What is the appropriate workup for a patient presenting with adenopathy?

Workup for Adenopathy

The workup for adenopathy must be tailored to the location, duration, and clinical context, with supraclavicular and epitrochlear nodes requiring immediate aggressive evaluation due to high malignancy risk, while localized peripheral adenopathy in the setting of recent infection may warrant a brief period of observation or empiric antibiotics before proceeding to imaging and biopsy.

Initial Clinical Assessment

History Taking - Key Red Flags

• Duration >2 weeks without fluctuation or uncertain duration significantly increases malignancy risk 1
• Constitutional symptoms ("B symptoms"): fever, night sweats, unintentional weight loss 1, 2
• Age >40 years, male sex, and white race increase malignancy risk 3
• Recent upper respiratory infection, dental problems, trauma, or insect bites suggest infectious etiology 1
• Occupational exposures, travel history, animal contacts, and sexual history 2
• Medication use and recent vaccination history (COVID-19 vaccines can cause transient adenopathy but should not be assumed without investigation) 4, 2
• Family history of malignancy or hereditary cancer syndromes 1

Physical Examination - Suspicious Features

Physical characteristics that mandate aggressive workup include 1:

• Size >1.5-2 cm 1, 2, 5
• Hard or firm consistency 1
• Fixed to adjacent tissues or matted/fused nodes 1, 2
• Ulceration of overlying skin 1
• Location in supraclavicular, epitrochlear (>5mm), popliteal, or iliac regions 3, 5

Complete examination must include 1:

• All lymph node regions to distinguish localized from generalized adenopathy 2
• Complete skin examination 1
• Breast examination in females with axillary adenopathy 1
• Head and neck examination including nasopharynx for cervical nodes 1
• Abdominal examination for organomegaly 1
• Testicular examination in males with retroperitoneal adenopathy 1

Location-Specific Workup Algorithms

Supraclavicular Adenopathy (Highest Risk)

Supraclavicular nodes are the most worrisome for malignancy and require immediate aggressive workup 5:

• Excisional biopsy is preferred over fine-needle aspiration for definitive diagnosis, particularly when lymphoma is suspected 4
• CT chest/abdomen/pelvis to evaluate for primary malignancy and additional sites of disease 4
• PET-CT for staging if lymphoma is suspected 4
• In pediatric patients, proceed directly to lymph node biopsy due to high risk of lymphoma, tuberculosis, or other serious pathology 4

Cervical Adenopathy

For squamous cell carcinoma involving cervical nodes: head and neck CT or CT/PET scan to identify occult primary 1

If infectious etiology suspected 1:

• Single course of broad-spectrum antibiotics is reasonable
• Mandatory reassessment within 2 weeks
• If not completely resolved, proceed to malignancy workup (partial resolution may represent infection in underlying malignancy)
• If resolved, reassess again in 2-4 weeks to monitor for recurrence

Axillary Adenopathy

In females 1:

• Diagnostic mammography or digital breast tomosynthesis (age ≥40) or ultrasound (age 30-39) 1
• Breast MRI if biopsy shows metastatic disease from occult primary 1
• Ultrasound can identify "snowstorm" appearance of silicone adenitis in patients with breast implants 1
• If morphologically abnormal nodes without breast findings: US-guided core biopsy 1
• Treatment approach: lymph node dissection ± radiation; mastectomy not required 1

In males with adenocarcinoma and bone metastases: check serum PSA to exclude prostate cancer 1

Inguinal/Pelvic Adenopathy

• Examine genitalia and lower extremities for primary lesions 2
• Consider sexually transmitted infections 2

Laboratory Evaluation

Initial Laboratory Tests

• Complete blood count with differential 1, 2
• Comprehensive metabolic panel 1
• C-reactive protein and erythrocyte sedimentation rate 2
• Lactate dehydrogenase (elevated in lymphoma) 1
• Tuberculosis testing 2

Specialized Testing Based on Clinical Context

• Serum PSA in males with adenocarcinoma and bone metastases 1
• Alpha-fetoprotein and beta-hCG in young males with midline/retroperitoneal adenopathy (to exclude extragonadal germ cell tumor) 1
• Aldosterone-to-renin ratio if hypertension/hypokalemia present (for adrenal incidentalomas) 1
• Plasma or 24-hour urinary metanephrines if catecholamine excess suspected 1
• Androgen testing if virilization present 1
• Estrogen/progesterone receptors in females with axillary metastases 1

Imaging Strategy

When to Image

Imaging is indicated when 2, 3:

• Lymphadenopathy persists beyond 4 weeks
• Systemic symptoms present
• High-risk features on examination
• Supraclavicular, epitrochlear, popliteal, or iliac location

Imaging Modalities

• CT chest/abdomen/pelvis with contrast: first-line for evaluating extent of disease and identifying primary malignancy 1, 4
• PET-CT or whole body FDG-PET/CT: valuable for staging lymphoma and identifying occult primary in cancer of unknown primary 1, 4
• MRI: alternative when contrast contraindicated or for specific indications (brain metastases, inferior vena cava involvement) 1
• Ultrasound: useful for characterizing superficial nodes and guiding biopsy 1, 2

Biopsy Approach

Indications for Biopsy

• Lymphadenopathy persisting >4 weeks without clear benign etiology 2, 3, 6
• Any supraclavicular adenopathy 4, 5
• High-risk features on history or examination 1, 2
• Generalized lymphadenopathy in adults (frequently indicates hematological disease) 6

Biopsy Technique Selection

Excisional biopsy is preferred when lymphoma is suspected because it provides adequate tissue for immunophenotyping, flow cytometry, and ancillary studies 4, 5, 6

Fine-needle aspiration has limited role and should not be relied upon when lymphoma is in the differential diagnosis due to inadequate tissue 1, 4

Core needle biopsy is an acceptable alternative to excisional biopsy in some contexts 3

Biopsy the most abnormal node to maximize diagnostic yield 5

Critical Pitfalls to Avoid

• Never assume COVID-19 vaccination as the cause of supraclavicular adenopathy without proper investigation 4
• Avoid corticosteroids before establishing diagnosis as they can mask histologic findings of lymphoma or malignancy 2, 3
• Do not perform adrenal mass biopsy routinely without first excluding pheochromocytoma 1
• Partial resolution with antibiotics does not exclude malignancy - complete resolution is required 1
• Do not rely solely on FNA when lymphoma is suspected 4
• Congestive heart failure commonly causes mediastinal adenopathy (68% incidence) - recognize this pattern to avoid unnecessary biopsies in patients with pulmonary edema and pleural effusions 7

Observation Period

A 3-4 week observation period is acceptable only when 1, 5:

• Localized peripheral adenopathy (not supraclavicular/epitrochlear)
• Benign clinical picture
• Recent infection or clear precipitating cause
• Mandatory close follow-up with low threshold for biopsy if not resolved