Introduction
Background
Anhalt et al1 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. 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.
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, Anhalt2 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.
Pathophysiology
Paraneoplastic pemphigus is an autoimmune disorder initiated by an underlying lymphoproliferative disorder. 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, the respiratory tract, and the gastrointestinal tract. It has also been reported to occur in association with benign tumors.
Passive transfer of paraneoplastic pemphigus sera causes blistering in neonatal mice, proving that the antibodies present are pathogenic.1 Paraneoplastic pemphigus patients also have pathogenic antibodies to desmoglein 3, the autoantigen of pemphigus vulgaris.3 Immunoblotting reveals that paraneoplastic pemphigus antibodies recognize plakin proteins, specifically the linker subdomain.4 This subdomain is required for plakin binding to intermediate filaments, desmosomes, and hemidesmosomes.5,6
A 2009 study looking at the role of autoantibodies against envoplakin and periplakin in paraneoplastic pemphigus showed that these antibodies reduce the adhesive strength of human epidermal keratinocytes and showed that a decrease in their levels corresponded to improvement in clinical symptoms within 6-12 weeks.7
Mortality/Morbidity
Paraneoplastic pemphigus is often fatal, especially when associated with malignancy. Mortality rates approach 90%. Causes of death include sepsis, with resultant multiorgan failure, and respiratory failure due to the direct effects of the disease on the respiratory tract epithelium. The latter is being increasingly recognized, and pulmonary involvement has been found to occur in approximately 30-40% of patients. The susceptibility to infection caused by the loss of skin integrity is exacerbated by the potent immunosuppressive medications used to treat the condition.
Race
No racial predilection is apparent for paraneoplastic pemphigus.
Sex
Males and females are affected equally by paraneoplastic pemphigus.
Age
The mean age at onset of paraneoplastic pemphigus is 60 years. However, paraneoplastic pemphigus can occur in children, and patients ranging in age from 7-76 years have been reported. In children, paraneoplastic pemphigus is often the presenting sign of Castleman disease, and an increased incidence of bronchiolitis obliterans is also recognized.
Clinical
History
Paraneoplastic pemphigus is usually associated with malignancy, although it can occur in association with benign neoplasms. The most common malignancy associated with paraneoplastic pemphigus is non-Hodgkin lymphoma.8,9,10 Other associated malignancies and conditions include chronic lymphocytic leukemia, Castleman disease,11,12,13 Waldenström macroglobulinemia,14 thymoma,12,15 sarcoma,15 and lung carcinoma.
An association reported in 2009 is with systemic mastocytosis,16 and an atypical case associated with endometrial carcinoma lacking mucosal involvement has been reported.17 Paraneoplastic pemphigus can coexist with bullous pemphigoid18 and has been reported to "shift" to pemphigus vulgaris.19
Also see Non-Hodgkin Lymphoma (pediatric focus), Chronic Lymphocytic Leukemia, Waldenstrom Hypergammaglobulinemia, and Thymoma
Patients present with painful oral erosions, often accompanied by a generalized cutaneous eruption. Oral erosions occur early and typically are severe, often involving the lateral tongue and vermilion. The eruption can assume a wide variety of morphologies. A classification system has been suggested, dividing lesions into pemphiguslike, pemphigoidlike, erythema multiforme–like, graft versus host disease–like, and lichen planus–like. Additionally, some patients report pruritus or pain. Cases without mucosal involvement have been reported, especially with the lichen planus –like variant, although these patients lacked autoantibodies.20
Physical
Mucosal findings
The earliest and most constant clinical finding in paraneoplastic pemphigus is painful oral erosions. Of those patients who present with a skin eruption, all go on to develop mucositis at some point during the course of the disease. Some patients only experience oral lesions.
The erosions of paraneoplastic pemphigus can occur anywhere in the mouth, including the buccal, labial, gingival, and lingual mucosae. All surfaces of the oropharynx can be affected. Erosions and subsequent crusting on the vermilion of the lips are typical and similar to that seen in persons with Stevens-Johnson syndrome. Genital mucosal surfaces can also be affected. Finally, nasal ulcers may cause epistaxis.
Cutaneous findings
The eruption of paraneoplastic pemphigus is highly variable. Patients may present with diffuse erythema, vesiculobullous lesions, papules, scaly plaques, exfoliative erythroderma, erosions, or ulcerations. The erythema can be macular, urticarial, or targetoid, and it may be polymorphous. Patients may initially present with erythema, and they may subsequently develop bullae and erosions.
Large areas of denudation with a positive Nikolsky sign can occur. Pustules have been reported. The papular lesions may resemble lichen planus, and the oral lesions may also be mistaken for lichen planus.21 A single patient has been reported with a solitary, pemphigus vegetans–like lesion that arose in a previous bulla. The palms and the soles may be involved.
Extracutaneous findings
Biopsy-confirmed paraneoplastic pemphigus has been reported in the gastrointestinal tract and the respiratory tract mucosa. The latter has been increasingly recognized and is a significant cause of mortality. Pulmonary involvement manifests as obstructive lung disease and progresses to bronchiolitis obliterans and death. Despite its ominous significance, signs of pulmonary involvement are subtle. Patients develop dyspnea, yet chest radiograph findings are normal. Ocular involvement ranges from mild conjunctivitis to symblepharon with corneal scarring.22
Causes
The association of paraneoplastic pemphigus with malignancy is strong. Only a handful of patients have had no associated diagnosis. Some patients have had benign neoplasms, including thymoma and Castleman disease. Only a single patient without a tumor has met the diagnostic criteria, yet this patient had a rapid demise and may have died with an undiagnosed malignancy. Patients have developed paraneoplastic pemphigus while in remission of their malignancy, leading some authors to prefer the term neoplasia-induced pemphigus.23
Treatment of the underlying malignancy does not necessarily halt progression of the paraneoplastic pemphigus, although some have observed that clinical manifestations improve as autoantibody titers decrease following resection of the tumor.
Circulating and tissue-bound antibodies in patients with this disease are directed against a group of molecules with sequence homology and belonging to the plakin family. These molecules are found in the intracellular attachment plaques of desmosomes and hemidesmosomes, and they play a key role in intermediate filament attachment. However, the number of reported target antigens has increased over time and varies between patients. This variability likely accounts for the clinical heterogeneity of this disease. By immunoprecipitation, target antigens (in decreasing order of incidence) include desmoglein 3, desmoglein 1, envoplakin (210 kd), periplakin (190 kd), desmoplakin I (250 kd), desmoplakin II (210 kd), and bullous pemphigoid antigen I (230 kd). Plectin (>400 kd) and an unidentified 170-kd protein have also been found.24
How tumors induce autoantibodies to plakin proteins is not known. Tumor cells have been demonstrated to produce autoantibodies that react to epidermal proteins. Other postulates include (1) cross-reactivity of tumor antigens and epidermal antigens and (2) tumor production of plakin proteins that initiate an autoimmune response. Dysregulated cytokine production by tumor cells, specifically interleukin 6, contributing to the autoimmune process is another hypothesis. The concept of epitope spreading, with which patients develop antibodies to multiple structurally related and unrelated proteins, may explain the multitude of antibodies produced in association with this disease.
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| References |
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Further Reading
Keywords
paraneoplastic pemphigus, PNP, pemphigus
