Prevalence of Hydropic Degeneration of Epidermal Basal Cells in Equine Inflammatory Skin Diseases

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1 獣医臨床皮膚科 20 (4): , 2014 Original Prevalence of Hydropic Degeneration of Epidermal Basal Cells in Equine Inflammatory Skin Diseases 馬の炎症性皮膚疾患における表皮基底細胞の空胞変性の発生率 Carolyn B. Emery 1, Danny W. Scott 1 *, Hollis N. Erb 2 1 Department of Clinical Sciences and 2 Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University Received July 7, 2014 and accepted September 29, 2014 Abstract: There is controversy in the veterinary literature over the importance and even the definition of hydropic degeneration of epidermal basal cells. We performed a retrospective histopathological study on the prevalence of hydropic degeneration of epidermal basal cells (strictly defined) in skin-biopsy specimens from 299 horses with various inflammatory dermatoses and 27 horses with normal skin. Hydropic degeneration of epidermal basal cells was significantly associated with a small group of immune-mediated dermatoses characterized by an interface dermatitis histopathological reaction pattern: adverse cutaneous drug reaction, discoid lupus erythematosus, erythema multiforme, and systemic lupus erythematosus. Key words: dermatohistopathology, horses, hydropic degeneration, skin 要約 : 獣医学文献においては, 表皮基底細胞の空胞変性に関する重要性のみならず, 定義についても未だ統一された見解が得られていない 本研究では各種炎症性皮膚疾患に罹患した 229 頭の馬と, 健常な皮膚を有する 27 頭の馬を対象に, 表皮基底細胞の空胞変性と明確に定義できる病理組織変化の発生率に関する後向き研究を行った 表皮基底細胞における空胞変性は免疫介在性皮膚疾患群と有意に関連して認められ, これらの症例では組織学的に境界部皮膚炎の反応パターンが認められた 前述の疾患群に含まれる疾患には, 皮膚薬物有害反応, 円板状エリテマトーデス, 多形紅斑, 全身性エリテマトーデスがみられた キーワード : 皮膚病理組織学, 馬, 空胞変性, 皮膚 (Jpn J Vet Dermatol 2014, 20 (4): ) Introduction Hydropic degeneration of epidermal basal cells (HD) is defined as intracellular edema restricted to keratinocytes of the basal cell layer (stratum basale) 1 4, 7, 14, 16, 21). Synonyms for HD include liquefaction degeneration, vacuolar degeneration, vacuolar alteration, and cloudy swelling 1, 5, 7, 14, 16 18, 21, 22). HD is a common histopathological finding in a cutaneous reaction pattern * Correspondence to: Danny W. Scott (Department of Clinical Sciences, College of Veterinary Medicine, Cornell University), Ithaca, New York , USA FAX shb3@cornell.edu termed interface dermatitis 1, 2, 4, 14, 16). The interface dermatitis reaction pattern is uncommon 8 10) and, if seen, is usually associated with various immune-mediated disorders 1, 2, 4, 14, 16). Some authors have suggested that HD is encountered in a variety of superficial inflammatory dermatoses in the horse and seems to lack the specificity it has in humans and other species of domestic animals 20). Other authors do not agree 16). In addition, we are not aware of any published studies that address the prevalence and specificity of HD in the dermatopathology of any host species. Our purpose in this study was to document the

2 218 Hydropic degeneration in horse skin prevalence of HD in skin-biopsy specimens from horses with normal skin or various inflammatory dermatoses. We were particularly interested to learn if there was a statistically significant association between the prevalence of HD and a group of specific dermatoses associated with an increased frequency of HD in the anecdotal equine literature. Materials and Methods A retrospective study of skin-biopsy specimens from 299 horses with inflammatory skin disease was performed. These were all of the equine inflammatory skin-biopsy specimens that had been procured with a 6-mm biopsy punch and submitted to the Pathology Service at the College of Veterinary Medicine at Cornell University from 1975 to 2007, processed routinely for histopathological evaluation, and stained with hematoxylin and eosin, and for which the Dermatology Service had follow-up information. All diagnoses (Table 1) were confirmed by standard clinical, clinicopathological, and histopathological criteria 16). In addition, skin-biopsy specimens were taken from the dorsolateral