Choroid plexus tumors (CPT) are rare and highly vascularized neoplasms that have three histologically confirmed diagnoses, including choroid plexus papilloma, atypical choroid plexus papilloma, and ...choroid plexus carcinoma (CPC). This study aimed to determine the epidemiology and survival of patients with CPTs and develop a nomogram to quantify the prognosis of the patients with CPT. Data of 808 patients who were diagnosed as CPT between 2000 and 2020 was obtained from the surveillance, epidemiology, and end results database. Descriptive analysis was used to assess the distribution and tumor-related characteristics of the patients with CPT. Independent prognostic factors for patients with CPT were identified by univariate and multivariate Cox regression analysis. The nomogram was established and evaluated by receiver operating characteristic curve, and decision curve analysis (DCA), calibration curves. The independent prognostic factors for patients with CPT are age, tumor size, surgery, chemotherapy, tumor number, pathologies, and race. For the prognostic nomogram, the area under the curve (AUC) of 60-, 120-, and 180-months were 0.855, 0.869 and 0.857 in the training set and 0.836, 0.864 and 0.922 in the test set. The DCA and calibration curve indicated the good performance of the nomogram. Patients with CPTs can be diagnosed at any age. Among the three histopathological tumors, patients with CPC had the worst prognosis. The nomogram was established to predict the prognosis of patients with CPT, which had satisfactory accuracy, and clinical utility may benefit for clinical decision-making.
PURPOSE Choroid plexus carcinomas are pediatric tumors with poor survival rates and a strong, but poorly understood, association with Li-Fraumeni syndrome (LFS). Currently, with lack of biologic ...predictors, most children are treated with aggressive chemoradiation protocols. PATIENTS AND METHODS We established a multi-institutional tissue and clinical database, which enabled the analysis of specific alterations of the TP53 tumor suppressor and its modifiers in choroid plexus tumors (CPTs). We conducted high-resolution copy-number analysis to correlate these genetic parameters with family history and outcome. Results We studied 64 patients with CPTs. All individuals with germline TP53 mutations fulfilled LFS criteria, whereas all patients not meeting these criteria harbored wild-type TP53 (P < .001). TP53 mutations were found in 50% of choroid plexus carcinomas (CPCs). Additionally, two sequence variants known to confer TP53 dysfunction, TP53 codon72 and MDM2 SNP309, coexisted in the majority of TP53 wild-type CPCs (92%) and not in TP53 mutated CPC (P = .04), which suggests a complementary mechanism of TP53 dysfunction in the absence of a TP53 mutation. High-resolution single nucleotide polymorphism (SNP) array analysis revealed extremely high total structural variation (TSV) in TP53-mutated CPC tumor genomes compared with TP53 wild-type tumors and choroid plexus papillomas (CPPs; P = .006 and .004, respectively). Moreover, high TSV was associated with significant risk of progression (P < .001). Five-year survival rates for patients with TP53-immunopositive and -immunonegative CPCs were 0% and 82 (+/- 9%), respectively (P < .001). Furthermore, 14 of 16 patients with TP53 wild-type CPCs are alive without having received radiation therapy. CONCLUSION Patients with CPC who have low tumor TSV and absence of TP53 dysfunction have a favorable prognosis and can be successfully treated without radiation therapy.
Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. ...Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC. Furthermore, a combination screen with a wide variety of targets revealed multiple synergistic combinations that may pave the way for novel therapeutical strategies against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic assays established increased brain penetrance with intra-arterial (IA) delivery over intra-venous (IV) delivery and demonstrated a higher CNS penetrance for the combination melphalan/elimusertib. The mechanisms of synergistic activity for melphalan/elimusertib were assessed through transcriptome analyses and showed dysregulation of key oncogenic pathways (e.g. MYC, mammalian target of rapamycin mTOR, p53) and activation of critical biological processes (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC.
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Abstract
Background
Choroid plexus carcinomas (CPCs) are rare aggressive pediatric tumors of the brain with no treatment standards. Genetic profiling of CPCs is often confined to possible association ...with Li–Fraumeni syndrome, though only about a half of CPCs develop from syndromic predispositions. Whole-chromosome gains and losses typical of CPCs reflect genomic instability of these tumors, but only partially explain the aggressive clinical course.
Methods
This retrospective study enrolled 25 pediatric patients with CPC, receiving treatment between January 2009 and June 2022. Molecular-genetic testing was performed for 20 cases with available tumor tissue and encompassed mutational status, chromosomal aberrations, and gene expression profiles. We analyzed several factors presumably influencing the outcomes, including molecular profiles and clinical parameters. The median follow-up constituted 5.2 years (absolute range 2.8–12.6 years).
Results
All studied CPCs had smooth mutational profiles with the only recurrent event being TP53 variants, either germline or somatic, encountered in 13 cases. Unbalanced whole-chromosome aberrations, notably multiple monosomies, were highly typical. In 7 tumors, chromosome losses were combined with complex genomic rearrangements: segmental gains and losses or signs of chromothripsis. This phenomenon was associated with extremely low 5-year survival: 20.0 ± 17.9% vs 85.7 ± 13.2%; P = .009. Transcriptomically, the cohort split into 2 polar clusters Ped_CPC1 and Ped_CPC2 differing by survival: 31.3 ± 17.8% vs 100%; P = .012.
Conclusion
CPCs split into at least 2 molecular subtypes distinguished both genomically and transcriptomically. Clusterization of the tumors into Ped_CPC1 and Ped_CPC2 significantly correlates with survival. The distinction may prove relevant in clinical trials for dedicated and patient-oriented optimization of clinical protocols for these rare tumors.
To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification ...and guide therapeutic options.
