Definition/General
Introduction:
Lymphoma represents a heterogeneous group of malignant neoplasms arising from lymphoid tissue
FNAC plays a crucial role in initial diagnosis and staging of lymphomas
It can differentiate between Hodgkin and non-Hodgkin lymphomas in many cases
However, histopathological confirmation with immunohistochemistry is usually required for definitive subtyping.
Origin:
Arises from lymphoid precursor cells (B-cells, T-cells, or NK cells)
Results from genetic alterations affecting cell cycle control and apoptosis
Most lymphomas are of B-cell origin (85-90%)
T-cell lymphomas comprise 10-15% of cases
NK-cell lymphomas are rare (<1%)
Primary nodal or extranodal origin possible.
Classification:
Broadly classified into Hodgkin lymphoma (HL) (10-15%) and Non-Hodgkin lymphoma (NHL) (85-90%)
HL characterized by Reed-Sternberg cells
NHL includes indolent (follicular lymphoma, marginal zone lymphoma), aggressive (diffuse large B-cell lymphoma), and highly aggressive (Burkitt lymphoma, T-cell lymphoblastic lymphoma) subtypes.
Epidemiology:
Accounts for 3-5% of all malignancies
Bimodal age distribution: peaks in 3rd decade (HL) and 6th-7th decades (NHL)
Male predominance in most subtypes
Geographic variation: higher incidence of certain subtypes in developing countries
EBV association common in Indian population.
Clinical Features
Presentation:
Painless lymphadenopathy (most common, 80-90%)
Progressive enlargement of lymph nodes
Mediastinal mass (especially in HL and T-lymphoblastic lymphoma)
Extranodal involvement (GI tract, CNS, bone marrow)
Superior vena cava syndrome in mediastinal disease
B-symptoms in 30-40% cases.
Symptoms:
B-symptoms: fever >38°C, night sweats, weight loss >10% in 6 months
Fatigue and weakness due to anemia
Shortness of breath if mediastinal involvement
Abdominal pain and early satiety if GI involvement
Neurological symptoms if CNS involvement
Alcohol-induced pain (characteristic of HL).
Risk Factors:
Immunosuppression (HIV, post-transplant, autoimmune diseases)
EBV infection
H
pylori infection (MALT lymphoma)
Chronic inflammatory conditions
Previous chemotherapy or radiation therapy
Family history of lymphoma
Genetic syndromes (ataxia telangiectasia, Wiskott-Aldrich syndrome).
Screening:
No standard screening for lymphoma
Clinical examination of all lymph node groups
Complete blood count with peripheral smear
LDH and beta-2 microglobulin levels
CT scan of chest, abdomen, and pelvis
PET-CT for staging
Bone marrow biopsy in selected cases.
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Gross Description
Appearance:
Enlarged lymph nodes with loss of normal architecture
Nodes may be firm to hard in consistency
Rubbery texture characteristic of lymphoma
Cut surface shows fish-flesh appearance with loss of normal architecture
Areas of necrosis may be present in high-grade lymphomas
Hemorrhage uncommon except in aggressive subtypes.
Characteristics:
FNAC yields abundant cellular material in most cases
Aspirate appears grayish-white to hemorrhagic
Single cell suspension with loss of cohesion
Background may show tingible body macrophages (starry-sky appearance)
Necrotic debris in aggressive lymphomas
Sclerotic areas may yield scanty material.
Size Location:
Variable node size from 1-20 cm
Cervical and mediastinal nodes commonly involved in HL
Generalized lymphadenopathy more common in NHL
Waldeyer ring involvement in certain NHL subtypes
Retroperitoneal and mesenteric involvement common
Extranodal sites (GI tract, CNS, bone) in NHL.
Multifocality:
Multi-site involvement common at presentation (60-70%)
Contiguous spread characteristic of HL
Random spread typical of NHL
Bilateral involvement suggests advanced disease
Bone marrow involvement in 10-30% cases
CNS involvement in aggressive subtypes.
Microscopic Description
Histological Features:
Hodgkin Lymphoma: Reed-Sternberg cells and variants in inflammatory background
Non-Hodgkin Lymphoma: Monotonous population of lymphoid cells
Low-grade NHL: Small mature lymphocytes with minimal atypia
High-grade NHL: Large lymphoid cells with prominent nucleoli and high mitotic activity
T-cell lymphomas: Often show anaplastic morphology.
Cellular Characteristics:
Reed-Sternberg cells: Large cells with multiple nuclei or multilobated nucleus, prominent nucleoli
Hodgkin cells: Mononuclear variants of Reed-Sternberg cells
Large B-cell lymphoma: Large cells with vesicular nuclei, prominent nucleoli, basophilic cytoplasm
Small lymphocytic lymphoma: Small mature lymphocytes with clumped chromatin
Follicular lymphoma: Mixture of centrocytes and centroblasts.
Architectural Patterns:
Diffuse pattern: Complete loss of nodal architecture (most NHL)
Follicular pattern: Neoplastic follicles (follicular lymphoma)
Marginal zone pattern: Expansion of marginal zones
Interfollicular pattern: Hodgkin lymphoma, T-cell lymphomas
Sinusoidal pattern: Intravascular lymphoma, certain T-cell lymphomas
Sclerotic pattern: Nodular sclerosis HL.
Grading Criteria:
Ann Arbor staging for anatomical distribution
WHO grading for follicular lymphoma (Grade 1-3 based on centroblast count)
International Prognostic Index (IPI) for risk stratification
Proliferation index (Ki-67) important for prognosis
Cell of origin classification (GCB vs non-GCB for DLBCL)
Molecular genetic features increasingly important.
