Plasma Cell Ratio Research Articles

Idiopathic multicentric Castleman's disease: a clinicopathologic study in comparison with IgG4-related disease

The present study aimed to compare clinicopathologic features between idiopathic multicentric Castleman's disease (n=22) and IgG4-related disease (n=26). Histology was analyzed using lymph node and lung biopsies. The expression of IL-6 mRNA in tissue was also examined by in situ hybridization and real-time PCR. Patients with idiopathic multicentric Castleman's disease were significantly younger than those with IgG4-related disease (p<0.001). Splenomegaly was observed in only idiopathic multicentric Castleman's disease (p=0.002), while pancreatitis and sialo-dacryoadenitis were restricted to IgG4-related disease (both p<0.001). Serum IgG4 concentrations were commonly elevated at >135 mg/dL in both groups (p=0.270). However, the IgG4/IgG ratio in IgG4-related disease was significantly higher than that in Castleman's disease (p<0.001). Histologically, sheet-like plasmacytosis was highly characteristic of idiopathic multicentric Castleman's disease (p<0.001), while plasmacytic infiltration in IgG4-related disease was always associated with intervening lymphocytes. Similar to laboratory findings, the IgG4/IgG-positive plasma cell ratio, but not the IgG4-positive cell count, was significantly higher in IgG4-related disease (p=0.002). Amyloid-like hyalinized fibrosis was found in 6/8 lung biopsies (75%) of Castleman's disease. The over-expression of IL-6 mRNA was not confirmed in tissue samples of Castleman's disease by either in situ hybridization or quantitative real-time PCR. In conclusion, useful data for a differential diagnosis appear to be age, affected organs, the serum IgG4/IgG ratio, sheet-like plasmacytosis in biopsies, and the IgG4/IgG-positive cell ratio on immunostaining. Since IL-6 was not over-expressed in tissue of idiopathic multicentric Castleman's disease, IL-6 may be produced outside the affected organs, and circulating IL-6 may lead to lymphoplasmacytosis at nodal and extranodal sites.

Diagnosis of IgG4 - related ophthalmic disease in a group of patients with various lesions of the eye and orbits.

To provide demographic, clinical, laboratory, ultrasound, radiological, morphological/ immunomorphological phenotype of IgG4-related ophthalmic diseases, which allowsmaking a differential diagnosis with granulomatous, autoimmune, inflammatory, endocrine and hematologic diseases affecting the eye and orbits. From 2004 to 2016 108 (78.2%) of the 138 patients were diagnosed with non-tumoral lesions of eye and orbits. In 48 patients (35%) at admission and 5 patients in the follow were diagnosed IgG4-related ophthalmic disease. In the analysis of 82 (f-44, m-38) patients with IgG4-related disease, localization of lesions in orbit observed in 53 (f-36, m-17) and it was the most frequent involvement in patients with IgG4-related disease (64.5%). Only 7 patients had isolated IgG4-related ophthalmic disease, whereas 46 patients (87%) had involvement of 2-7 locations, as a manifestation of IgG4-related systemic disease.During the examination, the average age of patients with IgG4-related ophthalmic disease was 47.5 years (19-73 years). Median time to diagnosis was 52.8 months before 2004 and 36 months 2004-2016. We noted the predominance of females in the ratio 2: 1 inthe group of patients with IgG4-related ophthalmic disease. Edema of the eyelids, nasal congestion (55-60%), tumor-like formations of the upper eyelids and increased lacrimation prevailed at the onset of the disease, whereas such functional impairment like limited mobility and pain in eyeballs, exophthalmos, ptosis and diplopia appeared later at 15-38% with a loss visual acuity in one case. Bilateral lesion (86%), mainly affecting the lacrimal glands (93.5%), infiltration of the ex- traocular muscles (83.5%) and retrobulbar tissue with a thickening of the optic nerve in one third of patients were the main localizations IgG4-related ophthalmic disease. Clinical symptoms were accompanied by the appearance of moderate inflammatory activity (38%), in- creased levels IgG (44%), IgG4(88%) and IgE (61%). Indicators of autoimmune disorders observed in 6-22% of patients, most often in pa- tients with simultaneous involvement of the salivary glands. Significant lymphoplasmacytic infiltration (94%) with a ratio of plasma cells (IgG4/IgG) secreting IgG4&gt; 40% (90%) with fibrosis formation (94%) and follicle formation (71%) with a moderate amount of eosinophils (34%) were the major morphological / immunomorphological manifestations of IgG4-related ophthalmic disease. Signs of vasculitis and obliterative phlebitis were found in a small amount of patients. Determination of elevated levels of IgG-4 / IgE in patients with edema, pseudotumor of the eyelid, sinusitis and increase of the palpebral lobe of the lacrimal gland suggests the presence of IgG4-related ophthalmic disease. Minimally invasive incisional biopsy of lacrimal glands and salivary glands followed by morphological / immunomorphological research is needed for the correct diagnosis. Diagnostic orbitotomy in ophthalmic hospitals in such cases is inexpedient, since it leads to the development of dry eye. Massive lymphoplasmacytic infiltration with IgG4 / IgG ratio more than 40%, advanced fibrosis in biopsiesof the orbits tissue or salivary glands when combined lesions are required for the making the diagnosis of IgG4-related ophthalmic disease.

