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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 6  |  Issue : 4  |  Page : 188-192

Osteosarcoma arising from preexisting Paget's disease of bone


1 Division of Orthopaedic Surgery, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
2 Division of Endocrine and Metabolism, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
3 Department of Pathology, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
4 Department of Orthopaedic Surgery, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan

Date of Submission22-Mar-2019
Date of Decision31-May-2019
Date of Acceptance04-Jun-2019
Date of Web Publication22-Nov-2019

Correspondence Address:
Dr. Jih-Hsi Yeh
Department of Orthopaedic Surgery, E-Da Hospital/I-Shou University, No. 1, Yi-Da Road, Yan-Chao, Kaohsiung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_14_19

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  Abstract 


Paget's disease of bone (PDB) was first described by Sir James Paget in 1877 and is a relatively benign metabolic bone disease. It is believed to be a more common among European populations but is rare among Scandinavian and Asian populations. Malignant transformation is a rare, but fatal complications of PDB can occur, and most patients are elderly. Herein, we present a case of a tumor detected incidentally at the left proximal femur that was initially treated as metastatic bone disease, but the final pathology was proven to be secondary malignant transformation from preexisting PDB. Recent studies suggest that PDB may be under-represented in Asian populations. Thus, it is important that physicians pay more attention to PDB and its treatments. Early interventions and novel therapeutic agents can achieve better disease control and also prevent the complication of malignant transformation, which still has a poor prognosis.

Keywords: Paget's disease, sarcoma, transformation


How to cite this article:
Li YC, Kao YH, Tsai JW, Yen CY, Tu YK, Yeh JH. Osteosarcoma arising from preexisting Paget's disease of bone. J Cancer Res Pract 2019;6:188-92

How to cite this URL:
Li YC, Kao YH, Tsai JW, Yen CY, Tu YK, Yeh JH. Osteosarcoma arising from preexisting Paget's disease of bone. J Cancer Res Pract [serial online] 2019 [cited 2019 Dec 5];6:188-92. Available from: http://www.ejcrp.org/text.asp?2019/6/4/188/271494




  Introduction Top


Paget's disease of bone (PDB) is a relatively benign metabolic bone disease characterized by disruption of bone formation and resorption.[1] It has been reported to be more common among European populations but is rare among Scandinavian and Asian populations.[2],[3]

The prevalence of PDB is 1%–2% in most countries and has decreased recently.[1] A positive family history of PDB was reported in nearly 15%–40% of the cases in two reports studying a large population,[1],[3] and genetic susceptibility is suggested by the linkage between the human leukocyte antigen-DQW1 haplotype and PDB.[4] The overall incidence of malignant transformation is <1%, but it is a fatal complication of PDB, and most victims are elderly.[3],[5],[6],[7]

We present a case of a tumor detected incidentally at the left proximal femur that was initially treated as metastatic bone disease. However, the final pathology was proven to be secondary malignant transformation from preexisting PDB.


  Case Report Top


A 61-year-old man visited our orthopedic clinic in the year 2013 with the chief complaint of progressive left hip pain for 3 months. He was previously healthy without any underlying disease and denied any personal or familial tumor history. There were no neurological deficits such as numbness or muscle weakness over the left lower limb. No palpable soft-tissue mass or lymphadenopathy was observed during a physical examination. Pelvis and left hip radiography showed an osteolytic lesion at the left proximal femur with endosteal reactions [Figure 1]. The tumor border was sclerotic with osteoblastic bone formation and mild cortical thickening at the subtrochanteric area. The inferior cortex of the femoral neck was damaged, which caused pain and a high risk of pathological fracture. Magnetic resonance imaging revealed a heterogeneous contrast-enhanced tumor mass with cortex breakthrough [Figure 2]. Due to his age, metastatic bone disease was the first diagnosis, but other malignant bone tumors with osteoblastic change, such as osteosarcoma, were also considered. Several tumor markers were evaluated, but all were within normal limits. However, elevated alkaline phosphatase (452 U/L [normal range: 104–338 U/L]) and lactic dehydrogenase (219 U/L [normal range: 106–211 U/L]) levels were noted. To prevent a pathological fracture and to collect a tumor specimen for pathological evaluation, a surgeon initially arranged a tumor biopsy and prophylactic internal fixation. A compression hip screw was applied at the left proximal femur to prevent a pathological fracture [Figure 3]. A tumor survey, including Tc-99 whole-body bone scan [Figure 4] and chest computed tomography, was performed immediately after the first operation; however, no evidence of tumor metastasis or skin lesions was found except at the left proximal femur, which was consistent with bony malignancy clinically. Unfortunately, the tumor was diagnosed as a primary bone malignancy, either dedifferentiated chondrosarcoma or chondroblastic osteosarcoma, rather than the expected metastatic bone disease. Consequently, the patient was transferred to the orthopedic oncology clinic for further treatment.
Figure 1: Anteroposterior and frog view of the hip joint revealing an osteolytic lesion with scattered calcification and sclerotic margin at the left proximal femur. The proximal femur was enlarged with cortical disruption in the inferior part of the femoral neck

