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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1525-1531 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.9947 Femoral Head Osteonecrosis in Pediatric and Young Adult Patients With Leukemia or Lymphoma
From the Departments of Radiological Sciences, Division of Diagnostic Imaging and Biostatistics, International Outreach Program, Division of Orthopedics, and Department of Hematology-Oncology, St Jude Children's Research Hospital; and the Department of Radiology, University of Tennessee School of Medicine, Memphis, TN Address reprint requests to Sue C. Kaste, DO, Division of Diagnostic Imaging, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: sue.kaste{at}stjude.org
Purpose: Osteonecrosis of the capital femoral epiphysis is a significant late toxicity of treatment for childhood leukemia and lymphoma. We determined clinical and imaging risk factors predicting clinical joint outcomes of femoral head osteonecrosis in pediatric patients with leukemia or lymphoma. Patients and Methods: We reviewed retrospectively medical records and magnetic resonance imaging scans of 80 patients with osteonecrosis of the capital femoral epiphysis. Logistic regression was used to examine relationships between risk factors and outcomes of joint surface collapse and arthroplasty. We used Kaplan-Meier survival curves to display the time to joint surface collapse and arthroplasty based on selected predictors. Results: Median time between primary diagnosis and diagnosis of osteonecrosis of the hip was 1.7 years (range, 0.1 to 17.5 years). Twenty-three patients (29%) underwent arthroplasty in 36 hips at a mean of 1.3 years (range, 0.5 to 8.6 years) after diagnosis of osteonecrosis. Median age at time of first arthroplasty was 20.1 years (range, 15.1 to 35.4 years). Joint outcome of osteonecrosis was predicted solely by lesion size at diagnosis of osteonecrosis. The worst prognosis was associated with lesions occupying more than 30% of the femoral head volume; 80% of hips with these lesions collapsed within 2 years of diagnosis and 50% required arthroplasty. Conclusion: Lesion size of osteonecrosis is the best predictor of clinical joint outcome of hip osteonecrosis in survivors of pediatric hematologic malignancy. Lesions occupying more than 30% of the femoral head have high likelihood of joint deterioration necessitating arthroplasty at a young age.
Osteonecrosis in patients treated for pediatric hematologic malignancy has been attributed to increasingly intensive corticosteroid therapy.1 Event-free survival in patients with leukemia has improved steadily1-3 but at the cost of increased toxicity, including musculoskeletal toxicities.4-9 Hence, attainment of high survival rates has heightened concern about the quality of the survivors’ lives related to long-term complications of therapy. Of these complications, osteonecrosis (ON) of the weight-bearing joints has been identified as one of the most severe for survivors of pediatric leukemia and lymphoma,1,4-7,9,10 affecting as many as one third of patients with acute lymphoblastic leukemia,9 and is associated with development of articular surface collapse and subsequent debilitating arthritis, potentially requiring arthroplasty.8,11 ON also has been reported in patients who have undergone hematopoietic stem-cell transplantation (SCT), and has been linked to corticosteroid use to control graft-versus-host disease.12,13 Among pediatric recipients of allogeneic stem-cell transplants, the prevalence of ON has been reported to be 15.2% to 44.2%.10,14
Several risk factors have been identified for the development of ON in children with hematologic cancers: age
Between January 1, 1990, and December 1, 2003, ON of the capital femoral epiphysis was diagnosed in 85 patients at St Jude Children's Research Hospital (Memphis, TN) who had a primary diagnosis of a hematologic malignancy. We included in our study only the 80 patients for whom follow-up magnetic resonance (MR) scans or radiographs of the 143 involved hips were available.
Diagnosis
Orthopedic Treatment
Corticosteroids We abstracted information regarding patients’ medical treatment and demographic information from the medical records, and reviewed the MR and radiographic images of the hip joints. The Institutional Committee on Human Research approved the study. Data capture and storage adhered to the Health Information Portability and Accountability Act of 1996.
ON Classification ON of the hip was stratified according to the stage at the initial imaging study demonstrating the condition. Because a subchondral fracture and/or collapse of the femoral head (Figs 1A and 1B) represent a crucial phase in the natural history of ON, two major groups were defined: pre- and postcollapse of the articular surface. ON of the hip that presented before the collapse of the articular surfaces was divided into subgroups based on lesion size, using two approaches. In the first approach, the extent of involvement was described as a percentage of the femoral head volume occupied by the osteonecrotic lesion according to the system of Steinberg et al18: mild (< 15% of the femoral head affected), moderate (15% to 30% of the femoral head affected), and severe (> 30% of the femoral head affected). The volume of osteonecrotic lesions on MR images was quantified by the method of Hernigou et al19 (Fig 2), by using a public domain image processing and analysis software program (National Institutes of Health ImageJ for Windows20). In the second approach, precollapse lesions were also described by using the classification introduced by Sugano et al21: the size of an ON lesion of the femoral head is estimated in relation to the weight-bearing portion of the acetabulum (Fig 3). 21 Type A lesions are less than the medial one third of the weight-bearing portion of the acetabulum; type B lesions are less than the medial two thirds of the weight-bearing portion, and type C lesions are more than two thirds of the weight-bearing portion. This grading system does not involve precise measurement of the lesions or image-processing software; therefore, it can be applied easily during clinical image review.
