Paraneoplastic pemphigus (paraneoplastic autoimmune multi-organ syndrome) is a severely debilitating blistering disease affecting skin and mucous membranes in patients with malignancy, particularly hematologic malignancies.

Epidemiology

• Incidence - very rare
• Age - mean age of onset is 60 years or older
• Sex - apparent female predominance

Risk Factors

• Malignancies
  • Most common - lymphoma, leukemia, and Castleman syndrome   
  • Less common include thymoma, sarcomas, Waldenström macroglobulinemia
  • Others include adenocarcinoma of the pancreas, colon, breast and prostate; hepatocellular carcinoma

Pathophysiology

• IgG antibodies to epithelial cell surface molecules with suprabasilar acantholysis and basal cell vacuolation; IgG antibodies to basement membrane zone may also be present
• May have interface inflammatory changes as in lichen planus
• May have features of pemphigus vulgaris and erythema multiforme
• Disease process may have multiple organ involvement

Clinical Presentation

• Skin lesions
  • Flaccid bullae
  • Lichenoid lesions
  • Erythematous maculopapular lesions with dusky centers mimicking erythema multiforme
  • Erythroderma
• Oral mucosal - characteristically involves vermilion border of lips
• Other organ system involvement
  • Gastrointestinal - esophagus mainly
  • Respiratory - bronchiolitis obliterans
  • Renal - nephrotic syndrome and glomerular nephritis

Treatment

• Treat malignancy
• Supportive care
• Potential therapies include glucocorticoids, other immunosuppressives, plasmapheresis

Diagnosis

• Indications for testing
  • Blistering disease and presence or suspected presence of malignancy
    • Neoplasm usually precedes skin disease
    • Strong suspicion of paraneoplastic pemphigus in the absence of known cancer should trigger a diagnostic evaluation for malignancy
• Laboratory testing
  • Perilesional skin biopsy for cutaneous direct immunofluorescence submitted in Michel’s (or Zeus) medium
    • Staining is usually positive for IgG deposited on the cell surfaces of epidermal and epithelial cells
    • IgG antibodies to basement membrane zone may also be observed
    • IgA antibodies may rarely be identified
  • Paraneoplastic pemphigus serum antibody screen - positive in most patients
    • Most sensitive if accompanied by fixed tissue histology and direct immunofluorescence skin biopsies
    • If antibody screen is positive without the presence of known malignancy, an aggressive evaluation for malignancy should be performed
    • Negative result should lead to other immunobullous disease evaluation - see Immunobullous Skin Diseases Testing Algorithm  

Differential Diagnosis

• Erythema multiforme, Stevens Johnson syndrome
• Lichenoid drug reaction
• Lichen planus
• Lupus erythematosus
• Pemphigoid
• Pemphigus vulgaris
• Toxic epidermal necrolysis