Randomized Controlled Trial

Authors: Sarah E S Leary, Roger J Packer, Yimei Li...

IMPORTANCE

Brain tumors are the leading cause of disease-related death in children. Medulloblastoma is the most common malignant embryonal brain tumor, and strategies to increase survival are needed.

OBJECTIVE

To evaluate therapy intensification with carboplatin as a radiosensitizer and isotretinoin as a proapoptotic agent in children with high-risk medulloblastoma in a randomized clinical trial and, with a correlative biology study, facilitate planned subgroup analysis according to World Health Organization consensus molecular subgroups of medulloblastoma.

DESIGN, SETTING, AND PARTICIPANTS

A randomized clinical phase 3 trial was conducted from March 2007 to September 2018. Analysis was completed in September 2020. Patients aged 3 to 21 years with newly diagnosed high-risk medulloblastoma from Children's Oncology Group institutions within the US, Canada, Australia, and New Zealand were included. High-risk features included metastasis, residual disease, or diffuse anaplasia.

INTERVENTIONS

Patients were randomized to receive 36-Gy craniospinal radiation therapy and weekly vincristine with or without daily carboplatin followed by 6 cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine with or without 12 cycles of isotretinoin during and following maintenance.

MAIN OUTCOMES AND MEASURES

The primary clinical trial end point was event-free survival, using the log-rank test to compare arms. The primary biology study end point was molecular subgroup classification by DNA methylation array.

RESULTS

Of 294 patients with medulloblastoma, 261 were evaluable after central radiologic and pathologic review; median age, 8.6 years (range, 3.3-21.2); 183 (70%) male; 189 (72%) with metastatic disease; 58 (22%) with diffuse anaplasia; and 14 (5%) with greater than 1.5-cm2 residual disease. For all participants, the 5-year event-free survival was 62.9% (95% CI, 55.6%-70.2%) and overall survival was 73.4% (95% CI, 66.7%-80.1%). Isotretinoin randomization was closed early owing to futility. Five-year event-free survival was 66.4% (95% CI, 56.4%-76.4%) with carboplatin vs 59.2% (95% CI, 48.8%-69.6%) without carboplatin (P = .11), with the effect exclusively observed in group 3 subgroup patients: 73.2% (95% CI, 56.9%-89.5%) with carboplatin vs 53.7% (95% CI, 35.3%-72.1%) without (P = .047). Five-year overall survival differed by molecular subgroup (P = .006): WNT pathway activated, 100% (95% CI, 100%-100%); SHH pathway activated, 53.6% (95% CI, 33.0%-74.2%); group 3, 73.7% (95% CI, 61.9%-85.5%); and group 4, 76.9% (95% CI, 67.3%-86.5%).

CONCLUSIONS AND RELEVANCE

In this randomized clinical trial, therapy intensification with carboplatin improved event-free survival by 19% at 5 years for children with high-risk group 3 medulloblastoma. These findings further support the value of an integrated clinical and molecular risk stratification for medulloblastoma.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT00392327.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cerebellar Neoplasms; Child; Child, Preschool; Disease-Free Survival; Humans; Isotretinoin; Male; Medulloblastoma; Young Adult

PubMed: 34292305
DOI: 10.1001/jamaoncol.2021.2224

Review

Authors: Charles G Eberhart, Peter C Burger

The variable clinical outcomes of medulloblastoma patients have prompted a search for markers with which to tailor therapies to individuals. In this review, we discuss clinical, histological and molecular features that can be used in such treatment customization, focusing on how histopathological grading can impact both patient care and research on the molecular basis of CNS embryonal tumors. Medulloblastomas span a histological spectrum ending in overtly malignant large cell/anaplastic lesions characterized by increased nuclear size, marked cytological anaplasia, and increased mitotic and apoptotic rates. These "high-grade" lesions make up approximately one quarter of medulloblastomas, and recur and metastasize more frequently than tumors lacking anaplasia. We believe anaplastic change represents a type of malignant progression common to many medulloblastoma subtypes and to other CNS embryonal lesions as well. Correlation of these histological changes with the accumulation of genetic events suggests a model for the histological and molecular progression of medulloblastoma.

