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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2017  |  Volume : 60  |  Issue : 2  |  Page : 189-195
Significance of vascular endothelial growth factor and CD31 and morphometric analysis of microvessel density by CD31 receptor expression as an adjuvant tool in diagnosis of psoriatic lesions of skin


1 Department of Pathology, BPS GMC, Sonepat, Haryana, India
2 Departments of Pathology, Venereology and Leprology, Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India
3 Departments of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India

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Date of Web Publication19-Jun-2017
 

   Abstract 

Background: Pathogenesis of psoriasis is a debated issue. Several mechanisms have been proposed to identify the etiology and pathogenesis so that specific treatments can be given to patients with psoriasis. Aims: (1) To compare pattern and distribution of vascular endothelial growth factor (VEGF) and CD31 in patients with psoriasis and other psoriasiform lesions of skin. (2) To study the correlation between VEGF and CD31 expression, clinical severity, and histopathology of psoriasiform lesions of skin. (3) Evaluation of microvessel density (MVD) by using computer-assisted quantitative image analysis in psoriatic skin lesions. Materials and Methods: This study was conducted on eighty cases, out of which forty were diagnosed cases of psoriasis and forty cases of clinically suspected psoriasiform lesions, submitted in the Department of Pathology, Pt. B.D. Sharma, University of Health Sciences, Rohtak, for histopathological examination. Histopathological sections were stained by routine hematoxylin and eosin staining, and these biopsies were further subjected to immunohistochemical staining with VEGF and CD31 as per standard technique. Results: Assessment of various histopathological features revealed strong correlation between epidermal hyperplasia, suprapapillary thinning, and elongation of rete ridges. Suprabasilar keratinocytes in psoriatic lesions stained intensely for VEGF. The difference for number of microvessels and MVD in psoriasis and psoriasiform lesions was statistically significant. Correlation between intensity of VEGF staining by suprabasilar keratinocytes and MVD was found to be highly significant in psoriatic lesions. Conclusion: The present study concluded that psoriatic lesions exhibit potent angiogenic activity. Early lesions show increased MVD along with other histomorphological parameters such as hypogranulosis, parakeratosis and Munro's microabscesses. Overexpression of VEGF by suprabasilar keratinocytes correlated with increased MVD in papillary dermis.

Keywords: CD31, keratinocytes, microvessel density, psoriasiform lesions, psoriasis, vascular endothelial growth factor

How to cite this article:
Chawla N, Kataria SP, Aggarwal K, Chauhan P, Kumar D. Significance of vascular endothelial growth factor and CD31 and morphometric analysis of microvessel density by CD31 receptor expression as an adjuvant tool in diagnosis of psoriatic lesions of skin. Indian J Pathol Microbiol 2017;60:189-95

How to cite this URL:
Chawla N, Kataria SP, Aggarwal K, Chauhan P, Kumar D. Significance of vascular endothelial growth factor and CD31 and morphometric analysis of microvessel density by CD31 receptor expression as an adjuvant tool in diagnosis of psoriatic lesions of skin. Indian J Pathol Microbiol [serial online] 2017 [cited 2019 Jul 16];60:189-95. Available from: http://www.ijpmonline.org/text.asp?2017/60/2/189/208415



   Introduction Top


Psoriasis vulgaris is fairly common chronic inflammatory dermatoses characterized by erythematous papules and plaques with overlying thick silvery scales, most commonly on extensor surfaces of extremities. Histologically, typical changes are observed both in epidermis and dermis in lesions of chronic psoriatic plaques. Epidermal findings include epidermal hyperplasia, elongated rete ridges, hypogranulosis, and parakeratosis. The epidermis becomes infiltrated by neutrophils and activated CD8+ T lymphocytes and munro's microabscesses and pustules of Kogoj are formed. Within the dermis, an inflammatory infiltrate composed of lymphocytes, macrophages, mast cells, and neutrophils are observed. Microvessels (MVs) in the papillary dermis of psoriatic plaques are elongated, dilated, and hyperpermeable.[1]

