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Extramedullary plasmacytoma of skeletal muscle. A case report with immunocytochemistry and ultrastructural study.

An uncommon origin of a rare tumor is described in a 60-year-old white man. Extramedullary plasmacytoma was localized in the left biceps muscle. Tumor immunostaining corresponded with immunocharacterization of the atypical midgamma band on electrophoresis or the serum monoclonal M protein of IgG kappa. The latter disappeared 6 months after the operation. The diagnosis was confirmed ultrastructurally.

Arm↗

Prostaglandins, but not tumor-derived IL-10, shut down concomitant tumor-specific CTL responses during murine plasmacytoma progression.

IL-10 is assumed to be a major immunosuppressive factor produced by most B-cell tumors. The immunosuppressive role of tumor-derived IL-10 was analyzed using the MHC class II-negative BALB/c plasmacytoma ADJ-PC-5 as a model tumor. Immune monitoring of tumor-bearing mice was based on the measurement of tumor burden, tumor-specific CTL cytotoxicity and intracellular cytokine staining using FACS. ADJ-PC-5 tumor progression in syngeneic recipients is associated with strong, concomitant, tumor-specific CTL responses during early stages of tumor progression which are sufficient to cause rejection of small s.c. autologous test tumors. These initial CTL responses gradually decline during later tumor stages. Blocking of IL-10 in vivo did not abolish CTL suppression or retard tumor growth. More strikingly, application of anti-IL-10 antibodies during early tumor stages abrogated CTL induction and markedly accelerated tumor growth. In contrast to anti-IL-10 treatment, application of cyclo-oxygenase inhibitors to ADJ-PC-5 tumor-bearing mice led to enhanced tumor-specific CTL responses throughout all stages of tumor progression, paralleled by retarded tumor growth and a significantly delayed onset of suppression. Both findings contradict a dominant immunosuppressive role of IL-10 during B-cell tumor progression. Tumor-derived IL-10 must therefore be considered an immunostimulating factor, which accounts for the high immunogenicity of B-cell tumors, whereas prostaglandins, which are not produced by the tumor cells themselves, are the dominant immunosuppressors in this system.

Animals↗

Thyroid plasmacytoma mimicking medullary carcinoma: a potential pitfall in aspiration cytology.

Extramedullary plasmacytoma (EMP), a malignant neoplasm of the soft tissues composed of plasma cells, may occur either as a solitary plasma-cell tumor (primary EMP) or as a manifestation of multiple myeloma (secondary EMP). We report on the aspiration cytology findings of an intriguing case of EMP of the thyroid that was initially misinterpreted as medullary carcinoma on clinical and cytologic examination. A major contributing cause for the cytologic misinterpretation was the presence of amyloid in the aspirate and the clinical impression of a "thyroid mass." Based on this experience, we suggest that EMP should be considered in the differential diagnosis of a neck mass that yields discohesive cells associated with amyloid/amyloid-like material. Clinical correlation and immunocytochemistry are crucial in avoiding pitfalls in this situation.

ADP-ribosyl Cyclase↗

Chromosomes 1 and 5 harbor plasmacytoma progressor genes in mice.

Mouse spectral karyotyping (SKY) was employed to analyze 29 primary BALB/c plasmacytomas (PCTs) for the presence of chromosomal aberrations that took place subsequent to the Myc-activating T(12F1;15D2) or T(6C1;15D2) translocations, the initiating oncogenic mutations in plasmacytomagenesis. Recurrent amplifications of chromosome (Chr) 1 (48% prevalence) and promiscuous non-reciprocal translocations of Chr 5 (52% prevalence) suggested the existence of important PCT progressor genes on bands 1B/C and 5F. The additional occurrence of sporadic aberrations (93% prevalence) most likely reflected the general instability of the PCT genome. This instability, however, was not consistent, as two PCTs lacked secondary cytogenetic changes detectable by SKY. Our findings led us to conclude that BALB/c PCTs show a remarkably similar degree of cytogenetic heterogeneity to human multiple myeloma, despite being genetically defined (inbred mouse strain) and uniformly initiated (deregulation of Myc). Published 2000 Wiley-Liss, Inc.

