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Paraneoplastic Pemphigus and Pemphigus Vulgaris

Synonyms:

None

Etiology:

Circulating antibodies (IgG) against keratinocyte cell surface peptides desmogleins (PV/PP), also envoplakin, periplakin, and desmoplakin in PP

Associations:

PV—Myasthenia gravis, thymoma, penicillamine, and captopril

PP—Non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Castleman's disease

Clinical:

Both variants show flaccid blisters with erosions and oral ulceration, PP associated with variable features including targetoid- and lichenoid-appearing lesions with tendency toward severe oral ulceration

Histology:

Intraepidermal acantholysis with bullae formation, PP may show a lichenoid/interface dermatitis or rarely, subepidermal bullae; both show intraepidermal IgG and C3 on immunofluorescence

IHC repertoire:

Not applicable

Staging:

None

Prognosis:

Overall: PV—5-year ~90% survival, PP—5-year ~50%

Adverse variables:

PV—Delay in diagnosis, advanced age, high-dose corticosteroids, associated infection PP—Non-Hodgkin's lymphoma and chronic lymphocytic leukemia

Treatment:

PV—Corticosteroids, cyclophosphamide, mycophenolate mofetil, plasmapheresis, IVIG PP—Problematic, treat underlying malignancy and corticosteroids

The disease pemphigus encompasses a group of related blistering conditions characterized by circulating antibodies against keratinocyte cell surface antigens important in mediating cell-to-cell adhesion (1,2). Of the various types and forms of the disease including pemphigus folia-ceus, pemphigus erythematosus, IgA pemphigus, and pemphigus vegetans, it is pemphigus vulgaris (PV) and paraneoplastic pemphigus (PP) that constitute the most important causes of mortality. Overall, these disorders are quite rare, with an estimated prevalence of between 1 in 100,000 for PV to less than 1 in 1,000,000 for PP. Both disorders are seen principally in aged adults with a near equal gender distribution. PV is more commonly observed among Jews and individuals of Mediterranean descent, whereas there is no known ethnic predilection for PP.

The etiology of both disorders involves circulating IgG antibody against specific adhesion molecules present on the cell surface of keratinocytes that mediate cell-to-cell adhesion and are localized to the desmosome apparatus (3,4). These antigens are transmembrane glycoproteins and include the desmogleins pathogenically important in PV and the plakins that are important in pathogenesis of PP. Antibodies directed against these peptides disrupt cell-to-cell adhesion or desmosome assembly, resulting in acantholysis and blister formation. Despite a similarly evoked mechanism of blister formation, it is thought that

Pemphigus Blisters
Figure 33.1. Widespread superficial ulcers in an elderly man with pemphigus vulgaris

the pathogenesis of antibody induction is different among these disorders. Patients with PV have a markedly increased frequency of certain class II major histocompatibility complex antigens including HLA-DR4 that predispose to antibody induction against desmogleins. In contrast, antibody induction in patients with PP is thought to involve tumor antigen cross-reactivity to normal cell surface constituents and dysregulated immune modulation mediated by host and tumor cytokine production (5). There are distinct disease associations with these disorders as well. PV is associated with myasthenia gravis, as well as the administration of certain medications including penicil-lamine and captopril (6). PP is invariably associated with the lymphoproliferative disorders, most commonly non-Hodgkin's lymphoma, followed by chronic lymphocytic leukemia, Castleman's disease, and Waldenstrom's mac-roglobulinemia. Interestingly, both disorders are associated with thymoma. There is no association between PP and the more common solid organ malignancies such as beast, lung, colorectal, or prostate adenocarcinoma.

