Primary hyperparathyroidism, which is characterized by abnormal excretion of parathyroid hormone (PTH) from the parathyroid glands, is the third most common endocrine disease (1). Excessive activity of the parathyroid glands is caused by hyperplasia, a benign tumor (adenoma), or a malignant tumor (carcinoma). In patients with parathyroid adenoma or carcinoma, surgical resection of the tumor is the standard treatment. Currently, asymptomatic hyperparathyroidism is quite common, whereas patients with bone lesions are rare, except for an insidious loss of bone density.

Brown tumor is a skeletal complication of severe hyperparathyroidism. In brown tumor, subperiosteal resorption, thinning of the cortical bone, and bone defects are caused by increased bone remodeling, resulting from excessive osteoclast activity due to increased PTH levels. This rare benign bone lesion, which comprises of reparative granulation tissue and proliferating fibrous tissue with hemosiderin deposition, can develop in the rib, clavicle, jaw, extremities, and pelvis (2,3). Multiple brown tumors are extremely rare complications of primary hyperparathyroidism, with an incidence of 1% (4). This case report presents the case of a 41-year-old woman with multiple cystic bone lesions diagnosed as brown tumors caused by primary hyperpara-thyroidism. Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

A 41-year-old woman without any disease history visited our hospital because of pain in the left knee for 2 years. Radiography and computed tomography (CT) revealed well-defined osteolytic lesions in the bilateral femurs and left tibia (Figure 1A-C). Magnetic resonance imaging (MRI) showed multiple cystic lesions with low intensity on T1-weighted images and high intensity on T2-weighted images in the bilateral femurs and left proximal tibia (Figure 2A). Additional radiography and MRI revealed cystic lesions in the left humerus and ulna, right proximal femur, and right ilium (Figure 1D, Figure 2B and C). Laboratory examination showed hypercalcemia (total calcium level, 14.6 mg/dl; normal range, 8.5-10.5 mg/dl; albumin-corrected calcium level, 13.9 mg/dl; normal range=7.9-9.8), hypophosphatemia (phosphate level, 1.6 mg/dl; normal range, 2.0-4.0), elevated alkaline phosphatase level (614 U/l), and markedly elevated PTH level (intact PTH level, 1,070 pg/ml; normal range=10-65 pg/ml). Free T3, free T4, thyroid stimulating hormone, liver function, and kidney function test results were within normal limits. Ultrasonography revealed a mass of 16.5×24.9×16.8 mm in the left upper parathyroid gland. ^99mTc-hexakis-2-methoxyisobutyl-isonitrile scintigraphy showed tracer accumulation in the left upper parathyroid gland (Figure 3). These results led to the diagnosis of multiple cystic bone lesions as multiple brown tumors caused by the parathyroid tumor. Although surgical resection of the parathyroid tumor was planned, the patient had an abrupt onset of numbness in the bilateral hands and feet and dizziness 1 month after diagnosis. Based on laboratory data, improvements in hypercalcemia and hyperparathyroidism (total calcium level, 8.1 mg/dl; albumin-corrected calcium level, 8.5 mg/dl; intact PTH level, 139 pg/ml) were observed, and ultrasonography showed tumor shrinkage, suggesting the development of parathyroid apoplexy, by either an infarction or hemorrhage within the tumor. After the episode, the PTH level gradually decreased, and normalized after 6 months. Two years after the diagnosis of hyperparathyroidism, she underwent parathyroid tumor excision because re-elevation of PTH level was observed. Histology of the resected specimen revealed a benign parathyroid adenoma with hemosiderin deposition and fibrosis. After excision of the parathyroid tumor, the serum calcium and PTH levels were normalized. Three years after the diagnosis of hyperparathyroidism, the patient had no symptoms in the limbs, and MRI showed shrinkage of the multiple cystic bone lesions (Figure 4).

