**2. Autoimmune blistering dermatoses**

ABD form a group of autoimmunity-driven diseases, where bullous lesions arise on the skin and/or multiple mucosa. Diverse ABD are evoked by different triggering mechanism and are characterized by different clinical onset, course and prognosis. Two main subdivisions can be separated: ABD with autoimmunity to enzymes and ABD with autoimmunity to structural proteins. The entities may be commonly distinguished by clinical, histopathological (presence or absence of acantholysis and differences of its localization, level of blistering and the composition of inflammatory infiltrate), immunohistochemical (localization and patterns of deposits and autoantibody immunoglobulin class) and molecular examination (ELISA, immunoblotting).

#### **2.1. ABD with autoimmunity to enzymes**

The entity is represented only by dermatitis herpetiformis (DH), also known as Duh‐ ring's disease - chronic, intensely itchy, blistering skin manifestation of the gluten sensi‐ tive enteropathy [4]. It affects symmetrically extensor surfaces of limps and the trunk – mainly buttocks and sacral area, where tiny vesicles, papules or even urticarial plaques occur in groups. The onset age is 20-60 years with peak about 35, and incidence ranging from 10 to 39 per 100,000 persons, depending on world region [1,5]. Patients have IgA autoantibodies to transglutaminases (TGs), that are considered major autoantigens in DH, yet other antigens were also reported (antiendomysial, antireticulin, antithyroid and antinuclear antibodies) [5]. It is thought that granular/fibrillar IgA deposits in tips of dermal papillae provoke neutrophile-mediated destruction of the dermal-epidermal junction (DEJ) and forming subepidermal vesicle [1,4,5] Histopathologically, microabscesses in dermal papillae with neutrophile infiltration are seen in bioptate, obtained preferably of perilesion‐ al skin of the affected buttocks [5,6].

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

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,

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

ABD form a group of autoimmunity-driven diseases, where bullous lesions arise on the skin and/or multiple mucosa. Diverse ABD are evoked by different triggering mechanism and are characterized by different clinical onset, course and prognosis. Two main subdivisions can be separated: ABD with autoimmunity to enzymes and ABD with autoimmunity to structural proteins. The entities may be commonly distinguished by clinical, histopathological (presence or absence of acantholysis and differences of its localization, level of blistering and the composition of inflammatory infiltrate), immunohistochemical (localization and patterns of deposits and autoantibody immunoglobulin class) and molecular examination (ELISA,

The entity is represented only by dermatitis herpetiformis (DH), also known as Duh‐ ring's disease - chronic, intensely itchy, blistering skin manifestation of the gluten sensi‐ tive enteropathy [4]. It affects symmetrically extensor surfaces of limps and the trunk – mainly buttocks and sacral area, where tiny vesicles, papules or even urticarial plaques occur in groups. The onset age is 20-60 years with peak about 35, and incidence ranging from 10 to 39 per 100,000 persons, depending on world region [1,5]. Patients have IgA autoantibodies to transglutaminases (TGs), that are considered major autoantigens in DH, yet other antigens were also reported (antiendomysial, antireticulin, antithyroid and antinuclear antibodies) [5]. It is thought that granular/fibrillar IgA deposits in tips of dermal papillae provoke neutrophile-mediated destruction of the dermal-epidermal junction (DEJ)

makes the time-onset relation between ABD and cancer usually uncertain.

squamous cell carcinoma).

160 Highlights in Skin Cancer

immunoblotting).

**2. Autoimmune blistering dermatoses**

**2.1. ABD with autoimmunity to enzymes**

This large group consists of several distinct circles of diseases with autoimmunity to different antigens – desmosomal, hemidesmosomal and others.

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

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 composed of:


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 change of desmoglein expression pattern.

Histologically, suprabasilar blistering may be observed, whereas direct immunofluorescence study (DIF) of perilesional skin/mucosa depicts IgG (mainly IgG4) pemphigus-type deposits of fishing net pattern in intercellular spaces of the lower epidermis [1]. With virtually no invasiveness, direct immunofluorescence study on a plucked scalp hair (hDIF) may serve as a good alternative for DIF, visualizing pemphigus IgG, IgG1 and IgG4 deposits in outer root sheath of hair follicle even in patients without cutaneous lesions [10]. Still used, indirect immunofluorescence (IIF) test for presence of pemphigus IgG circulating autoantibodies is regarded historical method and is widely replaced with molecular studies e.g. ELISA, enabling assessment in serum, saliva or blister fluid [11].

