Leg Pain in an 8-Year-Old Boy

An 8-year-old boy from a developing country reported left leg pain for 7 weeks before presenting to our institution. His complaints began after he fell on his left leg, without sustaining an obvious injury. He had been admitted to an institution in his home country for evaluation, where plain radiographs were taken (Fig 1). Plain radiographs were reported as normal and the patient was put on activity restriction for 2 weeks. During this 2-week period, the pain got worse and the patient could not bear weight on his left lower limb. In addition, he had several episodes of fever (38°C) and chills during this period with no weight loss. Repeat plain radiographs (Fig 2) and MRI scans (Figs 3, 4) were taken 4 weeks after the initial evaluation, revealing a destructive bone lesion on his left tibia.Fig 1A: –B. Plain (A) AP and (B) lateral radiographs of the left leg at the initial presentation.Figure: Continued.Fig: + 2A–C. Plain (A) AP, (B) close-up of AP, and (C) lateral radiographs of the left leg 4 weeks after initial presentation.Figure: Continued.Figure: Continued.Fig 3: Coronal T2-weighted MRI scan of the left leg.Fig 4: Axial T2-weighted MRI scan of the left leg.The patient’s medical history was significant for Henoch-Schönlein purpura, which was treated with steroids when he was 3 years old. In addition, the patient was diagnosed as having primary pulmonary complex (Ghon complex), indicating that he had asymptomatic primary pulmonary tuberculosis. He was the product of a full-term, uncomplicated pregnancy, and his developmental and family histories were noncontributory. On physical examination, the patient was a healthy appearing boy who reported moderate to severe pain over the area of the left midtibia. He was unable to bear weight on his left lower extremity. The neurovascular examination was normal. The patient had full ROM of the left knee and ankle. There was diffuse tenderness over the left midtibia with a mild soft tissue swelling. There was no erythema or increased warmth over the area. His abdomen was soft and nontender without masses or hepatosplenomegaly. There was no lymphadenopathy noted. Laboratory tests revealed a leukocyte count of 11,000 mL (normal, 4500–13,500 mL), a hemoglobin level of 13.9 g/dL (normal, 11.5–15.5 g/dL), a platelet count of 348,000 (normal, 140,000–440,000), and an erythrocyte sedimentation rate of 32 mm/hour (normal, 0–20 mm/hour). Prothrombin time and international normalized ratio were 11.6 seconds (normal, 9.4–12.5 seconds), and 2.3 (normal, 2.0–3.5), respectively. Biochemical and urine profiles were within normal levels. Based on the history, physical findings, and imaging studies, what is the differential diagnosis? RADIOGRAPHIC INTERPRETATION The initial plain radiographs of the left leg (Fig 1) showed subtle increased marrow density in the midtibial diaphysis. The plain radiographs of the left leg (Fig 2) obtained 4 weeks later showed a well-defined radiolucent lesion with surrounding medullary sclerosis and a continuous thickened periosteal reaction laterally in the midtibial diaphysis. Coronal and axial T2-weighted MRI scans (Figs 3, 4) showed diffuse high signal intensity in the medullary canal, periosteum, and adjacent soft tissue. Small foci of high signal extended through the cortex from the medullary cavity to the periosteum. DIFFERENTIAL DIAGNOSIS Langerhans cell histiocytosis Ewing’s sarcoma Subacute hematogenous osteomyelitis Lymphoma of bone Osteosarcoma Tuberculosis osteomyelitis After presentation to our institution, an incisional biopsy with an intraoperative frozen section was done; the photomicrographs are shown in Figures 5 and 6. Fig 5A: –B. Photomicrographs of the lesion (Stain, hematoxylin and eosin; magnification (A) ×200, and (B) ×400).Figure: Continued.Fig 6: Photomicrograph of the lesion (Stain, CD1a immunohistochemistry; magnification, ×400).Based on the history, physical findings, laboratory tests, radiographic studies, and the histologic picture, what is the diagnosis and how should this lesion be treated? See page 329 for the diagnosis and treatment of this lesion. Continuation of ORP Conference from page 328. HISTOLOGIC EVALUATION The specimen consisted of multiple small fragments of pink-red soft tissue, admixed with bone. Histologic examination revealed sheets of loosely cohesive mononuclear cells interspersed with inflammatory cells (Fig 5A). Tumor cells had moderate amounts of eosinophilic cytoplasm and nuclear features of deep clefts and coffee beanlike longitudinal grooves (Fig 5B). Nucleoli were inconspicuous, and mitotic activity was moderate. Rare giant cells also were present. There were numerous inflammatory cells interspersed among the mononuclear cells. Most of the inflammatory cells consisted of eosinophils, which tended to aggregate into eosinophilic microabscesses. Polymorphonuclear cells, lymphocytes, and plasma cells also were present, albeit in smaller numbers. Multifocal geographic zones of necrosis and hemorrhage also were present. There was no evidence of osteoid production. Immunohistochemistry revealed strong cytoplasmic staining for S-100 and crisp perimembranous staining for CD1a (Fig 6). DIAGNOSIS Langerhans cell histiocytosis TREATMENT AND DISCUSSION Langerhans cell histiocytosis is a rare childhood disease characterized by accumulation of histiocytes in various tissues of the body. It has been described as including three conditions: eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease. The etiology of this disease is unclear. Theories have included a disorder of immune regulation and a neoplastic process. The role of viruses in initiating this disease remains under study. 