Keywords
Paget's disease - osteitis deformans - bone metastasis - diagnostic imaging
Paget's Disease
Epidemiology
Paget's disease, or osteitis deformans, was first described in 1877 by Sir James Paget.[1] It is a bone pathology characterized by abnormal excessive remodeling of one or
more long bones. The exact frequency is hard to determine because the disease is usually
asymptomatic.[2] Prevalence has decreased significantly over the past 20 years, whereas it was 3
to 4% of patients > 45 years of age in the 1990s.[3] Etiology remains unknown, although several hypotheses have been proposed: inflammatory,
vascular, hormonal, autoimmune, infectious, metabolic, or neoplastic.[4] In 1974, the discovery of intranuclear viral inclusions in affected cells strengthened
the viral hypothesis, although no specific virus could be identified.[5] The decrease in prevalence suggests environmental factors.
Pathophysiology
Progression comprises three phases, each associated with specific clinical, radiologic,
and pathologic features.[6]
The early, or lytic phase, is characterized by intense osteoclastic activity with resorption of normal bone
by multinuclear giant cells and formation of Howship's lacunae. It is usually clinically
asymptomatic. Radiographs show an advancing wedge of bone resorption. In this phase,
the bone marrow is relatively normal.
The intermediate active phase is characterized by intense reactional osteoblastic activity stimulated by the osteoclastic
resorption of the previous phase. Bone resorption continues, but osteoblasts repopulate
the resorption areas and cement themselves to the denuded bone. When osteoblastic
repair exceeds bone resorption, the trabeculae thicken and become lined with several
layers, resulting in the classic mosaic bone pattern of Paget's disease. Abnormal
remodeling follows, repair being poor in collagen fibers, and alters bone architecture.
The bone marrow is usually hypervascularized. The disease is most often discovered
in this phase.
The late inactive phase is characterized by a progressive decline in osteoblastic and osteoclastic activity.
Fatty marrow predominates and hematopoietic elements disappear, although dilated vessels
persist.[6] Once affected, the bone never recovers its initial or its normal state. In this
late phase, affected bones continue to enlarge, thicken, and weaken due to defective
bone production.
Typical Imaging Features
Imaging features follow the histologic findings seen during the three phases, although
they are also influenced by the involved bone ([Table 1]).[6]
Table 1
Classical aspects of Paget's disease
|
Early phase
|
Intermediate phase
|
Late phase
|
|
Radiograph/CT
|
Bone advancing wedge of resorption
|
Advancing wedge of resorption
Trabecular thickening, cortical thickening, bone segment enlargement
|
Bone segment enlargement and deformation
|
|
CT
|
Like radiograph
|
Like radiograph plus disorganized trabeculae, persistent fatty density areas between
trabeculae; very dense star-shaped focal intracancellous areas
|
Like radiograph
|
|
MRI
|
Fatty signal
|
Fatty signal
Possible edematous remodeling
|
Hypervascularized fibrous bone marrow
|
|
Technetium99m scintigraphy
|
Low-intensity fixation
|
Intense fixation
|
Fixation sometimes less marked
|
|
FDG-PET/CT
|
Low-intensity or no fixation
|
Low-intensity fixation
|
Low intensity or no fixation
|
Abbreviations: CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance
imaging; PET, positron emission tomography.
Radiographically, in the early phase, osteoclastic activity results in an advancing
tip of V-shaped bone resorption, extending toward the diaphysis.[7] To be detectable on radiographs, resorption in the affected area has to involve
sufficiently thick cortical bone, and the progression front tends not to be identifiable
in areas mainly comprising cancellous bone, such as the spine, pelvis, or long-bone
epiphyses. In the skull, the advancing wedge of resorption is noted as enlarged areas
of radiolucency usually in the frontal and occipital bones and designated as “osteoporosis
circumscripta” ([Fig. 1a]). Skull lesions are most prominent in the inner calvarial tables and usually cross
the suture lines.
Fig. 1 Typical imaging features in the skull. (a) “Osteoporosis circumscripta” seen as a large area of radiolucency (between arrows).
(b) Bone resorption associated with areas of osteocondensation with blurred contours,
giving the skull a cotton wool appearance.
The intermediate phase features the four cardinal signs of Paget's disease:
These four radiographic features are essential to the diagnosis. Their presence rules
out the main differential diagnoses for densifying bone lesions: fibrous dysplasia,
osteitis, bone-densifying metastasis, and lymphoma. When identified, they are in themselves
pathognomic, and biopsy is unnecessary. In the late phase, bones are enlarged, deformed,
and brittle due to abnormal bone production.
Overall abnormal bone formation results in osseous weakening, despite the increased
density of bone, with deformity and fracture. Anterior or lateral bowing of the tibiae
and femora is typical; in the hip, deformity may manifest as protrusio acetabuli.
On computed tomography (CT), in addition to the four cardinal radiographic features,
these features are apparent:
-
- Fewer but thicker and disorganized trabeculae, giving a honeycomb aspect ([Fig. 2])
-
- Persistent areas of fatty density between trabeculae
-
- Very dense focal star-shaped intracancellous areas mimicking enostosis
Fig. 2 Incidental discovery of Paget's disease in a patient with lung cancer (fluorodeoxyglucose
positron emission tomography/computed tomography hyperfixation of the right humeral
head). (a) Axial computed tomography image shows fewer but thicker disorganized trabeculae,
resulting in a honeycomb appearance with persisting fatty density areas between trabeculae.
(b) Axial T1-weighted image shows normal fatty bone marrow between the trabeculae.
There are no soft tissue abnormalities.
In the spine, often the region in which the question of differential diagnoses arises,
screening looks for these characteristics ([Table 2]):
Table 2
Aspects suggestive of Paget's disease in the spine
|
Thick, rough vertical trabeculae
|
|
Transverse and anteroposterior vertebral enlargement compared with unaffected vertebrae
|
|
Increased sclerosis along the four edges of the vertebral body, particularly the superior
and inferior edges, leading to a “frame” aspect
|
|
Strong increase in bone mineral density, often extending to posterior elements, sometimes
leading to “ivory” vertebra
|
|
Flattening of the normal concavity of the anterior edge of the vertebral body
|
|
Sclerosis and enlargement of the posterior arch
|
|
Biconcave deformation by vertebral plate microfracture, leading to “fish” vertebra
|
-
- Harmonious involvement of the whole vertebral body and posterior arch ([Fig. 2])
-
- Transverse and anteroposterior enlargement of the vertebral body or loss of anterior
concavity in incipient forms
-
- Spinous process hypertrophy
-
- Cortical thickening along the four margins of the vertebral body with cortexes producing
the characteristic picture frame appearance[8]
In the skull, bone resorption is associated with areas of osteocondensation with blurred
contours, predominantly at the level of the internal table and giving the skull a
cotton wool appearance ([Fig. 1b]). Skull lesions are most prominent in the inner calvarial tables and usually cross
the suture lines.
On magnetic resonance imaging (MRI), Paget's disease can be overlooked because the
affected bone may present normal or relatively preserved signal intensity of the fatty
bone marrow on T1-weighted images. Cortical thickening and trabecular coarsening can
be difficult to identify on MRI, but a contrast between obvious radiographic or CT
abnormalities and a seemingly normal fatty marrow signal on MRI is highly suggestive
of Paget's disease ([Fig. 3]). In advanced stages, decreased corticocancellous differentiation can be responsible
for fatty signal intensity of the cortical bone. In the late phase, the bone marrow
becomes hypervascularized and fibrous.
Fig. 3 Incidental discovery of Paget's disease in a patient with colon cancer. (a) Axial computed tomography image shows loss of corticomedullary differentiation,
with sclerotic focal areas (star) and a fatty area (arrow). The bone marrow signal
intensity of the right femoral head is mildly decreased on T1 (b), normal on T2 short tau inversion recovery (c), and shows a mild enhancement after gadolinium administration (d). Biopsy confirmed Paget's disease.
There may be regions of fibrosis or sclerosis showing low T1 and T2 signal, or hypervascularized
marrow with low T1 and high T2 signal, enhancing after gadolinium administration.
In these difficult cases, once again, screening should search for islands of residual
fatty marrow to rule out medullary replacement of tumoral origin ([Fig. 4]). In very active forms, an adjacent edematous soft tissue reaction may be noted.
However, there is no soft tissue mass. Presence of the latter suggests either sarcomatous
degeneration or metastatic colonization.
Fig. 4 Incidental discovery of Paget's disease in a patient with endometrial cancer (L5
vertebra scintigraphic hyperfixation). (a) Axial computed tomography image shows disorganized vertebral trabecular architecture,
affecting both body and posterior arch. (b) Sagittal T1 and (c) short tau inversion recovery (STIR)-weighted images show involvement of the whole
vertebra with a partial fatty bone marrow signal on T1 and an edematous signal on
STIR.
