Multiple Myeloma Imaging

Multiple Myeloma Imaging

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Multiple myeloma is the most common primary malignant neoplasm of the skeletal system. The disease is a malignancy of plasma cells. Clinical definitions of the various myeloma subtypes have been updated as have the imaging definitions of what constitutes bone marrow disease and individual bony involvement. [1] The etiology of multiple myeloma 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. Radiologically, multiple destructive lytic lesions of the skeleton, as well as severe demineralization, characterize multiple myeloma. A focal lytic lesion must be ≥5mm in size to be considered a true abnormality by the latest International Myeloma Working Group (IMWG) criteria. [1, 2]

See the images below displaying different areas of the body affected by multiple myeloma.

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, 3, 4, 5, 6, 7]

The preferred initial imaging examination for the diagnosis and staging of myeloma (according to the 2014 IMWG consensus statement) remains the skeletal survey. [8] 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, with positron emission tomography PET/CT and MRI, also is advocated whenever possible for initial staging and follow up. Other whole body techniques, including low-dose CT scanning, 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%. [9]

Dimopoulos et al (writing 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 spinal cord compression. Standard 99mTc 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. [10]

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. [11]

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 International Myeloma Working Group guidelines for the standard investigative workup in patients wqith suspected multiple myeloma include the following [2] :

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; it can present with diffuse demineralization, which may be indistinguishable from the pattern found in patients with simple senile osteoporosis.

Magnetic resonance imaging (MRI) is advocated now 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. Extramedullary disease has been detected in as many as 50% of patients and is an independent predictor of a poorer prognosis. [12]

Morbidity and mortality, in myeloma patients, are directly related to the stage of disease at initial diagnosis. 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. [13, 14]

Stage IA – Normal skeletal survey or single lesion ≥5mm

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 may manifest as a “salt and pepper” pattern or minimal infiltration.

The classic radiographic appearance of multiple myeloma is that of multiple, small, well-circumscribed, lytic, punched-out, round lesions within the skull, spine, and pelvis. Lesions are lytic without reactive bone formation because of tumor factors that combine to activate osteoclasts and inhibit osteoblasts. The lesions tend to vary slightly in size. In addition, the bones of myeloma patients are, with few exceptions, diffusely demineralized. Because myeloma is a disease of the medullary compartment of the bone, more subtle lesions can be detected by the appearance of endosteal scalloping that is seen as slight undulation to the inner cortical margin of bone. This finding is indicative of myelomatous involvement in the appropriate clinical setting.

See the radiographic images of multiple myeloma below.

Although patients with advanced and extensive myeloma tend to have a number of circumscribed lytic lesions, some may simply have diffuse osteopenia on radiography. Fewer than 10% of patients present with a single myelomatous lesion, a plasmacytoma, found on radiographs. These lesions are most common in the vertebral bodies. In other skeletal sites, they may manifest as bubbly expansile lesions, often in a rib or posterior element of the spine, but they can have a variety of shapes and sizes. They are occasionally associated with a soft tissue mass.

There are 2 sclerotic forms of myeloma. One is a rare form, known as POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), that may demonstrate sclerotic lesions on radiographs or CT studies, but this condition is responsible for less than 1% of myeloma cases. Major and minor criteria to diagnose this condition have been established. The major criteria are polyneuropathy, monoclonal gammopathy, and presence of bone lesions. The second form is a standard multiple myeloma case with mixed lytic and sclerotic lesions. Radiographs or CT images of treated myeloma lesions also may rarely show areas of abnormal bone architecture with sclerosis. Usually, little reactive bone sclerosis or periosteal reaction is seen. [15]  However, some new treatment agents, such as Bortezomib, have been reported to show a higher degree of reactive new bone formation around treated lesions. [16]

As many as 90% of patients with newly diagnosed multiple myeloma demonstrate skeletal involvement. The finding of multiple lytic lesions on a skeletal survey invokes 2 primary differential considerations; myeloma and metastases. However, when lesions are found together with bone marrow plasmacytosis and elevated serum gamma-globulins, the diagnosis of myeloma is certain.

