Plasmacytoma with involvement of the urinary bladder. Report of a case diagnosed by urine cytology

BACKGROUND: Plasmacytoma of the bladder is a rare but important entity. We report a case of plasmacytoma of the bladder that was diagnosed by urinary cytology. CASE: A 71-year-old male with a history of multiple myeloma presented in renal failure. Renal ultrasound revealed right-sided, moderate hydronephrosis with a 4 x 4-cm, posterolateral, obstructing mass. Magnetic resonance imaging demonstrated a bladder mass involving the bladder base, right lateral wall and dome with extension into the perivesical tissues on the right. The mass showed a moderate degree of enhancement following intravenous gadolinium administration. Urine cytology was performed to evaluate for bladder carcinoma or other malignancies besides plasmacytoma. The specimen was signed out as multiple myeloma of the bladder. Cystoscopy and biopsy were subsequently performed on the bladder mass. The diagnosis of plasmocytoma was made, confirming the urine cytology diagnosis. CONCLUSION: Urinary cytology can be a diagnostic tool for plasmocytoma involving the bladder.     

Cytopathology of extramedullary plasmacytoma of the bladder: a case report

BACKGROUND: Plasmacytoma of the bladder is an extremely rare tumor, with all information concerning this neoplasm derived from case reports. It can be a major diagnostic pitfall on both histology and urine cytology. CASE: A 95-year-old woman presented with gross hematuria and a large bladder mass detected by ultrasound. The case was initially misdiagnosed as a high grade urothelial carcinoma. Since the urine cytology did not show the classical cytologic features of urothelial carcinoma, the histologic sections were reviewed and immunohistochemical staining performed. The final diagnosis was plasmacytoma of the bladder. Subsequently the patient underwent a skeletal survey and bone scan, which did not reveal any lesion suspicious for multiple myeloma. The patient was scheduled for radiotherapy. CONCLUSION: In this case of bladder plasmacytoma, urine cytology provided a clue to the diagnosis. Urine cytology can be a diagnostic tool to help make this diagnosis in the case of poorly differentiated bladder neoplasm, especially in a patient with a known history of multiple myeloma.     

Ascites as a presenting feature of relapsed multiple myeloma. Report of a case diagnosed by aspiration cytology.

A 68-year-old woman with IgG-type multiple myeloma (MM) in remission and a chief complaint of ascites was found to have peritoneal fluid involvement by myeloma cells on cytologic study. There are only a few reports describing the cytologic features in patients presenting with ascites as the first manifestation of relapsed MM. IgG myeloma, however, is one of the rarest types. The patient had had pancreatic involvement months before her presentation with ascites, which itself is a rare manifestation of relapsed MM. Cytologic smears of ascitic fluid showed isolated and incoherent groups of cells with plasmacytoid features. To recognize myeloma as a cause of ascites is important because it may respond well to therapy. Aspiration cytologic study can be considered a useful method for follow-up and diagnosis of MM relapse even without a biopsy.     

IFN-alpha induces autocrine production of IL-6 in myeloma cell lines.

IL-6 is a major tumor growth factor in human multiple myeloma. Myeloma cell lines, which have the same phenotypic characteristics and Ig gene rearrangements as the original fresh myeloma cells and whose growth is strictly dependent on exogenous IL-6 similar to fresh myeloma cells, have been reproducibly established. We show here that IFN-alpha stimulated the growth of five of six of these human myeloma cell lines by inducing an autocrine production of IL-6 in myeloma cells. Indeed, IFN-alpha induced IL-6 mRNA accumulation and IL-6 production in myeloma cells and the IFN-alpha-induced growth of these cells was inhibited by anti-IL-6 mAb. Moreover, IFN-alpha made possible the rapid emergence of autonomously growing myeloma cell sublines, which produced IL-6 as an autocrine growth factor. As IFN-alpha has a potential therapeutical interest for multiple myeloma, the present study opens up new directions for studying its effects on the myeloma clone in vivo.     

