Risk factors for inadequate bone marrow biopsies in children
Authors: Robert C. Grant, Furqan Shaikh, Mohamed Abdelhaleem, Sarah W. Alexander, Michaela Cada
Journal: American Journal of Hematology (2015)

Bone marrow biopsies are necessary to diagnose various diseases of the bone marrow and to stage malignancies 1. Although performing bone marrow biopsies rarely causes serious adverse events, the number of inadequate-for-interpretation biopsies should be minimized because the need for repeat testing causes a delay in making a diagnosis, causes unnecessary patient discomfort, and consumes healthcare resources. In the pediatric population, the risk factors for an inadequate bone marrow biopsy are unclear. Adult guidelines recommend that bone marrow biopsy cores be at least 1.5–2 cm in length in order to ensure that they are interpretable 2, 3. This may not apply to children because their bone marrow compositions differ from those of adults, and obtaining long cores may be difficult in smaller pelvises. To date, only a single group focusing on patients with neuroblastoma has studied the adequacy of bone marrow biopsies in the pediatric population 4, 5. In their studies, an inadequate biopsy was defined as a specimen with less than 0.5 cm of bone marrow and no obvious tumor, but no justification for this cut-off was provided 4. Subsequently, guidelines 1, 2 and study protocols 6 directed toward the general pediatric population have recommended that bone marrow biopsy cores be at least 0.5 cm in length without clear evidence for this recommendation. In addition, there are no studies in the adult or pediatric literature that analyze in a systematic way what other factors, if any, in addition to biopsy core length affect interpretability. We retrospectively collected data on all bone marrow biopsies performed at the Hospital for Sick Children in Toronto from July 1, 2006 to June 30, 2011 to assess inadequate bone marrow biopsies in a general pediatric patient population. Our primary outcome was inadequate biopsies, defined as biopsies without an interpretation provided in the “final diagnosis” section of the pathology report due to sample quality. We chose this primary outcome for its clinical relevance because, in practice, clinical decisions are made based on the adequacy of bone marrow biopsies as determined by the judgment of individual pathologists. In addition, there are no other evidence-supported measurable criteria of adequacy for interpretation of bone marrow biopsies in the literature. Univariate logistic regressions were performed to assess associations between biopsy characteristics and inadequate biopsies. Statistical significance was tested using likelihood ratios. Biopsy characteristics with a P < 0.2 in univariate regressions were entered into a multivariate logistic regression. Our institutional research ethics board approved this study. A total of 1,413 biopsies were performed on 977 patients (Table 1). Overall, 12.2% of biopsies were inadequate to reach a pathological diagnosis. Of these, 56.4% were due to insufficient marrow, 9.7% due to aspiration artifact, and the rest were due to both of these causes. Many of the characteristics had associations with inadequate biopsies in univariate models, but only the length of the longest core and which pathologist interpreted the biopsy were significantly associated with inadequate biopsies in the multivariate analysis. Length of the longest core had a strong association with biopsy adequacy. 35.7% of biopsies with the longest core measuring <0.5 cm were inadequate, compared with 17.5% of biopsies with the longest core measuring 0.5–0.9 cm, and 4.9% of biopsies with the longest core measuring 1 cm or longer. Only 0.9% of biopsies with specimens 1.5 cm or longer were inadequate. The proportion of biopsies with a core at least 1 cm in length increased with the number of cores (50.9, 56.1, 61.6, and 67.5% of biopsies with 1, 2, 3, and over 3 cores taken at one time, respectively). Biopsies 1 cm or longer were frequently achieved, even in children under 2 years of age, albeit at a lower rate; 30.2% of biopsies in children younger than 2 years of age contained a core 1 cm or longer, compared with 60.1% in older children. Which pathologist interpreted the biopsy was associated with biopsy adequacy, even after adjusting for other potential confounders, including length. The proportion of all biopsies interpreted as inadequate by the three pathologists were 9.3%, 7.5%, and 20.1%. Our findings question the current guidelines that pediatric bone marrow biopsies should contain a core of at least 0.5 cm in length 1, 2, 6. Indeed, bone marrow biopsies without a core longer than 0.5 cm had an unacceptably high probability of being inadequate in our study. In fact, the rate of inadequate biopsies for interpretation remained high until the length of the longest core was at least 1 cm. Inadequate biopsies decreased drastically when cores exceeded 1.5 cm, which corresponds to the guidelines for adult bone marrow biopsies 2, 3. Although obtaining a longer biopsy means achieving a higher probability of interpretability, longer is not always possible in pediatric patients because of patient size limitations. Moreover, the length required for an adequate sample may depend on the clinical setting. Regardless, our study demonstrates that the currently recommended length of 0.5 cm yields an unacceptable number of uninterpretable samples, and clinicians should aim to achieve a longer specimen. Based on our data, a target of 1 cm may achieve a balance between feasibility and adequacy. We observed significant interpathologist variation in the proportion of biopsies that were interpreted as inadequate. These differences could not be accounted for by observed biopsy characteristics. There are no established criteria for classifying biopsies as adequate or inadequate; thus, pathologists may each have their own unique notion of what constitutes an adequate biopsy. This is understandable considering the limited available evidence. However, interpathologist variability is important to understand because misclassifying an adequate biopsy as inadequate may result in unnecessarily repeated procedures; conversely, misclassifying an inadequate biopsy as adequate may result in incorrect diagnoses. Further research is needed to determine what factors truly contribute to biopsy adequacy. In conclusion, we recommend that every attempt should be made to obtain a core bone marrow biopsy of at least 1 cm in length in the pediatric population to reduce the rate of inadequate biopsies. We also recommend that standardized evidence-based criteria are developed to determine what constitutes an adequate pediatric bone marrow biopsy to reduce interpathologist variability. R.C.G., F.S., M.A., S.W.A., and M.C. designed the research. R.C.G. collected and analyzed the data, and wrote the manuscript. R.C.G., F.S., M.A., S.W.A., and M.C. reviewed and edited the manuscript. Robert C. Grant1, Furqan Shaikh2, Mohamed Abdelhaleem3, Sarah W. Alexander2, Michaela Cada2* 1Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 2Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; 3Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada