Skeletal Manifestations of Systemic Disease

Physiology.

On gross examination, bone marrow may be red because of hemoglobin in the erythrocytes and their precursors, indicating active hematopoietic marrow, or it may be yellow due to the presence of carotenoid derivatives dissolved in fat droplets within adipocytes. Hematopoietic marrow is rich in vascular sinusoids, whereas fatty marrow is considerably less vascular. During periods of decreased hematopoiesis, the fat cells increase in size and number. During periods of increased hematopoiesis, the fat cells atrophy.

The cellularity of bone marrow diminishes most rapidly in the first two decades of life. The cellularity of hematopoietic marrow is near l00% at birth and decreases to between 50% and 75% by 15 years of age. By adulthood, hematopoietic marrow is composed of approximately 40% fat, 40% water, and 20% protein, with 60% of cells being hematopoietic and 40% being adipocytes. In contrast, fatty marrow is composed of 80% fat, 15% water, and 5% protein, with 95% of cells being adipocytes ( e-Fig. 141.1 ).

Imaging.

Conventional radiography, computed tomography, and ultrasonography are of limited value in the assessment of bone marrow. Since the first reports of magnetic resonance imaging (MRI) of the marrow in children were published in 1984, MRI has emerged as the primary imaging modality to evaluate the bone marrow. It provides a noninvasive method for visualizing the gross anatomic structure of a large sample of the bone marrow and for inferring alterations in its chemical and cellular composition related to a variety of physiologic and pathologic processes. Furthermore, MRI can provide valuable information about regions of the bone marrow that may be inaccessible or difficult to biopsy.

The constituents of bone marrow that contribute to the signal characteristics on MRI are fat, water, and, to a lesser extent, mineralized matrix. Fat is the dominant contributor to both hematopoietic and fatty marrow signal intensity patterns. Most fat protons are in hydrophobic methylene (−CH ₂ −) groups of relatively heavy molecular complexes, conferring very efficient spin-lattice relaxation; this results in a short T1 relaxation time, which results in high signal intensity on T1-weighted sequences. The T2 relaxation time of fat is much shorter than that of free water protons, and water contributes much more to the signal intensity of hematopoietic marrow than fatty marrow. The mineralized matrix of bone has a low density of hydrogen protons that lack mobility within the crystalline structure of bone, accounting for very long T1 and short T2 relaxation times and low signal intensity of mineralized matrix on T1- and T2-weighted sequences. In addition, local field gradients at the trabecular surface are generated by the fixed dipole from the immobile protons and cause magnetic field inhomogeneity. This magnetic susceptibility effect, as well as that resulting from iron deposition, can play a large role in the signal characteristics of hematopoietic and fatty marrow on gradient echo (GRE) images.

The normal intervertebral disks, skeletal muscle, and subcutaneous fat have little interindividual and intraindividual signal intensity variation on T1-weighted sequences during childhood and consequently serve as convenient internal reference standards for comparison with bone marrow. Fatty marrow has high signal intensity on conventional spin echo T1-weighted sequences. The relative amounts of fat, water, and protein contribute in a complex fashion to produce a longer T1 relaxation time in hematopoietic marrow, with signal intensity that ranges from intermediate to low (less than that of muscle or intervertebral disks) in fat-poor hematopoietic marrow to intermediate-high (greater than that of muscle or the intervertebral disks but less than that of subcutaneous fat) in hematopoietic marrow with larger proportions of fat. In neonates, hematopoietic marrow contains minimal fat and has low signal intensity on T1-weighted sequences. With aging, hematopoietic marrow signal intensity progressively increases on T1-weighted sequences, reflecting a progressive increase in fat content. After the neonatal period, hematopoietic marrow has signal intensity equal to or slightly greater than muscle and the intervertebral disks but much less than subcutaneous fat on T1-weighted sequences, whereas fatty marrow approaches the signal intensity of subcutaneous fat on T1-weighted sequences. Because of the similar proton densities of hematopoietic and fatty marrow, proton density sequences without fat suppression are less useful than T1-weighted sequences.

On fat-suppressed fast spin echo (FSE) T2-weighted and short-tau inversion recovery (STIR) sequences, normal hematopoietic marrow in childhood shows higher signal intensity than fatty marrow and higher signal intensity than muscle; the signal intensity of hematopoietic marrow decreases with age and approaches that of muscle by adolescence.

