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2008; Wiley; Volume: 17; Issue: 5 Linguagem: Inglês

10.1111/j.1600-0625.2008.00712_5.x

1600-0625

Ichiro Kurokawa,

Oral Health Pathology and Treatment

Greek methodology has created the term ‘labyrinth’ for the convoluted indoor maze (Fig. 1a) that, according to legend, was constructed for King Minos of Crete (after the design by Daedalus) to hold the Minotaur (1), a creature half-man, half-bull. Classical labyrinth (a) and clinical (b) and histological labyrinth (c) in hidradenitis suppurativa. Ranging from its clinical and histological presentation to the many open questions posed by its pathobiology, hidradenitis suppurativa (HS), in many respects, represents such a labyrinth. Clinically (Fig. 1b), and on histological analysis (Fig. 1c), the undermined sinus tracts in HS indeed resemble a labyrinth (2). Despite intensive studies of HS (3), the aetiology of HS still remains unclear, and we are still trapped in a maze of possibilities and conflicting hypotheses. Let us walk, then, through this labyrinth, searching for the Minotaur around which it may have been built. This is best performed by considering selected key questions in HS research. The most pressing ones arise immediately, if one more carefully contemplates on: (a) the clinical signs and symptoms presented by HS patients; and (b) the proposal by Plewig et al. (4) that the term ‘HS’ should be changed to ‘acne inversa’. The characteristic lesions in HS are deep-seated subcutaneous nodules or abscess (2,5). In acne vulgaris, the primary lesions are either open or closed comedones (2,6). In HS, closed comedones are never present, and open comedones can be found as secondary lesions, but they are absent in early lesions of HS (2). They may appear in long-standing HS. Thus, the clinical appearance of HS and acne vulgaris is quite distinct, and it adds little to our understanding of HS pathogenesis to adopt the ‘acne inversa’ terminology. Plewig and Kligman stated that HS occurs in the terminal follicle bearing pilosebaceous unit (2,4). If this were so, we should find multiple thick hair shafts in HS. However, this is not really the case, and at least clinically (as opposed to histologically) terminal hair follicles actually are not the primary target in HS. In fact, despite some overlap, the areas of predilection for HS and the skin regions richest in terminal hair follicles seem to be rather distinct territories. In men, the buttock, a commonly affected site of HS lesions, bears hardly any terminal hair follicles at all. In addition, if terminal hair follicles were the key targets of HS, multiple tufted terminal hair shafts from the follicle should be observed in HS, as is characteristically seen in folliculitis decalvans (Fig. 2), dissecting folliculitis and perifolliculitis abscedens and suffodiens (Hoffman). Instead, multiple thick long terminal hairs are features one fails to notice in the characteristic fistulae of HS (Fig. 3). Tufted hairs from one hair pouch in folliculitis decalvans. Undermined fistulae in axilla in HS. Terminal hair follicles are not clinically affected in HS lesions. Thus, from a clinical perspective, it is quite dubious whether HS really occurs, as frequently claimed and reverberated uncritically, in terminal (rather than in vellus) hair follicles. But what about the apparent histopathological evidence for a predilection of HS for terminal hair follicles? Plewig and Kligman describe three types of hair follicles: vellus hair follicle, sebaceous follicle and terminal hair follicle (2). Well, in my personal experience, it is very difficult (if at all possible) to histologically detect terminal hair follicles in HS. Even in standard textbooks (2,4,7), the classical characteristics of terminal hair follicles (thick, medullated hair shafts and large sebaceous gland), as described so beautifully in Plewig’s book (2), are essentially absent in HS. Instead, Layton et al. (7) have observed tiny vellus hairs in follicular canals in HS. The lower part of hair follicles and sebaceous gland are uninvolved in HS. Taken together, therefore, it is very dubious that HS predominantly affects terminal hair follicles. Thus, even from the perspective of histopathology, HS is not a disorder of the terminal hair follicle. The fundamental change in HS is the retention hyperkeratosis of the infundibulum (2,4,7,8). More likely, HS predominantly occurs in the infundibulum of vellus hair follicles, whose tiny shafts can be observed in the follicular canal of affected pilosebaceous units. The keratin expression pattern in HS has been studied immunohistologically (9,10). Among cytokeratins, CK17 is neither expressed in the cyst wall in most cases of HS (9) nor is found in the pilonidal sinus of HS (11). CK 14 is more pronounced in the protruding epithelium in HS (9) (Fig. 4) In terminal hair follicles, CK 16 is detectable in the lower portion of hair follicle below the opening of sebaceous duct (9–12). The fact that CK16 was only found in two of 16 HS cases (9); therefore, further argues against terminal hair follicles as key targets in HS pathogenesis. However, as these immunohistological results illustrate, HS is definitely associated with abnormalities in keratinization. The next questions, then, are as follows. CK 14 is expressed in the protruding epithelium in a leaf-like structure. Based