IJC International Journal of Cancer
Appearance of monoclonal plasma cell diseases in whole-body magnetic resonance imaging and correlation with parameters of disease activity Jost K. Kloth1,2, Jens Hillengass2,3, Karin Listl1, Kerstin Kilk1, Thomas Hielscher4, Ola Landgren5, Weber1,2 Stefan Delorme2, Hartmut Goldschmidt3, Hans-Ulrich Kauczor1 and Marc-Andre 1
Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany Department of Radiology, German Cancer Research Center (dkfz), Heidelberg, Germany 3 Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany 4 Department of Biostatistics, German Cancer Research Center (dkfz), Heidelberg, Germany 5 Multiple Myeloma Section, National Cancer Institute, Nationl Institutes of Health, Bethesda, MD
Early Detection and Diagnosis
2
The aim of our study was to assess in which way different infiltration patterns of monoclonal plasma cell diseases in wholebody (wb) magnetic resonance imaging (MRI) are associated with clinical stages, plasma cell content in bone marrow samples and established serum markers of disease activity. Institutional review board approval was obtained. We performed wb-MRI in 547 consecutive, unselected and untreated patients with monoclonal gammopathy of undetermined significance (MGUS, n 5 138), smoldering myeloma (SMM, n 5 157) and multiple myeloma (MM, n 5 252) on two 1.5 T MRI-scanners with body array coils. The studies were evaluated in consensus by two experienced radiologists blinded to the diagnosis. We observed focal lesions in 23.9% (MGUS), 34.4% (SMM) and 81.3% (MM), respectively. A diffuse infiltration pattern was detected in 38.4%, 45.9% and 71%, respectively. The differences between all infiltration patterns were significant (p < 0.0001). The presence of focal lesions and the presence of a diffuse bone marrow infiltration was associated with an increased plasma cell percentage in bone marrow samples (median 22% vs. 14%, 26% vs. 10%, both p < 0.0001) and monoclonal protein concentration (median 18 g/dl vs. 13 g/dl, p 5 0.003, 20 g/dl vs. 11 g/dl, p < 0.0001). Further categorization of the diffuse infiltration patterns in wb-MRI into “salt-and-pepper,” moderate and severe identified significant associations with M-protein (median g/dl for S1P/moderate/severe 23/18/25, p 5 0.04), plasma cell percentage in the bone marrow (median 25%/24%/40%, p 5 0.02), and age (median years 67/60/57, p < 0.0001). Bone marrow infiltration in wb-MRI is significantly different between the various stages of plasma cell disease and correlates well with established markers of disease activity.
Monoclonal plasma cell diseases like multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) are a group of hematologic premalignant or malignant disorders associated with monoclonal proliferation of plasma cells mainly in the bone marrow.1,2 Although MGUS, being the most common disorder of plasma cells and occurring in 2% of persons older than 50 years, has an overall annual risk of progression of only 1% per year, the rate of transformation of SMM to
Key words: monoclonal plasma cell disease, magnetic resonance imaging, disease activity, multiple myeloma, correlation analysis Additional Supporting Information may be found in the online version of this article. DOI: 10.1002/ijc.28877 History: Received 11 Nov 2013; Accepted 20 Mar 2014; Online 7 Apr 2014 Correspondence to: Jost K. Kloth, Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany, Tel.: 149-6221-56-36804, E-mail: [email protected]
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MM or systemic amyloidosis (AL) has been shown to be 10% per year in the first 5 years.3–6 In the aforementioned monoclonal plasma cell disorders, the bone marrow involvement may be present in different patterns: diffuse bone marrow infiltration and focal lesions. Diffuse bone marrow infiltration is characterized by malignant plasma cells, mixed up with normal bone marrow cells, still preserving the cancellous bone structure. Focal lesions are circumscribed solid foci of plasma cells with the potential of destruction of the cancellous and cortical bone. To image these changes, plain radiographs (PRs), computed tomography (CT) and magnetic resonance imaging (MRI) are currently in routine use.7 Although PR has been an integral part of imaging for the last 25 years, osteolytic lesions can only be detected on plain films if more than 50% of bone loss is evident.8 For this reason, CT is most often recommended because it is more sensitive to depict destruction of mineralized bone and imminent osseous instability, especially in the vertebral column. However, myeloma infiltrates inside cancellous bone are difficult to detect as long as stimulation of osteoclast activity has not yet taken place to a major extent and the bone trabeculae are still preserved.9–11
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What’s new? Plasma-cell disorders such as multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) may produce different cellular patterns in the bone marrow. This study used whole-body magnetic resonance imaging (wb-MRI) to assess how these different infiltration patterns relate to clinical stages. The authors found that the number of focal lesions, as well as the presence and type of diffuse bone marrow infiltration, correlated with disease stage, as did serum markers of disease activity. Thus, wb-MRI is promising, non-invasive technique for more precisely staging and evaluating prognosis in MM and its asymptomatic precursors.
Material and Methods Patient population
This retrospective analysis was approved by the institutional ethics committee with waiver of informed consent. Between June 2006 and March 2010, a total of 547 patients with newly diagnosed monoclonal plasma cell disease underwent wbMRI. Median age was 60 years (range, 21 to 86 years). Patients with diagnosis of second malignancy as well as previous systemic treatment with corticosteroids or chemotherapy at the time of MRI were excluded. A total of 138 patients were classified as MGUS, 157 as SMM and 252 as MM according to the criteria of the international myeloma working group.1 Prognostic significance of whole-body MRI, M-protein level and age for the initiation of treatment, overall and progression-free survival has already been published for a part of the patient population (132 of 138 patients classified as MGUS).20 Whole-body MRI
All wb-MRI were performed on one of two identical 1.5 T R , Siemens Healthcare, MRI scanners (Magnetom AvantoV Erlangen, Germany) using phased-array, body-matrix surface coils (Siemens Healthcare, Erlangen, Germany). The sequence protocol included the following: T1-weighted turbo-spin echo sequences (repetition time (TR), 627 milliseconds [ms]; echo time (TE), 11 ms; section thickness (ST), 5 mm; acquisition time (TA), 2:45 min) and T2-weighted short-tau inversion C 2014 UICC Int. J. Cancer: 135, 2380–2386 (2014) V
recovery (STIR) sequences (TR, 5,300 ms; TE, 74 ms; ST, 5 mm; TA, 3:00) of the head, thorax, abdomen, pelvis and legs in coronal orientation; T1-weighted turbo-spin echo sequences (TR, 621 ms; TE, 11 ms; ST, 3 mm; TA, 1:38) and T2*-weighted gradient-echo fast low-angle shot (FLASH) sequences (TR, 4,000 ms; TE, 93 ms; ST, 4 mm; TA, 2:30) of the spine in sagittal orientation (Supporting Information Table 4). The patients were positioned with their arms along the body. The examinations covered the region between the skull vertex and the mid-calves. Depending on the body height of the patient, the distal calves and the feet were not always included. The total image acquisition time was approximately 40 min. Contrast medium was not given.
