Paraneoplastic Pemphigus Clinical Presentation
- Author: Lynne J Goldberg, MD; Chief Editor: Dirk M Elston, MD more...
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.[10, 11, 12] Other associated malignancies and conditions include chronic lymphocytic leukemia, Castleman disease,[13, 14, 15, 16] Waldenström macroglobulinemia, thymoma,[14, 18] sarcoma, , lung carcinoma, and malignant melanoma. It has recently been reported in a patient with HIV disease who was found to have intra-abdominal diffuse B-cell lymphoma.
An association reported in 2009 is with systemic mastocytosis, and an atypical case associated with endometrial carcinoma lacking mucosal involvement has been reported. Paraneoplastic pemphigus can coexist with bullous pemphigoid and has been reported to "shift" to pemphigus vulgaris.
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.
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. In contrast to pemphigus vulgaris, where oral lesions are discrete, oral involvement by paraneoplastic pemphigus tends to be more diffuse. . Paraneoplastic pemphigus also tends to affect the conjunctiva, unlike pemphigus vulgaris, and genital mucosal surfaces can also be affected. Finally, nasal ulcers can occur and may cause epistaxis.
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. A single patient has been reported with a solitary, pemphigus vegetans–like lesion that arose in a previous bulla. In addition to the pattern of mucosal involvement, clinical features distinguishing paraneoplastic pemphigus from pemphigus vulgaris include involvement of the palms and soles and sparing of the scalp in the former.
A recent study on prognostic factors of paraneoplastic pemphigus found the presence of erythema multiforme–like lesions heralded a worse prognosis, especially if there was keratinocyte necrosis on biopsy and severe skin or mucosal involvement.
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. However, pulmonary function testing reveals a severe obstructive pattern and decreased diffusion capacity. Ocular involvement ranges from mild conjunctivitis to symblepharon with corneal scarring.
The association of paraneoplastic pemphigus with malignancy is strong. 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.
Treatment of the underlying malignancy does not halt progression of the paraneoplastic pemphigus. Cases associated with benign neoplasms can improve dramatically when the tumor is resected, owing to the decreased production of autoantibodies.
Circulating and tissue-bound antibodies in patients with paraneoplastic pemphigus 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, periplakin, desmoplakin I, desmoplakin II, and bullous pemphigoid antigen I. Plectin and a recently identified 170-kd protein called alpha2-macroglobulin-like–1 have also been found.[30, 31]
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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