On conventional technetium 99m-hydroxydiphosphonate bone scintigraphy, fixation is
intense in the intermediate phase and highly suggestive; this is a marker of osteoblastic
activity, with increased resorption in the active phase ([Fig. 5]). In the late phase, fixation decreases. Scintigraphy is more sensitive than radiographs,
revealing up to 30% more lesions, especially in the ribs, sternum, and scapulae, which
are difficult to analyze on radiographs.[9] In noncomplicated cases, F-18 fluorodeoxyglucose uptake on positron emission tomography
is slight, a marker of glycolysis rather than of osteoblastic activity.[10] This examination can provide a key element in the differential diagnosis versus
metastasis.[11]
Fig. 5 Incidental discovery, on prostate cancer extension assessment, of abnormal right
iliac wing signal (arrow), heterogeneous with persistent large fatty areas on T1 (a) and edematous remodeling on STIR sequences (b), with enhancement under gadolinium (c). (d) Scintigraphy shows intense fixation. (e) On computed tomography, remodeling is subtle with slight sclerosis and global enlargement
of the iliac wing compared with the contralateral side. Biopsy confirmed Paget's disease.
Atypical Presentation of Paget's Disease
Atypical Presentation of Paget's Disease
Presentation of Paget's disease may be unusual clinically (e.g., age at onset < 40
years), in topography (limbs, extremities), or in imaging, raising the question of
a differential diagnosis with other bone diseases, notably tumoral. Even so, in most
cases, evidence from patient interview, clinical examination, and imaging leads to
a diagnosis without the need for biopsy.
Lesion Topography
Paget's disease begins in the long-bone epiphysis, progressively extending to the
diaphysis. The entire bone may thus be involved. In the spine, concomitant involvement
of the spinous apophysis on imaging strongly suggests Paget's disease[12] ([Fig. 6]). The pathology rarely originates in both extremities of a given bone. It does not
cross the joints, except in the case of bone ankylosis. In multifocal lesions, remodeling
may differ from bone to bone, suggesting differences in time of onset.[13] Thus phase, extension, and radiologic and pathologic characteristics vary considerably
from bone to bone or even from region to region within a given bone.
Fig. 6 (a) Incidental discovery, on breast cancer extension assessment, of moderate intensity
L3 vertebral body fluorodeoxyglucose-positron emission tomography fixation. (b) Axial computed tomography image shows heterogeneous sclerosis of the vertebral body,
with concomitant involvement of the spinous process, suggesting Paget's disease. (c) Sagittal T1-weighted images show a persistent fatty area at the posterior aspect
of the vertebral body, despite the diffuse sclerosis. (d) Sagittal short tau inversion recovery–weighted images show a mild enlargement and
increased signal of the vertebra.
Progression
Progression is slow, estimated at a little less than 1 cm per year.[14] In atypical Paget's disease, comparative analysis of previous examinations is essential
to rule out differential diagnoses.
After a fracture or prolonged immobilization, the pagetic bone may present significant
bone rarefaction with loss of cortical sharpness that may mimic a metastasis. This
pseudotumoral bone rarefaction is classic in the pelvis and femora.
Biology
Densifying metastasis, like Paget's disease, can lead to alkaline phosphatase elevation.
Levels may be normal in the early phase or in very late phases, between which the
assay does not discriminate. But high levels of acid phosphatase or prostate-specific
antigen suggest metastatic disease of prostate origin.
Absence of the Four Cardinal Radiographic Signs
In Paget's disease, imaging features may be unusual, such as the absence of one or
several cardinal features. Sclerotic changes may represent the main imaging feature,
especially in the spine.[15] Different patterns of diffuse or focal texture abnormalities, best visualized on
CT, have been described.[16] In diffuse abnormalities, the microcystic pattern is the most common: thin sclerotic
or normal remaining trabeculae delineate “cystic” spaces that range in size from small
(1–5 mm) to large (> 5 mm). The mesh pattern is characterized by scarce and thick
intersecting bone trabeculae ([Fig. 2]). The diffuse sclerotic pattern (ivory vertebra) shows diffuse homogeneous increase
in bone density of the vertebral body, whose size and contours remain normal. This
presentation is very difficult to distinguish from metastatic disease or lymphoma
([Fig. 3]). In the spine, depiction of concomitant involvement of the spinous apophysis or
of mild enlargement of the bone is highly suggestive of Paget's disease ([Fig. 6]).
Three types of focal bone texture abnormalities can be encountered[16]:
-
- Sclerotic foci seen as foci of compact bone with thorny edges ([Fig. 3]), usually associated with typical diffuse involvement, facilitating diagnosis of
Paget's disease
-
- Bone-within-bone appearance produced by bone apposition at the periosteal surface
of the vertebral body, resulting in a “double contour” sign
-
- Focal thickening of horizontal trabeculae converging toward the pedicles
In early forms, texture abnormalities may be absent. In such unusual forms, there
is never periosteal apposition or destruction of the cortical bone ([Fig. 7]).
Fig. 7 (a) Computed tomography image of a 69-year-old woman consulting for hip pain. The hypothesis
of a fracture (arrow) on Paget's disease due to cortical thickening and disorganized
aspect of the cortical trabeculation was proposed. Note that the small areas of cortical
osteolysis (arrowhead) and soft tissue thickening (stars) argue against this hypothesis.
