Definition/General
Introduction:
Primary ovarian lymphoma accounts for 1-2% of all ovarian malignancies and 5-10% of extranodal lymphomas
Diffuse large B-cell lymphoma (DLBCL) is the most common type (70%)
Burkitt lymphoma is the second most common (15%)
Must be distinguished from secondary ovarian involvement by systemic lymphoma.
Origin:
Arises from ovarian stromal lymphoid tissue or from lymphoid cells within ovarian follicles
Germinal center B-cells are the cell of origin for most cases
Chronic inflammatory conditions may predispose to lymphoma development
Viral infections (EBV, HIV) associated with some cases
Immunosuppression increases risk.
Classification:
WHO 2020 classification: Diffuse large B-cell lymphoma (70%) - aggressive, high-grade
Burkitt lymphoma (15%) - highly aggressive, EBV-associated
Follicular lymphoma (5%) - indolent, low-grade
MALT lymphoma (5%) - indolent, marginal zone
T-cell lymphomas (rare) - various subtypes
Hodgkin lymphoma extremely rare in ovary.
Epidemiology:
Peak incidence in 3rd-4th decades (younger than epithelial ovarian cancers)
Bilateral involvement in 50-60% cases
Stage I-II disease in 70% cases at presentation
Better prognosis than epithelial ovarian cancers when stage-matched
Indian population - similar incidence to global rates
HIV-associated cases increasing in endemic areas.
Clinical Features
Presentation:
Rapidly enlarging pelvic mass (85% cases)
Bilateral ovarian masses in 50-60% cases
B-symptoms (fever, night sweats, weight loss) in 30% cases
Abdominal distension and ascites (40% cases)
Better performance status compared to epithelial ovarian cancers
Younger age group (20-40 years typically).
Symptoms:
Pelvic/abdominal pain (70% cases)
Constitutional symptoms: fever (25%), night sweats (20%), weight loss >10% (15%)
Abdominal distension (50% cases)
Menstrual irregularities (30% premenopausal women)
Urinary symptoms from pelvic pressure (25%)
GI symptoms - early satiety, nausea (20%)
Lymphadenopathy may be present (15%).
Risk Factors:
Immunodeficiency states - HIV, organ transplant recipients
Autoimmune disorders - SLE, rheumatoid arthritis
Viral infections - EBV (Burkitt lymphoma), HTLV-1
Chronic inflammatory conditions
Previous malignancy with chemotherapy/radiation
Family history of hematological malignancies
Age 20-40 years (peak incidence).
Screening:
No specific screening for primary ovarian lymphoma
High-risk patients (HIV, immunosuppressed) need regular monitoring
LDH often elevated (80% cases)
β2-microglobulin may be elevated
Complete blood count may show cytopenias
Flow cytometry if ascites present
PET-CT for staging and monitoring response.
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Gross Description
Appearance:
Solid, lobulated masses with homogeneous cut surface
Fish-flesh appearance characteristic of lymphomas
Gray-white to tan coloration
Soft to firm consistency
Minimal necrosis compared to carcinomas
No cystic areas typically
Surface involvement may be present.
Characteristics:
Solid, fleshy consistency
Homogeneous gray-white cut surface
Fish-flesh appearance
Bulging cut surface
Absence of necrosis or hemorrhage in most cases
No calcifications
Well-circumscribed but may be infiltrative.
Size Location:
Variable size (5-25 cm, average 12-15 cm)
Bilateral involvement in 50-60% cases
Entire ovary replacement common
May involve ovarian surface
Fallopian tube involvement rare
Peritoneal implants less common than carcinomas.
Multifocality:
Bilateral ovarian involvement in 50-60% cases
Nodal involvement at presentation (30% cases)
Peritoneal involvement uncommon
Bone marrow involvement may occur
CNS involvement rare but possible
Stage I-II disease in 70% at presentation.
Microscopic Description
Histological Features:
DLBCL: diffuse sheets of large B-cells, starry-sky pattern may be present
Burkitt lymphoma: monomorphic medium-sized cells, prominent starry-sky pattern
Follicular lymphoma: follicular growth pattern, centrocytes and centroblasts
MALT lymphoma: marginal zone cells, lymphoepithelial lesions
Preservation of ovarian stroma between tumor cells.
Cellular Characteristics:
DLBCL: large cells (>2x small lymphocyte), vesicular nuclei, 2-3 nucleoli
Burkitt: medium-sized cells, round nuclei, multiple small nucleoli, high mitotic rate
Follicular: cleaved (centrocytes) and non-cleaved (centroblasts) cells
Prominent apoptosis and tingible body macrophages (starry-sky pattern).
Architectural Patterns:
Diffuse growth pattern (DLBCL, Burkitt)
Follicular pattern (follicular lymphoma)
Marginal zone pattern (MALT lymphoma)
Sinusoidal pattern may be seen
Angiocentric growth uncommon
Sclerosis may be present
Starry-sky pattern prominent in Burkitt.
Grading Criteria:
WHO grading based on histological subtype
Low-grade: follicular lymphoma, MALT lymphoma
High-grade: DLBCL, Burkitt lymphoma
Ki-67 proliferation index: >95% Burkitt, 60-80% DLBCL, <20% follicular
Mitotic count correlates with grade.
Immunohistochemistry
Positive Markers:
CD20 - positive in 95% B-cell lymphomas
CD79a - positive in B-cell lymphomas
PAX5 - positive in B-cell lymphomas
CD10 - positive in Burkitt lymphoma (90%), follicular lymphoma (85%)
BCL6 - positive in DLBCL (70%), Burkitt (30%)
MUM1/IRF4 - positive in DLBCL (60%)
Ki-67 - very high in Burkitt (>95%), high in DLBCL (>60%).
