Imaging review of lipomatous musculoskeletal lesions

Lipomatous lesions are common musculoskeletal lesions that can arise within the soft tissues, bone, neurovascular structures, and synovium. The majority of these lesions are benign, and many of the benign lesions can be diagnosed by radiologic evaluation. However, radiologic differences between benign and malignant lipomatous lesions may be subtle and pathologic correlation is often needed. The use of sonography, computed tomography (CT), and magnetic resonance imaging (MRI) is useful not only in portraying fat within the lesion, but also for evaluating the presence and extent of soft tissue components. Lipomas make up most soft tissue lipomatous lesions, but careful evaluation must be performed to distinguish these lesions from a low-grade liposarcoma. In addition to the imaging appearance, the location of the lesion and the patient demographics can be utilized to help diagnose other soft tissue lipomatous lesions, such as elastofibroma dorsi, angiolipoma, lipoblastoma, and hibernoma. Osseous lipomatous lesions such as a parosteal lipoma and intraosseous lipoma occur less commonly as their soft tissue counterpart, but are also benign. Neurovascular and synovial lipomatous lesions are much rarer lesions but demonstrate more classic radiologic findings, particularly on MRI. A review of the clinical, radiologic, and pathologic characteristics of these lesions is presented.


Introduction
Musculoskeletal lipomatous lesions form a diverse group of entities which arise from a broad range of tissues and range from benign to malignant. The majority of these lesions arise within the soft tissues, but lipomatous lesions within the bone, neurovascular structures, and synovium are also seen. Many of these lesions demonstrate a classic imaging appearance which can confidently make a diagnosis by imaging alone. However, other lipomatous lesions exist on a spectrum where imaging alone is not enough to differentiate the malignant lesions from the benign. The clinical, imaging, and pathologic characteristics of a variety of these lesions are presented and discussed.

Soft tissue lipomatous lesions Lipoma
Lipomas are benign soft tissue tumors composed of mature adipose tissue. These lesions are the most common soft tissue tumor, making up nearly 50% of all soft tissue tumors [1]. Lipomas are most commonly located within the superficial soft tissues of the extremities, back, and neck. These lesions are usually asymptomatic, but due to the superficial location these lesions commonly present less than 5 cm in size [2]. Lipomas deep to the superficial fascia also occur, but much less frequently. These lesions may be intramuscular or intermuscular and most frequently occur in the lower extremity [1][2][3]. Additional sites include the trunk, shoulder, and upper extremity. Lipomas within certain locations are rare, i.e. the retroperitoneum, hands, feet, and chest wall, and alternative diagnoses should also be considered for lesions in these locations. Unlike superficial lipomas which do not have a gender predilection, deep lipomas are seen slightly more in males [4]. Deep lipomas are often incidental findings and are larger at presentation than the superficial counterparts due to the lack of aesthetic effect.
Though these lesions are usually solitary, they can be multiple in 5-15% of patients [1,2,5]. Approximately 30% of these cases are hereditary in nature, a clinically distinct entity called familial multiple lipomatosis ( Figure 1); inheritance is most likely polygenic [6]. Patients with the hereditary form of multiple lipomas tend to present at a younger age in the 3rd to 4th decade of life. The lipomas can be very numerous, but the presence of a capsule around the lesion distinguishes them from lipomatosis, which is described as diffuse infiltrative mature adipose tissue.
Superficial lipomas can almost always be diagnosed clinically. In cases where imaging is obtained, lipomas have a characteristic appearance on ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). Large lipomas may appear as a radiolucency on radiographs, but the finding is not diagnostic. Sonographically, the lesions appear as well-defined, oblong, echogenic mass without posterior acoustic enhancement. In the larger lesions, fine linear striations may be seen coursing parallel to the skin [7]. Deep lipomas are isoechoic or hyperechoic to the adjacent muscle and may have posterior acoustic enhancement due to the greater acoustic transmission within fat compared to muscle. While it has been suggested that ultrasound can establish the diagnosis of a lipoma, studies have shown ultrasound to have a low accuracy [8], and further cross-sectional imaging is often needed.
On non-contrast CT, the classic appearance of a lipoma is a circumscribed, homogeneously low (fat) density mass ranging from À120 to À65 Hounsfield units [9,10]. Similarly, the characteristic lipoma is an encapsulated lesion isointense to the subcutaneous fat on all MRI sequences [11]. Intramuscular lipomas may not be encapsulated and instead may insinuate within the skeletal muscle; this appearance has never been described with liposarcoma. These distinguishing features are reportedly only present in 11-22% of cases [5,[9][10][11]; this surprisingly low percentage is felt to be related to the fact that most typical lipomas will be clinically diagnosed and will never be evaluated by imaging. Of the imaged lipomas, many demonstrate thin internal septa ( Figure 2). These septa usually do not enhance in benign lipomas (58%) compared to marked enhancement in well-differentiated liposarcomas (75%); no non-enhancing septa were seen in malignant lesions [10]. Though the septa are usually less than 2 mm, thick and nodular septa have been reported in up to 31% of lipomas [5,[9][10][11]; these lesions are indistinguishable from liposarcoma by imaging ( Figure 3).
Another complicating feature of some lipomas is mineralization, which is present in up to 11% of imaged lesions [5,9]. This can appear as either chondroid or osteoid matrix. The lipomas may also undergo necrosis or atrophy. Though lipomas are benign without risk of malignant transformation, if there is atypical appearance by imaging, biopsy should be considered to rule out liposarcoma.
Histopathologically lipomas are encapsulated tumors composed of mature adipocytes. Fibrous connective tissue may be seen which correlates with the thin septa seen on imaging. Lipomas have a rich vascular supply, though the tenuous vessels are often compressed by the large adipocytes. Marginal surgical excision is performed for symptomatic lesions [1,12]. In a lesion with an atypical appearance or with possible concern for malignancy, the presence of muscle fibers within the lesion can be a helpful indicator of benignity [13]. However, this is not completely diagnostic and if clinical concern is high, further immunohistochemical tests, such as MDM2 and CDK4 expression, should be performed [14]. It is suggested that fluorescence in situ hybridization (FISH) for MDM2 amplification should be considered for recurrent lesions, deep extremity lesions >10 cm, in patients older than 50 years of age, equivocal atypia, retroperitoneal or abdominopelvic lesions, and in certain warranted clinical situations [15].
The most common liposarcoma subtype is a welldifferentiated liposarcoma, which makes up approximately half of these lesions [12,16,17,19]. These lesions are also known as atypical lipomatous tumors. Up to 75% of these lesions are found within the deep soft tissues of the extremities [12,16,17,19]. In contradistinction to benign lipomas, deep-seated areas are common sites for liposarcomas, such as the retroperitoneum which accounts for 20-33% of lesions [12,16,17,19]. These often painless, slow-growing masses do not pose a metastatic risk, but may dedifferentiate into a malignant lesion. Histologically these lesions are further separated into five categories, though distinctions between these cannot be identified by imaging. The histologic appearance of the most common subtype, a lipoma-like well-differentiated liposarcoma, demonstrates mostly adipocytes with scattered interspersed lipoblasts. The expression of MDM2 and CDK4 in these lesions can help differentiate this lesion from a classic lipoma [20][21][22][23]. By imaging the lesion may appear similar to a lipoma, but care should be taken to identify thick (>2 mm) or irregular septa ( Figure 4). The enhancement of these is slightly more pronounced than the thin septa in a lipoma.
Myxoid liposarcoma, the next most common class of liposarcoma, occurs in the intermuscular space in up to 80% of the cases [24]. This subtype encompasses both myxoid tissue and round cell components. Predominately myxoid lesions are gelatinous with a thin plexiform vascular network. The corresponding imaging demonstrates high T2 signal throughout the myxoid portions of the tumor due to the high water content ( Figure 5). On T1-weighted imaging, linear or nodular areas of high intensity within the predominately low intensity mass create a marbled appearance; this high T1 signal corresponds with lesional fat. However, mature adipose tissue is scant and may be unidentifiable by imaging or histology in some lesions [21][22][23]25]. Occasionally the lesion will appear as a cystic mass with homogeneous high T2 signal. Postcontrast imaging can help distinguish this lesion from a cyst by demonstrating enhancement, though the enhancement   and T1W FS post-gadolinium (c) images demonstrate a predominately fat-signal mass in the left posterior chest wall, between the rhomboid and trapezius muscles. Few thin internal septa are seen without nodularity. Heterogeneous enhancement is seen on post contrast images, greater than expected than with a conventional lipoma, which raised concern for an atypical lipomatous tumor or angiolipoma. H&E 20· (d).
Corresponding pathology showed mature adipose tissue with uniform nuclei and no atypia, consistent with benign lipoma.
pattern and extent varies greatly among lesions. If the lesion is predominately composed of round cells, intermediate signal will be seen on both T1-and T2-weighted imaging. Less common types of liposarcoma include pleomorphic, dedifferentiated, and mixed-type. Pleomorphic and dedifferentiated subtypes are both high-grade malignancies. Pleomorphic liposarcomas are large, multinodular, welldefined masses. Heterogeneity on imaging is related to internal hemorrhage and necrosis. These lesions are often difficult to diagnose by imaging given their relative lack of adipose tissue [20,23,25]. Dedifferentiated liposarcomas share similar imaging features with well-differentiated liposarcoma; however, they also contain soft tissue nodules measuring greater than 1 cm, which represents the dedifferentiated portion of the lesion.

