Establishment and characterization of a human T-cell leukemia line (LALW-2) in nude mice.

Lymphoblasts from the peripheral blood of a 10-year-old boy who was treated for T-cell acute lymphoblastic leukemia were heterotransplanted intraocularly into nude mice. The resultant tumors and their metastases were serially passaged both intraocularly and subcutaneously in the mice. The mouse tumors closely resembled morphologically and cytochemically a human T-cell lymphoma. The primary cells, as well as cells from subsequent in vivo passages, were predominantly of a suppressor T-cell phenotype (OKT8-positive). No viral products were identified. Chromosome analysis revealed a near-diploid karyotype with a translocation between chromosomes 11 and 14. The tumorigenicity, morphology, cytochemistry, immunologic phenotype, and karyotypic pattern of the cells remained constant through six serial in vivo passages over a period of 10 months. This is the first report of direct heterotransplantation and long-term in vivo maintenance of primary human T-cells in immunologically unmanipulated nude mice.

B cell acute lymphocytic leukemia in adults. Clinical, morphologic, and immunologic findings.

Acute lymphocytic leukemia (ALL) is a heterogeneous group of disorders, clinically, immunologically, and pathologically. ALL of a B cell phenotype (B-ALL) is the least common. We have studied ten adult patients with B-ALL, none of whom had a tumor mass. The median age was 56 years (range, 30 to 90). A history of an altered immune state was noted in four cases: a distant history of Hashimoto's thyroiditis in one, pregnancy in one, and acquired immunodeficiency syndrome in two. Two patients presented with CNS involvement, and in two additional patients CNS leukemia developed during the course of disease. By the French-American-British (FAB) classification system, L3 leukemic morphology was present in nine, whereas L2 was present in one. Circulating leukemic blasts varied from less than 500/dL to greater than 15,000/dL. Eight patients were thrombocytopenic, and eight were anemic at presentation. Immunologic marker studies on leukemic blasts revealed monoclonal kappa light chain marking in nine and monoclonal lambda in one. Following chemotherapy, complete remission was achieved in three patients, two of whom experienced relapse within 9 months. The median survival for the group was 3 months, and only one patient experienced long-term, disease-free survival. We conclude that B-ALL in the adult presents with the classic L3 morphologic picture in the majority and is associated with extremely short survival.

Malignant lymphoma: cardiac involvement at initial presentation.

Malignant lymphoma rarely involves the heart at initial presentation. We have cared for nine cases in the past 8 years. The median age was 45 years (range, 27 to 68). Initial presenting symptoms included chest pain in four, gastrointestinal (GI) symptoms in three, and constitutional "B" symptoms in two. Echocardiography was the most useful noninvasive procedure, and was abnormal in the eight cases studied. Echocardiographic findings included pericardial effusion in six, and mass lesions within the heart in five. Morphologically, the lymphoma was high-grade small noncleaved in four, immunoblastic sarcoma in one, and diffuse large-cell type in four. Clinical staging workup revealed widely disseminated disease in seven. In spite of multiagent chemotherapy, survival was short (median, 1.5 months). Interestingly, four of these patients were homosexual or bisexual men, who fulfill the criteria for acquired immune deficiency syndrome (AIDS).

Radiation therapy for acquired immunodeficiency syndrome-related Kaposi's sarcoma.

Twenty-four patients with acquired immunodeficiency syndrome (AIDS) received 80 courses of radiation therapy for Kaposi's sarcoma (KS). Pain and other symptoms due to mass effects were well controlled, but KS lesions often persisted in irradiated sites. Acute radiation toxicity to doses of approximately 2,000 cGy in ten fractions to the oral cavity and/or the foot were significant and may limit the dose and the efficacy of radiotherapy in patients with the epidemic form of KS.

Results of initial lymph node biopsy in homosexual men with generalized lymphadenopathy.