The degree of contrast enhancement of normal marrow varies with the contrast dose, timing of image acquisition following contrast administration, age of the patient, and composition of the marrow. Marrow enhancement peaks within a minute of contrast administration and then slowly declines. Enhancement is greater in children than in adults, greater in the metaphyses than in the epiphyses, and greater in hematopoietic marrow than in fatty marrow. Enhancement can be imperceptible by visual inspection in the marrow of adults and in the marrow of the epiphyses in patients aged more than 2 years. The variation between individuals in the degree of enhancement is also substantial. If gadolinium-enhanced T1-weighted sequences are acquired without fat suppression, contrast between hematopoietic and fatty marrow is decreased, which potentially obscures marrow lesions or age-related marrow conversion changes. Image-subtraction and fat-suppression techniques facilitate the detection of abnormal marrow enhancement on postcontrast T1-weighted sequences.

A combination of T1-weighted and fat-suppressed FSE T2-weighted or STIR sequences is sufficient for the detection and characterization of most marrow lesions. Contrast-enhanced T1-weighted sequences increase the cost and duration of the MRI examination while providing only modest incremental added sensitivity; because of this, they should be reserved for cases with unclear findings on the precontrast sequences. GRE sequences are valuable for the assessment of the iron content of the marrow, and chemical-shift techniques are useful to detect subtle changes in the fat and water fractions of the marrow.

Practical time constraints initially limited MRI scanning of the marrow to only sections of the skeleton. This disadvantage has been mitigated by the development of fast, whole-body MRI scanning techniques that include FSE and single-shot sequences, parallel imaging, rolling table platforms with a large field of view, and global matrix coil concepts. Obscuration of lesions by motion artifact may be overcome to some extent by the use of respiratory triggering or other motion-suppression techniques. The lower signal-to-noise ratios in smaller children on whole-body MRI exams can be ameliorated by using magnetic resonance (MR) systems with a higher field strength.

Diffusion-weighted whole-body MRI holds particular promise as a technique to globally assess bone marrow for hematologic disorders and tumor metastases. A positive correlation exists between the degree of marrow cellularity and the marrow apparent diffusion coefficient (ADC). Hematopoietic marrow or marrow infiltrated by neoplastic cells has more abundant microvasculature and more intracellular and interstitial free water than fatty marrow, and it exhibits higher ADC values.

Motion and susceptibility artifacts are especially problematic in diffusion-weighting imaging (DWI) of the marrow, which is contained by bone and in proximity to physiologic motions, such as cerebrospinal fluid pulsations in the case of the spine. Recent advances have largely overcome these technological challenges, and diffusion-weighted whole-body MRI is being used to evaluate an increasing number of benign and malignant conditions that include chronic recurrent multifocal osteomyelitis, Langerhans cell histiocytosis, and bony metastases.

Physiology.

Hematopoiesis occurs in the yolk sac in the early stages of fetal development; later in gestation it shifts to the liver and to a lesser extent the spleen. Bone marrow begins hematopoiesis in the fourth intrauterine month, overtakes the liver in this function by the sixth month, and is entirely responsible for hematopoietic cell production by birth. Shortly before birth, conversion from hematopoietic to fatty marrow begins in the distal phalanges of the hands and feet and proceeds in a centripetal fashion from the distal to the more proximal portions of the appendicular skeleton. Within the long bones, conversion from hematopoietic to fatty marrow proceeds from the mid diaphyses to the distal metaphyses and then to the proximal metaphyses. Conversion also progresses from the central medullary canal to the endosteum. Fatty transformation in the epiphyses and apophyses begins almost as soon as they begin to ossify. In infants, the skull and limbs contain about half of the total amount of hematopoietic marrow. By early adulthood, hematopoietic marrow becomes confined to the vertebrae, sternum, ribs, pelvis, skull, proximal humeri, and proximal femurs. Approximately half of the bone marrow volume is fatty marrow in early adulthood and is located in the appendicular skeleton. The involution of hematopoietic marrow continues throughout adult life, although at a slower pace than during childhood. Unlike skeletal maturation, there are generally no gender differences in the rate of marrow conversion during childhood. Knowledge of the normal age-related changes in the distribution of hematopoietic and fatty marrow is necessary for the recognition of abnormal conversion and reconversion patterns and for the detection of marrow infiltration by other pathologic processes.

Imaging.

Conversion from hematopoietic to fatty marrow is readily detected by MRI because of the high sensitivity of T1-weighted spin echo sequences to fat ( e-Table 141.1 ). In fact, marrow conversion is observed earlier by MRI than by gross pathologic inspection because of the capability of MRI to detect microscopic fat present in marrow. Numerous publications detail the temporal and spatial sequence of marrow conversion revealed by MRI. Although there are discrepancies among these publications in the precise ages of transformation, the sequence of conversion is consistent along the long axes of individual bones and in the skeleton as a whole. Conversion occurs at a faster pace in the appendicular skeleton (extremities, shoulders, and pelvic girdle) than in the axial skeleton (skull, spine, ribs, and sternum).

