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
- 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
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
- Malignancies
- Most common – lymphoma (B cell most common), leukemia (chronic lymphocytic leukemia most common), 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
Treatment
- Treat malignancy
- Supportive care
- Potential therapies include glucocorticoids, other immunosuppressives, plasmapheresis
Paraneoplastic Pemphigus Antibody Screen 0092107
Method: Indirect Fluorescent Antibody
Assess patient with possible paraneoplastic pemphigus
If other, more common, types of pemphigus are of diagnostic consideration, order the antibody panel test for pemphigus first or concurrently with this test
If IgA paraneoplastic antibody testing is required, contact ARUP Laboratories
Use along with perilesional skin biopsy for DIF to aid in diagnosis of paraneoplastic pemphigus
Use to follow persistent or recurrent disease activity with antibody titers
See Immunobullous Skin Diseases Testing algorithm
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
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
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
For skin involvement, biopsy perilesional skin
For mucous membrane involvement, biopsy nonlesional mucosa
See Immunobullous Skin Diseases Testing algorithm
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
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)
General screen for immunobullous diseases
Test includes IgG and IgA 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 & 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
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
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
General References
AbreuVelez AM, 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, 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: August 2016
