ALK EXPRESSION DEFINES A DISTINCT GROUP OF T NULL LYMPHOMAS (ALK LYMPHOMAS) WITH A WIDE MORPHOLOGICAL SPECTRUM/

The t(2;5)(p23;q35) translocation associated with CD30-positive anapla stic large cell lymphoma results in the production of a NPM-ALK chimer ic protein, consisting of the N-terminal portion of the NPM protein jo ined 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 (AL Kc) that tends to react more strongly than a previously described ALK1 antibody with the nuclei of ALK-expressing tumor cells after microwav e heating in 1 mmol/L ethylenediaminetetraacetic add buffer, pH 8.0. T he ALKc monoclonal antibody reacted selectively with 60% of anaplastic large cell lymphoma cases (60 of 100), which occurred mainly in the f irst three decades of life and consistently displayed a T/null phenoty pe. This group of ALK-positive tumors showed a wide morphological spec trum 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-positiv e large anaplastic cells expressing the ALK protein both in the cytopl asm and nucleus represented the dominant tumor population in the commo n, Hodgkin's-like and percentage (often with a perivascular distributi on) also in cases with lymphohistiocytic and small cell features. In t his study, the ALKc antibody also allowed us to identify small neoplas tic cells (usually CD30 negative) with nucleus-restricted ALK positivi ty that were, by definition, more evident in the small cell variant bu t were also found in cases with lymphohistiocytic, common, and ''Hodgk in's-like'' features. These findings, which have not been previously e mphasized, strongly suggest that the neoplastic lesion (the NPM-ALK ge ne) must be present both in the large anaplastic and small tumor cells , and that ALK-positive lymphomas lie on a spectrum, their position be ing defined by the ratio of small to large neoplastic cells. Notably, about 15% of all ALK-positive lymphomas (usually of the common or gian t cell variant) showed a cytoplasm-restricted ALK positivity, which su ggests that the ALK gene may have fused with a partner(s) other than N PM. From a diagnostic point of view, detection of the ALK protein was useful in distinguishing anaplastic large cell lymphoma cases of lymph ohistiocytic and small cell variants from reactive conditions and othe r peripheral T-cell lymphoma subtypes, as well as for detecting a smal l number of tumor cells in lymphohemopoietic tissues. In conclusion, A LK positivity appears to define a clinicopathological entity with a T/ null phenotype (''ALK lymphomas''), but one that shows a wider spectru m of morphological patterns than has been appreciated in the past.