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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 2  |  Page : 421-427

Comparison of immunohistochemical expression of vascular endothelial growth factor and CD105 in oral squamous cell carcinoma: Its correlation with prognosis


1 Department of Head and Neck Oncology, Karnataka Cancer Therapy and Research Institute, Hubballi, India
2 Department of Molecular Biology and Immunology, Maratha Mandal's NGH Institute of Dental Sciences and Research Centre, Belagavi, Karnataka, India
3 Department of Oral Pathology and Microbiology, Maratha Mandal's NGH Institute of Dental Sciences and Research Centre, Belagavi, Karnataka, India

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Pradeep Somannavar
Department of Oral Pathology and Microbiology, Maratha Mandal's NGH Institute of Dental Sciences and Research Centre, Bauxite Road, Belagavi - 590 010, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.160908

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 > Abstract 


Objectives: Compare and correlate immunoexpression of vascular endothelial growth factor (VEGF) and CD105 in oral squamous cell carcinoma (OSCC), and correlate its expression with the prognosis of the patient.
Materials and Methods: A retrospective study was carried out on total of 49 cases of OSCC. Detailed demographic and clinical data were obtained, and tissue sections were stained with hematoxylin and eosin to grade the tumor. Later each case was subjected for immunohistochemical analysis of CD105 and VEGF.
Results: All the cases showed positivity for both CD105 and VEGF but high expression was noted with CD105 compared to VEGF. Average microvascular density for CD105 was higher (69.5) in moderately differentiated squamous cell carcinoma (MDSCC) when compared to well differentiated squamous cell carcinoma (WDSCC) (52.16). When expression of CD105 and VEGF was compared in WDSCC and MDSCC, it was statistically insignificant. However when expression of CD105 and VEGF was compared with survival of the patient, survival rate was <2 years in CD105 and was statistically significant, but VEGF did not show any significant difference with survival rate.
Conclusion: CD105 immunoexpression in OSCC predicts a poor outcome than VEGF. So it can be postulated that endoglin may have a particular role in the development of cancer and might be relatively more specific than commonly used endothelial markers for squamous cell carcinoma of the oral cavity.

Keywords: CD105, immunoexpression, microvessel density, oral squamous cell carcinoma, prognosis, vascular endothelial growth factor


How to cite this article:
Patil B R, Bhat K, Somannavar P, Hosmani J, Kotrashetti V, Nayak R. Comparison of immunohistochemical expression of vascular endothelial growth factor and CD105 in oral squamous cell carcinoma: Its correlation with prognosis. J Can Res Ther 2018;14:421-7

How to cite this URL:
Patil B R, Bhat K, Somannavar P, Hosmani J, Kotrashetti V, Nayak R. Comparison of immunohistochemical expression of vascular endothelial growth factor and CD105 in oral squamous cell carcinoma: Its correlation with prognosis. J Can Res Ther [serial online] 2018 [cited 2019 Nov 13];14:421-7. Available from: http://www.cancerjournal.net/text.asp?2018/14/2/421/160908




 > Introduction Top


Oral squamous cell carcinoma (OSCC) is the sixth most common malignant epithelial tumor of the head and neck region. The main risk factors related to OSCC are tobacco abuse and combination of tobacco, and alcohol.[1] OSCC is characterized by high rate of local invasion and cervical metastasis, which directly affects the prognosis of the individual.[2]

The prognosis of patients with OSCC largely remained unchanged despite many advances in diagnosis and treatment. Until, the most reliable prognostic factor is the presence of lymph node metastasis at the time of diagnosis this is mainly because OSCC is multifactorial, hence there is a need for better marker that can identify patients with poor prognosis in early stages of the disease.[3]

Tumor angiogenesis plays a critical role in the growth and systemic dissemination of different types of malignant tumors. A positive relationship between vessel density and a worse prognosis in head and neck cancer has been demonstrated, and a higher vascularity has been associated with metastasis, advanced tumor stage, and a poor prognosis in OSCC.[4]

It is now evident in breast carcinoma that microvessel density correlates with prognostic relevance and is being used consistently to determining prognosis in breast carcinoma. Angiogenic factors such as vascular endothelial growth factor (VEGF) or some matrix degrading enzymes are thought to play a major role in tumor angiogenesis, especially VEGF which is considered to be a leading marker as it induces the proliferation, differentiation and migration of vascular endothelial cells, increases capillary permeability and enhances endothelial cell survival by preventing apoptosis.[5]

