Choroid Plexus Carcinoma Research Articles

PTCT-01INTERCONTINENTAL MULTIDISCIPLINARY DATA COLLECTION AND TREATMENT OPTIMIZATION STUDY FOR PATIENTS WITH CHOROID PLEXUS TUMORS

BACKGROUND: Choroid plexus tumors (CPTs) are rare pediatric tumors. They are classified by the World Health Organization as Choroid plexus papillomas (CPP), Atypical choroid plexus papillomas (APP) and Choroid plexus carcinomas (CPC). Current recommendations for the treatment of CPTs include surgical resection followed by adjuvant chemotherapy and or radiation therapy. The CPT-SIOP 2009 protocol compared four different chemotherapy treatment arms (standard arm A-Cyclophosphamide/VP16/VCR (CycEV) alternating with Carboplatin/VP16/VCR CarbEV) blocks, arm B-Doxorubicin/Cisplatinum/Actinomycin-D/VCR, arm C-high dose Methotrexate and arm D-Temozolomide/Irinotecan). The study closed due to insufficient enrollment of formally randomized patients. Our study reviews the patient data registry, which includes non-randomized patients. METHODS: Clinical course was evaluated amongst patients enrolled in the CPT-SIOP 2009 protocol. Data was obtained from international institutions including Australia, New Zealand, Germany, Lebanon, Turkey, Switzerland and USA. Qualitative parameters included age, sex, presenting symptoms and adjuvant therapy. Overall survival and event free survival were analyzed. RESULTS: We identified 27 cases with CPTs (APP 5, CPP 5, CPC 17), 9 females and 15 males, (2 unknown). The mean age at presentation was 7 years with a median age of 2.4 years (range 0.16 to 58 years). Twelve patients were treated under arm A, (1 B, 4 C, 1 D, 3 in observation and 6 unknown). 2y overall survival/2y EFS for n = 12 CPC patients on arm A was 78%/ 35% with a median follow up of 1.7 years, compared to 76%/ 63% for n = 41 CPC patients treated with non-alternating blocks of CarbEV or CycEV in the SIOP-CPT database. CONCLUSION: The outcome of alternating CarbEV/CycEV appears inferior to non-alternating cycles of either CarbEV or CycEV and is no longer recommended as a guidance in the SIOP-CPT registry. Our aim is to continue following these patients over time to monitor overall and event free survival.

ATPS-53SURGICAL THERAPY FOR CEREBRAL VENTRICLE TUMOR IN INFANTS

BACKGROUND: Surgical treatment for infant ventricle tumors is a tough procedure. We summarize the clinical information, surgical experience and perioperative therapy for 14 patients. METHODS: The patients contained 8 males, 6 females and were treated from 2010-1 to 2014-12. The age ranged from 4 to 24 months with an average of 11.5 months. We used the approach of trigone area for 3 cases, interhemispheric transcallosal for 5 cases, and sub-occipital medline for 6 cases. RESULTS: Resection extent: 10 total resection (including 2 subtotal resection), 4 partial resection. Pathology categories: 5 choroid plexus papilomas (CPP), 1 choroid plexus carcinoma,1 mature teratoma, 1 anaplastic CPP, 3 anaplastic ependymoma (WHO III), 1 ependymoma (WHO I-II ), 1 glioma, 1 medulloblastoma. PROGNOSIS: 7 cases survive (4 cases survive with different complications); 5 infants died (all died for abandoning treatment); 1 case was lost. Overall, the prognosis is poor. CONCLUSIONS: 1. Infant cerebral ventricle tumors are often large before symptoms come up. Tumor's proximity to important brain regions makes it difficult for total resection. 2. Infants have a small blood volume and poor tolerance to operation, since great blood loss usually occurs intraoperation. Time-consuming operations, such as those for total resection, require a great deal of time under anaesthesia and blood loss. It's preferable to choose a stage operation when severe blood loss occurs. 3. Acute resection is a better choice to relieve hydrocephalus rather than drainage. 4. Close contact of qualified, specialist medical staff is necessary. Intensive care and nutritional support are important for postoperation therapy.

Preclinical studies of 5-fluoro-2′-deoxycytidine and tetrahydrouridine in pediatric brain tumors

Chemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. Here, as an example of the pipeline, data are presented for the combination of 5-fluoro-2′-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2′-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-015-1965-0) contains supplementary material, which is available to authorized users.