thorax of 27 horses with normal skin that had been submitted to our Necropsy Service in Because we wanted to follow routine procedures in diagnostic pathology, serial sections were not examined. One section of tissue was examined per slide. If multiple specimens were present on a slide, the section with the least amount of artifact was chosen for evaluation. One author (CBE), who was blinded to the diagnoses, examined all specimens for HD. For two-thirds of the cases with inflammatory skin disease and 100% of the normal horses, the second author (DWS) also examined the specimens to ensure reproducibility of the findings. For this study, HD was defined as intracellular edema of keratinocytes restricted to the stratum basale (Fig. 1). Intracellular edema of keratinocytes in multiple epidermal layers (stratum basale, stratum spinosum, stratum granulosum) (IE) (Fig. 2) was separately recorded and was not included in this study among the cases listed as HD. Statistical Analysis The 299 inflammatory dermatosis specimens were divided into two mutually exclusive groups: those conditions wherein HD is not frequently reported in the literature (inflammatory but not suspected to be HD-related = group NonSuspHDInfl) and those conditions wherein HD is frequently seen (or suspected ) (inflammatory and suspected to be HD-related = group SuspHDInfl) 2, 4, 14, 16). Group SuspHDInfl consisted of erythema multiforme (EM), discoid lupus erythematosus (DLE), systemic lupus erythematosus (SLE), and adverse cutaneous drug reaction (ACDR) 11 13, 16). Group Normal consisted of 27 horses with normal skin. The Wilson s score 95% confidence interval (CI) was calculated for each group. All groups were compared in 3 pair-wise (2-by-2 table) Fisher s exact tests for HD cells and then for 3 Fisher s exact tests for IE. We used Fisher s test because the expected values for HD did not meet the expected-value assumption for chisquare. Because multiple tests were run for both HD and IE, we compared the p-values to the Bonferroniadjusted two-sided p-value of (= 0.05/3). The Bonferroni adjustment or correction was used to calculate the new p-value criterion for each individual statistical test to be declared significant. The program used for the calculation was Statistix (Statistix 10.0, 2013, Analytical Software, Tallahassee, FL, USA). The programs used within Statistix: Hypothesis Test-One proportion (and the Wilson score CI with continuity correction) and Two by Two Tab. Results One or more areas of HD were seen in 13 of 299 horses with inflammatory dermatoses, for a prevalence of 4%. Twelve of the positive biopsies were in the 26 horses of group SuspHDInfl, for a prevalence of 46% (95% confidence interval: 27%, 66%). Only one horse (dermatophytosis due to Trichophyton equinum) among the 273 in group NonSuspHDInfl was positive for HD, giving a prevalence of 0.37% (95% confidence interval: 0.02%, 2%). Group Normal horses had a prevalence of 0% (0/27; 95% confidence interval 0%, 16%). Although the prevalence of HD might be as high as 16% in a different sample of normal horses, the lowest we would expect in an different sample of SuspHDIfl horses would be a prevalence of 27%. The prevalence of HD was significantly greater (p<0.0001; Fisher s exact tests) in SuspHDInfl horses (Fig. 3) than it was in group NonSuspHDInfl and group Normal (consistent with the non-overlap of the confidence intervals between the SuspHDInfl group

