Intratumoral heterogeneity in anaplastic large cell lymphoma of non-common subtype

Abstract

ALK-positive anaplastic large cell lymphoma (ALCL) with identical primary genetic aberration present with variable morphology. The eponymous anaplastic large cell morphology can be detected in the majority cases which are described as being of common type morphology. However, morphological variants displaying small tumor cells that are barely distinguishable from reactive lymphocytes occur often in combination with classical large tumor cells and characterize so-called non-common type ALCL. This subgroup has recently been shown to be associated with a weak immune response to the ALK1 protein and a poorer outcome in children. Expression of T cell markers like CD3 is often reduced or absent in these lymphomas, probably as a direct effect of the ALK1 protein. In non-common type ALCL, the expression of ALK is restricted to the nucleus, suggesting reduced activity of the enzyme. The goal of the present study was to gain insight into the intratumoral heterogeneity of these lymphomas and to understand how T cell marker expression is distributed among tumor cells. We analyzed the immunophenotype of ALK1-positive ALCL in 41 pediatric patients by fluorescence multi-staining and subsequent digital image analysis. The small tumor cells in non-common type ALCL expressed larger amounts of T cell surface markers such as CD3, CD5, and CD8 but less CD30 compared to the large tumor cells. Expression of ALK1 and phosphorylated STAT3 as well as cell proliferation measured by positivity for Ki67 was reduced in the small cells of non-common type ALCL. These data demonstrate heterogeneity of the immunophenotype of tumor cells within non-common type ALCL suggestive for differentiation of small tumor cells, thereby providing a possible first explanation for the reduced immunogenicity of non-common type ALCL.