title: ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum.
abstract: 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 paraffm 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.
authors.affiliation: Institute of Hematology, University of Perugia, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Falini
authors.forename: B
authors.initials: B
authors.lastname: Bigerna
authors.forename: M
authors.initials: M
authors.lastname: Fizzotti
authors.forename: K
authors.initials: K
authors.lastname: Pulford
authors.forename: S A
authors.initials: SA
authors.lastname: Pileri
authors.forename: G
authors.initials: G
authors.lastname: Delsol
authors.forename: A
authors.initials: A
authors.lastname: Carbone
authors.forename: M
authors.initials: M
authors.lastname: Paulli
authors.forename: U
authors.initials: U
authors.lastname: Magrini
authors.forename: F
authors.initials: F
authors.lastname: Menestrina
authors.forename: R
authors.initials: R
authors.lastname: Giardini
authors.forename: S
authors.initials: S
authors.lastname: Pilotti
authors.forename: A
authors.initials: A
authors.lastname: Mezzelani
authors.forename: B
authors.initials: B
authors.lastname: Ugolini
authors.forename: M
authors.initials: M
authors.lastname: Billi
authors.forename: A
authors.initials: A
authors.lastname: Pucciarini
authors.forename: R
authors.initials: R
authors.lastname: Pacini
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
authors.forename: L
authors.initials: L
authors.lastname: Flenghi
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000911:Antibodies, Monoclonal / Q000276:immunology; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells / Q000201:enzymology; D006413:Hematopoietic System / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000473:pathology; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D011993:Recombinant Fusion Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases