Rosdali Y Diaz Coronado1,2, Martin Mynarek3, Christian Koelsche4, Pamela Mora Alferez5, Sandro Casavilca Zambrano6, Antonio Wachtel Aptowitzer7, Felix Sahm8,9, Andreas von Deimling8,9, Ulrich Schüller3,10,11, Michael Spohn10,12, Dominik Sturm13,14,15, Stefan M Pfister13,14,16, Andres Morales La Madrid17, Raymundo Sernaque Quintana18, Gustavo Sarria Bardales2,19, Tatiana Negreiros Chinchihuara19, Luis Ojeda Medina20, Pamela Garcia-Corrochano Medina20, Danny A Campos Sanchez21, Jimena Ponce Farfan7, Stefan Rutkowski3, Juan L Garcia Leon1,2,7. 1. Pediatric Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru. 2. Delgado Clinic, Auna, Lima, Peru. 3. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4. Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 5. Genetics Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru. 6. Pathology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru. 7. Pediatric Oncology Service, Anglo Americana Clinic, Lima, Peru. 8. Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 9. Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany. 10. Research Institute Children's Cancer Center, Hamburg, Germany. 11. Institute of Neuropathology, University Medical Center Hamburg Eppendorf, Hamburg, Germany. 12. Bioinformatics Core Facility and Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 13. University Medical Center, Heidelberg, Germany. 14. Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany. 15. Pediatric Glioma Research Group, German Cancer Research Center, Heidelberg, Germany. 16. Division of Pediatric Neurooncology, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany. 17. Pediatric Oncology Department, Neuro Oncology Unit, Hospital San Joan De Deu, Barcelona, Spain. 18. Radiology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru. 19. Radiotherapy Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru. 20. Neurosurgery Department, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru. 21. Neurosurgery Service, Anglo Americana Clinic, Lima, Peru.
Abstract
BACKGROUND: A high frequency of primary central nervous system (CNS) sarcomas was observed in Peru. This article describes the clinical characteristics, biological characteristics, and outcome of 70 pediatric patients. METHODS: Data from 70 pediatric patients with primary CNS sarcomas diagnosed between January 2005 and June 2018 were analyzed. DNA methylation profiling from 28 tumors and gene panel sequencing from 27 tumors were available. RESULTS: The median age of the patients was 6 years (range, 2-17.5 years), and 66 of 70 patients had supratentorial tumors. DNA methylation profiling classified 28 of 28 tumors as primary CNS sarcoma, DICER1 mutant. DICER1 mutations were found in 26 of 27 cases, TP53 mutations were found in 22 of 27 cases, and RAS-pathway gene mutations (NF1, KRAS, and NRAS) were found in 19 of 27 tumors, all of which were somatic (germline control available in 19 cases). The estimated incidence in Peru was 0.19 cases per 100,000 children (<18 years old) per year, which is significantly higher than the estimated incidence in Germany (0.007 cases per 100,000 children [<18 years] per year; P < .001). Patients with nonmetastatic disease (n = 46) that were treated with a combination therapy had a 2-year progression-free survival (PFS) rate of 58% (95% CI, 44%-76%) and a 2-year overall survival rate of 71% (95% CI, 57%-87%). PFS was the highest in patients treated with chemotherapy with ifosfamide, carboplatin, and etoposide (ICE) after upfront surgery followed by radiotherapy and ICE (2-year PFS, 79% [59%-100%], n = 18). CONCLUSIONS: Primary CNS sarcoma with DICER1 mutation has an aggressive clinical course. A combination of surgery, chemotherapy, and radiotherapy seems beneficial. An underlying cancer predisposition syndrome explaining the increased incidence in Peruvian patients has not been identified so far. LAY SUMMARY: A high incidence of primary pediatric central nervous system sarcomas in the Peruvian population is described. Using sequencing technologies and DNA methylation profiling, it is confirmed that these tumors molecularly belong to the recently proposed entity "primary central nervous system sarcomas, DICER1 mutant." Unexpectedly, DICER1 mutations as well as all other defining tumor mutations (TP53 mutations and RAS-pathway mutations) were not inherited in all 19 patients where analyzation was possible. These tumors have an aggressive clinical course. Multimodal combination therapy based on surgery, ifosfamide, carboplatin, and etoposide chemotherapy, and local radiotherapy leads to superior outcomes.
BACKGROUND: A high frequency of primary central nervous system (CNS) sarcomas was observed in Peru. This article describes the clinical characteristics, biological characteristics, and outcome of 70 pediatric patients. METHODS: Data from 70 pediatric patients with primary CNS sarcomas diagnosed between January 2005 and June 2018 were analyzed. DNA methylation profiling from 28 tumors and gene panel sequencing from 27 tumors were available. RESULTS: The median age of the patients was 6 years (range, 2-17.5 years), and 66 of 70 patients had supratentorial tumors. DNA methylation profiling classified 28 of 28 tumors as primary CNS sarcoma, DICER1 mutant. DICER1 mutations were found in 26 of 27 cases, TP53 mutations were found in 22 of 27 cases, and RAS-pathway gene mutations (NF1, KRAS, and NRAS) were found in 19 of 27 tumors, all of which were somatic (germline control available in 19 cases). The estimated incidence in Peru was 0.19 cases per 100,000 children (<18 years old) per year, which is significantly higher than the estimated incidence in Germany (0.007 cases per 100,000 children [<18 years] per year; P < .001). Patients with nonmetastatic disease (n = 46) that were treated with a combination therapy had a 2-year progression-free survival (PFS) rate of 58% (95% CI, 44%-76%) and a 2-year overall survival rate of 71% (95% CI, 57%-87%). PFS was the highest in patients treated with chemotherapy with ifosfamide, carboplatin, and etoposide (ICE) after upfront surgery followed by radiotherapy and ICE (2-year PFS, 79% [59%-100%], n = 18). CONCLUSIONS: Primary CNS sarcoma with DICER1 mutation has an aggressive clinical course. A combination of surgery, chemotherapy, and radiotherapy seems beneficial. An underlying cancer predisposition syndrome explaining the increased incidence in Peruvian patients has not been identified so far. LAY SUMMARY: A high incidence of primary pediatric central nervous system sarcomas in the Peruvian population is described. Using sequencing technologies and DNA methylation profiling, it is confirmed that these tumors molecularly belong to the recently proposed entity "primary central nervous system sarcomas, DICER1 mutant." Unexpectedly, DICER1 mutations as well as all other defining tumor mutations (TP53 mutations and RAS-pathway mutations) were not inherited in all 19 patients where analyzation was possible. These tumors have an aggressive clinical course. Multimodal combination therapy based on surgery, ifosfamide, carboplatin, and etoposide chemotherapy, and local radiotherapy leads to superior outcomes.
Authors: Kevin X Liu; Helen H Shang; Chantel Cacciotti; Emily Everdell; Ayal A Aizer; Rifaquat Rahman; Seth Malinowski; David M Meredith; Junne Kamihara; Patrick Y Wen; Keith L Ligon; Susan N Chi; Karen J Marcus; Kee Kiat Yeo; Sanda Alexandrescu; Daphne A Haas-Kogan Journal: J Neurooncol Date: 2022-04-06 Impact factor: 4.130