The contribution of histopathology to the diagnosis of desquamative gingivitis

The term « desquamative gingivitis » although long-established, is both incorrect and ambiguous. Incorrect because, as rightly said by ^{Kuffer (1987)}, desquamation is a physiological process. In addition, several types of pathological desquamation exist and, by definition, whether normal or pathological, desquamation occurs in the stratum corneum. Moreover, we shall see that « desquamative gingivitis » includes mostly lesions that affect the Malpighian layer of the mucosa and the dermial-epidermial junction. The terminology is ambiguous because it uses a histopathological term to describe the clinical appearance of entities that are very different from a pathological point of view. Nevertheless, some clinicians continue to use it for practical reasons.

Significant progress has been made in recent years in our understanding of the pathology of the more common disorders that cause « desquamative gingivitis ». This article reviews the most recent data, in particular those relating to the structure, the nature and localisation of antigens, target autoantibodies, deposits which are biological markers and provide the basis for histological diagnosis of these conditions.

The term « desquamative gingivitis » was coined by ^{Prinz (1932)}. Actually, desquamative gingivitis is « defined » as a chronic gingival lesion characterised by erythema, erosions, vesico-bullous eruptions, ulcerations and desquamation of the free and attached gingiva. Three studies using direct immunofluorescence have shown that the most frequent causes are : cicatricial (mucous membrane) pemphigoid (63.6, 48.9 and 39 %, respectively), lichen plan (25, 23.6 and 36 %), pemphigus (18.4, 2.3 and 15 %) ^{(Sklavounou and Laskaris, 1983} ; ^{Nisengard and Rogers, 1987} ; ^{Vaillant et al., 2000)}. Other associations have been reported, especially with psoriasis, herpetiform dermatitis, linear IgA dermatitis and Pyostomatitis vegetans. Desquamative gingivitis could also appear in relationship to lupus erythematosus, plasmacell gingivitis, Crohn's disease, sarcoidosis, certain leukaemias, mouthwashes, chewing gums, dental materials and even pathomimesis ^{(Porter and Scully, 1994} ; ^{Scully and Laskaris, 1998)}. In the absence of convincing evidence of their aetiology, some of these latter disorders are placed in a group designated idiopathic desquamative gingivitis. Without denying the possibility of other aetiologies, we will restrict this histopathological review to those known to be associated with desquamative gingivitis : cicatricial (mucous membrane) pemphigoid (CP), pemphigus and lichen plan.

The pemphigoid group

Deposition of immunoglobulins and/or complement fractions in the area of the dermis-epidermis junction or the basement membrane is characteristic of the group of pemphigoids known as sub-epithelial vesiculo-bullous diseases. Progress in immunopathology enables us to recognise three disorders : bullous pemphigoid, which affects the elderly, is the most common and is mainly cutaneous, only 20-30 % having oral lesions ; CP, which affects younger people, with 80 % having oral lesions, 70 % conjunctival and 20 % cutaneous ; and pregnancy pemphigoid, or « herpes », which affects pregnant women in the last trimester. We will not deal with the latter because, to our knowledge, only one confirmed case with oral manifestations has been reported ^{(Nicolas et al., 1993} ; ^{Dabelsteen, 1998)}.

Bullous pemphigoid is a sub-epithelial bullous disease that affects the elderly. Although oral manifestations of bullous pemphigoid are less frequent than those of CP, it is necessary to deal with this one first because it has been studied in more detail and has a greater incidence : 7 cases per million. Also, it is often used for reference by comparison.

