Definition/General
Introduction:
Splenic lymphoma represents a heterogeneous group of malignant lymphoid neoplasms primarily involving the spleen
It includes both primary splenic lymphomas and secondary involvement by systemic lymphomas
Primary splenic lymphomas are uncommon, accounting for less than 1% of all lymphomas
The most common types include splenic marginal zone lymphoma, diffuse large B-cell lymphoma, and hairy cell leukemia.
Origin:
Arises from lymphoid cells within splenic compartments including white pulp, red pulp, and marginal zone
Primary splenic lymphomas originate from resident splenic lymphocytes
Secondary splenic involvement occurs through hematogenous spread from nodal or extranodal sites
The splenic microenvironment provides unique antigenic stimulation and growth signals.
Classification:
WHO Classification 2017: Splenic marginal zone lymphoma
Splenic diffuse red pulp small B-cell lymphoma
Hairy cell leukemia
Primary splenic DLBCL
T-cell lymphomas (rare)
Clinical Classification: Primary splenic (confined to spleen)
Secondary splenic (systemic disease with splenic involvement)
Histologic patterns: White pulp involvement
Red pulp involvement
Mixed pattern.
Epidemiology:
Median age 60-70 years
Male predominance (1.5:1)
Geographic variation with higher incidence in Mediterranean regions
Associated with Hepatitis C infection (30-50% cases)
Splenic marginal zone lymphoma most common primary type
Secondary involvement seen in 60-90% of advanced lymphomas.
Clinical Features
Presentation:
Massive splenomegaly (most common symptom)
Left upper quadrant pain and discomfort
Early satiety and abdominal fullness
B-symptoms in 30-40% cases (fever, night sweats, weight loss)
Cytopenia due to hypersplenism
Thrombocytopenia (70-80% cases)
Anemia (60-70% cases).
Symptoms:
Constitutional symptoms: Fatigue and weakness
Weight loss (>10% body weight)
Night sweats and fever
Abdominal symptoms: Left-sided abdominal pain
Early satiety
Abdominal distension
Bleeding manifestations due to thrombocytopenia
Recurrent infections due to neutropenia.
Risk Factors:
Infectious agents: Hepatitis C virus (30-50% association)
Epstein-Barr virus
Immunosuppression: Post-transplant state
HIV infection
Autoimmune disorders
Genetic factors: Family history of hematologic malignancies
Environmental factors: Pesticide exposure
Previous chemotherapy or radiation.
Screening:
High-risk populations: Hepatitis C positive patients with splenomegaly
Patients with unexplained cytopenia and splenomegaly
Diagnostic approach: Complete blood count with differential
Flow cytometry of peripheral blood
Imaging studies (CT/MRI)
Spleen biopsy or splenectomy for definitive diagnosis.
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Gross Description
Appearance:
Massive splenomegaly with weights ranging from 500g to >2000g (normal: 150-200g)
Cut surface shows homogeneous gray-white appearance
Effacement of normal architecture with loss of follicular pattern
May show hemorrhage and necrosis in aggressive types.
Characteristics:
Firm consistency with rubbery texture
Smooth capsular surface without nodular irregularities
Cut surface may show miliary nodules in marginal zone lymphoma
Areas of infarction may be present
Hilar lymph nodes usually not enlarged in primary splenic lymphoma.
Size Location:
Spleen weight typically >500g in symptomatic patients
May reach 3000-4000g in advanced cases
Uniform involvement of red and white pulp
Capsular involvement rare except in aggressive types
Extension to adjacent organs uncommon in primary disease.
Multifocality:
Diffuse involvement pattern most common
Multifocal nodular pattern in some marginal zone lymphomas
Splenic hilar lymph nodes involved in 10-20% cases
Concurrent involvement of liver, bone marrow, and peripheral blood
Extrasplenic disease suggests secondary involvement.
Microscopic Description
Histological Features:
Effacement of normal splenic architecture with infiltration of neoplastic lymphoid cells
White pulp expansion with atrophic or absent germinal centers
Red pulp infiltration with sinusoidal pattern
Preservation of reticulin framework in low-grade types
Increased mitotic activity in high-grade lymphomas.
Cellular Characteristics:
Small to medium-sized lymphoid cells in marginal zone lymphoma
Monotonous population with round to oval nuclei
Moderately abundant pale cytoplasm
Hairy cell morphology in hairy cell leukemia with characteristic cytoplasmic projections
Large cell morphology in DLBCL with vesicular nuclei and prominent nucleoli.
Architectural Patterns:
Marginal zone pattern: Expansion of marginal zones around residual follicles
Red pulp pattern: Diffuse infiltration of red pulp cords and sinuses
Nodular pattern: Multiple lymphoid nodules throughout parenchyma
Sinusoidal pattern: Preferential involvement of splenic sinuses.
Grading Criteria:
Low-grade lymphomas: Small cell size, low mitotic rate (<10/10 HPF), minimal cytologic atypia
High-grade lymphomas: Large cell size, high mitotic rate (>20/10 HPF), marked cytologic atypia
Proliferation index (Ki-67): <20% in low-grade, >60% in high-grade
Presence of necrosis and apoptosis in aggressive types.
