Falsely Negative F-18 FDG PET of Osteosarcoma Arising In Paget Disease.

We present the case of a large, painful pelvic bone tumor in a 53-year-old woman with severe Paget disease. Her presentation was complicated with bilateral total hip arthroplasty, history of spinal stenosis, and multiple lucent lesions in the spine and pelvis in severely affected pagetoid bone. This case features the rare but dreaded complication of osteosarcomatous transformation in Paget disease. A variety of imaging modalities including PET/CT were utilized in the evaluation of these lesions. The PET/CT findings were counter-intuitive with regard to the intense uptake of the underlying chronic disease process and the near-absence of uptake in the tumors. The histology of the pelvic mass is also intriguing, as it demonstrated a sarcoma with giant cell features. Conservative, non-operative management was chosen, due to the patient's poor medical condition, so we may never know the nature of the spinal lesion in this case, but will discuss the differential diagnosis for a lytic spinal lesion in a patient with severe Paget disease complicated by osteosarcoma with giant cell features.

Introduction

Paget disease of bone commonly affects 3-4% of the population over the age of 40 [1]. It is characterized by excessive and abnormal bone remodeling which may be predominantly lytic, mixed, or blastic [1]. The underlying etiology is not known; however, familial predisposition and a viral infection are likely contributory. The theory of viral origin is supported by giant osteoclasts with intranuclear inclusion bodies seen in Paget disease which are also seen in viral infections such as measles. Paramyxovirus, the cause of measles, is also seen in some patients with Paget disease of bone [1]. Intranuclear inclusion bodies have also been found in the osteoclasts of giant cell tumor complicating Paget disease of bone [2].

Approximately 15-40% of people affected by Paget disease of bone have a family history of the disease [3]. Certain populations also have higher prevalence of Paget disease, such as the Ashkenazi Jews with an associated increased frequency of HLA-DR2 serum marker, suggesting genetic susceptibility [1]. The actual classification of this disease process is controversial and a variety of other causes have been proposed including connective tissue disease, autoimmune disorder, vascular disease, metabolic disease related to parathormone, or a neoplastic process [4].

Malignant transformation to sarcoma has been estimated to occur in 0.15% to 1% of patients with longstanding Paget disease [5, 1]. Although this sounds like a relatively small risk of occurrence in an individual patient with Paget disease of bone, this still increases the risk of osteosarcoma in pagetic patients to 30 times greater than that of the general population of patients over the age of 40 [3, 5]. Usually a single focus of neoplasm is seen; however, in some instances, multiple foci are observed, which may reflect independent multicentric origin of tumor or metastasis from a single lesion [4, 6].

Case Report

The patient is a 53-year old woman with a history of advanced Paget’s disease and prior bilateral total hip arthroplasty. She presented with left hip pain and dysuria. The pain was described as constant with radiation to her left leg and was initially controlled by oral narcotics, but progressed to activity limitation until she was restricted to a wheelchair and required an intravenous morphine pump.

This patient’s family history is significant for having a sister and aunt with Paget disease. Her primary care provider reported a remote history of problems with the left hip prosthesis with several prior episodes of dislocation and presumed revision. It is not known whether the acetabular component was initially restrained or was revised with addition of the restraining screw to discourage further dislocations.

A radiograph of the pelvis (Fig. 1) demonstrates bilateral hip arthroplasty components; the device on the left is constrained by a single acetabular screw. On the left, there is destruction of the posteromedial wall of the acetabulum. Additional findings include spinal decompression with laminectomy at L4 and L5 and diffusely enlarged pagetoid bone with cortical and trabecular coarsening.

Figure 1

53-year-old woman with bone tumor arising in Paget disease. AP radiograph of the pelvis shows Paget disease and bilateral total hip arthroplasty. On the left (arrows) there is destruction of the posteromedial wall of the acetabulum. Additional findings include spinal decompression with laminectomy at L4 and L5 and diffusely enlarged pagetoid bone with cortical and trabecular coarsening.

A CT scan (Fig. 2) demonstrated a large intrapelvic mass, adjacent to and eroding the medial acetabular wall and quadrilateral plate of the left hemipelvis. Sagittal reformations of this study (Fig. 3) reveal a large lucent lesion in the T12 vertebral body with destruction of the posterior cortex of the vertebral body and slight protrusion into the spinal canal. At the level below the lesion, cortical and trabecular coarsening at L1 form a classic “picture frame” vertebral body pathognomonic of Paget disease. Compression fractures are evident at L2 and L4. Four consecutive vertebral bodies are involved with anterior bridging osteophytes and the disc spaces appear relatively preserved considering the degree of anterior ossification consistent with diffuse idiopathic skeletal hyperostosis (DISH) at T8-11.