3 Emery C.B., et al. 219 Table 1. Prevalence of hydropic degeneration of epidermal basal cells (HD) in horse with inflammatory dermatoses and horses with healthy skin Dermatosis # of cases # with HD % with HD Inflammatory but Not Suspected to be HD-Related Allergic dermatitis* Atopic dermatitis Bacterial cellulitis Bacterial folliculitis Bacterial granuloma Bullous pemphigoid Chorioptic mange Contact dermatitis Demodectic mange Dermatophilosis Dermatophytosis Eosinophilic granuloma Exuberant granulation tissue Foreign body granuloma Fungal granuloma Habronemiasis Hypodermiasis Insect hypersensitivity Multisystemic eosinophilic exfoliative disease Onchocerciasis Pediculosis Pemphigus foliaceus Photodermatitis Primary seborrhea Sarcoidosis Self-mutilation Sterile eosinophilic folliculitis Sterile granuloma Sterile panniculitis Unilateral papular dermatosis Urticaria* Vasculitis Ventral midline dermatitis Healthy skin Inflammatory and Suspected to be HD-Related Discoid lupus erythematosus Drug reaction Erythema multiforme Systemic lupus erythematosus *These horses had atopic dermatitis, food allergy, or both of these. Allergy testing was not performed. and the other two groups). The prevalence of HD was not significantly different p>0.99) between groups NonSuspHDInfl and Normal (as shown also in their greatly overlapping confidence intervals). The prevalence of IE was 16% for group NonSuspHDInfl, 12% for group SuspHDInfl (Fig. 4),

4 220 Hydropic degeneration in horse skin Fig. 1. Skin-biopsy specimen from a horse with erythema multiforme. Note marked hydropic degeneration of epidermal basal cells (black arrows), lymphocytic interstitial inflammation, dilated and engorged blood vessels (blue arrow), and pigmentary incontinence (yellow arrow). H&E stain 400. Fig. 2. S k i n - b i o p s y s p e c i m e n f r o m a h o r s e w i t h dermatophilosis. Note marked intracellular edema of keratinocytes (arrows) in all layers of the epidermis. H&E stain 400. Fig. 3. Skin-biopsy specimen from a horse with systemic lupus erythematosus. Note marked hydropic degeneration of epidermal basal cells (arrow). H&E stain 600. Fig. 4. Skin-biopsy specimen from a horse with systemic lupus erythematosus. Although there is intracellular edema of epidermal basal cells (black arrows), we did not classify it as hydropic degeneration due to the presence of intracellular edema of keratinocytes in other epidermal layers (yellow arrow). H&E stain 400. and 0% for group Normal. There was no significant difference (p=0.78) in the prevalence of IE between groups NonSuspHDInfl and SuspHDInfl. The prevalence of IE was significantly greater (p=0.02) in both groups NonSuspHDInfl and SuspHDInfl than it was in group Normal. Discussion Much inconsistency and, therefore, much confusion exist in the way the term hydropic degeneration is used in veterinary pathology. In dermatology, the term is specifically used to indicate intracellular edema that is restricted to the basal cell layer (stratum basale) of the 2, 4, 14, 16) epidermis. In general pathology, the term is used to describe intracellular edema in any or all layers of the 5, 17, 18, 22). epidermis In this study, we have shown that when HD is strictly defined and evaluated, it is significantly associated with

5 Emery C.B., et al. 221 a small group of interface dermatitides in horses: EM, DLE, SLE, and ACDR. Conversely, intracellular edema of keratinocytes in multiple epidermal layers does not distinguish between interface dermatitides and any other inflammatory dermatoses of horses. Interface dermatitis is an uncommon histopathological reaction in domestic animals 2, 4, 14, 16). It has been reported to account for 8%, 5.1%, and 3% of the inflammatory cutaneous reaction patterns in cows 8), horses 9), and cats 10), respectively. In our study of 299 horses with inflammatory dermatoses, interface dermatitis was present in 8.7% of the cases. HD was seen in 46% of the interface dermatitis reaction patterns in our study. Interface dermatitis is characterized by combinations of the following histopathological findings: (1) HD, (2) apoptotic keratinocytes, (3) pigmentary incontinence, (4) focal thickening of the basement membrane zone, and (5) a lymphocytic infiltration that obscures the dermoepidermal junction 2, 4, 14, 16). Not surprisingly, not all changes are present in every biopsy specimen. In the interface dermatitis cases in our study that did not have HD (16/26; 54%), at least 3 of 4 other findings listed above were present. In