Pemphigus vegetans of the Folds (Intertriginous Areas) Vincenzo Ruocco MD, Eleonora Ruocco MD, PhD, Stefano Caccavale MD, Alessio Gambardella MD, Ada Lo Schiavo MD PII: DOI: Reference:

S0738-081X(15)00075-9 doi: 10.1016/j.clindermatol.2015.04.011 CID 6946

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Clinics in Dermatology

Please cite this article as: Ruocco Vincenzo, Ruocco Eleonora, Caccavale Stefano, Gambardella Alessio, Schiavo Ada Lo, Pemphigus vegetans of the Folds (Intertriginous Areas), Clinics in Dermatology (2015), doi: 10.1016/j.clindermatol.2015.04.011

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ACCEPTED MANUSCRIPT CLINICS IN DERMATOLOGY

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Regional Dermatoses

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Issue titled:

II Fold Dermatoses – When Skin Touches Skin

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Guest Editors: Yalςin Tüzün and Ronni Wolf

Chapter 11

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Pemphigus vegetans of the Folds (Intertriginous Areas)

Eleonora Ruocco, MD, PhD Stefano Caccavale, MD

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Ada Lo Schiavo, MD

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Alessio Gambardella, MD

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Vincenzo Ruocco,MD

Department of Dermatology, Second University of Naples, Naples, Italy

Corresponding Author Prof. Vincenzo Ruocco, MD Department of Dermatology nd 2 University of Naples via Sergio Pansini, 5 80131 Napoli, Italy phone: +39.081.566.68.28 fax: +39.081.546.87.59 e-mail: [email protected]

ACCEPTED MANUSCRIPT Abstract Pemphigus vegetans (P Veg), the rarest form of pemphigus, is thought to be a variant of pemphigus

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vulgaris (PV). Classically, two subtypes of P Veg are recognized: Neumann P Veg, which usually

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begins as PV with vescicles and bullae that rupture to form hypertrophic granulating erosions, then evolving into vegetating exuding masses; Hallopeau P Veg, initially characterized by pustular

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lesions that, after rupturing, merge and gradually evolve into vegetating erosions with a centrifugal expansion. The disease typically affects the big folds (axillary, inframammary, inguinocrural,

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intergluteal), where semi-occlusion, maceration, and mixed infections continuously incite exudation and granulation tissue formation (wet P Veg). In non-intertriginous locations, the vegetating buttons can dry out to change into warty, fissured, painful, seborrheic keratosis-like lesions (dry P Veg). Histology shows hyperplastic epidermis with intramalpighian leukocyte microabscesses and

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indistinct traits of suprabasal acantholysis. Immunofluorescence findings are similar to those of PV.

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Diagnosis is straightforward when PV lesions coexist. Difficulties can arise in cases with nonflexural location. Cytology (Tzanck test), histology, immunofluorescence and ELISA search for

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anti-desmoglein antibodies are the diagnostic laboratory tools. Systemic treatment is similar to that

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for PV, being high-dose steroids the first choice therapy. Immunosuppressive agents and etretinate may allow a steroid-sparing effect. Topical treatment is aimed at countering the granulation tissue formation by means of several strategies (sublesional steroid injection, application of medicated gauzes in the involved flexures, chemical cautery or surgical excission of vegetating lesions).

Key words       

Pemphigus vegetans Neumann pemphigus vegetans Hallopeau pemphigus vegetans Flexural pemphigus Intertriginous pemphigus Wet pemphigus vegetans Dry pemphigus vegetans Definition, history, and epidemiology

ACCEPTED MANUSCRIPT The term pemphigus (from the Greek pemphix = blister) was introduced in the medical literature by François Boissier de Sauvages de Lacroix (1706–1767) with reference to a large group of acute and

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chronic bullous skin disorders. Since 1791, the term has been used for the disease we know today,

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thanks to Johann Ernst Wichmanns (1740-1802). [1]. It refers to a group of autoimmune bullous diseases of the skin and mucous membranes (with stratified or Malpighian epithelium) that have

