Paraneoplastic Pemphigus

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) and against desmoglein 1, 3; desmoplakin 1, 2; envoplakin; periplakin; BP230 and/or BP180
  • Positive antibody screen without known malignancy – perform aggressive evaluation for malignancy
  • Negative result – perform and/or correlate with 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) may also be present
  • Combination of cell surface and BMZ IgG antibody staining – indicates paraneoplastic pemphigus
  • IgA antibodies (cell surface and BMZ) – rarely identified

Differential Diagnosis

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

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 ≥60 years
• Sex – M<F

Risk Factors

• Malignancies
  • Most common – lymphoma (B cell most common), leukemia (chronic lymphocytic leukemia most common), Castleman disease   
  • 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 (see Clinical Presentation)

Clinical Presentation

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

Treatment

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

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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 Fluorescent Antibody	Panel includes epithelial cell surface IgG antibodies by IFA on intact human skin and monkey esophagus substrates, IgG desmoglein 1 and IgG desmoglein 3 antibodies by ELISAs Use to diagnose most major types of pemphigus and to monitor disease activity and therapeutic response Use along with pemphigoid panel and endomysial IgA antibody tests to initially diagnose and distinguish various immunobullous disorders in patients suspected or known to have any type of immunobullous disease IgG cell surface antibody staining is found in all cases; IgG desmoglein 1 and/or IgG desmoglein 3 antibody levels may be increased Concurrent perilesional skin biopsy evaluated by DIF is important for diagnosis because of increased sensitivity Clinical correlation is necessary because cell surface antibodies by IFA, usually in low titers, may be found in normal individuals (possible blood group reactivity) or in patients with fungal infections, burns, drug reactions and other dermatoses, including other immunobullous diseases Because of clinical overlap among immunobullous diseases and similar names, pemphigoid testing may be confused with pemphigus testing and inadvertently misordered Testing for IgG pemphigus antibody types (most common) also may be confused with IgA pemphigus testing (rare disorder) See Immunobullous Skin Diseases Testing algorithm If positive findings in pemphigus panel, consider use of pemphigus panel  or IgG Desmoglein 1 and Desmoglein 3 to follow disease activity
Pemphigoid Panel - Epithelial Basement Membrane Zone IgG & IgA, BP180 & BP230 IgG Antibodies 0092001 Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody	Panel includes epithelial basement membrane zone (BMZ) IgG & IgA antibodies by indirect immunofluorescence (IFA) on split human skin and monkey esophagus substrates, BP180 & BP230 IgG antibodies by ELISAs Use to diagnose most types of pemphigoid, epidermolysis bullosa acquisita, linear IgA disease (including linear IgA bullous dermatosis and chronic bullous disease of childhood), mixed immunobullous disease Use along with pemphigus panel and endomysial antibody IgA testing to initially diagnose and discriminate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease IgG basement membrane zone antibody staining is found in some paraneoplastic pemphigus cases; IgG BP180 and IgG BP230 antibody levels may be normal or increase Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity

Diagnostic Algorithm

  Immunobullous Skin Diseases Testing Algorithm