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International Journal of Pediatric Otorhinolaryngology 184 (2024) 112079 Contents lists available at ScienceDirect International Journal of Pediatric Oto...

International Journal of Pediatric Otorhinolaryngology 184 (2024) 112079 Contents lists available at ScienceDirect International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl Histological analysis of glucocorticoid receptor and eosinophilic cytokines in the adenoid mucosal epithelium Kosuke Tochigi a,* , Kazuhiro Omura b , Saaya Hattori a , Mikiya Asako c , Yasuhiro Tanaka a a Department of Otorhinolaryngology/Head and Neck Surgery, Dokkyo Medical University Saitama Medical Center, Saitama, Japan b Department of Otorhinolaryngology/Head and Neck Surgery, The Jikei University School of Medicine, Tokyo, Japan c Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University Medical Center, Osaka, Japan A R T I C L E I N F O A B S T R A C T Keywords: Objective: In recent years, the clinical efficacy of medications for adenoid hypertrophy has been demonstrated. Glucocorticoid receptor Topical nasal steroids have effects to shrink hypertrophic adenoids and improve symptoms of associated diseases. Sleep apnea However, the mechanism which topical steroid administrations cause adenoid shrinkage remains unclear, herein, Otitis media sensitivity for topical steroids in the mucosal epithelium of adenoids was evaluated histologically by comparing Eosinophilic inflammations with tonsils. Methods: Histological analysis was performed on adenoids and tonsils removed from 32 pediatric patients with adenoid hypertrophy. In hematoxylin-eosin-stained specimens, the morphology of the mucosal epithelium and eosinophil infiltration were evaluated. The expression of the glucocorticoid receptor (GR), interleukin (IL)-4, and IL-25 in the mucosal epithelium was evaluated, and the staining intensity was scored as 0 (none), 1 (weak), and 2 (strong). The number of eosinophils and expression scores of GR, IL-4, and IL-25 were statistically compared between adenoids and tonsils and analyzed correlations with adenoids sizes. Results: Adenoids were covered with ciliated epithelium, and eosinophils in the mucosal epithelium and sub­ mucosal area was higher than tonsils (p < 0.05). GR expression in the most superficial layer of the mucosal epithelium was observed in adenoids, and the expression intensity score was higher than that in tonsils (p < 0.05). IL-4 and IL-25 were more widely expressed in the mucosal epithelium of adenoids than in tonsils, and their expression intensity scores were also higher than in tonsils (p < 0.05). A correlation was found between adenoid size and the intensity of IL-25 expression in the adenoid epithelium (p < 0.05). Conclusion: Eosinophilic inflammations in adenoids mucosal epithelium could be one of etiology of adenoid hypertrophy, and the GR and eosinophilic inflammation in the adenoids mucosal epithelium might be target of topical nasal steroids to shrink hypertrophic adenoids. 1. Introduction adenoids has not been well studied [7–9]. The intensity of steroid receptor expression in the target tissue, in Adenoids sometimes grow excessively and cause upper airway addition to the concentration and total amount of steroids reaching the obstruction and eustachian tube dysfunction, leading to nasal conges­ tissue, determines the efficacy of topical steroid treatments [10,11]. tion, sleep apnea, and otitis media in childhood. In recent years, Studies have been conducted on the relationship between the intensity medical treatments have proven their effects in shrinking adenoids and of steroid receptor expression and the therapeutic effects of steroids improving symptoms in cases of sleep apnea and otitis media caused by across various disciplines, including dermatology, nephrology, and adenoid hypertrophy [2–6]. Especially in many medications, the effi­ rhinology [12–14]. However, few studies have investigated focusing on cacy and safety of topical nasal steroids for adenoid hypertrophy have the mucosal epithelium of adenoids, where nasal steroids directly reach been demonstrated in some clinical studies. Although the clinical and act, and the expression of steroid receptors has not been analyzed in effectiveness of topical nasal steroids has been well demonstrated, the detail. mechanism by which steroids administered through the nostrils shrink Ideally, it would be clarified whether topical nasal steroids have an * Corresponding author. 