In 1990, Anhalt et al.1 reported a new clinical entity named as “Paraneoplastic pemphigus”, fulfilling five diagnostic criteria. Subsequently, their findings were confirmed by several studies.2–9 Nguyen et al.10 described PNP as a heterogeneous autoimmune syndrome that affects several internal organs, and that its pathophysiology is not limited to antibodies targeting adhesion molecules like other subtypes of pemphigus. In 2001, they proposed the term “Paraneoplastic autoimmune multi-organ syndrome” instead of PNP. This is because the autoantibodies in the disease bind to the kidney, smooth and striated muscle, as well as the epithelium of the small intestine, colon and thyroid.3 The term more widely used in most reports and reviews, including the present paper, is PNP. About the position of PNP among skin disorders, some studies11–13 propose to include it as a type of pemphigus with an associated tumor, whereas others14–16 describe it as an independent autoimmune disorder; moreover, PNP does not fully meet Curth's criteria for cutaneous paraneoplastic syndrome (Table 1).

Paraneoplastic pemphigus is closely related to benign or malignant tumors. The most often reported malignancies are lymphomatoid and hematologic (B-cell lymphoma, chronic lymphocytic leukemia, Castleman's disease, Waldenstrom's macroglobulinemia, and thymoma, with or without myasthenia gravis). Interactions between the immune system and concomitant neoplasm seem to be key pathogenic steps with autoantibodies directed against both desmosomal and hemidesmosomal antigens. In PNP, most patients develop autoantibodies against periplakins and envoplakins.

In 1990, Anhalt et al.1 first described five cases of patients with a rare form of atypical pemphigus that were all associated with lymphoproliferative diseases. PNP mostly affects adults between 45 and 70 years old, but it may also be found in younger patients, in whom Castleman's disease is more commonly seen. There is no known correlation between incidence of the disease and specific gender, race, or geographical distribution.3

Based on its very unique clinical pictures, as well as its histologic and immunologic features, and most of all its elevated mortality (90% if untreated), diagnosis should be stated promptly.3,17–20 Prognosis depends on the nature of the associated tumor. Some patients experience rapid improvement after excision of a benign tumor, such as PNP associated to Castleman's disease. However, malignant tumors are often accompanied not only by higher mortality from the associated malignancy but also because the PNP can be severe and often recalcitrant.

The exact incidence of PNP is unknown but it is less common than pemphigus vulgaris or pemphigus foliaceus. There appears to be no age preference.4 Although PNP presents most often in older patients aged between 45 and 70 years, it also occurs in younger patients. The disease has been reported in patients ranging from 7 to 83 years-old.5 Ogawa et al.21 studied 496 patients with malignancy and recorded 25 cases of pemphigus (5%), an elevated number when compared with controls. There was a positive correlation with advancing age. The mean age of pemphigus patients with malignancy was 64.7 years.21 It appears to be no gender predilection.2,22

The associated malignant or benign neoplasm may be occult or already diagnosed at the point of PNP presentation. PNP may also develop after the tumor has been treated.6,7 The most commonly associated tumors are hematological, accounting for nearly 84% of all cases, these include non-Hodgkin's lymphoma (38.6%), chronic lymphocytic leukemia (18.4%), Castleman's disease (18.4%), thymoma (5.5%), Waldenström macroglobulinemia (1.2%), Hodgkin's lymphoma (0.6%) and monoclonal gammopathy (0.6%).4 Non-hematological neoplasms include carcinomas (8.6%), sarcomas (6.2%)23 and melanoma (0.6%).4

In children and adolescents, PNP is most commonly associated with Castleman's disease8 and PNP is often the presenting sign of Castleman's disease.9 This tumor is rare in the general population but is the third most common neoplasm associated with PNP.24

PNP is an autoimmune disorder launched by an underlying neoplasm (Fig. 1). Etiopathogenesis of PNP is not fully described.4 Skin lesions are thought to be originated by an antibody-mediated autoimmune response to tumor antigens that cross-react with epithelial antigens. Tumor autoantibodies produce and release cytokines (such as interleukin-6) that enhance B-cells differentiation5 and foster to develop the humoral response.