Topics: Anaplasia; Carcinoma, Large Cell; Cerebellar Neoplasms; Disease Progression; Gene Expression Profiling; Humans; Medulloblastoma; Neoplasm Metastasis; Neoplasms, Germ Cell and Embryonal

PubMed: 12946027
DOI: 10.1111/j.1750-3639.2003.tb00037.x

Review

Authors: Elisabet Pujadas, Liam Chen, Fausto J Rodriguez...

Many breakthroughs have been made in the past decade regarding our knowledge of the biological basis of the diffuse gliomas, the most common primary central nervous system (CNS) tumors. These tumors as a group are aggressive, associated with high mortality, and have a predilection for adults. However, a subset of CNS glial and glioneuronal tumors are characterized by a more circumscribed pattern of growth and occur more commonly in children and young adults. They tend to be indolent, but our understanding of anaplastic changes in these tumors continues to improve as diagnostic classifications evolve in the era of molecular pathology and more integrated and easily accessible clinical databases. The presence of anaplasia in pleomorphic xanthoastrocytomas and gangliogliomas is assigned a WHO grade III under the current classification, while the significance of anaplasia in pilocytic astrocytomas remains controversial. Recent data highlight the association of the latter with aggressive clinical behavior, as well as the presence of molecular genetic features of both pilocytic and diffuse gliomas, with the recognition that the precise terminology remains to be defined. We review the current concepts and advances regarding histopathology and molecular understanding of pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas, with a focus on their anaplastic counterparts.

Topics: Anaplasia; Astrocytoma; Brain Neoplasms; Carcinoma; Central Nervous System Neoplasms; Ganglioglioma; Glioma; Humans; Neuroglia; Proto-Oncogene Proteins B-raf

PubMed: 30859342
DOI: 10.1007/s10014-019-00336-z

Authors: Annekathrin Reinhardt, Damian Stichel, Daniel Schrimpf...

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Astrocytoma; Brain Neoplasms; Child; Child, Preschool; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Histones; Humans; Infant; Isocitrate Dehydrogenase; Kaplan-Meier Estimate; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Retrospective Studies; Signal Transduction; Tumor Suppressor Proteins; X-linked Nuclear Protein; Young Adult

PubMed: 29564591
DOI: 10.1007/s00401-018-1837-8

Review

Authors: Soo Ryang Kim, Soo Ki Kim, Yu-Ichiro Koma...

Hepatic inflammatory pseudotumors (IPTs) are defined as benign, non-malignant, non-metastasizing tumors characterized by the presence of myofibroblastic spindle cells, hetorogenous populations of inflammatory cells, particularly plasma cells, lymphocytes and macrophages, as well as locations of fibrosis and necrosis without cellular anaplasia or atypical mitoses. Despite subsequent reports in the references, hepatic IPT remains difficult to diagnose; while posing major issues specifically for its differential diagnosis compared with that of other various benign diseases and malignant hepatic tumors. Histopathological findings are always a requisite for confirming the diagnosis, particularly given that the pathogenesis of IPT remains ambiguous to date. Hepatic IPT is a heterogeneous entity in terms of its clinical features, pathological findings, and pathogenesis. Once the diagnosis is confirmed, however, needless surgery such as wedge resection and lobectomy should be avoided. Here, we discuss the heterogeneity of hepatic IPT, its clinical features, pathological findings, and pathogenesis, and describe its differential diagnosis.

PubMed: 37685395
DOI: 10.3390/diagnostics13172857

Review

Authors: Nesibe Kahramancetin, Tarik Tihan

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic neoplasm that commonly affects children and young adults, and presents with seizures. PXA is typically supratentorial with a predilection to the temporal lobe, and often involves the cortex and the meninges. PXAs have a favorable prognosis with a 10-year survival probability of >70%, and are WHO grade II neoplasms. Recent observations and studies demonstrate that PXAs are clinically, histologically and genetically distinct. Some PXAs recur and exhibit aggressive clinical behavior. In such cases, certain histological and clinical factors could account for the aggressive behavior. However, the histological features that predict adverse outcome are poorly defined. In the current WHO classification of CNS tumors, there is no option for a high-grade PXA, even if the tumor had numerous recurrences and poor outcome. In this review, we focus on aggressive clinical behavior and anaplasia in PXA, and discuss how our current experience suggests modifications in the current WHO classification. We also review recent discoveries on the molecular characteristics of PXA that could help us better understand their biological behavior.

