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Leukemic reticuloendotheliosis: report of a case with peripheral blood remission on androgen therapy.

Leukemic reticuloendotheliosis (LRE) has been generally considered to be poorly responsive to therapy other than splenectomy. The patient presented below developed a complete peripheral blood remission after prolonged therapy with an androgen (oxymetholone). There is very little published experience with androgen therapy in LRE. The experience with this patient suggests that androgens may produce a clinical remission by inducing significant improvement in the peripheral blood in some patients with this disease.

Adult↗

Malignant lymphoma simulating leukemic reticuloendotheliosis: a clinicopathologic study of ten cases.

We have studied ten patients with a lymphoproliferative disorder characterized by massive splenomegaly; minimal lymphadenopathy; varying degrees of blood cytopenias; circulating atypical lymphoid cells frequently with "hairy" cytoplasm; monoclonal serum paraprotein; and tartrate-resistant acid phosphatase reactivity in the tumor cells of five patients tested. Although the clinical and laboratory features in most cases prompted a clinical diagnosis of "hairy cell leukemia" (HCL), histologic, ultrastructural and immunohistologic studies of multiple organs revealed distinctive features recognizably different from leukemic reticuloendotheliosis (LRE). Because this B lymphocyte proliferation may be mistaken for LRE in cases where careful histologic study is not performed, it may be responsible in part for the conflicting data in attempts to characterize the cell of origin of the latter disease. Clinical and experimental data in HCL must be questioned if they do not include histopathologic confirmation of the diagnosis.

Acid Phosphatase↗

Coexistence of leukemic reticuloendotheliosis and histiocytic lymphoma: a case report.

A 65-year-old woman had pancytopenia, splenomegaly, and an inaspirable bone marrow. Diagnostic evaluation demonstrated that she had both leukemic reticuloendotheliosis (LRE), or hairy cell leukemia, and an additional lympho-reticular neoplasm, most likely a "histiocytic" lymphoma. The diagnosis of LRE was based on the histopathology of spleen tissue and of a bone marrow biopsy specimen. The diagnosis of diffuse "histiocytic" lymphoma was based on the histopathology of a splenic hilar and a mesenteric lymph node, tumor nodules in the kidney and spleen, and tissue from a mass obstructing a ureter. This is the first well-documented association of a second lympho-reticular neoplasm with LRE. Even relatively gently treatment of the "histiocytic" lymphoma resulted in fatal pancytopenia, illustrating the restricitons on therapy imposed by the marrow impairment due to the LRE.

Aged↗

Comparison of tartrate-resistant acid phosphatase in normal mouse tissues to that in the reticulum cells of leukemic reticuloendotheliosis.

A strong activity of the tartrate-resistant acid phosphatase, isoenzyme 5b, was observed in mouse spleen. The enzyme of the mouse spleen had similar electrophoretic mobility and related antigenicity to that of the reticulum cells of leukemic reticuloendotheliosis. Enzyme histochemical studies showed many non-phagocytic cells with strong tartrate-resistant acid phosphatase in spleen. The data suggest that mouse tissue is a good animal model to study the normal cell type with strong tartrate-resistant acid phosphatase.

Acid Phosphatase↗

A case of leukemic reticuloendotheliosis responding to oxymetholone.

A 63-year-old man presented with fever, easy bruisability, splenomegaly and pancytopenia. Bone marrow aspiration was unsuccessful, and marrow biopsy revealed crowding by sheets of mononuclear cells; a diagnosis of leukemic reticuloendotheliosis (LRE) was made and the patient underwent splenectomy. There was no hematologic improvement, and the patient continued to have a significant requirement for erythrocytes and platelet transfusions. Within two months of beginning oxymetholone therapy (50 mg orally three times a day) the patient's platelet count had normalized, followed by improved erythrocyte and leukocyte counts. When the drug was discontinued, the peripheral blood counts deteriorated drastically; he again demonstrated hematologic improvement when oxymetholone therapy was reinstated. We feel that by demonstrating a hematologic response to oxymetholone, relapse when it was withdrawn, and another remission upon readministration, that we have provided stronger evidence than previously reported for the efficacy of this drug in LRE.

Adult↗

Surface immunoglobulins and receptor sites for aggregated IgG on leukemic reticuloendotheliosis cells.