Image analysis
Each MR examination was analyzed in consensus by two experienced radiologists blinded to the clinical classification. Presence and absence of focal or diffuse infiltration patterns were evaluated using the following criteria: Bone marrow with a hyperintense signal compared to the intervertebral disk on T1-weighted images and a hypointense signal compared to paravertebral muscle tissue on T2-weighted STIR images was regarded as normal.21 Circumscribed lesions within the bone marrow with low signal intensity in T1-weighted and high signal intensity in T2-weighted STIR images were rated as focal lesions.22 Lesions larger than 5 mm in longest diameter were measured in three dimensions. Lesions smaller than 5 mm were considered non-specific and thus were not taken into account for statistical analysis.17 A so-called “salt-and-pepper” (S1P) pattern was described, when signal intensity on the T1-weighted images was patchy and suggestive of infiltration, but no focal lesions could be depicted on STIR images.22 According to literature, this pattern corresponds to an only low-grade diffuse infiltration of bone marrow intermingled with focal fat islets (with a hyperintense signal on T1-weighted images).23 Generally low signal intensity of the bone marrow on T1weighted images in combination with a general increased signal intensity on T2-weighted images were rated as diffuse infiltration pattern and subcategorized as “moderate” (hyperintense on T1-weighting compared to the intervertebral
Early Detection and Diagnosis
Among imaging methods, MRI is established as a tool for the diagnosis of bone marrow involvement in multiple myeloma before remodeling of the cancellous bone has taken place.8,12–14 MRI has a sensitivity of 68%, a specificity of 83%, a positive predictive value of 88% and is superior to PET-CT.15 Furthermore, the development of fast sequences allows MRI to be performed as a whole-body protocol (wbMRI), replacing the use of spinal MRI alone.16 Focal lesions and diffuse tumor cell infiltration detected by wb-MRI have been demonstrated to be of prognostic significance for predicting progression free and overall survival in monoclonal plasma cell diseases.17–19 Therefore, the aim of our study was to assess in which way different infiltration patterns are associated with clinical stages, plasma cell content in bone marrow samples and established serum markers of disease activity.
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Figure 1. Infiltration patterns at MR imaging: normal bone marrow (a), “Salt-and-pepper” infiltration pattern of the bone marrow with low signal intensity on T1-weighted images and focal islands of hyperintense fat tissue (b), moderate (c) and severe (d) diffuse bone marrow infiltration with decreasing signal intensity of bone marrow compared to the intervertebral disk.
Table 1. Infiltration patterns in subtypes of monoclonal plasma cell diseases MGUS All Focal lesions Diffuse bone marrow infiltration
SMM
138
157
MM 252
All 547
33 (23.9%)
54 (34.4%)
205 (81.3%)
292 (53.4%)
S1P
6 (4.3%)
19 (12.1%)
24 (9.5%)
49 (9.0%)
Moderate
42 (30.4%)
42 (26.8%)
97 (38.5%)
243 (44.4%)
Severe
5 (3.6%)
11 (7.0%)
58 (23.0%)
74 (13.5%)
All
53 (38.4%)
72 (45.9%)
179 (71.0%)
304 (55.6%)
Early Detection and Diagnosis
S1P 5 “salt-and-pepper.”
disc) or “severe” (hypo- or isointense on T1-weighting compared to the intervertebral disc) according to the previous recommendations (Fig. 1).22–24
Parameters of disease activity
MR findings were correlated to the established clinical markers monoclonal protein (M-protein) in serum, as well as plasma cell percentage in bone marrow biopsy. M-protein is an immunoglobulin or immunoglobulin light-chain, produced by the clonal proliferated plasma cells. The plasma cell percentage in bone marrow is estimated by a bone marrow biopsy of the iliac crest.25 Both parameters are used to subcategorize monoclonal plasma cell diseases: MGUS is defined by a serum concentration of M-protein of less than 30 g/l and a plasma cell percentage in the bone marrow of less than 10%. In SMM, the M-protein had to be equal to or higher than 30 g/l and/or bone marrow clonal cells equal to or more than 10%. No related organ or tissue impairment must be present.1 Statistical analysis
Focal lesions were analyzed as quantitative (number of focal lesions) and dichotomous parameter (focal lesions yes/no). Diffuse infiltration patterns were analyzed as dichotomous
(yes/no) and categorical parameter (normal/S1P/moderate/ severe). Fisher’s exact test was used to assess the association between dichotomous/categorical wb-MRI parameters and MM entities (MGUS/SMM/MM). The non-parametric Kruskal-Wallis test was used to assess the association between the number of focal lesions and MM entities. The association between dichotomous wb-MRI parameters and continuous parameters of disease activity, i.e., M-protein and plasma cell infiltration as well as patients’ age, was tested with the nonparametric Mann-Whitney Wilcoxon test. For comparisons across multiple groups (for instance different infiltration patterns), the Kruskal-Wallis test was used too. All tests were two-sided and p-values 0.05 were considered statistically significant. All analyses were performed using the statistical software environment R 2.15 (http://www.r-project.org/).26
Results Prevalence of infiltration patterns in MGUS, SMM and MM
We found focal lesions in 292 (53.4%) of all patients, and in 33 (23.9%), 54 (34.4%) and 205 (81.3%) of patients with MGUS, SMM and MM, respectively. The mean number of focal lesions was 1.2 and 1.4 per patient with a maximum of 46 in MGUS and 27 in SMM. The patient classified as MGUS, with the outstanding number of 46 focal lesions, C 2014 UICC Int. J. Cancer: 135, 2380–2386 (2014) V
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Figure 3. 78-year-old man with symptomatic MM and multiple focal lesions (a), for example in the right rib cage with a soft tumor component that displaces the lung (b). Another focal lesion is found in the right sacral bone with a soft tumor component (c). Diffuse bone marrow infiltration of the “salt-and-pepper” type is also seen (d).
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developed a diffuse large b-cell lymphoma 34 month later which might explain this exceptional finding. In patients with MM, the mean number of focal lesions was 18.1 with a maximum of 229. The differences in terms of quantity of focal lesions between all stages (MGUS, SMM and MM) were significant (p < 0.0001) (Table 1; Figs. 2 and 3; Supporting Information Table 3 and Fig. 5). A diffuse bone marrow infiltration was detected in 304 (55.6%) of all patients and in 53 (38.4%), 72 (45.9) and 179 (71.0%) of patients with MGUS, SMM and MM, respectively. Presence of diffuse bone marrow infiltration was also significant different between asymptomatic (MGUS and SMM) and symptomatic stages (p < 0.0001; Supporting Information Table 3). With regard to further categorization of diffuse infiltration patterns, a S1P pattern was found in 6 (4.3%), 19 (12.1%) and 24 (9.5%) cases, moderate diffuse bone marrow infiltration in 42 (30.4%), 42 (26.8%) and 97 (38.5%) and severe diffuse bone marrow infiltration in 5 (2.6%), 11 (7.0%) and 58 (23.0%) patients with MGUS, SMM and MM, respectively. Presence and ratio of diffuse bone marrow infiltration patterns were significantly different (p < 0.0001) between the subtypes of monoclonal plasma cell disease (Tables 1 and 2; Figs. 2 and 3; Supporting Information Table 3 and Fig. 6). In SMM, focal lesions were detected in 36 of 72 patients (50%) when diffuse bone marrow infiltration was present as well. In absence of diffuse infiltration, focal lesions were found in only 18 of 85 patients (22%). There was a significant association between the presence of focal lesions and diffuse bone marrow infiltration in this subgroup (p 5 0.0017). This did also apply to MGUS (p 5 0.05): focal lesions in MGUS were detected in 30.2% of all MGUS subjects in the presence and in 20% of all MGUS subjects in the
Early Detection and Diagnosis
Figure 2. 48-year-old man with SMM and one focal lesion in the intertrochanteric region of the left femur. Intralesional signal intensity is typically high in the T2w-STIR sequence (a) and low in the T1-weighted sequence (b). Signal intensity of the bone marrow is hyperintense compared to the intervertebral disk, therefore the marrow was regarded as normal (c).
