Skeletal Radiol DOI 10.1007/s00256-015-2144-2
CASE REPORT
Paget’s sarcoma of the patella Salman Ansari 1 & Fiona Bonar 2 & Paul Stalley 3 & Wendy Brown 1
Received: 29 January 2015 / Revised: 12 March 2015 / Accepted: 23 March 2015 # ISS 2015
Abstract Paget’s sarcoma is a rare complication of Paget’s disease and isolated Paget’s disease of the patella is extremely rare. We describe a unique case of Paget’s sarcoma of the patella in a 69-year-old male farmer who had a remote history of a fracture in the same patella 40 years previously. In this case, imaging and pathogenesis of Paget’s disease of bone is described and factors implicated in the development of Paget’s disease in this patient are evaluated. Keywords Paget’s sarcoma . Patella . Paget’s disease . Trauma
Introduction Paget’s disease of bone (PDB) is characterized by abnormal bone remodeling with increased activity of osteoclasts and osteoblasts and resultant disorganized bone architecture. It is a common skeletal disease seen in persons living in parts of Europe and in their descendants in countries such as Australia, New Zealand, South Africa, and North America, with prevalence increasing with age [1]. It is often identified incidentally on radiographs or diagnosed following investigation of pain. PDB commonly affects the pelvis, femur, lumbar spine, skull, * Wendy Brown [email protected] 1
Department of Radiology, Royal Prince Alfred Hospital, PO Box M118, Missenden Road, Camperdown, NSW 2050, Australia
2
Douglass Hanly Moir Pathology, 14 Giffnock Avenue, Macquarie Park, NSW 2113, Australia
3
Department of Orthopaedics, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
and tibia [2, 3]. Gene mutations that result in dysfunctional osteoclasts are implicated in disease pathogenesis. Other factors that are considered to play a role in its evolution include viral infection in particular and there are documented cases that postulate a role for mechanical or repetitive stress injury [4, 5]. Paget’s sarcoma can complicate PDB, usually affects the pelvis, femur, and humerus, and often represents the presenting feature [6]. We report a rare case of isolated PDB of the patella complicated by sarcoma in a 69-year-old male farmer who had sustained a patellar fracture 40 years previously. Paget’s sarcoma of the patella has not previously been described. This unique case has added interest as it lends further support for a role for trauma in the evolution of the disorder.
Case history Use of health data and access to medical records was approved by the author’s Local Health District Ethics Review Committee. Informed written consent was obtained from the patient. A 69-year-old male farmer who was otherwise well presented with pain and swelling of the kneecap noted for 3 weeks. He had sustained a fracture of the same patella 40 years previously, which was treated by internal fixation with subsequent removal of the hardware. He was otherwise well, was on no medications, and had no relevant family history. A lateral radiograph showed marked enlargement of the patella. An area of radiolucency was visible on the skyline view with coarse trabeculation at the perimeter of the patella. There was no cortical thickening. Accompanying severe patellofemoral joint osteoarthritis with joint space narrowing and marginal osteophytes was evident (Fig. 1). MRI
Skeletal Radiol
Fig. 1 a Lateral and b skyline X-ray views of the left knee of a 69-yearold man show enlargement of the patella, with coarse trabeculation, typical of PDB. Cortical thickening is absent. A central lytic lesion is present. Severe patellofemoral osteoarthrosis is shown with joint space narrowing and marginal osteophytes
confirmed the presence of an enlarged patella that comprised a central mass lesion, which appeared well defined and composed of multiple small lobulated areas that were T2 hyperintense. There were no fluid levels. No cortical breach or soft tissue mass was present. Elsewhere in the patella, at the perimeter of the central mass, ill-defined confluent areas of T2 hyperintensity with a heterogeneous pattern were noted. The presence of severe patellofemoral joint osteoarthritis was confirmed (Fig. 2). PET CT performed after a 3-week interval showed bone destruction centrally on CT, which appeared to have progressed with loss of the anterior cortex. A maximum SUVof 11.7 was recorded, which was predominant in the mid zone with a central area of low uptake. The peripheral aspect of the patella showed no abnormal uptake. The radiological diagnosis was that of PDB of the patella with features suspicious for central Paget’s sarcoma. Associated osteoarthritis was seen. Patellectomy with intraoperative frozen section was performed in which small fragments of hemorrhagic tissue were retrieved measuring 16×10×3 mm in aggregate. Malignant cells were identified on air-dried smears with immature osteoid on H&E-stained sections confirming a diagnosis of osteosarcoma. The patellectomy specimen included a cuff of
Fig. 2 a MRI axial fat-suppressed T2-weighted and b sagittal proton density sequences of the left knee in a 69-year-old man showing an enlarged patella and a well-defined central lesion. The central lesion demonstrates heterogeneous T2 hyperintensity with small cystic foci. There are no fluid-fluid levels. No overt aggressive features such as cortical breach or soft tissue mass are seen. Diffuse, less-marked T2 hyperintensity is present in the remainder of the patella. Patellofemoral osteoarthrosis is noted with full thickness chondral loss
surrounding soft tissues. Macroscopic examination confirmed a diagnosis of osteoarthritis with eburnation of the articular surface. On serial sectioning, a central, somewhat poorly defined, heterogeneous tumor mass 50×50×30 mm was noted in which there were firm, pale areas intermingled with hemorrhagic and cystic areas. The biopsy site was included anteriorly, however macroscopically the tumor appeared confined within the bone. Peripherally, the medullary bone had a more dense and pale appearance (Fig. 3a). Histological examination of the peripheral component showed characteristic features of PDB with variably thick trabeculae comprising coalescent plates of bone with a prominent mosaic pattern of cement lines. Florid osteoblastic and osteoclastic activity was evident with large multinucleated osteoclasts. The central tumor showed features of a high-grade osteosarcoma in which areas