Pathogenesis of psoriasis is a debated issue. Several mechanisms have been proposed to identify the etiology and pathogenesis so that specific treatments can be given to patients with psoriasis. The disease starts with the activation of T lymphocyte with an unknown antigen or gene product. T cells express the cell receptor known as T-cell receptor, which recognizes the peptide being presented by the antigen-presenting cell (APC) in the grove of major histocompatibility complex. The antigen-stimulated activation leads to the conversion of naive T-cells into an antigen-specific cell, which may develop into a memory cell that circulates in the body. After the activation of T cells, a cascade of cytokines, namely, granulocyte macrophage colony-stimulating factor, epidermal growth factor, interleukin (IL)-1, IL-6, IL-8, IL-12, IL-17, IL-23, fractalkine, tumor necrosis factor-α, etc., are secreted by the activated T-cells. Due to effect of these cytokines, there is keratinocyte proliferation, neutrophil migration, potentiation of Th-1 type response, angiogenesis, upregulation of adhesion molecule, and epidermal hyperplasia.[2]

The two most important histologic features of psoriasis are mounds of parakeratosis with Munro's microabscesses and spongiform pustules of Kogoj in the uppermost layers of spinous layer. All the other features may be seen in chronic eczematous dermatitis such as atopic dermatitis, nummular dermatitis, or allergic contact dermatitis, which then may appear to be psoriasiform. Other psoriasiform lesions of skin are lichen simplex chronicus, seborrheic dermatitis, and pityriasis rubra pilaris. Although the Kogoj spongiform pustules are highly diagnostic of psoriasis group of diseases, typical pustules may also occur in pustular dermatophytosis, bacterial impetigo, pustular drug eruptions, and candidiasis. Periodic acid-Schiff and Gram stains are useful for identifying the infectious organisms.

Morphological changes such as increase in tortuosity, dilatation, and permeability of dermal papillary capillaries precede hyperplastic changes in psoriasis. These changes correlate with enhanced cutaneous blood flow in lesional and perilesional areas. Normalization of the superficial microvascular dermal plexus precedes normalization of the epidermal structure. In addition, the papillary dermal MVs in psoriatic lesions show an increased expression of inflammation-associated adhesion molecules such as E-selectin, ICAM-1, and vascular cell-adhesion molecule-1. These adhesion molecules allow tethering and firm adhesion of leukocytes to the endothelium,[3] important requirements for lymphocyte extravasation, and the establishment of an inflammatory response. As angiogenesis is one of the key features of psoriasis, various studies have been carried out focusing on the identification of proangiogenic mediators in psoriatic skin.[4],[5],[6] Evidence for keratinocyte-derived proangiogenic signals came from a study comparing the angiogenic activity of conditioned media from keratinocytes isolated from either lesional or nonlesional skin of psoriasis patients.[7] Several studies indicate a crucial role of vascular endothelial growth factor (VEGF)-A in the pathogenesis of psoriasis: (i) epidermis-derived VEGF is strongly upregulated in psoriatic skin lesions;[8] (ii) VEGF serum levels correlate with disease severity;[9] (iii) a genetic predisposition caused by single-nucleotide polymorphisms of the VEGF gene may be involved in the pathogenesis of psoriasis;[10] and (iv) K14-VEGF transgenic mice expressing mouse VEGF164 in the epidermis spontaneously develop a chronic psoriasiform skin inflammation.[11] Platelet endothelial cell adhesion molecule, also known as CD31, is a 130-140 kD glycoprotein member of the immunoglobulin (Ig) superfamily. CD31-mediated endothelial cell–cell interactions are involved in angiogenesis. It confirms vascular origin of tumors, but may also stain nodal sinuses. Our study compared the pattern and distribution of VEGF and CD31 in patients with psoriasis and psoriasiform lesions of skin. Correlation between VEGF expression by suprabasilar keratinocytes and CD31 expression in MVs of papillary dermis was established, and evaluation of MV density (MVD) was done using immunohistochemical methods and computer-assisted quantitative image analysis in psoriatic and psoriasiform skin lesions.


