Diffuse Marrow Changes

Diffuse Marrow Changes Ferco H. Berger, M.D.,1 Cornelis F. van Dijke, M.D., Ph.D.,2 and Mario Maas, M.D., Ph.D.1

Magnetic resonance imaging (MRI) to date remains the only imaging modality allowing direct visualization of the bone marrow compartment, in general having high sensitivity for bone marrow abnormalities. However, signal intensity changes in many different diseases presented with diffuse bone marrow infiltration show more overlap than difference, resulting in poor specificity. Therefore, MRI cannot be applied for initial diagnostic purposes in most diseases but should be reserved for staging, monitoring of therapy, and detection of disease recurrence after treatment. Diffuse infiltrative disease occurring at the hematopoietically active bone marrow, the vertebrae, pelvis, and femora should be areas included in imaging studies at a minimum if whole-body imaging cannot be applied. In this article, in-depth information is provided on selected topics, including Gaucher’s disease, Hodgkin’s disease and non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and changes in bone marrow after different medication strategies, with overviews of the field provided by multiple recent papers in the literature. KEYWORDS: Magnetic resonance imaging, bone marrow, musculoskeletal, imaging

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agnetic resonance imaging (MRI) of diffuse marrow changes has been described extensively in several review articles.1–3 The aim of this article is to go into detail in selected topics (Gaucher’s disease, lymphoma, chronic leukemia, and post-medication changes), enabling the reader more in-depth information. For an overview of the field, additional reading is advisable.1–3 Positron emission tomography with computer tomography (PET-CT) adds functional to structural information but is primarily useful in focal disease, showing focally increased tracer uptake. MRI therefore has been the technique of choice for bone marrow imaging, especially in diffuse disease. In diffuse disease, bone marrow is affected in the regions where it is hematopoietically active. In adults, this means that scanning should include the spine, the pelvis, and the femora.

Because sensitivity of MRI to bone marrow disease is high but specificity is low, MRI does not give definite answers in differential diagnosis and should be used for staging purposes in known disease entities, with diagnosis made from the histology of peripheral blood smears or biopsy. In addition, MRI may be used to select biopsy location or to monitor treatment.

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New Perspectives in Imaging of the Bone Marrow; Guest Editor, Andrea Baur-Melnyk, M.D. Semin Musculoskelet Radiol 2009;13:104–110. Copyright # 2009 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: + 1(212) 584-4662. DOI 10.1055/s-0029-1220881. ISSN 1089-7860.

Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2Department of Radiology, Medical Center Alkmaar, Alkmaar, The Netherlands. Address for correspondence and reprint requests: Mario Maas, M.D., Ph.D., Department of Radiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (e-mail: [email protected]).

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GAUCHER’S DISEASE Gaucher’s disease (GD) is the most common of the lysosomal storage disorders. Affecting both the marrow and mineral compartment, bone disease is the most significant cause of morbidity and long-term disability, afflicting up to 75% of patients. The pathophysiology of GD impacts bone metabolism (turnover, remodeling,

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ABSTRACT

Figure 1 (A, B) Patient with adult type 1 Gaucher’s disease without therapy. There is marked low signal intensity on both T1weighted and T2-weighted images. Note the endplate depression in several vertebrae due to infarction. (C) The same patient, with marked low T1-weighted signal intensity in the femoral diaphysis and metaphysis with relative sparing of the epiphysis. Axial and peripheral marrow show extensive invasion of marrow cavities; however, axial is more invaded than peripheral. This illustrates the need for imaging axial marrow.

and mineralization), architecture, bone density, and bone strength.4 MRI is considered state of the art in assessing bone marrow invasion of GD. The use of MRI in analyzing bone marrow in GD was described as early as 1986.5,6 In general, the normal marrow is replaced by glucocerebroside-loaded macrophages, Gaucher’s cells, leading to a lowering of signal intensities both on T1and T2-weighted images.5,7,8 (Fig. 1A and B). The marked shorter T2 relaxation time and long T1 relaxation time due to fast-exchanging protons in the substrate glycoprotein of has been hypothesized as the most likely cause.6 In GD, both homogeneous and heterogeneous patterns of involvement are encountered.7,9 Marrow involvement generally follows the distribution of red cellular marrow in GD, progressing from axial to peripheral and in a long bone from proximal to distal with a tendency to spare epiphysis and apophysis5,10,11(Fig. 1A and C). Marrow infiltration in GD may remain silent for long periods of time before the appearance of clinically significant bone disease, thus these bones can be considered ‘‘bones at risk.’’ Since the introduction of enzyme replacement therapy more than 15 years ago, MRI has evolved as the modality of choice to monitor bone marrow response to therapy4,12,13 (Fig. 2). The most superior quantitative technique is Dixon’s quantitative chemical shift imaging (QCSI).11,14–18 This highly reproducible technique

