multiple myeloma and paget's disease imaging

1. PAGET’S DISEASE&MULTIPLE MYELOMA
Dr.Nagaraju.B

2. PAGET’S DISEASE
 Paget disease of bone, also known as osteitis
deformans, was first described in a small group of
patients in 1877 by Sir James Paget.
 Paget disease is extraordinarily common, affecting
3%–4% of the population over 40 years of age and
up to 10%–11% after 80 years of age, slight male
predilection is present.
 The disease is characterized by excessive and
abnormal remodeling of bone.

3. ETIOLOGY
 The cause of Paget disease remains uncertain.
Although still controversial, a probable viral origin
has been proposed because intranuclear inclusion
bodies (resembling those of a paramyxovirus
variety) are found in the osteoclasts in histologic
specimens of Paget disease.
 Ashkenazi Jews have a higher prevalence of Paget
disease, with an associated increased frequency of
the serum marker HLA-DR2, a finding that suggests
a possible genetic origin.

4.  Other purported causes include connective tissue
disease, autoimmune disorder, vascular disease,
metabolic disorder related to parathormone, or a
true neoplastic process.

5. CLINICAL FEATURES
 Paget’s disease has a predilection for the axial
skeleton and may be widespread at the time of
initial diagnosis.
 Local pain and tenderness are frequently present at
an affected skeletal site. Pain is often worse at
night and unrelated to exercise.
 Increasing size of bone may produce such clinical
findings as head enlargement or prominence of the
shins.

6.  Skeletal deformities include kyphosis and bowing of
the long bones of the extremities.
 Neurologic deficits result from impingement on the
spinal cord causing muscle weakness, paralysis,
and rectal and vesical incontinence.
 Platybasia is a result of involvement of the base of
the skull.
 Compression of cranial nerves in their foramina is
not common, although deafness may be apparent.

7.  Congestive heart failure has been noted in patients
with Paget’s disease, which may be related to the
presence of arteriovenous shunts in the involved
bone.
 Laboratory analysis in Paget’s disease generally
reveals elevated alkaline phosphatase levels in
serum and elevated hydroxyproline levels in serum
and urine.

8. PATHOPHYSIOLOGY
 Paget’s disease is a remarkable disorder of bone
that evolves through various stages, or phases.
 Active or Osteolytic phase
 Aggressive bone resorption with lytic lesions
 Replacement of hematopoietic bone marrow by
fibrous connective tissue with numerous large
vascular channels
 Inactive or Quiescent phase
 Decreased bone turnover with skeletal sclerosis
and thickening of the cortex
 Mixed pattern
 Lytic and sclerotic phases frequently coexist

9. RADIOGRAPHIC CORRELATION
 An initial phase of intense osteoclastic activity with
resorption of bone trabeculae may be detected on
radiographs as an “osteolytic” form of the disease.
 This imaging appearance is particularly common in
the skull, where it is termed osteoporosis
circumscripta.
 Osteolysis in the cranial vault is observed most
frequently in the frontal or occipital region and may
progress to involve the entire skull

10.  Osteolysis begins almost invariably in the
subchondral regions of the epiphysis and
subsequently extends into the metaphysis and
diaphysis; occasionally, the disease may appear at
both ends of an involved long bone.
 As the disease progresses, osteolysis may
advance into the diaphysis as a V- or wedge-
shaped radiolucent area, clearly demarcated from
adjacent bone.
 This appearance has been likened to a blade of
grass or a flame.
 Within the area of radiolucency, the remaining
trabeculae may appear thickened, although they
are frequently obliterated, and a hazy
“ground-glass” or “washed-out” pattern

12.  Radiographic evidence of increased density, or
sclerosis, of bone may be seen in the active or
inactive stages of the disease.
 In the cranium, bone sclerosis may produce circular
radiodense lesions in one area, whereas
osteoporosis circumscripta is noted elsewhere.
 Similarly, in the long bones, as the flame-shaped
advancing edge of osteolysis proceeds toward the
shaft, focal radiodensity may become evident in the
epiphysis and metaphysis.
 Cortical thickening, enlargement of bone, and
coarsened trabeculae are prominent.
 Eventually,radiographic evidence of osteolysis may
disappear, and the imaging picture is that of
osteosclerosis.

14. DISTRIBUTION OF DISEASE
 Paget’s disease is generally polyostotic in
distribution.
 Symmetrical is not typical , with the exception of
the innominate bones. Paget’s disease
predominates in the axial skeleton.
 Particularly characteristic is involvement of the
pelvis (30% to 75%); sacrum (30% to 60%); spine
(30% to 75%), especially the lumbar segment; and
skull (25% to 65%).

