What are the common causes of unilateral neck mass or lymphadenopathy?

Common Causes of Unilateral Neck Mass/Lymphadenopathy

In adults, approximately half of all persistent neck masses are malignant, making head and neck squamous cell carcinoma (HNSCC) and lymphoma the most critical diagnoses to consider, particularly in patients over 40 years with tobacco/alcohol use or those with HPV-related oropharyngeal cancer. 1

Primary Diagnostic Categories

The differential diagnosis for unilateral neck masses falls into three main categories, with malignancy being the predominant concern in adults:

Malignant Causes (Most Common in Adults)

• Head and Neck Squamous Cell Carcinoma (HNSCC): The leading cause of malignant neck masses, presenting as metastatic cervical lymphadenopathy from primary sites including oropharynx, oral cavity, larynx, hypopharynx, and nasopharynx 1

• HPV-Positive Oropharyngeal Cancer: Rapidly increasing in incidence, now representing over 70% of new oropharyngeal cancers, often presenting in younger patients (under 40) with minimal tobacco exposure and a unilateral neck mass as the sole presenting symptom 1

• Lymphoma: Both Hodgkin's and non-Hodgkin's lymphoma commonly present with cervical lymphadenopathy 2

• Thyroid Malignancy: Can present as lateral neck metastases 1, 2

• Salivary Gland Tumors: Particularly parotid gland malignancies 2

• Cutaneous Malignancies: Melanoma and squamous cell carcinoma of the face, scalp, or neck can metastasize to cervical nodes 1

• Metastases from Distant Sites: Less common but possible 1

Infectious/Inflammatory Causes

• Reactive Cervical Lymphadenopathy: Associated with viral or bacterial upper respiratory infections, typically self-limited and resolving within 2-4 weeks 1, 3

• Bacterial Lymphadenitis: Often caused by Staphylococcus aureus or Group A Streptococcus, characterized by warmth, erythema, tenderness, and systemic signs like fever 1, 2

• Tuberculous Lymphadenitis: Presents as chronic, often non-tender cervical adenopathy 2

• Cat-Scratch Disease: History of feline exposure with regional lymphadenopathy 2, 3

• Infectious Mononucleosis: Epstein-Barr virus causing bilateral or unilateral cervical adenopathy 2

• Deep Neck Space Infections: Abscesses requiring urgent evaluation 1

Congenital/Developmental Causes

• Branchial Cleft Cysts: Typically present in young adults as lateral neck masses 3

• Thyroglossal Duct Cysts: Midline masses that move with swallowing 3

• Cystic Hygroma/Lymphatic Malformations: Usually diagnosed in childhood but can present in adults 3

Critical Red Flags for Malignancy

The American Academy of Otolaryngology-Head and Neck Surgery identifies specific characteristics that mandate urgent evaluation for malignancy: 1

Physical Examination Features (High-Risk):

• Mass present ≥2 weeks or uncertain duration 1
• Size >1.5 cm 1
• Firm consistency 1
• Fixed to adjacent tissues/reduced mobility 1
• Ulceration of overlying skin 1
• Non-tender mass 1

Historical Features (High-Risk):

• Age >40 years 1
• Tobacco and alcohol use (synergistic risk factors) 1
• Absence of infectious etiology 1
• Prior head and neck malignancy 1

Associated Symptoms Suggesting Primary Malignancy:

• Ipsilateral otalgia with normal ear exam (referred pain from pharynx) 1
• Unilateral hearing loss (nasopharyngeal obstruction of Eustachian tube) 1, 4
• Dysphagia 1
• Voice change 1
• Tonsil asymmetry 1
• Oral cavity/oropharyngeal ulceration 1
• Nasal obstruction and epistaxis (ipsilateral to mass) 1
• Unexplained weight loss 1
• Skin lesions on face, neck, or scalp 1

Management Algorithm Based on Risk Stratification

High-Risk Patients (Any Red Flag Present):

Do NOT prescribe empiric antibiotics without clear evidence of bacterial infection (warmth, erythema, tenderness, fever, recent URI, dental infection, or trauma). 1 Most adult neck masses are neoplastic, not infectious, and antibiotic use delays cancer diagnosis. 1

Immediate workup required: 1

• Imaging (CT with contrast or MRI)
• Fine-needle aspiration (FNA) for tissue diagnosis
• Referral to otolaryngology for examination of upper aerodigestive tract
• If FNA non-diagnostic and suspicion remains high, panendoscopy with biopsy under anesthesia

Low-Risk Patients (No Red Flags, Suspected Infection):

If clear signs of bacterial infection are present, a single course of broad-spectrum antibiotics targeting Staphylococcus aureus and Group A Streptococcus is reasonable. 1

Mandatory reassessment within 2 weeks: 1

• If mass has NOT completely resolved → proceed with malignancy workup
• Partial resolution may represent infection in underlying malignancy → requires further evaluation
• If resolved → reassess again in 2-4 weeks to monitor for recurrence

Common Pitfalls to Avoid

The most dangerous error is assuming a neck mass in an adult is infectious and prescribing multiple courses of antibiotics without definitive diagnosis. 1 This delays cancer diagnosis and worsens outcomes through disease progression. 1

HPV-positive oropharyngeal cancer patients are frequently misdiagnosed as "low-risk" because they are younger, non-smokers, and otherwise healthy, leading to diagnostic delays. 1 Any persistent neck mass warrants evaluation regardless of traditional risk factors.

Supraclavicular, popliteal, and iliac lymph nodes are always abnormal when palpable, as are epitrochlear nodes >5 mm. 3 These locations have extremely high malignancy rates and require immediate workup.