Paraneoplastic Pemphigus

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

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
  • 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

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

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.

Paraneoplastic Pemphigus Antibody Screen 0092107
Method: Indirect Fluorescent Antibody

Limitations

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

Follow Up

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

Limitations

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

Follow Up

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

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

Limitations

Does not include testing for antibodies to target pemphigoid antigens, BP180 and BP230, or to target pemphigus antigens desmoglein 1 and 3 which may be more sensitive diagnostic markers in some cases (levels correlate with disease activity)

Although helpful in screening for immunobullous disease, test is not as sensitive as combination of pemphigus and pemphigoid panels

Follow Up

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

Related Tests

General References

AbreuVelez AMaria, Howard MS. Diagnosis and treatment of cutaneous paraneoplastic disorders. Dermatol Ther. 2010; 23(6): 662-75. PubMed

Frew JW, Murrell DF. Paraneoplastic pemphigus (paraneoplastic autoimmune multiorgan syndrome): clinical presentations and pathogenesis. Dermatol Clin. 2011; 29(3): 419-25, viii. PubMed

Parker SR S, MacKelfresh J. Autoimmune blistering diseases in the elderly. Clin Dermatol. 2011; 29(1): 69-79. PubMed

Plager D, Leiferman K, Pittelkow M. Structural and Functional Cutaneous Immunology. In Adkinson NF et al. Middleton’s Allergy Principles and Practice, 6th ed. Philadelphia: Mosby, 2003.

Schmidt E, Zillikens D. Modern diagnosis of autoimmune blistering skin diseases. Autoimmun Rev. 2010; 10(2): 84-9. PubMed

Sehgal VN, Srivastava G. Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome. Int J Dermatol. 2009; 48(2): 162-9. PubMed

Zhu X, Zhang B. Paraneoplastic pemphigus. J Dermatol. 2007; 34(8): 503-11. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Taintor AR, Leiferman KM, Hashimoto T, Ishii N, Zone JJ, Hull CM. A novel case of IgA paraneoplastic pemphigus associated with chronic lymphocytic leukemia. J Am Acad Dermatol. 2007; 56(5 Suppl): S73-6. PubMed

Medical Reviewers

Last Update: February 2016