Immunologic approaches to the classification of non-Hodgkin's lymphomas.
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Antibodies, Monoclonal↗
Biomedical subjects
C M Spier
Publications and source records attributed to C M Spier.
HLA-DR (Ia) immune phenotype predicts outcome for patients with diffuse large cell lymphoma.
The clinical utility for establishing the immune phenotype in patients with non-Hodgkin's lymphoma is controversial. To help resolve this dilemma, we studied 104 consecutive patients with diffuse large cell lymphoma, the most common subtype of potentially curable non-Hodgkin's lymphomas. The presence or absence of the human class II histocompatibility antigen was determined using the monoclonal antibody anti-HLA-DR (Ia), and the results correlated with pretreatment clinical features and survival. We found that eight HLA-DR negative patients had similar pretreatment clinical characteristics compared with 96 HLA-DR positive patients, but HLA-DR negative patients had a significantly shorter survival duration compared with HLA-DR positive patients (P = 0.003 log-rank). The median survival of the HLA-DR negative patients was 0.5 years compared to 2.8 yr for the HLA-DR positive patients. No HLA-DR negative patient survived beyond 1.5 yr. A multi-variate analysis, adjusting for prognostic factors of known clinical significance, confirmed the importance of HLA-DR as a prognostic factor (P = 0.016). We conclude that determining the presence of HLA-DR is a relatively simple pretreatment study that identifies a small but important group of patients who are not curable using currently available combination chemotherapy.
Aged↗
The aberrancy of immunophenotype and immunoglobulin status as indicators of prognosis in B cell diffuse large cell lymphoma.
To assess the prognostic significance of the immunophenotype in diffuse large cell lymphoma (DLCL), 105 DLCL patients were studied between 1978 and 1987 using a panel of 40 monoclonal antibodies applied to frozen tissue. Eighty-three patients were found to have B cell phenotypes, and 20 patients had T cell phenotypes. Focusing on markers relevant to clinical outcome among B cell LCL showed that lack of expression of the pan B antigens Leu14 and Leu16 were correlated with decreased survival (Leu14, P = 0.01; Leu16, P = 0.06; log-rank). HLA-DR activity also showed that lack of expression of this antigen correlated with poor survival (P = 0.004, log-rank). Kappa light chain immunoglobulin lack of expression showed predictive value for decreased survival as well (P = 0.005, log-rank). Multivariate analyses of known clinically important variables and the immune phenotypes confirm that the loss of HLA-DR and B cell aberrancy are independent factors predicting a poor clinical outcome. Losing some B activation/kappa antigens appears to be a broad biologic phenomenon linking surface antigen lack of expression with decreased survival. This suggests that aberrancy of immunophenotype and immunoglobulin status are key predictors of survival in B-LCL.
Antigens, Surface↗
Clonal ambiguity of human immunodeficiency virus-associated lymphomas. Similarity to posttransplant lymphomas.
Initial biopsy specimens from two patients with lymphadenopathy and human immunodeficiency virus antibody-positive serum presented considerable difficulty in making specific histologic and immunologic diagnoses, although subsequent biopsy specimens revealed clear progression to acquired immunodeficiency syndrome (AIDS)-associated lymphomas. The initial biopsy specimens revealed multifocal clusters of large blastic lymphoid cells, with some clusters showing a monoclonal lambda light chain predominance, whereas other clusters showed a kappa predominance, indicating considerable phenotypic ambiguity suggestive of polyclonality. This initial clonal ambiguity was followed within two to three months by overt histologic, phenotypic, and clinical malignant transformation to a diffuse high-grade monoclonal B-cell lymphoma. These data have significant implications for the clonality and pathogenesis of AIDS-associated lymphoproliferative disorders. AIDS-related lymphomas may evolve from an initial multiclonal B-cell expansion similar to that described in other severely immunosuppressed patients (eg, with posttransplantation lymphoma).
AIDS-Related Complex↗
The prognostic significance of the immunotype in diffuse large-cell lymphoma: a comparative study of the T-cell and B-cell phenotype.