16 The peak incidence of Langerhans cell histiocytosis is in patients 1 to 3 years,21,22 although it can present in patients at any age. The incidence in children has been estimated at 3 to 4 per million. It may affect males more than females. 4,12 There is no racial predominance or a strong genetic component. The two main prognostic factors for Langerhans cell histiocytosis are the age at time of diagnosis and the extent of organ involvement. 11 Eosinophilic granuloma, in which the lesions are confined to the bone, occurs in older children and has a low mortality rate. When the disease is more widespread and characterized by the triad of bone lesions, diabetes insipidus, and exophthalmos, it is termed Hand-Schüller-Christian disease. Letterer-Siwe disease is the disseminated form, characterized by wasting, generalized lymphadenopathy, hepatosplenomegaly, and anemia. This usually occurs in children younger than 2 years and the mortality rate is high. Langerhans cell histiocytosis is most commonly seen in the skeleton, the skin, and the lymph nodes. Investigations for possible generalized lesions include radiographs of the chest; examination of the eyes, the skin, and the gastrointestinal and respiratory systems; complete investigation of the blood; and ultrasound scanning of the liver and spleen. 3 In the current case, supplementary investigations revealed no other lesions. Skeletal manifestations of the disease most often involve the flat bones, with more than 50% found in the skull, spine, mandible, ribs, and pelvis. 5,8,21 Long bone involvement usually is limited to the diaphysis and metaphysis of the femur, tibia, and humerus. 15 Clinically, patients present with localized pain, tenderness, swelling, and a soft tissue mass adjacent to the site of skeletal lesion. 1, 21 Patients with lesions in the lower extremities may limp. Pathologic fractures in weightbearing long bones may accelerate healing of the lesion. Patients with vertebral involvement may present with back pain or, less commonly, neurologic symptoms resulting from a collapse of the vertebral body. 10 Systemic findings, such as fever, elevated erythrocyte sedimentation rate, or leukocytosis may be present. Langerhans cell histiocytosis lesions have varied and nonspecific radiographic appearances; hence, the term, the great imitator. Less aggressive lesions are lytic, and have poorly to well-defined margins with or without sclerosis. They may have a thin or slightly thickened, continuous periosteal reaction. More aggressive lesions cause a moth-eaten or permeative pattern of bone destruction with lamellated or spiculated periosteal reaction. Long bone lesions usually begin as poorly defined medullary destruction. The degree of cortical destruction ranges from endosteal erosion with associated cortical thinning to frank cortical destruction. The disease may penetrate the cortex and cause soft tissue edema. Periosteal new bone formation, with its typical onion skin lamellated appearance, may occur and mimic malignancy. A peculiar feature of Langerhans cell histiocytosis is the tempo phenomenon. Lesions may come and go entirely within a few months. New lesions may develop in the same bone just adjacent to, or far removed from, the previous site of involvement. 9 As healing occurs, the lytic areas become trabeculated, nonsclerotic margins become sclerotic, and the bones remodel with little or no residua of the lesions. 17 Screening for multiple bone lesions is done best with a radiographic bone survey. 18 Although bone scintigraphy is equally as sensitive, 6 plain radiographs always are indicated to confirm and characterize scintigraphic abnormalities. Moreover, conventional radiography is more sensitive for detection of old lesions. On MRI, most bone lesions are hypointense on T1-weighted images and hyperintense on T2-weighted images. 