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Platelet-Derived Growth Factor Receptor Expression and Amplification in Choroid Plexus Carcinomas

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Platelet-Derived Growth Factor Receptor Expression and Amplification in Choroid Plexus Carcinomas Modern Pathology (2008) 21, 265–270 & 2008 USCAP, Inc All rights reserved 0893-3952/08 $30.00 www.modernpathology.org Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas Nina N Nupponen1,*, Janna Paulsson2,*, Astrid Jeibmann3, Brigitte Wrede4, Minna Tanner5, Johannes EA Wolff 6, Werner Paulus3, Arne O¨ stman2 and Martin Hasselblatt3 1Molecular Cancer Biology Program, University of Helsinki, Helsinki, Finland; 2Department of Oncology–Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden; 3Institute of Neuropathology, University Hospital Mu¨nster, Mu¨nster, Germany; 4Department of Pediatric Oncology, University of Regensburg, Regensburg, Germany; 5Department of Oncology, Tampere University Hospital, Tampere, Finland and 6Children’s Cancer Hospital, MD Anderson Cancer Center, Houston, TX, USA Platelet-derived growth factor (PDGF) receptor signaling has been implicated in the development of glial tumors, but not yet been examined in choroid plexus carcinomas, pediatric tumors with dismal prognosis for which novel treatment options would be desirable. Therefore, protein expression of PDGF receptors a and b as well as amplification status of the respective genes, PDGFRA and PDGFRB, were examined in a series of 22 patients harboring choroid plexus carcinoma using immunohistochemistry and chromogenic in situ hybridization (CISH). The majority of choroid plexus carcinomas expressed PDGF receptors with 6 cases (27%) displaying high staining scores for PDGF receptor a and 13 cases (59%) showing high staining scores for PDGF receptor b. Correspondingly, copy-number gains of PDGFRA were observed in 8 cases out of 12 cases available for CISH and 1 case displayed amplification (six or more signals per nucleus). The proportion of choroid plexus carcinomas with amplification of PDGFRB was even higher (5/12 cases). PDGFRB amplification status and PDGF receptor b protein expression scores were significantly correlated (P ¼ 0.01, Spearman). Expression status of PDGF receptor a or PDGF receptor b was not significantly associated with progression- free survival. To conclude, expression and amplification of PDGF receptors, particularly PDGF receptor b, are frequent in choroid plexus carcinomas, providing a first rationale for the development of treatments targeting PDGF receptor signaling in these rare malignant pediatric tumors. Modern Pathology (2008) 21, 265–270; doi:10.1038/modpathol.3800989; published online 21 December 2007 Keywords: pediatric neuro–oncology; PDGFRA; PDGFRB; tyrosine kinase receptors; imatinib mesylate; prognosis Choroid plexus tumors are rare intraventricular necrosis.1,2,4 Surgery remains the therapeutic main- neoplasms that account for only 0.4–0.6% of all stay,3,5 but due to infiltrative growth and high intracranial tumors, but represent up to 13% of vascularity of these tumors, gross total resection brain tumors that occur throughout the first year of often cannot be achieved. Chemotherapy and cranial life.1 In contrast to benign choroid plexus papillo- irradiation do improve survival,6,7 but the latter is mas, choroid plexus carcinomas have a dismal usually not an option in very young children. prognosis2–4 and are characterized histologically by Therefore, development of novel therapeutic ap- frank signs of malignancy, that is, brisk mitotic proaches would be desirable. activity, nuclear pleomorphism, increased cellular Platelet-derived growth factor (PDGF) receptors density, blurring of the papillary growth pattern and are expressed in the developing brain.8,9 PDGFRA null mouse embryos display neural tube defects suggesting that PDGF receptor a signaling is crucial 10 Correspondence: Dr M Hasselblatt, MD, Institute of Neuropatho- for nervous system development. Interestingly, logy, University Hospital Mu¨nster, Domagkstrasse 19, Mu¨ nster PDGF receptor a as well as the structurally related 48129, Germany. receptor subtype PDGF receptor b might play a role E-mail: [email protected] in the development of the choroid plexus in rodents. *These two authors have contributed equally to this work. Received 9 July 2007; revised 24 September 2007; accepted 1 Here, PDGF receptor a has been found to be highly October 2007; published online 21 December 2007 expressed in choroid plexus epithelial cells,8,9 PDGF receptors in choroid plexus carcinomas NN Nupponen et al 266 whereas PDGF receptor b has been described to be rabbit monoclonal, 2 mg/ml (Cell Signaling Techno- expressed in the developing choroid plexus vascu- logy, Danvers, MA, USA)) or anti-PDGF receptor lature.11 a (no. 3164 rabbit polyclonal, 1:50 (Cell Signaling Furthermore, PDGF receptor