   Materials and Methods Top


The present study was conducted on eighty cases of psoriasis and psoriasiform lesions of skin, out of which forty were diagnosed cases of psoriasis and forty cases of clinically suspected psoriasiform lesions, submitted in the Department of Pathology, Pt. B.D. Sharma, University of Health Sciences, Rohtak, for histopathological examination, which was further subjected to immunohistochemical methods and morphometry. Clinically suspected cases of psoriasis and psoriasiform lesions were studied, and only those cases which were confirmed by histopathological examination were included in the study. Inclusion criteria were – (a) Manifest cases, in which strong clinical suspicion of psoriasis and psoriasiform lesions was evident and (b) Histopathological examination of the biopsy specimens showing histological features and alterations suggestive of psoriasis and psoriasiform lesions. After gross examination of the specimen and proper sampling, the tissues were processed by a routine histological technique for paraffin embedding and sectioning at 4 μ thickness. Histopathological sections were stained by routine hematoxylin and eosin staining of the sections as per standard technique. Histopathological diagnosis was established. Representative sections of lesional biopsies were subjected to immunohistochemical staining with VEGF and CD31 as per standard technique.

The quantitative morphometric studies were done by image analysis. MV was defined as any highlighted endothelial cell or endothelial cell cluster clearly separated from adjacent MVs or other connective tissue elements. Vessel lumens were not considered necessary for a structure to be defined as MV. MVD was assessed by light microscopy in representative areas of sections with highest number of capillaries and small venules (neovascular “Hot Spots”). The sections were first examined at low magnification (×100), and after the most intense area of neovascularization (Hot Spot) was identified, MV counts were done on a minimum of two fields of magnification ×400. The final MVD was calculated by taking the mean of MV counts in the two Hot Spots in psoriatic as well as psoriasiform lesions.

Computer-assisted image analysis was performed on all cells, tissues, and vessels expressing antibody staining while avoiding confounding background staining and including all possible staining vessels. Appropriate areas totaling most of the epithelium or most of the adjacent stroma fulfilling morphologic criteria were analyzed whereas contaminated areas were excluded using the pixel exclusion. The data were collected as the number of MVs in ×400 field using CD31 antibody. Mean of two microscopic fields was taken and was expressed as MVD per mm 2. Finally, all the data were tabulated in Excel sheet from which mean and median was calculated in all types of psoriatic and psoriasiform lesions.

Statistics

Data were calculated, tabulated, and statistically analyzed using Statistical Package for Social Studies statistical program version 18. The values entered were mean of morphometric parameters. In all tests, P< 0.05 were regarded as statistically significant. For correlating various histopathological parameters of psoriasis, Pearson correlation was applied and for comparison between psoriasis and psoriasiform lesions, Chi-square test was applied. To compare the number of MVs and MVD between psoriasis and psoriasiform lesions and to study their correlation with VEGF expression, t-test was applied.


   Results Top


The mean age of patients with psoriasis was 43.8 years, and psoriasiform lesions were 39.9 years. The incidence of psoriasis was very high in males as compared to females with a male:female ratio of 39:1. Of all patients studied, 97.5% were males. Of all 40 psoriasiform lesions studied, 72.5% were men. Male:female ratio was 2.6:1.