measures response in marrow fat fraction (Ff) in the lumbar vertebrae (L3, L4, and L5) within the first year of treatment.16,19 Normalization was established within 4 to 5 years.16,17 Conducted from the measured mean values in the lumbar spine, a normal mean Ff within a healthy adult population of 0.37 (standard deviation, 0.08) was found.19 Various semiquantitative scoring systems have been developed.7–9,20–22 The technique that is advised to assess bone marrow extension in both axial (lumbar spine) and peripheral (femoral) marrow is the bone marrow burden (BMB) score.4,13,23 One must consider that when no response is seen in the peripheral bone marrow, response may very well be present in the axial marrow. BMB correlates with QCSI and shows a high interobserver reliability.4,22 This technique has been used to assess various international populations: European, American, and Australian.23–25 Recommendations of evaluating skeletal manifestations in children with GD recently have been described. It is advised to evaluate GD children in centers with pediatric MR expertise with assessment of femurs, pelvis, and lumbar spine.12

HEMATOLOGICAL MALIGNANCIES Diagnosis of hematological malignancies relies on patient history, physical examination, laboratory studies,

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Figure 2 (A) Patient with adult type 1 Gaucher’s disease without therapy. Sagittal T1-weighted images show diffuse low signal intensity in the entire axial bone marrow when compared with the intervertebral disk. (B) Same patient after enzyme replacement therapy. Marked response is seen with normalization of the signal intensity within some years.

and tissue biopsies. Imaging studies are performed for the purpose of disease staging and depending on institution primarily include chest films, thoracic, abdominal, and pelvic CT, and 18-FDG (fluorodeoxyglucose) PET or PET-CT. Bone marrow imaging is not routinely performed for diagnosis or staging because bone marrow biopsy is still the standard of reference, but it may be indicated if clinical suspicion of bone marrow involvement arises and can be used for prognostic purposes, to guide biopsy, and to monitor treatment. Malignant bone marrow disease can be divided into diseases characterized by proliferation (e.g., multiple myeloma, leukemia, polycythemia vera, and Waldenstro¨ m’s macroglobulinemia), replacement (e.g., metastasis and lymphoma), and depletion (e.g., aplastic anemia and myelodysplastic syndrome). In this article we discuss imaging of bone marrow in lymphoma and chronic leukemia.

LYMPHOMA (REPLACEMENT OF FATTY TISSUE BY CELLULAR TISSUE) Bone marrow infiltration in Hodgkin’s disease (HD) and low-grade and high-grade non-Hodgkin’s lymphomas (NHL) is reported to occur in 5 to 15%, 50 to 80%, and 20 to 40% of patients at time of diagnosis, respectively. Prognosis and treatment may be changed if bone marrow

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involvement is detected, implying stage IV disease by definition.1,26,27 Given the possibility of sampling errors and the invasive character of blind iliac crest biopsies, imaging techniques have been investigated to detect bone marrow infiltration. MRI still is the only imaging technique that allows direct visualization of bone marrow and has high sensitivity for detection of bone marrow disease, except for cases with low disease burden. In a systematic review by Kwee et al, sensitivity of MRI ranged from 50 to 100% for bone marrow involvement in malignant lymphomas, with median sensitivity 100%.26 Specificity and positive and negative predictive value could not be assessed, but specificity of MRI changes on standard sequences is known to be low.1,28 Even though specificity is low, abnormalities detected in femoral MRI have prognostic value. Studies show poorer survival and higher relapse rates in both HD and NHL, even when bone marrow biopsies were negative.29,30 To increase specificity, several MRI sequences have been studied. Both diffusion-weighted imaging and in- and out-of-phase (chemical shift) imaging are able to distinguish hypercellular from normal or hypocellular bone marrow, but they are nonspecific in distinguishing the benign form of malignant hypercellularity, thereby not increasing diagnostic specificity. However, this technique can be used for quantification and may be used for monitoring of therapy.3,31,32 To differentiate benign from malignant marrow infiltration, different contrast agents have been studied, using both normal post-contrast as well as dynamic sequences. Rahmouni et al showed that with dynamic contrast imaging, maximal enhancement, slope, and washout were significantly different in 42 patients with proven marrow infiltration compared with normal subjects and also significantly differed between low- and high-grade disease found on histology.33 Iron-oxideenhanced MRI reliably differentiates neoplastic from benign bone marrow infiltration (tumor recurrence versus hematopoietic reconversion). Short tau inversion recovery sequence images after iron-oxide contrast infusion show a drop in signal intensity if no malignant infiltration is present.34,35 However, validation of this technique for detection of diffuse infiltration at initial staging should still be performed. Although MRI remains the only imaging technique to directly visualize bone marrow, PET and PETCT have been studied for detection of bone marrow involvement in lymphomas, and these techniques are used regularly for total body evaluation of tumor activity by obtaining functional information. In a retrospective study of 172 patients by Elstrom et al, FDG-PET was unreliable for the detection of diffuse bone marrow infiltration in all subtypes of lymphoma studied.36 The usefulness of FDG-PET in staging and detection of bone marrow involvement depends on lymphoma

