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Science, Technology and Medicine open access publisher.Publish, read and share novel research. Malignancy in Relation to Autoimmune Blistering Dermatoses: Molecular and Clinical AspectsPawel Pietkiewicz1, Justyna Gornowicz-Porowska1, Monika Bowszyc-Dmochowska1 and Marian Dmochowski1[1] Cutaneous Histopathology and Immunopathology Section, Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland1.
Introduction: Human papillomavirus (HPV) is the aetiological factor of condyloma acuminatum which are the most common benign genital tumors in both sex. INTRODUCTION AND OBJECTIVEHuman papilomavirus (HPV) belongs to the papillomavirus gender which belongs to the Papovaviridade family (1), made by circular, double-helix, non-enveloped DNA, with around 7200 to 8000 base pairs. Cervical cancer is the second most common cancer causing death in women with an annual incidence of around half a million and a mortality of almost 50%. The most important risk factor for the development of cervical cancer is genital infection with human papillomavirus (HPV). The high-risk types HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59 and -68, induce cervical squamous intraepithelial lesions (SIL), which in turn are classified in low (LSIL) and high grade (HSIL) in severity, and which may progress to cervical cancer.
Several studies have shown that a persistent HPV infection with the same high-risk type is a risk factor for the development and progression of lesions. F-HPV typing™ uses 15 primers amplifying within E6 and E7 regions of the HPV genome, the most likely to be retained after viral integration. Frequence of Appearance of Human Papillomavirus (HPV) in Oral Mucosa of Men with Anogenital HPV by a Molecular Technique. Currently, there is no doubt about the sexual transmission of this virus and it is recognized as the most frequent sexual transmitted disease nowadays. It can lead to several benign, pre-malign and malign diseases in mucosas and skin surfaces. In fact these 13 high-risk HPV types have been shown to be present in up to 99.7% of cervical cancer samples, the most frequently detected being HPV-16, followed by HPV-18, -31, -51, and -45.
If no high-risk specific HPV is present in a cervical sample, the patient has a very low risk to develop cancer for some years. Extracted DNA is amplified using a multiplex PCR with a set of 16 fluorescently labelled primers recognising HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 and a human STR used as internal control.
Painful well-tensed blisters, crusts and erosions on erythematous skin of the axillary area. Blisters and their evolutionary lesions on urticarial skin on the flexural surface of a forearm. They comprise of two main subdivisions: ABD with autoimmunity to enzymes (dermatitis herpetiformis only) and ABD with autoimmunity to mostly structural proteins (anti-desmosomal autoimmunity circle, anti-dermal-epidermal junction autoimmunity circle and others). At the oral cavity, HPV can lead to benign lesions such as squamous cell papilloma, focal epithelial hyperplasia, condyloma acuminatum and verruca vulgaris. The HPV are evaluated according to their nucleic acids, that is, their genotype, in different kinds (2). HPVs are classified into low and high-risk categories based on their association with malignant lesions.
However, if a patient treated of CIN has another positive HPV test within six months after treatment, it will be more predictive of a risk of recurrence for the patient. This sequence is added to check DNA integrity and PCR inhibitors; it is also helpful in detecting DNA mixtures due to sample mishandling. Based on the literature, the HPV prevalence at normal oral mucosa in patients with anogenital HPV infection is similar to the ones who have not anogenital HPV infection, what can suggest that this virus in the anogenital tract may not predispose others sites to be infected too. There are around 100 kinds of already-identified HPV (4) and, in terms of their malignity potential, they are classified into low (6, 11, 13, 32, 34, 40, 42, 44, 53, 54, 55 and 63 kinds) and into high risk of malignity (16, 18, 31, 33, and 35) (5).
The low-risk types include HPV-6, -11, -42 and -44, and mostly cause the development of genital condylomata (warts).
Different labelling of primers allows to generate amplicons of similar size in the same PCR reaction.
A part of neoplastic infiltrate in the wall of large intestine showing cramped glandular ducts with irregular shapes.
