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Retinoids Strongly and Selectively Correlate with Keratin 13 and Not Keratin 19 Expression in Cutaneous Warts of Renal Transplant Recipients

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Retinoids Strongly and Selectively Correlate with Keratin 13 and Not Keratin 19 Expression in Cutaneous Warts of Renal Transplant Recipients STUDY Retinoids Strongly and Selectively Correlate With Keratin 13 and Not Keratin 19 Expression in Cutaneous Warts of Renal Transplant Recipients Willeke A. M. Blokx, MD; Jurgen V. Smit, MD; Elke M .G. J. de Jong, MD, PhD; Monique M. G. M. Link; Peter C. M. van de Kerkhof, MD, PhD; Dirk J. Ruiter, MD, PhD Objective: To compare the expression of keratin (K) Results: A significantly higher percentage of warts of 13 and K19 in cutaneous warts of renal transplant re- RTRs expressed K13 compared with warts of ICIs (86% cipients (RTRs) and immunocompetent individuals (ICIs). vs 14%, 18 vs 3 cases, respectively; PϽ.001). In warts of RTRs, retinoid treatment correlated significantly with a Design: Retrospective, nonrandomized immunohisto- particularly strong, segmental K13 expression pattern, chemical study. which we termed zebroid. Without use of retinoids, K13 was mostly restricted to suprabasal single cells. Keratin Patients and Methods: Specimens from cutaneous 19 was absent in all warts of both patient groups. warts of RTRs and ICIs were retrieved from the archives of the Department of Pathology, University Medical Cen- Conclusions: Retinoids strongly correlate with K13 in ter St Radboud, Nijmegen, the Netherlands. Twenty- a characteristic zebroid pattern in warts of RTRs, mak- one warts from RTRs and 21 from ICIs were examined. ing K13 a sensitive marker for retinoid bioactivity in Nine RTRs (10 specimens) received either systemic ac- skin (lesions) of RTRs. In non–retinoid-treated RTRs, itretin or topical all-trans retinoic acid, and their effect K13 is also frequently found in warts but without the on both keratins was assessed. dramatic zebroid pattern noted in retinoid-treated warts. Main Outcome Measures: Frequency and expres- sion patterns of K13 and K19 in warts of RTRs vs ICIs and the effect of retinoids. Arch Dermatol. 2002;138:61-65 PITHELIAL KERATINS com- In the past few years, several murine prise a heterogenous group and in vitro studies have demonstrated that of acidic (type I) and neu- vitamin A and its derivates (retinoids) are tral-to-basic (type II) pro- important regulators of epidermal differ- teins. As a general rule, they entiation and affect keratin gene expres- Eare coexpressed in specific pairings, each sion. In cultured keratinocytes, the induc- pair consisting of a type I and a type II kera- tion of an embryonic type of differentiation tin (K). For instance, in normal adult skin, by retinoids with reinduction of K13 and keratin pairs K5/K14 and K1/K10 pre- K19 expression has been well docu- dominate in the basal layer and the su- mented.5,6 In vivo topical application of prabasal compartment, respectively.1 retinoids on photo-aged human skin also The type I keratins K13 and K19 are showed induction of K13.7 usually expressed separately in adult epi- Although retinoids are used as chemo- thelia. Combined expression occurs only in preventive agents for inhibiting skin cancer fetal skin. Both keratins are thought to be in renal transplant recipients (RTRs),8,9 to absent in normal skin of adults except at cer- the best of our knowledge there are no tain body sites, such as the penile foreskin, studies regarding the effects of retinoids on From the Departments of which still contains K13. Furthermore, K13 keratin expression in the skin or skin le- Pathology (Drs Blokx and is abundantly present in adults in internal sions of these patients. Ruiter and Ms Link) and Dermatology (Drs Smit, stratified epithelia and is associated (with Renal transplant recipients develop de Jong, and van de Kerkhof), terminal differentiation) with suprabasal ex- multiple warts and skin neoplasms. Immu- 1-4 University Medical Center pression. Expression of K19 in adults is nosuppressive treatment, sun exposure, and St Radboud, Nijmegen, the found in simple epithelia, such as most glan- viral infection with human papillomavirus Netherlands. dular epithelia. are all implicated in the etiology of cutane- (REPRINTED) ARCH DERMATOL / VOL 138, JAN 2002 WWW.ARCHDERMATOL.COM 61 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 MATERIALS AND METHODS verrucae plana, especially in ICIs, usually on the hands and feet. Condyloma acuminata and anogenital warts were not included. TISSUE SAMPLES IMMUNOHISTOCHEMICAL ANALYSIS For this retrospective immunohistochemical study, we re- trieved formalin-fixed and paraffin-embedded skin speci- Immunohistochemical analysis was performed on all speci- mens from warts of RTRs (21 specimens from 18 patients; mens by using standard avidin-biotin-peroxidase com- average age, 50.8 years; mean duration of immunosuppres- plex system with either diaminobenzidine and/or 3-amino- sion, 16.4 years) and healthy ICIs (21 specimens from 19 9-ethylcarbazole as the chromogens. In brief, 4-µm-thick patients; average age, 33.3 years) from archival material at paraffin sections were deparaffinized, hydrated, and washed the