Leg Pain in a 39-Year-old Man

HISTORY AND PHYSICAL EXAMINATION A 39-year-old carpenter was referred to the orthopaedic service with a 2-year history of increasing pain in his right leg, which began after a fall down a set of stairs. After the fall, he also noticed a small, painful mass in the mid-portion of his right leg, which did not change in size. The pain was dull, aching, nonradiating, and graded by the patient as 5 on a scale of 1 to 10 (with 10 being the most severe). It occurred intermittently, worsened with activity, and on occasion, awakened him from sleep. With time, the pain impaired the patient’s ability to walk and produced an antalgic gait. On physical examination a small, firm swelling in the middle third of the right tibia was noted posteriorly. No other masses were palpated. The overlying skin was intact, and there was no evidence of warmth, erythema, or induration. The hips, knees, and ankles had a normal range of motion (ROM). Neurologic and vascular examinations of the leg were unremarkable, and no evidence of lymphadenopathy was found. Radiologic investigations of the lesion included plain radiographs, a bone scan, computed tomography (CT) imaging, and magnetic resonance imaging (MRI). The results of these studies are shown in Figures 1, 2, 3, and 4. Based on the history, physical examination, and imaging studies, what is the differential diagnosis?Fig 1.: An AP plain radiograph of the right leg shows a lytic lesion.Fig 2.: A–B. (A) An unenhanced T1-weighted axial MRI scan shows cortical irregularity and the small intramedullary component of the lesion. (B) This T2-weighted axial shows the extraosseous portion of the lesion, with involvement of the cortex and medullary cavity.Fig 3.: An unenhanced axial CT scan of the right leg through the lesion shows the stellate lucencies in thickened cortex with a periosteal defect.Fig 4.: A–B. (A) An unenhanced T1-weighted axial MRI scan after open biopsy reveals a larger mass with more extensive cortical involvement. (B) A contrast enhanced T1-weighted axial MR scan after open biopsy shows enhancement of the lesion.IMAGING INTERPRETATION Radiographs taken 11 months after the onset of symptoms revealed a small, irregular lesion in the tibial diaphysis composed of several small lucencies, which involved a slightly thickened cortex (Fig 1). A three-phase bone scan done soon afterward showed abnormal activity at the site of the lesion on the flow, blood pool, and delayed images; the findings were interpreted as consistent with a stress fracture. One month later, MR images were obtained. These showed a small, rounded, soft tissue mass adjacent to and involving the tibial cortex with a small focus of extension into the medullary cavity. There was no bone or soft-tissue edema. The lesion measured 1.5 cm in greatest dimension (Fig 2). Approximately 6 months later, a CT scan using 3 mm sections was done without contrast enhancement and showed a small lesion in the posterior cortex of the mid-tibia composed of multiple, well-defined, stellate lucencies in a slightly thickened cortex with a sharply marginated defect in the outer surface of the cortex. The CT (unenhanced) did not show a detectable soft tissue mass or periosteal reaction (Fig 3). A second MRI study, obtained approximately 2 years after the previous MRI and after the patient had an open biopsy on the lesion, revealed a more irregular mass, which had become slightly larger (measuring 2.2 cm), when compared with the previous MRI. The lesion also showed internal contrast enhancement (Fig 4). DIFFERENTIAL DIAGNOSIS Stress fracture Infection Fibrous dysplasia Nonossifying fibroma Schwannoma Hemangioma Osteoid osteoma Periosteal desmoid Adamantinoma Osteosarcoma Metastasis An open biopsy was done and revealed the histologic pattern shown in Figures 5 and 6. Based on the history, physical examination, imaging studies, and histological picture, what is the diagnosis and how should the patient be treated?Fig 5.: A photomicrograph of the lesion is shown (stain, hematoxylin and eosin; magnification ×100).Fig 6.: A photomicrograph of the lesion is shown (stain, hematoxylin and eosin; magnification ×400).See page 286 for diagnosis and treatment. Continuation of ORP conference from page 285. HISTOLOGY INTERPRETATION Scanning magnification of the hematoxylin-and-eosin–stained specimen sections (Figs 5, 6) showed a proliferation of spindle cells of alternating