ALK expression defines a distinct group of T/null lymphomas ('ALK lymphomas') with a wide morphological spectrum

Brunangelo Falini, Barbara Bigerna, Marco Fizzotti, Karen Pulford, Stefano A. Pileri, Georges Delsol, Antonino Carbone, Marco Paulli, Umberto Magrini, Fabio Menestrina, Roberte Giardini, Silvana Pilotti, Alessandra Mezzelani, Barbara Ugolini, Monia Billi, Alessandra Pucciarini, Roberta Pacini, Pier Giuseppe Pelicci, Leonardo Flenghi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)875-886
Number of pages12
JournalAmerican Journal of Pathology
Issue number3
Publication statusPublished - Sep 1998

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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