Elastofibroma dorsi
Another benign fat-containing soft tissue lesion is an elastofibroma dorsi. This lesion classically occurs in the  infrascapular region, deep to serratus anterior and latissimus dorsi. These lesions are bilateral in up to 60% of cases and when unilateral are more often seen on the right than left [26]. Less commonly, an elastofibroma may be discovered at the ischial tuberosity, olecranon or at another site along the thoracic wall [26]. Though initially thought to be rare, these lesions can be found incidentally in up to 2% of all chest CTs [27]. An autopsy series suggested prevalence approaching 25% in women [28], though these figures may be exaggerated due to the small autopsy sample size. Nevertheless, elastofibromas occur more commonly than initially surmised. CT findings of a poorly defined, soft tissue density lesion with internal fat striations in the infrascapular region are diagnostic for elastofibroma dorsi; the soft tissue component demonstrates similar density to the adjacent skeletal muscle [29]. However, these lesions can appear homogeneous if the internal fat content is low. These lesions may be found on MRI or ultrasound imaging in the work-up of a symptomatic patient. Similar to CT, MRI findings demonstrate a fibrofatty lesion, with the fibrous tissue appearing isointense to skeletal muscle on T1-and T2-weighted imaging ( Figure 6). Sonographically these lesions appear as echogenic fibroelastic lesions with internal curvilinear streaks of relatively hypoechoic fat [30,31]. No treatment is required unless the patient is symptomatic. In those cases, the lesion can be surgically excised; rare reports of recurrence are thought to be related to incomplete excision [29].
On pathology, this non-encapsulated tumor demonstrates eosinophilic collagen bundles, stellate elastic fibers, and a variable amount of mature adipocytes [26].

Angiolipoma
One of the many subtypes of a lipoma is an angiolipoma, which is a soft tissue tumor composed of mature fat and small blood vessels. Angiolipomas are also known as hemangiolipomas, vascular lipomas, or fibromyolipomas. Originally, up to 17% of lipomas were felt to be angiolipomas [32], though a subsequent study found angiolipomas to represent only 5% of all lipomas [33]. Typically, these lesions involve the neck, chest wall, and upper extremities. Both non-infiltrating and infiltrating subtypes have been described. The non-infiltrating lesions present as painful, subcutaneous lesions and always demonstrate a thin capsule histologically. These wellcircumscribed lesions are typically less than 2 cm and be locally excised without high rate of recurrence [33]. The infiltrating lesions are non-encapsulated or only partially encapsulated and invade the adjacent skeletal muscle and fibrous tissues. The infiltrating lesions may be larger at presentation than the non-infiltrating type and require a wide excision. Imaging appearance will depend on the subtype, but both lesions will contain a mixture of soft tissue and fatty components on all imaging modalities, which may make it difficult to differentiate this lesions from a liposarcoma (Figure 7). Angiographic findings can be misleading because the coarse neovascularity suggests a more aggressive lesion. Rarely, epidural angiolipomas may also occur.

Lipoblastoma
Lipoblastomas are rare, benign mesenchymal tumors, which are discovered almost exclusively before three years of age [34]. Originally, these lesions were reported in the extremities in up to 72% of the cases [34], but more recent studies have described equal incidence of extremity and non-extremity lipoblastomas [35]. Microscopically these lesions demonstrate immature adipose tissue with lipoblasts, capillaries, and myxoid stroma [34], in contradistinction to lipomas which demonstrate mature adipocytes. Imaging appearance depends on the amount of myxoid stroma among the fat; the younger the patient, the more myxoid component present ( Figure 8). Enhancement occurs due to the rich capillary network. MRI is the modality of choice in order to define the extent of the mass and the possibility of local invasion ( Figure 9). Despite benignity, these lesions may become symptomatic related to the potential for local invasion and ability to grow rapidly in size, though this is uncommon. When local invasion does occur, it is referred to as lipoblastomatosis. These lesions are then surgically excised, with reports of recurrence ranging from 14 to 33% [34,36], related to incomplete excision. Recent studies have demonstrated a chromosomal rearrangement involving the 8q11-13 region in up to 61% of cases [37], which can be employed to differentiate this lesion from a liposarcoma.

