Skin Symptoms in Hemophagocytic Lymphohistiocytosis
Skin rash occurs as a supportive clinical finding in HLH and should prompt consideration of the diagnosis when present alongside fever, organomegaly, and cytopenias, though it is not part of the formal diagnostic criteria. 1
Clinical Presentation of Cutaneous Manifestations
Skin involvement in HLH is reported in up to 65% of patients and presents with highly variable morphologies: 2
- Morbilliform (maculopapular) eruptions are the most commonly described pattern 1
- Purpuric macules and papules (generalized distribution) 2
- Erythroderma (diffuse erythematous involvement) 2
- Panniculitis (subcutaneous inflammation, particularly associated with cytotoxic T-cell lymphoma subtypes) 3, 4
- Atypical targetoid lesions and bullae 5
- Pyoderma gangrenosum (rare presentation) 5
- Edema (listed as a supportive finding) 1
The cutaneous findings are typically nonspecific on histology, showing lymphohistiocytic infiltrates with edema, hemorrhage, and prominent phagocytic histiocytes that may demonstrate erythrophagocytosis. 5, 4
Diagnostic Significance
Skin rash is explicitly listed among "other abnormal clinical findings consistent with the diagnosis" in the HLH-2004 criteria, though it does not count toward the required 5 of 8 diagnostic criteria. 1 The presence of cutaneous eruptions should:
- Raise clinical suspicion for HLH when occurring with fever, cytopenias, hepatosplenomegaly, and hyperferritinemia 1, 2
- Prompt biopsy of suspicious lesions to exclude underlying lymphoma, particularly in patients with panniculitic presentations 1
- Signal potential disease recurrence when new cutaneous lesions appear during follow-up 2
Critical Diagnostic Pitfall: DRESS Syndrome Overlap
A patient presenting with fever, generalized rash, bicytopenia, and internal organ involvement after drug exposure should be evaluated for both DRESS syndrome and HLH, as these conditions overlap significantly and may represent a spectrum of immune dysfunction. 6 Key distinguishing features:
- Time-to-onset: DRESS typically presents 2-3 weeks after drug exposure 6
- Clinical worsening despite initial therapy (corticosteroids for presumed DRESS) should trigger HLH workup, which typically occurs 2.3 weeks after initial DRESS diagnosis 6
- Eosinophilia favors DRESS but does not exclude HLH 6
- Hemophagocytosis on biopsy confirms HLH component 6
Management Approach for Cutaneous Manifestations
The skin findings themselves do not require specific dermatologic therapy; management focuses on treating the underlying HLH. 1, 7
Primary HLH Treatment (addresses cutaneous symptoms):
- High-dose corticosteroids (methylprednisolone 1g/day for 3-5 days) as first-line therapy 7
- Monitor clinical response every 12 hours, including assessment of rash evolution 7
- Add cyclosporine A or anakinra if inadequate response within 24-48 hours 7
Special Considerations:
- If cutaneous lesions suggest lymphoma (particularly panniculitic patterns in subcutaneous tissue): biopsy is mandatory to exclude malignancy-triggered HLH, which requires lymphoma-directed chemotherapy 1, 3
- If drug-induced HLH/DRESS overlap is suspected: discontinue offending agent immediately and avoid steroid monotherapy, as viral reactivation with poor outcomes has been reported 6
- If EBV-triggered HLH with skin involvement: consider adding rituximab 375 mg/m² weekly for 2-4 doses alongside standard HLH therapy 1, 7
Monitoring for Treatment Response:
Improvement or resolution of skin rash serves as a clinical marker of treatment response alongside normalization of ferritin, sCD25, cell counts, and organ function. 7 Persistent or worsening cutaneous findings despite appropriate HLH therapy should prompt: