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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 1  |  Page : 7-15

A possible role of WNT5A expression in papulosquamous skin diseases


1 Department of Dermatology and Venereology, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission01-Dec-2019
Date of Decision06-Mar-2020
Date of Acceptance21-Mar-2020
Date of Web Publication02-Jun-2020

Correspondence Address:
Nashwa Naeem Elfar
Department of Dermatology and Venereology, Faculty of Medicine, Tanta University, Tanta
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdpdd.ijdpdd_59_19

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  Abstract 


Background: Wnt genes code for a family of secreted, lipid-modified glycoproteins. Wnt5a has important functions in cell proliferation, fate determination, and differentiation. Dysregulation of Wnt5a signaling implicated in multiple disease. Aim of Work: The aim is to elucidate the possible role of Wnt5a in pathogenesis of papulosquamous skin disorders through the evaluation of its expression immunohistochemically. Patients and Methods: This study included 80 patients with various papulosquamous diseases (psoriasis, lichen planus, ptyriasis rosea, and ptyriasis rubra pilaris), in addition to 20 healthy controls served as control. Punch skin biopsies were taken from all individuals for immunohistochemical staining with Wnt5a. Results: There was a highly statistically significant upregulation in Wnt5a expression in all stained skin specimens of the studied papulosquamous diseases in both epidermis and dermal lymphocytes compared to normal control. Conclusion: The upregulated expression of Wnt5a indicated its involvement in pathogenesis of papulosquamous diseases. Wnt5a and/or its receptor can be a challenging target for therapeutic intervention. Regular follow-up for these patients is recommended as Wnt5a also may be involved in their malignant transformation.

Keywords: Lichen planus, papulosquamous, pityriasis rosea, pityriasis rubra pilaris, psoriasis, Wnt5a


How to cite this article:
Mohamed LM, Hasby EA, Kassem HA, Elfar NN. A possible role of WNT5A expression in papulosquamous skin diseases. Indian J Dermatopathol Diagn Dermatol 2020;7:7-15

How to cite this URL:
Mohamed LM, Hasby EA, Kassem HA, Elfar NN. A possible role of WNT5A expression in papulosquamous skin diseases. Indian J Dermatopathol Diagn Dermatol [serial online] 2020 [cited 2020 Aug 13];7:7-15. Available from: http://www.ijdpdd.com/text.asp?2020/7/1/7/285805




  Introduction Top


Papulosquamous diseases comprise the largest conglomerate of diseases seen by the dermatologist.[1] They bound together by the fact that they all present clinically with scaly plaques and papules. These assume considerable importance because of their frequency of occurrence.[2] Some common papulosquamous dermatoses are psoriasis, pityriasis rosea, lichen planus (LP), seborrheic dermatitis, pityriasis rubra pilaris (PRP), and parapsoriasis. Drug eruption, tinea corporis, and secondary syphilis may also have papulosquamous morphology.[3]

The name Wnt is Portmanteau of names of two homologous genes; Wg (the Drosophila wingless gene) and Int (the murine homologue mouse mammary tumor virus integration site 1 gene).[4] Wnts constitute a large family of cysteine-rich secreted ligands.[5] There are 19 Wnt genes in the human genome which encode lipid-modified secreted glycoproteins.[6]

Wnt5a, a member of the Wnt family of proteins, and has been shown to play distinct roles during embryogenesis, organ homeostasis, and in adult cellular processes.[5]

We aimed to elucidate the possible role of Wnt5a in pathogenesis of papulosquamous skin disorders through evaluation of its expression immunohistochemically.


  Patients and Methods Top


The current study was a case–control study, carried out on 80 individuals had papulosquamous skin diseases. In addition to 20 healthy individuals served as control. They were collected from the outpatient clinics of dermatology of two governmental hospitals after obtaining the approval of the ethics committee (code No. 31400/02/17). An informed written consent was obtained from all participants in the study.

Patients who were under local or systemic treatment for their dermatological disease in the past 6 weeks, had history to be liable to form keloids, any other dermatological or systemic disease as (diabetes, cancer, allergy, metabolic diseases, and hemolytic disorders) and pregnant or lactating females were excluded from the study.

