Alan C. Aisenberg

Immunoglobulins on the surface of neoplastic lymphocytes.

Abstract Peripheral lymphocytes from 25 patients with chronic lymphocytic leukemia (CLL) and three with chronic lymphosarcoma-cell leukemia, and lymph-node cells from three of four with lymphocytic lymphoma bore on their cell surface IgM, which was readily demonstrated with fluorescein-conjugated antiserums. The lymphosarcoma cell differed from the cell of CLL in possessing much more surface immunoglobulin. Light-chain analysis of the surface IgM showed that cells bore either kappa or lambda determinants, but not both, indicating the clonal nature of these neoplasms. The serum of four leukemic patients was also found to contain small amounts of IgM M-components. Since the B lymphocyte (bone-marrow-derived) of laboratory animals bears large amounts of surface immunoglobulin and the T lymphocyte (thymus processed) does not, the findings favor the B-cell origin of these leukemic cells. A less likely possibility is that the CLL lymphocyte is a derepressed T cell.

High risk of breast carcinoma after irradiation of young women with Hodgkin's disease.

Treatment‐associated second neoplasms have emerged as a major threat to the continued survival of patients cured of Hodgkins disease. In this study, the authors investigated the risk of breast carcinoma in an irradiated Hodgkins disease population.

T-Cell chronic lymphocytic leukemia: Report of a case studied with monoclonal antibody

A previously healthy 74 year old woman presented with T-cell chronic lymphocytic leukemia, lymphadenopathy, hepatosplenomegaly and a mediastinal mass. The circulating lymphocytes were small to medium in size (some with convoluted nuclei) and W rosette-positive; they could be assigned to the inducer-helper subset of T cells with the acid of monoclonal antisera. These cells reacted with OKT3, which detects peripheral T cells; OKT4, which detects the inducer-helper subset of T cells; and OKT11, which detects the sheep cell receptor. It is noteworthy that they were also positive for the la-like antigen found on T cells only after activation. Microscopic examination of a lymph node biopsy specimen revealed a diffuse pattern of pleomorphic large cells characteristic of the T-cell lymphomas and lymphocytic leukemias reported from Japan. However, the lymph node cells lacked the T-cell differentiation antigens present on the circulating lymphocytes. The findings in this case provide insight into the pathogenesis of this unusual disorder and are relevant to our understanding of the spectrum of surface antigens in the more common malignant lymphomas.

Impaired Antibody Response to Pneumococcal Vaccine after Treatment for Hodgkin's Disease

To determine if a normal antibody response can develop after therapy for Hodgkins disease, we immunized 53 patients and 10 normal controls with dodecavalent pneumococcal vaccine. Antibody concentrations three weeks after immunization (geometric mean of 11 serotypes) were 1566 ng of protein nitrogen per milliliter in controls, 963 ng per milliliter after subtotal radiation (P less than 0.05 compared to controls), 658 ng per milliliter after chemotherapy (P less than 0.05), 377 ng per milliliter after subtotal radiation plus chemotherapy (P less than 0.01) and 283 ng per milliliter after total nodal radiation plus chemotherapy (P less 0.001). Low levels of antibody before immunization correlated with a poor response (r = +0.73, P less than 0.001). The ability to respond to immunization improved significantly but did not return to normal as long as four years after combined therapy. The antibody response to pneumococcal vaccine is profoundly impaired in patients who have received intensive treatment for Hodgkins disease: the ability of this vaccine to protect them from overwhelming postsplenectomy infections remains in doubt.

