Most patients (approximately two-thirds) who develop PNP have a preceding history of a neoplasm. In the remaining one-third of patients, the onset of PNP will precede the diagnosis of the malignancy. There are rare reports of no detectable malignancy at the time of the development of PNP. Specific neoplasms associated with PNP include non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman tumor (angiofollicular lymph node hyperplasia), thymoma, spindle cell neoplasms, epithelial neoplasms, sarcomas, and Waldenström macroglobulinemia.
The disease is thought to be due to cross-reactivity between tumor antigens and epithelial antigens, causing both mucosal and cutaneous lesions. Immunoglobulin G (IgG) antibodies develop against multiple antigens, such as members of the plakin and desmoglein families: desmoplakin I (DPI1), desmoplakin II (DPI2), plectin, envoplakin, periplakin, bullous pemphigoid antigen 230, desmoglein 1 (DSG1), and desmoglein 3 (DSG3).
The disease is most commonly identified in adults aged 45-70, as this is the demographic most likely to develop lymphoma. Patients with Castleman disease tend to be younger, in the second or third decade of life. There is no association with sex, race / ethnicity, or geographic region, although there may be an association with DRB1*03 and HLA-Cw*14 alleles.
Symptoms and signs include painful cutaneous and oral lesions secondary to the vesicles and bullae that form and subsequently rupture. Severe eye irritation may also be seen with conjunctival involvement, and esophageal, nasopharyngeal, vaginal, and penile mucosal lesions may also be seen. Pulmonary involvement, occurring in around 90% of patients, takes the form of bronchiolitis obliterans leading to dyspnea.
Prognosis depends on the associated malignancy. Removal of some tumors (thymoma or Castleman disease) may induce disease remission. However, patients with other malignancies may deteriorate, with death most often due to bronchiolitis obliterans, sepsis, gastrointestinal bleeding, or organ failure. Decreased survival has also been noted in patients with a bullous pemphigoid-like and a toxic epidermal necrolysis (TEN)-like picture as well as the presence of bronchiolitis obliterans.
L10.81 – Paraneoplastic pemphigus
402718003 – Pemphigus paraneoplastica
Differential Diagnosis & Pitfalls
- Pemphigus vulgaris – Oral erosions and ulcerations are usually the dominant feature for weeks to months before cutaneous vesicles and bullae begin to appear. Skin lesions in PNP are more pleomorphic than in pemphigus vulgaris.
- Pemphigus foliaceus
- Erythema multiforme – This condition may clinically appear virtually identical to PNP. Patients may have a history of previous episodes that resolved within 2-4 weeks. If classic targetoid lesions of the skin are present, this would be more consistent with erythema multiforme.
- Bullous pemphigoid – Cutaneous vesicles and bullae are the predominant feature of this condition, with only 20% of patients having oral involvement. Hemorrhagic crusting of the lips would be unusual.
- Mucous membrane pemphigoid – This condition mostly affects the mucosa at various sites, with only 20% showing cutaneous bullae. The relatively chronic, slow evolution of cicatricial pemphigoid would not be consistent with PNP either.
- Lichen planus – The erosive oral lesions of lichen planus are usually surrounded by radiating keratotic striae, a feature that is typically not evident in the oral lesions of PNP.
- Herpetic stomatitis – The oral ulcerations may be diffuse but are composed of smaller lesions (1-2 mm) that coalesce. Unlike PNP, significant cutaneous involvement in herpetic stomatitis would be unusual.
- Stevens-Johnson syndrome / TEN – Drug-induced, high fevers, skin tenderness, mucosal erosions, and skin detachment (necrolysis) about 1-3 weeks after the inciting medication is started.
- Staphylococcal toxic shock syndrome – Look for sudden onset of exanthematous eruption.
- Streptococcal toxic shock syndrome – Patients are usually aged 20-50 and have a deep soft-tissue infection.
- Acute graft-versus-host disease – Associated with history of bone marrow transplant.
- Drug hypersensitivity syndrome (drug reaction with eosinophilia and systemic symptoms [DRESS]) – Look for facial edema (hallmark of DRESS), eosinophilia, hepatitis, and other visceral involvement.
- Drug-induced erythroderma
- Erythrodermic psoriasis
- Atopic dermatitis with erythroderma
- Contact dermatitis
- Pityriasis rubra pilaris
- Sézary syndrome
- Phototoxic reaction
- Photoallergic reaction