7 Magnetic resonance imaging scans show more extensive marrow involvement and soft tissue abnormality than do plain radiographs. Magnetic resonance imaging scans also may show edema in the bone surrounding the lesion. In the radiologic differential diagnosis of the current case, the main considerations were Ewing’s sarcoma and subacute hematogenous osteomyelitis. Both lesions may involve the diaphysis of long bones in children, and have moth-eaten or permeative types of bone destruction with a lamellated onion skin periosteal reaction. Lymphoma of bone also was a consideration because it also may present as a solitary destructive lesion in the diaphysis of a long bone. However, bone lymphomas are very rare in children and rarely evoke any periosteal new bone formation and soft tissue mass. Although osteosarcoma also may present as a destructive bone lesion with varying degrees of periosteal reaction, it usually involves the metaphyseal, not the diaphyseal, regions of the long bones. In the current case, the very rapid progression of the lesion was a helpful radiographic feature suggestive of Langerhans cell histiocytosis. Tuberculosis still remains a major cause of skeletal infections in developing countries and extrapulmonary tuberculosis is more common among children. 20 Although the lungs are the most common site of initial infection in children, the tubercle bacilli may disseminate to bones or joints by lymphatic and hematogenous spread. Because the patient was from a developing country in which tuberculosis is endemic and because he had a history of primary pulmonary complex, tuberculosis osteomyelitis was in the differential diagnosis. However, bone lesions in tuberculosis osteomyelitis are almost purely destructive or lytic, with little or no bone reaction. In addition, tuberculosis osteomyelitis rarely involves the diaphysis. The histologic, immunohistochemical, and ultrastructural pathology is similar in all forms of Langerhans cell histiocytosis. The necessary element in making the diagnosis is the presence of aggregates of Langerhans cells.22 They have a characteristic nucleus, with a deep cleft (the Pacman nucleus) or a longitudinal groove, which resembles a coffee bean. There usually are many eosinophils, with a variable number of other inflammatory cells. There also may be numerous osteoclastlike giant cells. Electron microscopy can identify pathognomonic racquet or rod-shaped organelles known as Birbeck granules. 2 Immunohistochemical analysis shows cytoplasmic positivity for S-100, which is relatively nonspecific, and membranous positivity for CD1a, which is highly specific. The pathologic findings in this case were diagnostic of Langerhans cell histiocytosis. Despite the presence of a polymorphous infiltrate of several inflammatory cell types, subacute hematogenous osteomyelitis would be unlikely because of the presence of sheets of Langerhans cells and a diagnostic immunophenotype. Likewise, one could exclude lymphoblastic lymphoma and Ewing’s sarcoma. Ewing cells have little cytoplasm, tend not to have clefted or grooved nuclei, and do not express CD1a. Lack of cytologic atypia would make the diagnosis of large cell or Hodgkin’s lymphoma unlikely. Moreover, lymphomas do not express either S-100 or CD1a. Osteosarcoma also is unlikely because of the lack of osteoid production and the lack of cytologic atypia. The therapeutic approach to the patient with Langerhans cell histiocytosis still is controversial. Treatment approaches have been based on the severity and natural history of the disease rather than any understanding of its pathogenesis. The clinical course of patients with the localized form of Langerhans cell histiocytosis generally is benign. One osseous lesion usually does not require treatment other than the biopsy to confirm the diagnosis.22 Additional local therapy may be considered only for painful lesions, lesions in weightbearing bones with a risk of pathologic fracture, or lesions that could result in unacceptable dysfunction or deformity. Patients with painful lesions may respond to intralesional steroid injection, but patients with polyostotic disease may require a short course of systemic steroids and chemotherapeutic agents. Because of the possibility of inducing a malignancy, the role of radiotherapy is limited to the treatment of lesions that are inaccessible to intralesional steroid injections or those that potentially can compromise vital structures, such as the optic nerve and spinal cord. The treatment of the current patient included only an incisional biopsy (with a frozen section) of the tibial lesion to confirm the diagnosis. The patient did not require any local treatment for pain management. He used crutches for 2 weeks after the surgery with toe-touch weightbearing of the affected extremity and then gradually progressed to full weightbearing in the following 2 weeks. At 8 weeks followup, the patient was asymptomatic and was able to bear full weight on the affected extremity. His incision was healed without any signs of infection. The plain radiographs (Fig 7) of the left leg taken at the 5-month followup showed healing of the bone lesion with little residua. Fig 7A: –B. Plain (A) AP and (B) lateral radiographs of the left leg obtained at 5-month postoperative followup are shown.Figure: Continued.The role of the orthopaedic surgeon in the treatment of Langerhans cell histiocytosis should remain modest because of the frequent tendency of osseous lesions to heal spontaneously. A better understanding of the biology of the disease will help to improve the treatment of patients with this condition.