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variable clinical and prognostic features. They are all linked by the histologic characteristic of intraepithelial bulla, due to a loss of cohesion between epitheliocytes, and by the immunopathologic

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hallmark of specific tissue-damaging autoantibodies in the blood and in the lesional areas. These antibodies are directed against surface structures or adhesion molecules of the Malpighian epitheliocytes and are responsible for the loss of intercellular cohesion. The separation of

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Malpighian cells from each other, which is called acantholysis, has a specific histotopography: the detachment can occur in the lower part of the epithelium, immediately above the basal cell layer

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(deep or suprabasal acantholysis), or in the upper part of the epithelium, at the level of the granular layer, that is immediately below the stratum corneum (superficial or subcorneal acantholysis). This

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results in two main types of pemphigus, pemphigus with deep acantholysis [that includes

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pemphigus vulgaris (PV) and pemphigus vegetans (P Veg)] and pemphigus with superficial acantholysis or superficial pemphigus (that includes pemphigus foliaceus, endemic pemphigus or fogo selvagem, pemphigus erythematosus or Senear-Usher disease, and endemic pemphigus erythematosus of Abrèu), which differ clinically, prognostically, and antigenically [1-3]. P Veg, which represents only 1-2% of all pemphigus patients, is thought to be a variant of PV, characterized by vegetating erosions, primarily in flexures. Classically, two subtypes of P Veg are recognized: Neumann P Veg and Hallopeau P Veg, after the authors who described this disorder (in 1876 and in 1889, respectively) [1,4,5]. Although Neumann is generally given credit for first drawing attention to this condition, other authors had reported cases of P Veg under a different diagnosis earlier [i.e. De la Motte in 1773, Cazenave in 1844, Kohn (later known as Kaposi) in 1869] [5].

ACCEPTED MANUSCRIPT Analysis of reported cases in literature reveals that P Veg may occur in people of all age groups including children, but the disease predominantly affects middle-aged women (Sex-ratio: F/M =

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14/3). The median age at onset is 40-50 years [6].

Etiology and pathogenesis

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As P Veg is considered a rare variety of PV, there are only few papers in the literature specifically devoted to it, and most of them are case reports [4]. As a result, etiopathogenesis of P Veg still

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remains unclear. Vegetations develop on top of old erosive lesions. It is not clear why this occurs only in some cases of PV, few indeed, and not in all of them. It is certain, though, that there is the contribution of some factors related to the location of lesions (almost always in the folds), represented by semi-occlusion, maceration, and bacterial and/or fungal colonization; indeed, it

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seems reasonable to consider P Veg a peculiar morphologic ‘response’ of PV to intense and

outside the skin folds.

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recurrent bacterial and/or fungal infections [1,6]; however, this does not explain the lesions located

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Pemphigus has a genetic basis (the disease susceptibility is strongly associated with some class II

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HLA antigens). All variants of pemphigus are characterized by the production of pathogenic autoantibodies directed against different desmosomal proteins. In P Veg antibodies react with the same target antigens as in PV, i.e., desmoglein 3 and sometimes desmoglein 1 as well. Antibodies anti-desmoglein 3 (Dsg-3Ab) are responsible for suprabasal acantholysis in Malpighian mucosae, while antibodies anti-desmoglein 1 (Dsg1-Ab) cause superficial acantholysis in the epidermis. The presence of both antibodies gives rise to suprabasal acantholysis in both skin and mucous membranes [1,7]. The reactivity against Dsg1 is not surprising as P Veg is a clinical variant of PV, in which anti Dsg1 antibodies often accompany anti Dsg3 antibodies. Some studies have suggested that in P Veg there are additional, occasionally detected antibodies, which bind to other desmosomal proteins, such as desmocollins 1 and 2, and periplakine. This could be a possible explanation for the differences in clinical appearance between PV and P Veg [8]. One