Meta-analysis done by Panayiotis et al. suggests that VEGF is a promising prognostic marker in head and neck SCC but they are also of the opinion that it is not the only proposed angiogenic factor. They concluded that VEGF should be considered with other molecular markers such as angiogenin, interleukins 8 and 10; platelet derived endothelial growth factor, fibroblast growth factor, angiopoetins, and thrombospondin.[6]

Endoglin (CD105) is another new powerful marker of neovascularization and important prognostic indicator in solid malignancies.[7] Its expression is up-regulated in OSCC compared with normal healthy oral mucosa. Endoglin may have a significant role in the development of OSCC and might be relatively more specific than commonly used endothelial markers.[8] This is due to increased neovascularization that is 20–2000 times more in endothelial cells of solid tumors than that of normal tissues. Endoglin is been shown to be a predictor for poor prognosis of breast carcinoma,[9] cervical cancer,[10] colorectal cancer,[11] nonsmall cell lung cancer,[12] endometrial carcinoma,[13] and renal cell carcinoma.[14] However, there are only a few studies correlating the expression of CD105 and its correlation with survival in OSCC.[15],[16],[17],[18] Similarly, comparison between CD105 and VEGF is also lacking. So the present study is carried out to correlate VEGF and CD105 expression in OSCC and correlate its expression with the prognosis of the patient.


 > Materials and Methods Top


Samples

After obtaining the Institutional Ethical Committee clearance, 49 formalin fixed paraffin embedded tissue blocks diagnosed with OSCC were retrieved from the archives of the Institute. The clinical data regarding gender, age, tumor location, habit history, tumor stage, treatment carried out, and follow-up information (survival data and death) were obtained from medical records of the hospital. The study group comprised of 35 males and 14 females with primary OSCC. Age of the subjects ranged from 22 to 68 years with mean age of 49.9 years.

Of 49 cases of OSCC, 25 (51%) occurred in buccal mucosa, 13 (26.5%) in tongue, 3 (6.1%) cases each in hard palate and retro molar trigone, 2 (4%) cases each in upper lip and floor of the mouth and 1 (2%) case in lower lip. All the cases had a history of tobacco consumption habit in the form of either smoke or smokeless form and 10 (28%) cases also consumed alcohol. The duration of the habit ranged approximately from 5 to 40 years.

Paraffin embedded tissue blocks were sectioned. Three sections each of 4 μm thick were obtained. One section each was stained for hematoxylin and eosin (H and E), CD105 and VEGF. H and E stained section was analyzed to confirm the diagnosis of OSCC and graded according to WHO grading system.[19] Later it was correlated with tumor node metastasis (TNM) staging.[20]

Of 49 cases, 28 (57.1%) were well differentiated squamous cell carcinoma (WDSCC) [Figure 1]. Of 28 cases, 2 (7.1%), 2 (7.1%), 12 (42.9%) and 12 (42.9%) were of stage I, II, III, and IV, respectively. Remaining 21 (42.9%) cases were moderately differentiated squamous cell carcinoma (MDSCC) [Figure 2]. Of these 21 cases, 1 (7.1%), 11 (52.4%) and 9 (42.9%) were of stage II, III, and IV, respectively.
Figure 1: Photomicrograph showing well differentiated squamous cell carcinoma with keratin pearls

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Figure 2: Photomicrograph showing moderately differentiated squamous cell carcinoma

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All 49 cases were treated with radical neck dissection without prior radiotherapy or chemotherapy, and the follow-up was done for the period of 2 years. A total of 24 (48.9%) patients survived for more than 2 years, and 25 (51.1%) patients died in <2 years due to recurrence and distant metastasis.

Immunohistochemistry

Paraffin-embedded tissues were sectioned (4 μm) and collected in serial sections on glass slides coated with 2% 3-aminopropyltriethylsilane (Sigma-Aldrich, St. Louis, MO). The sections were deparaffinized in xylene and rehydrated through graded concentrations of alcohol. As antigen retrieval, we used microwave heating technique by keeping tissue sections in 10 mM citrate buffer, pH 6.0 for 10–20 min. About 3% hydrogen peroxide in phosphate buffered saline (PBS) for 15 min was then applied to block endogenous peroxidase activity. The sections were incubated overnight at 40°C with anti-human CD105 mouse monoclonal antibody (BioGenex, CA, USA). Poly horseradish peroxidase (HRP) reagent (BioGenex, CA, USA) was used for visualization of the expression of the antibody. Diaminobenzidine tetrahydrochloride (DAB) was used as a chromogen. All sections were then counterstained with Harris hematoxylin. Negative-control staining was done by omitting the primary antibodies and as external positive control were used uterus specimens.

