18F-FDG PET/CT in monoclonal plasma cell disorders.

Plasma cell disorders are a heterogeneous group caused by the monoclonal proliferation of lymphoplasmacytic cells in the bone marrow. Multiple Myeloma (MM) is the most serious and prevalent plasma cell dyscrasia, with a median age of onset of 60 years.MM displays significant genetic, biological and clinical heterogeneity with subsequent imaging heterogeneity, evident in contemporary imaging modalities (PET/CT and MRI). Evidence suggests that MM is always preceded by precursor stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma.

Outcome prediction by interim positron emission tomography and IgM monoclonal gammopathy in diffuse large B-cell lymphoma.

In diffuse large B-cell lymphoma (DLBCL), a positive interim positron emission tomography (PET) scan predicts treatment failure, but the proportion of high-risk patients thus identified is small. To improve prediction, we combined the interim PET result with the presence or absence of an associated IgM gammopathy. Of 108 DLBCL patients participating in a prospective trial, nine (8%) were interim PET positive and 19 (18%) had an IgM gammopathy. The monoclonal protein was not associated with distinguishing genetic features, and its light chain restriction was not always concordant with the light chain restriction of the lymphoma. The information provided by interim PET and IgM gammopathy was combined to dichotomize the population into sizeable high-risk (1-2 adverse factors) and low-risk groups (no adverse factor) with widely different outcomes (population size, 25% vs. 75%; 3-year risk of progression, 51% vs. 10%; 3-year overall survival, 64% vs. 95%). Multivariable analyses including established risk factors revealed the interim PET result and the IgM gammopathy status to be the only factors significantly associated with outcome. Information about interim PET response and IgM gammopathy may be useful in studies testing risk-adapted treatment strategies.

[Skeletal changes in plasma cell dyscrasias]. / Skelettveränderungen bei Plasmazelldyskrasien.

BACKGROUND: Plasma cell dyscrasias are a spectrum of diseases characterized by clonal plasma cell proliferation. Important entities within this group are monoclonal gammopathy of unknown significance, smoldering multiple myeloma, and symptomatic multiple myeloma. PURPOSE: The goal of this review is to illustrate plasma cell dyscrasia imaging findings of bone and bone marrow as seen on whole-body computed tomography (CT) and magnetic resonance imaging (MRI) and to discuss the relevance of imaging for management of patients with plasma cell dyscrasias. MATERIALS AND METHODS: Selective literature search with analysis of dedicated original research articles and reviews and discussion of clinical guidelines. RESULTS: Diagnostic classification of plasma cell dyscrasias is based on the SLiM-CRAB criteria. CT primarily represents imaging of mineralized bone to show osseous end organ damage by detecting osteodestruction. MRI is primarily used for bone marrow imaging to detect diffuse or focal bone marrow infiltration, even in the absence of bone destruction. Different patterns of bone marrow infiltration can be distinguished. Treatment response is associated with characteristic imaging signs of lesion regression. CONCLUSION: Imaging plays a prominent role in treatment stratification of patients with plasma cell dyscrasia at first diagnosis and during follow-up.

Quantitative and qualitative assessment of plasma cell dyscrasias in dual-layer spectral CT.

OBJECTIVES: Virtual non-calcium (VNCa) images could improve assessment of plasma cell dyscrasias by enhancing visibility of bone marrow. Thus, VNCa images from dual-layer spectral CT (DLCT) were evaluated at different calcium suppression (CaSupp) indices, correlating results with apparent diffusion coefficient (ADC) values from MRI. METHODS: Thirty-two patients with initial clinical diagnosis of a plasma cell dyscrasia before any chemotherapeutic treatment, who had undergone whole-body low-dose DLCT and MRI within 2 months, were retrospectively enrolled. VNCa images with CaSupp indices ranging from 25 to 95 in steps of 10, conventional CT images, and ADC maps were quantitatively analyzed using region-of-interests in the vertebral bodies C7, T12, L1-L5, and the iliac bone. Independent two-sample t-test, Wilcoxon-signed-rank test, Pearson's correlation, and ROC analysis were performed. RESULTS: Eighteen patients had a non-diffuse, 14 a diffuse infiltration in conventional MRI. A significant difference between diffuse and non-diffuse infiltration was shown for VNCa-CT with CaSupp indices from 55 to 95, for conventional CT, and for ADC (each p < 0.0001). Significant quantitative correlation between VNCa-CT and MRI could be found with strongest correlation at CaSupp index 65 for L3 (r = 0.68, p < 0.0001) and averaged L1-L5 (r = 0.66, p < 0.0001). The optimum CT number cut-off point for differentiation between diffuse and non-diffuse infiltration at CaSupp index 65 for averaged L1-L5 was -1.6 HU (sensitivity 78.6%, specificity 75.0%). CONCLUSION: Measurements in VNCa-CT showed the highest correlation with ADC at CaSupp index 65. VNCa technique may prove useful for evaluation of bone marrow infiltration if MRI is not feasible. KEY POINTS: • VNCa-CT images can support the evaluation of bone marrow infiltration in plasma cell dyscrasias. • VNCa measurements of vertebral bodies show significant correlation with ADC in MRI. • Averaging L1-L5 at CaSupp index 65 allowed quantitative detection of infiltration comparable to MRI ADC.

