Magnetic resonance imaging of bone marrow in oncology, Part 2
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Magnetic resonance imaging plays an integral role in the detection and characterization of marrow lesions, planning for biopsy or surgery, and post-treatment follow-up. To evaluate findings in bone marrow on MR imaging, it is essential to understand the normal composition and distribution of bone marrow and the changes in marrow that occur with age, as well as the basis for the MR signals from marrow and the factors that affect those signals; these points have been reviewed and illustrated in part 1 of this two-part article. Part 2 will emphasize the practical application of MR imaging to facilitate differentiation of normal marrow, tumor, and treatment-related marrow changes in oncology patients, and will review complementary MR techniques under development.
KeywordsMagnetic resonance imaging Marrow Metastases Tumor Sarcoma Treatment effects
Tumor in marrow
Malignant tumors in marrow can arise from the myeloid elements of marrow (resulting in leukemia, lymphoma, myeloma), from the mesenchymal elements of marrow (resulting in primary sarcoma of bone), or from hematogenous metastases to marrow. Tumor can also reach the marrow by direct extension from a location outside the bone. Tumors occur more commonly in red marrow because of its richer vascularity than that of yellow marrow.
In leukemia, the infiltration of bone marrow typically is diffuse, resulting in a diffuse decrease in marrow signal intensity on T1-weighted images. However, very early in the disease, tumor cells may not completely replace fat cells in marrow and thus the resultant marrow signals can be normal on T1- and T2-weighted spin echo (SE) images. In multiple myeloma, the amount of marrow fat can even increase initially because the tumor cells produce biochemical factors that inhibit hematopoiesis . When more extensive, lymphoproliferative tumors in marrow are low in signal intensity on T1-weighted SE images and high in signal intensity on T2-weighted SE images.
Bone marrow necrosis (BMN) is an unusual entity that has been reported to occur in close association with malignancy, particularly acute lymphocytic leukemia. BMN is characterized by a loss of myeloid tissue and marrow fat without trabecular destruction, unlike avascular necrosis . Despite its relative rarity (0.3–0.4% of marrow biopsies) [3, 4], it is important to recognize the close association between BMN and malignancy. In a study of 240 patients with BMN, Janssens et al.  reported that 91% of patients were found to have malignancy, with acute lymphocytic leukemia representing 18% of the cases. BMN may be found at the time of cancer diagnosis or later in its course. MR imaging findings of BMN are similar to those of avascular necrosis (AVN), although BMN tends to be more diffuse, involving the axial skeleton without vertebral collapse; AVN, in contrast, involves periarticular locations and may progress to vertebral fracture .
Bone marrow metastases are more commonly seen in red marrow but can be present anywhere that marrow exists. The MRI appearances of metastases vary depending on the balance between the tumor and the response of the host bone; metastases can be osteolytic, osteoblastic or mixed. When osteolytic, metastases are usually well circumscribed with low signal intensity on T1-weighted images and moderately high signal intensity on T2-weighted images. In osteoblastic metastases, such as those from breast and prostate carcinomas, metastases may show low signal intensity on both T1- and T2-weighted images because relatively less tumor is present between the sclerotic trabeculae (which themselves lack MR signal).
During and after treatment for tumors in marrow, the affected marrow undergoes substantial changes in its chemical and cellular composition [18, 19, 20]. Because MRI is sensitive and noninvasive in detecting changes in the composition of marrow, MRI findings have been extensively investigated to assess for early and late treatment-related changes and for the presence of residual tumor.
Changes in marrow signal due to radiation therapy
On both MRI and histopathologic evaluation, acute and chronic changes induced by radiation treatment (RT) have been well described [21, 22, 23, 24]. In the acute phase, cellular depletion, marrow edema, vascular congestion, and hemorrhage ensue during the first hours and days. Within 1–2 weeks, the observed increase in MR signal intensity in T2-weighted and STIR images is thought to represent a reduction in cellularity and an increase in fat and marrow edema [22, 24]. An increase in MR signal on STIR images can be observed as early as 8 days after initiation of RT .
The temporal evolution of MR signal changes in an individual patient depends upon several factors. In a study of 48 patients who underwent RT, Sacks et al.  reported that the two most important factors affecting the ability of marrow to regenerate are patient age and radiation dose. They found that younger patients had superior marrow recovery, with full marrow regeneration occurring in patients under 18 years of age, independent of radiation dose. Also, the capacity to regenerate marrow treated with a dose greater than 40 Gy was less than in marrow treated with a lower dose. Most regeneration occurred within 12 months of RT .
