Pemphigus vulgaris is a rare autoimmune intraepithelial blistering disease produced by circulating autoantibodies against keratinocyte desmogleins (Dsg) resulting in the loss of keratinocyte adhesion, through a process called acantholysis [3]. Autoantibodies against desmoglein 3 (Dsg3), prominent in the lower epidermis, are the main pathogenesis of PV. Keratinocyte detachment in the lower epidermis and tight attachment of basal keratinocytes to the basement membrane by hemidesmosomes give the appearance of suprabasal blisters (bullae) commonly seen in PV. Other autoantibodies include anti-desmocollin [4] and anti-desmoglein 1 (present in the upper epidermis). It should be underlined that the presence of anti-desmoglein 1 in serum leads to acantholysis of superficial keratinocytes similar to pemphigus foliaceus (PF) .

The earliest change in PV is epidermal edema (spongiosis) and exocytosis of eosinophils into spongiotic epidermis (eosinophilic exocytosis) (Fig. 9.1a). Acantholysis in the lower epidermis leads to the formation of slit-like suprabasal cleft or lacuna containing some acantholytic cells. Attachment of basal keratinocytes to the basement membrane and subsequent suprabasal acantholysis gives the characteristic appearance of a “tombstone” layer, in which a layer of basal keratinocytes is preserved (Fig. 9.1b). The suprabasal bulla may extend up to form an intraepidermal bulla or blister, which is interpreted as the regeneration of basal keratinocytes as the disease progresses. Epidermal necrosis, intraepidermal bulla, and extension of acantholysis into the adnexal structures may be seen in the progression of the disease (Fig. 9.1c) [3–5].

Dermal changes are non-specific, and the papillary dermis usually protrudes to the blister cavity, which is more prominent in the mucosal areas (Fig. 9.1d). Dermal inflammation is mild and consists of mixed inflammatory cell infiltrate including lymphocytes, neutrophils, and eosinophils around superficial vessels [6].

Immunohistochemistry staining by anti-desmoglein (anti-Dsg) monoclonal antibody 32-2B, which detects desmogleins 1 and 3, distinguishes drug-induced pemphigus from idiopathic pemphigus. A patchy pattern of staining was observed in idiopathic pemphigus, whereas drug-induced pemphigus shows normal pattern in 70% of cases and a patchy pattern in 30% of the cases. Normal pattern of staining is an indicator of a good prognosis in drug-induced pemphigus [7].

Immunolabeling with C3d and C4d in paraffin blocks was positive in 82% of pemphigus vulgaris cases, which roughly mirrors the intercellular pattern for IgG and complement seen by direct immunofluorescence [8].

The direct immunofluorescence (DIF) test could be replaced by immunohistochemistry staining of IgG4 and C3d on paraffin blocks in situations in which the DIF test is not available [9].

Detection of IgG antibodies by direct immunofluorescence is the gold standard test for the diagnosis of pemphigus vulgaris. In pemphigus vulgaris, IgG usually deposits in intercellular spaces of keratinocytes leading to a network or chicken wire feature of the epidermis (Fig. 9.2). C3, IgM, and IgA are less common antibodies that react in the epidermis [10, 11]. Negative DIF is a predictor of immunologic remission in pemphigus vulgaris. Plucked hair may be used as a substrate for the DIF test in the remission period, and it had 79% sensitivity, 48% specificity, 61% positive predictive value, and 68% negative predictive value [12]. Patients in clinical remission who had positive DIF are more prone to relapse than those with negative DIF [13–15].

Circulating antibodies bind to epidermal keratinocytes present in 80–90% of pemphigus vulgaris patients and are detected by the indirect immunofluorescence (IIF) test. In pemphigus vulgaris, monkey esophagus is a better substrate for the IIF test (react with anti-Dsg3 antibodies), whereas in pemphigus foliaceus , guinea pig esophagus or human skin is a better substrate (react with anti-Dsg1 antibodies) [16–19]. These antibodies have been reported in many inflammatory dermatoses, including burns [20].