Paraneoplastic Pemphigus

Paraneoplastic pemphigus, also referred to as paraneoplastic autoimmune multiorgan syndrome, is a severely debilitating blistering disease that affects skin and mucous membranes and nearly always involves an underlying neoplasm.  Paraneoplastic pemphigus is much less common than some other forms of pemphigus, such as pemphigus foliaceus and pemphigus vulgaris. Diagnosis can be challenging because of the tendency of paraneoplastic pemphigus to mimic other cutaneous diseases.  Accurate diagnosis requires assessment of clinical characteristics and histopathologic features, along with the detection of disease-specific autoantibodies in tissue and/or serum using methodologies such as direct immunofluorescence (DIF) microscopy, indirect fluorescent antibody (IFA) testing, and enzyme-linked immunosorbent assays (ELISAs).  The various immunobullous diseases associated with epithelial antibodies have overlapping clinical presentations, and broad serologic screening is recommended to establish a diagnosis unless a specific disease is suspected and/or supported by characteristic findings.

Quick Answers for Clinicians

What are some clinical indications that testing for paraneoplastic pemphigus may be appropriate?

Paraneoplastic pemphigus is associated with a variety of lesion types, including flaccid and/or tense bullae, erosions, urticarial lesions, erythema multiforme-like lesions, lichen planus-like lesions, and flat scaly papules.  Widespread, severe mucosal lesions occur in nearly all patients,  usually on oral surfaces.  The disease can affect various types of epithelia and can therefore lead to involvement of various organs, for example, the eyes, lungs, gastrointestinal tract, kidney, and thyroid.  Some patients develop bronchiolitis obliterans or myasthenia gravis (both of which are associated with increased mortality rates).  Because an underlying neoplasm is almost always present, any patient suspected of having paraneoplastic pemphigus but no previously detected neoplasm should undergo an immediate and thorough evaluation for malignancy. 

What is challenging about diagnosing paraneoplastic pemphigus?

Paraneoplastic pemphigus can present similarly to other cutaneous diseases, so much so that the five major subtypes of paraneoplastic pemphigus are referred to as bullous pemphigoid-like, erythema multiforme-like, graft-versus-host-disease-like, lichen planus-like, and pemphiguslike.  Moreover, drug reactions can have analogous presentations. Because of similarities and overlap in clinical presentation among blistering autoimmune diseases, broad serologic screening is generally recommended during initial evaluation.

Which neoplasms are most commonly associated with paraneoplastic pemphigus?

The most common neoplasms in paraneoplastic pemphigus are lymphoproliferative, eg, non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Castleman disease,  in particular, certain subtypes of Castleman disease.  Other associated malignancies include sarcomas, thymomas, squamous cell carcinomas, and carcinomas of the colon, lung, and stomach. 

Where can I find information on testing for other epithelial-antibody associated immunobullous diseases?

ARUP Consult has an overview of Immunobullous Diseases (Epithelial Antibody Associated), as well as specific information on other forms of pemphigus, along with information on pemphigoid, pemphigoid gestationis, epidermolysis bullosa acquisita (EBA), linear IgA disease, and dermatitis herpetiformis. Visit our algorithms for testing steps for the various diseases.

Indications for Testing

Testing for pemphigus is appropriate in patients with suspected malignancy (a neoplasm typically precedes skin disease) or cutaneous manifestations that are consistent with paraneoplastic pemphigus (see Quick Answers for Clinicians) and are not attributable to a more common cutaneous disorder. Strong clinical suspicion for paraneoplastic pemphigus in the absence of known cancer should prompt a thorough evaluation for possible malignancy. 

Laboratory Testing

Diagnosis

Diagnosis of paraneoplastic pemphigus is based on supportive histopathologic findings on examination of formalin-fixed tissue, immunohistopathologic features, with demonstration on DIF microscopy of characteristic immunoglobulin G (IgG) and/or complement component 3 (C3) reactivity patterns, detection of autoantibodies to epithelial components in serum, and compatible clinical features.

Immunohistopathology

DIF microscopy, used to detect tissue-bound autoantibodies, is performed on perilesional skin biopsy tissue and is an important part of an evaluation for paraneoplastic pemphigus.   The disease is characterized by cell surface IgG antibody staining and intercellular C3 deposition   and may demonstrate granular or linear IgG basement membrane zone (BMZ) antibodies at the dermal-epidermal junction.  A combination of cell surface plus BMZ IgG autoantibody reactivity characteristically is observed in paraneoplastic pemphigus. IgA autoantibodies (cell surface or BMZ) are rarely identified in this disease and may be found in an IgA variant of paraneoplastic pemphigus.