2-1-50 Minami-Koshigaya, Koshigaya-shi, Saitama, 343-8555, Japan. E-mail addresses: [email protected], [email protected] (K. Tochigi). https://doi.org/10.1016/j.ijporl.2024.112079 Received 20 April 2024; Received in revised form 7 August 2024; Accepted 19 August 2024 Available online 20 August 2024 0165-5876/© 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies. K. Tochigi et al. International Journal of Pediatric Otorhinolaryngology 184 (2024) 112079 anti-inflammatory effect on adenoids and reduce their size by per­ 2.4. Expression of cytokines related to eosinophilic inflammation in forming histological evaluations before and after topical steroids use mucosal epithelium within the same patient. However, due to ethical aspects, collecting tissues from patients especially before medical treatments is difficult. The expressions of interleukin (IL)-4 and IL-25 in the mucosal Therefore, the purpose of this study was to analyze histological features epithelium of the adenoids and tonsils were evaluated immunohis­ in the epithelium of adenoids and tonsils collected before the medica­ tochemically using primary antibodies (anti-IL-4 antibody [ab239508, tions, and to evaluate whether adenoids mucosal epithelium have a Abcam, Cambridge, UK] and anti-IL-25 antibody [ab108530, Abcam, sensitivity for topical steroid therapy. Cambridge, UK]) and a secondary antibody (Histofine Simple Stain Focusing on glucocorticoids, which are the main components of MAX-PO [Nichirei, Tokyo, Japan]). The staining intensity was evaluated topical steroids, the expression of glucocorticoid receptors in the and determined in the same manner as for GR staining. mucosal epithelium was immunohistochemically evaluated. Further­ more, eosinophilic inflammation, one etiology of adenoid hypertrophy 2.5. Statistical analysis and could be a target for topical steroids [1,15], was also analyzed in histology and immunohistochemically. Data were expressed as mean ± standard deviation. Normality was examined using the Shapiro-Wilk test, and a Mann-Whitney U test was 2. Materials and methods applied to compare the number of eosinophils and the expression in­ tensity scores of GR, IL-4, and IL-25. To evaluate the range of the This research protocol was approved by the Dokkyo Medical Uni­ mucosal epithelium in which GR, IL-4, and IL-25 were expressed, the versity Saitama Medical Center Clinical Research Ethics Review Com­ number of visual fields positive for GR, IL-4, and IL-25 was compared mittee (No. 22073) and informed consent was obtained in an opt-out between adenoids and tonsils using the chi-square test. The correlation form. between adenoid size, and the number of eosinophils and the expression intensity scores of GR, IL-4, and IL-25 in the epithelium was evaluated using the Spearman correlation rank test. SPSS version 28 (IBM, 2.1. Patient selection and patients’ status Armonk, NY, USA) was used for statistical analyses, and a p-value of less than 0.05 was considered statistically significant. Among the pediatric patients with sleep apnea syndrome, only who underwent both adenoidectomy and tonsillectomy, between 2021 and 2023, 32 patients were included who did not use topical nasal steroids in 3. Results the month before surgery to exclude their influence. The indications for surgery were when the 3 % Oxygen desaturation index (ODI), measured 3.1. Patients’ backgrounds and patients’ status using a portable sleep-monitoring device, was 1 or higher, and sleep disorders such as apnea or daytime sleepiness interfering with daily life The mean age of the patients was 5.0 ± 2.3 (range: 2–14) years. Among the 32 patients, 22 were male and 10 were female. All 32 pa­ and adenotonsillar hypertrophy were confirmed [16–18]. The history of allergic rhinitis, asthma, and atopic dermatitis were tients suffered from sleep apnea syndrome, and five were also compli­ cated by otitis media with effusion. The mean 3 % ODI in all patients was collected from medical records. The total white blood cell count, eosinophil percentage, and total eosinophil count were also collected 13.6 ± 22.2. Allergic rhinitis was present in 9 cases, asthma in 4 cases, and atopic dermatitis in 2 cases. Twelve cases were associated with any using results of blood tests performed before surgery. Using the same of these allergic diseases. The mean size of the adenoids, as measured by method with previous reports, the size of the adenoid, as pharyngeal tonsil thickness, was calculated by lateral X-rays measuring the distance lateral X-rays, was 17.6 ± 3.4 mm. Total white blood cell count was 7871.9 ± 2882.0/μL, the eosinophil percentage in preoperative blood from the bone of the nasopharynx to the tip of the adenoid [19,20]. tests was 4.2 ± 2.7 %, and the eosinophil count was 312.2 ± 198.7/μL. 2.2. Mucosal epithelial morphology and eosinophil infiltration 3.2. Mucosal epithelial morphology and eosinophil infiltration in HE- stained specimens The morphology of the mucosal epithelium covering the tissue sur­ face was evaluated using hematoxylin and eosin (HE) stained specimens A ciliated columnar epithelium was observed in adenoids of all cases. of adenoids and tonsils. Focusing on the presence of ciliated cells, the In contrast, a stratified squamous epithelium was observed in tonsils epithelium was classified as a ciliated columnar epithelium or stratified (Fig. 1A and B). The number of eosinophils observed in the mucosal squamous epithelium. epithelium and submucosal area was significantly higher in adenoids The mucosal epithelium and submucosal area were observed with a (4.7 ± 2.2/field) compared to tonsils (0.3 ± 0.5/field) (p < 0.05) microscope under a 400x field of view, and the number of eosinophils (Fig. 1C and Table 1). was counted in randomly selected fields. 