Aneuploidy↗

Treatment of postrenal transplantation lymphoproliferative disease manifesting as plasmacytoma with nonmyeloablative hematopoietic stem cell transplantation from the same kidney donor.

Posttransplantation lymphoproliferative disease (PTLD) presenting as an Epstein-Barr-virus (EBV)-related nasal plasmacytoma developed in a renal-allograft recipient 13 years after transplantation. Systemic dissemination occurred despite immunosuppression withdrawal, surgery, irradiation, and chemotherapy. A nonmyeloablative hematopoietic-stem-cell-transplantation (HSCT) with peripheral blood HSC from the kidney donor was performed. With the onset of graft-versus-host disease, resolution of the systemic disease was demonstrated clinically and molecularly by serial quantification of plasma EBV-DNA. Isolated relapse occurred in the central nervous system (CNS), a known tumour sanctuary site, ultimately leading to death. Nonmyeloablative HSCT might be considered a cellular therapy for PTLD, but possible CNS relapse must be effectively tackled.

Aged↗

Persistence of myeloma protein for more than one year after radiotherapy is an adverse prognostic factor in solitary plasmacytoma of bone.

BACKGROUND: Prognostic factors for solitary plasmacytoma of bone (SPB), whether measured before or after radiotherapy (RT), have not been established. The authors analyzed multiple factors for myeloma-free survival (MFS) and cause-specific survival (CSS) in SPB patients treated with RT alone. METHODS: Between 1965 and 2000, 60 patients with carefully staged SPB were treated with RT alone at the M. D. Anderson Cancer Center. Patient ages ranged from 29-77 years (median, 54 years), and 75% of patients had a myeloma (M) protein in the blood and/or urine. No patients showed other lesions on skeletal survey or, in recent years, magnetic resonance imaging (MRI) of the spine; marrow aspirate was normal in all patients. Radiotherapy to the solitary lesion was given to a total dose of 30-70 Gy (median, 46 Gy). The authors analyzed the impact of multiple factors on MFS and CSS, including resolution v. persistence of M protein after RT, secretory v. nonsecretory disease at diagnosis, presence v. absence of an associated soft tissue mass on computed tomography or MRI scan, magnitude of serum M protein elevation at diagnosis, age, spinal v. nonspinal location, Karnofsky performance status, total RT dose, and tumor size. RESULTS: Median follow-up was 7.8 years (range, 1.0-25.5 years). On multivariate analysis, persistence of M protein more than one year after RT was the only independent adverse prognostic factor for MFS (P = 0.005) and CSS (P = 0.04). Most patients with M protein that persisted for more than one year after RT were diagnosed with multiple myeloma within 2.2 years of treatment. CONCLUSIONS: Patients with M protein that persists for more than one year after RT should be monitored frequently and considered for standard chemotherapy followed by intensive consolidation therapy when they either develop symptoms or show an increasing M protein level.

Adult↗

Inhibition of antibody production in plasmacytoma cells by antigen.

Tissue culture-adapted MOPC 315 mouse plasmacytoma cells which secrete monoclonal anti-DNP IgA antibody, were cultured with a variety of DNP-carrier conjugates and the production of IgA measured by pulse labeling with [3H]leucine and by plaque-forming cell assays. DNP-coupled bovine, human and rabbit gamma-globulins (containing 9 to 12 DNP groups per 50 000 mol wt of carrier) inhibited the synthesis and secretion of IgA by 40 to 80%. This inhibition was specific, since unconjugated globulins were ineffective, non-IgA proteins and DNA synthesis remained unaffected, and DNP-globulins had no effect on X5563 cells which do not bind DNP. The degree of suppression of antibody production dependen on the concentration and epitone density of the antigen and on the duration of exposure of cells to it, and was no attributable to absorption of secreted antibody by cell-bound antigen. Comparably substituted DNP conjugates of F(ab')2 and intact globulins were equally inhibitory. The inhibition of antibody synthesis by DNP-BGG was reversible following removal of the antigen. This phenomenon is similar in many respects to the antigen-induced blockade of normal antibody-secreting cells, and provides a valuable model system for analyzing the mechanisms of antigen-mediated cellular inactivation.