The status of the physis (open or closed) and whether the ON lesion extended to the articular surface of the femoral head were also documented.
MR Imaging
Joint Outcomes
Risk Factors
Data Analysis
Of 80 patients, 43 were female and 66 were white. Sixty-three patients had bilateral involvement of the femoral head, and 17 patients had unilateral involvement. The median age at diagnosis of leukemia or lymphoma was 14.6 years (range, 2.0 to 20.4 years). Malignancies included acute lymphoblastic leukemia (ALL; n = 61), non-Hodgkin's lymphoma (n = 8), chronic myelogenous leukemia (n = 5), Hodgkin's disease (n = 5), and acute myeloid leukemia (n = 1). The median period between the primary diagnosis and diagnosis of ON of the hip was 1.7 years (range, 0.1 to 17.5 years). ON was diagnosed in one patient 29 days after the start of his treatment for ALL. However, during the 5 months before leukemia diagnosis, he had received corticosteroid treatment for bone pain believed to have been caused by rheumatoid arthritis. The median period of follow-up for each involved hip was 40.6 months (range, 1.3 to 175 months). Twenty-three patients required arthroplasty of 36 hips. The median age at first hip arthroplasty was 20.1 years (range, 15.1 to 35.4 years). The median time between primary oncologic diagnosis and first arthroplasty was 3.6 years (range, 1.7 to 18.1 years). Median time between diagnosis of ON and first hip arthroplasty was 1.3 years (range, 0.5 to 8.5 years). We evaluated host-, ON-, and intervention-related risk factors in relation to the radiologic and clinical joint outcomes. Several risk factors were associated with complications of ON (surface collapse and arthroplasty) in the univariable analysis (Table 1); however, in the multivariable analysis (Table 2), the size of osteonecrotic lesion was the only risk factor that remained significant.
Risk Factors for Joint Collapse (radiologic outcome) Factors associated with joint collapse included large femoral head lesion size (more than 30% of femoral head volume or type C according to the method of Sugano et al21; Table 1; Fig 4A), involvement of the articular surface, and previous core decompression. Only large femoral head lesion size achieved independent significance in the multivariable analysis.
Risk Factors for the Need for Arthroplasty (clinical outcome) Factors associated with the need for arthroplasty included non-ALL diagnosis, age  11 years, large lesion size (> 30% of femoral head volume or type C, Table 1; Fig 4B), ON of the opposite hip, and closed physis. Only large femoral head lesion size achieved independent significance in multivariable analysis.
This is the first long-term follow-up study to investigate the radiologic and clinical joint outcomes of ON of the capital femoral epiphysis among pediatric patients with hematologic malignancies. In our study, ON of the capital femoral epiphysis led to significant morbidity, with 29% of patients needing arthroplasty at a median of 1.3 years after diagnosis of ON. Overall, 36 of 143 hips (25%) diagnosed with ON of the capital femoral epiphysis eventually required replacement with an artificial joint. We evaluated many potential risk factors for progression of ON, defined as articular surface collapse or the need of arthroplasty. Similar to the adult experience, we found lesion size to be a strong predictor of joint outcome. Hips with lesions occupying 30% or more of the femoral head volume or type C lesions of by the method of Sugano et al21 had higher rates of joint collapse and need for arthroplasty. A simple grading system of clinical imaging by Sugano et al,21 which requires only that lesion size be estimated in relation to the weight-bearing portion of the acetabulum, is predictive of subsequent articular surface collapse, with type C lesions at the highest risk. We did not find a relationship between patient's sex, race, weight, previous SCT, cumulative dose of prednisone equivalents, and radiologic or clinical joint outcomes. Skeletal maturity (closure of physes) and older age were associated with a higher rate of arthroplasty but not with articular surface collapse in univariable analyses, possibly indicating a hesitance to perform arthroplasty on younger patients. Thirty-five core decompressions were performed, primarily in patients who were already predisposed to adverse joint outcome, having had a collapsed articular surface (six hips) or a lesion of the largest size category at diagnosis (15 hips). The effect of core decompression in relieving the acute pain associated with ON was not assessed in this study. We did not observe any evidence that surgical core decompression or lower dose of corticosteroids prevented or delayed joint surface collapse or arthroplasty. However, because of the retrospective nature of our study and our moderate sample size, we cannot determine definitively the role of core decompression or cessation of glucocorticoid therapy in preventing or slowing progression of joint destruction. A controlled, randomized, prospective study would be better suited for evaluation of these possible relationships. However, our findings demonstrate that when the patient has a large osteonecrotic lesion (eg, > 30% of femoral head volume), the chances of subsequent collapse and following arthroplasty are high, and it is unlikely that cessation of corticosteroids would prevent imminent collapse. Therefore, regarding the poor prognosis for the femoral head with a large (> 30% volume) osteonecrotic lesion, it seems reasonable to continue potentially life-saving antileukemic corticosteroid treatment as needed per protocol to ensure the highest