Skeletal Radiol
Fig. 3 a Gross findings: Axial section of patella of a 69-year-old man with central variably hemorrhagic tumor (red star) with defect anteriorly representing the intraoperative biopsy site. The tumor is bordered by pale sclerotic appearing bone at perimeter (blue solid arrow). The joint surface is devoid of articular cartilage (open blue arrows). b Microscopic findings of patella specimen of a 69-year-old man: A scanning view show the variegated tumor denoted by red stars, thick pagetic bone trabeculae denoted by solid blue arrows and osteoarthritic articular surface denoted by open blue arrows. c Microscopic findings of patella specimen of a 69-year-old man: Low-power view shows pagetic bone (blue arrows), sarcoma (red stars) and intermingled PDB and sarcoma
(red and blue arrows). d Microscopic findings of patella specimen of a 69-year-old man: High-power view illustrates the characteristic findings of PDB with thick coalescent plates of bone with a mosaic pattern of cement lines and vigorous osteoblastic and osteoclastic activity in a loose fibrovascular stroma. e Microscopic findings of patella specimen of a 69-year-old man: High-power view confirms osteosarcoma with malignant pleomorphic and anaplastic cells producing immature osteoid. f Microscopic findings of patella specimen of a 69-year-old man: Intermingled pagetic bone with mosaic pattern of cement lines is intimately associated with the surrounding osteosarcoma
of osteoblastic and chondroblastic differentiation were noted. Blood-filled spaces were included, giving the tissue a focally telangiectatic appearance. Malignant tumor cells producing osteoid were easily identifiable and in many areas intermingled sclerotic pagetoid bone and osteosarcoma were
seen (Fig. 3b–f). Anteriorly, focal disruption of the cortex was noted with vascular invasion in which a giant-cell-rich area of tumor was present. Osteoarthritis with loss of the articular cartilage and subchondral sclerosis was confirmed, the subchondral bone exhibiting extensive PDB.
Skeletal Radiol
The patellectomy was followed by a reconstruction with turndown of the quadriceps tendon to bridge across to the stump of the patella tendon. This reconstruction was augmented by a medial gastrocnemius flap graft. After 8 weeks of immobilization, free movement was allowed, with return of function to the knee joint. A subsequent skeletal survey yielded no other abnormalities. Alkaline phosphatase, which was elevated on presentation at 151 U/l (normal 50-100 U/l), fell post-operatively to within normal limits at 96 U/l. A diagnosis of isolated PDB of the patella complicated by Paget’s sarcoma and osteoarthritis was made.
Discussion PDB involving the patella is rare, affecting approximately 1 % of patients with polyostotic disease in larger series [7, 8]. PDB confined to the patella is extremely rare. On review of the literature, less than 20 cases are documented in which nine possible cases are included in the English literature [9–17] (Table 1). In Stull’s series of five cases, two were definitely polyostotic, one definitely monostotic, and in two cases data on extent of disease was not available. Although the case documented by Kleinbart et al. does not conclusively confirm that the patella alone was involved, one of the authors (Dr. Vincent Vigorita) recollects that this was so. On review of the last documented case (Ploumis et al.), convincing imaging or histological features to support a diagnosis of PDB are not presented and a diagnosis of stress fracture seems more likely. Six other cases are documented in the non-English literature from 1947 to 2010 [18–23]. In the English literature, of the eight cases in which the clinical data is elucidated, there were three male and five female patients with an age range from 44 to 90, a median age of 61, and a mean age of 62. There are no documented cases of Paget’s sarcoma of the patella, either in the isolated or polyostotic form of PDB. As such, this is a unique case of a rare tumor occurring in an extremely rare site. Table 1 Monostotic cases of Paget’s disease of the patella
Imaging Our patient had characteristic radiographic features of PDB including bone expansion and increased bony trabeculation, but lacked typical cortical thickening. Severe patellofemoral osteoarthritis, a common complication of PDB, was present in our case and has previously been described in the patella, the severity of which appears to be proportionate to patellar enlargement with encroachment of the joint space and cartilage loss [11, 13, 16]. The differential diagnosis in PDB at any site includes metastasis and chronic osteomyelitis in particular, depending on the degree of osteolysis and osteosclerosis related to remodeling. In vertebral lesions, trabeculation may mimic the striations of hemangioma. Fractures are a complication related to suboptimal biomechanics and have been documented in PDB of the patella [13, 14]. Fracture may also occur as a result of Paget’s sarcoma, which is usually characterized on imaging by a combination of bone destruction and a soft tissue mass in a setting of PDB [24, 25]. Osteosarcoma is the most common sarcoma complicating PDB, contributing to the second peak of osteosarcoma seen in the elderly [26]. Fibrosarcoma and undifferentiated sarcoma (previously designated MFH) may also occur. Sarcoma may have either osteolytic or osteosclerotic features on X-ray depending on the nature of the matrix. The osteolytic form occurs more frequently than the sclerotic form and this has been attributed to rapid rate of cell turnover [25]. Although this may reflect tumor type (fibrosarcomatous, fibrohistiocytic and telangiectatic subtypes of osteosarcoma) [27], osteolysis has also been noted in series where osteoblastic osteosarcoma predominated [28]. Giant cell tumor is also documented in PDB, occurs at any affected site, responds to simple therapies, and is very rare [29]. Other tumors including lymphoma and metastases are likely coincidental [25, 26]. Cystic change and even necrosis in PDB may mimic sarcoma on X-ray [30]. MRI enhances the diagnosis of the presence, nature, and extent of sarcoma. MRI is helpful in determining the presence and extent of soft tissue involvement and in our case allowed assessment of joint involvement. In the