Objective: The aim of this research is to determine oral HPV prevalence in male patients with anogenital HPV. In some cases, specific kinds of HPV are related to certain clinical entities, for example: kinds 6 and 11 are the main ones involved in laryngeals papillomas and in most of condylomas of genital tract (6) while the 16, 18, 31 and 35 kinds are detected in most of cervix carcinomas(7). Immunohistochemistry of subepidermal blister showing histological features of regeneration. The replacement of physiological autoimmunity by pathological autoimmunity and triggering blister formation in ABD still remain unexplored and essential issues. This is a preliminary study, in which we studied 10 patients with anogenital HPV, confirmed by molecular biology. The HPV persisting infection is considered the most important cause of cervix cancer (8), and its participation has also been implied in the development of other genital neoplasies such as vagina, vulva, penis, anus and oral cavity (9).
IIF study revealing no IgG antibodies binding either desmosomal proteins of keratinocytes or basement membrane antigens. It is suggested that malignancy may be a triggering factor inducing the development of pathological autoimmunity. In all patients we performed an oral clinical investigation by scraping - in patients without oral lesions and biopsy - in patients with oral lesions. The HPV is believed to be involved in 10 to 15% of human body neoplasies (4).The sexual contact is the main way of HPV transmission (10), but there are other ways such as the maternal-fetus one (11), self-inoculation from skin lesions (12) or from genital lesions (13) and orogenital sexual abuse (14). On the other hand, the development of malignancies during chronic immunosuppressive therapy may be observed [2]. Numerous erosions on non-inflammatory skin of the back, some of them covered with brownish-greenish crusts. 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. Conclusion: So, from this pilot project, the virus at the anogenital tract seems not to predispose the oral cavity to be infected too. Collectively, the literature data and our own experience indicate that ABD may be associated with different malignant tumors, both cutaneous and affecting internal organs. This conclusion is extremely important to patients with anogenital HPV infections since they are scared about the virus transmission to other sites of their bodies. From the molecular point of view, it is not known how an HPV infection remains latent and the other one, on the other hand, develops macroscopic lesion due to intense viral replication (4).Most of HPV infections are asymptomatic - latent and subclinical, and the infection proportion is very small - from 1 to 2 % - which lead to apparent lesions. Suprabasilar cleft with acantholysis in the lower lip specimen showing also features of SCC.
However, the issue if it is a mere coincidence or true pathogenetic relationship remains to be resolved.
Histology of perilesional skin: Subepidermal vesicle with admixture of eosinophils within it. It is known that in a state of perpetual activation of immune system, as in ABD, proinflammatory molecules (e.g. Nowadays, there is no doubt that such lesions are transmitted through sexual contact, and it is recognizably the most frequent sexually transmitted disease (16). Out of the 100 kinds of identified kinds of HPV, 24 of them have already been found in oral lesions (1, 2, 3, 4, 6, 7, 10, 11, 13, 16, 18, 31, 32, 33, 35, 45, 52, 55, 57, 58, 59, 69, 72 and 73 kinds) (17). Numerous merging erosions, some covered with bloody and greenish crusts on the skin of the neck area subjected to radiotherapy. DIF of perilesional skin: IgG4(++) deposits in the intercellular spaces of higher layers of epidermis. 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. In the oral cavity, the HPV is the etiologic agent of benign lesions such as scaly cell papilloma, focal epithelium hyperplasia, cancer and vulgaris wart (7). 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. Bearing in mind the HPV importance as a sexually transmitted disease, its high predominance in the population (16) and its strong involvement as a cervix cancer agent (8, 19), it is essential to investigate other mucous regions, in addition to the anogenital region, which may lodge the HPV, such as the oral cavity.
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 rising number of HPV anogenital infection and its high oncogenital potential make us think that other possible infection sites, little investigated as a routine or as a prevention, such as the oral cavity, may be recontamination nidus or even pre-malign and malign lesion development sites. Malignancy in relation to the autoimmunity in subepidermal blistering dermatoses: The role of the DEJ proteins6. The time period elapsed between the first symptoms and diagnosis, makes the time-onset relation between ABD and cancer usually uncertain.Molecular abnormalities of desmosomal proteins are observed in ABD and epithelial malignancies. In the last decades, several authors (13, 20-28) focused their attention on HPV infection in other anatomic sites in parallel to anogenital infection, in order to understand if the anogenital infection caused by such virus may be predisposing factor for infection in other sites, such as the oral cavity.Kellokoski et al (20), in 1990, performed prospective studies with 334 women with HPV genital infection in order to verify how frequently oral HPV would appear in those patients. The oral cavity has been examined at naked eye and abrasion of mouth vestibule mucous membrane has been performed bilaterally in 317 patients and, in 255 of them, biopsies for cytological and histological study have been performed. 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.
Oral lesions have been found in 127 patients out of 334 patients (38%), and the vulgar wart has been seen only in three patients (0.9%) and other lesions such as fibrous and papillary hyperplasia, candid infection, fissured tongue and leukoplakia have been found in the other patients. Interestingly, the altered desmosomal protein expression and subsequent changes in cell-cell cohesion are often associated with signal pathways (e.g.
Kellokoski et al (21), in 1992, performed a study in 262 women suffering from genital HPV in which they investigated HPV through abrasion, at naked eye, in mouth vestibule mucous membrane by using DB. Diverse ABD are evoked by different triggering mechanism and are characterized by different clinical onset, course and prognosis.
There has been agreement of oral and genital HPV in 30% of the cases and the most frequent kind of HPV found in the genital and oral cavity has been the 6 kind.Kellokoski et al (22), in the same year, performed oral biopsy at naked eye in 272 women suffering from genital HPV, and all of them were submitted to SB study and 85 of them to PCR. Two main subdivisions can be separated: ABD with autoimmunity to enzymes and ABD with autoimmunity to structural proteins. There has been agreement of oral and genital HPV in only 8% of the cases and the most frequent kind of HPV found in the genital and oral cavity has been the 6 and 11 kinds while in the genital region the 16 kind was found. ABD with autoimmunity to enzymes The entity is represented only by dermatitis herpetiformis (DH), also known as Duhring's disease - chronic, intensely itchy, blistering skin manifestation of the gluten sensitive enteropathy [4]. Van Doornum et al (23), in 1992, performed a study with 65 men and 111 women in whom an HPV research has been done in the oral and anogenital regions. 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. In the oral cavity, the HPV investigation has been done through abrasion at naked eye and the material has been analysed through the PCR technique. 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]. HPV has been found in 24 men and in 32 women in the anogenital region, although oral HPV has not been found in any of them. 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].
Panici et al (24), in 1992, investigated HPV in the oral cavity of 66 women and 35 men with genital HPV. The oral cavity examination has been performed with a colposcope and acetic acid has been used as a marker of possible HPV oral lesions, followed by their biopsies. Through histological criteria, acuminate condyloma has been diagnosed in 49 out of 101 cases (48%) and HIS of oral cavity samples has also been done. The main antigens for pemphigus circle are desmoglein 1 (DSG1) and desmoglein 3 (DSG3), yet there are forms of pemphigus without anti-desmoglein immunization [7]. In only eight patients there has been lesion which could be seen at naked eye, and in all of them acuminate condyloma has been confirmed through histological criteria.
With the use of a colposcope, suspect lesions have been observed in 83 patients and, through histological criteria, condyloma has been confirmed in 46% of the cases. Giraldo et al (25), in 1996, investigated HPV through cytological study in the oral mucous membrane of 51 women with genital HPV through abrasion, at naked eye. Conclusive cytological evidence of HPV infection has been considered due to koilocytosis, which has been present in 6% of the analysed oral cavity samples. Blistering in PV appears at suprabasal level as an effect of tissue-bound and serum IgG-driven autoimmunity against keratinocyte cell-surface antigens of aforelisted cadherin superfamily [9], with desmoglein 3 (DSG3) as the main autoantigen.

