Skin tags (STs) (acrochordons) are common benign tumors that occur mainly on the neck and major flexures. They present as small, soft, and pedunculated protrusions with equal incidence in both sexes. They may appear as single or multiple lesions with variable sizes 1. STs can be normochromic or hyperchromic, and although asymptomatic, they represent a cosmetic problem for patients because of their appearance or their frequent trauma caused by friction with clothes or jewelry 2.
STs are commonly associated with various conditions, including diabetes mellitus, obesity, acromegaly, Crohn’s disease, pregnancy, and human papilloma virus 3–8. Histopathologically, STs are polypoid lesions with loose to dense fibrovascular core together with an overlying mildly acanthotic epidermis 1.
Several theories have been proposed regarding the etiology of skin pigmentation in certain diseases. First, the presence of acanthosis and papillomatosis might be sufficient, without pigment-producing cells, to produce hyperpigmentation of the skin, as in acanthosis nigricans 9. Second, the interaction of mast cells and melanocytes can induce skin hyperpigmentation, as in urticaria pigmentosa 10. Third, nevus cells were found in about 30% of filiform growths, indicating that some STs might represent involuted melanocytic nevi 11.
In addition, other studies 12,13 have demonstrated a significantly higher mast cell count and increased tryptase expression in STs compared with normal skin, and they concluded that mast cell mediators are capable of inducing fibroblast proliferation and epidermal hyperplasia, thus highlighting the potentially important role of mast cells in the pathogenesis of STs.
This study was conducted to detect and compare the difference between flesh-colored and pigmented STs with respect to BMI, glucose tolerance (GT), degree of acanthosis and papillomatosis as well as both melanocyte and mast cell counts.
Patients and methods
The current study was approved by the dermatology research ethical committee, Kasr Al Aini Hospital, Cairo University. Twenty adult patients (Fitzpatrick skin types III–V) with clinically diagnosed flesh-colored and hyperpigmented STs, in relevance to patients’ skin phototype, were included in this study. The presence of both types of STs in the same patient within the neck area was a must for his/her recruitment. In intent to abolish the influence of hormonal factors on the color of STs, pregnant women as well as those on any hormonal method of contraception were excluded. Written informed consents were obtained from all participants before conducting the study. The study duration was 7 months (from June 2013 to January 2014).
Each participant was subjected to full history taking, general clinical examination, and skin examination for concomitant pathology. BMI was calculated and patients were classified as overweight (BMI=25–30), moderately obese (BMI=30–35), severely obese (BMI=35–40), or very severely obese (BMI>40) 14. Furthermore, glucose tolerance test was performed for all included patients and accordingly they were classified into normal glucose tolerance (NGT) [glucose level>7.8 mmol/l (140 mg/dl)] and impaired glucose tolerance (IGT) [glucose level between 7.8 and 11.1 mmol/l (140–200 mg/dl)] 15. The total number of STs and their color were documented in each participant.
Two punch biopsies were taken, one from a flesh-colored STs and another from a hyperpigmented STs. Specimens were fixed in formalin and processed to obtain paraffin blocks. Paraffin blocks were cut into 5–6-μm-thick sections and stained using hematoxylin and eosin to evaluate the degree of acanthosis and papillomatosis by one dermatopathologist blinded to the color of the ST. The estimation of acanthosis and papillomatosis was subjective and categorized as absent, mild, moderate, or severe. Furthermore, sections were immunohistochemically stained by the following:
- Melanoma marker (for detection of melanocytes): melanoma marker Ab-1 Pan Ab-1 (HMB45+M2-7C10+M2-9E3) is a monoclonal mouse primary antibody (catalog number MS 939-R7) that is a cocktail of anti-gp100 (HMB45) and MART-1 antibodies. It recognizes melanocytes and melanomas.
- Mast cell chymase (for detection of mast cells): mast cell chymase Ab-1 is a mouse monoclonal primary antibody (catalog number MS 1217-R7).
Immunostaining required pretreatment by boiling in 10 mmol/l citrate buffer (catalog number AP 9003) pH 6 for antigen retrieval. This was performed for 10 min and left to cool at room temperature for 20 min. Immunostaining for melanoma marker was completed using UltraVision biotin streptavidin detection system (UltraVision Polyvalent, HRP AEC, catalog number TP-015-HF). Counterstaining was performed using Mayer’s hematoxylin (catalog number TA-060-MH). Primary antibodies, UltraVision polyvalent, and Mayer’s hematoxylin were obtained from LabVision Cooperation (Fremont, California, USA) and Thermo Fisher Scientific (Cheshire, UK). Positive immunostaining for melanoma marker appeared as reddish cytoplasmic deposits.