Figure 2

53-year-old woman with bone tumor arising in Paget disease. Axial CT (A) through the level of the pelvic tumor (arrows) a large soft tissue mass adjacent to the medial wall of the acetabulum and obturator foramen is displacing the adjacent, contrast-filled bowel. Coarsened trabeculae, characteristic of pagetoid bone, is evident in the left acetabulum with lucency about the retaining screw of the left total hip arthroplasty. (B) At a lower level, the mass (arrows) has central low density. There is bony destruction of the medial wall of the acetabulum. (C) Coronal CT demonstrates a large soft tissue mass (arrows) with destruction of the medial wall of the left acetabulum. At T12, a lucent lesion is present in the vertebral body (arrowhead). Beam hardening artifact related to the dense metallic components of bilateral total hip arthroplasty implants is noted in the pelvis in all images.

Figure 3

53-year-old woman with bone tumor arising in Paget disease. (A) Sagittal CT (B) enlargement of sagittal to better demonstrated detail, and (C) axial images through T12. There is a large lucent lesion in the T12 vertebral body with destruction of the posterior cortex of the vertebral body and slight protrusion into the spinal canal (arrows). At the level below the lesion, cortical and trabecular coarsening at L1 form a classic “picture frame” vertebral body pathognomonic of Paget disease (arrow head). Compression fractures are evident at L2 and L4. Diffuse idiopathic skeletal hyperostosis (DISH) is present from T8-11.

A transvaginal biopsy of the pelvic mass revealed a spindle cell neoplasm with giant cells, foci of necrosis, and mitotic activity. The initial pathologic evaluation suggested, but could not confirm the sarcomatous nature of the tumor.

A PET scan (Fig. 4) was performed to further investigate the mass. Although intense uptake was present in a classic distribution for Paget disease of bone, neither the large pelvic tumor nor the vertebral body lesion demonstrated significant uptake.

Figure 4

53-year-old woman with bone tumor arising in Paget disease. F-18 FDG PET images, (A) frontal, (B) oblique (C) posterior, reveal a markedly hypermetabolic appearance of a portion of the calvarium, the right humerus, and both femurs which are also curved; findings which can be seen in Paget disease. Although there is uptake in the bilateral pedicles at T12, there is no significant uptake in the spinal lesion at T12 (arrow). Only mild uptake is seen in the posterior acetabulum in the region of the erosive lesion (arrow). No significant uptake is seen in the pelvic mass (arrows). The Axial image (D) obtained through the pelvis at the level of the mass confirms absence of activity at the medial wall of the left acetabulum as well as throughout the region of the mass (arrows). Urinary artifact is present below the pubic symphysis in images A, B, and C.

Due to the acetabular erosion adjacent to a hip prosthesis in severely pagetoid bone, considerations for the pelvic mass with bone destruction included a prosthesis complication with aggressive osteolysis and inflammatory giant cell mass with central necrosis. This however, would not explain the additional vertebral body lesion. Multifocal giant cell tumor has been reported in patients with Paget disease of bone and would be a consideration. Given the patient’s severe Paget disease, multiple brown tumors related to hyperparathyroidism is another possibility. Given the very low uptake of both lytic lesions on PET, sarcoma and giant cell tumor initially seemed less likely as both usually demonstrate intense uptake.

Differential diagnosis for the lytic spinal lesion included multifocal giant cell tumor, brown tumor, multifocal or metastatic osteosarcoma, with another metastatic disease considered less likely as the patient is a relatively young woman with no known malignancy.

The histological characteristics of the tumor were further investigated with an open biopsy, which showed a cellular fibroblastic spindle cell neoplasm with cytological atypia, necrosis, and mitotic activity (Fig. 5A) as well as regions of malignant bone and cartilage formation (Fig. 5B) and giant cell rich areas. The giant cell rich areas were somewhat distinct from the spindle cell and bone forming areas of the tumor raising the possibility of a concomitant benign giant cell tumor of Paget disease adjacent to a sarcoma; a collision lesion formed of both a benign and malignant component. Although we cannot entirely exclude this possibility, the giant cell rich areas contained similar spindle cells as the remainder of the tumor (Fig. 5C), and therefore, the pelvic mass was interpreted as a high grade osteosarcoma with giant cell features rather than as colliding lesions.

