scholarly journals Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders

2011 ◽  
Vol 64 (3) ◽  
pp. 237-243 ◽  
Author(s):  
Johanna D Strehl ◽  
Arndt Hartmann ◽  
Abbas Agaimy
Keyword(s):  
Inflammatory Response ◽  
Oral Cavity ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Systemic Disease ◽  
High Power Field ◽  
Histopathological Features ◽  
Inflammatory Conditions ◽  
Cell Counts ◽  
Gastrointestinal Lesions

BackgroundIgG4-related systemic fibrosclerosis is a recently defined disorder characterised by a diffuse or tumefactive inflammatory reaction rich in IgG4-positive plasma cells associated with sclerosis and obliterative phlebitis. Although characteristic histopathological features are essential for the diagnosis of these disorders, to date there exists no consensus regarding the cut-off values used to define a ‘significant IgG4-positive plasma cell count,’ and data regarding the distribution of IgG4-positive plasma cells under common (non-specific) inflammatory conditions are lacking.MethodsThe authors analysed 121 randomly selected histopathological specimens containing prominent lymphoplasmacytic infiltrates (11 obstructive sialadenitis, 27 inflammatory lesions of the oral cavity, 24 inflammatory gastrointestinal lesions, 15 rheumatoid synovitis, 15 non-specific synovitis, eight non-specific dermatitis and 21 primary carcinomas with a peritumoral inflammatory response). For comparison, seven cases of sclerosing sialadenitis (Küttner tumour) were examined.ResultsHigh counts of IgG4 plasma cells were found in sclerosing sialadenitis (mean 40/high-power field (hpf)), contrasting sharply with sialadenitis caused by sialolithiasis (mean 3/hpf). Greatly varied but generally high counts of IgG4-positive plasma cells were also seen in several of the other lesions, particularly in rheumatoid synovitis (mean 55/hpf), oral cavity lesions (mean 79/hpf) and carcinoma-associated inflammatory response (mean 24/hpf). The mean IgG4/IgG ratios for all lesions varied between 0 and 0.4.ConclusionsThe results demonstrate the ubiquitous occurrence of variably high numbers of IgG4-positive plasma cells under diverse non-specific inflammatory conditions, indicating that high IgG4-positive plasma cell counts and high IgG4/IgG ratios per se do not reliably distinguish IgG4-associated systemic disease from non-specific conditions, and that the IgG4 counts must be cautiously interpreted in the context of appropriate clinical and histopathological features.

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

2015 ◽  
Vol 68 (10) ◽  
pp. 802-807 ◽  
Author(s):  
Hannah Cottom ◽  
Alan J Mighell ◽  
Alec High ◽  
Adrian C Bateman
Keyword(s):  
Oral Mucosa ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Mucosal Inflammation ◽  
High Power Field ◽  
Immunoglobulin G4 ◽  
Cell Ratio ◽  
Related Disease ◽  
Inflammatory Conditions ◽  
Medical Histories

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 the possibility that specific plasma cell-rich oral inflammatory conditions have association with or represent an oral manifestation of immunoglobulin G4-related disease (IgG4-RD).MethodsTen patients with plasma cell-rich chronic inflammatory conditions of the oral mucosa were identified (seven—plasma cell mucositis and three—non-specific diffuse oral mucosal inflammation with ulceration). For each patient, the clinical record and H&E-stained sections were reviewed. Immunohistochemistry for IgG and IgG4 antibodies was performed on sections from the corresponding paraffin block, permitting calculation of the mean number of IgG4+ plasma cells per high-power field (HPF) and the IgG4+/IgG+ plasma cell ratio.ResultsIn all the cases, only one histological hallmark of IgG4-RD—a dense lymphoplasmacytic infiltrate—was seen. Review of the medical histories did not reveal any features representing other manifestations of IgG4-RD. The number of IgG4+ plasma cells exceeded 100 per HPF in half of the cases. Only two cases had an IgG4+/IgG+ plasma cell ratio of >40%; both of which were in the non-specific oral inflammatory group.ConclusionsOur study suggests that plasma cell mucositis does not meet microscopic criteria for IgG4-RD. It importantly reinforces the opinion that IgG4+ plasma cells are major components of chronic inflammation in the oral cavity and the pertinence of correct contextual interpretation of histopathological features with clinical findings.