The studied individuals were divided into five groups; Group I: included 20 patients who had chronic plaque psoriasis. Group II: included 20 patients who had LP. Group III: included 20 patients who had pityriasis rosea (PR). Group IV: included (20) patients who had PRP. Group V: included 20 healthy persons of the same age and gender of studied patients who served as controls. The studied individuals were subjected to:

  • Full medical history and dermatological examination including hair, nails and mucous membrane to determine the type, clinical distribution, and severity of the lesions
  • Clinical digital photographs and dermoscopic examination was done for each patient with type Dermlite dermoscopy II PRO HR 3Gen, USA.


Histopathological examination

4 mm punch biopsies were taken under local anesthesia (mepivacaine hydrochloride) and complete aseptic technique from lesional skin. Control biopsies were also obtained from healthy skin of the same age and gender of studied groups. The biopsies were immediately fixed in 10% formaldehyde and embedded in paraffin then were prepared at 3–5 micron thickness on glass slides for routine hematoxylin and eosin staining to be studied with light microscopy to confirm the clinical diagnosis, assess the general histopathological features.

Immunohistochemical examination

Sections were stained to detect expression of Wnt5a protein[7] with a polyclonal rabbit antihuman antibody (product code CSB – PA026138LA01HU, CUSABIO, Baltimore Avenue, Philadelphia, the United States of America).

Preparation of working color reagent

The Diaminobenzidine (DAB) chromogen was prepared by addition of one drop of DAB chromagen per 1 ml of buffered substrate. The components were mixed well and excess reagent was tapped off then washed for 5 min in phosphate buffered saline. Several drops of the working color reagent were placed on each slide and incubated for 5–10 min at room temperature then washed in tap water. Counter stain with Mayer's hematoxylin for 1 min was done then washed in tap water. Sections were dehydrated in alcohol and mounted in dibutyl phethalate xylene.

Interpretation of immunohistochemical staining

The expression of Wnt5a is considered positive in brownish staining was detected in the nucleus and/or cytoplasm in epidermal keratinocytes and/or dermal lymphocytes by means of ABC with (DAB) as the chromogene at a final dilution 1:100.

For each stained section in the study groups, multiple images were taken by Leica DM500 microscope with built-in Leica ICC50 digital camera. Images were then entered into Image J image analyzing system version # 1.50d. Images were then processed to identify mean area percentage of stained are and for optical density (OD) of staining area by immunohistochemical (IHC) profiler plugin.

Calculating the mean area percentage

The region of interest was determined by defining our selection on selected red-green-blue stalk and then adjusting the threshold in comparison to the original image. Measurements were limited to threshold and set to area, area fraction (percentage). The mean area percentage of staining of multiple images from the same section was then calculated.

Identifying the optical density

Color deconvolution is chosen and quantification of the DAB image that is represented with the colour-2 image. Then, we run analyze then set measurements and select “Mean gray value,” we then run analyze then measure to get the quantification in units of intensity. Finally, we convert the intensity numbers in the results to (OD) numbers with the following formula:

OD = log (max intensity/mean intensity), where max intensity = 255.

The score of mean area percentage of stained cells for each field was multiplied by the score of calculated (OD) of the same field to provide an immunostaining Density-Distribution Score (DDS). The score assigned by (ICH) profiler as: high positive = (3+), positive = (2+), low positive = (1+), and negative = (0). The means of different calculated scores in different study groups were calculated and statistically compared.[8]

Statistical analysis of the data

Statistical package for Microsoft Windows (SPSS Inc., Chicago, Illinois, USA) was used in this study. Both w2 and Fischer w2 testing were used for intergroup comparisons. The correlation between ordinal variables was performed using Spearman's rank correlation (rho) and P < 0.05 was considered statistically significant.