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Table 2. Presence or absence of focal lesions depending on diffuse infiltration pattern Bone marrow
Focal
Normal
S1P
Moderate
Severe
MGUS
SMM
MM
No
68 (49.3%)
67 (42.7%)
12 (4.8%)
Yes
17 (12.3%)
18 (11.5%)
61 (24.2%)
No
2 (1.4%)
9 (5.7%)
4 (1.6%)
Yes
4 (2.9%)
10 (6.4%)
20 (7.9%)
No
32 (23.2%)
21 (13.4%)
18 (7.1%)
Yes
10 (7.2%)
21 (13.4%)
79 (31.3%)
No
3 (2.2%)
6 (3.8%)
13 (5.2%)
Yes
2 (1.4%)
5 (3.2%)
45 (17.9%)
Early Detection and Diagnosis
S1P 5 “salt-and-pepper.”
Figure 4. Distribution of focal lesions compared to diffuse infiltration patterns in different subtypes of monoclonal plasma cell diseases.
absence of a diffuse bone marrow infiltration. In MM, focal lesions were found in 77.6% of all cases, when also a diffuse bone marrow infiltration was present, and in 83.6% of all MM patients in case of absence of a diffuse marrow infiltration, but a significant association was not found in this subgroup (p 5 0.85) (Fig. 4, Supporting Information Table 5). Association of infiltration pattern and markers of disease activity
The M-protein level was elevated in 445 patients. In wbMRI, 259 of these patients had focal lesions, and 264 showed a diffuse bone marrow infiltration. The plasma cell percentage in bone marrow was elevated in 436 patients, with 253 of them having focal lesions and 244 presenting with a diffuse bone marrow infiltration in wb-MRI. M-protein level (p 5 0.003) and plasma cell percentage in the bone marrow (p < 0.0001) were significantly increased in patients who had
a focal or a diffuse bone marrow infiltration in wb-MRI than in those patients with normal bone marrow in wb-MRI. There was no association between the presence or absence of focal or diffuse bone marrow infiltration and age (median years: focal lesions yes/no 60/59, p 5 0.9; diffuse infiltration yes/no 60/60, p 5 0.5). Regarding the various subtypes of the diffuse infiltration pattern, we could identify a significant association between S1P, moderate and severe diffuse infiltration patterns and the M-protein level in serum (median g/dl for S1P/moderate/severe 23/18/25, p 5 0.04), as well as the plasma cell percentage within the bone marrow (median 25%/24%/40%, p 5 0.02) and age (median years 67/60/57, p < 0.0001) (Supporting Information Figs. 7 and 8, Table 6). Particularly noticeable is a decrease of moderate and S1P infiltration pattern in favor of normal bone marrow signal intensity for patients with 50–60% plasma cell infiltration level, compared C 2014 UICC Int. J. Cancer: 135, 2380–2386 (2014) V
to patients with 40–50% and 60–70% in Supporting Information Figure 7.
Discussion Our study demonstrates a significantly different bone marrow infiltration pattern of MGUS, SMM and MM in wb-MRI. Also, a significant association to established markers of disease activity—M-protein and plasma cell percentage in bone marrow—has been identified. The prognostic value of the presence of focal lesions or a diffuse bone marrow infiltration in the spine has already been demonstrated in several studies.17,18,27 With faster MR sequences and large whole-body coils, wb-MRI has become clinically feasible.28 Bauerle et al. already recommended wbMRI instead of spinal MRI in the initial work-up of patients with MGUS and MM. Their study revealed that a significant number of focal lesions would have been missed, if the examination had been limited to the spine alone.16 In our study, the distribution of bone marrow abnormalities in monoclonal plasma cell diseases in wb-MRI and their association with established clinical markers of disease activity and stages of disease was evaluated for the first time in a large population. We found both focal lesions and a diffuse bone marrow infiltration in all subgroups of monoclonal plasma cell diseases. Although MGUS and SMM are defined as asymptomatic stages of monoclonal plasma cell diseases, where bone destruction has not taken place yet, these findings are not surprising: focal lesions in patients with asymptomatic MM have been demonstrated by other authors before.16,29,30 Nevertheless, the number of focal lesions observed in our study was significantly higher in patients with MM compared to those with MGUS and SMM. Equivalent results were observed for the presence of diffuse bone marrow infiltration as well as their further categorization into S1P, moderate or severe patterns. The significant association between the presence of focal lesions and diffuse bone marrow infiltration in MGUS and SMM subgroups might be explained by a different load of monoclonal plasma cells in patients with no pathological findings in MRI compared to those with focal lesions and/or diffuse bone marrow infiltration, which in some ways is not represented by clinical parameters M-protein and bone marrow biopsy. To best of our knowledge, no further investigations of these interesting findings have been published yet. M-protein level in serum and plasma cell percentage in bone marrow, until now the most widely accepted clinical risk factors for the progression of SMM into MM, were significantly correlated with all observed infiltration patterns. Although the measurement of M-protein level is based on a blood sample and is easily integrated into a clinical routine setting, the determination of the plasma cell percentage within the bone marrow is invasive, and possibly subject to sampling errors, owing to the often patchy distribution of the disease.31 In these cases, wb-MRI is helpful to better guide biopsies. We found no conclusive explanation for the C 2014 UICC Int. J. Cancer: 135, 2380–2386 (2014) V
noticeable decrease of moderate and S1P diffuse infiltration pattern for patients with 50–60% plasma cell infiltration level compared to those with more or less plasma cell infiltration (Supporting Information Fig. 7). However, some caveats have to be taken into account when evaluating diffuse infiltration pattern in MRI: classification of patients into different groups is influenced by age in two ways: comparison to the intervertebral disc, whose signal intensity lowers with age and physiological hematopoiesis which varies both depending on age and immunological status. In addition, although there is a grading from normal (or rather minimal) over medium to severe—the S1P pattern represents a different way of infiltration. Positron emission tomography (PET) with 18Fluorodeoxyglucose (FDG) is another frequently used imaging modality for monoclonal plasma cell diseases part of the Durie-Salmon plus staging system as well. Spinnato et al.32 reported PETCT on 210 examinations each as less sensitive, as compared to MRI in the general staging and in patients with MM recurrence. Shortt et al.15 reported equivalent findings as well—PET-CT was less sensitive (59%) and specific (75%) than wb-MRI (68% and 83%) in the assessment of MM disease activity. In our study, none of the study population underwent PET-CT examinations—one reason for this is that PET-CT is not remunerated by the health insurance companies in our country. Thus, PET-CT is not part of the routine staging. For this reason, a comparison could not be made which is a limitation of our study. Wb-MRI is nearly riskless, associated with neither contrast agent application nor radiation, and it gives a diagnostic overview over the axial skeleton as well as the extremities. Furthermore, the prognostic significance of focal lesions and diffuse infiltration pattern in wb-MRI has already been reported before. Hillengass et al.18 reported focal lesions to be the strongest adverse prognostic factor for progression into symptomatic MM. In our study, the observed significant association between the MRI appearance and several already established parameters of disease activity also substantiates the statement that wb-MRI can fully assess the bone marrow involvement and additionally indicates that wb-MRI can more precisely classify asymptomatic stages like MGUS and SMM. Limitations of our study
In MRI, whole-body protocols may have limitations regarding the image resolution compared to dedicated whole-spine protocols or MRI protocols focused to the extremities. However, substantial focal myeloma lesions are clearly detectable, and the clinical importance of focal lesions smaller than 5 mm is questionable.17,22 The classification of the bone marrow infiltration pattern in comparison to the signal intensity of the intervertebral disk is a widely used strategy. Nevertheless, signal alteration of the intervertebral disk due to degenerative disk disease might be misleading in some cases.
