Benign Musculoskeletal Tumors

Incidence

Simple bone cysts are benign tumors of childhood and adolescence. They represent approximately 3% of all primary bone tumors sampled for biopsy and nearly always occur during the first 2 decades of life, most often between 4 and 10 years of age. These cysts have a male predominance, with a 2:1 male-to-female ratio. Most cysts occur in the metaphyseal region of the proximal humerus or femur; approximately 50% of cases involve the humerus, and 18% to 27% affect the femur. The next most common sites are the proximal tibia and distal tibia. Occasionally, cysts may be found in the calcaneus, fibula, ulna, radius, pelvis, talus, lumbar spine, and other parts of the axial skeleton ( Fig. 25.1 ). ^a

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Rarely does more than one cyst occur in an individual, hence the term solitary bone cyst . The term unicameral bone cyst implies that one chamber exists. Although one large cavity is usually found, a cyst may become multiloculated after a fracture because of the formation of multiple bony septations, thus making the term unicameral technically incorrect.

Simple cysts are often categorized as “active” or “latent” based on their proximity to the growth plate. ^, A cyst that is juxtaphyseal (<0.5 cm from the physis) is considered active and possesses greater potential for growth. Epiphyseal involvement is rare, but if present it should be considered an aggressive form of an active lesion. A cyst that has grown away from the plate is considered latent and theoretically no longer has the capacity for growth ( Fig. 25.2 ). In reality, however, latent cysts continue to have growth potential, as proved time and again by their unexpected recurrence after treatment in the young patient. After skeletal maturity, it is uncommon for the cysts to recur or progressively worsen. However, Donaldson and Wright followed 24 patients over 7 years, and although 87% had closed growth plates, cyst size had not changed and none had healed.

Etiology

The cause of simple bone cysts remains uncertain. Any theory relating to the etiology of simple bone cysts should be able to explain the following factors: (1) more than 70% are discovered in childhood, (2) more than 95% arise from or involve the metaphysis, (3) most occur in the proximal humerus or femur, (4) a cyst wall and fluid high in protein content are common, and (5) simple bone cysts represent a benign process with a significant recurrence rate after treatment.

Mirra hypothesized an intraosseous synovial cyst in which a small amount of synovial tissue became entrapped in an intraosseous position during early infant development or secondary to trauma at birth. Over time, increased pressure secondary to secretions would lead to expansion within the bone. Jaffe and Lichtenstein postulated that cysts resulted from a localized failure of ossification in the metaphyseal area during periods of rapid growth. Cohen proposed that the cause of the cyst was blockage of the circulation (venous obstruction) and drainage of interstitial fluid in rapidly growing bone. He based this theory on the finding that the chemical constituents of the fluid in simple bone cysts are similar to those of serum. ^, Current literature further substantiates this theory of a disturbance in or occlusion of the intramedullary venous circulation. ^b

b References , , , , , .

Two genetic analyses of simple bone cysts identified single and multifocal cytogenetic rearrangements associated with the condition. ^, These findings emphasize the need for further studies clarifying the frequency and significance of chromosomal anomalies in this type of lesion.

Drilling, trepanation, and reaming of the medullary cavity to open vascular channels between cysts and the intramedullary venous system have been used to treat cysts with mixed results. The cyst fluid itself may be both a factor in cyst formation and an obstacle to healing. Bone-resorptive factors, such as prostaglandins, interleukin-1, and lysosomal enzymes, are found in cyst fluid. ^{, ,} In addition, Komiya and associates reported elevated levels of interleukin-6 and interleukin-1β in cyst fluid and the presence of tumor necrosis factor-α, interleukin-6, and interleukin-1β in cells in the cyst membrane. These findings, along with inducibility of production of nitrate and nitrite from cyst membrane cells in response to cytokine exposure, suggest that conditions within solitary bone cysts may promote production of nitric oxide. Oxygen free radicals, which are cytotoxic and known to be generated under ischemic conditions, have also been found in cysts.

Pathology

Simple bone cysts tend to expand by eroding the cortex and result in a localized bulge of the bone. Nonetheless, reactive or periosteal bone formation is not present unless a pathologic fracture occurs. Where the cortical tissue is thinnest, the wall can actually be fluctuant, and a bluish tinge from the underlying fluid can be seen. Once the affected bone has fractured, the cortical wall is thicker, and multiple bony septa may occur throughout the cyst.

The fluid found within simple bone cysts is straw colored or serosanguineous, a feature distinguishing simple bone cysts from aneurysmal bone cysts. Often, significant pressure within the cyst (which can be greater than 30 cm H ₂ O) is evident when a needle is introduced. After a fracture, however, the cyst may become filled with blood clot, granulation, or fibro-osseous tissues. The most characteristic histopathologic finding is the thin membranous lining of the cyst ( Fig. 25.3 ). Composed primarily of flattened to plump epithelium-like cells, the lining may also possess osteoclast-type giant cells, cholesterol cells, and fat cells. Hemosiderin, fibrin, calcification, and reactive bone may be seen in focal areas of the cyst.

Clinical Features

Clinically, cysts can be asymptomatic and may be discovered incidentally when radiographs, such as a chest film, are obtained for other reasons. More often, however, the cysts are diagnosed because of pain. The pain may be mild and reflect a microscopic pathologic fracture. More abrupt discomfort occurs when a pathologic fracture occurs after relatively minor trauma, such as a fall. These fractures occur in up to 90% of patients and heal readily, although the cysts do not. After these pathologic fractures, premature physeal closure has been reported in nearly 10% of patients. ^,

Radiographic Findings

Simple bone cysts have several characteristic radiographic features. Approximately 50% occur in the proximal humerus and 18% to 27% in the proximal femur. The cyst is metaphyseal and usually extends to, but not across, the physis. On rare occasions it crosses the physis into the epiphysis. ^, Typically the cyst is symmetrically expansile and radiolucent, with a thin cortical rim surrounding it. Over time the physis grows away from the cyst, thus changing from the active to the latent phase. In many newly diagnosed cases a pathologic fracture occurs with or without displacement. The one pathognomonic manifestation of a simple bone cyst is the “fallen fragment” sign. This represents a portion of fractured cortex that settles to the most dependent part of the fluid-filled cyst. However, it is seen in less than 10% of cases, and it should not be expected if the cyst has become multiloculated after a previous pathologic fracture.