Topics: Anaplasia; Astrocytoma; Central Nervous System Neoplasms; Humans; Neoplasm Grading; Neoplasm Recurrence, Local

PubMed: 25054822
DOI: 10.2217/cns.13.56

Review

Authors: David Cachia, Derek R Johnson, Timothy J Kaufmann...

Ependymomas are rare primary central nervous system (CNS) tumors in adults. They occur most commonly in the spinal cord, and have classically been graded histologically into World Health Organization (WHO) grades I, II, or III based on the level of anaplasia. Recent data are showing that genetic heterogeneity occurs within the same histological subgroup and that ependymomas arising from different CNS locations have different molecular signatures. This has renewed interest in developing targeting therapies based on molecular profiles especially given the variable outcomes with radiation and the poor results with cytotoxic agents. In this paper, we present the case of a 46-year-old woman with a classic presentation of spinal cord ependymoma and discuss the current histopathological and molecular classification for ependymomas as well as current guidelines for patient management.

PubMed: 31386035
DOI: 10.1093/nop/npy026

Review

Authors: Eugene B Cone, Stewart S Dalton, Megan Van Noord...

PURPOSE

Wilms tumor is the most common childhood renal malignancy and the fourth most common childhood cancer. Many biomarkers have been studied but there has been no comprehensive summary. We systematically reviewed the literature on biomarkers in Wilms tumor to quantify the prognostic implications of the presence of individual tumor markers.

MATERIALS AND METHODS

We searched for English language studies from 1980 to 2015 performed in patients younger than 18 years with Wilms tumor and prognostic data. The protocol was conducted per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Two reviewers abstracted data in duplicate using a standard evaluation form. We performed descriptive statistics, then calculated relative risks and 95% confidence intervals for markers appearing in multiple level II or III studies.

RESULTS

A total of 40 studies were included examining 32 biomarkers in 7,381 patients with Wilms tumor. Studies had a median of 61 patients, 24 biomarker positive patients per series and a median followup of 68.4 months. Median percentages of patients with stages 1, 2, 3, 4 and 5 tumors were 28.5%, 26.4%, 24.5%, 14.1% and 1.7%, respectively, and 10.2% had anaplasia. The strongest negative prognostic association was loss of heterozygosity at 11p15, with a risk of recurrence of 5.00, although loss of heterozygosity at 1p and gain of function at 1q were also strongly linked to increased recurrence (2.93 and 2.86, respectively).

CONCLUSIONS

Several tumor markers are associated with an increased risk of recurrence or a decreased risk of overall survival in patients with Wilms tumor. These data suggest targets for development of diagnostic tests and potential therapies.

Topics: Biomarkers, Tumor; Child; Humans; Kidney Neoplasms; Prognosis; Wilms Tumor

PubMed: 27259655
DOI: 10.1016/j.juro.2016.05.100

Review

Authors: Janna A Hol, Illja J Diets, Ronald R de Krijger...

TRIM28 was recently identified as a Wilms' tumour (WT) predisposition gene, with germline pathogenic variants identified in around 1% of isolated and 8% of familial WT cases. TRIM28 variants are associated with epithelial WT, but the presence of other tumour components or anaplasia does not exclude the presence of a germline or somatic TRIM28 variant. In children with WT, TRIM28 acts as a classical tumour suppressor gene, with both alleles generally disrupted in the tumour. Therefore, loss of TRIM28 (KAP1/TIF1beta) protein expression in tumour tissue by immunohistochemistry is an effective strategy to identify patients carrying pathogenic TRIM28 variants. TRIM28 is a ubiquitously expressed corepressor that binds transcription factors in a context-, species-, and cell-type-specific manner to control the expression of genes and transposable elements during embryogenesis and cellular differentiation. In this review, we describe the inheritance patterns, histopathological and clinical features of TRIM28-associated WT, as well as potential underlying mechanisms of tumourigenesis during embryonic kidney development. Recognizing germline TRIM28 variants in patients with WT can enable counselling, genetic testing, and potential early detection of WT in other children in the family. A further exploration of TRIM28-associated WT will help to unravel the diverse and complex mechanisms underlying WT development. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Topics: Genes, Wilms Tumor; Genetic Predisposition to Disease; Humans; Kidney Neoplasms; Mutation; Tripartite Motif-Containing Protein 28; Wilms Tumor

PubMed: 33565090
DOI: 10.1002/path.5639