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Localization of genes coding for cytokines and their receptors correlates frequently with breakpoints of chromosome aberrations in leukemogenesis and particular clinical and hematologic symptoms. In some cases a rearrangement of these genes and its relationship with disease course were proved.
This study establishes the prevalence of Human Gene Mapping 11 (HGM11) chromosome abnormalities in bone marrow (BM) samples from 3,996 patients with malignant hematologic disorders. Examination of the karyotype of the stemline in these patients showed that 71.6% had one abnormality and 26.4% had two or more; the remaining 2.1% had two different abnormal clones. We observed 9,431 chromosome abnormalities, of which 56% were structural and 44% numeric, but these figures varied slightly with karyotype complexity. Because the HGM11 committee studied published cases with a single chromosome abnormality to identify potential "primary anomalies," we examined the karyotype from our 2,860 patients with a single abnormality in their stemline. We observed all but 12 of the 34 HGM11 numeric abnormalities. Except for 21 patients with a +Y, we did not observe two or more patients with any non-HGM11 numeric abnormality. We observed 91 of the 124 HGM11 structural abnormalities and noted 6 that were not listed by HGM11, and each of these occurred in two or more patients. Among patients with two abnormal clones, 34% had a t(9;22)(q34;q11), del(20)(q11q13), or +8. In 50% of the males with two abnormal clones, one of the clones was -Y. We attempted to create a reference table that lists HGM11 abnormalities in hematologic disorders and their frequency in our series, the reported associated disorders, and photographs of representative chromosome abnormalities.
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An incidence of up to 30% of systemic fungal infections at autopsy, and difficulties in diagnosing systemic mycosis antemortem, have led to the empiric use of amphotericin B in patients with hematological malignancies. Routine empiric anti-fungal treatment was initiated at our institution in 1982. Amphotericin B and initially for 3 days flucytosine was given to granulocytopenic patients with unremitting (after 48-72 h) or recurrent fever during antibiotic treatment, or with newly detected pulmonary infiltrates, sinusitis, and skin and retinal lesions suggestive of fungal infection. With this approach the rate of systemic fungal infections decreased from 10% to 4% (p less than 0.02). The reduction was most prominent in patients with acute myelogenous leukemia, where fungal infections decreased from 16% to 4% (p less than 0.025).
Beta 2 microglobulin is a low molecular weight protein integrating the light chain HLA antigens. Its serum concentration is increased in different neoplasias and in renal failure. Using solid phase RIA we determined the concentration of beta 2 microglobulin in plasma and spinal fluid of 57 healthy individuals and patients with hematologic neoplasia. Serum levels were 1.34 +/- 0.34 mg/l and spinal fluid levels were 1.3 +/- 0.7 mg/l in healthy subjects. Serum levels in 29 patients with myeloma was 7.51 mg/l, significantly higher in those with renal failure (12.35 mg/l) compared to those without (4.54). In 30 patients with non-Hodgkin lymphoma the mean serum levels were 2.90 mg/l, significantly greater in those with active disease (3.18) than in those with remission (1.5). No difference was found according to the degree of malignancy. Patients with acute lymphatic leukemia had elevated values of beta 2 microglobulin while the disease was active (3.37 mg/l), decreasing to normal levels after remission (1.79 mg/l). Spinal fluid levels of beta 2 microglobulin were elevated only in patients with central nervous system involvement. Our results indicate that serum levels of beta 2 microglobulin are helpful in patients with hematologic neoplasia in assessing the activity of the disease and tumor mass, especially in multiple myeloma.
Several immunohistochemical methods are now available for the staining of neoplastic cells in tissue sections. The authors have found that the alkaline phosphatase-anti-alkaline phosphatase (APAAP) method is sensitive and reliable. Murine monoclonal or nonmurine polyclonal antibodies can be used to label a variety of membranous and/or cellular constituents in tissues that have been routinely processed in a histopathology laboratory. The monoclonal antibody against leukocyte common antigen (CD45) can be used to differentiate hematologic from nonhematologic tumors. Monoclonal antibodies (L26, LN1, LN2, LN3, MB1, MB2) label B-cell lymphomas, whereas other monoclonal antibodies (UCHL1, MT1) more characteristically stain T-cell lymphomas. Polyclonal antibodies against CD3 specifically mark neoplastic cells from T-cell lymphomas and leukemias but as yet are not commercially available. Monoclonal antibodies Leu-M1 (CD15), Ber H2 (Ki-1; CD30), and LN2 label Reed-Sternberg cells from most cases of nodular sclerosis, mixed cellularity, and lymphocyte-depleted Hodgkin's disease. Monoclonal antibodies Mac 387, KP1 (CD68), and NP57 (antielastase), as well as polyclonal antibodies against lysozyme, help identify subtypes of acute myeloid leukemia and extramedullary myeloid cell tumors. Although there are now excellent reagents ready for use, there is still a significant need for more lineage-specific (particularly against CD epitopes) monoclonal antibodies capable of labeling neoplastic cells in paraffin-embedded tissue sections from patients with hematologic malignancies.
