10.5826/dpc.1301a113
Introduction: Granuloma annulare (GA) is a non-infectious granulomatous disease that can affect children and adults. Although many studies have been conducted adult GA patients, the literature on pediatric GA cases is limited.
Objectives: Therefore, this study aimed to examine the demographic, clinical, and pathological features of pediatric GA cases.
Methods: This study was performed retrospectively in a single-center tertiary dermatology hospital. Demographic characteristics and clinical and histopathological features were recorded.
Results: Forty-one participants were included in this study, of which 66% were female. The mean age was 3.8 ± 2.6 years, and the mean lesion duration was 7.5 ± 10.3 months. The involvement of 78% of the patients was localized, and the remaining 22% was generalized. Asthma (30%) was the most common comorbid disease. Histopathological examination was performed on twenty-one patients, and the infiltrate pattern was interstitial in 71% of the cases and palisadic in 29%. Generalized distribution, trunk involvement, and concomitant disease tended to be higher in patients with an interstitial pattern than in those with a palisadic pattern.
Conclusions: Atopy and asthma should be questioned in pediatric GA cases. There are differences between involvement, distribution, concomitant disease, and histopathological patterns, which may indicate differences in pathogenesis. 
text/xml
2160-9381
2924
en
Ebru Sarıkaya  Tellal 
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
palisadic type
Clinical and Histopathological Evaluation of Forty-one Cases of Pediatric Granuloma Annulare
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-01-31
2022-10-18
2023-01-31
2023-02-27
e2023113
Dermatol Pract Concept
Introduction: Granuloma annulare (GA) is a non-infectious granulomatous disease that can affect children and adults. Although many studies have been conducted adult GA patients, the literature on pediatric GA cases is limited.
Objectives: Therefore, this study aimed to examine the demographic, clinical, and pathological features of pediatric GA cases.
Methods: This study was performed retrospectively in a single-center tertiary dermatology hospital. Demographic characteristics and clinical and histopathological features were recorded.
Results: Forty-one participants were included in this study, of which 66% were female. The mean age was 3.8 ± 2.6 years, and the mean lesion duration was 7.5 ± 10.3 months. The involvement of 78% of the patients was localized, and the remaining 22% was generalized. Asthma (30%) was the most common comorbid disease. Histopathological examination was performed on twenty-one patients, and the infiltrate pattern was interstitial in 71% of the cases and palisadic in 29%. Generalized distribution, trunk involvement, and concomitant disease tended to be higher in patients with an interstitial pattern than in those with a palisadic pattern.
Conclusions: Atopy and asthma should be questioned in pediatric GA cases. There are differences between involvement, distribution, concomitant disease, and histopathological patterns, which may indicate differences in pathogenesis. 
Ebru Sarıkaya  Tellal 
2023/01/31
10.5826/dpc.1301a113
e2023113
Health Sciences University, Istanbul Training and Research Hospital, Dermatology Clinic, Istanbul, Turkey
2160-9381
palisadic type
en
e2023113
Tan HH, Goh CL. Granuloma annulare: a review of 41 cases at the National Skin Centre. Ann Acad Med Singap. 2000;29(6):714–8.
Clinical and Histopathological Evaluation of Forty-one Cases of Pediatric Granuloma Annulare
https://dpcj.org/index.php/dpc/article/download/2924/1941
     Clinical and Histopathological Evaluation of
   Forty-one Cases of Pediatric Granuloma Annulare
       Ayşe Esra Koku Aksu1, Dilara İlhan Erdil1, Vildan Manav Baş1, Cemre Büşra Türk1,
                            Cem Leblebici2, Ebru Sarıkaya Tellal1


1 Health Sciences University, Istanbul Training and Research Hospital, Dermatology Clinic, Istanbul, Turkey
2 Health Sciences University, Istanbul Training and Research Hospital, Clinic of Medical Pathology, Istanbul, Turkey



Key words: Granuloma annulare, asthma, histopathology, interstitial type, palisadic type
Citation: Koku Aksu AE, İlhan Erdil D, Manav Baş V, Büşra Türk C, Leblebici C, Tellal ES. Clinical and Histopathological Evaluation
of Forty-one Cases of Pediatric Granuloma Annulare. Dermatol Pract Concept. 2023;13(1):e2023113. DOI: https://doi.org/10.5826/
dpc.1301a113
Accepted: January 4, 2023; Published: January 2023
Copyright: ©2023 Koku Aksu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Ayşe Esra Koku Aksu, Health Sciences University, Istanbul Training and Research Hospital, Dermatology Clinic,
Istanbul, Turkey. Email: esraaksu@gmail.com




  ABSTRACT             Introduction: Granuloma annulare (GA) is a non-infectious granulomatous disease that can affect
                       children and adults. Although many studies have been conducted in adult GA patients, the literature
                       on pediatric GA cases is limited.
                       Objectives: Therefore, this study aimed to examine the demographic, clinical, and pathological fea-
                       tures of pediatric GA cases.
                       Methods: This study was performed retrospectively in a single-center tertiary dermatology hospital.
                       Demographic characteristics and clinical and histopathological features were recorded.
                       Results: Forty-one participants were included in this study, of which 66% were females. The mean age
                       was 3.8 ± 2.6 years, and the mean lesion duration was 7.5 ± 10.3 months. The involvement of 78%
                       of the patients was localized, and the remaining 22% was generalized. Asthma (30%) was the most
                       common comorbid disease. Histopathological examination was performed on 21 patients, and the
                       infiltrate pattern was interstitial in 71% of the cases and palisadic in 29%. Generalized distribution,
                       trunk involvement, and concomitant disease tended to be higher in patients with an interstitial pattern
                       than in those with a palisadic pattern.
                       Conclusions: Atopy and asthma should be questioned in pediatric GA cases. There are differences
                       between involvement, distribution, concomitant disease, and histopathological patterns, which may
                       indicate differences in pathogenesis.