Immunohistochemistry
Positive Markers:
B-cell markers: CD20 (90-95%)
CD79a (85-90%)
PAX5 (95%)
Marginal zone markers: CD21 (follicular dendritic cells)
Hairy cell markers: CD103
CD11c
CD25
TRAP (tartrate-resistant acid phosphatase)
DLBCL markers: CD10 (30%)
BCL6 (70%)
MUM1 (60%).
Negative Markers:
T-cell markers: CD3
CD5
CD7
Other B-cell markers: CD23 (usually negative in marginal zone)
CD10 (negative in marginal zone)
Plasma cell markers: CD138 (except in plasmacytic differentiation)
Follicular markers: BCL2 (variable).
Diagnostic Utility:
Subtype identification: CD103/CD11c/CD25 for hairy cell leukemia
CD5/CD23 negative in marginal zone lymphoma
Differential diagnosis: Distinguishing from reactive lymphoid hyperplasia
Subclassification of B-cell lymphomas
Prognostic markers: Ki-67 proliferation index
p53 expression.
Molecular Subtypes:
Marginal zone lymphoma: CD20+, CD79a+, CD5-, CD10-, CD23-
Hairy cell leukemia: CD20+, CD103+, CD11c+, CD25+, TRAP+
DLBCL subtypes: GCB type (CD10+, BCL6+, MUM1-)
ABC type (CD10-, BCL6+/-, MUM1+)
Mantle cell lymphoma: CD20+, CD5+, cyclin D1+.
Molecular/Genetic
Genetic Mutations:
Marginal zone lymphoma: NOTCH2 mutations (20-25%)
KLF2 mutations (20%)
TNFAIP3 mutations (10-15%)
Hairy cell leukemia: BRAF V600E mutation (95-100%)
DLBCL mutations: MYC rearrangements (10-15%)
BCL2 rearrangements (20-30%)
BCL6 rearrangements (30-40%).
Molecular Markers:
Immunoglobulin gene rearrangements: Clonal IgH and IgL rearrangements in B-cell lymphomas
Chromosome abnormalities: del(7q) in marginal zone lymphoma
+3, +18 in marginal zone lymphoma
Gene expression profiling: Cell of origin classification in DLBCL.
Prognostic Significance:
BRAF V600E mutation pathognomonic for hairy cell leukemia and predicts response to BRAF inhibitors
TP53 mutations associated with poor prognosis and chemoresistance
MYC rearrangements indicate aggressive behavior
Double-hit lymphomas (MYC + BCL2/BCL6) have very poor prognosis.
Therapeutic Targets:
BRAF inhibitors (vemurafenib) for BRAF-mutated hairy cell leukemia
BTK inhibitors (ibrutinib) for marginal zone lymphoma
Anti-CD20 therapy (rituximab) for B-cell lymphomas
PI3K inhibitors for marginal zone lymphoma
Immunomodulatory agents (lenalidomide).
Differential Diagnosis
Similar Entities:
Reactive splenomegaly: Due to infections, autoimmune disorders, or portal hypertension
Other primary splenic neoplasms: Angiosarcoma, littoral cell angioma
Metastatic disease: From breast, lung, melanoma, or GI tract
Hematologic disorders: Chronic myeloid leukemia, myelofibrosis.
Distinguishing Features:
Lymphoma vs reactive: Monoclonal vs polyclonal population
Architectural effacement vs preserved structure
Primary vs secondary: Isolated splenomegaly vs systemic lymphadenopathy
B-cell vs T-cell: Immunophenotypic differences
Low-grade vs high-grade: Cell size, mitotic rate, Ki-67 index.
Diagnostic Challenges:
Small B-cell lymphomas can be difficult to distinguish from each other
Reactive hyperplasia may mimic low-grade lymphoma
Mixed patterns with both small and large cells
Secondary involvement vs primary splenic lymphoma
Transformation from low-grade to high-grade.
Rare Variants:
Primary splenic DLBCL with unique clinical behavior
Splenic T-cell lymphoma (hepatosplenic T-cell lymphoma)
Intravascular large B-cell lymphoma with sinusoidal involvement
Plasmablastic lymphoma in immunocompromised patients
Burkitt lymphoma with splenic involvement.
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
Spleen, [procedure type], weighing [X] g and measuring [X x X x X] cm
Gross Description
The spleen is [enlarged/normal] with smooth capsular surface. Cut surface shows [color and consistency] with [pattern of involvement]
Microscopic Findings
Sections show [architectural pattern] with infiltration by [cell type and morphology]. [Additional histologic features]
Immunohistochemical Studies
The neoplastic cells are positive for [positive markers] and negative for [negative markers]
Molecular Studies
Molecular analysis shows [specific findings such as gene rearrangements or mutations]
Diagnosis
[Specific lymphoma subtype] involving spleen, WHO grade [grade if applicable]
Staging Information
Stage [stage] based on extent of disease. [Additional staging parameters]
Prognostic Factors
Prognostic factors include [Ki-67 index, molecular markers, stage, etc.]