Serum Tests

In addition to tissue evaluation using DIF microscopy, assessment for pemphigus involves detection and identification of circulating autoantibodies in serum. Various serum epithelial autoantibodies and combinations of autoantibodies may develop in paraneoplastic pemphigus. IgG antibodies specifically associated with paraneoplastic pemphigus include autoantibodies against envoplakin, periplakin, and desmogleins 1 and 3, as well as autoantibodies against desmoplakin, plectin, desmocollins 1, 2, and 3, alpha (α)-2 macroglobulin-like protein 1 (A2ML1), epiplakin, BP 230, BP 180, and laminin-332.   A study of 104 patients with paraneoplastic pemphigus found autoantibodies against desmoglein 3; desmocollins 1, 2, or 3; and A2ML1 in a majority of patients (78%, 71%, and 60%, respectively). 

Available serum tests include IFA testing and ELISAs. In IFA testing, the patient serum is incubated with epithelial tissue substrates (eg, rodent substrates such as rat bladder  ) to detect autoantibodies that react with the target proteins expressed in the substrate tissues. Binding of IgG autoantibodies to the transitional epithelium in rodent bladder tissue is a characteristic finding because of the greater concentration of plakins in bladder tissue.  IFA testing in patients with paraneoplastic pemphigus typically reveals serum IgG autoantibodies that bind in an intercellular pattern to the surface of epithelial cells and also to the epithelial BMZ.  Patterns of antibody reactivity visualized by IFA have good clinical utility to support a diagnosis of paraneoplastic pemphigus. 

ELISA tests both detect and semiquantify autoantibodies.  ELISA testing is available for autoantibodies against desmoglein 1 and 3, BP 230, and BP 180, and may aid in diagnosis or in monitoring the disease. ELISA testing is in development for autoantibodies against envoplakin and periplakin, two primary antigenic targets with the greatest specificity for paraneoplastic pemphigus. (This testing is not currently performed at ARUP Laboratories.)

If an autoantibody screen yields positive results in patients without a known malignancy, an aggressive evaluation for malignancy is warranted. 

ARUP Laboratory Tests

Additional detail about each test listed below can be found in the ARUP Laboratory Test Directory (LTD). In addition, each test name links directly to the LTD.

Recommended Serologic Test

Use as antibody panel for initial assessment and disease monitoring in paraneoplastic pemphigus

Semiquantitative IFA; positive limiting-dilution end-point antibody titer(s)

Consider ordering concurrently with Immunobullous Disease Panel, Epithelial, or ELISAs for IgG desmoglein 1 and IgG desmoglein 3 antibodies and IgG bullous pemphigoid antigens, BP 180 and BP 230 antibodies; any of these epithelial antibodies may be increased in paraneoplastic pemphigus

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

If IgA paraneoplastic antibody testing is indicated, contact ARUP Client Services to request testing

Immunohistopathologic Test (DIF)

Components: IFA for IgG (epithelial) cell surface and BMZ antibodies, (cardiac) intercalating disk and (liver) portal tract antibodies, includes rat bladder substrate, mouse bladder substrate, mouse heart substrate, mouse liver substrate, and monkey esophagus substrate

Immunohistopathologic Test (DIF)

Perform along with serum antibody testing and formalin-fixed tissue histopathology for assessment of pruritic, urticarial, blistering, crusted, and/or erosive disorders (immunobullous diseases with or without blistering); perilesional specimen recommended for blisters and/or erosions

Correlate with histopathology examination of formalin-fixed tissue to assess inflammation in immune-mediated cutaneous diseases (such as lupus erythematosus, vasculitis, lichen planus); lesional specimen recommended

Optimal specimen location varies according to disease type, blistering or nonblistering

Components: cutaneous DIF, biopsy; biopsy; DIF includes IgG, IgG4, IgM, IgA, C3, and fibrinogen with diagnostic interpretation of staining patterns

Other Serologic Tests

Use as initial testing panel to aid in diagnosis of and to distinguish among skin and mucous membrane disorders that present with blistering, erosions, crusts, eczema, pruritus, and/or urticaria, including pemphigoid and pemphigus variants, epidermolysis bullosa acquisita (EBA), and linear IgA disease

