Referensi : http://radiopaedia.

org/articles/multiple-myeloma-1
Multiple myeloma is the most common primary malignant bone neoplasm in adults arising from red marrow due to monoclonal
proliferation of the plasma cells, and results in a wide range of radiographic abnormalities. Treatment remains difficult.

Terminology
Four main patterns are recognised:
1.

disseminated form: multiple well-defined "punched out"lytic lesions: predominantly affecting the axial skeleton

2.

disseminated form: diffuse skeletal osteopenia

3.

solitary plasmacytoma: single large/expansile lesion most commonly in a vertebral body or in the pelvis

4.

osteosclerosing myeloma

The remainder of this article relates to the disseminated forms. Please refer to the article plasmactyoma for discussion of the
latter.
Smoldering multiple myeloma refers to a form that exists between monoclonal gammopathy of unknown
significance (MGUS) and active multiple myeloma. These asymptomatic patients had biochemistry which was worse than
MGUS but did not have end-organ damage of active multiple myeloma 9.

Epidemiology
Multiple myeloma is a common malignancy of older patients above 40 years old (70% of cases are diagnosed between 50 and
70 years of age), which has a male predilection (M:F 2:1) 7. It accounts for 1% of all malignancies and 10% of all
haematological disease. Together with osteosarcoma, multiple myeloma account for approximately 50% of allprimary bone
malignancies 7.

Clinical presentation
Clinical presentation of patients with multiple myeloma is varied, and includes

bone pain:
o

initially intermittent, but becomes constant

worse with activity/weight bearing, and thus is worse during the day

anaemia:
o

1-2,7

typically normochromic/normocytic

renal failure/proteinuria

Presentation may also be with a complication, including:

pathological fracture:
o

vertebral compression fracture

long bone fracture (e.g. proximal femur)

amyloidosis

recurrent infection: e.g. pneumonia due to leukopaenia

plasmacytomas typically progress to multiple myeloma

Occasionally presentation is with polyneuropathy, when multiple myeloma is part of POEMS syndrome (mostly sclerotic form).
Laboratory findings include:

reverse albumin/globulin ratio (low albumin, high globulin)

monoclonal gammopathy (IgA and/or IgG peak)

proteinuria: Bence Jones proteins in urine (Ig light chains)

hypercalcaemia

decreased or normal ALP unless there is a pathologic fracture due to impaired osteoblastic function.

The International Staging System, the most popular staging system, uses the combination of beta 2 microglobulin and serum
albumin 6.
Approximately 1% of cases will have negative serum electrophoresis and negative urine Bence Jones proteins.

Pathology

Multiple myeloma results from monoclonal proliferation of malignant plasma cells which produce immunoglobulins (commonly
IgG) and infiltrate haemopoietic locations (i.e. red marrow).

Distribution
Distribution of multiple myeloma mirrors that of red marrow in the older individual, and thus this is mostly encountered in the
axial skeleton and proximal appendicular skeleton:

vertebrae (most common)

ribs

skull

shoulder girdle

pelvis

long bones

extra skeletal structures (extraosseous myeloma): rare

Radiographic features
Radiology has a number of roles in the diagnosis and management or multiple myeloma:
1.

suggest the diagnosis/exclude other causes

2.

assess possible mechanical complications (e.g. pathological fracture)

3.

assess disease progression

Disseminated multiple myeloma has two common radiological appearances, although it should be noted that initially
radiographs may be normal, despite the presence of symptoms. The two main diffuse patterns are:
1.

2.

numerous, well-circumscribed lytic bone lesions (more common):

o

punched out lucencies e.g. pepperpot skull or raindrop skull 7

endosteal scalloping

generalized osteopaenia (less common):

o

often associated with vertebral compression fractures/vertebra plana

Plain film
A skeletal survey is essential in not only the diagnosis of multiple myeloma, but also in assessing response, and pre-empting
potential complications (e.g. pathological fracture). A typical skeletal survey consists of the following films:
1.

lateral skull

2.

frontal chest film

3.

cervico-thoraco-lumbar spine

4.

shoulders

5.

pelvis

6.

femurs

The vast majority of lesions are purely lytic, sharply defined/punched out withendosteal scalloping when abutting cortex. In only
3% of patients are the lesions sclerotic 7.

