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Correlation of mast cell density and histopathological characteristics of syringoma: An immunohistochemical study
Corresponding author: Dr. Soyun Cho, Department of Dermatology, Seoul Metropolitan Government – Seoul National University Boramae Medical Center, Dongjak-Gu, Republic of Korea. sycho@snu.ac.kr
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Received: ,
Accepted: ,
How to cite this article: Kim TM, Cho S. Correlation of mast cell density and histopathological characteristics of syringoma: An immunohistochemical study. Indian J Dermatol Venereol Leprol. doi: 10.25259/IJDVL_1893_2024
Abstract
Background
Syringoma, a benign skin tumour characterised by stromal fibrosis and epithelial encirclement, suffers from limited treatment options.
Aim
This study aimed to analyse the correlation between mast cell density and histological features of syringomas, particularly stromal fibrosis and epidermal pigmentation.
Methods
Immunohistochemical staining with CD117 and estrogen receptor (ER)-α was performed in 49 samples from 47 patients of syringoma to assess mast cell density and ER-α expression.
Results
The study revealed a female predominance (4.2:1), with a median age of 42 years (range, 21–80 years) and an onset at the age 28.5 years (5–74). All 49 cases were localised, primarily to the eyelid (67.3%), followed by the face (18.4%), vulva (8.2%), and axilla/extremities (6.1%). Epidermal thickness correlated directly with tumour thickness (r=0.652, p<0.01), which varied across anatomical sites. Mast cell density significantly correlated with basal pigmentation (r=0.338, p=0.02), stromal fibrosis (r=0.308, p=0.03), and stromal ER-α (r=0.249, p=0.03), suggesting their involvement in syringoma pathogenesis. Acanthosis, basal hyperpigmentation, and stromal fibrosis were prevalent in 83.7%, 83.7%, and 100% of patients, respectively. ER-α positivity was observed in the syringoma stromal area in 30 cases (61.2%), whereas positivity in the tumour cell area was confirmed in only 3 cases (6.1%).
Limitations
The retrospective nature of the analysis and the limited sample size may affect the generalisability of the findings.
Conclusion
Our findings highlight a significant correlation between mast cells and stromal fibrosis, as well as basal hyperpigmentation in syringomas. This suggests the potential involvement of mast cells in their pathomechanism. Furthermore, the correlation of mast cell density with stromal ER-α may explain the female predominance.
Keywords
Fibrosis
immunohistochemistry
mast cells
pigmentation
syringoma
Introduction
Syringoma is a benign adnexal neoplasm originating from the acrosyringium, commonly affecting the face, particularly the eyelids and forehead.1 These lesions present as asymptomatic, flesh-coloured to reddish-brown papules, 1–2 mm in size, and show characteristic histological features, including tadpole-like structures, basal hyperpigmentation, and stromal fibrosis.2 Various treatments such as the CO2 laser, chemical peels, and surgical excision, though attempted, are not definitive, and often result in scarring or dyspigmentation.3
The pathophysiology of syringoma is unclear, with some suggesting reactive hyperplasia of eccrine ducts rather than true neoplasms.4 Hormonal influences, particularly oestrogen and progesterone, have been proposed, but receptor studies show conflicting results.5 Notably, mast cells, which play key roles in conditions like rosacea, are abundant in syringoma.3,6,7 The successful use of mast cell modulators, such as topical adelmidrol and oral tranilast, suggests their role in pathogenesis.3,8
The link between mast cells and stromal fibrosis, a hallmark of syringoma, remains unexplored. This study aims to examine the influence of mast cells on fibrosis, pigmentation, and oestrogen receptor expression to improve the understanding of syringoma pathogenesis and identify effective treatments.
Study population and data collection
We conducted a retrospective review of medical records from patients diagnosed with syringoma through skin biopsy at a single institute between January 2009 and January 2013. Data on age, sex, age at syringoma onset, location and type of lesions, and the presence of comorbidities were collected in accordance with IRB approval (No.10-2021-72).
Histopathological evaluation
Punch biopsy slides were analysed by a blinded dermatologist, focusing on basal pigmentation, skin fibrosis (graded 0 to 3: none, mild, moderate, severe), and the presence of acanthosis [Figure S1]. Epidermal and tumour thickness were measured from the granular layer to the lesion base, with three measurements averaged per specimen. For epidermal thickness, normal skin surrounding the lesion was used to minimise bias.
