Patients with less than completely resected CPC should receive chemotherapy.

Atypical choroid plexus papilloma (APP) represents a novel intermediate-grade subtype of choroid plexus tumor (CPT), the clinical outcome of which has not been described yet. We present the first analysis of a group of APP patients enrolled in the ongoing CPT-SIOP-2000 study of CPTs. A worldwide registration and a randomized trial for those patients who require chemotherapy started in 2000. For APP, maximal surgical resection was recommended. After surgery, patients who had undergone complete resection were observed, whereas patients with incompletely resected or metastasized APP were treated with six chemotherapy courses (etoposide and vincristine, combined with either carboplatin or cyclophosphamide). Risk-adapted radiotherapy was given only to patients older than 3 years of age. Of the 106 patients with a centrally confirmed CPT histology, 30 had APP, 42 CPP and 34 CPC. APP patients were significantly younger (median = 0.7 years) than patients with CPP or CPC (both medians = 2.3 years). Complete resection was achieved in 68 (64%) patients (79% in CPP, 63% in APP, and 47% in CPC). Metastases were present at diagnosis in 17% of APP patients, 5% of CPP patients, and 21% of CPC patients. All nine APP patients who received postoperative chemotherapy showed an early response after two cycles: two had complete remission, four had partial response, and three had stable disease. In the observation group of 15 patients, one event was seen, and all patients were alive. In the treatment group, one patient with a metastasized tumor and incompletely resected APP died. While APP was defined histologically, median percentages of both the Ki-67/MIB-1 proliferation marker and the p53 tumor suppressor protein increased across the three histological subtypes (from CPP to APP and then CPC), suggesting that the subtypes comprise an ordinal categorization of increasingly severe CPT tumors. This ordering was reiterated by clinical outcome in the 92 patients treated per the study protocol, with 5-year EFS rates of 92% in 39 CPP patients, 83% in 24 APP patients, and 28% in 29 CPC patients. A similar ordering was seen when all 106 patients were evaluated for EFS. APP responded favorably to chemotherapy. The intermediate position of APP between CPP and CPC was supported by the clinical data.

The prognostic significance of atypical histologic features in choroid plexus tumors remains uncertain. Therefore, a series of 164 choroid plexus tumors was evaluated for the presence of atypical histologic features, including mitotic activity, increased cellularity, nuclear pleomorphism, blurring of papillary growth pattern, and necrosis. The impact of histopathologic and clinical features on the probability of recurrence and survival was investigated. Twenty-four tumors displaying frank signs of malignancy were diagnosed as choroid plexus carcinoma according to World Health Organization criteria. Of 124 choroid plexus papillomas that had not received adjuvant treatment, 46 tumors (37%) displayed at least one atypical feature, including increased cellularity (n = 25 [20%]), mitotic activity (> or =2 mitoses per 10 high-power fields; n = 19 [15%]), nuclear pleomorphism (n = 16 [13%]), solid growth (n = 15 [12%]), and necrosis (n = 5 [4%]). Only one tumor-related death, but 10 recurrences, were observed on a mean observation time of 58 months. On univariate analysis, incomplete surgical resection (p = 0.03) and mitotic activity (p < 0.001) were the only clinicopathologic factors associated with recurrence. Using a multivariate model, an independent effect of mitotic activity on the probability of recurrence could be confirmed (p = 0.001). Because mitotic activity is the sole atypical histologic feature independently associated with recurrence, we propose to define atypical choroid plexus papilloma by mitotic activity (> or =2 mitoses per 10 high-power fields) corresponding to World Health Organization grade II, thus adjoining other intermediate tumor entities associated with increased mitotic activity such as atypical meningioma. Close follow up of patients harboring atypical choroid plexus papillomas may be warranted.

Atypical teratoid/rhabdoid tumors are malignant embryonal tumors characterized by the presence of rhabdoid cells, genetic alterations affecting the SMARCB1 gene (hSNF5/INI1), and a poor prognosis. Whether INI1 plays a role in the pathogenesis of other central nervous system tumors is uncertain. We report on cases of 2 young children with unusual intracranial nonrhabdoid neuroectodermal tumors within and around the third or fourth ventricle that are characterized by cribriform strands and trabeculae and well-defined epithelial membrane antigen-immunopositive surfaces and show INI1 protein loss. Histological and immunohistochemical features did not correspond to established tumor types, including atypical teratoid/rhabdoid tumors, medulloepithelioma, choroid plexus carcinoma, and ependymoma. Fluorescence in situ hybridization analyses failed to identify chromosomal alterations affecting the SMARCB1 locus, but sequencing revealed a homozygous 4-bp duplication in exon 4 (492duplCCTT) in one of the tumors. Both children responded well to conventional adjuvant therapy protocols and are alive and in complete remission longer than 5 years postoperatively. We suggest that cribriform neuroepithelial tumor (CRINET) is a nonrhabdoid ventricular tumor that shows loss of tumoral INI1 protein and has a relatively favorable prognosis.

The pathogenesis of choroid plexus papillomas, intraventricular papillary neoplasms most often occurring sporadically in children and young adults, remains poorly understood. To identify pathways operative in the development of choroid plexus papillomas, gene expression profiles obtained from laser-microdissected human choroid plexus papilloma cells (n = 7) were compared with that of normal choroid plexus epithelial cells laser microdissected from autopsy tissue (n = 8). On DNA microarray data analysis, 53 probe sets were differentially expressed in choroid plexus papilloma tumor cells (>7-fold). Up-regulation of TWIST1, WIF1, TRPM3, BCLAF1, and AJAP1, as well as down-regulation of IL6ST was confirmed using quantitative reverse transcription-PCR. Knockdown of Twist1 gene expression in the rat choroid plexus epithelial cell line Z310 significantly reduced proliferation as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and cell invasion in a Matrigel assay, whereas cell migration was not affected. Screening for expressional changes of cancer-related genes upon Twist1 knockdown revealed up-regulation of Cdkn1a, Cflar, and Serpinb2 and down-regulation of Figf. To conclude, using gene expression profiling, several genes differentially expressed in human choroid plexus papillomas could be identified. Among those, TWIST1 is highly expressed in choroid plexus papillomas and promotes proliferation and invasion.