For VEGF, slides were incubated overnight at 4°C with a rabbit monoclonal immunoglobulin of VEGF (1:200 dilution in PBS; Santa Cruz biotechnology, Inc., Europe). The next day, slides were washed in PBS and then incubated for 30 min in horse anti-rabbit secondary antibody (1:200 in PBS). After washes in PBS, samples were labeled with poly HRP reagent. After washing in PBS, slides were incubated with the chromogen DAB, counterstained with Harris hematoxylin, and mounted.

Antibody expression and microvascular density quantification

Two observers without knowledge of the clinical data performed evaluation of the staining. Quantitative analysis of the intratumoral microvessel density was performed according to Weidner.[21] Briefly, at a magnification of ×10, the areas of highest endoglin staining (hot spots) were noted. Three hot spot fields in each intratumoral tissue areas were chosen at the center of the tumor. Then, each of the hot-spot areas was assessed at ×40 magnification. Any brown staining endothelial cell or endothelial cell cluster that was clearly separate from adjacent microvessels, tumor cells, and other connective tissue elements was considered as single, countable microvessel. Areas of necrosis, hemorrhage, and sclerosis were excluded. The average of the vessel counts in three fields for each area was used as the final mean microvascular density (MVD) value in each intratumoral tissue. The expression of CD105 was determined as high or low based on mean average MVD. The number higher to mean average was considered high expression and below mean average MVD was considered as low. Since the aim is to compare the expression of CD105 and VEGF in OSCC we did not consider counting and comparing hot spots at center and periphery of the tumor.

Grading for intensity of immunostaining with vascular endothelial growth factor

The intensity of VEGF staining was classified into four grade scale: 0 - Absence of immunostaining or faint membranous staining, 1+ - Membranous staining, 2+ - Diffuse membranous and cytoplasmic staining and 3+ - Diffuse cytoplasmic staining.[21] Both 0 and 1+ were defined as low expression and both those of 2+ and 3+ as high expression.

The results were tabulated, and statistical analysis was done using Fischer exact test to correlate the expression with tumor grade, differentiation, and survival. Based on high and low expression in both VEGF and CD105, we compared and correlated the expression in various grades of OSCC.


 > Results Top


All 49 cases showed positivity for CD105. The average MVD was 52.16 in WDSCC. Similarly when MDSCC was analyzed, the average MVD was 69.5 [Table 1] which was higher compared to WDSCC. Of 28 cases of WDSCC, high expression of CD105 was observed in 15 (53.57%) cases and low expression in 13 (46.42%) cases [Table 2] and [Figure 3]. Whereas in MDSCC, of 21 cases, only 9 (42.85%) cases showed high expression and 12 (57.14%) cases showed low expression [Table 3] and [Figure 4].
Table 1: Mean MVD in WDSCC and MDSCC

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Table 2: Expression of CD105 and VEGF in WDSCC

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Figure 3: Photomicrograph showing immunoexpression of CD105 in endothelial cells in well differentiated squamous cell carcinoma

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Table 3: Expression of CD105 and VEGF in MDSCC

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Figure 4: Photomicrograph showing immunoexpression of CD105 in endothelial cells in moderately differentiated squamous cell carcinoma

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When VEGF expression was analyzed, all 49 cases showed positivity for VEGF. In WDSCC, 18 (64.28%) cases showed high expression for VEGF and 10 (35.71%) showed low expression [Table 2], whereas in MDSCC 11 (52.38%) cases showed high expression and 10 (47.61%) cases showed low expression [Table 3]. When expression of VEGF and CD105 was compared in WDSCC and MDSCC, it was statistically insignificant [Table 4] [Figure 5] and [Figure 6].
Table 4: Comparison of expression of CD105 and VEGF with relation to staging, survival, and expression

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Figure 5: Photomicrograph showing immunoexpression of vascular endothelial growth factor in cytoplasm of epithelial cells in well differentiated squamous cell carcinoma

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Figure 6: Photomicrograph showing immunoexpression of vascular endothelial growth factor in cytoplasm of epithelial cells in moderately differentiated squamous cell carcinoma