Although lesser and smaller, changes in MR signal are also observed in bone marrow located outside the radiation portal of the spine; the etiology of such changes remains unclear [22, 25]. Contrast enhancement of marrow both inside and outside the radiation portal decreases significantly with time; it has been speculated that this decrease in enhancement represents reductions in cellularity and vascularity, and an increase in fatty marrow in response to RT .
Radiation treatment-induced complications in the marrow include osteonecrosis, AVN, fractures, and radiation-induced neoplasm, and depend on factors such as radiation dose, patient age, size of the radiation field, and beam energy . Cell death and devascularization of bone occur after doses exceeding 5,000 cGy ; these events impair hematopoietic regeneration and normal bone formation. Osteonecrosis/AVN is localized within the radiation portal and usually is diagnosed years after RT; typical locations include the mandible, clavicle, humeral head, rib, and femur. On MRI, the presence of high signal intensity inside a low-intensity peripheral rim on T2-weighted images (the “double line” sign) is specific for the diagnosis of AVN .
Radiation treatment-induced bone tumors can be benign or malignant. The prevalence of (benign) osteochondroma after RT in patients with unfused physes has been reported to be 12% at 8 years—a prevalence incidence higher than in spontaneous osteochondroma (1%) . An RT-induced sarcoma of bone is rather rare, constituting less than 1.5% of all bone sarcomas . By definition, the sarcoma must be histologically distinct from the original treated lesion, and occur within the irradiated field, typically after a long latent period . Although the lowest dose required to induce a sarcoma is not established, studies have suggested that there is an association between the radiation dose and subsequent risk of sarcoma. In a study of 16 patients after RT for Ewing sarcoma, Kuttesch et al.  reported that no secondary sarcoma was observed if the radiation dose was less than 48 Gy; excess risk of a secondary sarcoma was associated with radiation doses greater than 60 Gy, confirming the findings of previous studies. High-grade osteosarcoma, fibrosarcoma and malignant fibrous histiocytoma are the most common histologic types of radiation-induced sarcomas. The mean latency period ranges from 14 to 17 years (although some have occurred as soon as 3 years after RT), and the tumors are usually radioresistant [32, 35]. RT-induced sarcomas were initially considered to have a grave prognosis compared with primary bone sarcoma, but subsequent studies have shown that aggressive treatment with chemotherapy and surgical resection improves the prognosis of RT-induced sarcomas, resulting in more than a 60% 5-year survival rate—approaching that of a primary bone sarcoma (50–80% 5-year survival rate) [33, 35].
Changes in marrow signal due to chemotherapy
Upon initiation of chemotherapy, marrow signal becomes hypointense on T1-weighted images and hyperintense in fat-suppressed T2-weighted and STIR images, reflecting marrow congestion . About 3–4 weeks into chemotherapy, reconversion from fatty marrow to hematopoietic marrow can occur, and is readily recognized as it usually occurs in the reverse sequence of marrow conversion, both bilaterally and symmetrically. After chemotherapy, depletion of hematopoietic marrow may result in a predominantly fatty marrow [18, 36].
Bisphosphonates (BP) are osteoclast inhibitors that can be used for the treatment of bone loss and bone pain in metastatic disease and multiple myeloma. Cases of osteonecrosis of the jaw in patients treated with BP have been recently and increasingly reported, strongly suggesting a causal link . Osteonecrosis of the jaw is usually painful and preceded by a dental procedure in 60% of cases. Oversuppression of bone turnover and antiangiogenic effects of BP are considered to be contributing factors [39, 40].
Complementary MR techniques under development
In order to increase the specificity and accuracy of MRI in the clinical setting, different MR techniques have been investigated, mainly focusing on the quantitative assessment of a variety of parameters. Techniques that have been evaluated include quantitative T1 relaxation time measurement, diffusion-weighted echo-planar imaging (EPI), chemical shift imaging, and dynamic contrast enhancement [47, 48, 49, 50, 51, 52, 53]. Although still in a relatively early stage of development, these techniques have shown the potential to complement conventional MRI. For example, in quantitative analyses of T1 relaxation time in leukemia by Vande Berg et al. , a decrease in T1 values in acute lymphocytic leukemia showed a correlation with therapy response (a mean 50% decrease in T1 values in patients with a response, versus a mean 18.7% decrease in patients without a response), whereas T1 values in acute myeloid leukemia did not. However, in a study of quantitative MRI using T1 relaxation times, Lecouvet et al.  reported that MRI failed to detect leukemic marrow infiltration in 41% of patients with chronic lymphocytic leukemia.