Hibernoma
A hibernoma is a rare lipomatous lesion composed of brown fat affecting middle-aged patients. These lesions most commonly arise in the thigh and subcutaneous tissues of the shoulder, upper back, and neck [38,39]. Though most of these lesions occur in the subcutaneous tissues, up to 10% have been reported as intramuscular and a few rare cases of intraosseous involvement have been described [40]. Four variants of hibernoma have been described including typical, myxoid, lipomalike, and spindle cell, in decreasing order of incidence [38]. Like other lipomatous lesions, the imaging appearance of these tumors depends upon the amount of fat within the lesion. The appearance on T1-and T2-weighted imaging is dependent on the lesion subtype. Typical hibernomas demonstrate signal intensity similar, but not identical to the subcutaneous fat, whereas the lipoma-like lesions will more closely match the subcutaneous fat signal intensity. Myxoid-type hibernomas demonstrate more fluid signal intensity. Despite the subtype, these lesions demonstrate prominent low-signal septa on both T1-and T2-weighted images. On post-contrast imaging, diffuse enhancement will be seen that is greater than expected in the other soft tissue lipomatous lesions. Sonographically these lesions will appear nearly identically to lipomas as a hyperechoic, well-defined mass; however, on color Doppler imaging, prominent vascularity helps differentiate the two lesions. On angiography, a hypervascular lesion with an intense blush and foci of arteriovenous shunting may be seen. One of the most distinctive imaging findings to help differentiate the lesion is the avid FDG uptake on positron emission tomography/computed tomography (PET/CT) due to hypervascularity and intense glucose metabolism of the brown fat ( Figure 10). Despite these suggestive imaging findings, at times it can be challenging to distinguish a hibernoma from a liposarcoma. Histologically hibernomas appear distinct from a lipoma or liposarcoma. The typical brown fat hibernomas pathologically appear as multivaculoated fat cells arranged in a lobular pattern with a prominent vascular supply. The prominent vascular supply of this lesion accounts for the previously mentioned imaging characteristics that help differentiate a hibernoma from an intermediate-grade or malignant lipomatous tumor. These lesions are not usually symptomatic, but may cause nerve compression or limited range of motion in certain locations. If symptomatic or for aesthetic reasons, these lesions can be removed without risk of recurrence [38,39].

Osseous lipomatous lesions Parosteal lipoma
Parosteal lipomas are benign lesions composed of mature adipose tissue. These lesions are much less common than their soft tissue counterparts, making up only 0.3% of all lipomas [41]. Parosteal lipomas are not merely soft tissue lipomas located adjacent to periosteum, but rather demonstrate intimate association with the periosteum. Osseous reaction is present in the underlying bone in up to 60% of cases [42]. Typically, the reaction is hyperostotic and manifests as cortical thickening, sclerosis, calcification, or formation of an osseous excrescence. If an osseous excrescence is formed, the radiologic appearance may be very similar to that of an osteochondroma; however, the lesion can be differentiated given the lack of medullary continuity ( Figure 11). Less commonly the reactive bone change can manifest as smooth cortical scalloping or  (a)  bowing, but bone destruction has not been reported. The lipoma itself demonstrates imaging findings identical to other soft tissue lipomas on CT and MRI [41]. Occasionally, hyaline cartilage can be seen along the larger osseous protuberances which appear as intermediate T1 and high T2 signal intensity. Fibrous tissue can also be seen, and can be differentiated from cartilage given its low-signal intensity on T2-weighted images. Most commonly these lesions are found along the femur or proximal radius. Motor and sensory deficits may be the presenting symptom due to mass effect on nearby neurovascular structures [42]. Muscle atrophy in a specific nerve distribution can be seen if the lesion is causing nerve compression. Though these lesions share histopathologic features with soft tissue lipomas, parosteal lipomas likely arise from periosteal mesenchymal cells [43]. Some of these lesions are associated with a HMGA2-LPP (high mobility group A2 LIM-containing lipoma-preferred partner) fusion gene secondary to a t(3;12)(q27-28-28;q14-15) translocation [44]. Since this fusion gene is only detectable in benign lesions [44], testing for the gene can be helpful in cases when the diagnosis cannot be made based upon imaging and biopsy alone.