Immunostaining for mast cell chymase was completed using Econo Tek HRP Antipolyvalent (DAB, catalog number AEX080-IFU; Sky Tek Laboratories Inc., Logan, Utah, USA). Positive immunostaining for mast cell chymase appeared as brown cytoplasmic deposits 16.
The number of cells positive for melanoma marker within the epidermis was counted by the same blinded dermatopathologist at magnification ×400 in five nonoverlapping fields (field area 7381.11 μm) in every specimen from both dark and light ST for all patients. The number of mast cells positive for mast cell chymase was similarly counted by the same blinded dermatopathologist within the dermis in specimens from both dark and light STs for all patients. This was performed at magnification ×400 in five nonoverlapping fields (field area 7381.11 μm). Image analysis was performed using Leica Qwin 500C Image Analyzer Computer System (Leica, Breckland, Linford Wood, UK) [The image analyzer is calibrated automatically to convert the measurement units (pixels) produced by the image analyzer program into actual μm units; magnification was performed using a standard measuring frame.] present in Histology Department, Faculty of Medicine, Cairo University. The numbers obtained were subjected for statistical analysis.
Data were statistically described in terms of mean±SD, median and range, or frequencies (number of cases) and percentages when appropriate. As data were proved to violate normal assumption, comparison of numerical variables was performed using the Mann–Whitney U-test for independent samples when comparing two groups and using the Kruskal–Wallis test when comparing more than two groups. For comparing categorical data, the χ2-test was performed. Exact test was used instead when the expected frequency is less than 5. Correlation between various variables was determined using the Spearman rank-correlation equation for non-normal variables. P values less than 0.05 was considered statistically significant. All statistical calculations were performed using computer programs statistical package for the social sciences (SPSS, version 15; SPSS Inc., Chicago, Illinois, USA) for Microsoft Windows.
The current study included 20 patients, each having both flesh-colored and hyperpigmented STs within the neck area. Eleven (55%) were women and nine (45%) were men. Positive family history was reported in four (20%) patients. Their age ranged between 35 and 60 years (mean±SD 45.85±8.27 years) and their BMI ranged between 30.5 and 43.1 (mean±SD 36.51±3.91). Thirteen patients were classified as being severely obese (BMI≥35) and 12 patients had IGT according to the results of the glucose tolerance test. None of the recruited patients reported any other associated diseases. The total number of STs in the 20 patients was 85, with the hyperpigmented type (n=55) being significantly more than the flesh-colored type (n=30) (P=0.02). The number of hyperpigmented STs was significantly higher in both IGT patients (n=41) and in those classified as severely obese (n=39) in comparison with NGT patients (n=14) and those classified as moderately obese (n=14) (P=0.001) (Table 1).
Examination of hematoxylin and eosin-stained sections revealed relatively normal appearance of the epidermis and dermis, with some of the specimens showing inflammatory cellular infiltration specifically around the blood vessels. Hyperpigmented STs demonstrated abundant melanin in the basal epidermal cells and numerous deep rete ridges. In contrast, flesh-colored STs had scanty melanin and few shallow rete ridges. The degrees of acanthosis and papillomatosis were significantly higher in hyperpigmented STs in comparison with the flesh-colored ones (P=0.001) (Table 2 and Fig. 1).
STs immunohistochemically stained for the melanoma marker demonstrated the presence of positive cells (melanocytes) within the basal layer of the epidermis of both the hyperpigmented and flesh-colored types of STs. However, the number of melanocytes in the hyperpigmented type ranged between 14 and 33 (mean±SD 21.8±5.7), which was significantly higher than that detected in the flesh-colored type of STs, which ranged between 4 and 18 (mean±SD 11.65±3.9) (P=0.001) (Table 2 and Fig. 2). There was a significant positive correlation between melanocytes and mast cells count in both hyperpigmented (r=0.63; P=0.03) and flesh-colored STs (r=0.56; P=0.02).
In sections immunostained for mast cell chymase, positive mast cells were present within the dermis of both hyperpigmented and flesh-colored types of STs. In hyperpigmented STs, mast cells were clearly localized in groups around the blood vessels in addition to others present diffusely within the upper dermis. The mast cell chymase-positive cells were significantly more abundant in hyperpigmented STs than in flesh-colored STs (Fig. 3). The number of mast cells in the hyperpigmented type ranged between 16 and 39 (mean±SD 27.1±6.1), whereas it ranged between 2 and 13 (mean±SD 6.75±3.2) in the flesh-colored ones (P=0.001) (Table 2).
The current study sheds light on the difference between flesh-colored and hyperpigmented STs (in relevance to patients’ skin phototype). The possible contributing factors to the difference in color include increased mast cell and melanocytes count as well as the thickness of the skin as evident through the increased acanthosis and papillomatosis, in the hyperpigmented type, as documented in the current work.
