Spatial architecture and malignant cell characterization of nodular lymphocyte-predominant Hodgkin lymphoma
Manabu Fujisawa
MD, PhDBC Cancer
Project Term: July 1, 2024 - June 30, 2026
Nodular lymphocyte-predominant Hodgkin lymphoma is recognized as a disease entity in a spectrum of related diseases, including T-cell rich B-cell lymphoma. Although treatments are generally effective, a subset of patients suffers from lymphoma progression and aggressive disease transformations. Here, we propose to analyze clonal evolution of tumor cells and describe the spatial architecture of tissues with the goal to improve molecular classification and develop novel therapeutic approaches.
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) was initially considered a subtype of Hodgkin lymphoma based on tumor cell morphology (LP cells), also known as "popcorn cells," and the characteristic tumor microenvironment (TME). However, clear differences in pathology, biology, and clinical behavior compared to classical Hodgkin lymphoma (cHL) led to its renaming as nodular lymphocyte-predominant B-cell lymphoma (NLPBL) in the current International Consensus Classification (ICC). The pathological 'Fan' patterns A, B, and C are classified as "typical" or grade 1, while patterns D, E, and F are considered "variant" and are grade 2. T-cell/histiocyte-rich large B-cell lymphoma (THRBCL) is part of the "variant" NLPHL continuum. While NLPHL often follows an indolent course and may be managed with a 'watch and wait' strategy, some cases, including THRBCL, can progress aggressively. Cases with “variant” may require treatment similar to large B-cell lymphoma (LBCL), but the efficacy of identical treatment strategies is uncertain due to the unique tumor microenvironment seen in the NLPBL/THRBCL spectrum. Thus, understanding the biological underpinnings of the diagnostic continuum between NLPHL, THRBCL, and transformed LBCL is essential. NLPHL/THRBCL may potentially originate from progressive transformation of germinal centers (PTGC), supported by common immunoarchitectural patterns. However, it's unclear whether PTGC harbor clonally related precursor lesions of NLPHL/THRBCL. This study proposes two specific aims: Aim 1) To elucidate the clonal evolutionary mechanisms of NLPHL/THRBCL through genetic mutation analysis on LP cells, germinal center B (GCB) cells from PTGC/NLPHL/THRBCL, and post-transformed LBCL cells. Aim 2) To characterize the tumor microenvironment of NLPHL/THRBCL using spatial transcriptomics on tissue microarrays. Genomic alterations in acquired immune tolerance mechanisms, as discovered in cHL, suggest potential therapeutic avenues for lymphoid cancers, including NLPHL. A combined approach of cancer genomics and imaging is crucial for understanding the cellular ecology and interplay within cancer.