Evaluation of IgG4+ Plasma Cell Infiltration in Patients with Systemic Plasmacytosis and Other Plasma Cell-infiltrating Skin Diseases

Systemic plasmacytosis is a rare skin disorder characterized by marked infiltration of plasma cells in the dermis. IgG4-related disease is pathologically characterized by lymphoplasmacytic infiltration rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, accompanied by elevated levels of serum IgG4. Reports of cases of systemic plasmacytosis with abundant infiltration of IgG4+ plasma cells has led to discussion about the relationship between systemic plasmacytosis and IgG4-related disease. This study examined IgG4+/IgG+ plasma cell ratios in 4 patients with systemic plasmacytosis and 12 patients with other skin diseases that show marked infiltration of plasma cells. Furthermore, we examined whether these cases met one of the pathological diagnostic criteria for IgG4-related disease (i.e. IgG4+/IgG plasma cells ratio of over 40%). Only one out of 4 patients with systemic plasmacytosis met the criterion. These results suggest that systemic plasmacytosis and IgG4-related disease are distinct diseases.

Analysis of Relationship between Serum Total Light Chain κ/λ Ratio and Proportion of Bone Marrow Plasma Cells in Patients with IgG type and IgA type Multiple Myeloma

To explore the relationship between serum total light chain κ/λ ratio (sTLC-κ/λ) and proportion of bone marrow plasma cells (BMPC) in patients with IgG type and IgA type multiple myeloma (MM) and its clinical significance. The levels of serum IgG, IgA, κ type and λ type total light chain were detected in 79 newly diagnosed patients with IgG type (n=52) and IgA type (n=27) MM by immuno-nephelometric assay and the sTLC-κ/λ ratio was calculated. The proportion of BMPC was determined by bone marrow smears in the corresponding period, and the changes in sTLC-κ/λ ratio and the proportion of BMPC were observed in 19 patients with IgG type(n=16) and IgA type (n=3) MM undergoing treatment, 26 cases of non-phasmocytic proliferative diseases were enrolled in control group. In MM patients with IgGκ type and IgAκ type, the sTLC-κ/λ ratio was significantly higher than that in the control group (P<0.01), while in MM patients with IgGλ type and IgAλ type, the sTLC-κ/λ ratio was significantly lower than that in the control group (P<0.01). In MM patients with IgGκ, the sTLC-κ/λ ratio was significantly higher than that in MM patients with IgAκ(P<0.01), while the sTLC-κ/λ ratio in MM patients with IgGλ was significantly lower than that in MM patients with IgAλ. The sTLC-κ/λ ratios in MM patients with IgGκ and IgAκ were positively correlated with the concentrations of IgG (r=0.778,P=0.000) and IgA (r=0.601,P=0.039), while the sTLC-κ/λ ratios of patients with IgGλ and IgAλ were negativily correlated with the IgG(r=-0.586,P=0.01) and IgA level(r=-0.718,P=0.003). In addition, a correlation between each type MM was not found except the IgGκ type MM which had a positive correlation between the sTLC-κ/λ ratio and proportion of BMPC (r=0.579,P=0.002). Nonetheless, 18 of 19 patients with IgG type and IgA type MM undergoing treatment showed concordance between the sTLC-κ/λ ratio and proportion of BMPC change. There is a lower correlation between the sTLC-κ/λ ratio and the proportion of BMPC in MM patients with IgG type and IgA type, but there is a high concordance between the sTLC-κ/λ ratio and the proportion of BMPC change in the same patient and it suggests that the sTLC-κ/λ ratio plays an important role in the diagnosis and monitoring of IgG type and IgA type MM.

Association of immunoglobulin G4 and free light chain with idiopathic pleural effusion.

The cause of pleural effusion remains uncertain in approximately 15% of patients despite exhaustive evaluation. As recently described immunoglobulin (Ig)G4-related disease is a fibroinflammatory disorder that can affect various organs, including the lungs, we investigate whether idiopathic pleural effusion includes IgG4-associated etiology. Between 2000 and 2012, we collected 830 pleural fluid samples and reviewed 35 patients with pleural effusions undiagnosed after pleural biopsy at Yamaguchi-Ube Medical Center. Importantly, IgG4 immunostaining revealed infiltration of IgG4-positive plasma cells in the pleura of 12 patients (34%, IgG4+ group). The median effusion IgG4 level was 41 mg/dl in the IgG4+ group and 27 mg/dl in the IgG4- group (P<0·01). The light and heavy chains of effusion IgG4 antibodies of patients in the IgG4+ group were heterogeneous by two-dimensional electrophoresis, indicating the absence of clonality of the IgG4 antibodies. Interestingly, the κ light chains were more heterogeneous than the λ light chains. The measurement of the κ and λ free light chain (FLC) levels in the pleural fluids showed significantly different κ FLC levels (median: 28·0 versus 9·1 mg/dl, P<0·01) and κ/λ ratios (median: 2·0 versus 1·2, P<0·001) between the IgG4+ and IgG4- groups. Furthermore, the κ/λ ratios were correlated with the IgG4+ /IgG+ plasma cell ratios in the pleura of the IgG4+ group. Taken together, these results demonstrate the involvement of IgG4 in certain idiopathic pleural effusions and provide insights into the diagnosis, pathogenesis and therapeutic opportunities of IgG4-associated pleural effusion.

Applicated value of multi-parameter flow cytometry and Ig gene rearrangement in early diagnosis of multiple myeloma

Objective To explore the clinical value of multi-parameter flow cytometry and Ig gene rearrangement in early diagnosis of multiple myeloma. Methods 19 cases of multiple myeloma were detected and analyzed by BD flow cytometry and Ig gene rearrangement, the multi-parameter analysis of tumor cell markers were CD45, CD138, CD10, CD19, CD20, CD22, CD13, CD33, CD117, CD56, CD38, cell oar kappa light chain(cκ), cell plasma lambda light chain(cλ). Results Abnormal plasma cells ratio was 1.40% ~32.8% detected by flow cytometry, which gate using CD45 and CD138; the proportions of antigen positive expression were CD138: 100.0%, CD38: 100.0%, CD56: 63.1%, CD117: 42.1%, CD13: 0.0%, CD33: 26.3%, CD20: 5.2%, CD22: 0.0%, CD10: 0.0%, CD19: 0.0%, respectively. The naive and mature plasma cell ratio was 2.5%~75.5% detected by bone marrow morphology. The both methodologies above had a correlation(r=0.702, P<0.01). The restricted expression of immunoglobulin cytoplasm in MM patients, 9 cases of cκ(9/19), 10 cases of cλ(10/19). The subtypes were 4 cases IgG+ κ, 2 cases IgA+ κ, 4 cases IgG+ λ, 1 case IgA+ λ, 3 cases κ and 5 cases λ detected by immunofixation electrophoresis; Ig gene rearrangement shown 8 cases of IGH FR1-JH rearrangement, 11 cases of IGH FR2-JH rearrangement, 2 cases of IgH DH-JH rearrangement, 11 cases of IGK Vk-Jk rearrangement, 8 cases of IGK Vk-Kde and intron-Kde rearrangement; combined with IgH and IgK gene rearrangement, the positive rate of early MM was 89.5%(17/19). Conclusion Multi-parameter flow cytometry can be more accurate to set the required analysis of abnormal plasma cell population, abnormal plasma cells most of the expressions of CD138, CD38, CD56 antigen, while does not express CD19, CD10, CD13, CD22.The diagnostic value of Ig in the diagnosis of MM is the combination of cell morphology examination and immunohistochemistry electrophoresis and the application of BIOMED 2 gene rearrangement technique. Key words: Multiple myeloma; Flow cytometry; Gene rearrangement; Diagnosis