scholarly journals Biofilms and inflammation in patients with chronic rhinosinusitis

2020 ◽  
Author(s):  
Lavinia-Gianina Manciula ◽  
Ionut Isaia Jeican ◽  
Lucian Barbu Tudoran ◽  
Silviu Albu
Keyword(s):  
Chronic Rhinosinusitis ◽  
Plasma Cell ◽  
Nasal Polyps ◽  
Nasal Polyposis ◽  
Inflammatory Cell ◽  
Plasma Cells ◽  
Strongly Correlated ◽  
Cell Counts ◽  
Deviated Septum ◽  
Nasal Pathology

Introduction. The aim of the present study is to evaluate the presence of biofilms in patients with chronic rhinosinusitis (CRS), with or without nasal polyps, and their relationship to eosinophils and plasma cells. We compared the results with those obtained in nonCRS patients. Methods. A total of 50 patients were included in the study, 30 CRSwNP patients, 10 CRSsNP cases and 10 control patients who were operated for deviated septum. Biofilm detection was performed by means of H&E staining and SEM. Eosinophil and plasma cell values were recorded and compared between groups. Results. Biofilms were identified in 30 patients (60%), 76.6% (23 out of 30) of the CRSwNP patients, 70% (7 out of 10) of the CRSsNP patients and none of the septoplasty patients. Eosinophil and plasma cell values were more elevated in CRS patients, being strongly correlated to biofilm presence and nasal polyposis. Conclusion. Biofilm presence was demonstrated in many of the CRS patients, with no evidence in the control cases. Our study findings indicate that inflammatory cell counts are higher in patients with CRS compared to controls, but also more elevated in patients with polyposis. In biofilm-positive patients, eosinophil and plasma cell counts were greater than those in patients without biofilms, demonstrating the proinflammatory action of the biofilm in the sino-nasal pathology.

scholarly journals IgG4-Related Disease of the Oral Cavity. Case Series from a Large Single-Center Cohort of Italian Patients

2020 ◽  
Vol 17 (21) ◽  
pp. 8179
Author(s):  
Andrea Rampi ◽  
Marco Lanzillotta ◽  
Gaia Mancuso ◽  
Alessandro Vinciguerra ◽  
Lorenzo Dagna
Keyword(s):  
Oral Cavity ◽  
Plasma Cells ◽  
Clinical Symptoms ◽  
Case Series ◽  
Histological Evaluation ◽  
High Power Field ◽  
Entire Cohort ◽  
Related Disease ◽  
Igg4 Related Disease ◽  
Serum Igg4

A series of destructive and tumefactive lesions of the oral cavity are increasingly recognized as part of the IgG4-related disease (IgG4-RD) spectrum. We herein examined the clinical, serological, radiological, and histological features of a series of patients referred to our clinic because of oral cavity lesions ultimately attributed to IgG4-RD. In particular, we studied 6 consecutive patients out of 200 patients referred to the immunology outpatient unit who presented with erosive and/or tumefactive lesions of the oral cavity. All patients underwent serum IgG4 measurement, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4+ plasma cells/High-Power Field (HPF) for calculation of the IgG4+/IgG+ plasma cell ratio. Six patients (3% of the entire cohort) were diagnosed with IgG4-RD of the oral cavity based on histological evaluation. A major complaint at presentation was oral discomfort due to bulging mass. A mild to no increase in serum IgG4 was observed. Different patterns of organ involvement were associated with oral lesions. Five patients were treated with immunosuppressive therapy and two patients promptly responded to B-cell depletion with rituximab. Watchful waiting was decided in one patient with no major clinical symptoms. Involvement of the oral cavity is an infrequent manifestation of IgG4-RD but should be taken into consideration as a possible differential diagnosis of tumefactive or erosive lesions once neoplastic conditions are excluded. A histological examination of biopsy samples from the oral cavity represents the mainstay for diagnosis of IgG4-RD.