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Figure 2: Coronal and axial view of the left hip magnetic resonance imaging image showing a mixed osteolytic and sclerotic lesion at the left proximal femur and focal cortical penetration with adjacent soft-tissue invasion at the posterior aspect of the femoral neck

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Figure 3: Anteroposterior (a) and lateral (b) view of the left femur after the first operation. A compression hip screw was applied at the left proximal femur to prevent a pathological fracture. The implants and surrounding soft tissue were all excised during the second stage of the operation for tumor-wide excision

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Figure 4: Tc-99 whole-body bone scan revealed intense radioactivity at the left proximal femur, which was consistent with bony malignancy. No other definite bony abnormalities were seen

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For definite disease control, the patient underwent a second operation for tumor-wide excision and limb salvage surgery with mega-prosthesis reconstruction 1 month after the first surgery [Figure 5]. During the operation, the implants and surrounding soft tissues, including the previous surgical bed, drainage tunnel, and part of the joint capsule, were all excised to prevent tumor contamination and local recurrence.
Figure 5: Pelvic anteroposterior and lateral view of the left hip. The proximal part of the femur was excised followed by tumor prosthesis reconstruction

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The tumor showed a high-grade osteosarcoma histologically characterized by undifferentiated neoplastic cells forming sheets and nests infiltrating the marrow spaces with osteoid and chondroid matrix production, which led to the initial diagnosis of chondroblastic osteosarcoma. However, when combined with thickening and coarse trabecular bones with features of Paget's bone formation, the final pathology was confirmed to be secondary osteosarcoma arising from preexisting Paget's disease, which is rare in Asian populations [Figure 6]. The surgical margin was negative for malignancy. The elevated bone metabolism marker, alkaline phosphatase, dropped to normal limit (284 U/L [normal range: 104–338 U/L]) 1 month after the second operation. An oncologist was consulted for postoperative treatment, but the patient refused further adjuvant systemic chemotherapy or local radiation control. He was regularly followed up at our orthopedic oncology clinic. Plain radiographs (left femur and chest) were checked every 3 months, and chest computed tomography and Thallium-201 whole-body tumor scans were arranged every 6 months. We followed this protocol for 5 years, and no evidence of tumor relapse was observed. The patient is still regularly followed up annually.
Figure 6: Clinical photograph of the specimen and microscopic images of different sections of the tumor. Paget's sarcoma was confirmed both clinically and microscopically. (a) A specimen from the proximal femur. On dissection, a destructive and ill-defined tumor measuring 13.0 cm × 3.5 cm × 3.0 cm occupying the intramedullary cavity, which extended from the metaphysis to diaphysis, was observed. (b) A high-grade osteosarcoma characterized by undifferentiated neoplastic cells forming sheets and nests infiltrating the marrow spaces with osteoid production and chondroid matrix production H- and E-stained section (×400). (c) Showing thickening and coarse trabecular bones with features of Paget's bone formation H and E-stained section (×40). H and E: hematoxylin and eosin