Mast cells are increased in number in many skin diseases 17. In addition to being able to mediate immediate hypersensitivity, mast cells are known to exert effects on T and B cells, keratinocytes, fibroblasts, Langerhans cells, and endothelial cells through an array of cytokines, chemokines, and growth factors they produce 18. The potential role of mast cells in the etiopathogenesis of STs could be through influencing fibroblast proliferation and collagen deposition 19 as well as by stimulating keratinocyte proliferation 20 and epidermal acanthosis 21. This was illustrated in several studies that reported a significantly higher mast cell count in STs in comparison with normal skin 12,13,22–24.
Furthermore, mast cells contribute to the occurrence of skin pigmentation in some diseases through their interaction with melanocytes, as activation of mast cells results in release of inflammatory mediators that stimulate melanocytes such as melanocyte growth stimulatory activity and leukotrienes B4 and C4 25. Interestingly, pigmented skin lesions in urticaria pigmentosa do not show significant increase in the number of melanocytes; yet, they showed increased mast cells count 26, thereby offering a possible explanation to the discrepancy of the color of STs, which is the number of mast cells and their interaction with other cells especially melanocytes. The current study demonstrated that both mast cell and melanocytes count were significantly higher in hyperpigmented STs compared with flesh-colored ones. In addition, a significant positive correlation between melanocytes and mast cells count was demonstrated in both hyperpigmented and flesh-colored STs.
As the presence of hyperkeratosis might be sufficient, without pigment-producing cells, to produce hyperpigmentation of the skin, as in acanthosis nigricans 9, the significantly increased degree of acanthosis and papillomatosis in hyperpigmented STs in comparison with flesh-colored ones demonstrated in the current study might provide an additional strength to this observation.
The presence of significantly higher number of hyperpigmented STs in patients with IGT and severe obesity in comparison with patients with NGT and moderate obesity in our study might represent another sequel to the impairment of BMI and GT, which is the difference in color of STs and not just their increased number. The fact that obese and diabetic patients have higher frequency of STs is considered a well-established fact that has been clarified in several previous studies 22,27,28, as in the one conducted by Salem et al.13, which concluded that STs are related to obesity as evidenced by high BMI and hypertriglyceridemia in all recruited patients. However, this study did not detect a relationship between STs and IGT. Furthermore, STs were also found to be directly associated with the grade of obesity 29,30 and with high insulin levels 29,31. Rasi et al. 2 even found that diabetes mellitus was more common in patients with STs and that having more than 30 STs considerably increased the risk for diabetes 2. In the current study, we further add that not only the number of STs, but also the color should be considered as an alarming sign. This assumption is based on the fact that we detected a significantly higher number of hyperpigmented STs in patients with IGT and severe obesity in comparison with patients with NGT and moderate obesity in our study. We believe that this points out to the possible factors (GT and BMI) that could contribute to the bias in the development of one color type more frequently than the other, and thereby the potential clinical implementation of STs color as a cutaneous sign for some internal diseases. This assumption could be attributed to the effect of high insulin concentration, in diabetics and obese, to induce direct activation of insulin receptors and activation in dermal fibroblasts and keratinocytes by insulin-like growth factor 1, thus promoting their proliferation 32, which could add to the increased acanthosis and papillomatosis that might be sufficient, without pigment-producing cells, to produce hyperpigmentation of the skin 9. Another explanation might be the fact that obese adipose tissue is characterized by chronic inflammation with massive accumulation of immune cells including mast cells and that immature mast cells that infiltrate into adipose tissue at the nonobese stage gradually mature with the progression of obesity and diabetes 33. The important postulated role of mast cells in the development of STs in general and their pigmentation in particular has already been highlighted, giving further proof to the link between GT and BMI on one hand and the dominance of hyperpigmented STs color on the other hand.
The duration of the presence of both types of STs could offer further explanation to the difference in color, although no change in color of both types of STs was reported, by patients included in the current study, by the course of time; still, it is a clinical variable that is worthy of assessment in future studies.
Limitations of the current study might include the following: relatively small number of recruited patients, lack of normal skin biopsies (control) due to ethical reasons (two biopsies were already taken from each patient), and lack of detailed analysis of the possible interaction between mast cells and melanocytes due to limited financial resources.
In conclusion, the difference in the color of STs could be attributed to several factors, including BMI, GT, melanocyte and mast cell count, implying their possible interaction as well as the degree of acanthosis and papillomatosis. Further studies are required for detailed analysis of the potential factors contributing to such difference and for its possible clinical implementation.
Conflicts of interest
There are no conflicts of interest.
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