On magnetic resonance imaging (MRI), simple bone cysts often have a complex appearance because of heterogeneous fluid signals and regions of nodular and thick peripheral enhancement caused by previous pathologic fracture and subsequent healing. MRI may reveal focal, thick peripheral, heterogeneous, or subcortical patterns, with focal nodules of homogeneous enhancement (diameter > 1 cm) within the cyst that are associated with areas of ground-glass opacification on plain film. MRI may also detect fluid levels, soft tissue changes, and septations not seen on plain film.

Differential Diagnosis

The diagnosis can usually be established based on the presence of typical radiographic findings. Other lesions to be considered in the differential diagnosis include aneurysmal bone cyst, monostotic fibrous dysplasia, and atypical eosinophilic granuloma. All these lesions may be radiolucent. Aneurysmal bone cysts and fibrous dysplasia may be expansile and metaphyseal. However, features typically associated with these lesions usually help differentiate them from simple bone cysts.

Treatment

A common misconception in the treatment of simple bone cysts in children is that once the pathologic fracture heals, the cyst also has an excellent chance of healing spontaneously. However, most investigators examining this phenomenon have found that the likelihood of spontaneous healing of the cyst after pathologic fracture is very low, probably less than 5%. ^{, , ,} Thus if treatment of the cyst is deemed necessary, it should be undertaken as soon as the fracture has healed. However, overtreatment in skeletally mature persons should be avoided. In these individuals, if the cyst has a sufficiently thick cortex and is located in the upper extremity, periodic observation may be all that is needed. If the patient is asymptomatic, restriction of activities may not be necessary.

The treatment approach is more aggressive for all simple bone cysts in younger children and in skeletally mature individuals when the cyst is located in weight-bearing bones of the lower extremities. In these cases plans should be made for definitive treatment of the cyst to prevent future fractures and possible associated complications (e.g., shortening resulting from growth arrest and deformity). Findings by Stanton and Abdel-Mota’al suggested that the rate of growth arrest as a complication of simple bone cysts of the humerus approximates 10%, a frequency more common than is generally appreciated.

The preoperative evaluation of patients with simple bone cysts rarely requires more than good-quality radiographs of the lesion. If the diagnosis is equivocal, a bone scan will verify the presence or absence of other abnormal areas. Computed tomography (CT) may be helpful in differentiating simple bone cysts from other lesions, such as aneurysmal bone cysts or fibrous dysplasia. MRI findings of double-density fluid levels and septation associated with low signal on T1-weighted images and high signal on T2-weighted images strongly suggest the presence of an aneurysmal bone cyst rather than a simple bone cyst. The diagnosis is usually confirmed at surgery, when straw-colored fluid is aspirated through a large-bore needle introduced into the cystic cavity.

Treatment modalities include injection of corticosteroids into the cyst, injection of autologous bone marrow, multiple drilling and drainage of the cavity, and curettage of the membranous wall followed by bone grafting. A relatively high recurrence rate has been historically associated with treatment of simple bone cysts. Older forms of treatment, such as subtotal resection with or without bone grafting and total resection, have been associated with increased cyst recurrence and are rarely, if ever, used today. Zhao and colleagues report a Cochrane Database System Review which in 2017 reanalyzed a multicenter prospective trial comparing bone marrow injection with steroid injection for simple cysts. They found that, with “very low quality evidence” the steroid group did slightly better than the bone marrow group. They were not able to find any new randomized controlled trials to evaluate.

Corticosteroid Injections

The successful healing of cysts after injections of methylprednisolone acetate was reported by Scaglietti and colleagues in 1979. These investigators noted favorable results in 90% of lesions and consequently concluded that treatment by curettage was seldom necessary. Healing was believed to have occurred if the cortex thickened and the cystic cavity became radiographically opaque. Filling of the cyst with “bone scar” was considered evidence of healing ( Fig. 25.4 ). Actual remodeling, with complete disappearance of the cystic cavity, often took several years. Subsequent reports have continued to substantiate the effectiveness of injecting steroids into cysts, although the success rates have been lower, ranging from 40% to 80%. ^c

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Ramirez and associates found that cysts in which radiographic contrast showed rapid venous outflow were less likely to heal than were cysts without this finding. This method continues to be a popular choice for the initial management of simple bone cysts. The antiprostaglandin action of steroids constitutes the rationale for their use in the treatment of cysts.

The patient is given a general anesthetic in the operating room, and the procedure is performed using strict aseptic techniques. Fluoroscopy with image intensification is used to locate the margins of the cyst. Two large needles with stylets (at least 14-gauge or Craig biopsy needles) are used. The first needle is introduced percutaneously, the stylet is withdrawn, and fluid is allowed to drip out. The presence of straw-colored (serosanguineous) fluid confirms the diagnosis of simple bone cyst. Vigorous aspiration must be avoided because blood may be returned, thus making it difficult to distinguish a simple bone cyst from an aneurysmal bone cyst. If straw-colored fluid is returned, contrast material (usually Renografin diluted 1:1 with normal saline) is injected to confirm the presence or absence of intracystic fibrous or osseous septa and loculation. Needles must be introduced into each separate cystic cavity to ensure delivery of the steroid; if the cyst is not filled completely, the incidence of failure of healing increases.

After the contrast material clarifies the structure of the cystic cavity, the second needle is introduced. The cavity is thoroughly flushed with normal saline solution. The operator should not aspirate when a second needle is in the cyst because air can be aspirated into the cyst from the second needle and can lead to an air embolus. When lavage with normal saline is completed, the second needle is withdrawn. Through the remaining needle, 40 to 120 mg (1–3 mL) of methylprednisolone acetate is introduced into the cyst, and a simple compression dressing is applied.

This procedure is usually repeated every 2 months. It requires between two and five injections, with three the usual minimal number to obtain healing. Because radiographic changes usually are not noted in the first 2 to 3 months, radiographs are not needed before then. Subsequently, radiographs are obtained every 2 to 3 months to assess healing. Evidence of healing includes diminution in the size of the cyst, cortical thickening, remodeling of the surrounding bone, and increased internal density (e.g., ground-glass ossification).