Immunohistochemistry
Positive Markers:
Hodgkin Lymphoma: CD30, CD15 (classical HL), CD20 weak, PAX5 weak
B-cell NHL: CD19, CD20, CD79a, PAX5
T-cell NHL: CD3, CD5, CD7
Follicular Lymphoma: CD10, Bcl-6, Bcl-2
Mantle Cell Lymphoma: Cyclin D1, CD5, CD20
ALCL: ALK, CD30.
Negative Markers:
Reed-Sternberg cells: CD45 negative/weak, CD20 negative/weak
B-cell lymphomas: T-cell markers negative (CD3, CD5, CD7)
T-cell lymphomas: B-cell markers negative (CD19, CD20, CD79a)
Anaplastic lymphoma: CD15 negative (unlike Hodgkin)
Reactive conditions: Monotypic markers negative.
Diagnostic Utility:
Essential for definitive lymphoma diagnosis
Helps differentiate B-cell vs T-cell lymphomas
Critical for lymphoma subtyping
Guides treatment decisions
Useful in differential diagnosis with reactive conditions
Important for prognostication
Required for targeted therapy selection.
Molecular Subtypes:
GCB vs Non-GCB subtypes of DLBCL (CD10, Bcl-6, MUM1 algorithm)
Double-hit lymphomas (MYC and BCL2/BCL6 rearrangements)
Triple-hit lymphomas
Primary mediastinal B-cell lymphoma
ALK-positive ALCL vs ALK-negative ALCL
Peripheral T-cell lymphoma subtypes.
Molecular/Genetic
Genetic Mutations:
IGH-BCL2 translocation t(14;18) in follicular lymphoma
IGH-BCL1 translocation t(11;14) in mantle cell lymphoma
MYC translocations t(8;14) in Burkitt lymphoma
ALK rearrangements in ALCL
BCL6 rearrangements in DLBCL
p53 mutations in aggressive lymphomas
NPM-ALK fusion in ALK-positive ALCL.
Molecular Markers:
Clonal immunoglobulin gene rearrangements in B-cell lymphomas
Clonal T-cell receptor rearrangements in T-cell lymphomas
EBV-EBER positive in some lymphomas
HHV-8 in primary effusion lymphoma
HTLV-1 in adult T-cell leukemia/lymphoma
MYD88 L265P mutation in lymphoplasmacytic lymphoma.
Prognostic Significance:
Cytogenetic abnormalities major prognostic factors
TP53 mutations associated with poor prognosis
Double-hit lymphomas have aggressive behavior
ALK-positive ALCL has better prognosis than ALK-negative
GCB subtype DLBCL has better outcome than non-GCB
Complex karyotype indicates poor prognosis.
Therapeutic Targets:
CD20: Rituximab for B-cell lymphomas
CD30: Brentuximab vedotin for HL and ALCL
ALK: ALK inhibitors for ALK-positive ALCL
Bcl-2: Venetoclax for certain B-cell lymphomas
BTK: Ibrutinib for mantle cell lymphoma
mTOR: Temsirolimus for certain T-cell lymphomas
HDAC: Vorinostat for CTCL.
Differential Diagnosis
Similar Entities:
Reactive lymphoid hyperplasia
Metastatic carcinoma
Infectious lymphadenitis (TB, atypical mycobacteria)
Autoimmune lymphadenopathy
Kikuchi disease
Castleman disease
Sarcoidosis
Hemophagocytic syndrome
Rosai-Dorfman disease.
Distinguishing Features:
Reactive hyperplasia: Polymorphous population, tingible body macrophages, polyclonal
Metastatic carcinoma: Epithelial clusters, positive cytokeratin
Hodgkin vs NHL: Reed-Sternberg cells, inflammatory background in HL
B-cell vs T-cell: Immunophenotype crucial
Low-grade vs high-grade: Cell size, mitotic activity, Ki-67 index.
Diagnostic Challenges:
Gray zone lymphomas with overlapping features
Hodgkin-like Reed-Sternberg cells in other conditions
T-cell rich B-cell lymphoma vs classical HL
Anaplastic large cell lymphoma vs Hodgkin lymphoma
Large cell transformation of indolent lymphomas
Composite lymphomas with multiple subtypes.
Rare Variants:
Primary effusion lymphoma
Intravascular large B-cell lymphoma
Lymphomatoid granulomatosis
Post-transplant lymphoproliferative disorder
EBV-positive mucocutaneous ulcer
Primary CNS lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma.
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
Fine needle aspiration cytology of [site] lymph node
Clinical History
Duration: [duration]. Associated symptoms: [B-symptoms present/absent]. Previous history: [relevant history]
Adequacy
Adequate for evaluation - cellular smears with adequate lymphoid tissue
Morphological Features
Cellular smears showing [monomorphic/polymorphic] lymphoid cell population. Cell size: [small/medium/large]. Nuclear features: [chromatin pattern, nucleoli]. Cytoplasm: [amount, basophilia]. Reed-Sternberg cells: [present/absent]
Immunophenotype
Flow cytometry/IHC results: B-cell markers: [results]. T-cell markers: [results]. Other markers: [CD30, CD15, etc.]. Clonality: [monoclonal/polyclonal]
Molecular Studies
Gene rearrangement studies: [if performed]. FISH studies: [if performed]. Other molecular tests: [if performed]
Cytological Diagnosis
[Specific lymphoma subtype if possible] / Lymphoma, favor [Hodgkin/Non-Hodgkin B-cell/T-cell]
Recommendations
Histopathological examination with immunohistochemistry recommended for definitive subtyping. Staging workup including CT/PET-CT, bone marrow biopsy. Hematology-oncology consultation advised
Comments
The cytological features are suspicious for lymphoma. Tissue biopsy with immunohistochemistry is essential for definitive diagnosis and appropriate subclassification