  Results Top


The dermographic data (sex, age and duration of the disease) and dermoscopic findings of the different studied groups were summarized in [Table 1] and [Table 2], respectively.
Table 1: Comparison between the different studied groups according to the demographic data of patients (sex, age, and duration of the disease)

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Table 2: Dermoscopic findings in the different studied groups

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All psoriatic patients (Group I) were chronic plaque psoriasis with variable severity, their severity according to PASI score ranged from 6 to 52.8 with mean ± standard deviation (SD) of 25.55 ± 17.39, 4 (40%) patients had mild psoriasis, 1 (10%) patient had moderate psoriasis, and 5 (50%) of the patients had severe psoriasis. In Group II, there were 12 (60%) patients had classic LP, 2 (10%) patients had bullous LP, 2 (10%) patients had hypertrophic, and 2 patients (10%) had atrophic LP. In Group III, all patients had classic PR. In Group IV, there were

18 (90%) patients had classical adult type and 2 (10%) patients had classical juvenile type of PRP.

Immunohistochemical results

In control group, Wnt5a expression was expressed in the epidermis (mainly the basal layer) of 12 (60%) individuals. The expression scored using IHC profiler plug-in and it was positive (2+) in 6 (30%) individuals, low positive (1+) in 6 (30%) individuals and negative in 8 (40%) individuals. The distribution of staining as represented by area percentage ranged from 0.46 to 3.13 (mean ± SD = of 1.66 ± 0.89). As regards the OD in this group, it ranged from 1.01 to 1.03 (mean ± SD = 1.017 ± 0.007). On calculating the density distribution score, it ranged from 0.47 to 3.19 (mean ± SD of 1.68 ± 0.91).

On studying WNT5a in the dermis of the control group, it was found that low positive (1+) expression was found in 4 (20%) individuals and negative expression (0) in 16 (80%) subjects. The area percentage ranged from 1.33 to 3.35 with mean ± SD of 2.42 ± 0.76. OD ranged from 1.00 to 1.03 with mean ± SD of 1.008 ± 0.007, and DDS ranged from 1.33 to 3.45 with mean ± SD of 2.44 ± 0.76 [Figure 1].
Figure 1: Normal skin: (a) The stained specimen showed positive (2+) Wnt5a nuclear and dermis immunohistochemical expression in epidermis (Density-Distribution Score was 1.39) and negative expression in dermis (Density-Distribution Score was 1.50) (DAB, ×200). (b) Area percentage of Wnt5a expression in epidermis (1.37) and dermis (1.49) (×200). (c) Optical density of Wnt5 expression in epidermis (1.10) and dermis (1.01) (×200)

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As regards the expression of Wnt5a in the patients groups, Wnt5a was expressed in the nucleus and/or cytoplasm of keratinocytes in all epidermal layers in all (100%) stained sections of studied groups of papulosquamous diseases, the DDS of Wnt5a expression was high positive (3+) in 8 (10%) patients, positive (2+) in 42 (52.5%) patients, and low positive (1+) in 30 (37.5%) patients.

Wnt5a expressed in dermal lymphocytes, the DDS was positive (2+) in 52 (65%) patients and low positive (1+) in 28 (35%) patients. There was a statistically highly significant increase of Wnt5a expression in both epidermal layers and dermal lymphocytes of studied groups in comparison to epidermis and dermis of control group (P value was [<0.001 and 0.001]) respectively [Table 3] and [Table 4].
Table 3: Wnt5a expression in epidermis and dermal lymphocytes in studied groups

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Table 4: Comparison between the studied groups according to density distribution of Wnt5a expression

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In Group I (Psoriasis), the expression of wnt5a in epidermis showed high positive (3+) expression in 8 (40%) patients, positive (2+) expression in 6 (30%) patients, and low positive (1+) expression in 6 (30%) patients [Table 5]. The area percentage of Wnt5a expression ranged from 24.16 to 41.92 (mean ± SD = 30.29 ± 4.9), OD ranged from 1.05 to 1.14 (mean ± SD = 1.104 ± 0.04), and DDS ranged from 25.4 to 44.1 (mean ± SD = 33.45 ± 5.45). In dermal lymphocytes, Wnt5a expression showed positive (2+) expression in 14 (70%) patients and low positive (1+) expression in 6 (30%) patients. The area percentage of Wnt5a expression ranged from 6.37 to 23.43 (mean ± SD = ±12.16 ± 7.8), OD ranged from 1.03 to 1.13 (mean ± SD = 1.071 ± 0.047) and DDS ranged from 6.56 to 26.48.