hypercellularity and hypocellularity, a so-called Antoni A and Antoni B pattern. The spindle cells contained plump oval to slightly wavy elongated nuclei with vesicular chromatin. No appreciable mitotic activity and only rare cells with a mild degree of pleomorphism and hyperchromasia were seen. The cells loosely were arranged and in areas of hypercellularity formed a subtle but characteristic palisading pattern. They were embedded in a delicate fibrillary myxoid matrix with a sprinkling of mononuclear cells. Numerous blood vessels were present, some of which showed hyalinization, and only rare fragments of reactive bone were noted. Immunohistochemical studies showed strong, diffuse reactivity for S100 protein and vimentin within the lesional cells. DIAGNOSIS Intraosseous schwannoma of the right tibia. DISCUSSION AND TREATMENT The lesion was fully removed with curettage, debridement, and bone grafting. The leg was placed in a long leg cast for a period of 4 weeks, and after cast removal, the patient received outpatient rehabilitation for 2 months. In this time, the wound healed uneventfully, and the bone graft was well accepted. Six months after surgery, the patient had full ROM of the knee and ankle, and the tibial shaft showed no sign of deformity. Intraosseous schwannoma, also known as intraosseous neurilemmoma, is a rare primary neoplasm within the bone that is derived from neurogenic Schwann cells. It accounts for less than 1% of primary bone tumors and shows no gender predilection.7,8 The mandible and the sacrum are the main sites of occurrence, but the tumor also has been reported in vertebrae, calvarium, maxilla, scapula, sternum, and long bones.5,6,7,8,10,14 Intraosseous schwannomas have been reported to occur in patients ranging in age from 2 years to 65 years.6,7,10,14 Most intraosseous schwannomas are painless lesions that are found incidentally on radiographic images.8 Radiologically, on plain radiographs and CT scans, intraosseous schwannomas present in three ways: 1) as intramedullary lesions with lytic centers, lobulated margins with marginal sclerosis, a thinned and expanded cortex with occasional cortical erosions, and infrequently with internal calcifications; 2) within a nutrient canal, showing a dumbbell shape with intramedullary and soft tissue components; and 3) as an extraosseous mass eroding bone and/or extending into bone, with a thickened cortex (as in the case presented). They may be surrounded by minimal edema in the soft tissue, best shown by MRI.1,2,10,13 On MR imaging, intraosseous and parosseous schwannomas are isointense to muscle on T1-weighted images and homogeneously or heterogeneously hyperintense on T2-weighted scans. The heterogeneity includes zones of relatively low signal intensity indicating hypercellular areas (so-called Antoni Type A tissue), and high signal intensity indicating myxoid areas (so-called Antoni Type B tissue).12,16 On CT and MR imaging, intraosseous schwannomas typically show contrast enhancement. Enhancement may be solid or nodular, with nodular enhancement found in the hypercellular components of the lesions. Aoki et al2 speculated that a nodular pattern of enhancement might suggest the diagnosis of an intraosseous schwannoma. At surgery, the neoplasms show macroscopically sharp circumscription and may be encapsulated. Two types of cell arrangements, Antoni A and Antoni B patterns, are seen histologically.13 The term Antoni A pattern is given to tissue that is composed of closely packed spindle-shaped cells arranged in bundles and cords. The nuclei of these cells are often aligned parallel to each other to form palisading rows, leaving strands of fine cytoplasmic processes to form the so-called Verocay bodies.17 Type B tissue, in contrast, consists of haphazardly scattered spindle cells that are embedded in a loose myxoid and fibrillar stroma. The blood vessels contained within the tumor mass are often thick walled and hyalinized. Microcystic areas with hemorrhage are common, and macrophages laden with lipid and hemosiderin may be prominent. The tumor cells are characteristically slightly wavy and have tapered nuclei with a normochromic fine chromatin pattern. Not uncommonly, nuclear pleomorphism is found focally or diffusely within a neurilemmoma. The cells may show strikingly bizarre nuclear outlines and hyperchromasia, a feature referred to as ancient change. Although alarming in appearance, these changes