Inhibition of BDNF in Multiple Myeloma Blocks Osteoclastogenesis via Down-Regulated Stroma-Derived RANKL Expression Both In Vitro and In Vivo

Brain-derived neurotrophic factor (BDNF) was recently identified as a factor produced by multiple myeloma (MM) cells, which may contribute to bone resorption and disease progression in MM, though the molecular mechanism of this process is not well understood. The purpose of this study was to test the effect of BDNF on bone disease and growth of MM cells both in vitro and in vivo. Co- and triple-culture systems were implemented. The in vitro results demonstrate that BDNF augmented receptor activator of nuclear factor kappa B ligand (RANKL) expression in human bone marrow stromal cells, thus contributing to osteoclast formation. To further clarify the effect of BDNF on myeloma bone disease in vivo, ARH-77 cells were stably transfected with an antisense construct to BDNF (AS-ARH) or empty vector (EV-ARH) to test their capacity to induce MM bone disease in SCID–rab mice. Mice treated with AS-ARH cells were preserved, exhibited no radiologically identifiable lytic lesions and, unlike the controls treated with EV-ARH cells, lived longer and showed reduced tumor burden. Consistently, bones harboring AS-ARH cells showed marked reductions of RANKL expression and osteoclast density compared to the controls harboring EV-ARH cells. These results provide further support for the potential osteoclastogenic effects of BDNF, which may mediate stromal–MM cell interactions to upregulate RANKL secretion, in myeloma bone diseases.     

Aspiration biopsy findings in amyloid tumor of the cervical vertebra. A case report

BACKGROUND: The differential diagnosis of destructive lytic lesions of the spine includes amyloid tumors. The diagnosis of amyloid tumor with fine needle aspiration biopsy (FNA) is challenging. Previous reports of FNA of osseous amyloid tumors have detailed the cytologic appearance of amyloid along with lymphocytes, plasma cells and histiocytes, occasionally multinucleate or forming granulomatous lesions. CASE: An 84-year-old man presented with neck pain. Radiologic studies showed a destructive, lytic lesion of C-6, with a large, soft tissue mass. FNA yielded many acellular smears containing abundant amyloid that was confirmed with special stains of corresponding tissue cores and subsequent surgical biopsies. CONCLUSION: Osseous amyloid tumors are destructive, lytic lesions that mimic other processes. Amyloid can be distinguished from other substances in FNA samples and amyloid tumor identified, even when amyloid is present without typical cellular components.     

Induced expression of B7-1 on myeloma cells following retroviral gene transfer results in tumor-specific recognition by cytotoxic T cells.

The aim of this study was to evaluate whether tumor cells from patients with multiple myeloma activate allogeneic and autologous T cells. Results showed that myeloma cells expressed few B7-2 and no B7-1 in six cell lines and primary cells from 11 patients. They expressed substantial levels of HLA class I, CD40, and a set of adhesion molecules. In accordance with the low density of B7 molecules on these cells, they were poor allogeneic CD8+ T cell stimulators. Neither IFN-gamma plus TNF-alpha nor CD40 stimulation significantly induced B7-1 or up-regulated B7-2 on human myeloma cell line or primary myeloma cells from six of seven patients. However, such induction was found on autologous bone-marrow nontumoral cells and on autologous dendritic cells following CD40 stimulation. High B7-1 expression was stably obtained on human myeloma cell line using transduction with a B7-1 retrovirus, enabling these cells to stimulate allogeneic CD8+, though not CD4+, T cell proliferation. For one patient with advanced disease, B7-1 gene transfer made it possible to amplify autologous cytotoxic T cells that killed autologous myeloma cells in an HLA class I-restricted manner, but not autologous PHA blasts. These results suggest that B7-1 gene transfer could be a promising immunotherapeutic approach in multiple myeloma.     

Eosinophils and Megakaryocytes Support the Early Growth of Murine MOPC315 Myeloma Cells in Their Bone Marrow Niches

Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro-environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315.BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315.BM cell growth in vitro, IL-5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient ΔdblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma.     