Author
Year of publication
Patient sex
Patient age
Clinical features
Pyper JB Gordon L Weinert CR D’Haem RJ Stull MA Kleinbart FA Abamor E Amr R Ploumis A
1958 1958 1979 1989 1990 1992 2001 2006 2008
M F M M * F F F F
46 57 44 67 * 65 70 90 54
Painful knee Painful knee Osteoarthritis Incidental Osteoarthritis Fracture post fall Painful knee Osteoarthritis Painful knee
*Patient demographics could not be determined from the data provided
Skeletal Radiol
setting of sarcoma, T1-weighted MR images demonstrate loss of normal fatty marrow signal. Conversely, the presence of preserved fatty marrow is used to exclude tumors [31]. In this case, the MRI was done prior to referral to our center and a T1weighted sequence had not been performed. The combination of proton density, fat-suppressed, T2-weighted MR images and X-rays were diagnostic of a sarcoma complicating PDB. MRI can assess background changes of PDB in bone adjacent to the tumor where T2 hyperintensity due to fibrovascular tissue replacement of the medulla or cortex, and thin linear low T1 signal due to thickened trabeculae occur [31]. In our case, the tumor was large, occupying much of the patella and was close to the patellofemoral joint, thus the T2 hyperintensity noted adjacent to the tumor could reflect PDB, peritumoral edema, or subchondral edema due to osteoarthritis (histology confirmed the presence of PDB in the surrounding bone). Bone scan or skeletal survey is used to assess the extent of PDB. Increased isotope uptake on bone scan is very sensitive but not specific for PDB as a range of other bone disorders may also cause increased uptake. F-18 FDG CT-PET is useful for the identification of metastatic Paget’s sarcoma and may confirm increased metabolic activity of the primary lesion. Although low-grade uptake on CT-PET has been described in patients with the active form of PDB, this is not a ubiquitous finding [32, 33]. In cases of increased uptake on bone scan, a lack of activity on CT-PET can be reassuring in excluding sarcoma or metastases in pagetoid bone.
Pathogenesis PDB, documented in 1877 [34], is characterized by disordered architecture predominating in the lumbar spine, pelvis, skull, femur, and tibia [3]. It is usually asymptomatic with few bones affected and multifocal generalized forms are well recognized but rare. Although it has been documented worldwide and in ancient remains [35], PDB predominates in Caucasians of European ancestry particularly in the United Kingdom (UK) and southern Europe and in migrants from these areas to Australia, New Zealand, South Africa, and North America [1]. Approximately 1–2 % of the population of the UK over the age of 50 are afflicted and at age 80, PDB is present in approximately 8 % of males and 5 % of females. The incidence and severity of the disease has diminished in recent decades [36–38]. It is rare in Africans, people from the Indian subcontinent, and Asians, although recent data suggests that Asians living in Western countries are increasingly affected [39]. PDB is characterized by increased osteoclastic and osteoblastic activity with elevation of alkaline phosphatase. Osteoclasts in PDB are large with up to 100 nuclei. They are derived from monocytes/macrophages under the influence of a variety of transcription factors and osteoclast precursors
from PDB patients have increased sensitivity to the major transcription factor RANKL in vitro [40]. Genetic associations in PDB are well documented. A family history pertains in 15 %, which appears to be autosomal dominant with incomplete penetrance. In first-degree relatives, there is a seven to tenfold increase in the incidence of the disease [1, 3, 40, 41]. Genetic predisposition to PDB appears to be regulated by variants in several genes involved in the differentiation and maturation of osteoclasts. SQSTM1 (sequestrome 1/p62) is considered to be an important protein in this axis. SQSTM1 gene mutations, most involving the ubiquitin binding domain, occur in 40–50 % of familial PDB and in about 5–10 % of individuals with sporadic PDB. The protein product is p62 (sequestrome 1), which affects regulation of RANK L-mediated activation of NF- β, which has a major role in osteoclast function [3, 40, 42–46]. Although there are some genotype phenotype relationships [45, 46], the severity of the disease appears to be diminishing despite the presence of mutations and not all individuals with mutations get PDB [40]. Many genes are known or suspected to predispose to PDB, all of which are involved in the evolution and differentiation of osteoclasts. These include TNFR SF11A (RANK) mutations, which occur in familial expansile osteolysis, early onset familial PDB, and expansile skeletal hyperplasia. TNFRSF11B (OPG) mutations occur in juvenile PDB. VCP (p97) mutations occur in inclusion body myopathy with PDB and fronto-temporal dementia and SQSTM1 (p62) gene mutations occur in classical PDB. It has been suggested that variant mutations of these alternate genes may pertain in adult PDB in which SQSTM mutations are absent. Although individually these cause no disease, combinations of such mutations may predispose to an increased risk of PDB due to dysregulation of osteoclasts [40]. Other factors in the pathogenesis of PDB have been the subject of much