Semiquantitative IFA and ELISA; positive limiting-dilution end-point antibody titer(s) (IFA) and antibody level in units (ELISA)

Components: IFA for IgG and IgA BMZ antibodies (pemphigoid, EBA, linear IgA disease), includes BMZ split-skin substrate (also known as salt split skin), and IgG and IgA cell surface antibodies (IgG and IgA pemphigus subtypes, nonclassical pemphigus, intercellular IgG/IgA dermatosis); ELISAs for IgG antibodies to BP 180, BP 230, type VII collagen, desmoglein 1, and desmoglein 3

Use as preferred serum antibody panel for initial assessment and disease monitoring in IgG-variant pemphigus

Semiquantitative IFA and ELISA; positive limiting-dilution end-point antibody titer(s) (IFA) and antibody level in units (ELISA)

To aid in diagnosis of pemphigus along with other possible immunobullous diseases, order concurrently with the BMZ antibody panel and the pemphigus antibody IgA test

The Immunobullous Disease Panel, Epithelial, can be ordered as an alternative to this test

Components: IFA for IgG epithelial cell surface antibodies; ELISAs for IgG antibodies to desmoglein 1 and desmoglein 3 (all components included in immunobullous disease panel)

Use as the preferred initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, crusts, eczema, pruritus, and/or urticaria from suspected BMZ antibody-associated disease, including pemphigoid, EBA, linear IgA disease, and bullous lupus erythematosus

Semiquantitative IFA and ELISA; positive limiting-dilution end-point antibody titer(s) (IFA) and antibody level in units (ELISA)

Alternatively, order Immunobullous Disease Panel, Epithelial, for initial diagnostic assessment

Components: IFA for IgG and IgA BMZ antibodies (pemphigoid, EBA, linear IgA disease), includes BMZ split-skin substrate (also known as salt split skin); ELISAs for IgG antibodies to BP 180, BP 230, and type VII collagen (all components included in immunobullous disease panel)

Use as antibody panel for initial assessment and disease monitoring in pemphigoid and linear IgA bullous dermatosis and to discriminate among the immunobullous skin diseases with epithelial BMZ antibodies

Semiquantitative IFA and ELISA; positive limiting-dilution end-point antibody titer(s) (IFA) and antibody level in units (ELISA)

Alternatively, order Basement Membrane Zone Antibody Panel or Immunobullous Disease Panel, Epithelial

Components: IFA for IgG and IgA BMZ antibodies (pemphigoid, EBA, linear IgA disease), includes BMZ split-skin substrate (also known as salt split skin); ELISAs for IgG antibodies to BP 180 and BP 230 (all components included in the immunobullous disease panel and in the BMZ antibody panel, but this panel does not include IgG antibodies to type VII collagen ELISA, testing that is included in others)

Use as general initial test for immunobullous diseases or to monitor EBA, linear IgA disease, and IgA pemphigus expression (test does not include ELISAs for disease-related antibodies to specific antigenic targets)

Semiquantitative IFA; positive limiting-dilution end-point antibody titer(s)

Consider ordering with ELISAs for IgG desmoglein 1 and IgG desmoglein 3 antibodies for suspected pemphigus, IgG bullous pemphigoid antigens, BP 180 and BP 230, and IgG type VII collagen antibody for suspected pemphigoid or EBA; alternatively, consider the Immunobullous Disease Panel, Epithelial

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

Components: IFA for IgG and IgA BMZ antibodies (pemphigoid, EBA, linear IgA disease) and IgG and IgA cell surface antibodies (IgG and IgA pemphigus subtypes, nonclassical pemphigus, and intercellular IgG/IgA dermatosis) (all components included in immunobullous disease panel)

Medical Experts

Contributor

Leiferman

Picture of Kristin M. Leiferman, MD

 

Co-Director, Immunodermatology Laboratory, Professor of Dermatology, and Adjunct Professor of Pathology, University of Utah
Medical Director, Immunodermatology, ARUP Laboratories
Contributor

Zone

 

Professor and Chairman Emeritus, Dermatology, and Adjunct Professor of Pathology, University of Utah
Co-Director, Immunodermatology Laboratory, ARUP Laboratories

References

Additional Resources
  • 28492232

    Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. Pemphigus. Nat Rev Dis Primers. 2017;3:17026.

    PubMed