If tests for these 2 parameters have not been performed (ie, bone marrow plasmacytosis, blood gamma-globulins), the finding of multiple lytic lesions statistically represents widespread metastatic disease in 60-70% of patients, with most of the remainder representing myeloma. Rarely, other conditions that may have multifocal involvement, including infection, sarcoidosis, and primary lymphoma of bone can mimic myeloma and metastatic disease. In diffuse osteopenia found on radiography, consider the diagnosis of myeloma and perform additional tests; however, most of these patients only have age-related decreased bone mineral density.

False-positive examinations are encountered when multiple lytic lesions are found. In these patients, perform additional studies because the most likely source of this pattern is metastatic disease, not myeloma.

Diffuse osteopenia that is found on radiographs is often a source of false-negative examinations because a substantial amount of cancellous bone must be destroyed before an intramedullary lesion becomes visible radiographically.

Computed tomography (CT) scanning readily depicts osseous involvement in multiple myeloma patients. However the usefulness of this modality is still being studied, and separate CT scanning alone is not required in most patients. Low-dose whole body CT, with newer multislice scanners, may be able to replace the standard skeletal survey at institutions where it is available. In one recent study of 42 patients, whole body CT scanning showed an average of nearly 4 times more lesions than conventional radiographic skeletal survey. [17]

One clinical situation in which CT scan study may be of value is in cases in which the patient has bone pain and a negative radiograph. [18] In this scenario, demonstration of a myeloma lesion may alter therapy significantly. CT scanning can also guide percutaneous biopsies, especially of osseous or extraosseous lesions that are suspected of being plasmacytomas.

See the CT images of multiple myeloma.

The literature also shows that the use of fluorine-18 fluorodeoxyglucose (18 F FDG) positron emission tomography (PET) scanning can be helpful in the staging and posttherapeutic monitoring of multiple myeloma by providing functional detection of high metabolic lesions. [19, 20] However, a preliminary report by Nanni et al in a small population of patients indicates that carbon-11 (11 C)-choline PET scanning may be more sensitive than18 F FDG PET scanning for detecting myeloma lesions. The authors cautioned that more large-scale studies are needed to verify their results. [20]

FDG PET scans that show a lesion with a standardized uptake value (SUV) greater than 11 has been reported as an indicator of a poorer prognosis. Additionally, patients with 3 or more FDG avid lesions that do not respond to treatment have poorer outcomes. [21]

In a prospective study of 24 multiple myeloma patients (15 newly diagnosed, 9 pretreated), diffusion-weighted imaging (DWI) was found to be more sensitive than FDG PET in detecting myeloma lesions in a mixed population of primary and pretreated patients, but FDG PET and DWI demonstrated equivalent sensitivities in the subpopulation of primary, untreated patients. [22]

Recognition of a single or serial increase of SUV to 3.5 at a given location, such as within a vertebral body, may help predict an impending pathologic fracture, especially if there is a correlating MRI that shows diffuse vertebral body involvement at the same level. [23]

Because of the small size of many myeloma lesions, PET scans must be carefully evaluated to decrease the number of false negatives. The usual SUV cutoff value of 2.5 does not apply to myeloma lesions that are less than 1 cm in size. For a lesion less than 5 mm, any degree of FDG uptake should be reported as active disease. Lesions between 5 and 10 mm are considered indeterminate.

