What are the possible causes of a 3 cm × 2 cm subcutaneous nodule in an adult?

Differential Diagnosis of Subcutaneous Nodules

A 3 cm × 2 cm subcutaneous nodule in an adult requires immediate consideration of soft tissue sarcoma until proven otherwise, followed by systematic evaluation for infectious, inflammatory, and benign etiologies based on clinical context and immune status.

Primary Diagnostic Framework

Malignant Causes (Rule Out First)

Soft tissue sarcomas are the most critical diagnosis to exclude given their rarity (4/100,000/year) but devastating consequences if missed 1. For any subcutaneous lesion:

• Lesions >5 cm are particularly concerning for malignancy and mandate imaging before biopsy 1, 2
• Contrast-enhanced MRI is the preferred imaging modality for limb and superficial trunk lesions 1
• Multiple core needle biopsies are the standard diagnostic approach 1
• Excisional biopsy is acceptable only for superficial lesions <5 cm 1

Critical pitfall: Never perform incisional biopsy without planning the pathway so the scar can be safely removed during definitive surgery 1.

Benign Causes (Most Common)

Lipomas are the most frequent subcutaneous nodules, typically occurring on trunk and proximal extremities 2. Key distinguishing features:

• Soft, mobile, painless masses
• Ultrasound confirms diagnosis for superficial lesions
• Deep lesions require MRI or CT to exclude liposarcoma and assess underlying structure involvement 2
• Up to 50% contain atypical fat cells, emphasizing need for imaging 2

Other common benign lesions include:

• Epidermal inclusion cysts (sebaceous cysts): asymptomatic unless infected 2
• Ganglion cysts: confirmed with ultrasound if diagnosis unclear 2

Infectious Causes (Context-Dependent)

In immunocompromised patients, infectious etiologies become paramount 3:

Fungal Infections

• Aspergillus, Rhizopus, Mucor: cause painful erythematous nodules that become necrotic 3
• Fusarium species: present with multiple erythematous macules evolving to necrotic nodules, preferentially on extremities (60-80% have skin lesions) 3
• Blood cultures positive in 40-50% of Fusarium cases 3

Mycobacterial Infections

• Nocardia: painless subcutaneous nodules or abscesses described as "cold to the touch" 3
• Usually represent metastatic foci from pulmonary source 3
• Nontuberculous mycobacteria: present as poorly resolving cellulitis, painless 1-2 cm nodules, or subcutaneous abscesses 3

Parasitic Infections

• Dirofilariasis (Dirofilaria repens): increasingly recognized cause of subcutaneous nodules, particularly in endemic areas 4, 5
• Can mimic malignancy or other pathologies 4
• Excisional biopsy is both diagnostic and therapeutic 5

Inflammatory Causes

• Nodular fasciitis: rare benign tumor in young adults, rapidly growing, can spontaneously resolve 6
• Difficult to differentiate from malignancy on ultrasound—biopsy required 6
• Subcutaneous granuloma annulare: tender subcutaneous nodules with normal overlying skin, more common in children but occurs in adults 7

Recommended Diagnostic Algorithm

1. Assess immune status and clinical context

   • Immunocompromised? Consider infectious causes first 3
   • Rapid growth in young adult? Consider nodular fasciitis 6
   • Size >5 cm or deep location? Prioritize malignancy workup 1, 2

2. Obtain appropriate imaging

   • Superficial lesions <5 cm: ultrasound acceptable 2
   • Deep lesions or >5 cm: MRI with contrast mandatory 1

3. Biopsy strategy

   • Core needle biopsy is standard 1
   • Plan biopsy pathway for potential definitive surgery 1
   • In immunocompromised patients with life-threatening presentation, consider early biopsy AND surgical debridement 3

4. For immunocompromised patients specifically

   • Immediate dermatology consultation 3
   • Consider empiric antimicrobials in life-threatening situations 3
   • Biopsy for culture, sensitivities, and histopathology 3

Critical caveat: The varied presentations and numerous disease associations make subcutaneous nodule evaluation challenging 8. Location, symptoms, growth rate, and patient immune status are essential discriminating factors that guide the diagnostic approach.