3.3. Immunohistology analysis for the glucocorticoid receptor, IL-4 and 2.3. Expression of the glucocorticoid receptor in the mucosal epithelium IL-25 Immunohistochemical staining for the glucocorticoid receptor (GR) In tonsils, GR expression was solely observed in the basal side of the was performed using a primary antibody (anti-GR antibody [24050-1- stratified squamous epithelium, with poor presence in cells located in AP; Proteintech, Chicago, IL, USA]) and a secondary antibody (Histo­ the most superficial layer. In contrast, GR expression was observed in a fine Simple Stain MAX-PO [Nichirei, Tokyo, Japan]). The staining in­ wide range of the ciliated columnar epithelium of adenoids (Fig. 2A). GR tensity in the most superficial cells of the mucosal epithelium, where expression was observed over a wider area in the surface layer of the topical steroids are expected to reach and act, was evaluated with a mucosal epithelium of adenoids (79.2 %, 76/96) compared to tonsils microscope under a 200x field of view. Compared to a negative control (22.9 %, 22/96) (p < 0.05) (Table 1). The expression intensity scores that was stained only with the primary antibody, the staining intensity were significantly higher in adenoids (0.9 ± 0.4) compared to tonsils was scored as 0 (non-stained), 1 (weak-moderate), and 2 (strong) based (0.2 ± 0.2) (p < 0.05) (Fig. 2B and Table 1). on prior literatures [21,22]. The average value of three randomly Expressions of IL-4 and IL-25 were observed in the mucosal epithe­ selected visual fields was determined as the GR expression intensity lium of tonsils and adenoids; however, it was weaker in tonsils, and score in one case. strong expression was observed in a wider area of adenoids. IL-4 was 2 K. Tochigi et al. International Journal of Pediatric Otorhinolaryngology 184 (2024) 112079 Fig. 1. Histological evaluation of HE-stained specimens Tonsils are covered with stratified squamous epithelium, and very few eosinophils are present (A). In contrast, adenoids are covered with ciliated columnar epithelium, and many eosinophils are observed particularly in the submucosal area (arrowhead in B). The number of eosinophils infiltrated into the mucosal epithelium and submucosal area is significantly higher in adenoids (4.7 ± 2.2/field) compared to tonsils (0.3 ± 0.5/field) (C). Scales: 100 μm, *p < 0.05. Images were captured from the patient with an adenoid size of 19 mm. Table 1 Comparison of histology and immunohistology findings between epithelium of adenoids and tonsils. Number of eosinophilsa Glucocorticoid receptor Interleukin-4 Interleukin-25 Positive ratea Intensity scoresa Positive ratea Intensity scoresa Positive ratea Intensity scoresa Adenoids 4.7 ± 2.2/field 79.2 % (76/96) 0.9 ± 0.4 97.9 % (94/96) 1.6 ± 0.5 96.9 %, 93/96 1.3 ± 0.4 Tonsils 0.3 ± 0.5/field 22.9 % (22/96) 0.2 ± 0.2 89.6 % (86/96) 1.2 ± 0.5 77.1 %, 74/96 0.8 ± 0.4 a p < 0.05. Fig. 2. Expression of glucocorticoid receptor (GR) in the mucosal epithelium In tonsils, GR expression is observed only in the basal side of the mucosal epithelium but not in the cells comprising the surface layer of the mucosal epithelium. GR expression is well observed throughout the ciliated columnar cells covering adenoids (A). The scores of GR expression intensity in the most superficial cells of the mucosal epithelium are significantly higher in adenoids (0.9 ± 0.4) compared to tonsils (0.2 ± 0.2) (B). Scales: 100 μm, *p < 0.05. Images were captured from the patient with an adenoid size of 21 mm. expressed in a wider range of adenoids (97.9 %, 94/96) than in tonsils and IL-25, results of blood tests, adenoids size, or 3 % ODI between (89.6 %, 86/96) (p < 0.05), and the expression intensity scores were the 12 cases with any of the allergic diseases and the 20 cases without higher in adenoids (1.6 ± 0.5) compared to tonsils (1.2 ± 0.5) (p < 0.05) allergic diseases. When confirming the correlation between adenoids (Fig. 3A, B and Table 1). A similar trend was observed in IL-25, which size and expression intensity scores in GR, IL-4 and IL-25, a