our study, only 1 horse without an interface dermatitis had HD: the horse had dermatophytosis associated with Trichophyton equinum. HD is rarely reported in dermatophytosis, specifically in dogs with Microsporum persicolor infection 6). In dogs, M. persicolor infection is associated with HD and an interface dermatitis, presumably as a result of an unusual lymphocytic cell-mediated immune response engendered by the fungus. HD was not seen in normal skin from 27 horses in our study. This is in agreement with previous reports wherein HD was not seen in normal equine skin from 35 different body sites 15, 19). In conclusion, we have demonstrated that HD as strictly defined in our study and by others 1 4, 14, 16, 21) is significantly associated with a small group of immunemediated equine dermatoses. We strongly encourage veterinary pathologists to adopt these strict criteria. Doing so will decrease the confusion that currently exists in the veterinary literature, as well as increase diagnostic precision for our patients. References 1) Ackerman, A.B pp In: Histologic Diagnosis of Inflammatory Skin Diseases. Lea & Febiger, Philadelphia. 2) Bettenay, S.V. and Hargis, A.M p. 66. In: Practical Veterinary Dermatopathology. Teton New Media, Jackson. 3) Elder, D.E., Elenitas, R., Johnson, B.L. and Murphy, G.F p In: Lever s Histopathology of Skin, 9 th ed. Lippincott Williams & Wilkins, Philadelphia. 4) Ginn, P.E., Mansell, J.E.K.L. and Rakich, P.M pp Skin and appendages. In: Maxie, M.G. (ed.). Jubb, Kennedy, and Palmer s Pathology of Domestic Animals, 5 th ed., vol. 1. Saunders Elsevier, Philadelphia. 5) Kumar, V., Abbas, A.K., Fausto, N. and Aster, J.C p. 13. In: Pathologic Basis of Disease, 8 th ed. Saunders Elsevier, Philadelphia. 6) Muller, A., Guaguère, E., Degorce-Rubiales, F. and Bourdoiseau, G Dermatophytosis due to Microsporum persicolor: a retrospective study of 16 cases. Can. Vet. J. 52: ) Pinkus, H Lichenoid tissue reactions: a speculative review of the clinical spectrum of epidermal basal cell damage with special reference to erythema dyschronicum perstans. Arch. Dermatol. 107: ) Scott, D.W Analyse de la modalité de réaction histopathologique dans le diagnostic des dermatoses inflammatoires chez les bovins. Point Vét. 23: ) Scott, D.W Diagnostic des dermatoses inflammatoires équines: analyse de la modalité de réaction histopathologique: étude personnelle portant sur 315 cas. Point Vét. 24: ) Scott, D.W Analyse du type de réaction histopathologique dans le diagnostic des dermatoses inflammatoires chez le chat: étude portant sur 394 cas. Point Vét. 26: ) Scott, D.W Le lupus discoïde équin: description de trois cas. Point Vét. 22: ) Scott, D.W. and Miller, W.H. Jr Idiosyncratic cutaneous adverse drug reactions in the horse: literature review and report of 19 cases ( ). Equine Pract. 19: ) Scott, D.W. and Miller, W.H. Jr Erythema

6 222 Hydropic degeneration in horse skin multiforme in the horse: literature review and report of 9 cases ( ). Equine Pract. 20: ) Scott, D.W. and Miller W.H. Jr p In: Muller & Kirk s Small Animal Dermatology, 6 th ed. W.B. Saunders, Philadelphia. 15) Scott, D.W Skin of the neck, mane, and tail of the curly horse. Equine Vet Educ 16: ) Scott, D.W. and Miller, W.H. Jr pp , In: Equine Dermatology, 2 nd ed. Elsevier Saunders, Maryland Heights. 17) Slauson, D.O. and Cooper, B.J pp In: Mechanisms of Disease. A Textbook of Comparative Pathology, 3 rd ed. Mosby, St. Louis. 18) Stegman, J.K p In: Stedman s Medical Dictionary, 28 th ed. Lippincott Williams & Wilkins, Philadelphia. 19) Talukdar, A.H., Calhoun, M.L. and Stinson, A.W Microscopic anatomy of the skin of the horse. Am. J. Vet. Res. 33: ) Von Tscharner, C., Kunkle, G. and Yager, J Stannard s illustrated equine dermatology notes - an introduction. Vet. Dermatol. 11: ) Weedon, D The lichenoid tissue reaction. Int. J. Dermatol. 21: ) Zachary, J.F. and McGavin, M.D p In: Pathologic Basis of Veterinary Disease, 5 th ed. Elsevier, St. Louis.