Animals↗

Antigen-antibody complexes suppress antibody production by mouse plasmacytoma cells in vitro.

Preformed complexes of 2,4-dinitrophenylated keyhole limpet hemocyanin (DNP-KLH) and anti-DNP or anti-KLH antibodies selectively, suppressed the production of anti-DNP IgA by the plasmacytoma cell line, MOPC 315, in vitro. Compexes made with DNP8.5KLH (8.5 moles DNP/10(5) daltons carrier) inhibited the secretion of IgA but not its synthesis, whereas complexes prepared with the more highly substituted DNP20KLH inhibited synthesis as well. Moreover, complexes of DNP-KLH and anti-DNP F(ab')2 fragments were as suppressive as those made with IgG antibodies, suggesting that the mode of presentation of antigenic determinants and not surface Fe receptors may play a major role in this phenomenon.

Animals↗

A search for hapten-binding mouse plasmacytoma proteins.

Six hundred and twelve mouse plasmacytomas were screened for hapten binding by using eleven different bacteriophage-hapten conjugates (phage T4 conjugated with haptens NP, NIP, DIP, DNP,BOC-ABA-Tyr, ABA-NP, ABA-MIP, ABS-HOP, PAB-HOP, penicillin G, cloxacillin). Fifteen ascites fluids (2.4%) inactivated at least one of the phage conjugates at a high dilution indicating binding. The specificity of these reactions was studied by titrating one ascites fluid with phage conjugates carring unrelated haptens, and by inhibiting the phage inactivation with free haptens. Of the 15 myeloma proteins, 10 had high titers (at least 30 times higher than the ascites fluid background) with the NIP-cap phage or the NP-cap phage or both. Four had high titers with the DNP-cap phage and one with the ABA-MIP phage. Thirteen of the 15 myeloma proteins were IgA, one was IgM and one IgG2b.

Animals↗

Cytotoxic T lymphocyte lines reactive against murine plasmacytoma antigens: dissociation of cytotoxicity and Lyt-2 expression.

The relationship between cell surface antigen expression and function in cytotoxic T cells directed against a non-H-2-restricted plasmacytoma antigen was examined using Lyt-2- variants of a continuous T cell line. This cytotoxic cell line originally had expressed Lyt-2 on all the cells as detected by flow microfluorometry, but after several months of culture, Lyt-2- variants spontaneously developed. Using cell sorting and limiting dilution cloning, Lyt-2- and Lyt-2+ cell lines were obtained, cultured and analyzed. These analyses indicated that such cytotoxic cells had similar activity regardless of Lyt-2 phenotype. This observation supports the concept that the Lyt-2 molecule is not obligatory for recognition and killing by cytotoxic T cells and emphasizes the need to clarify the precise relationship between cell surface phenotype and T cell function.

Animals↗

Evidence for a T suppressor cell-inducing antigenic determinant shared by ADJ-PC-5 plasmacytoma and syngeneic BALB/c spleen cells.

The BALB/c plasmacytoma ADJ-PC-5 induces in early stages of tumorigenesis specific T suppressor (Ts) cells apparently as the first reaction of the immune system towards the growing tumor. In attempts to apply the concept of early induction of Ts cells in neoplasia for the induction of tolerance to allografts we have tried to induce Ts cells against alloantigens by injecting allogeneic spleen cells in doses increasing exponentially from 10 to 10(5) cells/mouse. Experiments using various strain combinations failed to demonstrate induction of specific Ts cells by this procedure. To explain the apparent discrepancy between these and the tumor data the capacity of the ADJ-PC-5 tumor cells to induce Ts cells in allogeneic combinations was analyzed. ADJ-PC-5 cells are capable of inducing specific Ts cells in CBA/J mice. These Ts cells specifically suppress the induction of a primary cytotoxic T cell response of CBA/J spleen cells against BALB/c, BALB.B and (BALB/c X C57BL/6)F1 cells but not one against B10.D2 or C57BL/10 target cells. The ADJ-PC-5-induced CBA/J Ts cells have been further analyzed using a panel of different target or responder cells. From these experiments the following conclusions can be drawn: the CBA/J Ts cells are specific for an antigen which is shared by ADJ-PC-5 and normal BALB/c spleen cells. The antigen in question is not coded for by the H-2d major histocompatibility complex. The data suggest that the Ts cell-inducing antigen on ADJ-PC-5 tumor cells is not a tumor associated neoantigen but a self antigen also present on normal BALB/c lymphoid cells.