Clinical Significance of Mean Platelet Volume Determination in Multiple Myeloma

To investigate the clinical significance of mean platelet volume(MPV) in patients with multiple myeloma(MM). The clinical data of 198 patients with MM admitted in our hospital from March 2008 to March 2015 were collected and analyzed. The clinical data included the Ig type, hemoglobin level, platelet count, creatinine, calciumion albumin, β2-MG, LDH, plasmocytes in bone marrow, MPV, complications such as diabetes, a history of venous thromboembolism (VTE) and arterial events such as coronary artery disease, cerebrovascular disease, thrombosis and blood clotting. All patients were divided into low MPV group (≤8.50 fl) and high MPV group (>8.50 fl). The biochemical parameters and prognosis of the 2 groups were compared. When MPV was 8.50 fl, the higest sensitivety and specificity were 55.56% and 80.00% respectively. The area under curve (AUC) was 0.656 (95% CI: 0.515-0.797), the IgA type, creatinine level and IgH rearrangement in MM patients were related with MPV. The ratio of IgA and IgH rearrangements in patients with low MPV was higher than that in patients with high MPV, and the ratio of patients with creatinine >176.8 µmol/L was lower than that of patients with high MPV (P<0.05). The age, sex, ECOG PS, complications, ISS stage, hemoglobin level, platelet count, calcium ion, albumin, β2 microglobulin, lactate dehydrogenase and bone marrow plasma cell ratio were not statistically significantly different between the 2 groups. Patients with low MPV had a shorter OS (P=0.039) than those with higher MPV. Univariate analysis showed that MPV, BM plasma cell ratio and age>60 years correleted with OS. Multivariate analysis showed that the low MPV and BM plasma cell ratio were correlated with shorter OS (P<0.05). The low MPV is correlated with poor prognosis in patients with MM and may serve as an important indicator for disease progression and prognosis of patients with MM.

Clinical implications of c-maf expression in plasma cells from patients with multiple myeloma

BackgroundMultiple myeloma (MM) is a type of hematological malignancy with significant heterogeneity in clinical features and prognosis. Cytogenetic abnormalities are the major factors affecting patient outcomes. Studies have shown that immunohistochemistry (IHC)-based detection of cancer-related genes expression could be alternative indicators for the prognosis of MM.MethodsNuclear expression of c-maf protein in the bone marrow plasma cells of 128 multiple myeloma patients were examined by IHC, and its association with the clinicopathological features of MM patients was analyzed as well.ResultsAmong the 128 patients, the positive rate of c-maf protein expression was up to 30.5%, which had no correlation with patient age, M protein type, Durie-Salmon staging system, the International Staging System, abnormal plasma cell ratio in the bone marrow, or the level of peripheral blood hemoglobin, serum calcium or lactate dehydrogenase. However, the c-maf-positive patients had a significantly higher rate of hypoproteinemia (p = 0.026) and higher serum β2-microglobulin levels (>2500 μg/L) (p = 0.007). Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on progression-free survival or overall survival was observed.ConclusionPatients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on survival was observed. A further large-scale prospective study is required to verify these findings.

Expression of CC-chemokine Receptor 7 in Patiens with Multiple Myeloma and Its Relationship with Extramedullary Disease

To investigate the expression of CC-chemokine receptor 7(CCR7) in patients with multiple myeloma(MM) and its correlation with clinical features of MM. The level of CCR7 expression in bone marrow samples from 53 newly diagnosed MM patients was detected by flow cytometry(FCM). Statistical methods were used to analyze the correlation between CCR7 expression and clinical features, such as sex, age, M protein, peripheral blood cell count, biochemical indicators, plasma cell ratio of bone marrow, immunophenotype, osteopathy and extramedullary disease. The plasma cells in 24 out of 53 cases(45.28%) expressed CCR7. The rate of extramedullary disease in CCR7 positive group was significantly higher than that in CCR7 negative group (29.17% vs 3.45%)(P<0.05). The expression of CCR7 in patients with MM is high, moreover this high expression correlates with extramedullary disease, thus CCR7 can be used as an effective indicator for prediction of extramedullary disease.