Evaluation of an innovative new method for quantitation of plasma cells on CD138 immunohistochemistry

2021 ◽  
pp. jclinpath-2021-207828
Author(s):  
Ethan Gantana ◽  
Nomusa Mashigo ◽  
Ibtisam Abdullah ◽  
Ernest Musekwa ◽  
Robert Lohlun ◽  
...  
Keyword(s):  
Correlation Coefficient ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Intraclass Correlation ◽  
Estimation Method ◽  
High Plasma ◽  
New Method ◽  
Bone Marrow Biopsies ◽  
Cell Counts ◽  
Cell Densities

AimTo compare the frequently used CD138 immunohistochemistry-based method of plasma cell quantitation, to a proposed new method, using interobserver and intraobserver concordance parameters.MethodsArchival CD138 immunohistochemically stained slides made from paraffin-embedded bone marrow biopsies of 33 patients with a confirmed diagnosis of multiple myeloma were used. Light microscopic examination was performed using low magnification lenses (10×) for both the overview estimation method (method A) and the new method (method B), and high magnification lenses (50×), for method B only. For method B, reviewers selected three areas with low, intermediate and high plasma cell densities using 10× lenses. Using a well-defined technique, the 50× lens was then used to count plasma cells as a percentage of all nucleated cells. After blinded relabelling of all the slides, the nine reviewers repeated the plasma cell quantitation using both methods. The plasma cell counts were obtained, and the review times were recorded.ResultsOverall intraobserver concordance was comparable for method A (concordance correlation coefficient (CCC)=0.840) and method B (CCC=0.733). Interobserver concordance for method A (intraclass correlation coefficient (ICC)=0.793 and 0.713) and method B (ICC=0.657 and 0.658) indicated high similarity between reviewers. Method A showed poor interobserver concordance (ICC=0.105) at low plasma cell densities.ConclusionsThe new method is comparable to the frequently used overview estimation method in terms of intraobserver and interobserver concordance, and cost. The new method has superior interobserver concordance at low plasma cell densities. The new method appears more amenable to digital scanning and analysis.

scholarly journals Utility of Flow Cytometry and Fluorescence in Situ Hybridization in Follow-up Monitoring of Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1880-1880
Author(s):  
Saurav Chopra ◽  
Timothy Dunham ◽  
Benjamin Darbro ◽  
Carol J Holman
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Residual Disease ◽  
Initial Diagnosis ◽  
Detection Rates ◽  
Cell Counts ◽  
Ancillary Studies