Tissue microarray construction and immunohistochemical staining
Paraffin-embedded biopsy tissues were extracted to construct a tissue microarray. 4-μm sections were stained for markers such as carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), cytokeratin 5 (CK5), smooth muscle actin (SMA), tumor protein p63 (p63), progesterone receptor (PR), estrogen receptor alpha (ER-α), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and cluster of differentiation 117 (CD117, also known as c-kit) Staining intensity was scored on a five-point scale (0–4) [Table 1]. ER-α staining was performed to histologically distinguish between the syringoma tumour area, composed of numerous small ducts and epithelial cords, and the surrounding stromal area of the tumour lesion. Cases were classified based on the presence of ER-α positivity in each area, identifying those with tumour ER-α positivity and those with stromal ER-α positivity. Mast cell density was determined by counting CD117-positive cells in five consecutive fields at 400x magnification and expressed as cells/mm2.9
| Grade | Explanation |
|---|---|
| 0 | Negative or rare positive staining cells |
| 1+ | <10% of total cells show positive staining |
| 2+ | 10-50% of cells |
| 3+ | 50-90% of cells |
| 4+ | >90% of cells |
Statistical analysis
Continuous data were reported as mean ± standard deviation (SD), while categorical data were summarised as frequencies. Chi-square tests assessed the relationship between mast cell density and categorical variables like sex and lesion site. To analyse the correlation between histopathological features such as stromal fibrosis, basal pigmentation, epidermal thickness, and tumour thickness with mast cell density, we performed multiple regression analysis and a logistic regression model while accounting for potential confounding variables, including the anatomical site of the lesion. Partial correlation coefficients were then derived to assess the adjusted relationships. Statistical significance was set at p < 0.05, and all analyses were performed using SPSS version 23.0 (U.S.C., New York, USA).
Results
Demographic and clinical features of syringoma
A total of 49 syringoma tissue specimens were obtained from 47 patients. The median age was 42 years (range: 21-80), with a female-to-male ratio of 4.2:1, and 9 (19.1%) male patients. The mean age at syringoma onset was 28.5 years, and comorbidities were confirmed in 23 (48.9%) cases [Table 2]. All cases were of the localised type, with the majority occurring on the eyelids (33, 67.3%), followed by the face (9, 18.4%), vulva (4, 8.2%), and axilla/extremities (3, 6.1%) [Table 3].
| Syringoma patients (n=47) | |
|---|---|
| Age (years), mean (SD) | 42.0 (16.5) |
| Age of onset (years), mean (SD) | 28.5 (14.6) |
| Male sex (%) | 9 (19.1) |
| Comorbidity (%) | 23 (48.9) |
Data are presented as n (%). SD: Standard deviation.
| Syringoma location | Eyelid | Face | Vulva | Axilla/extremities | p-value |
|---|---|---|---|---|---|
| N (%) | 33 (67.3) | 9 (18.4) | 4 (8.2) | 3 (6.1) | - |
| Mast cell density (cells/mm2) | 122.9 (31.9) | 119.5 (20.9) | 81.4 (24.3) | 71.0 (9.5) | <0.01** |
| Tumour thickness (μm) | 765.8 (255.0) | 979.2 (259.5) | 1398.8 (113.0) | 688.5 (163.9) | - |
| Epidermal thickness (μm) | 121.2 (40.8) | 121.6 (31.8) | 275.9 (40.7) | 155.9 (21.5) | - |
| Tumour/epidermal thickness ratio | 6.3 (2.6) | 8.1 (3.0) | 5.1 (0.9) | 4.4 (0.8) | <0.01** |
Data are presented as value (SD). SD: Standard deviation, HPF: High-power field. *P < 0.05, **P < 0.01.
Histologic features of syringoma
Histological examination of the syringoma specimens revealed significant differences in epidermal and tumour thickness across various anatomical sites. Tumour thickness was greatest in syringomas located on the vulva (1398.8 μm), followed by facial lesions (979.2 μm), eyelid lesions (765.9 μm), with the thinnest tumours being found in the axillae/extremities [688.5 μm, Table 3]. Epidermal thickness also varied by location, with the thickest epidermis being found in the vulva (275.9 μm), followed by the axillae/extremities (155.9 μm), face (121.6 μm), and eyelid (121.2 μm). To account for regional variations in epidermal thickness, the tumour/epidermal thickness ratio was calculated. The highest ratio was observed in facial syringomas (8.1), while the lowest ratio was found in axillae/extremities (4.4). Syringomas on the eyelid and vulva showed ratios of 6.3 and 5.1, respectively [Table 3, p<0.01]. Correlation analysis revealed that epidermal thickness was correlated with age (r=-0.564, p<0.01) and tumour thickness (r=0.652, p<0.01).