BP circle, the commonest ABD, is characterized by heterogeneous clinical patterns. However, it has common molecular feature – autoimmunity to extracellular, non-collagenous NC16A domain of BP180 antigen (BPAG2, collagen XVII alpha1) [1,5,13] and less often BP230 (BPAG2e, protein belonging to plakin family) [1,5]. It begins as a moderate pruritus, papular lesions or urticarial plaques developing in months into chronic bullous eruption characterized by well-tense blisters containing either serous or sanguineus fluid. The localized/generalized lesions may be oval or round, and rupture easily over time [5]. The arciform or serpiginous pattern they present is sometimes described as string of beans or cluster of jewels. Diverse symptoms are consequence of targeting different epitopes of these components of hemides‐ mosome adhesion complex. It affects often elderly people in their 60's-90's [1,5] with incidence

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There are also other autoimmune blistering diseases e.g. ABD with autoimmunization to IQGAP1 protein, erythema multiforme with anti-desmoplakin 1 and anti-desmoplakin 2 antibodies, linear IgM gestationis dermatosis, linear IgM dermatosis with IgM gammapathy and others that cannot be fitted into above categories, yet these are isolated cases with

The issue of association of malignancy and ABD causes much controversy among research‐ ers. WHO reports from 2008 indicated, that the 13% of death worldwide is caused by cancer, being the major cause of death with toll of 7.6 million people per year [14]. Neoplasms are heterogeneous group of entities characterized by rapid creation of abnor‐ mal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs [14]. The leading malignancies worldwide are lung, breast, colon, stomach and prostate cancers [15]. Several malignant tumors were reported in association with ADB, including lymphoproliferative disorders (Castleman's tumor, non-Hodgkin's lymphoma, chronic lymphocytic leukemia), lung, gastrointestinal, prostate, ovarian, endometrial, breast, bladder, renal, laryngeal, pancreatic cancers,

As ABD are relatively rare/regarded as rare conditions, there is limited data covering the association with other diseases. Japanese retrospective study on malignancy in patients suffering from pemphigus and pemphigoid observed incidence of 5.0% and 5.8% respectively [17], whereas lesser studies set these numbers as 11.2% and 10.4% [16]. The association ratio of malignancy with pemphigus increases by age, while no such correlation is found in pemphigoid. No gender-predisposition in ABD was reported in these patients [16]. Interest‐ ingly, lung cancer was most common in pemphigus and gastrointestinal tumors (gastric cancer in particular) in bullous pemphigoid [17]. Moreover, age-dependent malignancy-association in PV patients under (6.5%) and above 60 years (15%) should not be omitted [16]. Studies on

of ca. 4.3 per 100,000 persons [8].

unknown relation to malignancy.

**2.3. Malignancies associated with ABD**

*2.2.3. Other, vaguely characterized, autoimmune blistering diseases*

thymoma and follicular dendritic cell sarcoma [16–22].

BP and malignancy did not reveal age-correspondence [23].

PF, the less common pemphigus circle condition, usually affects the skin of the face, scalp and trunk, but may generalize. The disease is characterized by autoantibodies binding DSG1, that participate in blister formation at superficial level (granular layer). Although blister is a primary PF lesion, it is hardly ever seen, as it rapidly evolves into crust-covered erosions [1,5]. Interestingly, as main PV DSG3-antigen (130kDa) and PF DSG1-antigen (160kDa) differ, that corresponds with different blistering subtype and clinical features [5].