There is no report of lesions frequency in the oral cavity.Sarruf and Dias (26), in 1997, performed prospective study in which 54 patients, 13 women and 41 men with HPV genital infection, have been examined. The disease starts initially affecting oral mucosa (50-70%), that may remain the only site involved, yet extraoral lesions may occur simultaneously. All patients have been submitted to a clinical analysis at naked eye followed by mouth wash with acetic acid at 2% in order to identify white stains due to acetic acid. The material gathering for oral cavity cytological and histological study has been performed in the white stains due to acetic acid or, when they were not present, in the mouth vestibule mucous membrane bilaterally. Only patients with oral lesions have been submitted to their exeresis and the material has been submitted to the HIS technique in order to identify the HPV DNA. The oral cavity examination has been normal in 45 patients and White stains due to acetic acid have been found in nine patients.
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. The cytological and histological evaluation have identified koilocytosis in seven patients, which corresponds to 13% of the cases. ELISA, enabling assessment in serum, saliva or blister fluid [11].PF, the less common pemphigus circle condition, usually affects the skin of the face, scalp and trunk, but may generalize. Oral lesions have only been found in two patients and the HIS study has identified HPV DNA in only one case.
The disease is characterized by autoantibodies binding DSG1, that participate in blister formation at superficial level (granular layer). Badaracco et al (27), in 1998, found oral HPV in 5 out of 10 women with genital HPV diagnosis through PCR and there was oral lesion in three of them. Although blister is a primary PF lesion, it is hardly ever seen, as it rapidly evolves into crust-covered erosions [1,5]. All patients have been submitted to oral cavity clinical analysis at naked eye and with colposcope, and the material has been gathered with abrasion of tongue dorsal and ventral faces or of previously identified lesion.
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]. There has been agreement of oral and genital HPV in 3 patients and the most frequent kind of HPV found in the genital and oral cavity has been the 16 kind.
Canadas et al (28), in 2004, investigated HPV in the oral and anogenital regions of 166 women through abrasion and PCR. PNP autoantibodies may target simultaneously multiple antigens – desmoplakin I and II, BP230, periplakin, envoplakin, plectin, 170kDa protein, desmoglein 1 and 3, desmocolin familly, and many yet unknown proteins.
HPV oral and genital infection concomitance has been found in 12.7% of the cases, and the HPV 16 and 6 have been the most frequent ones in the anogenital and oral regions respectively. PNP-type intercellular deposits can be visualized in IIF on transitional epithelium of rat bladder. There is no report of lesions frequency in the oral cavity.Smith et al (13), in 2004, investigated 165 pregnant women with genital HPV in order to investigate HPV in the oral cavity through PCR. Circulating autoantibodies affects not only mucocutaneus epithelium, but may bind organ-specific antigens of gastrointestinal tract or bronchioli – e.g.
The oral cavity has been examined at naked eye and the material has been gathered with saline solution mouth wash for 30 seconds.
In 14 patients (8.5%) HPV has been found in the oral cavity, and the HPV 16 has been the most frequent one in the oral and genital regions. The kind of HPV has not agreed in any patient in both studied sites and there is not any report of lesion frequency in the oral cavity.
Taking into account the extreme result variability on articles found in the medical literature about oral HPV predominance on patients with anogenital HPV, a higher scientific investigation on this topic has become necessary.The objective of this article is to determine how frequently HPV appears in the oral cavity of men with anogenital HPV confirmed through molecular biology.
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 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 hemidesmosome adhesion complex. Other, vaguely characterized, autoimmune blistering diseasesThere are also other autoimmune blistering diseases e.g. Malignancies associated with ABDThe issue of association of malignancy and ABD causes much controversy among researchers. 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 abnormal 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]. The association ratio of malignancy with pemphigus increases by age, while no such correlation is found in pemphigoid. Interestingly, 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]. As far as anti-enzyme ABD is concerned, association of DH with subsequent development of lymphoma seems well-documented [18,24,25]. 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].
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]. 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], anti-laminin 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.3. Development of paraneoplastic immunityThe autoimmunity in cancer is developed by distortion of immune system, arising from central tolerance disruption, peripheral immunity rearrangement and altering of self-antigens.
