CNS-PNET
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BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.
- MeSH
- forkhead transkripční faktory MeSH
- germinální a embryonální nádory * diagnóza genetika terapie MeSH
- lidé MeSH
- molekulární patologie MeSH
- nádory centrálního nervového systému * diagnóza genetika terapie MeSH
- nádory mozku * diagnóza genetika terapie MeSH
- primitivní neuroektodermové nádory * diagnóza genetika terapie MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "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 high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.
- MeSH
- dítě MeSH
- forkhead transkripční faktory genetika MeSH
- lidé MeSH
- metylace DNA * MeSH
- molekulární sekvence - údaje MeSH
- nádorové supresorové proteiny genetika MeSH
- nádory centrálního nervového systému klasifikace diagnóza genetika patologie MeSH
- neuroektodermové nádory klasifikace diagnóza genetika patologie MeSH
- protoonkogenní proteiny chemie genetika MeSH
- regulace genové exprese u nádorů MeSH
- represorové proteiny chemie genetika MeSH
- sekvence aminokyselin MeSH
- signální transdukce MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
- MeSH
- dítě MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- kojenec MeSH
- lidé MeSH
- metylace DNA MeSH
- nádorové supresorové proteiny genetika MeSH
- nádory centrálního nervového systému * genetika MeSH
- předškolní dítě MeSH
- primitivní neuroektodermové nádory * genetika MeSH
- proteiny buněčného cyklu genetika MeSH
- proteiny vázající RNA genetika MeSH
- signální dráha Wnt genetika MeSH
- transkripční faktory genetika metabolismus MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In 1918, Stout defined the lesion in which small round cells originating from the ulnar nerve formed a rosette as neuroepithelioma. It was claimed that this tumor originated from neuroectodermis and was different from the classical neuroblastoma (1, 2). The term primitive neuroectodermal tumor (PNET) involves a group of tumors of the soft tissue originating from neural crest and resulting from the brain, spinal cord and branches of the sympathetic nervous system. Extracranial primitive neuroectodermal tumors originate from neural crest cells outside the sympathetic and central nervous system. PNET also has some distinctive histological, immunohistochemical and ultrastructural features. It is usually encountered in children and young adults; most frequently located in thoracopulmonary region (Askin’s tumor). The second most commonly involved body part is the extremities. It is very rarely located on the face (3-8). PNET is an aggressive tumor. In fact, the disease has a rapid progression, causes local or distant metastases and 50% of the patients die within two years of the presentation (7). It is treated with aggressive surgery as well as chemotherapy and radiotherapy. In this report, we presented a case of PNET located on the right cheek with multiple distant metastases. Clinicians should be on alert when treating facial tumors, not to skip PNET, which is a very aggressive one.
- MeSH
- lidé MeSH
- primitivní neuroektodermové nádory diagnóza patologie MeSH
- tvář patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Úvod: Primitivní neuroektodermální tumor (PNĚT) se vyskytuje hlavně jako nádor gastrointestinálního traktu. Vzniká z neuroektodermálních buněk. Je zařazen do skupiny tzv. malobuněčných (kulatobuněčných) nádorů. Primární PNET ledviny je velmi vzácný nádor, vyskytující se spíše u mladších nemocných průměrného věku 28 let (4-69 let). Byl označován také jako extraskeletální Ewingův sarkom (ES), se kterým má shodné mnohé imunohisto chemické a cytogenetické rysy. Terapie PNET se liší od renálního karcinomu, proto je nutná exaktní histopatologická diferenciální diagnóza pomocí imunohistochemických metod. Prezentujeme kazuistiku 42letého pacienta s PNET ledviny. Kazuistika: Pacient byl v prosinci 2004 vyšetřen pro makroskopickou hematurii s renálními kolikami vpravo. Na CT byl popsán 75 mm tumor pars intermedia pravé ledviny postkontrastní denzity 80HU Byla provedena transperitoneálním nefrektomie. Histologicky se jednalo o PNET stadia pT1bNOMO. Přes adjuvantní chemoterapii (5 sérií VIDE, 7 sérií VAC) došlo k progresi onemocnění. V prosinci 2006 byla provedena horní lobektomie a parciální pleurektomie pro metastázu PNET. Podány 3 série paliativní chemoterapie (hycamtin, cyklofosfamid). V dubnu 2007 došlo k progresi onemocnění v mediastinu a na pleuře. Pacient zemřel v září 2007 za 45 měsíců od nefrektomie. Závěr: Primární PNET ledviny je velmi vzácným nádorem, který pomocí zobrazovacích metod nelze odlišit od dalších nádorů ledvin. Chirurgická léčba je stejná jako u jiných nádorů ledvin. Používané schéma adjuvantní chemoterapie je v současné době shodné s terapií ES. Vzhledem k malému počtu pacientů není otázka optimální léčby uzavřena. Přes nejlepší standardní terapii se jedná o agresivní onemocnění se špatnou prognózou.
Introduction: Primitive neuroectodermal tumour (PNET) occurs primaly as a tumour of gastro-intestinal tract. He rises from neuroectodermal and is classed into group of small-cells (round-cell) tumours. Primary PNET of kidney is very rare tumour, witch is occured rather in younger ill, average age 28 years (4-69 years). Tumour was represented either as extrasceletal Ewing sarcoma (ES), with which has coincident to many imunohistochemical and cytogenetic features. Therapy of PNET is different from renal carcinoma, therefore exact histopathologic differential diagnosis with ussing imunohistochemical methods is necessary. We present case report of 42 years old patient with PNET of kidney. Case report: Patient was investigated for macroscopic hemauria with renal colics on the right. On CT was described 75 mm tumour in pars intermedia of right kidney (density 80HU). Wes provided transperitoneal nephrectomy for PNET (category pTlbNOMO). Despite of adjuvantn chemotherapy (5 series aspect, 7 series VAC) gets to disorder progression. In December 2006 was performed upper lobectomy and partial pleurektomie for implantation of PNET. Patient give 3 series palliative chemotherapy (hycamtine, cyklofosfamide). Unfortunately in April 2007 got to progression disorder in mediastinum and in pleurae. Inmate died in September 2007, behind 45,2 months from nephrectomy. Conclusion: Primary PNET kidney is very rare tumour, which by the help of imaging methods is not possible distinguish from other renal tumours. Surgical treatment is the same as in other renal tumours. Used adjuvant chemotherapy scheme is at present coincident with therapy ES. Appearances to small number of patient is not reserved a question of optimal treatment. Despite of the best standard therapy discuss of aggressive disorder with wrong prognosis.
- MeSH
- lidé MeSH
- nádory ledvin patologie terapie MeSH
- nefrektomie MeSH
- primitivní neuroektodermové nádory mortalita terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
