345 37 Histopathology of Irritant Contact Dermatitis Carolyn M. Willis Contents the skin [1], and with a histopathology largely indis- tinguishable from that of the majority of chronic in- 37.1 Introduction . 345 flammatory dermatoses. 37.2 Acute Irritant Contact Dermatitis . 346 When considering the histopathology of ICD, it is 37.2.1 Epidermal Features . 346 important to bear in mind that all of the following pa- 37.2.2 Dermal Features . 348 rameters will influence the histopathological changes 37.2.3 Leukocyte Infiltration . 349 observed under the light microscope: 37.3 Chronic Irritant Contact Dermatitis . 350 37.3.1 Epidermal Features . 350 37.3.2 Dermal Features . 350 1. Chemical nature and concentration of irritant References . 350 chemical In addition to the physicochemical properties of an irritant, which have a direct bearing on the nature of the cellular damage inflicted, concentration effects are also profound. At sufficiently high concentration, 37.1 Introduction many irritants will cause overt tissue necrosis. Lower concentrations produce more subtle changes, partic- Irritant contact dermatitis is a heterogeneous inflam- ularly in the epidermis. matory condition, both clinically and histopathologi- cally. Arising primarily from contact with chemicals, 2. Mode and duration of exposure the inflammation may be acute or chronic in nature, The circumstances of irritant exposure, such as single, depending upon the irritation potential of the sub- occlusive patch testing or repetitive open testing, and stance and the circumstances of exposure. Chemicals the length of time the chemical is in contact with the such as acids, alkalis, and detergents will, at high con- skin, will all influence the severity and nature of re- centration, cause sufficient damage to the skin to in- sponse, and hence the histological picture. duce inflammation after single exposure, while more marginal irritants require repeated exposure to over- 3. Time of tissue sampling come the skin’s innate restorative capacity sufficiently The time at which the tissue sample is taken relative to induce an inflammatory response. to the course of the inflammation is clearly of signifi- The clinical spectrum of acute ICD ranges from a cance. Early onset of chronic ICD, for example, may mild reaction with transient erythema or chapping involve little more than stratum corneum disruption, through to a more florid dermatitis with edema, ve- while a site of healing acute ICD would be character- siculation, bullae formation, exudation, and necrosis ized primarily by epidermal proliferation. [1]. Histopathological features vary accordingly, but, importantly, for mild-to-moderate reactions at least, 4. Individual susceptibility they show a degree of irritant dependency, reflect- One of the idiosyncrasies of the development of ICD, ing the different mechanisms of action of structurally which is particularly apparent in experimental situa- varying chemicals on the cellular components of the tions, is the often very differing severities of reaction skin [2]. Chronic ICD, in contrast, is somewhat more exhibited by individuals under the exact same condi- uniform in appearance, being characterized clinically tions of exposure. In studies carried out in this de- by erythema, dryness, chapping, and thickening of partment, for example, patch testing with the cationic 346 Carolyn M. Willis detergent, benzalkonium chloride, at a concentration Table 1. Epidermal changes observed after single, occlusive of 1%, resulted in reactions severe enough to cause patch testing with selected irritants blistering of the skin in some individuals, but pro- Combined human and animal data [2, 4–18]. duced little or no visible skin damage in others [3]. Irritant Epidermal features The histopathology of such reactions is therefore cor- respondingly variable. Sodium lauryl sulphate Parakeratosis, spongiosis, 5. Species vesiculation, nuclear/intracyto- The histopathology of irritant reactions induced in plasmic vacuolation, necrosis, animals can differ from that observed in man. This is hydropic swelling, epidermal/ particularly true for the leukocyte inflammatory infil- dermal separation, exocytosis trate in acute ICD. Benzalkonium chloride Necrosis, spongiosis, exocyto- sis, nuclear/intracytoplasmic In the following sections, consideration will be vacuolation, hydropic swelling given to the epidermal and dermal cellular changes Dithranol Hydropic swelling, spongiosis, which occur in both acute and chronic ICD, includ- intracytoplasmic vacuolation, ing analysis of the distribution and phenotype of re- necrosis, parakeratosis sponding white blood cells. Nonanoic acid Dyskeratosis, spongiosis, nuclear/intracytoplasmic vacuolation, parakeratosis 37.2 Acute Irritant Contact Croton oil