Figure 1.

Pathogenesis of paraneoplastic pemphigus. Neoplasms develop immune dysregulation and therefore the production of autoantibodies against self-antigens. Antigen-processing cells assimilate antigens that are cross-reactive with several skin antigens, presenting them to CD4+ T cells, and therefore to the known immune cascade that ends in the formation of autoantibodies against different substrates. The tumor itself can develop an immune process with the release of proinflammatory cytokines (IL-12 and IFN). This mechanism can be enhanced by the epitope spreading creating secondary epitopes, increasing antibody production; this mechanism contributes to epidermal and subepidermal lesions (pemphigus and pemphigoid-like lesions). Cell-mediated immune activation (mainly CD8+ T cells) also develops and contributes to several skin lesions (lichenoid and graft-versus-host disease-like).

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PNP is often a clinical marker of benign and malignant neoplasms, most commonly malignancies of the lymphatic system.6 Ohzono et al.7 described the associated tumors in 104 PNP cases. Their clinical and histopathological findings were similar to those in previous reports.3,4,6

Some patients have tumors that are difficult to diagnose, such as follicular dendritic cell sarcomas located in the retroperitoneal space.8 Studies of patients with non-Hodgkin lymphoma revealed that most severe lesions during the PNP occur 2–3 years after diagnosis of lymphoma.6 Castleman's disease, also known as giant lymph node hyperplasia, occurs most commonly in children.

Previous studies have shown that HLA-DR4 and DR14 alleles confer strong susceptibility to pemphigus vulgaris and foliaceous; however, PNP is not associated with these alleles. HLA-DRB1*03 in Caucasian patients24 and Cw*14 in Chinese patients have been reported in PNP.25 These findings indicate that people with different racial backgrounds have a different susceptibility to PNP.

It is hypothesized that tumor antigens evoke not only a humoral response but a cellular one.4,5 While direct immunofluorescence findings of autoantibodies bound to the cell surface of affected epithelium support a humoral response, histopathological findings of individual keratinocyte necrosis with lymphocyte exocytosis support the role of cell-mediated immunity.

In order to explain such hypothesis, several explanations have been proposed, like production of autoantibodies to epithelial proteins by tumors, supported by finding B-cells-producing IgG antibodies directed to epidermal antigens in Castleman's disease26; cross-reactivity of tumor antigens and epidermal antigens; high levels of interleukin-6, which promotes B-cell differentiation and immunoglobulin production.27 Anti-IL-6 monoclonal antibody inhibitors (Tocilizumab) have been successfully used for treating Castleman's disease28–30; epitope spreading and cellular immunity-mediated processes have been reported in previous studies.31,32 Cummins et al.32 reported a series of four patients with a lichenoid variant of PNP without detectable autoantibodies. They inferred that these patients had disease mainly mediated by cytotoxic T lymphocytes rather than autoantibodies. Nguyen et al.10 also showed the presence of cytotoxic T lymphocytes, macrophages, and natural killer cells in tissues affected by PNP. These theories support that both cellular and humoral immunity are implicated in the pathogenesis of PNP.33

Various lesions may occur in patients with PNP. Although characterized by severe oral mucositis (Fig. 2), a generalized polymorphous cutaneous eruption and pulmonary involvement may develop. Typically, the first symptoms are usually florid, painful as well as intractable stomatitis, and also, it can involve the vermilion of the lips, oro and nasopharynx, the nose (Fig. 2), tongue, esophagus, stomach; duodenum, intestines and the pulmonary epithelium, as well as the conjunctiva34 and anogenital region (Fig. 3) are also affected.2,3,35–38

Figure 2.

Severe oral mucositis, also involving the nose.

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Figure 3.

Erosions affecting the glans of penis. It is evident the lichenoid lesions on the hands.

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The lesions are polymorphic, and symptoms include blisters, erosions, spots, papules, and plaques. Nikolsky sign can be present. Cutaneous lesions usually appear after the onset of mucosal lesions and may involve any site, mostly the upper body. Nguyen et al.10 proposed a classification including several clinical presentations of PNP. It is believed that each category occurs with nearly equal incidence.