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CHRONIC LYMPHOBLASTIC LEUKEMIA (PROLIFERATION OF NORMAL MARROW ELEMENTS) Leukemias are a heterogeneous group of hematopoietic malignancies originating from white cell lineage, with chronic lymphoblastic leukemia (CLL) the most common form in North America and Europe.2,43 CLL typically diffusely infiltrates the bone marrow compartment with cells rich in water content. As a result, bone marrow in T1-weighted sequences shows diffusely lowered signal intensity, bone marrow being diffusely hypointense compared with muscle or intervertebral disks, and diffusely increased signal intensity in T2-weighted and fat-suppressed sequences, typically higher than muscle.1–3,28,44 Although highly sensitive for detecting these changes in leukemic bone marrow infiltration, this MRI pattern is poorly specific, leaving the diagnosis of leukemia to peripheral blood smears and bone marrow biopsy. Although to date the clinical role of MRI in CLL has been barely studied,1,44 especially quantitative techniques may prove to be useful in the clinical management of CLL in the future.1,2 As for prognostic purposes, quantitative analysis of T1 relaxation times may be useful to indicate patients with short and long treatment-free survival, with respective abnormal and normal T1 relaxation times.45 However, quantitative MR methods failed to detect CLL marrow infiltration in 41% in another study of the same group,46 necessitating further research on this subject and also for answering the question of whether this technique may be used to assess the status of bone marrow after treatment. Diffusion-weighted imaging and T2-weighted echo planar imaging with segmenta-

tion of bone marrow may provide a method to assess total disease burden prior to therapy and monitor therapy given in leukemia if whole-body imaging is applied, but it needs further investigation.47

Changes in Bone Marrow Due to Medication Knowledge of the normal age-related bone marrow conversion and factors influencing bone marrow conversions or reconversion (e.g., physical status, myeloproliferative disorders, and medical treatment) is essential to differentiate normal cellular marrow from focal or diffuse neoplasmic marrow involvement and to assess treatment effects or tumor recurrence. An ongoing communication between clinician and radiologist regarding prescribed medication is essential. STEROID THERAPY

Steroids in high-dose treatment may induce changes in the bone leading to fat conversion or avascular necrosis (AVN). The magnitude of fat conversion correlates with steroid intake and is higher in patients with ischemic bone lesions.48 AVN is caused by vascular insufficiency, compromised bone marrow perfusion, and finally anoxia and death of bone marrow cells. AVN is a well-known complication in 10% of long-term survivors of bone marrow transplantation receiving high doses of steroids49 and is seen in 1 to 10% of patients in the initial treatment phase of leukemias or lymphomas.50 MRI is very sensitive in depicting AVN.51 CHEMOTHERAPY

Large areas of red marrow can be replaced by fat due to chemotherapy. Chemotherapy in patients with multiple myeloma, for example, cause changes in bone marrow that can be well depicted on MR. The signal intensity changes reflect the vascular and cellular alterations in the composition of the bone marrow. In the first week of therapy, edematous and hypocellular marrow was seen on histological examination.52 The edematous bone marrow shows low signal on T1-weighted images and high signal on fat-saturated T2-weighted images. Because active foci of myeloma, focal necrosis, and inflammation are all high on T2-weighted images, the usefulness of T2-weighted imaging in treatment follow-up is limited. In the second week, multilocular fat cells appear in the marrow followed by unilocular fat cells essential for hematopoietic marrow regeneration.53 The fat cells increase over time, and after 3 to 15 weeks the bone marrow contains more fat compared with age-related healthy individuals. Although evaluation of immunoglobulin production provides an excellent guide to the total multiple myeloma tumor burden response,54 assessment of local response of the nodules is essential because patients may have symptomatic improvement without remission and vice versa. Dynamic contrast-enhanced MRI may help detect active