Tubulointerstitial nephritis with monotypic lympho-plasmacytic infiltrates in a patient with primary Sjögren's syndrome accompanied by IgA-type monoclonal gammopathy.

BACKGROUND: Although most cases of tubulointerstitial nephritis in paraproteinemia are monoclonal light chain deposition-mediated, interstitial nephritis as neoplastic interstitial cell infiltration has rarely been described. On the other hand, lympho-plasma-cell-rich tubulointerstitial nephritis, in which the infiltrative cells are usually polytypic, is often evident in primary Sjögren's syndrome (pSS). Herein we present a rare case of pSS in a patient who had been diagnosed as having IgA kappa-type monoclonal gammopathy of undetermined significance (MGUS) and developed tubulointerstitial nephritis with monotypic (IgA kappa) lympho-plasmacytic infiltrates. CASE PRESENTATION: A 74-year-old Japanese woman with pSS who had been diagnosed as having IgA kappa-type MGUS developed progressive renal dysfunction. Renal biopsy revealed tubulointerstitial nephritis with abundant plasma cell-rich mononuclear cell infiltrates without atypia. Immunohistochemical staining for immunoglobulins and light chains showed that most infiltrates were positive for IgA and kappa. Most of the infiltrative cells were positive for CD38 and CD138, and cells positive for CD 19 and CD 45 were also widely evident. Electron microscopy and immunofluorescence studies revealed no apparent immunological deposits in the glomeruli and tubules. Bone marrow and whole-body radiological examinations revealed no findings suggestive of multiple myeloma or lymphoma. Renal function improved rapidly with prednisolone 40 mg daily and has been maintained at the same level on low-dose prednisolone and azathioprine for 18 months. CONCLUSION: Tubulointerstitial nephritis with monotypic cell infiltrates, without immunological deposits, is a quite rare histological picture in MGUS, and might be a unique renal manifestation in patients with pSS.

International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders.

Recent advances in the treatment of multiple myeloma have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the investigation of multiple myeloma and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease is important for prognosis determination and treatment planning, and it has underscored an unmet need for sensitive imaging methods that accurately assess patient response to multiple myeloma treatment. Low-dose whole-body CT has increased sensitivity compared with conventional skeletal survey in the detection of bone disease, which can reveal information leading to changes in therapy and disease management that could prevent or delay the onset of clinically significant morbidity and mortality as a result of skeletal-related events. Given the multiple options available for the detection of bone and bone marrow lesions, ranging from conventional skeletal survey to whole-body CT, PET/CT, and MRI, the International Myeloma Working Group decided to establish guidelines on optimal use of imaging methods at different disease stages. These recommendations on imaging within and outside of clinical trials will help standardise imaging for monoclonal plasma cell disorders worldwide to allow the comparison of results and the unification of treatment approaches for multiple myeloma.

Noninvasive assessment of corneal alterations associated with monoclonal gammopathy.

Aggregation of monoclonal immunoglobulin can lead to organ damage. However, the necessity of invasive examination such as biopsy has hampered better understanding of the pathophysiology. Corneal crystalline deposition is a rarely reported but known ocular manifestation of multiple myeloma. It is unclear whether the cornea is a common target of monoclonal immunoglobulin deposition. We conducted a prospective clinical case-control study to objectively quantify monoclonal gammopathy-associated corneal changes as well as any therapeutic response. Using an ophthalmic Scheimpflug camera imaging for noninvasive corneal assessments, we quantified densitometry values in 30 patients. Although none had crystalline keratopathy, corneal transparency in monoclonal gammopathy patients was significantly impaired compared to that in age-matched controls, based on noninvasive Scheimpflug camera imaging. Furthermore, treatment for multiple myeloma seemed to eradicate the diffuse aggregation of monoclonal proteins. Our results indicate that exposure to monoclonal immunoglobulin may induce the accumulation of monoclonal immunoglobulin in the cornea, and ophthalmic examinations such as corneal densitometry measurements with a Scheimpflug camera may be useful for noninvasive evaluation of monoclonal immunoglobulin deposition diseases.

Generalized crystal-storing histiocytosis with diffuse large B-cell lymphoma and monoclonal gammopathy in a Chinese elderly woman: a case report.

