Large Cell Neuroblastoma A Distinct Phenotype of Neuroblastoma with Aggressive Clinical Behavior Tama ´ s Torno ´ czky, M.D., Ph.D. 1,2 Endre Ka ´ lma ´ n, M.D. 1 Pa ´ l G. Kajta ´ r, M.D., Ph.D. 3 Tibor Nya ´ ri, Ph.D. 2,4 Andrew D. J. Pearson, M.D., Ph.D. 2 Deborah A. Tweddle, M.D., Ph.D. 2 Julian Board, B.Sc. 5 Hiroyuki Shimada, M.D., Ph.D. 6 1 Department of Pathology, Faculty of Medicine, Medical and Health Sciences Center, University of Pe ´cs, Pe ´ cs, Hungary. 2 Department of Child Health, Sir James Spence Institute of Child Health, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, United Kingdom. 3 Department of Pediatrics, Oncohematology Divi- sion, Faculty of Medicine, Medical and Health Sci- ences Center, University of Pe ´cs, Pe ´ cs, Hungary. 4 Department of Medical Informatics, University of Szeged, Szeged, Hungary. 5 Department of Pathology, Sir James Spence In- stitute of Child Health, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, United Kingdom. 6 Department of Pathology and Laboratory Medi- cine, Childrens Hospital Los Angeles, Los Angeles, California. Supported by the Hungarian Eo ¨ tvo ¨ s Fellowship. The authors thank Professor Alastair Burt (Depart- ment of Pathology, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, United Kingdom) for his help with the current study and Lisa Price and Lorna More (Sir James Spence Institute of Child Health, Royal Victoria Infirmary, University of New- castle, Newcastle upon Tyne, United Kingdom) for their help in collecting the clinical data. Address for reprints: Tama ´ s Torno ´ czky, M.D., Ph.D., Department of Pathology, Faculty of Medicine, Med- ical and Health Sciences Center, University of Pe ´ cs, Pe ´ cs, Hungary, Szigeti u ´ t 12. H-7643; Fax: (011) 36 72 536 281; E-mail: yst@pathology.pote.hu Received July 11, 2003; revision received October 6, 2003; accepted October 13, 2003. BACKGROUND. Among cases of undifferentiated and poorly differentiated tumors in the neuroblastoma (Schwannian stroma–poor) category, the authors histologically identified a group of rare tumors, known as large cell neuroblastomas (LCNs), that are composed of large cells with sharply outlined nuclear membranes and 1– 4 prominent nucleoli. METHODS. Histologic and immunohistochemical features of LCN were characterized. Morphologic characteristics, clinical features, and MYCN status were compared be- tween LCNs and conventional neuroblastomas documented in the files of two Euro- pean centers (the Sir James Spence Institute of Child Health, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, United Kingdom, and the Medical and Health Sciences Center, University of Pe ´cs, Pe ´cs, Hungary). RESULTS. Of 92 peripheral neuroblastic tumors (pNTs; including neuroblastoma [n = 81]; ganglioneuroblastoma, intermixed [n = 6]; and ganglioneuroblastoma, nodular [n = 5]), 7 (7.6%) qualified as LCN. All 7 LCNs were classified as having unfavorable histology (UH) according to the International Neuroblastoma Pathol- ogy Classification. The LCNs were composed of monomorphous undifferentiated neuroblasts and shared certain histologic features, such as a high incidence of high mitosis-karyorrhexis index and a low incidence of calcification, with other neuro- blastomas in the conventional UH (c-UH) group. These features were significantly different from those of neuroblastomas in the conventional favorable histology (c-FH) group. On immunohistochemical analysis, LCN tumor cells were positive for neuron-specific enolase (5 of 5 cases), protein gene product 9.5 (5 of 5 cases), synaptophysin (5 of 5 cases), tyrosine hydroxylase (focally in 3 of 3 cases), and NB84 (3 of 5 cases) and negative for CD99. Patients with LCN and patients with c-UH disease had similar clinical features (diagnosis at age  1 year, often with distant metastasis). The clinical features of these patients also were significantly different from those of patients with c-FH disease. Further analysis demonstrated that the LCN group was significantly different from both the c-UH and c-FH groups with respect to MYCN status (MYCN amplification, 4 of 5 vs. 3 of 17 vs. 8 of 17, respectively; P = 0.023) and survival rate (4-year expected survival, 0% vs. 71% vs. 17%, respectively; P  0.01). CONCLUSIONS. Because of its unique clinicopathologic features, the authors pro- pose that LCN be recognized as a distinct entity within the undifferentiated and poorly differentiated subtypes of the neuroblastoma category. Cancer 2004;100: 390 –7. © 2003 American Cancer Society. KEYWORDS: neuroblastoma, International Neuroblastoma Pathology Classification, large cell, neuroblastic, phenotype, nucleolus, MYCN. I n 1999, the International Neuroblastoma Pathology Committee (INPC), emphasizing the prognostic significance and biologic rele- vance of histopathology, recommended a new classification system for peripheral neuroblastic tumors (pNTs). This system consisted of 390 © 2003 American Cancer Society DOI 10.1002/cncr.20005