On blood lymph nodes and spleen cells of 4 patients with leukemic reticuloendotheliosis (LR) the binding of 125-J-labelled IgG aggregates as well as binding of 125J-labeled anti immunoglobulin sera was studied. Moreover the capacity to form spontaneous rosettes with sheep red blood cells to bind immune complement complexes as well as the proliferative response in the presence of PHA were investigated. On the surface of hairy cells a variety of immunoglobulins were demonstrable. IgG of both types was found to be the predominant surface bound immunoglobulin and evidence was obtained, that these antibodies were adsorbed from the serum via Fc-receptors. In all LR-cases the percentages of T-cell rosettes as well as the PHA responses were decreased when compared with the normal controls. The numbers of immune complement complex binding cells were in the range of the normal controls. Results are discussed with respect to the origin of hairy cells in LR.

Adult↗

Spontaneous rupture of spleen in leukemic reticuloendotheliosis.

Leukemic reticuloendotheliosis, or "hairy cell leukemia," is a neoplasm of the reticuloendothelial system. It is characterized by the presence of many "hairy cells" in blood, marrow, lymph nodes, and spleen; by anemia, leukopenia, thrombocytopenia, and often, by massive splenomegaly. Three such patients with spontaneous rupture and one patient with multiple infarctions of the spleen all had spleens which were large, congested, and diffusely infiltrated by "hairy cells." The lacerations in all three ruptured spleens were located in areas of extensive infarction. Indications for splenectomy in this disease include hypersplenism, severe cytopenia, hemodilution, splenomegaly with severe pressure symptoms, massive splenomegaly, rupture, or infarction.

Adenocarcinoma↗

Studies of intracellular distribution of acid phosphatase 5 in the spleen cells of leukemic reticuloendotheliosis by isopycnic gradient centrifugation.

A fresh spleen sample obtained from a patient with leukemic reticuloendotheliosis was homogenized and subjected to centrifugation on a sucrose density gradient. A major portion of acid phosphatase band 5 was observed in the lysosome, confirming that the elevated phosphatase activity in the neoplastic spleen is a lysosomal enzyme. However, a significant amount of brand 5 was also observed in the microsome. The microsomal and lysosomal enzymes have different affinity to CM-cellulose. The relationship between lysosomal and microsomal enzymes has not been established.

Acid Phosphatase↗

Expression of the v-rel oncogene in reticuloendotheliosis virus-transformed fibroblasts.

Reticuloendotheliosis virus (REV-T) induces a rapidly fatal lymphoma in chickens through the expression of its oncogene, v-rel, REV-T also morphologically transforms avian fibroblasts in vitro. These transformed cells displayed limited anchorage-independent growth and reached higher saturation density than uninfected or REV-A-infected fibroblasts. Morphologically transformed fibroblasts were tumorigenic when injected into the wing web of chickens. In transformed fibroblasts, the v-rel oncogene was expressed as a 57 kDa phosphoprotein with a half-life of 2 to 4 hr. A cellular phosphoprotein of about 40 kDa was also observed in immunoprecipitates of transformed fibroblasts. The subcellular location of the v-rel-encoded protein was determined using cell fractionation procedures and immunofluorescent staining. In acutely infected, nontransformed fibroblasts, pp57v-rel was associated with the nuclear region, but in morphologically transformed cells the v-rel protein was found in the cytoplasm. These observations suggest that the expression of the v-rel oncogene is insufficient for transformation and that the cellular localization of this transforming protein to the cytoplasm may be required for the progression to an altered cell phenotype in avian fibroblasts.

Alpharetrovirus↗

The v-rel oncogene of avian reticuloendotheliosis virus transforms immature and mature lymphoid cells of the B cell lineage in vitro.

Heavy chain gene rearrangements were analyzed in 67 independently derived reticuloendotheliosis virus (REV-T) transformed avian lymphoid cell lines. The status of the heavy chain genes in these REV-T transformed cell lines was determined, in part, by the age of the chicken whose spleen cells were transformed. Cell lines derived by the in vitro transformation of splenic lymphocytes obtained from embryos did not contain heavy chain gene Ig rearrangements. By contrast, splenic lymphocytes transformed by REV-T obtained from birds 1 week or older generally exhibited heavy chain gene rearrangements. The REV-T transformed lymphoid cell lines with heavy chain rearrangements also had light chain gene rearrangements. The Ig gene rearrangements in REV-T transformed cells were functional. The majority of the cells which had heavy chain rearrangements expressed a 2.2-kb mu transcript and synthesized and secreted IgM. An REV-T transformant was also identified which produced IgG, suggesting that v-rel can transform a terminally differentiated cell. Irrespective of their Ig chain gene status the REV-T transformed cell lines expressed variable amounts of some but not all normal B cell-specific markers and failed to express T cell markers. All the cell lines analyzed expressed the B-L (Ia-like) antigen as well as a common leukocyte antigen. Based on the expression of these surface molecules, the transformants with or without Ig gene rearrangements all appear to be committed to the B cell pathway.