Figure 5A

53-year-old woman with bone tumor arising in Paget disease. Cellular primitive fibroblastic spindle cell proliferation with primitive cytological atypia, mitotic activity, and intercellular bone formation (center left and center right).

Figure 5B

53-year-old woman with bone tumor arising in Paget disease. Chondro-osseous matrix containing anaplastic chondrocytic cells.

Figure 5C

53-year-old woman with bone tumor arising in Paget disease. Giant cell rich areas with proliferating spindle cells.

In this case, following multi-disciplinary review, chemotherapy and possible later hemipelvectomy were chosen as preferred management. However, the patient subsequently became too ill to initiate chemotherapy. Biopsy of the spinal lesions was also deferred as unnecessarily invasive and unlikely to provide benefit to this patient.

Discussion

Due to the confounding findings of PET in this case, some review of the expected behavior of benign and malignant lesions of bone seems pertinent. In the study of PET uptake in benign and malignant primary bone lesions by Aoki et al., there was considerable overlap in SUV values for some benign and malignant primary bone tumors with both osteosarcoma (malignant) and giant cell tumor (usually benign), demonstrating relatively high uptake [7]. Cook et al. also identified that benign disease such as Paget disease of bone, sarcoidosis, and tuberculosis may cause FDG uptake that was so high as to mimic that of malignant bone lesions [8]. It appears that PET cannot be used to distinguish between osteomyelitis and osteosarcoma, which was not a clinical question in this case, but is worth keeping in mind when pressed to use imaging to assess the etiology of an aggressive bone lesion [9].

Cook et al. further evaluated 18 patients with Paget disease and identified that pagetoid bone was avid for Tc99-MDP on bone scan, but usually did not exhibit markedly elevated FDG uptake. However, in 33% some variable degree of FDG uptake was demonstrated, and in 17%, the uptake was high enough to mimic malignancy or metastatic disease [10]. Thus, there is potential for FDG uptake in Paget disease to mimic metastatic disease when staging malignancy with PET [11].

Aoki et al. also discuss the controversy regarding whether the presence of giant cells in primary bone tumors are reactive or neoplastic. Bone lesions commonly associated with giant cells include osteoblastoma, chondromyxoid fibroma, aneurysmal bone cyst, giant cell reparative granuloma, brown tumors, and malignant fibrous histiocytoma [7].

In the article by Murphey et al. discussing giant cell tumor and giant cell reparative granuloma of bone, they recommend drawing calcium, phosphate, and parathormone levels to distinguish GCT from brown tumor, as they can be indistinguishable both by imaging features and histologically [12, 13].

This case demonstrates an osteosarcoma with giant cell features in a patient with advanced Paget disease. The Paget disease demonstrates remarkable metabolic activity on PET whereas the two tumors show negligible activity on PET and could potentially be overlooked. The patient’s bilateral hip arthroplasty components shower the pelvis with beam hardening artifact which decreases the visibility of the tumor and further expands the initial differential diagnosis of the pelvic mass to include problems related to her arthroplasty in addition to complications of Paget disease.

When viewed initially as complication of total hip arthroplasty in a patient with severe Paget disease, loosening, infection, particle disease, tumor, or aggressive pagetoid osteolysis were all reasonable considerations [14, 15]. Cross sectional imaging demonstration of the pelvic mass increased the concern for tumor and there was no clinical evidence of infection; thus decreasing the likelihood of abscess.

While the histology of the additional spinal lesion is unknown, it is interesting to reflect on what it might be. It could be a giant cell tumor, brown tumor, or a simultaneously occurring sarcoma or a sarcomatous metastasis. With regard to distinguishing between brown tumor and giant cell tumor, they may appear identical by imaging and histology and although our patient had normal to low serum calcium, her serum phosphate and PTH are unknown.

The fact that the aunt and sister of our patient also had Paget disease initially sounded remarkable, however, since 15-44 % of patients with Paget disease will have an affected relative, this appears statistically less striking.

Our patient is a relatively young woman and it seems uncharacteristic that she would have such severe Paget disease and the rare complication of osteosarcoma. The presence of additional lesions and counter-intuitive PET results further enhance the tragic uniqueness of this case.