The histopathology of bullous pemphigoid is characterized by the presence of sub-epithelial bullae/vesicles due to pronounced cleavage at the dermis-epidermis junction. The whole of the epithelium, which is unaffected in early lesions, forms the roof of the bulla. The connective tissue papilla represents the floor of the bulla. It rapidly loses its outline due to the effect of the pressure of the fluid within the bulla. The level of cleavage is easily visible at the extremeties of the bulla. It contains a mixture of inflammatory cells, eosinophils, but there is no cellular acantholysis ^{(Mehregan et al., 1995} ; ^{Yancey and Egan, 2000)}. Direct immunofluorescence on frozen biopsy sections in the peri-bullous zones show the presence of linear deposits of IgG along the length of the basement membrane in 89.6 % of cases and of C3 in almost 100 % cases, sometimes associated with deposits of IgA and, rarely, IgM. This routine, standard diagnostic method requires frozen tissue in order to preserve the antigens which are denatured by formalin fixation. Serum antibodies, directed against components of the basement membrane of skin and mucous membranes, are present in most patients. However, the titles of the various circulating antibodies are independent of the severity of disease ^{(Laskaris and Nicolis, 1980} ; ^{Chorzelsky et al., 1987} ; ^{Vaillant et al., 1998)}.

Two antigens of bullous pemphigoid have been identified : BPAG-1, or BP-230, which is an intracellular protein of 230 kDa. It is associated with hemidesmosomes at the insertion of the intermediate filaments of keratin. The other is BPAG-2, or BP-180 or collagen XVII, a transmembrane protein of 180 kDa. It causes an alteration in the membrane which renders BP-230 accessible, in particular its C terminal part ^{(Ishiko et al., 1993} ; ^{Bédane et al., 1997} ; ^{Pierrard et al., 1999} ; ^{Skaria et al., 2000)}.

Cicatricial pemphigoid, still referred to as benign mucous membrane pemphigoid and ocular pemphigoid, is an uncommon chronic sub-epithelial vesiculo-bullous disease with an incidence of 1 case per million. It mostly affects women over the age of 50 years. It is characterized by its selective effect on mucosa and by the later formation of scars. It is this latter feature which distinguishes cicatricial pemphigoid from bullous pemphigoid and pregnancy pemphigoid. As far as the ocular lesions of cicatricial pemphigoid are concerned, symblepharon is a frequent complication but scarring of oral lesions only occurs rarely. This is why, for oral lesions, some authors prefer the terminology " mucous membrane pemphigoid ". In addition to oral and ocular lesions, cicatricial pemphigoid can affect the pharyngeal, laryngeal, nasal, genital and anal mucosal. Associated cutaneous lesions are only present in less than 25 % of cases and then are few in number. Usually multiple sites are affected but single lesions do occur, especially oral or ocular ^{(Bernard, 1993} ; ^{Yancey and Egan, 2000)}. In 90 % of patients with oral involvement, lesions are situated on the gingivae and hard palate and give rise to desquamative gingivitis. This distribution must be due to the attachment of the mucosa to bone by the periosteum. The epithelium detaches under the slightest friction (Kuffer's sign) ^{(Kuffer, 1987} ; ^{Kuffer, 1996)}.

As in bullous pemphigoid, the histopathology is characterized by sub-epithelial detachment without acantholysis, accompanied by a major lympho-plasmacytic infiltration of the lamina propria with a few neutrophils and eosinophils (^{fig. 1}.). A laminar fibrosis under the lesions is considered to be characteristic, but only occurs late. Diagnosis is made by direct immunofluorescence on frozen sections (^{fig. 2}). Fluorescent deposits are seen at the basement membrane in 82.88 % of cases (IgG 69 %, IgA 22 %, IgM 16 % and C3 69 %) ^{(Dayan et al., 1999)}. Contrary to the finding in bullous pemphigoid, circulating antibodies are unusual and then in low concentrations ^{(Bernard et al., 1990} ; ^{Niimi et al., 1992)}.

Recent immunological studies have shown that cicatricial pemphigoid is not a single entity and more is being revealed as our knowledge of the basement membrane increases. In the majority of patients (78 %), the main target antigen is extracellular BP-180. There are two sites for the antigen, one non-collagen and the other in the area of the carboxy-terminal ^{(Balding et al., 1996} ; ^{Roh et al., 2000)}. In other patients the target antigen is the α3 unit of laminin 5/epiligrin/kalinin/niceine/BM600, situated at the lower surface of the lamina lucida at its interface with the lamina densa ^{(Kirtschig et al., 1995)}. A third group of patients presents with both antigens simultaneously ^{(Kawahara et al., 1998)}. A last group possesses other antigens, such as the γ2 unit of laminin 5 or laminin 6, etc. ^{(Chan et al., 1997} ; ^{Nousari et al., 1999)}. Lastly, a purely ocular form of cicatricial pemphigoid representing a distinct clinical entity with an antigen of 45 kDa situated in the basement membrane, has been reported (^{Chan et al., 1993} ; ^{Pazderka Smith et al., 1993)}.