The skull and vertebral column pathology of Ancient Egyptians. A study of the Marro Collection

The skull and vertebral column pathology of the Ancient Egyptian skeletal remains of the Marro Collection (1118 individuals) is mainly represented by “common” degenerative and inflammatory osteo-articular alterations. Apart from these, three cases of ankylosing spondylitis and two cases of probable multiple myeloma are described in detail. The frequency of these conditions seems to be almost the same as in modern times. Furthermore, a skull with larger osteolitic areas of probable metastatic origin is described.     

Circulating Serum MicroRNA-130a as a Novel Putative Marker of Extramedullary Myeloma

Poor outcome of extramedullary disease in multiple myeloma patients and lack of outcome predictors prompt continued search for new markers of the disease. In this report, we show circulating microRNA distinguishing multiple myeloma patients with extramedullary disease from myeloma patients without such manifestation and from healthy donors. MicroRNA-130a was identified by TaqMan Low Density Arrays and verified by quantitative PCR on 144 serum samples (59 multiple myeloma, 55 myeloma with extramedullary disease, 30 healthy donors) in test and validation cohorts as being down-regulated in myeloma patients with extramedullary disease. Circulating microRNA-130a distinguished myeloma patients with extramedullary disease from healthy donors with specificity of 90.0% and sensitivity of 77.1%, patients with extramedullary disease from newly diagnosed multiple myeloma patients with specificity of 77.1% and sensitivity of 34.3% in the test cohort and with specificity of 91.7% and sensitivity of 30.0% in the validation cohort of patients. Circulating microRNA-130a in patients with extramedullary myeloma was associated with bone marrow plasma cells infiltration. Further, microRNA-130a was decreased in bone marrow plasma cells obtained from patients with extramedullary myeloma in comparison to bone marrow plasma cells of myeloma patients without such manifestation, but it was increased in tumor site plasma cells of patients with extramedullary disease compared to bone marrow plasma cells of such patients (p<0.0001). Together, our data suggest connection between lower level of microRNA-130a and extramedullary disease and prompt further work to evaluate this miRNA as a marker of extramedullary disease in multiple myeloma.     

原癌基因c-maf在多发性骨髓瘤中的研究进展

人类多发性骨髓瘤是一种难以治愈的B淋巴细胞恶性分化的疾病,其细胞遗传学特征表现在染色体异常.原癌基因c-maf在多发性骨髓瘤细胞中高水平表达,其编码的c-Maf蛋白作为转录因子,通过作用于5个下游靶基因CCND2、ITGB7、CCR1、SPP1和ARK5,与细胞周期调控、肿瘤细胞的黏附性、肿瘤侵袭和转移、血管发生等方面有关.原癌基因c-maf和/或c-Maf蛋白有可能作为治疗多发性骨髓瘤的新靶点.     

Interactions of myeloma cells with osteoclasts promote tumour expansion and bone degradation through activation of a complex signalling network and upregulation of cathepsin K, matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA)

Bone destruction is one of the most debilitating manifestations of multiple myeloma (MM) and results from the interaction of myeloma cells with the bone marrow microenvironment. Within the bone marrow, the disturbed balance between osteoclasts and osteoblasts is important for the development of lytic lesions. However, the mechanisms behind myeloma-mediated bone destruction are not completely understood. In order to address the importance of myeloma cell-osteoclast interactions in MM pathogenesis, we have developed a functional coculture system. We found that myeloma-osteoclast interactions resulted in stimulation of myeloma cell growth and osteoclastic activity through activation of major signalling pathways and upregulation of proteases. Signals from osteoclasts activated the p44/p42 MAPK, STAT3 and PI3K/Akt pathways in myeloma cells. In turn, myeloma cells triggered p38 MAPK and NF-kappaB signalling in osteoclasts. Myeloma-osteoclast interactions stimulated the production of TRAP, cathepsin K, matrix metalloproteinase (MMP)-1, -9, and urokinase plasminogen activator (uPA). Consistent data with myeloma cell lines and primary myeloma cells underlined the biological relevance of these findings. In conclusion, we demonstrated the critical role of myeloma cell-osteoclast interactions in the existing interdependence between tumour expansion and bone disease. The identified molecular events might provide the rationale for novel treatment strategies.     