Early Detection and Diagnosis
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Because of the retrospective character of the study and because of the fact that during the first years of the application of wb-MRI in myeloma patients in our center, the actual M-protein was not measured in all patients (but only the total immunoglobulin concentration). Thus, not all values were available for analysis.
Conclusion
The bone marrow infiltration in wb-MRI is significantly different between the various stages of plasma cell disease and correlates well with established markers of disease activity. Thus, wb-MRI should be integrated into the standard diagnostic work-up of all patients with plasma cell disease.
References
Early Detection and Diagnosis
1.
International Myeloma Working G. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749–57. 2. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36:842–54. 3. Blade J, Dimopoulos M, Rosinol L, et al. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol 2010;28:690–7. 4. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. New Engl J Med 2006;354: 1362–9. 5. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. New Engl J Med 2002;346:564–9. 6. Collins CD. Multiple myeloma. Cancer Imaging 2004;4 Spec No A:S47–53. 7. Dimopoulos M, Kyle R, Fermand JP, et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood 2011;117: 4701–5. 8. Ghanem N, Lohrmann C, Engelhardt M, et al. Whole-body MRI in the detection of bone marrow infiltration in patients with plasma cell neoplasms in comparison to the radiological skeletal survey. Eur Radiol 2006;16:1005–14. 9. Kropil P, Fenk R, Fritz LB, et al. Comparison of whole-body 64-slice multidetector computed tomography and conventional radiography in staging of multiple myeloma. Eur Radiol 2008;18: 51–8. 10. Horger M, Kanz L, Denecke B, et al. The benefit of using whole-body, low-dose, nonenhanced, multidetector computed tomography for followup and therapy response monitoring in patients with multiple myeloma. Cancer 2007;109: 1617–26.
11. Giuliani N, Colla S, Rizzoli V. New insight in the mechanism of osteoclast activation and formation in multiple myeloma: focus on the receptor activator of NF-kappaB ligand (RANKL). Exp Hematol 2004;32:685–91. 12. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al. Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 2000;96:2037–44. 13. Moulopoulos LA, Dimopoulos MA, Alexanian R, et al. Multiple myeloma: MR patterns of response to treatment. Radiology 1994;193:441–6. 14. Ludwig H, Fruhwald F, Tscholakoff D, et al. Magnetic resonance imaging of the spine in multiple myeloma. Lancet 1987;2:364–6. 15. Shortt CP, Gleeson TG, Breen KA, et al. Wholebody MRI versus PET in assessment of multiple myeloma disease activity. Am J Roentgenol 2009; 192:980–6. 16. Bauerle T, Hillengass J, Fechtner K, et al. Multiple myeloma and monoclonal gammopathy of undetermined significance: importance of wholebody versus spinal MR imaging. Radiology 2009; 252:477–85. 17. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 2007;25: 1121–8. 18. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010;28:1606–10. 19. Moulopoulos LA, Dimopoulos MA, Kastritis E, et al. Diffuse pattern of bone marrow involvement on magnetic resonance imaging is associated with high risk cytogenetics and poor outcome in newly diagnosed, symptomatic patients with multiple myeloma: a single center experience on 228 patients. Am J Hematol 2012; 87:861–4. 20. Hillengass J, Weber MA, Kilk K, et al. Prognostic significance of whole-body MRI in patients with monoclonal gammopathy of undetermined significance. Leukemia 2014;28:174–8. 21. Baur A, Stabler A, Bartl R, et al. MRI gadolinium enhancement of bone marrow: age-related
22.
23.
24.
25. 26.
27.
28.
29.
30.
31.
32.
changes in normals and in diffuse neoplastic infiltration. Skeletal Radiol 1997;26:414–8. Fechtner K, Hillengass J, Delorme S, et al. Staging monoclonal plasma cell disease: comparison of the Durie-Salmon and the Durie-Salmon PLUS staging systems. Radiology 2010;257:195–204. Stabler A, Baur A, Bartl R, et al. Contrast enhancement and quantitative signal analysis in MR imaging of multiple myeloma: assessment of focal and diffuse growth patterns in marrow correlated with biopsies and survival rates. Am J Roentgenol 1996;167:1029–36. Baur-Melnyk A, Reiser M. [Staging of multiple myeloma with MRI: comparison to MSCT and conventional radiography]. Der Radiologe 2004; 44:874–81. Raab MS, Podar K, Breitkreutz I, et al. Multiple myeloma. Lancet 2009;374:324–39. RCoreTeam. A language and environment for statistical computing: R Foundation for Statistical Computing, Vienne, Austria, 2012. Baur A, Stabler A, Nagel D, et al. Magnetic resonance imaging as a supplement for the clinical staging system of Durie and Salmon? Cancer 2002;95:1334–45. Johnson KM, Leavitt GD, Kayser HW. Totalbody MR imaging in as little as 18 seconds. Radiology 1997;202:262–7. Van de Berg BC, Lecouvet FE, Michaux L, et al. Stage I multiple myeloma: value of MR imaging of the bone marrow in the determination of prognosis. Radiology 1996;201:243–6. Moulopoulos LA, Dimopoulos MA, Smith TL, et al. Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 1995;13: 251–6. Schmidt GP, Baur A, Stabler A, et al. [Estimation of diffuse bone marrow infiltration of the spine in multiple myeloma: correlation of MRT with histological results]. RoFo 2005;177:745–50. Spinnato P, Bazzocchi A, Brioli A, et al. Contrast enhanced MRI and (1)(8)F-FDG PET-CT in the assessment of multiple myeloma: a comparison of results in different phases of the disease. Eur J Radiol 2012;81:4013–8.