CT
CT does not have a great role in the diagnosis of disseminated multiple myeloma, however it may be useful to determine the
extent of extra-osseous soft tissue component in patients with a large disease burden.
It may also better assess the risk of fracture in severely affected bones.

MRI
MRI is generally more sensitive in detecting multiple lesions compared to the standard plain film skeletal survey. Infiltration and
replacement of bone marrow is exquisitely visualised, and newer scanners are able to perform whole body scans for this
purpose which has been shown to be superior to both CT and skeletal surveys 8.

Nuclear medicine
Bone scintigraphy appearance of patients with disseminated multiple myeloma is variable due to the potential lack of
osteoblastic activity. Larger lesions may be hot or cold. Bone scans may also be normal. Therefore bone scans usually do not
contribute significant information in the work-up of patients with suspected or established disseminated multiple myeloma, as
the sensitivity of detecting lesions is less than that of a plain film skeletal survey 7.

PET-CT has a growing role to play in the management of this disease, as it is effective in identifying the distribution of disease.
Uptake of the F18-FDG molecule by the myeloma lesions corresponds to areas of bone lysis seen on CT.

Treatment and prognosis

Currently multiple myeloma remains incurable although the introduction of thalidomide, lenalidomide and bortezomib
(proteasome inhibitor) have provided significant treatment gains 6. These are typically used in combination with older agents
such as cyclophosphamide, melphalan, prednisolone and doxyrubicin 6.
Treatment response is usually assessed by measuring serum markers and bone marrow sampling.
Stem-cell harvest and autologous stem cell transplant post chemotherapeutic/radiotherapy bone marrow ablation is also used,
although relapse is inevitable.

Differential diagnosis
The main differential is that of widespread bony metastases. Findings that favour the diagnosis of bony metastases over that of
multiple myeloma include:

more commonly affect the vertebral pedicles rather than vertebral bodies

rarely involve mandible, distal axial skeleton

although both entities have variable bone scan appearances (both hot and cold) unlike myeloma, extensive bony
metastases rarely have a normal appearance

Other rare entities include:

Waldenstrom macroglonulinaemia

Related articles
Bone tumours
The differential diagnosis for bone tumours is dependent on the age of the patient, with a very different set of differentials for
the paediatric patient.

bone tumours
o

bone-forming tumours[+]

cartilage-forming tumours[+]

fibrous bone lesions[+]

bone marrow tumours

Langerhans cell histiocytosis

multiple myeloma

solitary bone plasmacytoma

Ewing sarcoma

primary bone lymphoma

secondary bone lymphoma

other bone tumours or tumour-like lesions[+]

skeletal metastases[+]

Reference : http://emedicine.medscape.com/article/391742-overview
Multiple myeloma is the most common primary malignant neoplasm of the skeletal system. The disease is a malignancy of plasma cells.
Radiologically, multiple destructive lytic lesions of the skeleton, as well as severe demineralization, characterize multiple myeloma. The
etiology of the disease is the monoclonal proliferation of plasma B cells, with resultant marrow infiltration and increase of a single
immunoglobulin and its fragments in the serum and urine. Electrophoretic analysis shows increased levels of immunoglobulins in the
blood as well as light chains (Bence-Jones protein) in the urine.
See the images below displaying different areas of the body affected by multiple myeloma.

Lateral radiograph of the skull. This image demonstrates

numerous lytic lesions, which are typical for the appearance of widespread myeloma.

Lateral radiograph of the lumbar spine. This image shows

deformity of the L4 vertebral body that resulted from a plasmacytoma.

Radiograph of the right femur. This image demonstrates the typical

appearance of a single myeloma lesion as a well-circumscribed lucency in the intertrochanteric region. Smaller lesions are seen at the greater trochanter.