15.  In addition, the proximal portions of the long bones
are commonly affected, particularly the femur (25%
to 35%).
 No bone is exempt, although changes in the ribs,
fibula, and small bones in the hand and foot are
infrequent.
 In some patients, the disease is initially or totally
monostotic, a pattern that is evident in10% to 35%
of cases

16. SPECIFIC SITES INVOLVEMENT
 Cranium. Pagetic alterations of the skull vary from
typical osteoporosis circumscripta to widespread
sclerosis.
 Inner and outer table involved
Leads to diploic widening.
In contrast to the exuberant facial changes that
may be seen in fibrous dysplasia, extensive
alterations of the facial bones are infrequent in
Paget’s disease.
 Basilar invagination is seen in about one third of
patients with Paget’s disease of the skull, and it
increases in frequency with progressive severity of
the disease.

17.  Basilar invagination is characterized by upward
protrusion of the foramen magnum and surrounding
bone as a result of the effect of gravity and muscle
pull
 Additional clinical findings are related to
impingement on other cranial nerves by the
enlarging pagetic bone.

19. VERTEBRAL COLUMN
 involves the particularly the lumbar spine and the
sacrum.
 Thoracic and cervical involvement and monostotic
disease of the spine may be observed.
 Five mechanisms have been emphasized in the
pathogenesis of the neurologic complications:
 collapse of affected vertebral bodies; increased
vascularity of pagetic bone, which “steals” blood
from the spinal cord; mechanical interference with
the spinal cord blood supply; narrowing of the
spinal canal because of new bone formation or soft
tissue and ligament ossification; and stenosis of
neural foramina resulting from involvement of the
vertebral posterior elements.

20.  In the lumbar spine, Paget’s disease can lead to
compression of the cauda equina and
encroachment on the foramina.
 In the thoracic spine, cord compression and
intervertebral foraminal impingement may be seen.
 With cervical involvement, Paget’s disease can lead
to cord compression and even spastic quadriplegia.
 Coarse trabeculations at periphery of bone.
 "Picture-frame vertebra" mimics bone-within-bone
appearance
 "Ivory vertebra" is a blastic vertebra with increased
density.

22. LONG BONES
 "Candle flame" or "blade of grass" pattern of lysis is the
advancing tip of V-shaped lytic defect in diaphysis of
long bone originating in subarticular site
 Lateral curvature of femur
 Anterior curvature of tibia (commonly resulting in
fracture)
 Pelvis
 Thickened trabeculae in sacrum, ilium
 Rarefaction in central portion of ilium (looks like a
large lytic lesion)
 Thickening of iliopectineal line
 Acetabular protrusio with secondary degenerative
joint disease

24. BONE SCAN
 Both osteolytic and osteoblastic lesions of Paget’s
disease produce high uptake on a bone scan.
 Late in the course, the disease may become
quiescent, and relatively little or no increased
uptake may be present on the bone scan.
 Bone scanning is more sensitive than radiography
in the detection of lesions of Paget’s disease.
 Symptomatic lesions in Paget’s disease are almost
always characterized by increased uptake.

25.  Pagetic lesions that are positive on radiographs and
negative on bone scans are usually asymptomatic
and sclerotic
 In osteolytic Paget’s disease of the skull
(osteoporosis circumscripta), high uptake of the
radionuclide may be noted only at the edge or
margin of the lesion.
 In the spine, there is involvement in the vertebral
body and, sometimes, in the posterior elements,
including the spinous process.
 This may give a characteristic appearance
described as the “Mickey Mouse sign” .

27. COMPUTED TOMOGRAPHY
 CT scanning is generally not required in the
evaluation of uncomplicated Paget’s disease.
 When used, this technique reveals the coarsened
trabecular pattern, thickened cortex, increased size
of the bone, and decreased size of the medullary
cavity that are typical of the disorder .
 CT is useful in the further delineation of a number
of complications of Paget’s disease

28. MRI
Show different findings depending on phase of disease.
 Hypointense area / area of signal void on T1WI + T2WI
(cortical thickening, coarse trabeculation)
 Widening of bone
 Reduction in size and signal intensity of medullary cavity
due to replacement of high-signal-intensity fatty marrow
by medullary bone formation
 Focal areas of higher signal intensity than fatty marrow
(from cyst-like fat-filled marrow spaces)
 Areas of decreased signal intensity within marrow on
T1WI and increased intensity on T2WI ( fibrovascular
tissue resembling granulation tissue)