The clinical significance of immunophenotyping of the non-Hodgkin's lymphomas is controversial. Therefore, we conducted the present study of 103 consecutively accrued diffuse large-cell lymphoma (DLCL) patients to define, independently of histologic subtypes, the prognostic importance of phenotyping. We used an extensive panel of monoclonal antibodies to T- and B-cell antigens to assign all patients immunologically into the T-cell (20 patients) or B-cell group (83 patients). The only significant differences in pretreatment clinical variables between the two patient groups were the higher frequency of bulky disease (greater than 10 cm) in B-cell patients (P = .008) and more frequent skin involvement in the T-cell group (P less than or equal to .001). Multiagent doxorubicin-containing chemotherapy regimens were employed as initial therapy in over 83% of the patients in each group. Our study revealed that disease-free survival (DFS) was significantly shorter in the T-cell patients than in the B-cell DLCL patients (median DFS, 10.8 months for T-cell and 42.7 months for B-cell; P = .01, log rank). No patient with T-cell DLCL remained disease free for longer than 2 years, whereas 55% of the B-cell group were disease free at 2 years. Univariate and multivariate analyses of all major prognostic factors of DFS suggest that the T-cell phenotype indicates an incurable subset of DLCL patients. Although the B-cell group had a twofold advantage in median survival (35 months v 18 months), actuarial overall survival was not significantly different between the two patient groups (P = .23). Our results indicate the need for new approaches in the search for a curative treatment for T-cell DLCL.
Adolescent↗
Nuclear contour irregularity correlates with Leu-9-, Leu-8- cells in benign lymphoid infiltrates of skin. An ultrastructural morphometric and quantitative immunophenotypic analysis suggesting the normal T-cell counterpart to the malignant mycosis fungoides/Sézary cell.
The purpose of the present study was to determine if a nonmalignant skin-associated T-cell might exhibit nuclear irregularity and represent the normal counterpart to the malignant Sézary T-cell found in mycosis fungoides (MF) and the Sézary syndrome (SS). Punch skin biopsies from ten benign lymphoid infiltrates of skin were subjected to ultrastructural morphometric analysis and quantitative immunohistochemistry (on serial frozen sections) using a battery of monoclonal antibodies. Form factor (FF) (4 pi A/p2) was used to assess nuclear contour irregularity. The lymphoid infiltrates were morphometrically heterogeneous (range of FF values: 0.482-0.704). Immunophenotypically, there was marked variation in host response to the variety of antigens presented. Linear regression analysis was used to determine if nuclear contour irregularity showed any statistical relationship to immunophenotypically defined lymphocyte subpopulations. It was determined that nuclear contour irregularity (mean FF values) did not correlate with the presence of any surface antigen tested. This included the antigens Leu-2a, Leu-3a + b, Leu-4, Leu-6, Leu-7, Leu-8, Leu-9, Leu-14, and Ia. There was, however, significant correlation of increased nuclear contour irregularity with the presence of Leu-9- and Leu-8- cells (r = 0.7 and 0.6, respectively), lymphocyte subsets reportedly deficient in MF and the SS. This finding leads to the speculation that the Leu-9-, Leu-8- reactive T-cell with an irregular nucleus might represent the normal counterpart to the malignant clonally expanded T-cell found in MF and the SS. It was also determined that helper to suppressor ratios varied 68-fold from 0.2 to 13.5 among these ten benign lymphoid infiltrates of skin. This finding underscores the futility of using helper to suppressor ratios as a diagnostic tool in defining T-cell malignancies.
Adult↗
Independent prognostic significance of a nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67.
To assess the prognostic significance of the growth fraction in diffuse large cell lymphoma (DLCL), we studied 105 DLCL patients with the monoclonal antibody Ki-67 applied to frozen tissue sections. Ki-67 detects a nuclear antigen associated with cell proliferation not found in resting cells. Ki-67 findings and other clinical prognostic factors were correlated with outcome using univariate and multivariate analyses in the proportional hazards model. High proliferative activity, defined as nuclear Ki-67 expression in greater than 60% of malignant cells (Ki-67 greater than 60), was found to be a strong predictor of poor survival among these patients (P = .003, log-rank). The 19 patients with Ki-67 greater than 60% had a median survival of 8 months compared with a median survival of 39 months for the 86 patients with Ki-67 less than or equal to 60%. Examination of pretreatment clinical variables indicated the patient groups were similar with regard to age, sex, stage, B symptoms, tumor bulk, and lactate dehydrogenase (LDH). Both patient groups received comparable curative intent therapy and showed comparable complete response rate precluding treatment differences as modifying outcome. Multivariate analysis indicated Ki-67 is an independent predictor of survival (multivariate P = .006). Further statistical analysis using only B-cell DLCL patients treated with CHOP (63 patients) indicated that Ki-67 greater than 60 retained strong prediction of poor outcome (P = .002, log-rank) among this homogeneous group. We conclude that high proliferative activity (Ki-67 greater than 60) is an independent factor allowing laboratory prediction of probable poor outcome of DLCL.
Adolescent↗
Lethal midline granuloma with a novel T-cell phenotype as found in peripheral T-cell lymphoma.
