Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. 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. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Myeloid sarcoma (MS) is a rare neoplasm whose knowledge is largely based on case reports and/or technically dated contributions. Ninety-two MSs in adulthood with clinical data available were evaluated both morphologically and immunohistochemically. Seventy-four cases were also studied by fluorescent in situ hybridization on tissue sections and/or conventional karyotyping on bone marrow or peripheral blood. Histologically, 50% of the tumors were of the blastic type, 43.5% either monoblastic or myelomonocytic and 6.5% corresponded to different histotypes. CD68/KP1 was the most commonly expressed marker (100%), followed by myeloperoxidase (83.6%), CD117 (80.4%), CD99 (54.3%), CD68/PG-M1 (51%), CD34 (43.4%), terminal-deoxy-nucleotidyl-transferase (31.5%), CD56 (13%), CD61/linker for activation of T cells (2.2%), CD30 (2.2%) and CD4 (1.1%). Foci of plasmacytoid monocyte differentiation were observed in intestinal cases carrying inv16. Chromosomal aberrations were detected in about 54% of cases: monosomy 7(10.8%), trisomy 8(10.4%) and mixed lineage leukemia-splitting (8.5%) were the commonest abnormalities, whereas t(8;21) was rare (2.2%). The behavior was dramatic irrespective of presentation, age, sex, phenotype and cytogenetics. Most if not all, long survivors received bone-marrow transplantation. The present report expands the spectrum of our knowledge showing that MS has frequent monoblastic/myelomonocytic differentiation, displays distinctive phenotypic profile, carries chromosomal aberrations other than t(8;21), and requires supra-maximal therapy.

Peripheral T cell lymphoma, unspecified (PTCL/U), the most common form of PTCL, displays heterogeneous morphology and phenotype, poor response to treatment, and poor prognosis. We demonstrate that PTCL/U shows a gene expression profile clearly distinct from that of normal T cells. Comparison with the profiles of purified T cell subpopulations (CD4⁺, CD8⁺, resting [HLA-DR^–], and activated [HLA-DR⁺]) reveals that PTCLs/U are most closely related to activated peripheral T lymphocytes, either CD4⁺ or CD8⁺. Interestingly, the global gene expression profile cannot be surrogated by routine CD4/CD8 immunohistochemistry. When compared with normal T cells, PTCLs/U display deregulation of functional programs often involved in tumorigenesis (e.g., apoptosis, proliferation, cell adhesion, and matrix remodeling). Products of deregulated genes can be detected in PTCLs/U by immunohistochemistry with an ectopic, paraphysiologic, or stromal location. PTCLs/U aberrantly express, among others, PDGFRα, a tyrosine-kinase receptor, whose deregulation is often related to a malignant phenotype. Notably, both phosphorylation of PDGFRα and sensitivity of cultured PTCL cells to imatinib (as well as to an inhibitor of histone deacetylase) were found. These results, which might be extended to other more rare PTCL categories, provide insight into tumor pathogenesis and clinical management of PTCL/U.

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

One-third of peripheral T-cell lymphomas are “not otherwise specified” (PTCL-NOS), but they have been subdivided into 2 subgroups based on gene expression profiling. Amador and colleagues generated an immunohistochemical algorithm that parallels the molecular separation of PTCL-NOS and provides useful prognostic information.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary end points were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced-stage disease. Eighty-one percent received anthracycline-based regimens, and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ≥60 years, Eastern Cooperative Oncology Group performance status >2, elevated C-reactive protein, and elevated β2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low-, intermediate-, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared with only 6% for patients with POD24 (P < .0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need, and novel therapeutic approaches are required.