BACKGROUND: The quantitative assessment of neuroblastoma cell content in bone marrow aspirates for response evaluation has been introduced recently. Data on the concordance of interobserver reports are lacking so far. METHODS: Investigators of seven European countries representing national reference or large oncological centers convened in 2016. They agreed to quantitatively assess routine bone marrow smears of the participating institutions and to discuss the discrepant results in joint meetings. RESULTS: From 2017 through 2019, three cytology rounds with 24, 28, and 28 bone marrow samples were run evaluating the representativity of the smears (yes/[restricted]/no) and the presence of tumor cells (yes/no and %). The comparison of the reports using κ (Fleiss) and α (Krippendorff) statistics demonstrated no robust reliabilities. The agreement on the representativity was moderate to poor, on the presence of tumor cells moderate to good, and on the percentage of tumor cells slight to moderate. Though the value of cytology is unquestioned to detect even tiny metastatic cells in bone marrow, the investigators unanimously agreed that a reliable quantification of the tumor cell content in bone marrow smears is unrealistic. For the key issue of representativity, a new practical definition was developed. CONCLUSION: For any work with bone marrow aspirates, the representativity of the material is of paramount importance. A practical definition is proposed. A reliable quantitative cytological assessment of tumor cell content in bone marrow aspirates is not feasible in metastatic neuroblastoma. Therefore, its use as response criterion should be reconsidered.

Centro de Investigación Biomédica en Red de Cáncer CIBERONC Instituto de Salud Carlos 3 Madrid Spain

Department of Haematology and Oncology Cytomorphology Laboratory IRCCS G Gaslini Institute Genoa Italy

Department of Hematology Cytomorphology Laboratory Diagnosis Unit La Fe University and Polytechnic Hospital Valencia Spain

Department of Paediatric Haematology University Hospital Brno Brno Czech Republic

Department of Paediatric Oncology Haematology The Royal Marsden NHS Foundation Trust Sutton Surrey UK

Department of Pediatric Oncology and Hematology National Neuroblastoma Reference Cytology Lab University of Cologne Cologne Germany

Diagnostisch Laboratorium Prinses Maxima Centrum Utrecht The Netherlands

Faculty of Medicine and University Hospital Cologne Institute of Medical Statistics and Computational Biology University of Cologne Cologne Germany

La Fe Health Research Institute Hematology Research Group Valencia Spain

Service de Pathologie Pôle de médicine diagnosique et théranostic Institut Curie Paris France

Pediatr Blood Cancer. 2021 Aug;68(8):e28999. doi: 10.1002/pbc.28999. PubMed

Zobrazit více v PubMed

Cohn SL, Pearson AD, London WB, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27(2):289-297.

Berthold F, Spix C, Kaatsch P, Lampert F. Incidence, survival, and treatment of localized and metastatic neuroblastoma in Germany 1979-2015. Paediatr Drugs. 2017;19(6):577-593.

Park JR, Bagatell R, Cohn SL, et al. Revisions to the international neuroblastoma response criteria: a consensus statement from the National Cancer Institute clinical trials planning meeting. J Clin Oncol. 2017;35(22):2580-2587.

Burchill SA, Beiske K, Shimada H, et al. Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone Marrow Working Group. Cancer. 2017;123(7):1095-1105.

Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11(8):1466-1477.

Beiske K, Burchill SA, Cheung IY, et al. Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. Br J Cancer. 2009;100(10):1627-1637.

Fleiss JL. Measuring nominal scale agreement among many raters. Psychol Bull. 1971;76(5):378-382.

Krippendorff K. Reliabilty in content analysis: some common misconceptions and recommemdations. Hum Commun Res. 2004;30(3):411-433.

Lewandowski K, Kowalik MM, Pawlaczyk R, Rogowski J, Hellmann A. Microscopic examination of bone marrow aspirate in healthy adults - comparison of two techniques of slide preparation. Int J Lab Hematol. 2012;34(3):254-261.

Bain BJ. Bone marrow aspiration. J Clin Pathol. 2001;54(9):657-663.

Craig FE. Bone marrow evaluation in pediatric patients. Semin Diagn Pathol. 2003;20(3):237-246.

Lee SH, Erber WN, Porwit A, Tomonaga M, Peterson LC, International Council for Standardization In Hematology. ICSH guidelines for the standardization of bone marrow specimens and reports. Int J Lab Hematol. 2008;30(5):349-364.

Pasquale D, Chikkappa G. Comparative evaluation of bone marrow aspirate particle smears, biopsy imprints, and biopsy sections. Am J Hematol. 1986;22(4):381-389.

Swerts K, Ambros PF, Brouzes C, et al. Standardization of the immunocytochemical detection of neuroblastoma cells in bone marrow. J Histochem Cytochem. 2005;53(12):1433-1440.

Ambros PF, Ambros IM, Brodeur GM, et al. International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer. 2009;100(9):1471-1482.

Corrias MV, Faulkner LB, Pistorio A, et al. Detection of neuroblastoma cells in bone marrow and peripheral blood by different techniques: accuracy and relationship with clinical features of patients. Clin Cancer Res. 2004;10(23):7978-7985.

Van Paemel R, Vlug R, De Preter K, et al. The pitfalls and promise of liquid biopsies for diagnosing and treating solid tumors in children: a review. Eur J Pediatr. 2020;179(2):191-202.

National Cancer Institute (US). Neuroblastoma Treatment (Physician Data Query): Health Professional Version. PDQ Cancer Information Summaries. Bethesda, MD: National Cancer Institute; 2020.