Lethal midline granuloma (LMG), initially a clinical description, includes an uncommon group of disorders characterized by a relentless, destructive process involving the upper respiratory structures. Its etiology and pathogenesis are uncertain, probably varied, and the distinction between inflammatory and malignant processes is difficult despite extensive clinical and histopathologic evaluation. The need for new techniques for rapid diagnosis has important therapeutic implications. Using an extensive panel of T- and B-cell monoclonal antibodies the authors describe a patient with clinically and pathologically typical LMG demonstrating an "activated" T-cell phenotype with a "novel" pattern characteristic of peripheral T-cell lymphoma, strongly implying that some cases of LMG are more closely related to neoplastic T-cell lymphoproliferative disorders than to inflammatory conditions. Further studies using these immunotyping techniques may help clarify the pathogenesis of LMG, and may uncover specific diagnostic and prognostic phenotypic patterns.
Adult↗
Mantle zone lymphoma with central nervous system involvement.
A 68-year-old man with a 7-year history of lymphocytosis and lymphadenopathy is described. Accelerated disease, indicated by bilateral optic nerve and cerebrospinal fluid involvement, prompted thorough histologic and immunologic assessment. Although initially believed to have chronic lymphocytic leukemia (CLL), results showed mantle zone lymphoma (MZL) with central nervous system (CNS) involvement. The authors believe that this represents the first case of MZL with CNS involvement.
Aged↗
Immunophenotypes in "well-differentiated" lymphoproliferative disorders, with emphasis on small lymphocytic lymphoma.
The histologic, immunophenotypic, and clinical findings in 24 cases of "well-differentiated" lymphoproliferative disorders are presented, with an emphasis on small lymphocytic lymphoma (SLL; well-differentiated lymphocytic lymphoma, WDLL). SLL was diagnosed in 18 patients, Waldenström's macroglobulinemia in one, mantle zone lymphoma (MZL) in four, and intermediate differentiated lymphocytic lymphoma (IDL) in one. Immunophenotypic analysis revealed one SLL to be of T-cell derivation, while a monoclonal B-cell phenotype was found in the remaining 23 patients; 20 of these neoplasms co-expressed the pan-T-cell antigen Leu-1. This included three of the four patients with MZL and the patient with IDL. All SLLs with pseudofollicular growth centers stained for transferrin receptor. Additionally, a survey of 248 non-Hodgkin's lymphomas of all types revealed four of 70 patients with B-cell large cell lymphoma (LCL; diffuse histiocytic lymphoma, DHL) that also co-expressed the same Leu-1 antigen. Immunoperoxidase study of both frozen tissue sections and cytocentrifuge preparations eliminated the limitations of faint antigen expression and/or interstitial immunoglobulin staining. In addition to detailing the immunophenotype of SLL, the immunologic kinship of MZL/IDL to SLL and the uncommon co-expression of Leu-1 in B-cell LCLs are demonstrated.
Aged↗
Immunotyping malignant lymphomas. A boon to diagnosis.
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Humans↗
Differentiation of chronic lymphocytic leukemia from other "well to intermediate differentiated" lymphoproliferative disorders by the mouse rosette assay.
The usefulness of the mouse rosette (MR) assay in differentiating among various "well to intermediate differentiated" lymphoproliferative disorders (LPD) is presented. Thirty patients with a suspected LPD were studied. By standard histologic, cytologic, immunologic (surface immunoglobulin and monoclonal antibody markers), and clinical criteria, the following diagnoses (independent of MR data) were made: chronic lymphocytic leukemia (CLL) (n = 12), CLL in transformation (n = 2), well-differentiated lymphocytic lymphoma (WDLL) (n = 5), intermediate-differentiated lymphoma (IDL) (n = 2), hairy cell leukemia (HCL) (n = 3), prolymphocytic leukemic (PLL) (n = 1), poorly differentiated lymphocytic lymphoma (PDL) (n = 1), and no disease or reactive lymphocytosis (n = 4). There were 11 B-CLL cases and one T-CLL case. The percent of MR in all cases of B-CLL ranged from 26 to 76% (m = 62%); 10/11 cases had greater than or equal to 50% MR. The case with 26% MR was atypical in that it occurred in a 26-year-old patient. The percent of MR ranged from 0 to 42% (m = 16%) in the cases of well to intermediate differentiated lymphomas. Similar to previous reports intermediate proportions of MR were seen in HCL (12-41%); and low values were seen in PDL (4%) and PLL (4%). In summary, the MR assay may be a useful tool for differentiating CLL from other well to intermediate differentiated LPD involving the peripheral blood. Also, since the MR receptor is normally found only on functionally immature cells, this differential mouse rosetting capability suggests that CLL arises from a less mature cell than WDLL or IDL.