should not be mistaken for a malignant process arising in a benign lesion. Mitotic activity may, on occasion, also be noted. The cytoplasm is faintly eosinophilic and the cytoplasmic borders are ill defined. The diffuse immunoreactivity for S100 protein and vimentin is indicative of the Schwann cell origin of these cells and helps distinguish this tumor from other spindle cell lesions of similar histology. Ultrastructural studies show cells with thin, convoluted processes of their cytoplasm that are surrounded by a continuous basal lamina. Often, Luse bodies are found within the surrounding stroma. These are characteristic “long-spacing” fibers of collagen. The ultrastructural features of schwannoma are diagnostic.8 Intraosseous schwannomas can have different locations in relation to the bone in which they arise and may be difficult to diagnose clinically. They may be found in the medullary cavity, within the nutrient canal, or on the surface of bone.14 In general, schwannomas arise most commonly from the peripheral nerves of the head and neck and spinal and cranial nerves and prefer nerves with sensory function.2,8 A relatively common site for an intraosseous schwannoma to develop is the long intraosseous path of the mandibular nerve.7 When the tumor arises in the long bones, it most commonly appears around the nutrient canal in the metadiaphysis.6,7 It has been postulated by de la Monte et al6 that the paucity of sensory nerve fibers within bone may account for the exceedingly rare occurrence of intraosseous schwannoma. Intraosseous schwannomas are solitary lesions and are not thought to be associated with neurofibromatosis.6 The etiology of intraosseous schwannomas is not known, but the trauma that our patient had is not thought to be a factor in the development of his lesion. Although histopathologically distinct, these tumors may be misdiagnosed by clinical and radiographic means. In the case of the current patient, the lack of limb overuse, such as marching, dancing, or other strenuous exercise, makes the possibility of a stress fracture less likely. Infectious processes to consider are subacute osteomyelitis, also known as Brodie’s abscess, and sclerosing osteomyelitis. Osteomyelitis can present with pain and a mass on imaging. A biopsy taken from such a lesion shows bone marrow, which is altered by a chronic and active inflammatory infiltrate, that is associated with reactive bone formation and fibrosis. Only rarely are bacterial colonies found. Fibrous dysplasia should be included in the differential diagnosis of an intramedullary, intraosseous schwannoma. Fibrous dysplasia is a benign lesion that can be asymptomatic or found incidentally. Symptomatic cases usually present in children or young adults, particularly when a major weight-bearing bone is involved. Presenting features often include pain, swelling, and deformity of the affected bone. On plain radiographs and CT scans, fibrous dysplasia appears less dense than the surrounding bone with a characteristic ground-glass appearance. Margins of the affected area are well defined, and the affected bone often shows expansion and thinning of the cortex. Periosteal reaction is rare in the absence of a stress fracture through the compromised bone. Microscopically, fibrous dysplasia appears as a bland fibrous tissue containing unevenly distributed trabeculae of woven bone in a characteristic curlicue, Chinese-letter configuration. Scattered cytokeratin-positive cells may be identified. Like fibrous dysplasia, nonossifying fibromas may be discovered incidentally on routine radiographs. Symptoms rarely arise and are mainly mechanical in nature. Histologically, nonossifying fibromas are indistinguishable from benign fibrous histiocytoma of bone. Their radiographic appearance, however, is characteristic. On plain radiographs and CT, the characteristic appearance is an eccentrically located ovoid radiolucency with the long axis parallel to the axis of the bone. The endosteal margins may be scalloped, and periosteal reaction is not seen. On MR imaging, T1-weighted and T2-weighted images show low signal intensity. Immunohistochemical stains will highlight their fibroblastic origin and readily distinguish them from a neural lesion, as they are S100-protein negative. Another benign lesion to consider in the clinical differential diagnosis of this patient is a hemangioma that involves bone. These vascular tumors can present