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Another complicated case of malignant transformation in Paget's disease of bone
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An 81-year-old black woman was referred to the endocrine clinic for progressive deformity of her right lower leg. She had noted warmth, pain and bowing and shortening of her right lower leg for more than 20 years. She denied hearing loss or bone fractures. Her family history was negative for bone deformities, bone pain, arthritis or fractures.
By exam, she had increased skin warmth over the right tibia deformity. Plain X-ray revealed anterior bowing of the right tibia with diffuse sclerosis and expansion consistent with Paget’s disease with sparing of the fibula (figure 1A). A Technetium (Tc)-99m hydroxymethylene diphosphonate bone scan demonstrated intense isotope uptake in the skull and right tibia (figure 1B). Biochemical testing showed a stable elevated alkaline phosphatase (ALP) of 1,486 U/L to 1,500 U/L (reference, 35-120) during the prior two years. Additional testing showed a calcium of 10 mg/dL; albumin 4.5 g/dL; 25 hydroxyvitamin D 20.8 ng/mL (reference, 10-64); phosphorus 4.2 mg/dL; intact parathyroid hormone 25 pg/mL (reference, 10-65); and an elevated urine type I collagen N-terminal cross-linked telopeptide (NTX) 654 nMBCE/mM (premenopausal, 14-70).
 Ana Junqueira |
 Stephanie L. Lee |
The patient was diagnosed with Paget’s disease with extremely active involvement of her entire skull and right tibia. Because of the severity of her bone deformity, she was treated with pamidronate infusions. At that time, we used a protocol of four weekly IV 60-mg doses of pamidronate that was adjusted to every two weeks based on her age and reduced glomerular filtration rate, followed by weekly oral alendronate 70 mg. Her ALP immediately fell after the initial pamidronate infusions to the upper normal range within eight weeks and remained stable at the upper end of reference range for the next seven years (figure 2). Because of the normalization of her NTX to 67 nMBCE/mM, the infusions were terminated after three doses. The heat over her pagetic right tibia subjectively returned to normal and has remained so. Although the tibia deformity is stable and nonpainful, she has an abnormal gait with progressive degenerative disease and pain in her lumbar-sacral spine, bilateral hips and knees.
Two years after the pamidronate infusion, she noted painless swelling of her right cheek. On exam, a hard mass was felt and a CT scan of the skull revealed a 2-cm by 3-cm soft tissue mass in the anterior wall of the right maxillary antrum with lytic destruction of the anterior maxillary wall (figure 3). The soft tissue mass extended outside the maxillary sinus, as well as into the sinus. Biopsy of the mass was consistent with a giant cell tumor. The tumor was resected with negative margins and the pathology confirmed a giant cell tumor (figure 4). She continues to be tumor-free since the surgery and was recently converted from oral alendronate to an annual infusion of zoledronic acid 5 mg with normal ALP (81 U/L) and NTX (17 nMBCE/mM) levels.
The etiology of Paget’s disease remains unknown. A positive family history is found in 15% to 25% of patients, with a seven to 10-fold increase in prevalence among first-degree relatives. Among the mutations in four of the genes associated with Paget’s disease, the most important is sequestosome 1 (SQSTM1), which is a scaffold protein in the receptor activator of nuclear factor kappaB ligand signaling pathway (RANKL). Patients with SQSTM1 mutations have severe Paget’s with increasing age; transgenic mice with this mutation have increased osteoclastic activity but do not develop Paget’s disease, suggesting that other yet unknown factors are needed for Paget’s disease.
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Photos courtesy of: Stephanie L. Lee, MD, PhD |
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 Figure 3: CT scan of the maxillary sinus. Axial images of the maxillary sinuses (blue asterisks) show a mass (red arrow) in the anterior wall of the right maxillary antrum with extension of the mass outside and within the maxillary sinus. There is a lytic destruction of the anterior maxillary wall. |
 Figure 4: Histology of giant cell tumor. Large number of multinuclear giant cells in the tumor removed from the maxillary bone and sinus. An individual cell with many nuclei is indicated by red arrow. |
Pain is the most common presenting symptom and may result from increased bony vascularity, expanding lytic lesions, fractures and deformity of bones. Hypervascularity of affected bone may cause palpable warmth. Adjacent joints may be damaged if there is bone deformity and osteoarthritis can develop, especially in hips and knees. Fractures are the most common complications of pagetic lesions and usually occur in long bones with advancing lytic lesions. Cranial expansion may narrow cranial foramina and cause neurologic complications, including hearing loss from cochlear nerve damage from temporal bone involvement. Treatment is usually reserved for symptomatic patients or patients at risk for fractures or hearing loss with inhibitors of osteoclastic bone resorption — such as the newer generations of nitrogen-containing bisphosphonates. Results of clinical trials with these medications in Paget’s disease have demonstrated reduction of pain, deposition of normal lamellar bone and normalization of markers of bone formation such as serum ALP and bone resorption such as urine NTX.
The incidence of bone tumors is markedly increased in patients with Paget’s disease but the tumors only occur in 0.7% to 1% of cases. Constant and worsening bone pain, new mass or sudden fracture should raise concern about malignant transformation. Osteosarcomas (see Imaging Analysis from Boston Medical Center, April 2009) are the most common tumors and are associated with a poor prognosis. Giant cell tumors, usually benign and located in the skull and facial bones, are another rare complication of Paget’s disease. These tumors may be clinically indistinguishable from sarcoma, but pathologically they are found to consist of clusters of large osteoclasts (osteoclastoma). Giant cell tumors must be distinguished from giant cell reparative granulomas, which usually occur in the jaw. Giant cell tumors in Paget’s disease are usually successfully treated with surgery and radiation therapy. Findings from recent studies have identified a key role for the osteoclast differentiation factor, RANKL, in the genesis of giant cell tumors. A clinical trial using a human monoclonal antibody against RANKL, denosumab, had results that indicated an 86% response rate, and denosumab may be an effective treatment of unresectable giant cell tumors.
Paget’s disease is diagnosed from radiologic and biochemical abnormalities. The degree of serum ALP elevation, a marker of bone formation, reflects the extent and severity of the disease. Response to treatment is followed by markers of bone formation and resorption: ALP and NTX are the tests of choice for assessing response to therapy. Radiographic findings typical of Paget’s disease include bone enlargement or expansion with cortical thickening, coarsening of trabecular markings and lytic and sclerotic changes. Radionuclide Tc-99m bone scans are less specific but are more sensitive than standard radiographs for identifying sites of active skeletal lesions. Suspected areas of malignant transformation are best distinguished from pagetic bone by CT or MRI. Definitive diagnosis of malignancy requires bone biopsy, as was performed in this patient.
Although the bisphosphonate zoledronate has shown impressive results in Paget’s disease with 96% of the patients having a therapeutic response at six and 24 months, further studies are needed to determine whether bisphosphonates can prevent the development of complications such as malignant transformation and tumor formation in asymptomatic patients.
Ana Junqueira, MD, is a Resident in Internal Medicine, and Stephanie L. Lee, MD, PhD, is Associate Chief of the Section of Endocrinology, Diabetes and Nutrition and Associate Professor of Medicine, both at Boston University Medical Center.
For more information:
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