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Anaplastic large cell lymphoma (ALCL) has been recognized recently as a distinct clinicopathologic entity, restricted to a subset of CD30-positive diffuse large cell lymphomas of T/null lineage. Some of the characteristic features of ALCL, such as CD30 antigen expression and the presence of large pleomorphic lymphoid cells infiltrating lymph node sinuses, can be found rarely in diffuse large B-cell lymphomas. We collected 11 such cases, and their clinical, morphologic, and immunophenotypic features are reviewed. The age of the patients ranged from 36 to 82 years (mean, 63.2 years) with a male to female ratio of 1:1.2. All neoplasms were nodal with a sinusoidal infiltrative pattern, although four neoplasms also had foci of confluent growth. Eight tumors were composed predominantly of large pleomorphic cells with occasional Reed-Sternberg-like cells. The other three tumors had a higher proportion of large monomorphic lymphoid cells. Necrosis and admixed granulocytes were other common features. Immunophenotypically, all cases were positive for CD30 and CD20 or CD79a. All eight cases examined for anaplastic lymphoma kinase-1 immunoreactivity were negative. In situ hybridization for Epstein-Barr virus RNA was performed in eight cases; two were positive. Excluding one consultation case with no available clinical follow-up data, six patients died of the disease within 3 years and one had disease relapse within 1 year. We conclude that an unusual variant of diffuse large B-cell lymphoma can closely mimic ALCL. However, these neoplasms can be distinguished from ALCL by virtue of their B-lineage and lack of anaplastic lymphoma kinase-1 expression. Evidence of Epstein-Barr virus infection can be found in a small subset of these neoplasms.
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PMID:Sinusoidal CD30-positive large B-cell lymphoma: a morphologic mimic of anaplastic large cell lymphoma. 1075 32

Primary cutaneous (PC) CD30-positive large cell lymphoma and lymphomatoid papulosis (LyP) represent the spectrum of PC CD30-positive lymphoproliferative disorders (LPDs) associated with a favorable prognosis. Noncutaneous CD30-positive anaplastic large cell lymphoma (ALCL), although morphologically similar to PC CD30-positive LPDs, seems to be a biologically distinct entity. Cell lines derived from noncutaneous ALCL express CD95 and undergo CD95-induced apoptosis. Little is known about expression or function of CD95/CD95L in cutaneous lesions. We examined a series of PC CD30-positive LPDs and noncutaneous ALCL for expression of CD95/CD95L to investigate possible differences between these histologically similar but biologically distinct entities. Paraffin-embedded, formalin-fixed tissue sections from 25 cases of CD30-positive LPDs (10 noncutaneous ALCL, 15 PC CD30-positive LPDs) were immunostained for CD3, CD20 (L26), CD43 (Leu22), CD30 (BerH2), anaplastic lymphoma kinase (ALK-1), CD95, and CD95L (C-33). One hundred large atypical cells and 100 small lymphocytes were counted to determine the percentage of CD95/ CD95L-positive cells. Statistical analysis using the Mann-Whitney U test was performed. CD95 expression was slightly higher in the large atypical cells of noncutaneous ALCL compared with PC CD30-positive LPDs (median, 100% versus 94%; P = .003) because of the lower expression of CD95 in LyP. CD95L expression was higher in the surrounding small lymphocytes in PC CD30-positive LPDs (median, 3% versus 13%; P = .002). Expression of CD95 in the small lymphocytes and CD95L in the large atypical cells was not significantly different. These results support the biologic distinction between cutaneous and noncutaneous CD30-positive LPDs and may have implications in the differing clinical behavior of these entities. Further study of expression and function of apoptosis-related proteins in these entities is warranted.
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PMID:Immunohistochemical analysis of CD30-positive lymphoproliferative disorders for expression of CD95 and CD95L. 1078 13

There is controversy in the literature as to whether anaplastic large-cell lymphoma of B-cell phenotype is related to the t(2;5)-positive T- or 'null' cell lymphoma of the same morphology. We report a study of 24 lymphomas with morphological features of anaplastic large-cell lymphoma which expressed one or more B-cell markers and lacked T-lineage markers. Clinical features were more in keeping with large B-cell lymphoma than with classical t(2;5)-positive anaplastic large-cell lymphoma, and immunostaining for anaplastic lymphoma kinase (ALK) protein provided no evidence for the (2;5) translocation (or one of its variants). The staining patterns for CD20 and CD79 were typical of diffuse large B-cell lymphoma, CD30 expression was variable, and most cases (15/22) lacked epithelial membrane antigen (EMA). These findings support the view that 'B-cell anaplastic large-cell lymphoma' is unrelated to t(2;5)-positive (ALK-positive) lymphoma, and that it represents a morphological pattern occasionally encountered among diffuse large B-cell lymphomas. By the same reasoning, most tumours diagnosed as 'ALK-negative anaplastic large-cell lymphoma of T-cell or null phenotype' probably belong to the spectrum of peripheral T-cell lymphomas.
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PMID:Anaplastic large-cell lymphomas of B-cell phenotype are anaplastic lymphoma kinase (ALK) negative and belong to the spectrum of diffuse large B-cell lymphomas. 1088 8