ACCEPTED MANUSCRIPT group reported an immunoprecipitation analysis, using extracts of cultured normal keratinocytes, in a patient with the Neumann type of P Veg [9]. The patient’s serum precipitated not only 130 and 85

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kDa polypeptides, but also other polypeptides of unknown significance. The 85 kDa component

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appeared not to be disease-specific, and represented an adhering junction molecule, plakoglobin. P Veg could differ from PV in having, in addition to the antibodies typical of PV, antibodies directed

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against other, as yet uncharacterized, antigens [9]. From a functional point of view, all pemphigus antigens are to be considered antigens of differentiation, related to the process of keratogenesis. The

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antigens of P Veg have their highest expression in the lower part of the Malpighian epithelium, which, functionally speaking, represents the pre-keratin zone. Under normal conditions, the prekeratin zone is present both in the epidermis and in non-keratinizing Malpighian epithelia (oral, laryngeal, esophageal mucosae). This could be the reason why the lesions of P Veg usually manifest

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also with an oral involvement [1].

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Binding of the above mentioned autoantibodies to desmosomal components induces a disjunction of desmosomal areas, leading to acantholysis and the formation of intraepithelial blisters [4].

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Under discussion are also immunopathological factors such as Th-2-mediated immune reaction with

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the involvement of IgG autoantibodies and cytokines that play a role in the epithelial proliferation and eosinophils chemotaxis [6]. Another group has reported detection of all IgG isotypes bound in the lesional skin of P Veg patients, with a predominance of IgG2 and IgG4, whereas in PV patients the autoantibody activity resides mainly in the IgGl and IgG4 subclasses. This led the authors to speculate that the higher lesional concentration of complement-activating IgG isotypes, i. e. IgG1,2 and 3, might largely be responsible for the distinct histological and clinical appearance of P Veg [7]. These results demonstrate that, although patients with P Veg and patients with PV both produce autoantibodies against the same antigens, the IgG sub-classes of the antibodies that are generated differ in P Veg and PV, with a higher titer of complement-fixing antibody in P Veg compared with PV [7].

ACCEPTED MANUSCRIPT The role of complement in the pathogenesis of pemphigus is still a matter of debate. Acantholytic, non-inflammatory blisters in the epidermis can be induced in vitro by complement-independent

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antibodies. This suggests that complement does not have a significant role in the production of

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acantholysis in pemphigus. However, the complement-fixing ability of intercellular antibodies is higher in P Veg compared with other types of pemphigus. In particular, in epidermal cell lysates

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from P Veg patients (and in contrast with PV), the complement-fixing antibody titer was as high as the intercellular antibody titer. This suggests a special pathophysiological role of complement in

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this particular form of pemphigus. It is well known that activation of the complement cascade in skin lesions attracts inflammatory cells, including polymorphonuclear leukocytes. Deposition of high levels of complement-fixing autoantibodies in the intercellular spaces may lead to activation of the complement cascade within the epidermis, resulting in marked cutaneous infiltration of

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neutrophils and eosinophils, typically observed in P Veg. These events possibly cause a severe

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characteristic of P Veg [7].

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inflammatory response, with the formation of intraepidermal abscesses and vegetative lesions, both

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Inducing factors and associations In some reported observations, the outbreak of P Veg seems to be favored by HIV infection, intranasal heroin abuse, drug intake (captopril), organ transplantation (liver and kidney), or split thickness skin graft [6]. P Veg-like lesions have rarely been described in paraneoplastic pemphigus in association with lymphoproliferative disorders (lymphosarcoma, non-Hodgkin-lymphoma and chronic lymphocytic leukemia) or internal tumors (lung, colonic and gastric cancer). As suggested for other bullous diseases [2,3,10,11], in paraneoplastic P Veg patients, reactivity against Dsg3, Dsg 1, and non-Dsg molecules could be explained by the presence of an immunologic cross-reactivity between epidermis and cancer epithelial antigens, resulting in an epitope spreading phenomenon.