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  Discussion Top


The incidence of Paget's disease among Asian populations was believed to be rare compared to that among Caucasian populations, and most patients were treated for joint arthritis or other musculoskeletal disorders. However, according to the latest reports, the prevalence of PDB may be underestimated in Asian populations because a large number of reported cases were discovered incidentally.[1] The introduction of novel therapeutic agents, including bisphosphonates and denosumab, had led to an improvement in PDB control. A single dose of intravenous long-acting bisphosphonate (zoledronic acid) has been reported to induce a therapeutic response within 6 months in 98% of patients with <1% recurrence rate after up to 6 years of follow-up.[8] Most patients can therefore have good functional recovery and quality of life. However, Paget's sarcoma, an uncommon but lethal complication, is still a concern for patients with PDB. The incidence of sarcomatous transformation in Paget's disease is estimated to be approximately 1% and is most common in patients with polyostotic disease, which has been estimated at 10%.[3],[5],[9] The incidence of malignant transformation is several 1000-fold higher in PDB patients than in the general population, and Paget's sarcoma accounts for 50% of osteosarcoma cases in patients aged >60 years, with the pelvis, proximal femur, and proximal humerus being the most affected.[5],[9],[10]

Radiographically, the early phase of PDB features an osteolytic region, which is later followed by coarsened trabeculae and cortical thickening. Giant cell tumor of the bone, which is more frequently seen in younger patients, is mainly osteolytic and can be distinguished from PDB. Interruption of the trabeculae with more osteoblastic change than the adjacent pagetic bone or soft-tissue extension with partially calcified tumor mass all indicate malignant transformation of preexisting PDB.[11]

Histologically, nonneoplastic multinucleated giant cells might be present in PDB, PDB with sarcomatous change, benign and malignant giant cell tumors of the bone, and conventional osteosarcoma (giant cell-rich variant). Prominent osteoclasts usually appear in the osteolytic phase of PDB, which is primarily composed of woven bone with a focal mosaic pattern of nearby lamellar bone. As in the conventional osteosarcoma, PDB with sarcomatous change shows neoplastic woven bones. Scattered macrophages and large osteoclast-like giant cells are among neoplastic mononuclear stromal cells in giant cell tumor of the bone, while malignant giant cell tumor of the bone has an area of highly pleomorphic mononuclear cells. These histological features help in the differential diagnosis between these giant cell-rich neoplasms.

The familial occurrence of the disease is estimated to involve 15%–30% of individuals with PDB. The most significant discovery has been that approximately 30% of familial PDB is associated with the SQSTM1 gene mutation, which encodes the ubiquitous multidomain intracellular scaffold protein, p62, and affects osteoclast differentiation, activity, and survival. Around 5% of those with sporadic PDB also carry these mutations. PDB has also been confirmed to be associated with multisystem proteinopathy, which is associated with five gene mutations: VCP, HNRNPA2B1, HNRNPA1, SQSTM1, and MATR3. However, in animal models, some authors have argued the role of SQSTM1 alone in creating the Paget-like phenotype, because mice expressing measles virus nucleocapsid protein in osteoclasts also developed Paget-like osteoclasts even without p62.[8] As a result, the true pathology of PDB may be multifactorial.

The impact of genetic mutations on malignant transformation has been addressed in many connective tissue malignancies. A case report from Japan also suggested a possible role of the TP53 mutation in the malignant transformation of PDB,[9] while another study addressed the result of tumor-specific loss of constitutional heterozygosity on chromosome 18.[12]

The 5-year survival rate of Paget's sarcoma is approximately 10%, much worse than that of conventional osteosarcoma, which has increased to nearly 70% with the improvement of neoadjuvant chemotherapy.[5],[10] Most tumors show a poor response to standard chemotherapy regimens used for conventional osteosarcoma. Failure to make an early diagnosis due to the absence of symptoms, underlying distortion of the pathologic bone, and old age of the patients may be the causes of poor prognosis in Paget's sarcoma patients.[6],[7],[13],[14]