Interferons are new and effective agents in the treatment of various haematological neoplasias. Alpha-interferon (natural or recombinant) has a high efficacy (90% response rate) in hairy cell leukaemia. Complete remissions are, however, rare and definite cure of the disease is unlikely. Alpha-interferon induces haematological remissions in about two thirds of patients with chronic myeloid leukaemia and leads to a reduction in Philadelphia chromosome in about 40% of patients. It is uncertain, however, whether this treatment will actually prolong the life of these patients as compared with conventional treatment. Alpha-interferon has a beneficial effect in some patients with low malignant non-Hodgkin lymphomas (in particular follicular lymphomas). The response rate in myeloma is rather small (20%). Gamma-interferon is not effective in hairy cell leukaemia, non-Hodgkin lymphoma and myeloma. It is, however, of some efficacy in chronic myeloid leukaemia (the response rate in lower than with alpha-interferon) and possibly has some effect in patients with acute myeloid leukaemia and myelodysplastic syndromes. The toxicity of interferons (alpha and gamma) consists of an influenza-like syndrome during the first days of treatment. Low doses of alpha-interferon show virtually no long-term toxicity. However, bone and muscular pain is sometimes dose-limiting with intermediate doses (5 to 15 million units) of alpha-interferon.
This report aims to review briefly the current status of treatment of haematological malignancies with interferon-alpha (IFN-alpha). Overall hairy cell leukemia and chronic myelogenous leukemia appear to be most sensitive to IFN-alpha. We started to investigate, how interferon exerts its antileukemic activity and in which way interferon therapy can be optimized. Our preliminary results fail to support the view of interferon mediated enhancement of host responses. They rather indicate direct effects of IFN on leukemic cells in vitro. By means of IFN-dependent biological markers (e.g. beta-2-microglobulin, neopterin) clinically effective but atoxic doses of IFN-alpha could be defined for HCL and CML. In final conclusion, the recent studies on the clinical efficacy of IFN-alpha revealed its potent antitumoral effect in hematological malignancies. However, the further proof of the potential benefit of IFN treatment versus conventional therapeutic strategies remains to be elucidated.
Circulating immune complexes (CIC) in human cancer are known to be very heterogeneous in size and composition. In 95 staged malignant melanoma patients and 71 individuals with leukemia and lymphoma, this heterogeneity was analyzed biochemically in sera positive for CIC. CICs were measured by a multiassay system and individual complexes were isolated and analyzed by immunological and biochemical methods. Analyses of sera from 100 normal individuals, from 25 rheumatoid women, and a group of 12 laboratory staff who work with human melanoma were included for comparison. Three basic patterns of complexes were identified circulating in the sera of the cancer patients. Type I are medium-sized (17-23S), complement-fixing complexes usually occurring in combinations. The prototype in melanoma contained IgG antibody and additional glycoprotein components and bound complement by the classical pathway. In hematological malignancies four subtypes could be identified depending on whether the antibody class was IgG or IgM, the nonimmunoglobulin component was glycoprotein or protein, and whether complement fixation occurred by the classical or alternate pathway. Type II complexes were noncomplement-fixing, medium-sized complexes (15-21S), which in melanoma contained IgG antibody and additional protein components. In the hematologic malignancies two subtypes could be identified depending on whether the antibody class was IgG or IgM. Both subtypes contained a glycoprotein nonimmunoglobulin component. Both melanoma and hematologic tumors had type III heavy complexes (36-44S) which were noncomplement-fixing and contained only immunoglobulin components, either IgG-IgG or IgM-IgG. As expected the rheumatoid arthritis patients frequently had both 7S and 21-23S CICs containing IgG as well as IgM rheumatoid factor with complement fixation via the classical pathway. No CICs were detected in normal young men and women (20-30 years); a few individuals in middle age (31-50 years) had small (7-11S) CICs which bound complement by the classical pathway and contained IgG and a protein nonimmunoglobulin component. The frequency of these 7S complexes increased with advancing age, with the appearance of 23S IgG-IgG or IgM-IgG complexes. IgG antibodies from only the melanoma patients reacted with cytoplasmic components of fresh melanoma cells, except the laboratory workers where all of their isolated CIC antibodies also reacted with melanoma cells. Thus the heterogeneity of complexes in melanoma is not random, but can be classified into three basic biochemical patterns. The hematologic group provides a slightly richer variation of subtypes within this basic scheme.
