John C. Long

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.

Terminal deoxynucleotidyl transferase in the diagnosis of leukemia and malignant lymphoma.

Neoplastic cells from 253 patients with leukemia and 46 patients with malignant lymphoma were studied for the presence of terminal deoxynucleotidyl transferase (TdT) by biochemical and fluorescent antibody technics. TdT was detected in circulating blast cells from 73 of 77 patients with acute lymphoblastic leukemia, 24 of 72 patients with chronic myelogenous leukemia examined during the blastic phase of the disorder and in cell suspensions of lymph nodes from nine of nine patients with diffuse lymphoblastic lymphoma. Blast cells from six of 10 patients with acute undifferentiated leukemia were TdT positive, but the enzyme was found in only two of 55 patients with acute myeloblastic leukemia. TdT was not detected in other lymphocytic or granulocytic leukemias or in other types of malignant lymphomas. The fluorescent antibody assay for TdT permits rapid and specific identification of the enzyme in single cells. The TdT assay is clinically useful in confirming the diagnosis of acute lymphoblastic leukemia, evaluating patients with blastic chronic myelogenous leukemia, and distinguishing patients with lymphoblastic lymphoma, whose natural history includes rapid extranodal dissemination, from patients with other poorly differentiated malignant lymphomas.

Mycosis fungoides with extracutaneous dissemination: a distinct clinicopathologic entity.

The clinical and histopathologic findings in 15 autopsied cases of mycosis fungoides with extracutaneous dissemination were reviewed. Mycosis fungoides involvement of the skin was present for an average of 22 months (range of 7 months to 6 years) from the time of diagnostic skin biopsy until the onset of clinical signs indicating systemic involvement. The clinical findings associated with dissemination of mycosis fungoides were fever, weight loss, generalized peripheral and hilar lymphadenopathy, palpable enlargement of the liver and spleen, and peripheral blood eosinophilia and lymphocytosis. The average survival from the development of these signs was 11 months (range of 3 to 18 months). At autopsy in all 15 cases cutaneous mycosis fungoides was associated with malignant lymphoma, mycosis fungoides type, involving lymphoid organs and viscera. The cellular infiltrates within extracutaneous sites of involvement were similar to those of the skin infiltrates and included variable numbers of pleomorphic mycosis cells admixed with many inflammatory cells. In none of the cases was there evidence of transition to a malignant lymphoma of a different cell type. Extracutaneous dissemination is a clinicopathologically distinct aspect of the natural history of mycosis fungoides and is not due to the development of a different type of malignant lymphoma.

Malignant lymphoma of the skin. A clinicopathologic study of lymphoma other than mycosis fungoides diagnosed by skin biopsy

The clinical and histopathologic findings in 25 cases of malignant lymphoma of the skin other than mycosis fungoides were reviewed. All patients had skin lesions as a primary manifestation of the disorder, and none had histopathologic evidence of extracutaneous involvement at the time of skin biopsy. The majority of patients had solitary nodules involving the skin of the head and neck region. Twenty‐two of the skin biopsy specimens were interpreted as lymphocytic lymphoma, well or poorly differentiated, nodular or diffuse. Only three cases of histiocytic lymphoma (reticulum cell sarcoma) were encountered, and there were no cases of Hodgkins disease of the skin. Twenty‐two patients (88%) subsequently developed extracutaneous lymphoma: the interval from the occurrence of apparently localized skin lesions to involvement of lymph nodes and/or viscera ranged from 6 months to 5 years (mean duration of 21 months). Sixteen patients (64%) died of disseminated lymphoma, with survivals that ranged from 8 months to 12 years (mean survival of 3.7 years). Only three patients survived without disease for greater than 1 year. There was no definite relationship between either the histologic subtype of the tumor or the mode of therapy and prognosis. The pathologic findings indicate that a definite diagnosis of malignant lymphoma can be made by skin biopsy in patients with disease apparently confined to the skin. Careful, detailed examination of the skin biopsy specimen provides a basis for distinguishing malignant lymphoma from cutaneous lymphoid hyperplasia. The clinical findings and survival data support the conclusion that malignant lymphoma with skin lesions as a primary manifestation almost invariably disseminates to extracutaneous organs and usually has a fatal outcome.

Malignant lymphoma obscured by concomitant extensive epithelioid granulomas: report of three cases with similar clinicopathologic features.

Three similar cases are described of an unusual combination of malignant lymphoma and extensive non‐necrotic granulomas. The three patients presented with prominent splenomegaly without peripheral lymphadenopathy. They had normal or moderately elevated lymphocyte counts, abnormal lymphoid cells in the peripheral blood and bone marrow, and abnormalities of serum immunoglobulins. The lymphoid tumor was difficult to recognize but it was best identified in abdominal lymph nodes, it was composed of small atypical lymphocytes proliferating in a vaguely nodular pattern. The presence of multiple epithelioid granulomas obscured the neoplastic proliferation in the spleens and misled or delayed the final interpretation of the malignant disease. Abdominal lymph nodes and liver also contained granulomas although to a lesser extent. Studies of the lymphocyte surface characteristics in one patient suggested that the neoplasm derived from a monoclonal proliferation of B cells. The relationship between the exuberant epithelioid granulomas and the underlying neoplastic lymphoid proliferation is not clear. Regardless of whether it represents a distinct clinicopathological entity, recognition of this remarkable association has important practical implications since the lesions may be erroneously interpreted by the pathologist.

Cell surface phenotype in lymphoproliferative disease.

