Family Medicine Board Review · Hematology / Oncology · Source: AAFP 9/2025
Lymphadenopathy: High-Yield Board Summary
History red flags, exam findings that separate benign from malignant, site-specific differentials, the correct evaluation pathway, and when (and with what) to treat.
History — Red Flags for Malignancy
Reassuring pattern: lymphadenopathy present <2 weeks, OR present without growth for >1 year → usually benign in both children and adults.
- Increased malignancy risk: persistent lymphadenopathy, male sex, age >40, and B symptoms (fever, unintentional weight loss, night sweats)
- Unintentional weight loss >4.5 kg in the past 6–12 months, hemoptysis, fever, or night sweats → raise suspicion for malignancy or tuberculosis (lymphadenitis or pulmonary)
- History of rash, arthralgias, or myalgias → increases risk of an autoimmune cause
Board trap: "persistent + male + >40 + B symptoms" is the classic high-risk combination — a young patient with none of these and a short duration node is very unlikely to need aggressive workup.
Medications & Vaccines Associated With Lymphadenopathy
| Medications (generic) | Vaccines |
|---|
| Allopurinol | Bacillus Calmette-Guérin (BCG) |
| Atenolol | COVID-19 vaccine |
| Captopril | HIV vaccine |
| Carbamazepine | MMR |
| Cephalosporins | Rubella |
| Gold | Typhoid vaccine |
| Penicillin | Smallpox |
| Phenytoin | |
| Primidone | |
| Pyrimethamine | |
| Quinidine | |
| Sulfonamides | |
| Sulindac | |
Pearl: always ask about recent vaccination and new medications before ordering imaging or biopsy — a temporally-linked drug/vaccine exposure can avoid an unnecessary invasive workup.
Physical Examination — Three Key Features
1. Size
- Normal node: <1 cm
- Normal inguinal node: <2 cm
- In children, persistent node >2–3 cm is abnormal → prompts further workup
2. Texture
- Stony, hard → suggests metastasis
- Firm, rubbery, mobile → may relate to lymphoma
- Fixed nodes → often malignant
- Mobile nodes → can be benign or malignant (not reassuring alone)
3. Tenderness
- Tender, fluctuant, not fixed → associated with bacterial infection
Board trap: "mobile" is not synonymous with "benign" — mobility rules out neither infection nor lymphoma. It's specifically fixed nodes that point strongly toward malignancy.
Localized Lymphadenopathy by Site
Head & Neck
- Supraclavicular lymphadenopathy is highly suggestive of malignancy in all age groups — mainly breast, lung, or retroperitoneal primary. Can also be due to vaccination, TB, or thyroid disease.
- Cervical chain lymphadenopathy is usually due to URTI or infection of the nasopharynx/oropharynx.
Pearl: supraclavicular = the single most concerning location on exam. Always ask about breast, lung, and GI symptoms when you find it.
Axillary / Epitrochlear
- Benign: cat-scratch disease, tularemia, sporotrichosis (inoculation + lymphatic drainage)
- Malignant: breast carcinoma, melanoma, lymphoma
- Epitrochlear lymphadenopathy without apparent infection is especially concerning for malignancy (lymphoma, melanoma)
Inguinal
- Benign: cellulitis, sexually transmitted infections
- Malignant: metastatic penile or vulvar squamous carcinoma, melanoma, lymphoma
Generalized Lymphadenopathy
Defined as involvement of two or more noncontiguous lymph node regions.
Indicates systemic illness: EBV, medications, autoimmune disease, HIV, rheumatoid arthritis, SLE.
EBV pattern (high-yield): bilateral posterior cervical, axillary, and inguinal lymph nodes. Appears within the first week of EBV exposure, improves over 2–3 weeks. Presents with generalized lymphadenopathy, low-grade fever, fatigue, and prolonged malaise.
Evaluation
Labs
- Only needed if suspecting a specific cause, or lymphadenopathy is persistent >1 month — otherwise not routinely needed
- CBC: look for anemia, neutrophilia, lymphocytosis, pancytopenia, thrombocytosis, or blast cells
- Autoimmune suspected: ANA, anti-CCP, dsDNA, CRP, ESR, RF, complement levels
- LDH: if suspecting lymphoma or leukemia
- IGRA: if suspecting TB
Imaging
| Modality | Use |
|---|
| Ultrasound | First-line imaging for peripheral lymphadenopathy in children ≤14 years |
| Contrast CT or MRI neck | First-line in adults with neck lymphadenopathy, especially high risk for malignancy |
| CXR | Chronic localized or generalized lymphadenopathy — look for mediastinal widening (lymphoma, sarcoidosis), hilar lymphadenopathy and calcification (TB) |
Pathology (Diagnostic Standard)
- Obtained via fine-needle aspiration (FNA), core needle biopsy, or excisional biopsy
- FNA and core biopsy are minimally invasive and can accurately diagnose reactive hyperplasia, infections, granulomatous lymphadenopathies, lymphomas, and metastatic malignancies
- FNA: best choice when a small needle is preferred (e.g., specific/select nodes)
- Core needle biopsy is a better initial test than FNA, especially when lymphoma is suspected
Board trap: don't reflexively pick FNA as the "best" pathology test across the board — when lymphoma is the leading concern, core needle biopsy outperforms FNA as the initial test (architecture matters more for lymphoma subclassification).
Treatment
Antibiotics
- Indicated if suspecting bacterial infection: unilateral lymphadenopathy with erythema and tenderness, or a node >2–3 cm
- Not to be used as routine therapy for lymphadenopathy in general
- Most common causative organisms: methicillin-susceptible Staphylococcus aureus and group A Streptococcus
- Amoxicillin-clavulanate or cephalexin — appropriate coverage for both organisms
- Cat-scratch disease suspected → azithromycin is the antibiotic of choice
Exam pearl: match the antibiotic to the clinical scenario — unilateral, tender, erythematous node >2–3 cm → amoxicillin-clavulanate or cephalexin (staph/strep coverage). History of cat exposure/scratch → azithromycin instead.