Laboratory investigation of reactive plasmacytosis in patients with severe fever with throbocytopenia syndrome

Objective To investigate the immunological characteristics and clinical significance of reactive plasmacytosis in patients with severe fever with throbocytopenia syndrome (SFTS). Methods Bunyavirus-infected patients who were diagnosed with SFTS were collected from March 2015 to October 2015 in Taizhou Hospital. Morphology analysis of bone marrow and peripheral blood (PB) smear, as well as flow cytometry analysis of plasma cell immune phenotype from peripheral blood were conducted. Serum immunoglobulin levels and helper T hymphocytes (Th)1/Th2 cytokine expressions were detected. Mann-Whitney U test was used. Results PB plasma cells from all of the SFTS patients increased in varying degrees, and the phenotype of the plasma cells was CD19+ CD38+ + CD45+ CD138+ , which indicated normal mature plasma cells. The ratio of PB plasma cells was >0.030 in 10/16 patients, and >0.300 in 2/16 patients. The ratios of PB plasma cells in the patients with severe and critical groups were significantly higher than that in the mild group (0.052 vs 0.016, P 0.05). The serum IgG, IgA and IgM levels did not increase in acute stage, with the median of 11.6 g/L, 2.56 g/L and 1.60 g/L (reference value 0.46 to 3.04 g/L), respectively. Conclusion The patients with SFTS show excessive humoral and cellular immunity, and the severity of disease is positively correlated with the ratio of peripheral plasma cells and the levels of cytokines IL-6 and IL-10. Key words: Novel bunyavirus; Severe fever with throbocytopenia syndrome; Reactive plasmacytosis; Lymphohistiocytosis, hemophagocytic; Cell morphology; Plasma cells; Cytokines

The prognostic value of multiparametric flow cytometry in AL amyloidosis at diagnosis and at the end of first-line treatment

AbstractMultiparametric flow cytometry (MFC) in amyloid light-chain (AL) amyloidosis has not been widely adopted and, consequently, there is little information on its clinical relevance. We studied 173 patients with AL amyloidosis who underwent MFC immunophenotyping of bone marrow sample at diagnosis and 82 patients at the end of the first line of treatment (EOT). The number of monotypic plasma cells (PCs) and the polytypic PCs/bone marrow PCs (pPCs/BMPCs) ratio were analyzed. At diagnosis, ≥2.5% monotypic PCs was associated with a shorter progression-free survival (PFS) and overall survival (OS) compared with patients with <2.5% monotypic PCs (2-year PFS 41% vs 56%, P = .007; 2-year OS 55% vs 70%; P = .01). Additionally, patients with a pPCs/BMPCs ratio of ≤5% had a shorter PFS compared with patients with pPCs/BMPCs ratio >5% (2-year PFS 43% vs 55%; P = .02), but without OS difference (2-year OS 60% vs 67%; P = .19). In a multivariate analysis, the monotypic PCs retained an independent prediction for PFS/OS, whereas the pPCs/BMPCs ratio retained significance only for PFS. At EOT, ≥0.1% monotypic PCs was associated with a shorter PFS and OS compared with patients with <0.1% monotypic PCs (2-year PFS 31% vs 87%; P < .0001; 2-year OS 87% vs 98%, P = .02). In a subgroup analysis among patients who attained a very good partial response or better, the monotypic PCs at the 0.1% cutoff was predictive for progression rate but not for PFS/OS. MFC is prognostic for AL amyloidosis at diagnosis and at EOT. MFC may have a role in the definition of hematologic response.

Neural Stem Cell Marker Nestin As a Novel Unfavorable Prognostic Biomarker for Multiple Myeloma