chances for patient survival. However, due to frequent multiple-site involvement (not necessarily simultaneous) in a patient with corticosteroid-induced ON, there is always a possibility that continuous treatment with corticosteroids will cause more lesions. Corticosteroids are the major component of modern chemotherapy for pediatric leukemia and lymphoma,22 for which there is no effective alternative at present. Widespread application of corticosteroid-based chemotherapy dramatically improved hematologic cancer survival rates in pediatric patients (currently > 80% for ALL compared with 4% in 1960s),2,23 but resulted in numerous incidents of severe joint deterioration.1,4,24 The association of core decompression with a higher rate of joint surface collapse found in the univariable analysis most likely resulted from selection bias of patients for this intervention. It is likely that core decompression was offered and performed in patients who were perceived to be at greater risk of progression and complications of ON. In any case, this association was not confirmed in the multivariable analysis. The high rate of articular surface collapse and artificial joint placement that we found emphasizes the serious prognosis that ON of the capital femoral epiphysis carries in a child receiving treatment for a hematologic malignancy. Degenerative joint changes leading to the need for a joint replacement are especially devastating in a young person, due to higher rate of postoperative complications, expected arthroplasty revisions associated with longer life span, and more strenuous activity levels in younger patients that may compromise the artificial joint.25 An additional factor compromising quality of life is the fact that corticosteroid-induced ON frequently has multijoint involvement and degenerative changes with subsequent joint replacements may involve more than one joint. The high rate of complications of ON reported here might be explained in part by the strict diagnostic criteria: we only included patients who demonstrated geographic areas of decreased signal on T1-weighted images and increased signal on STIR images in the capital femoral epiphysis. We did not evaluate patients with ON outside of the capital femoral epiphysis or patients with bone marrow edema, which sometimes is reported with ON in pediatric patients with hematologic malignancies. In addition, 29 hips in this study already had collapse of the articular surface at the time of diagnosis of ON, which predisposed them to the subsequent need for arthroplasty. Joint outcomes of ON of the femoral head in patients with pediatric hematologic malignancy seem to depend solely on the size of the osteonecrotic lesion at diagnosis of ON. Associated with the worst prognosis are the lesions occupying more than 30% of the femoral head volume; 80% of hips with these lesions collapsed within 2 years of diagnosis and 50% required arthroplasty. Therefore, future research should focus on prevention of ON and on identifying factors that predispose patients to development of ON that affects a large portion of the femoral head.
The authors indicated no potential conflicts of interest.
Conception and design: Evguenia J. Karimova, Shesh N. Rai, Scott C. Howard, Michael Neel, Lunetha Britton, Ching-Hon Pui, Sue C. Kaste Provision of study materials or patients: Michael D. Neel, Ching-Hon Pui, Sue C. Kaste Collection and assembly of data: Evguenia J. Karimova, Shesh N. Rai, Scott C. Howard, Michael Neel, Lunetha Britton, Ching-Hon Pui, Sue C. Kaste Data analysis and interpretation: Evguenia J. Karimova, Shesh N. Rai, Scott C. Howard, Michael Neel, Lunetha Britton, Ching-Hon Pui, Sue C. Kaste Manuscript writing: Evguenia J. Karimova, Shesh N. Rai, Scott C. Howard, Michael Neel, Lunetha Britton, Ching-Hon Pui, Sue C. Kaste Final approval of manuscript: Evguenia J. Karimova, Shesh N. Rai, Scott C. Howard, Michael Neel, Lunetha Britton, Ching-Hon Pui, Sue C. Kaste
Supported by Grants No. RO1-CA600419 and P30-CA21765 from the National Institutes of Health and by the American Cancer Society and the American Lebanese Syrian Associated Charities. C.-H.P. is the American Cancer Society F.M. Kirby Clinical Research Professor. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
inversion recovery (STIR) images (TR/TE, 3,550/28 msec), and sagittal fast low-angle shot two-dimensional images (TR/TE, 588/10.5 msec). All MR imaging was performed by using one of following Siemens 1.5 T scanners: Helicon, Vision, or Symphony (Siemens, Erlangen, Germany) with a torso-phased array coil. ON was confirmed as a geographic area of decreased signal on T1-weighted images and increased signal on STIR images. 
20 years, sex-specific BMI-for-age percentiles were used: normal (BMI-for-age < 85th percentile), overweight (BMI-for-age 85th percentile to < 95th percentile), or obese (BMI-for-age 
level of .05 to be statistically significant. The median values were used as cutoff points for stratification of cumulative doses of prednisone equivalents. Risk factors significant at the level of .1 in univariable analysis were included in multivariable analysis. Before we decided on the final model for the multivariable analysis, variables not significant in the univariable model were also included with and without interaction (one variable and its interaction at a time), given that some of them could be multivariably significant. For selected predictors, Kaplan-Meier survival curves were used to display the time to the two outcomes. Statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC) and S-PLUS version 6.2 (Statistical Sciences, Seattle, WA) software. 