PNP cutaneous lesions can be classified into several groups according to the types of changes:

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  Pemphigus-like: flaccid blisters, erosions, crust, and erythema.

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  Bullous pemphigoid-like: scaly erythematous papules and stretched vesicles. These are more commonly seen on the extremities.

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  Erythema multiforme-like: polymorphic changes, mainly erythematous peeling pellets with erosions and sometimes even with recalcitrant ulcerations (Fig. 4).

  
  

  Figure 4.

  Several erosions on the palms of the hands, often recalcitrant.

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  Graft-versus-host disease: scattered dusky red scaly papules.

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  Lichen planus-like: the presenting picture consists in flat, red-brown scaly papules and plaques, as well as intense mucous membrane involvement, more commonly seen in children on the trunk and extremities (Fig. 3), and rapidly extending to the face and neck.38 Scaly lesions on the palms and soles may accompany the lichenoid lesions.

Patients with PNP can develop life-threatening restrictive bronchiolitis obliterans. The frequency of the involvement of the respiratory system and its pathological mechanisms are unknown.39 In a study of 17 patients with PNP, restrictive bronchiolitis was found only in three patients. However, in another analysis where 28 patients with PNP and concomitant Castleman's disease were examined, the respiratory system was affected in 26 cases.40,41 Pulmonary disease, when present, is irreversible despite aggressive therapy.2,3,42 The recently discovered autoantigen, epiplakin, has demonstrated correlation with development of bronchiolitis obliterans in Japanese patients.43 Epiplakin is present in the respiratory bronchiole, and mice injected with epiplakin autoantibody showed abnormal changes in the histopathology of their pulmonary epithelia. While more research is needed, these early results indicate that epiplakin may represent a specific autoantigen in PNP-related bronchiolitis obliterans.

Differential diagnosis of PNP is extensive (Table 3), and includes pemphigus vulgaris, mucous membrane pemphigoid, erythema multiforme, Stevens–Johnson syndrome, lichen planus, graft-versus-host disease, and herpes simplex virus infection. When PNP is suspected, an extensive baseline workup should be conducted, including: blood cell count, lactate dehydrogenase, flow cytometry, as well as chest, abdomen, and pelvis CT scan. The existence of a neoplasm is often recognized prior to PNP (30% of cases approximately).22

The overall prognosis of PNP is poor. The mortality rate ranges from 75% to 90%, being respiratory failure the main cause of death.81 The prognosis is better when the disease is associated with benign tumors and may even remit when tumors are excised.

The outcome of PNP, however, does not simply parallel the course of the underlying malignancy. Complications resulting from PNP and its treatment contribute significantly to morbidity and mortality. These include sepsis, multi-organ failure, gastrointestinal hemorrhage and respiratory failure related to bronchiolitis obliterans.83

Ohzono et al.7 in a study of 104 PNP patients, of whom 40 died; the main cause of death in these patients was bronchiolitis obliterans (n=16/40, 40%), while the second cause (n=24/40, 60%) was infection (mainly pneumonia) and the third cause related to the associated tumor.

Bronchiolitis obliterans correlates with poor prognosis. Pulmonary involvement occurs in 30–92.8% of patients and it is estimated that one-third of the deaths in PNP are due to pulmonary insufficiency. It is known that constrictive bronchiolitis can continue to worsen despite improvement in muco-cutaneous manifestations after immunosuppressive therapy and resection of tumor.85 A prompt diagnosis and early introduction of treatment are mandatory.

Through this literature review, we acquired a global context of paraneoplastic pemphigus. We present the main clinical features, the fundamental principles of its etiopathogeny, review the diagnostic aspects that integrate criteria distinguishing the entity from others such as pemphigus vulgaris; the main associated tumors, where we share part of the experience obtained in these almost 20 years studying autoimmune bullous diseases; finally the main treatment options and the prognostic factors of the disease are discussed. We emphasize the importance of making a timely diagnosis and choosing the most appropriate treatment option for each specific case.

The authors declare no conflict of interests.