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.

Tabs Content

Clinical Overview

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
- 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 diseases
  - 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 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

Background

Epidemiology

Incidence – very rare
Age – mean onset ≥60 years
Sex – M<F

Risk Factors

Malignancies
- Most common – lymphoma (particularly B cell), leukemia (particularly chronic lymphocytic leukemia), 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

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

Paraneoplastic Pemphigus Antibody Screen 0092107

Method: Indirect Fluorescent Antibody

Order concurrently with serum antibody testing and fixed tissue histopathology for assessment of patient with pruritic, urticarial, blistering, 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

Cutaneous Direct Immunofluorescence, Biopsy 0092572

Method: Direct Immunofluorescence

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

Immunobullous Disease Panel, Epithelial 3001409

Method: Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay

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

Epithelial Skin Antibody 0090299

Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

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

Pemphigus Antibody Panel - Epithelial Cell Surface Antibodies and Desmoglein 1 and Desmoglein 3 Antibodies, IgG 0090650

Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

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

Basement Membrane Zone Antibody Panel 3001410

Method: Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay

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

Pemphigoid Antibody Panel - Epithelial Basement Membrane Zone Antibodies, IgG and IgA, BP180 and BP230 Antibodies, IgG 0092001

Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

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

Leiferman, Kristin M., MD, Consultant, Immunodermatology at ARUP Laboratories; Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah

Zone, John J., MD, Co-Director, Immunodermatology Laboratory at ARUP Laboratories; Professor and Chairman, Dermatology, University of Utah

References

General References

Buggiani G, Krysenka A, Grazzini M, Vašků V, Hercogová J, Lotti T. Paraneoplastic vasculitis and paraneoplastic vascular syndromes. Dermatol Ther. 2010; 23(6): 597-605. 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, 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

Resources 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

Testing Algorithms

Epithelial Antibody-Associated Immunobullous Diseases Testing

Read more about Epithelial Antibody-Associated Immunobullous Diseases Testing

Immunobullous Diseases Testing Algorithm – Neoplastic Disease

Read more about Immunobullous Diseases Testing Algorithm – Neoplastic Disease

Educational Videos

Last Update: October 2019

Paraneoplastic Pemphigus

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Epithelial Antibody-Associated Immunobullous Diseases Testing

Immunobullous Diseases Testing Algorithm – Neoplastic Disease

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Paraneoplastic Pemphigus. ARUP Consult^©. Retrieved October 18, 2019, from: https://arupconsult.com/content/paraneoplastic-pemphigus

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Paraneoplastic Pemphigus

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Epithelial Antibody-Associated Immunobullous Diseases Testing

Immunobullous Diseases Testing Algorithm – Neoplastic Disease

ARUP Laboratories

ARUP Websites

ARUP Consult