Negative Markers:
Cytokeratins (AE1/AE3, CAM5.2) - negative (excludes carcinoma)
PAX8 - negative (excludes ovarian epithelial tumors)
WT1 - negative (excludes serous carcinoma)
Inhibin - negative (excludes sex cord-stromal tumors)
CD3 - negative in B-cell lymphomas
TdT - negative in mature B-cell lymphomas.
Diagnostic Utility:
B-cell lineage confirmation: CD20+, CD79a+, PAX5+ establish B-cell origin
Subtype classification: CD10+, BCL6+ suggest germinal center origin
Burkitt lymphoma: CD10+, BCL6+, MUM1-, Ki-67 >95%, c-MYC+
DLBCL classification: GCB vs non-GCB based on CD10, BCL6, MUM1
Staging workup: Flow cytometry of ascites/pleural fluid.
Molecular Subtypes:
DLBCL subtypes: GCB (CD10+, BCL6+, MUM1-) vs ABC (CD10-, BCL6-, MUM1+)
Double-hit lymphoma: c-MYC and BCL2/BCL6 rearrangements
Burkitt lymphoma: c-MYC rearrangement (>95%), Ki-67 >95%
Follicular lymphoma: BCL2 rearrangement (85%), CD10+, BCL6+
MALT lymphoma: CD43+, cyclin D1-.
Molecular/Genetic
Genetic Mutations:
c-MYC rearrangement (Burkitt lymphoma 95%, DLBCL 15%)
BCL2 rearrangement (follicular lymphoma 85%, DLBCL 20%)
BCL6 rearrangement (DLBCL 30%, follicular 10%)
TP53 mutations (aggressive lymphomas 30%)
MYD88 mutations (ABC-DLBCL 40%)
CREBBP/EP300 mutations (follicular lymphoma 70%).
Molecular Markers:
Ki-67 proliferation index (>95% Burkitt, 60-80% DLBCL)
p53 overexpression (poor prognosis)
BCL2 protein expression
c-MYC protein expression
CD5 expression (rare in ovarian lymphomas)
EBV status (EBER ISH)
Kappa/lambda light chains (clonality assessment).
Prognostic Significance:
Stage most important prognostic factor
Age >60 years poor prognosis
High LDH adverse factor
Double-hit lymphoma (c-MYC + BCL2/BCL6) very poor prognosis
GCB vs ABC subtype (GCB better prognosis)
Ki-67 >90% may indicate Burkitt lymphoma
IPI score prognostic in DLBCL.
Therapeutic Targets:
CD20 (rituximab - standard therapy)
BCL2 (venetoclax for BCL2+ lymphomas)
BTK inhibitors (ibrutinib for ABC-DLBCL)
c-MYC inhibitors under development
CAR-T cell therapy for relapsed/refractory DLBCL
Checkpoint inhibitors (pembrolizumab)
Bispecific antibodies (blinatumomab).
Differential Diagnosis
Similar Entities:
High-grade serous carcinoma - solid growth pattern
Poorly differentiated carcinoma - lack of glandular differentiation
Granulosa cell tumor - diffuse growth pattern
Metastatic lymphoma from nodal primary
Leukemic infiltration of ovary
Inflammatory pseudotumor - reactive lymphoid infiltrate.
Distinguishing Features:
Epithelial carcinoma: Cytokeratin+, PAX8+ (serous), WT1+ (serous), CD20-
Granulosa cell tumor: Inhibin+, calretinin+, CD20-, nuclear grooves
Metastatic lymphoma: Bilateral, extraovarian disease, same immunophenotype as nodal disease
Reactive lymphoid infiltrate: Polymorphous population, germinal centers, polyclonal by flow cytometry.
Diagnostic Challenges:
Solid growth pattern mimicking carcinoma - IHC essential
Primary vs secondary lymphoma - staging studies required
Crush artifact in small biopsies - adequate tissue sampling needed
Burkitt vs DLBCL - Ki-67 and molecular studies help
Large cell transformation of low-grade lymphoma
Concurrent epithelial tumor - collision tumors possible.
Rare Variants:
T-cell lymphoma - CD3+, CD20-, various subtypes (ALK+ ALCL, PTCL-NOS)
Hodgkin lymphoma - Reed-Sternberg cells, CD30+, CD15+
Plasmablastic lymphoma - HIV-associated, CD138+, EBV+
Intravascular lymphoma - tumor cells in vascular lumina
Lymphomatoid granulomatosis - EBV+ B-cell proliferation with T-cell reaction.
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
[Bilateral/Unilateral] salpingo-oophorectomy, measuring [size] cm
Diagnosis
[Lymphoma subtype], [stage]
Classification and Grade
[DLBCL/Burkitt/Follicular/MALT] lymphoma, [high/low]-grade
Histological Features
Shows [diffuse/follicular/marginal zone] growth pattern with [large B-cells/medium-sized cells], Ki-67 [X]%
Size and Extent
Tumor size: [X] cm, [unilateral/bilateral], stage [I/II/III/IV]
Node Status
Lymph nodes: [X] examined, [X] positive
Special Studies
IHC: CD20 (+), PAX5 (+), CD79a (+), CD3 (-), Ki-67 [X]%, [subtype-specific markers]
FISH: c-MYC [result], BCL2 [result], BCL6 [result]; EBER ISH [result]
Flow cytometry: [B-cell phenotype with light chain restriction]
Prognostic Factors
Subtype: [type]; Grade: [high/low]; Stage: [I-IV]; Ki-67: [X]%; LDH: [elevated/normal]
Staging Information
Ann Arbor Stage [I/II/III/IV][A/B]; IPI score: [low/intermediate/high] risk
Final Diagnosis
Primary [lymphoma subtype] of [bilateral/unilateral] ovary, Stage [stage]