Lymphocyte surface characteristics in malignant lymphoma

The surface of lymphocytes obtained from fresh biopsy specimens from 41 patients with malignant lymphoma and from 30 normal subjects or patients with non-neoplastic lymphadenopathy were investigated. Immunoglobulin on the cell surface was used to identify B cells, whereas T cells were recognized by their reactivity with an antithymocyte antiserum and their ability to form rosettes with sheep erythrocytes. Normal and inflammatory lymph nodes were composed predominantly of T lymphocytes, as were nodes from 14 patients with Hodgkins disease. Two thymomas were T cell proliferations, whereas a node from a patient with ataxia-telangiectasia was devoid of T lymphocytes. The presence of immunoglobulin on the cell surface indicated that 19 of 21 lymphocytic lymphomas were B cell proliferations, whereas the cells from 3 histiocytic lymphomas (reticulum cell sarcomas) and 1 mixed histiocytic and lymphocytic lymphoma were devoid of surface immunoglobulin. In immunoglobulin-positive tumors, one predominant heavy chain and one predominant light chain could usually be identified, thus establishing the clonal character of the neoplastic proliferation. Ten of 11 diffuse poorly differentiated lymphocytic lymphomas were composed of cells with large amounts of surface immunoglobulin, whereas only 1 of 5 diffuse well differentiated lymphocytic tumors contained such abundant surface immunoglobulin. The surface immunoglobulin data indicate the existence of at least two subspecies of B cell neoplasms. A small lymphocyte with sparse surface immunoglobulin proliferates as diffuse well differentiated lymphocytic lymphoma and chronic lymphocytic leukemia, whereas a larger lymphocyte with abundant surface immunoglobulin proliferates as diffuse poorly differentiated lymphocytic lymphoma and lymphosarcoma cell leukemia.

Cell-surface immunoglobulins in chronic lymphocytic leukemia and allied disorders.

Abstract Immunoglobulin on the surface of peripheral blood lymphocytes from 57 patients with chronic lymphocytic leukemia (CLL) and allied disorders was investigated by fluorescence microscopy and correlated with circulating immunoglobulin. In 38 of 48 patients with CLL, the predominant surface immunoglobulin identified on peripheral blood lymphocytes was M (IgM) of either kappa or lambda light chain type. In five patients, the predominant surface protein was immunoglobulin G (IgG) of either kappa or lambda type. In three others, the lymphocyte surface immunoglobulin could not be definitely identified and in two, no surface immunoglobulin was detected. Circulating immunoglobulin levels, particularly IgM, were depressed in the majority of patients with CLL. In three subjects with IgM-bearing lymphocytes, the serum contained a circulating IgM M component and three of the five subjects with IgG-bearing cells, had a circulating IgG M component. In three patients with CLL, immunoglobulin disappeared from the cell surface with progression of the disorder, although neoplastic cells remained in the circulation. The amount of immunoglobulin on the surface of cells from patients with chronic lymphosarcoma cell leukemia was much greater than that on cells from patients with CLL, and the surface immunoglobulin pattern in hairy cell leukemia also appeared distinctive. Study of immunoglobulin on the surface of lymphocytes has helped to define the cellular origin and monoclonal nature of CLL, the source of circulating M components in this disease, and the relationship of CLL to other lymphoproliferative disorders. Although technically demanding, the study of surface immunoglobulin should prove useful in clinical medicine.

Rearrangement of the gene for the beta chain of the T-cell receptor in T-cell chronic lymphocytic leukemia and related disorders

Although monoclonal B-cell populations can be identified both by surface-marker analysis and by immunoglobulin-gene rearrangements, this has not been possible with T cells. We have employed cDNA probes that are specific for the entire beta chain of the T-cell receptor, and for its constant and variable regions, to investigate gene rearrangements in T-cell chronic lymphocytic leukemia and related disorders. In three malignant proliferations of helper (T4-positive) T cells, rearrangements of the beta-chain constant-region gene were readily demonstrated. A patient from the Caribbean who had adult T-cell lymphoma and antibody to human T-cell lymphotrophic virus Type I (HTLV-I), a patient with virus-negative chronic lymphocytic leukemia, and a patient with cutaneous T-cell lymphoma (Sézary variant) made up the T4-positive group. Three additional patients with chronic T8 (cytotoxic-suppressor) lymphocytosis and neutropenia were studied; in two; rearrangements were found. In all five patients with constant-region rearrangements, deletions of variable-region restriction fragments were observed as well. The presence of rearrangements of a T-cell receptor gene provides presumptive evidence for the clonal nature of T-cell proliferation and for its neoplastic character.

