Lymphoma Disease Discovery and Definition

Division Of Clinical Sciences - Nci

Investigators

Linked publications & trials

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. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Terminology of 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. Primary cutaneous follicle center lymphoma has been distinguished from nodal follicular lymphoma based on genomic and clinical features. The nature of other extranodal follicular lymphomas is not well defined. We reported 15 cases of follicle center lymphoma involving the lower female genital tract. Cases were evaluated using an immunohistochemical panel for B-cell lymphoma, B-cell clonality, fluorescence in situ hybridization for BCL2 gene rearrangement, and next-generation sequencing. All patients had localized disease with no evidence of bone marrow involvement. Most cases (12/15, 80%) had a follicular pattern, at least focally. Large centrocytes were a prominent feature leading to concern for diffuse large B-cell lymphoma by referring pathologists. Neoplastic cells were positive for CD20 and BCL-6, while BCL-2 was positive in 2/15 (13%) cases. Fluorescence in situ hybridization for BCL2 gene rearrangement was negative in 10/11 (91%) cases. Next-generation sequencing performed in 10 cases revealed TNFRSF14 as the most frequently mutated gene in 6/10 (60%) cases. No case had CREBBP or KMT2D mutations as seen in nodal FL. None of the patients had progressive disease with durable complete remission achieved in 10/12 (83%) cases. The median follow-up period was 7.8 years (range: 0.2 to 20.5 y) with a 5-year overall survival of 100%. We concluded that follicle center lymphoma of the lower female genital tract is a novel variant of primary cutaneous follicle center lymphoma. Despite a frequent component of large cells, it is characterized by localized disease and low risk for dissemination. Awareness and recognition are important to distinguish these lesions from aggressive B-cell lymphomas. We have been exploring the clinical and genomic heterogeneity of histiocytic neoplasms, with new data on phenotypic markers helpful for diagnosis. We recently observed the differential expression of another marker - macrophage colony stimulating factor receptor or colony stimulating factor-1 receptor (CSF1R/CD115) - between the dendritic cells of dermatopathic lymphadenitis and and the lesional cells of Langerhans cell histiocytosis (LCH). In published work we showed its value in the diagnosis of Langerhans cell neoplasms. Indeterminate cell histiocytosis (ICH) is a rare subtype of histiocytic neoplasm, first described in 1985. It is characterized by a proliferation of histiocytes, which mimic the neoplastic cells of the Langerhans cell histiocytosis) cytologically and immunophenotypically (positive for CD1a and S100 protein) but lack Langerin and Birbeck granules characteristic of LCH. The ICH has been documented in sporadic case reports and small case series and proposed to be a unique entity with recurrent ETV3::NCOA2 fusions. The full clinicopathologic and molecular spectra of ICH remain, however, poorly characterized. In hopes of clarifying the clinical and molecular features of ICH, we assembled ICH patient data across 2 institutions in Europe and the United States with a specific research focus on histiocytosis. We have compiled the largest study of ICH to date, with detailed clinicopathologic data of 33 patients. We show major differences between primary and secondary ICH. Primary cases mainly present in the skin, and have a mostly benign clinical course, whereas secondary cases arising with other lymphoid or myeloid neoplasms, have more aggressive behavior. Our findings highlighted genetic heterogeneity with common occurrence of MAPK pathway alterations. This work was presented at the USCAP meeting in 2023 and received an award from the Society for Hematopathology for the best paper presented by a trainee (resident or fellow).