Intraosseous lipoma
Another benign lipomatous lesion is an intraosseous lipoma. Patients are usually within their 4th to 5th decades of life at presentation and classically have focal pain. These lesions occur within the lower extremity up to 71% of the time [45]; the calcaneus is often referred to as a classic location, though there is actually a wide variation of calcaneal prevalence reported within the literature, ranging from 8 to 63% [45]. Radiographically these lesions appear as lucent lesions with partial or complete marginal sclerosis in 74% of patients ( Figure 12) [45]. Intralesional calcification is present in more than half the patients and is overwhelmingly dystrophic in appearance and central in location (Figure 13) [45]. Many lesions may mimic an intraosseous lipoma on radiography including fibrous dysplasia, aneurysmal bone cyst, simple cyst, bone infarct, and chondroid tumors ( Figure 14). Bone infarcts can be differentiated from intraosseous lipomas by the location of the calcification, which is peripheral and serpentine in bone infarcts and central and dystrophic in intraosseous lipomas. On cross-sectional imaging these lesions demonstrate expected fat density/signal intensity ( Figure 15). Histologically these lesions are staged according to the amount of viable adipocytes within the lesion versus necrosis and calcification [46] ( Table 1).

Neurovascular lipomatous lesions Fibrolipomatous hamartoma
A fibrolipomatous hamartoma (FLH), also known as lipomatosis of nerve by WHO, refers to adipocyte proliferation within a peripheral nerve. These lesions most commonly occur in infants and children and often present as compressive neuropathy of the affected nerve. The median nerve is involved in up to 50-85% of the cases [47], followed by radial or ulnar nerve involvement. The lower extremity nerves are rarely effected. Fibrolipomatous hamartomas have been associated with macrodystrophia lipomatosa in approximately 25% of patients [48,49]; macrodystrophia lipomatosa is a disorder of localized gigantism related to mesenchymal overgrowth within specific nerve distribution. Histologically, the adipocyte proliferation occurs around the nerve fascicles, separating the individual nerve bundles (Figure 16). Perineural and endoneural fibrosis can also be seen. This entity is nicely visualized by ultrasound which demonstrates hypoechoic coaxial nerve bundles encased by echogenic infiltrating fat. The MRI findings are pathognomonic; the low-T1 signal intensity nerve fascicles are engulfed by high-T1 signal intensity fat (Figures 17, 18). Relative sparing of the involved nerve may be seen within the carpal and cubital tunnels, likely related to restricted ability for the nerve to expand [48]. Conservative therapy is preferred as long as the patient is asymptomatic.

Lipomatous lesions within synovial spaces Lipoma arborescens
Frond-like lipomatous proliferation of the synovium is a benign process known as lipoma arborescens, occurring within joints, bursae, and tendon sheaths. Two categories are reported: the primary form of lipoma arborescens is idiopathic and is much less common than the secondary form, which occurs in the setting of osteoarthritis, rheumatoid arthritis, trauma, or synovitis [4,50]. Both forms are usually monoarticular, but multifocal or bilateral involvement can occur [51,52]. The knee is most commonly involved (Figure 19), though the wrist, hip, shoulder, and elbow can also be affected. Rare cases of ankle involvement have been reported [53]. Although these lesions are usually intra-articular, bursal and tendon sheath involvement can occur. Histologically these lesions demonstrate replacement of synovial tissue by mature adipocytes. Radiographic and ultrasound findings are nonspecific, though a joint effusion and synovial hypertrophy may be seen sonographically. Demonstration of infiltrative fat within the synovium is diagnostic, making magnetic resonance imaging the modality of choice. The signal intensity of the lesion should mirror that of fat on all sequences. Joint effusions and bone erosions may be seen [50]. The synovium may enhance on post-contrast imaging due to chronic inflammation. The frond-like appearance of the hypertrophied synovium is the basis of the name lipoma arborescens (Figures 20, 21). Treatment for this benign lesion is synovectomy. However, if the underlying inflammatory etiology persists, the lesion may recur, though reported cases of recurrence are uncommon ( Table 2).

Conclusion
Lipomatous lesions are common throughout the musculoskeletal system and encompass both benign and malignant lesions. Though the radiographic manifestation of the lesion may be helpful in the diagnosis, radiographic findings can overlap among various lesions and histologic diagnosis may be necessary. Imaging can help in management by targeting the biopsy to the non-lipomatous components of the mass. Ultimately, the understanding of the wide range of musculoskeletal lipomatous lesions and their radiologic appearance is essential to the appropriate treatment of patients. -Low T1 signal nerve fascicles engulfed by high T1 fat intensity -Nerve within regions with restricted expansion (e.g. carpal and cubital tunnels) may be spared -Nerve bundles, but not surrounding fat, will enhance Lipoma arborescens -Fat density synovial mass -Frond-like appearance -High T1 signal matches subcutaneous fat -Signal loss with fat suppression -Synovium will enhance, but fat will not