Alleles↗

Combined immunodeficiency and reticuloendotheliosis with eosinophilia.

A generalized erythematous scaly rash, alopecia, lympadenopathy, and hepatosplemonegaly developed in an infant girl during the first 6 weeks of life. Repeated bacterial and fungal infections, persistent diarrhea, and generalized wasting complicated the course of her illness, and death occurred at 5 1/2 months of age. Lymph node architecture was completely obliterated by histiocytes and eosinophils; no plasma cells or germinal centers were present. Both humoral and cellular immune systems were severely but not completely impaired. Familial reticuloendotheliosis with eosinophilia is, in some cases, associated with combined immune deficiency.

Antibody Formation↗

The cytotoxic T lymphocyte response in reticuloendotheliosis virus-infected chickens is mediated by alpha beta and not by gamma delta T cells.

We induced a virus-specific cytotoxic T lymphocyte (CTL) response in B2 chickens by i.v. inoculation with 100 TCID50 of the reticuloendotheliosis virus (REV). Chickens were sacrificed 7 days after the infection and cytotoxic activity of the spleen cells against various target cells was assayed in a 4 h 51Cr-release assay at an effector to target ratio of 100:1. In addition, T cell receptor (TCR) alpha beta and TCR gamma delta cells were negatively selected from the REV-immune spleen cells and used as effector cells against REV-infected B2 target cells. (On average 40% of spleen T cells express TCR gamma delta in the chicken.) By inhibition of the cytotoxic activity of the immune spleen cells against REV-infected syngeneic target cells with monoclonal antibodies specific for chicken CD3 and CD8 molecules, the effector cells could be identified as CD8+ T cells. The cytotoxic activity was MHC-restricted, as only syngeneic but not allogeneic REV-infected target cells were lysed by REV-immune spleen cells, and virus-specific, as no cytotoxic activity could be found using uninfected syngeneic target cells. When assaying the activity of the negatively selected, > 98% pure alpha beta and gamma delta T cells, it was found that alpha beta T cells exerted virus-specific CTL activity ranging from 26 to 62% specific 51Cr-release, while gamma delta T cells showed only 2-4% 51Cr-release. These data indicate that REV-specific CTL response is mediated by alpha beta T cells and that gamma delta T cells are not involved in virus-specific CTL activity in the spleen of REV-infected chickens.

Animals↗

Nondefective spleen necrosis virus-derived vectors define the upper size limit for packaging reticuloendotheliosis viruses.

We constructed a nondefective retrovirus vector based on spleen necrosis virus (SNV), a replication-competent reticuloendotheliosis virus. We introduced different DNA sequences into this vector and studied the ability of the resulting viruses to replicate in chicken embryo fibroblasts. The replication efficiency of SNV-derived viruses decreased with increasing virus size. Viruses larger than 9.4 kilobases (kb) were rapidly overgrown by replication-competent deletion mutants. The size restriction for the efficient replication of nondefective SNV-derived viruses prevented the production of viruses larger than 10.0 kb. Analysis of the kinetics of virus particle release indicated that the size restriction occurred during virus encapsidation.

Capsid↗

Use of the bone marrow imprint in the diagnosis of leukemic reticuloendotheliosis ("hairy cell leukemia").

Leukemic reticuloendotheliosis is a distinct entity, often misdiagnosed as chronic lymphocytic leukemia or lymphoma. The neoplastic cells have a specific tartrate-resistant acid phosphatase isoenzyme by which the diagnosis may be secured. Most individuals are leukopenic, and when, as in our case, rare or no circulating cells with tartrate-resistant acid phosphatase activity are found in the peripheral blood, an alternate site must be sought. Bone marrow aspirations often result in "dry taps," however, and cryostat sections of the bone marrow biopsy necessary to demonstrate tartrate-resistant acid phosphatase activity are involved and impractical to obtain for most laboratories. This report illustrates and recommends the simple technic of imprinting the core biopsy, which yields a satisfactory sample with which the specific cytochemical activity can be demonstrated.