Primary Non-Hodgkin's lymphoma of the mediastinum

Non‐Hodgkins lymphoma localized to the mediastinum and adjacent structures occurred in 12 of 215 (6%) non‐Hodgkins lymphoma patients seen at the Massachusetts General Hospital between 1975 and 1979. Lymphangiography, radionuclide scanning and whole body computerized tomography were used to exclude patients with extrathoracic disease at presentation. Eleven of the 12 patients presented with extensive contiguous extranodal disease (Stage IIE) with involvement of either the pericardium, sternum, chest wall, pulmonary parenchyma or, in four cases, with superior venacaval obstruction. Diffuse large cell lymphoma (eight cases) and diffuse poorly differentiated lymphocytic lymphoma (four cases) were the prevalent histlogic subtypes; no instances of lymphoblastic lymphoma without extrathoracic spread were encountered. None of four lymphomas studied could be characterized as either B‐ or T‐cell tumors utilizing conventional surface marker techniques. Ten of the 12 patients achieved complete remissions, either after treatment with combination chemotherapy alone (three patients) or after both chemotherapy and mediastinal irradiation (seven patients). Two of these ten have subsequently relapsed, but median survival has not been reached after a mean period of observation of 28 months. Primary nonlymphoblastic non‐Hodgkins lymphoma of the mediastinum is more common than previously realized, displays aggressive contiguous spread within the chest and responds well to combination chemotherapy with or without adjuvant mediastinal irradiation.

Mediastinal large cell lymphoma. An uncommon subset of adult lymphoma curable with combined modality therapy.

Thirty adults with large cell lymphoma predominantly localized to the mediastinum diagnosed at the Massachusetts General Hospital between 1976 and 1985 were identified. The median age of the 20 females and 10 males was 34 years. All but one presented with symptoms due to an enlarging mediastinal mass, which was localized in 22 patients (73%) and exceeded 10 cm in maximal diameter in 65%. Superior vena cava syndrome and large pleural and pericardial effusions were common. Employing CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) and consolidation radiation therapy in most cases, 80% achieved a complete remission and 59% survive failure‐free at 5 years by actuarial calculation, the size of the mediastinal mass adversely affected failure‐free survival (89% vs. 40%, P < 0.05). No other pretreatment risk factor predicted outcome, but more intense chemotherapy was associated with improved survival (P = 0.035). Large cell mediastinal lymphoma is a locally invasive, often bulky malignancy with a predilection for young women; disease of low or moderate bulk is curable with full dose CHOP chemotherapy and consolidation radiation, but bulky disease requires more aggressive treatment.

Primary large cell lymphoma of the mediastinum. A histologic and immunophenotypic study of 29 cases.

We studied the morphologic and immunologic features of 29 cases of primary nonlymphoblastic non-Hodgkins lymphoma of the mediastinum. The patients ranged in age from 15 to 73 years, with a median of 32 years. The mean age for the 11 men (50 years) was significantly higher than that for the 18 women (32 years) (p < 0.05). All had diffuse large cell lymphomas (six immunoblastic, 14 large cell not otherwise specified, six large cell noncleaved, one large cell cleaved, and two not subclassifiable). Sclerosis was prominent in 11 cases, none of them immunoblastic, and did not correlate with superior vena cava syndrome. The mean age (54 years) of patients with immunoblastic lymphomas was higher than that for patients with other subtypes (35 years) (p < 0.02). Frozen-section immunoperoxidase staining disclosed monotypic immunoglobulin in 13 cases, with a high frequency of heavy-chain class switching (seven IgG, two IgA, four IgM). Sixteen cases were immunoglobulin negative; 14 of 15 cases expressed B-lineage antigens, and none expressed T-lineage antigens. Three of four cases showed immunoglobulin heavy- or light-chain gene rearrangement by the Southern blot technique. None showed rearrangement of the T-cell receptor beta-chain-gene constant region. There was no correlation between immunophenotype and morphologic subtype. The immunoglobulin-negative group was predominantly female (13 of 16 cases; p < 0.02), and younger (mean age, 34 years versus 44 years; p = NS) than the immunoglobulin-positive group; however, the difference in age was not statistically significant. The actuarial 5-year survival was 57%, and there was no correlation between survival and either histologic subtype or immunophenotype. Mediastinal large cell lymphoma is a B-cell tumor, which frequently lacks immunoglobulin, may be primary in the thymus, has a predilection for young women, and can be cured with aggressive therapy.