Occurrence of Neuroblastoma among TP53 p.R337H Carriers.

The high incidence of adrenocortical tumors and choroid plexus carcinoma in children from South and Southeastern regions of Brazil is associated with the germline p.R337H mutation of TP53 gene. The concomitant occurrence of neuroblastoma and adrenocortical tumors in pediatric patients harboring the p.R337H mutation at our institution prompted us to investigate the putative association between p.R337H and pediatric neuroblastoma. Genomic DNA samples from 83 neuroblastoma patients referred to a single institution during the period of 2000–2014 were screened for the p.R337H mutation. Available samples from carriers were investigated for both nuclear p53 accumulation and loss of heterozigosity in tumor. Clinical data were obtained from medical records in order to assess the impact of 337H allele on manifestation of the disease. Seven out 83 neuroblastoma patients (8.4%) were carriers of the TP53 p.R337H mutation in our cohort. Immunohistochemical analysis of p.R337H-positive tumors revealed nuclear p53 accumulation. Loss of heterozigosity was not found among available samples. The presence of 337H allele was associated with increased proportion of stage I tumors. Our data indicate that in addition to adrenocortical tumors, choroid plexus carcinoma, breast cancer and osteosarcoma, genetic counseling and clinical surveillance should consider neuroblastoma as a potential neoplasia affecting p.R337H carriers.

Abstract 3280: Sequencing approaches define the mutation and fusion landscape of choroid plexus carcinomas

Abstract Background & Purpose: Choroid plexus carcinomas (CPCs) are aggressive intraventricular tumors accounting for ∼20% of brain tumors in children under 2 years of age. The clinical outcome of CPC patients is variable having an average 5-year overall survival of 50%. A recent study from our group has characterized copy number, DNA methylation and gene expression aberrations in these tumors and identified that a greater number of mutated copies of TP53 is significantly associated with reduced survival. The mutational landscape of these tumors is largely unknown, although this information is crucial to refine the understanding of CPC tumorigenesis and identify novel therapeutic targets. The purpose of this study is to complement the in-depth analysis of the molecular abnormalities driving CPC development by investigating single nucleotide alterations (SNAs), and structural variations (SVs) in CPC DNA and RNA. Methods: A cohort of 29 high quality samples from 25 pediatric CPC patients was used for this study. DNA from 4 blood-tumor pairs and RNA from 27 CPCs were used for whole genome sequencing (WGS) and RNA sequencing (RNA seq), respectively, as part of the Pediatric Cancer Genome Project (PCGP) at St. Jude Children's Research Hospital, using the Illumina Genome Analyzer IIx or HiSeq platform with 100bp read length. Eighty-two percent of samples were primary tumors, while 17.2% were recurrences. Only one sample had sufficient high quality nucleic acid material to conduct both DNA and RNA sequencing. Results: CPCs exhibited very low levels of SNAs ranging from 1 to 11 SNAs per genome. Copy number analysis using WGS confirmed the high levels of copy number alterations in CPCs. RNAseq analysis revealed that primary and recurrent CPC samples exhibited 100% similarity in fusion breakpoints, suggesting very little clonal divergence in these pediatric brain tumors. A recurrent fusion in chromosome 3 was observed in two independent CPCs (7%). Other fusion events generated in-frame alterations in genes involved in the MAP kinase pathway, such as PPP2R1A, and in apoptosis and cell proliferation pathways. The sample for which WGS and RNAseq was generated exhibited chromothripsis with numerous SVs affecting chromosomes 1 and 19. No other SV events were found in our CPC cohort. Conclusions: CPCs exhibit very few SNAs and SVs, but are characterized by recurrent chromosome-wide copy number aberrations. Various RNA fusion events altering the MAP kinase pathway have been identified, suggesting a key role for kinase pathways in the development and growth of these devastating brain tumors. Citation Format: Diana M. Merino, Yongjin Li, Xiaotu Ma, Jinghui Zhang, David Malkin, Richard J. Gilbertson. Sequencing approaches define the mutation and fusion landscape of choroid plexus carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3280. doi:10.1158/1538-7445.AM2015-3280

Abstract 1002: Molecular characterization of aggresome formation in choroid plexus carcinoma

