What is the workup for a patient with a lymph node enlargement and overlying skin discoloration, considering potential causes such as infection (e.g. tuberculosis, cat-scratch disease) or malignancy (e.g. lymphoma, metastatic cancer)?

Workup for Lymph Node with Overlying Skin Discoloration

Immediate Priority: Exclude Malignancy

A lymph node with overlying skin discoloration requires urgent evaluation for malignancy, as skin ulceration overlying a neck mass indicates metastatic cancer that has broken through the lymph node capsule and directly invaded the skin, or represents a cutaneous malignancy with direct extension into the neck. 1

---

High-Risk Features Requiring Immediate Action

The presence of skin discoloration/ulceration is itself a red flag that mandates aggressive workup. Additional concerning features include:

• Size >1.5 cm 1
• Firm or hard consistency 1
• Fixation to adjacent tissues (reduced mobility) 1
• Duration ≥2 weeks 1
• Age >40 years 1
• Tobacco and/or alcohol use 1

---

Algorithmic Workup Approach

Step 1: Confirm Tissue Diagnosis

• Fine-needle aspiration (FNA) is strongly preferred over open biopsy for initial tissue sampling 1, 2, 3
• Open biopsy should be avoided as it can complicate subsequent treatment and delay definitive care 1
• Send tissue for:
  • Histopathology with immunophenotyping 3
  • Cytogenetic/molecular analysis if lymphoma suspected 3
  • Mycobacterial culture if granulomatous disease present 4

Step 2: Imaging Studies

• Contrast-enhanced CT of neck (or MRI) is mandatory to assess extent of disease and identify primary tumor 1, 2, 3
• PET-CT should be considered to identify occult primary malignancy and assess for distant metastases 1, 2
• For melanoma specifically: chest imaging and consideration of brain MRI if any neurologic symptoms 5, 6

Step 3: Targeted Physical Examination

• Direct visualization of upper aerodigestive tract including larynx, base of tongue, and pharynx by otolaryngologist 3
• Complete skin examination to identify primary melanoma or other cutaneous malignancy 5, 6
• Examination of all lymph node basins 5, 3

Step 4: Laboratory Testing

• Complete blood count, comprehensive metabolic panel 3
• Lactate dehydrogenase (LDH) - prognostic marker for lymphoma and melanoma 5, 3
• Hepatitis B, C, and HIV serology if malignancy confirmed and treatment planned 3
• Tuberculosis testing (PPD or IGRA) if granulomatous disease suspected 4

---

Critical Differential Diagnoses

Malignancy (Most Likely)

1. Metastatic squamous cell carcinoma from head/neck primary 1, 2
2. Melanoma with in-transit metastases or direct skin invasion 5, 6
   • Skin discoloration may represent melanoma pigmentation
   • Requires complete dermatologic examination 5
3. Cutaneous lymphoma (CD30+ lymphoproliferative disorders, anaplastic large cell lymphoma) 7
4. Lymphoma with extranodal extension 3

Infectious Causes (Less Likely but Important)

1. Nontuberculous mycobacterial (NTM) infection 4
   • More common in children 1-5 years old
   • Typically unilateral, may have violaceous skin discoloration
   • Excisional biopsy is treatment of choice (95% success rate) 4
2. Tuberculosis 4
   • Requires PPD/IGRA testing
   • Critical to distinguish from NTM for public health tracking 4
3. Cat-scratch disease (Bartonella henselae) 8, 9, 10
   • History of cat exposure (though not always present)
   • Can present with persistent lymphadenopathy and skin changes
   • Serology and PCR on tissue for diagnosis 9, 10

---

Common Pitfalls to Avoid

• Never prescribe empiric antibiotics without clear signs of acute bacterial infection (fever, rapid onset, tenderness, erythema), as this delays cancer diagnosis 1, 2
• Do not assume cystic appearance on imaging is benign - HPV-positive oropharyngeal cancer frequently presents as cystic cervical metastases mimicking branchial cleft cysts 2
• Avoid corticosteroids - they mask histologic diagnosis of lymphoma and other malignancies 11, 12
• Do not rely on normal laboratory values - they provide false reassurance and do not exclude malignancy 2
• Partial resolution after antibiotics does not exclude malignancy - infection can coexist with underlying cancer 2, 3

---

Urgent Specialist Referral

Immediate referral to otolaryngology (head/neck surgery) or surgical oncology is mandatory for any lymph node with overlying skin changes 1, 2, 3. This is not a "wait and see" scenario - skin involvement indicates advanced local disease requiring urgent evaluation and treatment planning.