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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 immunofluorescence (IIF) 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, immunopathologic 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.

Immunopathology

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, BP230, BP180, and laminin-332.    The plakins are predominant antigenic targets in paraneoplastic pemphigus, especially envoplakin and periplakin. 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 IIF testing and ELISAs. With IIF 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.  IIF 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 IIF have good clinical utility to support a diagnosis of paraneoplastic pemphigus. 

ELISA tests both detect and semiquantify autoantibodies.  ELISA testing for paraneoplastic pemphigus includes autoantibodies against envoplakin, desmoglein 1 and 3, BP230, and BP180, which may aid in diagnosis and in monitoring the disease. Of these antigenic targets, envoplakin is among the most specific for paraneoplastic pemphigus.

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 the tests below can be found in the ARUP Immunobullous Disease Testing Comparison table.

Recommended Serologic Test

Preferred expanded panel to assess and monitor paraneoplastic pemphigus

Includes IgG envoplakin antibodies by ELISA and IgG antibodies by IIF

Testing should be correlated initially with concurrent DIF biopsy, histopathological examination of formalin-fixed tissue, and assessment of other epithelial antibodies

Consider ordering concurrently with Immunobullous Disease Antibody Panel for broad epithelial antibody assessment

If other more common types of pemphigus are diagnostic considerations, concurrently order Pemphigus Antibody Panel, IgG with or without the rarer IgA pemphigus variant test

Use to assess and monitor paraneoplastic pemphigus, a rare paraneoplastic disease associated with lymphoproliferative disorders/malignancies and demonstrating clinical features of severe pemphigus

Testing should be correlated initially with concurrent DIF biopsy, histopathological examination of formalin-fixed tissue, and assessment of other epithelial antibodies

Consider ordering concurrently with Immunobullous Disease Antibody Panel for broad epithelial antibody assessment

If other more common types of pemphigus are diagnostic considerations, order Pemphigus Antibody Panel, IgG with or without the rarer IgA pemphigus variant test, concurrently with this test

Use in conjunction with Paraneoplastic Pemphigus (Paraneoplastic Autoimmune Multiorgan Syndrome) Screening Antibodies by IIF to aid in the diagnosis of paraneoplastic pemphigus

Testing should be correlated initially with concurrent DIF biopsy, histopathological examination of formalin-fixed tissue, and assessment of other epithelial antibodies

May be used to monitor disease in individuals with increased IgG envoplakin antibody levels

Immunopathologic Test (DIF)

Use with serum immunobullous disease/epithelial antibody testing and formalin-fixed tissue histopathology for assessment of pruritic, urticarial, blistering, and/or erosive disorders

Use with formalin-fixed tissue histopathology for assessment of inflammatory, immune-mediated cutaneous disease

Optimal specimen location and complementary serum testing and/or histopathology examination vary according to disease type; note that specimen location and transport medium/fixative are different for direct immunofluorescence testing and fixed-tissue histopathology

Other Serologic Tests

Use as initial comprehensive testing panel to aid in the diagnosis of and distinguishing among skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria

Use for assessment of suspected epithelial antibody-associated immunobullous diseases, pemphigoid and pemphigus and their variants, that are not clinically distinguishable, have nonspecific features, potentially express overlapping epithelial antibodies, and/or are indicated by concurrent DIF biopsy

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA; collagen type VII antibodies, IgG by ELISA; cell surface antibodies, IgG by IIF; desmoglein 1 and 3 antibodies, IgG by ELISA; cell surface antibodies, IgA by IIF

Use as the preferred serum antibody panel to assess and monitor IgG pemphigus variants (includes pemphigus foliaceus and pemphigus vulgaris), which present with blistering and erosive disease affecting skin and mucous membranes

Testing should be correlated initially with concurrent DIF biopsy

Components: cell surface antibodies, IgG by IIF; desmoglein 1 and desmoglein 3 antibodies, IgG by ELISA

Use as the preferred initial diagnostic panel for suspected BMZ antibody-associated skin and mucous membrane disorders that present with blistering, erosions, eczema, urticaria, pruritus, and/or mucositis

May be indicated by concurrent DIF biopsy

Alternatively, order the comprehensive Immunobullous Disease Antibody Panel for initial serum diagnostic assessment of epithelial antibody-associated diseases, pemphigoid, pemphigus, and their variants

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA; collagen type VII antibodies, IgG by ELISA 

Use to assess and monitor epithelial antibody expression in paraneoplastic pemphigus

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA

Use to monitor linear IgG and IgA BMZ antibody-associated diseases and IgG and IgA cell surface antibody-associated diseases in which antibody levels by ELISAs may not be increased and/or to assess for changing patterns of epithelial antibody expression

May be used as general initial serum test for immunobullous diseases; however, for more sensitive and specific serum testing with ELISAs for pemphigoid and EBA or for IgG variant pemphigus, refer to Basement Membrane Zone Antibody Panel or Pemphigus Antibody Panel, IgG

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; cell surface antibodies, IgG by IIF; cell surface antibodies, IgA by IIF

References

Additional Resources

  • 28492232

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

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