discussion over the decades. A viral cause was suggested on the basis of the epidemiology of the disease and because of the presence of apparent viral-like inclusions identified particularly in the familial variant of the disease [47]. Members of the paramyxovirus family, in particular measles, canine distemper virus and respiratory syncytial virus, were alluded to. Evidence for a viral cause and persistence of infection remains conflicting and controversial. Paramyxovirus viral proteins can modulate osteoclasts and there appears to be a subset of patients who have persistent measles virus nucleocapsid protein [1, 3, 40]. The identity of the inclusions is not fully established, however it is thought that they may represent dysfunctional osteoclasts as similar inclusions are seen in osteopetrosis, hereditary oxalosis, familial expansile osteolysis (in whom RANK L mutations are present) and in mice models with SQSTM1 mutations [40]. It has been suggested that these are related to undegraded protein aggregates due to dysregulation of protein autophagy. Autophagosomes are spherical structures with a
Skeletal Radiol
double-layered membrane responsible for intracellular degradation of cytoplasmic contents including proteins, protein aggregates, and organelles. The autophagosome encapsules the target and fuses with lysosomes or endosomes, which contain hydrolases. Proteins involved in this process include p62 receptors, which bind the autophagosome membrane allowing docking of the lysosome. In any setting where autophagy does not occur, accumulation of the aggregates leads to dysfunctional osteoclasts with accumulation of the viral-like structures within the cytoplasm [40]. Environmental associations have long been considered important and these have included low dietary calcium, vitamin D deficiency, and environmental toxins. A role for trauma or repetitive mechanical loading of bones has been suggested and, in the UK in particular, individuals living in a rural rather than an urban setting seem more likely to develop the disease. This may reflect exposure to cattle or dogs, possibly reflecting the effects of canine distemper virus [40]. Although the relationship to trauma is often mooted in the literature, it has never been clarified. The two papers most commonly cited are from 1979, in which one of the affected patients was a keen billiard player and the other a long-term treadle machine operator [3, 4]. The distribution of PDB in both distinctly correlated with the severity of the mechanical forces applied in repetitive manner. In the billiard player, there was increased trabeculation and expansion of the lower right radius, upper halves of both humeri, first metacarpal of the right hand, and the proximal phalanges of the second and fourth fingers on the left side. In the treadle machine operator, the changes predominated in the right ilium, lower right femur, and upper right tibia. The latter patient had pedaled with her right foot from during the First World War to the 1950s. Of note in our case is the definite history of a remote fracture. Although one of the nine cases of isolated PDB affecting the patella cited in the literature presented with a recent fracture, a conclusive prior remote history of trauma is not available in any. Paget’s sarcoma is rare. In a study from the Mayo Clinic comprising 3964 cases of PDB, less than 1 % of individuals (38 cases) presented with a sarcoma, none of which were in the patella. In this study, all had polyostotic disease, 29 % had metastasis at diagnosis, and the 5-year survival was dismal at less than 8 % [24]. More recently, two further studies of Paget’s sarcoma are available, one an update on the Mayo series now documenting 70 cases of Paget’s sarcoma from 1927 through to 2007 and a second study from the UK documenting 32 cases from 1975 to 2009 [6, 48]. Interestingly, the mean age of the patients in the Mayo series (from 1927) was 66, while that of the UK series in the cohort diagnosed pre-1996 was 70.4 and post-1996 was 76.6, findings which support observations that patients are presenting at a later age. In addition, in contrast to the initial Mayo series, nearly half of the cases of Paget’s sarcoma occurred on a
background of isolated/monostotic PDB (47 and 42.3 %, respectively). The distribution of sarcoma was similar in both with involvement of the axial and appendicular skeleton and in the latter commonly involving the humerus. None involved the patella. Survival remains poor with 5-year survival of between 10 and 12.5 % [6, 48]. In general, most Paget’s sarcomas represent osteosarcoma histologically; the remainder are documented as fibrosarcoma or malignant fibrous histiocytoma, which currently would be characterized as undifferentiated sarcoma [49]. Interestingly, in the UK series, two individuals had a low-grade sarcoma, one of whom had a prolonged survival [6]. There is no evidence in the literature of any specific benefit in Paget’s sarcoma from chemotherapy or radiotherapy [28] and data on any risk factors for the evolution of sarcoma in PDB is elusive.
Conclusions Isolated PDB of the patella is extremely rare with less than 20 cases documented. This case of Paget’s sarcoma of the patella represents a unique phenomenon. Of great interest is the fact that the patient has a definite history of a fracture 40 years previously. He is also a farmer exposed to cattle and dogs. As such, he has several factors that have been mooted to be important in the evolution of PDB. Although he has no family history of PDB, we cannot exclude the possibility of any specific gene mutation, as such testing is not available to us. Trauma may have been coincidental in the development of PDB but nonetheless in this possibly genetically susceptible individual with isolated disease in an exquisitely rare location and a remote but clear history of prior fracture, the role for trauma warrants consideration. Conflict of interest The authors declare that they have no conflicts of interest.
