Paraneoplastic Pemphigus

Clinical Background

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 onset is ≥60 years
  • Sex – M<F

Risk Factors

  • Malignancies
    • Most common – lymphoma, leukemia, Castleman syndrome   
    • Less common – thymoma, sarcomas, Waldenström macroglobulinemia
    • Other malignancies – pancreatic adenocarcinoma, hepatocellular carcinoma, colon, breast, prostate

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 involve multiple organs

Clinical Presentation

  • Skin lesions – polymorphous skin eruption
    • Flaccid bullae
    • Lichenoid lesions
    • Erythematous maculopapular lesions with dusky centers mimicking erythema multiforme
    • Erythroderma
  • Oral mucosal – characteristically involves vermilion border of lips (may be first symptom)
  • Other organ systems involved
    • Gastrointestinal – esophagus (mainly)
    • Respiratory – bronchiolitis obliterans
    • Renal – nephrotic syndrome, 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

  • Paraneoplastic pemphigus serum antibody screen 
    • Positive screen – indicates serum antibodies to multiple epithelia (simple, columnar, transitional)
    • Positive antibody screen without known malignancy – perform aggressive evaluation for malignancy
    • Negative result – perform perilesional skin biopsy; consider evaluation for other immunobullous disease
      • See Immunobullous Skin Diseases Testing Algorithm
  • Perilesional skin biopsy for cutaneous direct immunofluorescence submitted in Michel’s (or Zeus) medium
    • Staining is usually positive for IgG antibodies deposited on the surface of epidermal and epithelial cells (cell surface antibodies)
    • IgG antibodies to basement membrane zone (BMZ) also may be present
    • The combination of cell surface and BMZ IgG antibody staining is an indicator of paraneoplastic pemphigus
    • IgA antibodies – rarely identified

Differential Diagnosis

  • Erythema multiforme major
  • Stevens-Johnson syndrome (SJS)
  • Lichenoid drug reaction
  • Lichen planus
  • Systemic lupus erythematosus (SLE)
  • Pemphigoid
  • Pemphigus
  • Linear IgA bullous dermatosis
  • Epidermolysis bullosa acquisita
  • Toxic epidermal necrolysis

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Paraneoplastic Pemphigus Antibody Screen 0092107
Method: Indirect Immunofluorescence

Indirect immunofluorescence testing of serum for paraneoplastic pemphigus IgG antibodies in patient suspected of having a blistering disease associated with malignancy

Uses substrates from rodents, including mouse heart, liver, bladder and rat bladder to detect characteristic staining

Consider concurrent pemphigus panel test to detect and monitor pemphigus antibodies, if present (including IgG desmoglein-1 and desmoglein-3 antibodies)

Clinical correlation is necessary because results may overlap with other types of pemphigus and with pemphigoid

Rarely, patients may also have IgA paraneoplastic pemphigus antibodies; IgA paraneoplastic pemphigus testing can be performed by request

Monitor paraneoplastic pemphigus antibodies and/or pemphigus panel, particularly if IgG desmoglein-1 and/or -3 antibodies are increased
Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence

Determine presence and staining pattern of immunoglobulins (IgG, IgM, IgA), third component of complement (C3) and fibrinogen in perilesional skin or mucosal biopsy specimens from patients suspected of having paraneoplastic pemphigus or other immunobullous disease

May be inaccurate if tissue not taken from correct location; type and age of lesion may also be important (perilesional is optimal with intact epithelium/epidermis)

Tissue must be submitted in Michel’s or Zeus medium; this test cannot be performed on formalin-fixed tissue

  
Additional Tests Available
 
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Pemphigus Panel - IgG Epithelial Cell Surface Antibodies and Levels of IgG Desmoglein 1 and Desmoglein 3 Antibodies, Serum 0090650
Method: Enzyme-Linked Immunosorbent Assay/Indirect Immunofluorescence

IgG cell surface antibody staining is found in all cases; IgG desmoglein-1 and/or IgG desmoglein-3 antibody levels may be increased