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Paraneoplastic Pemphigus. ARUP Consult®. Retrieved August 13, 2020, https://arupconsult.com/content/paraneoplastic-pemphigus

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Paraneoplastic Pemphigus

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

Quick Answers for Clinicians

Which testing algorithms are related to this topic?
Immunobullous Diseases Testing Algorithm - Epithelial Antibody Associated
Immunobullous Diseases Testing Algorithm - Neoplastic Disease

Diagnosis

Indications for Testing

  • Blistering disease
  • Suspected 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 (indirect immunofluorescence [IFA] on rodent substrates; includes rat bladder, mouse bladder, mouse heart, mouse liver)
    • Positive screen
      • Indicates serum antibodies to any component(s) of multiple epithelia (simple, columnar, transitional), including envoplakin; periplakin; desmoglein 1, 3; desmoplakin 1, 2; BP230, BP180; alpha-2-macroglobulinlike-1 (A2ML1 protease inhibitor); and/or, rarely, laminin-332
        • IFA testing has good clinical utility for detecting epithelial antibodies associated with paraneoplastic pemphigus
        • Enzyme-linked immunosorbent assay (ELISA) testing is available for antibodies against desmoglein 1,3; BP230; and BP180, and may add diagnostic information and be helpful in following disease
        • ELISA testing is in development for antibodies against two desmoplakins, envoplakin and periplakin, primary antigenic targets with the most specificity (not currently performed at ARUP Laboratories)
      • Various serum epithelial antibodies and combinations of antibodies may develop in paraneoplastic pemphigus
    • Positive antibody screen without known malignancy – perform aggressive evaluation for malignancy
    • Negative result – perform and/or correlate with a lesional biopsy for histopathology  and a perilesional skin biopsy for direct immunofluorescence; consider serologic evaluation for other immunobullous diseases
  • Perilesional skin biopsy for cutaneous direct immunofluorescence submitted in Michel’s or Zeus medium
    • Staining is usually positive for IgG antibodies deposited on 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

Background

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

ARUP Lab Tests

Assess patient with possible paraneoplastic pemphigus

If other, more common, types of pemphigus are of diagnostic consideration, order antibody panel test for pemphigus first or concurrently with this test

If IgA paraneoplastic antibody testing is required, contact ARUP Laboratories

See Immunobullous Skin Diseases Testing algorithm

Order concurrently with serum antibody testing and fixed tissue histopathology for assessment of patient with pruritic, urticarial, blistering, crusted, and/or erosive disorders, including possible pemphigoid and pemphigoid variants, pemphigus and pemphigus subtypes, dermatitis herpetiformis, epidermolysis bullous acquisita, porphyria, and pseudoporphyria

Order concurrently with fixed tissue histopathology for assessment of patient with inflammatory, immune-mediated cutaneous disease, including possible lupus and lupus variants, vasculitis, drug reactions, lichen planus, and lichenoid reactions

See Immunobullous Skin Diseases Testing algorithm

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

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria, including pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, linear IgA disease variants, and IgG-pemphigus subtypes

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody level assessments and tracking and for persistent unexplained disease and/or worsening disease activity

General screen for immunobullous diseases

Test includes IgG and IgA basement membrane zone (BMZ) antibodies (pemphigoid, epidermolysis bullosa acquisita, linear IgA disease) and IgG and IgA cell surface antibodies (IgG and IgA pemphigus subtypes)

Consider ordering concurrently with IgG bullous pemphigoid (BP180 and 230) antigens for suspected pemphigoid and/or IgG desmoglein 1 and 3 antibodies for suspected pemphigus

For more sensitive and specific testing for pemphigoid or pemphigus, refer to antibody panels for pemphigus or pemphigoid

See Immunobullous Skin Diseases Testing algorithm

Related Tests

Preferred panel for initial assessment and disease monitoring in IgG-variant pemphigus

Panel components include antibody testing for IgG epithelial cell surface and IgG desmoglein 1 and 3; to order individual component tests, refer to epithelial skin antibody and/or desmoglein 1 and 3 antibodies in pemphigus, IgG

To screen for pemphigus along with other possible immunobullous diseases, order concurrently with antibody panel test for pemphigoid, IgG collagen type VII antibody, AND perilesional skin biopsy for direct immunofluorescence (DIF)

See Immunobullous Skin Diseases Testing algorithm

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria from suspected basement membrane zone antibody-associated disease (eg, bullous pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, and linear IgA disease variants)

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody assessments and tracking

Preferred antibody panel for initial diagnostic assessment and disease monitoring in pemphigoid, epidermolysis bullosa acquisita, and linear IgA bullous dermatosis

To screen for pemphigoid along with other possible immunobullous diseases, order concurrently with pemphigus antibody panel, IgG collagen type VII antibody, AND perilesional skin biopsy for DIF

Panel components include IgG and IgA epithelial BMZ antibodies and IgG bullous pemphigoid BP180 and 230 antigens

To order individual component tests, refer to antibody testing for IgG BMZ, IgA BMZ, and/or IgG bullous pemphigoid BP180 and 230 antigens

Medical Experts

Contributor

Leiferman

 

Kristin M. Leiferman, MD

Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah

Consultant, Immunodermatology at ARUP Laboratories

Contributor

Zone

 

John J. Zone, MD

Professor and Chairman, Dermatology, University of Utah

Co-Director, Immunodermatology Laboratory at ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®

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