Hyperkeratosis, epidermal hyperplasia, hypogranulosis, suprapapillary thinning, and inflammatory infiltrate were graded on a scale of 0–3, i.e., Grade 0 - absent, Grade 1+ - mild, Grade 2+ - moderate, and Grade 3+ - marked. About 50% of psoriasis cases had Grade 1+ hyperkeratosis, and 30% had Grade 3+ hyperkeratosis [Figure 1]. The majority of patients with psoriasiform lesions fell into Grade 0 hyperkeratosis, and Grade 3+ hyperkeratosis was found in just 7.5% cases. Parakeratosis, Munro's microabscesses, and Pustules of Kogoj were graded as absent or present. Parakeratosis was present in 100% of psoriasis cases as compared to 42.5% of psoriasiform cases. Parakeratosis was thus found to have significant positive correlation with psoriasis than psoriasiform lesions (P < 0.01). Munro's microabscesses and pustules of Kogoj were present in 65% cases of psoriasis and just 7.5% cases of psoriasiform lesions. The P value was highly significant (<0.01), and thus these are definitely more a feature of psoriasis. It was observed that majority of psoriasis patients (57.5%) were found to have Grade 2+ epidermal hyperplasia [Figure 1]. Most of the patients with psoriasiform lesions (62.5%) were found to have Grade 1+ epidermal hyperplasia. More severe epidermal hyperplasia was thus associated with psoriasis rather than psoriasiform lesions (P < 0.01). All psoriasis cases (100%) showed hypogranulosis and only 22.5% cases of psoriasiform lesions were found to have some degree of hypogranulosis. About 52.5% of psoriasis cases showed severe, i.e., Grade 3+ hypogranulosis whereas none of psoriasiform lesions had Grade 3+ hypogranulosis. The correlation between hypogranulosis and psoriasis was found to be highly significant (P = 0.000). It was observed that all psoriasis patients had some degree of suprapapillary thinning. Majority had Grade 2+ (45%) and Grade 3+ (27.5%) suprapapillary thinning [Figure 1]. It was also evident that no suprapapillary thinning (Grade 0) was present in 60% of psoriasiform patients. Grade 3+ suprapapillary thinning was found in just 1 case of lichen simplex chronicus. It was, thus, observed that suprapapillary thinning was more a feature of psoriasis rather than psoriasiform lesions (P < 0.01). 22.5% cases of psoriasis and 7.5% of psoriasiform lesions had Grade 3+ inflammatory infiltrate. Thus, it was found that more severe inflammatory infiltrate could be associated with psoriasis; however, the P value was not statistically significant (P = 0.055). About 20% of psoriasis lesions revealed marked elongation of rete ridges. All psoriasis lesions revealed some degree of elongation of rete ridges, but 35% of psoriasiform cases revealed no elongation of rete ridges.
Figure 1: Marked hyperkeratosis, elongation of rete ridges, suprapapillary thinning, and epidermal hyperplasia in psoriasis (H and E, ×40)

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[Table 1] shows comparison of grade of VEGF staining in psoriasis and psoriasiform lesions. About 45% of psoriasis lesions stained intensely with VEGF, i.e., Grade 3+ staining. About 45% cases showed moderate staining with VEGF [Figure 2]. On the other hand, only 2.5% of psoriasiform lesions were intensely positive [Figure 3]. The majority of psoriasiform lesions, i.e., 90% were either negative or showed mild VEGF staining. Thus, the correlation between psoriasis and VEGF staining of suprabasal keratinocytes was highly significant (P < 0.01). [Table 2] shows association of various morphological parameters with each other in psoriasis patients. The grade of epidermal hyperplasia and hyperkeratosis showed a positive correlation with each other (P = 0.033) and also with suprapapillary thinning and elongation of rete ridges (P = 0.000). Inflammatory infiltrate also revealed some correlation with epidermal hyperplasia (P = 0.02). Hyperkeratosis was also strongly related to elongation of rete ridges (P = 0.004). Hypogranulosis was seen in all patients of psoriasis but did not have any significant correlation with other parameters. Suprapapillary thinning was associated with epidermal hyperplasia and elongation of rete ridges (P < 0.01). Inflammatory infiltrate showed some correlation with epidermal hyperplasia and elongation of rete ridges (P < 0.05). Suprabasal keratinocytes in psoriasis patients expressed VEGF intensely and showed high correlation with capillary proliferation, i.e., number of MVs and MVD (as expressed by immunostaining with CD31 antibody). The total number of MVs for forty cases of psoriasis was 830.5 whereas that for psoriasiform lesions was 531.5 [Figure 4] and [Figure 5]. The average of total number of MVs in psoriasis using CD31 antibody at ×400 was 20.76 ± 7.17 with a median of 18. In psoriasiform lesions, the average number of MVs was 13.49 ± 5.84 with a median of 8. The average MVD at ×400 for psoriasis was 86.53 ± 29.91 per mm 2 with a median of 75. The average MVD for psoriasiform lesions was 56.20 ± 24.34 per mm 2 with a median of 33.33 per mm 2. The P value of the number of MVs and MVD between psoriasis and psoriasiform lesions was calculated and was statistically significant (P = 0.000) [Table 3]. [Table 4] shows correlation between intensity of VEGF staining by suprabasilar keratinocytes and MVD at ×400. In psoriasis patients, the correlation was statistically significant (P < 0.01), i.e., the more the intensity of VEGF staining, more the number of MVs, and MVD. In psoriasiform lesions, the correlation was not statistically significant, i.e., VEGF staining did not correspond with MVD in psoriasiform lesions (P > 0.05).
Figure 2: Intense vascular endothelial growth factor staining (Grade 3+) in psoriasis (VEGF, ×40)