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CASE REPORT
Paget’s sarcoma of the patella Salman Ansari 1 & Fiona Bonar 2 & Paul Stalley 3 & Wendy Brown 1
Received: 29 January 2015 / Revised: 12 March 2015 / Accepted: 23 March 2015 # ISS 2015
Abstract Paget’s sarcoma is a rare complication of Paget’s disease and isolated Paget’s disease of the patella is extremely rare. We describe a unique case of Paget’s sarcoma of the patella in a 69-year-old male farmer who had a remote history of a fracture in the same patella 40 years previously. In this case, imaging and pathogenesis of Paget’s disease of bone is described and factors implicated in the development of Paget’s disease in this patient are evaluated. Keywords Paget’s sarcoma . Patella . Paget’s disease . Trauma
Introduction Paget’s disease of bone (PDB) is characterized by abnormal bone remodeling with increased activity of osteoclasts and osteoblasts and resultant disorganized bone architecture. It is a common skeletal disease seen in persons living in parts of Europe and in their descendants in countries such as Australia, New Zealand, South Africa, and North America, with prevalence increasing with age [1]. It is often identified incidentally on radiographs or diagnosed following investigation of pain. PDB commonly affects the pelvis, femur, lumbar spine, skull, * Wendy Brown [email protected] 1
Department of Radiology, Royal Prince Alfred Hospital, PO Box M118, Missenden Road, Camperdown, NSW 2050, Australia
2
Douglass Hanly Moir Pathology, 14 Giffnock Avenue, Macquarie Park, NSW 2113, Australia
3
Department of Orthopaedics, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
and tibia [2, 3]. Gene mutations that result in dysfunctional osteoclasts are implicated in disease pathogenesis. Other factors that are considered to play a role in its evolution include viral infection in particular and there are documented cases that postulate a role for mechanical or repetitive stress injury [4, 5]. Paget’s sarcoma can complicate PDB, usually affects the pelvis, femur, and humerus, and often represents the presenting feature [6]. We report a rare case of isolated PDB of the patella complicated by sarcoma in a 69-year-old male farmer who had sustained a patellar fracture 40 years previously. Paget’s sarcoma of the patella has not previously been described. This unique case has added interest as it lends further support for a role for trauma in the evolution of the disorder.
Case history Use of health data and access to medical records was approved by the author’s Local Health District Ethics Review Committee. Informed written consent was obtained from the patient. A 69-year-old male farmer who was otherwise well presented with pain and swelling of the kneecap noted for 3 weeks. He had sustained a fracture of the same patella 40 years previously, which was treated by internal fixation with subsequent removal of the hardware. He was otherwise well, was on no medications, and had no relevant family history. A lateral radiograph showed marked enlargement of the patella. An area of radiolucency was visible on the skyline view with coarse trabeculation at the perimeter of the patella. There was no cortical thickening. Accompanying severe patellofemoral joint osteoarthritis with joint space narrowing and marginal osteophytes was evident (Fig. 1). MRI
Skeletal Radiol
Fig. 1 a Lateral and b skyline X-ray views of the left knee of a 69-yearold man show enlargement of the patella, with coarse trabeculation, typical of PDB. Cortical thickening is absent. A central lytic lesion is present. Severe patellofemoral osteoarthrosis is shown with joint space narrowing and marginal osteophytes
confirmed the presence of an enlarged patella that comprised a central mass lesion, which appeared well defined and composed of multiple small lobulated areas that were T2 hyperintense. There were no fluid levels. No cortical breach or soft tissue mass was present. Elsewhere in the patella, at the perimeter of the central mass, ill-defined confluent areas of T2 hyperintensity with a heterogeneous pattern were noted. The presence of severe patellofemoral joint osteoarthritis was confirmed (Fig. 2). PET CT performed after a 3-week interval showed bone destruction centrally on CT, which appeared to have progressed with loss of the anterior cortex. A maximum SUVof 11.7 was recorded, which was predominant in the mid zone with a central area of low uptake. The peripheral aspect of the patella showed no abnormal uptake. The radiological diagnosis was that of PDB of the patella with features suspicious for central Paget’s sarcoma. Associated osteoarthritis was seen. Patellectomy with intraoperative frozen section was performed in which small fragments of hemorrhagic tissue were retrieved measuring 16×10×3 mm in aggregate. Malignant cells were identified on air-dried smears with immature osteoid on H&E-stained sections confirming a diagnosis of osteosarcoma. The patellectomy specimen included a cuff of
Fig. 2 a MRI axial fat-suppressed T2-weighted and b sagittal proton density sequences of the left knee in a 69-year-old man showing an enlarged patella and a well-defined central lesion. The central lesion demonstrates heterogeneous T2 hyperintensity with small cystic foci. There are no fluid-fluid levels. No overt aggressive features such as cortical breach or soft tissue mass are seen. Diffuse, less-marked T2 hyperintensity is present in the remainder of the patella. Patellofemoral osteoarthrosis is noted with full thickness chondral loss
surrounding soft tissues. Macroscopic examination confirmed a diagnosis of osteoarthritis with eburnation of the articular surface. On serial sectioning, a central, somewhat poorly defined, heterogeneous tumor mass 50×50×30 mm was noted in which there were firm, pale areas intermingled with hemorrhagic and cystic areas. The biopsy site was included anteriorly, however macroscopically the tumor appeared confined within the bone. Peripherally, the medullary bone had a more dense and pale appearance (Fig. 3a). Histological examination of the peripheral component showed characteristic features of PDB with variably thick trabeculae comprising coalescent plates of bone with a prominent mosaic pattern of cement lines. Florid osteoblastic and osteoclastic activity was evident with large multinucleated osteoclasts. The central tumor showed features of a high-grade osteosarcoma in which areas