Background:Neural stem cell marker nestin is a suitable diagnostic and prognostic indicator of malignancy and potential cancer stem cells marker in solid tumors. Currently, nestin has been demonstrated as an epithelial-to-mesenchymal transition related protein associated with tumor metastasis, chemoresistance, and metabolic changes through altering mitochondrial dynamics in solid tumors. However its role in hematological malignancies remains unknown. Our recent work confirmed nestin protein as a tumor-specific marker for CD138+38+ plasma cells (PC) of multiple myeloma (MM) and potential predictor of worse response to conventional and novel therapy but prognostic potential of nestin has never been studied in MM so far.Aim:The aim of this study was to evaluate whether pretreatment levels of nestin can predict overall (OS) and progression-free (PFS) survival of MM patients.Methods: Nestin was detected in CD138+38+PC of 84 newly diagnosed MM patients (36M/48F; median age 70 years) by flow cytometry. Nestin was assessed as the percentage of nestin-positive PC (Nes+PC) and ratio of median fluorescence intensity of nestin (MFI ratio) and isotypic control. Survival cut-off points were established based on time-dependent ROC analysis. P-values below 0.05 were considered as statistically significant in all analyses. Cox proportional hazards models were used to assess the association of prognostic factors with OS and PFS. The independence of the marker was assessed by multivariate Cox regression model. Survival rates were estimated using the Kaplan-Meier method. Differences in survival among subgroups of patients were compared using the log-rank test.Results: ROC analysis divided patients into 2 groups: high (>50) and low (≤50) %Nes+PC subgroup and high (>4) and low (≤4) MFI subgroup. High %Nes+PC subgroup were associated with shorter OS (p=0.042) and PFS (p=0.003). High MFI ratio subgroup (>4.4) were significantly associated with shorter OS (p=0.005); and PFS (p=0.025) (Fig.1). Univariate hazard ratios (HR) showed prognostic impact of %Nes+PC (p=0.003) and of MFI ratio (p=0.017) for OS; %Nes+PC (p=0.005) and of MFI ratio (p=0.028) for PFS (Tab.1). 5 parameters: ISS: stage 3 vs. stage 1, del p53, age (at diagnosis), M protein type: IgG vs. other, LDH (µkat/l) and Beta2 microglobulin (mg/l) were significantly associated with OS after adjustment by nestin. However %Nes+PC or MFI ratio did not achieve independent prognostic status in multivariable model (p=0.223 and p=0.989).Conclusion: These data demonstrate for the first time that nestin protein might have prognostic implication for MM. However, it does not appear to be independently associated with MM outcome when considering standard prognostic factors. The growing importance of nestin in key cell processes responsible for tumorigenesis and metastasis emphasizes the need for further investigation in MM. This pilot study requires to be further validated on a larger cohort of patients.Supported by NT14575, RVO-FNOs/2014/17P, IRP201550, SGS03/LF/2015-2016. [Display omitted] [Display omitted] DisclosuresBesse:Mundipharma-EDO: Other: travel support. Hájek:Takeda: Consultancy; BMS: Honoraria; Janssen: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding.

Application Value of CD138 MACS-FISH in the Genetic Diagnosis of Plasma Cell Dyscrasia

To investigate the cytogenetic characteristics of the various plasma cell dyscrasia using the CD138 MACS-FISH, to elucidate the application value of MACS-FISH in the genetic diagnosis of plasma cell dyscrasia, and to explore the standardization of FISH detection for plasma cell dyscrasia. A total of 232 patients with newly diagnosed plasma cell dyscrasia were collected, including 203 cases of MM, 24 cases of AL amyloidosis and 5 cases of MGUS, whose cytogenetic abnormalities were detected by MACS-FISH, and the differences of the positive detection rates of chromosome karyotype analysis, C-FISH and MACS-FISH in MM cytogenetic abnormality were compared. The sensitivity of C-FISH and MACS-FISH were analyzed and compared according to the proportion of bone marrow plasma cells. The correlation between the positive cell rates of C-FISH and MACS-FISH and the proportion of plasma cells were analyzed respectively. The differences in the clone size detected by C-FISH and MACS-FISH were compared. The incidence of cytogenetic abnormality of MM, AL amyloidosis and MGUS detected by MACS-FISH were 85.9%, 62.5%, 60%, respectively. The incidence rate of MM cytogenetic abnormality detected by Chromosome karyotype analysis and C-FISH were 20.0% and 64.7%, respectively, which were significantly lower than that of MACS-FISH(P<0.001). The positive rate of 14q32 translocation, del(14q32), t(11;14), +17p13 and the coexistence of 2 and ≥3 kinds of cytogenetic abnormalities detected by MACS-FISH were significantly higher than that detected by C-FISH(P<0.05). When the plasma cell ratio was less than or equal to 5%, the positive detection rate of MACS-FISH was significantly higher than that of C-FISH (P=0.001), and there was no significant difference in different plasma cell proportion group of MACS-FISH. However, when the plasma cell ratio was less than or equal to 5%, the positive detection rate of C-FISH detection was significantly lower than that of the other 3 groups (P=0.013,P=0.001,P<0.001). The positive cell rates of all cytogenetic abnormalities in C-FISH group and +1q21 and 14q32 translocation in MACS-FISH group were significantly positively correlated with the proportion of plasma cells(P<0.05). The clone size of various cytogenetic abnormalities in MACS-FISH group were significantly higher than that in C-FISH group(P<0.001). MACS-FISH may significantly enhance the detection rate of cytogenetic abnormalities in various plasma cell dyscrasia, and it can better reflect the cytogenetic abnormality of plasma cell dyscrasia and its clone size. MACS-FISH may be recommended as a standard method for the genetic diagnosis of plasma cell dyscrasia, the risk stratification of MM and SMM, as well as the genetic diagnosis and research of MGUS and AL amyloidosis.