Original Article | Dermatol Pract Concept. 2023;13(1):e2023113                                                                        1
Introduction                                                       Mann–Whitney U test was used when evaluating non-­
                                                                   normally distributed (non-parametric) variables between the
Granuloma annulare (GA) is a non-infectious granuloma-             two groups. When presenting the categorical variables, the
tous skin reaction with potential triggers that can affect adult   frequency and percentage values of the variables were used,
and pediatric populations. The etiology of GA is unknown,          and the analysis of the categorical variables was carried out
but medication, infection, trauma, insect bites, and vaccina-      using the chi-squared (exact) test. The Bonferroni multiple
tion have been reported as triggering factors [1–3]. Solitary,     comparison test was used to investigate the reason for the
erythematous, annular papules, and plaques are found pre-          significant differences between the groups. Cases with a
dominantly in the acral regions. Histopathologically, colla-       P value below 0.05 were considered statistically significant.
gen degeneration, mucin deposition, and lymphohistiocytic
infiltrate are typically observed [4]. Diabetes mellitus, hyper-
                                                                   Results
lipidemia, and malignancy have been associated with adult
GA [5–6].                                                          Forty-one participants were included in this study, 66% of
                                                                   which were females. Their mean age was 3.8 ± 2.6 years,
                                                                   and their mean lesion duration was 7.5 ± 10.3 months.
Objectives
                                                                   Seventy-eight% of the patients had localized GA (LGA),
While there are many studies on clinical and pathological          while the remaining 22% had generalized GA (GGA)
features and associated diseases in patients with adult GA,        ­(Figure 1). The lower extremities were the most commonly
few studies have examined pediatric GA patients. Therefore,        affected area, and the most common type of lesion was the
clinical and histopathological evaluations of pediatric GA         plaque type (79%). The mean size of the lesions was 3.8 ±
cases were planned for our study.                                  1.9 cm (Table 1). There was no statistically significant differ-
                                                                   ence between clinical criteria and gender (P > 0.05). How-
                                                                   ever, upper extremity involvement was significantly more
Methods
                                                                   common in patients with GGA compared to those with LGA
This study was performed retrospectively in a single-center        (P < 0.004). No significant differences were found between
tertiary dermatology hospital in Istanbul. Ethical approval        GGA and LGA in terms of other parameters.
was obtained from the Clinical Research Ethics Committee of           Information on the concomitant diseases was evaluated
the Istanbul Training and Research Hospital on 11/03/2022          in 30 of the 41 cases. The evaluation found the following: ac-
(2011-KAEK-50). Patients under the age of 18 years who             companying disease (30.0%, N = 9), asthma (10.0%, N = 3),
were admitted to the dermatology outpatient clinic between         and one case each of atopic dermatitis, autoimmunity (type
2008–2021 and diagnosed with GA were scanned from the              1 diabetes mellitus, Hashimoto thyroiditis), congenital heart
hospital database and patient photograph archive. Cases            disease, pustular psoriasis, and thalassemia. In addition in-
with an uncertain diagnosis were excluded. Written informed        formation on the concomitant disease was evaluated in
consent was obtained from the parents of the patients par-         146 patients in the age- and gender-matched control group,
ticipating in the study. Cases with dermatological findings        which resulted in the following: asthma (3.4%, N = 5), hypo-
recorded in detail and/or diagnosed histopathologically were       thyroidism (1.4%, N = 2), atopic dermatitis (0.7%, N = 1),
included in the study. In total, 41 patients diagnosed with GA     and plaque-type psoriasis (0.7%, N = 1).
were included. Demographic features, lesion localization,             The most common differential diagnoses in GA cases
lesion characteristics (size, elementary lesion, and color),       were sarcoidosis, tinea corporis, and erythema annulare
involvement (localized/generalized), histopathological fea-        centrifuge, respectively. Histopathological examination was
tures, concomitant diseases, differential diagnoses in cases       performed on 21 patients (Table 2). The infiltrate pattern
with histopathology, regression time, and recommended              was interstitial in 71% of the cases and palisadic in 29%
treatments were recorded. Missing data were questioned by          (Figures 2 and 3). Eosinophil infiltration was observed in
calling the patients by phone. Age- and gender-matched pa-         19% of the cases, and lymphohistiocytic infiltration was ob-
tients of the pediatric outpatient clinic were included in the     served in 90%. Eosinophils were detected in the histopatho-
study as the control group to evaluate comorbidities.              logical examinations of 4 patients, and in 2 of these cases
    Statistical analyses were performed using SPSS ver-            the presence of concomitant asthma was also noted. Trunk
sion 23.0. The conformity of the variables to the normal           involvement was detected in 5 (33%) out of 15 patients with
distribution was examined by histogram graphics and the            an interstitial pattern, but it was not detected in any of the
Kolmogorov–Smirnov/Shapiro–Wilk tests. The mean, stan-             patients with the palisadic pattern. The difference was sta-
dard deviation, median, minimum, and maximum values                tistically significant (P = 0.01). All palisadic patterns (N = 6)
were used when presenting the descriptive analyses. The            were LGA, and 6 (40%) of those with interstitial patterns



2                                                                      Original Article | Dermatol Pract Concept. 2023;13(1):e2023113
                Figure 1. (A) Annular, peripherally raised, pale erythematous, 4 cm in diameter plaque on the dorsum of
                the left foot (B) Multiple, annular, erythematous plaque lesions around the knee. (C) Annular lesions on
                the finger. (D) Annular plaque formed by a combination of millimetric papules on the lateral malleolar
                region of the right foot.