Multiple myeloma: a prototypic disease model for the characterization and therapeutic targeting of interactions between tumor cells and their local microenvironment

The interaction between tumor cells and the local milieu where are homing has recently become the focus of extensive research in a broad range of malignancies. Among them, multiple myeloma (MM) is now recognized as a prototypical tumor model for the characterization of these interactions. This is due not only to the propensity of MM cells to target the skeleton and form lytic bone lesions, but because interactions of MM cells with normal cells of the bone milieu can attenuate the anti-tumor activity of conventional therapies, such as glucocorticoids and standard cytotoxic agents, including alkylators. Herein, we highlight the recent advances in our understanding of cellular and molecular mechanisms of interactions between MM cells and their milieu. Particular emphasis is placed on the interface between MM cells and normal cell compartments of the BM, especially bone marrow stromal cells (BMSCs), and on the development of a series of new classes of therapeutic agents, including the proteasome inhibitor bortezomib, thalidomide and lenalidomide, which counteract specific aspects of those MM-BM interactions. The significant clinical activity of these novel therapies has not only led to a new era in the therapeutic management of this disease, but also underscored the importance of comprehensively characterizing the role of the local microenvironment in the pathophysiology of human neoplasias.     

Assessing the efficiency of free light chain assay in monitoring patients with multiple myeloma before and after autologous stem cell transplantation along with serum protein electrophoresis and serum protein immunofixation

Monoclonal gammopathies are a group of disorders, referred to as paraproteinaemias, dysproteinaemias or immunoglobulinopathies, associated with monoclonal proliferation of plasma cells. Monoclonal immunoglobulin secreted by these cells is an indicator of clonal proliferation. The aim of this study is to analyze the efficiency of three methods: serum protein electrophoresis (SPE), serum protein immunofixation (IFE) and FLC (free light chain) assay for the diagnosis and monitoring of the tumor burden in multiple myeloma. In this study we have presented the dynamic evolution of 7 patients with intact immunoglobulin multiple myeloma (IIMM) (2 IgG, kapa; 3 IgG, lambda; 1 IgA, kappa; 1 IgA, lambda) and 2 patients with light chain multiple myeloma before and after autologous peripheral blood stem cell transplantation (PBSCT). All 7 patients fulfilled the four criteria for the diagnosis of IIMM: bone marrow plasma cells exceeding 20%, lytic bone lesions, identification and quantification of M protein by scanning densitometry of electrophoresis gels, IFE (immunofixation protein electrophoresis) confirmed and typed the M protein. All patients had been given cytotoxic chemotherapy (VAD or VELCADE) before autologous (PBSCT). In two of the patients with IIMM both SPE and kappa/lambda ratio fell towards normal range after autologous PBSC and both reported a relapse of the disease after 23 months and 19 months respectively. SPE could not normalize after chemotherapy and transplantation in three patients with IIMM, the kappa/lambda ratio being the only marker used to monitor the tumor kill. In one patient the kappa/lambda ratio could not normalize even after PBSCT still indicating the presence of plasma cell disorder at the time when IFE was still negative. 16 months after PBSCT both SPE and FLC indicated a relapse of the disease. Classical SPE failed to demonstrate the presence of M-protein in light chain multiple myeloma, the diagnosis being established by using IFE and the FLC assay. Because IFE is a qualitative method and its interpretation may be sometimes subjective, FLC was the only method used to follow the disease course. The measurement of kappa/lambda ratio proved to be more sensitive than SPE, IFE and the levels of free light chains kappa or lambda individually indicating whether the treatment is effective or not.     

A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma

Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9. This compound also showed in vivo activity against multiple myeloma cell line KMS34 tumor xenografts in ICR/SCID mice. By means of mRNA display selection on a microfluidic chip, the target protein of TC11 was identified as nucleophosmin 1 (NPM). Binding of TC11 and NPM monomer was confirmed by surface plasmon resonance. Immunofluorescence and NPM knockdown studies in HeLa cells suggested that TC11 inhibits centrosomal clustering by inhibiting the centrosomal-regulatory function of NPM, thereby inducing multipolar mitotic cells, which undergo apoptosis. NPM may become a novel target for development of antitumor drugs active against multiple myeloma.     

