**1. Introduction**

Autoimmune blistering dermatoses (ABD) are a group of relatively rare autoantibody-driven diseases affecting primarily skin and/or multiple mucosa. They comprise of two main subdi‐ visions: ABD with autoimmunity to enzymes (dermatitis herpetiformis only) and ABD with autoimmunity to mostly structural proteins (anti-desmosomal autoimmunity circle, antidermal-epidermal junction autoimmunity circle and others). As both coexistent development of organ specific autoimmunity (e.g. myasthenia gravis) and transition between ABD groups are possible, ABD seem to be a part of pathological multiorgan autoimmunization syndrome [1]. The replacement of physiological autoimmunity by pathological autoimmunity and triggering blister formation in ABD still remain unexplored and essential issues. It is suggested that malignancy may be a triggering factor inducing the development of pathological auto‐ immunity. On the other hand, the development of malignancies during chronic immunosup‐ pressive therapy may be observed [2].

In this chapter, we discuss an important and interesting area of research, focused on identifying the relationships, on both clinical and molecular level, between ABD and malignancy. Collectively, the literature data and our own experience indicate that ABD may be associated with different malignant tumors, both cutaneous and affecting internal organs. However, the issue if it is a mere coincidence or true pathogenetic relationship remains to be resolved. It is known that in a state of perpetual activation of immune system, as in ABD, proinflammatory molecules (e.g. cytokines) may cause tissue damage leading to chronic inflammation and subsequently increase the risk of carcinogenesis [3]. At both

clinical and molecular level ABD and malignancy-associated ABD (MAABD) may seem similar; nevertheless, the pathogenesis of those entities plausibly is fundamentally distinct. However, broadly observed associations between ABD and cancer indicate that various molecular pathways may contribute to elevated risk of malignancy in these patients. Most importantly, the coexistence of malignancy with ABD changes the management of such patients compared to patients with ABD alone. For a long months and years, many cases of ABD and MAABD are undiagnosed, misdiagnosed and subsequently mistreated due to relative rarity and therefore low awareness of autoimmunity-driven blistering dermatoses among practitioners. The time period elapsed between the first symptoms and diagnosis, makes the time-onset relation between ABD and cancer usually uncertain.

and forming subepidermal vesicle [1,4,5] Histopathologically, microabscesses in dermal papillae with neutrophile infiltration are seen in bioptate, obtained preferably of perilesion‐

Malignancy in Relation to Autoimmune Blistering Dermatoses: Molecular and Clinical Aspects

http://dx.doi.org/10.5772/55240

161

This large group consists of several distinct circles of diseases with autoimmunity to different

Anti-desmosomal autoimmunity circle or pemphigus group refers to a group of chronic ABD characterized by the presence of autoantibodies (IgG or/and IgA) binding desmosomal structures and keratinocyte cell-surface antigens, leading to acantholysis and intraepithelial blister formation. The main antigens for pemphigus circle are desmoglein 1 (DSG1) and desmoglein 3 (DSG3), yet there are forms of pemphigus without anti-desmoglein immuniza‐ tion [7]. The commonest subcircle is characterized by IgG-mediated autoimmunity and is

**•** pemphigus foliaceus (PF) circle (PF, endemic PF, sebaceous PF, and PF herpetiformis, paraneoplastic pemphigus, drug-mediated PF showing PF-indicative autoantibody profile),

**•** pemphigus vulgaris (PV) circle (mucosal-dominant PV, mucocutaneous PV, pemphigus vegetans, and paraneoplastic pemphigus, PV herpetiformis, drug-mediated PV showing

**•** paraneoplastic pemphigus (PNP) with neither anti-DSG3 nor anti-DSG1 antibodies [1].

A model disease for pemphigus circle and the commonest clinical type of pemphigus is PV. This life-threatening chronic/acute ABD affects the mucocutaneous surfaces significant‐ ly debilitating quality of life [5]. The onset age is 40-60 years, and incidence ca. 0.7 per 100,000 persons [5,8]. Blistering in PV appears at suprabasal level as an effect of tissuebound and serum IgG-driven autoimmunity against keratinocyte cell-surface antigens of aforelisted cadherin superfamily [9], with desmoglein 3 (DSG3) as the main autoantigen. The disease starts initially affecting oral mucosa (50-70%), that may remain the only site involved, yet extraoral lesions may occur simultaneously. Intraepithelial blisters evolve into aching erosions and ulcers. Predilection sites include face, parietal region of the scalp, sternal and interscapular regions of the trunk, intertriginous sites (umbilicus, interdigital spaces, scrotum, inguinal and axillary folds), scars and skin appendages – nail apparatus, hair follicles [1] and areas with transitional epithelium, what could be explained by the

al skin of the affected buttocks [5,6].

PV-indicative autoantibody profile),

change of desmoglein expression pattern.

**•** PV/PF-coexistence cases,

composed of:

**2.2. ABD with autoimmunity to structural proteins**

antigens – desmosomal, hemidesmosomal and others.

*2.2.1. Anti-desmosomal autoimmunity circle / pemphigus group*

**•** pemphigus as a part of multiorgan autoimmunity syndrome,

**•** pemphigus shifting inside one circle or between circles,

Molecular abnormalities of desmosomal proteins are observed in ABD and epithelial malignancies. A key function of desmosomal proteins is the maintenance of adhesion. However, in malignancy, where cells may separate, detach and metastasize, it is possible that alterations in their expression may be the reason of carcinogenesis process. Interesting‐ ly, the altered desmosomal protein expression and subsequent changes in cell-cell cohe‐ sion are often associated with signal pathways (e.g. epidermal growth factor – EGF in squamous cell carcinoma).
