What is the pathophysiology and genetics of Pediatric Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)?

Pathophysiology and Genetics of Pediatric Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

Cellular Pathophysiology

The defining pathologic feature of pediatric NLPHL is the presence of lymphocyte-predominant (LP) cells, also termed "popcorn cells" or "lymphocytic and histiocytic" (L&H) cells, which are malignant B-cells surrounded by a nodular background of non-neoplastic small B-lymphocytes. 1, 2

Malignant Cell Characteristics

The LP cells in NLPHL demonstrate a fundamentally different cellular origin and immunophenotype compared to classical Hodgkin lymphoma:

• LP cells are mature B-cells that have undergone germinal center differentiation, maintaining their B-cell identity throughout malignant transformation 2
• These cells arise from germinal center B-cells that have escaped normal apoptotic mechanisms, allowing continued survival and proliferation 2
• The malignant LP cells constitute only a small fraction of the total cellular population within affected lymph nodes, typically representing 0.1-1% of cells, with the remainder being reactive inflammatory infiltrate 3

Immunophenotypic Profile

The immunophenotype of LP cells is pathognomonic and critical for diagnosis:

• LP cells consistently express CD20, CD45, CD79a, BCL6, and PAX-5 (all B-cell markers) 1
• LP cells are uniformly negative for CD15 and CD30, which distinguishes them from Reed-Sternberg cells of classical Hodgkin lymphoma 1, 2
• CD3 is negative, confirming B-cell rather than T-cell lineage 1
• This immunophenotype reflects the preserved B-cell program in LP cells, unlike the near-complete loss of B-cell identity seen in classical Hodgkin lymphoma 2

Microenvironmental Architecture

Nodular Growth Pattern

NLPHL demonstrates a characteristic nodular or nodular-and-diffuse growth pattern, with LP cells residing within expanded B-cell-rich nodules that resemble disrupted germinal centers. 2

• The nodular architecture consists of LP cells surrounded by small B-lymphocytes forming rosettes around the malignant cells 2
• These nodules contain follicular dendritic cell meshworks that support the LP cells 2
• The background lymphocytes are predominantly CD20+ B-cells, contrasting with the T-cell-rich background of classical Hodgkin lymphoma 2

Immunoarchitectural Patterns (IAPs)

Recent classification recognizes distinct immunoarchitectural patterns that may have clinical implications:

• Six IAPs have been described based on the distribution of B-cells, T-cells, and follicular dendritic cells 4
• IAP E (a specific pattern with increased T-cell infiltration) has been associated with higher risk of transformation to aggressive B-cell lymphoma (hazard ratio 1.81) 4
• However, IAPs were not independently associated with progression-free survival or overall survival in the largest international study 4

Genetic and Molecular Pathogenesis

Clonality and Genetic Rearrangements

LP cells are clonal B-cells that harbor immunoglobulin heavy chain variable region (IGHV) gene rearrangements, confirming their origin from a single transformed germinal center B-cell. 1

• Polymerase chain reaction (PCR) for IGHV gene rearrangements can establish clonality when diagnosis is uncertain 1
• The presence of somatic hypermutations in the immunoglobulin genes indicates that LP cells have undergone germinal center selection 2
• Ongoing somatic hypermutation may occur in LP cells, suggesting continued interaction with the germinal center microenvironment 2

Chromosomal Abnormalities

While specific recurrent chromosomal translocations have not been definitively established as pathognomonic for NLPHL:

• FISH (fluorescence in situ hybridization) for major translocations may be performed when diagnosis is equivocal 1
• Unlike some other B-cell lymphomas, NLPHL lacks the characteristic translocations seen in follicular lymphoma (t(14;18)) or mantle cell lymphoma (t(11;14)) 1
• Cytogenetic analysis may reveal various chromosomal abnormalities, but no single defining translocation has been identified 1

Molecular Signaling Pathways

The pathogenesis involves dysregulation of normal B-cell survival and differentiation pathways:

• BCL6 expression in LP cells indicates active germinal center B-cell programming, which normally regulates B-cell differentiation 1
• The CD20 positivity makes LP cells susceptible to anti-CD20 targeted therapy (rituximab), which has shown efficacy in pediatric NLPHL 5, 6
• Loss of normal apoptotic mechanisms allows LP cells to survive beyond their normal lifespan in the germinal center 2

Clinical-Pathologic Correlations in Pediatric Patients

Age and Presentation Patterns

Pediatric NLPHL comprises less than 10% of all Hodgkin lymphoma cases in children, with a median age at diagnosis of approximately 12 years and marked male predominance (male-to-female ratio approximately 9:1). 5, 6

• The disease typically presents with indolent lymphadenopathy that may precede diagnosis by months to years 5
• Most pediatric patients (approximately 84%) present with early-stage disease (stage I-II) 6
• B symptoms (fever, night sweats, weight loss >10%) are rare, occurring in less than 10% of pediatric cases 5, 2

Biological Behavior

The pathophysiology translates to distinct clinical behavior:

• NLPHL follows an indolent clinical course with excellent overall survival (100% in pediatric series) but a pattern of late relapses and potential transformation to aggressive B-cell lymphoma. 5, 6
• The 5-year progression-free survival in pediatric patients is approximately 81.6%, reflecting the tendency for late relapses 6
• Transformation to diffuse large B-cell lymphoma occurs in approximately 4.8% of cases at 10 years, with IAP E pattern conferring higher risk 4
• Splenic involvement, when present, indicates more aggressive biology and worse prognosis 4

Prognostic Factors

The recently developed Lymphocyte-Predominant International Prognostic Score (LP-IPS) identifies high-risk patients based on biological and clinical factors:

• Risk factors include age ≥45 years (less relevant in pediatrics), stage III-IV disease, hemoglobin <10.5 g/dL, and splenic involvement, with each factor contributing 1 point. 4
• Increasing LP-IPS score correlates with worse progression-free survival (HR 1.52), overall survival (HR 2.31), and transformation risk (HR 1.41) 4
• In pediatric patients, stage III-IV disease, hemoglobin <10.5 g/dL, and splenic involvement are the most relevant prognostic factors 4

Diagnostic Implications

The unique pathophysiology necessitates specific diagnostic approaches:

• Excisional lymph node biopsy is mandatory to provide adequate tissue for architectural assessment and immunophenotyping 1
• Fine-needle aspiration alone is insufficient because the nodular architecture and immunoarchitectural patterns cannot be assessed 1
• Core needle biopsy combined with flow cytometry and immunohistochemistry may be adequate in selected circumstances, but excisional biopsy remains preferred 1
• An expanded immunophenotyping panel is required when diagnosis is equivocal to distinguish NLPHL from other B-cell lymphomas 1