The use of serial steroid injections is the most popular treatment mode because the procedure is simple, injury to the adjacent physis is avoided, the procedure causes a minimal operative scar, little morbidity occurs, the patient is able to return promptly to a previous activity level, and the reported results are excellent. A potential disadvantage is a temporary systemic response to the steroid (Cushing syndrome). It is best not to exceed a total of 120 mg of methylprednisolone during any one injection.

Autologous Bone Marrow Injections and Other Bone Substitutes

Interest in the injection of other materials to stimulate healing led to the successful use of autologous bone marrow. ^{, , ,} In one study, Docquier and Delloye reported successful cyst regression in 15 of 17 cases after a single bone marrow injection, with recurrence in 12% of cases during a subsequent 3-year period. Collagen, demineralized bone matrix, and calcium phosphate paste are other injectable materials that are under investigation. ^{, ,} In a small series of 11 patients, Killian and colleagues reported complete cyst healing in 9 patients after primary treatment with demineralized bone matrix, with no recurrences detected during a 2-year follow-up period. In addition, by using a combination of autologous bone marrow and demineralized bone matrix, Rougraff and Kling noted complete cyst healing in 16 of 23 patients, with 5 recurrences reported during 4 years of follow-up. At our institution, we have been encouraged with the early results using injectable bioresorbable calcium phosphate paste (alpha-BSM), and this is becoming our treatment of choice ( Fig. 25.5 ).

Incidence

An aneurysmal bone cyst is a solitary, expansile, radiolucent lesion usually located in the metaphyseal region of the long bones. Seen much less often than simple bone cysts, aneurysmal bone cysts represent 1% of all primary bone tumors sampled for biopsy; the annual incidence of primary aneurysmal cysts approximates 0.1 per 10 ⁹ individuals. ^, Nearly 70% of affected patients are between 5 and 20 years of age, and approximately half of these cysts occur in the second decade of life, although the lesion has been reported in infants. ^d

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No sex predilection is reported.

Aneurysmal bone cysts can be found throughout the skeleton and may also arise in soft tissue. ^, The most common sites are the femur, tibia, spine, humerus, pelvis, and fibula, with approximately half of reported cases occurring in the long bones of the extremities. ^, Although they usually involve the metaphyseal region, aneurysmal cysts may on occasion cross the physis into the epiphysis or may extend into the diaphysis.

Approximately 20% of aneurysmal bone cysts involve the spine. They may occur anywhere between the axis ^, and the sacrum and can cause spinal cord compression or spinal deformity. ^{, ,} Within the vertebra itself, the cyst may be found in the body, pedicles, lamina, and spinous process ( Fig. 25.6 ). Involvement of two or more adjacent vertebrae is not uncommon. Aneurysmal bone cysts may also occur in the maxilla, frontal sinus, orbit, zygoma, ethmoid, temporal bone, mandible, sternum, clavicle, hands, and feet. ^e

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Etiology

Aneurysmal bone cysts represent either a primary neoplastic condition or a secondary response (arteriovenous malformation) to the destructive effects of an underlying primary tumor. Their presence has been linked to genetic abnormalities involving chromosome segments 7q, 16p, and 17p11–13, ^f

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specifically to USP6 oncogene and CDH11 promoter rearrangements. Insulin-like growth factor I may also play a role in the pathogenesis of aneurysmal bone cysts, and the condition may be inherited in some cases. ^,

Development of an aneurysmal cyst as a secondary response is supported by the association of aneurysmal cysts with other primary lesions, such as nonossifying fibromas, fibromyxomas, fibrous dysplasia, chondroblastomas, giant cell tumors, simple bone cysts, telangiectatic osteosarcomas, chondrosarcomas, and metastatic disease. ^{, ,} Sixty-five percent of aneurysmal bone cysts have been reported to be primary, and 35% are believed to be secondary to other lesions. ^, Thus once the diagnosis of aneurysmal bone cyst is considered, a thorough preoperative evaluation is necessary, adequate tissue must be obtained at the time of surgery, and careful pathologic studies are needed to ensure that the aneurysmal cyst is not secondary to a more serious primary neoplasm.

Pathology

Aneurysmal bone cysts vary considerably in size, with the potential to become large during the rapid, destructive growth phase. On gross inspection, the cyst consists of an encapsulated mass of soft, friable, reddish-brown tissue, usually contained within a thin subperiosteal shell of new bone. At the time of surgery, a large amount of blood may exude from a mesh of honeycomb spaces. In most cases the blood is dark red as a result of slow but continuous circulation. If the circulation to a portion of the aneurysmal cyst has been blocked, the cyst may be filled with serous or serosanguineous fluid or with focal organized blood clots.

Microscopy discloses a variable number of vascular spaces whose walls are lined with tissue composed of fibroblastic cells with collagen, giant cells, hemosiderin, and osteoid (secondary to microfractures; Fig. 25.7 ). Extensive sampling should be performed to identify possible benign or malignant precursor lesions, as well as to identify transformation into malignant lesions such as malignant fibrous histiocytoma or osteosarcoma. The histologic diagnosis of primary aneurysmal bone cyst should be made only after other possible lesions have been excluded. Fibrous tissue, bone, and giant cells are the usual elements seen in most other benign precursor lesions associated with an aneurysmal bone cyst. Any solid area that is 1 cm or larger should raise the suspicion that it may represent another lesion.

Another entity is a solid aneurysmal bone cyst or giant cell reparative granuloma. ^{, ,} This solid yet radiolucent lesion appears grayish brown and often is friable. Histologic features include fibrous proliferation with giant cells, fibromyxoid areas, and bone production. Characteristically the giant cells, which are clustered in areas of recent and old hemorrhage, are found throughout the lesion. The solid aneurysmal bone cyst lacks the normally large blood-filled channels ( Fig. 25.8 ). In a review of a large series of aneurysmal bone cysts, the incidence of the solid entity was 7.5%.

Clinical Features

The clinical presentation includes localized pain of several weeks’ or months’ duration, tenderness, and, if the aneurysmal bone cyst occurs in an extremity, swelling. When the cyst involves the spine, progressive enlargement may compress the spinal cord or nerve roots and result in neurologic deficits such as motor weakness, sensory disturbance, and loss of bowel or bladder control. The cysts may also cause other spinal lesions such as vertebra plana. Spinal involvement therefore mandates urgent intervention.