MRI has high sensitivity for the early detection of marrow infiltration by myeloma cells. It has the ability to detect spinal cord or nerve compression and the presence of soft tissue masses and is recommended for the workup of solitary bone plasmacytoma. [24]  MRI is useful for imaging multiple myeloma because of its superior soft-tissue contrast resolution. The typical appearance of a myeloma deposit is a round, low signal intensity (relative to muscle) focus on T1-weighted images, which becomes high in signal intensity on T2-weighted sequences. The images below demonstrate the appearance of a typical myeloma lesion in the proximal humerus. Myeloma lesions tend to enhance with gadolinium administration. In addition, diffuse areas of marrow replacement may be seen, resulting in large regions of low T1-weighted signal. [25]

Fast whole body techniques are available on some magnet systems. [26] MRI also can provide important information for prognosis. One study of 611 myeloma patients showed that the presence of more than 7 focal lesions was an independent predictor of poorer prognosis and that resolution of all focal lesions was an indicator of superior survival. [27]  More recent reports indicate that a sequential increase in the number of focal lesions (without a specific cutoff number) is associated with an adverse prognosis. [28]

See the images below of myeloma of the shoulder

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

Unfortunately, almost any musculoskeletal tumor has the same signal-intensity profile and enhancement pattern as myeloma. MRI, although sensitive to the presence of disease, is not disease specific. Additional tests must be used to diagnose myeloma, such as measurement of gamma-globulin levels and direct aspiration of bone marrow to assess for plasmacytosis. Because of this, MRI may understage or overstage patients with myeloma.

In patients with extraosseous lesions, MRI is the study of choice to define the degree of involvement and to evaluate for cord compression.

A study of 27 newly diagnosed patients with multiple myeloma found that the combination of anatomical information from conventional MRI with functional information from  dynamic contrast-enhanced MRI and diffusion-weighted imaging was useful for monitoring therapy. [29]

PET/MRI was compared with PET/CT in 30 multiple myeloma patients. The hybrid PET/MRI provided good image quality in all cases without artifacts and identified 65 of the 69 lesions that were detected with PET/CT (94.2%). However, both standardized uptake value (SUV)average and SUVmax were significantly higher on PET/CT than on PET/MRI. [30]

Myeloma is a disease that results in overactivity of osteoclasts, with resultant liberation of bone and suppression of osteoblasts. Nuclear medicine bone scans rely on osteoblastic activity (bone formation) for diagnosis. As such, standard technetium-99m (99m Tc) bone scans have underestimated the extent and severity of disease and should not be used routinely. [31]

However, a study by Erten et al appeared to demonstrated that whole body scintigraphy with technetium-99m 2-methoxy-isobutyl-isonitrile (99m Tc-MIBI) may be a useful adjunct for the diagnostic imaging of multiple myeloma. [32] The authors reported that in 24 patients,99m Tc-MIBI demonstrated the extent and intensity of bone marrow infiltration equally as well as MRI, and they suggested that99m Tc-MIBI may serve as an alternative to MRI in cases in which MRI is not readily available or when its use is limited. Another, larger study by Mele et al of 397 scintigrams showed a sensitivity of 77% and a specificity of 86% for MIBI. [33]

Khalafallah et al in 2013 reported that MIBI predicted overall disease outcome and mortality better than whole body MRI in their study of 62 patients. [34]

The false-negative rate of standard99m Tc bone scintigraphy in diagnosing multiple myeloma is high, up to 50%. Scans may be positive with normal radiographs, requiring another test for confirmation.

Angiographic findings are nonspecific. Lesions may have a peripheral zone of increased vascularity. Generally, this technique is not used for the diagnosis of myeloma.

Goel A, Carlson SK, Classic KL, et al. Radioiodide imaging and radiovirotherapy of multiple myeloma using VSV({Delta}51)-NIS, an attenuated vesicular stomatitis virus encoding the sodium iodide symporter gene. Blood. 2007 Oct 1. 110(7):2342-50. [Medline].

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Agool A, Slart RH, Dierckx RA, Kluin PM, Visser L, Jager PL, et al. Somatostatin receptor scintigraphy might be useful for detecting skeleton abnormalities in patients with multiple myeloma and plasmacytoma. Eur J Nucl Med Mol Imaging. 2009 Jul 14. [Medline]. [Full Text].

Bäuerle T, Hillengass J, Fechtner K, Zechmann CM, Grenacher L, Moehler TM, et al. Multiple myeloma and monoclonal gammopathy of undetermined significance: importance of whole-body versus spinal MR imaging. Radiology. 2009 Aug. 252 (2):477-85. [Medline].