Cancer-associated impairment of the function of immune system may take place at many stages. Rearrangement of T-cell receptor (TCR) genes proceeding in thymus cortex promotes T-cell education to recognize major histocompatibility complex (MHC) molecules of self-cells. The negative 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. Self-antigens 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]. 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 autoantigens.
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. 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. Along with antigen sequestration theory, the determinants of cell proteins released in tumor necrosis can be exposed by antigen presenting cells to matured T-cells that migrate to lymph nodes.
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. Ligation of CD40 on APC cells leads to increase co-stimulatory capacity and antigen presentation ability enhancement. It was suggested that T-cells may omit the “APC guarding stations” in lymph nodes and directly infiltrate the tumor.
Thus, the tumor itself may act as a "T-cell kidnapper" and support naive T-cell infiltration, activation and differentiation into effector cells [96], hypothetically programming or "indoctrinating" T-cells to achieve autoimmune potential. Thus, FcRs function may be a key purpose in the treatment with monoclonal antibodies (mAbs) therapy. It was demonstrated that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicated that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner Fc?RIIB [101].
Interestingly, rituximab – the chimeric monoclonal IgG1antibody specific for the B-cell marker CD20 – was recently approved for the treatment of B-cell lymphoma. Genetic predispositionThere seems to be a causative relation between HLA-association and autoimmunity in ABD, especially in pemphigus [103–109] and pemphigoid [110], yet these observations may vary geographically.
HLA-DQB1*0301 allele, associated with MMP [111–114], was reported in patients with esophageal squamous cell carcinoma [113], gastric cancer [115], HPV-associated cervical neoplasia [116]. It was hypothesized, that the gene may have a role in T-cell recognition of basement membrane antigens resulting in production of IgG autoantibodies binding basement membrane antigens [117]. It is also possible, that the link exists between certain malignancies and HLA or autoimmunity predisposition connected to defective apoptotic genes. The role of cytokinesThere is eventuality of oversecretion of certain cytokines regulating the mRNA expression and polarization of certain T helper (Th) cell population [118,119], as the most common neoplasms in relation to ABD seem to be lymphoproliferative malignancies.
It has been reported that qualitative as well as quantitative alterations in cytokine production can result in activation of inefficacious effector mechanisms and therefore, complex and severe impairment in immune functions [119]. Polarization to Th1-mediated immunity via IL-1, IL-4, IL-5, IL-6, IL-8 and IFN-gamma was observed in BP [120], while Th2-mediated reaction via IL-10 and IL-4, in conjunction with decrease in IL-2 and IFN-gamma levels, were shown in PV [119]. The cytokines that promote cancer growth (e.g IL-8 for colon and gastric cancer) [121,122] may collaterally initiate Th population shift to the profile promoting ABD. Likewise, a proliferation inducing ligand (APRIL) of TNF family plays an important role in several autoimmune diseases, including ABD, and in several malignancies. Sex hormonesAs some entities of ABD have sex-predisposition, just as some malignancies, the role of sex hormones on development of MAABD need to be investigated. Certain tumors prevail in female (breast cancer, non-Hodgkin lymphoma), in man (gastrointestinal tumor, laryngeal cancer, Hodgkin lymphoma or kidney cancer) or are typical for one sex for anatomical reasons (prostate cancer, ovarian cancer) [15].
Sex-associated distribution of PV and BP seems equal with slight female dominance, while other ABD promote males (DH – 2:1) or are exquisitely female domain (PG) [5,127].

Therefore, menopause may be followed by change in cytokine profile affecting immune response. Interestingly, studies on endocrine hormones in PV- and BP-patients have revealed increased serum levels of both adrenocorticotropic hormone (ACTH) and hydrocortisone [129]. It was hypothesized, that slight female predominance of women in PV may be contributed to hormone replacement therapy (HRT) [130]. HRT is known risk factor for ovarian cancer, yet the impact on neoplasm induction in breast cancer and endometrial cancer is uncertain [131].4. Viral infection (TTV, HSV2, HHV6, HHV8, HSV1, HSV2, EBV, HBV, HIV-1, Coxsackie virus) [136–143] has been put forward as a causative agent of ABD-type autoimmunity in PV, PF, BP and pemphigus vegetans.