as painful lesions or may be asymptomatic. Hemangiomas, commonly found in vertebrae, rarely occur in the long bones. However, when they do, the ends of the bone are often involved with a radiolucent, loculated, expansile appearance on plain radiographs and CT imaging. Hemangiomas are generally blood-filled tumors that, on microscopic examination, are composed of a network of dilated thin-walled vascular channels rather than the sheets and fascicles of spindled cells and relatively rare, thick-walled blood vessels seen in schwannomas. The endothelial cells lining these vascular channels are bland and innocuous in appearance and can be stained with vascular markers like factor-8-related antigen (von Willebrand factor), CD31, and CD34. Osteoid osteomas tend to have a typical clinical pattern with pain predominantly at night that can be readily alleviated with medication like aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Computed tomography scans and plain radiographs show a characteristic nidus, surrounded by a sclerotic, thickened cortex that is diagnostic for this tumor. Magnetic resonance imaging studies, in contrast, may be misleading and may give the impression of a more aggressive lesion because of extensive surrounding bone and soft-tissue edema. When surgically removed, the nidus shows a characteristic microscopic picture of irregular osteoblastic bone production associated with a spindle cell component that is very rich in vasculature. Periosteal desmoid has a radiologic appearance that can be similar to that of an intraosseous schwannoma involving the external surface of bone. This is a rare fibrous lesion that typically presents in the second decade of life. Periosteal desmoid originates subperiosteally, resulting in destruction of the outer margin of the cortex. The endosteal margin of the cortex remains well demarcated. A small amount of periosteal reaction usually occurs, and a small soft-tissue mass may also be found.11 Microscopically, intercellular collagen and adult fibroblasts are seen. Bone erosion caused by osteoclastic activity may also be found. An example of a low-grade malignant neoplasm of bone in the differential is an adamantinoma. Adamantinomas are primary bone tumors most often found in the tibia with biphasic morphology. Within these lesions, a bland spindle cell population is found to surround distinct epithelial islands. These can be basaloid, tubular, or squamous in appearance and are highlighted with immunohistochemical stains for cytokeratins and epithelial membrane antigen. Some cases of adamantinoma may be composed predominantly of spindle cells, and the epithelial islands may not be apparent, which may complicate the differentiation of this lesion from neurilemmoma. In these circumstances, immunohistochemistry shows cells stained for vimentin, but not S100 protein. In contrast to the benign lesions of bone, which may clinically and radiologically mimic neurilemmoma of bone, malignant tumors frequently have radiologic features that distinguish them from their benign counterparts. A biopsy, in conjunction with clinical and radiologic findings, confirms the diagnosis of osteosarcoma and other malignancies of bone. Osteosarcoma is composed of a proliferation of atypical osteoblasts that is generally associated with osteoid production, often referred to as malignant osteoid. The malignant cells can be spindled and may dominate the lesion. In contrast to the cells in schwannomas, these cells generally show marked mitotic activity. These cells also show a high degree of atypia, as seen in schwannomas. Rarely, a metastatic lesion may also be considered in the differential diagnosis of neurilemmoma of bone. A biopsy readily reveals it as such with the demonstration of epithelial cell clusters occupying the bone and marrow space. The lesion in our patient is a schwannoma because it is composed of a proliferation of benign appearing slender spindle cells with slightly wavy nuclei that are embedded in a fibrillary background, a pattern commonly seen in neural and related neoplasms. Antoni A and Antoni B areas are noted within this tumor, and the lesional cells form palisades characteristic for schwannoma. In addition, the tumor is diffusely positive for S100 protein by immunohistochemistry, supporting its Schwann cell origin. Acknowledgments We thank Dr. Deborah Van Allen and Sandy Costello for their contributions to this case report.