Radiographic Findings

The classic radiographic feature of aneurysmal bone cysts was described by Jaffe as a periosteal “blowout” or ballooned-out lesion that is outlined by a thin shell of subperiosteal new bone formation. In approximately 80% of cases the cyst involves the metaphyseal region of the long bones and, unlike simple bone cysts, is eccentric in its location. In the spine, it more often involves the posterior elements (spinous process, transverse process, and pedicles) than the vertebral body. In the shorter tubular bones of the feet, the cysts are more central and extend into the diaphysis and subarticular region (this is explained by the smaller size of the bones).

Three phases of aneurysmal cysts have been described. The incipient phase is characterized by either a small eccentric lucent lesion or a pure lifting off of the periosteum from the host bone without evidence of an intramedullary lesion. Most patients do not present with disease in this phase. Except for focal cortical thinning, the cortex may otherwise be preserved, and the periosteum may show no reaction. In this phase, the lesion can be mistaken for a simple bone cyst, nonossifying fibroma, or possibly a lytic osteosarcoma. The midphase designates the period of rapid, destructive growth and is characterized by extreme lysis of the bone, focal cortical destruction, and the development of Codman triangles (periosteal ossification at the corner of the expanded cyst). It is during this phase that the “blowout” appearance is seen on radiographs, and aneurysmal bone cysts can easily be mistaken for an aggressive malignant lesion. In the late healing or stabilization phase, the lesion grows more slowly, and the periosteum has sufficient time to lay down new bone. The cyst will exhibit the following features: eccentric (or possibly concentric), smooth-bordered expansion; a trabeculated or “bubbly” intramedullary appearance; and surrounding host bone sclerosis.

Capanna and colleagues proposed a radiographic classification system that is commonly used today. ^{, ,} Inactive cysts have a complete periosteal shell, with the intraosseous margin defined by a sclerotic rim of reactive bone. Active cysts have an incomplete periosteal shell and a sharply defined intraosseous border. Aggressive cysts show no evidence of reparative osteogenesis, no periosteal shell, and an ill-defined endosteal margin.

Once these lesions are identified on radiographs, the tumor can be better clarified with CT, particularly if it is located in the spine. The extent of involvement of the vertebra and any encroachment of the spinal canal are readily evident. CT also demonstrates the characteristic fluid–fluid levels if the patient is able to lie still long enough for the serosanguineous fluid to separate from the blood within the chambers of the cyst that do not have active circulation. MRI is indicated if the patient has evidence of spinal cord compression or if the edges of the rapidly expanding cyst cannot be defined with CT. Fluid–fluid levels are readily evident on MRI ( Fig. 25.9 ). MRI is most valuable in the differential diagnosis because it can delineate the multicystic appearance, hypointense rim, contrast-enhancing cyst walls, double-density fluid levels, and adjacent soft tissue edema that are typical of this lesion, as well as the extent of the lesions. ^{, , ,} Gadolinium-enhanced MRI may be helpful for distinguishing the solid variant from conventional aneurysmal bone cyst. The differential diagnosis includes atypical osteosarcoma and telangiectatic osteosarcoma, which may rarely mimic aneurysmal bone cyst radiologically. ^,

Treatment

Although spontaneous healing of aneurysmal bone cysts has been reported, it is uncommon. Thus expectant management should be considered only when the diagnosis has been made with confidence and the lesion is in a location and at a stage that do not entail any risk of fracture or further destruction. More often, when the diagnosis of aneurysmal bone cyst is made, active treatment is recommended.

Curettage and Adjunctive Therapy

Curettage followed by bone grafting of aneurysmal cysts has been the standard treatment for many years ( Fig. 25.10 ). Unfortunately, this tumor has a high incidence of local recurrence (14%–59%) after curettage, ^{, , , ,} although Gibbs and colleagues reported rates of local control approaching 90% following curettage with use of a mechanical burr in 40 patients with aneurysmal bone cyst of an extremity. In this series, very young age and open growth plates were associated with increased risk of local recurrence. A promising report of a new technique called “curopsy” combines a diagnostic biopsy with limited curettage of the cyst in lesions with a typical radiographic appearance. The authors use a 5 to 10 mm incision and perform a core needle biopsy using a T-Lok needle (Medical Device Technologies Inc., Gainesville, FL) under image intensification. In addition they use a pituitary rongeur or a curette to obtain lining membrane from various quadrants of the lesion as part of the biopsy. In their report 81% of the lesions resolved, compared to a 90% cure rate of cases treated with open curettage with or without adjuvant therapy. Juxtaphyseal aneurysmal bone cysts may be treated satisfactorily with excision, curettage, and bone grafting, with careful preservation of the growth plate.

A number of reports cite success with adjuvant agents combined with curettage of the cyst. Cryotherapy used as an adjunct to curettage and bone grafting has been shown to increase the likelihood of cyst healing. ^, Steffner reported that among several techniques, the lowest rate of recurrence (7.5%) was obtained with curettage with a high-speed burr with argon beam coagulation. Garg and colleagues reported a significantly reduced rate of recurrence (0 of 8 cases) when a four-step approach of intralesional curettage, use of a high-speed burr, electrocautery, and bone grafting was used as an alternative to traditional intralesional curettage and bone grafting. If the cyst is located in an expendable bone, such as a rib or fibula, the surgeon should consider performing a wide or en bloc excision. A number of papers suggest that adjunctive therapy, such as cementation, cryotherapy, or embolization, should be considered along with curettage. ^{, ,}

On the contrary, Kececi reviewed 76 cases treated with curettage and found no better healing in the ones in which adjuvants (phenol or alcohol) were used.

Adjuvants have been used successfully without curettage as well. Embolization has been used as the sole treatment for aneurysmal bone cysts, ^, but it is much more commonly used before surgery to interrupt the vascularity of the lesion. Embolization is useful in treating aneurysmal cysts located in areas of limited access, such as the spine and pelvis. ^{, , , ,} Repeated embolization as the sole treatment was reported in a lesion of the pelvis in a 3-year-old child.