30. COMPLICATIONS
 Associated neoplasia (0.7-20%)
 Sarcomatous transformation into osteosarcoma
(22-90%), fibrosarcoma /malignant fibrous
histiocytoma (29-51%), chondrosarcoma (1-15%).
 Sarcomas are usually osteolytic in pelvis, femur,
humerus.
 Giant cell tumor occurs in 3-10%
 Lytic expansile lesion in skull, facial bones.
 Lymphoma or plasma cell myeloma are reported.

31.  Fracture
 "Banana fracture" = tiny horizontal cortical
infractions (“Looser lines”)on convex surfaces of
lower extremity long bones (lateral bowing of
femur, anterior bowing of tibia)
 Compression fractures of vertebrae
 Early-onset osteoarthritis.

35. DIFFERENTIAL DIAGNOSIS
 Depends on the bone in which it occurs
 Skull
 Osteolytic or osteoblastic metastases
 Long bones
 Metastases
 Chronic osteomyelitis (thickened cortex)
 Old trauma (thickened cortex)
 Hodgkin’s disease
 Spine
 Hemangioma
 Metastases

37. IMAGING ASPECTS OF THERAPY
 Scintigraphy has advantages over radiography in
monitoring the response of pagetic bone to any of
the therapeutic agents.
 A distinct decrease in radionuclide accumulation in
diseased areas is characteristic of the pagetic
response to treatment.
 In general, good correlation is noted between
scintigraphic and biochemical parameters of
disease activity.
 Recurrence of the disorder is typically accompanied
scintigraphically by a rise in activity in one or more
bones in a diffuse or circumscribed pattern or by
the spread of disease into adjacent normal bone

38. MULTIPLE MYELOMA
 Multiple myeloma is the most common primary
malignant neoplasm of bone.
 There is production of an abnormal paraprotein
leading to a wide M-band on plasma
electrophoresis.
 Production of light chain immunoglobulins results in
Bence Jones proteinuria in over half the patients.
 Hypercalcemia, hypercalcuria and amyloidosis can
occur, but serum alkaline phosphatase and serum
phosphorus are normal.

39. CLINICAL PRESENTATION
 Age: This is a disease of the elderly. Seventy-five
percent of those affected are over the age of 50
with a peak over 80 years.
 Sex: A male predominance of up to 2:1 is seen.
 Clinical picture: Persistent bone pain is the most
common symptom which is worse during the day, is
relieved by rest and aggravated by weight bearing.
 Pathological fracture is a common complication.
Associated weight loss, anemia and cachexia
occur.
 Bacterial infections occur in 10 percent of cases,
most of which are respiratory in nature.

40.  With coexistent amyloidosis, additional clinical
manifestations may be the result of macroglossia or
cardiac and renal failure.
 Laboratory findings reveal a normochromic,
normocytic anemia, thrombocytopenia,
hypercalcemia, hyperglobulinemia with a reversed
A:G ratio, hyperuricemia and Bence Jones’
proteinuria.
 ESR is often raised over 100 mm/h.
 Bone marrow biopsy confirms the plasma cell
dyscrasia.
 Site: The spine, pelvis, skull, ribs and scapula are
the most frequently involved bones.

41. PATHOGENESIS & PATHOLOGICAL FEATURES
 It is now known that plasma cells can produce an
osteoclast stimulating factor that may be
responsible for the osteolytic lesions that are
characteristic of myeloma. This factor also leads to
inhibition of osteoblasts.
 Myelomatous involvement of the skeleton is
variable in extent and predominates in regions of
red marrow.
 Extraosseous involvement is most common in the
spleen, liver, and lymph nodes.
 Pathologic fractures are frequent especially in the
vertebrae and ribs.

42. IMAGING FEATURES
 The preferred initial imaging examination for the
diagnosis and staging of myeloma (according to the
2009 International Myeloma Working Group
consensus statement) remains the skeletal survey.
 The classical appearance of multiple myeloma on
plain radiographs consists of well-defined,
osteolytic “punched out” lesions throughout the
skeleton, most characteristic in the skull.
 These lesions can also be seen in the pelvic bones,
clavicles, ribs, and long bones.
 lesions may be differentiated from lytic metastatic
lesions by the more uniform size of the lesions in
multiple myeloma.

