Lineage-negative lymphoma with a helper innate lymphoid cell phenotype

Helper innate lymphoid cells (ILCs) were recently recognized as lineage-negative lymphoid cells that do not express rearranged receptors and have important effector and regulatory functions in innate immunity. However, to our knowledge, no cases of hematological malignancies arising from helper ILCs have ever been reported in the literature. Here, we report a case of a 17-year-old man with multiple lymphadenopathy who was diagnosed with lineage-negative lymphoma that displayed a helper ILC phenotype. Histological examination showed large monomorphic atypical lymphoid cells with prominent nucleoli and abundant eosinophilic cytoplasms with scattered and patchy distributions. Large amounts of histiocytes and infiltrating lymphocytes were observed in the background. Immunostaining revealed positive LCA and CD79a expression but negative expression of all lineage markers. IG and TCR rearrangement analysis showed no clonal rearrangements. Tumor cells strongly expressed helper ILC phenotypic markers, such as CD127, IL-1R, GATA3, ST2, IL-17Rβ, and RANKL, and helper ILC-produced cytokines, such as IL-4 and GM-CSF. PD-L1/PD-L2-positive histiocytes and FOXP3-positive Tregs were observed in the tumor microenvironment. Flow cytometry of bone marrow at recurrence was positive for IL-1R and negative for T, B, NK, and myelogenous lineage markers. TP53 sequencing showed that exon 5 was replaced with an intergenic sequence of chromosome 21. Next-generation sequencing demonstrated a novel IGLV2-14/IGLL5 fusion and mutations or deletions of tumor suppressor genes, such as PTPRB, PPP2CB, and UPK1A. This tumor was very aggressive, resistant to chemotherapy, recurred with bone marrow involvement, and caused the death of the patient within 6 months. To our knowledge, this is the first report of a hematological malignancy potentially arising from helper ILCs. We propose negativity for lineage markers and positivity for CD127/IL-1R in combination with specific transcription factor expression as markers of this tumor. This finding represents a novel addition to the growing spectrum of hematological malignancies.