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subtype.37–39 However, results primarily are positive for focal disease, with all 17 cases of diffuse marrow infiltration proven by biopsy missed by FDG-PET.27 A new PET tracer, 18F-FLT, was able to assess cellularity of bone marrow, distinguishing patients with hypercellular bone marrow (myelodysplastic syndrome and myeloproliferative disorder) and hypocellular bone marrow (myelofibrosis and aplastic anemia) from normal subjects.40 Whether this tracer will be useful in initial diagnosis of bone marrow infiltration of HD and NHL patients remains to be studied. Setting aside diffuse bone marrow infiltration, FDG-PET/CT as a fused modality seems to outperform the individual modalities in staging lymphoma.41 One recent study prospectively compared wholebody MRI (WB-MRI) with PET-CT and bone marrow biopsy for detection of bone marrow infiltration in aggressive lymphoma, finding two patients with focal lesions outside the hematopoietic regions with both WB-MRI and PET-CT, with overall sensitivities similar and higher than bone marrow biopsy.42

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tumor in treated marrow.55 Gadolinium enhancement of >40% or lack of ultrasmall-particle superparamagnetic iron ore uptake may indicate a tumor progression or recurrence.49 After treatment the bone marrow can be returned to normal or residual signal alternations of the bone may remain.55 ANGIOGENESIS-INHIBITING DRUGS

Angiogenesis-inhibiting drugs, increasingly used in oncology, may induce bone marrow alterations. Antiangiogenic drugs (e.g., tumor necrosis factor alpha) are antivascular agents intended to stop new vessel formation and selective destruct tumor vessels. These drugs are in general noncytotoxic. Antiangiogenic drugs can in clinical practice be combined with cytotoxic drugs focused on tumor cells. Bone marrow microvessel density is correlated with decreased survival in myeloma patients and relapse or resistance to chemotherapy in lymphoma. New drugs with antiangiogenic activity, such as bevacizumab that binds and inactivates vascular endothelial growth factor (VEGF) or VEGF-tyrosine kinase inhibitors, have shown promising results in phase 1 trials.56 New macromolecular contrast medium (MMCM) agents can most likely monitor this treatment response in patients. In animal models, MMCM was able to define anti-VEGF effects as early as 1 day after initiation of therapy.57 A reversible asymptomatic metaphyseal bone lesions after treatment with bevacizumab in a child with cutaneovisceral angiomatosis with thrombocytopenia syndrome was reported in 2008 by Smith et al.58 Because of the potential for altered bone growth and metabolism, children receiving VEGF inhibitors should be monitored closely for bony toxicity.58

Bone Marrow Reconversion Due to Growth Factors Administration of hematopoietic growth factors may delay the fatty transformation of bone marrow or may cause reconversion of fatty to hematopoietic marrow. Hematopoietic growth factors can be used for a broad range of malignancies, including primary malignant musculoskeletal tumors59 as well as for stem cell mobilization of healthy donors for allogenic stem cell transplantation.60 The white blood count (WBC) correlates moderately well with red marrow reconversion in patients receiving granulocyte-stimulating factors (GSF) with chemotherapy in musculoskeletal tumors.61 Red marrow conversion in patients receiving granulocyte colony-stimulating factor (G-CSF) has been reported in children and in adults.61–64 Differentiating bone marrow conversion from infiltrating bone tumor can be difficult without the knowledge of the effect of GSF and can mimic an increase in tumor volume or could be mistaken for metastasis.61,64 In patients experiencing red marrow conversion, the sites in which red marrow first

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appears are those areas that last converted to yellow marrow, and this process then proceeds in reverse physiological order.65 Reconversion of the bone marrow due to GSF can be seen on T1-weighted images as a diffuse low signal of the bone marrow and an inhomogeneous increase on fat-suppressed T2-weighted images.28,61 Low T1-weighted intensity in the bones of patients with known musculoskeletal malignancy treated with chemotherapy and GSF is most likely due to red marrow conversion, especially when encountered in the proximal long bones and pelvis and not due to metastasis. In case it remains uncertain whether dealing with conversion or a metastasis ,a follow-up scan after a short interval rather then biopsy is recommended by Hartman et al,61 especially in a primary area of expected conversion and a corresponding WBC response. To summarize, although MRI lacks specificity in diffuse marrow disorders, it is the imaging modality of choice for staging and detecting response to therapy.

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