Although the prevalence of PDB has decreased in certain countries over the past decades, with the increasing number of global intermarriages, the incidence may increase in the future.[1] Patients with a longer duration and severity of PDB have a higher risk of developing Paget's sarcoma.[5],[11] However, in most studies, more than half of the patients had no known history of PDB at the time of diagnosis.[5] Thus, physicians treating Asian patients must pay more attention to PDB and its treatments to provide effective care for the patients. Early interventions can achieve better disease control and improved quality of life for these patients and can also prevent the complication of malignant transformation, which still has a poor prognosis.[15]

The IRB disclosure

This is a case report and no names or initials will be published. The manuscript is prepared in accord with the regulations of the HIPAA privacy regulations and IRB approval is not required.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the forms, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be presented.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Merashli M, Jawad A. Paget's disease of bone among various ethnic groups. Sultan Qaboos Univ Med J 2015;15:e22-6.  Back to cited text no. 1
    
2.
Knapper T, Logan K, Gheorghiu D. Paget's disease-current concepts. Ann Orthop Rheumatol 2017;5:1082.  Back to cited text no. 2
    
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Singer F. Paget's disease of bone. In: Endotext. South Dartmouth (MA): MDText. Com, Inc.; 2016.  Back to cited text no. 3
    
4.
Kaplan FS, Singer FR. Paget's disease of bone: Pathophysiology, diagnosis, and management. J Am Acad Orthop Surg 1995;3:336-44.  Back to cited text no. 4
    
5.
Deyrup AT, Montag AG, Inwards CY, Xu Z, Swee RG, Krishnan Unni K. Sarcomas arising in Paget disease of bone: A clinicopathologic analysis of 70 cases. Arch Pathol Lab Med 2007;131:942-6.  Back to cited text no. 5
    
6.
Joo MW, Shin SH, Kang YK, Kawai A, Kim HS, Asavamongkolkul A, et al. Osteosarcoma in Asian populations over the age of 40 years: A multicenter study. Ann Surg Oncol 2015;22:3557-64.  Back to cited text no. 6
    
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Porretta CA, Dahlin DC, Janes JM. Sarcoma in Paget's disease of bone. J Bone Joint Surg Am 1957;39-A: 1314-29.  Back to cited text no. 7
    
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Cundy T. Paget's disease of bone. Metabolism 2018;80:5-14.  Back to cited text no. 8
    
9.
Akaike K, Toda-Ishii M, Suehara Y, Takagi T, Kaneko K, Yao T, et al. Case report Paget's sarcoma with sarcoma-specific TP53 mutation arising from a Japanese patient. Int J Clin Exp Pathol 2016;9:3978-86.  Back to cited text no. 9
    
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Mankin HJ, Hornicek FJ. Paget's sarcoma: A historical and outcome review. Clin Orthop Relat Res 2005;438:97-102.  Back to cited text no. 10
    
11.
Moore TE, King AR, Kathol MH, el-Khoury GY, Palmer R, Downey PR. Sarcoma in Paget disease of bone: Clinical, radiologic, and pathologic features in 22 cases. AJR Am J Roentgenol 1991;156:1199-203.  Back to cited text no. 11
    
12.
Nellissery MJ, Padalecki SS, Brkanac Z, Singer FR, Roodman GD, Unni KK, et al. Evidence for a novel osteosarcoma tumor-suppressor gene in the chromosome 18 region genetically linked with Paget disease of bone. Am J Hum Genet 1998;63:817-24.  Back to cited text no. 12
    
13.
Mangham DC, Davie MW, Grimer RJ. Sarcoma arising in Paget's disease of bone: Declining incidence and increasing age at presentation. Bone 2009;44:431-6.  Back to cited text no. 13
    
14.
Seitz S, Priemel M, Zustin J, Beil FT, Semler J, Minne H, et al. Paget's disease of bone: Histologic analysis of 754 patients. J Bone Miner Res 2009;24:62-9.  Back to cited text no. 14
    
15.
Hadjipavlou A, Lander P, Srolovitz H, Enker IP. Malignant transformation in Paget disease of bone. Cancer 1992;70:2802-8.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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