Skeletal Radiol
Fig. 3 a Gross findings: Axial section of patella of a 69-year-old man with central variably hemorrhagic tumor (red star) with defect anteriorly representing the intraoperative biopsy site. The tumor is bordered by pale sclerotic appearing bone at perimeter (blue solid arrow). The joint surface is devoid of articular cartilage (open blue arrows). b Microscopic findings of patella specimen of a 69-year-old man: A scanning view show the variegated tumor denoted by red stars, thick pagetic bone trabeculae denoted by solid blue arrows and osteoarthritic articular surface denoted by open blue arrows. c Microscopic findings of patella specimen of a 69-year-old man: Low-power view shows pagetic bone (blue arrows), sarcoma (red stars) and intermingled PDB and sarcoma
(red and blue arrows). d Microscopic findings of patella specimen of a 69-year-old man: High-power view illustrates the characteristic findings of PDB with thick coalescent plates of bone with a mosaic pattern of cement lines and vigorous osteoblastic and osteoclastic activity in a loose fibrovascular stroma. e Microscopic findings of patella specimen of a 69-year-old man: High-power view confirms osteosarcoma with malignant pleomorphic and anaplastic cells producing immature osteoid. f Microscopic findings of patella specimen of a 69-year-old man: Intermingled pagetic bone with mosaic pattern of cement lines is intimately associated with the surrounding osteosarcoma
of osteoblastic and chondroblastic differentiation were noted. Blood-filled spaces were included, giving the tissue a focally telangiectatic appearance. Malignant tumor cells producing osteoid were easily identifiable and in many areas intermingled sclerotic pagetoid bone and osteosarcoma were
seen (Fig. 3b–f). Anteriorly, focal disruption of the cortex was noted with vascular invasion in which a giant-cell-rich area of tumor was present. Osteoarthritis with loss of the articular cartilage and subchondral sclerosis was confirmed, the subchondral bone exhibiting extensive PDB.
Skeletal Radiol
The patellectomy was followed by a reconstruction with turndown of the quadriceps tendon to bridge across to the stump of the patella tendon. This reconstruction was augmented by a medial gastrocnemius flap graft. After 8 weeks of immobilization, free movement was allowed, with return of function to the knee joint. A subsequent skeletal survey yielded no other abnormalities. Alkaline phosphatase, which was elevated on presentation at 151 U/l (normal 50-100 U/l), fell post-operatively to within normal limits at 96 U/l. A diagnosis of isolated PDB of the patella complicated by Paget’s sarcoma and osteoarthritis was made.
Discussion PDB involving the patella is rare, affecting approximately 1 % of patients with polyostotic disease in larger series [7, 8]. PDB confined to the patella is extremely rare. On review of the literature, less than 20 cases are documented in which nine possible cases are included in the English literature [9–17] (Table 1). In Stull’s series of five cases, two were definitely polyostotic, one definitely monostotic, and in two cases data on extent of disease was not available. Although the case documented by Kleinbart et al. does not conclusively confirm that the patella alone was involved, one of the authors (Dr. Vincent Vigorita) recollects that this was so. On review of the last documented case (Ploumis et al.), convincing imaging or histological features to support a diagnosis of PDB are not presented and a diagnosis of stress fracture seems more likely. Six other cases are documented in the non-English literature from 1947 to 2010 [18–23]. In the English literature, of the eight cases in which the clinical data is elucidated, there were three male and five female patients with an age range from 44 to 90, a median age of 61, and a mean age of 62. There are no documented cases of Paget’s sarcoma of the patella, either in the isolated or polyostotic form of PDB. As such, this is a unique case of a rare tumor occurring in an extremely rare site. Table 1 Monostotic cases of Paget’s disease of the patella
Imaging Our patient had characteristic radiographic features of PDB including bone expansion and increased bony trabeculation, but lacked typical cortical thickening. Severe patellofemoral osteoarthritis, a common complication of PDB, was present in our case and has previously been described in the patella, the severity of which appears to be proportionate to patellar enlargement with encroachment of the joint space and cartilage loss [11, 13, 16]. The differential diagnosis in PDB at any site includes metastasis and chronic osteomyelitis in particular, depending on the degree of osteolysis and osteosclerosis related to remodeling. In vertebral lesions, trabeculation may mimic the striations of hemangioma. Fractures are a complication related to suboptimal biomechanics and have been documented in PDB of the patella [13, 14]. Fracture may also occur as a result of Paget’s sarcoma, which is usually characterized on imaging by a combination of bone destruction and a soft tissue mass in a setting of PDB [24, 25]. Osteosarcoma is the most common sarcoma complicating PDB, contributing to the second peak of osteosarcoma seen in the elderly [26]. Fibrosarcoma and undifferentiated sarcoma (previously designated MFH) may also occur. Sarcoma may have either osteolytic or osteosclerotic features on X-ray depending on the nature of the matrix. The osteolytic form occurs more frequently than the sclerotic form and this has been attributed to rapid rate of cell turnover [25]. Although this may reflect tumor type (fibrosarcomatous, fibrohistiocytic and telangiectatic subtypes of osteosarcoma) [27], osteolysis has also been noted in series where osteoblastic osteosarcoma predominated [28]. Giant cell tumor is also documented in PDB, occurs at any affected site, responds to simple therapies, and is very rare [29]. Other tumors including lymphoma and metastases are likely coincidental [25, 26]. Cystic change and even necrosis in PDB may mimic sarcoma on X-ray [30]. MRI enhances the diagnosis of the presence, nature, and extent of sarcoma. MRI is helpful in determining the presence and extent of soft tissue involvement and in our case allowed assessment of joint involvement. In the
