Paraneoplastic Pemphigus

Updated: Mar 04, 2016
  • Author: Lynne J Goldberg, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Anhalt et al [1] first described paraneoplastic pemphigus in 1990. The authors reported 5 patients with underlying neoplasms who developed oral erosions and bullous skin eruptions. Skin biopsy samples showed both suprabasal acantholysis and interface dermatitis. Direct immunofluorescence (DIF) testing and indirect immunofluorescence (IDIF) testing revealed intraepidermal intercellular staining with immunoglobulin G (IgG); DIF testing also revealed deposition of complement at the dermoepidermal junction (see the image below). By immunoprecipitation, target antigens were identified from skin extracts with molecular weights of 250, 230, 210, and 190 kd. Since then, many patients with paraneoplastic pemphigus have been reported, and patients previously believed to have other diseases have been retrospectively diagnosed.

Direct immunofluorescence microscopy performed on Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.

A summary of the original criteria for the diagnosis of paraneoplastic pemphigus includes the following:

  • Painful mucosal erosions, sometimes with a skin eruption that eventually results in blisters and erosions, in the setting of confirmed or occult malignancy
  • Histopathologic changes of acantholysis, keratinocyte necrosis, and interface dermatitis
  • DIF observation of immunoreactants, typically IgG and complement (C3) within the epidermal intercellular spaces as well as at the epidermal basement membrane
  • IDIF observation of circulating antibodies specific for stratified squamous or transitional epithelia (transitional epithelium)
  • Immunoprecipitation of a complex of proteins with typical molecular weights, as described in Other Tests

Because not all patients demonstrate these original criteria, Anhalt [2] has proposed the following new, minimal criteria for the diagnosis of paraneoplastic pemphigus:

  • Painful, progressive stomatitis
  • Histopathologic changes of acantholysis or lichenoid/interface dermatitis
  • Demonstration of antiplakin antibodies
  • Demonstration of an underlying lymphoproliferative neoplasm

Note, however, that while a tumor is essential in the diagnosis, patients with tumors other than lymphoproliferative neoplasms can develop paraneoplastic pemphigus. These include thymoma, sarcoma, and lung carcinoma.

Although it is rare, the exact incidence of paraneoplastic pemphigus is unknown. In 2010, there were 450 reported cases in the literature. [3]  There is an association between paraneoplastic pemphigus and HLA class II DRB I*03 and HLA-Cw*14 (in Chinese patients). [4, 5]

Unlike other forms of pemphigus, paraneoplastic pemphigus affects organ systems other than the integument. Thus, the term "paraneoplastic autoimmune multiorgan syndrome", or "PAMS", has been suggested as a more appropriate name for the syndrome. [6]

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Pathophysiology

Paraneoplastic pemphigus is an autoimmune disorder initiated by an underlying neoplasm. Tumor antigens are hypothesized to evoke both a humoral and a cellular immune response that leads to blistering in mucosa and other epithelia. Affected organ systems include the integument, respiratory tract, and gastrointestinal tract. A patient with renal and neurologic involvement has been reported. [7] Most patients have had an associated malignancy, often a lymphoproliferative disorder, but it has also been reported to occur in association with benign tumors. [8] Associated neoplasms include non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, thymoma, Waldenström macroglobulinemia, Hodgkin lymphoma, various carcinomas, sarcomas, and malignant melanoma. [9]

Passive transfer of paraneoplastic pemphigus sera causes blistering in neonatal mice, proving that the antibodies present are pathogenic. [1] Paraneoplastic pemphigus patients exhibit many different autoantibodies to proteins of the plakin family, an intracellular component of desmosomes and hemidesmosomes, including envoplakin (210-kd), periplakin (190-kd), bullous pemphigoid antigen I (230-kd), desmoplakin I (250-kd), desmoplakin II (210-kd), plectin (500-kd), and alpha2-macroglobulin-like–1 (170-kd). They can also exhibit antibodies to antigens associated with pemphigus vulgaris (desmoglein 3, 130-kd) and pemphigus foliaceus (desmoglein 1, 160-kd), as well as several others.

In a 2011 review, Czernik et al summarize the increasing role of cellular immunity in paraneoplastic pemphigus, evidenced by lesional mononuclear cells and elevated IL-6 levels in sera from paraneoplastic pemphigus patients. [6]

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Epidemiology

Race

No racial predilection is apparent for paraneoplastic pemphigus.

Sex

Males are affected more than females. [6]

Age

Paraneoplastic pemphigus has been reported in patients aged 7-83 years. It typically affects patients aged 45-70 years, but it can also be seen in children and adolescents. [9]

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