Abstract Our long-term goal is to define and characterize the mechanisms underlying aggresome formation in choroid plexus carcinoma a rare pediatric tumor. Protein misfolding is inevitable, 30% of newly synthesized polypeptides can end up misfolded, such proteins are either refolded or eliminated by cellular quality control pathways which include the ubquitin proteosome system and autophagy. In recent years, protein misfolding has been implicated in the pathophysiology of many diseases such as diabetes, neurological disorders and cancer. Studies from our laboratory have shown that choroid plexus carcinoma tumors are characterized by the formation of aggresomes at the microtubules organizing centers (MTOC) in FFPE tumor tissues. This was further conformed by the development of choroid plexus carcinoma cell line (CPC-45) which was characterized by the constitutive formation of aggresomes at MTOC. When examining the soluble and insoluble fractions, vimentin was only identified in the insoluble fraction. These results were further confirmed using electron microscopy. Aggresome formation implies presence of toxic protein over load and/or defective autophagy. CPC-45 cells displayed normal LC3B (an indicator of autophagosome) expression and regulation upon nutrient deprivation. To further monitor autophagy, CPC-45 and SHY-5Y cells were infected with the dual Tandem Sensor RFP-GFP-LC3B to label autophagosome and its maturation to autolysosome. While SHY-5Y displayed both green and red fluorescence upon infection, CPC-45 was only positive after serum starvation thus confirming the targeting of aggresomes by LC3B mediated autophagy. Recently, the LC3B paralog LC3AV1 was found to be silenced by DNA methylation in several cancer cell lines and reported as major player in autophagy and as a potential tumor suppressor. To further explore the role of LC3A in aggresome formation, CPC-45 cells were transfected with either GFP empty vector or LC3AV1-GFP construct. Only LC3A-GFP transfected cells were positive for aggresome formation while in GFP transfected we did not observe any signal. Consistent with previous reports that over expression of GFP results in protein accumulation at the aggresomes. Our results suggest that LC3A is the mediator of the basal quality control function of autophagy which is different from the stress induced autophagy mediated by LC3B. Based on our findings, we propose that perturbation in the autophagic pathway due lack of LC3Av1 expression lead to a failure in the aggresome degradation process and hence provide an advantage to tumor cells to overcome protein misfold overload thus contributing to the tumorigenicity of the disease. Citation Format: Heba Samaha, Marwa Nassar, Myret Ghabriel, Maha Yehia, Hala Taha, Dina Yassin, Sherine Salem, Khaled Shaaban, Mariem Omar, Shahenda M. El-Naggar. Molecular characterization of aggresome formation in choroid plexus carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1002. doi:10.1158/1538-7445.AM2015-1002

Abstract 2749: Cumulative cancer risk in the NCI Li-Fraumeni Syndrome Cohort

Abstract Background: Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer predisposition syndrome characterized by the early onset of a wide range of cancers and a very high lifetime cumulative cancer risk. Despite significant progress in understanding LFS, uncertainty remains regarding the cancer incidence rates and cancer spectrum for TP53 mutation carriers. In addition, the cancer incidence for members of families meeting the clinical diagnostic criteria of LFS or Li-Fraumeni like (LFL) syndrome but in which no TP53 mutation has been identified (TP53- families) has not been established. Methods: The NCI's LFS Study (NCT01443468) is a natural history study that opened to accrual in August 2011. Inclusion criteria include LFS or LFL syndrome; a germline TP53 mutation; or a personal history of choroid plexus carcinoma, adrenocortical carcinoma (ACC), or ≥3 primary cancers. Participants complete a detailed family history and individual information questionnaires. Confirmation of all reported cancer diagnoses is pursued. Results: Of the 122 families enrolled to date, 95 families have a germline TP53 mutation (TP53+ families) and 27 are TP53-families. TP53+ families: 243 mutation carriers from 95 mutation-positive families were included in the cancer risk estimates. The cumulative risk to first cancer diagnosis for the entire group is 43% by age 30 and close to 100 by age 70, with males having higher risk in childhood adolescence and females having higher risk starting in the 20s, mostly due to breast cancer. When examined by cancer type, the cumulative risk to age 70 is 35% for breast cancer, 16% for soft tissue sarcoma, 10% for brain cancer, 7% for bone cancer, 2% for leukemia, 2% for ACC, and 26% for others. Overall survival is approximately 80% by age 50. TP53- families: The underlying etiology contributing to cancer risk in the TP53- families is not known at this time; therefore, for the estimation of cancer risk among these families, we included all bloodline members belonging to the lineage contributing to the eligibility criteria. Among the 522 individuals from the 27 TP53- families, the cumulative risk to first cancer diagnosis is 7% by age 30 and 45% by age 70. The lifetime cumulative risk is higher for breast, brain, lung cancer, and melanoma compared with other cancer types. Overall survival is approximately 90% by age 50. Conclusion: We report the cumulative cancer incidence and overall survival among TP53 mutation carriers in TP53+ families as well as among members of TP53- families. Identification of additional causative gene(s) in TP53- families will help refine the cancer risk of family members. We are evaluating the risks of second primary cancers, and whether the rate is dependent on the type of the first cancer in all families. Citation Format: Phuong L. Mai, Philip S. Rosenberg, June A. Peter, Rosamma DeCastro, Payal P. Khincha, Jennifer T. Loud, Renee Bremer, Sharon A. Savage. Cumulative cancer risk in the NCI Li-Fraumeni Syndrome Cohort. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2749. doi:10.1158/1538-7445.AM2015-2749