Pemphigus vulgaris

The term pemphigus includes a groups of auto-immune diseases of the skin and mucous membranes in adults. It is relatively uncommon at 1 to 5 cases per million inhabitants and is characterized by the production of autoantibodies directed against interkeratinocyte substance, producing cutaneous and/or mucosal acantholytic bullae. There is a strong association with certain haplotypes (HLA-DR4 and DR6) suggesting a predisposition in some subjects. Five types of pemphigus have been identified : Pemphigus vulgaris and its reactive form, Pemphigus vegetans ; Pemphigus foliaceus and its variant Pemphigus erythematosus ; iatrogenic (drug-related) pemphigus ; IgA pemphigus ; paraneoplastic pemphigus, associated with malignant lesions frequently of haematological origin. Pemphigus vulgaris, which can be fatal, is the most common and, importantly, presents with oral manifestations before cutaneous involvement. These lesions, in the form of desquamative gingivitis, may be the cause of the patient's initial consultation ^{(Shklar et al., 1978} ; ^{Nicolas et al., 1995} ; ^{Cohen et al., 1997} ; ^{Sirois et al., 2000)}. It is for these reasons that this review will be limited to this form of the disease.

The characteristic histopathological picture of Pemphigus vulgaris is of an acantholytic bulla, usually in the suprabasal area, with basal keratinocyctes attached to the basement membrane and separated from one another producing, according to the classic description, a " row of tombstone " appearance (^{fig. 3}). The roof of a newly-formed bulla is made up of the intact upper layers of epithelium. In the bulla are rounded acantholytic keratinocytes with a dense peripheral cytoplasm in the form of a wreath and with a large, sometimes monstrous, nucleus. These are called Tzanck cells and may be present singly or in groups (^{fig. 4}). Before immunofluorescent techniques became generally available, the detection of Tzanck cells from a freshly opened bulla served to establish the diagnosis ^{(Civatte and Belaïch, 1964} ; ^{Cohen et al., 1997)}. Pemphigus vulgaris is caused by pathogenic autoantibodies, mainly IgG4, directed against surface antigens on the supra-basal keratinocytes. Circulating antibodies are always present. Intercellular deposits of IgG in a " hairnet " pattern are demonstrated in lesions by direct immunofluorescence in frozen sections in 80-90 % of cases (^{fig. 5}). They provide a positive diagnosis ^{(Nicolas et al., 1995)}.

The target antigen in Pemphigus vulgaris is desmoglein 1 (Dsg1) (160 kDa) and/or desmoglein 3 (Dsg3) (130 kDa). These are adhesin molecules belonging to the cadherin family and are present in the desmosomes of stratified squamous epithelium. Dsg1 predominates in the upper layers of the epithelium and Dsg3 in the basal and immediately supra-basal layers. It seems that autoantibodies become fixed in the intercellular parts of the desmosomes. Patients with muco-cutaneous Pemphigus vulgaris have antibodies anti-Dsg1 and anti-Dsg3, whereas patients with mucosal Pemphigus vulgaris only possess anti-Dsg3. Sometimes C3 is present in lesions, but not at the periphery (^{Ding et al., 1999} ; ^{Amagai et al., 1999}).