Acanthosis of the epidermis was observed in 41 cases (83.7%), with no statistically significant influence of lesion location (p=0.112). Basal hyperpigmentation was identified in 83.7% of cases, with 44.9% classified as mild, 22.4% as moderate, and 16.3% as severe. No statistically significant correlation was found between lesion location and basal hyperpigmentation (p=0.312). Stromal fibrosis was uniformly present in all syringoma tissues, with 2% classified as mild, 28.6% as moderate, and 39.4% as severe. Stromal ER-α positivity was observed in 30 cases (61.2%), whereas tumour ER-α positivity was identified in only 3 cases (6.1%), demonstrating a notable difference [Table 4]. There was no significant statistical association between lesion location and the grade of stromal fibrosis (p=0.876) or stromal ER-α positivity (p=0.520).
| Histologic feature | N (%) | Mast cell density (cells/mm2) | Correlation coefficient | p-value | |
|---|---|---|---|---|---|
| Acanthosis | |||||
| none | 8 (16.3) | 114.3 | 0.022 | 0.31 | |
| present | 41 (83.7) | 116.2 | |||
| Basal hyperpigmentation | |||||
| none | 8 (16.3) | 95.2 | 0.338 | 0.02* | |
| mild | 22 (44.9) | 114.3 | |||
| moderate | 11 (22.4) | 122.4 | |||
| severe | 8 (16.3) | 132.4 | |||
| Stromal fibrosis | |||||
| none | 0 (0) | - | 0.308 | 0.03* | |
| mild | 1 (2.0) | 133.3 | |||
| moderate | 14 (28.6) | 94.8 | |||
| severe | 34 (69.4) | 123.8 | |||
| Tumour cell ER-α (Tumour ER-α) | |||||
| negative | 46 (93.9) | 115.8 | -0.024 | 0.87 | |
| positive | 3 (6.1) | 112.7 | |||
| Tumour stromal ER-α (Stromal ER-α) | |||||
| negative | 19 (38.8) | 104.8 | 0.249 | 0.03* | |
| positive | 30 (61.2) | 123.8 | |||
Data are presented as n (%). ER: Estrogen receptor, HPF: High-power field. *P < 0.05, **P < 0.01.
Immunohistochemical staining and mast cell density
Immunohistochemical staining using CD117 revealed discernible variations in mast cell density contingent on the anatomical site of the syringoma tissue. Mast cell density per mm2 was highest in eyelid lesions at 122.9, followed by 119.5 in facial lesions, 81.4 in vulvar lesions, and the lowest at 71.0 in lesions located in the axillae/extremities. Mast cell density demonstrated statistically significant differences based on the location of the pathology, as indicated by the analysis presented in Table 3 (p<0.01).
Correlation between mast cell density and histologic features
Mast cell density did not show a statistically significant difference between lesions with and without acanthosis (116.2 vs. 114.3 cells/mm2, p=0.31) [Table 4 & Figure 1a]. In tumour ER-α positive syringoma tissues, mast cell density was 112.7, while in tumour ER-α negative tissues, it was 115.8, showing no statistically significant difference [Table 4]. However, in stromal ER-α -positive tissues, mast cell density was 123.8, whereas in negative tissues, it was 104.8, indicating a positive correlation (r=0.249, p=0.03) [Figures 1b & 2]. Table 4 illustrates that mast cell density increases with the severity of basal pigmentation (none: 95.2, mild: 114.3, moderate: 122.4, severe: 132.4) with a statistically significant positive correlation (r=0.338, p=0.02) [Figures 1c & 3]. Stromal fibrosis grade also showed a positive correlation with mast cell density, with values of 133.3, 94.8, and 123.8 for mild, moderate, and severe fibrosis, respectively (r=0.308, p=0.03) [Table 4, Figures 1d and S1].
- Correlation between mast cell density and acanthosis. A positive correlation was observed, with a weak correlation coefficient of r = 0.022.
- Correlation between mast cell density and ER-α expression. A positive correlation was observed, with a correlation coefficient of r = 0.249, which was statistically significant (p = 0.03)..
- Correlation between mast cell density and basal hyperpigmentation. A positive correlation was observed, with a correlation coefficient of r = 0.338, which was statistically significant (p = 0.02).