ACCEPTED MANUSCRIPT In some cases, patients had previously been affected by other clinical forms of pemphigus that

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subsequently evolved into the ‘vegetans’ form [6].

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Clinical features and course

P Veg is clinically characterized by the presence of fleshy buttons, deep red in color, supple and

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smelly, which can merge and fuse into extensive mammillated plaques, irregularly shaped and often with polycyclic margins. The lesions are bordered by a macerated epithelial collarette. The sites

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most frequently involved are the big folds (axillary, inframammary, inguinocrural, intergluteal) (Figure 1), but sometimes areas with small folds are also involved (nasolabial folds, labial folds, periumbelical area). Typical intertriginous locations feature the classical clinical picture of ‘wet pemphigus vegetans’. However, vegetations may occur at any site and not solely in intertriginous

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areas [1,6]. In non-flexural sites the granulation tissue can dry out and then produce a warty surface

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with painful fissures, which somehow evokes the clinical appearance of seborrheic keratoses (‘dry pemphigus vegetans’). Oral involvement is exceedingly common (60 to 80% in the literature) and

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often since the beginning of the disease (75% in literature), leading sometimes to malnutrition.

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Initially, P Veg may be confined to a single site, usually corresponding to the oral mucosa, but usually it becomes multifocal in time, with a varying body surface involvement [6]. Oral vegetations are rare, but occasionally the tongue develops a ‘cerebriform’ appearance which is typical of this condition [12]. Other particular features are verrucous plaques along lips vermilion borders and at the angles of mouth or around nares, gingival proliferation, verrucous paronychia with pachyonychia, onychorrhexis, onychomadesis, presence of pustules under plate-nail and nail loss [6]. Historically, two types of P Veg have been distinguished: 1) the Neumann’s type, actually beginning as PV, in which vesicles and bullae rupture to form hypertrophic granulating erosions, which bleed easily. The lesions evolve into vegetating masses

ACCEPTED MANUSCRIPT exuding serum and pus. The edges are studded with small pustules. Erosions at the edge of the lesions induce new vegetations, which eventually become dry, hyperkeratotic and fissured [13];

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2) the Hallopeau’s type (synonyms pyodermite végétante, pyoderma vegetans), in which the initial

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lesions are not bullae but pustules that, with their rupture, evolve into infected erosions, which, by multiplying and merging, gradually become painful vegetating lesions with a centrifugal expansion

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[1,13].

Today, however, this distinction is considered somewhat artificial, since the two clinical pictures

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are probably related to the variable response of the patient’s tissue and not to different pathogenic ‘noxae’ [1].

Histopathology

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P Veg, although merely a variant of PV, exhibits strikingly different histological features.

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Suprabasal acantholysis, which is the hallmark of PV, is present only in the early stages of P Veg, with formation of small (often blurred) clefts in a suprabasal location (Figure 2); subsequently it can

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be missing or masked by the exuberant proliferation of involved epidermis, which shows

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papillomatous, verrucous or pseudoepitheliomatous hyperplasia (Figure 3). Intraepidermal microabscesses consisting of eosinophils and neutrophils, sometimes interspersed with apoptotic or necrotic keratinocytes, are often seen (Figures 3 and 4). They can also invade the hair follicle or sweat duct epithelium. The cavities containing microabscesses may be lined by a laminar layer of keratin, which probably developed subsequent to the cell separation and degeneration. Foci of spongiosis with mere cell-cell detachment (desmolysis), or accompanied by frank acantholytic changes of the involved keratinocytes (acantholysis), can be observed in the hyperplastic epidermis (Figure 5). The dermis is edematous, characterized by elongation of papillae with formation of protruding villi, vasodilatation, and intense mixed inflammatory infiltrate consisting of polymorphonuclear leukocytes, eosinophils, lymphocytes and plasma cells.

ACCEPTED MANUSCRIPT Pemphigus vegetans in domestic animals P Veg is the rarest form of pemphigus in domestic animals and has mainly been studied in dogs. No

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age, breed, or sex predilections have emerged. The disease presents as a vescico-pustular disorder

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that evolves into verrucous vegetations and papillomatous proliferations, which ooze and are studded with pustules. The Nikolsky sign may be present. Pruritus and pain are variable, and the

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dogs usually are otherwise healthy. Histology shows epidermal hyperplasia, papillomatosis, and intraepidermal microabscesses, which contain predominantly eosinophils and acantholytic

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keratinocytes, like in humans [14]. The main difference between the canine and human disease resides in the antigen recognized by circulating autoantibodies. Whereas in humans P Veg autoantibodies principally recognize Dsg-3, in dogs antikeratinocyte antibodies identify Dsg-1, the

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major human and minor canine pemphigus foliaceus antigen [15].

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Diagnosis

The diagnosis of P Veg is based on clinical manifestations, cytodiagnostic examination (or Tzanck

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test) and histology. Tzanck test shows acantholytic cells and often also characteristic cytoadherence

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phenomena (Sertoli’s rosette, leukocyte adherence with formation of ‘streptocytes’) [16]. Histopathologically, P Veg lesions show indistinct suprabasal acantholysis, irregular epidermal hyperplasia, papillomatosis, microabscesses composed of eosinophils and neutrophils [17]. Immunofluorescence findings in P Veg are indistinguishable from those of PV. Direct immunofluorescence demonstrates deposition of IgG and C3 on the cell surface of keratinocytes. Indirect immunofluorescence reveals circulating antiepithelial cell-surface IgG. A deposit of IgA, isolated or combined with other auto-antibodies or reactants (IgG, IgM, C3, C1q) is rarely observed and may be a clue for the efficacy of dapsone in the disease control. ELISA identifies autoantibodies against Dsg3, whereas autoantibodies against Dsg1, desmocollin 1 and 2, and periplakine are only occasionally detected [18]. Moreover, it is not yet clear whether the antibodies

ACCEPTED MANUSCRIPT occurring in PV and P Veg show any differences. IgG1 and IgG4 autoantibodies are typical of PV,

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whereas the presence of IgG2 and IgG4 isotypes can be detected in the lesional skin of P Veg [7].

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Differential diagnosis

The clinical appearance of P Veg is characteristic and only a few other disorders have to be

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considered in the differential diagnosis. Oral erosions may simulate acute herpetic stomatitis, erythema multiforme, aphthous ulcers or erosive lichen planus. Bullae are transient in the mouth

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and biopsies of erosions may not be diagnostic. Smears taken from the base of an erosion may show acantholytic cells (Tzanck test). Direct immunofluorescence is the most accurate way to diagnose mucosal pemphigus [19]. In the oral cavity, the differential diagnosis of P Veg may include pyostomatitis vegetans. Both conditions show similar clinical and histopathological findings, but

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direct and indirect immunofluorescence studies enable the clinician to distinguish between these

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two disorders. In pyostomatitis vegetans, the immunofluorescence findings are negative [20]. Vegetating, pustular lesions in flexures must be differentiated from chronic infections (condilomata

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acuminata, condilomata lata, candidal intertrigo, blastomycosis) or Hailey-Hailey disease.

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Vegetating plaques mimicking P Veg can be seen in IgA pemphigus [21], paraneoplastic pemphigus [22], and halogenoderma (iododerma or bromoderma). The hyperkeratotic lesions of chronic P Veg may simulate cutaneous tumors [23]. When P Veg occurs in non-intertriginous sites (dry P Veg), the lesions should be differentiated from seborrheic keratoses [24-26]. The histological differential diagnosis includes Darier’s disease, Hailey-Hailey disease and transient acantholytic dermatosis (Grover’s disease). These conditions have distinctive clinical features in addition to negative immunofluorescence findings. Eosinophilic spongiosis may be an early histological sign of either pemphigus or bullous pemphigoid. Immunofluorescence studies are needed to clarify the diagnosis [27].