Concerning association with malignancy, PNP resembles clinically and histologically features of PV and erythema multiforme [5]. However, it differs in autoantibody profile. PNP autoan‐ tibodies may target simultaneously multiple antigens – desmoplakin I and II, BP230, peripla‐ kin, envoplakin, plectin, 170kDa protein, desmoglein 1 and 3, desmocolin familly, and many yet unknown proteins. PNP-type intercellular deposits can be visualized in IIF on transitional epithelium of rat bladder. Circulating autoantibodies affects not only mucocutaneus epitheli‐ um, but may bind organ-specific antigens of gastrointestinal tract or bronchioli – e.g. causing non-reversible and life-threatening constrictive bronchiolitis. Although rare, PNP is charac‐ terized with very high mortality [12].

#### *2.2.2. Subepidermal autoimmune blistering dermatoses*

Subepidermal ABD circle consists of chronic bullous diseases with autoantibodies binding mostly structural proteins forming DEJ:


BP circle, the commonest ABD, is characterized by heterogeneous clinical patterns. However, it has common molecular feature – autoimmunity to extracellular, non-collagenous NC16A domain of BP180 antigen (BPAG2, collagen XVII alpha1) [1,5,13] and less often BP230 (BPAG2e, protein belonging to plakin family) [1,5]. It begins as a moderate pruritus, papular lesions or urticarial plaques developing in months into chronic bullous eruption characterized by well-tense blisters containing either serous or sanguineus fluid. The localized/generalized lesions may be oval or round, and rupture easily over time [5]. The arciform or serpiginous pattern they present is sometimes described as string of beans or cluster of jewels. Diverse symptoms are consequence of targeting different epitopes of these components of hemides‐ mosome adhesion complex. It affects often elderly people in their 60's-90's [1,5] with incidence of ca. 4.3 per 100,000 persons [8].

#### *2.2.3. Other, vaguely characterized, autoimmune blistering diseases*

There are also other autoimmune blistering diseases e.g. ABD with autoimmunization to IQGAP1 protein, erythema multiforme with anti-desmoplakin 1 and anti-desmoplakin 2 antibodies, linear IgM gestationis dermatosis, linear IgM dermatosis with IgM gammapathy and others that cannot be fitted into above categories, yet these are isolated cases with unknown relation to malignancy.

#### **2.3. Malignancies associated with ABD**

Histologically, suprabasilar blistering may be observed, whereas direct immunofluorescence study (DIF) of perilesional skin/mucosa depicts IgG (mainly IgG4) pemphigus-type deposits of fishing net pattern in intercellular spaces of the lower epidermis [1]. With virtually no invasiveness, direct immunofluorescence study on a plucked scalp hair (hDIF) may serve as a good alternative for DIF, visualizing pemphigus IgG, IgG1 and IgG4 deposits in outer root sheath of hair follicle even in patients without cutaneous lesions [10]. Still used, indirect immunofluorescence (IIF) test for presence of pemphigus IgG circulating autoantibodies is regarded historical method and is widely replaced with molecular studies e.g. ELISA, enabling

PF, the less common pemphigus circle condition, usually affects the skin of the face, scalp and trunk, but may generalize. The disease is characterized by autoantibodies binding DSG1, that participate in blister formation at superficial level (granular layer). Although blister is a primary PF lesion, it is hardly ever seen, as it rapidly evolves into crust-covered erosions [1,5]. Interestingly, as main PV DSG3-antigen (130kDa) and PF DSG1-antigen (160kDa) differ, that

Concerning association with malignancy, PNP resembles clinically and histologically features of PV and erythema multiforme [5]. However, it differs in autoantibody profile. PNP autoan‐ tibodies may target simultaneously multiple antigens – desmoplakin I and II, BP230, peripla‐ kin, envoplakin, plectin, 170kDa protein, desmoglein 1 and 3, desmocolin familly, and many yet unknown proteins. PNP-type intercellular deposits can be visualized in IIF on transitional epithelium of rat bladder. Circulating autoantibodies affects not only mucocutaneus epitheli‐ um, but may bind organ-specific antigens of gastrointestinal tract or bronchioli – e.g. causing non-reversible and life-threatening constrictive bronchiolitis. Although rare, PNP is charac‐

Subepidermal ABD circle consists of chronic bullous diseases with autoantibodies binding

**•** Bullous pemphigoid (BP) circle (urticarial BP, BP herpetiformis, sebaceous BP, erythroder‐ mic BP, BP vegetans, pretibial BP, prurigo-nodularis-like BP, trauma-induced BP, pemphi‐ goid gestationis (PG), lichen planus pemphigoides (LPP), lamina lucida-type linear IgA

**•** Epidermolysis bulosa acquisita (EBA) circle (EBA, bullous systemic lupus erythematosus,

**•** Linear IgA bullous dermatosis (LABD) (non-EBA circle LABD, non-BP circle LABD),

corresponds with different blistering subtype and clinical features [5].

assessment in serum, saliva or blister fluid [11].