Radiograph of the right humerus. This image demonstrates a destructive lesion of the diaphysis. Pathologic
fracture is seen.

A T1-weighted magnetic resonance image of the

humerus. This image demonstrates a predominantly hypointense to isointense myelomatous lesion in the medullary space of the diaphysis. The lesion
extends through the anterior aspect of the cortex.

A T1-weighted magnetic resonance image of the

shoulder. This image shows the full extent of myelomatous involvement within the glenoid and coracoid process.

The marrow infiltration process may involve any bone, but the predominant sites include the vertebral column, ribs, skull, pelvis, and
femora. Although the osseous structures may appear radiographically normal or simply osteopenic, the classic appearance is of
multiple, discrete, small, lytic lesions. Occasionally, a single lytic lesion is discovered and is termed a plasmacytoma (solitary myeloma).
Patients with a single focus of disease often progress to multiple sites of myelomatous involvement. [1, 2, 3, 4, 5, 6]

Preferred examination
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. Patients suspected of having multiple myeloma based on bone
marrow aspirate results or hypergammaglobulinemia should undergo a radiographic skeletal survey. Conventionally, this skeletal survey
consists of a lateral radiograph of the skull, anteroposterior (AP) and lateral views of the spine, and AP views of the humeri, ribs, pelvis,
and femora. Inclusion of at least these bones is important for both diagnosis and staging. Whole body imaging, especially with new MR
techniques, is advocated when possible. Other whole body techniques, including low-dose CT scanning, positron emission tomography
(PET) scanning with fluorodeoxyglucose (FDG), and scintigraphy with 2-methoxy-isobutyl-isonitrile (MIBI) are still being evaluated.
Shortt et al compared FDG PET, whole body MRI, and bone marrow aspiration and biopsy in 24 patients (13 women, 11 men; mean
age, 67.1 years; range, 44-83 years) with multiple myeloma proven by bone marrow biopsy. Whole body MRI had a higher sensitivity
and specificity than PET, and the positive predictive value of whole body MRI was 88%. When used in combination and with concordant
findings, PET and whole body MRI had specificity and positive predictive values of 100%. [7]
Dimopoulos et al (writing in 2009 for the International Myeloma Working Group) reviewed the literature of all imaging modalities used in
multiple myeloma and provided recommendations for each modality. Conventional radiography, according to the authors, remains the
criterion standard for staging newly diagnosed cases and in cases of relapse. MRI can provide information that is complementary to a
skeletal survey and was recommended for use in patients with normal radiographic images and in all patients with an apparently solitary
plasmacytoma of bone.
According to Dimopoulos et al, urgent MRI or CT (if MRI is not available) is the diagnostic procedure of choice to assess suspected cord
compression. Standard99mTc bone scintigraphy should play no role in the routine staging of myeloma, and sequential dual-energy
radiographic absorptiometry (DXA) scans are not recommended, according to the authors. PET or MIBI imaging are also not
recommended for routine use, according to the study findings, although both techniques may be useful in selected cases that warrant
clarification of previous imaging findings.[8]
Agool et al studied somatostatin receptor scintigraphy (SRS) in 29 myeloma patients and compared the results with radiographic
findings. A positive SRS was demonstrated in 44% of 9 newly diagnosed patients; 83% of the 18 relapsed patients; and both of the
patients with plasmacytoma. In 40% of the patients, the SRS findings corresponded with radiographic abnormalities, but in 60% of
relapsed patients, SRS uptake was demonstrated in areas without new radiographic abnormalities. [9]
Focused examinations of newly painful bones are of value for assessment of impending pathologic fracture. Correlation with all other
available imaging studies should be done to help determine the risk of pathologic fracture.
The unequivocal diagnosis of myeloma is made when the following 3 criteria are satisfied:

A minimum 10-15% of a bone marrow aspirate demonstrates abnormal plasma cells

Radiographic survey demonstrates typical lytic lesions
Monoclonal immunoglobulins are present in the urine or blood