One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes.
Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%-46.5% vs. 66.7%, 28.2%-87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%-71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival.
Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs.
To evaluate the incidence of infant brain tumors and survival outcomes by disease and treatment variables.
The Surveillance, Epidemiology, and End Results (SEER) Program November 2008 submission ...database provided age-adjusted incidence rates and individual case information for primary brain tumors diagnosed between 1973 and 2006 in infants less than 12 months of age.
Between 1973 and 1986, the incidence of infant brain tumors increased from 16 to 40 cases per million (CPM), and from 1986 to 2006, the annual incidence rate averaged 35 CPM. Leading histologies by annual incidence in CPM were gliomas (13.8), medulloblastoma and primitive neuroectodermal tumors (6.6), and ependymomas (3.6). The annual incidence was higher in whites than in blacks (35.0 vs. 21.3 CPM). Infants with low-grade gliomas had the highest observed survival, and those with atypical teratoid rhabdoid tumors (ATRTs) or primary rhabdoid tumors of the brain had the lowest. Between 1979 and 1993, the annual rate of cases treated with radiation within the first 4 months from diagnosis declined from 20.5 CPM to <2 CPM. For infants with medulloblastoma, desmoplastic histology and treatment with both surgery and upfront radiation were associated with improved survival, but on multivariate regression, only combined surgery and radiation remained associated with improved survival, with a hazard ratio for death of 0.17 compared with surgery alone (p = 0.005). For ATRTs, those treated with surgery and upfront radiation had a 12-month survival of 100% compared with 24.4% for those treated with surgery alone (p = 0.016). For ependymomas survival was higher in patients treated in more recent decades (p = 0.001).
The incidence of infant brain tumors has been stable since 1986. Survival outcomes varied markedly by histology. For infants with medulloblastoma and ATRTs, improved survival was observed in patients treated with both surgery and early radiation compared with those treated with surgery alone.
Papillary tumor of the pineal region (PTPR) is a neuroepithelial brain tumor, which might pose diagnostic difficulties and recurs often. Little is known about underlying molecular alterations. We ...therefore investigated chromosomal copy number alterations, DNA methylation patterns and mRNA expression profiles in a series of 24 PTPRs. Losses of chromosome 10 were identified in all 13 PTPRs examined. Losses of chromosomes 3 and 22q (54%) as well as gains of chromosomes 8p (62%) and 12 (46%) were also common. DNA methylation profiling using Illumina 450k arrays reliably distinguished PTPR from ependymomas and pineal parenchymal tumors of intermediate differentiation. PTPR could be divided into two subgroups based on methylation pattern, PTPR group 2 showing higher global methylation and a tendency toward shorter progression‐free survival (P = 0.06). Genes overexpressed in PTPR as compared with ependymal tumors included SPDEF, known to be expressed in the rodent subcommissural organ. Notable SPDEF protein expression was encountered in 15/19 PTPRs as compared with only 2/36 ependymal tumors, 2/19 choroid plexus tumors and 0/23 samples of other central nervous system (CNS) tumor entities. In conclusion, PTPRs show typical chromosomal alterations as well as distinct DNA methylation and expression profiles, which might serve as useful diagnostic tools.
Tumors arising inside the ventricular system are rare but represent a difficult diagnostic and therapeutic challenge. They usually are diagnosed when reaching a big volume and tend to affect young ...children. There is a wide broad of differential diagnoses with significant variability in anatomical aspects and tumor type. Differential diagnosis in tumor type includes choroid plexus tumors (papillomas and carcinomas), ependymomas, subependymomas, subependymal giant cell astrocytomas (SEGAs), central neurocytomas, meningiomas, and metastases. Choroid plexus tumors, ependymomas of the posterior fossa, and SEGAs are more likely to appear in childhood, whereas subependymomas, central neurocytomas, intraventricular meningiomas, and metastases are more frequent in adults. This chapter is predominantly focused on choroid plexus tumors and radiological and histological differential diagnosis. Treatment is discussed in the light of the modern acquisition in genetics and epigenetics of brain tumors.
Aberrant Notch signalling has been linked to many cancers including choroid plexus (CP) tumours, a group of rare and predominantly paediatric brain neoplasms. We developed animal models of CP ...tumours, by inducing sustained expression of Notch1, that recapitulate properties of human CP tumours with aberrant NOTCH signalling. Whole-transcriptome and functional analyses showed that tumour cell proliferation is associated with Sonic Hedgehog (Shh) in the tumour microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumour cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate differentiation. A Shh-driven signalling cascade in the primary cilium occurs in tumour cells but not in epithelial cells. Lineage studies show that CP tumours arise from monociliated progenitors in the roof plate characterized by elevated Notch signalling. Abnormal SHH signalling and distinct ciliogenesis are detected in human CP tumours, suggesting the SHH pathway and cilia differentiation as potential therapeutic avenues.
Objective
To describe a telovelar approach to the fourth ventricle for excision of a choroid plexus tumor within the ventricle.
Animal
A 3‐year‐old entire male Chihuahua.
Study design
Case report
...Methods
A 3‐year‐old dog with two‐month history of progressive vestibular signs and subdued mentation was diagnosed with a fourth ventricle tumor. Gross total resection of the tumor was achieved through a telovelar approach to the fourth ventricle.
Results
Complete removal of the tumor was confirmed on immediate postoperative MRI. The dog recovered from the surgical procedure without complications, displaying some neurological deficits as preoperatively. His neurological examination was normal 2 weeks after surgery and remained so until the time of writing this case report (28 months) without additional treatment.
Conclusion
The telovelar approach allowed complete excision of a choroid plexus tumor located in the fourth ventricle of the dog reported here.
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