Treatment

ACCEPTED MANUSCRIPT Treatment of P Veg is similar to that for PV, being systemic glucocorticoids the first choice therapy. Prednisone at 1.0 mg/kg/day is the preferred initial dosage. If there is no response in 10-15 days,

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other options can be employed. Addition of immunosuppressive agents or etretinate may improve

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remission rates and allow a steroid-sparing effect. The most common associations of systemic steroid therapy are with azathioprine, dapsone, cyclophosphamide, mycophenolate mofetil, or

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cyclosporine [3]. In the presence of persistent, stubborn verrucous vegetations, alternative therapeutic regimens, such as a combination of nicotinamide with tetracycline and etretinate, or

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corticosteroids with etretinate, are to be considered [28]. Topical triamcinolone acetonide proves to be useful in P Veg. Sublesional intradermal injections (3-10 mg/mL) are given every week or every two weeks [29]. A plain (often overlooked) therapeutical measure is applying gauzes soaked in soluble steroids and antiseptics between the skin surfaces of the involved flexures. This application,

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renewed twice a day, reduces the granulation tissue formation in the intertriginous areas.

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For resistant P Veg, extracorporeal photopheresis, and lesion treatment with pure silver nitrate in the form of pencil (caustic effect), carbon dioxide laser or even surgical excision have been

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proposed [30-33]. TNFα blockers have been used in therapy-refractory patients [31]. As a rule, one

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should consider that, whatever the treatment, the Hallopeau type is relatively benign, requiring lower doses of systemic corticosteroids and having a prolonged remission; on the opposite, patients with the Neumann type may have a severe course of the disease, similar to that of PV, requiring higher doses of corticosteroids, with frequent relapses after remissions [34].

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ACCEPTED MANUSCRIPT 3. Ruocco E, Wolf R, Ruocco V, et al. Pemphigus: associations and management guide-lines. Facts and controversies. Clin Dermatol 2013; 31: 382-390.

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4. Joly P, Litrowski N. Pemphigus group (vulgaris, vegetans, foliaceus, herpetiformis,

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8. Hashimoto K, Hashimoto T, Higashiyama M, et al. Detection of anti-desmocollins I and II

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autoantibodies in two cases of Hallopeau type pemphigus vegetans by immunoblot analysis. J Dermatol Sci 1994; 7: 100-106.

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9. Parodi A, Stanley JR, Ciaccio M, et al. Epidermal antigens in pemphigus vegetans. Report

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of a case. Br J Dermatol 1988; 119: 799-802. 10. Lo Schiavo A, Ruocco E, Brancaccio G, et al. Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies. Clin Dermatol 2013; 31: 391-399. 11. Ruocco E, Wolf R, Caccavale S, et al. Bullous pemphigoid: associations and management guidelines: facts and controversies. Clin Dermatol 2013; 31: 400-412. 12. Harman KE, Albert S, Black MM. Pemphigus vegetans. In: Katsambas A D, Lotti T M (Eds): European Handbook of Dermatological Treatments (2nd edition). Berlin: SpringerVerlag, 2003: 388-389. 13. Ahmed AR. Clinical features of pemphigus. Clin Dermatol 1983; 1: 13-21. 14. Scott DW. Pemphigus in domestic animals. Clin Dermatol 1983; 1: 141-152.

ACCEPTED MANUSCRIPT 15. Heimann M, Beco L, Petein M, et al. Canine hyperplastic intraepidermal pustular and suprabasal acantholytic dermatoses with features of human pemphigus vegetans. Vet Pathol

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2007; 44: 550-555.

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16. Ruocco E, Baroni A, Donnarumma G, et al. Diagnostic procedures in dermatology. Clin Dermatol 2011; 29: 548-556.

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18. Morizane S, Yamamoto T, Hisamatsu Y, et al. Pemphigus vegetans with IgG and IgA antidesmoglein 3 antibodies. Br J Dermatol 2005; 153:1236–1237. 19. Helander SD, Rogers RS. The sensitivity and specificity of direct immunofluorescence testing in disorders of mucous membranes. J Am Acad Dermatol 1994; 30: 65-75.