signaling has been Technology)). After washes in PBT, slides were shown to contribute to multiple tumor-associated incubated with a biotinylated goat anti-rabbit sec- processes as follows: PDGF receptors are involved in ondary antibody (E0432, 1:500 (Dako)) for 45 min different aspects of tumor growth, including auto- at room temperature following incubation with crine stimulation of malignant cells, angiogenesis the ABC kit (SK6100, Vectastain ABC-HRP, Vector and recruitment of tumor stroma12,13 and can be Laboratories, Burlingame, CA, USA) for 45 min after inhibited by protein tyrosine kinase inhibitors such washing in PBT. The signal was developed using the as imatinib mesylate (Glivec). Indeed, early clinical DAB substrate kit, (SK4100, Vector Laboratories) and studies suggest efficacy of imatinib mesylate in sections were counterstained with hematoxylin. combination with hydroxyurea for the treatment of PDGF receptor staining was evaluated semiquanti- gliomas.14,15 Results from pilot trials employing tatively by scoring the percentage of stained cells imatinib mesylate for the treatment of children with (0 (absent), 1 (o10%), 2 (10–50%), 3 (51–80%), solid tumors16 as well as recurrent malignant 4 (81–100%)) as well staining intensity (0 (absent), 1 gliomas17 point toward a favorable safety profile of (weak), 2 (distinct), 3 (strong)). Both scores imatinib mesylate in that age group. were then multiplied to give a maximal staining We therefore investigated protein expression of score of 12. PDGF receptors a and b, as well as amplification status of the respective genes, PDGFRA and PDGFRB, in a large retrospective series of choroid Chromogenic In Situ Hybridization plexus carcinomas. Freshly cut paraffin-sections for chromogenic in situ hybridization (CISH) were available for 12 of the choroid plexus carcinomas. CISH methodology is Materials and methods described elsewhere in detail.21 Briefly, digoxigenin- Patients labeled (DIG-Nick mix Roche, Mannheim, Germany) BAC-probes were used for PDGFRA (a mixture of A total of 22 primary choroid plexus carcinomas clones, IDs RP11-117E8 and RP11-626H4) and for were retrieved from the archives of the Institute of PDGFRB (clone ID RP11-754J8, Invitrogen Ltd, Neuropathology, University Hospital Mu¨ nster. All Paisley, UK). Gene copy numbers were evaluated cases were sporadic. Some of the children had been using a Leica DM2000 (Leica Microsystems GmbH, examined as part of the Socie´te´ Internationale d’ Germany) with  63 and  100 magnification. Oncologie Pe´diatrique choroid plexus tumor study Gained gene copy number (low-level amplification) (CPT-SIOP-2000).18 All cases were reevaluated was defined as 3–5 signals per nucleus. Amplifica- neuropathologically according to the current tion was defined as six or more signals per nucleus. WHO criteria4 including immunohistochemistry for INI119,20 as well as choroid plexus-specific markers.20 Data on tumor location, extent of surgical Statistics resection, adjuvant treatment and postoperative course were compiled by reviewing patient records. Comparison of patient characteristics was carried Moreover, general practitioners, pediatricians and out by Fisher’s exact test or Mann–Whitney U-test. neurosurgeons were contacted to provide follow-up Probabilities of survival were estimated using the information on recurrence and survival. Kaplan–Meier method. The effect of PDGF receptor expression status on the probability of survival was investigated on univariate analysis using Immunohistochemistry the log-rank test. Correlations were tested using the Spearman’s test. All statistical analyses were Sections were deparaffinized, rehydrated and then performed using SPSS version 13.0 (SPSS Inc., washed in distilled H2O. For antigen retrieval, slides Chicago, IL, USA). were microwaved for 2  7 min at 650 W in antigen retrieval buffer, high pH (S3307, Dako, Glostrup, Denmark), for PDGF receptor b, or in 1 mM EDTA pH Results 8 for PDGF receptor a. Sections were then left to cool Patients for at least 30 min before being washed in PBS with 0.1% Tween 20 (PBT). Endogenous peroxidase The median age of the patients was 2 years activity was quenched by incubation in PBT (quartiles: 1–4 years). Even though the vast majority containing 3% H2O2 for 10 min, then was washed of tumors was located supratentorially (95%), gross in PBT for 3  5 min. Slides were blocked in 20% total resection of the tumors could only be achieved goat serum diluted in PBT for 30 min and then in 50% of the children. Further patient character- incubated with anti-PDGF receptor b (no. 3169 istics have been compiled in Table 1. Modern Pathology (2008) 21, 265–270 PDGF receptors in choroid plexus carcinomas NN Nupponen et al 267 Table 1 Patient characteristics of PDGF receptors a or b was not significantly associated with progression-free survival. Because Age
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