Overview.

Reconversion is a process by which established fatty marrow is replaced by hyperplastic hematopoietic marrow in response to conditions that create a demand for increased hematopoiesis. In children, reconversion is commonly encountered in patients with chronic anemia—such as from sickle cell disease, thalassemia, and spherocytosis—and in those administered hematopoietic growth factors, such as G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin.

Etiology, Pathophysiology, and Clinical Presentation.

The stimulus for increased oxygen-carrying capacity of the blood in cyanotic congenital heart disease patients, endurance athletes, heavy smokers, and high-altitude dwellers also induces hematopoietic marrow hyperplasia and reconversion. Because marrow conversion is a process that occurs throughout childhood, some of what is construed as reconversion in children actually represents an arrest or delay in conversion from hematopoietic to fatty marrow and is attributable to increased hematopoietic demands ( e-Fig. 141.9 ).

Reconversion occurs in the reverse order of normal marrow conversion, beginning in the axial skeleton and proceeding sequentially to the proximal metaphyses, distal metaphyses, and diaphyses of the long bones of the appendicular skeleton. The more distal long bones are the last to undergo this process. The epiphyses are usually spared but can undergo reconversion in response to very high hematopoietic demands.

Imaging.

On MRI, reconverted marrow follows the signal intensity of hematopoietic marrow and tends to involve the appendicular skeleton in a symmetric fashion. The reconverted hematopoietic marrow may be distributed in either a homogeneous or patchy pattern and may have an appearance overlapping with that of pathologic processes, such as leukemia and storage disorders. Although MRI is very sensitive to changes in marrow fat content, disease specificity is low. Also, some of the conditions that exhibit marrow reconversion have additional superimposed marrow processes that complicate MRI interpretation, such as transfusion hemosiderosis in thalassemia and marrow infarction and fibrosis in sickle cell disease. Positron-emission tomography (PET) with 18-fluorodeoxyglucose (FDG) is also sensitive to marrow conversion and may reveal increased FDG uptake in areas of marrow hyperplasia because of the metabolic demands of increased hematopoiesis.

Etiology, Pathophysiology, and Clinical Presentation.

Thalassemia is an inherited hemoglobinopathy characterized by ineffective erythropoiesis, intramedullary hemolysis, and anemia. With effective transfusion therapy, hematopoietic to fatty marrow conversion may proceed in the extremities by puberty. However, hematopoietic marrow hyperplasia in the skull, spine, and pelvis can remain pronounced. The paranasal sinuses often fail to develop, in part as a result of abrogation of the normal fatty conversion of marrow that precedes sinus pneumatization.

Thalassemia patients are at increased risk of pathologic fractures from osteopenia, arthralgias that are believed to result from iron overload or the use of chelation therapy, and back pain from scoliosis and early intervertebral disk degeneration.

Imaging.

The radiographic changes of thalassemia are due to chronic hematopoietic marrow hyperplasia. These include diffuse osteopenia, undertubulization of bone, premature physeal fusion, “hair-on-end” appearance of the calvarium with widening of the diploic space ( Fig. 141.10 ), decreased pneumatization of the paranasal sinuses, coarse trabeculation of appendicular bones, expansion of costochondral junctions, scoliosis, and soft tissue masses related to extramedullary hematopoiesis.

The appearance of the bone marrow on MRI is a reflection of the diffuse erythroid marrow hyperplasia, chronic transfusions, and iron chelation therapy. Iron deposition in the marrow results in lowered signal intensity on T1-, T2-, and especially T2*-weighted sequences because of T2 relaxation-time shortening and magnetic susceptibility effects. Excess iron deposition can even be identified by MRI in some patients whose chelation is thought to be clinically adequate on the basis of serum ferritin levels, and the degree of iron deposition in bone marrow and other organs can be quantified by R2 relaxometry with MRI. In severe cases of thalassemia, bone marrow transplantation may be pursued as a potentially curative treatment, and MRI can reveal the consequent degree of marrow conversion. FDG-PET in patients with thalassemia shows diffuse increased marrow uptake.

Treatment.

Transfusion therapy suppresses the marrow hyperplasia of thalassemia but at the cost of iron overload. The iron deposition occurs preferentially in areas of hematopoietic marrow and is reduced by chelation therapy.