Choroid plexus carcinoma: A case report

A 3-year-male child was operated for 4th ventricular choroid plexus carcinoma. He presented with features of raised intracranial pressure and midline posterior fossa syndrome. A total excision of tumor could be achieved as there was no parenchymal invasion or adherence with the walls of 4th ventricle. Cerebrospinal fluid pathway was reestablished and hydrocephalus resolved gradually. The child developed peritoneal and liver metastases at follow-up of 14-month without local recurrence. A choroid plexus carcinoma metastasizes to the liver and peritoneum.

Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers.

The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.

Abstract B01: Sustained clinical response to treatment directed by genomic expression profiling suggests mTOR signaling is an effective target in choroid plexus carcinoma

Abstract Background: Choroid plexus tumors comprise 10-20% of intracranial tumors in children less than one year of age, the majority of these are benign papillomas, however some are highly aggressive carcinomas. Choroid Plexus Carcinoma (CPC) is derived from the choroid plexus which is neuroepithelial tissue that normally produces CSF and lines the intracranial ventricles. The prognosis of choroid plexus carcinomas is poor with 5 year event free survival rates varying between 10%-50% while relapsed or metastatic CPC is usually fatal. A patient with relapsed CPC who had progressed on 5 previous salvage chemotherapy combinations was enrolled on Neuroblastoma Medulloblastoma Translational Research Consortium (NMTRC) Molecular-Guided Therapy Trial for the Treatment of Patients with Relapsed or Refractory Childhood Cancer in which we performed genomic profiling allowing a targeted approach to therapeutic decision making. Methodology: The patient with multiply relapsed metastatic CPC enrolled on NMTRC Molecular Guided Therapy Clinical Trial after obtaining written informed consent. A tumor biopsy was sent to the Clinical Reference Laboratory (CRL) for mRNA expression analysis using U133 2.0 Plus GeneChip, and to Translational Genomics Research Institute (TGen) for high-performance RNA-seq analysis and DNA exome analysis. The differential expression data was interpreted in the context of systems biology annotation. Analysis of RNA expression results were discussed in a NMTRC tumor board leading to a therapeutic plan using study targeted treatments. Patient response was determined by clinical examination with serial MRI of the brain. Results: In this CPC specimen the PI3K/Akt/mTOR pathway was found to be highly expressed as well as PDGF, FGF2 and HDAC3 which were chosen by the tumor board for targeted therapy. Exomes analysis confirms mutation in RPTOR involved in mTOR activation. Treatment with sirolimus (mTOR), thalidomide (FGF2), Sunitinib (PDGF), and vorinostat (HDAC3) resulted in a 68% tumor reduction and the patient maintains a continuous response after 11 months while continuing to receive this therapy. This treatment combination has been well tolerated with no serious adverse events and excellent quality of life. Conclusion: Genomic Profiling analyses revealed activation of the mTOR pathway in this chemo-resistant Choroid Plexus Carcinoma. Targeted therapy has demonstrated clinical benefit suggesting a novel therapeutic approach. Further investigation of the mTOR pathway as a therapeutic target in CPC warranted. Citation Format: Albert S. Cornelius, Jessica Foley, Deanna Mitchell, Abhinav Nagulapally, Jeff Bond, Matthew Huntelman, Jason Corneveaux, Jeff Trent, Giselle Sholler. Sustained clinical response to treatment directed by genomic expression profiling suggests mTOR signaling is an effective target in choroid plexus carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B01.