Animals↗

Interleukin-HP1-related hybridoma and plasmacytoma growth factors induced by lipopolysaccharide in vivo.

Serum of lipopolysaccharide (LPS)-treated mice was found to support the growth of interleukin-HP1 (HP1)-dependent hybridoma and plasmacytoma cell lines. This growth-promoting activity, which was undetectable in normal serum, rose more than 1000-fold within 2 h after i.v. injection of the toxin and disappeared in less than 1 day. It could be traced to a single component, which behaved like HP1 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and reverse phase high performance liquid chromatography, and was completely inhibited by a rabbit anti-HP1 antiserum. The LPS-induced factor was apparently not of T cell origin, as indicated by the strong activity found in the serum of LPS-treated nude mice. In vitro, LPS also considerably enhanced the production by macrophages of a factor with similar characteristics.

Animals↗

High-affinity binding sites for human 26-kDa protein (interleukin 6, B cell stimulatory factor-2, human hybridoma plasmacytoma growth factor, interferon-beta 2), different from those of type I interferon (alpha, beta), on lymphoblastoid cells.

The human 26-kDa glycoprotein (26K) is a cytokine produced by lymphoid as well as nonlymphoid cells. So far it is active as (a) a potent hybridoma and plasmacytoma growth factor on mouse cells, (b) a B cell differentiating factor on human cells, and (c) (for some authors) an interferon (IFN). Internally labeled recombinant human 26K, obtained by translation of mRNA in Xenopus oocytes, was used to investigate the presence of specific receptors for this new cytokine and to analyze its binding to responsive cells. The results indicate that (a) the 26K-responsive human lymphoblastoid CESS cells express about 1500 high-affinity (Kd = 30 pM) binding sites for this cytokine, (b) this binding is not competed for by interleukin (IL)1, IL2, tumor necrosis factor (TNF), IFN-alpha 2, IFN-beta or IFN-gamma, and (c) these 26K-binding sites are different from the classical type I (alpha-beta) IFN receptors by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Binding Sites↗

Location of Myc, Igh, and Igk on Robertsonian fusion chromosomes is inconsequential for Myc translocations and plasmacytoma development in mice, but Rb(6.15)-carrying tumors prefer Igk-Myc inversions over translocations.

The location of the Myc and immunoglobulin (Ig) loci on metacentric Robertsonian (Rb) fusion chromosomes may affect the development of mouse plasmacytomas (Pcts) by changing the probability with which chromosomal Myc-Ig translocations occur. To test this hypothesis, we induced Pcts in BALB/c (C) mice that carried Rb(4.12) and/or Rb(6.15) chromosomes. The Rb mice developed Pcts (n = 198) with similar onset and incidence to that in the inbred C mice. Karyotyping of 70 Rb-carrying Pcts demonstrated that in these tumors, just as in their counterparts in inbred C mice, the Igh heavy-chain locus was translocated with Myc more often than was the Igk light-chain locus. Pcts harboring Igh or Igk on normal and Rb chromosomes showed no bias toward either in generating Myc translocations. These findings indicated that the location of Myc, Igh, and Igk on normal or Rb chromosomes is inconsequential for Myc translocation and Pct development. In contrast, in Rb(6.15) mice, in which chromosomal inversions competed with chromosomal translocations for Igk-Myc juxtapositions, the former occurred more frequently than the latter in the resulting Pcts. This suggested that spatial proximity of Igk and Myc on the same chromosome facilitates the rearrangement of these loci. Myc translocation-dependent mouse Pct may provide a good model system for furthering our understanding of the relationship of higher-order genome organization in the interphase nucleus, origin of chromosomal translocations, and development of cancer.

Animals↗

Extraosseous IL-6 transgenic mouse plasmacytoma sometimes lacks Myc-activating chromosomal translocation.

