-PNETs(22,23). Another point worth mentioning is the 3.3% chance of brain metastases and 9% chances of skull bone metastases in ESs(24,25). Hence, PET-CT has some role in ruling out occult extracranial primary ES with intracranial metastases. F-18 FDG PET-CT has been shown to localise the primary disease in carcinoma of unknown primary (CUP) in 40% cases, with the detection rate being 77% in case of CUP with brain lesions(26,27).
The surgical approach has been maximum safe resection with the aim of gross total resection (GTR). The improvement in outcomes in patients with minimal residual disease has been well demonstrated in non-disseminated MBs, though similar evidence is lacking for cPNETs(28). It should also be the aim of surgery to maintain neurologic function. Surgery is conventionally followed by radiotherapy and chemotherapy. RT guidelines are similar to high-risk MB, though the need of CSI in non-disseminated cPNET has never been proven and focal RT has been tried in well-localised lesions post GTR(19). Chemotherapy is also planned on similar lines as high-risk MB, with concurrent and adjuvant chemotherapy. Multiple attempts have been done to further intensify the treatment in view of poor outcomes with the conventional treatment. A report from the ANCS0332 randomized trial focussed on the molecular heterogeneity within the umbrella term cPNET and showed that the outcomes of these patients were considerably better when histologically cPNET, but molecularly high-grade gliomas (HGGs) were excluded from the analysis using DNA methylation profiling(29). This trial also showed that unlike high-risk MB patients, cPNET patients did not derive any event-free survival (EFS) benefit with the use of carboplatin concurrently with radiotherapy, so vincristine is sufficient for cPNET patients.
Non-PB cPNET was found to be resistant to Packer’s chemotherapy regimen(30). Intensive chemotherapy without radiotherapy was found to jeopardize the survival, and so was the omission of CSI(31). A report of the Head Start I and II trials experience, however, showed that postoperative intensified induction chemotherapy followed by myeloablative chemotherapy and autologous stem cell transplant, without irradiation was associated with better outcomes and avoidance of CSI-associated adverse effects. RT was reserved for salvage setting; local recurrences were much higher than local and distal recurrences and 60% patients alive at 5 years had no RT exposure. However, long-term data are not available(32). Massimino et al., after debulking surgery, used high-dose chemotherapy (methotrexate, etoposide, cyclophosphamide and carboplatin ± vincristine), followed by hyperfractionated accelerated RT, two daily 1.3 Gy fractions, to a dose of 31.2Gy and 39Gy in less than 10 and more than 10 years old patients respectively. Local boost was delivered in two daily 1.5 Gy fractions, up to 59.7-60 Gy. RT was followed by myeloablative dose of thiotepa and autologous stem cell rescue. Upon the observation that local failure was seen even after CSI and that no isolated distal relapse occurred in first 15 patients treated, local conventionally fractionated RT to a dose of 54 Gy was attempted in rest of the patients with localized disease and with no progression during induction chemotherapy. The results of focal RT, analysed separately were better than the entire series(33). Chintagumpala et al. classified cPNET patients into average-risk (M0 and residual tumor < 1.5 cm2) and high-risk (neuraxial dissemination or residual > 1.5 cm2) and planned adjuvant RT as per MB guidelines for each risk group, i.e., lower CSI dose for average risk. RT was followed by 4 cycles of nonmyeloablative high-dose chemotherapy (high-dose cyclophosphamide, cisplatin, and vincristine), each cycle with stem cell support. Average-risk cPNET treated with lower CSI dose and high-dose chemotherapy with stem cell rescue had excellent 5-year EFS of 75%, thereby highlighting the advantage of risk-adapted approach(34). Timmerman et al analysed the results of two trials, done on less than 3 years old children with supratentorial PNET to compare intensive postoperative chemotherapy alone and adjuvant induction chemotherapy followed by delayed RT. They concluded that RT should not be omitted despite intensive chemotherapy and even in less than 3 years old, RT should not be delayed for more than 6 months(31).
Our first patient had a residual tumour more than 1.5cm2 post-surgery without any evidence of CSF dissemination, and was treated as per high-risk MB protocol, though vincristine, and not carboplatin was used concurrently with RT(29). The adjuvant chemotherapy planned was Packer’s A regimen. However, the second patient had a smaller residual (0.8 cm2) post-surgery, without any CSF dissemination. She was also treated as per high-risk MB protocol with vincristine concurrent with RT and adjuvant chemotherapy as per Packers A regimen.