BACKGROUND: Crystal-storing histiocytosis (CSH) is a rare lesion characterized by sheets of crystal-laden non-neoplastic histiocytes. CSH shows a prominent association with lymphoproliferative disorders that express monoclonal immunoglobulins, mainly multiple myeloma (MM), lymphoplasmacytic lymphoma (LPL) and monoclonal gammopathy of undetermined significance (MGUS). However, no aggressive B cell lymphoma has been reported to be associated with CSH. CASE PRESENTATION: A 74-year-old Chinese woman presented with multiple subcutaneous masses, abdominal pain, and fever. An IgM kappa type of monoclonal gammopathy (MG) was noted by immunofixation performed on the patient's serum. Computed tomographic (CT) scan revealed subcutaneous masses on the left upper arm and at the waist and multiple low-density lesions in the spleen. Microscopically, sections of subcutaneous masses revealed sheets of large polygonal and spindle cells with abundant eosinophilic cytoplasm, round to ovoid eccentric nuclei, reticulate chromatin, and median nucleoli. Massive needle-shaped crystals were confined to the cytoplasm. Immunohistochemically, these crystal-containing cells were positive for CD68/PGM1, CD163, IgM, and Igκ. Meanwhile, the splenic tumour was diagnosed as diffuse large B-cell lymphoma (DLBCL), non-germinal-centre B (non-GCB) subtype (Hans algorithm). Immunohistochemistry for IgM was positive in the cytoplasm of some neoplastic cells. Immunoglobulin heavy chain (IgH) gene rearrangement was detected by PCR analysis of the subcutaneous mass and the splenic tumour. CONCLUSION: To the best of our knowledge, this is the first case of generalized CSH with DLBCL and MG. Although the rarity of CSH and separate locations of CSH and lymphoma led to a diagnostic dilemma, the presence of MG was a clue to appreciate the relation between CSH and DLBCL. This case stressed a full investigation into the underlying lymphoproliferative disorder for integrated diagnosis and correct treatments.

C3 glomerulonephritis associated with monoclonal gammopathy of renal significance: case report.

BACKGROUND: Morbidity associated with monoclonal gammopathy of renal significance is high due to the severe renal lesions and the associated systemic alterations. Accordingly, early diagnosis is fundamental, as is stopping the clonal production of immunoglobulins using specific chemotherapy. CASE PRESENTATION: A 75-year-old man with chronic renal disease of unknown origin since 2010 experienced rapid worsening of renal function over a period of 6 mos. Bone marrow biopsy showed monoclonal gammopathy of undetermined significance. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence and a membranoproliferative pattern on light microscopy. Skin biopsy showed endothelial deposition of complement. Given both the renal and cutaneous involvement the patient was considered to have monoclonal gammopathy of renal significance. We considered an underlying pathogenic mechanism for the renal alteration secondary to activation of the alternative complement pathway by the anomalous immunoglobulin. Despite treatment with plasmapheresis, bortezomib and steroids, advanced chronic kidney disease developed. CONCLUSIONS: The possible underlying cause of the monoclonal gammopathy of renal significance suggests that monoclonal gammopathy should be considered in adult patients with membranoproliferative glomerulonephritis.

Imaging of Sjögren Syndrome and Immunoglobulin G4-Related Disease of the Salivary Glands.

The salivary glands are commonly affected in systemic autoimmune disease and diseases of unknown pathogenesis. Sjögren syndrome (SjS) can be affected by other systemic diseases. Immunoglobulin G4-related disease (IgG4-RD) commonly affects salivary glands. Imaging findings are usually nonspecific; however, radiologists should be familiar with the manifestations to avoid diagnostic delay. Findings of early-stage SjS are difficult to identify on routine computed tomography or MR imaging. Chronic SjS can be diagnosed from MR imaging and sialographic findings. Multiglandular and localized involvement of IgG4-RD is difficult to differentiate from malignant lymphoma for multiglandular disease and salivary gland carcinoma for localized disease.

Current applications of multiparameter flow cytometry in plasma cell disorders.

Multiparameter flow cytometry (MFC) has become standard in the management of patients with plasma cell (PC) dyscrasias, and could be considered mandatory in specific areas of routine clinical practice. It plays a significant role during the differential diagnostic work-up because of its fast and conclusive readout of PC clonality, and simultaneously provides prognostic information in most monoclonal gammopathies. Recent advances in the treatment and outcomes of multiple myeloma led to the implementation of new response criteria, including minimal residual disease (MRD) status as one of the most relevant clinical endpoints with the potential to act as surrogate for survival. Recent technical progress led to the development of next-generation flow (NGF) cytometry that represents a validated, highly sensitive, cost-effective and widely available technique for standardized MRD evaluation, which also could be used for the detection of circulating tumor cells. Here we review current applications of MFC and NGF in most PC disorders including the less frequent solitary plasmocytoma, light-chain amyloidosis or Waldenström macroglobulinemia.

