Lymphoma Disease Discovery and Definition

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994, subsequent updates of the classification of mature lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years, with many new insights provided by genomic studies, have changed the definition of some entities, and have led to the recognition of other entities. With my collaborators, I have led a major international effort to update the classification of lymphoid neoplasms, culminating in the publication of the International Consensus Classification in 2022, and a series of follow-up articles in 2023. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. As an author of a collaborative report, we have addressed differences between the ICC and WHO classifications, and strategies to resolve discrepancies, with proposals to achieve consensus for the 6th Edition of the WHO classification. This consensus report was published in 2024 in the Journal of Clinical Oncology. Recent studies have been conducted related to neoplasms derived from B-cells, T-cells and histiocytes. The proper categorization of mature T-cell neoplasms with co-expression of CD30/CD15 is unresolved. Prior studies suggested overlap with ALK-negative anaplastic large cell lymphoma (ALCL). We evaluated the morphologic, immunophenotypic, and molecular features of 28 T-cell lymphomas co-expressing CD30/CD15, and performed a comparison with 8 ALK/CD15-negative ALCL and published data. Clinical information was retrieved from the submitting physician. Immunohistochemistry, TRG and IG gene rearrangement, DNA and RNA targeted next-generation sequencing, and fluorescence in situ hybridization for DUSP22 rearrangement were performed. Cases were classified as conforming to three histological variants: ALCL-like, Hodgkin-like, and PTCL-NOS-like. The JAK-STAT pathway was frequently altered due to mutations in JAK1, STAT3 and JAK2 fusions. PI3K-AKT-mTOR pathway alterations due to PIK3R1 mutations were also frequent and mutually exclusive with JAK-STAT pathway activation. In summary, most T-cell neoplasms with CD30/CD15 co-expression share clinical, morphologic, immunophenotypic, and molecular features with ALK-negative ALCL but do not segregate as a homogeneous entity as defined by histological or genetic features. Turning to B-cell lymphomas, pediatric-type follicular lymphoma (PTFL) is a rare and indolent B-cell lymphoma that mostly affects children and young adults. Although typically nodal, rare lesions have been reported in the conjunctiva. We identified 22 conjunctival lymphoid lesions in patients aged 7 to 33 years, with a male predominance (20 males and 2 females). Our findings broaden the clinical and anatomic spectrum of PTFL. Similar to nodal PTFL, cases in the conjunctiva can show evidence of marginal zone differentiation, suggesting this is a spectrum of one disease. This study underscores the need for integrated histologic and molecular assessment in pediatric conjunctival lymphoid proliferations to ensure accurate classification. We have also uncovered new insights into the diagnosis of histiocytic neoplasms. Indeterminate dendritic cell histiocytosis (IDCH) is a rare and poorly understood entity characterized by accumulation of CD1a+/S100+ histiocytes , but with reduced-absent expression of Langerin/CD207. We assembled 43 cases of IDCH (defined by CD1a+/CD207<20% immunophenotypic profile) and examined the clinical, pathologic, and molecular landscape. Median age at presentation was 70. Eighteen (42%) individuals had an associated non-histiocytic hematopoietic neoplasm ('secondary' IDCH) while 7 of 43 (16%) had a concurrent non-IDCH histiocytosis ('mixed' histiocytosis). Most cases exhibited morphology indistinguishable from LCH but with CD1c+/CSF1R(CD115)-phenotype, mirroring the signature of normal indeterminate cells and conventional dendritic cell type 2. Mutational analysis revealed frequent KRAS (13/32; 41%), and BRAF p.V600E (11/36, 31%) mutations that were nearly mutually exclusive. RNAseq analysis uncovered ETV3::NCOA2 fusion in 6 other patients presenting as a sole genetic alteration without any other concurrent histiocytic or hematopoietic neoplasm. BRAF and MAP2K1 alterations were significantly associated with partial/retained (1-20%). Paired sequencing of IDCH and concurrent non-IDCH hematopoietic neoplasm in four individuals revealed shared mutations. Age at diagnosis and any nodal involvement at diagnosis predicted inferior overall survival, but BRAF/RAS pathway alterations did not impact outcome. These data have implications for the diagnostic evaluation, classification, and therapeutic management of Indeterminate dendritic cell histiocytosis.