162 Highlights in Skin Cancer

terized with very high mortality [12].

mostly structural proteins forming DEJ:

bullous dermatosis),

**•** Pemphigoid Brunsting-Perry,

*2.2.2. Subepidermal autoimmune blistering dermatoses*

**•** Mucous membrane pemphigoid (MMP)/cicatrical pemphigoid,

**•** anti-laminin gamma1 pemphigoid (former anti-p200 pemphigoid) [1].

sublamina densa-type linear IgA bullous dermatosis),

The issue of association of malignancy and ABD causes much controversy among research‐ ers. WHO reports from 2008 indicated, that the 13% of death worldwide is caused by cancer, being the major cause of death with toll of 7.6 million people per year [14]. Neoplasms are heterogeneous group of entities characterized by rapid creation of abnor‐ mal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs [14]. The leading malignancies worldwide are lung, breast, colon, stomach and prostate cancers [15]. Several malignant tumors were reported in association with ADB, including lymphoproliferative disorders (Castleman's tumor, non-Hodgkin's lymphoma, chronic lymphocytic leukemia), lung, gastrointestinal, prostate, ovarian, endometrial, breast, bladder, renal, laryngeal, pancreatic cancers, thymoma and follicular dendritic cell sarcoma [16–22].

As ABD are relatively rare/regarded as rare conditions, there is limited data covering the association with other diseases. Japanese retrospective study on malignancy in patients suffering from pemphigus and pemphigoid observed incidence of 5.0% and 5.8% respectively [17], whereas lesser studies set these numbers as 11.2% and 10.4% [16]. The association ratio of malignancy with pemphigus increases by age, while no such correlation is found in pemphigoid. No gender-predisposition in ABD was reported in these patients [16]. Interest‐ ingly, lung cancer was most common in pemphigus and gastrointestinal tumors (gastric cancer in particular) in bullous pemphigoid [17]. Moreover, age-dependent malignancy-association in PV patients under (6.5%) and above 60 years (15%) should not be omitted [16]. Studies on BP and malignancy did not reveal age-correspondence [23].

As far as anti-enzyme ABD is concerned, association of DH with subsequent development of lymphoma seems well-documented [18,24,25]. It is possible that gluten intolerance is the factor associated with malignancies. Some data suggested, that following a strict gluten-free diet is protective against malignancy [26]. Moreover, researchers postulate that the risk of malignancy decreases with time from diagnosis of gluten-sensitive enteropathy to nearly the same as occurs in the general population. In light of above, it is postulated that the increased risk of malignancy in patients with DH may be the result of a polyclonal stimulation of lymphocytes by gluten that causes transformation into a malignant clone [18]. Still, in our over 20 years of clinical/laboratory experience as a clinician/clinical researchers we do not recall a DHassociated lymphoma patient.

selection, being the following stage, is conducted in thymus medulla, where T-cells are exposed to plethora of tissue specific self-antigens (TSAs) by medullary thymic epithelial cells. Selfantigens presented to T-cells are previously processed, thus some T-cells expressing TCR with high affinity to poorly presented antigens may evade negative selection achieving maturation [88]. The process is controlled by autoimmune regulator (AIRE) transcription factor [89]. Autoaggressive thymocytes are being terminated in apoptosis. Impairment of any of these stages – positive selection, negative selection, antigen processing, antigen presentation by malignancy, might have impact on T-cell set and scope of activity in periphery. Thymoma is the most common neoplasm of thymus, outrunning lymphomas, germ cell tumor, thymic carcinoma, carcinoid tumors and others [90]. One of the syndromes in relation to thymoma is paraneoplastic pemphigus, where diverse autoantibodies target diverse structural autoanti‐ gens. While pemphigus vulgaris (PV) and paraneoplastic (PNP) pemphigus may both target the same antigen, the difference is within the range of them and difference in epitopes bound (e.g. mucocutaneus PV preferably targets DSG3 N-terminal determinant, while PNP binds multiple epitopes). Another distinctive feature is IgG subclass – predominant PV IgG autoan‐