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Appearance of monoclonal plasma cell diseases in whole-body magnetic resonance imaging and correlation with parameters of disease activity Jost K. Kloth1,2, Jens Hillengass2,3, Karin Listl1, Kerstin Kilk1, Thomas Hielscher4, Ola Landgren5, Weber1,2 Stefan Delorme2, Hartmut Goldschmidt3, Hans-Ulrich Kauczor1 and Marc-Andre 1
Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany Department of Radiology, German Cancer Research Center (dkfz), Heidelberg, Germany 3 Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany 4 Department of Biostatistics, German Cancer Research Center (dkfz), Heidelberg, Germany 5 Multiple Myeloma Section, National Cancer Institute, Nationl Institutes of Health, Bethesda, MD
Early Detection and Diagnosis
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The aim of our study was to assess in which way different infiltration patterns of monoclonal plasma cell diseases in wholebody (wb) magnetic resonance imaging (MRI) are associated with clinical stages, plasma cell content in bone marrow samples and established serum markers of disease activity. Institutional review board approval was obtained. We performed wb-MRI in 547 consecutive, unselected and untreated patients with monoclonal gammopathy of undetermined significance (MGUS, n 5 138), smoldering myeloma (SMM, n 5 157) and multiple myeloma (MM, n 5 252) on two 1.5 T MRI-scanners with body array coils. The studies were evaluated in consensus by two experienced radiologists blinded to the diagnosis. We observed focal lesions in 23.9% (MGUS), 34.4% (SMM) and 81.3% (MM), respectively. A diffuse infiltration pattern was detected in 38.4%, 45.9% and 71%, respectively. The differences between all infiltration patterns were significant (p < 0.0001). The presence of focal lesions and the presence of a diffuse bone marrow infiltration was associated with an increased plasma cell percentage in bone marrow samples (median 22% vs. 14%, 26% vs. 10%, both p < 0.0001) and monoclonal protein concentration (median 18 g/dl vs. 13 g/dl, p 5 0.003, 20 g/dl vs. 11 g/dl, p < 0.0001). Further categorization of the diffuse infiltration patterns in wb-MRI into “salt-and-pepper,” moderate and severe identified significant associations with M-protein (median g/dl for S1P/moderate/severe 23/18/25, p 5 0.04), plasma cell percentage in the bone marrow (median 25%/24%/40%, p 5 0.02), and age (median years 67/60/57, p < 0.0001). Bone marrow infiltration in wb-MRI is significantly different between the various stages of plasma cell disease and correlates well with established markers of disease activity.
Monoclonal plasma cell diseases like multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) are a group of hematologic premalignant or malignant disorders associated with monoclonal proliferation of plasma cells mainly in the bone marrow.1,2 Although MGUS, being the most common disorder of plasma cells and occurring in 2% of persons older than 50 years, has an overall annual risk of progression of only 1% per year, the rate of transformation of SMM to
Key words: monoclonal plasma cell disease, magnetic resonance imaging, disease activity, multiple myeloma, correlation analysis Additional Supporting Information may be found in the online version of this article. DOI: 10.1002/ijc.28877 History: Received 11 Nov 2013; Accepted 20 Mar 2014; Online 7 Apr 2014 Correspondence to: Jost K. Kloth, Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany, Tel.: 149-6221-56-36804, E-mail: [email protected]
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MM or systemic amyloidosis (AL) has been shown to be 10% per year in the first 5 years.3–6 In the aforementioned monoclonal plasma cell disorders, the bone marrow involvement may be present in different patterns: diffuse bone marrow infiltration and focal lesions. Diffuse bone marrow infiltration is characterized by malignant plasma cells, mixed up with normal bone marrow cells, still preserving the cancellous bone structure. Focal lesions are circumscribed solid foci of plasma cells with the potential of destruction of the cancellous and cortical bone. To image these changes, plain radiographs (PRs), computed tomography (CT) and magnetic resonance imaging (MRI) are currently in routine use.7 Although PR has been an integral part of imaging for the last 25 years, osteolytic lesions can only be detected on plain films if more than 50% of bone loss is evident.8 For this reason, CT is most often recommended because it is more sensitive to depict destruction of mineralized bone and imminent osseous instability, especially in the vertebral column. However, myeloma infiltrates inside cancellous bone are difficult to detect as long as stimulation of osteoclast activity has not yet taken place to a major extent and the bone trabeculae are still preserved.9–11
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What’s new? Plasma-cell disorders such as multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) may produce different cellular patterns in the bone marrow. This study used whole-body magnetic resonance imaging (wb-MRI) to assess how these different infiltration patterns relate to clinical stages. The authors found that the number of focal lesions, as well as the presence and type of diffuse bone marrow infiltration, correlated with disease stage, as did serum markers of disease activity. Thus, wb-MRI is promising, non-invasive technique for more precisely staging and evaluating prognosis in MM and its asymptomatic precursors.
Material and Methods Patient population
This retrospective analysis was approved by the institutional ethics committee with waiver of informed consent. Between June 2006 and March 2010, a total of 547 patients with newly diagnosed monoclonal plasma cell disease underwent wbMRI. Median age was 60 years (range, 21 to 86 years). Patients with diagnosis of second malignancy as well as previous systemic treatment with corticosteroids or chemotherapy at the time of MRI were excluded. A total of 138 patients were classified as MGUS, 157 as SMM and 252 as MM according to the criteria of the international myeloma working group.1 Prognostic significance of whole-body MRI, M-protein level and age for the initiation of treatment, overall and progression-free survival has already been published for a part of the patient population (132 of 138 patients classified as MGUS).20 Whole-body MRI
All wb-MRI were performed on one of two identical 1.5 T R , Siemens Healthcare, MRI scanners (Magnetom AvantoV Erlangen, Germany) using phased-array, body-matrix surface coils (Siemens Healthcare, Erlangen, Germany). The sequence protocol included the following: T1-weighted turbo-spin echo sequences (repetition time (TR), 627 milliseconds [ms]; echo time (TE), 11 ms; section thickness (ST), 5 mm; acquisition time (TA), 2:45 min) and T2-weighted short-tau inversion C 2014 UICC Int. J. Cancer: 135, 2380–2386 (2014) V
recovery (STIR) sequences (TR, 5,300 ms; TE, 74 ms; ST, 5 mm; TA, 3:00) of the head, thorax, abdomen, pelvis and legs in coronal orientation; T1-weighted turbo-spin echo sequences (TR, 621 ms; TE, 11 ms; ST, 3 mm; TA, 1:38) and T2*-weighted gradient-echo fast low-angle shot (FLASH) sequences (TR, 4,000 ms; TE, 93 ms; ST, 4 mm; TA, 2:30) of the spine in sagittal orientation (Supporting Information Table 4). The patients were positioned with their arms along the body. The examinations covered the region between the skull vertex and the mid-calves. Depending on the body height of the patient, the distal calves and the feet were not always included. The total image acquisition time was approximately 40 min. Contrast medium was not given.