Deconstructing IgG4-related disease involvement of midline structures: Comparison to common mimickers

Objective: A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity.Methods: We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4 + plasma cells/HPF for calculation of the IgG4+/IgG + plasma cell ratio.Results: Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG + plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD.Conclusions: Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.

Sclerosing mesenteritis: A real manifestation or histological mimic of IgG4‐related disease?

We present three cases of sclerosing mesenteritis and review the literature to learn whether or not sclerosing mesenteritis is an IgG4-related disease (IgG4-RD). Our patients were all adult males. Their mesenteric masses ranged from 6.5 to 14.5 cm in the greatest diameter. Tissue specimens showed moderate to severe lymphoplasmacytic infiltration with occasional eosinophils against a background of irregular fibrosis. Both obliterative phlebitis and storiform fibrosis were noted in all cases. IgG4+ plasma cells were moderately increased in number (46 to 85 cells/high-power field). However, unlike IgG4-RD, the IgG4+/IgG+ plasma cell ratio was <40% (28% to 35%). Serum IgG4 concentrations were also within the normal range (43.2 to 105 mg/dL; normal range <135 mg/dL). Two biopsy cases showed spontaneous regression on imaging approximately 5 months later. No sclerosing conditions were found in other organs. The literature review identified 11 additional cases of sclerosing mesenteritis with IgG4+ plasma cell infiltration. However, conclusive cases with four characteristic features (high serum IgG4 levels, tissue IgG4 elevation, multi-organ involvement, and effective response to glucocorticoid therapy) have never been reported. In conclusion, although sclerosing mesenteritis shares histological features with IgG4-RD, most cases are less likely to be IgG4-related. IgG4-RD seemingly seldom, if ever, affects this anatomical site.

Rising Plasma Cell Proliferation By Ki67/CD138 Ratio at Relapse Is a Marker of High Risk Disease in Multiple Myeloma

Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) for years but utilization remains limited. We recently developed a novel immunohistochemical (IHC) co-staining technique for CD138 and Ki67 expression to quantify plasma cells in active cycling. Previously presented results from newly diagnosed patients demonstrate that having an elevated ratio of plasma cells in active cycle by co-expression of CD138 and Ki67 (>5%) is associated with aggressive disease and poor outcomes including shorter overall survival (OS). The expansion of subclones with higher proliferative capacity following initial therapy may be an indicator of a higher risk relapse event and indicate poor prognosis. Here we assess MM patients (pts) with Ki67/CD138 co-staining on bone marrow samples both at diagnosis and relapse to assess the impact of changes in cell cycling ratio on outcomes with subsequent therapy and overall clinical course.Methods: A retrospective cohort study of pts with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital (WCMC/NYPH). For inclusion in the analysis, pts must have had bone marrow evaluation with double-staining for Ki67 and CD138 by immunohistochemistry both at diagnosis and relapse. Pts must have completed their first line and relapse treatments at WCMC/NYPH. The Ki67% was calculated as the ratio of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on alterations in Ki67% between diagnosis and relapse.Results: We identified 37 pts with bone marrow sampling that was evaluated for CD138 and Ki67 co-expression both at diagnosis and at the time of relapse. These pts had undergone a median of 2 lines of prior treatment at the time of relapse bone marrow biopsy (range 1-7). 19 pts were identified to have a rising Ki67% between diagnosis and relapse defined at a 5% or greater increase, the other 18 pts had stable or decreased Ki67%. Pts with a rising Ki67% at relapse had a shorter OS with a median of 72 months vs not reached (p=0.0069), Figure 1. Pts who had rising Ki67% at relapse had shorter progression free survival (PFS) on first line treatment with a median of 25 vs 47 months (p=0.036), Figure 2. Additionally pts with rising Ki67% had a trend towards shorter PFS with the treatment they received after relapse with median of 12.5 vs 3.5 months (p=0.09). Relapse regimens were most commonly carfilzomib (n=9), pomalidomide (5) or ixazomib (4) based. 37% of pts (7/19) with rising Ki67% achieved PR or better on relapsed treatment vs 67% (12/18) with stable Ki67%.Discussion: The presence of clonal evolution and selection of higher risk clones under therapeutic pressure in multiple myeloma is a key feature of disease progression. The ability to improve risk stratification at the time of relapse may help guide clinical decision making to best suit individual patient needs. We have identified rising plasma cell proliferation through quantification of Ki67/CD138 co-expression at relapse to be a useful marker of high risk disease evolution. This appears to help identify the emergence of higher risk clones which are ultimately responsible for treatment resistant disease. Patients with rising Ki67% were more likely than patients with stable Ki67% to have early relapses to initial therapy, were less likely to achieve responses to relapse regimens or to maintain their response and had shorter overall survival. Further evaluation is needed to identify if different approaches to patients with increasing proliferation may improve outcomes in these patients. [Display omitted] [Display omitted] DisclosuresMark:Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rossi:Calgene: Speakers Bureau. Pearse:Celegen: Consultancy. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Perry:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Niesvizky:Celgene: Consultancy, Speakers Bureau.

