Pitfalls in the Diagnosis of Nodular Lymphocyte Predominant Hodgkin Lymphoma: Variant Patterns, Borderlines and Mimics

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) represents approximately 5% of Hodgkin lymphoma and typically affects children and young adults. Although the overall prognosis is favorable, variant growth patterns in NLPHL correlate with disease recurrence and progression to T-cell/histiocyte-rich large B-cell lymphoma or frank diffuse large B-cell lymphoma (DLBCL). The diagnostic boundary between NLPHL and DLBCL can be difficult to discern, especially in the presence of variant histologies. Both diagnoses are established using morphology and immunophenotype and share similarities, including the infrequent large tumor B-cells and the lymphocyte and histiocyte-rich microenvironment. NLPHL also shows overlap with other lymphomas, particularly, classic Hodgkin lymphoma and T-cell lymphomas. Similarly, there is overlap with non-neoplastic conditions, such as the progressive transformation of germinal centers. Given the significant clinical differences among these entities, it is imperative that NLPHL and its variants are carefully separated from other lymphomas and their mimics. In this article, the characteristic features of NLPHL and its diagnostic boundaries and pitfalls are discussed. The current understanding of genetic features and immune microenvironment will be addressed, such that a framework to better understand biological behavior and customize patient care is provided.