Adhesion of multiple myeloma cells to the bone marrow microenvironment: implications for future therapeutic strategies

Multiple myeloma is characterized by excess plasma cells within the bone marrow in association with monoclonal antibody protein in the serum and/or urine. Tumor cells localize within the marrow via an interaction of cell-surface adhesion molecules with their respective ligands on marrow stromal cells and extracellular matrix proteins. Stimulation of myeloma cells via these cell-surface molecules, either directly or via tumor cell adhesion to stromal cells, can induce autocrine or paracrine tumor cell growth mediated by interleukin 6. It might therefore be possible to develop innovative treatment strategies either to inhibit interleukin 6 production or to interrupt interleukin 6 signal transduction in multiple myeloma.     

Suppression of IL-2-induced T cell proliferation and phosphorylation of STAT3 and STAT5 by tumor-derived TGF beta is reversed by IL-15.

IL-2 responses are susceptible to suppression by TGFbeta, a cytokine widely implicated in suppression of inflammatory responses and secreted by many different tumor cell types. There have been conflicting reports regarding inhibition of IL-2-induced STAT3 and STAT5 phosphorylation by TGFbeta and subsequent suppression of immune responses. Using TGFbeta-producing multiple myeloma tumor cells we demonstrate that tumor-derived TGFbeta can block IL-2-induced proliferation and STAT3 and STAT5 phosphorylation in T cells. High affinity IL-2R expression was required for the suppression of IL-2 responses as a novel CD25(-) T cell line proliferated and phosphorylated STAT3 when cultured with tumor cells or rTGFbeta1. Activating T cells with IL-15, which does not use the high affinity IL-2R, completely restored the ability of T cells to phosphorylate STAT3 and STAT5 when cultured with tumor cells. IL-15-treated T cells proliferated normally when cocultured with tumor cells or rTGFbeta1, whereas IL-2 responses were consistently inhibited. Preincubation with IL-15 also restored the ability of T cells to respond to IL-2 by phosphorylating STAT3 and STAT5, and proliferating normally in the presence of tumor cells. IL-2 pretreatment did not restore T cell function. IL-15 also restored T cell responses by T cells from multiple myeloma patients, and against freshly isolated bone marrow tumor samples. Thus, activation of T cells by IL-15 renders T cells resistant to suppression by TGFbeta1-producing tumor cells and rTGFbeta1. This finding may be exploited in the design of new immunotherapy approaches that will rely on T cells avoiding tumor-induced suppression.     

多发性骨髓瘤遗传学的研究进展

多发性骨髓瘤起源于后生发中心的B细胞,是一种不可治愈的慢性进展性骨髓浆细胞恶性肿瘤,约占血液系统肿瘤的10%。多发性骨髓瘤存在明显的遗传学改变,其早期的遗传学改变是免疫球蛋白重链基因位点的易位,而这些易位常常导致11q13区域的cyclin D1、4p16.3区域的FGFR3/MMSET、16q23区域的c-maf、6p21区域的cyclin D3等癌基因的失调,同时还存在抑癌基因位点13q14的丢失以及13号染色单体的缺失,这些染色体异常与疾病的预后密切相关。并且N-RAS、K-RAS的突变,以及c-Myc改变等继发性的改变和癌基因的活化等也与疾病的进展密切关联。近年来,随着医学技术的不断进步,人们对该病的遗传学改变认识进一步加深。本文对多发性骨髓瘤的遗传学改变研究进展进行综述,旨在为指导临床有效治疗多发性骨髓瘤,有效评估预后提供参考。     

Nephrogenic adenoma of the urinary bladder. Histologic and cytologic observations in a case

The histologic and cytologic features of multiple tissue and voided urine specimens from a man with nephrogenic adenoma of the urinary bladder are described. The urinary cytology showed papillary fragments, with cells showing palisade formation. The cells were round to oval, with a centrally placed nucleus with a fine chromatin pattern. These cells were identical to those seen in a low-grade papillary transitional-cell carcinoma. Tissue biopsy is needed to separate these two very different pathologic conditions.