The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we ...prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
PURPOSEExamining a cohort of patients suspicious of neurofibromatosis type 1 (NF1) we compared the revised diagnostic criteria with the previous National Institutes of Health (NIH) diagnostic ...criteria. We asked whether the refinement improved distinguishing between NF1, Legius syndrome, and constitutional mismatch repair deficiency (CMMRD). METHODSA database search in the hospital information system of the University Children's Hospital Augsburg between 2017 and 2020 ascertained patients with International Classification of Diseases-10 code Q85.0; their clinical phenotype was evaluated by retrospective chart review. RESULTSA total of 75 patients were identified (median age 11.0 years range 1.1-22.6 years; 35 female). At first suspicion of NF1, 44 patients met the NIH criteria and 56 met the revised diagnostic criteria. In total, 12 patients were diagnosed with NF1 after performing molecular genetic testing. In 31 patients, only pigmentary findings were present, whereas nonpigmentary NF1 manifestations presented with time in 9 patients. In 1 patient a heterozygous variant of uncertain significance was identified in SPRED1. Requirements for CMMRD testing were fulfilled in another patient. A total of 3 patients presented with segmental clinical findings. Three additional patients did not meet the NIH criteria, 1 of them presented with 1 additional feature of CMMRD without fulfilling requirements for testing. CONCLUSIONIn our pediatric cohort, the revised diagnostic criteria discovered more patients with proven NF1 than the NIH criteria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that are associated with cancer predisposition syndromes in up to 80% of affected children. PPGLs can be divided ...into molecularly defined groups with comparable pathogenesis and biology: (1) pseudohypoxic, (2) kinase signaling, and (3) Wnt‐altered.
Methods
We report the data of children and adolescents diagnosed with PPGL who have been registered with the German GPOH‐MET registry since 1997.
Results
By December 2019, a total of 88 patients with PPGL were reported. Pheochromocytoma occurred in 56%, paraganglioma in 35%, and synchronous PPGLs in 9.1%. A total of 16% of patients presented with lymph node (5.7%) and distant metastases (10%). Median follow‐up was 4.2 years (range 0–17.1). Overall and disease‐free survival (DFS) were 98.6% and 54.0%, respectively. Local relapses, metastases, and subsequent PPGLs occurred in 11%, 4.5%, and 15% of patients. Germline mutations were detected in 83% of patients (51% in VHL, 21% in SDHB, 7.8% in SDHD, and one patient each in RET and NF1). One patient was diagnosed with Pacak–Zhuang syndrome. A total of 96% of patients presented with PPGL of the pseudohypoxic subgroup (34% TCA cycle‐related, 66% VHL/EPAS1‐related). In multivariate analyses, extent of tumor resection was a significant prognostic factor for DFS.
Conclusions
Most pediatric PPGLs belong to the pseudohypoxia subgroup, which is associated with a high risk of subsequent PPGL events and metastatic disease. Comprehensive molecular profiling of children and adolescents with newly diagnosed PPGLs will open new avenues for personalized diagnosis, treatment, and surveillance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in
SMARCB1
or ...(rarely) in
SMARCA4.
ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to
SMARCB1
mutated cases. Based on their DNA methylation profiles and transcriptomics,
SMARCB1
mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of
SMARCB1
alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from
SMARCB1
mutated ATRTs and from other
SMARCA4
-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or
SMARCA4
mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous
SMARCA4
mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in
SMARCB1
deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Paediatric appendiceal neuroendocrine tumours (appNET) are very rare tumours, mostly detected incidentally by histopathological evaluation after appendectomy. Treatment recommendations are based on ...adult data considering high-risk NET as defined by European Neuroendocrine Tumour Society (ENETS) guidelines for completion right-sided hemicolectomy (RHC). Recent data suggest that less aggressive therapy may be justified.
Analysis of children and adolescents with appNET prospectively registered with the German Malignant Endocrine Tumour (MET) studies between 1997 and 2022.
By December 2022, 662 patients (64.7% females, 35.3% male) had been reported. Median age was 13.3 years 4.5–17.9, median duration of follow-up 2.2 years 0–10.9. No distant metastases were reported. Tumour size was <1 cm in 63.5%, 1–2 cm in 33.2%, and >2 cm in 3.2% of patients. WHO grade 1 and 2 tumours were diagnosed in 76.9% and 23.1% of patients, respectively. Lymphovascular invasion and lymph node metastases were associated with tumour size ≥1.5 cm. 27.0% of patients presented with high-risk NET according to ENETS criteria. Of those, only 55.9% underwent secondary oncological right hemicolectomy. Neither distant metastases, nor recurrences or disease-related deaths occurred in patients with appendectomy only as well as in patients with completion RHC. Overall and event-free survival were both 100%.
Internationally harmonized consensus recommendations on treatment of children and adolescents with appendiceal NET are urgently needed to avoid completion RHC in high-risk patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Extracranial malignant rhabdoid tumors (extracranial MRT) are rare, highly aggressive malignancies affecting mainly infants and children younger than 3 years. Common anatomic sites comprise the ...kidneys (RTK - rhabdoid tumor of kidney) and other soft tissues (eMRT - extracranial, extrarenal malignant rhabdoid tumor). The genetic origin of these diseases is linked to biallelic pathogenic variants in the genes
, or rarely
, encoding subunits of the SWI/SNF chromatin-remodeling complex. Even if extracranial MRT seem to be quite homogeneous, recent epigenome analyses reveal a certain degree of epigenetic heterogeneity. Use of intensified therapies has modestly improved survival for extracranial MRT. Patients at standard risk profit from conventional therapies; most high-risk patients still experience a dismal course and often therapy resistance. Discoveries of clinical and molecular hallmarks and the exploration of experimental therapeutic approaches open exciting perspectives for clinical and molecularly stratified experimental treatment approaches. To ultimately improve the outcome of patients with extracranial MRTs, they need to be characterized and stratified clinically and molecularly. High-risk patients need novel therapeutic approaches including selective experimental agents in phase I/II clinical trials.
Reference intervals for laboratory test results have to be appropriate for the population in which they are used to be clinically useful. While sex and age are established partitioning criteria, ...patients' origin also influences laboratory test results, but is not commonly considered when creating or applying reference intervals. In the German population, stratification for ethnicity is rarely performed, and no ethnicity-specific hematology reference intervals have been reported yet. In this retrospective study, we investigated whether specific reference intervals are warranted for the numerically largest group of non-German descent, individuals originating from Turkey. To this end, we analyzed 1,314,754 test results from 167,294 patients from six German centers. Using a name-based algorithm, 1.9% of patients were identified as originating from Turkey, in line with census data and the algorithm's sensitivity. Reference intervals and their confidence intervals were calculated using an indirect data mining approach, and Turkish and non-Turkish reference limits overlapped completely or partially in nearly all analytes, regardless of age and sex, and only 5/144 (3.5%) subgroups' reference limits showed no overlap. We therefore conclude that the current practice of using common reference intervals is appropriate and allows correct clinical decision-making in patients originating from Turkey.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a
C11orf95-RELA
or a
YAP-MAMLD1
fusion, respectively. ...There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-
RELA/
non-
YAP
supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified—
RELA
-like (
n
= 9) and tanycytic ependymomas (
n
= 6). In the
RELA
-like group histologically assigned to WHO grade III and resembling
RELA
-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative
C11orf95
fusions to
MAML2
or
NCOA1
. A methylation-based brain tumor classifier assigned two
RELA
-like tumors to the methylation class “EP,
RELA
-fusion”; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked
MN1
breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with
RELA
-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (
RELA
-like and tanycytic) exist.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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