CONTEXT: The epidural space is a well-known, albeit uncommon, location for lymphomatous involvement, estimated to occur in less than 3% of all systemic lymphomas. Initial presentation of the patient with disease in this site (i.e. primary spinal epidural lymphoma) has been considered to be "rare". When it has been reported, many studies have emphasized the occurrence of aggressive lymphomas with a poor prognosis. DESIGN: A 10-year retrospective search of our files generated 7 patients who presented initially with back pain, incontinence and/or lower extremity weakness, and by neuroimaging studies were found to have masses causing spinal cord compression syndromes necessitating neurosurgical intervention. RESULTS: The 7 patients included 4 males and 3 females with thoracic and lumbar epidural masses. Tumor types included high-grade non-Hodgkin lymphoma, B cell type (n = 4), indolent B cell lymphoma (n = 1), nodular sclerosing Hodgkin lymphoma (n = 1) and plasmacytoma (n = 1). Advanced disease (stage 4) was subsequently identified in all 7 patients. Despite this, survival varied greatly with therapy, from 3 weeks to almost 6 years, underscoring the need for correct classification of the lymphoma in order to optimize chemotherapeutic choices. The epidural space was the site of presentation of disease in 4% of all lymphomas diagnosed at our institution. CONCLUSIONS: Combining all reports in the literature, epidural presentation of lymphoma is not rare. Epidural lymphomas are distinct from both primary central nervous system lymphomas and from primary dural lymphomas. A broad range of systemic hematological tumor types can present as epidural masses. A full work-up for lymphoma classification may only be possible from the tissues received at the time of the neurosurgical decompression or biopsy procedure.
An 18-year-old male with Klinefelter's syndrome presented with a mature teratoma of the mediastinum. He was treated with debulking surgery and brief cisplatin-based chemotherapy. Ten years later, he presented with paraplegia and was found to have an isolated epidural mass. The mass was composed of mature histiocytoid cells reminiscent of those seen in malignant histiocytosis. There was no evidence of medullary dissemination and there was no evidence of recurrence of the germ cell tumor. He received local radiation therapy and a single course of leukemic induction. He remains well 4 years later. This case represents a localized variant of the diffuse histiocytic malignancies associated with malignant mediastinal germ cell tumors.
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Fragile sites are specific regions of chromosomes prone to breakage when cells are cultured under specific conditions. These sites are divided into two classes: common and rare. Common fragile sites are expressed in all individuals at different frequencies, whereas rare ones are found only in certain individuals. Common and rare fragile sites have been shown to display a number of characteristics of instability being preferential sites for chromosomal deletions, duplications, and rearrangements. Moreover, a majority of mapped oncogenes are located at or near these fragile sites. These observations have led to the suggestion that both classes of fragile sites may play a significant role in chromosomal rearrangements involved in oncogene activation or tumor supressor gene inactivation. For these reasons, involvement of common and rare fragile sites and their relevance to specific chromosome breakpoints in cancer have received much attention. In this study, which reports on the cytogenetic findings obtained from 256 patients with chronic myelocytic leukemia, 103 with acute myelocytic leukemia, 40 with acute lymphocytic leukemia, 33 with myelodysplastic syndrome, we documented the fragile sites involved in chromosomal aberrations involving oncogenes, tumor supressor genes, and other known genes important in cell cycle regulation localized at these sites.
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The association of systemic lupus erythematosus (SLE) and B-cell malignancy is widely reported in the literature. Here we report nine cases of concurrent of SLE or discoid lupus erythematosus (DLE) and lymphoma or plasma cell disorder. A MEDLINE search was done using the keywords, 'SLE' and 'lymphoma' and the characteristics of all identified cases were summarized and analyzed, along with data from our own cases. Numerous variants of B-cell malignancies were encountered in these patients. B-cell malignancy occurs after the diagnosis and treatment of SLE in most reported cases, although it may precede SLE, or occur synchronously with it. The age at onset of the B-cell neoplasm in SLE patients is similar to that in the general population. Mortality in patients with both diseases is associated with progressive B-cell neoplasm, sepsis secondary to either disease, or both. B-cell malignancy and SLE seem to run independent clinical courses rather than being affected by each other. The use of immunosuppressive drugs is common in patients with SLE diagnosed prior to B-cell lymphoma, arguing that the effect of immunosuppression on the pathogenesis of lymphoma can not be excluded. Three areas worthy of study regarding the probable mechanisms for the occurrence of SLE and B-cell malignancies are discussed. A tumor suppressor gene PTEN may link the two disorders via a defective apoptosis pathway to eliminate hyperactive B and T cells in SLE. The accumulation of clonally expanded hyperactive B-cells that recognize self-antigens in the lymph nodes of SLE may predispose these B-cells to DNA breaks, facilitating tumorigenesis. Lastly, EBV infection, found to have a high prevalence in SLE patients, may serve as a common etiological factor in both disorders.