Persistent, generalized lymphadenopathy (PGL) is considered part of the acquired immunodeficiency syndrome (AIDS)-related complex. The clinical course is usually benign, although some patients may evolve to AIDS. Characteristic features on lymph node biopsy have been described. Recently, large series of PGL have been reported in which many study patients have not undergone initial diagnostic biopsy. The value of such biopsy has been questioned. We report the clinical, pathologic, and laboratory findings in six homosexual men initially considered as potential candidates for study of the natural history of PGL. They were excluded by initial lymph node biopsy, which revealed small-cleaved lymphoma in two, focal Kaposi's sarcoma in two, disseminated mycobacterium tuberculosis in one, and histoplasma encapsulatum in one. The clinical and laboratory data from these six patients were compared with those from 34 patients with biopsy-proven PGL; no statistically significant difference in any prebiopsy clinical parameter was found. We conclude that initial lymph node biopsy may reveal changes other than reactive hyperplasia in homosexual men with generalized lymphadenopathy.

Human T-cell lymphotropic virus type III associated disorders. The spectrum in the heterosexual population.

Eleven heterosexual patients (nine women, two men) without classic risk factors for development of acquired immunodeficiency syndrome (AIDS) were seen between March 1983, and April 1985, and diagnosed as having AIDS (four), persistent, generalized lymphadenopathy (PGL) (four), or asymptomatic human T-cell lymphotropic virus type III (HTLV-III) carrier state (three). The clinical presentations and course of those with AIDS or PGL were similar to those reported in homosexual men with AIDS or PGL, with reversed T4/T8 ratio, and the presence of antibody to HTLV-III. Asymptomatic carriers had normal T4/T8 ratios, had an absence of HTLV-III antibodies, but had HTLV-III virus cultured from blood. We conclude that the heterosexual population, with or without history of sexual exposure to individuals at risk for AIDS, may develop a wide range of clinical manifestations secondary to HTLV-III, varying from AIDS to the asymptomatic carrier state.

Rectal lymphoma in homosexual men.

Lymphoma of the rectum is a rare tumor and in most studies is not separated from other lymphomas of the large intestine. We have recently examined four homosexual men with lymphoma presenting in the rectum. Symptoms included rectal bleeding in three, pain on defecation in two, and mucoid rectal discharge in two. Systemic "B" symptoms (ie, fever, night sweats, and/or weight loss), as well as a rectal mass, were present in all four. All were high-grade tumors, with B-cell immunoblastic sarcoma in two and small noncleaved Burkitt-like lymphoma in two. Intracytoplasmic immunoperoxidase staining revealed monoclonal kappa light chains in three tumors, whereas the fourth was nonstaining. Immunologic abnormalities were similar to those reported in patients with acquired immunodeficiency syndrome. Antibodies to human T-cell lymphotropic virus type III were found in the three cases tested, and retrovirus was cultured from lymphomatous tissue in one. Despite multiagent chemotherapy, two patients died within six months of diagnosis and a third has recently suffered relapse within the central nervous system.

B-cell lymphoma in two monogamous homosexual men.

Opportunistic infections and malignant neoplasms have been described in homosexual men in association with immunologic abnormalities. We observed the development of malignant B-cell lymphomas in two homosexual men who had had a monogamous relationship for two years. Patient 1 had an aggressive, monoclonal, small, noncleaved, non-Burkitt's lymphoma ("undifferentiated lymphoma"), associated with severe immunocompromise. Patient 2 manifested a monoclonal, small, cleaved, follicular center cell lymphoma, with a follicular pattern, two months later. No common acute infection was detected. Staining for Epstein-Barr nuclear antigen in malignant tissue was negative in the second patient. However, the possibility of a transmissible agent as a causative factor cannot be excluded, and further study of similar patients is warranted.

Functional outcome following spinal cord injury. A comparison of specialized spinal cord injury center vs general hospital short-term care.

The functional outcomes of 185 patients with spinal cord injuries undergoing rehabilitation who were initially treated in a specialized short-term care unit (center patients) were compared with those of 153 patients initially treated in general hospitals (noncenter patients). After stabilization, all patients were admitted to the Rehabilitation Institute of Chicago (Ill) and received the same rehabilitation program. The groups were comparable in terms of demographic, injury, and medical characteristics at the time of rehabilitation center admission, but the duration from injury to rehabilitation was more than twice as long for noncenter patients. While center patients were discharged from the rehabilitation center at equivalent functional skill levels, their daily rate of functional gains during the rehabilitation center stay was significantly greater than that of noncenter patients although the length of stay at the rehabilitation center was comparable for the two groups. These results support the practice of specialized short-term spinal cord injury care as a means of enhancing rehabilitation outcome.