(mean ± SD = 13.30 ± 9.06) [Figure 2].
Table 5: Correlation between expression of Wnt5a in epidermis and dermal lymphocytes with psoriasis area severity index score in Group I

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Figure 2: Plaque Psoriasis: (a) the stained specimen showed acanthosis, suprapapillary epidermal thinning, dermal inflammatory infiltrate, and dilated tortuous capillaries (H and E, ×200). (b) It showed low-positive (1+) nuclear and cytoplasmic Wnt5a expression in epidermis (Density-Distribution Score was 6.62) and positive (2+) expression in dermis (Density-Distribution Score was 31.56), (DAB, ×200). (c) Area percentage of Wnt5a expression in epidermis (28.59) and dermis (6.37) (×200). (d) Optical density in epidermis (1.10) and dermis (1.04) (×200)

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In Group II (LP), Wnt5a expression in the epidermis showed positive (2+) expression in 12 (60%) patients and low positive (1+) expression in 8 (40%) patients [Table 6]. The area percentage of Wnt5a expression ranged from 9.06 to 36.30 (mean ± SD = 22.41 ± 9.6), OD ranged from 1.07 to 1.14 (mean ± SD = 1.09 ± 0.03) and DDS ranged from 9.06 to 36.30 (mean ± SD = 24.56 ± 10.75). In dermal lymphocytes, Wnt5a showed positive (2+) expression in 12 (60%) of specimens and low positive (1+) expression in 8 (40%) of specimens. The area percentage of Wnt5a expression ranged from 7.04 to 35.24 (mean ± SD = 21.39 ± 12.29), OD ranged from 1.06 to 1.15 (mean ± SD = 1.099 ± 0.03), and DDS ranged from 7.58 to 39.09 (mean ± SD = 23.76 ± 13.89) [Figure 3].
Table 6: Expression of Wnt5a in epidermis and dermal lymphocytes according to the clinical types of lichen planus in Group II

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Figure 3: Lichen planus; (a) The stained specimen showed hyperkeratosis, irregular acanthosis, and band-like inflammatory infiltrate with slightly dilated subpapillary capillaries and pigment incontinence (H and E, ×200). (b) It showed high positive (2+) Wnt5a expression in epidermis (Density-Distribution Score was 40.80) and low positive (1+) expression in dermis (Density-Distribution Score was 32.58) (DAB, ×200). (c) Area percentage of Wnt5a expression in epidermis (35.86) and dermis (28.58) (×200). (d) Optical density in epidermis (1.14) and dermis (1.14) (×200)

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In Group III (PR), Wnt5a expression in the epidermis showed positive (2+) expression in 16 (80%) patients and low positive (1+) expression in 4 (20%) patients. The area percentage of Wnt5a expression ranged from 9.42 to 26.81 (mean ± SD = 16.39 ± 5.59), OD ranged from 1.12 to 1.17 (mean ± SD = 1.14 ± 0.02) and DDS ranged from 10.74 to 30.04 (mean ± SD = 18.61 ± 6.26). In dermal lymphocytes, Wnt5a expression showed positive (2+) expression in all (100%) patients. The area percentage of Wnt5a expression ranged from 5.11 to 13.95 (mean ± SD = 10.62 ± 3.35), OD ranged from 1.12 to 1.17 (mean ± SD = 1.142 ± 0.019), and DDS ranged from 5.72 to 16.32 (mean ± SD = 12.15 ± 3.84) [Figure 4].
Figure 4: (a) Pityriasis rosea; the stained specimen showed slight epidermal hyperplasia, mounds of parakeratosis and dermal superficial perivascular mononuclear cellular (H and E, ×100). (b): It showed positive (2+) nuclear and cytoplasmic Wnt5a expression in epidermis (Density-Distribution Score was 13.80) and low positive (1+) expression in dermis (Density-Distribution Score was 13.66) (DAB, ×200). (c): Area percentage of Wnt5a expression in epidermis (12.35) and dermis (11.88) (×200). (d) Optical density of Wnt5a expression in epidermis (1.12) and dermis (1.15) (×200)