A surprisingly large variety of agents have been recently reported to cause aneurysmal cysts to heal. Agents reported include denosumab, a monoclonal antibody to RAML (resolution of a single large sacral lesion). Other agents include Ethibloc, Aetoxisclerol, absolute alcohol, and absolute alcohol gel (complete resolution in 85%). A report of sclerotherapy with polidocanol showed healing in all but one of 38 patients after a median of four injections. The authors recommended this method for lesions in areas not amenable to surgical approach. Repeated injections of Doxycycline resulted in at least partial healing of 20 cases in another report. Other reports include oral dexamethasone (an angiostatic agent), percutaneous intralesional injection with calcitonin and methylprednisolone, endoscopic curettage without bone grafting, and the use of multiple Kirschner pins inserted into the cyst. Incidences of significant complications including fatal Ethibloc embolization of the vertebrobasilar system have been reported.

Incidence

The term fibrous dysplasia was originally proposed by Lichtenstein in 1938. He, along with Jaffe, McCune, and Albright, described this disorder of bone, as well as other extraskeletal abnormalities with which it is occasionally associated. ^{, , ,} Their descriptions remain among the best for fibrous dysplasia—a benign, nonfamilial disorder characterized by the presence of expanding intramedullary fibro-osseous tissue in one or more bones. The incidence of fibrous dysplasia is not known, but it is not an uncommon primary bone tumor. It occurs more frequently in girls than in boys, particularly the polyostotic form. Although most lesions are probably present in early childhood, they usually do not become evident before late childhood to adolescence. Of interest, a fibrous dysplasia lesion was found in the rib of a 120,000-year-old Neandertal skeleton.

Classification

In general, fibrous dysplasia can be classified into one of three categories. Monostotic fibrous dysplasia involves only one bone, and many of these patients remain asymptomatic unless a fracture or swelling occurs. The polyostotic form is more severe, involving multiple bones. Nearly any bone in the body may be affected, including the long bones of the extremities, skull, vertebrae, pelvis, scapula, ribs, and bones of the hands and feet. Often one side of the body (in particular, one of the lower extremities) is more severely affected, resulting in deformity and limb length discrepancy. ^, Craniofacial involvement occurs in nearly 50% of patients with polyostotic disease. The third category, polyostotic form with endocrine abnormalities, is the least common form. Precocious puberty, premature skeletal maturation, hyperthyroidism, hyperparathyroidism, acromegaly, and Cushing syndrome can occur in these patients. The triad of precocious puberty (endocrinopathy), café au lait spots, and polyostotic bone involvement is commonly referred to as McCune-Albright (or Albright) syndrome.

Etiology

The exact cause of fibrous dysplasia is not known. The condition is not believed to be hereditary. Fibrous dysplasia probably results from a failure of maturation from woven to lamellar bone. Studies have reported an abnormality of a gene encoding the α subunit of the stimulatory protein Gs which causes a structural subversion of bone and bone marrow. A mouse model based on this mutation produces a direct replica of human fibrous dysplasia.

Pathology

The outer surface of expanded bone is usually smooth and covered by reactive periosteal bone. The underlying dysplastic tissue is firm and grayish white, and the proliferative tissue is fibrous. It may feel gritty when palpated, almost like sandpaper. Degenerative cystic changes resulting from cellular necrosis may be evident. Islands of hyaline cartilage may be seen.

Histologically, irregular foci of woven (nonlamellar) bone trabeculae are seen in a cellular fibrous stroma ( Fig. 25.11 ). ^, Under the microscope, the bony spicules are often described as looking like the letters C, J, or Y or resembling Chinese characters. Osteoclastic resorption may be seen, but osteoblastic rimming of the bony spicules is uncommon. In unusual cases, as much as 95% of the lesional tissue may be fibrous. Cartilage islands, multinucleated giant cells, foamy histiocytes, and callus may be seen if a fracture has occurred. The histologic features of polyostotic lesions are identical to those of monostotic lesions.

Clinical Features

The clinical manifestations are usually mild in monostotic fibrous dysplasia. Pain and a limp may be evident when the neck of the femur is involved. Local swelling may be seen when the lesion is in a superficial bone, such as the mandible, skull, or tibia. The skeletal changes are usually more severe in the polyostotic form and may result in pain, swelling, deformity, and limb length discrepancies. The classic example of this is found in the proximal femur. ^, Repetitive microfractures can lead to a “shepherd’s crook” deformity with pain, significant varus at the femoral neck, shortening of the femur, an obvious Trendelenburg gait, and limited mobility. Deformity can occur in all the long bones, but usually not to the degree seen in the femur. In patients with polyostotic disease, the peak incidence of fractures is during the first decade of life, followed by a decrease thereafter. When the facial bones are affected, progressive deformity may become evident to the patient and family. Numerous reports of craniofacial abnormalities are found in the dental and maxillofacial literature ( Fig. 25.12 ). ^{, ,} Spinal lesions and scoliosis may be more common in patients with polyostotic fibrous dysplasia than was previously thought. ^{, ,} Dysplastic lesions of the spine, primarily involving the posterior elements, have been reported in 63% of patients, and scoliosis has been reported in 40% of patients. There have also been reports of vertebral collapse, angular deformity, and possible spinal cord compression. ^,

The most common nonskeletal manifestation associated with fibrous dysplasia is abnormal cutaneous pigmentation, or café au lait spots. These have irregular borders (“coast of Maine”), are not raised from the surrounding skin, and may be extensive, involving large areas of the trunk, face, or limbs. The café au lait spots can coexist with polyostotic fibrous dysplasia without endocrine changes or precocious puberty, or they may be absent when endocrinopathies accompany fibrous dysplasia. The pigmentation changes usually are not present in monostotic fibrous dysplasia.

When sexual precocity occurs, it is most often seen in the female patient secondary to premature ovarian stimulation, and it may occur as early as 1 year of age. Most cases of McCune-Albright syndrome occur in girls and are accompanied by accelerated maturation and advanced skeletal age. In such children, abnormally rapid growth may result in tall stature at a young age. Ultimately, however, their adult stature is usually below average because of their early maturation.

Malignant transformation of fibrous dysplasia is rare but has been reported.

Radiographic Findings

Fibrous dysplasia can affect any bone. In the long bones, the lesions start in the metaphysis or diaphysis and rarely involve the epiphysis. The flat bones, ribs, jaw, and skull are commonly involved. Spinal involvement is uncommon, 12% in one study, and may produce scoliosis.