Primary central nervous system lymphoma in homosexual men. Clinical, immunologic, and pathologic features.

Primary central nervous system lymphoma constitutes one of the criteria for the acquired immune deficiency syndrome (AIDS), yet a paucity of information is currently available regarding the clinical, immunologic, or pathologic features of these patients. Six homosexual men presenting with primary central nervous system lymphoma were evaluated. Five of these patients presented with altered mental status. All lymphomas were intracranial. B cell immunoblastic sarcoma was found in five. Immune phenotyping studies performed in five patients revealed monoclonal lambda light chain in three, whereas one expressed only IgG heavy chain, and one demonstrated another B cell (LN-1) surface antigen. Hypodense, contrast-enhancing lesions were apparent on computed axial tomographic scanning of the brain, in sharp contrast to isodense or hyperdense lesions reported in primary central nervous system lymphomas without underlying immunodeficiency. Immunologic abnormalities in these patients were similar to those in AIDS presenting as Kaposi's sarcoma or with opportunistic infections. In spite of therapeutic interventions, survival was short, and only one patient is currently alive.

Progressive histopathologic abnormalities in the persistent generalized lymphadenopathy syndrome.

Using a quantitative classification, we evaluated serial lymph node biopsies in 20 homosexual men with Persistent Generalized Lymphadenopathy (PGL), and correlated the results with peripheral blood lymphocyte counts and clinical findings. In a median follow-up interval of 19 months, ten patients (50%) had progression from one histologic subtype of this disorder to another. Lymph nodes from the other 10 patients also demonstrated decreased numbers of organized follicles in the most recent specimens, in addition to progressive abnormalities of other histologic parameters and peripheral blood T4 counts. This suggests that these patients do not have stable disease. However, in a median follow-up interval of 19 months, only one (5%) of the patients had developed AIDS. We conclude that progressive lymph node histopathologic subtypes do not correlate well with decreased T4 lymphocyte counts or clinical course over a short time interval.

Coccidioides immitis meningitis with arthroconidia in cerebrospinal fluid: report of the first case and review of the arthroconidia literature.

The authors report the first case in which the spherules and arthroconidia of Coccidioides immitis were identified from an indwelling cerebrospinal fluid reservoir. The organism was recovered in culture. Present as isolated meningitis, the patient's infection disseminated over a 12-year period despite intrathecal and intravenous administration of amphotericin B. The unusual findings in this patient are compared with findings in 95 cases of infections containing arthroconidia reported since 1940. Arthroconidia is most likely to be found in the tissues of white male patients who are in the third or fourth decade of life and have pulmonary lesions.

Pathology of Mycobacterium avium-intracellulare infection in acquired immunodeficiency syndrome.

The clinical setting, gross organ distribution, and microscopic pathologic findings of disseminated Mycobacterium avium-intracellulare (MAI) infection are described at autopsy in 12 patients with acquired immunodeficiency syndrome (AIDS). All patients were diagnosed by premortem mycobacterial cultures. The clinical course of MAI infection was often prolonged, and death was usually due to an additional infection. In every patient, the distinctive microscopic feature on hematoxylin--eosin staining was a poorly defined granuloma consisting of pale blue, striated histiocytes filled with mycobacteria. Well-formed granulomas with fibrosis, necrosis, and epithelioid histiocytes were present in less than one third of cases. MAI is an opportunistic pathogen that may complicate the course of AIDS but only rarely leads to death. The characteristic appearance of striated histiocytes may aid in the recognition of this infection.

Necropsy findings in acquired immunodeficiency syndrome: a comparison of premortem diagnoses with postmortem findings.