Introduction Diagnosis and follow-up monitoring of Multiple Myeloma (MM) requires documentation of (clonal) plasma cells using morphological bone marrow assessment and other ancillary studies including CD138 immunohistochemistry (IHC), flow cytometry (FC), and myeloma-specific fluorescence in situ hybridization (FISH). While IHC and FC have traditionally been shown to be the more sensitive methods for the assessment of residual disease, the detection rates of FISH have markedly increased with the recent use of magnetic cell sorting for CD138 cell enrichment. We, therefore, aimed to revisit the clinical utility of these ancillary studies in the diagnosis and follow-up of MM. Methods We retrospectively reviewed the reports of bone marrow biopsy specimens received for the initial diagnosis or follow-up assessment of MM from October 2015 to January 2019. All cases that had both FC and FISH performed were included in the analysis. Patient demographics, treatment history and the results of bone marrow evaluation were recorded. Results During the study period, we evaluated a total of 1,712 biopsy specimens from 464 MM patients (mean±SD age: 64.0±9.4 years; females 41.4%). Of these, 87 cases were submitted for initial diagnosis and 1,625 cases had already established MM and were being evaluated for post-treatment residual disease. For both initial diagnosis and follow-up cases, CD138+ IHC demonstrated highest plasma cell burden (mean: 49.1% and 4.6%, respectively) followed by morphological aspirate count (mean: 29.6% and 2.3%, respectively) and FC (mean: 10.9% and 1.8%, respectively). Both FC and FISH had comparable detection rates at the time of initial diagnosis (95.4% versus 97.7%, respectively) and for follow-up cases (28.6% versus 28.2%, respectively). The FC and FISH results were concordant in 97.7% of the initial diagnosis cases and 89.7% of follow-up cases. Discordant cases with positive FISH results and negative FC results included 2 (2.3%) initial diagnosis cases and 81 (5.0%) follow-up cases whereas those with negative FISH and positive FC results included 87 (5.3%) follow-up cases. In comparison with all concordant cases, the FISH positive, FC negative discordant cases were older in age, more likely to have received treatment with Daratumumab, and less likely to have received stem cell transplantation (p <0.05) (Table 1). When compared to the FC and FISH positive concordant cases; both discordant groups had significantly lower plasma cell counts detected by the aspirate smear and CD138+ IHC (Figure 1). Among all FC positive cases, the discordant cases had lower FC detected plasma cell counts and were less likely to have aberrant CD56 expression as compared to the concordant cases (p <0.05) (Table 2). Finally, among all FISH positive cases, the discordant cases were less likely to have 13q lesion and aneuploidy of chromosomes 5, 9, and 15 (p <0.05) as compared to the concordant cases. Also, between these groups, the percentage of plasma cells with individual FISH aberrations was significantly lower among the discordant cases (Table 3). Conclusion Overall, FISH (with magnetic cell sorting) and FC have comparable detection rates at the initial diagnosis and follow-up assessment. Approximately 10% of the follow-up cases have discordant FISH and FC results where residual disease is detected by only one of these modalities. Also, the discordant cases have significantly lower plasma cell counts as compared to the FC and FISH positive concordant cases. Therefore, this study suggests that both FC and FISH are useful for the follow-up monitoring of MM, especially in the cases with low plasma cell burden. Finally, the higher frequency of Daratumumab treatment in FISH positive, FC negative discordant cases might suggest Daratumumab's potential interference with the residual disease detection by FC. Disclosures No relevant conflicts of interest to declare.

Hepatocyte Growth Factor Expression in Bone Marrow Microenvironment Is Critical for Progression of MGUS to Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4766-4766
Author(s):  
Karthik Ramasamy ◽  
Stephen Schey ◽  
Ghulam J. Mufti ◽  
Farzin Farzaneh ◽  
Yolanda Calle
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Bone Marrow Microenvironment ◽  
Cytoplasmic Staining ◽  
Cell Counts ◽  
Grade 3 ◽  
Hepatocyte Growth