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Figure 3: Keratinocytes are negative for vascular endothelial growth factor staining (Grade 0) in seborrheic dermatitis (VEGF, ×200)

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Figure 4: Microvessels in psoriasis (CD31, ×100)

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Figure 5: Microvessels in pityriasis rubra pilaris (CD31, ×200)

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Table 1: Grades of vascular endothelial growth factor staining in psoriasis and psoriasiform lesions

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Table 2: Association of various morphological parameters with each other in psoriasis lesions

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Table 3: Comparison of number of microvessels and microvessel density in psoriasis and psoriasiform lesions

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Table 4: Correlation of microvessel density with vascular endothelial growth factor in psoriasis and psoriasiform lesion patients

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   Discussion Top


Pathogenesis of psoriasis is still debated. Role of T cells, APCs, keratinocytes, Langerhans cells, macrophages, natural killer cells, Th1 type cytokines, VEGF, keratinocyte growth factor have been suggested to play a key role in pathogenesis of psoriasis. Differential diagnosis of psoriasis includes all psoriasiform lesions of the skin which include all types of chronic eczematous dermatitis such as atopic dermatitis, nummular dermatitis and allergic contact dermatitis, lichen simplex chronicus, seborrheic dermatitis, pityriasis rubra pilaris, Reiter's disease, and psoriasiform secondary syphilis. Mounds of parakeratosis; Munro's microabscesses and spongiform pustules of Kogoj in the uppermost layers are the two most important histologic features of psoriasis which help in making the correct diagnosis. In our study, it was observed that most patients of psoriasis presented in the fifth decade of life. The mean age of patients with psoriasis was 43.8 years. Patients with psoriasiform lesions had slightly lower mean age of onset, i.e., 39.9 years. Our findings suggested a later onset of psoriasis, i.e., maximum patients (50%) were above 40 years of age at time of presentation. Our findings correlated more with Moorchung et al. than with other studies. Okhandiar et al. and Bedi et al.[12],[13],[14] noted earlier onset of psoriasis, i.e., in third and fourth decade of life. In the present study, the incidence of psoriasis was found to be much higher in males than females (39:1). 97.5% of patients with psoriasis were males. Incidence of psoriasiform lesions was also found to be higher in men. Male:female ratio was 2.6:1. Our findings correlated well with most studies which also showed higher incidence in males. Assessment of various histopathological features was done in psoriasis and psoriasiform lesions. Higher grades of hyperkeratosis, epidermal hyperplasia, hypogranulosis, suprapapillary thinning, elongation of rete ridges, and inflammatory infiltrate were found in psoriasis than psoriasiform lesions. Parakeratosis was present in 100% of psoriasis lesions. On the other hand, the percentage of psoriasiform lesions positive for parakeratosis was 42.5%. Munro's microabscesses and pustules of Kogoj were present in 65% of patients of psoriasis but in only 7.5% cases of psoriasiform lesions. The correlation of parakeratosis and Munro's microabscesses with psoriasis was found to be highly statistically significant (P < 0.01). An assessment of these histopathological features with each other was also done, and correlation was found between some of them. Strong correlation was found between epidermal hyperplasia, suprapapillary thinning, and elongation of rete ridges. Rana et al. found that the difference in grades of inflammation was not statistically significant, but the difference in CD8+ T-cells in epidermis, upper and lower dermis was statistically significant in psoriasis, and psoriasiform lesions of the skin.[15] Moorchung et al. observed strong correlation of epidermal hyperplasia and hyperkeratosis with parakeratosis. They also observed strong correlation of inflammatory infiltrate with capillary proliferation and grade of suprapapillary thinning suggesting the role of inflammation in the pathogenesis of psoriasis.