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In Group IV (PRP), Wnt5a expression in epidermis showed positive (2+) expression in 8 (40%) patients and low positive (1+) expression in 12 (60%) patients [Table 7]. The area percentage of Wnt5a expression ranged from 1.065 to 19.67 (mean ± SD = 6.93 ± 6.03), OD ranged from 1.03 to 1.15 (mean ± SD = 1.07 ± 0.05) and DDS ranged from 1.11 to 20.74 (mean ± SD = 7.519 ± 6.57). In dermal lymphocytes, Wnt5a showed positive (2+) expression in 6 (30%) patients and low positive (1+) expression in 14 (70%) patients. The area percentage of Wnt5a expression ranged from 1.72 to 22.72 (mean ± SD = 9.16 ± 6.191), OD ranged from 1.04 to 1.17 (mean ± SD = 1.085 ± 0.055 and DDS ranged from 1.79 to 26.59 (mean ± SD = 9.99 ± 6.83) [Figure 5].
Table 7: Expression of Wnt5a in epidermis and dermal lymphocytes according to the clinical types of ptyriasis rubra pilaris in Group IV

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Figure 5: (a): Pityriasis rubra pilaris; the stained specimen showed discrete foci of lamellar hyperkeratosis filled with keratin plugs, suprapapillary hypergranulosis, acntholysis, irregular elongation of rete ridges and perivascular inflammatory lymphocytic infiltrate (H and E, ×200). (b) It showed positive (2+) Wnt5a expression in epidermis (Density-Distribution Score was 24.10) and positive (2+) expression in dermis (Density-Distribution Score was 1.11) (DAB, ×200). (c) Area percentage of Wnt5a expression in epidermis (1.07) and dermis (22.71) (×200). (d) Optical density of Wnt5a expression in epidermis (1.04) and dermis (1.10) (×200)

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  Discussion Top


Wnt5a, a member of the Wnt family of proteins has been shown to play distinct roles during embryogenesis, organ homeostasis, and in adult cellular processes.[3] Wnt5a has been implicated both in inflammatory responses of human mononuclear cells and vascular proliferation. It initiates the production of various inflammatory cytokines which are involved in the progression of chronic inflammation.[9]

The control group in the current study showed mild nuclear and/or cytoplasmic staining of Wnt5a in the epidermis mainly at the basal layer and in the dermis.

In the studied psoriatic lesions, a statistically highly significant increase of Wnt5a expression was detected in nucleus and/or cytoplasm of keratinocytes in all epidermal layers and nucleus and/or cytoplasm of infiltrating dermal lymphocytes. There was no significant difference between Wnt5a expression in epidermis or dermal lymphocytes and severity of psoriasis. These results were in agreement with Kim et al., in 2016[10] who reported increased expression of Wnt5a in all layers of lesional skin in comparison with non-lesional and normal skin. Zhang et al., in 2015,[11] reported that Wnt5a expression was confined to the stratum basal in the control samples, but was highly expressed in all the epidermal layers in psoriasis lesions. In the dermis of the lesions, Wnt5a was mainly expressed in inflammatory and endothelial cells.

Wnt5a participates in two pathomechanisms of psoriasis, the first relates to similarities between events associated with psoriatic keratinocytes and wound healing, as Wnt5a is mostly involved in fibroblast activation. Moreover, dermal fibroblasts in psoriasis are strongly positive for Wnt5a. The second possible pathomechanism involves the link between increased Wnt5a in psoriatic epidermis and inflammation.[10],[12]

Another study showed that genetic expression of Wnt5a did not return to the baseline after restoring psoriatic epidermis to normal appearing skin, dermal CD8+ cells were not fully resolved. These findings suggest that Wnt5a is associated with a network of cytokines and inflammatory responses in psoriasis.[13] Wnt5a is dramatically upregulated in macrophages by lipopolysaccharides and interferon (IFN-γ), and induces the production of the pro-inflammatory cytokines interleukin (IL-1), IL-6, and IL-8.[10] It has also been shown to be expressed by human antigen-presenting cells through stimulation through toll like receptors and directly by tumor necrosis factor (TNF-α) in lesional dermis.[14]