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Some authors hypothesized that tumor cells alone may produce the autoantibodies [91,92]. The thesis of in-tumor immature T-cell improper maturation, without negative selection, leading to autoaggression may be supported by findings in patient with follicular dendritic cell sarcoma [93]. Malignancy is based on breakage of cell cycle guarding and dysregulation of gene expression resulting in over- or underexpression of proteins. Via gene mutation, the neoplastic cell changes the antigen suit, by exposing altered self-antigens or "hiding" those already known. The reaction of immune system to cancer growth is immune cells recruitment (T-cells, NK cells, mast cells) and inflammation by various mediators causing apoptosis of both neoplastic and non-neoplastic cells. One T-cell can recognize many antigens presented by different MHC molecules. The condition of recognition is the compatibility of antigen fragment with lymphocyte TCR. Along with antigen sequestration theory, the determinants of cell proteins released in tumor necrosis can be exposed by antigen presenting cells to matured Tcells that migrate to lymph nodes. B-cells in response start to produce polyclonal antibodies against novel tumor epitopes. However, T-cells may also react with cancer antigens starting the chain of events leading to production of certain antibody cross-binding both neoplastic

The role of immune system protection against malignancy can be exemplified by noticeable higher cancer incidence in patients given immunosuppressive drugs impairing self/foreignantigens recognition. Hence hypothetically, the distortion in immune system function in ABD may contribute to further susceptibility to the development of malignancy. Naive T-cell activation in the periphery alone is thought to be insufficient for autoimmunity induction and co-stimulation by CD28, a co-stimulatory molecule activating T-cells, seem to be necessary [94]. CD28 is able to bind CD80 molecule and CD86 molecule, constitutionally expressed on B-cells, subsequently enhancing IgG antibody production [95]. CD80 molecule appear also scantly on other antigen-presenting cells (APC – primarily B-cells, macrophages and dendritic cells) and is upregulated after APC activation. Active APC present CD40, a ligand for CD40L expressed

tibody subclass is IgG4, while in PNP – subclass is IgG1 and IgG2 [1].

antigens and self-antigens [90].

There is a wide group of malignancies concomitant with ADB. Lung cancer has been reported in coexistence with wide range of ABD: PV [17,27,28], PNP [29], pemphigus vegetans [30,31], pemphigus herpetiformis [32], IgA pemphigus [33], BP [34] and MMP [35]. In some BP cases, tumor resection led to complete recovery [36] supporting the thesis of close interrelation of the diseases. Gastrointestinal tumors have been reported in association with BP [17,37], PNP [38], pemphigus vegetans [39], PV [40–45] and MMP [46] sometimes with post-excisional remission [47,48]. Both chronic leukemia and lymphoma have been reported with DH [49–51] and PNP [52–54]. Based on few case reports, MMP [55–57] is not rare finding in leukemia. There has been only one case of BP reported in patient with leukemia [58]. Thymoma and PV appears in numerable patients [43] with post-excisional remissions not uncommon [59]. Among reported thymoma-related ABD, there are also cases of PF [60,61], BP [62] and MMP [63]. Malignant tumor of the pancreas seem to be generally connected to MMP [64,65] and sometimes PNP [66]. Renal neoplasm has been reported to occur in with BP [67–70] and occasionally with MMP [71], PNP [72] and PF [73]. Ovarian cancer was incidentally described in relation with BP [74], antilaminin gamma1 pemphigoid [75] and MMP [76]. Concerning prostatic cancer, single cases of PNP [77], pemphigus herpetiformis [78], PF [79] and MMP [80] were described in literature. There are numerous case reports on ABD and breast cancer including predominantly BP [20,81–85] and PV [86,87] with well-documented BP-lesion induction with radiotherapy.