There has been multiple factors suspected of prostatic cancerogenesis, including viruses (BK, HSV2, HSV6, HSV11, HSV16, HSV18, HSV31, HSV33, HHV8, XMRV, CMV) and microbial agents (Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, Neisseria gonorrhoeae and Treponema pallidum), yet data was inconclusive or supported no relation [144–151].
Surprisingly, Epstein-Barr virus infection has been found statistically associated with increased breast carcinoma risk [152]. The data covering the issue of exogenous factors contributing to both malignancy and ABD is yet generally inconclusive.Constant activation of immune system in ABD sustains chronic inflammation leading to tissue degeneration by proinflammatory molecules.
Furthermore, there is a hypothesis that the multiplicity of target antigens in ABD may result from intra- and intermolecular epitope spreading.
The effect of epitope spreading in ABD is well-known fact and it seems to be a constitutional compound of autoimmunity.
Structural similarities between autoantigen epitope and to-be-autoantigen epitope may lead to production of autoaggresive cross-reacting immunoglobulins [9,155]. This phenomenon, which represents a broadening of the immune response from a single epitope to additional epitopes, is also described in cancer and recent findings suggests that epitope spreading may be a more significant predictor of effective immunity [156]. The initial anti-cancer immunity may ricochet to autoaggresion by epitope spreading and bystander effect alike [157]. Molecular mechanisms: The possible connection between malignancies and ABDABD are characterized by autoantibodies against structural proteins of the skin, including molecules of dermal-epidermal junction and desmosomes. Cancer progression is a complex and multi-step process in which components of DEJ as well as a desmosomal molecules play a pivotal role in the development of metastasis. Probably, more than 90% of human cancers are of epithelial origin [159] and the autoimmunity against epidermal structures may play important role in those carcinogenesis.
In light of this, understanding the molecular basis of pathological autoinflammation induction in autoimmune blistering dermatoses in relation to the mechanisms of malignant transformation is paramount for early detection and treatment of epithelial-derived cancers [160]. However, the precise molecular mechanisms underlying the association of malignancy with ABD still remain unknown.
Malignancy in relation to the autoimmunity in pemphigus group: The role of desmosomes componentsPemphigus group is characterized by presence of autoantibodies against desmosomal cadherins.
Research on human and animal models indicated that alternation in desmosomes components may lead to tumor progression and metastasis. It is clear, that the origin and maintenance of epidermis requires the coordinated regulation of proliferation, adhesion, migration and differentiation. Conceptually, desmosome complexes form when desmosomal cadherins – DCs (desmogleins – DSGs and desmocollins – DSCs) participate in heterotypic interactions that bring the plasma membranes of adjacent cells in close apposition [161]. The data describing desmosome protein expression during human cancer progression are conflicting [161–163].
Molecular abnormalities of desmosomal proteins (DPs) are observed in ABD and epithelial malignancies. However, in malignancy, where cells may separate, detach and metastasize, it is possible that alterations in DPs expression may be the reason of carcinogenesis process.
Several studies demonstrated that downregulation of DCs occurs during the progression of cancers and is often correlated with and predictive of tumor metastasis [161,162]. On the other hand, other studies reported overexpression of DCs during the cancer progression, and this pattern is associated with poor prognosis [163]. Genetic changes as mutation, deletion, and gene rearrangement of DCs have been poorly found in cancer and ABD. Possible mechanism may also involve post-translational modification of protein, like phosphorylation, acetylation or methylation. Thus, further analysis of methylation status of DCs DNA may be useful to predict clinical outcomes in patients with malignancy.Alternatively, the possible link between desmosomal components and malignancy may be the Perp protein. The Perp tetraspan membrane protein was originally identified as a transcriptional target of the p53 tumor suppressor upregulated during apoptosis [161,165].