Necropsies were performed in 12 patients who fulfilled the Centers for Disease Control (CDC) criteria for acquired immunodeficiency syndrome (AIDS), and the postmortem findings were compared with the premortem diagnoses. All of the patients were men with a male sexual preference and histories of multiple episodes of venereal diseases. Four patients were intravenous drug abusers, while two abused amyl nitrate. All 12 of the patients had evidence of cellular immune deficiency at presentation. The causes of death were a variety of opportunistic infections and neoplasms. Pneumocystis carinii pneumonia was diagnosed prior to death in seven patients. Despite current therapy, all seven of those patients had persistent Pneumocystis carinii pneumonia at necropsy, as well as clinically undiagnosed cytomegalovirus infection. In addition, two cases of acid-fast infections, two of visceral candidiasis, one of pneumocystis pneumonia, one of central nervous system lymphoma, one of gram-negative bacterial pyelonephritis, and one of cutaneous aspergillosis were clinically unrecognized and untreated. Nine patients died with two or more infections. Thus, necropsy is a valuable tool for recognizing clinically undiagnosed infections and malignant disorders in AIDS.

Immunoblastic sarcoma of T- and B-cell types: morphologic description and comparison.

Immunoblastic sarcoma (IBS) is a large cell lymphoma conceptually related to transformed T and B lymphocytes of the extrafollicular compartment of the immune system (immunoblasts). This light microscopic study of a series of 47 immunologically defined cases of IBS was undertaken in an attempt to define more precisely the morphologic features of the T- and B-cell subtypes. A remarkable morphologic spectrum characterized T-IBS (31 cases), which could be divided into two main groups: 1) tumors composed of varying mixtures of small, medium-sized, and large transformed cells; and 2) tumors with more homogeneous populations of medium-sized or large transformed cells. These cells, in all sizes, generally had abundant pale-staining cytoplasm, delicate nuclear membranes, finely dispersed chromatin, and one to several, small or medium-sized, prominent nucleoli. A distinctive background of small, irregular lymphocytes was frequently present. Plasmacytoid differentiation, seen most consistently as amphophilic staining of the cytoplasm, generally characterized B-IBS (16 cases). B-IBS similarly showed a morphologic spectrum that occurred in two main forms: 1) tumors consisting of a spectrum of transformed cells, with the smaller cells often showing the most striking plasmacytoid differentiation; and 2) tumors consisting predominantly of medium-sized to large transformed cells with varying degrees of plasmacytoid differentiation. With this constellation of features, all but two cases of T-IBS and one case of B-IBS were morphologically distinguishable.

An immunohistochemical study of hemoglobin A, hemoglobin F, muramidase, and transferrin in erythroid hyperplasia and neoplasia.

The bone marrow biopsy specimens of 35 patients with benign and malignant erythroid hyperplasias were examined for the presence of hemoglobin A, hemoglobin F, muramidase (lysozyme), and transferrin, using an indirect immunoperoxidase method (PAP) on Zenker's-fixed paraffin-embedded bone marrow biopsy specimens and particles. Five cases of each of the following entities were studied: erythroleukemia and erythremic myelosis, acute granulocytic leukemia with maturation (FAB M2), polycythemia rubra vera, myeloproliferative syndrome in childhood, megaloblastic anemia (B12 and folate deficiency), erythroid hyperplasia (regenerating bone marrow and hemolytic anemia), and Ph' chromosome positive chronic granulocytic leukemia. Hemoglobin A was present in both the early and late erythroid precursors in all conditions. Hemoglobin F was the predominant hemoglobin in early erythroblasts of pernicious anemia and in both early and late erythroid elements in erythroleukemia and erythremic myelosis. Small quantities of hemoglobin F were present in a few isolated clusters in other conditions. Staining for hemoglobin F may be useful in identifying immature erythroid precursors and in distinguishing some cases of dysplastic erythroid hyperplasia from neoplasia. Additionally, these findings suggest that the maturational switch in hemoglobin synthesis operates with distinct pathways under different conditions.

Acute leukemias with both myeloid and lymphoid surface markers. Cytoplasmic alpha-1-anti-chymotrypsin and alpha-1-anti-trypsin as possible indicators of early granulocytic differentiation.