IgG4-related disease simulating Hodgkin lymphoma in a child

Immunoglobulin (Ig) G4-related disease is a recently described syndrome characterized by mass forming lymphoplasmacytic tissue infiltration and elevated serum IgG4 concentrations usually affecting middle-aged or older individuals. Lymphadenopathy is frequently observed and is sometimes the first or only manifestation of the disease. We report a case of IgG4-related disease mimicking Hodgkin lymphoma in a 13-year-old girl. The patient presented with progressive unilateral cervical lymphadenopathy of several months duration. Biopsy showed follicular hyperplasia with progressive transformation of germinal centers. Interfollicular areas were expanded by small lymphocytes, histiocytes, eosinophils and fibrosis with occasional CD30 positive cells initially concerning for interfollicular Hodgkin lymphoma. Immunohistochemical analysis revealed an intrafollicular plasmacytosis with an IgG4-positive/IgG-positive plasma cell ratio of 50% supporting a diagnosis of IgG4-related lymphadenopathy, progressively transformed germinal centers type. Laboratory studies were supportive with elevated serum IgG4 (178mg/dL) and IgE (30.40kU/L) levels along with an elevated serum IgG4/IgG ratio (0.16). Very few cases of IgG4-related disease have been described in children. Within this age group, there is considerable clinical overlap between IgG4-related disease associated lymphadenopathy and Hodgkin lymphoma. In addition, lymphadenopathy secondary to IgG4-related disease demonstrates substantial histologic diversity with the potential to simulate the inflammatory background and fibrosis of Hodgkin lymphoma. The importance of accurate diagnosis is underscored by the prognostic implications considering the marked response of the syndrome to steroid therapy. In addition, appropriate follow up is critical to monitor for relapse and additional organ involvement.

Are plasma cell-rich inflammatory conditions of the oral mucosa manifestations of IgG4-related disease?

AimThe aim of this study was to characterise plasma cell infiltrates, in terms of IgG4 positivity, in specific and non-specific plasma cell-rich chronic inflammatory conditions of the oral mucosa. Exploring...

Limitations of component therapy for massive haemorrhage: is whole blood the whole solution?

Limitations of component therapy for massive haemorrhage: is whole blood the whole solution?

Lymph node granulomas in immunoglobulin G4‐related disease

Immunoglobulin (Ig)G4-related disease (IgG4-RD) is an increasingly recognized fibroinflammatory condition that commonly exhibits multisystem involvement, with localized (e.g. inflammatory pseudotumours that can mimic malignancy) or diffuse (leading to organ dysfunction) patterns of tissue involvement. The 2012 Boston criteria have standardized the histopathological approach to the diagnosis of IgG4-RD and require one or more of the cardinal morphological features with prominence of IgG4(+) plasma cells and an IgG4(+) /IgG(+) plasma cell ratio of at least 40%. The relative prevalence of the morphological criteria varies between anatomical sites, but granulomas are rarely found and, indeed, their presence would usually deter a pathologist from making this diagnosis. The aim was to characterize two cases of IgG4-RD in which granulomas were present and to highlight this as an unusual feature of the condition. We describe two cases in which the features of IgG4-RD were present within lymph nodes, together with granulomas. This is a recognized but rare morphological pattern of IgG4-RD. While an unusual finding, the presence of granulomas should not preclude a diagnosis of IgG4-RD in the appropriate clinicopathological context.