However, Perp may have function as a target of the p53-related transcription factor (p63) involved in maintaining epithelial integrity by promoting desmosomal cell-cell adhesion. Electron microscopy and biochemical analyses showed that the blistering phenotype observed in the Perp-deficient epithelia is accounted for by both a reduction in desmosome number and compromised desmosome complex formation.
It is suggested, that pemphigus autoantibodies may trigger internalization of Perp, which enhances adhesion defects [166]. Perp’s position downstream of p63 and p53, as well as its essential role in normal desmosome function, suggest that it may be a target for mutation in human blistering diseases or cancer [167]. An interesting issue remains why a p53 target would play such a prominent role in adhesion in the skin. It was suggested [167], that this role relates to Perp being a key component of the transcriptional program for stratified epithelial development and maintenance specified by the p53 family member p63. Beyond a role in epithelial function, Perp’s status as a p53 target involved in apoptosis may suggest a potential role as a tumor suppressor. Given that loss of both p53 and p63 cooperate in tumorigenesis, loss of Perp similarly may be expected to promote cancer development in some context. The future analysis of Perp will provide new insight into the role of desmosomes in epithelial homeostasis and cancer [167]. It was disputed, that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss and inflammation, and fundamental role for Perp and desmosomes in tumor suppression [161]. Interestingly, it seems that DSC3 is a p53 response gene and addition of wild-type p53 was found to be sufficient to induce expression of DSC3 in breast cancer [169]. Thus, it was of great interest to investigate whether this pathway is also active in tumor cells. In light of above, the induction of p53 may have impact on expression of DCs [164].Malignancy may be also associated with pemphigus group via pemphigus-antibodies-induced signaling pathways. Thus, cadherins expression can function as a tumor and invasion suppressor due to its participation in processes such as morphological differentiation and contact inhibition of growth and motility. A signaling cascade initiated by pemphigus vulgaris antibodies may results in reduced availability of plakoglobin and abrogation of its function as transcriptional repressor of the proto-oncogene c-Myc. BCC) may be dependent on several signaling pathways [170], which can be shared with pathological autoimmunity induction in pemphigus group.
Other signaling pathways may engagement of Src, Wnt, hedgehog, epidermal growth factor receptor (EGFR) kinase (EGFRK), cAMP, protein kinases A and C (PKC), phospholipase C, mTOR, p38 MAPK, JNK [166]. Especially, it is postulated that DSG3 is a key player in Src signaling and overexpression of DSG3 elicited a phenotype similar to this with increased Src activity.
On the other hand, MAPK is involved in the process of acantholysis in pemphigus group.Furthermore, some data [173,174] demonstrated possibility that switching of DCs could play an important role in the development of some kind of cancer. Tumor development is in part characterized by the ability of cells to destruct of cell-cell adhesion and invade the surrounding tissue.
Perhaps, the disturbances in desmosomal cadherin (as DSCs) expression could affect beta-catenin signaling [174]. It is known, that increased beta-catenin signaling is a common causative event in some kind of cancer (e.g.
Malignancy in relation to the autoimmunity in subepidermal blistering dermatoses: The role of the DEJ proteinsPathogenesis of blister formation in subepidermal blistering dermatoses is associated with destruction of dermal-epidermal junction and anchoring fibers.
Recent studies shown interesting function of the hemidesmosome (HD) components in signal transduction, involving effect on cell behavior in tumor invasion [175]. Data indicated altered expression of DEJ proteins at different stages of carcinogenesis, what may suggest the association between tumor progression.
