Definition/General
Introduction:
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) represents 5-10% of all Hodgkin lymphomas
It is characterized by lymphocyte and histiocyte (L&H) cells in a nodular background
These cells are also known as popcorn cells or lymphocytic and histiocytic (L&H) Reed-Sternberg variants
The disease shows distinct immunophenotypic and molecular characteristics that differentiate it from classical Hodgkin lymphoma.
Origin:
Originates from germinal center B-cells that have undergone somatic hypermutation
The L&H cells retain B-cell markers unlike classical Reed-Sternberg cells
Shows evidence of ongoing somatic hypermutation suggesting germinal center origin
Lacks Epstein-Barr virus (EBV) association in most cases
Represents a distinct entity in the WHO classification.
Classification:
Classified under Hodgkin lymphoma in WHO classification
Distinct entity separate from classical Hodgkin lymphoma
Previously known as lymphocyte predominant Hodgkin disease
Shows predominantly nodular growth pattern
Rarely shows diffuse areas
Grade is not applicable as it is a distinct entity
Stage follows Ann Arbor staging system.
Epidemiology:
Peak incidence in 3rd-4th decades
Male predominance (M:F = 3:1)
More common in Western populations
Represents 5-10% of all Hodgkin lymphomas
Often presents as localized disease
Better prognosis than classical Hodgkin lymphoma
Indian population shows lower incidence compared to classical Hodgkin lymphoma.
Clinical Features
Presentation:
Painless lymphadenopathy (most common presentation)
Predominantly peripheral lymph nodes
Often involves axillary and inguinal nodes
Mediastinal involvement is uncommon (unlike classical Hodgkin lymphoma)
Extranodal involvement is rare at presentation
Localized disease (Stage I-II) in 80% of cases
Absence of B-symptoms in most cases.
Symptoms:
Asymptomatic in majority of patients
B-symptoms (fever, night sweats, weight loss) are uncommon (<10%)
Pruritus is rare
Alcohol-induced pain is uncommon
Symptoms related to mass effect if large nodes
Fatigue may be present
Performance status usually preserved.
Risk Factors:
Male gender (3:1 male predominance)
Age (peak in 3rd-4th decades)
Genetic predisposition may play a role
Immunodeficiency states (less common than in classical Hodgkin lymphoma)
Family history of lymphoma
EBV infection not associated
Environmental factors not well established.
Screening:
No specific screening recommendations
Physical examination for lymphadenopathy
Complete blood count and peripheral smear
Imaging studies for staging
LDH and ESR as prognostic markers
Bone marrow biopsy rarely needed
PET-CT for staging and response assessment.
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Gross Description
Appearance:
Enlarged lymph nodes with preserved architecture
Gray-white cut surface with fish-flesh appearance
Nodular pattern may be visible grossly
Nodes are firm to rubbery in consistency
No necrosis or hemorrhage typically
Size varies from 1-10 cm
Multiple nodes may be involved.
Characteristics:
Fish-flesh appearance on cut surface
Homogeneous gray-white color
Firm consistency without fluctuation
Well-defined capsule usually intact
No calcification typically seen
No fibrosis grossly evident
Nodular architecture may be apparent.
Size Location:
Node size typically 2-8 cm
Most commonly involves axillary lymph nodes
Inguinal nodes frequently involved
Cervical nodes less commonly involved
Mediastinal involvement is uncommon (<20%)
Abdominal nodes involved in advanced disease
Multiple anatomical sites may be involved.
Multifocality:
Multifocal nodal involvement is common
Contiguous spread pattern typical
Skip lesions are uncommon
Bilateral involvement may occur
Extranodal sites rarely involved at presentation
Spleen involvement in advanced cases
Bone marrow involvement is rare (<5%).
Microscopic Description
Histological Features:
Nodular architecture with effaced normal lymph node structure
Lymphocyte and histiocyte (L&H) cells scattered within nodules
L&H cells have multilobated nuclei (popcorn cells)
Small lymphocytes predominate in background
Histiocytes are admixed
Minimal eosinophils and neutrophils
Absence of classical Reed-Sternberg cells.
Cellular Characteristics:
L&H cells are large cells with multilobated or polylobated nuclei
Vesicular chromatin with prominent nucleoli
Abundant cytoplasm with indistinct cell borders
Nuclei show irregular contours (popcorn appearance)
Mitotic activity is usually low
Background lymphocytes are small and mature
Histiocytes have kidney-shaped nuclei.
Architectural Patterns:
Nodular pattern is characteristic and predominant
Effacement of normal lymph node architecture
Residual germinal centers may be present
Interfollicular areas show lymphocyte infiltration
Diffuse areas may be present (<20% of cases)
Progressive transformation of germinal centers may be seen
Reactive follicles at periphery.
Grading Criteria:
No grading system applicable as it is a distinct entity
Nodular vs diffuse pattern has prognostic significance
Percentage of diffuse areas should be reported
Presence of classical Reed-Sternberg cells excludes the diagnosis
L&H cell count varies but should be identifiable
Background cellularity predominantly lymphocytes
Fibrosis is typically minimal.
