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

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

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
Test Name and Number Recommended Use Limitations Follow Up
Paraneoplastic Pemphigus Antibody Screen 0092107
Method: Indirect Fluorescent Antibody

This test uses substrates from rodents, including mouse heart, liver, bladder, and rat bladder, to detect characteristic antibody staining by IFA

Use to support the diagnosis of paraneoplastic in patient suspected of having a blistering disease associated with malignancy

Consider concurrent pemphigus panel testing to detect and monitor pemphigus antibodies, if present (including IgG desmoglein 1 and desmoglein 3 antibodies) and concurrent pemphigoid panel test to detect and monitor basement membrane zone (BMZ) 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; if IgA antibodies suspected or test results otherwise unexplained, IgA paraneoplastic pemphigus testing can be performed by request

Use paraneoplastic pemphigus antibody test and/or pemphigus panel, particularly if IgG desmoglein 1 or 3 antibodies are increased, to monitor paraneoplastic pemphigus disease activity

Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

Use to determine the presence and characteristic staining pattern of immunoglobulins (IgG, IgM, IgA), third component of complement (C3) and fibrinogen in skin or mucous membrane biopsy specimens (biopsy site is critical; see below) from patients suspected of having immunobullous skin and/or mucous membrane disease; perform this test with serum paraneoplastic pemphigus test and serum pemphigoid and pemphigus panel tests

For skin involvement, biopsy perilesional skin

For mucous membrane involvement, biopsy nonlesional mucosa

May be inaccurate if tissue not taken from correct perilesional location (attached/intact epithelium or epidermis is needed

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

Initial concurrent and repeat serum testing with paraneoplastic pemphigus screen, pemphigus panel, and pemphigoid panel is the most sensitive for diagnosis, for determining antibody profiles and following disease activity

Patients with indeterminate results should have repeat DIF biopsy

Patients with changing clinical features should have repeat DIF biopsy because antibody profiles may change over time

See Immunobullous Skin Diseases Testing algorithm

Epithelial Skin Antibody 0090299
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Panel includes epithelial basement membrane zone (BMZ) IgG and IgA antibodies by IFA and IgG and IgA cell surface antibodies by IFA on split human skin, intact human skin and monkey esophagus substrates

Use as alternate to pemphigoid and pemphigus panel tests to initially diagnose and discriminate among clinically similar immune-mediated skin diseases such as pemphigus, linear IgA disease, pemphigoid, epidermolysis bullosa acquisita, and dermatitis herpetiformis in patients suspected of having or known to have any type of subepidermal immunobullous disease

 

Use epithelial skin antibody test or both pemphigoid and pemphigus panels to follow patients with changing clinical features because antibody profiles may change over time

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 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