Animals↗
Chronic lymphocytic leukemia in young adults.
The occurrence of chronic lymphocytic leukemia (CLL), B-cell type, is thought to be distinctly uncommon in patients younger than 40 years of age. Previous case reports of CLL in young adults and children were published before the widespread use of immunologic surface markers in the diagnosis of lymphoproliferative disorders. The authors report four patients with B-cell CLL, all diagnosed with the aid of immunologic markers. The patients were 30 years of age or younger at the time of diagnosis. Their subsequent course has been similar to B-cell CLL in the older age group: one is alive without progression of disease 30 months after diagnosis; one has shown progression of the disease but is alive, after chemotherapy, 36 months after diagnosis; while the other two had continued progression of disease and died, one at six and a half years and the other at 14 months, after diagnosis. The occurrence of B-cell CLL in young adults and its potential implications are discussed.
Adult↗
Malignant lymphoma with primary presentation in the spleen. A study of 20 patients.
We describe 20 adult patients with malignant lymphoma with primary presentation in the spleen. The most common presenting symptoms were fever, malaise, and weight loss. Physical examination revealed prominent splenomegaly without palpable lymphadenopathy. Small lymphocytic lymphoma was the most frequent histologic type (11/20), followed by large cell lymphoma and mixed cell lymphoma (3/20 each). Bone marrow involvement was found in ten of 17 patients. At laparotomy, lymph node involvement, usually retroperitoneal, was found in six of 13 patients. There was liver involvement in seven of 15 patients. Follow-up has been relatively short, with an average of 24 months (range, one to 48 months). Four patients died as a result of progressive disease, one died of sepsis after splenectomy, and one died two years after diagnosis of a stroke. The prognosis in primary splenic lymphoma appears to be similar to that in nodal lymphoma.
Adult↗
Pre-B cell acute lymphoblastic leukemia in the newborn.
Leukemia in the newborn is an infrequent disease that has not been well defined using modern laboratory techniques. We describe two infants, one at birth and one at four weeks, with acute lymphoblastic leukemia. The blasts from each patient were studied in great detail, using a battery of cytochemical and immunologic procedures in addition to ultrastructural studies. Immunologic cell marker studies, not previously reported in congenital leukemia, showed the lymphoblasts from each infant to be of the pre-B cell phenotype. Each infant relapsed, one after a 17-week clinical remission and the other after a 44-week remission. The former has died while the latter is in a second remission. The subtype of pre-B cell acute lymphoblastic leukemia (ALL) which in childhood appears to confer an unfavorable prognosis, may have the same significance in neonatal ALL.
Antineoplastic Agents↗
Lymphomas of the mediastinum.
The purpose of this clinicopathologic overview is to describe the types of lymphomas that present in the mediastinum. A comparison of the frequency of the different subtypes of lymphoma that are found in children and adults is provided. In general, immunohistochemistry and immunophenotyping studies are essential to the laboratory workup of neoplasms presenting in the mediastinum. An assessment of proliferative index in lymphoma is most helpful to determine tumor aggressiveness and patient prognosis. Electron microscopy is most helpful in the differential diagnosis of mediastinal neoplasms, where lymphomas may be distinguished from nonlymphomatous neoplasms using key ultrastructural features. The role of electron microscopy in the subclassification of lymphomas is mostly academic, with a few exceptions. The varied ultrastructural appearance of Hodgkin's cells and of different subtypes of non-Hodgkin's lymphoma is illustrated, using cases from our patient files. An ultrastructural study of lacunar cells in Hodgkin's disease provides evidence that the formation of lacunae may have a structural and/or physiologic basis. Mummified cells showing some of the features of a physiologic form of cell death, called apoptosis, are also described.
Humans↗
A multidisciplinary approach to the diagnosis of cutaneous T-cell lymphomas.
The cutaneous T-cell lymphomas (CTCLs) comprise a spectrum of non-Hodgkin lymphomas with a predilection for the skin. This heterogeneous group of CTCLs include the prototypic CTCL mycosis fungoides (MF) and the recently described Ki-1+ lymphomas. MF is notoriously difficult to diagnose in its early stages. The histologic appearance of early MF is indistinguishable from that of chronic dermatitis. The limitations of light microscopy in the diagnosis of the CTCLs have led to the development of other diagnostic laboratory techniques. The best approach to the diagnosis of the CTCLs is a multidisciplinary one and should include ultrastructural morphometry, immunophenotyping, immunogenotyping, and histologic evaluation whenever possible. It is the purpose of this overview to point out the strengths and weaknesses of each of these techniques and, together with clinical input, to provide a comprehensive and rational approach to patient care.
Gene Rearrangement↗