Abstract Hepatocyte growth factor (HGF) augments proliferation, survival and increases migration of plasma cells in vitro and in addition it induces haemangiogeneis and lymphangiogenesis. C-met (HGF receptor) is expressed on plasma cells and HGF is constitutively elevated in serum of patients with myeloma (MM) and MGUS patients. We investigated the distribution of HGF in bone marrow biopsies to better understand its role in progression of monoclonal gammopathy. Materials and methods: Bone marrow trephines were analysed by immunohistochemistry of paraffin embedded bone marrow (BM) trephine specimens. Trephines were dewaxed without antigen retrieval. Plasma cell enumeration was done using CD38 staining (Novocastra, UK). HGF (Goat antihuman IgG, R&D systems) staining was performed using Vectastain® ABC kit with DAB reactivity. Slides were analysed using an Optical microscope (Zeiss Standard 20, Germany). Results: Archived BM specimens of MM (n= 7), MGUS (n= 5) and normal controls (n=6) were stained in duplicate. Trephines were graded from Grade 1–3 (weak, moderate, strong) based on the intensity of staining. The localisation of staining to paratrabecular, perivascular and intertrabecular areas was analysed. Interstitial and cytoplasmic staining patterns were analysed. HGF staining localised to paratrabecular regions was observed in all normal individuals with staining intensity of Grade 1–2 in 3/6(50%) and Grade 3 in 3/6(50%). In 4/5(80%) patients with MGUS a distinct intertrabecular pattern of staining was observed in discrete regions, where plasma cells were localised. Intensity of staining was Grade 2 in 3/5(60%) and Grade 3 in 2/5(40%) MGUS patients. Plasma cell percentages were between 5–20% in MGUS patients. In MM patients we found a correlation between the plasma cell counts and the degree of HGF staining. In 2/7 (28.5%) patients plasma cell percentages ranged between 5% and 15% and Grade 1–2 discrete paratrabecular staining was observed with none or low perivascular staining. In 5/7 (71.5%) MM patients plasma cell percentages were >20% and Grade 3 confluent staining with interstitial and cytoplasmic location of HGF was observed. In addition, patients with Grade 3 staining presented a strong perivascular localisation of HGF. Conclusion: HGF distribution in bone marrow microenvironment of MGUS and MM patients is non random. We observed that MGUS patients have a discrete intertrabecular pattern and MM patients have a confluent interstitial pattern of staining with strong perivascular localisation. Other groups have shown that high HGF levels increase angiogenesis. We hypothesise that HGF localisation and pattern of distribution in BM microenvironment leads to neo angiogenesis and progression from MGUS to MM. Ongoing studies are evaluating this hypothesis.

A study in the plasma cell and lymphocyte reaction in rabbit tissue homografts

1952 ◽  
Vol 236 (637) ◽  
pp. 463-503 ◽  
Keyword(s):  
Blood Vessels ◽  
Plasma Cell ◽  
Positive Relationship ◽  
Plasma Cells ◽  
Methyl Green ◽  
Reticular Cell ◽  
Causative Role ◽  
Tissue Destruction ◽  
Cell Counts ◽  
Graft Tissue