on the above keratin expression patterns and the unconvincing evidence that terminal hair follicles are the key organ where HS manifests itself, I propose the following hypothesis. The sinus epithelium in HS is not a late, but a very early event and does not primarily arise from the hair follicle epithelium, but by invagination from the epidermis (Fig. 1c). This invagination of the epidermis may result in the formation of infundibulum-like epithelium that protrudes into the deep dermis as epidermal cysts. Resident microflora may cause the adherence of the epithelium. Coagulase-negative Staphylococcus (CNS), in normal flora on the skin, is the most common bacterium isolated from HS lesions (13). CNS is also the most common bacterium isolated from epidermal cysts (14). Therefore, CNS may tend to adhere to the adjacent, closed serrated epidermis in the intertriginous area, resulting in infundibular-like epithelium (cyst formation) in both HS and epidermal cyst. An alternative explanation may be that HS patients exhibit an altered immunologic response to CNS antigens, compared with normal individuals. Another possibility is that anaerobic bacteria (15) play a key role in retention hyperkeratosis, resulting in both sinus and cyst formation. Often, the protruding epithelium that forms from the wall of HS cysts shows a leaf-like structure, as shown in Fig. 4. Why do such leaf-like structures arise? Formation of the epithelial and mesenchymal interactions might be related to undifferentiated keratin expression (CK14). In addition, anastomosing epithelium that links sinus tracts into a complex maze of tracts is frequently found in HS (Fig. 1c). Kurzen et al. (10) studied desmoplakin and desmocollin in epithelia in HS, and demonstrated their differences between three types of epithelium (10). Altered epithelial adhesion properties in HS might also result from abnormalities in e-cadherin expression. It is clear that bacterial infection is not the primary cause of HS. However, bacteria, their products, and immune responses raised against bacterial antigens may well greatly influence the clinical phenotype of HS lesions as well as the course of HS in any given patient. From normal skin microflora, CNS, Staphylococcus aureus, Stereptococcus, Peptostreptococcus, etc. are isolated in HS, e.g. in perirectal and vulvovaginal lesions (16,17). However, it is unclear whether these clinical isolates are involved in the pathogenesis of HS or not. CNS obstructs the intra-epidermal sweat duct, resulting in miliaria formation (18). Thus, it is conceivable that sinus formation in HS involves a similar mechanism. In terms of natural immunity, patients with HS may respond abnormally to these bacteria (e.g. Propionibacterium acnes), whose products stimulate Toll-like receptors (19), producing pro-inflammatory cytokines such as IL-1α, and giving rise to abnormal keratinization (20). The hair follicle was recently recognized as one of the immune organs of skin (21). In particular, the infundibulum, which belongs to the distal arm of the human hair follicle immune system, appears to represent a special organ involved in immune response (22). These areas are the preferred sites for perifollicular inflammatory cells in dermatoses such as lichen planopilaris, systemic lupus erythematosus, scleroderma and folliculitis decalvans (23). Therefore, HS may just represent a certain clinical phenotype that reflects a disturbed hair follicle immune system. In consequence, infundibular immunology, therefore, needs to be systematically dissected in future. For example, Toll-like receptors may be related to the initiation of inflammation in the infundibulum. In this context, the impact of pro-inflammatory cytokines on abnormal keratinization in HS should also be carefully investigated. Other important areas for future HS research include for example the precise mechanism by which new epithelium is formed in the process of sinus drainage (in HS and other diseases where this occurs). Scar formation involves a cell-mediated response that deserves study to clarify the pathogenesis of HS, like in acne vulgaris (24). With regard to possibly increased carcinogenesis in HS, the CK expression in well-differentiated SCC arisen from HS epithelium is similar to that in normal infundibulum (25). By contrast, poorly differentiated SCC in HS contained simple epithelial keratins (CK7, 8, 18, 19). Thus, it deserves to be carefully studied whether CK expression patterns reflect the clinical prognosis. Finally, the terminal stage of keratinization is related to filament-aggregating protein (filaggrin), a major component of keratohyaline granules (26). Filaggrin expression has been linked to the pathogenesis of acne vulgaris (27), epidermal cyst (28) and nevus comedonicus (29). Therefore, an immunohistochemical study of filaggrin expression should be undertaken. As comprehensive ultrastructural studies of HS remain to be performed, this should be complemented by electron microscopy. In the long run, at least the ‘floor plan’ of the HS labyrinth is becoming better defined, defined scenarios can be developed on how it is being constructed and evidence is emerging that its epithelial walls show distinct abnormalities of keratinization. But what is the Minotaur it may contain? Is ‘altered epithelial adhesion’ and/or ‘altered immune response against bacteria’ the answer…?