Abstract The surface phenotype of peripheral blood lymphocytes from 45 patients with chronic lymphocytic leukemia (CLL) and of lymphoid tissue from 100 patients with other lymphoproliferative disease was determined. Surface immunoglobulin (SIg) and complement receptor were employed as B cell markers, and reactivity with sheep erythrocytes (E rosettes) and antithymocyte globulin was used to identify T cells. Of these markers, only SIg and E rosettes reliably identified cells of the respective lineages. SIg identification with fluorescent antiserums had the added advantages of allowing the discrimination between different B cell subsets on the basis of staining intensity, and establishing the clonal character of a proliferation by the presence of predominant light and heavy chains. A uniform surface phenotype was observed in CLL, characterized by faintly staining SIgM with or without SIgD (one sixth of the patients were SIgG-positive instead), the presence of complement receptor, and the absence of reactivity with either sheep erythrocytes or antithymocyte globulin. Nodular (poorly differentiated lymphocytic) lymphoma was also uniformly of B cell lineage, but staining for SIgM was brighter (one third of these tumors were instead SIgG-bearing): Although cell suspensions of these neoplasms were uniformly E rosette-negative, the presence of complement receptor and reactivity with antithymocyte globulin were variable. Diffuse poorly differentiated lymphocytic lymphoma and two cases of Burkitts lymphoma were very bright SIgM-positive, E rosette-negative neoplasms. Sixty per cent of the diffuse histiocytic lymphomas exhibited either SIgM- or SIgG-positive B cells which stained brightly, but the other 40 per cent comprised tumors either of T cell lineage or of a phenotype which could not be conclusively identified. The mixed histiocytic and lymphocytic lymphomas, which occupy an awkward place in pathology, could not be defined by surface markers. Surface markers should not replace routine pathologic criteria as the basis of classifying lymphoma, but cell phenotype is proving an increasingly useful added dimension for understanding and classifying this complex group of diseases.

Multiple granulocytic tumors of the skin. Report of six cases of myelogenous leukemia with initial manifestations in the skin

The clinical and pathologic findings in six patients with myelogenous leukemia presenting initially as multiple granulocytic tumors of the skin were reviewed. The skin of the trunk was most commonly involved with multiple, confluent erythematous plaques and soft, tender, non‐ulcerated, violaceous nodules. Two patients had been treated for malignant lymphoma eight and nine years prior to the onset of skin lesions (Hodgkins disease and nodular lymphocytic lymphoma, respectively), and cutaneous granulocytic leukemia developed in sites of irradiated skin. The skin biopsies in all cases were originally misinterpreted by the pathologist as malignant lymphoma and the correct diagnosis of granulocytic leukemia was not established in any of the cases until overt extra‐cutaneous involvement was detected. The interval in the six patients from skin biopsy to definite involvement of blood and bone marrow by acute granulocytic leukemia ranged from three weeks to six months with a mean interval of 3.8 months. The mean duration of survival from the diagnosis of extracutaneous dissemination was 12.7 months (range of three months to two and one‐half years). Poorly differentiated myelogenous leukemia was demonstrated at postmortem examination in all cases. Cytochemical stains of formalin‐fixed, paraffin‐embedded tissues confirmed the granulocytic origin of the neoplasm: leukemic cells in skin biopsies, bone marrow aspirates, and autopsy specimens contained abundant naphthol AS‐D chloracetate esterase. The findings indicate that granulocytic leukemia may rarely present with skin tumors as the original manifestation of the disease. Recognition of the distinctive clinical, histopathologic, and enzyme histochemical features of the lesion provide a basis for distinguishing granulocytic sarcoma of the skin from mycosis fungoides and other cutaneous malignant lymphomas.

Circulating immune complexes in Hodgkin's disease

Levels of circulating immune complexes (CIC) in the serum of patients with Hodgkins disease were measured by the Raji cell radioimmunoassay. Elevated levels of immune complexes (mean value of 49 microgram/ml +/- 21 SE) were detected in 20 of 40 (50 per cent) untreated patients. After treatment, the level of CIC was normal (less than 15 microgram/ml) in 39 of 41 patients. Recurrent disease developed in two of the 39 patients with normal post-treatment levels of CIC and in one of the two patients with elevated post-treatment levels during the follow-up period of six months to six years. Elevated levels of CIC were detected in patients with Hodgkins disease in stages I, II and III but not in stage IV. No significant correlations were found in the frequency of elevated levels of CIC or the values observed, and the presence or absence of symptoms (fever, sweats, weight loss) or the histologic subtype of the tumor. Our data indicate that the measurement of CIC by the sensitive and specific raji cell assay may prove useful in the management of patients with Hodgkins disease. In particular, serial measurement of the level of CIC could be employed to monitor the response to treatment and to detect recurrent diseases.

Malignant lymphoma diagnosed at splenectomy and idiopathic splenomegaly. A clinicopathologic comparison

The clinical, laboratory, and histopathologic findings in 15 cases of malignant lymphoma presenting as splenomegaly and diagnosed at splenectomy were compared with 10 cases of idiopathic splenomegaly. The ages of the patients, the duration of splenomegaly, the hematologic parameters, and the weights of the spleen were similar in the two groups of patients. None of the 15 patients with malignant lymphoma initially diagnosed at splenectomy was considered cured: 8 died with disseminated disease within 2 years, 2 have survived for longer than 3 years with progression to chronic lymphosarcoma cell leukemia, and 5 have been followed for less than 12 months. Idiopathic splenomegaly, an apparently benign inflammatory lesion, may simulate lymphoma clinically and be confused with nodular lymphoma pathologically, particularly when associated with lymphocytic infiltrates of the liver and bone marrow and atypical lymphocytes in the peripheral blood. Splenectomy is indicated in patients with persistent splenomegaly without known contributing or related disease, and care must be exercised in the pathologic distinction between splenic lymphoma and idiopathic splenomegaly.