showed GGA. However the difference was not statistically              difference was detected in another study [10]. Hyperlipid-
significant (P > 0.05). Concomitant disease was present in 5          emia and diabetes have been found to be the most common
(33%) out of 15 patients with the interstitial pattern, but it        comorbidities in adult GA [5,6]. In our study, unlike in adult
was not detected in any patients with the palisadic pattern.          GA case series, asthma was found to be the most common
    All of the treated cases received a topical steroid, and          accompanying disease.
the mean duration of the lesions after treatment was 6 ± 5.4              In our study, 10% of the patients with GA had asthma,
months. When 28 (68%) out of the 41 cases were reached                a higher rate than the control group (3.4%). Additionally,
by phone, complaints were still present in 14% (N = 4). The           13% of the GA cases had atopy (atopic dermatitis and
disease regressed in 86% of the cases within one year.                asthma). Previous research has reported even higher rates of
                                                                      atopy (up to 30%) in GA cases [9]. However, to the best of
                                                                      our knowledge, the relationship between pediatric GA and
Conclusions
                                                                      asthma has not been previously reported. The presence of
GA can be observed in pediatric and adult populations; how-           asthma, which is a characteristic of atopic march, suggests
ever, there are limited data about demographic, clinical, and         that these patients should be evaluated for other atopic con-
histopathological features and associated diseases in pediat-         ditions such as atopic dermatitis, and allergic rhinitis.
ric GA patients.                                                          The coexistence of GA and atopy may indicate a com-
    In this study, female predominance was evident (66%),             mon pathogenesis. In recent years, it has been shown that
similar to adult cases [7]. Notably, male predilection was ap-        in addition to T-helper 1 and T-helper 2 cell types, the Janus
parent in two pediatric GA case series [8,9], and no gender           ­Kinase-Signal Transducer Transcription Activator (JAK-STAT)



Original Article | Dermatol Pract Concept. 2023;13(1):e2023113                                                                    3
Table 1. Descriptive statistics of demographic, clinical, and treatment features of pediatric granuloma
                                           annulare cases.
                                   Characteristic
 Gender, N (%)                                      Girl                                        27                    (66)
                                                    Boy                                         14                    (34)
 Age, years, mean ± SD /median (min–max)                                                   3.8 ± 2.6            3.00 (1.0–12.0)
 Lesion duration, months, mean ± SD /median (min–max)                                     7.5 ± 10.4            4.00 (1.0–54.0)
 Localization, N (%)                                Upper extremity                             14                   (34.1)
                                                    Lower extremity                             30                   (75.0)
                                                    Trunk                                       7                    (17.1)
                                                    Gluteal                                     3                     (7.3)
 Elementary lesion, N (%)                           Papule                                      5                    (14.3)
                                                    Nodule                                      1                     (2.9)
                                                    Patch                                       6                    (17.6)
                                                    Plaque                                      27                   (79.4)
 Color, N (%)                                       Light brown                                 1                     (4.3)
                                                    Brown                                       9                    (39.1)
                                                    Purple                                      1                     (4.3)
                                                    Pink                                        11                   (47.8)
                                                    Orange                                      1                     (4.3)
 Mean size of the lesions (cm), ± SD                                                       3.9 ± 2.0             4.0 (1.0–7.0)
 Involvement, N (%)                                 Localized                                   32                   (78.1)
                                                    Generalized                                 9                    (21.9)
 Concomitant disease, N (%)                         Asthma                                      3                    (10.0)
                                                    Atopic dermatitis                           1                     (3.3)
                                                    Congenital heart disease                    1                     (3.3)
                                                    Thalassemia                                 1                     (3.3)
                                                    Pustular psoriasis                          1                     (3.3)
                                                    Type 1 DM                                   1                     (3.3)
                                                    Hashimoto thyroiditis                       1                     (3.3)

DM = diabetes mellitus; SD = standard deviation.