Author
Year of publication
Patient sex
Patient age
Clinical features
Pyper JB Gordon L Weinert CR D’Haem RJ Stull MA Kleinbart FA Abamor E Amr R Ploumis A
1958 1958 1979 1989 1990 1992 2001 2006 2008
M F M M * F F F F
46 57 44 67 * 65 70 90 54
Painful knee Painful knee Osteoarthritis Incidental Osteoarthritis Fracture post fall Painful knee Osteoarthritis Painful knee
*Patient demographics could not be determined from the data provided
Skeletal Radiol
setting of sarcoma, T1-weighted MR images demonstrate loss of normal fatty marrow signal. Conversely, the presence of preserved fatty marrow is used to exclude tumors [31]. In this case, the MRI was done prior to referral to our center and a T1weighted sequence had not been performed. The combination of proton density, fat-suppressed, T2-weighted MR images and X-rays were diagnostic of a sarcoma complicating PDB. MRI can assess background changes of PDB in bone adjacent to the tumor where T2 hyperintensity due to fibrovascular tissue replacement of the medulla or cortex, and thin linear low T1 signal due to thickened trabeculae occur [31]. In our case, the tumor was large, occupying much of the patella and was close to the patellofemoral joint, thus the T2 hyperintensity noted adjacent to the tumor could reflect PDB, peritumoral edema, or subchondral edema due to osteoarthritis (histology confirmed the presence of PDB in the surrounding bone). Bone scan or skeletal survey is used to assess the extent of PDB. Increased isotope uptake on bone scan is very sensitive but not specific for PDB as a range of other bone disorders may also cause increased uptake. F-18 FDG CT-PET is useful for the identification of metastatic Paget’s sarcoma and may confirm increased metabolic activity of the primary lesion. Although low-grade uptake on CT-PET has been described in patients with the active form of PDB, this is not a ubiquitous finding [32, 33]. In cases of increased uptake on bone scan, a lack of activity on CT-PET can be reassuring in excluding sarcoma or metastases in pagetoid bone.
Pathogenesis PDB, documented in 1877 [34], is characterized by disordered architecture predominating in the lumbar spine, pelvis, skull, femur, and tibia [3]. It is usually asymptomatic with few bones affected and multifocal generalized forms are well recognized but rare. Although it has been documented worldwide and in ancient remains [35], PDB predominates in Caucasians of European ancestry particularly in the United Kingdom (UK) and southern Europe and in migrants from these areas to Australia, New Zealand, South Africa, and North America [1]. Approximately 1–2 % of the population of the UK over the age of 50 are afflicted and at age 80, PDB is present in approximately 8 % of males and 5 % of females. The incidence and severity of the disease has diminished in recent decades [36–38]. It is rare in Africans, people from the Indian subcontinent, and Asians, although recent data suggests that Asians living in Western countries are increasingly affected [39]. PDB is characterized by increased osteoclastic and osteoblastic activity with elevation of alkaline phosphatase. Osteoclasts in PDB are large with up to 100 nuclei. They are derived from monocytes/macrophages under the influence of a variety of transcription factors and osteoclast precursors
from PDB patients have increased sensitivity to the major transcription factor RANKL in vitro [40]. Genetic associations in PDB are well documented. A family history pertains in 15 %, which appears to be autosomal dominant with incomplete penetrance. In first-degree relatives, there is a seven to tenfold increase in the incidence of the disease [1, 3, 40, 41]. Genetic predisposition to PDB appears to be regulated by variants in several genes involved in the differentiation and maturation of osteoclasts. SQSTM1 (sequestrome 1/p62) is considered to be an important protein in this axis. SQSTM1 gene mutations, most involving the ubiquitin binding domain, occur in 40–50 % of familial PDB and in about 5–10 % of individuals with sporadic PDB. The protein product is p62 (sequestrome 1), which affects regulation of RANK L-mediated activation of NF- β, which has a major role in osteoclast function [3, 40, 42–46]. Although there are some genotype phenotype relationships [45, 46], the severity of the disease appears to be diminishing despite the presence of mutations and not all individuals with mutations get PDB [40]. Many genes are known or suspected to predispose to PDB, all of which are involved in the evolution and differentiation of osteoclasts. These include TNFR SF11A (RANK) mutations, which occur in familial expansile osteolysis, early onset familial PDB, and expansile skeletal hyperplasia. TNFRSF11B (OPG) mutations occur in juvenile PDB. VCP (p97) mutations occur in inclusion body myopathy with PDB and fronto-temporal dementia and SQSTM1 (p62) gene mutations occur in classical PDB. It has been suggested that variant mutations of these alternate genes may pertain in adult PDB in which SQSTM mutations are absent. Although individually these cause no disease, combinations of such mutations may predispose to an increased risk of PDB due to dysregulation of osteoclasts [40]. Other factors in the pathogenesis of PDB have been the subject of much discussion over the decades. A viral cause