Spongiosis, vesiculation, Dermatitis exocytosis, nuclear/intracyto- plasmic vacuolation, hydropic 37.2.1 Epidermal Features swelling, parakeratosis Dinitrochloro-benzene Necrosis, epidermal/dermal Much of our understanding of the microscopical fea- separation, spongiosis, nuclear/ tures of the epidermis in acute ICD has come, not intracytoplasmic vacuolation from clinical material, but from skin sites experimen- Sodium hydroxide Epidermal/dermal separation, tally subjected to single, occlusive patch tests con- spongiosis, necrosis, nuclear/in- taining known irritant substances. Table 1 provides tracytoplasmic vacuolation a summary of the predominant histopathological features induced by selected chemicals tested in this Hydrochloric acid Spongiosis, intracytoplas- way [2, 4–18]. Damage is seen to occur at all levels mic vacuolation, necrosis of the epidermis, from the stratum granulosum down Potassium dichromate Intracytoplasmic vacuolation, to the dermo-epidermal junction. Although there is spongiosis, necrosis, epider- little doubt that the majority of these irritants have mal/dermal separation the capacity to cause overwhelming cellular destruc- Toluene Acantholysis, pyknosis, spon- tion if applied at high concentration, under ethically giosis, bullae, necrosis acceptable patch test conditions, the most commonly Trichloroethylene Acantholysis, spongiosis, observed morphological changes are intracellular nuclear vacuolation, necrosis vacuolation and nuclear pyknosis, the extent to which Acetone Acantholysis, spongiosis, nuclear/ these occur being both irritant and concentration de- intracytoplasmic vacuolation pendent. Spongiosis is also widely described, but is again variable in magnitude between irritants and the tion into the epidermis, making them largely indistin- concentration at which they are applied. In the main, guishable from those of ACD. however, spongiosis is much less marked in ICD than In a study comparing the cellular responses to six in allergic contact dermatitis (ACD), although there different irritants after 48-h patch testing, the use of are exceptions, most notably in the reactions to croton plastic embedding media, which facilitates high reso- oil, a mixture of chemicals including 12-O-tetradec- lution light microscopy, permitted the visualization anoylphorbol-13-acetate, where extensive spongiosis of subtle changes to keratinocytes which highlight and vesiculation frequently arise (Fig. 1). Exocytosis, the irritant-dependent nature of ICD [2]. In reactions also, is generally less pronounced in ICD, although, judged visually to be mild to moderate, the anionic again, reactions to croton oil show extensive infiltra- detergent, sodium lauryl sulphate, for example, in- 37 Histopathology of Irritant Contact Dermatitis 347 Fig. 1. Toluidine blue-stained 1-µm plastic section of skin Fig. 2. Skin biopsy taken from an individual patch tested for taken from a healthy individual patch tested for 48 h with cro- 48 h with the anionic detergent, SLS (4%). Marked parakerato- ton oil (0.08%). Extensive spongiosis and exocytosis of pre- sis in the epidermis is evident, a characteristic feature of reac- dominantly mononuclear cells are induced in the epidermis, tions to this irritant and one that is indicative of an increased making the reaction largely indistinguishable from that of density of proliferating keratinocytes (haematoxylin and eosin acute ACD (original magnification ×200) stained paraffin section; original magnification ×400) Fig. 3. Frozen sections immunoperoxidase labeled with a monoclonal antibody to the Ki-67 (proliferation associated nuclear) anti- gen. (A) The baseline density of dividing keratinocytes in a biopsy of normal volar forearm skin. (B) The marked increase in the num- ber of proliferating keratinocytes seen in the same individual after 48-h patch testing with SLS (4%) (original magnifications 00)×2 Fig. 4. 48-h human patch test reaction to the 12C long-chain fatty acid, nonanoic acid (80%), showing by light (A; toluidine blue- stained 1 µm plastic section; original magnification ×200) and electron microscopy B( ; original magnification ×4000), the tongues of dyskeratotic keratinocytes extending downwards from the stratum granulosum into the stratum spinosum, commonly induced by this irritant duced primarily parakeratosis, a feature indicative of in vitro studies [20–23]. Of significance to our under- enhanced keratinocyte proliferation (Fig. 2). Confir- standing of the pathogenesis of ICD is the fact that not mation that this is indeed a significant physiological all detergents exert this effect after 48 h; the cationic response to SLS at this time point was subsequently detergent, benzalkonium chloride, tested in parallel obtained immunocytochemically using an antibody on