In contrast, Wnt5a expression can also occur independently of TNF-α. Interestingly, neutralization of Wnt5a led to a decrease in the production of the cytokines IFN-γ, IL-12, and IL-23 which have been shown to be crucial in the pathogenesis of psoriasis through the maintenance and effector functions of Th1 and Th17 cells.[15]

Wnt5a expression in LP sections showed a significant upregulation in both epidermal layers and dermal lymphocytes in comparison to epidermis and dermis of control group. There was no significant difference between Wnt5a expression in epidermis or dermal lymphocytes with different studied clinical types of LP. These results were in agreement with a Zhang, et al., in 2015,[11] Wnt5a expression was strongly overexpressed in all the epidermal layers and in dermal lymphocytes, but confined to the stratum basal in the control skin. Furthermore, El-Tatawy et al., in 2018,[16] reported that Wnt5a expression was significantly increased in LP patients; it was detected in the nucleus and/or cytoplasm of keratinocytes in all epidermal layers and in dermal lymphocytes.

Wnt5a inducing marked angiogenesis and proliferation of endothelial cells in lesional skin, influencing epidermal proliferation, and promoting the expression of pro-inflammatory or inflammatory cytokines and amplification of inflammatory responses. [8,17] Angiogenesis and increased vascular endothelial growth factor were shown to be present in cutaneous LP, and there was an association of these events with the degree of inflammation in LP.[18]

As regard expression of Wnt5a in pityriasis rosea; it was expressed in the nucleus and/or cytoplasm of keratinocytes in all epidermal layers and in dermal lymphocytes in comparison with control group. However, there is no previous study elucidated the role of Wnt5a in the pathogenesis of PR. Previous studies have suggested the association of viral infection and some drugs with the development of PR.[19],[20] Urbina et al., in 2017,[21] reported increased amounts of CD4 T cells and Langerhans cells are present in the dermis suggesting the role of T-cell mediated immunity in the development of PR. Wnt5a produced by dendritic cells (DCs) which exerts its regulatory effect both on DCs and T cells, through autocrine and paracrine modes and it promotes both IL-12 secretion and the priming of CD4+ T lymphocytes, enhancing the secretion of IFN - γ and IL-2 cytokines.[22]

Wnt5a was expressed in lesional sections of PRP in the nucleus and/or cytoplasm of keratinocytes in all epidermal layers stained sections and in dermal lymphocytes. There was not a significant difference of Wnt5a expression in epidermis or dermal lymphocytes with different clinical types of PRP. However, there was no previous study elucidated the role of Wnt5a in the pathogenesis of PRP.

A study made by Hanfstingl et al., in 2018,[23] characterized the expression profile of various cytokines in skin biopsies of PRP lesions. In line with the clinical similarities of PRP with psoriasis, they found Th17 cell and Th1 profile by mRNA expression analyses.

Patients with psoriasis had an increased risk for the development of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).[24] Wnt5a was strongly expressed in both SCC and BCC and localized to the leading edge of tumors.[25] Furthermore, incidence of SCC complicating cutaneous lichen planus is 0.4% and the most reported case are hypertrophic LP.[26] There are reports that PRP can be associated with an underlying malignancy such as cholangiocarcinoma and adenocarcinoma of the lung have been documented.[27] Wnt5a can be considered a cutaneous marker of leukemia, sezary syndrome and cutaneous T-cell lymphoma.[28] Therefore, such lesions should be subjected to regular histopathological examination for early detection of skin cancer.[29]


  Conclusion Top


It could be concluded that Wnt5a may induce marked angiogenesis and proliferation of endothelial cells in lesional skin, influencing epidermal proliferation, and promoting the expression of pro-inflammatory or inflammatory cytokines and amplification of inflammatory responses in papulosquamous skin disorders. Wnt5a and/or its receptor can be a challenging target for therapeutic intervention.

The limitations in our study were the small sample size of patients with different clinical presentations of papulosquamous skin disorders. In addition, the lack of prior research studies on the same topic of the current study which reduced data comparison.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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