Limitations of techniques
The skeletal survey has limitations. Most importantly, a large number of patients diagnosed with asymptomatic myeloma may have
radiographically occult myeloma deposits. At least 30% cancellous bone loss is required to visualize an intramedullary destructive
process, such as myeloma, with radiographs. In addition, myeloma is a disease of older patients; the disease can present with diffuse
demineralization, which may be indistinguishable from the pattern found in patients with simple senile osteoporosis.
Magnetic resonance imaging (MRI) has been suggested as an additional imaging examination in patients with myeloma. MRI has the
advantage of rapidity and sensitivity for the presence of disease; however, specificity is limited. Whole body imaging is preferred but if
this is not possible, at least an MRI examination of the spine should be done, because radiographically occult lesions or extramedullary
lesions may be found that can change the stage and influence the need for therapeutic intervention.

Staging
Morbidity and mortality, in myeloma patients, are directly related to the stage of disease at initial diagnosis. 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. Radiologists should use
the revised system (outlined below) to accurately stage these patients. [10, 11]

Stage IA Normal skeletal survey or single lesion

Stage IB - Five focal lesions or mild diffuse spine disease
Stage IIA/B - Five to 20 focal lesions or moderately diffuse spine disease

Stage IIIA/B - More than 20 focal lesions or severe diffuse spine disease
Subclasses A and B (A = normal renal function, B = abnormal renal function)
Mild, moderate, and diffuse spine disease is established by MR imaging. Moderate diffuse disease is defined as vertebral body signal
intensity brighter than adjacent disc on a T1-weighted sequence. Severe diffuse disease is defined as vertebral body signal intensity
less than or equal to the adjacent disc on a T1-weighted sequence. Mild disease has not been precisely defined.

Reference : http://radiopaedia.org/articles/skeletal-metastases

Skeletal metastases
Dr Matt A. Morgan and Dr Frank Gaillard et al.

Skeletal metastases are common and result in significant morbidity in patients with metastatic disease. Although the diagnosis
is often straightforward, especially as in many cases there is well documented history of metastatic malignancy, sometimes
they may mimic benign disease or other primary malignancies.

Epidemiology
Skeletal metastases account for 70% of all malignant bone tumours, and are seen in a vast number of primary cancers,
although lung cancer, breast cancer, renal cell carcinoma and prostate cancer account for approximately 80% of all skeletal
metastases 1. This is due to not only the propensity of these tumours to metastasisse to bone, but also the fact that these are
some of the most common tumours.

Clinical presentation
The majority of metastases to bone are asymptomatic. Symptoms can arise in a number of scenarios
1.

local bone pain

2.

soft issue mass resulting in:

3.

1,3

direct compression of adjacent structures by extra-osseous soft tissue mass (e.g. cord compression)

palpable mass

deformity

pathological fracture(s)

In most cases the diagnosis of metastatic disease is already known. If no known primary exists, or there is uncertainty
regarding the diagnosis (e.g. no known metastases; unusual imaging appearances) then a bone biopsy can allow usually
definitive diagnosis.
Laboratory investigations are of limited value, but will often demonstrate increased serum calcium and alkaline phosphatase
Increase in hydroxyproline excretion may also be present 3.

1,3

Pathology
The major route of spread of tumour to bone is hematogenous, although lymphatic spread is also seen (e.g. in pelvic tumours
spreading to para-aortic nodes, and then directly into bone c.f the more common hematogenous spread from the same
tumours) 3. Although direct extension of tumours in bone is also not infrequently seen (e.g. oral cavity tumours into mandible
or Pancoast tumours into first rib or upper thoracic vertebrae) this is not usually what is considered metastatic disease.
Regardless of the route of spread, metastases lead to both bone loss and bone formation, in varying amounts. The former is
most likely due to direct enzymatic destruction and osteoclast activation. The latter can be due to stromal bone formation
(formation of bone within tumour substrate; the case in prostate cancer metastases) or reactive new bone formation which
represents the normal adjacent bone's response to the presence of tumour and is similar to callus formation 3.

