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Expression of vascular endothelial growth factor is a clinically useful predictor for aggressive basal cell carcinoma

Objectives: Basal cell carcinoma (BCC) tumors are locally invasive but rarely metastatic. However, aggressive metastatic variants are being increasingly reported in elderly people. Here we investigated the clinical utility of vascular endothelial growth factor (VEGF) as a predictive biomarker for aggressive BCC variants. Methods: Thirty-five pathologically confirmed cases of BCC that underwent surgical removal in the Plastic Surgery Department between January 1, 2011 and December 31, 2012 were studied. VEGF expression was analyzed in formalin-fixed paraffin-embedded tumor tissue by immunohistochemical staining. Positive staining was defined as more than 10% of the tumor cells showing immunoreactivity. The associations of VEGF expression with various clinicopathologic parameters were analyzed. Results: The face was the most prevalent site (28/35), with 15 cases from the nose, 6 cases from the eyelid, and 5 cases from the cheek. The patients were aged between 41 and 86 years, with a mean age of 69.26 ± 173.903 years. The mean BCC size was 1.34 ± 3.853 cm, with a range of 0.3 cm to 12.0 cm. The mean tumor invasion depth from the basement epidermal membrane was 0.17 ± 0.035 cm, with a range of 0.03 cm to 1.10 cm. A mean of 5.66 ± 20.938 intraoperative frozen section slides were examined. VEGF was not expressed in 14 of the 35 patients (40.0%), whereas 42.9% of the patients had low expression and 17.1% of the patients had high expression. VEGF expression was significantly associated with age (P = 0.022), size (P = 0.030), site (P = 0.013), tumor invasion depth (P = 0.019), and number of intraoperatively frozen sections (P = 0.003). Conclusions: These results suggest that VEGF expression as assessed by immunohistochemistry can predict aggressive or poor prognosis in BCC.

Basal cell carcinoma (BCC) is the most common skin cancer, accounting for about 80% of skin cancers in America. 1 These tumors are low-grade malignant and rarely metastatic. However, their public health relevance is increasing and their global incidence is rising due to increases in life span. 2 Some pa-tients have a high risk of developing additional tumors within 5 years of diagnosis with BCC. 2 These tumors are locally invasive, causing disfigurement and increasing morbidity due to frequent facial localization. 1 Early diagnosis and prompt management of BCCs is of crucial importance in order to prevent local tissue destruc-tion and subsequent disfigurement. 3,4 Although various noninvasive or minimally invasive techniques have increased the diagnostic accuracy of BCC and progress has been made regarding treatment options for BCC, more aggressive variants of BCC still pose significant challenges for the healthcare system. 3 Angiogenesis, a process consisting of growth and expansion of the vasculature, is involved in the growth and metastasis of many cancers. 5 Angiogenesis is a prognostic indicator for a variety of tumors, suggesting proliferation of neoplastic cells into the circulation and metastasis. 6 Several molecules such as cell surface receptors, growth factors, and enzymes are involved in this process. Moreover, antiangiogenic therapy for cancer was proposed over 20 years ago as a valid target for anticancer drug development.
Vascular endothelial growth factor (VEGF) is a potent proangiogenic factor and several studies have established a critical role for VEGF in skin cancer. 6 Hence, VEGF has become the primary antiangiogenic drug target. 6 For example, an intralesional anti-VEGF antibody (bevacizumab) was recently shown to be feasible for adjuvant treatment of locally advanced BCCs. 7 Regarding oncogenesis, VEGF may involve carcinogenesis. 8 VEGF may also have direct effects on keratinocytes and skin tumor cells, specifically by promoting skin carcinogenesis by altering the survival, proliferation, or stemness of keratinocytes and tumor cells in an autocrine manner. [9][10][11] Clinically, BCCs are rarely metastatic tumors.

Tissue samples
Thirty-five patients with BCC who underwent plastic surgery to remove a BCC tumor mass be- Cell staining was scored as follows: 0 (no staining), 1 (< 50% staining), or 2 (> 50% staining). For all assessments, HF was used as an internal standard and was considered to be 100% positive. Positive staining was defined as immunoreactivity of more than 10% of the tumor cells.

Statistical analysis
Statistical analyses were carried out using SPSS  (Table 1). Frozen sections were not obtained from five patients.

DISCUSSION
Angiogenesis is a crucial process in the progression and metastasis of many cancers, including skin cancer. [8][9][10][11][12] Typically, angiogenesis is required for tumors to grow beyond 1-2 mm in size and offers a pathway for tumor cells to spread to metastatic sites. [8][9][10][11][12][13] Hence, tumor angiogenesis has been a challenging therapeutic target of many cutting-edge strategies. 14 To induce angiogenesis, tumor cells and stromal cells in the tumor mass microenvironment must break the balance of pro-and anti-angiogenetic factors, favoring an "angiogenic switch". 15 The conversion of pro-angiogenic signals to anti-angiogenic signals allows capillary sprouting by proliferation and migration of endothelial cells.14 Eventually, the newly formed vessels supply oxygen and nutrients to the tumor; this is required for progression. 14 VEGF has been identified as a potent angiogenic factor. 15 VEGF mRNA levels in normal epidermis are low.
However, differentiated epidermal cell layers have been shown to have higher VEGF expression than less differentiated epidermal cells. 16 In this study, distinct expression of VEGF was not identified by immunohistochemistry. In human BCCs, weak VEGF expression is typically seen in tumor cells predominantly localized to the invading front margin. 17 We observed a similar expression pat- VEGF expression is low in animal skin and increases gradually during tumor development. 19 Moreover, VEGF is suspected to be clinically upregulated in more aggressive tumors. 7 We found that VEGF expression was significantly  has also functions as negative regulator for pericytes 22 and VEGF inhibits tumor cell invasion in some condition. 23 Therefore, we could presume that VEGF has a crucial role in tumor invasion in early stage, however, in later stage of invasion of the basal cell carcinoma, the expression of VEGF become lower, comparing to early stage.