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Regular Articles |
From the Institutes of Hematology*
and Internal
Medicine,
University of Perugia, Perugia, Italy;
University Department of Cellular Science,
John
Radcliffe Hospital, Oxford, United Kingdom; Institute of
Pathology,§
University of Bologna, Bologna, Italy;
Institute of Pathology,¶
Purpan Hospital, Toulouse,
France; Department of Pathology,||
Centro Oncologico
Aviano, Aviano, Italy; Institute of Pathology,**
University of Pavia,
Pavia, Italy; Institute of Pathology,
University of
Verona, Verona, Italy; Istituto Nazionale Tumori,
Milan, Italy; and Istituto Oncologico Europeo,§§
Milan, Italy.
The t(2;5)(p23;q35) translocation associated with CD30-positive anaplastic large cell lymphoma results in the production of a NPM-ALK chimeric protein, consisting of the N-terminal portion of the NPM protein joined to the entire cytoplasmic domain of the neural receptor tyrosine kinase ALK. The ALK gene products were identified in paraffin sections by using a new anti-ALK (cytoplasmic portion) monoclonal antibody (ALKc) that tends to react more strongly than a previously described ALK1 antibody with the nuclei of ALK-expressing tumor cells after microwave heating in 1 mmol/L ethylenediaminetetraacetic acid buffer, pH 8.0. The ALKc monoclonal antibody reacted selectively with 60% of anaplastic large cell lymphoma cases (60 of 100), which occurred mainly in the first three decades of life and consistently displayed a T/null phenotype. This group of ALK-positive tumors showed a wide morphological spectrum including cases with features of anaplastic large cell lymphoma "common" type (75%), "lymphohistiocytic" (10%), "small cell" (8.3%), "giant cell" (3.3%), and "Hodgkin's like" (3.3%). CD30-positive large anaplastic cells expressing the ALK protein both in the cytoplasm and nucleus represented the dominant tumor population in the common, Hodgkin's-like and giant cell types, but they were present at a smaller percentage (often with a perivascular distribution) also in cases with lymphohistiocytic and small cell features. In this study, the ALKc antibody also allowed us to identify small neoplastic cells (usually CD30 negative) with nucleus-restricted ALK positivity that were, by definition, more evident in the small cell variant but were also found in cases with lymphohistiocytic, common, and "Hodgkin's-like" features. These findings, which have not been previously emphasized, strongly suggest that the neoplastic lesion (the NPM-ALK gene) must be present both in the large anaplastic and small tumor cells, and that ALK-positive lymphomas lie on a spectrum, their position being defined by the ratio of small to large neoplastic cells. Notably, about 15% of all ALK-positive lymphomas (usually of the common or giant cell variant) showed a cytoplasm-restricted ALK positivity, which suggests that the ALK gene may have fused with a partner(s) other than NPM. From a diagnostic point of view, detection of the ALK protein was useful in distinguishing anaplastic large cell lymphoma cases of lymphohistiocytic and small cell variants from reactive conditions and other peripheral T-cell lymphoma subtypes, as well as for detecting a small number of tumor cells in lymphohemopoietic tissues. In conclusion, ALK positivity appears to define a clinicopathological entity with a T/null phenotype ("ALK lymphomas"), but one that shows a wider spectrum of morphological patterns than has been appreciated in the past.
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L. Hernandez, M. Pinyol, S. Hernandez, S. Bea, K. Pulford, A. Rosenwald, L. Lamant, B. Falini, G. Ott, D. Y. Mason, et al. TRK-Fused Gene (TFG) Is a New Partner of ALK in Anaplastic Large Cell Lymphoma Producing Two Structurally Different TFG-ALK Translocations Blood, November 1, 1999; 94(9): 3265 - 3268. [Abstract] [Full Text] [PDF]
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W. Pfeifer, E. Levi, T. Petrogiannis-Haliotis, L. Lehmann, Z. Wang, and M. E. Kadin A Murine Xenograft Model for Human CD30+ Anaplastic Large Cell Lymphoma : Successful Growth Inhibition with an Anti-CD30 Antibody (HeFi-1) Am. J. Pathol., October 1, 1999; 155(4): 1353 - 1359. [Abstract] [Full Text] [PDF]
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A. Rosenwald, G. Ott, K. Pulford, T. Katzenberger, J. Kuhl, J. Kalla, M. M. Ott, D. Y. Mason, and H. K. Muller-Hermelink t(1;2)(q21;p23) and t(2;3)(p23;q21): Two Novel Variant Translocations of the t(2;5)(p23;q35) in Anaplastic Large Cell Lymphoma Blood, July 1, 1999; 94(1): 362 - 364. [Abstract] [Full Text] [PDF]
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K. Pulford, B. Falini, J. Cordell, A. Rosenwald, G. Ott, H.-K. Muller-Hermelink, K. A. MacLennan, L. Lamant, A. Carbone, E. Campo, et al. Biochemical Detection of Novel Anaplastic Lymphoma Kinase Proteins in Tissue Sections of Anaplastic Large Cell Lymphoma Am. J. Pathol., June 1, 1999; 154(6): 1657 - 1663. [Abstract] [Full Text] [PDF]
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B. Falini, S. Pileri, P. L. Zinzani, A. Carbone, V. Zagonel, C. Wolf-Peeters, G. Verhoef, F. Menestrina, G. Todeschini, M. Paulli, et al. ALK+ Lymphoma: Clinico-Pathological Findings and Outcome Blood, April 15, 1999; 93(8): 2697 - 2706. [Abstract] [Full Text] [PDF]
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J. L. Cordell, K. A.F. Pulford, B. Bigerna, G. Roncador, A. Banham, E. Colombo, P.-G. Pelicci, D. Y. Mason, and B. Falini Detection of Normal and Chimeric Nucleophosmin in Human Cells Blood, January 15, 1999; 93(2): 632 - 642. [Abstract] [Full Text] [PDF]
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