Intravenous Immunoglobulins Improve Survival in Monoclonal Gammopathy-Associated Systemic Capillary-Leak Syndrome.

BACKGROUND: Monoclonal gammopathy-associated systemic capillary-leak syndrome, also known as Clarkson disease, is a rare condition characterized by recurrent life-threatening episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. This study was conducted to better describe the clinical characteristics, natural history, and long-term outcome of monoclonal gammopathy-associated systemic capillary-leak syndrome. METHODS: We conducted a cohort analysis of all patients included in the European Clarkson disease (EurêClark) registry between January 1997 and March 2016. From diagnosis to last follow-up, studied outcomes (eg, the frequency and severity of attacks, death, and evolution toward multiple myeloma) and the type of preventive treatments administered were monitored every 6 months. RESULTS: Sixty-nine patients (M/F sex ratio 1:1; mean ± SD age at disease onset 52 ± 12 years) were included in the study. All patients had monoclonal gammopathy of immunoglobulin G type, with kappa light chains in 47 (68%). Median (interquartile range) follow-up duration was 5.1 (2.5-9.7) years. Twenty-four patients (35%) died after 3.3 (0.9-8) years. Fifty-seven (86%) patients received at least one preventive treatment, including intravenous immunoglobulins (IVIg) n = 48 (73.8%), theophylline n = 22 (33.8%), terbutaline n = 22 (33.8%), and thalidomide n = 5 (7.7%). In the 65 patients with follow-up, 5- and 10-year survival rates were 78% (n = 35) and 69% (n = 17), respectively. Multivariate analysis found preventive treatment with IVIg (hazard ratio 0.27; 95% confidence interval, 0.10-0.70; P = .007) and terbutaline (hazard ratio 0.35; 95% confidence interval, 0.13-0.96; P = .041) to be independent predictors of mortality. CONCLUSIONS: We describe the largest cohort to date of patients with well-defined monoclonal gammopathy-associated systemic capillary-leak syndrome. Preventive treatment with IVIg was the strongest factor associated with survival, suggesting the use of IVIg as the first line in prevention therapy.

Infraorbital nerve involvement on magnetic resonance imaging in European patients with IgG4-related ophthalmic disease: a specific sign.

OBJECTIVES: To measure the frequency of infraorbital nerve enlargement (IONE) on magnetic resonance imaging (MRI) in European patients suffering from an IgG4-related ophthalmic disease (IgG4-ROD) as compared to patients suffering from non-IgG4-related ophthalmic disease (non-IgG4-ROD). METHODS: From January 2006 through April 2015, 132 patients were admitted for non-lymphoma, non-thyroid-related orbital inflammation. Thirty-eight had both pre-therapeutic orbital MRI and histopathological IgG4 immunostaining. Fifteen patients were classified as cases of IgG4-ROD and 23 patients as cases of non-IgG4-ROD. Two readers performed blinded analyses of MRI images. The main criterion was the presence of an IONE, defined as the infraorbital nerve diameter being greater than the optic nerve diameter in the coronal section. RESULTS: IONE was present in 53% (8/15) of IgG4-ROD cases whereas it was never present (0/23) in cases of non-IgG4-ROD (P < 0.0001). IONE was only present in cases where, on MRI, the inflammation of the inferior quadrant was present and in direct contact with the ION canal. CONCLUSIONS: In European patients suffering from orbital inflammation, the presence of IONE on an MRI is a specific sign of IgG4-ROD. Recognition of this pattern may facilitate the accurate diagnosis for clinicians and allow for the adequate management and appropriate care of their patients. KEY POINTS: • IONE on an MRI is a specific sign of IgG4-ROD. • IONE recognition allows for a quicker diagnosis and appropriate management. • IONE appears when inflammation is in direct contact with the ION canal.

State-of-the-Art Imaging and Staging of Plasma Cell Dyscrasias.

Monoclonal gammopathy of unknown significance (MGUS) is a clinically asymptomatic premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. Smoldering multiple myeloma, also called asymptomatic multiple myeloma, is an intermediate stage between MGUS and symptomatic multiple myeloma. As the name implies, extraosseous or extramedullary myeloma refers to the presence of myeloma deposits outside the skeletal system. Waldenström macroglobulinemia is a distinct subtype of plasma cell dyscrasia characterized by lymphoplasmacytic lymphoma in the bone marrow with an associated IgM monoclonal gammopathy. Amyloidosis is a condition characterized by extracellular deposition of fibrils composed of a variety of normal serum proteins.