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20. Mesquita Kde C, Igreja AC. Pyodermatitis-pyostomatitis vegetans: a differential diagnosis

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of pemphigus vegetans. An Bras Dermatol 2012; 87: 339. 21. Weston WL, Friednash M, Hashimoto T, et al. A novel childhood pemphigus vegetans

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variant of intraepidermal neutrophilic IgA dermatosis. J Am Acad Dermatol 1998; 38: 635-

22. Sapadin AN, Anhalt GJ. Paraneoplastic pemphigus with a pemphigus vegetans-like plaque as the only cutaneous manifestation. J Am Acad Dermatol 1998; 39: 867-871. 23. Venning V, Burge S, Dalziel K, et al. Pemphigus vegetans masquerading as multiple squamous cell carcinoma. Br J Dermatol 1990; 123: 112-113. 24. Bruckner N, Katz RA, Hood AF. Pemphigus foliaceus resembling eruptive seborrheic keratoses. Arch Dermatol 1980; 116: 815-816. 25. Kahana M, Trau H, Schewach-Millet M, et al. Pemphigus foliaceus presenting as multiple giant seborrheic keratoses. J Am Acad Dermatol 1984;11: 299-300. 26. Jacyk WK, Simson IW. Pemphigus erythematosus resembling multiple seborrheic keratoses. Arch Dermatol 1990; 126: 543-544.

ACCEPTED MANUSCRIPT 27. Crotty C, Pittelkow M, Muller SA. Eosinophilic spongiosis: a clinicopathologic review of seventy-one cases. J Am Acad Dermatol 1983; 8: 337-343.

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28. Ichimiya M, Yamamoto K, Muto M. Successful treatment of pemphigus vegetans by

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addition of etretinate to systemic steroids. Clin Exp Dermatol 1998; 23: 178-180. 29. Mignogna MD, Fortuna G, Leuci S, et al. Adjuvant triamcinolone acetonide injections in

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oro-pharyngeal pemphigus vulgaris. J Eur Acad Dermatol Venereol 2010; 24: 1157-1165. 30. Kaiser J, Kaatz M, Elsner P, et al. Complete remission of drug resistant pemphigus vegetans

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treated by extracorporeal photophoresis. J Eur Acad Dermatol Venerol 2007; 21: 843–844. 31. Lin MH, Hsu CK, Lee JY. Successful treatment of recalcitrant pemphigus vulgaris and pemphigus vegetans with etanercept and carbon dioxide laser. Arch Dermatol 2005; 141: 682.

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32. Motomura H, Tsuruta D, Yamanaka K, et al. The use of test skin grafting in pemphigus

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vegetans. J Plast Reconstr Aesthet Surg 2009; 62: 506–508. 33. Ruocco V, Guerrera V, Lo Schiavo A, et al. Il trattamento del pemfigo oggi. G Ital

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Dermatol Venereol 1997; 132: 259-269.

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34. Ahmed AR, Blose DA. Pemphigus vegetans. Neumann type and Hallopeau type. Int J Dermatol 1984; 23: 135-141. Legends for figures

Figure 1. Mammillated plaques formed by merging and fusing of vegetating fleshy lesions. From Ruocco and Ruocco [1] with Editor’s permission.

Figure 2. Indistinct, irregular suprabasal splitting (arrow) in the lower epidermis.

Figure 3. Hyperplastic epidermis with microabscessual cavities.

ACCEPTED MANUSCRIPT Figure 4. Microabscess containing neutrophils and eosinophils interspersed with apoptotic

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and necrotic keratinocytes.

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Figure 5. Spongiosis. Left: Cell-cell detachment with no or slight acantholytic changes of involved keratinocytes (desmolysis). Right: Cell-cell detachment with overt

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acantholytic changes of involved keratinocytes (acantholysis).

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