In a study of lymphoma involving iliac bone marrow by Yasumoto et al. , the sensitivity and specificity of diffusion-weighted EPI imaging (77% and 97%, respectively) were statistically similar to those of fast SE STIR imaging (85% and 97% respectively). T1-weighted imaging had higher sensitivity (92%) but lower specificity (77%) than diffusion-weighted EPI . The EPI technique is limited by poor spatial resolution and by susceptibility and chemical shift effects . Quantitative chemical-shift imaging enables the quantitative assessment of fat content in bone marrow, thus allowing for noninvasive monitoring of temporal changes in marrow composition [48, 53]. In a study of 11 patients with acute leukemia by Gerard et al. , sequential increases in fat fraction were correlated with the estimated fat fraction on biopsy, which reflects clinical remission; however, the baseline fat fraction and the increases in fat fraction were variable across individuals.
For more than a decade, a potential role for dynamic contrast-enhanced MRI has been explored in the assessment of the percentage of necrosis present within a bone tumor after treatment. This research is motivated by the finding that the percentage of necrosis following neoadjuvant chemotherapy portends patient prognosis in osteogenic sarcoma [54, 55]. In a study of 50 cases of osteogenic sarcoma and Ewing sarcoma by Dyke et al. , quantitative estimates of tumor necrosis obtained using dynamic contrast-enhanced MRI were shown to be strongly correlated with the percentage of necrosis determined by pathologic evaluation (using the Huvos grading system), particularly in making the clinically relevant distinction between those tumors that are less or more than 90% necrotic. These findings suggest that dynamic MRI could be valuable for noninvasively assessing treatment response during neoadjuvant therapy, potentially allowing a change to be made in that therapy for those patients whose response is poor. Currently, the software used for data analysis is developed at each institution that performs necrosis studies; until some such proprietary software is made commercially available, the utility of this technique will be limited.
Recent advances in MR technology have made whole-body MRI (WBMRI) possible in a single session. For example, the introduction of a rolling-table platform with integrated surface coils has eliminated previously time-consuming changes in position of both patient and coils, and sequences such as breath-hold gradient echo and whole-body turbo STIR have substantially shortened scan time—in some cases to a total scan time of less than 15 min—while also providing good spatial resolution [56, 57, 58]. Given its high sensitivity in the detection of marrow lesions and excellent soft tissue contrast, WBMRI is under investigation as a screening and staging modality in oncology patients [56, 57, 58, 59, 60, 61]. For example, WBMRI appears to be both more sensitive and specific than radiographic skeletal survey in assessing the extent of multiple myeloma, which is critical in determining the appropriate therapy [58, 59]. In a study of 51 patients, Lauenstein et al.  compared WBMRI with CT, conventional dedicated MRI, and bone scanning; they found that WBMRI was more sensitive than those conventional modalities in detection of hepatic and osseous metastases. WBMRI and CT showed hepatic metastases in 18 and 16 patients, respectively, whereas WBMRI and bone scanning showed osseous metastases in 24 and 21 patients, respectively. They also found that WBMRI and conventional modalities possess specific advantages in different anatomic regions; for example, WBMRI detected more osseous metastases in the spine and pelvis, whereas bone scanning detected more metastases in the skull and ribs. In a study of 129 patients, Ghanem et al.  reported an 81% concordance between WBMRI and bone scanning; among 24 discordant cases, WBMRI detected osseous metastases in 15 cases that bone scanning did not. Given the ongoing development of faster and more efficient scanning techniques, the clinical utility of WBMRI is likely to increase in the future.
Magnetic resonance imaging is an excellent noninvasive modality for evaluating bone marrow and detecting marrow lesions, as it provides information at the level of cellular and chemical composition, in addition to gross morphologic data. Knowledge of normal marrow components and composition and their variation, as well as of factors that alter MR signal intensity, is important for optimal interpretation of MR images. The signal intensity, morphology, and location of marrow findings on MRI can be used to provide more accurate diagnoses, to guide treatment, and to follow therapy-related changes. Various MRI techniques are available to accentuate the different chemical and cellular compositions of normal marrow and marrow diseases. Although MRI is more sensitive than specific in detecting marrow changes, integrating all the clinical and radiologic data can result in more useful interpretations. Recognition of post-treatment effects, such as those associated with RT and granulocyte-colony-stimulating factors, are important for proper interpretation of MRI. In an attempt to overcome the current limitations of MRI, several newer techniques are under investigation that could increase the ability of MRI to provide even more clinically relevant information about marrow in oncology patients.
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