Image analysis
Each MR examination was analyzed in consensus by two experienced radiologists blinded to the clinical classification. Presence and absence of focal or diffuse infiltration patterns were evaluated using the following criteria: Bone marrow with a hyperintense signal compared to the intervertebral disk on T1-weighted images and a hypointense signal compared to paravertebral muscle tissue on T2-weighted STIR images was regarded as normal.21 Circumscribed lesions within the bone marrow with low signal intensity in T1-weighted and high signal intensity in T2-weighted STIR images were rated as focal lesions.22 Lesions larger than 5 mm in longest diameter were measured in three dimensions. Lesions smaller than 5 mm were considered non-specific and thus were not taken into account for statistical analysis.17 A so-called “salt-and-pepper” (S1P) pattern was described, when signal intensity on the T1-weighted images was patchy and suggestive of infiltration, but no focal lesions could be depicted on STIR images.22 According to literature, this pattern corresponds to an only low-grade diffuse infiltration of bone marrow intermingled with focal fat islets (with a hyperintense signal on T1-weighted images).23 Generally low signal intensity of the bone marrow on T1weighted images in combination with a general increased signal intensity on T2-weighted images were rated as diffuse infiltration pattern and subcategorized as “moderate” (hyperintense on T1-weighting compared to the intervertebral
Early Detection and Diagnosis
Among imaging methods, MRI is established as a tool for the diagnosis of bone marrow involvement in multiple myeloma before remodeling of the cancellous bone has taken place.8,12–14 MRI has a sensitivity of 68%, a specificity of 83%, a positive predictive value of 88% and is superior to PET-CT.15 Furthermore, the development of fast sequences allows MRI to be performed as a whole-body protocol (wbMRI), replacing the use of spinal MRI alone.16 Focal lesions and diffuse tumor cell infiltration detected by wb-MRI have been demonstrated to be of prognostic significance for predicting progression free and overall survival in monoclonal plasma cell diseases.17–19 Therefore, the aim of our study was to assess in which way different infiltration patterns are associated with clinical stages, plasma cell content in bone marrow samples and established serum markers of disease activity.
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Figure 1. Infiltration patterns at MR imaging: normal bone marrow (a), “Salt-and-pepper” infiltration pattern of the bone marrow with low signal intensity on T1-weighted images and focal islands of hyperintense fat tissue (b), moderate (c) and severe (d) diffuse bone marrow infiltration with decreasing signal intensity of bone marrow compared to the intervertebral disk.
Table 1. Infiltration patterns in subtypes of monoclonal plasma cell diseases MGUS All Focal lesions Diffuse bone marrow infiltration
SMM
138
157
MM 252
All 547
33 (23.9%)
54 (34.4%)
205 (81.3%)
292 (53.4%)
S1P
6 (4.3%)
19 (12.1%)
24 (9.5%)
49 (9.0%)
Moderate
42 (30.4%)
42 (26.8%)
97 (38.5%)
243 (44.4%)
Severe
5 (3.6%)
11 (7.0%)
58 (23.0%)
74 (13.5%)
All
53 (38.4%)
72 (45.9%)
179 (71.0%)
304 (55.6%)
Early Detection and Diagnosis
S1P 5 “salt-and-pepper.”
disc) or “severe” (hypo- or isointense on T1-weighting compared to the intervertebral disc) according to the previous recommendations (Fig. 1).22–24
Parameters of disease activity
MR findings were correlated to the established clinical markers monoclonal protein (M-protein) in serum, as well as plasma cell percentage in bone marrow biopsy. M-protein is an immunoglobulin or immunoglobulin light-chain, produced by the clonal proliferated plasma cells. The plasma cell percentage in bone marrow is estimated by a bone marrow biopsy of the iliac crest.25 Both parameters are used to subcategorize monoclonal plasma cell diseases: MGUS is defined by a serum concentration of M-protein of less than 30 g/l and a plasma cell percentage in the bone marrow of less than 10%. In SMM, the M-protein had to be equal to or higher than 30 g/l and/or bone marrow clonal cells equal to or more than 10%. No related organ or tissue impairment must be present.1 Statistical analysis
Focal lesions were analyzed as quantitative (number of focal lesions) and dichotomous parameter (focal lesions yes/no). Diffuse infiltration patterns were analyzed as dichotomous
(yes/no) and categorical parameter (normal/S1P/moderate/ severe). Fisher’s exact test was used to assess the association between dichotomous/categorical wb-MRI parameters and MM entities (MGUS/SMM/MM). The non-parametric Kruskal-Wallis test was used to assess the association between the number of focal lesions and MM entities. The association between dichotomous wb-MRI parameters and continuous parameters of disease activity, i.e., M-protein and plasma cell infiltration as well as patients’ age, was tested with the nonparametric Mann-Whitney Wilcoxon test. For comparisons across multiple groups (for instance different infiltration patterns), the Kruskal-Wallis test was used too. All tests were two-sided and p-values 0.05 were considered statistically significant. All analyses were performed using the statistical software environment R 2.15 (http://www.r-project.org/).26
Results Prevalence of infiltration patterns in MGUS, SMM and MM
We found focal lesions in 292 (53.4%) of all patients, and in 33 (23.9%), 54 (34.4%) and 205 (81.3%) of patients with MGUS, SMM and MM, respectively. The mean number of focal lesions was 1.2 and 1.4 per patient with a maximum of 46 in MGUS and 27 in SMM. The patient classified as MGUS, with the outstanding number of 46 focal lesions, C 2014 UICC Int. J. Cancer: 135, 2380–2386 (2014) V
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Figure 3. 78-year-old man with symptomatic MM and multiple focal lesions (a), for example in the right rib cage with a soft tumor component that displaces the lung (b). Another focal lesion is found in the right sacral bone with a soft tumor component (c). Diffuse bone marrow infiltration of the “salt-and-pepper” type is also seen (d).
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developed a diffuse large b-cell lymphoma 34 month later which might explain this exceptional finding. In patients with MM, the mean number of focal lesions was 18.1 with a maximum of 229. The differences in terms of quantity of focal lesions between all stages (MGUS, SMM and MM) were significant (p < 0.0001) (Table 1; Figs. 2 and 3; Supporting Information Table 3 and Fig. 5). A diffuse bone marrow infiltration was detected in 304 (55.6%) of all patients and in 53 (38.4%), 72 (45.9) and 179 (71.0%) of patients with MGUS, SMM and MM, respectively. Presence of diffuse bone marrow infiltration was also significant different between asymptomatic (MGUS and SMM) and symptomatic stages (p < 0.0001; Supporting Information Table 3). With regard to further categorization of diffuse infiltration patterns, a S1P pattern was found in 6 (4.3%), 19 (12.1%) and 24 (9.5%) cases, moderate diffuse bone marrow infiltration in 42 (30.4%), 42 (26.8%) and 97 (38.5%) and severe diffuse bone marrow infiltration in 5 (2.6%), 11 (7.0%) and 58 (23.0%) patients with MGUS, SMM and MM, respectively. Presence and ratio of diffuse bone marrow infiltration patterns were significantly different (p < 0.0001) between the subtypes of monoclonal plasma cell disease (Tables 1 and 2; Figs. 2 and 3; Supporting Information Table 3 and Fig. 6). In SMM, focal lesions were detected in 36 of 72 patients (50%) when diffuse bone marrow infiltration was present as well. In absence of diffuse infiltration, focal lesions were found in only 18 of 85 patients (22%). There was a significant association between the presence of focal lesions and diffuse bone marrow infiltration in this subgroup (p 5 0.0017). This did also apply to MGUS (p 5 0.05): focal lesions in MGUS were detected in 30.2% of all MGUS subjects in the presence and in 20% of all MGUS subjects in the
Early Detection and Diagnosis
Figure 2. 48-year-old man with SMM and one focal lesion in the intertrochanteric region of the left femur. Intralesional signal intensity is typically high in the T2w-STIR sequence (a) and low in the T1-weighted sequence (b). Signal intensity of the bone marrow is hyperintense compared to the intervertebral disk, therefore the marrow was regarded as normal (c).