The t(12;21)(p13;q22) fusion gene is the most frequent genetic lesion described in precursor B cell acute lymphoblastic leukemia (ALL) of childhood occurring in a quarter of cases. This gene rearrangement is associated with a good outcome presenting a high response rate to chemotherapy. In spite of its potential clinical relevance, the t(12;21) translocation usually goes undetected with conventional cytogenetic procedures. In the present study we utilized an objective flow cytometric approach (multiparametric quantitative analysis) for the phenotypic characterization of this type of ALL. We studied a total of 74 precursor B-ALL children, including 21 t(12;21)+ and 53 t(12;21)- cases. Our results show that the t(12;21)(p13;q22)+ ALLs display a higher intensity of CD10 (P = 0.0016) and HLADR (P = 0.005) expression together with lower levels of the CD20 (P = 0.01), CD45 (P = 0.01), CD135 (P = 0.003) and CD34 (P = 0.03) antigens as compared to the t(12;21) cases. Moreover, as regards CD34 expression, we observed a more heterogeneous antigen expression within individual patients with higher coefficients of variation (median of 202 vs 88, P = 0.0001). A multi-variate analysis disclosed that with the immunophenotypic approach used identification of t(12;21)+ cases can be achieved with a sensitivity of 86% and a specificity of 100%. We conclude that childhood precursor B-ALL carrying the t(12;21) translocation display characteristic phenotypic features which could provide a rapid, simple, sensitive and specific screening method to select for those cases that should undergo confirmatory molecular analysis.
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PMID:Quantitative multiparametric immunophenotyping in acute lymphoblastic leukemia: correlation with specific genotype. I. ETV6/AML1 ALLs identification. 1091 46

Neutrophil-rich anaplastic large cell lymphoma (ALCL) is an uncommon morphologic variant of ALCL. We report 2 cases of neutrophil-rich T-cell ALCL that presented as scalp masses in HIV-positive men. Histologically, the neoplastic cells extensively infiltrated the dermis and subcutaneous tissue. The neoplastic cells strongly expressed CD30 and were of T-cell lineage, positive for CD3 and CD45RO, and negative for CD20. The neoplastic cells were negative for anaplastic lymphoma kinase-1. Numerous admixed neutrophils also were present, representing up to 70% of all cells in some microscopic fields. Neither patient had peripheral blood leukocytosis. One patient had relative neutrophilia, 79% (0.79; reference range, 50%-70% [0.50-0.70]). The absolute CD4 counts were 160 cells/microL (160 x 10(6)/L) and 150 cells/microL (150 x 10(6)/L), respectively (reference range, 431-1,623/microL [431-1,623 x 10(6)/L]). Both patients were treated with multiagent chemotherapy but died of Pneumocystis carinii pneumonia within 6 months of diagnosis. In our review of the literature, we identified 5 similar T-cell cases, including 1 in an HIV-positive patient. Neutrophil-rich T-cell ALCL is a rare morphologic variant of ALCL that should be considered in the histologic evaluation of neutrophil-rich biopsy specimens.
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PMID:Neutrophil-rich anaplastic large cell lymphoma of T-cell lineage. A report of two cases arising in HIV-positive patients. 1160 Nov 44

The acquisition of genetic abnormalities in human B-lineage acute lymphoblastic leukemia (ALL) culminates in the clonal expansion of bone marrow (BM)-derived leukemic blasts. However, the response of leukemic cells to signals transduced by the BM microenvironment is not completely understood. The present study describes a new human B-lineage ALL cell line designated BLIN-4 (B LINeage-4). BLIN-4 cells respond to multiple cytokines/human BM stromal cell-derived molecules. One subline (BLIN-4E) undergoes cell death in the absence of BM stromal cells or cytokines and slowly proliferates on human BM stromal cells supplemented with interleukin (IL)-7 + FLT3-ligand. Another subline (BLIN-4L) slowly proliferates in the absence of cytokines and BM stromal cells and shows robust proliferation on BM stromal cells supplemented with IL-7 + FLT3-ligand. Although human BM stromal cells are comparable with IL-7 + FLT3-ligand in supporting proliferation of BLIN-4L cells, neutralizing antibody experiments demonstrate that BLIN-4L expansion on BM stromal cells is IL-7/FLT3-ligand independent. BLIN-4L could also respond to human thymic stromal lymphopoietin. BLIN-4E and BLIN-4L have the identical immunoglobulin heavy chain rearrangement and a CD10(+)/CD19(+)/CD20(-)/CD22(+)/CD40(+)/mu heavy chain(-) phenotype. The original BM leukemic blasts harbored a ring chromosome 4 with a low percentage of cells also having either trisomy 8 or trisomy 18. The BLIN-4 sublines maintained the ring chromosome 4, but the trisomy 8 and trisomy 18 segregated into BLIN-4E and BLIN-4L, respectively. Thus, the BLIN-4 sublines exhibit biological characteristics consistent with a potential evolution in B-lineage ALL involving subclones with decreasing requirements on the BM microenvironment.
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PMID:Clonal variation in the B-lineage acute lymphoblastic leukemia response to multiple cytokines and bone marrow stromal cells. 1143 69