The failure of tissue grafts from one animal to another of the same species (homografts) in mammals is known to result from an active immunization of the recipient animal. But attempts to show that circulating antibody is the agent of destruction have so far been unsuccessful. The present study was undertaken chiefly to test the widely entertained alternative hypothesis that the breakdown of these homografts is, in part at least, caused by the ‘lymphocytes’ whose infiltration into the graft is so characteristic a feature of the process. The method was to implant a set of grafts intradermally in each rabbit from a single donor and to excise one graft for histological study every fourth day thereafter. Sections stained with methyl-green pyronin were counted for lymphocytes and plasma cells (both m ature and presumptive im m ature). The cell counts were then subjected to various statistical tests. The invading cells were found to include, besides small lymphocytes, a large num ber of cells staining strongly with pyronin. Some of the latter were characteristic m ature plasma cells; the rest were, according to the evidence, probably im mature ones. The immature forms were largely lymphocytic in appearance, but some had reticular cell characteristics; m aturation occurred at the graft site. It appeared likely that a fate of the non-pyronin-staining lymphocytes was to become plasma cells; but others underwent destruction at the time of failure of the graft’s blood vessels. On the fourth day after implantation very few invading cells were present in the grafts. On the eighth day large numbers were present, and in most grafts the blood vessels were greatly dilated and engorged and tissue destruction was just beginning. At this time there was evidence of a positive relationship between the lymphocyte content of the grafts and the speed with which the grafts were going to be destroyed. No such relationship was found for the plasma cells. On the twelfth day the destruction was well advanced in most grafts and vascular breakdown widespread. No relationships were found between the concentrations of the invading cells and the stage of graft destruction achieved. But there was evidence that the increase in the number of m ature plasma cells in the grafts from the eighth to the twelfth day was positively related to the amount of graft tissue destroyed during that time; the lymphocyte increment, on the other hand, tended to be negatively related to the amount of tissue destroyed. It was seen that the percentage of im mature forms among the plasma cells was high in grafts at the beginning of breakdown and that it thereafter declined, but it tended to remain relatively high as long as graft tissue persisted. There was a positive relationship between this percentage in the grafts on the eighth day and the speed of graft breakdown. No graft was destroyed unless this percentage reached over fifty. It would appear to be an index of the progress of the host reaction against the graft. The grafts in one animal contained a massive infiltration of lymphocytes and plasma cells on the eighth and twelfth day without undergoing any tissue destruction. Lymphocytes were frequently observed in such close contact with the graft cells as to give the appearance of having penetrated them. Im m ature plasma cells were also found in such positions, but not frequently. Grafts were transplanted to animals previously sensitized by a set of grafts from the same donor. The second set of grafts in general underwent an accelerated destruction and had a much greater infiltration of plasma cells, but not of lymphocytes. Those second-set grafts which were slowest to breakdown contained most plasma cells. There was a striking correlation between the mature plasma-cell concentrations in an anim al’s first and second set of grafts, at any rate after graft breakdown was moderately advanced. It appeared that this cell concentration was determined by the response of the host animal rather than by the graft. Since the ranking of animals according to the speed of breakdown of their grafts was different for the first- and second-set grafts, this suggested that these cells were unlikely to be an important cause of graft destruction. In a few animals the second set of grafts was destroyed no quicker than the first set, yet their infiltration by plasma cells was much greater. This too was taken to be evidence against an important causative role for these cells. From these and other considerations it was concluded that the results do not support the hypothesis that the plasma cells which infiltrate these homografts are a significant cause of their destruction. The same would also appear to hold, though with less evidence, for the lymphocytes. At the same time it appeared likely that the plasma-cell response is specifically connected with the immune reaction. O f the m ain theories of plasma-cell function that of resorption would best explain the findings in these grafts. If the infiltrating plasma cells secrete specific antibody against the graft tissue this contribution to graft destruction would not appear to be significant.

Schwannoma with monoclonal plasma cell infiltration

2009 ◽  
Vol 111 (3) ◽  
pp. 509-511 ◽  
Author(s):  
Joshua Plaut ◽  
Malcolm Galloway ◽  
Anna Childerhouse ◽  
Robert Bradford
Keyword(s):  
Cell Population ◽  
Plasma Cell ◽  
Vestibular Schwannoma ◽  
Light Chain ◽  
Histological Analysis ◽  
Plasma Cells ◽  
Systemic Disease ◽  
Lambda Light Chain ◽  
Plasma Cell Neoplasm ◽  
Polymerase Chain

The authors report a very rare case of a vestibular schwannoma with an infiltrate of monoclonal plasma cells. A 45-year-old woman underwent routine excision of a presumed vestibular schwannoma. Histological analysis revealed the presence of a distinct lambda light chain restricted plasma cell population within the schwannoma. The light chain restriction and polymerase chain reaction–demonstrated monoclonality of the plasma cell population suggested the co-occurrence of a plasma cell neoplasm within a schwannoma. A search for systemic disease of plasma cell origin was unremarkable. A search of the literature suggests that this is the first report of such an occurrence.