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Table 2. Presence or absence of focal lesions depending on diffuse infiltration pattern Bone marrow
Focal
Normal
S1P
Moderate
Severe
MGUS
SMM
MM
No
68 (49.3%)
67 (42.7%)
12 (4.8%)
Yes
17 (12.3%)
18 (11.5%)
61 (24.2%)
No
2 (1.4%)
9 (5.7%)
4 (1.6%)
Yes
4 (2.9%)
10 (6.4%)
20 (7.9%)
No
32 (23.2%)
21 (13.4%)
18 (7.1%)
Yes
10 (7.2%)
21 (13.4%)
79 (31.3%)
No
3 (2.2%)
6 (3.8%)
13 (5.2%)
Yes
2 (1.4%)
5 (3.2%)
45 (17.9%)
Early Detection and Diagnosis
S1P 5 “salt-and-pepper.”
Figure 4. Distribution of focal lesions compared to diffuse infiltration patterns in different subtypes of monoclonal plasma cell diseases.
absence of a diffuse bone marrow infiltration. In MM, focal lesions were found in 77.6% of all cases, when also a diffuse bone marrow infiltration was present, and in 83.6% of all MM patients in case of absence of a diffuse marrow infiltration, but a significant association was not found in this subgroup (p 5 0.85) (Fig. 4, Supporting Information Table 5). Association of infiltration pattern and markers of disease activity
The M-protein level was elevated in 445 patients. In wbMRI, 259 of these patients had focal lesions, and 264 showed a diffuse bone marrow infiltration. The plasma cell percentage in bone marrow was elevated in 436 patients, with 253 of them having focal lesions and 244 presenting with a diffuse bone marrow infiltration in wb-MRI. M-protein level (p 5 0.003) and plasma cell percentage in the bone marrow (p < 0.0001) were significantly increased in patients who had
a focal or a diffuse bone marrow infiltration in wb-MRI than in those patients with normal bone marrow in wb-MRI. There was no association between the presence or absence of focal or diffuse bone marrow infiltration and age (median years: focal lesions yes/no 60/59, p 5 0.9; diffuse infiltration yes/no 60/60, p 5 0.5). Regarding the various subtypes of the diffuse infiltration pattern, we could identify a significant association between S1P, moderate and severe diffuse infiltration patterns and the M-protein level in serum (median g/dl for S1P/moderate/severe 23/18/25, p 5 0.04), as well as the plasma cell percentage within the bone marrow (median 25%/24%/40%, p 5 0.02) and age (median years 67/60/57, p < 0.0001) (Supporting Information Figs. 7 and 8, Table 6). Particularly noticeable is a decrease of moderate and S1P infiltration pattern in favor of normal bone marrow signal intensity for patients with 50–60% plasma cell infiltration level, compared C 2014 UICC Int. J. Cancer: 135, 2380–2386 (2014) V
to patients with 40–50% and 60–70% in Supporting Information Figure 7.
Discussion Our study demonstrates a significantly different bone marrow infiltration pattern of MGUS, SMM and MM in wb-MRI. Also, a significant association to established markers of disease activity—M-protein and plasma cell percentage in bone marrow—has been identified. The prognostic value of the presence of focal lesions or a diffuse bone marrow infiltration in the spine has already been demonstrated in several studies.17,18,27 With faster MR sequences and large whole-body coils, wb-MRI has become clinically feasible.28 Bauerle et al. already recommended wbMRI instead of spinal MRI in the initial work-up of patients with MGUS and MM. Their study revealed that a significant number of focal lesions would have been missed, if the examination had been limited to the spine alone.16 In our study, the distribution of bone marrow abnormalities in monoclonal plasma cell diseases in wb-MRI and their association with established clinical markers of disease activity and stages of disease was evaluated for the first time in a large population. We found both focal lesions and a diffuse bone marrow infiltration in all subgroups of monoclonal plasma cell diseases. Although MGUS and SMM are defined as asymptomatic stages of monoclonal plasma cell diseases, where bone destruction has not taken place yet, these findings are not surprising: focal lesions in patients with asymptomatic MM have been demonstrated by other authors before.16,29,30 Nevertheless, the number of focal lesions observed in our study was significantly higher in patients with MM compared to those with MGUS and SMM. Equivalent results were observed for the presence of diffuse bone marrow infiltration as well as their further categorization into S1P, moderate or severe patterns. The significant association between the presence of focal lesions and diffuse bone marrow infiltration in MGUS and SMM subgroups might be explained by a different load of monoclonal plasma cells in patients with no pathological findings in MRI compared to those with focal lesions and/or diffuse bone marrow infiltration, which in some ways is not represented by clinical parameters M-protein and bone marrow biopsy. To best of our knowledge, no further investigations of these interesting findings have been published yet. M-protein level in serum and plasma cell percentage in bone marrow, until now the most widely accepted clinical risk factors for the progression of SMM into MM, were significantly correlated with all observed infiltration patterns. Although the measurement of M-protein level is based on a blood sample and is easily integrated into a clinical routine setting, the determination of the plasma cell percentage within the bone marrow is invasive, and possibly subject to sampling errors, owing to the often patchy distribution of the disease.31 In these cases, wb-MRI is helpful to better guide biopsies. We found no conclusive explanation for the C 2014 UICC Int. J. Cancer: 135, 2380–2386 (2014) V
noticeable decrease of moderate and S1P diffuse infiltration pattern for patients with 50–60% plasma cell infiltration level compared to those with more or less plasma cell infiltration (Supporting Information Fig. 7). However, some caveats have to be taken into account when evaluating diffuse infiltration pattern in MRI: classification of patients into different groups is influenced by age in two ways: comparison to the intervertebral disc, whose signal intensity lowers with age and physiological hematopoiesis which varies both depending on age and immunological status. In addition, although there is a grading from normal (or rather minimal) over medium to severe—the S1P pattern represents a different way of infiltration. Positron emission tomography (PET) with 18Fluorodeoxyglucose (FDG) is another frequently used imaging modality for monoclonal plasma cell diseases part of the Durie-Salmon plus staging system as well. Spinnato et al.32 reported PETCT on 210 examinations each as less sensitive, as compared to MRI in the general staging and in patients with MM recurrence. Shortt et al.15 reported equivalent findings as well—PET-CT was less sensitive (59%) and specific (75%) than wb-MRI (68% and 83%) in the assessment of MM disease activity. In our study, none of the study population underwent PET-CT examinations—one reason for this is that PET-CT is not remunerated by the health insurance companies in our country. Thus, PET-CT is not part of the routine staging. For this reason, a comparison could not be made which is a limitation of our study. Wb-MRI is nearly riskless, associated with neither contrast agent application nor radiation, and it gives a diagnostic overview over the axial skeleton as well as the extremities. Furthermore, the prognostic significance of focal lesions and diffuse infiltration pattern in wb-MRI has already been reported before. Hillengass et al.18 reported focal lesions to be the strongest adverse prognostic factor for progression into symptomatic MM. In our study, the observed significant association between the MRI appearance and several already established parameters of disease activity also substantiates the statement that wb-MRI can fully assess the bone marrow involvement and additionally indicates that wb-MRI can more precisely classify asymptomatic stages like MGUS and SMM. Limitations of our study
In MRI, whole-body protocols may have limitations regarding the image resolution compared to dedicated whole-spine protocols or MRI protocols focused to the extremities. However, substantial focal myeloma lesions are clearly detectable, and the clinical importance of focal lesions smaller than 5 mm is questionable.17,22 The classification of the bone marrow infiltration pattern in comparison to the signal intensity of the intervertebral disk is a widely used strategy. Nevertheless, signal alteration of the intervertebral disk due to degenerative disk disease might be misleading in some cases.