Some of the smaller lesions of fibrous dysplasia remain confined to the intramedullary region, are often surrounded by sclerosis, and may appear “bubbly” or trabeculated. Normally, however, slow replacement of the cortex is evident as expansion takes place. Larger lesions may result in an even or eccentric, smooth-bordered expansion of the bone, but they usually remain confined within a rim of periosteal bone. Angular deformity may occur in the long bones, such as the shepherd’s crook deformity in the proximal femur and occasionally in the humerus. This deformity is usually a result of remodeling of the bone after repetitive microfractures or obvious fractures through the dysplastic bone ( Fig. 25.13 ).

The radiographic density of the lesions depends on the amount of woven bone produced and on the amount of cortex replaced. If the lesion is small, has produced little woven bone, or has not replaced cortex, it appears radiolucent compared with surrounding normal bone. If the cortex is thinned and if the fibrous dysplasia has expanded and replaced most of the normal bone, the characteristic ground-glass appearance is seen. When this feature is extensive, it is nearly pathognomonic of fibrous dysplasia. CT clearly demonstrates this appearance. A bone scan demonstrates increased uptake throughout the lesion and is helpful in determining the extent of the disorder if radiographs are unable to do so.

Malignant transformation is rare, but should be suspected when there are larger areas of pure radiolucency, cortical destruction, and presence of a soft tissue mass.

Differential Diagnosis

With monostotic fibrous dysplasia, it may be difficult to differentiate small lesions from simple bone cysts on radiographs. Less often, small lesions may be confused with histiocytosis or enchondromas. In these cases a biopsy may be necessary. Larger lesions with cortical thinning and a ground-glass appearance usually do not require a biopsy to confirm the diagnosis. Polyostotic fibrous dysplasia is readily identified on radiographs.

Treatment

Surgical Treatment

A proposed exception to the nonoperative approach in children (in the absence of fracture or deformity) is infantile fibrous dysplasia. In these children with polyostotic disease, early surgical treatment to prevent development of skeletal deformities that are difficult to correct later may provide long-term benefit. Prophylactic intramedullary nailing with nails of appropriate size was found to be most effective. In the adult, bone grafting in fibrous dysplasia has been reported to be more successful in healing the dysplastic bone.

Operative intervention is needed when repeated pathologic fractures have occurred, when lesions cause significant or progressive deformity that jeopardizes the integrity of the long bone or that results in unacceptable disfigurement, or when associated pain becomes persistent. Pathologic fractures can occur after mild trauma. These fractures are often minimally displaced, and they heal at a normal rate. Delayed union or non-union is not a problem, but progressive deformity can result in severe disability. The primary goal of treatment is to realign the deformed bone, particularly in the weight-bearing lower extremities. This objective, along with ready healing of the fracture, can often be achieved with cast immobilization in the young child. If repeated fractures occur in long bones or if a fracture involves the proximal femur, surgical intervention is the preferred treatment approach. For mild upper femoral varus deformity, correction with compression screws with side plates has some success. ^{, , , ,} The mechanical nature of the fibrous dysplasia bone often results is gradual loss of fixation and recurrent varus deformity, ultimately leading to a “shepherd’s crook” deformity. Intramedullary fixation of the femoral neck and shaft along with corrective osteotomies offers the best chance at stabilizing the deformation. ^{, , , ,} These procedures are difficult in that the lack of bone cortices makes passing of intramedullary rods very challenging. Intraoperative blood loss may be excessive because of increased vascularity in the bone. Despite the successful use of internal fixation and nearly anatomic bone realignment, progressive deformity can still occur and can lead to the need for additional surgery.

Some authors advocate attempts to augment bone strength in addition to or in place of internal fixation. Enneking and Gearen reported that cortical strut grafting was effective in strengthening the bone in the proximal femur ( Fig. 25.14 ). In their opinion, the strength of the bone was greater if cortical rather than cancellous graft was used. Allograft cortical struts avoid the morbidity of harvesting autogenous graft and also appear to slow the resorption process by the dysplastic bone. Vascularized grafts, both fibular and iliac crest, have had some reports of success.

An extensive study of 23 subjects with 52 bone grafting procedures, with a mean follow-up time of 19.6 years, showed a high probability of graft resorption over time. Grafts in older patients lasted longer than those in young patients. Structural graft, allograft, and autograft all fared equally poorly.

Treatment alternatives for skeletally mature patients are also plagued with difficulty. Total hip replacement as well as total knee replacement may provide some years of pain relief and improved function, but eventually they loosen because the bony interface lacks cortical stability.

Incidence

Osteofibrous dysplasia of the tibia and fibula has been described as a variant of fibrous dysplasia. However, molecular investigations have found that the Gs-alpha mutation at the Arg201 codon is present in fibrous dysplasia but is absent in osteofibrous dysplasia. These data suggest that the two disorders have different pathogeneses. Osteofibrous dysplasia may also have a histogenetic relationship with adamantinoma. ⁱ

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Cytokeratin-positive cells are found in the stroma of both osteofibrous dysplasia and adamantinomas, but not in fibrous dysplasia.

The disorder was first reported in the literature in 1921 by Frangenheim, who used the term congenital osteitis fibrosa. Other terms for this disorder include congenital fibrous dysplasia, congenital fibrous defect of the tibia, and ossifying fibroma. Osteofibrous dysplasia of the tibia and fibula was proposed by Campanacci in 1976. ^,

Osteofibrous dysplasia differs from the more common fibrous dysplasia with regard to age distribution, site, radiographic features, and clinical course. The lesion is slightly more common in boys. The symptoms almost always appear in the first decade of life. Nearly two thirds of the lesions are noted before 5 years of age, and the disorder has been noted in infants. ^, The tibia is almost always involved, and the ipsilateral fibula may be affected. Bilateral involvement has been reported, ^, as has involvement of the radius and ulna. Mainly the diaphysis is affected, with localization to the middle third in the tibia. Extension into the proximal or distal metaphysis is seen sometimes. Rarely, diffuse involvement of the entire shaft of the tibia occurs. When the disorder is limited to the fibula, the distal third of the bone is affected.

Etiology

The pathogenesis of osteofibrous dysplasia remains unknown ; however, several theories have been proposed: (1) it results from excessive resorption of bone with fibrous repair of the defect, (2) it is a congenital lesion or a variant of fibrous dysplasia, and (3) it results from abnormal blood circulation in the periosteum. The report of this disorder in a family may also support a genetic component to its etiology. The literature suggests that the disorder is either a reactive process secondary to adamantinoma or a precursor to adamantinoma. ^j

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Pathology

On gross inspection the periosteum is intact. The affected cortex is thinned and may be perforated. The lesion has been described as either whitish yellow or reddish.