Distribution

The distribution of skeletal metastases roughly mirrors the distribution of red-marrow, presumably reflecting increased blood
flow in red-marrow compared to yellow-marrow. Thus, metastases are usually found in:

vertebrae
o

especially posterior vertebral body, extending into pedicles (see: vertebral metastases)

pelvis

proximal femur

proximal humerus

skull

Metastases distal to the elbow and knee are distinctly uncommon (see distal appendicular skeletal metastases).

Radiographic features
Skeletal metastases invariably incite a mixture of bone resorption and bone formation and can thus take on one of three
patterns, depending on the dominant process:
1.

lytic metastases

2.

sclerotic metastases

3.

mixed lytic and sclerotic metastases

Additionally, metastases can have different morphological characteristics:

diffuse

focal

expansile (see: blow-out bone metastases)

Plain film
As is the case with other other bone lesions, skeletal metastases can be difficult to identify on plain films on account of
extensive (30-50%) bone mineral loss is required before the density loss is visible 1.
In many other cases the lesion is visible due to destruction of cortex, or the presence of visible sclerosis.
It is important to note that unlike primary bone tumours, in general metastases incite no or only limited periosteal reaction. The
occasional exception to this general rule includes prostate cancer, some gastrointestinal
malignancies, retinoblastoma andneuroblastoma 3.

CT
CT does not have a role in primary assessment for the presence of metastases (except for difficult areas to image such as the
spine) but is excellent at defining the extent of bony involvement and in helping assess the risk of pathological fracture.

MRI
Whole body MRI is not widely used, but is highly sensitive to replacement of normal bone marrow 2.

Nuclear medicine
Bone scans are the most sensitive routine imaging modality to try and identify both sclerotic and lytic lesions 1. In most cases
they demonstrate increased uptake (hot spot) although occasionally (in very aggressive purely lytic lesions) a photopaenic
defect (cold spot) may be visible. A superscan is also a possible pattern where extensive diffuse metastatic disease results in
uniform increase in uptake 3.

Treatment and prognosis

In general treatment can be thought of as systemic (e.g. chemotherapy or hormonal therapy) or local (e.g. radiotherapy or
surgery). Pain management is also often an important part of managing patients with skeletal metastases.
When metastases involve the majority of the cross section of a bone, especially is structurally critical bones such as the femur,
prophylactic pinning may be required to prevent a pathological fracture.
No single statement can be made in regards to the prognosis of patients with skeletal metastases as this will vary greatly
depending on the primary tumour.

Differential diagnosis
There are, unfortunately, no specific features of metastases, although often the diagnosis is straight forward in the setting
of known advanced malignancy and multiple lesions.
When no history of malignancy is present, but lesions are multiple in an elderly patient, the main differential is multiple
myeloma.
When no helpful features are present (in other words a solitary lesion in an otherwise supposedly well patient) one needs to
consider numerous entities:

benign and malignant tumour

infection

trauma

osteonecrosis

The differential can be narrowed according to specific appearances and locations:

lytic bone metastases

sclerotic bone metastases

mixed lytic and sclerotic bone metastases

expansile bony lesion

solitary lesions
o

solitary sclerotic bone lesion

solitary lucent bone lesion: FOG MACHINES is a good place to start

solitary lucent skull lesion

Related articles
Bone tumours
The differential diagnosis for bone tumours is dependent on the age of the patient, with a very different set of differentials for
the paediatric patient.

bone tumours
o

bone-forming tumours[+]

cartilage-forming tumours[+]

fibrous bone lesions[+]

bone marrow tumours[+]

other bone tumours or tumour-like lesions[+]

skeletal metastases

morphology

sclerotic bone metastases

lytic bone metastases

mixed lytic and sclerotic bone metastases

blow out bone metastases

cookie bite skeletal metastases

location

skull metastases

vertebral metastases

distal appendicular skeletal metastases