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Expression of CD105 and VEGF was compared in TNM stages of WDSCC and MDSCC. All cases of stage I and stage II in WDSCC showed high expression for CD105; however, in stage III, 6 (50%) of cases showed both high and low expression. In stage IV, 5 (33.38%) cases showed high expression for CD105 and 7 (46.6%) cases showed low expression for CD105 [Table 2]. Similarly in MDSCC, 1 case in stage II showed low expression; in stage III, 3 (37.5%) cases showed high expression and 8 cases showed low expression, whereas in stage IV, 6 cases showed high expression and 3 cases showed low expression for CD105 [Table 3]. When expression of VEGF was compared with TNM staging in WDSCC 1 case in stage I and 2 cases in stage II showed high expression. In stage III, 8 cases showed high expression and 4 cases showed low expression. In stage IV, 7 cases showed high expression and 5 cases showed low expression [Table 2].

Similar comparison was made in MDSCC, 1 case in stage I showed low expression. Totally, 7 cases showed high expression and 4 cases showed low expression of VEGF in stage III. In stage IV, 4 cases showed high expression and 5 cases showed low expression of VEGF [Table 3].

In CD105, cases which showed low expression survived after 2 years in both WDSCC and MDSCC, whereas in VEGF 44.4% of cases which showed high expression survived <2 years and 2 cases which showed low expression also survived <2 years and 7 cases which showed high expression of VEGF survived for more than 2 years [Table 2]. In MDSCC, 3 cases that showed high expression of VEGF survived <2 years and 8 cases which showed high expression survived <2 years. A total of 6 cases that showed low expression of VEGF also showed survival <2 years and 4 cases that showed survival more than 2 years, had low expression of VEGF [Table 3].

When comparison was made between survival and expression, clinical stage and expression, clinical stage, and survival in both WDSCC and MDSCC, it was statistically insignificant for VEGF whereas statistically significant difference was found when CD105 was compared with expression and survival [Table 5].
Table 5: Comparison of expression of CD105 and VEGF

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 > Discussion Top


The increasing number of different therapeutic modalities in head and neck cancer lead to the search for prognostic factors of clinical relevance in order to enable comparison between the different types of treatment. Thus numerous studies have been done at molecular level to understand the biology of tumor growth so that adequate treatment can be provided to the patients by targeting the molecules.[22],[23] One of the factors that govern tumor growth is to develop their own blood supply through angiogenesis by the formation of new blood vessels from preexisting endothelium.[24]

Tumor neovascularization promotes growth because the crowded cell population needs these new vessels to allow exchange of nutrients, oxygen and waste products for which the simple diffusion is not adequate. In addition to this, endothelial cells of vessels secrete important paracrine growth factors for tumor cells such as insulin growth factor-2, basic fibroblast growth factor, platelet-derived growth factors. By releasing collagenases, urokinases, and plasminogen activators, they facilitate spread of tumor into adjacent fibrin-gel matrix and connective tissue stroma. Tumor neovasculature also has structural and functional abnormalities, thus increasing the opportunity of tumor cells to enter the circulation. Altered morphology such as shunt perfusion, absence of vasomotion, blood circulation, and obstruction of microvessels by leukocytes and tumor cells results in functional abnormalities.[25]

Presently, there are many endothelial cell specific markers available which can detect angiogenesis with adequate specificity. Markers such as CD31, CD34, and von Willebrand factor are pan endothelial markers that are expressed in normal vasculature and also in tumor vasculature. On the contrary, CD105 is expressed on endothelial cells of tumors, but weakly or not at all expressed in normal tissue, thus making this marker superior in detecting tumor angiogenesis.[25] CD105 is specifically proliferation-associated endothelial marker of tumor neovasculature. Various studies in the literature have demonstrated increased expression of CD105 being associated with poor prognosis in various carcinomas.[26],[27]

Vascular endothelial growth factor is one more angiogenic marker that is used extensively in determining prognosis of various tumors. It is mitogenic for endothelial cells in vitro and a potent angiogenesis-promoting factor in vivo. It also plays an important role in the induction of tumor cell motility, metalloproteinase secretion and the augmentation of vascular permeability, and favoring the occurrence of metastasis.

On literature search, we found CD105 and VEGF were used individually to determine the prognosis of OSCC. Studies were lacking where comparison of the two markers were made in OSCC to determine the prognosis of the lesion and also to know which would serve as a better marker in determining prognosis of OSCC. Thus, the present was ventured to compare the prognostic value of CD105 and VEGF.

