Comparison of Lymphadenopathies: Infectious Mononucleosis, Tubercular Lymphadenopathy, Lymphomas, and HIV Lymphadenopathy
The most critical distinguishing features between these conditions are age of presentation, pattern of lymphadenopathy, specific clinical symptoms, and characteristic pathological findings including immunophenotyping and molecular markers.
Infectious Mononucleosis
Presentation and Age
- Typically affects adolescents and young adults (median age 18 years)
- Acute onset with sore throat, cervical lymph node enlargement, fatigue, and fever lasting several weeks 1
Clinical Features
- Triad of fever, pharyngitis, and lymphadenopathy
- Splenomegaly in 50% of cases
- Palatal petechiae and periorbital edema may be present
- Fatigue may persist for weeks to months
Pathology
- Polymorphous infiltrate with immunoblastic proliferation
- Reed-Sternberg-like cells present in 44% of cases
- Necrosis (56%) and mucosal ulceration (40%) may be present
- Immunoblasts are CD20+ B cells with post-germinal center immunophenotype:
- MUM1/IRF4 strongly positive (100%)
- CD10 negative (100%)
- BCL-6 negative (89%)
- Variable weak BCL-2 expression
- Polyclonal κ and λ immunoglobulin light chains (81%)
- Reed-Sternberg-like cells are CD30+, CD15-, BOB.1+, OCT-2+ 2
Tubercular Lymphadenopathy
Presentation and Age
- Can affect any age group, but most common in young adults (20-40 years)
- Subacute to chronic presentation
Clinical Features
- Painless, firm, matted lymph nodes, most commonly cervical (scrofula)
- Constitutional symptoms: low-grade fever, weight loss, night sweats
- May have concurrent pulmonary or extrapulmonary TB
Pathology
- Three main cytomorphological patterns:
- Caseation necrosis with ill-formed granulomas
- Well-formed epithelioid granulomas with or without necrosis
- Reactive hyperplasia with caseation necrosis
- Acid-fast bacilli (AFB) positivity highest in nodes with caseation necrosis
- Culture on Löwenstein-Jensen medium more sensitive than Ziehl-Neelsen staining 3
Diffuse Large B-Cell Lymphoma (DLBCL)
Presentation and Age
- Median age 60-70 years, but can occur at any age
- Constitutes 30-58% of non-Hodgkin lymphomas 4
Clinical Features
- Rapidly enlarging, non-tender lymphadenopathy
- B symptoms (fever, night sweats, weight loss) in 30% of cases
- Extranodal involvement in 40% of cases
Pathology
- Diffuse infiltrate of large cells erasing normal lymph node architecture
- Immunophenotype:
- CD20+, CD79a+ B cells
- Variable expression of CD10, BCL6, and BCL2
- Classified as germinal center B-cell-like (GCB) or activated B-cell-like (ABC) subtypes
- Hans algorithm uses CD10, BCL6, and MUM1 for classification
- Molecular subtypes:
Follicular Lymphoma
Presentation and Age
- Median age 60 years
- Indolent course with waxing and waning lymphadenopathy
Clinical Features
- Painless, widespread lymphadenopathy
- B symptoms uncommon at presentation
- Bone marrow involvement in 70% of cases
Pathology
- Follicular pattern with effacement of normal architecture
- Mixture of centrocytes (small cleaved cells) and centroblasts (large cells)
- Graded 1-3 based on proportion of centroblasts
- Immunophenotype:
- CD20+, CD10+, BCL2+, BCL6+
- CD5-, CD43-, cyclin D1-
- t(14;18) translocation involving BCL2 in 85-90% of cases 4
Marginal Zone Lymphoma
Presentation and Age
- Median age 60 years
- Indolent course
Clinical Features
- Depends on subtype:
- MALT lymphoma: extranodal sites (stomach, lung, thyroid)
- Nodal MZL: painless lymphadenopathy
- Splenic MZL: splenomegaly, peripheral blood involvement
Pathology
- Expansion of marginal zone with medium-sized B cells