The major function of PTH is to maintain the calcium balance in the bloodstream and tissues by regulating calcium absorption and excretion. Hyperparathyroidism, a metabolic disorder of calcium and phosphate due to the hypersecretion of PTH, predominantly develops in postmenopausal women (5). The symptoms of hyperparathyroidism include general malaise, nausea, vomiting, polydipsia, polyuria, and depression (6). Currently, asymptomatic disease is common, and severe hyperparathyroidism is rare, presumably because of the increased recognition of hyperparathyroidism and use of screening tests for blood calcium levels.

Severe hyperparathyroidism causes bone lesions called brown tumors (osteitis fibrosa cystica) (7,8). Brown tumors have solitary or multiple bone lesions, which represent the terminal stage of hyperparathyroidism-dependent bone pathology. Excessively activated osteoclasts, due to increased PTH level, cause bone loss within the lesions and hemorrhage, and the normal bone marrow is replaced by reparative granulation tissue and proliferating fibrous tissue with hemosiderin deposition, which causes brown coloration. Brown tumors, which commonly affect the jaws, skull, pelvis, clavicle, ribs, femurs, and spine, may cause swelling, bone pain, and pathological fractures (9,10).

On radiographs, brown tumors show well-defined, lucent, lytic lesions with thin or broken cortex (11). CT images show irregular, multi-loculated osteolytic lesions, with “ground glass opacification” involving the cortex that may be interrupted; contrary to bone cysts, these lesions take the contrast media (12). Although cystic lesions were reported as one of the common types of the brown tumors, a large proportion of the lesions have been assessed with X-ray and/or CT (13-23). In contrast, MR images are useful to differentiate between solid and cystic lesions of brown tumors. In Table I, we summarized the MRI findings from previous reports (Table I) (24-38). In MR images, solid components have heterogenous signal intensity on T2-weighted images, whereas cystic components have hyperintensity on T2-weighted images (35). Based on the components, lesions of brown tumors can be classified into three types: solid lesions with low-iso intensity on T1 and T2 weighted images and contrast enhancement by gadolinium; mixed solid and cystic lesions with low-iso intensity on T1 weighted images and iso-high intensity on T2 weighted images, contrast enhancement of solid portions and the septa of cystic lesions; cystic lesions with high intensity on T2 weighted images and contrast enhancement of the periphery and septa of the lesions (39). Because of the multiple osteolytic lesions, brown tumors sometimes mimic metastatic carcinoma, bone cysts, osteosarcoma, and giant cell tumors of the bone (15,20,22,36,40-43). In the present case, most multiple cystic lesions were filled with fluid. Although differential diagnoses of cystic bone lesions include solitary bone cysts, subchondral bone cysts, intraosseous ganglions, osteonecrosis, osteomyelitis, and aneurysmal bone cysts, these cystic bone lesions are usually solitary. Conversely, differential diagnoses of multiple bone lesions include metastatic bone tumors, multiple myeloma, enchondromatosis, fibrous dysplasia, and eosinophilic granuloma, and these lesions are commonly filled with solid tissues. However, multiple cystic bone lesions are very rare, and diagnosis is difficult because of atypical radiological findings.

In the present case, increased serum calcium levels and extremely elevated PTH levels were observed, indicating hyperparathyroidism. Marked elevation of PTH level is one of the limited factors for predicting parathyroid carcinoma, but the parathyroid tumor of the current patient was diagnosed as an adenoma by postoperative pathologic analysis. The necrotic region observed within the resected tumor was compatible with the clinical course suggesting parathyroid apoplexy, which, in many reported cases, does not lead to complete remission of hyperparathyroidism long-term (44,45). In the differential diagnosis of multiple cystic bone lesions, hyperparathyroidism should be considered, and laboratory data may be useful for differentiating brown tumors and other bone lesions.

In summary, we report a case of severe hyperparathyroidism with multiple cystic bone lesions. Although hyperparathy-roidism with multiple cystic bone lesions is rare, it should be considered as a differential diagnosis in cases of multiple bone lesions.

The Authors declare that they have no competing interests in relation to this study.

All listed Authors substantially contributed to the following aspects of the manuscript: SM, TT, HA, SY, and TO participated in patient diagnosis and treatment and data acquisition. SM and HA collected the findings and drafted the manuscript. SM and HT revised the manuscript. All Authors read and approved the final manuscript.