Histologically, the tissue is similar to fibrous dysplasia, with irregular spicules of trabecular bone and fibrous or collagenous stroma. In contrast to fibrous dysplasia, the spicules are usually lined with osteoblasts ( Fig. 25.15 ). The finding of woven bone with juxtaposed lamellar bone (from osteoblasts) is thought to be characteristic of osteofibrous dysplasia. Immunohistochemical studies have demonstrated isolated cytokeratin-positive cells in the stroma of osteofibrous dysplasia. ^k

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These cells are not seen in fibrous dysplasia but are found in adamantinomas. Based on this finding, a relationship between osteofibrous dysplasia and differentiated adamantinoma is believed to exist; however, it is not certain whether osteofibrous dysplasia represents a possible precursor of or is a secondary reaction to adamantinoma. Nests of epithelial cells are a consistent histologic finding in adamantinomas, but they are not found in osteofibrous dysplasia.

Clinical Features

The common presenting complaint is firm swelling localized over the tibia with associated mild to moderate anterior tibial bowing. Osteofibrous dysplasia is usually painless unless the patient has a coexisting pathologic fracture.

Radiographic Findings

The lesion usually is extensive, involving the anterior cortex of either the diaphysis or the metaphysis of the tibia; the epiphysis usually is not affected. Characteristic eccentric, intracortical osteolysis is found, with moderate or marked expansion of the cortex ( Fig. 25.16 ). In small areas the cortex may actually appear absent, and a “bubbled” appearance may be evident. In some areas the osteolytic areas may have a ground-glass appearance. The tibia may be bowed anteriorly or anterolaterally. If the fibula is involved, the condition is usually evident in the distal third of the bone, and it affects nearly the entire circumference of the shaft.

Differential Diagnosis

The two entities that must be distinguished from osteofibrous dysplasia are monostotic fibrous dysplasia and adamantinoma. In contrast to osteofibrous dysplasia, fibrous dysplasia is characterized by the following features: (1) it is usually detected after 10 years of age; (2) it is not routinely associated with anterior or anterolateral tibial bowing; (3) it is noted to be intramedullary on radiographs, with a ground-glass appearance; (4) histologically, the bony trabeculae in the fibrous stroma are rarely surrounded by osteoblasts; and (5) it should have the Gs-alpha mutation at the Arg201 codon. Adamantinomas usually occur in patients older than 10 years of age and contain epithelial components histologically. In adolescents, an open biopsy is needed to differentiate osteofibrous dysplasia from adamantinoma. This tissue must be carefully evaluated because of the difficulty in distinguishing between the two entities.

Treatment

The natural history of osteofibrous dysplasia varies. The lesion may grow slowly or it may expand rapidly into the entire diaphysis. Spontaneous healing of the lesion has been reported. The most common clinical course is one of steady growth and expansion during the first 5 to 10 years of life. Growth then slows, and after maturity the lesion stops expanding. Treatment depends on the course of the specific lesion.

In the young child, marginal subperiosteal resection or curettage has been reported to be successful, but this form of treatment is often followed by recurrence of the lesion. A wide extraperiosteal en bloc resection will presumably achieve a cure, but such a radical procedure is rarely, if ever, indicated. Minimally invasive osteotomy and plate fixation to correct the deformity may be a useful alternative. When the deformity is mild, a conservative approach (observation) is recommended. Bracing, consisting of an ankle-foot orthosis with anterior shell, is indicated if the tibia shows a progressive angular deformity. Cast immobilization of a pathologic fracture is recommended unless angular deformity requires correction; if so, internal fixation may be needed.

Conservative management also is recommended in the treatment of adolescents with osteofibrous dysplasia. If the radiographic appearance is unchanging, the patient should probably be observed indefinitely. If the lesion grows, marginal excision followed by bone transport through distraction osteogenesis has been reported to be successful.

Incidence

Osteochondroma is the most common benign bone tumor, and it reportedly accounts for 36% to 41% of all such tumors. ^, It is characterized by a cartilage-capped osseous projection protruding from the surface of the affected bone. The exostosis is produced by progressive enchondral ossification of the hyaline cartilaginous cap, which essentially functions as a growth plate. More than 50% of solitary osteochondromas occur in the metaphyseal area of the distal femur, proximal tibia, and proximal humerus. Other areas in which solitary osteochondromas may be found include the distal radius, the distal tibia, the proximal and distal fibula, and occasionally the flat bones such as the scapulae, ilium, and ribs. The presence of these solitary lesions within the spinal canal, with resultant neurologic compromise, has received much attention in the literature. ^l

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Etiology

A focal herniation of the medial or lateral component of the epiphyseal plate results in the formation of an aberrant, cartilage-capped, eccentric small bone. Several theories have been proposed to explain this phenomenon. Virchow in 1891 put forth the physeal theory, according to which a portion of the physeal cartilage becomes separated from the parent tissue, rotates 90 degrees, and grows in a direction transverse to the long axis of the bone. However, he did not provide an explanation for the separation and rotation of the detached physeal cartilage. In 1920, Keith proposed that the cause was a defect in the perichondral ring surrounding the physis. Müller in 1913 theorized that the exostoses were produced by small nests of cartilage derived from the cambium layer of the periosteum. By producing osteochondroma using physeal cartilage transplantation, D’Ambrosia and Ferguson provided support for the physeal plate defect theory. Current thought is that the cause is misdirected growth of a portion of the physeal plate, with lateral protrusions causing the development of the eccentric cartilage-capped bony prominence.

Unlike the more extensive hereditary (autosomal dominant) multiple exostoses, solitary osteochondromas do not appear to be genetically transmitted.

Pathology

Solitary osteochondromas may be sessile (broad based) or pedunculated (narrow based). The surface usually is lobular, with multiple bluish-gray cartilaginous caps covering the irregular bony mass. The cartilaginous caps are covered by either thin or comparatively thick perichondrium, which may adhere to the underlying irregular surface and is continuous with that of the adjacent bony cortex. When this perichondrium is removed, the shiny cartilaginous cap is exposed. The cartilaginous cap is usually 1 to 3 mm thick, but in the younger patient it may be noticeably thicker. The thickness of the cartilaginous cap may be much greater if the tumor has undergone sarcomatous change. On cut section the cartilaginous cap varies in thickness and often has an opaque yellow appearance that reflects calcification within the cartilaginous matrix.