Aberrant expression of DEJ proteins, which are associated with subepidermal blistering dermatoses (e.g. BP180, BP230, alfa6beta4 integrin, laminin-322) in epithelial cancers was demonstrated, what may indicate their role in tumor development and invasion [175]. Reduced expression of HD components may results in the detachment of cells from the basement membrane, facilitating piling or migration of cells [176]. On the other hand, carcinoma cells may upregulate the expression of HD molecules to enhance the attachment capacity of metastatic cells to the DEJ at the metastatic site in order to establish metastatic growth.The aberrant expression of DEJ component may reflect dysfunction of HD, that occurs as an early event in multistep carcinogenesis of epithelium [177]. Downregulation of BP180 – one of the major autoantigen in bullous pemphigoid – was found in basal cells in mild dysplasias, upregulation of BP180 in suprabasal keratinocytes in moderate and severe dysplasis as well as in the central cells of squamous cell carcinomas (SCC; G2 and G3) using immunohistochemical (IHC) and in situ hybridization (ISH) methods [175]. Furthermore, this group of researchers indicated that overexpression of BP180 was found at the invasive front of the tumors.
Authors suggested that reduced BP180 expression at the early step of carcinogenesis may reflect disturbed keratinocyte adhesion to the basement membrane.
Previous findings obtained by the same authors revealed reduced BP180 expression in the peripheral cells of carcinoma islands in solid and keratotic basal cell carcinomas (BCC) and in the basal cells of invading buds in superficial BCCs [178].
The altered expression of DEJ proteins is likely to coincide with the disassembly of HD, which is an essential step in keratinocyte migration and carcinoma cell invasion [175]. Moreover, downreguation of BP180 and other hemidesmosome components was previously detected in vivo in prostate cancer and in the invasive cells of ductual mammary carcinoma [179,180]. On the other hand, upregulation of HD components has been reported in a variety of SCCs [177,181]. It was argued that BP180 upregulation in carcinoma cells at the invasive front of malignant tumors is important in the carcinoma cell migration [175]. Other study described upregulation and altered distribution of BP230 and alfa6beta4 integrin in the areas of invasive growth of head and neck SCCs [181]. PMA is a potent tumor promoter capable of inducing several genes that have a role in carcinogenesis and tumor invasion [182].
It is known, that laminin-332 gamma2 chain gene promoter is one of the targets of PMA activation, occurring via interaction with the activator protein 1 complexes [183]. Enhanced expression and abnormal distribution of BP180 in various precancerous and cancerous tissues was revealed, including e.g. SCCs and Bowen’s disease [177].As it was demonstrated that expression of BP180 was decreased or absent in cutaneous neoplasms [184], some authors speculated that some type of carcinomas itself might expose BP180 antigenic epitope, which would normally be hidden, thus inducing the production of autoantibodies that lead to the onset of BP [185].
Laminin-322 (previously named laminin-5) is the main autoantigen in anti-epiligrin cicatricial pemphigoid, mucouse membrane pemphigoid. Laminin-332 and alfa6beta4integrin may play an important role in tumor progression via activation of phosphatidylinositol-3 kinase signaling (PI3K) [187]. There was shown, that it is highly expressed in several types of squamous and other epithelial tumours [188]. Moreover, in these tumors, laminin-322 shows tendency to accumulate at the interface of the tumor with the surrounding stroma, and expression of this proteins correlates with tumor invasiveness [188]. Interestingly, keratinocytes from patients with junctional epidermolysis bullosa, that did not express laminin-322 or beta4integrin, showed a lack of tumorigenecity in immunodeficient mice after transformation [188].
Perhaps, the binding of collagen VII to laminin-322 may be essential for tumorigenesis [188]. As mentioned above, constitutive activation of the PI3K pathway leading to RAC1 GTPase activation may be the triggering factor inducing tumor invasion.6. Case reports of MAABDAs the association between ABD and malignancy is noted in many case reports, the question of causal connection is raised. There are three situations possible concerning the relation: i) malignancy preceding ABD, ii) malignancy coexisting with ABD, iii) malignancy following ABD. For a long months and years, many cases of ABD are undiagnosed, misdiagnosed and subsequently mistreated due to relative rarity and therefore low awareness of ABD and its symptoms.
Unfortunately, usually there is no experimental data indicating if it is a random coincidence or cause-and-effect relationship in individual patient. Histopathological examination of the retromolar mucosa of the left alveolar process of maxilla showed paraepidermoid epithelium with focal high-grade dysplasia and few neoplastic cells.

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