eMedicine Specialties > Dermatology > Bullous Diseases

Pemphigus, Paraneoplastic: Differential Diagnoses & Workup

Author: Lynne J Goldberg, MD, Associate Professor, Departments of Dermatology and Pathology, Boston University School of Medicine
Coauthor(s): Nauman Nisar, MD, Fellow, Department of Dermatology, Section of Dermatopathology, Boston University Medical Center
Contributor Information and Disclosures

Updated: Nov 6, 2009

Differential Diagnoses

Bullous Pemphigoid
Erythema Multiforme
Cicatricial Pemphigoid
Lichen Planus
Drug Eruptions
Pemphigus Vulgaris
Epidermolysis Bullosa
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Epidermolysis Bullosa Acquisita

Workup

Laboratory Studies

The evaluation of patients suspected of having paraneoplastic pemphigus includes obtaining samples by skin biopsy for routine microscopy and direct immunofluorescence (DIF) testing, followed by more sophisticated testing when indicated.

  • If the histologic features and DIF results suggest the diagnosis, serum should be sent for indirect immunofluorescence (IDIF) testing. The choice of substrate for the IDIF is important because different substrates express different antigens. Monkey esophagus is considered more sensitive than human skin. Transitional epithelium, such as rat bladder, can also be used. If IDIF results are negative, additional assays should be performed.25 A case of paraneoplastic pemphigus in which the DIF and IDIF results were negative initially and became positive after 6-14 weeks, respectively, has been reported.26
  • Immunoprecipitation, immunoblotting and enzyme-link immunosorbent assay (ELISA) are sensitive assays that are very helpful in confirming the diagnosis of paraneoplastic pemphigus. Several new assays have been described27,28,29 ; however, commercial availability is variable, and they may only be obtainable at research laboratories.
  • Once the diagnosis of paraneoplastic pemphigus is established, further evaluation for malignancy may be necessary.

Other Tests

DIF testing
Skin biopsy samples for DIF testing should be taken from noninvolved, perilesional skin. IgG, with or without complement, binds in an intercellular pattern within the epidermis. Immunoglobulin A (IgA) and immunoglobulin M (IgM) also may be detected. Staining can be diffuse or focal. Positive findings limited to adnexal structures have been described.30

Some patients have granular or linear deposition of complement, IgG, and/or IgM along the dermoepidermal junction. The combination of intercellular and subepidermal deposition of immunoreactants is a clue to the diagnosis of paraneoplastic pemphigus.

IDIF testing 
IDIF testing is performed by using sera obtained from patients suspected of having paraneoplastic pemphigus and is a good screening test for this disease. Patients with high-titer antibodies exhibit both intercellular intraepidermal antibody deposition and deposition along the dermoepidermal junction. Patients with low titers only exhibit deposition intercellularly in a pattern identical to that of pemphigus vulgaris.

Because circulating antibodies that bind to the cell surface of stratified squamous epithelia are common to all forms of pemphigus, other substrates, such as rodent bladder, can be useful in distinguishing paraneoplastic pemphigus from pemphigus vulgaris or pemphigus foliaceus. Binding to rat bladder transitional epithelium is specific for circulating autoantibodies from patients with paraneoplastic pemphigus, with a specificity of 83%25 ; sensitivity ranges from 75-86% depending on the study.

Immunoprecipitation and immunoblotting
Sera from patients with paraneoplastic pemphigus contain autoantibodies directed at several members of the plakin family, including desmoplakin I (250 kd), BPAG I (230 kd), desmoplakin II (210 kd), envoplakin (210 kd), periplakin (190 kd), plectin (500 kd), and an unidentified 170-kd protein.

Desmoglein I and desmoglein III antigens, targeted in pemphigus vulgaris and pemphigus foliaceus, respectively, have also been found in the sera of patients with paraneoplastic pemphigus. These antibodies are directed against transmembrane antigens. Disruption of the keratinocyte membrane may allow formation of antibodies against plakins, which are intracellular.

Immunoprecipitation or immunoblotting is the standard diagnostic test for paraneoplastic pemphigus because either has a higher specificity and sensitivity than IDIF testing. Unfortunately, neither is widely available; however, they can be performed in some research settings.

Sensitivity and specificity
In one study, IDIF identification of autoantibodies with a rat bladder substrate and immunoblotting detection of autoantibodies against periplakin (190 kd) and envoplakin (210 kd) were the most specific and sensitive tests for paraneoplastic pemphigus. Tests that are specific but not highly sensitive are DIF and immunoblot recognition of desmoplakin I and bullous pemphigoid antigen 1.

Histologic Findings

Vesicular lesions express the most characteristic histopathologic features. Oral and cutaneous lesions show variable epidermal necrosis, suprabasal acantholysis, dyskeratotic keratinocytes, vacuolar interface dermatitis, and lymphocytic exocytosis. Substantial inflammation can be present, even in early lesions.

Oral mucosal lesions show the greatest acantholysis, while some skin lesions may not have any acantholysis. Biopsy specimens of severe stomatitis may reveal only ulceration. When present, suprabasal acantholysis can result in clefts and tombstoning, which is the appearance of the basal cell layer below the cleft, and it can be indistinguishable from pemphigus vulgaris.

A distinctive feature of paraneoplastic pemphigus is dyskeratosis. Dyskeratosis is a constant feature, but the number of dyskeratotic keratinocytes is variable. Dyskeratotic keratinocytes are found at all levels in the epidermis, especially within the zones of acantholysis, and they can be found in cutaneous adnexa. The presence of dyskeratosis in a person with a suprabasal acantholytic bullous disorder is a clue to the presence of paraneoplastic pemphigus.

Interface dermatitis is a frequent finding in persons with paraneoplastic pemphigus, and it can be found both with and without acantholysis. Exocytosis of inflammatory cells into the epidermis is common, and the amount and degree are directly proportional to the degree of dyskeratosis. Satellite cell necrosis (a lymphocyte adjacent to a necrotic keratinocyte) can occur. Lesions showing marked vacuolar alteration are accompanied by melanophages in the papillary dermis.

Dermal changes include a superficial perivascular infiltrate of variable intensity, which is mostly composed of lymphocytes. The inflammation can sometimes be lichenoid, leading to a misdiagnosis of lichen planus. Papillary dermal edema is present in early lesions, whereas older lesions may exhibit mild dermal fibrosis.

More on Pemphigus, Paraneoplastic

Overview: Pemphigus, Paraneoplastic
Differential Diagnoses & Workup: Pemphigus, Paraneoplastic
Treatment & Medication: Pemphigus, Paraneoplastic
Follow-up: Pemphigus, Paraneoplastic
References
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References

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Further Reading

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Keywords

paraneoplastic pemphigus, PNP, pemphigus

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Contributor Information and Disclosures

Author

Lynne J Goldberg, MD, Associate Professor, Departments of Dermatology and Pathology, Boston University School of Medicine
Lynne J Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society of Dermatopathology, Massachusetts Academy of Dermatology, New England Dermatological Society, North American Hair Research Society, Phi Beta Kappa, and Women's Dermatologic Society
Disclosure: Nothing to disclose.

Coauthor(s)

Nauman Nisar, MD, Fellow, Department of Dermatology, Section of Dermatopathology, Boston University Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Ponciano D Cruz Jr, MD, Vice-Chair, JB Shelmire Professor, Department of Dermatology, University of Texas Southwestern Medical Center
Ponciano D Cruz Jr, MD is a member of the following medical societies: Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Honoraria Consulting; Centocor Honoraria Consulting; Medicis Honoraria Consulting; Celgene Honoraria Consulting

CME Editor

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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