- Correlation between mast cell density and stromal fibrosis. A positive correlation was observed, with a correlation coefficient of r = 0.308, which was statistically significant (p = 0.03).
- Stromal ER-α reactivity and mast cell density in the stroma of syringoma by immunohistochemical staining (a): IHC with ER-α (250x), sample #20, ER-α positivity (indicated by black arrows) is predominantly observed in the syringoma stroma area (b): IHC with CD117 (250x), sample #20, CD117-positive mast cells (indicated by arrowheads) are widely distributed throughout the syringoma stromal tissue; IHC: Immunohistochemistry
- Representative image of syringoma with marked basal hyperpigmentation and elevated stromal mast cell density (CD117 IHC, 250x; Sample #36).
- Representative image of syringoma with diminished basal hyperpigmentation and reduced stromal mast cell density (CD117 IHC, 250x; Sample #8).
Discussion
This study elucidates the clinical and histopathological characteristics of syringoma while highlighting correlations between immunohistochemical results, particularly mast cell density, and features such as stromal fibrosis and basal hyperpigmentation. Higher mast cell density in syringoma lesions correlated with increased grades of stromal fibrosis and basal hyperpigmentation, along with a significant positive correlation with stromal ER-α.
Our study identified a 4.2-fold higher prevalence of syringoma in females, consistent with previous reports.1,2,10, 11 Associations with post-pregnancy and oral contraceptive use have been established.12 Similar to prior studies that found no oestrogen or progesterone receptors in vulvar syringoma, we observed ER-α positivity in only 6.1% of cases within tumour cell area but in 61.2% of cases exhibited positivity in the stromal cell area.13,14 Mast cells are known to exhibit ER-α positivity, which enables degranulation in response to oestradiol, leading to fibrosis.15 Oestradiol stimulation has been shown to promote TGFβ1 expression in dermal fibroblasts, implicating mast cells in stromal fibrosis and syringoma pathogenesis.16,17 This suggests that female hormones may play a significant role in syringoma development.
CD117 staining revealed a decreasing trend in mast cell density from eyelid to axilla/forearm regions, aligning with syringoma predilection sites. Mast cell density in normal skin varies across anatomical regions, with facial and vulvar areas exhibiting elevated levels.18-20 This distribution pattern supports the potential role of mast cells in syringoma development. Histamine, a key immune mediator released from mast cells, binds to the H2 receptor of human melanocytes, leading to an increase in intracellular cAMP levels. The accumulated cAMP subsequently activates protein kinase A, which drives melanogenesis.21 Moreover, histamine released through mast cell degranulation not only promotes melanocyte proliferation via the H2 receptor but also enhances melanocyte migration speed in vivo, contributing to hyperpigmentation.21, 22 Mast cells also activate TGF-β through chymase, contributing to skin fibrosis.23-25 Our study demonstrated a positive correlation between mast cell density and the severity of stromal fibrosis and basal hyperpigmentation, suggesting mast cell involvement in syringoma pathogenesis. The therapeutic efficacy of mast cell modulators like tranilast and adelmidrol further supports this role.3, 8
Correlation analysis revealed coefficients of 0.249 with stromal ER-α, 0.338 with basal hyperpigmentation, and 0.308 with stromal fibrosis, indicating weak correlations. While coefficients of 0.4 or higher suggest a moderate correlation, the limited sample size precludes definitive conclusions. Larger studies are needed to confirm these findings. Nonetheless, the statistically significant correlations observed underscore the need for further investigation, offering valuable insights into syringoma pathology.
Limitations
This study is limited by its single-institution design and focuses solely on the localised type of syringoma, with fewer lesions analysed from less common sites like the vulva and extremities.
Conclusion
In summary, this study demonstrates a significant correlation between mast cells, stromal fibrosis, and basal hyperpigmentation in syringoma. Furthermore, considering the positive correlation with stromal ER-α, mast cells are implicated not only in the pathogenesis but also in the female dominance of syringoma. Further research on mast cells’ role in syringoma could enhance understanding and lead to effective treatments.
Ethical approval
The research/study was approved by the Institutional Review Board at Seoul Metropolitan Government Seoul National University Boramae Medical Center Institutional Review Board , number No.10-2021-72, dated July 20th, 2021.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent.
Financial support and sponsorship
This study was supported by a research fund from Seoul National University Boramae Medical Center.
Conflicts of interest
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
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