Lymphoma Disease Discovery and Definition

Division Of Clinical Sciences - Nci

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Abstract

Pediatric nodal marginal zone lymphoma (PNMZL) is an uncommon B-cell neoplasm affecting mainly male children and young adults. This indolent lymphoma has distinct characteristics that differ from conventional nodal marginal zone lymphoma (NMZL). Clinically, it shows overlapping features with pediatric-type follicular lymphoma (PTFL). To explore the differences between PNMZL and adult NMZL and its relationship to PTFL, a series of 45 PNMZL cases was characterized morphologically and genetically using an integrated approach including whole exome sequencing in a subset of cases, targeted next generation sequencing, and copy number (CN) and DNA methylation arrays. Fourteen cases (31%) were diagnosed as PNMZL, whereas 31 cases (69%) showed overlapping histological features between PNMZL and PTFL including a minor component of residual serpiginous germinal centers reminiscent of PTFL and a dominant interfollicular B-cell component characteristic of PNMZL. All cases displayed low genomic complexity (1.2 alterations/case) with recurrent 1p36/TNFRSF14 copy number-neutral loss of heterozygosity alterations and CN loss (11%). Similar to PTFL, the most frequently mutated genes in PNMZL were MAP2K1 (42%), TNFRSF14 (36%), and IRF8 (34%) DNA-methylation analysis showed no major differences between PTFL and PNMZL. Genetic alterations typically seen in conventional NMZL, were absent in PNMZL. In summary, we demonstrated overlapping clinical, morphological and molecular findings including low genetic complexity, recurrent alterations in MAP2K1, TNFRSF14 and IRF8, and similar methylation profiles. Our results indicate that PNMZL and PTFL are likely part of a single disease with variation in the histological spectrum. As a single entity, it could designated as pediatric-type follicular lymphoma, with or without marginal zone differentiation. Extranodal forms of follicular lymphoma differ from nodal follicular lymphoma based on the frequent absence of BCL2-rearrangement (BCL2-R) and the tendency to remain confined to the skin without dissemination. The nature of other extranodal follicular lymphoma, including those of the lower female genital tract, is not well defined. We studied 15 cases of follicular lymphoma of the lower female genital tract involving cervix and vagina to determine their clinicopathological and molecular characteristics. All patients had localized disease, with no evidence of bone marrow involvement. The majority of cases had a diffuse pattern and large centrocytes were a prominent feature. This led to the concern for diffuse large B-cell lymphoma by most referring pathologists. All the cases had a follicle center derivation. The majority (91%) were negative for BCL2 gene rearrangement by FISH. NGS showed these cases specifically lacked mutations in chromatin modifying genes (CREBBP and KMT2D) which are hallmark of nodal FL. The most mutated gene was TNFRSF14(60% cases). None of the patients had progressive disease with all achieving durable complete remission regardless of the treatment received. Median follow-up period was 7.8 years (range: 0.2-20.5 years and mean: 8.9 years) with 100% overall survival. Together these findings show that this tumor distinct from nodal FL and is clinicopathologically and molecularly like primary cutaneous follicle center lymphoma. Despite component of large cells, it is characterized by limited stage presentation and invariably benign behavior. Awareness and recognition of this entity is very important to distinguish it from higher grade lymphomas and to prevent unnecessary treatment as it remains localized with low risk of progression and relapse. This work was presented orally at the pathology meetings in 2022, and is being prepared for final publication. 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. 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. Some categories considered provisional are now upgraded to definite entities. 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. The conclusions of this work are summarized in our published report in 2022 as the proposed International Consensus Classification (ICC) of mature lymphoid, histiocytic, and dendritic cell tumors.