Identification of Atypical Plasma Cells in Patients with MGUS or Multiple Myeloma Through Expression of Immunoreceptor CD229

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4969-4969
Author(s):  
Markus Ertmer ◽  
Djordje Atanackovic ◽  
Lucia Vankann ◽  
Stefan Wilop ◽  
Eray Gökkurt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Cell Phenotype ◽  
Surface Markers ◽  
Myeloma Cells ◽  
Cell Counts ◽  
Exact Function

Abstract Abstract 4969 Introduction: While multiparameter flow cytometry (MPF) is an integral part in the diagnosis, disease staging and response evaluation for hematologic malignancies such as acute leukemia or non-hodgkin-lymphoma, MPF for multiple myeloma (MM) is still mostly restricted to research studies or only performed by specialised laboratories experienced in the technique of immunophenotyping. Furthermore, the exact phenotype of malignant myeloma cells is still a matter of debate. Recently, we have identified CD229, a surface marker belonging to the family of signaling lymphocytic activation molecules (SLAM) involved in lymphocyte activation as a potential novel target for diagnosis and treatment of MM. CD229 is expressed on freshly isolated myeloma cells including their clonogenic precursors and several myeloma cell lines. In order to further validate our findings from a previous pilot study, we now analysed 151 samples from 81 patients with suspected or proven MM or monoclonal gammopathy of uncertain significance (MGUS) via MPF. Methods: Between May 2010 and May 2012, specimens (bone marrow (n=142), peripheral blood (n=10), cells from isolated plasmocytoma (n=1)) from patients (pts) with MM (n=65), plasmocytoma (n=1), MGUS (n=6), lymphoplasmacytic lymphoma (n=1) and patients with suspected MM (n=8) were simultaneously analysed via cytology and 8-colour MPF. 19 pts. were analysed at least 3 times during the course of their disease so that CD229 expression could be followed under therapy. Plasma cells were specified using surface markers CD38, CD138, CD45 and cytoplasmatic light chain restriction. Antigens analysed on plasma cells were CD19, CD28, CD33, CD56, CD81, CD117, CD200, CD221 and CD229. Results: Although plasma cell numbers determined by MPF were constantly considerably lower compared to simultaneously determined cytology results, linear regression model showed a highly significant correlation between plasma cell percentages in bone marrow measured by MPF with cytology (p<0. 0001). Plasma cell enumeration in pB also showed a strong correlative trend between cytologic and MPF results, however, due to lower numbers (n=10), this was not statistically significant (p = 0. 057). CD229 could be detected on all atypical plasma cells irrespective if they were found in MGUS or MM samples. The median of mean fluorescence intensity (MFI) of CD229 expression on plasma cells was 3, 63 (range −144. 1 – 34, 23). Median MFI on MM samples (3, 62; range −144 − 34, 23; n=131) did not differ from MFI on atypical plasma cells in pts with MGUS (3, 74, range 1. 07 – 8, 65; n=9). CD229 expression was highest on atypical plasma cells with expression of CD56 compared to CD56 negative plasma cells (p<0. 0001). This was confirmed when correlation of marker expression was evaluated. CD229 expression was clearly correlated with expression of CD56 (n=141, p = 0. 03), CD117 (n=139, p = 7E–08) and CD200 (n=140; p = 0. 03), while it was inversely correlated with expression of CD19 (n=140; p = 0. 03). Serial CD229 expression (>= twice) was determined in 39 patients. Except for three samples, where plasma cell counts became less than 1% of bone marrow cells, CD229 expression remained stable throughout the various analyses. Conclusion: While the exact function of the immunoreceptor CD229 on myeloma cells is still unknown, CD229 allows identification of atypical plasma cells by MPF. Our results show that CD229 is constantly expressed on atypical plasma cells independent of therapy and can be used in addition to other surface markers for determination of malignant plasma cell phenotype and to monitor minimal residual disease (MRD) under treatment. Disclosures: No relevant conflicts of interest to declare.