Immunohistochemistry
Positive Markers:
L&H cells: CD20 (positive)
L&H cells: CD79a (positive)
L&H cells: PAX5 (positive)
L&H cells: BCL6 (positive)
L&H cells: OCT2 (positive)
L&H cells: BOB1 (positive)
L&H cells: J-chain (positive)
Background T-cells: CD3
Background T-cells: CD57 (rosetting around L&H cells).
Negative Markers:
L&H cells: CD15 (negative)
L&H cells: CD30 (negative)
L&H cells: EBER (negative)
L&H cells: LMP1 (negative)
L&H cells: CD10 (usually negative)
L&H cells: IRF4/MUM1 (negative)
L&H cells: ALK (negative)
These negative markers help distinguish from classical Hodgkin lymphoma.
Diagnostic Utility:
B-cell markers (CD20, PAX5) distinguish from classical Hodgkin lymphoma
Absence of CD15 and CD30 is diagnostic criterion
BCL6 positivity supports germinal center origin
CD57+ T-cell rosettes around L&H cells are characteristic
EBER negativity in most cases
Immunoglobulin gene rearrangement may be demonstrated
Ki-67 shows low proliferation index.
Molecular Subtypes:
No molecular subtypes recognized for NLPHL
Clonal immunoglobulin gene rearrangements present
Somatic hypermutations in variable regions
BCL6 translocations may be present
Ongoing somatic mutations suggest germinal center origin
EBV association is rare (<10%)
Cytogenetic abnormalities less common than classical Hodgkin lymphoma.
Molecular/Genetic
Genetic Mutations:
Clonal immunoglobulin heavy and light chain gene rearrangements
BCL6 gene rearrangements in 20-30%
REL amplification in some cases
JUNB overexpression may be present
TP53 mutations are uncommon
JAK/STAT pathway alterations may occur
CREBBP mutations in subset of cases.
Molecular Markers:
Immunoglobulin expression maintained in L&H cells
BCL6 expression indicates germinal center origin
IRF4/MUM1 typically negative
GCET1 may be positive
CD10 usually negative
Cyclin D1 negative
p53 expression variable.
Prognostic Significance:
Better prognosis than classical Hodgkin lymphoma
Slow progression and indolent course
Risk of transformation to diffuse large B-cell lymphoma (3-5%)
Late relapses may occur
Overall survival >90% at 10 years
Localized disease has excellent prognosis
Diffuse areas may indicate worse prognosis.
Therapeutic Targets:
CD20 targeting with rituximab
Radiation therapy for localized disease
Chemotherapy for advanced disease
Anti-CD30 therapy not effective (CD30 negative)
Immunomodulatory agents under investigation
PD-1 inhibitors may be effective
Watch and wait approach for asymptomatic patients.
Differential Diagnosis
Similar Entities:
Classical Hodgkin lymphoma (Reed-Sternberg cells, CD15+, CD30+)
T-cell/histiocyte-rich large B-cell lymphoma (CD20+ large cells, lack nodular pattern)
Progressive transformation of germinal centers (reactive process, no L&H cells)
Follicular lymphoma (CD10+, BCL2+, t(14;18))
Mantle cell lymphoma (cyclin D1+, blastoid variant)
Marginal zone lymphoma (monocytoid B-cells).
Distinguishing Features:
NLPHL: CD20+, CD15-, CD30-, nodular pattern
Classical Hodgkin lymphoma: CD15+, CD30+, mixed inflammatory background
T-cell/histiocyte-rich DLBCL: lacks nodular pattern, more pleomorphic cells
Progressive transformation: reactive, no monoclonal B-cells
Follicular lymphoma: CD10+, BCL2+, centrocytes and centroblasts
Immunohistochemistry is crucial for distinction.
Diagnostic Challenges:
Distinguishing from T-cell/histiocyte-rich DLBCL
Diffuse areas in NLPHL may mimic DLBCL
Progressive transformation may precede or coexist with NLPHL
Reactive hyperplasia with prominent germinal centers
Limited tissue may prevent accurate diagnosis
Immunohistochemistry panel essential for diagnosis
Clinical correlation important.
Rare Variants:
NLPHL with diffuse areas (>25% diffuse growth)
NLPHL with classical Reed-Sternberg cells (composite lymphoma)
NLPHL with increased histiocytes
NLPHL with plasmacytic differentiation
NLPHL with T-cell rich areas
NLPHL transforming to DLBCL
Pediatric NLPHL (rare in children).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Lymph node biopsy from [site], measuring [size] cm
Primary Diagnosis
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)
WHO Classification
Hodgkin lymphoma, nodular lymphocyte predominant type
Histological Features
Shows nodular architecture with lymphocyte and histiocyte (L&H) cells in background of small lymphocytes and histiocytes
Architectural Pattern
Architecture: [nodular/nodular with diffuse areas], diffuse component: [percentage]%
Cellular Composition
L&H cells (popcorn cells) scattered in background of small lymphocytes and histiocytes
Immunohistochemistry
L&H cells: CD20+, PAX5+, CD15-, CD30-; Background: CD3+ T-cells with CD57+ rosetting
Molecular Studies
EBER: negative; Clonal B-cell population demonstrated
Staging
Clinical stage: [I/II/III/IV] based on imaging and clinical findings
Final Diagnosis
Nodular lymphocyte predominant Hodgkin lymphoma (WHO 2016)