The cellular oncogene MYC and plasma cell growth, differentiation, and survival factor IL-6 play critical roles in the natural history of human plasma cell neoplasms such as multiple myeloma (MM). Myc and IL-6 also are at the center of neoplastic plasma cell transformation in BALB/c mice that carry a human IL-6 transgene and, therefore, predictably develop plasmacytomas (PCTs). We showed previously that, much like advanced MM or human myeloma cell lines (HMCLs), in which MYC is frequently deregulated in cis because of complex cytogenetic aberrations juxtaposing MYC to immunoglobulin enhancers, IL-6 transgenic PCTs commonly deregulate Myc in cis by chromosomal translocation, predominantly T(12;15)(Igh-Myc). In this article, we show that, analogous to primary MM in which MYC is mostly deregulated in trans by signaling pathways converging at the MYC promoter, IL-6 transgenic PCTs sometimes develop in the absence of Myc translocations, thus activating Myc in trans. We present cytogenetic and molecular evidence on two IL-6 transgenic PCTs that contained overexpressed Myc protein but lacked T(12;15)(Igh-Myc) and two related Myc--deregulating translocations that juxtapose Myc to immunoglobulin light-chain instead of heavy-chain enhancers: T(6;15)(Igkappa-Pvt1) and T(15;16)(Pvt1-Iglambda). We conclude that Myc translocations are not strictly required for IL-6-driven PCT development in mice. IL-6 transgenic PCTs may provide a valuable model system for elucidating both trans and cis mechanisms of Myc deregulation of great relevance for MYC deregulation in human MM.

Animals↗

Juxtaposition of N-myc and Ig kappa through a reciprocal t(6;12) translocation in a mouse plasmacytoma.

Nearly all mouse plasmacytomas (MPCs) carry an Ig/myc translocation. Any one of the three Ig loci may participate, while the myc contribution has been limited to c-myc, excluding other members of the myc gene family. The same is true for the other two known Ig/myc translocation-carrying tumors, Burkitt's lymphoma and rat immunocytoma. It is believed that the Ig/myc juxtaposition plays a decisive, rate limiting role in the genesis of the three tumors, acting through the constitutive activation of myc that makes it refractory to normal regulation. Here we describe the molecular analysis of a unique t(6;12)(CI;B) translocation that we previously identified in an exceptional MPC that expressed N-myc but not c-myc. We now show that the translocation led to the juxtaposition of N-myc and Ig kappa. This is the first case of an Ig/myc-carrying tumor that involves N-myc rather than c-myc. These findings suggest that the translocation may already have occurred at the pro- or pre-B cell stage at which N-myc is open for transcription. According to this interpretation, constitutive activation of N-myc would suppress the expression of c-myc, but would not interfere with the differentiation of the pro-B cell into a fully mature plasma cell. Its tumorigenic influence would become manifest only at the time when the cell would normally be programmed to leave the cycling compartment, in connection with its terminal differentiation.

Animals↗

Extramedullary plasmacytoma of the parotid.

Primary extramedullary plasmacytoma (PEMP) is a tumor of atypical neoplastic cells that arise outside the bone marrow in patients without clinical evidence of existing multiple myeloma. These rare tumors, which can occur in virtually any part of the body, have shown a clear predilection for the head and neck. Yet despite the fact that nearly 80% of these tumors can be found in the upper respiratory tract or oral cavity, their involvement in the parotid is singularly rare. The clinical behavior of this tumor is not yet well-defined, and local recurrence, distant metastasis, and transformation to multiple myeloma have all been reported. Since the first case of parotid PEMP was reported in 1965, 8 additional cases have been noted in the literature. This is the 9th case of PEMP of the parotid to be described.

Humans↗

Immunoperoxidase characterization of extramedullary plasmacytoma of the head and neck.

A retrospective analysis of 18 cases of extramedullary plasmacytoma (EMP) was done to characterize the type of immunoglobulin being synthesized by the neoplastic cells. The immunoperoxidase stain can be performed on previously fixed tissue and offers a means of predicting the likelihood of progression to multiple myeloma (MM). Tumors producing IgG make up the majority of cases of EMP in the literature and only 9% have progressed to MM. Smaller numbers of tumors producing other immunoglobulin classes have been studied, but it is clear that their prognosis is much more grave.

Adult↗