was suggested on the basis of the epidemiology of the disease and because of the presence of apparent viral-like inclusions identified particularly in the familial variant of the disease [47]. Members of the paramyxovirus family, in particular measles, canine distemper virus and respiratory syncytial virus, were alluded to. Evidence for a viral cause and persistence of infection remains conflicting and controversial. Paramyxovirus viral proteins can modulate osteoclasts and there appears to be a subset of patients who have persistent measles virus nucleocapsid protein [1, 3, 40]. The identity of the inclusions is not fully established, however it is thought that they may represent dysfunctional osteoclasts as similar inclusions are seen in osteopetrosis, hereditary oxalosis, familial expansile osteolysis (in whom RANK L mutations are present) and in mice models with SQSTM1 mutations [40]. It has been suggested that these are related to undegraded protein aggregates due to dysregulation of protein autophagy. Autophagosomes are spherical structures with a
Skeletal Radiol
double-layered membrane responsible for intracellular degradation of cytoplasmic contents including proteins, protein aggregates, and organelles. The autophagosome encapsules the target and fuses with lysosomes or endosomes, which contain hydrolases. Proteins involved in this process include p62 receptors, which bind the autophagosome membrane allowing docking of the lysosome. In any setting where autophagy does not occur, accumulation of the aggregates leads to dysfunctional osteoclasts with accumulation of the viral-like structures within the cytoplasm [40]. Environmental associations have long been considered important and these have included low dietary calcium, vitamin D deficiency, and environmental toxins. A role for trauma or repetitive mechanical loading of bones has been suggested and, in the UK in particular, individuals living in a rural rather than an urban setting seem more likely to develop the disease. This may reflect exposure to cattle or dogs, possibly reflecting the effects of canine distemper virus [40]. Although the relationship to trauma is often mooted in the literature, it has never been clarified. The two papers most commonly cited are from 1979, in which one of the affected patients was a keen billiard player and the other a long-term treadle machine operator [3, 4]. The distribution of PDB in both distinctly correlated with the severity of the mechanical forces applied in repetitive manner. In the billiard player, there was increased trabeculation and expansion of the lower right radius, upper halves of both humeri, first metacarpal of the right hand, and the proximal phalanges of the second and fourth fingers on the left side. In the treadle machine operator, the changes predominated in the right ilium, lower right femur, and upper right tibia. The latter patient had pedaled with her right foot from during the First World War to the 1950s. Of note in our case is the definite history of a remote fracture. Although one of the nine cases of isolated PDB affecting the patella cited in the literature presented with a recent fracture, a conclusive prior remote history of trauma is not available in any. Paget’s sarcoma is rare. In a study from the Mayo Clinic comprising 3964 cases of PDB, less than 1 % of individuals (38 cases) presented with a sarcoma, none of which were in the patella. In this study, all had polyostotic disease, 29 % had metastasis at diagnosis, and the 5-year survival was dismal at less than 8 % [24]. More recently, two further studies of Paget’s sarcoma are available, one an update on the Mayo series now documenting 70 cases of Paget’s sarcoma from 1927 through to 2007 and a second study from the UK documenting 32 cases from 1975 to 2009 [6, 48]. Interestingly, the mean age of the patients in the Mayo series (from 1927) was 66, while that of the UK series in the cohort diagnosed pre-1996 was 70.4 and post-1996 was 76.6, findings which support observations that patients are presenting at a later age. In addition, in contrast to the initial Mayo series, nearly half of the cases of Paget’s sarcoma occurred on a
background of isolated/monostotic PDB (47 and 42.3 %, respectively). The distribution of sarcoma was similar in both with involvement of the axial and appendicular skeleton and in the latter commonly involving the humerus. None involved the patella. Survival remains poor with 5-year survival of between 10 and 12.5 % [6, 48]. In general, most Paget’s sarcomas represent osteosarcoma histologically; the remainder are documented as fibrosarcoma or malignant fibrous histiocytoma, which currently would be characterized as undifferentiated sarcoma [49]. Interestingly, in the UK series, two individuals had a low-grade sarcoma, one of whom had a prolonged survival [6]. There is no evidence in the literature of any specific benefit in Paget’s sarcoma from chemotherapy or radiotherapy [28] and data on any risk factors for the evolution of sarcoma in PDB is elusive.
Conclusions Isolated PDB of the patella is extremely rare with less than 20 cases documented. This case of Paget’s sarcoma of the patella represents a unique phenomenon. Of great interest is the fact that the patient has a definite history of a fracture 40 years previously. He is also a farmer exposed to cattle and dogs. As such, he has several factors that have been mooted to be important in the evolution of PDB. Although he has no family history of PDB, we cannot exclude the possibility of any specific gene mutation, as such testing is not available to us. Trauma may have been coincidental in the development of PDB but nonetheless in this possibly genetically susceptible individual with isolated disease in an exquisitely rare location and a remote but clear history of prior fracture, the role for trauma warrants consideration. Conflict of interest The authors declare that they have no conflicts of interest.
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