Nodular Lymphocyte-Predominant Hodgkin Lymphoma

• The neoplastic cell is the LP cell (formerly "L&H" cell), so named for its large, folded, multilobated nucleus resembling a popcorn kernel, with a thin rim of cytoplasm and small nucleoli
• It derives from a germinal-centre B cell that has undergone somatic hypermutation and, unlike the Reed-Sternberg cell, has retained a functional B-cell transcriptional programme — expressing CD20, CD79a, BCL6, OCT2 and BOB1, and often immunoglobulin
• Classical Hodgkin Reed-Sternberg cells, by contrast, have lost their B-cell identity through downregulation of the transcription factors that maintain it, which is why they lose CD20 and CD45
• Growth is nodular, within expanded meshworks of follicular dendritic cells, in a background of small reactive B lymphocytes — again unlike classical Hodgkin lymphoma, whose background is rich in T cells, eosinophils and plasma cells
• LP cells are characteristically rosetted by PD-1-positive T follicular helper cells, a helpful diagnostic feature
• EBV is not implicated — LP cells are EBV-negative, in contrast to a substantial proportion of classical Hodgkin lymphoma
• Variant (non-classical) growth patterns, particularly diffuse and T-cell-rich patterns, exist on a continuum with T-cell/histiocyte-rich large B-cell lymphoma and predict a higher risk of relapse and transformation

• Male predominance of roughly 3:1 — more pronounced than in classical Hodgkin lymphoma
• Age — a broad distribution with a peak in the fourth and fifth decades; it also occurs in children, where it is often localized and highly curable
• Family history of lymphoma is more frequent than in classical Hodgkin lymphoma, and familial clustering is reported
• No EBV association, unlike classical Hodgkin lymphoma
• Autoimmune lymphoproliferative syndrome (ALPS) carries a markedly increased risk and should be considered in children and young adults, particularly with a history of cytopenias and splenomegaly
• No established environmental, occupational or infectious risk factor

• Painless peripheral lymphadenopathy, most often cervical, axillary or inguinal — frequently a single region, sometimes present and slowly enlarging for months or years before evaluation
• Localized stage I-II disease in roughly 70-80% at diagnosis
• Mediastinal involvement is uncommon — a clear contrast with nodular sclerosis classical Hodgkin lymphoma, which characteristically presents with a mediastinal mass in a young woman
• B symptoms are rare (under 10%); their presence should prompt a search for transformation
• Splenic involvement occurs; bone marrow involvement is uncommon
• Advanced-stage disease at presentation is unusual and carries a higher risk of relapse and transformation
• Late relapse is characteristic — recurrences at five, ten or more years are well recognized, and unlike classical Hodgkin lymphoma this does not necessarily denote poor prognosis
• Features suggesting transformation to diffuse large B-cell lymphoma: rapidly enlarging nodes, new B symptoms, rising LDH, or extranodal disease

The immunophenotype is the whole diagnosis, and it is the inverse of classical Hodgkin lymphoma

• NLPHL — LP cells: CD20 positive, CD45 positive, CD79a positive, BCL6 positive, OCT2 and BOB1 positive, EMA often positive, and CD15 negative, CD30 negative
• Classical Hodgkin lymphoma — Reed-Sternberg cells: CD15 positive, CD30 positive, and CD45 negative, CD20 negative or weak and variable, with OCT2/BOB1 typically lost
• Memorably: NLPHL is CD20-positive and CD15/CD30-negative; classical Hodgkin lymphoma is CD15/CD30-positive and CD20/CD45-negative. Every marker points the opposite way

Histology

• Nodular architecture with expanded follicular dendritic cell meshworks and a background of small B cells
• Popcorn (LP) cells — large cells with folded, multilobated nuclei and small basophilic nucleoli — scattered within the nodules
• PD-1-positive T-cell rosettes surrounding LP cells
• Excisional biopsy is essential; a needle core frequently cannot demonstrate the architecture, and the architecture is diagnostic

The key differential

• T-cell/histiocyte-rich large B-cell lymphoma — overlaps morphologically and immunophenotypically, is aggressive, and is treated as diffuse large B-cell lymphoma. Diffuse variant patterns of NLPHL sit on the boundary, and expert review is warranted
• Classical Hodgkin lymphoma, separated by the immunophenotype above
• Progressive transformation of germinal centres — a benign reactive condition that may coexist with, precede or mimic NLPHL and must not be overtreated
• Follicular lymphoma — CD10-positive, BCL2-positive, with t(14;18)

Staging

• PET-CT, and bone marrow biopsy where advanced disease or cytopenias exist
• LDH, full blood count, and standard lymphoma baseline studies
• Any discordant, rapidly growing or highly FDG-avid site should be biopsied to exclude transformation