Early Detection and Diagnosis
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Because of the retrospective character of the study and because of the fact that during the first years of the application of wb-MRI in myeloma patients in our center, the actual M-protein was not measured in all patients (but only the total immunoglobulin concentration). Thus, not all values were available for analysis.
Conclusion
The bone marrow infiltration in wb-MRI is significantly different between the various stages of plasma cell disease and correlates well with established markers of disease activity. Thus, wb-MRI should be integrated into the standard diagnostic work-up of all patients with plasma cell disease.
References
Early Detection and Diagnosis
1.
International Myeloma Working G. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749–57. 2. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36:842–54. 3. Blade J, Dimopoulos M, Rosinol L, et al. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol 2010;28:690–7. 4. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. New Engl J Med 2006;354: 1362–9. 5. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. New Engl J Med 2002;346:564–9. 6. Collins CD. Multiple myeloma. Cancer Imaging 2004;4 Spec No A:S47–53. 7. Dimopoulos M, Kyle R, Fermand JP, et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood 2011;117: 4701–5. 8. Ghanem N, Lohrmann C, Engelhardt M, et al. Whole-body MRI in the detection of bone marrow infiltration in patients with plasma cell neoplasms in comparison to the radiological skeletal survey. Eur Radiol 2006;16:1005–14. 9. Kropil P, Fenk R, Fritz LB, et al. Comparison of whole-body 64-slice multidetector computed tomography and conventional radiography in staging of multiple myeloma. Eur Radiol 2008;18: 51–8. 10. Horger M, Kanz L, Denecke B, et al. The benefit of using whole-body, low-dose, nonenhanced, multidetector computed tomography for followup and therapy response monitoring in patients with multiple myeloma. Cancer 2007;109: 1617–26.
11. Giuliani N, Colla S, Rizzoli V. New insight in the mechanism of osteoclast activation and formation in multiple myeloma: focus on the receptor activator of NF-kappaB ligand (RANKL). Exp Hematol 2004;32:685–91. 12. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al. Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 2000;96:2037–44. 13. Moulopoulos LA, Dimopoulos MA, Alexanian R, et al. Multiple myeloma: MR patterns of response to treatment. Radiology 1994;193:441–6. 14. Ludwig H, Fruhwald F, Tscholakoff D, et al. Magnetic resonance imaging of the spine in multiple myeloma. Lancet 1987;2:364–6. 15. Shortt CP, Gleeson TG, Breen KA, et al. Wholebody MRI versus PET in assessment of multiple myeloma disease activity. Am J Roentgenol 2009; 192:980–6. 16. Bauerle T, Hillengass J, Fechtner K, et al. Multiple myeloma and monoclonal gammopathy of undetermined significance: importance of wholebody versus spinal MR imaging. Radiology 2009; 252:477–85. 17. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 2007;25: 1121–8. 18. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010;28:1606–10. 19. Moulopoulos LA, Dimopoulos MA, Kastritis E, et al. Diffuse pattern of bone marrow involvement on magnetic resonance imaging is associated with high risk cytogenetics and poor outcome in newly diagnosed, symptomatic patients with multiple myeloma: a single center experience on 228 patients. Am J Hematol 2012; 87:861–4. 20. Hillengass J, Weber MA, Kilk K, et al. Prognostic significance of whole-body MRI in patients with monoclonal gammopathy of undetermined significance. Leukemia 2014;28:174–8. 21. Baur A, Stabler A, Bartl R, et al. MRI gadolinium enhancement of bone marrow: age-related
22.
23.
24.
25. 26.
27.
28.
29.
30.
31.
32.
changes in normals and in diffuse neoplastic infiltration. Skeletal Radiol 1997;26:414–8. Fechtner K, Hillengass J, Delorme S, et al. Staging monoclonal plasma cell disease: comparison of the Durie-Salmon and the Durie-Salmon PLUS staging systems. Radiology 2010;257:195–204. Stabler A, Baur A, Bartl R, et al. Contrast enhancement and quantitative signal analysis in MR imaging of multiple myeloma: assessment of focal and diffuse growth patterns in marrow correlated with biopsies and survival rates. Am J Roentgenol 1996;167:1029–36. Baur-Melnyk A, Reiser M. [Staging of multiple myeloma with MRI: comparison to MSCT and conventional radiography]. Der Radiologe 2004; 44:874–81. Raab MS, Podar K, Breitkreutz I, et al. Multiple myeloma. Lancet 2009;374:324–39. RCoreTeam. A language and environment for statistical computing: R Foundation for Statistical Computing, Vienne, Austria, 2012. Baur A, Stabler A, Nagel D, et al. Magnetic resonance imaging as a supplement for the clinical staging system of Durie and Salmon? Cancer 2002;95:1334–45. Johnson KM, Leavitt GD, Kayser HW. Totalbody MR imaging in as little as 18 seconds. Radiology 1997;202:262–7. Van de Berg BC, Lecouvet FE, Michaux L, et al. Stage I multiple myeloma: value of MR imaging of the bone marrow in the determination of prognosis. Radiology 1996;201:243–6. Moulopoulos LA, Dimopoulos MA, Smith TL, et al. Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 1995;13: 251–6. Schmidt GP, Baur A, Stabler A, et al. [Estimation of diffuse bone marrow infiltration of the spine in multiple myeloma: correlation of MRT with histological results]. RoFo 2005;177:745–50. Spinnato P, Bazzocchi A, Brioli A, et al. Contrast enhanced MRI and (1)(8)F-FDG PET-CT in the assessment of multiple myeloma: a comparison of results in different phases of the disease. Eur J Radiol 2012;81:4013–8.
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