Atypical Cellular Disorders

Hematology ◽  
2004 ◽  
Vol 2004 (1) ◽  
pp. 283-296 ◽  
Author(s):  
Kenneth L. McClain ◽  
Yasodha Natkunam ◽  
Steven H. Swerdlow
Keyword(s):  
Clinical Trials ◽  
Inflammatory Response ◽  
Plasma Cell ◽  
Langerhans Cells ◽  
Plasma Cells ◽  
Response To Therapy ◽  
Bone Lesions ◽  
Cell Type ◽  
Rosai Dorfman Disease ◽  
Plasma Cell Type

Abstract Some immunologic diseases are characterized by profound loss or primary dysfunction of a given population of cells. The atypical cellular disorders discussed here all bear some similarities in that abnormal proliferations of lymphocytes and macrophages or dendritic cells result in lymphadenopathy, skin rashes, bone lesions and infiltrations of nearly any other organ system. What are the similarities and the differences between Langerhans cell histiocytosis (LCH), sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease, and Castleman’s disease (CD)? Studies on LCH have some advantages since it was described before the others, and organized clinical trials have been done since the 1980s. The understanding of SHML benefited from a registry maintained by Drs. Rosai and Dorfman. CD was described fifty years ago and for one subtype has the most clearly defined etiology (HHV-8 infection) of the three atypical cellular disorders discussed here. In Section I, Dr. Kenneth McClain examines the unanswered question of whether LCH is a malignant clonal disorder or an inflammatory response triggered by aberrant cytokine expression or a virus. Advocates of the malignant proliferation theory rest their case primarily on the following two points: Clonality of the CD1a+ Langerhans cells was demonstrated by analysis of the human androgen receptor in patients with single bone lesions (Low Risk) or multisystem disease including spleen, liver, bone marrow, or lung (High Risk). Although no consistent chromosomal abnormalities have been reported, loss of heterozygosity (LOH) has been defined by comparative genomic hybridization. Those in the “inflammatory response” camp note that non-clonal proliferation of Langerhans cells in adult pulmonary LCH also have LOH by the same method. The pathologic cells have not been successfully grown in culture or immune-deficient mice and don’t have a “malignant” morphology. While the basic scientific arguments continue, important advances in the treatment of LCH have been made by international collaborations of the Histiocyte Society. Risk groups have been clearly defined and the response to therapy after the initial 6 weeks is known to be the strongest prognostic variable for outcome. In Section II, Dr. Yasodha Natkunam reviews the features of SHML, which most often presents as painless cervical lymphadenopathy, although many patients can have extranodal involvement as well. These sites include the skin, respiratory tract, bone, lung, gastrointestinal tract, and brain. The diagnosis rests on finding intact lymphocytes in the cytoplasm of activated macrophages as well as accumulation of mature plasma cells. Hemolytic or non-hemolytic anemias, hypergammaglobulinemia, and elevated erythrocyte sedimentatin rate (ESR) are often found with SHML. An intriguing finding of human herpesvirus (HHV)-6 viral proteins in SHML has been reported in several patients, but needs further study. SHML associated with lymphoproliferations triggered by defects in apoptosis are discussed since this mechanism may provide a clue to the etiology. Therapy for SHML varies greatly in reported case series. Many patients have spontaneous regression or resolution after surgical removal of isolated node groups. Others with systemic involvement may benefit from chemotherapy, but no clinical trials have been done. In Section III, Dr. Steven Swerdlow clarifies key features of the four types of CD. Localized cases are divided into the hyaline vascular type and plasma cell type. Both are usually cured by surgical excision and have symptoms mainly of a mass lesion, although the latter often also has constitutional symptoms. The two types are distinguished largely by the nature of the follicles and the number of interfollicular plasma cells. Interleukin (IL)-6 expression is increased in the plasma cell type. Multicentric CD of the plasmablastic type is most often found in HIV-positive patients with coincident HHV-8 infection. Many have lymphomas or Kaposi sarcomas. Other cases of multicentric CD are also most like the plama cell type, however, with disseminated disease and constitutional symptoms. A wide variety of anti-neoplastic drugs, radiation therapy, anti-IL-6 and rituximab or atlizumab have been used with varying success in patients with multicentric CD. Clinical trials are needed for SHML and CD and registration of adult and pediatric patients on current LCH trials are encouraged.

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