Concurrent Gain of Oncogenes Drives Choroid Plexus Carcinoma.

TAF12, NFYC, and RAD54L are oncogenes required to initiate and maintain choroid plexus carcinoma (CPC).

Choroid Plexus Neoplasms: Toward a Distinction between Carcinoma and Papilloma Using Arterial Spin-Labeling.

Pediatric choroid plexus papillomas and carcinomas are highly vascularized neoplasms, which are difficult to distinguish with conventional imaging. We aimed to analyze the diagnostic accuracy of PWI, by using both pseudocontinuous arterial spin-labeling and DSC-PWI. We reviewed the PWI of 13 children with choroid plexus neoplasms (7 papillomas and 6 carcinomas). We quantified CBF, relative CBF, and relative CBV in each lesion and compared papillomas and carcinomas. Relative CBF values by using arterial spin-labeling were significantly higher for carcinomas (P = .028). The median value of relative CBF was 1.7 (range, 1.4-1.9) for carcinomas and 0.4 (range, 0.3-0.6) for papillomas. The CBF median value was 115 mL/min/100 g (range, 90-140 mL/min/100 g) for carcinomas and 41 mL/min/100 g (range, 10-73 mL/min/100 g) for papillomas (P = .056). Measures with DSC-PWI were more variable and not significantly different (P = .393). Arterial spin-labeling is a promising technique to differentiate choroid plexus carcinomas and papillomas.

Neoadjuvant chemotherapy reduces blood loss during the resection of pediatric choroid plexus carcinomas.

OBJECT Choroid plexus carcinomas (CPCs) are rare brain tumors originating from the ventricular choroid plexus. They account for 2%-4% of all pediatric brain tumors and are most frequently seen in very young children. This pediatric proclivity, in combination with a marked vascularity, renders an aggressive resection a difficult and often dangerous endeavor. Blood losses of several total blood volumes in small children are not uncommon, sometimes forcing the neurosurgeon to abort the procedure, often leaving residual tumor. Great extent of tumor resection is an accepted beneficial factor for overall survival. Therefore, a second resection usually follows the administration of adjuvant chemotherapy. Second-look surgery appears to be associated with markedly decreased blood loss. Histological examination of specimens obtained at a second intervention shows decreased vascularity and fibrotic changes in tumor tissue. At the Hospital for Sick Children in Toronto, this empirical finding led to the strategy of neoadjuvant chemotherapy to minimize blood loss and maximize cytoreduction. The authors undertook this study to assess the potentially beneficial effect of neoadjuvant chemotherapy on blood loss during surgery for CPCs. METHODS In this retrospective cohort review, the demographic, clinical, and treatment parameters of 22 consecutive patients diagnosed with CPC are presented. All underwent surgical treatment at the Hospital for Sick Children from 1982 to 2013. Special attention was given to the impact of neoadjuvant chemotherapy on extent of resection and intraoperative blood loss. Extent of resection was calculated based on perioperative neuroimaging, and amount of blood loss was estimated based on transfusion parameters and perioperative changes in hematocrit. RESULTS Ten patients did not receive neoadjuvant chemotherapy, and 12 were treated with 2-5 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy in a neoadjuvant fashion. The 22 patients included in the study underwent a total of 37 tumor resection surgeries. In all of the cases in which neoadjuvant chemotherapy was used, at least a near-total resection (> 95% of tumor volume) was achieved. Patients who underwent gross-total resection had prolonged overall survival. Of the 37 resections, 18 were performed after chemotherapy. Mean blood loss in the neoadjuvant chemotherapy group was 22% of total estimated blood volume as opposed to 96% in patients without preoperative chemotherapy. CONCLUSIONS In children with CPC, the administration of neoadjuvant chemotherapy decreases intraoperative blood loss and increases extent of resection with a significant positive effect on overall survival.