(b, c) Moreover, magnetic resonance imaging shows medullary replacement on T1 and soft
tissue involvement on short tau inversion recovery. Biopsy confirmed the diagnosis
of bone lymphoma.
In these difficult cases lacking the cardinal radiographic signs, complementary MRI
is indispensable. A fatty signal intensity of bone marrow favors Paget's disease in
doubtful cases. Scintigraphy showing hyperfixation, with normal bone marrow signal
on MRI, reinforces the diagnosis of Paget's disease.
Misleading Bone Marrow Appearance
Several misleading bone marrow appearances can be encountered[16]:
-
- At the earliest stages, the bone marrow is preserved or only minimally involved.
Paget's disease may therefore be overlooked on MRI ([Fig. 5]).
-
- At the intermediate stage, nonspecific bone marrow edema can be seen. It occurs
in 30% of patients with vertebral Paget's disease. Features suggesting edema rather
than bone marrow replacement include mild and homogeneous signal intensity changes
on both T1- and T2-weighted images, mild homogeneous enhancement after gadolinium
administration, preservation of bone texture, and absence of an adjacent soft tissue
mass on all MRI sequences ([Fig. 4]).[17]
-
- A sclerotic pattern with low signal intensity on both T1- and T2-weighted images.
The presence of vertebral shape abnormalities, involvement of the entire vertebra,
and depiction of residual fatty foci are particularly helpful for the diagnosis.
In diffuse densifying Paget's disease, MRI shows the bone marrow as hypointense in
both T1 and T2 due to increased trabecular thickening, bone marrow sclerosis, and
fibrosis ([Fig. 6]). In these particular cases, abnormal vertebral morphology and involvement of the
whole vertebra favor the diagnosis of Paget's disease.
The clues for the diagnosis of Paget's disease on MRI in the presence of unusual presentations
include comparison with radiographs, CT, or bone scintigraphy, depiction of residual
fatty foci, depiction of minor shape abnormalities, involvement of the whole vertebra
in the spine, and the absence of an adjacent soft tissue mass ([Table 3]).
Table 3
Checklist for differential diagnosis between Paget's disease and metastasis
|
Bone structure remodeling on radiographs without bone marrow signal abnormality: Paget's
disease
|
|
Radiographic abnormalities without bone marrow abnormality, with intense fixation
on scintigraphy: Paget's disease
|
|
Scintigraphy shows the best sensitivity in detecting polyostotic disease. Involvement
may be asynchronous, with aspects varying between affected bone segments
|
|
In case of signal abnormality or bone marrow enhancement on magnetic resonance imaging,
screen for persistent fatty islands to rule out medullary replacement
|
|
Progression of Paget's disease is very slow; comparison with previous imaging examinations,
if available, assessing progressiveness, is a key factor in diagnosing Paget's disease
|
|
In case of vertebral involvement, posterior arch involvement is characteristic of
Paget's disease
|
|
Soft tissue infiltration is exceptional
|
Particular Case of Metastasis in Paget-affected Bone
Given the advanced age of most Paget patients, association with other malignancies
such as metastases, myeloma, and primary lymphoma can be expected.[18] Because metastatic disease is usually multifocal, lesions within pagetic bone are
unlikely to pose much of a diagnostic problem.[18] Onset of osteolysis with cortical destruction and an associated soft tissue mass
are highly suggestive. Interestingly, metastases tend to occur in an eccentric location
when present in long bones, in contrast to the central origin of osteosarcomas.[18] Primary lymphoma superimposed on Paget's disease can also present as a focal permeative
lesion with or without a soft tissue mass ([Fig. 7]).[18] However, metastases, myeloma, and lymphoma may be indistinguishable from Paget's
sarcoma when arising within bone affected by Paget's disease. Although not malignant,
giant cell tumor can also occasionally involve pagetic bone.
Particular Case of Sarcomatous Transformation
Paget's sarcoma is rare, and its incidence is decreasing due to the fall in prevalence
and in clinical severity of Paget's disease. Osteosarcoma is the predominant histologic
subtype. Onset of pain either due to the tumor itself or secondary to a pathologic
fracture is a cause for alarm. Imaging shows a rapidly enlarging osteolysis with cortical
destruction and a soft tissue mass.[19] MRI shows medullary replacement of normal T1-weighted hyperintense fatty bone marrow
signal intensity.[20]
Conclusion
Increasing use of imaging leads to more incidental discoveries of asymptomatic bone
lesions. Paget's disease is one possible diagnosis. In most cases, semiology is typical
and straightforward, with four cardinal signs. When more difficult, imaging associating
CT, MRI, and scintigraphy allows diagnosis and rules out differential diagnoses of
densifying tumoral bone lesions, without resorting to biopsy.