Department of Pathology, University Medical Center in buffered phosphate. St Radboud, Nijmegen, the Netherlands. For K13 staining, sections were cooked in buffered ci- trate (10mM, pH 6.0) in a microwave oven 2 times for 5 RETINOID TREATMENT minutes each (600 W). After a cooling down period of (at least) 20 minutes and preincubation with 20% normal horse Nine RTRs (10 specimens) received retinoids. In 3 pa- serum for 15 minutes, the sections were incubated with un- tients (4 specimens), topical all-trans retinoic acid (con- diluted primary antibody overnight at 4°C. We used 2 mouse centration, 0.025%-0.05%) was used, and 6 patients re- monoclonal primary antibodies, 1C7 (immunoglobulin G2a) ceived systemic acitretin (dose at time of biopsy, 10-35 mg). and 2D7 (immunoglobulin G2b), both recognizing K13.17 Patients taking systemic acitretin participated in a clinical As a positive control, normal esophageal tissue was used. trial, unrelated to the present study, studying the effects After incubation with primary antibodies, sections were in- of systemic retinoids on cutaneous carcinogenesis in RTRs. cubated for 30 minutes with biotinylated horse antimouse Inclusion criteria for this trial were either the presence of (1:200 dilution) (Vector Laboratories, Burlingham, Calif), at least 1 squamous cell carcinoma (SCC) in the patient’s followed by incubation for 45 minutes with avidin-biotin history or the presence of 10 or more actinic keratoses, with complex (1:50 dilution) (Vector Laboratories). For devel- at least 1 confirmed histologically. Initially, most patients opment with 3-amino-9-ethylcarbazole, avidin-biotin com- taking acitretin started with 30 to 35 mg/d, a dosage that plex concentrations were doubled. prevented SCCs in RTRs in an earlier study.8 However, in For K19 immunohistochemical analysis, (mouse) a relatively large number of patients, doses of acitretin had monoclonal antibody RCK 108 (Biogenex, San Ramon, to be lowered because of mucocutaneous adverse effects Calif) was used. Besides different pretreatment (0.1% pro- (peeling of palms and soles and/or cheilitis). Retinoid- and nase for 10 minutes), the same procedure as used for K13 non–retinoid-treated patients showed no obvious differ- was followed. Eccrine ducts and sweat glands served as posi- ences with respect to duration, dosage, and type of immu- tive internal controls. Sections were counterstained with nosuppression, all factors implied in the etiology of skin Mayer hematoxylin for 2 minutes. cancers in immunosuppressed patients (data not shown). Immunoreactivity was scored as negative, slightly posi- tive in a suprabasal single-cell pattern (Ͻ10% lesional ke- HISTOPATHOLOGIC EXAMINATION ratinocytes positive), or strongly positive in a suprabasal segmental columns pattern (zebroid pattern). Scoring was Histologic examination of all studied lesions was revised performed without knowledge of patient history and use according to World Health Organization definitions of ver- of retinoid therapy. rucae.16 The verrucae consisted predominantly of com- The Pearson ␹2 test was used for all statistical analy- mon warts or verrucae vulgares, with a smaller group of ses, and significance was set at PϽ.05. ous tumorigenesis in RTRs.10-14 The frequent simulta- of retinoids on K19 expression in these patients. Retinoid- neous occurrence of warts and skin cancers in RTRs led related K13 expression in epithelial skin lesions of RTRs us to the assumption that the verrucae or warts in RTRs displays a highly characteristic pattern, which we termed might be more prone to become malignant than equiva- zebroid, making K13 a useful marker for evaluating the lent lesions in healthy immunocompetent individuals (ICIs). effect of retinoid treatment in these patients. The existence of high- and low-risk papillomas was pre- viously shown in mice models of cutaneous carcinogen- esis.15 Interestingly, these high-risk papillomas expressed RESULTS K13, which was absent in low-risk papillomas. The present study shows that RTR-associated warts GENERAL ASPECTS OF IMMUNOSTAINING in contrast to warts in normal ICIs indeed show pro- FOR K13 AND K19 nounced K13 expression.This suggests that altered kera- tin expression may reflect an important molecular event In all cases, immunostaining for K13 was restricted to inherent in the malignant degeneration of warts in RTRs. the cytoplasm. Slight variations in staining intensity were Furthermore, this K13 expression in warts of RTRs observed in lesional skin comparing antibodies 1C7 and strongly correlates with retinoid therapy, but, in con- 2D7 with overall stronger staining with the 2D7 anti- trast to findings in animal studies and in cultured hu- body. Principally, however, the staining pattern of le- man keratinocytes,5 we could not demonstrate an effect sional skin with both antibodies was identical. Normal (REPRINTED) ARCH DERMATOL / VOL 138, JAN 2002 WWW.ARCHDERMATOL.COM 62 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 1. K13-Positive and K13-Negative Warts in RTRs and ICIs* Warts, No. (%) RTRs ICIs (n = 21) (n = 21) A B K13 positive 18 (86) 3 (14) K13 negative 3 (14) 18 (86) *K13 indicates keratin 13; RTRs, renal transplant recipients; and ICIs, immunocompetent individuals.
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