pathway is involved in the pathogenesis of GA [11]. Treatment      histiocytes, while an interstitial pattern comprises histio-
with JAK-STAT inhibitors resulted in the downregulation of         cytes localized to the papillary or middle dermis distributed
cytokine levels and clinical improvement in GA [12]. In addi-      between collagen fibers and blood vessels [16]. There is a
tion, topical JAK-STAT pathway inhibitor administration is         paucicellular appearance, with minimal mucin traces in the
clinically effective in the treatment of GA [13]. The pathway      interstitial pattern [17].
is also involved in the pathogenesis of atopy and asthma. Sim-           In this study, histopathological examination of 21 pa-
ilarly, JAK-STAT pathway inhibitors have been effective in         tients was performed. The histopathological pattern was pal-
the treatment of atopic dermatitis and asthma [14,15]. JAK-        isading in 6 patients, while the remaining (N = 15 patients)
STAT pathway is also related with eosinophils, in our study        showed interstitial pattern. Trunk involvement was detected
the presence of eosinophils in histopathological examinations      in 5 (33%) out of 15 patients with an interstitial pattern, but
was associated with an increased probability of concomitant        it was not detected in any patients with a palisadic pattern.
asthma. Further studies on this subject may contribute to the      Another striking finding was that all of the palisadic pat-
understanding of GA pathogenesis.                                  terns were LGA, and 6 (40%) of those with an interstitial
    Regarding histopathology, GA comprises granulomatous           pattern showed GGA. The concomitant disease was present
inflammation in a palisading or interstitial pattern accompa-      in 5 (33%) out of 15 patients with an interstitial pattern,
nied by mucin. A palisading pattern comprises a central zone       whereas none of the patients with a palisadic pattern had
containing necrobiotic collagen surrounded by palisadic            concomitant disease. As a result, trunk involvement, GGA,


4                                                                        Original Article | Dermatol Pract Concept. 2023;13(1):e2023113
  Table 2. Descriptive statistics of histopathological features of pediatric granuloma annulare cases.
                             Histopathological features                                               N                      %
 Epidermal findings                             Regular                                               14                    (73.7)
                                                Hyperkeratosis, Acanthosis                             1                     (5.3)
                                                Hyperplasia                                            1                     (5.3)
                                                Orthokeratosis, Acanthosis                             1                     (5.3)
                                                Pigmentation increase                                  2                    (10.5)
 Pattern of infiltrate                          Interstitial                                          15                    (71.4)
                                                Palisadic                                              6                    (28.5)
 Depth of infiltrate                            Deep dermis                                            3                    (17.6)
                                                Dermis                                                 3                    (17.6)
                                                Medium                                                 2                    (11.7)
                                                Middle and lower                                       1                     (5.9)
                                                Medium and deep                                        5                    (29.4)
                                                Upper and middle                                       2                    (11.8)
                                                Superficial and deep                                   1                     (5.9)
 Collagen degeneration                          Absent                                                 0                     (0.0)
                                                Present                                               21                   (100.0)
 Multinuclear giant cells                       Absent                                                18                    (90.0)
                                                Present                                                2                    (10.0)
 Mucin                                          Absent                                                 1                     (5.6)
                                                Present                                               17                    (94.4)
 Eosinophils                                    Absent                                                17                    (80.9)
                                                Present                                                4                    (19.1)
 Lymphohistiocytic                              Absent                                                 2                     (9.5)
                                                Present                                               19                    (90.5)




               Figure 2. (A) Palisading granuloma with a necrobiotic center in dense dermal infiltration (H&E,x100). (B)
               histiocyte palisade around fragmented and partially granular collagen structures and sparse lymphocytes
               and karyorrhectic debris (H&E, x400).


and accompanying diseases were detected in the interstitial            patterns of GA may indicate the possibility of different
pattern in a ratio of approximately 30%–40%, while these               pathogenic mechanisms underlying these patterns. The pal-
features were not present in the palisadic pattern.                    isading pattern may be induced by external factors, such as
    The differences found between the involvement, distribu-           trauma or insect bites [1,18]. This may explain localized
tion, and concomitant disease in interstitial and palisading           clinical involvement and a predilection for the extremities.


Original Article | Dermatol Pract Concept. 2023;13(1):e2023113                                                                       5
                Figure 3. (A) Busy dermis with dermal infiltration at low magnification (H&E,1x00). (B) Histiocytic
                dissemination in the interstitial space between degenerated (thick/swollen) collagen fibers (H&E, x400).



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Original Article | Dermatol Pract Concept. 2023;13(1):e2023113                                                                                  7