Clinically effective cancer immunotherapy has been sought for more than 100 years and has been recently applied most successfully in strategies that passively deliver immune effectors such as monoclonal antibodies (anti-CD20 for lymphoma and anti-HER2/neu for breast cancer), donor lymphocyte infusions in chronic myelongenous leukemia and non-myeloablative allogeneic peripheral blood progenitor transplants for renal cell carcinoma. There is mounting enthusiasm for strategies employing active stimulation of antitumour immune responses. These include vaccines based on tumour antigen proteins and peptides, autologous, allogeneic or gene-modified tumour cells, dendritic cells and antigen-encoding viral vector constructs. Indeed, randomised Phase III clinical trials of autologous tumour cell vaccines for colorectal cancer demonstrated an improvement in disease free survival and a trend toward improved overall survival [1]. Despite these preliminary successes, it is clear that the many strategies under development cannot all be evaluated for survival benefit in large clinical trials that require many years, patients and resources to complete. This highlights the need to develop intermediate markers to help prioritise which agents to test in prospective randomised Phase III trials.
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PMID:Surrogate markers of response to cancer immunotherapy. 1172 26

Phenotypic and genotypic analyses of cells are increasingly essential for understanding pathogenetic mechanisms as well as for diagnosing and classifying malignancies and other diseases. We report a novel multicolor approach based on the FICTION (fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms) technique, which enables the simultaneous detection of morphological, immunophenotypic, and genetic characteristics of single cells. As prerequisite, multicolor interphase fluorescence in situ hybridization assays for B-cell non-Hodgkin's lymphoma and anaplastic large-cell lymphoma have been developed. These assays allow the simultaneous detection of the most frequent primary chromosomal aberrations in these neoplasms, such as t(8;14), t(11;14), t(14;18), and t(3;14), and the various rearrangements of the ALK gene, respectively. To establish the multicolor FICTION technique, these assays were combined with the immunophenotypic detection of lineage- or tumor-specific antigens, namely CD20 and ALK, respectively. For evaluation of multicolor FICTION experiments, image acquisition was performed by automatic sequential capturing of multiple focal planes. Thus, three-dimensional information was obtained. The multicolor FICTION assays were applied to well-characterized lymphoma samples, proving the performance, validity, and diagnostic power of the technique. Future multicolor FICTION applications include the detection of preneoplastic lesions, early stage and minimal residual diseases, or micrometastases.
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PMID:Multicolor-FICTION: expanding the possibilities of combined morphologic, immunophenotypic, and genetic single cell analyses. 1216 66

In the past few years, new agents based on monoclonal antibodies have been developed in Oncology. Indeed in some case tumor cells express antigenic targets at higher levels than normal cells. There are 2 main types of monoclonal antibodies that can be either conjugated to cytotoxic drugs or radio-active compounds or be non-conjugated. Among the last category, some are currently used in the treatment of patients, including 2 monoclonal antibodies targeting receptors with tyrosine kinase activity (HER2: Herceptin (DCI: trastuzumab), EGFr: Erbitux (DCI: cetuximab). A third monoclonal antibody is commonly used in cancer treatment, which targets CD20, a transmembrane marker of B lymphoma (MabThera (DCI: rituximab). Both Herceptin and MabThera have been associated with improved survival in patients with breast carcinoma and lymphoma, respectively. New promising agents are under investigation such anti EGFr in colon and head and neck carcinoma or new compounds such as anti-VEGF. These examples outline the importance of the recent progress in selectively targeting tumor antigen and the potential impact of these approaches in Oncology.
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PMID:[Principal therapeutic uses of monoclonal antibodies in oncology]. 1258 79

Peripheral T-cell lymphoma primary to the central nervous system is a rare occurrence. The authors report a case of an 89-year-old woman who presented with a 3-month history of worsening confusion and recent onset of headache, nausea and vomiting, and upper limb tremors. Computed tomography and magnetic resonance imaging examinations demonstrated a 4.5-cm solitary brain mass in the right basal ganglia with compression along the ventricular system. No other lesion was found in the patient. Histologic and immunohistochemical studies of a stereotactic biopsy of the mass showed a T-cell lymphoproliferative lesion positive for CD3, CD8, CD57, and T-cell intracellular antigen 1 and negative for CD4, CD56, CD30, anaplastic lymphoma kinase, and CD20. A monoclonal T-cell receptor-gamma gene rearrangement was detected by polymerase chain reaction analysis of genomic DNA isolated from paraffin-embedded tumor tissue sections. These findings were consistent with peripheral T-cell lymphoma of cytotoxic/suppressor phenotype, resembling the phenotype of T-cell large granular cell leukemia. To the authors' best knowledge, this represents the first reported case of primary brain T-cell lymphoma with a cytotoxic/suppressor immunophenotype. A brief review of the literature of primary brain T-cell lymphoma is also presented.
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PMID:Primary central nervous system cytotoxic/suppressor T-cell lymphoma: report of a unique case and review of the literature. 1271 53


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