Blast cells from ten patients (seven adults, three children) with acute lymphoblastic leukemias (ALL) contained immunoreactive cytoplasmic alpha-1-anti-trypsin (alpha-1-AT) and alpha-1-antichymotrypsin (alpha-1-ACT). Cytochemically positive reactions for block-like periodic acid-Schiff and a localized acid phosphatase suggested that the cells were of lymphoid origin rather than myeloid origin: negative for sudan black-B, nonspecific esterase, chloroacetate esterase, and myeloperoxidase. By surface phenotype, the leukemia showed positive reactions for both lymphoid (common acute lymphoblastic leukemia antigen, Ia, OKT-10) and myeloid (OKM-1, Leu M-1) antigens. Three of three patients tested portrayed the Philadelphia chromosome. Nine patients were Mexican-American and one was Japanese: all were of Asian ethnic derivation. Both myeloid and lymphoid treatment regimens were employed, with survival less than expected. Early granulocytic differentiation detectable by cytoplasmic alpha-1-AT and alpha-1-ACT in lymphoid blasts is discussed.

Immunohistochemical characterization of reactive and neoplastic mast cells.

Mast cells are connective tissue elements likened to unicellular endocrine organs because of the wide diversity of physiologic and pathologic events associated with the secretion of biologically active compounds. Using an immunoperoxidase method (PAP), we studied tissue from patients with benign and malignant systemic mastocytosis and with a variety of reactive conditions. The following immunoreactive antigens were identified in mast cells: a heparinlike compound or compounds (HLC), prostaglandin, serotonin, and fibronectin. HLC is constantly present, staining mast cells in a granular fashion from most lesions. Serotonin and prostaglandin stain in a diffuse cytoplasmic manner in occasional lesions. Fibronectin is found in a surface location in selected cases. We found no clear association between the immunoreactivity of one compound in mast cells and one clinical symptom, e.g., HCL with bleeding, prostaglandin, or serotonin with systemic vasomotor activity or fibronectin with increased tissue fibrosis. However, patients with localized and systemic disease had symptoms that might have been attributed to more than one compound. Only occasional patients with reactive conditions showed such symptoms. The presence of these compounds, either alone or in combination, did not separate benign from malignant conditions. Other cells within selected tissues also stained with the antibodies tested. Despite the lack of exclusivity, these antibodies are useful in identifying mast cells within tissue sections and may have a role in the study of mast cell constituents.

Immunohistology of persistent generalized lymphadenopathy. Evidence for progressive lymph node abnormalities in some patients.

Immunohistologic analysis of cellular changes in serial lymph node biopsies of eight patients with persistent generalized lymphadenopathy (PGL) syndrome was performed and correlated with clinical and laboratory findings to better determine the natural history of human immunodeficiency virus (HIV) infection. The authors observed decreased follicle size and area in the second biopsies of six of the eight patients, associated in some with increased numbers of B-cells in medullary regions (four of eight) and more involuted follicles (four of eight). Five cases showed progressively increased paracortical areas in the second biopsies, with increased numbers of T-cytotoxic/suppressor cells and decreased T-helper cells. Seven of the patients also had a progressive loss of T-helper cells in the peripheral blood. These findings provide tissue and peripheral blood evidence for progressive immunologic deterioration in some patients with PGL.

Mycosis fungoides/Sezary's syndrome progressing to immunoblastic sarcoma. A T-cell lymphoproliferation with both helper and suppressor phenotypes.

Multiparameter studies of an unusual patient exhibiting cutaneous manifestations of both mycosis fungoides and Sezary's syndrome are presented. The neoplastic cells of dermal and nodal infiltrates and peripheral blood expressed both helper and suppressor immunologic phenotypes. Cytofluorographic analysis of cells isolated from lymph node and peripheral blood showed a population of neoplastic cells that were stained with the monoclonal antibodies OKT 3, 4, 8, and 11. Immunoperoxidase staining of frozen sections with monoclonal antibodies Leu 1, 2, and 3 provided a topographical identification of an identically marking population of cells in dermis and lymph node. In light of current models depicting normal T-cell lineage, the authors suggest that the neoplastic population in this patient, expressing both helper and suppressor phenotypes, reflected a phenotypic stage of immunologic maturation (OKT 6-, OKT 10-, OKT 3+, OKT 11+, OKT 4+, OKT 8+) in which the neoplastic cells had not yet segregated into distinctive T-cell subsets. While excess helper activity was suggested by serum hypergammaglobulinemia, in vitro helper and suppressor function was not determined. The range of studies employed illustrates the wide variety of technics required to adequately characterize complex clinico-immunopathologic disorders, as represented by this case, and the wealth of information that can be gleaned.