Acid Phosphatase↗

Functional studies of hairy cell leukemia (leukemic reticuloendotheliosis).

Reports proposing that the cell or origin of "hairy cell" leukemia (leukemic reticuloendotheliosis) is a B lymphocyte have been based primarily on the presence of surface immunoglobulin markers, frequently in "cap" form. Most of the immunoglobulin markers in this series of patients with hairy cell leukemia were multiclass, but were present in cap form under conditions not usually inducing cap formation in normal or leukemic human lymphocytes. In five cases the authors were able to remove these surface immunoglobulins by trypsinization or overnight incubation in serum-free tissue-culture medium. There was no evidence of synthesis of surface immunoglobulins in these cases following incubation in serum-free tissue-culture medium; however, surface immunoglobulins could again be detected after subsequent reintroduction of these hairy cells into the patients' own sera. The peculiar cap formation could not be prevented with sodium azide, a standard inhibitor of cap formation. Phagocytized latex particles and neutral red dye produced similar caplike structures. These findings suggest that hairy cells readily adsorb and pinocytose circulating immunoglobulins, but do not synthesize them.

Azides↗

Phenotype of the hairy cells of leukemic reticuloendotheliosis defined by monoclonal antibodies.

Hairy cell populations of greater than 90 purity were prepared from six samples obtained from four patients with leukemic reticuloendotheliosis (LRE). These then were analyzed for surface immunoglobulin (SIg) and antigens specified by a panel of monoclonal antibodies. The hairy cells from all patients displayed SIg and antigens reactive with OKIa-1 and OKM-1 antibodies; these markers often were expressed simultaneously. T-cell-specific antigens were not displayed on the surface of hairy cells. The simultaneous expression of SIg and OKM-1 which ordinarily are unique for B cells or myeloid cells, respectively, suggests that hairy cells may represent an aberrant form of either cell type with defective regulation of antigen expression. It alternatively suggests the possibility that B cells and myeloid elements develop along a common pathway and that the hairy cell is a component of such a pathway.

Adult↗

'Hairy' cell leukaemia (leukaemic reticuloendotheliosis): a scanning electron microscopic study of eight cases.

Eight cases of 'hairy' cell leukaemia (leukaemic reticuloendotheliosis) were evaluated by scanning electron microscopy. The surface of critical-point-dried 'hairy' cells was characterized by prominent and exaggerated broad-based, ruffled membranes and scattered small clusters of stub-like microvilli. The surface morphology resembled that of normal and leukaemic monocytes, but differed from that of normal and leukaemic lymphocytes. Some cells with features of both lymphocytes and monocytes were difficult to categorize; the overall impression of the surface architecture of most 'hairy' cells suggests, however, that they are related to the monocytic series. From the examination of these cases it is evident that scanning electron microscopy may be used as a means of distinguishing chronic lymphocytic leukaemia from 'hairy' cell leukaemia on the basis of surface ultrastructure.

Cell Membrane↗

Fc receptor bearing 'hairy cells' of leukaemic reticuloendotheliosis bind soluble antigen--antibody complexes and adhere to immobilized complexes, but fail to mediate antibody dependent cellular cytotoxicity.

The majority of hairy cells from three patients with leukaemic reticuloendotheliosis were adherent cells bearing surface immunoglobulin, complement receptors, and Fc receptors. Highly purified populations of malignant hairy cells, which readily bound soluble antigen-antibody complexes in suspension and were able to adhere to immobilized antigen-antibody complexes, were examined for their ability to mediate ADCC. Two patients with greater than 90% FcR positive cells failed to mediate ADCC. When initially examined, a third patient, with fewer malignant cells, demonstrated a less marked impairment of cytolysis. When reexamined at a later date, this patient had an increased number of hairy cells and concomitantly demonstrated more impaired ADCC effector cell activity. Absorption of surface immunoglobulin bearing cells onto plastic surfaces coated with goat anti-human immunoglobulin resulted in a complete depletion of FcR, sIg positive, hairy cells. The remaining nonadherent fraction, containing 5.5% FcR positive, sIg negative cells, was able to mediate ADCC as effectively as the normal controls. These results indicate that although FcR bearing hairy cells readily bind soluble antigen-antibody complexes and adhere to immobilized complexes, they were unable to mediate ADCC.

Adult↗