The governing principle is proportionality — most patients are overtreated if classical Hodgkin protocols are applied

Early-stage disease (stage IA-IIA, non-bulky)

• Involved-site radiotherapy alone is standard and produces excellent long-term disease control with minimal toxicity
• In children with a completely excised solitary node, surgical excision alone with observation is an accepted approach — an unusually conservative but evidence-supported strategy
• Combined modality therapy is used for less favourable early-stage presentations, though the trend is toward de-escalation given the excellent prognosis and the significance of late toxicity in a young population

Advanced-stage or symptomatic disease

• Rituximab-containing chemoimmunotherapy — R-CHOP or R-CVP, and ABVD with rituximab in some protocols. The addition of rituximab is what distinguishes this from classical Hodgkin lymphoma management
• Rituximab monotherapy produces high response rates and is appropriate for selected patients, though remissions are often not durable and relapse is common
• Variant histology or suspected transformation is treated as diffuse large B-cell lymphoma with R-CHOP

Relapsed disease

• Late relapse is common and does not carry the ominous meaning it does in classical Hodgkin lymphoma
• Re-biopsy at relapse is mandatory to exclude transformation before choosing therapy
• Options include rituximab, further radiotherapy for localized recurrence, chemoimmunotherapy, and autologous transplantation for repeated or transformed relapse

Surveillance

• Long-term follow-up is required — relapses beyond ten years occur, as does transformation
• Survivors need late-effects surveillance: secondary malignancy, particularly breast cancer after chest radiotherapy, cardiovascular disease, and thyroid dysfunction

Prognosis

• Ten-year overall survival exceeds 80-90%, and for early-stage disease approaches that of the general population
• Most deaths in long-term survivors are from secondary malignancy and cardiovascular disease rather than lymphoma — which is precisely why avoiding overtreatment matters

• Transformation to diffuse large B-cell lymphoma in roughly 7-14%, most often the T-cell/histiocyte-rich variant — the principal cause of lymphoma-related death
• Repeated late relapse, requiring decades of surveillance and cumulative treatment exposure
• Secondary malignancy: breast, lung and thyroid cancer after radiotherapy, and therapy-related myelodysplasia and acute myeloid leukaemia after alkylating agents
• Cardiovascular disease after mediastinal radiotherapy and anthracycline exposure — a leading cause of late mortality in Hodgkin survivors generally
• Hypothyroidism after neck irradiation
• Infertility from alkylating chemotherapy, warranting fertility counselling before treatment in a predominantly young male population
• Hypogammaglobulinaemia and infection after repeated rituximab exposure
• Hepatitis B reactivation after rituximab in unscreened patients
• Overtreatment itself — arguably the most important avoidable complication, since applying classical Hodgkin lymphoma intensity to a disease with near-normal life expectancy converts an excellent prognosis into decades of late-effect risk

• "Popcorn" (LP) cells — large cells with folded, multilobated nuclei — define NLPHL, in contrast to the binucleate "owl-eye" Reed-Sternberg cell of classical Hodgkin lymphoma
• The immunophenotypes are exact opposites. NLPHL: CD20+, CD45+, CD15−, CD30−. Classical Hodgkin: CD15+, CD30+, CD20−/weak, CD45−. This is the single most examined point in the topic
• Because LP cells express CD20, rituximab works in NLPHL — and does not work in classical Hodgkin lymphoma, whose Reed-Sternberg cells have lost their B-cell programme
• EBV is not associated with NLPHL, unlike a substantial fraction of classical Hodgkin lymphoma
• Male predominance about 3:1, peripheral nodes (cervical, axillary, inguinal), mediastinal involvement uncommon — the reverse of nodular sclerosis classical Hodgkin lymphoma in a young woman
• B symptoms are rare — if present, look for transformation
• Most patients present at stage I-II and are treated with involved-site radiotherapy alone; in children a completely excised solitary node may simply be observed
• Transformation to diffuse large B-cell lymphoma occurs in roughly 7-14%, usually the T-cell/histiocyte-rich variant — re-biopsy at every relapse
• Late relapse at five, ten or more years is characteristic and does not carry the poor prognosis that late relapse implies in classical Hodgkin lymphoma
• Ten-year survival exceeds 80-90%, and most late deaths are from secondary cancer and cardiovascular disease, not lymphoma — which is the argument for treating lightly
• Excisional biopsy, not a needle — nodular architecture and PD-1 T-cell rosettes are diagnostic and cannot be assessed on a core
• Progressive transformation of germinal centres is benign and may coexist with or mimic NLPHL — do not treat it as lymphoma