Lichen planus

Lichen plan is a relatively common muco-cutaneous disease that affects 1-4 % of the population and whose aetiology remains unknown. The prevalence of oral Lichen planus is of the order of 0.7-1.89 %. The predominance in women is more apparent in the oral form than the cutaneous. A gingivo-vulvo-vaginal syndrome is recognized and lesions of the scalp, nails, oesophagus and eyes have been reported in association with oral lesions. Koebner phenomenon, or isomorphic response, is normal in lichen plan and can be induced by all types of trauma. In contrast to the cutaneous lesions that can go into a spontaneous remission after one or two years or sometimes longer, mucosal lesions are, as a general rule, chronic in character. A relationship between erosive oral lichen plan and chronic viral hepatitis C has been established. Lichenoid lesions have also been reported to be associated with many drug treatments and with organ transplant rejection. Gingival lesions have been classified into four categories : white papular keratosis, vesiculo-bullous, erosive or ulcerative lesions and atrophic. The latter ones frequently correspond to the clinical diagnosis of desquamative gingivitis. It has been observed that the incidence of desquamative gingivitis in patients with oral Lichen planus is increased in the presence of plaque and calculus ^{(Thorn et al., 1988} ; ^{Bork, 1988} ; ^{Pelisse, 1989} ; ^{Mattsson et al., 1992} ; ^{Dupond et al., 1998} ; ^{Eisen, 1999} ; ^{Ramon-Fluixa et al., 1999)}.

From the histopathological viewpoint, the main characteristic of lichen plan is alteration of the basal germinal layer at the epithelial-connective tissue interface ; there is hydropic degeneration and necrosis of the keratinocytes associated with a more or less dense band of lymphocytic and histiocytic infiltration in the sub-epithelial papillary connective tissue and the lamina propria. This is of limited depth but invades the basal and supra-basal layers of the epithelium. A diminution of the epithelial ridges gives them a saw-tooth appearance and the basement membrane becomes blurred (^{fig. 6}). Sometimes, minor splits at the dermo-epidermal junction or Max Joseph fissures may appear. They precede the formation of bullae in bullous lichen planus. Some keratinocytes alter and give rise to colloidal or Civatte bodies that are found in the deeper layers of the epithelium or in the connective tissue adjacent to the epithelium. Secondary chronic alterations to the surface epithelium become apparent, namely orthohyperkeratosis and irregular hypergranulosis (^{Lauffer and Kuffer, 1970} ; ^{Mehregan et al., 1995)}.

The mononuclear cell population in the connective tissue is mainly composed of the T-lymphocytes, CD4 and CD8 and the number and/or activity of Langerhans cells increase. Lichen plan is considered to be a delayed hypersensitivity reaction. It has been shown that the production of the pro-inflammatory cytokines, interferon-gamma and interleukin 6 are increased, modulating the differentiation of cytotoxic T-lymphocytes, originating from the apoptosis of undifferentiated basal keratinocytes ^{(Takeuchi et al., 1988} ; ^{Farthing et al., 1990} ; ^{Fayyazi et al., 1999)}. A specific antigen (LPSA), present in the body of the mucosa and the granular cell layer, has been identified in 80 % of patients with cutaneous lichen plan, but not in all lesions and never in oral lichen plan. The antibodies, anti-LPSA, have not been detected in all patients and are considered to be a sign of the disease and not the cause itself. The same applies to the deposits of fibrinogen that are commonly identified by direct immunofluorescence in the area of the basement membrane, extending into the lamina propria ^{(Olsen et al., 1984} ; ^{Camisa et al., 1986)}. Therefore, the diagnosis of lichen plan is solely based on routine histological examination, contrary to what we have seen for bullous pemphigoid, cicatricial pemphigoid and pemphigus vulgaris where direct immunofluorescence of frozen sections is required.

Conclusion

This work is not a complimentary review of the terminology leading simply to a metaphorical dismemberment of desquamative gingivitis. The terminology « desquamative gingivitis », inaccurate as it is, can be retained as long as it is not used to evade a proper approach to diagnosis. The histopathological diagnosis, by identifying a disease hiding behind desquamative gingivitis is of real benefit to the patient. In particular, it confirms or eliminates the existence of two serious diseases, cicatricial pemphigoid and pemphigus vulgaris, which together represent between 41.3 and 82 % of the causes of desquamative gingivitis. Cicatricial pemphigoid can eventually lead to very debilitating scarring and adhesions. Pemphigus vulgaris is a potentially lethal condition whose initial stage is often limited to the oral mucosa. Early treatment of cicatricial pemphigoid and Pemphigus vulgaris improves the prognosis.

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