The tumor often resembles a cauliflower; however, it may also be flat, hemispheric, or tubular with a prominent end. Its base is contiguous with the normal cortical bone, and the interior of the lesion (spongiosa bone) blends with that of the host bone.

A bursa may develop over the osteochondroma, particularly in larger lesions, where movement of the adjacent soft tissue leads to irritation. This bursal sac may contain mucinous fluid and fibrinous rice bodies.

Histologically, the cartilaginous cap is composed of bland hyaline cartilage. Variable degrees of cellularity are seen, but anaplastic cells are not characteristically evident. Normal enchondral ossification is seen at the cartilage–bone junction. In younger patients, cartilage cores may be present within the subchondral spongiosa near the physes, and these cores may be responsible for recurrence of the lesion should an incomplete resection be performed. Aside from the cartilage cores, the cancellous bone underlying the cartilaginous cap resembles that of the host, although on occasion the marrow in the interior is predominantly fatty.

The appearance of the cartilaginous cap depends on the stage of growth, becoming thinner over time. Remnants of the quiescent cap may persist well into adult life. Should increased thickness of the cartilage become evident in an adult, malignant degeneration must be considered, and the lesion should be carefully examined on histologic sections.

Clinical Features

In the majority of affected individuals, the osteochondroma becomes evident between the ages of 10 and 20 years. The condition has a slight male preponderance. An osteochondroma may be discovered as an incidental radiographic finding, or it may be detected on palpation of a protruding bump. Other factors that often draw attention to the osteochondroma include localized pain, growth disturbance of an extremity, compromised joint motion, abnormal cosmetic appearance, or secondary impingement of soft tissues (tendon, nerves, and vessels). Swelling of the lower extremity, accompanied by pain, has been reported as a result of vascular compression by an osteochondroma at the knee. On occasion, a fracture may occur through a stalk of a pedunculated (narrow-based) lesion after minor trauma. If the patient experiences progressive lower extremity weakness or numbness, MRI evaluation of the neural axis is needed, and extradural compression of the spinal cord from an osteochondroma should be given consideration.

Radiographic Findings

Several pathognomonic radiographic findings are associated with an osteochondroma ( Fig. 25.17 ) :

• 1.

  The lesion protrudes from the host bone on either a sessile (broad-based) or pedunculated bony stalk.

• 2.

  It occurs either in the metaphysis or, as the main epiphyseal plate grows away from the lesion, in the diaphysis. It is never found in the epiphysis.

• 3.

  The cortex and cancellous bone of the osteochondroma blend with the cortex and cancellous bone of the host. This is the main radiographic finding, and any deviation from this feature should raise suspicion of a more serious lesion.

• 4.

  The lesion ranges in size from 2 to 12 cm.

Slight metaphyseal widening may occur at the site of the exostosis. Although the cartilaginous cap is not radiographically visible, partial calcification of the cartilage may be seen as small areas of radiopacity.

In the flat bones, such as the ilium or scapulae, exostoses are usually sessile and are located near the cartilaginous ends of the bone. Osteochondromas rarely develop in the carpal and tarsal bones, but they may involve the phalanges. The rare osteochondroma in the spine (occurring primarily in hereditary multiple exostoses) is rarely visualized on plain radiographs. If evidence of spinal cord compression exists, CT and MRI will clearly show the impingement.

Bursal osteochondromatosis overlying an osteochondroma of the rib has been described and, on occasion, ultrasonography may help delineate the extent of the swollen bursa. If there is concern over a progressively enlarging mass, ultrasonography may also help determine the thickness of the cartilaginous cap. Steady growth of the cartilaginous cap is acceptable during childhood and early adolescence, but growth should cease when skeletal maturity is reached. If the cartilaginous cap continues to grow after skeletal maturity, malignant transformation should be considered, and the appropriate follow-up studies should be undertaken.

Differential Diagnosis

Because of their typically distinct radiographic appearance, solitary osteochondromas are usually easily diagnosed. Occasionally they may be confused with a juxtacortical chondroma or, less commonly, with myositis ossificans with a cartilaginous cap. Juxtacortical chondromas usually have a scalloped cortical defect with a sclerotic margin. With myositis ossificans, the apparent tumor does not blend with the cortex and cancellous bone of the host bone, even though it may be attached to the periosteum. This is usually apparent radiographically, thus distinguishing the long-standing lesion of mature myositis ossificans from an osteochondroma. In the skeletally mature individual, enlargement of a solitary osteochondroma (particularly one that is associated with progressive discomfort) must alert the physician to the possibility of malignant degeneration into a chondrosarcoma.

Sarcomatous Change

Malignant degeneration of a peripheral solitary osteochondroma leads to chondrosarcoma. However, malignant degeneration of solitary osteochondromas is rare, probably occurring in less than 0.25% of lesions. Although Jaffe and Lichtenstein stated that 1% of these lesions undergo malignant change and Dahlin reported an incidence of 4.1% in solitary osteochondromas treated surgically at the Mayo Clinic (Rochester, Minn.), these figures represent select cases referred to oncology centers. Malignant change evolves very slowly, usually manifesting in adult life. ^{, , ,} When malignant changes occur, the lesions become painful and show evidence of growth.

MRI has been found useful in evaluating possible sarcomatous deterioration. The imaging modality delineates extension of the tumor mass into the adjacent soft tissues and allows proper planning of a wide resection of an underlying chondrosarcoma. Scintigraphic imaging with technetium-99m methylene diphosphonate has not been shown qualitatively to differentiate benign active exostoses from chondrosarcoma. Similarly, gallium scans cannot sufficiently distinguish between benign and sarcomatous lesions. Imaging criteria differentiating osteochondroma from chondrosarcoma are provided in Table 25.1 .

Biopsy before surgical excision of a presumed chondrosarcoma may be of limited value because of the significant chance of a nonrepresentative biopsy and the potential risk of seeding the biopsy tract. The prognosis after excision of a chondrosarcoma is excellent.