43.  Generalized osteopenia is another important form
of presentation.
 A pathological fracture affects about half of the
patients at some time or the other.
 Examples of purely sclerotic myeloma have been
occasionally reported. They may take the form of
diffuse osteosclerosis, patchy sclerotic areas
throughout the skeleton and, very rarely, small
numbers of focal sclerotic lesions.
 Involvement of the spine is usually in the lower
thoracic and upper lumbar regions, and is seen as
diffuse osteopenia.

45.  In the spine, preferential destruction of the vertebral
bodies, with sparing of the posterior elements, has
been emphasized.
 Paraspinal and extradural extension of tumor is
quite characteristic of myeloma.
 Myeloma may demonstrate a predilection for
mandibular involvement.
 Sternal involvement in myeloma is not infrequent
and may lead to pathologic fracture.

46.  Particularly distinctive in plasma cell myeloma is a
subcortical circular or elliptic radiolucent shadow,
most often observed in the long tubular bones.
 An associated mild periosteal proliferation may act
as a buttress that prevents or resists fracture.
 The subcortical defects cause erosion of the inner
margins of the cortex and, when extensive, create a
scalloped and wavy contour throughout the
endosteal bone.
 This appearance is highly suggestive of plasma cell
myeloma, is occasionally seen in cases of rapid
and aggressive osteoporosis

48. RADIONUCLIDE EXAMINATION
 Although radionuclide bone scanning is valuable in the
early detection of most neoplastic processes of the
skeleton, the results of this examination are less
predictable in patients with myeloma.
 False-negative scans are common. The current belief is
that radionuclide examination in patients with myeloma
does not reveal all lesions and radiography is a more
valuable technique for assessing the distribution of
lesions, with the possible exception of rib abnormalities,
which may be seen more easily with scintigraphy.
 fractures account for augmented radionuclide uptake in
a large percentage of patients with myeloma.

50.  Clinical and laboratory evidence of patient
improvement is commonly associated with a lack of
change on serial radiographic studies.
 Reports indicate that scintigraphy is a potential aid
in monitoring patients with myeloma who are
receiving chemotherapy; remission is characterized
by significant regression or disappearance of the
scintigraphic abnormalities in many of these
patients.

52.  In contrast to plain film
radiography, in which
extensive osseous
destruction is required
before abnormalities
become apparent,
computed tomography
(CT) may indicate
minor alterations in
radiodensity that reflect
the presence of
intramedullary
myelomatous foci.

53. MRI
 Spin echo techniques are not ideal for the
assessment of some marrow alterations because
they are relatively insensitive to subtle changes in
free water content, with signal intensities that are
most dependent on the presence or absence of fat.
 Irrespective of which MR imaging sequence is
chosen, detection of myelomatous involvement of
the vertebral bodies (or elsewhere) is dependent on
contrast differences between regions of tumor
infiltration and background tissue composed of
areas of either hematopoietic or fatty marrow, or
both.

55.  Gadolinium-supplemented T1-weighted images are
characterized by widely disseminated or
inhomogeneous enhancement of diffuse or
variegated marrow involvement.
 The pattern of enhancement of myelomatous foci
differs from that typically encountered in regions of
hematopoietic bone marrow.
 Although normal marrow may enhance markedly
when a gadolinium-based contrast agent is
administered intravenously to young children, such
enhancement has been reported to be subtle or
absent in adults.

56.  In plasma cell myeloma, especially in cases of
more aggressive disease, the degree of
enhancement of signal intensity in involved marrow
tends to be greater than that of normal marrow.
 Further, gadolinium-related diffuse enhancement of
marrow in vertebral bodies occurs not only in
myeloma but also in lymphomas, leukemias, and
myelofibrosis.
 Short tau inversion recovery (STIR) sequences may
allow the detection of small focal collections of
tumor that escape visualization with standard spin
echo MR imaging methods.

58. STAGING
 In 1975, Durie and Salmon proposed the initial clinical
staging system for multiple myeloma.
 The system was revised in 2003 and is now referred to
as the Durie/Salmon PLUS system, since additional
information from advanced imaging modalities has been
added.
 Stage IA: normal skeletal survey or single lesion
 Stage IB: 5 focal lesions or mild diffuse spine disease
 Stage IIA/B: 5 to 20 focal lesions or moderately diffuse
spine disease
 Stage IIIA/B: >20 focal lesions or severe diffuse spine
disease
 Subclasses A and B (A = normal renal function, B =
abnormal renal function).