Cross-Species Genomics Identifies TAF12, NFYC, and RAD54L as Choroid Plexus Carcinoma Oncogenes

Choroid plexus carcinomas (CPCs) are poorly understood and frequently lethal brain tumors with few treatment options. Using a mouse model of the disease and a large cohort of human CPCs, we performed a cross-species, genome-wide search for oncogenes within syntenic regions of chromosome gain. TAF12, NFYC, and RAD54L co-located on human chromosome 1p32-35.3 and mouse chromosome 4qD1-D3 were identified as oncogenes that are gained in tumors in both species and required for disease initiation and progression. TAF12 and NFYC are transcription factors that regulate the epigenome, whereas RAD54L plays a central role in DNA repair. Our data identify a group of concurrently gained oncogenes that cooperate in the formation of CPC and reveal potential avenues for therapy.

The role of chemotherapy and surgical removal in the treatment of Choroid Plexus carcinomas and atypical papillomas.

We performed a retrospective study on clinical assessment, tumor location, radiological imaging, histopathological characteristics, and therapeutic management of 7 patients affected by choroid plexus carcinoma (CPC) or atypical choroid plexus papilloma (ACPP) who have been observed in the last 12 years. Four patients fulfilled the criteria for classification as ACPP and three cases as CPC. The median age of the patients at the diagnosis was 42 months (range 3-190 months). Except one older patient (15 years old), all patients were younger than 3 years of age. In all patients affected by ACPP, a total surgical resection was achieved. Two children relapsed 12 and 8 months following radical removal. Both of them underwent adjuvant chemotherapy (carboplatin, cyclophosphamide, etoposide, doxorubicin, and methotrexate); a complete remission was maintained in all cases. In all three patients with CPC, it was impossible to achieve complete resection at first surgery. The response to chemotherapy was variable: in one case, it was complete with complete remission following 6 months; in one case, it was partial with reduction on volume (the patient underwent second-look surgery with complete resection); in the third case, there was no response and the patient progressed and finally died with metastatic disease, 8 months after chemotherapy was started. For children with CPC, the OS was 75% at 6 years. In our series, surgery associated with chemotherapy led to long-term survival in 4/4 patients affected by ACPP and 2/3 patients affected by CPC. Clinical results achieved in our series confirm that our therapeutic regimen is feasible and efficient as a possible adjuvant treatment for both CPC and ACPP. It also suggests that surgery has a pivotal role in the management of most children affected by CPTs.

Single Agent Therapy with Bevacizumab for the Treatment of Atypical Choroid Plexus Tumor

Introduction Choroid plexus tumors are rare tumors of the brain. They account for 0.3-0.6% of all brain tumors. Fifty percent of these tumors occur in the lateral ventricle, 40% in the fourth ventricle, 5% in the third ventricle, and 5% are multifocal. Grading of choroid plexus tumors is based on World Health Organization (WHO) classification. Choroid plexus papilloma is grade I, atypical choroid plexus papilloma is grade II, and choroid plexus carcinoma is grade III. For both choroid plexus papilloma and choroid plexus carcinoma, age at presentation correlates with the location of the tumor. Lateral ventricle tumors are more common in children less than 10 years old, while fourth ventricle tumors are distributed evenly up to 50 years of age. Choroid plexus papilloma is welldifferentiated and usually has a benign course and carries a good prognosis after complete resection. Occasionally, there can be a malignant transformation to a choroid plexus carcinoma at recurrence. These are aggressive tumors characterized by brisk mitotic activity, increased cellularity, nuclear pleomorphism, focal necrosis, loss of papillary architecture, and invasion of neural tissue. Presenting symptoms often are related to cerebrospinal fluid obstruction, such as headache, diplopia, and ataxia. We present a rare case of atypical choroid plexus papilloma in an adult who was treated with single agent chemotherapy. Case Report A 52-year-old woman was referred for chemotherapy of recurrent atypical choroid plexus papilloma. She initially was diagnosed with choroid plexus papilloma and underwent resection. The tumor recurred on multiple occasions and the patient was treated with surgery (three resections) and stereotactic radiosurgery. The last surgery was thirteen years post diagnosis. The pathology result was positive for atypical choroid plexus papilloma (Figure 1). Her last MRI (Figure 2) showed the recurrence of the tumor in the pons area. Due to the location of the tumor, she was not recommended for surgery and referred to medical oncology for systemic chemotherapy. At relapse, the patient complained of headaches and neuropathic pain in the right neck when rotated. She also had right facial nerve palsy with numbness secondary to previous surgeries.

