High prevalence of osteonecrosis among the hemophagocytic lymphohistiocytosis population: Single institution 10‐year retrospective data review
Authors: Paul Craig, Shelly Marette, Jutta Ellermann, Surbhi Shah, Takashi Takahashi
Journal: American Journal of Hematology (2017)

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder that is characterized by overactive natural-killer and cytotoxic T cells that improperly trigger macrophages and subsequently leads to hemophagocytosis in bone marrow, spleen, liver, and lymph nodes. HLH can be found in primary (familial) or in secondary (acquired) forms. Diagnosis is made by Henter's criteria. Bone marrow biopsy can be used for confirmation of diagnosis, if needed, and demonstrates elevated cellular activity and hemophagocytosis. Treatment for HLH consists of a chemo-immunotherapy regimen of etoposide, dexamethasone, and cyclosporine. Treatment is followed by transplant for patients with familial HLH or patients with secondary HLH who have severe or reactivated disease. To date, osteonecrosis in the setting of HLH is limited to individual case reports.1, 2 Between 2005 and 2015, a total of 30 patients met the HLH diagnosis criteria, but 8 patients were excluded due to lack of cross-sectional imaging. Of the 22 patients with cross-sectional imaging, 10 patients were female and 12 patients were male. Five patients were diagnosed with familial HLH, while the remaining 17 patients fit the category of secondary HLH. The average age of diagnosis of HLH was 20.8 years, range 2 weeks to 74 years. HLH-2004 therapy was started on 18 patients, and all remaining patients received high-dose steroids. A total of 44 post-treatment cross-sectional imaging studies were reviewed by three musculoskeletal radiologists. By independent agreement, osteonecrosis was confirmed by imaging in 5/22 cases (22.72%). This prevalence is similar to other diseases which require high doses of corticosteroids, such as SLE and ALL .3, 4 Average time between diagnosis of HLH and imaging diagnosis of osteonecrosis was 17.6 months, range 8 days to 3.6 years (Table 1). Patients with secondary HLH had imaging evidence of osteonecrosis in 5/17 (29.4%) cases, while familial HLH patients had no imaging evidence of osteonecrosis 0/5 (0%). Of note, 1 patient with familial form HLH had severe compression deformity of the T12 vertebral body; however, no other imaging evidence of osteonecrosis was present in this patient elsewhere, nor signs of intravertebral gas or fluid were evident, which are factors suggestive of osteonecrosis. While there was no statistical difference in the rate of osteonecrosis between primary and secondary HLH using Fisher's test (P = .2899), the complete lack of osteonecrosis in the primary group is notable. This negative finding may be related to the limited sample size. The overall difference in prevalence may be due to the different pathology between familial and secondary osteonecrosis, or could be related to age-related protective factors in the younger patients. In the patients with osteonecrosis, multiple lesions were found, with an average of five lesions per patient (range 2–8; Table 1). By location, the most common site of osteonecrosis was the femoral head (10/26 lesions, n = 5 patients), followed by the distal femur (5/26 lesions, n = 3 patients). By modality, MR was used for the diagnosis of 20 lesions, and CT for the diagnosis of 6 lesions. For patients with multiple imaging modalities, there was no discordance between CT and MR images in the diagnosis of osteonecrosis. Due to lack of specific symptoms, clinical diagnosis of the osteonecrosis is often difficult. All patients in this study presented with pain, and the extent of disease was widely variable per case. Complications of osteonecrosis include fracture and articular surface collapse which can lead to secondary osteoarthritis. Once discovered, therapy such as bisphosphonates or potential surgical intervention could be utilized to prevent these lifelong complications. American College of Radiology (ACR) recommends plain film as the first line of imaging modality for clinically suspected cases of osteonecrosis in the hip. MR is the most sensitive and specific imaging modality in the detection of osteonecrosis, and it plays a crucial role in the diagnosis of osteonecrosis prior to skeletal-related events.5 Given the relatively high prevalence of osteonecrosis in HLH patients, we believe that clinicians should have a low imaging threshold to evaluate for osteonecrosis in order to avoid subsequent complications. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Statistical consultation was provided by Scott Lunos from the Biostatistical Design and Analysis Center, Clinical and Translational Science Institute. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114. No conflict of interest by any of the authors. P.C. analyzed data, performed statistical analyses, interpreted results, and wrote the manuscript; S.M and J.E. interpreted imaging and reviewed the manuscripts; S.S. reviewed the manuscript with particular clinical emphasis/validation; and T.T. designed the study, performed statistical analyses, interpreted imaging, and edited the manuscript.