- Monocytoid appearance with abundant pale cytoplasm
- Immunophenotype:
- CD20+, BCL2+
- CD5-, CD10-, BCL6-, cyclin D1-
- May have t(11;18), t(1;14), t(14;18) involving MALT1, or t(3;14) 4
Hodgkin Lymphoma
Presentation and Age
- Bimodal age distribution: 15-35 years and >50 years
- More common in males
Clinical Features
- Painless, firm lymphadenopathy, often cervical or mediastinal
- B symptoms in 30% of cases
- Pruritus may be present
Pathology
- Classic Hodgkin lymphoma:
- Reed-Sternberg cells in inflammatory background
- Immunophenotype: CD30+, CD15+, PAX5 weak+, CD20-/+, CD45-
- Nodular lymphocyte predominant Hodgkin lymphoma:
- Lymphocyte predominant cells ("popcorn cells")
- Immunophenotype: CD20+, CD45+, BCL6+, CD30-, CD15- 4
HIV Lymphadenopathy
Presentation and Age
- Affects HIV-infected individuals of any age
- Presentation varies with CD4+ count
Clinical Features
- Persistent generalized lymphadenopathy (PGL) common in early HIV
- Opportunistic infections and malignancies more common with declining CD4+ counts
- Lymphadenopathy etiologies correlate with CD4+ count:
Pathology
- Four main cytomorphological patterns:
- Reactive hyperplasia with follicular hyperplasia
- Caseation necrosis (TB or atypical mycobacteria)
- Well-formed granulomas (histoplasmosis, cryptococcosis)
- Lymphoma (primarily DLBCL or Burkitt lymphoma)
- HIV-associated DLBCL:
Key Distinguishing Features
Age distribution:
- Infectious mononucleosis: Adolescents and young adults
- Tubercular lymphadenopathy: Young adults
- DLBCL and other lymphomas: Older adults (except Burkitt and HIV-associated)
- HIV lymphadenopathy: Any age with HIV infection
Lymph node characteristics:
- Infectious mononucleosis: Tender, mobile cervical nodes
- Tubercular lymphadenopathy: Firm, matted, often with sinus formation
- DLBCL: Rapidly enlarging, firm nodes
- Follicular lymphoma: Multiple sites, waxing and waning
- Hodgkin lymphoma: Rubbery, painless, often cervical or mediastinal
Pathological hallmarks:
- Infectious mononucleosis: Polymorphous infiltrate, MUM1+/CD10-/BCL6- immunoblasts
- Tubercular lymphadenopathy: Caseating granulomas, AFB+
- DLBCL: Diffuse large cell infiltrate, CD20+
- Follicular lymphoma: Follicular pattern, t(14;18), CD10+/BCL2+/BCL6+
- Marginal zone lymphoma: Marginal zone expansion, CD20+/CD5-/CD10-
- Hodgkin lymphoma: Reed-Sternberg cells, CD30+/CD15+
- HIV lymphadenopathy: Variable, depends on etiology and CD4+ count
Clinical Approach to Differential Diagnosis
First, assess patient age and HIV status:
- Young adult with acute onset: Consider infectious mononucleosis
- HIV-positive patient: Consider HIV-related causes based on CD4+ count
- Older adult: Higher suspicion for lymphoma
Evaluate pattern and distribution of lymphadenopathy:
- Localized vs. generalized
- Presence of B symptoms
- Associated organomegaly
Perform appropriate diagnostic tests:
- Complete blood count with differential
- Monospot or EBV serology for suspected mononucleosis
- HIV testing if status unknown
- CD4+ count if HIV-positive
- Excisional biopsy for definitive diagnosis (FNA alone insufficient) 4
Pathological evaluation should include:
- Histomorphology
- Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, cyclin D1, CD21/CD23
- Flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10
- Molecular studies as indicated: FISH for translocations, PCR for clonality 4
Remember that Reed-Sternberg-like cells can be seen in both infectious mononucleosis and Hodgkin lymphoma, making immunophenotyping crucial for differentiation (CD15- in mononucleosis, CD15+ in Hodgkin lymphoma) 2.