What is the diagnosis and treatment for a patient presenting with subcutaneous (under the skin) nodules on the legs, persistent cough, and unintentional weight loss?

Diagnosis: Tuberculosis or Lung Cancer Until Proven Otherwise

In a patient presenting with subcutaneous nodules on the legs, persistent cough, and unintentional weight loss, the most critical diagnoses to rule out immediately are tuberculosis (TB) and lung cancer, as both present with this triad and carry significant mortality if diagnosis is delayed. 1, 2

Immediate Diagnostic Workup

Step 1: Chest Radiography (Perform Today)

• Obtain a chest X-ray immediately as the initial study—this is the standard first-line test for suspected TB or lung cancer 3, 2
• Look specifically for:
  • Upper lobe infiltrates or cavitations (classic for TB) 1, 2
  • Hilar or mediastinal lymphadenopathy 1, 2
  • Masses or nodules (concerning for malignancy) 1, 4
  • Miliary pattern (disseminated TB) 5

Step 2: CT Chest with IV Contrast (If X-ray Abnormal or High Clinical Suspicion)

• Proceed with CT chest even if chest X-ray is normal but clinical suspicion remains high, as CT has superior sensitivity for detecting early disease 2
• CT is essential for characterizing nodules, detecting bronchiectasis, and identifying mediastinal involvement 1, 4

Step 3: Urgent Microbiological Studies

• Collect three morning sputum samples for:
  • Acid-fast bacilli (AFB) smear and culture 1, 2
  • Xpert MTB/RIF rapid molecular testing (sensitivity ~60%, detects rifampicin resistance) 2
• Initiate respiratory isolation immediately if imaging is suggestive of TB while awaiting culture results 1, 2

Step 4: Biopsy of Subcutaneous Nodules

• The subcutaneous nodules are a critical diagnostic opportunity—biopsy one of these lesions urgently 6, 7
• Send tissue for:
  • Histopathology (look for granulomas, acid-fast bacilli, malignant cells) 6
  • Mycobacterial culture and PCR 6
  • Fungal culture (coccidioidomycosis, histoplasmosis can present similarly) 8
  • Mass spectrometry if atypical mycobacteria suspected 6

Critical Differential Diagnoses

Tuberculosis (Most Likely)

• The combination of cough, weight loss, and subcutaneous nodules is highly suggestive of disseminated TB 1, 5
• TB should be considered in any patient with persistent cough >2-3 weeks plus weight loss, even without fever or night sweats 1, 2
• Risk factors to assess: HIV status, diabetes, immunosuppression, contact with TB cases, residence in or travel to endemic areas 1
• Cutaneous TB manifestations (erythema nodosum, tuberculosis cutis) can present as subcutaneous nodules 7

Lung Cancer with Metastases

• Weight loss with persistent cough obligates ruling out lung cancer, especially with risk factors (smoking, age >50) 1, 4
• Subcutaneous nodules may represent cutaneous metastases 1
• If CT shows suspicious mass or nodule, bronchoscopy with biopsy is indicated 1
• Ensure sufficient tissue is obtained for molecular testing (EGFR, ALK) if adenocarcinoma is found 1

Atypical Mycobacterial Infection

• Mycobacterium chelonae and other non-tuberculous mycobacteria can cause disseminated disease with cutaneous nodules and pulmonary involvement 6
• More common in immunocompromised patients 6
• Requires mass spectrometry for definitive identification 6

Endemic Fungal Infections

• Coccidioidomycosis can present with cough, weight loss, pulmonary nodules, and migratory shadows on imaging 8
• Consider if patient has traveled to endemic areas (southwestern US, Central/South America) 8
• Histoplasmosis and blastomycosis can also cause similar presentations 1

Sarcoidosis with Erythema Nodosum

• Can present with subcutaneous nodules (erythema nodosum), cough, and constitutional symptoms 1
• Less likely given the weight loss, which is not typical for sarcoidosis 1

Red Flags Requiring Expedited Evaluation

• Any amount of weight loss with respiratory symptoms has high specificity for serious disease (TB, cancer, chronic infections) 2
• Subcutaneous nodules in the context of pulmonary symptoms suggest disseminated disease 6, 7
• Immunosuppression (HIV, corticosteroids, biologics) dramatically increases risk of disseminated TB and atypical infections 1, 5

Management While Completing Evaluation

• Initiate respiratory isolation immediately if TB is suspected based on clinical presentation or imaging findings 1, 2
• Do NOT start empirical TB treatment without diagnostic confirmation unless patient is critically ill and unable to provide samples 2
• Test for HIV—all patients with suspected TB should undergo HIV testing 1
• Assess CD4+ count if HIV-positive (counts <200 cells/μL increase risk of opportunistic infections including disseminated TB) 1

Common Pitfalls to Avoid

• Do not dismiss the diagnosis of TB based on absence of fever or night sweats—these symptoms may be absent in early presentations 2
• Do not delay biopsy of accessible lesions (subcutaneous nodules)—this provides the fastest path to diagnosis 6, 7
• Do not assume a single etiology—multiple conditions can coexist (e.g., TB with underlying bronchiectasis) 4
• Do not overlook atypical mycobacteria—if standard TB testing is negative but clinical suspicion remains high, pursue cultures and mass spectrometry 6