correlation was expressed in a wider range of adenoids (96.9 %, 93/96) compared to was found in adenoids size and the adenoid IL25 score (r = 0.419, p < tonsils (77.1 %, 74/96) (p < 0.05), and the expression intensity scores 0.05), but statistical correlation was not found in other parameters were higher in adenoids (1.3 ± 0.4) than in tonsils (0.8 ± 0.4) (p < 0.05) (Fig. 4A and B). (Fig. 3C, D and Table 1). No difference was found in expression intensity scores in GR, IL-4 3 K. Tochigi et al. International Journal of Pediatric Otorhinolaryngology 184 (2024) 112079 Fig. 3. Expression of IL-4 and IL-25 in the mucosal epithelium In tonsils, weak IL-4 expression is observed only in the basal side of the mucosal epithelium; in contrast, in adenoids, IL-4 is strongly expressed throughout the mucosal epithelium (A). The expression intensity scores are higher in adenoids (1.6 ± 0.5) compared to tonsils (1.2 ± 0.5) (B). A similar tendency is observed for IL- 25, which is weakly expressed in the mucosal epithelium of tonsils and strongly expressed in the mucosal epithelium of adenoids (C). The expression intensity scores are higher in adenoids (1.3 ± 0.4) compared to tonsils (0.8 ± 0.4) (D). Scales: 100 μm, *p < 0.05. Images were captured from the patient with an adenoid size of 21 mm. Fig. 4. Relationship between adenoid size and results of histological evaluation Scatter plots and regression lines between adenoid size, number of eosinophils in the mucosal epithelium and submucosal area, and expression scores of GR, IL-4 and IL-25 in the mucosal epithelium (A). Spearman correlation rank test shows a positive correlation between adenoid size and expression score of IL-25 (B). 4 K. Tochigi et al. International Journal of Pediatric Otorhinolaryngology 184 (2024) 112079 4. Discussion epithelium of hypertrophic adenoids and adenoids size have a correla­ tion with expression of IL-25 in adenoids epithelium, could support that In the present study, the expression of glucocorticoid receptor (GR) inflammations caused by IL-4 and IL-25 expressed in the mucosal and cytokines related to eosinophilic inflammation, interleukin (IL)-4 epithelium and eosinophils infiltrating the submucosal area might be and IL-25, in the mucosal epithelium was histologically analyzed, one etiology of adenoid hypertrophy and target of topical nasal steroids compared between adenoid and tonsils removed from patients with potentially leading to adenoid shrinkage (Fig. 5). adenoid hypertrophy and analyzed correlations with adenoids size. GR In our study, histological and immunohistology analyses was con­ was found to be strongly expressed over a wider area of the mucosal ducted in hypertrophied adenoids and revealed findings on GR and epithelial surface, whereas eosinophils, IL-4, and IL-25 were found to be eosinophilic inflammations in adenoids mucosal epithelium, but several strongly expressed in the mucosal epithelium and submucosal area of issues remain regarding the complete elucidation of the mechanism. adenoids compared to tonsils. Adenoids size had a correlation with Firstly, the hypothesis that steroids bind to GR in the mucosal epithelium expression of IL-25 in adenoids epithelium. of adenoids and suppress eosinophilic inflammation leading to tissue Peripheral tonsillar tissues are divided into adenoids, palatine ton­ shrinkage, was difficult to prove in studies that involve only patients sils, and lingual tonsils. The morphology of the mucosal epithelium who were not receiving topical steroid therapy. In particular, collecting differs within different locations. Adenoids, which are closer to the nasal and evaluating specimens before and after nasal steroid use from the cavity, are covered with ciliated epithelium, whereas the palatine and same patient is ethically difficult. Future research involving in vitro lingual tonsils are covered with squamous epithelium. It has also studies and animal experiments consider necessary to completely been reported that the immune functions differ depending on the loca­ elucidate the mechanism which topical steroids cause adenoid tion in peripheral tonsils [24,25]. Adenoid hypertrophy occurs due to shrinkage. Secondly, in addition to eosinophilic inflammation, accu­ the involvement of complex factors such as immune responses to anti­ mulation of B cells in germinal centers of lymphoid follicles is also one gens, hormonal factors, genetic factors, gastro-esophageal reflex, and etiology of adenoid hypertrophy. Inflammatory cytokines secreted passive smoking, in addition to eosinophilic inflammation. In our by activated T cells induce differentiation and proliferation of B cells study, among various pathological factors related to adenoid hypertro­. IL-4 and IL-25, which were examined in present study, are thought