Expression of VEGF was seen mainly in the cytoplasm of the tumor cells. When VEGF expression was compared with various histological grades, no significant difference was found also no significant difference was found with tumor staging and survival of the subjects. Oliveira-Neto et al.[28] found high expression of VEGF but did not find statistically significant difference between lip OSCC and oral cavity SCC. Smith et al. and Kyzas et al.[6] found higher expression of VEGF in cytoplasm of SCC cell when compared to larynx SCC. This could be attributed to the fact that OSCC is associated with tobacco habits which releases nicotine that is a potent inducer of VEGF production. Nicotine is said to be more specific component in inducing expression of VEGF and induces angiogenesis in cancer cells. Schimming et al.[29] did not find any correlation between VEGF expressions with clinicopathological parameters. Moriyama et al.[30] failed to establish expression of VEGF as prognostic marker in oral cancer. Whereas Smith et al.[31] found a significant correlation between VEGF expression and tumor prognosis. There appear to be controversies existing in expression of VEGF and its association with tumor progression. These results demonstrate that in squamous cell carcinoma (SCC) of Head and neck, VEGF not only express in tumor cells but also are expressed frequently by inflammatory cells infiltrating the tumor and also cells of histologically normal adjacent tissues. Our results also suggest that angiogenic factors other than VEGF might provide the positive regulatory signals needed for tumor angiogenesis. Thus, this led to the search of newer marker for establishing prognosis in a tumor.

CD105 which is a promising marker of recent years helps in determining the angiogenic factor in tumor progression through MVD. MVD in the present study was determined using CD105. So far, the density and number of microvessel are one of the most thoroughly examined parameters for angiogenesis.[21] Microvessel density has repeatedly been shown to be a prognostic marker in breast cancer,[9] but data for SCC are controversial.[15],[16],[17],[18] The first quantitative evidence that angiogenesis in tumors can predict the probability of metastasis has been reported for melanoma,[32] of which other studies confirmed this for different tumors.[7],[13] However, some reports were unable to find a relation between tumor prognosis and MVD. Curiously another study has found an association with high MVD and better prognosis.[33] Thus, the controversy in this subject still exists. There are several reasons for these discrepancies. The most probable are differences in the patient population studied, variability in the reactivity of endothelial cell antibodies, differences in tissue pretreatment procedures, MVD determination methods, above all various pan endothelial markers used have low sensitivity and specificity in evaluation of intratumoral vessels density.[7],[34] The existing controversies can be addressed to certain extent using a novel marker CD105 that is associated with tumor angiogenesis, mainly in solid tumors. Studies have also proved significant association of high MVD with poor prognosis in various neoplasms. A correlation has been found between levels of CD105 expression and markers of cell proliferation in tumor endothelia. These findings together with the demonstration that a greater intensity of staining for CD105 is detectable in blood vessel endothelia within neoplastic tissues, compared with those within normal tissues indicate that CD105 is a powerful marker of neovascularization in solid malignant tumors. Thus, CD105 is known to be an ideal marker to quantify tumor angiogenesis and can be an independent predictor of prognosis in patients with breast cancer.[7]

In the present study, CD105 was found to be positive in all the cases. Statistically significant difference was seen when CD105 expression was compared with histological grades, TNM staging, and survival rates. High expression was associated with increasing grade of malignancy. Schimming et al.[35] and Oliveira-Neto et al.[28] found high MVD in tumor and concluded that increased MVD in tumor tissue directly affect the biological behavior of the tumor. Ronald et al. found significant association of CD105 expression with metastasis. Whereas Chien et al.[8] found decrease expression of CD105 was associated with decreased survival, increased expression with metastasis. MVD count with CD105 is significantly correlated with overall disease-free survival. Multivariate analysis has also confirmed MVD as independent prognostic factor.

On comparison between VEGF and CD105 expression, we found significant correlation with CD105 and survival rate of the patient. Similar correlation was found between histological grades and TNM staging in CD105. High expression was associated with low survival; whereas no significant correlation was found with expression of VEGF with survival, also with TNM staging and histological grading. Our finding suggests that CD105 is good marker to predict prognosis of OSCC when compared to VEGF.


 > Conclusion Top


The results of our study suggest that CD105 expression is highly associated with OSCC when compared to VEGF. So it can be postulated that CD105 may have a particular role in the development of cancer and might be relatively more specific than commonly used endothelial markers for SCC of the oral cavity. However, whether inhibition of angiogenesis may become a useful, new treatment for OSCC in the near future is still unanswered and needs additional, prospective studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

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



 

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