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Erten N, Saka B, Berberoglu K, et al. Technetium-99m 2-methoxy-isobutyl-isonitrile uptake scintigraphy in detection of the bone marrow infiltration in multiple myeloma: correlation with MRI and other prognostic factors. Ann Hematol. 2007 Nov. 86(11):805-13. [Medline].

Mele A, Offidani M, Visani G, Marconi M, Cambioli F, Nonni M. Technetium-99m sestamibi scintigraphy is sensitive and specific for the staging and the follow-up of patients with multiple myeloma: a multicentre study on 397 scans. Br J Haematol. 2007 Mar. 136(5):729-35. [Medline].

Khalafallah AA, Snarski A, Heng R, Hughes R, Renu S, Arm J, et al. Assessment of whole body MRI and sestamibi technetium-99m bone marrow scan in prediction of multiple myeloma disease progression and outcome: a prospective comparative study. BMJ Open. 2013. 3(1):[Medline]. [Full Text].

Michael E Mulligan, MD Professor, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine; Chief of Radiology, University of Maryland Rehabilitation and Orthopedic Institute; Assistant Chief of Musculoskeletal Imaging, MSK Fellowship Program Director, University of Maryland Medical Center

Michael E Mulligan, MD is a member of the following medical societies: American Roentgen Ray Society, International Skeletal Society, Radiological Society of North America, Society of Skeletal Radiology

Disclosure: Nothing to disclose.

Bernard D Coombs, MB, ChB, PhD Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand

Disclosure: Nothing to disclose.

Wilfred CG Peh, MD, MHSc, MBBS, FRCP(Glasg), FRCP(Edin), FRCR Clinical Professor, Yong Loo Lin School of Medicine, National University of Singapore; Senior Consultant and Head, Department of Diagnostic Radiology, Khoo Teck Puat Hospital, Alexandra Health, Singapore

Wilfred CG Peh, MD, MHSc, MBBS, FRCP(Glasg), FRCP(Edin), FRCR is a member of the following medical societies: American Roentgen Ray Society, British Institute of Radiology, International Skeletal Society, Radiological Society of North America, Royal College of Physicians, Royal College of Radiologists

Disclosure: Nothing to disclose.

Felix S Chew, MD, MBA, MEd Professor, Department of Radiology, Vice Chairman for Academic Innovation, Section Head of Musculoskeletal Radiology, University of Washington School of Medicine

Felix S Chew, MD, MBA, MEd is a member of the following medical societies: American Roentgen Ray Society, Association of University Radiologists, Radiological Society of North America

Disclosure: Nothing to disclose.

Carol L Andrews, MD Consulting Musculoskeletal Radiologist, Mink Radiologic Imaging; Consulting Staff, Department of Radiology, Antelope Valley Medical Center

Disclosure: Nothing to disclose.

Amilcare Gentili, MD Professor of Clinical Radiology, University of California, San Diego, School of Medicine; Consulting Staff, Department of Radiology, Thornton Hospital; Chief of Radiology, San Diego Veterans Affairs Healthcare System

Amilcare Gentili, MD is a member of the following medical societies: American Roentgen Ray Society, Radiological Society of North America, and Society of Skeletal Radiology

Disclosure: Nothing to disclose.

Sulabha Masih, MD Associate Professor of Diagnostic Radiology, University of California, Los Angeles, David Geffen School of Medicine; Consulting Staff, Department of Radiology, Section of Musculoskeletal Radiology, West Los Angeles Veterans Affairs Medical Center

Sulabha Masih, MD is a member of the following medical societies: American Roentgen Ray Society, Radiological Society of North America, and Society of Skeletal Radiology

Disclosure: Nothing to disclose.

Steven M Sorenson, MD Department of Radiology, Coast Radiology Imaging and Intervention.

Steven M Sorenson is a member of the following medical societies: Radiological Society of North America

Disclosure: Nothing to disclose.

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