The clinical manifestations of PV consist of flaccid blisters with erosions that develop anywhere on the skin surface (7,8). The blisters may develop on normal appearing or erythematous skin (Figure 33.1). Vegetative lesions with excessive granulation tissue may be seen in the inter-triginous areas. Mucous membrane involvement, most importantly of the oral cavity, is present in nearly all cases of PV and is often a heralding symptom. It may antedate the development of skin lesions for several months and often persists following skin resolution. The most common presentation is of painful shallow ulcerations most frequently involving the buccal mucosa, palate, floor of mouth, tongue, and less commonly the pharynx, larynx, conjunctiva, vagina, penis, or anus. The clinical findings in PP are more varied, although mucous membrane involvement is characteristic of the disorder (Figure 33.2). The skin lesions often occur episodically as waves of tense or flaccid blisters surmounted on an erythematous base situated on the trunk or extremities. Individually, the lesions may appear as shallow ulcerations similar to PV, tense blisters similar to bullous pemphigoid, as confluent and erosive patches similar to erythema multiforme/toxic epidermal necrolysis, or flat-topped papules similar to lichen planus (9-12). Lichenoid-appearing lesions may be observed on the palms and soles as well as the paronychial skin in established cases, constituting an important means of clinically distinguishing this disorder from PV. The most important facet of the clinical presentation is stomatitis. It is usually the earliest sign of the disorder, often persisting throughout the course of the disease, and is usually refractory to therapy. Painful erosions and ulceration is typically encountered throughout the oropharynx, although lateral tongue involvement with extension to and involvement of the vermilion border of the lips is characteristic of this disorder.

Severe Mucositis
Figure 33.2. Severe mucositis seen in paraneoplastic pemphigus. Note involvement of the nasal mucosa.

The histopathology of PV is distinctive. Early lesions show exocytosis of neutrophils with accompanying intercellular spongiosis and focal acantholysis. Established lesions show a mixture of dermal and epidermal neutro-phils and eosinophils with conspicuous epidermal acantholysis and bullae formation (Figure 33.3). The acantholyis characteristically spares the basilar layer of epithelium, imparting an appearance likened to that of "tombstones." Chronic lesions, in particular derived from intertriginous areas, are apt to show acanthosis with neu-trophilic and eosinophilic abscesses. Although the histo-pathology of PP may be identical to that of PV, more often, considerable histologic variation capable of simulating lichenoid/interface dermatitis or bullous pemphi-goid is encountered. This histologic diversity may be seen in disparate lesions biopsied synchronously or in meta-chronous lesions from the same individual. The lichenoid interface pattern often shows striking dyskeratosis with a tendency toward confluent basilar necrolysis (Figure 33.4). The inflammatory infiltrate of PP often shows a predominance of lymphocytes. Oral biopsies obtained from patients with both disorders show a variable degree of acantholysis with intramucosal or submucosal vesicu-lation. The inflammatory infiltrate characteristically shows a predominance of neutrophils. The direct immu-nofluorescence (DIF) findings are similar and consist of interepithelial staining with antibodies to IgG and C3 of lesional skin (13,14). DIF is more likely to be negative among patients with PP or to additionally show basement membrane staining. Distinction of these disorders can also be attained with indirect immunofluorescence involving cell extract immunoblotting or incorporating a rat bladder substrate with IgG antibodies directed toward the plakins.

The prognosis of PV is generally favorable, particularly since the advent of noncorticosteroid immunosuppressive therapy (15). Historically, corticosteroid-induced iatro-genesis, and in particular, predisposition for opportunistic infection, was the principal mechanism responsible for a 15%—25% mortality rate. Today, the 5-year mortality rate is much lower and is due to more effective steroid-reducing therapies such as cyclophosphamide, mycophe-nolate mofetil, and intravenous immunoglobulin. Although infection, in particular with Staphylococcus aureus, remains the most important risk, the mortality rate still remains close to 10%. The prognosis of younger patients with PV or those cases associated with medications, myasthenia gravis, and/or thymoma is generally more favorable. Overall, the prognosis of PP is grave with a 5-year mortality rate of 50%. More favorable outcomes are observed among patients with resectable tumors including thymoma or among patients with indolent lym-phoproliferative disorders such as chronic lymphocytic leukemia. The treatment of this disorder tends to be more difficult with the oral and skin lesions often refractory to most therapies. Oral corticosteroids alone or in combination with cyclosporine will usually result in partial improvement of lesions.

Lupus Pemphigus

Figure 33.4. Dense lichenoid inflammatory infiltrate with increased necrotic keratinocytes and incipient subepidermal blister formation seen in paraneoplastic pemphigus.

Lupus Pemphigus

Figure 33.4. Dense lichenoid inflammatory infiltrate with increased necrotic keratinocytes and incipient subepidermal blister formation seen in paraneoplastic pemphigus.

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