Choroid plexus tumour treatment at Hospital Infantil Niño Jesús in Madrid: Our experience over the last three decades

To review childhood patients with choroid plexus tumors (CPT) who underwent surgery at Hospital Infantil Niño Jesús of Madrid since January 1981 to September 2014. Registered charts were analyzed based on the epidemiology, tumor grade, clinical profile, location, dissemination characteristics, therapy, prognosis and complications. Seventeen childhood patients were recorded with CPT. Cases were distributed so that 9 cases were choroid plexus-papilloma (CPP) (52.9%), 2 cases atypical CPP (11.7%) and 6 cases choroid plexus-carcinoma (CPC) (35.2%). Age at diagnosis was less than 2 years in 14 of the 17 patients (82.3%) and the incidence was higher in males (82.3% of the cases). Gross total resection was performed in 16 patients (94.1%). Adjuvant treatment was used in 6 patients (all this cases with CPC) (35.2%). Two of the 17 patients died (11.7%), showing an incidence density of 0.01 deaths/year. Our case series is consistent with previous published in scientific literature regarding epidemiology, tumor grade, clinical presentation, radiological features and therapeutic approach. Gross total resection is considered the therapeutic gold standard for choroid plexus tumors. Chemotherapy and radiotherapy should be used as adjuvant treatment in CPC and recurrent or remaining atypical CPP.

Choroid plexus carcinoma in children: The Head Start experience

Choroid plexus carcinoma (CPC) is a rare aggressive intracranial neoplasm with a predilection for young children and a historically poor outcome. Currently, no defined optimal therapeutic strategy exists. The Head Start (HS) regimens have included irradiation-avoiding strategies in young children with malignant brain tumors using high dose chemotherapy to improve survival and minimize neurocognitive sequelae. Three sequential HS studies have been conducted from 1991 to 2009. HS treatment strategy has consisted of maximal surgical resection followed by five cycles of intensive induction followed by consolidation myeloablative chemotherapy with autologous hematopoietic stem cell rescue (AuHCR). Irradiation was given following recovery from consolidation based on the patient's age and evidence of residual disease. Twelve children with CPC (median age of 19.5 months) have been treated with HS regimens. Ten patients had >95% resection. Three patients had disseminated disease at diagnosis. Ten patients completed consolidation of whom five are alive, irradiation and disease free at 29, 43, 61, 66 and 89 months from diagnosis. Seven patients experienced tumor recurrence/progression at a median time of 13 months (range 2-43 months). Five patients received irradiation, one for residual disease and four upon progression or recurrence, of whom one is alive at 61 months. The 3- and 5-year progression-free survivals are 58% and 38% and overall survivals 83% and 62% respectively. Late deaths from disease beyond 5 years were also noted. Head Start strategies may produce long-term remission in young children with newly diagnosed CPC with avoidance of cranial irradiation.

Molecular characterization of choroid plexus tumors reveals novel clinically relevant subgroups.

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.

Choroid Plexus Tumors: Experience of 10 Cases with Special References to Adult Cases

Choroid plexus tumors (CPTs) are rare intraventricular neoplasms accounting for about 0.3–0.6% of all intracranial tumors. This retrospective study on CPTs presents clinico-pathological features and management strategies based on a 20-year single-institutional experience. This series included 10 consecutive patients with pathologically proven CPTs; 5 choroid plexus papillomas (CPPs), 3 atypical CPPs (ACPPs), and 2 choroid plexus carcinomas (CPCs). Their clinical, radiological, and histopathological features as well as management including follow-up studies were reviewed. The patients included five males and five females, aging from 0 years to 61 years with median of 28 years. The affected site was lateral ventricle in two adults and fourth ventricle in eight patients; four children and four adults. The most common symptoms were gait disturbance and memory disturbance. All the patients underwent craniotomy with total, subtotal, and partial removals achieved in 50%, 40%, and 10% of the patients, respectively. The occurrence of the high grade subtypes was 50% in both the adult and pediatric groups. The Ki-67/MIB-1 index increased across the three histological subtypes, from CPP to ACPP and then to CPC. Adjuvant therapy was administered in three patients. The two patients (one adult and one child) with CPC died of whole central nervous system dissemination. At a median of 62-month follow-up, the other eight patients were alive, with only one patient having recurrence and reoperation. The results demonstrate that gross total resection is usually curative for CPP and ACPP, and adjuvant chemoradiotherapy would be required for CPC and incompletely resected ACPP.