phy, histological and immunohistochemical analysis were conducted to act on the differentiation and activation of T cells [38,39]. The in­ focusing on GR and eosinophilic inflammation in adenoids mucosal hibition of cytokines production in mucosal epithelium by topical nasal epithelium, which may be the main target of the anti-inflammatory ef­ steroids might suppress the activation of T cells and proliferation B cells fect of topical nasal steroids. leading an adenoid shrinkage. Future investigations on the change of Glucocorticoids bind to the GR expressed in cells and translocate to these cell-distributions depending on topical steroid use would be the nucleus, suppressing the production of proteins, including inflam­ required for elucidating the mechanism for adenoid shrinkage effects of matory cytokines, and exerting anti-inflammatory effects. In this topical nasal steroids. study, GR expression was observed in a wide range of ciliated epithelial cells covering the surface of the adenoids, contrasting with the presence 5. Conclusion of stratified squamous epithelial cells on the surface of the tonsils. In other fields, such as dermatology, nephrology, and rhinology fields, the Adenoids and tonsils removed from patients with adenoid hyper­ relationship between steroid receptor expression in tissues where topical trophy were histologically analyzed to confirm whether the mucosal steroids act and therapeutic effects has been investigated, and it has epithelium of adenoids had sensitivity for topical steroids. In adenoids, been reported that steroids have a strong therapeutic effect on tissues GR was widely expressed in the surface layer of mucosal epithelium with strong steroid receptor expression [12–14]. Our results indicate the compared to tonsils. Strong eosinophilic infiltration, IL-4 and IL-25 possibility that topical nasal steroids reach at adenoids, bind to the GR expression were observed in mucosal epithelium of adenoids. expressed in the epithelial cells of the mucosal surface and exert an anti-inflammatory effect. Eosinophilic inflammation is strongly involved in the development of adenoid hypertrophy along with the anti-inflammatory effects of ste­ roids [15,27]. The mechanism of mucosal hypertrophy has been eluci­ dated especially in eosinophilic inflammatory diseases of the nasal sinuses, in which topical steroids exert a therapeutic effect similar to that of adenoid hypertrophy. Inflammatory cytokines secreted by the mucosal epithelial cells induce eosinophil infiltration and contribute to mucosal tissue hypertrophy. Although degrees of eosinophilic inflammation have been analyzed in the entire adenoid tissue [24,25], eosinophilic infiltration and cytokines’ expressions focused on the mucosal epithelium and submucosal area have not yet been well investigated. IL-4 is known to promote IgE secretion from B cells, causing eosin­ ophilic inflammation, mobilizing inflammatory cells, and involved in mucosal proliferation [24,30,31]. IL-25 is produced by T lymphocytes, mast cells, eosinophils, and mucosal epithelial cells and induces strong inflammation, leading to hyperplasia of epithelial cells, recruitment of Fig. 5. Expression of GR, IL-4 and IL25, and eosinophil infiltration in the inflammatory cells to the interstitial area, and participation in mucosal adenoid mucosa of adenoid hypertrophy proliferation [31,32]. Studies on sinusitis have reported that Results of the present study show that GR, IL4, and IL25 are strongly expressed, and eosinophils are also infiltrated at adenoid mucosal epithelium in patients IL-4-positive cells and IL-25-positive cells were targets of steroid treat­ with adenoid hypertrophy. The expression of these cytokines and eosinophils ment and that steroids suppressed the expression of these cytokines [33, could be one of the pathological conditions of adenoid hypertrophy. Local 34]. Eosinophils further exacerbate inflammation in the surrounding steroids administered through the nose and reaching the adenoid mucosal tissue, resulting in interstitial edema and epithelial hyperplasia, which is epithelium might bind to GR on the surface of the mucosal epithelium, suppress also suppressed in response to steroid treatment [15,35]. Our results, the secretion of inflammatory cytokines from the mucosal epithelium, and that IL-4 and IL-25 were more strongly expressed in the mucosal suppress eosinophilic inflammations in hypertrophic adenoid. 5 K. Tochigi et al. International Journal of Pediatric Otorhinolaryngology 184 (2024) 112079 Eosinophilic inflammations in adenoids mucosal epithelium could be A.B. Mehta, N.J. Nadkarni, S.P. Patil, K.V. Godse, M. Gautam, S. Agarwal, Topical corticosteroids in dermatology, Indian J. Dermatol. Venereol. 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