[16] Our study was in consonance with that of Moorchung et al. in respect of correlation between epidermal hyperplasia, suprapapillary thinning, and elongation of rete ridges. However, correlation between inflammatory infiltrate and grades of epidermal hyperplasia, suprapapillary thinning, and capillary proliferation was not statistically significant. Our study also correlated with that of Rana et al.[15] in respect of inflammation in psoriasis and psoriasiform lesions and we found that the difference in grades of inflammatory infiltrate was not significant. Thus, our study suggested that there was no role of inflammation in the pathogenesis of psoriasis. In our study, we observed higher intensity of VEGF staining in suprabasilar keratinocytes of psoriasis as compared to psoriasiform lesions. About 45% of psoriasis lesions stained intensely with VEGF, i.e., Grade 3 + and 45% stained moderately with VEGF, i.e., Grade 2+. Majority of psoriasiform lesions, i.e., 90% were either negative or showed mild, i.e., Grade 1 + VEGF staining. The P value was found to be highly significant. Our study, thus, suggested a definite role of VEGF in pathogenesis of psoriasis. Our findings are in concordance with all the above studies of Man et al.,[17] Young et al.,[18] Canavese et al.,[19] Nofal et al.,[20] Xia et al.,[8] Simonetti et al.,[21] Detmar et al.,[1] Schonthaler et al.,[9] and Zhu et al.[22] suggesting the role of VEGF in pathogenesis of psoriasis. Psoriasis is associated with angiogenesis in superficial dermal vasculature in initial lesions. Several researchers have correlated the degree of angiogenesis with the presence and severity of psoriasis. Antiangiogenic agents may thus prove to be a novel therapeutic approach for psoriasis patients. The total number and average number of MVs was much higher in psoriasis lesions. The average and median MVD was also greater in psoriasis lesions as compared to psoriasiform lesions. The P value of number of MVs and MVD between psoriasis and psoriasiform lesions was statistically significant (P < 0.01). Two cases of psoriasiform dermatitis and Reiter's disease each showed increase in MVD ranging from 96.87 ± 7.36 to 85.42 ± 8.84 which may be related to any of the mechanism leading to idiopathic angiogenesis. Several authors have evaluated the MVD and MV area in psoriatic lesions using different antibodies. Our findings were in concordance with the studies done by Simonetti et al.,[21] Creamer et al.,[23] Barton et al.,[24] Gupta et al.,[25] Detmar et al.,[26] Hern et al.,[27] Krajewska et al.,[28] and Tursen et al.,[29] all of them showed increase in microvasculature in psoriasis as compared to their respective controls. In the present study, the MVD was found to be a little higher than that observed by other authors. The correlation between intensity of VEGF staining by suprabasilar keratinocytes and MVD was highly statistically significant in psoriasis lesions (P < 0.001) but was insignificant in psoriasiform lesions (P = 0.66). Our study correlated with all the above studies suggesting that VEGF expression in epidermal keratinocytes promotes vascular proliferation in papillary dermis in psoriasis patients. Thus, our study supports the theory of role of angiogenesis and VEGF in pathogenesis of psoriasis. The present study revealed that overexpression of VEGF correlated well with increased MVD which showed an increasing trend in psoriasis as compared to psoriasiform lesions. While it was also observed that early lesions of psoriasis indicated increased MVD along with their histomorphological parameters such as hypogranulosis, Parakeratosis, and Munro's microabscesses. Hence, MVD may be considered a prognostic marker for antiangiogenic therapy in the early lesions of psoriasis to minimize the progression of disease to severe stages. Thus, the present study concluded that psoriatic lesions exhibit potent angiogenic activity. Early lesions show increased MVD along with other histomorphological parameters such as hypogranulosis, parakeratosis and Munro's microabscesses. Overexpression of VEGF by suprabasilar keratinocytes correlated with increased MVD in papillary dermis. It can be concluded that VEGF drives angiogenic activity in psoriatic lesions and plays an important role in the pathogenesis of psoriasis. Thus, VEGF and MVD may be considered as prognostic markers for angiogenic therapy, especially in early lesions of psoriasis to minimize the progression of disease to more severe stages.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Correspondence Address:
Nitika Chawla
House No. 425, Sector 14, Faridabad, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_862_15

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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